Toxicology Handbook

TOXICOLOGY HANDBOOK

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TOXICOLOGY HANDBOOK
Second edition
Lindsay Murray | Frank Daly | Mark Little | Mike Cadogan
Sydney Edinburgh London New York Philadelphia St Louis Toronto

Churchill Livingstone
is an imprint of Elsevier
Elsevier Australia. ACN 001 002 357

(a division of Reed International Books Australia Pty Ltd)
Tower 1, 475 Victoria Avenue, Chatswood, NSW 2067
This edition © 2011 Elsevier Australia
This publication is copyright. Except as expressly provided in the Copyright Act 1968
and the Copyright Amendment (Digital Agenda) Act 2000, no part of this publication
may be reproduced, stored in any retrieval system or transmitted by any means (including
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and would welcome any information to redress the situation.
This publication has been carefully reviewed and checked to ensure that the content is as
accurate and current as possible at time of publication. We would recommend, however, that
the reader verify any procedures, treatments, drug dosages or legal content described in this
book. Neither the author, the contributors, nor the publisher assume any liability for injury
and/or damage to persons or property arising from any error in or omission from this publication.
National Library of Australia Cataloguing-in-Publication Data
___________________________________________________________________
Title: Toxicology handbook / Lindsay Murray ... [et al.].
Edition: 2nd ed.
ISBN: 9780729539395 (pbk.)
Notes: Includes index.
Subjects: Toxicology--Australia--Handbooks, manuals, etc. Toxicology--Oceania--Handbooks,

manuals, etc.
Other Authors/Contributors: Murray, Lindsay.
Dewey Number: 571.95
________________________________________________________________
Publisher: Sophie Kaliniecki

Developmental Editor: Neli Bryant
Publishing Services Manager: Helena Klijn
Project Coordinator: Geraldine Minto
Edited by Sybil Kesteven
Proofread by Kerry Brown
Cover design by Georgette Hall
Internal design and typesetting by TnQ Books and Journals
Index by Robert Swanson
Printed by 1010 Printing International Limited
CONTENTS
Foreword ix
Preface x
Authors xi
Contributors xi
Reviewers xii
CHAPTER 1 APPROACH TO THE POISONED PATIENT

1.1 Overview 2
1.2 Resuscitation 4
1.3 Risk assessment 10
1.4 Supportive care and monitoring 13
1.5 Investigations 15
1.6 Gastrointestinal decontamination 17
1.7 Enhanced elimination 24
1.8 Antidotes 29
1.9 Disposition 30
CHAPTER 2 SPECIFIC CONSIDERATIONS

2.1 Approach to snakebite 36
2.2 Approach to mushroom poisoning 44
2.3 Approach to plant poisoning 50
2.4 Coma 55
2.5 Hypotension 59 v
2.6 Approach to seizures 61
2.7 Delirium and agitation 62
2.8 Serotonin syndrome 66
2.9 Anticholinergic syndrome 72
2.10 Cholinergic syndrome 76
2.11 Neuroleptic malignant syndrome 80
2.12 Alcohol abuse, dependence and withdrawal 85
2.13 Amphetamine abuse, dependence and withdrawal 93
2.14 Opioid dependence and withdrawal 94
2.15 Sedative-hypnotic dependence and withdrawal 97
2.16 Solvent abuse, dependence and withdrawal 100
2.17 Body packers and stuffers 104
2.18 Osmolality and the osmolar gap 107
2.19 Acid–base disorders 109
2.20 The 12-lead ECG in toxicology 113
2.21 Poisoning during pregnancy and lactation 119
2.22 Poisoning in children 120
2.23 Poisoning in the elderly 126
CHAPTER 3 SPECIFIC TOXINS

3.1 Alcohol: Ethanol 130
3.2 Alcohol: Ethylene glycol 133
3.3 Alcohol: Isopropanol (isopropyl alcohol) 136
3.4 Alcohol: Methanol (methyl alcohol) 138
3.5 Alcohol: Other toxic alcohols 142
3.6 Amiodarone 144
3.7 Amisulpride 146
3.8 Amphetamines 148
3.9 Angiotensin converting enzyme inhibitors 152
3.10 Anticoagulant rodenticides 154
3.11 Anticonvulsants: Newer agents 157
3.12 Antihistamines (non-sedating) 159
3.13 Antihistamines (sedating) 162
3.14 Arsenic 164
3.15 Beta-blockers 168
3.16 Baclofen 171
3.17 Barbiturates 173
3.18 Benzodiazepines 177
3.19 Benztropine 179
3.20 Bupropion 181
3.21 Button batteries 184
3.22 Calcium channel blockers 186
3.23 Cannabinoids (marijuana) 190
3.24 Carbamazepine 193
3.25 Carbon monoxide 196
3.26 Chloroquine and hydroxychloroquine 200
3.27 Chloral hydrate 202
contents
3.28 Clonidine 205

3.29 Clozapine 208
3.30 Cocaine 210
3.31 Colchicine 214
3.32 Corrosives 216
3.33 Cyanide 219
3.34 Digoxin: Acute overdose 222
vi
3.35 Digoxin: Chronic poisoning 226
3.36 Diphenoxylate-atropine 230
vi
3.37 Gamma-hydroxybutyrate (GHB) 232

TOXICOLOGY HANDBOOK
3.38 Glyphosate 235

3.39 Hydrocarbons 237
3.40 Hydrofluoric acid 240
3.41 Hydrogen peroxide 244
3.42 Insulin 247
3.43 Iron 250
3.44 Isoniazid 254
3.45 Lead 256
3.46 Lithium—acute overdose 260
3.47 Lithium—chronic poisoning 263
3.48 Local anaesthetic agents 265
3.49 Mercury 269
3.50 Metformin 273
3.51 Methotrexate 276
3.52 Mirtazapine 279
3.53 Monoamine oxidase inhibitors (MAOIs) 280
3.54 Non-steroidal anti-inflammatory drugs (NSAIDs) 284
3.55 Olanzapine 287
3.56 Opioids 290
3.57 Organochlorines 295
3.58 Organophosphorus agents (organophosphates
and carbamates) 298
3.59 Paracetamol: Acute overdose 302
3.60 Paracetamol: Repeated supratherapeutic ingestion 312
3.61 Paraquat 316
3.62 Phenothiazines and butyrophenones (antipsychotic agents) 320
3.63 Phenytoin 323
3.64 Potassium chloride 326
3.65 Quetiapine 328
3.66 Quinine 331
3.67 Risperidone 334
3.68 Salicylates 336
3.69 Selective serotonin reuptake inhibitors (SSRIs) 340
3.70 Strychnine 343
3.71 Sulfonylureas 346
3.72 Theophylline 348
3.73 Thyroxine 352
3.74 Tramadol 354
3.75 Tricyclic antidepressants (TCAs) 357
3.76 Valproic acid (sodium valproate) 361
3.77 Venlafaxine and desvenlafaxine 364
3.78 Warfarin 368
CHAPTER 4 ANTIDOTES
contents
4.1 Atropine 372
4.2 Calcium 373
4.3 Cyproheptadine 376
4.4 Desferrioxamine 377
4.5 Dicobalt edetate 379
4.6 Digoxin immune Fab 381
4.7 Dimercaprol 383 vii
4.8 Ethanol 385
4.9 Flumazenil 387
4.10 Folinic acid 389
TOXICOLOGY HANDBOOK
4.11 Fomepizole 391
4.12 Glucagon 392
4.13 Glucose 394
4.14 Hydroxocobalamin 396
4.15 Insulin (high dose) 398
4.16 Intravenous lipid emulsion 400
4.17 Methylene blue 401
4.18 N-acetylcysteine 403
4.19 Naloxone 406
4.20 Octreotide 408
4.21 Penicillamine 410
4.22 Physostigmine 411
4.23 Pralidoxime 413
4.24 Pyridoxine 415
4.25 Sodium bicarbonate 417
4.26 Sodium calcium edetate 420
4.27 Sodium thiosulfate 422
4.28 Succimer 424
4.29 Vitamin K 426
CHAPTER 5 ENVENOMINGS
5.1 Black snake 430
5.2 Brown snake 433
5.3 Death adder 436
5.4 Tiger snake 439
5.5 Taipan 442
5.6 Sea snake 445
5.7 Australian scorpions 447
5.8 Bluebottle jellyfish (Physalia species) 449
5.9 Stonefish 450
5.10 Box jellyfish (Chironex fleckeri) 452
5.11 Irukandji syndrome 454
5.12 Blue-ringed octopus 457
5.13 Redback spider 459
5.14 Funnel-web (big black) spider 461
5.15 White-tailed spider 463
5.16 Ticks 465
CHAPTER 6 ANTIVENOMS
6.1 CSL Black Snake Antivenom 470
6.2 CSL Brown Snake Antivenom 471
6.3 CSL Death Adder Antivenom 473
6.4 CSL Tiger Snake Antivenom 475
contents
6.5 CSL Taipan Antivenom 477

6.6 CSL Sea Snake Antivenom 479
6.7 CSL Polyvalent Snake Antivenom 481
6.8 CSL Stonefish Antivenom 482
6.9 CSL Box Jellyfish Antivenom 484
6.10 CSL Redback Spider Antivenom 486
viii 6.11 CSL Funnel-web Spider Antivenom 488
vi
ii
APPENDICES
Appendix 1: Poisons information telephone numbers 492
TOXICOLOGY HANDBOOK
Appendix 2: Example ECGs 493

Appendix 3: Conversion factors and therapeutic ranges
for important toxins 498
Appendix 4: Alcohol pathways 499
Appendix 5: Theraupeutic over-warfarinisation 500
Appendix 6: Management of allergic reactions to antivenoms 502
Index 503
FOREWORD
Poisoning is a common emergency department presentation, and the third

major injury cause of hospital admissions after falls and motor vehicle
crashes. Alcohol, benzodiazepines, antidepressants, paracetamol and heroin
are frequently involved, yet there are literally thousands of hazardous
substances that can be ingested, as well as envenomings by terrestrial animals
and sea creatures.
The challenge for the emergency physician is to be able to recognise the
poisoned patient, provide supportive care, administer a specific antidote in a
minority of cases, escalate management up to a full intensive care level when
necessary, and know when a patient is safe to be ‘medically cleared’ pending
a thorough psychiatric examination (in cases of deliberate self-harm). This
presents a huge challenge to any doctor, who individually may infrequently see
a severe poisoning and/or can be confronted with a first case of a particular type.
Clinical Toxicology has developed rapidly as a subspecialty of Emergency
Medicine in Australasia, led by a small group of expert clinicians dedicated
to providing information, advice, research and teaching in this important area.
The authors are in the vanguard of this group. All regularly direct and assist
toxicology patient care in emergency departments, intensive care units and
small rural hospitals across the country, locally as well through the national
Poisons Information Centres. ix
Their risk assessment-based approach is maintained in this new version that
builds on the success of the first edition. This handbook has been updated and
expanded with the addition of many new chapters, yet it retains its award-winning
format recognised for its lucidity and readability. The compact size of the book
belies the true wealth of clear, practical evidence-based information covering a
vast array of poisonings and their management in a logical, consistent format.
This book should live in the pocket or at the bedside, be used daily and
be referred to as a prevailing standard of care not just in Australasia, but
internationally. With the exception of some envenomings, the book will be just
as valuable to clinicians in the UK, Europe and Asia as no doubt it will again
prove to be here in Australasia. It is a truly outstanding text that will improve
the care of poisoned patients to their benefit, and the reader’s edification.
Professor Anthony FT Brown MB ChB, FRCP, FRCS(Ed), FACEM, FCEM

Senior Staff Specialist, Department of Emergency Medicine, Royal
Brisbane and Women’s Hospital
Professor, Discipline of Anaesthesiology and Critical Care, University
of Queensland
Editor-in-Chief, Emergency Medicine Australasia
Senior Court of Examiners, ACEM
August 2010
PREFACE
The overwhelmingly enthusiastic response to the first edition of the
Toxicology Handbook confirmed the need amongst emergency medical
personnel for readily accessible and practical toxicology information in the
context of a systematic approach to the care of the poisoned patient.
Feedback from the users of the handbook from Poisons Information
Centres and Emergency Departments in urban, regional and rural settings has
allowed us to expand and refine the factual information for the second edition
while retaining the standardised formats and risk assessment based approach
of the first edition. Routine use of the handbook by junior medical staff in
our own Emergency Departments and Toxicology Units in Perth has allowed
us to refine any written advice that is potentially liable to misinterpretation
by inexperienced users. For the second edition we have added chapters to
provide an approach to poisoning by plants and mushrooms and an approach
to dealing with the issues of drug dependence, tolerance and withdrawal that
frequently complicate management of the poisoned patient. We have also
added new chapters for a number of important specific toxins and antidotes,
and extensively revised the envenoming chapters in the light of recently
published research.
Our sincere hope is that the Toxicology Handbook continues to contribute
x to excellence in the provision of care of the poisoned patient.
x
Lindsay Murray Kerry Hoggett

Frank Daly David McCoubrie
Mark Little Mark Monaghan
Mike Cadogan Jessamine Soderstrom
Jason Armstrong Ovidiu Pascu
A UTHORS
Lindsay Murray MBBS FACEM, Consultant Emergency Physician and
Clinical Toxicologist, Sir Charles Gairdner Hospital, Perth, WA; Clinical
Associate Professor of Emergency Medicine, University of Western
Australia
Frank Daly MBBS FACEM, Consultant Clinical Toxicologist, Emergency
Physician and Director of Clinical Service Redesign, Royal Perth Hospital;
Professor in Emergency Medicine, University of Western Australia;
Consultant Clinical Toxicologist WA and NSW Poisons Information
Centres
Mark Little MBBS DTM&H (Lond) FACEM MPH&TM IDHA, Consultant
Emergency Physician and Clinical Toxicologist, Royal Perth Hospital;
Clinical Senior Lecturer in Emergency Medicine, University of Western
Australia; Consultant Clinical Toxicologist, WA and NSW Poisons
Information Centres
Mike Cadogan MA (Oxon) MBChB FACEM, Consultant Emergency
Physician, Sir Charles Gairdner Hospital, Perth
xi
CONTRIBUTORS
Jason Armstrong MBChB FACEM, Consultant Emergency Physician and
Clinical Toxicologist, Sir Charles Gairdner Hospital, Perth; Clinical
Senior Lecturer in Emergency Medicine, University of Western Australia;
Medical Director, WA Poisons Information Centre; Consultant Clinical
Toxicologist, NSW Poisons Information Centre
Kerry Hoggett MBBS GCertClinTox FACEM, Emergency Physician, Clinical
Toxicology Fellow, Royal Perth Hospital
David McCoubrie MBBS FACEM, Consultant Emergency Physician
and Clinical Toxicologist, Royal Perth Hospital; Consultant Clinical
Toxicologist, WA and NSW Poisons Information Centres
Mark Monaghan MBBS FACEM, Consultant Emergency Physician and
Fellow in Clinical Toxicology 2005–2007, Fremantle Hospital; Consultant
Clinical Toxicologist, WA and NSW Poisons Information Centres
Jessamine Soderstrom MBBS FACEM Grad Cert Toxicology, Clinical
Toxicologist, Emergency Physician, Royal Perth Hospital, Perth, Clinical
Senior Lecturer, University of Western Australia
Ovidiu Pascu MD FACEM, Consultant Emergency Physician and Clinical
Toxicologist, Sir Charles Gairdner Hospital, WA, WA and NSW Poisons
Information Centres; Clinical Senior Lecturer in Emergency Medicine,
University of Western Australia
REVIEWERS
Belinda Bray PhD, Lecturer, Science Communication, University of Auckland
Philip G. Kerr PhD, Lecturer in Medicinal Chemistry, School of Biomedical
Sciences, Charles Sturt University; Australasian Regional Representative
for International Council for Medicinal and Aromatic Plants (ICMAP)
Ian Spence BSc PhD, Associate Dean (International), Faculty of Science
and Honorary Associate Professor, Discipline of Pharmacology, Sydney
Medical School, The University of Sydney
Scott Twaddell BMedSc(Hons) BMed GCClinTox FRACP, Clinical
Pharmacologist and Toxicologist, Respiratory and General Physician, Staff
Specialist Physician, John Hunter Hospital and Calvary Mater Newcastle
Hospital; Conjoint Lecturer in Medicine, University of Newcastle
xii
xi
i
CHAPTER 1
APPROACH TO THE POISONED PATIENT
1.1 verview
O 2
1.2 Resuscitation 4
1.3 Risk assessment 10
1.4 Supportive care and monitoring 13
1.5 Investigations 15
1.6 Gastrointestinal decontamination 17
1.7 Enhanced elimination 24
1.8 Antidotes 29
1.9 Disposition 30
1.1 OVERVIEW
Acute poisoning is a common emergency medicine presentation. Between
150 and 400 acute poisoning presentations annually can be expected
for each 100 000 population served by an emergency department.
Acute poisoning is a dynamic medical illness that frequently represents
a potentially life-threatening exacerbation of a chronic psychosocial
disorder. However, this is a highly heterogeneous patient population:
deliberate self-poisoning, recreational drug abuse, occupational poisoning
and envenoming challenge with myriad potential presentations. The
clinician needs a robust and simple clinical approach that can address
this heterogeneity, but which allows the development of a management
plan tailored to the individual patient at that particular presentation at that
particular medical facility.
2
Risk assessment is pivotal to that robust approach. It is a distinct
cognitive process through which the clinician attempts to predict the
2
likely clinical course and potential complications for the individual at

TOXICOLOGY HANDBOOK
that particular presentation. Risk assessment should wherever possible be

quantitative and take into account the agent, dose and time of ingestion,
clinical features and progress, and individual patient factors (e.g. weight
and co-morbidities).
Toxicology management guidelines frequently focus on the agent
involved. This makes adaptation of treatment recommendations to an
individual patient in a particular location difficult. A risk-assessment-
based approach ensures the clinician addresses potentially time-critical
management priorities in an appropriate order, but avoids unnecessary
investigations or interventions.
Risk assessment is secondary only to resuscitation in the management
of acute poisoning. It allows subsequent management decisions regarding
supportive care and monitoring, investigations, decontamination, use of
enhanced elimination techniques, antidotes and disposition to be made in
a sensible structured manner.
Ideally, this risk-assessment-based approach is supported by a
healthcare system designed to address both the medical and psychological
needs of the poisoned patient. Where the medical needs of a patient
exceed local resources, a risk-assessment-based management approach
ensures that this is identified early and disposition planning and
communication occur in a proactive manner within that organised system.
In this handbook, the authors offer a systematic risk-assessment-
based approach to the management of acute poisoning as it presents to
the emergency department. Separate chapters cover the pharmaceutical,
chemical and natural toxins of most importance to the practitioner in
emergency departments in Australia and New Zealand. It will also be of
TABLE 1.1.1 Risk assessment-based approach to poisoning
Resuscitation
Airway
Breathing
Circulation
Detect and correct
— hypoglycaemia
— seizures
— hyper-/hypothermia
Emergency antidote administration
Risk assessment
Agent
Dose
Time since ingestion
Clinical features and course
Patient factors
Supportive care and monitoring 3
Investigations
Screening—12-lead ECG, paracetamol
Specific
TOXICOLOGY HANDBOOK
Decontamination
Enhanced elimination
Antidotes
Disposition
use to ambulance and emergency paramedic personnel and staff of general

intensive care units. The approach to acute poisoning presented in this book
is honed at the bedside and on the telephone. The authors collectively have
directly cared for over 30 000 patients in the Western Australian Toxicology
Service and offered consultation in over 12 000 acute poisonings across
Australia and overseas via the Western Australian, New South Wales and
Queensland Poisons Information Centres (PICs). The agents covered are
carefully selected to cover all common poisonings, rare but life-threatening
poisonings, poisonings where particular interventions make a difference to
outcome, or which result in frequent consultations with clinical toxicologists
through the PIC network. Chapters are also offered on the important
antidotes and antivenoms with practical information on administration, dose
and adverse effects. All chapters have a risk assessment. All chapters have
special sections on ‘pitfalls’ and ‘handy tips’. These are not for show! They
are designed to respond to the real questions and mistakes that regularly
occur in clinical practice across Australasia.
Clinical toxicology has rightly become an area of expertise of the
emergency physician but the infinite variation in presentation constantly
confounds and surprises all of us. We hope that the information in this
book, when combined with a structured approach, will improve the care
delivered to the poisoned patient.
Poisoning is most frequently the presentation of an individual
suffering from exacerbation of very significant underlying psychiatric,

social or drug and alcohol problems. Excellence in care of the poisoning
delivered in a compassionate manner offers an opportunity to intervene
and produce a happy outcome in this vulnerable group of patients.
1.2 RESUSCITATION
INTRODUCTION
Poisoning is a leading cause of death in patients under the age of 40 years
and is a leading differential diagnosis when cardiac arrest occurs in a
young adult.
Unlike cardiac arrest in the older population, resuscitation following
acute poisoning may be associated with good neurological outcomes even
4
after prolonged periods (hours) of cardiopulmonary resuscitation (CPR).
Therefore, while poisoning is considered part of the differential diagnosis
4
in a patient with cardiac arrest, resuscitation should continue until

TOXICOLOGY HANDBOOK
expert advice can be obtained. Cardiopulmonary bypass has been used

successfully in a number of poisonings.
Attempts at decontamination of the skin or gastrointestinal tract
never take priority over resuscitation and institution of supportive care
measures.
AIRWAY, BREATHING AND CIRCULATION

Acute poisoning is a dynamic medical illness and patients may deteriorate
within a few minutes or hours of presentation. Altered conscious state,
loss of airway protective reflexes and hypotension are common threats to
life in the poisoned patient.
TABLE 1.2.1 Resuscitation
Airway
Breathing
Circulation
Detect and correct:
Seizures
Always generalised when due to toxicologic causes
Benzodiazepines first-line
Hypoglycaemia
Check bedside blood sugar level (BSL) in all patients with altered
mental status
Treat if BSL <4.0mmol/L
Hyper-/hypothermia
Temp >38.5°C prompts urgent intervention
Emergency antidote administration
As in all life-threatening emergencies, attention to airway, breathing

and circulation are paramount. These priorities are usually managed along
conventional lines. Basic resuscitative and supportive care measures
ensure the survival of the vast majority of patients.
Although commonly used to describe a patient’s mental
status, clinical scores such as the Glasgow Coma Scale (GCS) or
Alert-Verbal-Pain-Unresponsive (AVPU) system have never been
systematically validated across all poisonings. A patient’s ability to
guard their airway is not well correlated to GCS. An increased risk of
aspiration has been noted with GCS less than 12. Moreover, a patient’s
ability to guard the airway and ventilate effectively may change within
a short period of time.
In some specific situations, standard resuscitation algorithms do not
apply (see Table 1.2.2).
DETECT AND CORRECT SEIZURES 5
Toxic seizures are generalised, and can usually be controlled with

intravenous benzodiazepines (e.g. diazepam, midazolam, lorazepam or
TOXICOLOGY HANDBOOK
clonazepam). The most common causes of seizures in poisoned patients in
Australasia are venlafaxine, bupropion, tramadol and amphetamines.
The presence of focal or partial seizures indicates a focal neurological
disorder that is either a complication of poisoning or due to a non-
toxicologic cause, and prompts further investigation.
Barbiturates are second-line therapy for refractory seizures in acute
poisoning. Pyridoxine is a third-line agent that may be indicated in
intractable seizures secondary to isoniazid.
Phenytoin is contraindicated in the management of seizures related to
acute poisoning.
DETECT AND CORRECT HYPOGLYCAEMIA

Hypoglycaemia is an easily detectable and correctable cause of significant
neurological injury. Bedside serum glucose estimation should be
performed as soon as possible in all patients with altered mental status.
If the serum glucose is less than 4.0 mmol/L, 50 mL of 50% dextrose
should be given intravenously (5 mL/kg 10% dextrose in children) to
urgently correct hypoglycaemia. The result may be confirmed later with a
formal serum glucose measurement.
Hypoglycaemia in acute poisoning is associated with insulin,
sulfonylurea oral hypoglycaemic agents, beta-blockers, quinine,
chloroquine, salicylates and valproic acid.
DETECT AND CORRECT HYPER-/HYPOTHERMIA

Hyperthermia is associated with a number of life-threatening acute
poisonings and is associated with poor outcome.
6
TOXICOLOGY HANDBOOK APPROACH TO THE POISONED PATIENT
6
TABLE 1.2.2 Specific resuscitation situations in toxicology where conventional algorithms or approaches may not apply
Life-threat Mechanism Agent(s) Comments
AIRWAY
Airway compromise Corrosive injury to l Alkalis l Stridor,dysphagia and dysphonia indicate

oropharynx l Acids airway injury and potential for imminent airway
l Glyphosate compromise
l Paraquat l Early endotracheal intubation or surgical airway
often required
BREATHING
Acidosis Various l Ethylene glycol l Untillate in the clinical course there is usually
Acidaemia l Methanol prominent respiratory compensation
l Salicylates l Intubation and ventilation at standard settings may
worsen acidaemia and precipitate rapid clinical
deterioration, if not death.
l Avoid normo- or hypoventilation
l Maintain hyperventilation and consider bolus IV
NaHCO3 1–2 mmol/kg to prevent worsening of
acidaemia
Hypoventilation Opioid mu receptor l Opioids l Prompt administration of naloxone may obviate

stimulation need for intubation and ventilation
Respiratory failure Cholinergic crisis l Carbamates l Rapid administration of atropine by serial doubling
l Nerve agents of atropine dose to achieve dry respiratory
l Organophosphates secretions may restore adequate oxygenation
Acidosis; Oxygen-free l Paraquat l Avoid supplemental oxygen
Hypoxaemia; radical mediated l If hypoxia occurs, titrate supplemental
oxygen to
Multiple organ cellular injury, maintain oxygen saturation of ~90% or PaO2 60
failure (MOF) particularly type II mmHg
pneumocytes
CIRCULATION
Ventricular Hypocalcaemia l Hydrofluoricacid l Defibrillation alone unlikely to be efficacious

fibrillation ingestion or massive l Bolus IV calcium (e.g. 60–90 mL 10% calcium
cutaneous burn gluconate) repeated as required every 2 minutes
until defibrillation restores perfusing rhythm
Ventricular Fast Na+ channel l Chloroquine l Cardioversion or defibrillation unlikely to be

tachycardia blockade l Cocaine efficacious
l Flecainide l Urgently intubate and hyperventilate
l Local anaesthetic l Bolus IV NaHCO3 1–2 mmol/kg repeated every 1–2
agents minutes until restoration of perfusing rhythm
l Procainamide l Do not await determination of serum pH prior to
l Propranolol intubation and NaHCO3 boluses
l Quinine l Lignocaine is third-line therapy when pH is
l Tricyclic established at >7.5
antidepressants l Amiodarone and Vaughan Williams type Ia
antiarrhythmic agents (e.g. procainamide) are
contraindicated
Ventricular ectopy/ Halogen-induced l Chloral hydrate l Cardioversion or defibrillation unlikely to be

Ventricular myocardial l Organochlorines efficacious
tachycardia sensitisation to l Administer IV beta-blockers, titrate to ectopy
catecholamines response
Continued

7
8
8
TABLE 1.2.2 Specific resuscitation situations in toxicology where conventional algorithms or approaches may not apply—cont’d
Life-threat Mechanism Agent(s) Comments
Refractory Various l Beta-blockers l High-dose insulin–dextrose therapy

hypotension l Calcium channel
blockers
l Localanaesthetic
agents
Tachycardia Central and l Amphetamines l Beta-blockers contraindicated

peripheral l Cocaine l Administer IV benzodiazepines, titrated to gentle
sympathomimetic sedation and heart rate control
response
Supraventricular Adenosine l Theophylline l Urgent haemodialysis indicated

tachycardia antagonism
Hypertension Central and l Amphetamines l Beta-blockers contraindicated

peripheral l Cocaine l Administer IV benzodiazepines, titrated to gentle
sympathomimetic sedation and heart rate control
response l If further therapy necessary use agents that can be
given by titratable intravenous infusion
— Glycerol trinitrate (GTN)
— Phentolamine
— Nitroprusside
Asystole Na+/K+ ATPase l Digoxin l Usual resuscitation interventions futile

Bradycardia pump inhibition l Digoxin-specific antibodies
Tachycardia
Bradycardia Calcium channel l Calcium channel l Atropine and pacing unlikely to be efficacious
Hypotension blockade blockers l Bolus IV calcium (e.g. 60 mL 10% calcium
Cardiac conduction gluconate) may provide temporary haemodynamic
defects stability by increasing HR and BP, while other
treatments are organised
l High-dose insulin–dextrose therapy
Acute coronary Central and l Amphetamines l Beta-blockers contraindicated

syndrome peripheral l Cocaine l Benzodiazepines
sympathomimetic l GTN
response l Antiplatelet and anticoagulation therapy if no
neurological deficits (otherwise cranial CT first)
l Reperfusion therapy along conventional lines
OTHER
Hyperkalaemia Na+/K+ ATPase l Digoxin l Calcium salts are contraindicated

pump inhibition l Digoxin-specific antibodies
Hypoglycaemia Hyperinsulinaemia l Sulfonylureas l Difficult

to maintain euglycaemia with dextrose
supplementation alone
l Octreotide administration obviates need for
dextrose supplementation
Refractory seizures Inhibition of GABA l Isoniazid l IVpyridoxine 1 g per gram of isoniazid ingested,
production up to 5 g
Seizures Adenosine l Theophylline l Urgent haemodialysis indicated

antagonism

9
A temperature greater than 38.5°C during the resuscitation phase of
management is an indication for continuous core-temperature monitoring.

A temperature greater than 39.5°C is an emergency that requires prompt
management to prevent multiple organ failure and neurological injury.
Neuromuscular paralysis with intubation and ventilation leads to a cessation
of muscle-generated heat production and a rapid reduction of temperature.
Profound hypothermia (core temperature <29°C) may mimic or cause
cardiac arrest. Clinical manifestations include coma, fixed and dilated
pupils, bradycardia (usually atrial fibrillation) and hypotension. Vital
signs may be difficult to elicit and the cardiac rhythm may degenerate to
ventricular fibrillation or asystole. In the patient with undetectable vital
signs, aggressive exogenous rewarming is indicated while CPR continues.
Cardiopulmonary bypass, if available, is the most effective means. An
alternative measure is pleural lavage through an intercostal catheter with
10
large volumes of fluid warmed to 40–45°C.
EMERGENCY ANTIDOTE ADMINISTRATION
10
Administration of antidotes is sometimes indicated during the

TOXICOLOGY HANDBOOK
resuscitation phase of management. As with all drugs, antidotes have

indications, adverse effects and contraindications. The decision to
administer an antidote during resuscitation will depend on the perceived
benefit compared to possible adverse effects.
Examples where early administration of an antidote is necessary to
ensure a successful resuscitation include intravenous sodium bicarbonate
in tricyclic antidepressant poisoning, naloxone in severe opioid
intoxication, atropine in severe organophosphorus agent intoxication,
and digoxin-specific antibodies for patients with suspected digoxin
intoxication with cardiovascular compromise.
References
Albertson TE, Dawson AH, de Latorre F et al. TOX-ACLS: Toxicologic-oriented
advanced cardiac life support. Annals of Emergency Medicine 2001; 37:S78–90.
Australian Resuscitation Council. Adult advanced life support: Australian Resuscitation
Council guidelines 2006: Guideline 11.6. Emergency Medicine Australasia 2006;
18:337–356.
Isbister GK, Downes F, Sibbritt D et al. Aspiration pneumonitis in an overdose population:
frequency, predictors, and outcomes. Critical Care Medicine 2004; 32:88–93.
1.3 RISK ASSESSMENT

Risk assessment should occur as soon as possible in the management
of the poisoned patient. Only resuscitation is a greater priority. Risk
assessment is a distinct quantitative cognitive step through which the
clinician attempts to predict the likely clinical course and potential
complications for the individual patient at that particular presentation.
TABLE 1.3.1 Steps for construction of a risk assessment
Distinct cognitive step

Quantitative
Takes into account
1 Agent(s)
2 Dose(s)
3 Time since ingestion
4 Clinical features and progress
5 Patient factors (weight and co-morbidities)
The five key components of the history and examination required to

construct a risk assessment are listed in Table 1.3.1.
Risk assessment is pivotal as it allows the clinician to identify
potential problems and make specific balanced decisions about all
subsequent management steps (supportive care and monitoring, screening
and specialised testing, decontamination, enhanced elimination, antidotes 11
and disposition).
Provided their mental status is normal, patients with deliberate self-
TOXICOLOGY HANDBOOK
poisoning are generally both willing and able to give a good history from
which an accurate risk assessment can be constructed. Physicians ignore
the patient’s history at their peril.
If altered mental status precludes obtaining a direct history, back-up
strategies are employed to gather the necessary information. These include:
1 Asking ambulance officers or family to search for agents
2 Counting missing tablets
3 Checking medical records for previous prescriptions
4 Questioning relatives about agents potentially available to the patient.
Under these circumstances, the risk assessment is less accurate
and is often based on a ‘worst-case scenario’. This is commonly the
case with small children where ingestions are rarely witnessed. As the
clinical course progresses, the risk assessment and management plan
may be refined.
In unknown ingestions, the patient’s clinical status is correlated
with the clinician’s knowledge of the agents commonly available in that
geographic area. For example, CNS and respiratory depression associated
with miotic pupils indicates opioid intoxication in a young adult male
in urban Australia, but is more likely to indicate organophosphate
intoxication in rural Sri Lanka.
The agent, dose and time since ingestion should correlate with the
patient’s current clinical status. If they do not, the risk assessment needs to
be reviewed and revised.
Acute poisoning is a dynamic process and important decisions can
often be made at particular time points. For example, following tricyclic
antidepressant self-poisoning, life-threatening events occur within 6 hours
(and usually within the first 2 hours) of ingestion. Therefore, low-risk
patients can be identified on clinical grounds at 6 hours post-ingestion.

In contrast, following deliberate self-poisoning with sustained-release
calcium channel blockers, patients may not exhibit clinical features
of poisoning during the first few hours. Indeed, the risk assessment
anticipates delayed severe cardiovascular effects.
In the majority of cases, the risk assessment allows early recognition
of medically trivial poisonings. This reassures attending staff, family
and patient and permits the avoidance of unnecessary investigations,
interventions and observation. Early psychosocial assessment and discharge
planning may begin. This usually shortens hospital length of stay.
Less commonly but very importantly, risk assessment allows early
identification of potentially serious poisoning and the implementation
of a tailored proactive management plan. Balanced decisions about
12
gastrointestinal decontamination can be made and appropriate investigations
selected. If a specialised procedure or antidote might be required in the next
12
few hours, early communication and disposition planning may begin.

TOXICOLOGY HANDBOOK
ROLE OF THE POISONS INFORMATION CENTRE

The clinician’s ability to construct an accurate risk assessment relies on
knowledge and experience of the toxic agents concerned. Although this is
straightforward for many exposures, new or unusual agents are frequently
encountered. A variety of sources of information may be used to obtain
the information necessary to formulate a risk assessment. Textbooks
and databases are often difficult to interpret and apply to the individual
patient. When faced with a time-critical poisoning emergency, a call to the
poisons information centre is the most rapid mechanism to obtain accurate
information and individualised risk assessment.
The Australian Poisons Information Centre network comprises centres
located in Sydney, Perth, Brisbane and Melbourne that can be accessed
nation-wide by calling 131126. The New Zealand Poisons Information
Centre located in Dunedin is accessed by calling 0800-POISON (0800
764 766). Trained poisons information specialists with a background in
pharmacy or medical science are familiar with accessing information from
computerised databases and other information sources. They can assist in
the identification of commercial products and their constituents and in the
formulation of a risk assessment, provided the clinician is able to provide
the basic dataset. Where necessary, medical callers treating an acute
poisoning case are referred to an on-call clinical toxicologist who is able to
offer more detailed individualised risk assessment and management advice.
References
Daly FF, Little M, Murray L. A risk assessment based approach to the management of
acute poisoning. Emergency Medicine Journal 2006; 23:396–399.
1.4 SUPPORTIVE CARE AND MONITORING
Following resuscitation and risk assessment, supportive care and
disposition planning can begin.
Poisoning morbidity and mortality usually result from the acute effects
of the toxin on the cardiovascular, central nervous or respiratory systems.
Support of these and other systems for the duration of the intoxication will
ensure a good outcome for the vast majority of acute poisonings. Monitoring
is essential to detect the progress of the intoxication and the timing of
institution, escalation and withdrawal of supportive care and other measures.
An initial period of close observation in the emergency department is
usually appropriate. During this time the patient’s clinical status is monitored
closely to ensure that it correlates with the previous risk assessment. If early
complications are expected (e.g. decreased level of consciousness requiring
13
intubation in the following 2 hours), preparations can be made to secure
the airway as soon as the intoxication declares itself, and before the patient
is moved elsewhere. If unexpected deterioration occurs at any time, the
TOXICOLOGY HANDBOOK
clinician’s priorities revert to resuscitation prior to revising the risk assessment.
The duration of observation depends on the agent(s) ingested, the
formulations involved (e.g. sustained-release preparations) and potential
complications. For example, patients with significant beta-blocker and
tricyclic antidepressant deliberate self-poisoning develop symptoms and
signs of major intoxication within 2–4 hours of ingestion. In contrast, patients
with sustained-release calcium channel blocker or valproic acid deliberate
self-poisoning may take 6–12 hours to develop signs of major toxicity.
Disposition from the emergency department depends on the current
and expected clinical status of the patient. If specific complications are
anticipated, the chosen inpatient clinical area must be resourced to detect
and manage them.
The accuracy and skill of the initial management and risk assessment
is wasted if the subsequent plan of management is not documented
and communicated to the treating team. Good practice includes the
documentation of a comprehensive management plan that informs the
team looking after the patient of:
1 xpected clinical course
E
2 Potential complications according to the individual risk assessment
3 Type of observation and monitoring required
4 Endpoints that must trigger notification of the treating doctor or
further consultation
5 Management plans for agitation or delirium
6 Criteria for changing management
7 Provisional psychosocial risk assessment with contingency plan should
the patient attempt to abscond prior to formal psychosocial assessment.
The needs of the vast majority of patients can be met in the emergency
department, emergency observation unit or intensive care unit. The

emergency observation unit is appropriate for the ongoing management
of most acute poisonings, where the general supportive measures outlined
below can be provided.
Criteria for admission to an emergency observation unit following
acute poisoning include:
1 Ongoing cardiac monitoring not required
2 Adequate sedation achieved
3 Clinical deterioration not anticipated.
Criteria for admission to an intensive care unit following acute
poisoning include requirements for:
1 Airway control
2 Ventilation
14 3 Prolonged or invasive haemodynamic monitoring or support
4 Haemodialysis.
14
TOXICOLOGY HANDBOOK
TABLE 1.4.1 Supportive care measures
Airway
Intubation
Breathing
Supplemental oxygen
Ventilation
Circulation
Intravenous fluids
Inotropes
Control of hypertension
Cardiopulmonary bypass
Sedation
Titrated IV benzodiazepines
Seizure control/prophylaxis
IV benzodiazepines
Metabolic
Ensuring normoglycaemia
Control of pH
Fluids and electrolytes
Renal function
Adequate hydration
Haemodialysis
General
Nutrition
Respiratory toilet
Bladder care (indwelling catheter)
Prevention of pressure areas
Thrombo-embolism prophylaxis
Mobilisation as mental status changes resolve
1.5 INVESTIGATIONS
Investigations in acute poisoning are employed either as screening tests or
for specific purposes.
Screening refers to the performance of a medical evaluation and/or
diagnostic test in asymptomatic persons in the hope that early diagnosis
may lead to improved outcome. In the acutely poisoned patient, screening
tests aim to identify occult toxic ingestions for which early specific
treatment is indicated.
The recommended screening tests for acute poisoning are the 12-lead
electrocardiogram (ECG) and the serum paracetamol level.
The ECG is a readily available non-invasive tool that assists in
the identification of occult but potentially lethal cardiac conduction
abnormalities, such as those in tricyclic antidepressant cardiotoxicity.
15
Paracetamol is a ubiquitous analgesic in the western world. Deliberate
self-poisoning with paracetamol is common, comprising up to 15% of
adult poisoning presentations in Australasia. Life-threatening paracetamol
TOXICOLOGY HANDBOOK
poisoning may be occult in the early stages but progression to fulminant
hepatic failure and death can be prevented by timely administration of
N-acetylcysteine. Although a thorough cost–benefit analysis has never
been performed, it is postulated that the cost of several thousand serum
paracetamol measurements is offset by the detection of one potentially
preventable paracetamol-related death or liver transplant. For this reason,
it is advisable to screen for paracetamol in all cases of known or suspected
acute deliberate self-poisoning. Screening is particularly important where
altered mental status precludes obtaining an ingestion history directly
from the patient.
The screening paracetamol level may be performed at presentation and
does not need to be delayed until 4 hours after ingestion. A non-detectable
paracetamol level greater than 1 hour after ingestion excludes significant
paracetamol ingestion and further paracetamol levels are not required.
If paracetamol poisoning is suspected after the initial risk assessment,
then a screening paracetamol level is not required. Instead, a timed
TABLE 1.5.1 Screening tests
12-lead ECG
Rate
Rhythm
PR interval
QRS interval
QT interval
Dominant R wave in aVR
Serum paracetamol level
paracetamol level should be performed as soon as possible after 4-hours
post-ingestion as an additional risk assessment tool.

Serum salicylate and tricyclic antidepressant assays have been
advocated as routine screening tests. Salicylate poisoning is now
relatively uncommon in Australasia. Significant acute intoxication is
associated with an easily recognised pattern of symptoms and acid–base
disturbances and is rarely occult. Therefore, routine screening for
salicylate in patients without symptoms or signs of salicylism does not
comply with the rationale for screening. Serum tricyclic antidepressant
levels are correlated to complications and outcome following acute
poisoning. However, the major complications of tricyclic antidepressant
poisoning usually occur within 2–4 hours of ingestion. The 12-lead ECG,
correlated to the patient’s clinical status, reflects target organ effects more
accurately and is the preferred screening test.
16
Many poisoned patients are young and have few medical
co-morbidities. After appropriate risk assessment and the institution of
16
supportive care they may require no further investigation beyond the

screening ECG and serum paracetamol measurement. In a young and
TOXICOLOGY HANDBOOK
otherwise healthy patient presenting with normal mental status and

vital signs, additional tests such as electrolytes, full blood picture, liver
function tests and coagulation studies are not routinely indicated.
Other investigations are ordered selectively where it is anticipated that
the results will assist risk assessment or management. Potential indications
for specific tests in the acute poisoning patient are shown in Table 1.5.2.
For most patients and poisonings, the risk assessment and subsequent
clinical course dictate management decisions. Drug concentrations do
not usually assist decision making. Some of the few agents where serum
levels assist in risk assessment or management decisions are shown in
Table 1.5.3.
Qualitative urine screens for drugs of abuse (e.g. opioids,
benzodiazepines, amphetamines, cocaine, barbiturates and cannabinoids)
rarely alter the management of the acutely poisoned patient. Patients with
acute intoxication with one or more of these agents may be managed
according to their clinical presentation. False positives and negatives
TABLE 1.5.2 Indications for other investigations
Refine risk assessment or prognosis

Exclude or confirm an important differential diagnosis
Exclude or confirm an important specific poisoning
Exclude or confirm a complication that requires specific management
Establish an indication for antidote administration
Establish an indication for institution of enhanced elimination
Monitor response to therapy or define an end point for a therapeutic
intervention
TABLE 1.5.3 Useful drug levels that may assist risk assessment or
management in specific settings
Carbamazepine Lithium Salicylate

Digoxin Methanol Theophylline
Ethanol Methotrexate Valproic acid
Ethylene glycol Paracetamol
Iron Phenobarbitone
occur. A positive result from a patient without corresponding symptoms of

intoxication rarely alters acute medical management.
References
Ashbourne JF, Olson KR, Khayam-Bashi H. Value of rapid screening for acetaminophen
in all patients with intentional drug overdose. Annals of Emergency Medicine 1989;
18(10):1035–1038.
Goldman L. Cost awareness in medicine. In: Isselbacher KJ, Braunwald E, Wilson JD et 17
al, eds. Harrison’s Principles of Internal Medicine. 13th edn. New York: McGraw-
Hill Inc.; 1994:38.
Sporer KA, Khayam-Bashi H. Acetaminophen and salicylate serum levels in patients
TOXICOLOGY HANDBOOK
with suicidal ingestion or altered mental status. American Journal of Emergency
Medicine 1996; 14(5):443–446.
1.6 GASTROINTESTINAL DECONTAMINATION

Physicians have long directed great effort into attempts at gastrointestinal
decontamination following ingestion of toxic substances. They have
employed a variety of methods (see Table 1.6.1) in the reasonable
FIGURE 1.6.1 Gastrointestinal decontamination triangle
Risk Assessment
DECONTAMINATION
Given current clinical

What are the potenal
status, what are potenal
benefits to outcome?
adverse effects?
Source: Bailey B. Gastrointestinal decontamination triangle. Clinical Toxicology 2005;

1:59–60.
expectation that by reducing the dose absorbed they will also reduce
the subsequent severity and duration of clinical toxicity. Unfortunately,

the tendency has been to overestimate the potential benefits while
underestimating the potential hazards of gastrointestinal decontamination
procedures. These procedures do not provide significant benefit when
applied to unselected deliberate self-poisoned patients and are no longer
considered routine.
The theoretical benefits of gastrointestinal decontamination in selected
poisonings have not been evaluated. The decision to decontaminate is one
of clinical judgment in which the potential benefits are weighed against
the potential risks and the resources required to perform the procedure
(see Figure 1.6.1 and Table 1.6.2).
Employing this rationale, gastrointestinal decontamination is reserved
for cases where the risk assessment predicts severe or life-threatening
18
toxicity and where supportive care or antidote treatment alone is
insufficient to ensure a satisfactory outcome. There should be reasonable
18
grounds to believe that a significant amount of agent remains unabsorbed

and is amenable to removal by the selected procedure. This requires some
TOXICOLOGY HANDBOOK
knowledge of the absorption kinetics of the agent(s) involved. For most

ingested agents, absorption is virtually complete within 1 hour.
Gastrointestinal decontamination is never performed to the detriment
of basic resuscitation or supportive care. To avoid pulmonary aspiration,
the procedure is not performed without first securing the airway in a
patient with a depressed level of consciousness or in whom the risk
TABLE 1.6.1 Methods of gastrointestinal decontamination
l Induced emesis (syrup of ipecac)

l Gastric lavage
l Activated charcoal
l Whole bowel irrigation
TABLE 1.6.2 Gastrointestinal decontamination: risk–benefit analysis
Potential benefits Potential risks

l Improved clinical outcome l Pulmonary aspiration
(morbidity and mortality) l Gastrointestinal complications
l More benign clinical course — bowel obstruction
requiring lower level of — perforation
supportive care l Distraction of staff from
l Reduced need for other resuscitation and supportive
potentially hazardous care priorities
interventions or expensive l Diversion of departmental
antidotes resources for performance of
l Reduced hospital length of stay procedure
assessment indicates a potential for imminent seizures or decline in

conscious state.
INDUCED EMESIS (SYRUP OF IPECAC)

Emptying the stomach by inducing emesis has a long tradition in clinical
toxicology. In recent times it has been achieved almost exclusively by
the administration of syrup of ipecac. This preparation contains powerful
plant-derived emetics and, when administered at the recommended dose,
reliably induces vomiting via central and peripheral mechanisms. The mean
time from administration to vomiting is 18 minutes. For many years it
was routinely recommended for home use following accidental paediatric
ingestions with the intention of reducing the time to decontamination and the
need for hospital referral. It is now clear that the amount of toxin removed is
unreliable and decreases rapidly with time to the point that it is negligible by
1 hour. Syrup of ipecac-induced vomiting renders subsequent administration 19
of activated charcoal more difficult. The potential benefits of syrup of ipecac
theoretically outweigh the risks when it is administered promptly after
ingestion of an agent in a dose likely to cause significant toxicity, that does
TOXICOLOGY HANDBOOK
not involve rapid onset of depressed level of consciousness or seizures and
where activated charcoal is not readily available or known not to bind to the
agent. Such a scenario arises so infrequently that emergency departments
no longer stock syrup of ipecac and poisons information centres no longer
advise it to be kept in homes with small children.
Technique
l Give 15 mL (children) or 15–30 mL (adults) with a glass of water
l Ifvomiting has not occurred within 30 minutes the dose may be
repeated.
Contraindications
l Non-toxic ingestion
l Dose ingested known to be sub-toxic
l Seizures or decreased level of consciousness
l Risk assessment indicates potential for seizures or decreased level of
consciousness within the next few hours
l Activated charcoal available within 1 hour and known to bind agent
l Infants <12 months of age
l Corrosive ingestion
l Hydrocarbon ingestion.
Potential complications
l Prolonged vomiting (10–20% vomit for more than 1 hour)
l Diarrhoea (20–30%)
l Lethargy (10%)
l Pulmonary aspiration if decreased mental status or seizures
l Physical
injuries secondary to vomiting (rare)
— Mallory Weiss tear
— Pneumomediastinum
— Gastric perforation.
GASTRIC LAVAGE
This technique attempts to empty the stomach of toxic substances by the
sequential administration and aspiration of small volumes of fluid from
the stomach via an orogastric tube. This previously widely favoured
method of gastrointestinal decontamination has now been all but
abandoned and few emergency departments remain experienced in its use.
The amount of toxin removed by gastric lavage is unreliable and
negligible if performed after the first hour. It does not confer any clinical
20 benefit when performed routinely on unselected patients presenting to the
emergency department following deliberate self-poisoning. There are few
20
situations where the expected benefits of this procedure might be judged

to exceed the risks involved and where administration of charcoal would
TOXICOLOGY HANDBOOK
not be expected to provide equal or greater efficacy of decontamination.
Technique
l This procedure is performed in a resuscitation bay
l Do not perform in any patient with an impaired level of consciousness
unless the airway is protected by a cuffed endotracheal tube
l Position the patient in the left decubitus position with 20° head down
l Measure the length of tube required to reach the stomach externally
before beginning the procedure
l Pass a large bore 36–40 G lubricated lavage tube extremely gently
down the oesophagus. Stop if any resistance occurs
l Confirm tube position by aspirating gastric contents and auscultating
for insufflated air at the stomach
l Administer a 200 mL aliquot of warm tap water or normal saline into
the stomach via the funnel and lavage tube
l Drain the administered fluid into a dependent bucket held adjacent to
the bed
l Repeat administration and drainage of fluid aliquots until the effluent
is clear
l Activated charcoal 50 g may be administered via the tube once lavage
complete.
Absolute contraindications
l Initialresuscitation incomplete
l Risk assessment indicates good outcome with supportive care and
antidote therapy alone
l Unprotected airway where there is a decreased level of consciousness

or risk assessment indicates potential for this complication during the
procedure
l Small children
l Corrosive ingestion
l Hydrocarbon ingestion.
Potential complications
l Pulmonary aspiration
l Hypoxia
l Laryngospasm
l Mechanical injury to the gastrointestinal tract
l Water intoxication (especially in children)
l Hypothermia
l Distraction of staff from resuscitation and supportive care priorities.
21
SINGLE-DOSE ACTIVATED CHARCOAL
Activated charcoal (AC) is produced by the super-heating of distilled
TOXICOLOGY HANDBOOK
wood pulp. The resulting fine porous particles are suspended in water or
sorbitol prior to oral or nasogastric administration. The enormous surface
area provided by these particles reversibly adsorbs most ingested toxins
preventing further absorption from the gastrointestinal tract.
Oral AC is generally the preferred method of decontamination.
However, it does not improve clinical outcome when applied to unselected
patients with self-poisoning and should not be regarded as routine. It is
indicated where it is likely that toxin remains in the gastrointestinal tract
(within the first hour for most agents) and where the potential benefits
outweigh the potential risks. The major risk is charcoal pulmonary
aspiration due to loss of airway reflexes associated with impaired level of
consciousness or seizures.
There are no data to support the use of AC in sorbitol or other cathartic
agent over AC in water.
Complications
l Vomiting (30% of patients given AC vomit within 1 hour)
l Mess
l Direct administration into lung via misplaced nasogastric tube
(potentially fatal)
l Impaired absorption of subsequently administered oral antidotes or
other therapeutic agents
l Corneal abrasions
l Distraction of attending staff from resuscitation and supportive care
priorities.
TABLE 1.6.3 Agents poorly bound to activated charcoal
Hydrocarbons and alcohols Metals Corrosives

Ethanol Lithium Acids
Isopropyl alcohol Iron Alkalis
Ethylene glycol Potassium
Methanol Lead
Arsenic
Mercury
Contraindications
l Initialresuscitation incomplete
l Non-toxic ingestion
l Sub-toxic dose
l Risk assessment indicates good outcome with supportive care and
22 antidote therapy alone

l Decreased level of consciousness, delirium or poor cooperation
22
(unless airway protected by endotracheal intubation)

l Risk assessment suggests potential for imminent onset of seizures or
TOXICOLOGY HANDBOOK
decreased level of consciousness.

l Agent not bound to AC (see Table 1.6.3)
l Corrosive ingestion.
Note: Ileus is not a contraindication to single-dose AC.
Technique
l Give 50 g (adults) or 1 g/kg (children) as a single oral dose placed in a
cup for self-administration
l Mixing with ice cream improves palatability for children
l In the intubated patient, AC may be given via oro- or nasogastric tube
after tube placement is confirmed on chest x-ray.
Note: If mental status precludes self-administration, AC is withheld
until the patient is intubated if and when this becomes clinically necessary.
The decision to intubate is based on standard criteria. Only in very rare
circumstances does the risk assessment justify intubation specifically for the
purpose of facilitating administration of AC.
WHOLE BOWEL IRRIGATION
This aggressive and labour-intensive form of gastrointestinal
decontamination attempts to cleanse the entire bowel by administering
large volumes of osmotically balanced polyethylene glycol electrolyte
solution (PEG-ELS). It is rarely performed because risk–benefit
analysis reserves this intervention for life-threatening ingestions of
sustained-release or enteric-coated preparations, or agents that do not
bind to charcoal and where good clinical outcome is not expected with
supportive care and antidote administration and the patient presents before
established severe toxicity (see Table 1.6.4).
TABLE 1.6.4 Whole bowel irrigation potentially useful
l Iron overdose >60 mg/kg

l Slow-release potassium chloride ingestion >2.5 mmol/kg
l Life-threatening slow-release verapamil or diltiazem ingestions
l Symptomatic arsenic trioxide ingestion
l Lead ingestion
l ‘Body packers’ (see Chapter 2.17: Body packers and stuffers)
Whole bowel irrigation has been performed on unconscious ventilated

patients but this is hazardous as fluid may pool in the oropharynx and flow
past the tube cuff to produce pulmonary aspiration.
Complications
l Nausea, vomiting and abdominal bloating
l Non-anion gap metabolic acidosis
23
l Distraction from resuscitation and supportive care priorities
l Delayed retrieval to a hospital offering definitive care.
TOXICOLOGY HANDBOOK
Contraindications
l Risk assessment suggests good outcome can be assured with
supportive care and antidote therapy
l Uncooperative patient
l Inability to place a nasogastric tube
l Uncontrolled vomiting
l Risk assessment suggests potential for decreased conscious state or
seizure in the subsequent four hours
l Ileus or intestinal obstruction
l Intubated and ventilated patient (relative contraindication).
Technique
l Assign a single nurse to carry out procedure (this is a full-time job for
up to 6 hours)
l Obtain sufficient supplies of PEG-ELS and make up solution as directed
l Place nasogastric tube
l Give activated charcoal 50 g (children 1 g/kg) via the nasogastric tube
in non-metallic ingestions
l Administer PEG solution via the nasogastric tube at 2 L/hour (children
25 mL/kg/hour)
l Administer metoclopramide to minimise vomiting and enhance gastric
emptying
l Position patient on a commode if possible to accommodate explosive
diarrhoea
l Continue irrigation until the effluent is clear. This may take up to 6 hours
l Cease whole bowel irrigation if abdominal distension or loss of bowel
sounds are noted
l Abdominal x-ray is useful to assess effectiveness of decontamination
of radio-opaque substances such as iron and potassium salts

l Expelled packages may be counted in body packers.
References
American Academy of Clinical Toxicology and the European Association of Poison
Centres and Clinical Toxicologists. Position Paper: Whole bowel irrigation. Clinical
Toxicology 2004; 42:843–854.
Centres and Clinical Toxicologists. Position Paper: Single-dose activated charcoal.
Clinical Toxicology 2004; 43:61–87.
Centres and Clinical Toxicologists. Position Paper: Ipecac syrup. Clinical
Toxicology 2004; 42:133–143.
Centres and Clinical Toxicologists. Position Paper: Gastric lavage. Clinical
Toxicology 2004; 42:933–943.
24
Bailey B. Gastrointestinal decontamination triangle. Clinical Toxicology 2005; 1:59–60.
24
TOXICOLOGY HANDBOOK
1.7 ENHANCED ELIMINATION

Techniques of enhanced elimination (see Table 1.7.1) are employed to
increase the rate of removal of an agent from the body with the aim of
reducing the severity and duration of clinical intoxication.
These interventions are only indicated if it is thought they will
reduce mortality, length of stay, complications or the need for other more
invasive interventions. In practice, these techniques are useful in the
treatment of poisoning by only a few agents that are characterised by:
l Severe toxicity
l Poor outcome despite good supportive care/antidote administration
l Slow endogenous rates of elimination
l Suitable pharmacokinetic properties.
Accurate risk assessment allows early identification of those patients
who may benefit from enhanced elimination and institution of the
intervention before severe life-threatening intoxication develops. Some
of these techniques require specialised equipment and staff and early
identification of candidates facilitates the timely communication, planning
and transport necessary to ensure a good outcome.
The final decision as to whether to initiate a technique of enhanced
elimination depends on a risk–benefit analysis in which the expected
benefits of the procedure are balanced against the resource utilisation and
risks associated with the procedure.
Techniques of enhanced elimination are never carried out to the
detriment of resuscitation, good supportive care, decontamination and
antidote treatment.
TABLE 1.7.1 Techniques of enhanced elimination and amenable agents
Multiple-dose activated charcoal Haemodialysis and

Carbamazepine haemofiltration
Dapsone Lithium
Phenobarbitone Metformin lactic acidosis
Quinine Potassium
Theophylline Salicylate
Urinary alkalinisation Theophylline
Phenobarbitone Toxic alcohols
Salicylate Valproic acid
Charcoal haemoperfusion
Theophylline
Once the decision to initiate a technique of enhanced elimination is

made, it is important to establish pre-defined clinical or laboratory end
25
points for therapy.
TOXICOLOGY HANDBOOK
MULTIPLE-DOSE ACTIVATED CHARCOAL (MDAC)
Rationale
Repeated administration of oral activated charcoal progressively fills the
entire gut lumen with charcoal. This has the potential to enhance drug
elimination in two ways:
l Interruption of entero-hepatic circulation
— A number of drugs are excreted in the bile and then reabsorbed
from the distal ileum. Charcoal in the small intestine binds drug
and prevents reabsorption thus enhancing elimination
— This is only significant if a drug not only undergoes entero-hepatic
circulation but also has a relatively small volume of distribution
l Gastrointestinal dialysis
— Drug passes across the gut mucosa from a relatively high
concentration in the intravascular compartment to a low
concentration in the gut lumen, which is maintained by continuing
adsorption to charcoal
— This is only effective if the drug is a relatively small molecule, lipid
soluble, has a small volume of distribution and low protein binding.
Indications
Enhanced elimination by this technique has been proposed as clinically
useful in the following scenarios:
l Carbamazepine coma
— Most common indication for MDAC
— Used in the expectation that enhanced elimination will reduce
duration of ventilation and length of stay in intensive care
l Phenobarbitone coma
— Rare
— Used in the in the expectation that enhanced elimination will
reduce duration of ventilation and length of stay in intensive care
l Dapsone overdose with methaemoglobinaemia
— Very rare
— MDAC may enhance elimination of dapsone and reduce the
duration of severe prolonged methaemoglobinaemia
l Quinine overdose
— Although MDAC might enhance drug elimination, good outcome
can be expected with aggressive supportive care
l Theophylline overdose
— Attempts at enhanced elimination with MDAC should never delay
more effective elimination with haemodialysis following life-
26
threatening overdose.
26
Absolute contraindications
l Decreased level of consciousness or anticipated decreased level of
TOXICOLOGY HANDBOOK
consciousness without prior airway protection

l Bowel obstruction
Complications
Although rare in carefully selected patients, they may include:
l Vomiting (30%)
l Charcoal aspiration, especially if there is decreased mental status or
seizures
l Constipation
l Charcoal bezoar formation, bowel obstruction, bowel perforation
(rare)
l Corneal abrasion
l Distraction of attending staff from resuscitation and supportive care
priorities.
Technique
l Give an initial dose of activated charcoal 50 g (adults) or 1 g/kg
(children) PO
l Give repeat doses of 25 g (0.5 g/kg in children) every 2 hours
l In the intubated patient, activated charcoal is given via oro- or
nasogastric tube after tube placement has been confirmed on chest
x-ray
l Check for bowel sounds prior to administration of each dose
l Cease further administration if bowel sounds are inaudible
l Reconsider the indications and clinical end points for therapy every 6
hours. MDAC should rarely be required beyond 6 hours.
URINARY ALKALINISATION

Rationale
The production of an alkaline urine pH promotes the ionisation of highly
acidic drugs and prevents reabsorption across the renal tubular epithelium,
thus promoting excretion in the urine. For this method to be effective
the drug must be filtered at the glomerulus, have a small volume of
distribution and be a weak acid.
Indications
Only two drugs of significance in clinical toxicology have the required
pharmacokinetic properties for this method to be of interest in
management of poisoning.
l Salicylate overdose
— Salicylates are normally eliminated by hepatic metabolism and
fail to be excreted in acidic urine. In overdose, metabolism is 27
saturated and elimination half-life greatly prolonged
— Urinary alkalinisation greatly enhances elimination and is
TOXICOLOGY HANDBOOK
indicated in any symptomatic patient in an effort to reduce the
duration and severity of symptoms or to avoid progression to
severe poisoning and the need for haemodialysis
— Severe established salicylate toxicity indicates immediate
haemodialysis rather than a trial of urinary alkalinisation
— Note: Not generally useful in chronic salicylate toxicity due to
co-morbidities.
— May be attempted in an effort to reduce duration of coma and
length of stay in intensive care
— Not first-line as MDAC is superior.
Contraindications
l Fluid overload.
Complications
l Alkalaemia (usually well-tolerated)
l Hypokalaemia
l Hypocalcaemia (not usually clinically significant).
Technique
l Correct hypokalaemia if present
l Given 1–2 mmol/kg sodium bicarbonate IV bolus
l Commence infusion of 100 mmol sodium bicarbonate in 1000 mL 5%
dextrose at 250 mL/hour
l 20 mmol of potassium chloride may be added to infusion to maintain
normokalaemia
l Follow serum bicarbonate and potassium at least every 4 hours
l Regularly dipstick urine and aim for urinary pH >7.5

l Continue until clinical and laboratory evidence of toxicity is
resolving.
EXTRACORPOREAL TECHNIQUES OF ELIMINATION

A number of such techniques have been used to enhance elimination of
toxins including:
l Haemodialysis
— Intermittent
— Continuous
l Haemoperfusion
l Plasmapheresis
l Exchange transfusion.
28 All of the above techniques are invasive and require specialised
staff, equipment and monitoring and may be associated with
28
significant complications. For these reasons they are reserved for life-
TOXICOLOGY HANDBOOK
threatening poisonings where a good outcome cannot be achieved

by other means, including aggressive supportive care and antidote
administration.
Haemodialysis is the most frequently used of these techniques and
effectively enhances elimination of any drug that is a small molecule,
has a small volume of distribution, rapid redistribution from tissues and
plasma, and slow endogenous elimination. Clinical situations that involve
life-threatening poisoning with agents fulfilling these criteria include:
l Toxic alcohol poisoning
— Methanol
— Ethylene glycol
l Theophylline poisoning
l Severe salicylate intoxication
— Chronic intoxication with altered mental status
— Late-presentation acute overdose with established severe
toxicity
l Severe chronic lithium intoxication
l Metformin lactic acidosis
l Massive valproate overdose
l Massive carbamazepine overdose
l Potassium salt overdose with life-threatening hyperkalaemia.
Precise clinical indications for haemodialysis in each of these

important poisonings are discussed in the relevant sections of Chapter 3.
The decision to dialyse should be made early as soon as the risk
assessment indicates potential lethality. In general, intermittent dialysis
achieves greater clearance rates than continuous haemodialysis techniques

and is preferred where available.
References
Anonymous. Position Statement and Practice Guidelines on the use of multi-dose
activated charcoal in the treatment of acute poisoning. Clinical Toxicology 1999;
37(6):731–751.
Dorrington CL, Johnson DW, Brant R. The frequency of complications associated with
the use of multiple-dose activated charcoal. Annals of Emergency Medicine 2003;
41(3):370–377.
Pond SM, Olson KR, Osterloh JD et al. Randomised study of the treatment of
phenobarbital overdose with repeated doses of activated charcoal. Journal of the
American Medical Association 1984; 251:3104–3108.
Proudfoot AT, Krenzelok EP, Vale JA. Position paper on urine alkalinization. Journal of
Toxicology Clinical Toxicology 2004; 42:1–26.
Winchester JF. Dialysis and haemoperfusion in poisoning. Advances in Renal
Replacement Therapy 2002; 9(1):26–30.
29
1.8 ANTIDOTES
TOXICOLOGY HANDBOOK
Antidotes are drugs that correct the effects of poisoning. Only a few
antidotes exist for a limited number of poisonings and many are used only
extremely rarely. Specific antidotes likely to be used in clinical practice
are discussed in Chapter 4 of this book.
Like all pharmaceuticals, antidotes have specific indications,
contraindications, optimal administration methods, monitoring
requirements, appropriate therapeutic end points and adverse effect
profiles.
The decision to administer an antidote to an individual patient is
based upon a risk–benefit analysis. An antidote is administered when the
potential therapeutic benefit is judged to exceed the potential adverse
effects, cost and resource requirements. An accurate risk assessment
combined with pharmaceutical knowledge of the antidote is essential to
clinical decision making.
Many antidotes are rarely prescribed, expensive and not widely
stocked. Planning of stocking, storage, access, monitoring, training and
protocol development are essential components of rational antidote use.
It is often appropriate for stocking to be coordinated on a regional basis
in association with regional policies concerning the treatment of poisoned
patients. It is frequently cheaper and safer to transport an antidote to a
patient rather than vice versa.
References
Dart RC, Borrow SW, Caravati EM et al. Expert consensus guidelines for stocking of
antidotes in hospitals that provide emergency care. Annals of Emergency Medicine
2009: 54:386–394.
1.9 DISPOSITION
A medical disposition is required for all patients who present with
poisoning or potential exposure to a toxic substance. Those who have
deliberately self-poisoned also require psychiatric and social review.
A risk-assessment-based approach to the management of acute poisoning
allows early planning for appropriate medical and psychosocial disposition.
Patients must be admitted to an environment capable of providing an
adequate level of monitoring and supportive care and, if appropriate,
where staff and resources are available to undertake decontamination,
administration of antidotes or enhanced elimination techniques.
Early risk assessment in the pre-hospital setting, usually by poisons
information centre staff, often allows non-intentional exposures to be
observed outside of the hospital environment. For those that present to
30
hospital, it minimises the duration and intensity of monitoring. Frequently
patients can be ‘cleared’ for medical discharge directly from the
30
emergency department immediately following assessment or following a

TOXICOLOGY HANDBOOK
few hours of monitoring. No arrangements for admission to hospital need

be made unless unexpected signs or symptoms of toxicity develop.
At other times the risk assessment will indicate the need for ongoing
observation, supportive care or the need for specific enhanced elimination
techniques or antidote administration. Under these circumstances, the
patient must be admitted to an environment capable of providing a level of
care appropriate for the anticipated clinical course. In many hospitals, this is
now the emergency observation unit rather than the general medical ward.
Where ongoing airway control, ventilation or advanced haemodynamic
support is required then admission to an intensive care unit is appropriate.
EMERGENCY OBSERVATION UNITS

Emergency observation units (EOUs) have been established in many
emergency departments in Australasia and elsewhere. These units vary in
capacity, design and staffing. Ideally, they are located adjacent to emergency
departments, staffed by emergency physicians and provide short-term
focused goal-oriented care. They have been remarkably successful in:
l Streamlining treatment in suitable conditions
l Reducing total bed days
l Increasing patient satisfaction
l Reducing inappropriate discharges and litigation.
TOXICOLOGY PATIENTS IN THE EMERGENCY OBSERVATION UNIT

In most hospitals where EOUs are established, the units appear to provide
an ideal environment for the management of acute poisoning beyond the
initial assessment and monitoring phase. Advantages of using the EOU
to admit toxicology patients include the ready availability of appropriate

resources, staff and training, 24-hour availability of experienced
medical staff, an open-plan environment that facilitates observation,
and an emergency department ethos that is geared towards assessment
and disposition. Adequate resources must be dedicated to the EOU,
particularly medical, nursing, psychiatric and social services.
Ideal design features and staffing that facilitate the management of
toxicology patients in the EOU include:
l Central nursing stations with clear vision of all areas
l An environment that protects from self-harm
l Secure entrances
l Dedicated areas for private interviews
l Dedicated social work, drug and alcohol, plus outpatient liaison services
l Appropriate monitors +/- telemetry
l Dedicated resuscitation equipment 31
l Duress alarms
l Appropriate staff, skills and equipment
l Appropriate 24/7/365 senior staff coverage
TOXICOLOGY HANDBOOK
l Dedicated psychiatric services
l Nurse–patient ratios appropriate for the acuity of patients (e.g. 1:4 for
monitored ‘step-down’ patients; 1:8 for non-monitored general patients).
Criteria need to be developed for admission to the EOU following
acute poisoning. Such criteria might include:
l Cardiac monitoring not required (but this can be provided in some
EOUs)
l Adequate sedation in cases of delirium
l Deterioration not anticipated (based on accurate risk assessment and
initial period of observation in the emergency department).
Admission of toxicology patients to the EOU helps counter several of
the difficulties encountered when poisoned patients are admitted to other
areas of the hospital:
l Admissions scattered all over hospital
l Less experienced nursing staff
l Poor availability of medical staff
l Frequent security incidents/absconding patients
l Most clinicians managing patients on general medical wards are junior
and have no formal or informal training in clinical toxicology
l Longer admissions.
RETRIEVAL OF THE POISONED PATIENT

Usually the initial receiving hospital is adequately resourced to provide
an acceptable level of supportive care, monitoring and therapy for the
poisoned patient. If this is not the case then transfer is necessary. Risk
TABLE 1.9.1 Principles of retrieval of the poisoned patient
l Risk assessment is vital

l Identify patients who may need retrieval to another hospital as soon as
possible
l Patients should only be retrieved for specific clinical indications
l Recognise that transport may occur during the worst phase of the
intoxication
l Consider bringing expertise and resources to the patient, rather than
vice versa
l Assess, manage and stabilise potential resuscitation and supportive
care priorities prior to transfer
l Ensure that transport does not lead to an interval of lower level of care
l Transport to a centre capable of definitive care
32 assessment ensures that the need to transfer is recognised early so that

appropriate planning and consultation takes place in an effort to ensure
32
as smooth a retrieval as possible. Poisoning is unusual in that transfer

frequently takes place during the most severe phase of the illness.
TOXICOLOGY HANDBOOK
Resuscitation
The need to retrieve a patient to another centre should not distract attending
staff from resuscitation and supportive care priorities. Attention to airway,
breathing and circulation ensure an optimum outcome in the majority of
cases. Whenever possible, the patient should be stabilised before retrieval
begins. Interventions such as intubation, ventilation, initial resuscitation
of hypotension, cessation of seizures, assessment of blood glucose and
management of hyperthermia are completed before a patient is placed in
the transport vehicle, where further assessment and detailed management
are often impossible. If the referring team does not possess the necessary
skills or resources to complete these resuscitation and stabilisation tasks
adequately, this should be communicated to the receiving and retrieval
teams, so that these resources can be brought to the patient.
Transport
As transport usually occurs during the most severe phase of the poisoning,
the patient should never be subjected to an interval of a lower level of care
during the transfer. Consideration of the mode and staffing of transport
takes this into account.
Planning
Planning is required to ensure that any potential complications are
identified and managed in a proactive fashion. Thus, if coma requiring
intubation and ventilation is anticipated in the next few hours (e.g.
controlled-release carbamazepine), early intubation and ventilation should
occur prior to transfer. Similarly, if significant hypotension is expected

(e.g. calcium channel blockers), then appropriate monitoring, intravenous
access and resuscitation resources should be ready prior to transfer.
Communication
Communication is vital. Retrieval is always to a higher level of care. Thus
transport must occur to a facility with appropriate resources to manage the
potential complications identified by the risk assessment. For example, if
haemodialysis may be required (e.g. theophylline or salicylate poisoning),
the patient must be transported to a facility capable of instituting this
intervention at short notice. Ideally, communication should include the
team of clinicians who will ultimately manage the patient. Consultations
with other specialist teams (e.g. paediatricians, intensivists or clinical
toxicologists) may also occur to assist the process. This improves
continuity of care and decreases the inefficiencies and errors that may be 33
associated with multiple handovers.
Antidotes
TOXICOLOGY HANDBOOK
If an antidote is likely to definitively treat the patient and render them
stable (e.g. N-acetylcysteine; digoxin-specific antibodies), then it is
preferable to transfer the antidote to the patient, start treatment, then move
the patient only if necessary.
Psychosocial assessment
Most episodes of acute poisoning represent an exacerbation of an
underlying psychosocial disorder and the final disposition of the patient
is made in this context. All patients with deliberate self-poisoning should
undergo psychosocial assessment prior to discharge. Ideally, this process
begins before the medical treatment of the poisoning is complete so that
final disposition is facilitated.
References
Daly FFS, Little M, Murray L. A risk assessment based approach to the management of
acute poisoning. Emergency Medicine Journal 2006; 23:396–399.
Ross MA,Graff LG. Principles of observation medicine. Emergency Medicine Clinics of
North America 2001; 19(1):1–17.
Warren J, Fromm RE, Orr RA, et al. Guidelines for the inter- and intrahospital transport
of critically ill patients. Critical Care Medicine 2004; 32:256–262.

CHAPTER 2
SPECIFIC CONSIDERATIONS
2.1 pproach to snakebite

A 36
2.2 Approach to mushroom poisoning 44
2.3 Approach to plant poisoning 50
2.4 Coma 55
2.5 Hypotension 59
2.6 Approach to seizures 61
2.7 Delirium and agitation 62
2.8 Serotonin syndrome 66
2.9 Anticholinergic syndrome 72
2.10 Cholinergic syndrome 76
2.11 Neuroleptic malignant syndrome 80
2.12 Alcohol abuse, dependence and withdrawal 85
2.13 Amphetamine abuse, dependence and withdrawal 93
2.14 Opioid dependence and withdrawal 94
2.15 Sedative-hypnotic dependence and withdrawal 97
2.16 Solvent abuse, dependence and withdrawal 100
2.17 Body packers and stuffers 104
2.18 Osmolality and the osmolar gap 107
2.19 Acid–base disorders 109
2.20 The 12-lead ECG in toxicology 113
2.21 Poisoning during pregnancy and lactation 119
2.22 Poisoning in children 120
2.23 Poisoning in the elderly 126
2.1 APPROACH TO SNAKEBITE
See also specific sections in Chapter 5: Black Snake, Brown Snake, Death
Adder, Sea Snake, Taipan, Tiger Snake
Definite or suspected snakebite is a regular presentation in most parts
of Australia. In contrast, severe envenoming is a rare but potentially lethal

presentation. Few clinicians have the opportunity to develop sufficient
clinical experience to feel comfortable managing envenoming.
Snakebite is a time-critical emergency presentation and a simple
but robust approach is required to ensure adequate treatment should
envenoming develop (see Table 2.1.1).
The clinical effects of the medically important Australian snakes are
summarised in Table 2.1.2.
RISK ASSESSMENT
36 Once it is appreciated that snakebite is a possibility, the risk assessment
is straightforward: there is a risk of life-threatening envenoming and a
36
formal process must begin to exclude that possibility in an appropriate

TOXICOLOGY HANDBOOK
setting.
TABLE 2.1.1 Treatment approach to snakebite

PRE-HOSPITAL
First aid
Pressure-immobilisation bandaging (PIB)
Transport
The patient is transported as soon as possible to a hospital that meets
all of the following criteria:
Doctor(s) able to manage snakebite
Laboratory capable of operating all hours
Adequate antivenom stocking for definitive treatment
HOSPITAL
Resuscitation
Determine if the patient is envenomed
Assessment is performed serially over at least 12 hours and is based
upon:
History
Physical examination
Laboratory investigations
Determine the type of monovalent antivenom required
Geographic area (prevalent indigenous snakes)
Clinical and laboratory features
CSL Snake Venom Detection Kit (SVDK)
Administer the dose of monovalent antivenom required to definitively treat
the envenoming
Adjuvant and supportive treatment
TABLE 2.1.2 Clinical effects of Australian Elapidae snakes
Venom-induced
Category consumptive Neurotoxicity Neurotoxicity
(Genus) coagulopathy (pre-synaptic) (post-synaptic) Rhabdomyolysis Renal failure Other effects
Brown Always present Very rare Not present Not present Uncommon Microangiopathic
(Pseudonaja) with significant Primary mechanism haemolytic anaemia
envenoming poorly understood and thrombocytopenia
Tiger Always present Slow onset Not present Slow onset over Uncommon Microangiopathic
(Notechis) with significant over hours hours Primary mechanism haemolytic anaemia
envenoming (possibly up to May be severe poorly understood and thrombocytopenia
May resolve 12–24 hours) and result in renal May also occur
spontaneously failure secondary to
in 12–24 hours rhabdomyolysis
Death adders Not present Not present Slow onset Not present Not present Local bite site pain
(Acanthophis) over hours often present
(possibly up to
12–24 hours)
Continued
TOXICOLOGY HANDBOOK SPECIFIC CONSIDERATIONS

37
38
38
TABLE 2.1.2 Clinical effects of Australian Elapidae snakes—cont’d
Venom-induced
Category consumptive Neurotoxicity Neurotoxicity
(Genus) coagulopathy (pre-synaptic) (post-synaptic) Rhabdomyolysis Renal failure Other effects
Black Not present Not present Not present May develop over Secondary to Bite site pain may be
(Pseudechis) Mild hours to days rhabdomyolysis significant
anticoagulant May be severe Envenoming usually
effect may be and result in renal associated with
seen with raised failure nausea, vomiting,
APTT abdominal pain and
Fibrinogen headache
remains normal
Taipan Always present May be rapid Not present May develop over Uncommon Microangiopathic
(Oxyuranus) with significant in onset minutes to hours Primary mechanism haemolytic anaemia
envenoming poorly understood and thrombocytopenia
May occur
secondary to
rhabdomyolysis
Sea snakes Not present May be rapid Not present May develop over Secondary to
(Hydrophiidae) in onset minutes to hours rhabdomyolysis
There is no clinical risk stratification process that allows the clinician
to identify patients who can be discharged early or without laboratory
investigations. Patients with no obvious bite mark and no symptoms may
be envenomed. As a result, many patients each year who turn out not to be
envenomed are transferred to larger centres for investigation and observation.
It is unusual that a snake is identified with sufficient reliability to
preclude further observation or investigation.
PRE-HOSPITAL CARE
First aid
First aid aims to delay lymphatic spread of venom proximally from the
bite site and delay systemic effects until the patient is in a facility that can
administer adequate doses of antivenom if required.
l Keep the patient as calm and still as possible
l Do no harm and avoid unproven and harmful techniques such as
tourniquets, ice, cutting, sucking or electric shocks 39
l Apply pressure-immobilisation bandaging (PIB)
— Pressure bandage over the entire limb
— Immobilisation of limb
TOXICOLOGY HANDBOOK
— Immobilisation of the whole patient
l If the bite is on the trunk, apply local pressure over the site and
immobilise the patient
l PIB may be left on for many hours while subsequent management
steps are completed. There are anecdotal reports of sudden
deterioration upon removal of the bandage up to 12 hours after
the bite. No patient who received early and appropriate PIB has
subsequently died
l Do not wash the wound, as a wound swab may be required later for
the CSL Snake Venom Detection Kit (SVDK)
l The PIB is not removed until:
— The patient has been fully assessed in an appropriate hospital
and found to show no objective evidence of envenoming (normal
initial physical examination and laboratory investigations)
OR
— Antivenom administration has commenced if found to be
envenomed.
Transport
All patients should be transported to a hospital that complies with all the
following criteria:
1 Doctor(s) present, able and willing to undertake snakebite
management, including definitive treatment of severe envenoming and
potential early complications (e.g. anaphylaxis)
2 Laboratory facilities capable of performing necessary investigations
on a 24-hour basis
3 Antivenom stocks adequate for definitive treatment of severe
envenoming by all snakes indigenous to that geographic area, or able
to obtain antivenom within a clinically suitable timeframe.
If the initial receiving hospital does not comply with these criteria,
the stable patient is transferred or retrieved to a hospital that does. If the
patient is unstable, resuscitation commences and antivenom is brought
in by a retrieval service or any other means possible. During the retrieval

phase the patient should be observed for clinical evidence of envenoming.
If there is objective evidence of envenoming (e.g. definite history of a bite
with hypotension or abnormal bleeding) antivenom treatment may begin
at the peripheral site, or commence during transfer.
HOSPITAL MANAGEMENT
Resuscitation
l Most patients present with a history of possible bite and do not require
40 immediate resuscitation
l Until early envenoming is excluded, patients should be assessed and
40
managed in an area equipped with cardio-respiratory monitoring and

resuscitation
TOXICOLOGY HANDBOOK
l Establish intravenous access

l Rarely, management of immediate threats to airway, breathing and
circulation, or control of seizures is required. Resuscitation proceeds
along conventional lines as outlined in Chapter 1.2: Resuscitation
l Potential early life-threats associated with Australian terrestrial snake
envenoming include:
— Hypotension (brown, taipan, tiger)
— Respiratory failure secondary to paralysis (death adder, taipan,
tiger; rarely, brown)
— Seizures (taipan)
— Severe venom-induced consumptive coagulopathy (VICC) with
uncontrolled haemorrhage (brown, taipan, tiger).
Determine whether the patient is envenomed or not
The aim is to seek objective evidence of envenoming based on history,
physical examination and laboratory data (see Table 2.1.3). Serial physical
examinations (looking for bleeding, neurotoxicity and rhabdomyolysis)
and investigations (FBE, EUC, CK and coagulation studies) are
performed until envenoming is diagnosed or 12 hours have expired.
Abnormalities on initial physical examination or laboratory studies
consistent with snake envenoming prompt immediate antivenom therapy
as outlined below.
If the patient remains clinically well and initial laboratory studies are
normal, the PIB is removed. If there is sudden clinical deterioration, it
is immediately reapplied, laboratory studies repeated and antivenom
administered.
TABLE 2.1.3 Assessment of snakebite
Laboratory
History Physical examination investigations
Geographic area of Vital signs Whole blood clotting

bite Mental status test utilising a clean
Appearance of snake glass tube
Evidence of bite (lack (Useful at peripheral
(Usually only useful of any evidence
for death adders sites; clotting
does not exclude time >20 minutes
and red-bellied envenoming)
black snakes) abnormal)
Lymphadenopathy Coagulation profile
Anatomic site of bite
Evidence of abnormal (INR and APTT
Number of strikes bleeding (e.g. required)
Use of PIB gingival sulci) Fibrinogen, D-Dimer,
Early symptoms Evidence of fibrin degradation
(e.g. collapse, descending products
nausea, vomiting, symmetrical flaccid Full blood count
bleeding, paralysis (ocular,
41
weakness) small muscles of Creatine kinase (CK)
Pre-hospital course face and bulbar Renal function and
TOXICOLOGY HANDBOOK
(e.g. hypotension, function affected urinalysis (blood/
bleeding from first) myoglobin)
IV sites, urine Respiratory function Consider also lactate
output) (e.g. PEFR) dehydrogenase
(LDH)
Note: The Commonwealth Serum Laboratories Snake Venom Detection Kit (SVDK) is
not used to determine whether a patient is envenomed (see section below).
If there is no discernible deterioration upon removal of the PIB the

patient is observed and physical examination and laboratory studies
repeated at 1, 6 and 12 hours. If at any time clinical examination or
laboratory results suggest envenoming, antivenom is administered.
If there is no evidence of envenoming at 12 hours after removal of
PIB the patient is ready for discharge. However, patients should not be
discharged at night as subtle delayed neurotoxicity might not be detected.
Determine the type of monovalent antivenom required

Monovalent antivenom is recommended in preference to polyvalent
antivenom as it is more specific, cheaper, safer and associated with a
lower probability of serum sickness.
Polyvalent antivenom contains the equivalent of one ampoule of each
monovalent antivenom. It contains a large protein load.
The choice of monovalent antivenom is based upon:
l Knowledge of snakes found in the area
l Clinical presentation
l Constellation of laboratory abnormalities
l Commonwealth Serum Laboratories Snake Venom Detection Kit (SVDK).
Determine the dose of monovalent antivenom required to treat the

envenoming definitively
l Once the appropriate monovalent antivenom(s) is selected, the dose
should be considered. Ideally, antivenoms are given in an initial dose

likely to provide definitive treatment.
l Currently recommended doses of antivenom are largely based
on clinical experience and consensus but have recently been
revised in the light of prospective studies measuring snake venom
concentrations. Dosing recommendations may be further modified as
improved data is acquired regarding venom, antivenom and target-
organ interactions in human cases
l For current dosing recommendations refer to the sections on specific
monovalent antivenoms in Chapter 6.
42 l Clinician(s) administering antivenom must be prepared to manage
anaphylaxis (see Appendix 6).
42
l Given the low prevalence of severe anaphylactic and anaphylactoid

TOXICOLOGY HANDBOOK
reactions to CSL antivenoms (1% for monovalent; 5% for polyvalent),

premedication to prevent allergic reactions is not routinely indicated
l Following the administration of antivenom, the patient’s clinical status
is monitored and laboratory investigations repeated after 6 and 12
hours and then every 12 hours until normalised
l Even with adequate antivenom administration, it may take from 10 to 20
hours for coagulation studies to return to normal in patients with VICC
l Further doses of antivenom are unlikely to be required unless the
patient’s clinical condition appears to be deteriorating.
Adjuvant therapy
Patients who receive snake antivenom are counselled about the possibility
of serum sickness 4–21 days after antivenom administration. Prednisolone
1 mg/kg/day (up to 50 mg/day) for 5 days may attenuate the severity of
serum sickness.
TABLE 2.1.4 Indications for polyvalent antivenom
l Appropriate monovalent antivenoms not available

l No SVDK result available and the range of possible snakes requires the
mixing of three or more monovalent antivenoms
l Severe envenoming, there is insufficient time to wait for SVDK results and
the range of possible snakes would require the mixing of three or more
monovalent antivenoms
l Exhausted monovalent AV stocks
Source: White J. CSL Antivenom Handbook. Melbourne: CSL Ltd, 2001.

BOX 2.1.1 The CSL Snake Venom Detection Kit (SVDK)
The SVDK indicates the right monovalent antivenom to use once a decision
has been made to give antivenom.
The SVDK is not used to determine whether or not a patient is envenomed.
False positives and negatives occur; if the SVDK does not match the clinical
picture, treat the patient not the SVDK result.
If there is doubt about the snake responsible for the envenoming and the
SVDK is not helpful (e.g. possible early tiger or brown snake envenoming in a
geographic location where the two snakes coexist), two monovalent antiven-
oms are superior to polyvalent antivenom.
The SVDK is ideally performed by a meticulous and experienced technician
according to the enclosed instructions.
The SDVK is performed using a bite-site swab, which can be accessed by
cutting a ‘key-hole’ in the PIB.
The SVDK may also be performed on urine (second-line).
The SVDK should not be performed on serum or blood.
The first test well to turn blue within the allotted time (10 minutes) gives 43
the result. Other wells may subsequently turn blue but are ignored. If no
well turns blue within the allotted time the test is negative and subsequent
changes are ignored.
TOXICOLOGY HANDBOOK
The use of blood products such as fresh frozen plasma or cryoprecipitate
in the management of venom-induced consumptive coagulopathy (VICC)
is controversial. There is some evidence that the administration of these
products following antivenom administration is associated with earlier
recovery from VICC and randomised controlled clinical trials are currently
being conducted to determine the efficacy and safety of clotting factor
replacement after venom neutralisation in VICC. Blood products are
indicated if there is uncontrolled or life-threatening haemorrhage.
Other direct complications of Australian snake envenoming that may
require specific monitoring or treatment include:
l Paralysis
l Rhabdomyolysis
l Acute renal failure
l Microangiopathic haemolytic anaemia (MAHA) and
thrombocytopenia
l Local wound complications.
References
Brown SGA, Caruso N, Borland M et al. Clotting factor replacement and recovery from
snake venom-induced consumptive coagulopathy. Intensive Care Medicine 2009;
35(9):1532–1538.
Clinical Toxinology Resources web site at http://www.toxinology.com
Sutherland SK, Coulter AR, Harris RD. Rationalisation of first-aid measures for elapid
snakebite. Lancet 1979; 1(8109):183–185.
White J. CSL Antivenom Handbook. Melbourne: CSL Ltd, 2001.
2.2 APPROACH TO MUSHROOM POISONING
Poisoning from ingestion of mushrooms occurs worldwide usually
when wild mushrooms containing toxins are misidentified as comestible
species, collected and eaten. More than one individual may be poisoned
simultaneously. The most common presentation is a benign self-limited

gastrointestinal disturbance but a number of other important toxic syndromes,
including potentially lethal hepatotoxicity, are recognised. Assessment and
management is based on the recognition of the principal clinical syndromes
that may develop following ingestion of toxic mushrooms. Patients may
present with mixed poisoning after ingestion of multiple mushroom species.
RISK ASSESSMENT
l The vast majority of mushroom poisoning cases in Australasia
manifest with acute gastrointestinal toxicity. A rapid resolution of
44 symptoms and good outcome with supportive care is anticipated
l A variety of other toxic syndromes may develop and a favourable
44
outcome can usually be anticipated with good supportive care

l Worldwide, cyclopeptide hepatotoxic poisoning accounts for the
TOXICOLOGY HANDBOOK
majority of mushroom-related deaths. This form of poisoning is

reported but extremely rare within Australasia
l Cyclopeptide hepatotoxic poisoning must be considered where
gastrointestinal symptoms develop greater than 6 hours following
ingestion of mushrooms
l Children: Accidental ingestion of wild mushrooms by children is
usually benign.
MUSHROOM SPECIES AND TOXINS
There are thousands of mushroom species and reliable mushroom
identification, even by expert mycologists, is difficult. In the clinical
setting, identification is frequently impossible because the mushrooms are
either unavailable, decomposing, partly digested or cooked.
Numerous toxins are identified and are usually species-specific (see
Table 2.2.1).
Acute gastroenteritis is the most frequent manifestation of mushroom
poisoning. The causative toxins are not well-identified and probably
heterogeneous in nature. The cholinergic syndrome is secondary to
muscarine, a quarternary ammonium peripheral muscarinic agonist that
does not stimulate nicotinic receptors and does not cross the blood–brain
barrier. Glutaminergic toxicity is due to muscimol, which resembles GABA
and stimulates central GABA receptors, and ibotenic acid, which resembles
glutamic acid and stimulates central glutaminergic receptors. Gyromitrin is
activated to monomethylhydrazine, which has a similar mode of action to
isoniazid and inhibits pyridoxine-dependent synthesis of GABA. Psilocybin
resembles lysergic acid diethylamide (LSD). Coprine inhibits acetaldehyde
TABLE 2.2.1 Clinical syndromes of mushroom poisoning
Toxin
Syndrome Clinical features Clinical course (mushroom species)
EARLY ONSET (WITHIN 6 HOURS)
Miscellaneous Malaise, abdominal pain, nausea, vomiting, Onset 30 min–3 hours Multiple mushroom genera
gastrointestinal* diarrhoea Resolution 6–24 hours but toxic mechanisms not
identified
Cholinergic* Vomiting, diarrhoea, lacrimation, salivation, Onset 30 min–2 hours Muscarine
urinary incontinence, bronchorrhoea, (Clitocybe and Inocybe
bronchospasm, miosis species)
Hallucinogenic* Ataxia, anxiety, mydriasis, tachycardia, Onset within minutes Psilocybin
dyskinesias, delirium and hallucinations (Psilocybe species)
Disulfiram-like* Nausea, vomiting, tachycardia, facial flushing, Onset following ethanol Coprine
sweating, chest pain consumption within (Coprinus species)
2 hours of mushroom
ingestion
Duration up to 6 hours
Glutaminergic* Dizziness, drowsiness, delirium, dysphoria, Onset 30 min–2 hours Ibotenic acid
hallucinations, myoclonus, hyperreflexia, Muscimol
seizures (Amanita muscaria and
pantherina)
Continued

45
46
46
TABLE 2.2.1 Clinical syndromes of mushroom poisoning—cont’d
Toxin
Epileptogenic Nausea, vomiting, diarrhoea GI symptoms within 4–6 Gyromitrin (Gyromitra
Headache, ataxia, fatigue, nystagmus, tremor, hours species)
vertigo, seizures (rare)
Delayed hepatotoxicity with raised Onset 2–3 days
transaminases (rare)
Delayed haemolysis and Onset 1–3 days after
methaemoglobinaemia (rare) hepatic injury
Immunohaemolytic Nausea, vomiting, epigastric pain and Onset 30 min–3 hours Paxillus species
diarrhoea
Haemolytic anaemia, haemoglobinuria, In the following days
immune-complex nephritis and acute renal
failure
Pneumonic Nausea, vomiting and rhinitis Onset within 6 hours Inhalation of dried
Acute bronchopneumonia Within days Lycoperdonosis spores
DELAYED ONSET (6–24 HOURS)
Hepatotoxic* Nausea, vomiting, abdominal cramps and Onset 6–24 hours Three classes of
diarrhoea cyclopeptide
Transient clinical improvement during 18–36 hours l matoxins
A
asymptomatic increase in hepatic l Phallotoxins
transaminases l Virotoxins
Severe gastroenteritis with fulminant hepatic 2–6 days (Amanita, Galerina and
failure and pancreatitis Lepiota species)
TABLE 2.2.1 Clinical syndromes of mushroom poisoning—cont’d
Toxin
Erythromelalgia Burning pain, redness and oedema of the Onset 24–72 hours Acromelic acids
hands and feet, exacerbated by heat and Resolution 8 days to 5
relieved by cold months
GREATLY DELAYED ONSET (>24 HOURS)
Nephrotoxic Anorexia, headache, nausea, vomiting, Onset 24–36 hours Orellanine

abdominal pain and flank pain (Cortinarius and A.
Interstitial nephritis and acute renal failure smithiana species)
Rhabdomyolysis Fatigue, myalgias, muscle weakness and Onset 24–72 hours (Tricholoma and Russula
myocarditis (very rare) species)
*denotes syndromes described in Australia

47
dehydrogenase, a mode of action similar to disulfiram. Amatoxins (chiefly
α-amanitin) inactivate RNA polymerase II and inhibit protein synthesis.
CLINICAL FEATURES
A variety of clinical syndromes may develop following ingestion of toxic
mushrooms. They are diagnosed on the basis of the clinical features and the
timing of the onset and duration of clinical features in relation to mushroom

ingestion (see Table 2.2.1). Laboratory abnormalities are important in the
diagnosis of some syndromes, especially hepatotoxicity. Identification of
the mushroom species by a mycologist is frequently difficult or impossible
but may provide important supportive evidence if available.
Conventional food poisoning should be considered in the differential
diagnosis of the patient who presents with gastrointestinal symptoms
following ingestion of mushrooms.
MANAGEMENT
48 Resuscitation
48
Patients may present with altered conscious state, seizures, cholinergic

crisis or significant hypovolaemia secondary to gastrointestinal fluid
TOXICOLOGY HANDBOOK
losses. These priorities are managed along conventional lines as outlined

in Chapter 1.2: Resuscitation.
Supportive care
Patients may have significant gastrointestinal losses and require large
volumes of crystalloid solutions. Meticulous supportive care includes
laboratory monitoring of electrolytes as clinically indicated. Seizures,
delirium and hallucinations are managed along conventional lines as outlined
in Chapter 2.6: Approach to seizures and Chapter 2.7: Delirium and agitation.
Decontamination
Administration of activated charcoal 50 g (1 g/kg in a child) is indicated if
onset of gastrointestinal symptoms is delayed beyond 6 hours after ingestion.
Investigations
Examination of any available mushrooms by a mycologist is useful,
particularly in cases where ingestion of species containing cyclopeptide
hepatotoxins is considered.
Electrolytes and creatinine should be monitored where significant
gastrointestinal fluid losses occur. Liver function tests should be
monitored for 24–48 hours where ingestion of mushrooms containing
cyclopeptide hepatotoxins is suspected.
Methods of enhanced elimination are frequently considered in patients
with potential cyclopeptide hepatotoxic mushroom poisoning but their
effect on outcome has not been studied in controlled trials. If cyclopeptide
hepatotoxic mushroom poisoning is suspected, multiple-dose activated
charcoal (see Chapter 1.7: Enhanced elimination) may be useful because
α-amanitin undergoes enterohepatic circulation.
Antidotes
Multiple antidotes and adjuvant therapies have been advocated in
patients with potential cyclopeptide hepatotoxic mushroom poisoning
but their effect on outcomes has not been evaluated in controlled trials.
They include high-dose benzyl penicillin (penicillin G), cimetidine,
N-acetylcysteine and silibinin. If delayed onset of gastrointestinal
symptoms or rising hepatic transaminases raises suspicion of possible
cyclopeptide hepatotoxic mushroom poisoning commence:
l N-acetylcysteine (see Chapter 4.18: N-acetylcysteine)
l Penicillin 1 million units/kg/day
l Silibinin (if available) 5 mg/kg by intravenous infusion over 1 hour
49
followed by a continuous infusion of 20 mg/kg/day for up to 3 days.
Atropine may be considered in patients with peripheral cholinergic
signs and symptoms (see Chapter 4.1: Atropine).
TOXICOLOGY HANDBOOK
Management of seizures secondary to monomethylhydrazine
poisoning from ingestion of Gyromitra mushrooms is similar to the
management of isoniazid poisoning and includes administration of
pyridoxine (see Chapter 4.24: Pyridoxine).
Disposition and follow-up
l Asymptomatic paediatric patients may be observed at home following
suspected ingestion of wild mushrooms
l Patients with early onset gastrointestinal illness are managed supportively
in a ward environment. They may be discharged when clinically well.
Patients with significant symptoms lasting greater than 6 hours should
have liver function tests and renal function checked prior to discharge.
Abnormal liver or renal function prompts further inpatient management
l Patients with coma requiring intubation or significant CNS effects
require management in an intensive care setting
l Cyclopeptide hepatotoxic mushroom poisoning is extremely rare and
most clinicians have very limited clinical experience. If this syndrome
is suspected due to delayed onset gastrointestinal symptoms or rising
hepatic transaminases, early consultation with a hepatic unit and
clinical toxicologist is recommended.
References
Diaz JH. Syndromic diagnosis and management of confirmed mushroom poisonings.
Critical Care Medicine 2006; 33:427–436.
Enjalbert F, Rapior S, Nouguier-Soulé J et al. Treatment of amatoxin poisoning: 20-year
retrospective analysis. Journal of Toxicology-Clinical Toxicology 2002; 40(6):715–757.
2.3 APPROACH TO PLANT POISONING
Numerous pharmacologically-active substances are produced by plants
and many pharmaceutical agents and recreational drugs are of plant origin.
Serious human poisoning from plant exposures is, however, extremely rare.
Exposure to toxic plants may occur unintentionally when they are

mistakenly identified as edible plants or when young children ingest parts of
plants, usually berries or seeds. Intentional exposure to toxic plants occurs with
recreational or medicinal intent or, less commonly, as an attempt at deliberate
self-harm. It often involves the ingestion of teas made from the plant. Non-
intentional cutaneous and ocular exposures may also cause symptoms.
Assessment of plant exposures is difficult even when the plant is
positively identified because it is virtually impossible to quantify dose;
there is enormous variation in toxin concentrations between species, plant
part, location and season.
50
RISK ASSESSMENT
50
l Most plant exposures are asymptomatic or cause minor irritative

TOXICOLOGY HANDBOOK
symptoms only
l Plants containing calcium oxalate crystals may cause more severe
irritation to exposed mucous membranes
l A few plants or parts of plants are capable of causing severe poisoning
when ingested in sufficient quantity
l Accurate plant identification usually allows refinement of the risk
assessment
l In the absence of accurate plant identification, risk assessment relies
on knowledge of local plants and observation of clinical features and
progress
l Children: Significant plant poisoning is extremely rare. Ingestion
of yellow oleander or castor beans seeds can theoretically cause
significant poisoning but hospital assessment is not indicated unless
symptoms develop.
IMPORTANT PLANT TOXINS
Calcium oxalate
Some plants contain needle-like calcium oxalate crystals packaged into
bundles that can cause mechanical injury to mucosal membranes when
ingested. The plants most commonly associated with this type of injury
are Dieffenbachia spp. and Philodendron spp.
Toxins capable of causing severe poisoning
A number of plant toxins are known to have caused significant human
poisoning or death following ingestion of fresh plant material. Important
examples are listed in Table 2.3.1 and discussed here.
TABLE 2.3.1 Plant toxins with potential to cause serious toxicity or
death following a single acute ingestion
Toxin(s) Plant(s) Clinical features
Aconite Aconitum spp. Tachycardia, GI

Delphinium spp. disturbance, multi-system
organ failure, lactic
acidosis
Belladonna Datura spp. (jimsonweed, Anticholinergic poisoning:

alkaloids angel’s trumpet) tachycardia, delirium,
Atropa belladonna agitation, ileus, urinary
retention
Hyoscyamus niger
(henbane)
Cardiac Digitalis spp. (foxglove) Bradycardia, dysrhythmias,

glycosides Nerium spp. (pink oleander) GI disturbance,
hyperkalaemia
Thevetia spp. (yellow 51
oleander)
Colchicine Colchicum autumnale GI disturbance, bone
TOXICOLOGY HANDBOOK
(autumn crocus) marrow depression, multi-
Gloriosa superba (glory lily) system organ failure
Coniine Conium maculatum (poison Bradycardia, tachycardia,

hemlock) GI disturbance, ascending
paralysis, rhabdomyolysis,
renal failure
Cyanogenic Prunus spp. seed kernels Tachycardia, bradycardia,

glycosides (apricots, plum, pear, cherry, coma, acidosis, multi-
almond) system organ failure
Hypoglycin Blighia sapia (ackee) Hypoglycaemia,

acidaemia, vomiting,
seizures
Nicotine Nicotiana spp. (tobacco) Tachycardia, hypotension,

tremor, sweating, GI
symptoms, seizures
Psychotropic Ipomea spp. (morning glory) Acute psychosis, visual

alkaloids seeds hallucinations
Lophophora williamsonii
(peyote cactus)
Ricin Ricinus communis (castor GI disturbance, multi-

beans) system organ failure
Taxine Taxus spp. (yew) Bradycardia, dysrhythmias,

GI disturbance
Aconite (Aconitum spp. and Delphinium spp.) is found in some Asian
herbal medicines. It binds to voltage-dependent sodium channels leading
to permanent activation of cardiac muscle and voltage-dependent nervous
tissue receptors. Dose-dependent toxicity develops rapidly after ingestion
and manifests with CNS, cardiovascular and gastrointestinal effects.
Bradycardia and hypotension may progress to tachydysrhythmias and
cardiac arrest, paraesthesiae may progress to CNS depression, respiratory

depression, paralysis and seizures, and nausea and vomiting may progress
to diarrhoea and abdominal cramping.
Belladonna alkaloids (atropine, scopolamine, hyoscyamine) are
found in numerous plant species. Those most commonly associated with
human poisoning are belladonna (Atropa spp.), angel’s trumpet (Datura
spp.) and henbane (Hyoscyamus spp.). These alkaloids cause competitive
blockade of central and peripheral acetylcholine muscarinic receptors
leading to the anticholinergic syndrome (see Chapter 2.9: Anticholinergic
syndrome).
52 Cardiac glycosides of various types are found in all parts of several
plants, including foxglove (Digitalis purpurea), pink oleander (Nerium
52
spp.) and yellow oleander (Thevetia spp.). These all have digoxin-like
TOXICOLOGY HANDBOOK
effects on cardiac conduction and Na-K ATPase (see Chapter 3.34:

Digoxin: acute poisoning).
The antimitotic agent, colchicine, is found in all parts of the autumn
crocus (Colchicum autumnale) and glory lily (Gloriosa superba) and
human colchicine poisoning (see Chapter 3.31: Colchicine) is reported
after ingestion of bulbs and leaves.
Coniine is an alkaloid found in poison hemlock (Coniium maculatum).
It is structurally related to nicotine and produces both nicotinic effects and
neuromuscular blockade with potential for death by respiratory failure.
Amygdalin is a cyanogenic glycoside found in the seeds or pits of
apricots, almonds, apples, peaches and wild cherries (Prunus spp.).
Laetrile, derived from amygdalin from apricot pits, is sometimes marketed
as a health food. After ingestion, amygdalin is hydrolysed to produce
cyanide (see Chapter 3.33: Cyanide).
Hypoglycin A is found in the unripe fruit and seeds of the ackee tree
(Blighia sapida). It interferes with fatty acid metabolism and causes
hypoglycaemia. It also causes vomiting, CNS depression and seizures.
Nicotine is found in the tobacco plant (Nicotiana tabacum). Excessive
ingestion, inhalation or transdermal exposure leads to overstimulation
of nicotinic receptors. This manifests with GI symptoms, sweating,
mydriasis, tachycardia, hypertension and seizures.
Psychotropic alkaloids include lysergic acid and mescaline. They act
as direct serotonin agonists and can produce vivid visual hallucinations.
Lysergic acid is found in morning glory seeds (Ipomea spp.) and
mescaline in the peyote cactus (Lophophora williamsonii).
Ricin, a lectin, is found in the castor bean plant (Ricinus communis).
The highest concentration is in the seeds. An intracellular toxin, it inhibits
protein synthesis, leading to a severe gastrointestinal disturbance together
with cardiac, haematologic, hepatic and renal toxicity.
Taxine is a mixture of alkaloids found in yew trees (Taxus spp.)
which inhibit both sodium and calcium currents. Ingestion of seeds has
produced gastrointestinal symptoms, paraesthesiae, mental status changes,
bradycardia, conduction blocks, ventricular dysrhythmias and cardiac arrest.
CLINICAL FEATURES
The vast majority of plant exposures remain asymptomatic. Minor
transient gastrointestinal symptoms may be observed.
The clinical features of oxalate crystal ingestion are immediate onset of
pain and swelling usually affecting the lips, tongue, oral cavity and pharynx.
Rarely, severe exposures may produce dysphagia, profuse salivation and
upper airways obstruction. It may take days for symptoms to subside.
Potentially serious exposures manifest onset of signs and symptoms 53
suggestive of the toxic mechanism. As detailed above, the clinical
syndromes that may develop include anticholinergic syndrome, nicotinic
TOXICOLOGY HANDBOOK
poisoning, cardiac glycoside poisoning, colchicine or cyanide poisoning.
MANAGEMENT
Resuscitation
Immediate resuscitation is unlikely to be required except in the patient
with delayed presentation after severe poisoning. An important exception
is aconite poisoning in which death from ventricular dysrhythmias or
respiratory paralysis may occur within hours of ingestion. Resuscitation
follows standard ACLS protocols. Successful outcome from cardiac arrest
from aconite poisoning using cardiopulmonary bypass is reported.
Supportive care and monitoring
The management of most plant poisonings entails supportive care and
monitoring along the standard lines described in Chapter 1.4: Supportive
care and monitoring. Particular attention to fluid and electrolyte status is
required with colchicine (see Chapter 3.31: Colchicine), aconite and ricin
poisoning. Maintenance of euglycaemia with dextrose infusion is required
in ackee fruit poisoning. Management of seizures and delirium requires
administration of titrated doses of benzodiazepines as outlined in Chapter
2.6: Approach to seizures and Chapter 2.7: Delirium and agitation.
Investigations
Investigations are performed as dictated by clinical signs and symptoms.
Serum digoxin levels do not accurately reflect toxicity from cardiac
glycoside poisoning of plant origin.
Decontamination
Administration of oral activated charcoal 50 g (1 g/kg in a child) is
indicated where the risk assessment suggests the possibility of life-
threatening toxicity. Where there is any potential for imminent depression
in the level of consciousness or seizures the airway must be secured prior
to administration of activated charcoal.
Skin exposure requires thorough washing of the exposed skin and eye
exposure requires thorough irrigation of the affected eye.
Antidotes
Physostigmine is useful in reversing severe anticholinergic poisoning (see
Chapter 4.22: Physostigmine). Cyanide antidotes may be useful in treating
cyanogenic glycoside poisoning (see Chapter 4.14 Hydroxocobalamin and
Chapter 4.27 Sodium thiosulfate). Digoxin immune Fab in relatively high
doses has been used successfully to reverse cardiotoxicity from oleander
poisoning (see Chapter 4.6: Digoxin immune Fab).
54
54
Not useful in plant poisoning.

TOXICOLOGY HANDBOOK
Disposition
Hospital assessment or observation is not required if the patient is
asymptomatic or has minor gastrointestinal symptoms only and the plant
is identified as not having potential for serious toxicity. This is the case for
the vast majority of plant exposure cases.
Hospital assessment and observation is necessary if there has been
significant ingestion of plant material containing potentially life-threatening
toxins. Any patient with symptoms beyond minor gastrointestinal ones
should also be assessed in hospital. The period of observation continues until
all risk of serious toxicity has elapsed. Where significant toxicity develops,
the level of care and length of stay will be determined by the clinical course.
Dermal, mucosal and ophthalmic plant exposures
A wide variety of plants are able to cause either primary or allergic contact
dermatitis. Some plants such as nettles have specialist stinging apparatus that
act like a hypodermic syringe to deliver irritant chemical to the skin. Contact
dermatitis is frequently associated with exposure to the sap of certain plants
such as the mango tree. It is rarely serious. Allergic contact dermatitis results
from type IV hypersensitivity response to plant exposures. Certain plants
have a greater propensity to cause allergic contact dermatitis.
References
Challoner KR, McCarron MM. Castor bean intoxication. Annals of Emergency
Medicine 1990; 19:1177–1183.
Chan TY. Aconite poisoning. Clinical Toxicology 2009; 47(4):279–285.
Eddleston M, Ariaratnam CA, Sjostrom L et al. Acute yellow oleander (Thevetia
peruviana) poisoning: cardiac arrhythmias, electrolyte disturbances, and serum
cardiac glycoside concentrations on presentation to hospital. Heart 2000; 83:301–306.
Eddleston M, Rajapakse S, Rajakanthan et al. Anti-digoxin Fab fragments in
cardiotoxicity induced by ingestion of yellow oleander: a randomised controlled
trial. Lancet 2000; 355:967–972.
Froberg B, Ibrahim D, Furbee RB. Plant poisoning. Emergency Clinics of North
America 2007; 25:375–433.
Rajapakse S. Management of yellow oleander poisoning. Clinical Toxicology 2009;
47(3):206–12.
Schep LJ, Slaughter RJ, Beasley DM. Nicotinic plant poisoning. Clinical Toxicology
2009; 47(8):771–781.
Suchard JR, Wallace KL, Gerkin RD. Acute cyanide toxicity caused by apricot kernel
ingestion. Annals of Emergency Medicine 1998; 32:742–744.
2.4 COMA
Coma describes an altered mental status where the patient cannot be
roused. It is a common manifestation of acute poisoning by many agents 55
(see Table 2.4.1).
In a potentially poisoned patient, coma may be the result of:
TOXICOLOGY HANDBOOK
l Direct toxic effect on the CNS: wakefulness and consciousness
depend on complex mechanisms involving many pathways and
neurotransmitter systems
l Secondary effect of poisoning on CNS: hypoxaemia, hypoglycaemia,
hyponatraemia, hypotension, seizures or cerebral oedema
l Alternative non-toxicological diagnoses: metabolic
encephalopathy, neurotrauma, space occupying lesion or
meningoencephalitis.
Coma presents an immediate threat to life, irrespective of the
underlying cause. Assessment and management is a core emergency
competency. With a few important exceptions, most agents that cause
toxic coma produce a relatively benign and temporary alteration in mental
status that has a good prognosis with thorough supportive care.
MANAGEMENT
Resuscitation
Establishment of airway and ventilation is the immediate priority
irrespective of the aetiology of coma. This is initially achieved using
positioning techniques, oropharyngeal airway, and bag and mask
ventilation with 100% oxygen. Definitive control is then achieved as
soon as practical with emergency rapid sequence induction of anaesthesia
and endotracheal intubation. The only exceptions to this process are
when hypoglycaemia is detected or there is clinical suspicion of opioid
intoxication. In these circumstances, bag and mask ventilation may
continue while awaiting a response to administration of concentrated
TABLE 2.4.1 Toxicological causes of coma
PRIMARY NEUROLOGICAL EFFECT
Alcohols Cholinergic agents

Ethanol Carbamates
Ethylene glycol Dementia acetylcholinesterase
Isopropyl alcohol inhibitors (e.g. donepezil)

Methanol Nicotine
Antipsychotic agents Organophosphates
Amisulpride Hydrocarbons
Chlorpromazine Eucalyptus oil
Clozapine Toluene
Olanzapine Local anaesthetics
Quetiapine Bupivacaine
Anticonvulsant agents Cocaine
Carbamazepine Lignocaine
Lamotrigine Ropivicaine
Tiagabine Mushrooms
Valproic acid Gyromitra species
56
Antidepressants Non-steroidal anti-inflammatory
Selective serotonin reuptake agents
56
inhibitors Ibuprofen
TOXICOLOGY HANDBOOK
Tricyclic antidepressants Mefenamic acid

Antihistamines Opioids
Diphenhydramine Codeine
Antimalarial agents Heroin
Chloroquine Morphine
Hydroxychloroquine Methadone
Quinine Sedative-hypnotic agents
Baclofen Benzodiazepines
Beta-adrenergic blockers Barbiturates
Propranolol Chloral hydrate
Centrally acting alpha2-agonists Gamma-hydroxybutyrate
Clonidine Non-benzodiazepine agents
Oxymetazoline (zolpidem, zopiclone)
SECONDARY EFFECT
Cerebral oedema Neuroleptic malignant syndrome

Salicylates Antipsychotic agents
Valproic acid Seizures
Hypoglycaemia Bupropion
Insulin Isoniazid
Sulfonylureas Tramadol
Hypotension Venlafaxine
Calcium channel blockers Serotonin syndrome
Cardiac glycosides (e.g. digoxin) Selective noradrenaline re-
Hypoxaemia (systemic or cellular) uptake inhibitors (e.g.
Agents causing venlafaxine)
methaemoglobinaemia Selective serotonin reuptake
Carbon monoxide inhibitors
Cyanide Monoamine oxidase inhibitors
Hydrogen sulfide
dextrose solution or naloxone. If coma does not rapidly resolve, proceed
with rapid sequence endotracheal intubation.
Poisoning is a dynamic illness. The patient’s ability to maintain an
airway and ventilate effectively may change in a short period of time.
This is ideally anticipated and prepared for on the basis of an early risk
assessment. For example, the patient who presents conscious shortly after
ingesting >30 mg/kg of a tricyclic antidepressant is expected to have a
rapid decline in level of consciousness within 2 hours.
A common pitfall in acute poisoning management is to assume that
coma is likely to be short-lived and to leave the airway unprotected for a
prolonged period of time. This increases the risk of pulmonary aspiration,
hypoxaemia and hypoventilation. Unlike trauma, where convention
dictates intubation at a Glasgow Coma Scale (GCS) of 8, there is no
definite measure of conscious state in poisoning that predicts the need for
intubation. A patient’s ability to guard their airway is poorly correlated to
GCS. The probability of aspiration is increased with any GCS less than
15, especially where there is delay to presentation. 57
Once neuromuscular paralysis and intubation is achieved, it is vital to
ventilate the patient at an appropriate minute volume. Several poisonings
TOXICOLOGY HANDBOOK
are associated with metabolic acidosis and compensatory hyperventilation
to achieve respiratory alkalosis (e.g. salicylate, methanol, ethylene
glycol). If hyperventilation is not maintained following paralysis and
mechanical ventilation, acute respiratory acidosis results in rapid clinical
deterioration and possibly death.
Risk assessment
Coma is usually a predictable response to poisoning where the agent and
dose are known. Where the original risk assessment did not predict coma,
it must be reassessed. It usually means that there has been ingestion of a
different or additional agents, a larger dose has been ingested or that the
patient has a non-toxicological cause for coma.
Where the patient presents with coma of unknown origin and there is
no definite history of ingestion, the clinician must rigorously evaluate the
historical, clinical and laboratory features of the case in order to:
l Diagnose alternative non-toxicological causes of coma
l Diagnose important complications of coma
l Diagnose specific toxicities where specific interventions (enhanced
decontamination techniques or antidotes) are necessary to ensure a
good outcome.
Toxic agents usually act on the CNS in a global and symmetrical
fashion and any focal or unilateral neurological sign is highly suggestive
of an alternative cause.
Patients may present having had significant impairment in level of
consciousness in the pre-hospital phase for varying periods of time. These
patients are at risk of a number of secondary complications, which may
have greater impact on morbidity and mortality than the intoxication
itself. These complications must be specifically sought and managed in
any patient presenting with coma. They include:
l Rhabdomyolysis
l Acute renal failure

l Compartment syndromes
l Pressure areas
l Hypoxic brain injury.
Supportive care, monitoring and disposition

All patients requiring intubation and ventilation are admitted to an
intensive care unit for ongoing supportive care. The following are
important to minimise the complications of coma in the admitted patient:
l Monitoring of conscious state and airway
58
l Respiratory toilet and prophylaxis (mobilisation and/or physiotherapy)
58
l Fluid monitoring and management

l Bladder care (indwelling catheter)
TOXICOLOGY HANDBOOK
l Prevention of pressure areas

l Thromboembolism prophylaxis
l Mobilisation as mental status changes resolve.
Investigations
l Screening (12-lead ECG and serum paracetamol level)
— These tests are particularly important in the comatose patient
where no ingestion history is available
— A measurable paracetamol level may mandate empiric NAC if
dose or time of ingestion can not be determined
l To detect toxic ingestions for which specific interventions are
required
— Arterial blood gases, anion gap and lactate
— Osmolality and osmolar gap
— Specific drug levels: carbamazepine, ethanol, ethylene glycol (when
available), methanol (when available), salicylate, valproic acid
l To detect and assess complications
— Urea and electrolytes
— Liver function tests
— CK
— Chest x-ray
l To exclude or confirm important differential diagnoses
— Urea and electrolytes
— Liver function tests
TABLE 2.4.2 Agents causing coma that may require specific
intervention
Carbamazepine Salicylate (severe poisoning only)

Multi-dose activated charcoal Haemodialysis
Haemodialysis Toxic alcohols (ethylene glycol,
Isoniazid methanol)
Pyridoxine Ethanol/fomepizole
Organophosphates Haemodialysis
Atropine Valproic acid
Pralidoxime Haemodialysis
Phenobarbitone
Multi-dose activated charcoal
Haemodialysis
— Cranial CT scan
— Lumbar puncture
— Blood and urine cultures 59
— EEG.
Enhanced elimination techniques and antidote administration
TOXICOLOGY HANDBOOK
The vast majority of patients presenting with or developing toxic coma
are assured of a good outcome with timely institution of supportive
care. There are a small number of specific agents where specific
interventions are indicated (see Table 2.4.2). Details of management
of these agents are found in the relevant toxin and antidote sections
in Chapter 3 and Chapter 4. Poisoning with carbamazepine, valproic
acid or phenobarbitone should be excluded with specific drug levels in
any comatose patient with access to these anticonvulsant agents. Toxic
alcohol and salicylate poisoning must be excluded in any comatose
patient with metabolic acidosis.
References
Daly FFS, Little M, Murray L. A risk assessment approach to the management of acute
poisoning. Emergency Medicine Journal 2006; 23:396–399.
International Liaison Committee on Resuscitation, 2005 American Heart Association
Guidelines for Cardiopulmonary and Emergency Cardiovascular Care–Part 10.2:
Toxicology in ECC. Circulation 2005; 112(24 Supplement I): IV126–IV132.
Isbister GK, Downes F, Sibbritt D et al. Aspiration pneumonitis in an overdose population:
Frequency, predictors and outcomes. Critical Care Medicine 2004; 32:88–93.
2.5 HYPOTENSION
Hypotension is assessed and managed during the resuscitation phase
of poisoning management. If detected later in the clinical course, the
clinician returns to the resuscitation phase and specifically addresses
priorities in the usual order (initially airway, breathing and circulation).
Hypotension is common in poisoned patients. It is usually mild,
secondary to peripheral vasodilation and responsive to basic fluid
resuscitation. However, poisoning secondary to cardiotropic medications
is frequently associated with refractory hypotension of multifactorial
origin and mortality is much higher. Similarly, hypotension that is
refractory to basic fluid resuscitation heralds a much worse outcome
unless perfusion is rapidly restored.

In a hypotensive patient, following attention to airway and breathing,
a series of interventions may be followed until a satisfactory response is
achieved:
1 Check cardiac rhythm and review a current 12-lead ECG. Commence
continuous ECG monitoring until patient is stabilised and risk
assessment is reviewed
2 Ensure adequate intravenous access
3 Correct cardiac dysrhythmias. Under certain circumstances,
standard resuscitation guidelines need to be disregarded and the
60
administration of specific antidotes may be a priority (see Chapter
60
1.2: Resuscitation)
4 Give 10–20 mL/kg of IV crystalloid to ensure euvolaemia. Further
TOXICOLOGY HANDBOOK
fluid challenge may be indicated but depends on the individual risk

assessment. For example, in iron, colchicine, theophylline or salicylate
intoxication fluid losses may be large and fluid resuscitation ongoing.
In contrast, in calcium channel blocker intoxication excessive fluid
resuscitation may lead to pulmonary oedema
5 Consider specific antidotes:
l Digoxin-specific antibodies (digoxin)
l Calcium (calcium channel blockers)
6 Consider atropine and pacing. Unfortunately, these rarely provide a
definitive solution in the poisoned patient
7 Commence inotropic agents. The agent of choice depends on the
intoxication and the results of invasive haemodynamic monitoring. It
is usually wise to commence with the agent most available and with
which the attending staff are most familiar. Choices include:
l Noradrenaline (norepinephrine)
l Adrenaline (epinephrine)
l Dopamine
8 Commence central haemodynamic monitoring
9 Consider high-dose insulin therapy (see Chapter 4.15: Insulin (high dose))
10 Consider extraordinary manoeuvres such as cardiopulmonary bypass.
References
International Liaison Committee on Resuscitation, 2005 American Heart Association
Guidelines for Cardiopulmonary and Emergency Cardiovascular Care—Part 10.2:
Toxicology in ECC. Circulation 2005; 112(24 Supplement I):126–132.
2.6 APPROACH TO SEIZURES
Toxic seizures are usually generalised and self-limiting and easily
controlled with intravenous benzodiazepines. The most common causes
of toxic seizures in Australasia are venlafaxine, bupropion, tramadol and
amphetamines.
In certain poisonings, seizures herald severe intoxication and a grave
prognosis unless definitive care is rapidly instituted (e.g. chloroquine,
propranolol, salicylates, theophylline, tricyclic antidepressants).
Seizures of any cause are treated as a matter of priority. Prolonged
seizure activity is associated with irreversible CNS injury. Secondary
hypoxia and acidosis increase the susceptibility for dysrhythmias.
Secondary hyperpyrexia and rhabdomyolysis may lead to dehydration,
hyperkalaemia and renal failure.
Phenytoin is not indicated in the management of toxic seizures.
The presence of focal or partial seizures indicates a focal neurological 61
disorder that is either a complication of poisoning or non-toxicologic in
origin. In either case, prompt further investigation is warranted.
TOXICOLOGY HANDBOOK
TABLE 2.6.1 Toxicological causes of seizures
Anticonvulsants Local anaesthetic agents

Carbamazepine Lignocaine
Topiramate Nicotine
Tiagabine Non-steroidal anti-inflammatory
Antidepressants agents
Buproprion Mefenamic acid
Citalopram Opioids
Tricyclics Dextropropoxyphene
Venlafaxine Pethidine
Antidysrhythmic agents Tramadol
Quinidine Propranolol
Antihistamines Salicylates
Antimalarial agents Sympathomimetic agents
Chloroquine Amphetamine and its
Hydroxychloroquine derivatives
Quinine Cocaine
Antipsychotic agents Theophylline
Butyrophenones Withdrawal syndromes
Phenothiazines Alcohol
Atypical antipsychotics Barbiturates
Olanzapine Benzodiazepines
Quetiapine Non-benzodiazepine sedative-
Isoniazid hypnotic agents (e.g.
Hypoglycaemic agents gamma hydroxybutyrate)
Insulin
Sulfonylureas
MANAGEMENT
See Chapter 1.2: Resuscitation
1 Attention to airway, breathing and circulation. If coma preceded onset
of seizures (e.g. tricyclic antidepressant poisoning), proceed to rapid
sequence intubation and ventilation as the steps below are taken
2 Administer oxygen
3 Check cardiac rhythm and output
4 Establish intravenous access
5 Check bedside blood glucose level and correct hypoglycaemia if present
6 Give an intravenous benzodiazepine (e.g. diazepam 5–10 mg; children
0.1–0.3 mg/kg/dose over 3–5 minutes). Repeat if necessary
7 Consider barbiturates as second-line therapy for refractory seizures in
acute poisoning (e.g. phenobarbitone 100–300 mg slow IV; children
10–20 mg/kg slow IV or thiopentone 3–5 mg/kg if ventilated)
8 Pyridoxine is a third-line agent that may be indicated in intractable
62 seizures secondary to isoniazid and other hydrazines (gram for gram
dose to match suspected isoniazid dose, or 5 g IV; children 70 mg/kg
62
not exceeding 5 g).

TOXICOLOGY HANDBOOK
References
Kunisaki TA, Augenstein WL. Drug- and toxin-induced seizures. Emergency Medical
Clinics of North America 1994; 12(4):1027–1056.
2.7 DELIRIUM AND AGITATION

See also Chapter 2.9: Anticholinergic syndrome
Delirium is characterised by an altered conscious state with impaired
cognition. The key diagnostic features are shown in Table 2.7.1. Intoxication
with a variety of agents may present with agitation and delirium (Table
2.7.2). The alteration in CNS function is usually a transient direct toxic
effect that resolves along with other features of intoxication. Secondary
complications or concomitant medical emergencies may contribute to
altered CNS function and these are listed in Tables 2.7.3 and 2.7.4.
TABLE 2.7.1 Diagnostic features of delirium (based on DSM-IV criteria)
1 Altered conscious state with impaired attention

2 Decreased cognition manifested by disorientation, memory deficits or
abnormal speech
3 Acute onset (usually hours or days) and fluctuating course (distinct from
dementia)
4 Evidence of an associated medical condition on history, examination or
investigations
5 In broad terms, the associated medical condition may be non-
toxicological, toxicological, due to drug withdrawal or multiple factors
DUTY OF CARE
The patient with delirium has an altered mental state with cognitive
impairment and is not competent to make decisions about their own
welfare. The clinician has a duty of care to the patient to protect them
from serious harm or death. The clinician also has a duty of care to other
patients, staff, visitors and the community at large to protect them from
being harmed by the actions of the delirious patient. Failure to control the
situation (allowing the patient to abscond or injure themselves) represents
an act of omission. While the delirium persists, temporary physical
restraint and pharmacological sedation, perhaps against the patient’s
wishes at the time, is appropriate.
TABLE 2.7.2 Toxicological causes of agitation and delirium
Alcohol
Anticholinergic syndrome
Antidepressants 63
Bupropion
Monoamine oxidase inhibitors
Venlafaxine
TOXICOLOGY HANDBOOK
Atypical antipsychotic agents
Olanzapine
Benzodiazepines and other sedative-hypnotic agents (e.g. zolpidem)
Cannabis
Hallucinogenic agents
Dimethyltryptamine (DMT)
Ketamine
Phencyclidine
2,5-dimethoxy-4-iodophenethylamine (2C-I)
Neuroleptic malignant syndrome (NMS)
Nicotine
Salicylates
Serotonin syndrome
Sympathomimetic syndrome
Amphetamine and its derivatives
Cocaine
Theophylline
Withdrawal syndromes
TABLE 2.7.3 Complications of agitation in the poisoned patient
Aspiration pneumonitis
Deep vein thrombosis and pulmonary embolism
Fluid, electrolyte and acid–base disturbances, most commonly dehydration
Hypoventilation, hypoxia
Hyperthermia
Physical injury to the patient or others
Rhabdomyolysis
TABLE 2.7.4 Other conditions mimicking or contributing to agitation
Acid–base disturbance
Behavioural disturbance
CNS infection (e.g. encephalitis)
Dementia
Electrolyte disturbance (e.g. hyponatraemia)
Endocrine emergency (e.g. thyroid storm)

Hypoglycaemia
Hypoxia
Organ failure (e.g. hepatic encephalopathy)
Psychosis
Seizures (e.g. non-convulsive status)
Stroke
Trauma (e.g. subdural haemorrhage)
Withdrawal (e.g. alcohol or sedative-hypnotic agents)
MANAGEMENT
64 Resuscitation
64
Airway, breathing and circulation are managed as appropriate.

Atypical seizures or non-convulsive status epilepticus should be
TOXICOLOGY HANDBOOK
considered and treated with benzodiazepines.

Check bedside serum glucose as soon as possible in all patients with
altered mental status to exclude hypoglycaemia. If the serum glucose is
<4.0 mmol/L, 50 mL of 50% glucose (5 mL/kg 10% glucose in children)
is given intravenously. The result may be confirmed later with a formal
serum glucose measurement. If hypoglycaemia is detected, the underlying
cause must be considered and managed.
A temperature >38.5°C is an indication for continuous core-temperature
monitoring. A temperature >39.5°C is an emergency that requires prompt
management to prevent multiple organ failure and neurological injury.
Risk assessment
Delirium is usually a predictable response to poisoning where the agent
and dose are known. If the original risk assessment did not predict
delirium, it must be reassessed. It usually indicates that there has been
ingestion of different or additional agents, or that the patient has a non-
toxicological cause for delirium.
Where the patient presents with delirium but no definite history of
ingestion, the clinician must rigorously evaluate the historical, clinical and
laboratory features of the case in order to diagnose:
l Important complications of delirium (see Table 2.7.3)
l Alternative (non-toxicological) causes (see Table 2.7.4)
l Toxicities or syndromes where specific interventions (enhanced
decontamination techniques or antidotes) are necessary to ensure a
good outcome (see Table 2.7.5).
TABLE 2.7.5 Agents or syndromes associated with delirium and
agitation that may require specific interventions
Agent Possible interventions
Anticholinergic agents Physostigmine (see Chapter 4.22:

Physostigmine)
Neuroleptic malignant syndrome Bromocriptine
Serotonin syndrome Cyproheptadine (see Chapter 4.3:

Cyproheptadine)
Neuromuscular paralysis, intubation
and ventilation
Salicylates Urinary alkalinisation

Haemodialysis
Theophylline Multi-dose activated charcoal

Haemodialysis
65
The patient is managed in a calm environment to minimise external
TOXICOLOGY HANDBOOK
stimulation and crowding. Repeated reassurance and explanation are
important. One-on-one nursing is usually necessary to allow close
observation and management during the initial stages. If the patient
remains extremely agitated with an immediate risk of harming themselves
or others, temporary physical restraint is required until pharmacological
sedation can be achieved. The medical team’s duty of care to the patient
should be explained. Physical restraint is achieved quickly by broad-
based control of the arms and legs. It must never threaten the airway
or breathing and is only used as a temporary measure until appropriate
pharmacological sedation is instituted.
For sedation, intravenous benzodiazepines titrated to effect are first-
line agents. It is best to use an agent with a duration of effect likely to
match the anticipated duration of delirium, usually diazepam. In mild
cases, oral dosing may be appropriate. In more severe cases, or in any
case with physical restraint, intravenous dosing will be required. Repeated
doses of intravenous diazepam 5 mg should be given every 2–5 minutes
until gentle sedation is achieved.
Antipsychotic agents such as haloperidol or droperidol are second-line
agents. They are highly effective but associated with acute extrapyramidal
(akathisia and dystonia) and anticholinergic effects. They should be
avoided if anticholinergic syndrome is suspected. Droperidol has been
associated with QT prolongation, cardiac arrhythmias and sudden death
in a very small number of cases. Recent reviews suggest this is extremely
rare, but it should be avoided if QT prolongation or significant electrolyte
disturbance is suspected.
Atypical antipsychotic agents (e.g. olanzapine) are rapidly acting and
frequently have a calming effect without major sedation in patients with
prominent psychotic symptoms. They may be given sublingually, orally or
intramuscularly. They are associated with less extrapyramidal effects than
haloperidol or droperidol.
Once agitation is adequately controlled, the patient is admitted
to an area capable of providing a sufficient level of ongoing close

supervision and monitoring, and where further intravenous sedation can be
administered if required. This is usually an emergency observation or high-
dependency unit. Delirium may persist for days, depending on the cause.
General supportive care as detailed in Chapter 1.4: Supportive care
and monitoring includes:
l Monitoring of conscious state and airway
l Respiratory toilet and prophylaxis (mobilisation and/or chest
physiotherapy)
l Fluid monitoring and management
66
l Bladder care (indwelling urinary catheter)
66
l Prevention of pressure areas

l Thromboembolism prophylaxis
TOXICOLOGY HANDBOOK
l Mobilisation as mental status changes resolve.
Investigations
Investigations in acute poisoning are used either as screening tests or for
specific purposes. Specific investigations in the patient with agitation
or delirium should be ordered selectively where it is anticipated that the
results will refine risk assessment, exclude significant complications or
exclude potential non-toxicological diagnoses.
Enhanced elimination techniques and antidote administration
There are relatively few instances where these interventions are required
in the management of agitation or delirium (see Table 2.7.5). For the use of
physostigmine in anticholinergic delirium see Chapter 2.9: Anticholinergic
syndrome and Chapter 4.22: Physostigmine.
Reference
Carter LC, Dawson AH. Acute delirium. In: Dart RC, ed. Medical Toxicology. 3rd edn.
Philadelphia: Lippincott Williams & Wilkins; 2004: Ch 15.
2.8 SEROTONIN SYNDROME

Serotonin syndrome is the clinical manifestation of excessive stimulation
of serotonin receptors in the CNS. This occurs when excess serotonin
(5-hydroxytryptamine) accumulates in the CNS, secondary to a number
of pharmacological mechanisms; inhibition of serotonin metabolism
TABLE 2.8.1 Clinical features of serotonin syndrome
Autonomic Neuromuscular
Mental status changes stimulation excitation
Apprehension Diarrhoea* Clonus (esp. ocular and

Anxiety Flushing ankle)*
Agitation, psychomotor Hypertension Hyperreflexia*
acceleration and Hyperthermia† Increased tone (lower
delirium* Mydriasis* limbs >upper limbs)*
Confusion Sweating* Myoclonus*
Tachycardia* Rigidity
Tremor
*Clinical features significantly associated with diagnosis (Hunter Serotonin Toxicity

Criteria)
†Hyperthermia >38°C is not significantly associated with the diagnosis but is present in
severe cases
(monoamine oxidase inhibitors), prevention of serotonin reuptake in nerve 67

terminals (serotonin reuptake inhibitors), serotonin release or increased
intake of serotonin precursors (tryptophan).
TOXICOLOGY HANDBOOK
CLINICAL FEATURES
Serotonin syndrome manifests as a wide variety of signs and symptoms
that reflect the triad of mental status changes, autonomic stimulation and
neuromuscular excitation (see Table 2.8.1).
There is a continuous clinical spectrum of severity ranging
from very mild symptoms in ambulatory patients to a fulminant
life-threatening syndrome characterised by generalised rigidity,
autonomic instability, marked mental status changes and hyperthermia.
Without prompt intervention, this severe syndrome progresses to
rhabdomyolysis, renal failure, disseminated intravascular coagulation
(DIC) and death.
Symptoms are usually of rapid onset and may be evident within
hours of changes in medication or overdose. Similarly, the syndrome
resolves over hours (up to 24–48 in severe forms) following
discontinuation of the causative agent and the institution of supportive
care. Serotonin syndrome after deliberate self-poisoning usually
develops within the first 8 hours and frequently after the patient presents
to hospital.
DIAGNOSIS
Serotonin syndrome is a clinical diagnosis and requires the history of
ingestion of one or more serotonergically-active agents (or a change in
their dose), the presence of characteristic clinical features and a high
index of suspicion. Some symptoms are more significantly associated
FIGURE 2.8.1 Algorithm for diagnosis of serotonin syndrome
Serotonergic agent
ingestion or overdose
S
Spontaneous clonus yes E
R
Agitation O
no OR T
Diaphoresis O
OR N
I
Inducible clonus OR Hypertonia AND N
yes yes
Ocular clonus Pyrexia (>38oC)
T
O
no no X
I
C
I
Tremor yes Hyperreflexia yes T
68 Y
68
no no
TOXICOLOGY HANDBOOK
NOT clinically significant serotonin toxicity
Source: Isbister GK, Buckley NA, Whyte IM. Serotonin toxicity: a practical approach to
diagnosis and treatment. Medical Journal of Australia 2007; 187(6):361–365.
with the diagnosis (see Table 2.8.1) and diagnostic algorithms have been
developed (see Figure 2.8.1).
Clinical settings in which serotonin syndrome may develop include:
l Introduction or increase in dose of a single serotonergic drug
l Change in therapy from one serotonergic drug to another without an
adequate intervening ‘washout’ period
l Drug interaction between two serotonergic agents
l Interaction between serotonergic drug and an illicit drug or herbal
preparation
l Deliberate self-poisoning with serotonergic agent(s).
Numerous agents are implicated in the development of serotonin

syndrome, of which the most important ones are listed in Table 2.8.2. The
severe life-threatening form most commonly develops after deliberate
self-poisoning with multiple serotonergic medications, especially a
selective serotonin reuptake inhibitor (SSRI) in combination with a
monoamine oxidase inhibitor (MAOI). Life-threatening serotonin
syndrome does not develop after ingestion of single SSRIs.
TABLE 2.8.2 Agents implicated in development of serotonin syndrome
Analgesics and antitussives Selective serotonin reuptake

Dextromethorphan inhibitors (SSRIs)
Fentanyl Citalopram
Pethidine Escitalopram
Tramadol Fluoxetine
Antidepressants Fluvoxamine
Tricyclic antidepressants Paroxetine
Drugs of abuse Sertraline
Amphetamines Serotonin and noradrenaline
Methylenedioxymethamphetamine reuptake inhibitors (SNRIs)
(MDMA; ecstasy) Bupropion
Herbal preparations Venlafaxine
St John’s wort (Hypericum Tryptophan
perforatum)
Lithium
Monoamine oxidase inhibitors
(MAOIs)
Moclobemide 69
Phenelzine
TOXICOLOGY HANDBOOK
DIFFERENTIAL DIAGNOSIS
Careful consideration of drug history, clinical features and clinical course
is essential to distinguish serotonin syndrome from neuroleptic malignant
syndrome, anticholinergic syndrome and malignant hyperthermia (see Table
2.8.3). Other differential diagnoses include CNS infections and intoxication
with salicylates, theophylline, nicotine or sympathomimetic agents.
MANAGEMENT
Resuscitation
l Attention to airway, breathing and circulation. If there is coma,
recurrent seizures, hyperthermia greater than 39.5°C or severe rigidity
compromising ventilation, proceed to rapid sequence intubation and
ventilation while continuing with the steps below
l Administer oxygen
l Check bedside blood glucose level
l Check temperature
A temperature >38.5°C is an indication for continuous core-temperature

monitoring. A temperature >39.5°C is an emergency and requires prompt
intervention with neuromuscular paralysis, intubation and ventilation to
prevent further muscle-generated heat production, and severe hyperthermia
leading to multiple organ failure, neurological injury and death
l Give titrated intravenous benzodiazepines (e.g. diazepam 5–10 mg;
children 0.1–0.3 mg/kg/dose over 3–5 minutes) to achieve gentle sedation
70
70
TABLE 2.8.3 Differential diagnosis of serotonin syndrome

Vital Bowel Neuromuscular Mental
Condition Drug history Cadence signs Pupils Skin sounds tone Reflexes status
Serotonin 5HT2A or <12 hours ↑HR, Mydriasis Sweaty Hyperactive Increased, Hyperreflexia Agitation
syndrome 5HT1A BP, especially and clonus progressing
agonist RR and lower limbs to coma
Temp
Neuroleptic Dopamine Days ↑HR, Mydriasis Sweaty Normal Lead-pipe Bradyreflexia Mutism,
malignant antagonist BP, or normal but pale rigidity staring,
syndrome RR and bradykinesia,
Temp coma
Anticholinergic Anticholinergic <12 hours ↑HR, Mydriasis Hot, red Decreased Normal Normal Agitated
syndrome agent BP, and dry or absent delirium
RR and
Temp
Malignant Inhalational Minutes- ↑HR, Normal Sweaty Decreased Generalised Hyporeflexia Agitation
hyperthermia anaesthetic 24 hours BP, and rigidity
RR and mottled
Temp
Adapted from Boyer EW, Shannon M. The serotonin syndrome. New England Journal of Medicine 2005; 352(11):1112–1120.
l Hypertension and tachycardia usually respond satisfactorily to
benzodiazepines given to achieve sedation. If refractory, a short-acting
intravenous infusion of a vasodilator such as GTN or nitroprusside is
commenced and titrated to effect.
Risk assessment
Mild serotonin syndrome (normal mental and vital signs) is a self-limiting
condition. Complete resolution over a period of hours is anticipated.
More severe forms of serotonin syndrome are potentially life-
threatening if not recognised and treated promptly. This complication
should be anticipated and specifically observed for following deliberate
self-poisoning with multiple serotonergic medications, especially an
MAOI in combination with an SSRI.
Investigations
In the context of deliberate self-poisoning, screening tests (paracetamol
level and 12-lead ECG) are indicated. 71
Depending on severity, further investigations including creatine
kinase, electrolytes, renal function tests and troponin may be required to
TOXICOLOGY HANDBOOK
exclude significant complications.
Supportive care
l Cease causative agent(s)
l Reassure
l Intravenous fluids and fluid balance monitoring
l Careful observation of vital signs, including temperature, mental
status and muscle tone, until clinical improvement documented
l Benzodiazepine sedation as required.
Antidote therapy: Specific serotonin antagonists

There may be a role for specific serotonin antagonists in the management
of mild–moderate serotonin syndrome, refractory to benzodiazepine
administration. A number of serotonin antagonists have been used to treat
serotonin syndrome although their efficacy has not been established in
controlled trials. Cyproheptadine (see Chapter 4.3: Cyproheptadine) can
be given orally, or crushed via a nasogastric tube. Commence with 8 mg.
If a clinical response is observed, further doses of 8 mg may be repeated
every 8 hours for the next 24 hours. Alternative agents are chlorpromazine
(25–100 mg given in 100 mL of normal saline IV over 30–60 minutes) or
olanzapine 10 mg SL. Adverse effects are common with chlorpromazine
and include significant sedation, orthostatic hypotension and
anticholinergic side effects.
Serotonin antagonists are not indicated for severe serotonin syndrome
where a good outcome can only be achieved with timely institution of
aggressive supportive care including cooling, endotracheal intubation,
ventilation and neuromuscular paralysis.
Disposition
The patient with mild serotonin syndrome related to therapeutic
drug administration may be discharged once the offending agent is
ceased. They should be advised of the adverse effect and appropriate

arrangements made for review of their pharmacotherapy.
Patients at risk of developing serotonin syndrome following deliberate
self-poisoning should be observed for this complication for at least 8
hours and overnight.
Any patient with altered mental status or vital signs requires admission
for observation, supportive care and consideration of a trial of serotonin
antagonist therapy. The duration of admission will usually be less than
24 hours.
Patients who develop severe serotonin syndrome requiring
72 neuromuscular paralysis, intubation and ventilation are admitted to an
intensive care unit. Resolution of the syndrome with complete recovery
72
can be anticipated within 24–48 hours.

TOXICOLOGY HANDBOOK
References
Boyer EW, Shannon M. The serotonin syndrome. New England Journal of Medicine
2005; 352(11):1112–1120.
Dunkley EJ, Isbister GK, Sibbritt D et al. The Hunter Serotonin Toxicity Criteria:
simple and accurate diagnostic decision rules for serotonin toxicity. Quarterly
Journal of Medicine 2003; 96:635–642.
Isbister GK, Buckley NA, Whyte IM. Serotonin toxicity: a practical approach to
diagnosis and treatment. Medical Journal of Australia 2007; 187(6):361–365.
2.9 ANTICHOLINERGIC SYNDROME

Anticholinergic (antimuscarinic) syndrome arises due to competitive
inhibition of central and peripheral acetylcholine muscarinic receptors and
is potentially life threatening.
CLINICAL FEATURES
Anticholinergic syndrome is best characterised as an agitated delirium
associated with variable signs of peripheral muscarinic blockade (see
Table 2.9.1).
The diagnosis of anticholinergic syndrome is clinical, usually based
on the characteristic appearance of the delirium, the presence of some
peripheral signs, and a history of ingestion of a known anticholinergic
agent (see Table 2.9.2). Signs and symptoms are variable and no particular
pattern of central or peripheral signs reliably diagnoses the syndrome.
TABLE 2.9.1 Clinical features of anticholinergic syndrome
Central Peripheral
Agitated delirium characterised by: Mydriasis

Tachycardia
l Fluctuating mental status
Dry mouth
l Confusion
Dry skin
l Restlessness
Flushing
l Fidgeting
Hyperthermia
l Visual hallucinations
Sparse or absent bowel sounds
l Picking at objects in the air
Urinary retention
l Mumbling slurred speech
l Disruptive behaviour
Tremor
Myoclonus
Coma
Seizures (rare)
73
TOXICOLOGY HANDBOOK
TABLE 2.9.2 Anticholinergic agents
Antiparkinsonian drugs Atypical antipsychotic agents

Amantadine Olanzapine
Benztropine Quetiapine
Antihistamines Anticonvulsant agents
Brompheniramine Carbamazepine
Chlorpheniramine Motion sickness agents
Cyproheptadine Hyoscine-scopolamine
Dexchlorpheniramine Meclizine
Dimenhydrinate Antimuscarinic agents
Diphenhydramine Atropine
Doxylamine Hyoscyamine
Pheniramine Glycopyrrolate
Promethazine Topical ophthalmological agents
Trimeprazine Cyclopentolate
Antitussives Homatropine
Dextromethorphan Tropicamide
Antidepressants Urinary antispasmodic agents
Tricyclic antidepressants Oxybutynin
Antipsychotic agents Muscle relaxants
(butyrophenones and Cyclobenzaprine
phenothiazines) Orphenadrine
Chlorpromazine Plants and herbal remedies
Droperidol Selected mushrooms
Fluphenazine Datura species
Haloperidol
Thioridazine
Trifluoperazine
TABLE 2.9.3 Differential diagnosis of anticholinergic syndrome
Encephalitis Neurotrauma
Hypoglycaemia Sepsis
Hyponatraemia Serotonin syndrome
Ictal phenomenon Subarachnoid haemorrhage
Neuroleptic malignant syndrome Wernicke’s encephalopathy
Many anticholinergic pharmaceuticals and plants also have other toxic

effects, which may obscure or modify the anticholinergic aspect of their
clinical presentation in poisoning. If a clear history of ingestion is not
forthcoming, a differential diagnosis should be considered (see Table 2.9.3).
Focal neurological signs do not occur as part of the syndrome and their
presence prompts immediate investigation for an alternative diagnosis.
When inadequately managed, patients with anticholinergic syndrome
are at risk of a number of complications that significantly affect their
74 clinical course. These include:
l Injury to themselves or others
74
l Dehydration
TOXICOLOGY HANDBOOK
l Hyperthermia
l Rhabdomyolysis
l Pre-renal failure
l Pulmonary aspiration and atelectasis.
In the patient who presents late to medical care, some or all of these
complications may already be present.
MANAGEMENT
Resuscitation
l Attentionto airway, breathing and circulation
l Detect and correct seizures (give benzodiazepines)
l Detect and correct hypoglycaemia
l Detect and correct hyperthermia.
Risk assessment
The development of anticholinergic syndrome is anticipated following
deliberate self-poisoning with potent anticholinergic agents. It usually
manifests within the first few hours of ingestion. Once established, it is
difficult to predict the duration of delirium but it may persist for up to
5 days in some circumstances, such as deliberate self-poisoning with
benztropine or carbamazepine.
Supportive care
l Manage in a quiet but well-lit area
l Reassurance
l Intravenous fluid resuscitation and maintenance. Patients are frequently
unable to drink and may already be dehydrated at presentation
l Insert an indwelling urinary catheter if any evidence of urinary
retention
l Treat agitation with diazepam 5–10 mg (0.1 mg/kg in children) PO
or IV every 10–15 minutes until the patient is resting quietly but
able to be roused easily. Repeat doses are often required but beware
over-sedation, as pulmonary atelectasis and/or aspiration are frequent
complications of prolonged sedation. Diazepam is the preferred
benzodiazepine because its longer duration of action more closely
matches the duration of delirium
l One-on-one nursing is frequently necessary to maintain adequate
levels of supervision, reassurance and sedation
l Avoid using drugs with known anticholinergic effects (e.g.
haloperidol, chlorpromazine).
Investigations 75
l Screening tests (12-lead ECG and serum paracetamol) if deliberate
self-poisoning is suspected. Also check a paracetamol level in
TOXICOLOGY HANDBOOK
accidental paediatric poisoning if anticholinergic syndrome could be
due to an over-the-counter paracetamol-containing combination cough
or cold preparation
l Specific testing as dictated by the individual agent (e.g. carbamazepine
levels)
l Electrolytes and renal function
l Creatine kinase
l Consider further investigations to address the differential diagnosis.
Decontamination
The need for gastrointestinal decontamination is determined by a risk–
benefit analysis guided by the individual risk assessment.
The need for enhanced elimination is determined by a risk–benefit
analysis guided by the individual risk assessment.
Antidotes
Physostigmine is a centrally acting acetylcholinesterase inhibitor that
may be used to reverse anticholinergic delirium in selected patients,
particularly where it proves difficult to achieve adequate sedation with
titrated benzodiazepines. It sometimes also proves useful to confirm
the diagnosis of anticholinergic delirium and avoid the need for further
investigation to exclude alternative diagnoses. For further details on this
antidote see Chapter 4.22: Physostigmine.
References
Liang HK, Clinical evaluation of the poisoned patient and toxic syndromes. Clinical
Chemistry 1996; 42(8):1350–1355.
Patel RJ, Saylor T, Williams SR et al. Prevalence of autonomic signs and symptoms in
antimuscarinic drug poisonings. Journal of Emergency Medicine 2004; 26(1):
89–94.
2.10 CHOLINERGIC SYNDROME

The cholinergic syndrome is the result of increased acetylcholine
activity at central and peripheral muscarinic and nicotinic receptors
and is potentially lethal. Acetylcholine is the neurotransmitter at pre-
and post-ganglionic parasympathetic, pre-ganglionic sympathetic
and somatic nerves. It is also an important neurotransmitter in the
CNS. Cholinergic syndrome arises from either acetylcholinesterase
enzyme inhibition or direct agonist action at muscarinic or nicotinic
76 receptors.
Most cases of clinically significant cholinergic syndrome are due to
76
poisoning from organophosphate or carbamate pesticides.

TOXICOLOGY HANDBOOK
A comprehensive list of causative agents is shown in Table 2.10.1.
TABLE 2.10.1 Cholinergic syndrome: causative agents

ACETYLCHOLINESTERASE INHIBITION
Organophosphate insecticides Chemical warfare nerve agents

Chlorpyrifos Tabun (GA)
Coumafos Sarin (GB)
Diazinon Soman (GD)
Dimethoate VX
Fenthion Agents used in dementia
Malathion Donepezil
Carbamate insecticides Galantamine
Aldicarb Rivastigmine
Arasan Tacrine
Cycloate Agents used in myasthenia
Terbucarb gravis
Thiram Edrophonium
Neostigmine
Physostigmine
Pyridostigmine
ACETYLCHOLINE AGONISTS
Muscarinic agents Nicotinic agents

Acetylcholine Nicotine (tobacco, gums,
Bethanechol patches)
Carbachol Mushrooms
Pilocarpine
TABLE 2.10.2 Clinical features of cholinergic syndrome
Central Sympathetic
nervous Parasympathetic nicotinic
system Neuromuscular muscarinic effects effects
Agitation Fasciculation Abdominal Hypertension
Central Muscle cramping Mydriasis
respiratory weakness Bradycardia Sweating
depression Bronchoconstriction Tachycardia
Coma Bronchorrhoea
Confusion Diarrhoea
Lethargy Lacrimation
Seizures Miosis
Salivation
Urinary
incontinence
Vomiting
77
CLINICAL FEATURES
Excessive stimulation of cholinoreceptors produces a constellation of
CNS, autonomic and neuromuscular effects (see Table 2.10.2). Classically,
TOXICOLOGY HANDBOOK
the patient in cholinergic crisis has copious secretions, vomiting,
diarrhoea and altered mental status. Fasciculation and muscle weakness
may be prominent. Death is secondary to respiratory failure from
excessive respiratory secretions and weakness of ventilatory muscles.
Signs and symptoms are variable. Although bradycardia secondary to
increased vagal tone is expected, tachycardia is very common secondary
to hypoxia, peripheral vasodilation and the effects of nicotinic stimulation.
The diagnosis is clinical and based on the characteristic clinical
features and progress, usually supported by an exposure history. Miosis
appears to be a consistent feature of chemical warfare nerve agent
poisoning. Laboratory testing is useful to exclude other diagnoses (see
risk assessment below and Table 2.10.3) or complications. Complications
may include:
l Rapid onset of respiratory failure
l Seizures
l Dehydration
l Medium and long-term neurological sequelae of organophosphate
intoxication.
MANAGEMENT
Resuscitation
In the setting of insecticide poisoning, efforts to decontaminate the patient
or use sophisticated personal protective equipment should not delay
resuscitation efforts.
TABLE 2.10.3 Differential diagnosis of cholinergic syndrome
Causes of weakness (neurotoxic snake bite, Guillain-Barré, myasthenia

gravis, botulism)
Cardiotropic intoxication resulting in bradycardia and vomiting (digoxin,
oleander, beta-adrenergic blockers, calcium channel blockers)
Gastroenteritis and abdominal emergencies
Ictal phenomena
Mushroom ingestion
Respiratory disorders (asthma, congestive cardiac failure)
Salicylate intoxication
Serotonin syndrome
Sympathomimetic syndrome
Theophylline intoxication
l Attention to airway, breathing and circulation is paramount. Early

78 control of pulmonary secretions and administration of oxygen is the
key to survival
78
l Give supplemental oxygen

TOXICOLOGY HANDBOOK
l Administer atropine if there are any objective signs of muscarinic

excess, such as cough, dyspnoea, respiratory failure, vomiting,
diarrhoea, salivation, lacrimation or bradycardia. Repeated escalating
doses are given (see Chapter 4.1: Atropine) until drying of respiratory
secretions is achieved
l Control seizures with benzodiazepines
l If adequate oxygenation and ventilation are not rapidly achieved
with oxygen and atropine, proceed immediately to intubation and
ventilation.
Risk assessment
The risk assessment for cholinergic syndrome depends on the underlying
cause. Deliberate self-poisoning with any organophosphate agent is
expected to lead to a life-threatening cholinergic crisis. Any ingestion of
an organophosphate agent by a child is also regarded as potentially life
threatening. The need for large doses of atropine should be anticipated.
If a clear history of ingestion is not forthcoming, a differential diagnosis
should be considered (see Table 2.10.3).
Supportive care
l In insecticide poisoning, staff should manage the patient in a well-
ventilated room using universal precautions. Sophisticated personal
protective equipment is not required
l Reassurance
l Commence fluid resuscitation. Patients may already be dehydrated
at presentation and require intravenous fluid resuscitation.
Increased insensible fluid losses are likely and often patients cannot
drink, so ongoing intravenous fluid management is frequently
required
l Insert an indwelling catheter. Monitor fluid balance until the patient is
drinking normally.
Investigations
l Screening tests (12-lead ECG and serum paracetamol level) are
indicated if deliberate self-poisoning is suspected
l Specific testing as dictated by the individual agent (e.g. cholinesterase
levels)
l Chest x-ray
l Arterial blood gases
l Electrolytes and renal function
l Consider further testing to address the differential diagnosis. 79
Decontamination
TOXICOLOGY HANDBOOK
The need for gastrointestinal decontamination is determined by a risk–
benefit analysis that incorporates the risk assessment. In the setting
of insecticide poisoning, efforts to decontaminate the patient or use
sophisticated personal protective equipment should not delay resuscitation
efforts.
The need for enhanced elimination will be determined by a risk–benefit
analysis that incorporates the risk assessment.
Antidotes
Atropine (see Chapter 4.1: Atropine)
Pralidoxime (see Chapter 4.23: Pralidoxime) for organophosphate or
nerve agent intoxication.
References
Liang HK. Clinical evaluation of the poisoned patient and toxic syndromes. Clinical
Chemistry 1996; 42(8):1350–1355.
Little M, Murray L. Consensus statement: risk of nosocomial organophosphate
poisoning in emergency departments. Emergency Medicine Australasia 2004;
16:456–458.
Eddleston M, Dawson A, Karalliedde L et al. Early management after self-poisoning
with an organophosphorus or carbamate insecticide: a treatment protocol for junior
doctors. Critical Care 2004; 8(6):R391–R397.
2.11 NEUROLEPTIC MALIGNANT SYNDROME
Neuroleptic malignant syndrome (NMS) is a rare but potentially
lethal syndrome complicating the use of neuroleptic medications. It
is characterised by neuromuscular rigidity, altered mental status and
autonomic instability.
The aetiology of NMS remains controversial. Although a central

deficiency of dopaminergic neurotransmission at nigrostriatal, mesolimbic
and hypothalamic-pituitary pathways appears pivotal, peripheral mechanisms
involving altered skeletal muscle mitochondrial function may also be
involved. The syndrome develops in 0.02–2.5% of patients taking neuroleptic
medication and this incidence does not appear to have changed significantly
with the introduction of atypical antipsychotics into clinical practice.
CLINICAL FEATURES
The syndrome is characterised by altered mental status, autonomic instability
80 and neuromuscular dysfunction (see Table 2.11.1). The onset of NMS
typically occurs over 24–72 hours. Recovery may take many days to months.
80
DIAGNOSTIC CRITERIA
TOXICOLOGY HANDBOOK
The diagnosis is clinical, based on a high index of suspicion, presence of

characteristic signs and symptoms, and the history of ingestion of one or
more neuroleptic agents. Neuroleptic malignant syndrome is a clinical
diagnosis made after other medical conditions have been considered and
excluded as necessary.
Strict criteria have been proposed but they may lack sensitivity in
milder cases.
Elevation of CK was considered a requirement for the diagnosis
of NMS, but currently accepted diagnostic criteria allow the diagnosis
without elevated CK (see Table 2.11.2).
TABLE 2.11.1 Clinical features of neuroleptic malignant syndrome
Central nervous
system Autonomic instability Neuromuscular
Confusion Hyperthermia ‘Lead-pipe’ rigidity

Delirium Tachycardia Generalised
Stupor Hypertension bradykinesia or
Coma Respiratory irregularities akinesia
Cardiac dysrhythmias Mutism and staring
Dysarthria
Dystonia and abnormal
postures
Abnormal involuntary
movements
Incontinence
TABLE 2.11.2 Diagnostic and Statistical Manual of Mental Disorders
fourth edition (DSM-IV) criteria for diagnosis of NMS
A. The development of severe muscle rigidity and elevated temperature

associated with the use of antipsychotic medication
B. Two or more of the following:
Diaphoresis
Elevated blood pressure
Tachycardia
Incontinence
Dysphagia
Mutism
Tremor
Changes in the level of consciousness ranging from confusion to coma
Leucocytosis
Laboratory evidence of muscle injury (e.g. elevated CK)
C. The symptoms in criteria A and B are not due to another substance
(e.g. phencylidine), neurologic or other medical condition (e.g. viral
encephalitis)
D. The symptoms in criteria A and B are not better accounted for by a 81
mental disorder (e.g. mood disorder with catatonic features)
TOXICOLOGY HANDBOOK
Leucocytosis, ranging up to 40 000 cells/microL, is common.
Alterations of hepatic and renal function, metabolic acidosis,
hypocalcaemia, hypomagnesaemia and decreased serum iron may also
be seen. Cranial CT and MRI are normal. Lumbar puncture, usually
performed to exclude encephalitis, may show elevated CSF protein in
up to 37% of cases. Generalised slow wave activity, consistent with a
metabolic encephalopathy, is seen on electroencephalogram (EEG).
The following risk factors for NMS have been suggested:
l High doses of neuroleptic agent
l Increased dose of neuroleptic agent within the previous 5 days
l Large magnitude dosage increase
l Parenteral administration
l Simultaneous use of two or more neuroleptic agents
l Use of haloperidol or depot fluphenazine
l Young age
l Male sex
l Psychiatric co-morbidity
l Genetic factors
l Preexisting organic brain disorders (infectious encephalitis, AIDS,
tumours)
l Dehydration
l High CK levels during episodes of psychosis not associated with NMS
l Other preexisting medical disorders (trauma, infection, malnutrition,
premenstrual phase, thyrotoxicosis).
Neuroleptic malignant syndrome is a diagnosis of exclusion and the
following important alternative diagnoses that share some general features
with NMS must be considered:
l Acute lethal (malignant) catatonia
l Malignant hyperthermia
l Serotonin syndrome (see Chapter 2.8: Serotonin syndrome)
l Anticholinergic syndrome (see Chapter 2.9: Anticholinergic syndrome)

l Sympathomimetic syndrome
l Encephalitis
l Metabolic encephalopathies
The clinical features of NMS are compared with those of serotonin

syndrome, anticholinergic syndrome and malignant hyperthermia in Table
2.8.3.
Acute lethal (malignant) catatonia is clinically very similar to NMS. The
diagnostic criteria are nearly identical but NMS is distinguished by a history
82 of recent antipsychotic medication use. Neuroleptic malignant syndrome
is usually characterised by bradykinesia and mutism, whereas acute lethal
82
catatonia may be characterised by abnormal posturing and waxy flexibility.

TOXICOLOGY HANDBOOK
COMPLICATIONS
l Respiratory failure
l Dehydration
l Renal failure
l Multiple-organ failure
l Thromboembolism
l Residual
catatonia and parkinsonian symptoms
l Recurrence
after rechallenge with an antipsychotic agent may occur in
30–50% of patients who suffer NMS.
MANAGEMENT
Resuscitation
l Attention to airway, breathing and circulation. If there is coma,
hyperthermia >39.5°C or severe rigidity compromising ventilation,
proceed to rapid sequence intubation and ventilation while continuing
with the steps below
l Administer oxygen
l Detect and correct hyperthermia. A temperature >38.5°C is an
indication for continuous core-temperature monitoring. A temperature
>39.5°C is an emergency and requires prompt intervention with
neuromuscular paralysis, intubation and ventilation to prevent further
muscle-generated heat production, and severe hyperthermia leading to
multiple organ failure, neurological injury and death
l Avoid any agent with dopamine antagonist effects
l Intravenous benzodiazepines are controversial in the management
of NMS. They are frequently used to achieve muscle relaxation and
control of delirium in mild-to-moderate cases (e.g. diazepam 5–10 mg
over 3–5 minutes titrated to achieve gentle sedation). However, because
benzodiazepines may play a role in the aetiology of NMS, more
specific agents such as bromocriptine are preferred in severe cases
l Hypertension and tachycardia may initially be treated with a
parenteral vasodilator such as GTN or nitroprusside. Bromocriptine
(see below) is indicated if there is significant autonomic instability.
Investigations
Depending on severity, further investigations may be required to exclude
alternative diagnoses and detect significant complications.
l Chest x-ray
l 12-lead ECG 83
l Full blood count
l Renal function and electrolytes
l Creatine kinase
TOXICOLOGY HANDBOOK
l Serum calcium and magnesium
l Liver function tests
l Blood and urine cultures
l Cranial CT
l Lumbar puncture
l MRI brain
l Electroencephalogram.
Supportive care
l Cease causative agent(s)
l Reassure patient
l Administer intravenous fluids and institute fluid balance monitoring
l Monitor temperature
l In mild-to-moderate cases, supplemental benzodiazepine sedation may
be indicated
l Consider thromboembolism prophylaxis.
Antidote therapy
The roles of bromocriptine, dantrolene and electroconvulsive therapy
(ECT) have not been defined by prospective trials. It is not known
whether they increase survival or shorten the clinical course when
compared with good supportive care alone.
Bromocriptine is a dopamine agonist that may be given orally or via
a nasogastric tube. It is indicated in moderate and severe cases. Dosing
commences at 2.5 mg every 8 hours, increasing to 5 mg every 4 hours
(30 mg/day). Adverse effects include postural hypotension, headache,
nausea, vomiting, dyskinesia and erythromelalgia (painful erythematous
lower limbs). Autonomic instability and fever usually improve within 24
hours of commencing bromocriptine therapy but neuromuscular changes
and delirium may take longer to resolve (1–2 days and several days
respectively). If bromocriptine is used, it should be continued for 1–2
weeks before tapering the dose.

Dantrolene is indicated if there is severe muscle rigidity and fever. It is
administered intravenously 2–3 mg/kg/day up to a total dose of 10 mg/kg/
day. Once oral treatment can be tolerated, it may be given in an oral dose
of 100–400 mg/day in divided doses for 10 days, or the patient may be
switched to bromocriptine.
Electroconvulsive therapy (ECT) has been reported to improve fever,
sweating and conscious level in some patients. It is thought to act by
increasing central dopaminergic activity. Improvement may be seen after
the third or fourth treatment. It has been advocated for:
84
l Severe NMS refractory to supportive care and antidote treatment
84
l Severe NMS that is difficult to differentiate from acute lethal catatonia

l Treatment of residual catatonic symptoms after NMS
TOXICOLOGY HANDBOOK
l When the psychiatric disorder underlying severe NMS is psychotic

depression or catatonia.
Following cessation of the causative agent, patients with normal mental
status (no delirium or seizures) and normal vital signs may be reassured
and considered for discharge following a period of observation (e.g. 12
hours). An oral benzodiazepine (e.g. diazepam 5 mg 6–8 hourly) may be
used for symptomatic treatment for 24 hours.
Other patients usually require admission for further supportive care
with or without specific antidote treatment.
The patient should be advised of the adverse effect or drug interaction
prior to discharge and subsequent psychopharmacotherapy will need
careful review. Recurrence after rechallenge with an antipsychotic agent
may occur in 30–50% of patients who suffer NMS.
References
Bhanushali MJ, Tuite PJ. The evaluation and management of patients with neuroleptic
malignant syndrome. Neurology Clinics of North America 2004; 22:389–411.
Neuroleptic malignant syndrome. In: Diagnostic and Statistical Manual of Mental
Disorders. 4th edn. Washington DC: American Psychiatric Association; 1994: 739–742.
Rusyniak DE, Sprague JE. Toxin-induced hyperthermic syndromes. Medical Clinics of
North America 2005; 89:1277–1296.
Trollor JN, Chen X, Sachdev PS. Neuroleptic malignant syndrome associated with
atypical antipsychotic drugs. CNS Drugs 2009; 23(6):477–492.
2.12 ALCOHOL ABUSE, DEPENDENCE
AND WITHDRAWAL
BOX 2.12.1 Psychiatric definitions of substance abuse

and dependence (DSM-IV)
Abuse
Maladaptive pattern of substance use leading to clinically significant im-
pairment or distress, manifested within a 12-month period by one or more
of the following:
l Failure to fulfil role obligations at home, work or school
l Recurrent use in physically hazardous situations
l Substance-related legal problems
l Continued use despite substance-related social or interpersonal problems
l Symptoms have never met criteria for substance dependence
Dependence
Maladaptive pattern of substance use leading to clinically significant im-
pairment or distress, manifested within a 12-month period by three or more 85
of the following:
l Tolerance (either increasing amounts or diminished effects with the
same amounts)
TOXICOLOGY HANDBOOK
l Withdrawal (withdrawal symptoms or use to relieve or avoid symptoms)
l Use of larger amounts over a period longer than intended
l Persistent desire or unsuccessful attempts to cut down or control use
l Great deal of time spent obtaining or using or recovering from use
l Important social, occupational or recreational activities given up or reduced
l Continued use despite knowledge of substance-related physical or
psychological problems
Adapted from Diagnostic and Statistical Manual of Mental Disorders. 4th edn.
Washington DC: American Psychiatric Association; 1994.
Alcohol abuse and dependence along with other forms of substance abuse
and dependence have formal psychiatric definitions (see Box 2.12.1).
Alcohol withdrawal is a potentially life-threatening medical condition.
More harm occurs in the community as a result of the acute health
and social effects of alcohol intoxication and abuse than from the
consequences of long-term alcohol dependence (see Table 2.12.1).
Upwards of 30% of all emergency department presentations are alcohol-
related. The incidence of alcohol-related problems is even higher in the
population that presents to emergency departments with deliberate self-
poisoning with either self-harm or recreational intent.
SCREENING AND BRIEF INTERVENTION STRATEGIES
Presentation to the emergency department, particularly with acute
poisoning, provides an ideal opportunity to identify individuals with
alcohol-related problems and provide brief intervention with the aim of
improving long-term outcomes.
TABLE 2.12.1 Medical complications of chronic alcohol abuse
Cardiovascular Malignancy
Atrial fibrillation Breast
Cardiomyopathy Colorectal
Electrolytes Hepatic
Hypocalcaemia Larynx
Hypokalaemia Oesophagus
Hypomagnesaemia Oropharynx
Hypophosphataemia Malnutrition
Endocrine Folate deficiency
Hypoglycaemia Niacin deficiency (pellagra)
Hypogonadism Stomatitis
Osteoporosis Vitamin C deficiency (scurvy)
Steatosis Neurological
Haematological Dementia
Anaemia Cerebellar degeneration
Coagulopathy Korsakoff’s syndrome
Leucopenia Peripheral neuropathy
Macrocytosis Wernicke’s encephalopathy
86 Thrombocytopenia Psychiatric
Gastrointestinal Alcoholic hallucinosis
86
Alcoholic hepatitis Depression and suicide

Cirrhosis Delusions
TOXICOLOGY HANDBOOK
Gastritis
Malabsorption
Oesophageal varices and
gastrointestinal haemorrhage
Pancreatitis
Adapted from Sivilotti ML. Ethanol, isopropanol and methanol. In: Dart RC, ed. Medical
Toxicology. 3rd edn. Philadelphia: Lippincott Williams & Wilkins; 2003.
In most settings, physicians identify fewer than 50% of patients with

alcohol-related problems. Factors associated with failure to identify these
individuals include:
l Inadequate training about substance abuse
l Negative attitudes towards patients with substance abuse
l Scepticism about effectiveness of treatments
l Belief that alcohol problems are not in the realm of the generalist
clinician
l Excessive time required to perform formal screening procedures.
A number of tools have been developed to assist identification of
potentially hazardous alcohol consumption and are suitable for application
in the emergency department. The Alcohol Use Disorders Identification
Test (AUDIT) identifies patients with at-risk, hazardous or harmful
drinking with a sensitivity of 51–97% and a specificity of 78–96% (see
Box 2.12.2). The ‘CAGE’ questions detect alcohol abuse and dependence
with a sensitivity of 43–94% and specificity of 70–97% (see Box 2.12.3).
BOX 2.12.2 The Alcohol Use Disorders Identification Test (AUDIT) Score (WHO 1992)
Questions pertain to behaviour in the last year
Score 0 1 2 3 4
How often do you have a drink containing alcohol? Never Monthly or Two to four Two to three Four or more
less times per times per times per
month week week
How many drinks containing alcohol do you have on 1 or 2 3 or 4 5, 6 or 7 8 or 9 10 or more
a typical day when you are drinking?
How often do you have 6 or more drinks on one Never Less than Monthly Weekly Daily or
occasion? monthly almost daily
How often during the last year have you found that Never Less than Monthly Weekly Daily or
you were not able to stop drinking once you had monthly almost daily
started?
How often during the last year have you failed to do Never Less than Monthly Weekly Daily or
what was normally expected from you because of monthly almost daily
drinking?
How often during the last year have you needed a Never Less than Monthly Weekly Daily or
first drink in the morning to get yourself going after monthly almost daily
a heavy drinking session?
How often during the last year have you had a Never Less than Monthly Weekly Daily or
feeling of guilt or remorse after drinking? monthly almost daily
How often during the last year have you been Never Less than Monthly Weekly Daily or
unable to remember what happened the night monthly almost daily
before because you had been drinking?
Continued

87
88
88
BOX 2.12.2 The Alcohol Use Disorders Identification Test (AUDIT) Score (WHO 1992)—cont’d
Questions pertain to behaviour in the last year
Score 0 1 2 3 4
Have you or someone else been injured as a result No Yes, but not in the Yes, during
of your drinking? last year the last year
Has a relative or friend or doctor or other health No Yes, but not in the Yes, during
worker been concerned about your drinking or last year the last year
suggested you cut down?
Score >20 Hazardous alcohol usage. Help required
Score 16–19 Hazardous alcohol usage. Help urged
Score 8–15 Drinking exceeding safe levels
Score 0–7 Normal usage
BOX 2.12.3 ‘CAGE’ questions
Two or more positive responses identify patients with lifetime risk of alcohol
problems
Cut down: Have you ever tried to cut down your drinking?
Annoyed: Have you ever been annoyed by criticism of your drinking?
Guilty: Do you feel guilty about your drinking?
Eye-opener: Do you need an eye-opener when you get up in the morning?
BOX 2.12.4 ‘FRAMES’ acronym
Feedback: review problems caused by alcohol with the patient
Responsibility: point out that changing behaviour is the patient’s responsibility
Advice: advise the patient to cut down or abstain from alcohol
Menu: provide options to assist the patient to change behaviour
Empathy: use an empathetic approach
Self-efficacy: encourage optimism that the patient can change behaviour
The following single question when administered to trauma patients,

using a cut-off of three drinks, correlates well with the AUDIT score: 89
‘On a typical day when you are drinking, how many drinks do you have?’
Abbreviated screening tools such as this consume minimal time and do
TOXICOLOGY HANDBOOK
not require detailed training.
Early detection of alcohol problems allows implementation of brief
intervention strategies such as ‘FRAMES’ which has been shown to
decrease alcohol consumption in non-dependent patients (see Box 2.12.4).
ALCOHOL WITHDRAWAL
The alcohol withdrawal syndrome usually develops within 6–24 hours of
cessation or reduction in alcohol consumption in dependent individuals. It
commonly develops in patients admitted to hospital.
PATHOPHYSIOLOGY
Ethanol dependence affects multiple neurotransmitter systems. Down-
regulation of neuro-inhibitory GABA receptors leads to symptoms of
GABA excess in withdrawal. Alcohol also inhibits the excitatory NMDA
glutamate receptor and withdrawal abruptly removes this inhibition.
Increased dopaminergic and noradrenergic neurotransmission also occur.
CLINICAL FEATURES
Alcohol withdrawal manifests as a constellation of clinical autonomic and
neurological features with a wide spectrum of severity and a typical time
course:
Autonomic excitation
l Occur within hours of cessation and peak at 24–48 hours
— Tremor
— Anxiety and agitation
— Sweating
— Tachycardia
— Hypertension
— Nausea and vomiting
— Hyperthermia
Neuro-excitation
l Occurwithin 12–48 hours of cessation

— Hyperreflexia
— Nightmares
— Hallucinations (visual, tactile and occasionally auditory)
— Generalised tonic–clonic seizures
Delirium tremens
l Severe form with mortality approaching 8%
l Up to 20% of patients admitted to urban hospitals with alcohol
withdrawal
l Associated with medical co-morbidities and delayed presentation
90 — Hallucinations
— Confusion, disorientation and clouding of consciousness
90
— Autonomic hyperactivity
TOXICOLOGY HANDBOOK
— Respiratory and cardiovascular collapse

— Death.
CO-MORBIDITIES
A number of important co-morbidities should be considered, detected and
managed in all patients with alcohol withdrawal:
l Wernicke’s encephalopathy
l Dehydration
l Electrolyte abnormalities
l Alcoholic gastritis and gastrointestinal bleeding
l Pancreatitis
l Alcoholic liver disease and hepatic encephalopathy
l Subdural haemorrhage
l Alcoholic ketoacidosis.
MANAGEMENT
Mild forms of alcohol withdrawal are managed with simple supportive care
in an outpatient setting. Symptoms typically settle in 2–7 days. Relapse is
common without implementation of adequate psychosocial support.
Withdrawal in a residential setting with professional supervision with
or without medication is more appropriate in the following circumstances:
l History of severe alcohol withdrawal
l Poor social support
l Failure of unsupervised outpatient withdrawal
Inpatient alcohol withdrawal is indicated for the minority of patients
in whom there is a significant risk of delirium tremens, seizures or
significant co-morbidities:
l Presentation with severe alcohol withdrawal
— Abnormal vital signs after initial treatment
— Hallucinations
— Altered conscious state
— Seizures
l Presence of medical complications or co-morbidities (see above)
l Presence of significant psychiatric co-morbidities.
MANAGEMENT APPROACH TO SEVERE ALCOHOL WITHDRAWAL

IN HOSPITAL SETTING
Resuscitation, supportive care and monitoring
l Florid delirium tremens constitutes a medical emergency and is
managed in an area fully equipped for resuscitation and monitoring
with the following priorities: 91
— Immediate attention to airway, breathing and circulation
— Establishment of IV access
— Control of seizures and delirium by administration of repeated
TOXICOLOGY HANDBOOK
doses of IV diazepam 5–10 mg until seizures and agitation are
controlled
— Detect and treat hypoglycaemia
l Alcohol withdrawal onset, severity, progress and response to therapy
is best monitored with an alcohol withdrawal chart incorporating an
easily calculated alcohol withdrawal score (AWS) (see Box 2.12.5)
l Institute monitoring for alcohol withdrawal in any patient judged to be
at risk of developing alcohol withdrawal, not just patients who present
in established withdrawal
l Give regular oral diazepam 5–20 mg PO as dictated by AWS to
maintain adequate control of withdrawal
l Give thiamine 100 mg IV or PO daily
l Ensure adequate hydration, electrolyte balance and nutrition
l Detect and treat co-morbidities
l Note: Phenytoin is not indicated in the treatment or prevention of
alcohol-related seizures.
Investigations as indicated
l EUC, FBE, LFTs, coagulation profile, serum lipase.
l Medicaladmission is indicated if:
— Large doses of diazepam are required to control withdrawal
— Medical co-morbidities require care
BOX 2.12.5 Alcohol withdrawal score (AWS)
Orientation 0—Orientated = The patient is fully orientated in
time, place and person
1—Disorientated = Disorientated but cooperative
2—Uncooperative = Disorientated and uncooperative
Agitation/ 0—Calm = Rests normally
anxiety 1—Anxious = Appears anxious

2—Panicky = Appears very agitated all the time,
panics or gets out of bed for no
reason
Hallucination 0—None = No evidence of hallucinations
1—Anxious = Distortion of real objects or hallu-
cinations but accepted as not real
when pointed out
2—Can’t dissuade = Believes the hallucinations are real
and cannot be reassured
Perspiration 0—Nil = No abnormal sweating
1—Moist/wet = Mild-to-moderate perspiration
92 2—Soaking = Soaking sweat
92
Tremor 0—Nil = No tremor

1—With intention = Tremor when moving hands and
TOXICOLOGY HANDBOOK
arms
2—At rest = Constant tremor of arms even at rest
Temperature 0—37.5°C or less
1—37.6°C to 38.5°C
2—>38.5°C
Adapted with permission from the Alcohol Withdrawal Chart at Sir Charles Gairdner
Hospital, Nedlands, Western Australia.
l Referral to residential or home detoxification and rehabilitation

services for assessment and psychosocial support is considered once
acute withdrawal is controlled or resolving.
References
Hall W, Zador D. The alcohol withdrawal syndrome. Lancet 1997; 349:1897–1900.
Holmwood C. Alcohol related problems in Australia: Is there a role for General
Practice? The Medical Journal of Australia 2002; 177:102–103.
Kosten TR, O’Connor PG. Management of drug and alcohol withdrawal. New England
Lieber CS. Medical disorders of alcoholism. New England Journal of Medicine 1995;
333(16):1058–1065.
O’Connor PG, Schottenfeld RS. Patients with alcohol problems. New England Journal
of Medicine 1998; 338(9):592–601.
Reed DN, Saxe A, Montanez M et al. Use of a single question to screen trauma patients
for alcohol dependence. Journal of Trauma 2005; 59:619–623.
Tjipto AC, Taylor D McD, Liew H. Alcohol use among young adults presenting to the
emergency department. Emergency Medicine Australasia 2006; 18(2):125–130.
2.13 AMPHETAMINE ABUSE, DEPENDENCE
AND WITHDRAWAL
TABLE 2.13.1 Effects of long-term amphetamine abuse
Medical
Weight loss
Cardiomyopathy (rare)
Poor dentition
Psychiatric
Confusion
Emotional lability
Insomnia
Memory loss
Paranoia
Paranoid psychosis
Social
Damage to social relationships
Neglect of social, interpersonal and occupational responsibilities
93
Amphetamine-related presentations represent a significant burden
TOXICOLOGY HANDBOOK
on emergency departments, accounting for over 1% of emergency
department presentations. Most of these presentations relate to medical,
social and psychiatric sequelae of acute amphetamine intoxication. The
management of these presentations together with the clinical toxicology
of amphetamines is dealt with in Chapter 3.8: Amphetamines.
Long-term amphetamine abuse is associated with medical, psychiatric
and social sequelae (see Table 2.13.1). These sequelae may result directly
in hospital presentation or complicate the management of intercurrent
illness. Amphetamines, particularly methamphetamine, are highly
addictive and patients may also present in withdrawal or develop
withdrawal during admission for other reasons.
No pharmacological agent has been demonstrated to be effective in the
treatment of amphetamine withdrawal, dependence or abuse. Management
relies on counselling and social support.
Definitions for amphetamine abuse and dependence are based on those
for substance abuse and dependence in general and detailed in Box 2.12.1.
AMPHETAMINE WITHDRAWAL
Prolonged or heavy use of amphetamines results in tachyphylaxis
(reduced response to repeated doses). This phenomenon is thought to be
due to depleted concentrations of neurotransmitters. The symptoms are
largely psychiatric and mood related, and include depression, fatigue,
insomnia, increased appetite and cognitive impairment. Symptoms usually
peak 2–4 days following cessation of use but may continue for 7–14 days.
Amphetamine withdrawal in itself is rarely severe enough to warrant
medical admission. Management consists of referral for appropriate
psychosocial support.
References
Romanelli F, Smith KM. Clinical effects and management of amphetamines.
Pharmacotherapy 2006; 26(8):1148–1156.
Shoptaw SJ, Kao U, Heinzerling K et al. Treatment for amphetamine withdrawal.

Cochrane Database of Systematic Reviews 2009; 2:C0003021.
Srisurapanont M, Jarusuraisin N, Krittirattanapaiboon P. Treatment for amphetamine
dependence and abuse. Cochrane Database of Systematic Reviews 2001; 4:C0003022.
2.14 OPIOID DEPENDENCE AND WITHDRAWAL

Opioid withdrawal syndrome is the physiological response that develops
when there is abrupt cessation or rapid reduction in opioid dose in a
dependent individual, or when that individual is administered an opioid
94 antagonist or partial agonist.
94
PATHOPHYSIOLOGY
The opioids exert their analgesic effects by agonist activity at CNS μ
TOXICOLOGY HANDBOOK
receptors. These mediate their effects by decreasing intracellular cAMP

via membrane-bound G-proteins. Prolonged opioid use leads to a process
of cellular adaptation and down-regulation through multiple mechanisms.
When opioids are ceased a withdrawal syndrome develops.
CLINICAL FEATURES
Although unpleasant, uncomplicated opioid withdrawal is not life
threatening. This is in contrast to withdrawal from alcohol or sedative-
hypnotics. The symptoms are usually sufficiently uncomfortable to
prompt efforts to obtain opioids by the individual concerned.
The timing of onset of symptoms depends on the elimination
kinetics of the specific opioid, the usual dose ingested and the degree
of dependence. Symptoms may begin within 6 hours of the last heroin
dose, peak at 36–48 hours and resolve within 1 week. In contrast, onset
of symptoms may be delayed 2–3 days after cessation of methadone,
peak at several days and last for up to 2 weeks. Patients may present with
withdrawal symptoms associated with cessation of more than one agent.
The clinical manifestations of opioid withdrawal include intense
craving, dysphoria, autonomic hyperactivity and gastrointestinal distress.
More specifically, symptoms include:
l Anxiety, restlessness and dysphoria
l Insomnia
l Intense craving
l Yawning
l Lacrimation
l Salivation
l Rhinorrhoea
l Anorexia, nausea and vomiting
l Abdominal cramps and diarrhoea
l Mydriasis
l Piloerection
l Diaphoresis
l Flushing
l Myalgia and arthralgia
l Hypertension and tachycardia in severe cases.
Altered mental status, delirium, hyperthermia and seizures do not
occur. Their presence should alert the clinician to an alternative diagnosis
or complication.
CO-MORBIDITIES
Co-morbidities that should be considered in patients with opioid
withdrawal include: 95
l Alcohol or sedative-hypnotic withdrawal syndrome
l Dehydration
TOXICOLOGY HANDBOOK
l Infective complications of intravenous drug abuse
l Psychiatric morbidities.
MANAGEMENT
Administration of opioids in sufficient dose will abolish all physiological
manifestations of the withdrawal syndrome. Administration of opioids to
control withdrawal may be the appropriate course of action particularly
where the management of co-morbidities demands attention.
Managed withdrawal (detoxification) is a necessary step towards drug-
free treatment. The aims of early management of drug detoxification are
safe cessation or dose reduction, management of symptoms and medical
complications, and retention of the patient in a treatment program.
Most patients with opioid withdrawal can be managed in an outpatient
setting. Information and reassurance provided in a non-judgmental way
are vital to engage the patient in a realistic withdrawal treatment program.
Admission to hospital may be required in the following circumstances:
l Severe withdrawal syndrome (e.g. following administration of
antagonist)
l Significant complications (e.g. severe dehydration)
l Significant intercurrent illness (e.g. sepsis)
l Psychiatric co-morbidity.
Pharmacologic treatment of opioid withdrawal is categorised into
three types: opioid replacement therapy (e.g. methadone; buprenorphine),
antagonist detoxification (e.g. naltrexone), and symptomatic treatment.
1 Opioid replacement therapy
Methadone is used in opioid withdrawal and for maintenance in
abstinence programs. Patients on methadone maintenance have markedly
reduced mortality (25%) compared with those continuing illicit opioid
use, due to decreased rates of heroin overdose or suicide. Methadone
programs do not reduce mortality from non-heroin overdose, violence,
trauma or natural causes.
To commence methadone, patients should be referred for evaluation

and ongoing management by a specialist drug and alcohol service.
Methadone doses typically start at 20–40 mg/day and are tapered over
many weeks (e.g. by 3–5% each week).
Buprenorphine is a high-affinity partial μ-opioid agonist used as an
alternative to methadone. Buprenorphine treatment is superior to clonidine
and as effective as methadone in ameliorating withdrawal, treatment
retention and treatment completion. Doses may start at 4–16 mg/day, and
are also tapered over many weeks.
96 2 Detoxification
Rapid detoxification, using naltrexone, buprenorphine and clonidine
96
in various combinations, or rapid tapering of methadone has been

successful in selected patients. Efficacy depends on patient selection and
TOXICOLOGY HANDBOOK
TABLE 2.14.1 Symptomatic treatment of opioid withdrawal
Dehydration
Fluid resuscitation
Nausea and vomiting
Metoclopramide 10 mg or prochlorperazine 5 mg PO, 6 hourly as
required
Abdominal cramps and diarrhoea
Hyoscine 20 mg PO every 6 hours or atropine–diphenoxylate (2.5 mg–
25 mg) two tablets PO every 6–8 hours
Myalgia and arthralgia
Paracetamol (1 g every 4 hours, not exceeding 4 g per day) or ibuprofen
(400 mg every 6 hours)
Anxiety, dysphoria and insomnia
Diazepam 5–10 mg PO every 6–8 hours for 2–3 days
Clonidine
Centrally acting alpha2-adrenergic receptor agonist used to attenuate
the physical and psychological symptoms of opioid withdrawal
Adverse effect is postural hypotension, especially in patients with
dehydration and bradycardia
Give a test dose of 75 micrograms PO, followed by lying and standing
blood pressure monitoring for 1 hour
If symptomatic postural hypotension does not occur, commence 50
micrograms PO three times a day. The dose may be increased if
tolerated (e.g. up to 200–300 micrograms three times daily) before
tapering over the subsequent 5 days.
close clinical supervision by a team experienced in specialised drug and
alcohol treatment. Ultra-rapid detoxification is an invasive procedure
involving the precipitation of severe opioid withdrawal using naltrexone,
often under general anaesthesia. This technique remains unproven and
controversial.
Supportive care
Patients should be reassured and assessed for potential co-morbidities
and complications. Fluid resuscitation for dehydration may be required.
The presence of altered mental status, fever or seizures prompts further
investigation for an alternative cause. Several medications are of value in
providing symptomatic relief (see Table 2.14.1).
Presentation with drug-related problems provides an opportunity for
patient counselling regarding the risks of drug abuse and dependence and
engagement in strategies to change behaviour.
References
Kosten TR, O’Connor PG. Management of drug and alcohol withdrawal. New England 97
Olmedo R, Hoffman RS. Withdrawal syndromes. Emergency Medicine Clinics of North
America 2000; 18(2):273–288.
TOXICOLOGY HANDBOOK
Tetrault JM, O’Connor PG. Substance abuse and withdrawal in the critical care setting.
Critical Care Clinics 2008; 24:767–788.
Webster IW (Chair of the Detoxification Guidelines Project Steering Committee). New
South Wales Detoxification Guidelines. NSW Health Department 1999. State
Health Publication Number (DTPU) 990049, May 1999.
2.15 SEDATIVE-HYPNOTIC DEPENDENCE

AND WITHDRAWAL
Abrupt cessation or reduction in dose of a sedative-hypnotic agent can
produce a characteristic withdrawal syndrome in a dependent individual
not dissimilar to that of alcohol withdrawal. Withdrawal syndromes are
described for:
l Benzodiazepines
l Barbiturates
l Non-benzodiazepine sedative-hypnotic agents (zolpidem, zopiclone)
l Baclofen
l Gamma-hydroxybutyrate (GHB)
l Chloral hydrate
l Paraldehyde.
PATHOPHYSIOLOGY
The sedative-hypnotic agents all modulate activity of the gamma amino-
butyric acid (GABA) neurotransmitter complex. Abrupt withdrawal leads
to symptoms of GABA excess.
CLINICAL FEATURES
There is a high degree of inter-individual difference in the rate of onset,
type and severity of withdrawal symptoms. Variability is determined
by dose and duration of therapy, rapidity of withdrawal, elimination
kinetics of the agent and patient factors. Onset of symptoms generally
occurs within 2–10 days of abrupt cessation, although withdrawal
of very short acting agents (e.g. GBH) or agents administered by the
intrathecal route (e.g. baclofen) may produce symptoms within hours.

The clinical presentation may reflect withdrawal from more than one
class of agent.
A severe and potentially lethal syndrome similar to delirium tremens
and including seizures occurs rarely. This is in contrast to opioid or
cannabis withdrawal, which does not cause delirium, autonomic instability
or seizures (see Chapter 2.14: Opioid dependence and withdrawal and
Chapter 3.23: Cannabinoids (marijuana)).
The commonly observed clinical features resemble those of
alcohol withdrawal (see Chapter 2.12: Alcohol abuse, dependence and
98 withdrawal), although psychomotor and autonomic nervous system signs
may be more prominent:
98
l Irritability and agitation

TOXICOLOGY HANDBOOK
l Anorexia
l Inattention
l Memory disturbances
l Insomnia
l Palpitations
l Perceptual disturbances, including photophobia and hyperacusis
l Hallucinations
l Increased spasticity (baclofen).
CO-MORBIDITIES
Co-morbidities that should be considered in patients with sedative-
hypnotic withdrawal include:
l Alcohol withdrawal syndrome
l Dehydration
l Psychiatric morbidities.
MANAGEMENT
Where withdrawal develops as a result of an interruption in regular
benzodiazepine (or other sedative-hypnotic agent) use due to an intercurrent
medical illness, it is best to reverse the withdrawal syndrome by
reinstitution of the offending agent until the precipitating illness is treated.
Where the aim is to achieve permanent safe withdrawal or dose
reduction then alternative management strategies are adopted. The usual
strategy is to substitute a longer acting benzodiazepine for the agent
being ceased and then to slowly taper the dose. Tapering is titrated to
individual patient symptoms. If withdrawal symptoms increase, the
dose may be increased transiently or tapering attempted more slowly.
Typically, withdrawal takes weeks to complete with dosage decreases of
approximately 15% per week.
Management of severe sedative-hypnotic withdrawal with delirium
or seizures is similar to alcohol withdrawal syndrome (see Chapter 2.12:
Alcohol abuse, dependence and withdrawal).
Several scores have been used to assess the severity of the
benzodiazepine withdrawal syndrome in order to guide admission
decisions and benzodiazepine dosing. However, most scores have not
been prospectively validated and should be used with caution.
DISPOSITION
In most patients, sedative-hypnotic withdrawal is mild and management
in an outpatient setting is appropriate. Presentation with drug-related
problems provides an opportunity for patient counselling regarding the 99
risks of drug abuse and dependence and engagement in strategies to
change behaviour.
TOXICOLOGY HANDBOOK
Withdrawal in a residential setting, with supervision by specialised
staff with training in drug and alcohol issues is appropriate in selected
circumstances:
l History of severe withdrawal
l Poor social support
l Failure of unsupervised outpatient withdrawal.
Inpatient sedative-hypnotic withdrawal is appropriate for a minority of

patients in whom there is a significant risk of delirium or seizures:
l Presentation in severe withdrawal
l Abnormal vital signs after initial treatment
l Hallucinations
l Altered conscious state
l Seizures
l Presence of medical complications or co-morbidities
l Presence of significant psychiatric co-morbidities.
References
Kosten TR, O’Connor PG. Management of drug and alcohol withdrawal. New England
Leo RJ, Baer D. Delirium associated with baclofen withdrawal: A review of common
presentations and management strategies. Psychosomatics 2005; 46:503–507.
McDonough M, Kennedy N, Glasper A et al. Clinical features of gamma-hydroxybutyrate
(GHB) withdrawal: a review. Drug and Alcohol Dependence 2004; 75:3–9.
Olmedo R, Hoffman RS. Withdrawal syndromes. Emergency Medicine Clinics of North
America 2000; 18(2):273–288.
2.16 SOLVENT ABUSE, DEPENDENCE
AND WITHDRAWAL
A solvent is defined as a liquid that has the ability to dissolve, suspend or
extract another material without chemical change to either the material or
solvent. Organic solvents are found in numerous household and industrial
products, including glues, household cleaners, degreasers, thinners, paints,

pharmaceuticals, cosmetics and pesticides. The group includes aliphatic,
cyclic, aromatic and halogenated hydrocarbons, ethers, esters, glycols,
ketones, aldehydes and amines (see Table 2.16.1). Common solvents
include isopropanol, toluene and xylene. Other volatile hydrocarbons
more commonly used as fuels, such as petrol, kerosene and butane (used
TABLE 2.16.1 Chemicals used for inhalational abuse
Aliphatic hydrocarbons Nitrites

100 Acetylene Amyl nitrite
10
n-Butane Butyl nitrite

0
Isobutane Cyclohexyl nitrite

n-Hexane Oxygenated compounds
TOXICOLOGY HANDBOOK
Propane Acetone
Aromatic hydrocarbons Butanone
Cyclopropane Diethyl ether
Toluene Dimethyl ether
Xylene Ethyl acetate
Mixed hydrocarbons Methyl acetate
Petrol Methyl isobutyl ketone
Kerosene Nitrous oxide
Halogenated hydrocarbons
Bromochlorodifluoromethane
Carbon tetrachloride
Chlorodifluoromethane
Chloroform
Dichlorodifluoromethane
Dichloromethane (methylene
chloride)
1,2-Dichloropropane
Enflurane
Ethyl chloride
Halothane
Isoflurane
Methoxyflurane
Tetrachloroethylene
1,1,1-Trichloroethane
Trichloroethylene
Trichlorofluoromethane
Adapted from Flanagan RJ, Ruprah M, Meredith TJ et al. An introduction to the clinical
toxicology of volatile substances. Drug Safety 1990; 5:359–383.
as lighter fuel), have similar physicochemical properties, clinical effects
and abuse potential.
The recreational abuse of solvents involves inhalation of these
volatile substances for the purposes of achieving an alteration in mental
status, principally euphoria. Inhalational organic solvent abuse is a major
public health problem particularly afflicting adolescents and Indigenous
communities. The agent with the highest potential for abuse is toluene,
found primarily in glues, spray paints and lacquers.
PHYSICOCHEMICAL PROPERTIES
The organic solvents are all volatile liquids and well absorbed via the
inhalational route. Peak blood concentrations are achieved within 15–30
minutes of inhalation. These agents are highly lipid soluble and following
absorption are preferentially distributed to lipid-rich organs notably the
CNS and liver. After inhalation stops, excretion by the lungs takes place.
Solvents are also metabolised by the liver with elimination half-lives in
the order of 15–72 hours.
101
MECHANISM OF TOXICITY
While agents vary in their end-organ specificity, acute solvent toxicity
TOXICOLOGY HANDBOOK
generally correlates with the volatility of an agent. They are lipophilic and
potent CNS depressants. High volatility is associated with a greater risk of
micro-aspiration and pneumonitis. Myelin toxicity is thought to be the cause
of the neuropsychiatric consequences associated with long-term inhalational
abuse and occupational exposure. Myocardial sensitisation to catecholamines
may be associated with cardiac dysrhythmias and sudden death.
MODES OF ABUSE
Solvent abusers always employ the inhalational route with the following
methods described:
l ‘Huffing’: the liquid solvent is poured into a bag or piece of cloth such
as a sock and the liquid-soaked material is then held up to the face as
the abuser inhales deeply
l ‘Bagging’: the liquid is poured into a bag and the bag held over the head
l ‘Sniffing’ or ‘snorting’: liquid is inhaled directly from the container.
CLINICAL FEATURES
The solvent abuser may present with acute solvent neurotoxicity or with
the CNS, metabolic, behavioural and social complications associated with
chronic abuse.
Acute inhalational exposure
Acute inhalation predominantly affects the CNS, causing altered
cognition that resembles ethanol intoxication. General impairment of
psychomotor function, as measured by reaction time, manual dexterity,
coordination and body balance occurs. Patients are euphoric, disinhibited,
lethargic and ataxic with slurred speech and inappropriate affect. More
severe intoxication is characterised by confusion, depressed level of
consciousness, seizures and coma.
Inhalational exposure to solvents also causes intense irritation to the
mucous membranes of the eye, nose and throat. Inadvertent aspiration can
induce chemical pneumonitis.
Sudden death, particularly associated with butane and propane, may

occur during acute exposure. Possible mechanisms are asphyxiation or
cardiac dysrhythmias induced by sensitisation of the myocardium to
endogenous circulating catecholamines.
Chronic inhalational abuse
There is strong evidence to suggest that long-term toluene exposure leads
to persistent neurotoxicity characterised by structural and functional brain
abnormalities, as well as neuropsychological impairment. Neuro-imaging
studies suggest injury preferentially affects white matter structures (lipid-
102 rich myelinated structures), a pattern which could be explained by the
lipid-dependent distribution to myelinated areas of the brain.
10
Persistent neurotoxicity is characterised by impaired cognition and

2
poor performance on most neuropsychological tests, including those testing

TOXICOLOGY HANDBOOK
working memory and executive cognitive function. Although the individuals

engaging in chronic toluene abuse are likely to come from a background of
psychomotor, emotional and social deprivation, it does appear that the abuse
itself is associated with adverse effects in cognitive and intellectual abilities.
These effects further exacerbate the preexisting problems and complicate
efforts to achieve detoxification, long-term abstinence and rehabilitation.
It remains controversial as to whether long-term abstinence is
associated with significant improvement in neuropsychological function.
Chronic toluene abuse is also associated with a normal anion gap
metabolic acidosis largely due to distal renal tubular acidosis. Acidaemia,
hyperchloraemia and hypokalaemia may be profound (25% of chronic
abusers have serum K+ <2 mmol/L).
MANAGEMENT
The solvent abuser who presents with acute solvent neurotoxicity
requires standard resuscitative measures for management of coma and
seizures. Behavioural disorders frequently necessitate early sedation with
titrated doses of intravenous benzodiazepine. Avoidance of secondary
complications such as hypoxia, hypoglycaemia and prolonged seizures
usually ensures survival.
Cardiac dysrhythmias, while a cause of early sudden death, are
rarely observed after arrival at hospital. Management along ACLS
guidelines with consideration of early use of beta-blocking agents for
tachydysrhythmias is appropriate.
Acid–base and electrolyte status should be checked early in the
patient suspected of chronic solvent abuse. Acidaemia may be prominent
even in a relatively asymptomatic patient. Patients may present with
life-threatening acidaemia requiring intensive care, sodium bicarbonate
replacement and management of profound hypokalaemia.
DISPOSITION
A period of observation lasting hours to days may be required until the
acute CNS and metabolic disorders resolve. This might occur in the
emergency department or intensive care unit but continuous and adequate
supervision is essential to prevent injury to the patient and staff.
After resolution of acute toxicity, the issues associated with chronic
solvent abuse must be addressed. Management is challenging and as much
socio-political as medical. Achieving sustained abstinence in the setting
of ongoing social deprivation is difficult. Many of the neuropsychiatric
effects associated with chronic abuse are likely to be irreversible and
further complicate management.
103
SOLVENT WITHDRAWAL
Physical withdrawal from solvents is generally mild with lethargy,
TOXICOLOGY HANDBOOK
headaches, anxiety or depressed mood. It may last from several days to a
few weeks and does not require any specific treatment.
SOLVENT ABUSE DURING PREGNANCY AND LACTATION

Most solvents, including toluene, are very lipid soluble and so cross the
placenta easily. A fetal solvent syndrome similar to fetal alcohol syndrome
is described. Abstinence phenomenon similar to alcohol withdrawal in the
postpartum period is also described.
References
Carlisle EJF, Donnelly SM, Vasuvattakul S et al. Glue-sniffing and distal renal tubular
acidosis: sticking to the facts. Journal of the American Society of Nephrology 1991;
1:1019–1027.
Dick FD. Solvent neurotoxicity. Occupational and Environmental Medicine 2006;
63:221–226.
Flanagan RJ, Ruprah M, Meredith TJ et al. An introduction to the clinical toxicology of
volatile substances. Drug Safety 1990; 5:359–383.
Maruff P, Burns CB, Tyler P et al. Neurological and cognitive abnormalities associated
with chronic petrol sniffing. Brain 1998; 121:1903–1917.
Rosenberg NL, Grigsby J, Driesbach J et al. Neuropsychological impairment and MRI
abnormalities associated with chronic solvent abuse. Clinical Toxicology 2002;
40(1):21–24.
Yucel M, Takagi M, Walterfang M et al. Toluene misuse and long-term harms:
a systematic review of the neuropsychological and neuroimaging literature
Neuroscience and Biobehavioural Reviews 2008; 32:910–926.
2.17 BODY PACKERS AND STUFFERS
‘Body packing’ refers to the internal concealment of illicit drugs (usually
in large quantities) for transportation across international borders. The
drug is usually of a single type and meticulously packaged in plastic,
latex, condoms or balloons. Many hours have usually elapsed before
presentation to the emergency department, so most packets have

already entered the small or large intestine. The vagina and rectum
are not usually used for body packing, as they are more likely to be
discovered on physical examination. Cocaine, heroin, amphetamine,
3-4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’), cannabis and
hashish have all been reported to have been transported by body packing.
Up to 1 kg of drug, divided into 50–100 packets, may be transported
by a single individual. Body packers (often referred to as ‘mules’ or
‘swallowers’) use constipating agents such as atropine-diphenoxylate to
slow gastrointestinal transit such that it may take from days to weeks for
104 all packages to pass.
‘Body stuffing’ refers to the hasty internal concealment of illicit drugs
10
4
immediately prior to apprehension by authorities. The packages are more

TOXICOLOGY HANDBOOK
likely to contain multiple different drugs, are usually prepared in a rushed

manner and much more likely to leak. They may consist simply of a small
plastic bag or foil pouch. The delay from ingestion to presentation to
the emergency department is much shorter and the ingested packets are
frequently still within the stomach. The vagina and rectum are alternative
sites for drug concealment in ‘body stuffing’.
The management of body packers and body stuffers poses multiple
challenges:
l Many times the lethal dose of illicit drug may have been ingested
l Patients may not provide an accurate history, making risk assessment
problematic
l The treating clinician may be directed by law enforcement officers to
conduct procedures for which the patient has not consented
l There are few prospective studies to guide management.
CLINICAL PRESENTATION
Body packers present in three settings:
l Acute drug intoxication or fear of impending rupture and intoxication
l Request for medical assessment following arrest
l Development of surgical complications, usually bowel obstruction but
bowel perforation, oesophageal obstruction and oesophageal rupture
are also reported.
MANAGEMENT OF ‘BODY STUFFERS’
Patients are initially observed in a monitored environment with
intravenous access. If the patient presents within 1 hour and is
cooperative, a single dose of 50 g oral activated charcoal is indicated.
Abdominal radiographs are of limited value in body stuffers. Urine
toxicology screens for drugs of abuse rarely alter clinical management.
Asymptomatic patients may be discharged at 8 hours post-ingestion.
Patients with clinical features of intoxication are treated accordingly.
MANAGEMENT OF ‘BODY PACKERS’
Body packers are given high triage priority and are initially managed
in an area equipped for cardiopulmonary monitoring and resuscitation.
Immediate resuscitation priorities are attended to as outlined in Chapter
1.2: Resuscitation. These include administration of supplemental oxygen,
obtaining intravenous access and commencement of continuous cardiac
monitoring. 105
Risk assessment
Body packers transport many times the lethal dose of cocaine, heroin
TOXICOLOGY HANDBOOK
or amphetamines. The onset of signs of drug intoxication may herald
imminent catastrophic deterioration.
There is a need to obtain an accurate history if possible. The type of
drug, number and construction of packages, and time of ingestion are
vital components of the history. The physical examination should look for
any evidence of drug intoxication and surgical complications (e.g. bowel
obstruction).
Supportive care and disposition
The patient should be admitted to a clinical area equipped and staffed to
observe for, and manage, the rapid onset of drug intoxication. In most
settings this will be an intensive care unit or emergency observation
ward. Staff are briefed on the potential symptoms of intoxication that
will prompt urgent review and aggressive therapy. Senior medical staff
must be available 24 hours a day. Intravenous access is maintained until
discharge. Continuous ECG and pulse oximetry monitoring are kept in
place when the patient is not ambulating, and especially when asleep.
Asymptomatic patients may eat a normal diet. Ambulation around the
ward is encouraged, as bed rest appears to be a risk factor for bowel
obstruction. Patients are observed until three package-free stools are
passed and repeat radiographic testing is negative (see below). The mean
time to pass all packages is approximately 5 days.
Investigations
Urine toxicology screening has been advocated but has low sensitivity.
A positive test suggests the need for further investigation and observation
but a negative test does not exclude body packing or indicate that the
patient is safe for discharge.
Plain abdominal x-rays (supine and erect) are frequently used as first-
line investigations. Large series suggest the sensitivity in body packing is
85–95%. Abdominal x-rays are useful to confirm the diagnosis in patients

where there is a high index of suspicion but their value as a screening test
is controversial. A negative x-ray does not rule out body packing. Contrast
abdominal CT is more sensitive and considered the imaging investigation
of choice. There is less data regarding the sensitivity of abdominal
ultrasound.
At the end of observation, when three package-free stools are passed, a
repeat contrast abdominal CT is performed to confirm passage of all packages.
Decontamination
106 Cooperative asymptomatic patients may be administered 50 g activated
charcoal, in case of package leakage or rupture.
10
6
There is consensus that asymptomatic patients, even those transporting

cocaine, may be treated conservatively and observed until all packages
TOXICOLOGY HANDBOOK
are retrieved. The incidence of serious complications such as late-onset

drug intoxication, bowel obstruction, urgent laparotomy or death is less
than 5% with conservative management. A light or liquid diet plus gentle
laxatives are often ordered in an effort to speed passage of packages.
The role of more aggressive decontamination using whole bowel
irrigation is more controversial. It is not indicated for heroin body packers
where a good outcome in the event of package rupture can be assured with
supportive care and antidote administration.
Endoscopy has been used to retrieve packages from the stomach but is
not feasible because packages have already moved beyond the pylorus at
presentation. The procedure carries with it a risk of package rupture and is
not recommended.
Patients with cocaine body packing who show signs of significant
intoxication should be resuscitated and managed supportively pending
urgent transfer to theatre for laparotomy, enterotomy and careful removal
of packages. Similarly, patients who develop signs of bowel obstruction or
perforation should have their packages surgically removed.
Antidotes
Naloxone is an adjunct to the management of opioid intoxication. In body
packers, large initial doses may be required (e.g. 2–10 mg) followed by
an intravenous infusion. See Chapter 4.19: Naloxone. The management
of cocaine and amphetamine intoxication is described in Chapter 3.8:
Amphetamines. The management of cannabis intoxication is supportive.
References
Beckley I, Ansari NA, Khwaja HA et al. Clinical management of cocaine body packers:
the Hillingdon experience. Canadian Journal of Surgery 2009: 52(5):417–421.
Das D, Ali B, Mackway-Jones K. Conservative management of asymptomatic cocaine
body packers. Emergency Medicine Journal 2003; 20:172–174.
Hergan K, Kofler K, Oser W. Drug smuggling by body packing: what radiologists
should know about it. European Radiology 2004; 14(4):736–742.
Traub SJ, Hoffman RS, Nelson LS. Body packing—the internal concealment of illicit
drugs. New England Journal of Medicine 2003; 349:2519–2526.
2.18 OSMOLALITY AND THE OSMOLAR GAP

Osmolality and osmolar gap assist in the identification of osmotically
active toxic alcohols. They are particularly useful when laboratory
estimation of serum methanol and ethylene glycol levels are not readily
available.
Osmolality refers to the number of osmotically active particles in
a kilogram of solution (mOsmol/kg). It is a measured value, usually 107
determined by freezing point depression.
Osmolar gap is an artificial, derived value, calculated by subtracting
the calculated osmolality from the true osmolality measured by the
TOXICOLOGY HANDBOOK
laboratory.
Calculated Osmolality (mOsmol/kg) = 2 × [sodium mmol/L] +
[urea mmol/L] + [glucose mmol/L] + [ethanol mmol/L]
Osmolar Gap = Measured Osmolality − Calculated Osmolality

Note: All concentrations must be in mmol/L (SI units). If ethanol is reported
in non-SI units, it is converted to mmol/L as follows: ethanol mg/dL/4.6 or
ethanol % x 218
A normal osmolar gap is <10. A small gap exists because the

calculation does not take into account osmotic activity generated by
chloride, potassium, sulfate, phosphate, calcium, magnesium, lactate,
ammonia, serum proteins and lipids.
To safely interpret an elevated osmolar gap, the following principles
apply:
l Elevated osmolality and osmolar gap suggest the presence of
unmeasured (and potentially toxic) osmotically active compounds
(see Table 2.18.1)
l A number of non-toxicological conditions also cause elevated
osmolality and osmolar gap (see Table 2.18.2)
l In suspected toxic alcohol ingestion (due to history of ingestion
or presence of anion gap metabolic acidosis), high osmolality and
osmolar gap support the diagnosis
TABLE 2.18.1 Exogenous agents associated with elevated osmolar gap
Acetone Isopropyl alcohol

Ethanol Mannitol
Ethylene glycol Methanol
Glycerol Propylene glycol (diluent in several
Glycine medications e.g. diazepam, phenytoin)
Adapted from Dart RC, ed. Medical Toxicology. 3rd edn (text). Philadelphia: Lippincott
Williams & Wilkins; 2004.
TABLE 2.18.2 Non-toxicological conditions associated with elevated

osmolar gap
Alcoholic ketoacidosis Massive hypermagnesaemia

Chronic renal failure Severe lactic acidosis
Diabetic ketoacidosis Shock
Hyperlipidaemia Trauma and burns
Hyperproteinaemia
108
Adapted from Dart RC, ed. Medical Toxicology. 3rd edn (text). Philadelphia: Lippincott
10
Williams & Wilkins; 2004.

8
TOXICOLOGY HANDBOOK
TABLE 2.18.3 Estimated alcohol levels based on osmolar gap

To calculate the serum alcohol level in mg/dL multiply the osmolar gap by
the conversion factor
Alcohol Conversion factor
Ethanol 4.6
Ethylene glycol 6.2
Isopropyl alcohol 6.0
Methanol 3.2
Propylene glycol 7.2
Adapted from Olsen KR. Poisoning and Drug Overdose. 2nd edn. Norwalk, CT:
Appleton and Lange; 1994.
l Normal osmolality and osmolar gap do not exclude potentially life-

threatening toxic alcohol ingestion for the following reasons:
— Small concentrations of toxic alcohols not detected by this
surrogate measure may still cause significant intoxication
— Late in the clinical course, the parent compounds (alcohols) are
already metabolised to non-osmotically active compounds.
The serum concentration of a particular alcohol suspected to be
present can be estimated from the osmolar gap. Multiply the osmolar gap
by the conversion factors (the molecular weight of the alcohol divided
by 10) listed in Table 2.18.3 to estimate the alcohol concentration in
conventional units (mg/dL).
References
Koga Y, Purssell RA, Lynd LD. The irrationality of the present use of the osmole gap:
applicable physical chemistry principles and recommendations to improve the
validity of current practices. Toxicological Reviews 2004; 23(3):203–211.
Purssell RA, Lynd LD, Koga Y. The use of the osmole gap as a screening test for the
presence of exogenous substances. Toxicological Reviews 2004; 23(3):189–202.
2.19 ACID–BASE DISORDERS

The assessment of acid–base abnormalities is a core competency in
critical care and clinical toxicology. These disorders are manifestations
of underlying disease processes and not diagnoses in themselves.
Several potentially lethal poisonings produce characteristic acid–base
abnormalities. The detection of any acid–base disorder during assessment 109
of the poisoned or potentially poisoned patient mandates careful
characterisation to produce a differential diagnosis as the initial step to
TOXICOLOGY HANDBOOK
definitive diagnosis and management.
Assessment and characterisation of an acid–base disturbance requires
information derived from the history, physical examination and basic
investigations including electrolytes, creatinine, blood sugar and arterial
blood gases.
In the history and physical examination, particular attention is paid to:
l Past medical history
— Diabetes
— Renal failure
l Current medications
— Metformin
— Salicylates
l Potential chemical or pharmaceutical ingestions
l Diarrhoea or vomiting
l Level of consciousness
l Respiratory rate
l Hydration and urine output.
This information can be evaluated in a systematic function using the

five-step approach proposed by Whittier and Rutecki:
Step 1: What is the pH (primary acid–base disturbance)?
Acidaemia exists if pH <7.40
Alkalaemia exists if pH >7.44.
Note: The body always compensates for an acid–base disturbance but
this compensation is never complete (the pH cannot return to normal).
Therefore, if a single acid–base disturbance exists, the primary process
can be identified by the serum pH. If there is significant abnormality
of HCO3- and PaCO2 with normal pH, there must be at least two
counteracting pathologies.
Step 2: Determine whether the primary process is respiratory,

etabolic or both
m
Respiratory acidosis exists if PaCO2 >44 mmHg
Respiratory alkalosis exists if PaCO2 <40 mmHg
Metabolic acidosis exists if HCO3- <25 mEq/L
Metabolic alkalosis exists if HCO3- >25 mEq/L.
Step 3: Calculate the anion gap
Anion gap = Na+ - (Cl- + HCO3-)
Notes: Normal anion gap ranges from 2 to 10 mEq/L.
110
Addition of K+ to the anion gap calculation is not required.
Correct for hypoalbuminaemia (albumin is an anion) if present. For
11
every 10 g/L below normal, add 2.5 to the anion gap.

0
Minor degrees of acidosis and elevation of anion gap are common in

TOXICOLOGY HANDBOOK
clinical practice. An idiopathic minor abnormality prompts supportive

care and re-evaluation in 4 hours. In most cases the abnormality will
be improving. An anion gap that is rising or >20 at any time prompts
immediate investigation (see Table 2.19.1).
TABLE 2.19.1 Causes of anion-gap acidosis (mnemonic

‘CAT MUDPILES’)
C Carbon monoxide, cyanide

A Alcohol, alcoholic ketoacidosis
T Toluene
M Metformin, methanol
U Uraemia
D Diabetic ketoacidosis
P Phenformin, paracetamol, propylene glycol, paraldehyde
I Iron, isoniazid (INH)
L Lactic acidosis (numerous causes)
E Ethylene glycol
S Salicylates
Note: In a study of 57 hospital patients a clear cause of the AG acidosis was found in
only 14% of patients with anion gaps of 17–19 mEq/L. All patients with anion gaps
greater than 30 mEq/L had lactic acidosis or DKA. For AG >30 also consider toxic
alcohol intoxication and alcoholic ketoacidosis.
TABLE 2.19.2 Causes of a low anion gap (<6)
Increased unmeasured cations Artefactual hyperchloraemia
Hypercalcaemia Bromism
Hypermagnesaemia Iodism
Lithium intoxication Hypertriglyceridaemia
Multiple myeloma and other Propylene glycol
gammopathies
Decreased unmeasured anions
Dilution
Hypoalbuminaemia
TABLE 2.19.3 Causes of non-anion gap metabolic acidosis
Abnormal bicarbonate loss or Using the mnemonic ‘USED

chloride retention CARP’
Drugs U Ureterostomy
Acetazolamide (+ others S Small bowel fistula
with carbonic anhydrase E Extra Cl-
activity e.g. topiramate) D Diarrhoea 111
Acidifying agents (e.g. C Carbonic anhydrase
ammonium chloride) inhibitors
Cholestyramine A Adrenal insufficiency
TOXICOLOGY HANDBOOK
Gastrointestinal bicarbonate loss R Renal tubular acidosis
Diarrhoea P Pancreatic fistula
Pancreatic fistula
Rapid hydration with normal
saline (increased chloride)
Renal bicarbonate loss
Renal tubular acidosis
Uretoenterostomy
TABLE 2.19.4 Causes of metabolic alkalosis
Administration of bases Urinary acid loss

Antacids Adrenogenital syndrome
Dialysis Bartter’s syndrome
Milk-alkali syndrome Cushing’s syndrome
Gastrointestinal acid loss Diuretics
Protracted vomiting or Licorice (glycyrrhizic acid)
nasogastric suction Primary hyperaldosteronism
(chloride loss) Volume contraction
Renal bicarbonate retention
Chronic hypercapnia
Hypochloraemia
Hypokalaemia
TABLE 2.19.5 Causes of respiratory acidosis
Acute Chronic
Airway obstruction Lung diseases
Aspiration Neuromuscular disorders
Bronchospasm Obesity
Drug-induced CNS depression
Hypoventilation of CNS or
muscular origin
Pulmonary disease
TABLE 2.19.6 Causes of respiratory alkalosis
CNS-mediated hyperventilation Pulmonary

Increased intracranial pressure Congestive cardiac failure
Cerebrovascular accidents Mechanical hyperventilation
Psychogenic Pneumonia
Hypoxia-mediated Pulmonary emboli
hyperventilation Sepsis
112 Altitude Toxin-induced hyperventilation
Anaemia Nicotine
11
V/Q mismatch Salicylate

2
Xanthines
TOXICOLOGY HANDBOOK
TABLE 2.19.7 Causes of hyperlactataemia
Type A: Imbalance between Type B: Metabolic derangements

oxygen demand and supply Beta2-agonists
Carbon monoxide poisoning Cancer
Excessive oxygen demand- Cyanide
seizure, hyperpyrexia, Ethanol (increased hepatic
shivering, exercise NADH and decreased
Shock conversion of lactate to
Severe anaemia pyruvate)
Severe hypoxia Hepatic failure
Inborn errors of metabolism
Ketoacidosis
Metformin
Sepsis
Vitamin deficiency (thiamine,
biotin)
Step 4: Check the degree of compensation

Metabolic acidaemia: For every 1 mEq/L decrease in HCO3-, PaCO2
should decrease by 1.3 mmHg
Metabolic alkalaemia: For every 1 mEq/L increase in HCO3-, PaCO2
should increase by 0.6 mmHg
Respiratory acidaemia: For every 10 mmHg increase in PaCO2,
HCO3- should increase by 1 mEq/L (acute) or 4 mEq/L (chronic)
Respiratory alkalaemia: For every 10 mmHg decrease in PaCO2,
HCO3- should decrease by 2 mEq/L (acute) or 5 mEq/L (chronic).
Step 5: Determine if there is a 1:1 relationship between anions in the
blood (presence of ‘delta-gap’)
This is used if:
l A metabolic disturbance is suspected but not detected up until this point
l Anion and non-anion gap acidoses are suspected to coexist.
There should be a 1:1 relationship between the anion gap and decrease
in HCO3-. If they do not correspond, a delta gap is said to exist.
Example: If anion gap is elevated by 10–20, then the HCO3-
should decrease by 10 from 25 mEq/L to 15 mEq/L. If HCO3- is
actually higher, there is coexisting metabolic alkalosis.
If HCO3- is actually lower, then an additional non-anion gap
acidosis is also present.
References
Gabow PA, Kaehny WD, Fennessey PV et al. Diagnostic importance of an increased
serum anion gap. New England Journal of Medicine 1980; 303(15):854–858.
Levy B. Lactic acidosis and hyperlactatemia. In: Vincent J-L, ed. 2006 Yearbook of
Intensive Care and Emergency Medicine. Berlin: Springer-Verlag; 2006: 91. 113
Whittier WL, Rutecki GW. Primer on clinical acid–base problem solving. Disease
Monitoring 2004; 50:117–162.
TOXICOLOGY HANDBOOK
2.20 THE 12-LEAD ECG IN TOXICOLOGY
The 12-lead ECG is a non-invasive, inexpensive and readily available tool
that identifies occult but potentially lethal cardiac conduction abnormalities,
such as those seen in tricyclic antidepressant cardiotoxicity. For these
reasons, it is recommended as a screening test in all patients who present
following deliberate self-poisoning. The 12-lead ECG provides valuable
real-time prognostic information that is based on toxic effects at the target
organ, often not available from clinical evaluation or serum drug assays.
Serial ECGs provide valuable monitoring of the progression or regression
of cardiotoxicity during the clinical course. They inform decision making
with regard to level of care and monitoring, and disposition.
ELECTROPATHOPHYSIOLOGY
The changes in rate, rhythm and intervals detected on the 12-lead ECG in
acute poisoning reflect a variety of toxic effects on the cardiac conducting
system (see Figure 2.20.1). Normal intervals are shown in Figure 2.20.2.
Pathophysiological mechanisms include:
Fast sodium channel blockade (agents listed in Table 2.20.1)
l Slowed sodium influx during phase 0 of the cardiac action potential
manifests as:
— Widened QRS
— Right axis deviation of the terminal QRS (see Figure 2.20.3)
FIGURE 2.20.1 The myocardial action potential and corresponding
ECG trace
2
Measured Potential (mv)
0 3
Action Potential
Na+ Channel Blocker Toxicity

+
K Efflux Blocker Toxicity
ECG
114 Time (mS)
11
4
Diagram from Holstege CP, Eldridge DL, Rowden AK. ECG manifestations: the poi-
soned patient. Emergency Medicine Clinics of North America 2006; 159–177.
TOXICOLOGY HANDBOOK
FIGURE 2.20.2 Normal ECG parameters
Rate 60–100/minute
PR interval: <200 ms (5 small squares)
QRS duration: <100 ms (2.5 small squares)
QTC interval: <450 ms
QTC = QT/√R-R
R
T
P
Q
S
PR
QRS
QT
TABLE 2.20.1 Agents associated with fast sodium channel blockade
(QRS widening)
Tricyclic antidepressants Local anaesthetics

Amitriptyline Bupivacaine
Desipramine Cocaine
Dothiepin Ropivacaine
Imipramine Phenothiazines
Nortriptyline Thioridazine
Class 1A antidysrhythmic agents Amantadine
Disopyramide Carbamazepine
Procainamide Chloroquine
Quinidine Diltiazem
Class 1C antidysrhythmic agents Diphenhydramine
Encainide Hydroxychloroquine
Flecainide Propoxyphene/
dextropropoxyphene
Propranolol
Quinine
115
FIGURE 2.20.3 ECG changes in tricyclic antidepressant (or other fast
Na channel blocker) toxicity
TOXICOLOGY HANDBOOK
Features consistent with fast sodium channel blockade:
• QRS >100 ms in lead II
• Right axis deviation of terminal QRS
— Terminal R wave >3 mm in AVR
— R/S ratio >0.7 in AVR
TCA LEAD II AVR
Dominant R wave in aVR
Widening of the QRS

TABLE 2.20.2 Agents associated with blockade of potassium
efflux (QT prolongation)
Antipsychotic agents Other antidepressants

Amisulpride Mianserin
Chlorpromazine Citalopram
Droperidol Escitalopram
Haloperidol Bupropion
Olanzapine Moclobemide
Quetiapine Antihistamines
Thioridazine Diphenhydramine
Class 1A antidysrhythmic agents Astemizole
Quinidine Loratadine
Disopyramide Terfenadine
Procainamide Chloroquine
Class 1C antidysrhythmic agents Hydroxychloroquine
Encainide Quinine
Flecainide Macrolides
Class III antidysrhythmic agents Erythromycin
Sotalol
116 Tricyclic antidepressants
Amitriptyline
11
6
Desipramine
Doxepin
TOXICOLOGY HANDBOOK
Imipramine
Nortriptyline
— Bradycardia (although tachycardia secondary to other factors is

more commonly observed)
— Ventricular tachycardia and ventricular fibrillation
Blockade of potassium efflux during cardiac repolarisation (agents
listed in Table 2.20.2)
l Prolongation of the QT interval
l Torsades de pointes
Na+-K+-ATPase pump blockade (cardiac glycosides)
l Increased automaticity
l Decreased AV node conduction
— 1st degree heart block (prolonged PR interval)
— 2nd degree heart block
— 3rd degree (complete) heart block
Calcium channel blockade
l Sinus bradycardia
l Intraventricular conduction defects
Beta-adrenergic receptor blockade
l Bradycardia
Myocardial ischaemia
l ST segment depression or elevation
l Conduction abnormalities
Hyperkalaemia
l Peaked T waves
l Conduction abnormalities
Hypocalcaemia
l QT prolongation.
TRICYCLIC ANTIDEPRESSANTS
A QRS duration >100 ms suggests blockade of cardiac fast sodium
channels. In combination with right axis deviation of the terminal QRS, it 117
is virtually pathognomonic (see Figure 2.20.3). Most studies examine ECG
changes in TCA intoxication and are small or retrospective. However, the
TOXICOLOGY HANDBOOK
following appear to be associated with major toxicity:
l QRS >100 ms (2.5 small squares) is associated with seizures
l QRS >160 ms (4 small squares) is associated with ventricular
dysrhythmias
l Right axis deviation of the terminal QRS as defined by
a Terminal R wave >3 mm in AVR
b R/S ratio >0.7 in AVR.
SYSTEMATIC ANALYSIS OF THE 12-LEAD ECG OF A POISONED

PATIENT
1 D etermine rate and rhythm
2 Determine PR interval—is there any degree of heart block?
3 Determine QRS duration in lead II
The studies examining QRS duration in tricyclic antidepressant
intoxication use manual measurements to measure QRS in limb
lead II. This may not correspond with the QRS as calculated by an
automated ECG machine using complex algorithms. It is best to check
the interval manually in lead II.
4 Check for right axis deviation of the QRS
A large terminal R wave in AVR or increased R/S ratio indicates slow
rightward conduction and is characteristic of fast sodium channel
blockade. If not pathological, it remains static in appearance and
severity throughout the course of the poisoning. Comparison with pre-
poisoning ECGs is useful.
5 D
etermine QT interval
A prolonged QT interval predisposes to the development of torsades
de pointes, a polymorphic ventricular tachycardia. Torsades de
pointes is potentially fatal because of its propensity to degenerate into
ventricular fibrillation. Torsades de pointes is more likely to occur
where there is coexisting bradycardia. The arrhythmogenic risk for
drug-induced QT prolongation is accurately predicted by the ‘QT
nomogram’, which plots QT versus heart rate (see Figure 2.20.4).

6 Check for evidence of increased cardiac ectopy or automaticity
7 Check for evidence of hyperkalaemia
8 Check for evidence of myocardial ischaemia.
FIGURE 2.20.4 QT interval nomogram for determining ‘at risk’ QT-HR

pairs from a single 12-lead ECG
118
QT interval
11
8
(msec)
TOXICOLOGY HANDBOOK
20 40 60 80 100 120 140 160
Heart rate (bpm)
The mean QT interval as measured manually on multiple leads of a 12-lead ECG is

plotted against the heart rate (HR) measured on the ECG. If the point is above
the line then the QT-HR is regarded ‘at risk’ for the development of torsades de
pointes.
Chan A, Isbister GK, Kirkpatrick CMJ et al. Drug-induced QT prolongation and tor-
sades de pointes: evaluation of a QT nomogram. Quarterly Journal of Medicine
2007:100:609–615.
References
Boehnert MT, Lovejoy FH. Value of the QRS duration verus the serum drug level in
predicting seizures and ventricular arrhythmias after an acute overdose of tricyclic
antidepressants. New England Journal of Medicine 1985; 313:474–479.
Chan A, Isbister GK, Kirkpatrick CMJ et al. Drug-induced QT prolongation and
torsades de pointes: evaluation of a QT nomogram. Quarterly Journal of Medicine
2007; 100:609–615.
Holstege CP, Eldridge DL, Rowden AK. ECG manifestations: the poisoned patient.
Emergency Medicine Clinics of North America 2006; 159–177.
Liebelt EL, Francis D, Woolf AD. ECG lead AVR versus QRS interval in predicting
seizures and arrhythmias in acute tricyclic antidepressant toxicity. Annals of
Emergency Medicine 1995; 26:195–201.
Niemann JT, Bessen HA, Rothstein RJ et al. Electrocardiographic criteria for tricyclic
antidepressant cardiotoxicity. American Journal of Cardiology 1986; 57:1154–1159.
Wolfe TR, Caravati EM, Rollins DE. Terminal 40-ms frontal plane QRS axis as a marker for
tricyclic antidepressant overdose. Annals of Emergency Medicine 1989; 18:348–351.
2.21 POISONING DURING PREGNANCY
AND LACTATION
Management decisions regarding poisoning or envenoming in the
pregnant or lactating patient take into consideration the risks to the fetus
or infant of the poisoning or its treatment.
Pregnancy-induced physiological changes affect drug
pharmacokinetics and pharmacodynamics in the following ways:
1 Absorption—delayed gastric emptying and intestinal transit time slow
drug absorption and may prolong the period where decontamination is
of potential benefit
2 Distribution—increased blood volume (45–50%) increases volume
of distribution and potentially decreases plasma levels; dilution of
plasma proteins increases free drug levels
3 Elimination—hepatic enzyme systems are altered by circulating
hormones; renal blood flow and glomerular filtration rate increase.
119
Most drugs cross the placenta by diffusion and maternal blood levels
are the most significant determinant of fetal exposure. Maternal blood
levels are usually greater than those of the fetus, although for some agents
TOXICOLOGY HANDBOOK
they are the same and for others fetal levels exceed maternal levels (e.g.
valproic acid and diazepam).
On a practical level, acute management of overdose in the pregnant
patient rarely differs from that of the non-pregnant patient. In particular,
paracetamol and iron overdose, which are relatively common in this
group, are managed along standard lines.
Excellence in supportive care of the poisoned mother ensures the
best physiological conditions to minimise fetal compromise. Hypoxia,
hypotension, hypoglycaemia and seizures in the mother are avoided where
possible. If they occur they are promptly identified and corrected.
Greater circulating volumes, increased respiratory rate and
physiological resting tachycardia in the pregnant patient disguise
hypovolaemia and respiratory compromise until later stages.
Oral activated charcoal and whole bowel irrigation do not pose any
special risks to pregnant patients and these forms of decontamination are
implemented whenever indicated as for non-pregnant patients.
Poisoning with a limited number of agents poses a potentially greater
risk to the fetus than the mother and the threshold for treatment is
lowered. These include:
l Carbon monoxide
l Methaemoglobin-inducing agents
l Lead
l Salicylates.
Consideration of the need to emergently deliver near-term infants in
poisoned mothers is a complicated issue that should be managed with
toxicology and obstetric expertise.
In general if the fetus survives a maternal intentional ingestion, the
risk of teratogenicity is low. The teratogenic risk is theoretically greater
when the exposure occurs during the first trimester. It is important
that the pregnant patient be counselled regarding these risks once she
has recovered. Australian drug risk classifications for pregnancy are

available for all therapeutic agents. Paracetamol overdose treated with
N-acetylcysteine does not appear to be associated with fetal abnormality
even when the exposure occurs during the first trimester.
The decision to continue breastfeeding during acute poisoning
involves a risk–benefit analysis. Most drugs are excreted in breast milk.
The percentage of maternal dose likely to be received by an infant is very
low (<2–3%) and usually does not pose a poisoning risk. Nonetheless, it is
usually best to interrupt breastfeeding until the mother recovers, provided
this can be done without compromising infant nutrition.
120
12
References
0
Anderson GD. Pregnancy-induced changes in pharmacokinetics: A mechanistic-based

TOXICOLOGY HANDBOOK
approach. Clinical Pharmacokinetics 2005; 44(10):989–1008.

McElhatton PR, Sullivan FM, Volans GN. Paracetamol overdose in pregnancy: analysis
of the outcomes of 200 cases referred to the teratology information service.
Reproductive Toxicology 1997; 10:85–94.
Syme MR, Paxton JW, Keelan JA. Drug transfer and metabolism by the human
placenta. Clinical Pharmacokinetics 2004; 43(8):487–514.
Wiles JM, Clark LE, Herrera JL. Acetaminophen overdose in pregnancy. Southern
Medical Journal 2005; 98(11):1118–1122.
2.22 POISONING IN CHILDREN

Unintentional paediatric exposures generate over 80 000 calls to
Australian poisons information centres (PICs) each year. Many children
are also brought directly to emergency departments without initial PIC
consultation. The following information refers to unintentional exposures
in children under the age of 6 years. Older children and adolescents may
present with deliberate self-poisoning and these cases are assessed and
managed according to the principles outlined for adults.
MANAGEMENT
Resuscitation
Paediatric resuscitation in poisoning follows the principles outlined in
Chapter 1.2: Resuscitation. Attention to airway, breathing and circulation
are paramount and ensure survival in the vast majority of patients.
Risk assessment
The principles of risk assessment in acute paediatric poisoning are the
same as outlined for adults in Chapter 1.3: Risk assessment. However,
the process is influenced by the difficulty in obtaining an accurate history
regarding dose and agent, and the different range of agents ingested by
small children.
Paediatric unintentional exposures occur most frequently with children
in the 12–36 months age group. It is normal behaviour at that age to
ingest small items found in the immediate environment. Not surprisingly,
the range of agents ingested differs substantially from that ingested by
adolescents or adults who deliberately self-poison (see Table 2.22.1). The
ingested agent is more likely to be non-pharmaceutical and often virtually
non-toxic when ingested in the readily available dose (see Table 2.22.2).
The toxic effects exerted by most agents on a mg/kg basis are the
same for children as for adults. Small children rarely ingest more than 2–3
tablets or a mouthful of most agents, which equates to doses well below
those ingested by adults or adolescents intending self-harm. However,
some pharmaceutical agents, particularly large-dose controlled-release 121
preparations, have the potential to cause serious toxicity if ingested by a
TOXICOLOGY HANDBOOK
TABLE 2.22.1 Agents involved in accidental paediatric exposures
Pharmaceuticals 40%
Household cleaning products 14%
Plants 13%
Cosmetics 10%
Pesticides 6%
TABLE 2.22.2 Non-toxic household exposures
Antacids Inks
Antibiotics Laxatives
Bath oil Lipstick
Candles (wax) Matches (red phosphorus)
Chalk Newsprint
Cigarette butts Oral contraceptives
Colognes and perfumes Paint
Corticosteroids Shampoo
Cosmetics Shaving cream
Deodorants Shoe polish
Detergents (sips) Silica
Fertilisers Soap
Glues Suntan lotions
Hair products Thermometer mercury
Hand lotions Vaseline (petroleum jelly)
Incense
10-kg toddler in one, two or three dose units (see Table 2.22.3). Some
non-pharmaceutical agents are also potentially lethal to children in small
doses (see Table 2.22.4). In envenoming cases, the dose of venom is
determined by the venomous creature, not the victim, and children receive
a larger venom dose on a microgram/kg basis.
TABLE 2.22.3 Pharmaceuticals with potential for severe toxicity

if two tablets ingested by a 10-kg toddler
Agent Features of severe toxicity
Amphetamines Agitation, confusion, hypertension,

Amphetamine hyperthermia
Methamphetamine
MDMA (ecstasy)
Calcium channel blockers Delayed onset of bradycardia,

Diltiazem CD 180, 240 or 360 mg hypotension, conduction defects,
Verapamil SR 160, 180 or 240 mg refractory shock
122 Chloroquine 155 mg Rapid onset of coma, seizures and
12
Hydroxychloroquine 200 mg cardiovascular collapse

2
Dextropropoxyphene 100 mg Ventricular tachycardia

TOXICOLOGY HANDBOOK
Opioids Coma, respiratory arrest.

Oxycodone 5 mg Note: Onset of toxicity may be
Methadone 10 mg delayed with diphenoxylate/
Morphine sulfate 5, 10, 15, 30, atropine and controlled-release
60, 100, 200 mg (controlled morphine
release)
Diphenoxylate 2.5 mg/atropine
25 microgram
Propranolol 160 mg Coma, seizures, ventricular

tachycardia, hypoglycaemia
Sulfonylureas Hypoglycaemia. Onset may be

Glibenclamide 5 mg delayed up to 8 hours.
Glibenclamide/Metformin
1.25/250 mg, 2.5/500 mg, 5/500 mg
Gliclazide 80 mg
Gliclazide modified-release 30 mg
Glimepiride 1, 2, 3, 4 mg
Glipizide 5 mg
Theophylline SR 200, 250, 300 mg Seizures, supraventricular

tachycardia, vomiting
Tricyclic antidepressants Coma, seizures, hypotension,

Dothiepin 75 mg ventricular tachycardia
Adapted from McCoubrie D, Murray L, Daly FFS et al. Ingestion of two unidentified
tablets by a toddler. Emergency Medicine Journal 2006; 23:718–720.
TABLE 2.22.4 Non-pharmaceuticals with potential for severe toxicity
if sip or mouthful ingested by a 10-kg toddler
Agent Features of severe toxicity
Organophosphate and carbamate Cholinergic symptoms

insecticides Seizures
Depressed level of consciousness
Paraquat Oropharyngeal burns
Multiple organ failure
Pulmonary fibrosis
Hydrocarbons Rapid depressed level of

Solvents consciousness
Eucalyptus oil Seizures
Kerosene Aspiration pneumonia
Camphor Rapid depressed level of

consciousness
Seizures
Hypotension 123
Naphthalene (one mothball) Methaemoglobinaemia

NB: Most mothballs contain Haemolysis
TOXICOLOGY HANDBOOK
paradichlorobenzene, which
is non-toxic after a single
unintentional ingestion
Agents that do not cause significant toxicity when ingested in one,

two or three dose units by small children include paracetamol (greater
than four 500 mg tablets, or greater than 42 mL of 240 mg/5 mL solution
required to exceed 200 mg/kg), iron (six or more tablets containing
105 mg elemental iron required to exceed 60 mg/kg), colchicine (10
or more 0.5 mg tablets required to exceed 0.5 mg/kg), digoxin (16 or
more 250 microgram tablets required to exceed 4 mg) and anticoagulant
rodenticides (less than one packet is generally considered non-toxic
following a single unintentional ingestion).
Unfortunately, accurate estimation of dose and time is frequently
challenging because of the inability to obtain an accurate dosing history.
Risk assessment and subsequent management decisions are always based
on a ‘worst-case scenario’ determined as follows:
1 The time of ingestion is assumed to be the latest possible time
2 Assume all missing or unaccounted agent(s) have been ingested
3 Do not attempt to account for spillage, which is difficult to estimate
4 If more than one child is involved, it is assumed that each child
ingested all the missing or unaccounted agent(s).
This approach means that many children are assessed and observed in
hospital but do not go on to develop toxicity.
TABLE 2.22.5 Management of a toddler who ingests unidentified tablets
l Admit for a minimum 12-hour observation period

l Ensure healthcare facility has appropriate resources to observe,
resuscitate and treat patient if evidence of poisoning occurs
l IV access can be deferred until early evidence of toxicity is apparent
l Check bedside glucose level at presentation, if there is clinical evidence
of hypoglycaemia, and at discharge
l Brief staff regarding clinical features for which the patient is being
observed (see Table 2.22.3).
l Monitor level of consciousness, vital signs (pulse, blood pressure and
respiratory rate) and early clinical features of hypoglycaemia
l Cardiac monitoring may be instituted if there is any abnormality of
conscious state or vital signs
l Discharge patient only during daylight hours
Ingestion of a few unidentified tablets, often found in a public space,

presents a difficult scenario around which to construct a risk assessment.
124 If a tablet remains available for inspection, a PIC may be consulted to
12
assist with identification. If this cannot be done with complete accuracy,

4
the risk assessment assumes that the ingested tablets are one of the
TOXICOLOGY HANDBOOK
potentially lethal agents (see Table 2.22.3). A management plan based on

this risk assessment is shown in Table 2.22.5.
Supportive care and disposition
Most ingestions are benign and do not need referral to hospital or
gastrointestinal decontamination (see Table 2.22.2). For those ingestions
that require management in a hospital setting, risk assessment based on
the ‘worst-case scenario’ guides a defined period of focused observation.
Investigations
The screening tests performed on all adolescents and adults who
deliberately self-poison are not indicated in the context of unintentional
paediatric poisoning. Investigations are performed only for specific
purposes and are usually not necessary. Early measurement of drug
levels, such as paracetamol, digoxin or theophylline, may be useful to
exclude ingestion and obviate the need for prolonged observation, further
investigation or transfer between facilities.
Decontamination
Gastrointestinal decontamination following unintentional paediatric
ingestion is not routine. It is unusual that even the risk assessment based
on a ‘worst-case scenario’ implies potential benefits that outweigh the risk
associated with gastrointestinal decontamination procedures in children.
Where activated charcoal is indicated, mixing with ice cream improves
its palatability and the ease of administration. Administration of activated
charcoal via a nasogastric tube inadvertently placed in the bronchial tree
has resulted in paediatric death. Decontamination should be reserved for
severe or life-threatening poisoning where the risk assessment suggests
that supportive care or antidote treatment alone may not be adequate to
ensure a satisfactory outcome.
Enhanced elimination and antidotes
Antidotes and enhanced elimination techniques have specific indications,
contraindications, methods of administration, monitoring requirements,
appropriate therapeutic end points and adverse effect profiles. The
risk–benefit analysis is rarely in favour of these interventions following
paediatric exposures. Doses of antidotes, where indicated, are usually the
same as for adults on a mg/kg basis. However, antivenom doses are the
same as for adults in absolute terms.
DISPOSITION AND FOLLOW-UP

The vast majority of paediatric exposures are benign and do not require
referral to hospital for assessment or observation. This decision based on
risk assessment is often made by a PIC when contacted by parents, carers 125
or medical professionals working outside of hospital; in less than 7%
of such cases is the child referred to hospital by the PIC. Most children
referred or presenting to hospital can be discharged home if clinical
TOXICOLOGY HANDBOOK
evidence of toxicity does not develop within a short period of observation.
Those who develop toxicity require admission to a facility able to provide
an appropriate level of care.
Following any unintentional paediatric exposure, the circumstances
of exposure are evaluated and parents or carers advised on safe storage
of medicines and chemicals in the home if indicated. Unusually severe
intoxication suggesting large, repeated or unusual exposure prompts
consideration of non-accidental injury (NAI). This diagnosis is also
considered if poisoning is diagnosed in an infant under 12 months of age.
Children in this age group are not normally capable of self-administering
tablets or other foreign materials. They may be administered toxins by
adult carers with malicious intent, or by older siblings.
References
Bar-Oz B, Levichek Z, Koren G. Medications that can be fatal for a toddler with one
tablet or teaspoonful. Pediatric Drugs 2004; 6:123–126.
McCoubrie D, Murray L, Daly FFS et al. Ingestion of two unidentified tablets by a
toddler. Emergency Medicine Journal 2006; 23:718–720.
Mofenson HC, Greensher J, Carraccio TR. Ingestions considered non-toxic. Emergency
Medicine Clinics of North America 1984; 2(1):159–174.
New South Wales Poisons Information Centre. 2008 Annual Report. Children’s Hospital
at Westmead, Westmead, New South Wales.
2.23 POISONING IN THE ELDERLY
The assessment and management of the poisoned elderly patient is
challenging.
The coexistence of limited physiological reserves, deteriorating
cognition, multiple medical problems and their multiple prescribed
medications provides the basis for exaggerated and unpredictable

responses to any toxicological insult. The risk assessment for an overdose
in the elderly patient predicts a more severe clinical course for the same
agent taken in the same dose by a healthy young adult. Higher levels
of vigilance, supportive care and monitoring are necessary. The clinical
course of overdose or chronic poisoning is likely to be more severe
and also have a higher complication rate. Age is highly correlated with
case fatality rate and it is estimated that each 10-year increase in age is
associated with a 36% increase in the odds ratio for death as an outcome
following poisoning. Elderly patients are more likely to require hospital
126 care as a result of accidental exposures and adverse drug effects.
Pharmacokinetic changes with ageing include delayed gastrointestinal
12
6
absorption, decreased protein binding with resultant increased free drug

TOXICOLOGY HANDBOOK
levels, and reduced hepatic metabolic function and glomerular filtration

rate with resultant impaired elimination. Acute renal failure secondary to
intercurrent medical problems or prescribed medications commonly leads
to poisoning syndromes in the elderly, such as chronic lithium or digoxin
toxicity.
Pharmacodynamic differences in the elderly are a result of drug
actions on physiologically impaired organs. This is particularly seen
with cardiovascular, respiratory and CNS depressant agents. An elderly
patient’s ability to respond to cardiovascular compromise with usual
mechanisms such as peripheral vasoconstriction and increased cardiac
output varies greatly. Clinical assessment of volume status in order
to optimise renal and cardiac function is often unreliable and a lower
threshold for invasive monitoring is required in these patients.
Most elderly patients will have a relatively delayed recovery from
serious poisoning. The complications of immobility and hospital
admission are observed more frequently in the elderly. These include
atelectasis, pneumonia, pulmonary embolism, catheter-induced sepsis,
muscle wasting and acute confusional states.
Reference
Roger JJ, Heard K. Does age matter? Comparing case fatality rates for selected
poisonings reported to U.S. poison centers. Clinical Toxicology 2007; 45:705–708.
CHAPTER 3
SPECIFIC TOXINS
3.1 lcohol: Ethanol

A 130
3.2 Alcohol: Ethylene glycol 133
3.3 Alcohol: Isopropanol (isopropyl alcohol) 136
3.4 Alcohol: Methanol (methyl alcohol) 138
3.5 Alcohol: Other toxic alcohols 142
3.6 Amiodarone 144
3.7 Amisulpride 146
3.8 Amphetamines 148
3.9 Angiotensin converting enzyme inhibitors 152
3.10 Anticoagulant rodenticides 154
3.11 Anticonvulsants: Newer agents 157
3.12 Antihistamines (non-sedating) 159
3.13 Antihistamines (sedating) 162
3.14 Arsenic 164
3.15 Beta-blockers 168
3.16 Baclofen 171
3.17 Barbiturates 173
3.18 Benzodiazepines 177
3.19 Benztropine 179
3.20 Bupropion 181
3.21 Button batteries 184
3.22 Calcium channel blockers 186
3.23 Cannabinoids (marijuana) 190
3.24 Carbamazepine 193
3.25 Carbon monoxide 196
3.26 Chloroquine and hydroxychloroquine 200
3.27 Chloral hydrate 202
3.28 Clonidine 205
3.29 Clozapine 208
3.30 ocaine
C 210
3.31 Colchicine 214
3.32 Corrosives 216
3.33 Cyanide 219
3.34 Digoxin: Acute overdose 222
3.35 Digoxin: Chronic poisoning 226
3.36 Diphenoxylate-atropine 230
3.37 Gamma-hydroxybutyrate (GHB) 232
3.38 Glyphosate 235
3.39 Hydrocarbons 237
3.40 Hydrofluoric acid 240
3.41 Hydrogen peroxide 244
3.42 Insulin 247
3.43 Iron 250
3.44 Isoniazid 254
3.45 Lead 256
3.46 Lithium: Acute overdose 260
3.47 Lithium: Chronic poisoning 263
3.48 Local anaesthetic agents 265
3.49 Mercury 269
3.50 Metformin 273
3.51 Methotrexate 276
3.52 Mirtazapine 279
3.53 Monoamine oxidase inhibitors (MAOIs) 280
3.54 Non-steroidal anti-inflammatory drugs (NSAIDs) 284
3.55 Olanzapine 287
3.56 Opioids 290
3.57 Organochlorines 295
3.58 Organophosphorus agents (organophosphates
and carbamates) 298
3.59 Paracetamol: Acute overdose 302
3.60 Paracetamol: Repeated supratherapeutic ingestion 312
3.61 Paraquat 316
3.62 Phenothiazines and butyrophenones (antipsychotic
agents) 320
3.63 Phenytoin 323
3.64 Potassium chloride 326
3.65 Quetiapine 328
3.66 Quinine 331
3.67 Risperidone 334
3.68 Salicylates 336
3.69 Selective serotonin reuptake inhibitors (SSRIs) 340
3.70 Strychnine 343
3.71 ulfonylureas
S 346
3.72 Theophylline 348
3.73 Thyroxine 352
3.74 Tramadol 354
3.75 Tricyclic antidepressants (TCAs) 357
3.76 Valproic acid (sodium valproate) 361
3.77 Venlafaxine and desvenlafaxine 364
3.78 Warfarin 368
3.1 ALCOHOL: ETHANOL
See also Chapter 2.12: Alcohol abuse, dependence and withdrawal
Ethanol causes CNS depression that is synergistic with other CNS
depressants and potentially lethal. It is frequently co-ingested with other
agents during deliberate self-poisoning and the history of alcohol co-
ingestion may not be forthcoming unless specific enquiry is made. Care is
supportive.
RISK ASSESSMENT
l thanol ingestion causes rapid, dose-related CNS depression, with
E
a high degree of inter-individual variability
SPECIFIC TOXINS
l Dose may be estimated if the number of standard drinks consumed

is known:
— Standard drinks containing approximately 10 g ethanol
– 375 mL can of mid-strength beer (3.5%)
– 100 mL glass of wine
– 30 mL shot of spirit
l Co-ingestion of other CNS depressants (e.g. sedative-hypnotic
agents, antidepressants, opioids) increases the risk of respiratory
130 depression
l Seizures may occur in the setting of ethanol intoxication or withdrawal.
13
0
Toxic mechanism
TOXICOLOGY HANDBOOK
The molecular sites of action are uncertain. Augmentation of the GABAA receptor complex
is thought to be central to its CNS depressant effects. Glycine, N-methyl-D-aspartate,
serotonin (5HT3), adenosine and L-type calcium channel effects also appear to be
involved. In addition, ethanol causes dose-dependent cardiovascular depression and
impairs gluconeogenesis, thus causing hypoglycaemia in susceptible individuals.
Toxicokinetics
Ethanol is rapidly absorbed following oral administration. It distributes readily across the
total body water (volume of distribution 0.6 L/kg). Ethanol is oxidised by cytosolic and
microsomal alcohol dehydrogenases to form acetaldehyde, which in turn is metabolised
by aldehyde dehydrogenase to acetyl CoA (see Appendix 4: Alcohol pathways).
Both cytosolic steps involve the reduction of NAD to NADH. Above a serum ethanol
concentration of 4 mmol/L (2 mg/dL), zero order kinetics apply, so a constant amount
of ethanol is metabolised per unit time. In most patients, serum ethanol levels decrease
by approximately 4 mmol/L/hour (20 mg/dL/hour; 0.02%/hour). The production of
NADH decreases conversion of lactate to pyruvate (hyperlactataemia), and inhibits
gluconeogenesis and fatty acid oxidation (hypoglycaemia).
CLINICAL FEATURES
l linical features are progressive with increasing degrees of
C
intoxication (see Table 3.1.1)
l Disinhibition, emotional lability and euphoria
l Nystagmus, ataxia, slurred speech
l Agitation, aggression and disorientation
l Nausea, vomiting
l Tachycardia, hypotension, hypothermia
l Coma with loss of airway protective reflexes, respiratory
depression and hypotension
Improvement in conscious state is usually seen within 2–4 hours, but 6–12
hours may elapse before patients are ambulant.
TABLE 3.1.1 Guide to dose-related serum ethanol concentrations and
clinical features
Serum ethanol concentration
Ethanol Conventional units
dose SI units
(g/kg) (mmol/L) mg/dL g/dL (%) Clinical features
0.5 11 50 0.05 Disinhibition and euphoria
1 22 100 0.10 Slurred speech. Significant

CNS depression in non-
tolerant individuals,
especially children
SPECIFIC TOXINS
2 43 200 0.20 Potential for coma, although
ethanol-dependent
individuals are usually
ambulant
>5 >87 >400 >0.40 Coma, respiratory

depression, hypotension,
except in patients with 131
marked tolerance
Note: To convert SI units to mg/dL, multiply by 4.61. To convert mg/dL to SI units,
multiply by 0.22.
TOXICOLOGY HANDBOOK
INVESTIGATIONS
Screening tests in deliberate self-poisoning
l 12-lead ECG, BSL and paracetamol level
Specific investigations as indicated
l Serum, blood and breath alcohol levels
l Serum ethanol levels assist risk assessment in patients with CNS
depression. However, elevated serum ethanol concentrations
cannot be assumed to be the sole contributor to CNS
depression and an appropriate evaluation for other causes is
required
l Serum ethanol concentration is not the same as whole blood
ethanol level, which defines legal driving limits. Whole blood
concentrations are approximately 10% lower than corresponding
serum concentrations
l Breath ethanol estimation provides a convenient bedside
estimation of blood ethanol concentration but the result is
influenced by minute ventilation.
MANAGEMENT
l Attention to airway, breathing and circulation are paramount. These
priorities are managed along conventional lines as outlined in
Chapter 1.2: Resuscitation
l asic resuscitative measures ensure the survival of the vast
B
majority of patients
l General supportive care measures are indicated, as outlined in
Chapter 1.4: Supportive care and monitoring
l Give thiamine 100 mg PO or IV to patients with potential thiamine
deficiency
l Close clinical and physiological monitoring is indicated
l Monitor for urinary retention and place an indwelling urinary
catheter as required
Decontamination
l Activated charcoal is not indicated
SPECIFIC TOXINS
l Elimination of ethanol is enhanced by haemodialysis. However, as

a good outcome is ensured with thorough supportive care, it is not
routinely indicated
Antidotes
l None available.

l atients with mild CNS depression are managed supportively in
P
132 a ward environment. When the patient is cooperative, clinically
13
well, ambulant, passing urine, eating and drinking, discharge may

2
occur
TOXICOLOGY HANDBOOK
l Patients with significant CNS depression require intubation and

admission to an intensive care unit
l Where appropriate, patients are counselled regarding ethanol
abuse prior to discharge, as discussed in Chapter 2.12: Alcohol
abuse, dependence and withdrawal.
HANDY TIPS
l serum ethanol concentration confirms the diagnosis of ethanol
A
intoxication but does not exclude other causes of CNS depression
(e.g. co-ingestion, trauma, metabolic disorder)
l Anticipate alcohol withdrawal during the observation period in
patients with alcohol dependence.
PITFALLS
l ailure to regard ethanol intoxication as potentially life threatening
F
l Failure to detect and manage coexisting intoxications or other
medical conditions in the ethanol intoxicated patient
l Discharge of ethanol intoxicated patients before they are
competent to make decisions about their own welfare and ensure
their own safety.
Presentations
Ethanol is found in varying concentrations in a large number of beverages, and
domestic and commercial products:
Beers: 2.8–12.0%
Wines: 9–14%
Spirits: 35–50%
ethylated spirits: 95% (Australia)
M
Mouth wash, food extracts and flavourings (e.g. vanilla extract 35% ethanol),
cough and cold syrups, perfumes and cosmetics
References
Baselt RC. Disposition of toxic drugs and chemicals in man. 5th edn. Foster City,
California: Chemical Toxicology Institute; 2000.
Lieber CS. Medical disorders of alcoholism. New England Journal of Medicine 1995;
333(16):1058–1065.
O’Connor PG, Schottenfeld RS. Patients with alcohol problems. New England Journal of
Medicine 1998; 338(9):592–602.
Tjipto AC, Taylor DMcD, Liew H. Alcohol use among young adults presenting to the
emergency department. Emergency Medicine Australasia 2006; 18(2):125–130.
SPECIFIC TOXINS
3.2 ALCOHOL: ETHYLENE GLYCOL
Ethylene glycol (EG) is a toxic alcohol. Deliberate self-poisoning is usually
lethal without timely intervention.
RISK ASSESSMENT
l Ingestion of >1 mL/kg is potentially lethal
l All deliberate self-poisonings are assumed to be potentially lethal 133
l Unintentional ingestion of less than a mouthful is benign and does
not require hospital evaluation unless symptoms develop
l Co-ingestion of ethanol complicates risk assessment (see
TOXICOLOGY HANDBOOK

Investigations below)
l Dermal and inhalation exposure does not lead to EG intoxication
l Children: Minor ingestions such as a taste or lick do not require

hospital evaluation unless symptoms develop.
Toxic mechanism
Ethylene glycol causes CNS effects similar to those of ethanol. The more important
toxic effects are due to metabolites rather than the parent compound. A severe anion
gap metabolic acidosis develops secondary to accumulation of glycolic acid and lactate
(increased NADH and decreased conversion of lactate to pyruvate). Calcium oxalate
crystals form in tissues, including renal tubules, myocardium, muscles and brain.
Hypocalcaemia follows. Acute oliguric renal failure occurs secondary to the nephrotoxic
effects of both glycolic acid and calcium oxalate.
Toxicokinetics
Ethylene glycol is rapidly absorbed following ingestion. Peak concentrations occur within
1–4 hours. It is distributed across the total body water with rapid CNS penetration.
Ethylene glycol is metabolised sequentially by alcohol dehydrogenase (ADH) and aldehyde
dehydrogenase (ALDH) to glycoaldehyde and glycolic acid, which in turn is converted to
glyoxylic acid and oxalic acid (see Appendix 4: Alcohol pathways). In the absence of
ADH inhibition (ethanol or fomepizole) the elimination half-life of EG is 3 hours. Ethanol
in a serum concentration of 11–22 mmol/L (50–100 mg/dL) competitively inhibits ADH
preventing metabolism of EG to glycoaldehyde. Elimination half-life increases to 17 hours,
as EG has to be eliminated exclusively by the kidney.
CLINICAL FEATURES
l he clinical course of EG intoxication is often described as
T
occurring in three stages (CNS, cardiopulmonary and renal), but
these are artificial descriptions of a rapid clinical course
l Initial clinical features develop within the first 1–2 hours and are
similar to those of ethanol intoxication:
— Euphoria, nystagmus, drowsiness, nausea and vomiting
l Progressively severe features develop over the subsequent 4–12
hours
— Dyspnoea, tachypnoea, tachycardia, hypertension and
decreased conscious level progressing to shock, coma,
seizures and death
l Flank pain and oliguria indicate acute renal failure
l Late cranial neuropathies (involving cranial nerves II, V, VII, VIII, IX,
X and XII) are described up to 5–20 days later.
INVESTIGATIONS
SPECIFIC TOXINS

Specific investigations
l UC (including chloride), serum lactate, serum osmolality and
E
arterial blood gases
— Elevated osmolar gap, anion gap acidosis and
hyperlactataemia are surrogate markers of intoxication
— Venous bicarbonate concentration is a useful surrogate marker
134
of intoxication in the asymptomatic patient if ABGs are not
13
available
4
— Anion gap acidosis with elevated lactate (+/- elevated osmolar

TOXICOLOGY HANDBOOK
gap), associated with hypocalcaemia and rising creatinine is

pathognomonic of EG intoxication
— See Chapter 2.18: Osmolality and the osmolar gap and
Chapter 2.19: Acid–base disorders for discussion of
interpreting acid–base disturbances, anion and osmolar gaps
l Breath or serum ethanol level
— Required to determine whether there has been co-ingestion of
ethanol, or to titrate ethanol treatment
l Serum EG level
— Not readily available at most locations in a clinically useful
timeframe. Where available, it provides definitive confirmation
of EG intoxication
l Urine microscopy
— Presence of calcium oxalate crystals in the urine is
pathognomonic of ethylene intoxication but their absence does
not exclude the diagnosis.
MANAGEMENT

priorities are managed along conventional lines, as outlined in
l Patients with severe EG intoxication are acidaemic with a degree of
respiratory compensation:
— Intubation without maintaining hyperventilation exacerbates
acidaemia and may result in an acute decompensation, and
even death
— M aintain hyperventilation and consider bolus IV sodium
bicarbonate 1–2 mmol/kg to prevent worsening of acidaemia
pending haemodialysis
l Treat seizures with IV benzodiazepines as discussed in Chapter
2.6: Approach to seizures
l Detect and correct hypoglycaemia, hyperkalaemia and
hypomagnesaemia. Correct hypocalcaemia only if there are
refractory seizures or prolonged QT
l Monitor fluid balance and urine output
Decontamination
l Gastrointestinal decontamination is not indicated
SPECIFIC TOXINS
l Haemodialysis is the definitive management of EG intoxication.
During haemodialysis, the elimination half-life of EG is reduced to
2.5–3.5 hours, depending on flow rates
l Lactate-free dialysates with added bicarbonate may assist
correction of acidaemia
l Indications for haemodialysis:
— History of large EG ingestion with osmolar gap >10
— Acidaemia with pH <7.25 135
— Acute renal failure
— Ethylene glycol level >8 mmol/L (50 mg/dL) if available
l End points for haemodialysis:
TOXICOLOGY HANDBOOK

— Correction of acidosis
— Osmolar gap <10
— Ethylene glycol level <3.2 mmol/L (20 mg/dL) if available
l Acid–base status and electrolytes are repeated every 4 hours for
12 hours following cessation of haemodialysis to confirm that
further dialysis is not required
Antidotes
l Ethanol (see Chapter 4.8: Ethanol) and fomepizole (see Chapter
4.11 Fomepizole) are used in the treatment of suspected or
confirmed EG poisoning as temporising measures while awaiting
haemodialysis
l Note: Fomepizole is not currently available in Australasia.

l hildren who remain clinically well after suspected
C
unintentional ingestion and have a normal venous bicarbonate
level (≥20 mEq/L) at 4 or more hours post-ingestion, may be
discharged
l Adult patients who remain clinically well following accidental
ingestion and have a normal venous bicarbonate level (≥20 mEq/L)
4 hours after serum or breath ethanol level is demonstrated to be
undetectable, are fit for medical discharge
l All symptomatic patients, and those with deliberate ingestion,
are assumed to have potentially lethal EG intoxication, and
are admitted to hospital for further evaluation and definitive
management if required
l If established renal failure develops, ongoing dialysis may be
required for several weeks but renal function usually returns to
normal
l Patients who survive severe intoxication are followed up to exclude
the development of cranial neuropathies.
HANDY TIPS
l o-ingestion of ethanol delays the onset of clinical features of EG
C
intoxication
l Plan for transfer to a facility with haemodialysis as soon as the
provisional diagnosis of EG intoxication is made.
PITFALLS
SPECIFIC TOXINS
l bsence of symptoms does not exclude a significant ingestion

A
l Normal osmolar gap (<10) does not exclude significant intoxication
l False reliance on normal serum bicarbonate level to exclude
significant ingestion when ADH is blocked by ethanol.
Sources
Radiator coolants and antifreeze in concentrations 20–98%
De-icing solutions
Solvents
136 Brake fluids
13
6
References
Barceloux DG, Krenzelok EP, Olsen K et al. Ad Hoc Committee on the Treatment
TOXICOLOGY HANDBOOK
Guidelines for Ethylene Glycol Poisoning on behalf of the American Academy of

Clinical Toxicology. American Academy of Clinical Toxicology. Practice guidelines
on the treatment of ethylene glycol poisoning. Clinical Toxicology 1999; 37(5):
537–560.
Caravati EM, Erdman AR, Christianson G et al. Ethylene glycol exposure: an evidence
based consensus guideline for out-of-hospital management. Clinical Toxicology 2005;
43:327–345.
Jolliff HA, Dart RC, Bogdan GM et al. Can the diagnosis of ethylene glycol (EG) toxicity be
made without serum EG levels and osmolality values (abstract). Journal of Toxicology-
Clinical Toxicology 2000; 38(5):539–540.
3.3 ALCOHOL: ISOPROPANOL (isopropyl alcohol)

Isopropanol produces a CNS intoxication syndrome identical to that of
ethanol, but is more potent. It causes marked gastrointestinal irritation
and ketosis without directly causing acidosis. Management is supportive.
RISK ASSESSMENT
l Isopropanol causes dose-related CNS depression following
ingestion, although there is a high degree of inter-individual
variability
l As little as 1 mL/kg of a 70% solution causes symptoms of
inebriation and more than 4 mL/kg may cause coma and
respiratory depression
l Co-ingestion of other CNS depressants (e.g. sedative-hypnotic
agents, opioids) increases the risk of respiratory depression
hospital evaluation unless symptoms develop. Ingestions of >30
mL are associated with symptoms of CNS depression within
2 hours and warrant hospital evaluation. Significant toxicity is
reported from dermal absorption following application of ‘rubbing
alcohol’ to small children as an antipyretic measure.
Toxic mechanism
As with ethanol, the molecular sites of action of isopropanol are uncertain. Augmentation
of the GABAA receptor complex is thought to be central to effects. Production of acetone
and severe ketonaemia may contribute to CNS depression. Severe anion gap acidosis is
not a feature of isopropanol intoxication, as acetone is not further metabolised to any great
extent. Isopropanol is a gastrointestinal irritant and causes dose-dependent cardiovascular
depression.
SPECIFIC TOXINS
Toxicokinetics
Isopropanol is rapidly and well absorbed following ingestion, dermal contact or inhalation.
It distributes rapidly across the total body water with volume of distribution 0.6 L/kg. Forty
per cent of an absorbed dose is excreted unchanged by the lungs and kidneys. The rest
is metabolised by hepatic ADH to form acetone. Acetone is mostly excreted unchanged
via the lungs and, to a lesser extent, the kidney. The affinity of ADH for isopropanol is
much less than for ethanol and elimination of isopropanol is correspondingly slower
(elimination half-life up to 16 hours). Acetone frequently accumulates during isopropanol
intoxication.
137
CLINICAL FEATURES
l n intoxication syndrome identical to ethanol develops rapidly
A
TOXICOLOGY HANDBOOK
following ingestion.
l Loss of airway protective reflexes, respiratory depression and
hypotension accompany coma
l The duration of inebriation is longer than following ethanol
ingestion
l Ketosis may be indicated by the breath odour of acetone.
INVESTIGATIONS
l EUC (including Cl-), serum osmolality, serum acetone level, ABG
— Elevated osmolality and osmolar gap in the absence of
severe anion gap acidosis (as occurs with ethylene glycol and
methanol) suggests isopropanol intoxication
— Isopropanol levels are not routinely available and do not assist
management
— Serum acetone level is elevated
l Urinalysis for ketones.
MANAGEMENT
l Basic resuscitative measures ensure the survival of the vast
l eneral supportive care measures are indicated, as outlined in
G
l Give thiamine 100 mg IV or PO to patients with potential thiamine
deficiency
l Monitor for urinary retention and place an indwelling urinary
catheter if required
Decontamination
l Haemodialysis is highly effective at removing isopropanol but is
indicated only if there is profound coma and hypotension refractory
SPECIFIC TOXINS
to fluid resuscitation
Antidotes
l None available.

l atients with mild CNS depression are managed supportively and
P
discharged when clinically well
l Patients with significant CNS depression require intubation and
138 intensive care admission.
13
8
HANDY TIPS
TOXICOLOGY HANDBOOK
l Isopropanol intoxication mimics ethanol intoxication.
Sources
Isopropanol (50–70% concentration) is found in disinfectants, solvents, window cleaners
and perfumes.
References
Baselt R. Disposition of toxic chemicals and drugs in man (text), 5th edn. Foster City,
California: Chemical Toxicology Institute; 2000.
Stremski E, Hennes H. Accidental isopropanol ingestion in children. Pediatric Emergency
Care 2000; 16(4):238–240.
Zaman F, Pervez A, Abreu K. Isopropyl alcohol intoxication: a diagnostic challenge.
American Journal of Kidney Diseases 2002; 40(3):E12.
3.4 ALCOHOL: METHANOL (methyl alcohol)

Methanol is a toxic alcohol. Deliberate self-poisoning is usually lethal
without appropriate intervention.
RISK ASSESSMENT
l Ingestion of >0.5 mL/kg is potentially lethal
l Deliberate self-poisonings are assumed to be potentially lethal
l Ingestion of less than a mouthful is benign and does not require
hospital evaluation unless symptoms develop
l Co-ingestion of ethanol complicates risk assessment (see
Investigations below)
l ermal and inhalation exposure is unlikely to lead to methanol
D
intoxication
hospital evaluation unless symptoms develop. Ingestion of >
0.25 mL/kg (2.5 mL in a 10-kg toddler) can theoretically lead to
development of toxicity requiring specific management.
Toxic mechanism
Production and accumulation of formic acid produces a severe anion gap acidosis and
direct cellular toxicity due to inhibition of cytochrome oxidase. Retinal injury and oedema
leads to blindness. In the brain, subcortical white matter haemorrhages and putamenal
oedema classically occur. Late hyperlactataemia occurs due to inhibition of cellular
oxidative metabolism.
SPECIFIC TOXINS
Toxicokinetics
Methanol is rapidly absorbed after ingestion with peak levels occurring within 30–60
minutes. Dermal and inhalational absorption occur, but reports of intoxication are rare. It
is rapidly distributed across the total body water with a volume of distribution of 0.7 L/kg.
Methanol is metabolised in the liver by alcohol dehydrogenase (ADH) to formaldehyde,
which in turn is metabolised by aldehyde dehydrogenase (ALDH) to formic acid (see
Appendix 4: Alcohol pathways). The elimination half-life is 24 hours. Ethanol in a
serum concentration of 22 mmol/L (100 mg/dL; 0.1%) competitively inhibits ADH so that
methanol cannot be metabolised to formaldehyde. Methanol elimination half-life increases
to 43 hours, as methanol is eliminated exclusively by the kidney. 139
CLINICAL FEATURES
TOXICOLOGY HANDBOOK
l ild CNS depression similar to that of ethanol intoxication is
M
evident within 1 hour of ingestion. Nausea, vomiting and abdominal
pain may occur
l Following a latent period of 12–24 hours, symptoms of headache,
dizziness, vertigo, dyspnoea, blurred vision and photophobia develop
l Features of severe intoxication include tachypnoea, drowsiness,
and blindness
l Progressive obtundation leading to coma and seizures heralds
the onset of cerebral oedema. Papilloedema is characteristic with
progressive demyelination and up to one-third of patients suffer
irreversible visual complications
l Those who recover from serious CNS toxicity frequently display
extrapyramidal movement disorders.
INVESTIGATIONS
l EUC (including chloride), serum lactate, serum osmolality and
— Anion gap acidosis, hyperlactataemia and elevated osmolar
gap are surrogate markers of intoxication
— Venous bicarbonate concentration is a useful surrogate marker of
intoxication in the asymptomatic patient if ABGs are not available
l Serum methanol levels
— Not readily available in a clinically useful timeframe
l Radiology
— Brain CT scan demonstrates characteristic injury to the basal
ganglia in patients with permanent neurological sequelae.
MANAGEMENT
SPECIFIC TOXINS
l Patients with severe methanol intoxication are acidaemic with a

degree of respiratory compensation:
acidaemia and may result in an acute decompensation, or even
death
— Maintain hyperventilation and consider bolus IV sodium
140 — Systemic acidosis enhances formic acid inhibition of
cytochrome oxidase. If pH <7.30 administer bicarbonate in 50
14
mmol aliquots to raise the pH above this level

0
l Treat seizures with IV benzodiazepines, as discussed in Chapter

TOXICOLOGY HANDBOOK

l Cofactor therapy: Folinic acid is given at 2 mg/kg IV every 6 hours
and continued until poisoning is definitively treated (see Chapter
4.10: Folinic acid)
Decontamination
l Haemodialysis is the definitive management of methanol intoxication.
It removes methanol and formic acid and corrects acidosis
l Lactate-free dialysate with added bicarbonate may assist
correction of acidaemia.
l Indications for haemodialysis:
— Any patient who fulfils criteria for ADH blockade
— Acidaemia with pH <7.3
— Visual symptoms
— Renal failure
— Deterioration of vital signs or electrolyte status despite
supportive care
— Methanol level >16 mmol/L (50 mg/dL) if available
l End points for haemodialysis:
— Correction of acidosis
— Osmolar gap <10
— Methanol level <6 mmol/L (20 mg/dL) if available
l cid–base status and electrolytes are repeated every 4 hours for
A
12 hours following cessation of haemodialysis to confirm that
further dialysis is not required
Antidotes
4.11 Fomepizole) are used in the treatment of suspected or
confirmed methanol poisoning as temporising measures while
awaiting haemodialysis

l hildren who remain clinically well after suspected unintentional
C
ingestion, and have a normal venous bicarbonate level (≥20 mEq/L)
SPECIFIC TOXINS
at 8 or more hours post-ingestion, may be discharged
l All symptomatic patients, and those with deliberate ingestion,
are assumed to have potentially lethal methanol intoxication,
and are admitted to hospital for further evaluation and
management. 141
HANDY TIPS
l ‘Methylated spirits’ available in Australia do not contain methanol
TOXICOLOGY HANDBOOK

but up to 5% may be found in New Zealand products
l Co-ingestion of ethanol delays the onset of clinical features of
methanol intoxication
l Plan for transfer to a facility with haemodialysis as soon as the
provisional diagnosis of methanol intoxication is made
l Serum bicarbonate levels provide a surrogate marker of formic acid
production.
PITFALLS
l bsence of symptoms does not exclude a significant
A
ingestion
l Normal osmolar gap (<10) does not exclude significant
intoxication.
Sources
Chemical applications in industry and science
Solvent in thinners, varnishes, paints and enamels
Model aeroplane fuel
Fuel additive
Dyes and stains
Wood alcohol, wood spirits
References
Barceloux DG, Bond R, Krenzelok EP et al. American Academy of Clinical Toxicology
practice guidelines on the treatment of methanol poisoning. Journal of Toxicology-
Kostic MA, Dart RC. Rethinking the toxic methanol level. Journal of Toxicology-Clinical
Toxicology 2003; 41(6):793–800.
3.5 ALCOHOL: OTHER TOXIC ALCOHOLS
Benzyl alcohol, Diethylene glycol, Dipropylene glycol, Ethylene glycol
monobutyl ether (EGBE), Ethylene glycol monoethyl ether (EGME),
Propylene glycol, Triethylene glycol
These alcohols are found in a variety of automotive products, solvents and
pharmaceuticals. Deliberate self-poisoning is potentially lethal.
RISK ASSESSMENT
l ccidental oral ingestions do not cause significant toxicity
A
l Deliberate self-poisonings are assumed to be potentially lethal
SPECIFIC TOXINS
l Ingestion of >1 mL/kg of 100% diethylene glycol is potentially

lethal
l Ingestion of >0.5 mL/kg of glycol ether (EGBE or EGME) is
potentially lethal
l The toxic effects of propylene glycol are a function of dose and
rate of administration
l Dermal and inhalation exposures do not lead to intoxication

142 hospital evaluation unless symptoms develop.
14
2
Toxic mechanism
These alcohols cause CNS effects similar to those of ethanol. More significant toxicity
TOXICOLOGY HANDBOOK
is a consequence of accumulation of metabolites, including lactate. Diethylene glycol

metabolism also indirectly leads to lactic acidosis. The cardiovascular and CNS effects of
propylene glycol appear to be a direct toxic action.
Toxicokinetics
These alcohols are rapidly absorbed following ingestion and peak levels occur within
1 hour. They are distributed across total body water with volumes of distribution of 0.6
L/kg. They are metabolised sequentially by hepatic alcohol dehydrogenase (ADH) to
pyruvate and lactate (propylene glycol), and aldehyde dehydrogenase (ALDH) to various
alkoxyacetic acid products.
CLINICAL FEATURES
l Initial clinical features develop within the first 1–2 hours and are
similar to those of ethanol intoxication: euphoria, nystagmus,
drowsiness, nausea and vomiting
l Progressively severe features develop over subsequent hours as
metabolism progresses and lactic acidosis worsens
l Severe effects include coma, seizures, refractory shock and renal
failure
l Onset of severe toxicity may be delayed up to 48 hours following
ingestion of glycol ethers (EGBE, EGME)
l Over-rapid intravenous administration of excessive propylene glycol
(administration of large quantities of drug with propylene glycol as a
diluent) is associated with sudden cardiovascular collapse.
INVESTIGATIONS
l EUC (including chloride), serum lactate, serum osmolality and
— Anion gap acidosis, hyperlactataemia and elevated osmolar
gap are surrogate markers of intoxication
— Venous bicarbonate concentration is a useful surrogate marker
of intoxication if ABGs are not available
l Serum toxic alcohol levels
SPECIFIC TOXINS

— Not readily available in a clinically useful timeframe.
MANAGEMENT
l Patients with severe toxic alcohol poisoning are acidaemic with a
degree of respiratory compensation: 143
acidaemia and may result in an acute decompensation, or even
death
TOXICOLOGY HANDBOOK
— Maintain hyperventilation and consider bolus IV sodium
l Treat seizures with IV benzodiazepines, as discussed in Chapter
l Severe acidaemia with pH <7.0 is corrected with IV sodium
bicarbonate pending haemodialysis
Decontamination
Haemodialysis is highly effective at removing toxic alcohols and the
resultant acids. Indications include:
l Serum pH <7.3
l Serum bicarbonate <20 mEq/L
l Osmolar gap >10
l Worsening severe lactic acidosis despite supportive care
l Deteriorating vital signs despite supportive care
Antidotes
4.11 Fomepizole) are used in the treatment of glycol ether (EGBE,
EGME) poisoning prior to definitive treatment with haemodialysis in
the same way as they are for ethylene glycol poisoning
l he role of these antidotes in other toxic alcohol poisoning is not
T
established

l hildren who remain clinically well after suspected unintentional
C
at 8 or more hours post-ingestion, may be discharged
l All symptomatic patients, and those with deliberate ingestion, are
SPECIFIC TOXINS
assumed to have potentially lethal intoxication and are admitted to

hospital for further evaluation and management.
HANDY TIPS
l erum bicarbonate and arterial pH are the chief surrogate markers
S
of toxic acid production.
PITFALLS
144 l bsence of symptoms does not exclude a significant ingestion
A
l Normal osmolar gap (<10) does not exclude significant intoxication
14
l Failure to recognise the potential for delay in development of

4

toxicity in glycol ether and diethylene glycol ingestions.
TOXICOLOGY HANDBOOK
CONTROVERSIES
l he efficacy of and indications for haemodialysis and antidote
T
therapy in the management of these toxic alcohols is not well defined.
Sources
Diethylene glycol: hydraulic fluids, solvents
Glycol ethers (ethylene glycol monoethyl ether EGME, ethylene glycol monobutyl ether
EGBE): brake fluids, cleaning products, many solvents
Propylene glycol: solvents, many parenteral drug formulations
Benzyl alcohol: bacteriostatic agent frequently found in parenteral drug formulations
References
Megarbane B, Borron SW, Baud FJ. Current recommendations for treatment of severe
toxic alcohol poisonings. Intensive Care Medicine 2005; 31:189–195.
Schep LJ, Slaughter RJ, Temple WA et al. Diethylene glycol poisoning. Clinical Toxicology
2009; 47(6):525–535.
3.6 AMIODARONE
Acute ingestion uncommonly produces toxicity, irrespective of the dose.
Chronic toxicity is common.
RISK ASSESSMENT
l cute oral overdose is usually benign, regardless of the dose
A
ingested
l elayed cardiac effects, including hypotension, atrial flutter and T
D
wave inversion, have been reported. The clinical features associated
with chronic toxicity are not observed following acute overdose
l There are no reported fatalities from acute oral overdose
l Chronic toxicity is common and clinical manifestations include:
— Pulmonary toxicity
— Cardiovascular effects (bradycardia, AV blocks, torsades de
pointes, hypotension and negative inotropy)
— Thyroid dysfunction (hypo-/hyperthyroidism)
— Hepatic toxicity
— Corneal micro-deposits
l Children: Ingestion of one or two tablets does not cause

symptoms and does not require hospital assessment.
SPECIFIC TOXINS
Toxic mechanism
In addition to its predominant Vaughan-Williams class III effects, amiodarone also has
class I, II and IV properties. Its principal class III effects are secondary to blockade of
potassium channels, which prolong phase 4 of the cardiac action potential and the
refractory period of atrial and ventricular tissue.
Toxicokinetics
Oral bioavailability is variable but generally poor. Almost completely protein bound, it has
a large volume of distribution (65 L/kg). Amiodarone undergoes first-pass metabolism by 145
cytochrome p450 to produce an active metabolite, desethylamiodarone. Elimination is
predominantly biliary and very slow: up to 80 hours following acute ingestions and up to
100 days for chronic therapy (similar slow elimination for the active metabolite).
TOXICOLOGY HANDBOOK
CLINICAL FEATURES
Patients are usually asymptomatic, but delayed onset (more than 24
hours) of bradycardia, hypotension and self-limiting atrial and ventricular
tachyarrhythmias has been reported.
INVESTIGATIONS
l Serial ECGs for 24 hours.
MANAGEMENT
l Resuscitation is rarely required and management is entirely supportive
l Cardiovascular effects can be delayed. Cardiac monitoring for 24
hours is recommended
l Bradycardia can be resistant to atropine and may require
adrenaline, isoprenaline or pacing
l Hypotension responds to vasopressors
Decontamination
l Consider single-dose activated charcoal if presentation is within 2
hours
l Not clinically useful
Antidotes
l None available.

l dmit for 24 hours of cardiac monitoring. Patients may be
A
medically cleared if asymptomatic and have a normal ECG at the
end of that time.
CONTROVERSIES
l uration of monitoring of an asymptomatic patient. The risk
D
of significant cardiac toxicity is low but could theoretically be
markedly delayed in onset.
SPECIFIC TOXINS
Presentations
Amiodarone hydrochloride 100 mg tablets (30)
Amiodarone hydrochloride 200 mg tablets (30)
Amiodarone hydrochloride 150 mg/3 mL ampoules
Reference
Leatham EW, Holt DW, McKenna WJ. Class III antiarrhythmics in overdose: Presenting
features and management principles. Drug Safety 1993; 9(6):450–462.
146
3.7 AMISULPRIDE
14
6
TOXICOLOGY HANDBOOK
Amisulpride overdose is associated with QT prolongation and torsades de

pointes. Ingestions of >4 g should be monitored for at least 16 hours and
until all ECG intervals are normal.
RISK ASSESSMENT
l he risk assessment for amisulpride is still being refined
T
l Small overdoses (<8 g) are generally benign but prolonged QT and
torsades de pointes have been documented following ingestion of
as little as 4.6 g
l Larger ingestions (>8 g) pose an increasing risk of:
— Bundle branch blocks
— QT prolongation
— Ventricular arrhythmias, including torsades de pointes
— Hypotension
— Coma
l Children: All suspected ingestions require assessment in hospital.
Toxic mechanism
Amisulpride is an atypical antipsychotic (benzamide derivative). It acts as a dopamine
antagonist (binds to D2 and D3 receptors) with minimal affinity for serotonin, histamine and
muscarinic receptors.
Toxicokinetics
Amisulpride has an oral bioavailability of about 50% with two absorption peaks, one
at 1 hour and the other at 4 hours. Peak serum concentrations may occur later than
this in overdose. It has a moderately large volume of distribution (5.8 L/kg) and limited
metabolism to inactive metabolites. Most drug is excreted unchanged via faecal and renal
routes, with an elimination half-life of about 12 hours following therapeutic doses.
TABLE 3.7.1 Dose-related risk assessment: Amisulpride
<8 g Mild–moderate sedation and mild anticholinergic features

QT prolongation and torsades de pointes have been reported
in this dose range
8–15 g Increasing sedation and risk of delayed depressed level of

consciousness
Cardiotoxicity including hypotension, QRS and QT prolongation,
bundle branch blocks and torsades de pointes
>15 g Significant risk of delayed coma and cardiotoxicity, including

hypotension, QRS and QT prolongation, bundle branch
blocks and torsades de pointes
SPECIFIC TOXINS
CLINICAL FEATURES
Large ingestions may appear mildly symptomatic for some hours,
although QRS and QT prolongation are usually evident on early 12-lead
ECGs. Onset of coma, hypotension, bundle branch blocks and torsades
de pointes may occur abruptly up to 12 hours following ingestion.
147
INVESTIGATIONS
TOXICOLOGY HANDBOOK
l Serial ECGs
— The key investigation is the ECG. Any prolongation of the
QRS or QT is significant and mandates continuous cardiac
monitoring until normalisation (see Chapter 2.20: The 12-lead
ECG in toxicology for a discussion of QT prolongation and risk
of torsades de pointes)
l EUC
— Check for abnormalities in Ca2+, K+ and Mg2+ concentrations if
ECG abnormalities are detected.
MANAGEMENT
l Amisulpride overdose is a life-threatening emergency and
managed in an area equipped for cardiorespiratory monitoring and
resuscitation
l Clinical features that require immediate intervention include:
— Cardiac dysrhythmias, including torsades de pointes
— Coma
l The patient who presents with established severe toxicity may
require intubation, ventilation and control of torsades de pointes
with magnesium and chemical or electrical pacing
l Continuous cardiac and haemodynamic monitoring with serial 12-
lead ECGs for a minimum of 16 hours is mandated if the ingested
dose exceeds 4 g
l Continue monitoring until the patient is asymptomatic and the ECG
has normalised
Decontamination
l Oral activated charcoal is appropriate following ingestion of >4 g
within the previous 4 hours
Antidote
l None available.

l atients who ingest <4 g and have a normal 12-lead ECG do not
P
require further observation or monitoring
l Patients who ingest >4 g and remain asymptomatic and have
SPECIFIC TOXINS
a normal ECG at 16 hours do not require further observation or

monitoring
l Symptoms or QT prolongation mandate continued cardiac
monitoring until these abnormalities resolve. Large overdoses
require intensive care admission for advanced supportive care.
HANDY TIPS
l ollowing large ingestions patients may demonstrate only mild
F
symptoms for many hours prior to sudden deterioration
148 l ECG should demonstrate normal QT prior to discontinuing
14
monitoring.
8
TOXICOLOGY HANDBOOK
PITFALLS
l Failure to closely examine the ECG intervals.
CONTROVERSIES
l The threshold dose for risk of QT prolongation.
Presentations
Amisulpride 100 mg tablets (30)
Reference
Isbister GK, Murray L, John S et al. Amisulpride deliberate self poisoning causing severe
cardiac toxicity including QT prolongation and torsades de pointes. Medical Journal
of Australia 2006; 184:354–356.
3.8 AMPHETAMINES
Dexamphetamine, Methamphetamine, Methylphenidate,
3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxy-
methamphetamine (MDMA, ecstasy)
See also Chapter 2.13: Amphetamine abuse, dependence and withdrawal
Amphetamines produce central and peripheral sympathomimetic effects.
Lethal complications include severe hyperthermia, acute coronary
syndrome, cardiac dysrhythmias, aortic dissection and intracranial
haemorrhage. Repeated use leads to long-term neuropsychiatric
sequelae. Supportive care and benzodiazepines are crucial to
management.
RISK ASSESSMENT
l mall doses, particularly in non-tolerant patients, may result in
S
significant intoxication
l The presence of hyperthermia, headache, focal neurological signs
or chest pain herald potentially life-threatening complications and
warrant aggressive management and investigation
l Seizures occur in up to 4% of amphetamine emergency
presentations
l Children: One illicit amphetamine-derivative pill may lead to life-
threatening sympathomimetic toxicity.
SPECIFIC TOXINS
Toxic mechanism
Amphetamine is structurally related to ephedrine. Substitutions on the basic amphetamine
structure yield numerous derivatives with varying receptor affinities. Amphetamines
enhance catecholamine release and block their reuptake. Inhibition of monoamine
oxidase also occurs. CNS and peripheral noradrenergic, dopaminergic and serotonergic
stimulation occurs. Long-term CNS effects occur due to neurotransmitter and receptor
adaptation, as well as permanent destruction of dopaminergic neuro-pathways. MDMA at
standard recreational doses sometimes induces the syndrome of inappropriate antidiuretic
hormone secretion (SIADH), leading to profound hyponatraemia, coma and convulsions. 149
Toxicokinetics
The amphetamines are well absorbed following ingestion and insufflation. They are lipid-
TOXICOLOGY HANDBOOK
soluble weak bases and have large volumes of distribution (methamphetamine 3.5 L/kg).
Most amphetamines undergo hepatic metabolism to form metabolites that are excreted in
the urine. Elimination half-life varies from 8–30 hours.
CLINICAL FEATURES
Patients may present with symptoms of acute intoxication, medical
complications of abuse or psychiatric sequelae. The most frequent
presentation is agitation with sweating, tachycardia and hypertension.
Acute clinical features may persist for 24 hours and include:
l Central nervous system
— Euphoria
— Anxiety, dysphoria, agitation and aggression
— Paranoid psychosis with visual and tactile hallucinations
— Hyperthermia, rigidity and myoclonic movements
— Seizures
l Cardiovascular
— Tachycardia and hypertension
— Dysrhythmias
— Acute coronary syndrome
— Acute cardiomyopathy
— Acute pulmonary oedema
— Haemoptysis
l Peripheral sympathomimetic
— Mydriasis, sweating and tremor
l Clinical features associated with medical complications
— Rhabdomyolysis, dehydration and renal failure
— Hyponatraemia and cerebral oedema following MDMA ingestion,
due to temporary SIADH and increased water ingestion
— Aortic and carotid artery dissection
— Subarachnoid and intracerebral haemorrhage
— Ischaemic colitis
l Note: Psychotic symptoms such as paranoid ideation may
accompany acute intoxication and persist as part of a post-
amphetamine psychosis when other features of acute intoxication
have resolved.
INVESTIGATIONS
l EUC
SPECIFIC TOXINS
— Detect hyponatraemia and renal failure

l ECG, CK and troponin
— Detect myocardial ischaemia, acute coronary syndrome and
rhabdomyolysis
l Chest x-ray
— Detect aortic dissection and aspiration
l Decreased mental status or focal neurological signs prompts
exclusion of hyponatraemia, hypoglycaemia, aortic dissection or
150 intracranial haemorrhage
l Note: Serum or urine amphetamine levels are not readily available
15
and do not assist acute management.

0
TOXICOLOGY HANDBOOK
MANAGEMENT
l Amphetamine intoxication is a potentially life-threatening
emergency and patients should be managed in an area capable of
cardiorespiratory monitoring and resuscitation
— Hypertension
— Seizures and agitated delirium
— Hyperthermia
— Hyponatraemia (MDMA)
l Treat tachycardia and hypertension with titrated parenteral
benzodiazepines. If hypertension is refractory to benzodiazepine
sedation consider:
— Phentolamine 1 mg IV repeated every 5 minutes
— Titrated vasodilator infusion (sodium nitroprusside, glyceryl
trinitrate)
— Note: Beta-adrenergic blockers are contraindicated (see Handy
tips)
l Seizures are managed with IV diazepam (see Chapter 2.6:
Approach to seizures)
l Agitation is managed with titrated diazepam. Oral diazepam may
be considered in mild cases (10–20 mg diazepam PO with further
doses of 10 mg every 20 minutes until agitation controlled) but IV
diazepam should be instituted early where agitation is moderate or
severe. Give diazepam 2.5–5 mg IV. Further doses of 10–20 mg IV
every 5–10 minutes to a maximum dose of 60 mg may be required
(See Chapter 2.7: Delirium and agitation). Second-line drugs in
resistant cases include droperidol 2.5 mg IV or olanzapine 10 mg IM.
l yperthermia:
H
Temperature >38.5°C is an indication for continuous core-
temperature monitoring, benzodiazepine sedation and fluid
resuscitation
Temperature >39.5°C requires rapid external cooling to prevent
multiple organ failure and neurological injury. Paralysis, intubation
and ventilation may be required
l Hyponatraemia:
Immediate correction with hypertonic saline is indicated if profound
(serum Na+ <120 mmol/L) and associated with altered mental
status or seizures. Give hypertonic saline (3% sodium chloride)
4 mL/kg over 30 minutes and repeat serum sodium. Further
doses should be given to achieve a serum Na+ >120 mmol/L
until resolution of SIADH manifests by diuresis and spontaneous
SPECIFIC TOXINS
correction of hyponatraemia (this usually occurs within 24 hours)
Decontamination
l Amphetamines are rapidly absorbed and associated with an
increased risk of seizures and delirium; therefore, activated
charcoal is not advised
151
Antidotes
l None available.
TOXICOLOGY HANDBOOK
l hildren with potential ingestions should be observed in hospital
C
for 4 hours. If they do not develop symptoms during that period
they may then be safely discharged
l Patients whose intoxication is adequately controlled with
benzodiazepine sedation and have a normal blood pressure and
12-lead ECG may be managed supportively in a ward environment.
They may be discharged when clinically well
l Patients with significant alteration of conscious state, hyperthermia
or ongoing chest pain are admitted to a high-dependency or
intensive care unit.
HANDY TIPS
l arly control of agitation with adequate doses of IV
E
benzodiazepines calms the patient and improves tachycardia,
hypertension and hyperthermia
l Ongoing chest pain or headache requires further investigation
l Acute coronary syndrome is managed according to normal
protocols. CT brain should be performed prior to anticoagulation or
angiography if headache is a feature
l Administration of beta-adrenergic blockers is contraindicated in
the acute management of amphetamine intoxication as it leads to
unopposed alpha stimulation and vasoconstriction.
PITFALLS
l ailure to adequately sedate the agitated patient
F
l Failure to recognise and treat hyperthermia
l ailure to detect and treat hyponatraemia in a patient presenting
F
with altered mental status or seizures following MDMA use—
permanent neurological injury can result.
CONTROVERSIES
l he role of antipsychotics in acute amphetamine intoxication. They
T
are frequently effective in the treatment of persistent psychosis but
have theoretical drawbacks in acute intoxication: anticholinergic
side effects and lowered seizure threshold.
Presentations
Prescription medications: Illicit amphetamine-derivative pills:
Dexamphetamine 5 mg tablets (100) Methamphetamine: Ice, Speed
SPECIFIC TOXINS
Methylphenidate 10 mg tablets (100) 3,4-methylenedioxymethamphetamine

Methylphenidate 20 mg capsules (30) (MDMA): Ecstasy, XTC
Methylphenidate 30 mg capsules (30) 3,4-methylenedioxyamphetamine
Methylphenidate 40 mg capsules (30) (MDA): Love drug
Methylphenidate 18 mg extended-
release tablets (30)
152 Methylphenidate 54 mg extended-
15
2
References
TOXICOLOGY HANDBOOK
Gray SD, Fatovich DM, McCoubrie DL et al. Amphetamine related presentations to an

inner city tertiary emergency department: a prospective evaluation. Medical Journal of
Australia 2007; 186(7):336–339.
Jenner L, Spain D, Whyte I et al. Management of patients with psychostimulant
toxicity: guidelines for emergency departments. Canberra: Australian Government
Department of Health and Ageing; May 2006. Available online at: http://www.health.
gov.au/internet/drugstrategy/publishing.nsf/Content/publications-psychostimulant-
emergency
3.9 ANGIOTENSIN CONVERTING ENZYME INHIBITORS

Captopril, Enalapril, Fosinopril, Lisinopril, Perindopril, Quinapril, Ramipril,
Trandolapril
Overdose with angiotensin converting enzyme (ACE) inhibitors is relatively
benign. The principal toxic effect is mild to moderate hypotension usually
responsive to fluid therapy alone.
RISK ASSESSMENT
l verdose with these agents is generally benign, irrespective of the
O
dose ingested
l Mild hypotension can occur. It is usually apparent within 2 hours
of ingestion, may last several hours and is easily managed with
intravenous fluid administration
l Children: Ingestion of up to two times the defined daily dose
(DDD) for adults does not produce symptoms and does not require
hospital evaluation.
Toxic mechanism
Angiotensin converting enzyme inhibitors bind to and inactivate angiotensin converting
enzyme (ACE) in a reversible manner. This prevents conversion of angiotensin I to
angiotensin II, a powerful vasopressor. Angiotensin II also has a number of endocrine
effects and its inhibition leads to a reduction in circulating aldosterone, which can lead to
hyperkalaemia.
Toxicokinetics
These agents are all rapidly and well absorbed orally with peak levels occurring within
1–2 hours. Many agents are pro-drugs and require hepatic conversion to become active.
Elimination is renal.
CLINICAL FEATURES
Patients are usually asymptomatic. The principal clinical feature is mild
SPECIFIC TOXINS
hypotension. If this occurs, it will manifest within 2 hours of the ingestion and
may last several hours. The duration of hypotension will relate to both the
preparation and the dose ingested.
INVESTIGATIONS
Specific investigations as indicated 153
l EUC
— Mild hyperkalaemia and renal impairment may be observed.
TOXICOLOGY HANDBOOK
MANAGEMENT
l Resuscitation is rarely required and management is entirely
supportive
l Patients presenting with significant hypotension usually respond
to a fluid bolus of 10–20 mL/kg of intravenous crystalloid
solution
l Ongoing fluid administration may sometimes be necessary
l Standard observations are sufficient
Decontamination
l Oral activated charcoal may be given to the patient who presents
within 1 hour of ingestion but is unlikely to significantly alter the
clinical course
Antidotes
l None available.

l he patient who remains asymptomatic with normal blood pressure
T
at 4 hours following ingestion does not require further medical care
or observation
l The symptomatic or hypotensive patient is admitted to a non-
monitored bed for ongoing supportive care until clinical features of
poisoning resolve.
CONTROVERSIES
l oth naloxone and angiotensin have been advocated as antidotes
B
for hypotension following ACE inhibitor overdose. A trial of these
agents does not appear justified given the benign and reversible
nature of the hypotension.
Presentations Perindopril erubumine 4 mg tablets (30)

Captopril 12.5 mg tablets (90) Perindopril erubumine 8 mg tablets (30)
Captopril 25 mg tablets (90) Perindopril erubumine 4 mg/indapamide
Captopril 50 mg tablets (90) hemihydrate 1.25 mg tablets (30)
Enalapril maleate 5 mg tablets (30) Quinapril hydrochloride 5 mg tablets (30)
Enalapril maleate 20 mg/ Ramipril 1.25 mg tablets (30)
SPECIFIC TOXINS
hydrochlorothiazide 6 mg (30) Ramipril 2.5 mg tablets (30)

Fosinopril sodium 10 mg tablets (30) Ramipril 5 mg tablets (30)
Fosinopril sodium 20 mg tablets (30) Ramipril 10 mg tablets (30)
Fosinopril sodium 10 mg/ Trandolapril 0.5 mg tablets (28)
hydrochlorothiazide 12.5 mg tablets (30) Trandolapril 1 mg tablets (28)
Fosinopril sodium 20 mg/ Trandolapril 2 mg tablets (28)
hydrochlorothiazide 12.5 mg tablets (30) Trandolapril 4 mg tablets (28)
Lisinopril dihydrate 5 mg tablets (30) Trandolapril 2 mg/verapamil hydrochloride
Lisinopril dihydrate 10 mg tablets (30) 180 mg sustained-release tablets (28)
Lisinopril dihydrate 20 mg tablets (30) Trandolapril 4 mg/verapamil hydrochloride
154 Perindopril erubumine 2 mg tablets (30) 240 mg sustained-release tablets (28)
15
4
References
TOXICOLOGY HANDBOOK
Balit CR, Gilmore SP, Isbister GK. Unintentional paediatric ingestions of angiotensin
converting enzyme inhibitors and angiotensin II receptor antagonists. Journal of
Paediatrics and Child Health 2007; 43(10):686–668.
Christie GA, Lucas C, Bateman DN et al. Redefining the ACE-inhibitor dose-response
relationship: substantial blood pressure lowering after massive doses. European
Journal of Clinical Pharmacology 2006; 62(12):989–993.
Varughese A, Taylor AA, Nelson EB. Consequences of angiotensin-converting enzyme
inhibitor overdose. American Journal of Hypertension 1989; 2:355–357.
3.10 ANTICOAGULANT RODENTICIDES

Brodifacoum, Bromadiolone, Chlorphacinone, Difenacoum, Diphacinone,
Flocoumafen
Long-acting anticoagulant rodenticides or ‘superwarfarins’ were
developed to counter rodent resistance to warfarin. Single unintentional
paediatric ingestions are non-toxic. In contrast, massive or repeated
dosing leads to profound and prolonged (weeks to months)
anticoagulation. Warfarin is discussed in Chapter 3.78: Warfarin.
RISK ASSESSMENT
l ingle accidental ingestion does not cause significant anticoagulation
S
l Massive single ingestion of >0.1 mg/kg of brodifacoum will cause
anticoagulation but this equates to 2 g/kg of 0.005% bait or 3 x
50-g pellet packs in a 75-kg adult
l Anticoagulation is usually associated with repeated ingestion. In
this scenario, severe, prolonged (weeks to months) anticoagulation
requiring massive doses of vitamin K is anticipated
l Children: It is estimated that a young child needs to ingest >30 g
of a 0.005% preparation as a single dose to cause significant
anticoagulation. This has never been reported.
Toxic mechanism
These agents inhibit hepatic vitamin K-dependent production of clotting factors II, VII,
IX and X in the same way as warfarin. Several mechanisms confer increased potency
and prolonged duration of action: greater affinity for vitamin K1-2,3-epoxide reductase,
disruption of vitamin K cycle at several sites and hepatic accumulation. These agents have
prolonged elimination half-lives.
Toxicokinetics
These agents are completely absorbed following oral administration. They are highly
lipid soluble and have large volumes of distribution. They are concentrated in the liver.
SPECIFIC TOXINS
Superwarfarins undergo hepatic metabolism and enterohepatic recirculation and have very
prolonged elimination phases of weeks to months.
CLINICAL FEATURES
l atients are usually asymptomatic
P
l Severe coagulopathy manifests as bruising, petechial or purpural
rashes, gingival bleeding, epistaxis or haematuria
l Following acute single ingestions, coagulopathy may not be
evident for 12 hours, and is frequently delayed 24–48 hours. Peak 155
effects occur at 72–96 hours.
INVESTIGATIONS
TOXICOLOGY HANDBOOK
l INR
— In patients who are not anticoagulated, INR will be normal
during the first 6–12 hours after deliberate overdose. Following
massive overdose, perform serial INRs every 12 hours for
48 hours to rule out toxicity. Vitamin K must be withheld
until anticoagulation is documented. Normal INR at 48 hours
excludes toxic ingestion
— Following repeated ingestion over several days, INR is
abnormal at presentation. Vitamin K therapy may commence
immediately. Outpatient INR estimations are required to
monitor therapy
l Superwarfarin levels
— Useful in cases where paediatric non-accidental injury or occult
poisoning is suspected.
MANAGEMENT
l In patients with evidence of haemorrhage, attention to airway,
breathing and circulation are paramount. These priorities can
usually be managed along conventional lines, as outlined in
Chapter 1.2: Resuscitation.
l If there is active uncontrolled haemorrhage, administer fresh frozen
plasma (10–15 mL/kg), Prothrombinex-HT (25–50 IU/kg) and
vitamin K 10 mg IV
G
Chapter 1.4: Supportive care and monitoring.
Decontamination
l Activated charcoal is not indicated following accidental ingestions
l Following massive single acute deliberate self-poisoning,
administer 50 g activated charcoal to cooperative patients who are
able to drink it themselves and present within 12 hours of ingestion
Antidotes
l Vitamin K is indicated where there is documented anticoagulation
from repeated deliberate ingestion or following acute deliberate
SPECIFIC TOXINS
self-poisoning. Prophylactic vitamin K is contraindicated. In

patients with proven anticoagulation, vitamin K is titrated to
achieve safe INR levels (<4). Very large daily doses of oral Vitamin
K are required for weeks or months. Initial daily dose is variable
and determined under close medical supervision with repeated INR
estimations. See antidote Chapter 4.29: Vitamin K for details.

156 l inor unintentional ingestions by adults or children do not require
M
hospital observation or investigation
15
6
l Referral for an INR is indicated where there is suspicion of

repeated ingestion or abnormal bleeding. A normal INR 48 hours
TOXICOLOGY HANDBOOK
after the last ingestion excludes toxicity

l Following massive single ingestions, INR is monitored for 48 hours.
A normal INR at 48 hours excludes toxicity and the patient does
not require further medical monitoring
l Established anticoagulation requires hospital admission for
stabilisation on high dose oral vitamin K. Prolonged supervision of
INRs and compliance with vitamin K therapy is essential and arranged
prior to discharge in consultation with mental health services
PITFALLS
l mpiric vitamin K therapy following an acute ingestion masks
E
subsequent toxicity, delays diagnosis and prolongs the need for
medical supervision.
Presentations
Pellets, wax blocks, paste and liquid concentrate. Often coloured blue, green or red and
may contain a bittering agent
Typical concentration is 0.005% (5 mg/100 g)
Pellet packs are typically 50 g (i.e. contain 2.5 mg brodifacoum)
Concentrates may be up to 0.25% (250 mg/100 g).
References
Ingels M. Lai C, Tai, W et al. A prospective study of acute, unintentional, pediatric
superwarfarin ingestions managed without decontamination. Annals of Emergency
Medicine 2002; 40(1):73–78.
Shepherd G. Klein-Schwartz W, Anderson BD. Acute unintentional pediatric brodifacoum
ingestions. Pediatric Emergency Care 2002; 18(3):174–178.
Watt BE, Proudfoot AT, Bradberry SM et al. Anticoagulant rodenticides. Toxicological
Reviews 2005; 24(4):259–269.
3.11 ANTICONVULSANTS: NEWER AGENTS
Gabapentin, Lamotrigine, Levetiracetam, Oxcarbazepine, Pregabalin,
Tiagabine, Topiramate, Vigabatrin
The newer anticonvulsants are generally much less toxic in overdose
than the older agents – phenobarbitone (see Chapter 3.17: Barbiturates),
carbamazepine (see Chapter 3.24: Carbamazepine), phenytoin (see Chapter
3.63: Phenytoin) and valproic acid (see Chapter 3.76: Valproic acid (sodium
valproate)). Sedation and non-specific neurological symptoms may occur.
Treatment is supportive and a favourable outcome can be anticipated.
SPECIFIC TOXINS
RISK ASSESSMENT
l Most overdoses with these agents produce no symptoms or mild
transient CNS symptoms only
l Symptoms usually appear within 2 hours and resolve with 24 hours
l Coma and seizures are rare
l Children: Unintentional paediatric ingestion is benign and referral

to hospital is only indicated if symptoms develop.
Toxic mechanism 157

Most of these agents exert an anticonvulsant effect by potentiating gamma-amino
butyric acid (GABA) neurotransmission—either by enhancing GABA release or inhibiting
GABA re-uptake at the synapse. Lamotrigine and topiramate also have effects on
TOXICOLOGY HANDBOOK
voltage-dependent Na+ channels and topiramate inhibits carbonic anhydrase. Pregabalin
decreases release of excitatory neurotransmitters, especially glutamate, by blockade of
calcium channels.
Toxicokinetics
All agents are well absorbed orally, with linear kinetics. Most undergo hepatic metabolism
to inactive metabolites, and are excreted renally. Levetiracetam, pregabalin and topiramate
are primarily excreted unchanged in the urine. Absorption of gabapentin from the GI tract
is saturable at higher doses and this may act to limit toxicity following overdose.
CLINICAL FEATURES
l Gabapentin overdose
— Nausea, vomiting, tachycardia, hypotension, drowsiness
— These clinical features, if present at all, are mild and resolve
with 10 hours
l Lamotrigine overdose
— Ataxia, nystagmus, slurred speech, drowsiness, transient
intraventricular conduction delay (rare) and seizures (rare)
— Clinical features are of rapid onset and resolve within 24–48
hours
l Levetiracetam overdose
— Agitation, depressed level of consciousness, coma, respiratory
depression
l Oxcarbazepine overdose
— Sedation, usually mild even after massive overdose
l Pregabalin overdose
— Drowsiness only
l Tiagabine overdose
— Sedation, coma, respiratory depression and seizures
l Topiramate overdose
— Ataxia, sedation, coma, seizures, hypotension and metabolic
acidosis
— The CNS effects are of rapid onset, usually within hours, and
resolve within 24 hours
— Non-anion gap metabolic acidosis is secondary to carbonic
anhydrase inhibition and may persist for up to 7 days. It is of
little clinical significance
l Vigabatrin overdose
— Drowsiness and delirium.
INVESTIGATIONS
SPECIFIC TOXINS

l EUC, acid–base status for topiramate
l Specific drug levels are neither readily available nor clinically
useful.
MANAGEMENT
158
15

8

TOXICOLOGY HANDBOOK
— Coma: intubation and ventilation are indicated

— Respiratory depression: intubation and ventilation are indicated
— Seizures: control with titrated doses of benzodiazepines as
described in Chapter 2.6: Approach to seizures
Decontamination
l In view of the relatively minor toxicity associated with most of these
agents, and their rapid absorption from the gastrointestinal tract,
routine gastrointestinal decontamination is not indicated
l A dose of activated charcoal 50 g (1 g/kg in children) may be given
via a nasogastric tube to the patient with coma or seizures after the
airway is secured with endotracheal intubation
l Notclinically useful
Antidotes
l None available.

l Children may be observed at home following suspected
unintentional ingestion of these agents. They need only be referred
for hospital assessment and observation if symptoms develop
l Patients who remain asymptomatic 6 hours post-ingestion are
medically fit for discharge. Those who develop symptoms are
admitted for further observation and supportive care until those
symptoms resolve, usually within 24 hours.
HANDY TIPS
l Although coma is reported with very large doses of some of the
newer anticonvulsants, other toxicological causes should be
considered in these cases. In particular it is essential to exclude
coma from carbamazepine, valproic acid or barbiturate overdose,
with drug levels if necessary
l Oxcarbazepine, although structurally similar to carbamazepine, is
much less toxic in overdose.
Presentations
Gabapentin 100 mg capsules (100) Oxcarbazepine 60 mg/1 mL oral
Gabapentin 300 mg capsules (100) suspension (250 mL)
Gabapentin 400 mg capsules (100) Pregabalin 25 mg capsules (56)
SPECIFIC TOXINS
Gabapentin 600 mg tablets (100) Pregabalin 75 mg capsules (56)
Gabapentin 800 mg tablets (100) Pregabalin 150 mg capsules (56)
Lamotrigine 5 mg tablets (56) Pregabalin 300 mg capsules (56)
Lamotrigine 25 mg tablets (56) Tiagabine hydrochloride 5 mg tablets (50)
Lamotrigine 50 mg tablets (56) Tiagabine hydrochloride 10 mg
Lamotrigine 100 mg tablets (56) tablets (50)
Lamotrigine 200 mg tablets (56) Tiagabine hydrochloride 15 mg tablets (50)
Levetiracetam 250 mg tablets (60) Topiramate 25 mg tablets (60)
Levetiracetam 100 mg/1 mL oral solution Topiramate 200 mg tablets (60) 159
(300 mL) Topiramate 15 mg sprinkle capsules (60)
Levetiracetam 500 mg/5 mL vials Topiramate 25 mg sprinkle capsules (60)
Oxcarbazepine 150 mg tablets (100) Topiramate 50 mg sprinkle capsules (60)
TOXICOLOGY HANDBOOK
Oxcarbazepine 300 mg tablets (100) Vigabatrin 500 mg (100)
Oxcarbazepine 600 mg tablets (100) Vigabatrin 500 mg sachets (60)
References
Fischer JH, Barr AN, Rogers SL et al. Lack of serious toxicity following gabapentin
overdose. Neurology 1994; 44(5):982–983.
Klein-Schwartz W, Shepherd JG, Gorman S et al. Characterization of gabapentin overdose
using a poison center case series. Journal of Toxicology-Clinical Toxicology 2003;
41(1):11–15.
Lofton AL, Klein-Schwartz W. Evaluation of lamotrigine toxicity reported to poison centers.
Annals of Pharmacotherapy 2004; 38:1811–1815.
Traub JS, Howland MA, Hoffman RS et al. Acute topiramate toxicity. Journal of Toxicology-
Wade JF, Dang CV, Nelson L et al. Emergent complications of the newer anticonvulsants.
Journal of Emergency Medicine 2010; 38(2):231–237.
Wisniewski M, Lukasek-Glebocka M, Anand JS. Acute topiramate overdose—clinical
manifestations. Clinical Toxicology 2009; 47:317–320.
3.12 ANTIHISTAMINES (non-sedating)

Cetirizine, Desloratadine, Fexofenadine, Levocetirizine, Loratadine
See also Chapter 3.13: Antihistamines (sedating)
The non-sedating antihistamines produce mild CNS depression in
overdose. They are notable for their association with QT prolongation in
therapeutic and supratherapeutic doses, although this association is less
marked with the newer currently available agents.
RISK ASSESSMENT
l Mild sedation or anticholinergic effects are anticipated following
overdose
l QT prolongation following overdose of currently available agents
is reported but rare. It is more likely following a large ingestion or
where there is co-ingestion of another pro-dysrhythmic agent
l Children: Ingestion of one to three tablets may be observed at
home. Refer to hospital for supportive care if significant drowsiness
or anticholinergic symptoms develop.
Toxic mechanism
Non-sedating antihistamines are mildly lipophilic and less able to cross the blood–brain
SPECIFIC TOXINS
barrier than sedating antihistamines. They are selective competitive reversible inhibitors of
peripheral H1 receptors. Compared to sedating antihistamines, they have lower affinity for
central H1, muscarinic (M1), α1-adrenergic and serotonergic (5HT) receptors. In overdose,
selectivity may be lost and some sedation, anticholinergic effects and hypotension may be
seen. QT interval prolongation is secondary to cardiac potassium channel blockade.
Toxicokinetics
Non-sedating antihistamines are well absorbed, reach peak effects in 1–3 hours and have
volumes of distribution of less than 1.5 L/kg. Hepatic metabolism is minor and half-lives
are variable, ranging from 8–24 hours.
160
CLINICAL FEATURES
16
0
l Minor sedation, nausea and ataxia

l Mild anticholinergic symptoms
TOXICOLOGY HANDBOOK
l Symptoms develop within 4–6 hours of ingestion and resolve within

12–24 hours.
INVESTIGATIONS
l Serial 12-lead ECGs
l Perform ECGs every 4 hours until there is clear evidence of clinical
improvement.
MANAGEMENT
l Resuscitation is rarely required but the patient should be monitored
initially and for 12 hours if symptomatic because of the small risk of
QT prolongation
l Manage anticholinergic delirium as outlined in Chapter 2.9:
l Severe QT prolongation with torsades de pointes is largely a
theoretical risk. Treatment should it occur includes correction of
hypoxia and hypokalaemia, administration of magnesium sulfate
10 mmol (0.05 mmol/kg in children) IV over 15 minutes and, if heart
rate is less than 100 beats/minute, isoprenaline infusion IV (1–10
microgram/minute or 0.05–2.0 microgram/kg/minute in children) or
overdrive pacing to maintain heart rate 100–120 beats/minute.
Decontamination
l Activated
charcoal is not indicated
Antidotes
l Physostigmine administration is considered in patients with severe
anticholinergic delirium not controlled with benzodiazepines (see
Chapter 4.22: Physostigmine).

l Symptomatic patients have continuous cardiac monitoring and
12-lead ECGs every 4 hours until there is clear evidence of clinical
SPECIFIC TOXINS
improvement
l The patient is fit for medical discharge when clinically well,
ambulant, passing urine, eating and drinking
l Patients with significant agitation or cardiac dysrhythmias require
admission to a high-dependency or intensive care unit.
HANDY TIPS
l Most ingestions are benign and have a good outcome with minimal
supportive care. 161
PITFALLS
l Failingto recognise the potential for QT prolongation in
TOXICOLOGY HANDBOOK

overdose.
CONTROVERSIES
l The degree of QT prolongation that warrants prophylactic
magnesium and chronotropic therapy in the setting of established
QT prolongation.
Presentations
Cetirizine hydrochloride 10 mg tablets (7, Fexofenadine hydrochloride 180 mg
10, 30) tablets (10, 20, 30, 50)
Cetirizine hydrochloride 1 mg/1 mL oral Fexofenadine hydrochloride 60 mg/
solution (75, 200 mL) pseudoephedrine 120 mg tablets (10)
Cetirizine hydrochloride 10 mg/1 mL oral Levocetirizine 5 mg tablets (10, 30)
drops (20 mL) Loratadine 10 mg tablets (10, 30, 50)
Desloratadine 5 mg tablets (7, 28) Loratadine 1 mg/1 mL syrup (100 mL, 150
Fexofenadine hydrochloride 30 mg tablets mL, 200 mL)
(10, 20) Loratadine 5 mg/pseudoephedrine 120
Fexofenadine hydrochloride 60 mg tablets mg modified-release tablets (6)
(10, 20)
Fexofenadine hydrochloride 120 mg
tablets (10, 20, 30, 50)
References
Hoffman RJ, de Souza I, Stetz JE. Prolonged QT segment and syncope with loratadine use
(abstract). Journal of Toxicology-Clinical Toxicology 2001; 39:505.
Pinto YM, Van Gelder IC, Heeringa M et al. QT lengthening and life-threatening arrhythmias
associated with fexofenadine. Lancet 1999; 353:980.
3.13 ANTIHISTAMINES (sedating)
Brompheniramine, Chlorpheniramine, Cyproheptadine,
Dexchlorpheniramine, Dimenhydrinate, Diphenhydramine, Doxylamine,
Pheniramine, Promethazine
See also Chapter 3.12: Antihistamines (non-sedating)
Overdose is characterised by dose-dependent sedation and anticholinergic
effects. Cardiovascular toxicity is associated with massive ingestions.
RISK ASSESSMENT
l Dose-dependent sedation, anticholinergic effects and orthostatic
SPECIFIC TOXINS
hypotension occur
l All agents lower seizure threshold, but seizures are infrequent
l Massive overdose may result in cardiac conduction abnormalities
(increased QRS or QT intervals) and hypotension requiring inotropes
l Children: Ingestion is associated with drowsiness and
anticholinergic delirium.
Toxic mechanism
162 Antihistamines act by competitive inhibition of histamine (H1) receptors. Side effects and
toxicity are due to antagonism at muscarinic (M1), α1-adrenergic and serotonergic (5HT)
16
receptors. Some agents lower seizure threshold but mechanisms are unclear. Cardiac
2
sodium and potassium channel blockade is reported in massive ingestions.

TOXICOLOGY HANDBOOK
Toxicokinetics
Antihistamines are well absorbed after ingestion, reaching peak levels in 2–3 hours. They
are lipid soluble, have large volumes of distribution (>4 L/kg) and are metabolised in the
liver. Half-lives are variable and range between 6 and 18 hours.
CLINICAL FEATURES
l CNS depression
l Anticholinergic syndrome including delirium (see Chapter 2.9:
Anticholinergic syndrome)
l Seizures, hyperthermia and rhabdomyolysis are rare
l Significant hypotension requiring inotropic support and cardiac
conduction abnormalities secondary to fast sodium channel
blockade (e.g. diphenhydramine) occur rarely after massive overdose.
INVESTIGATIONS
— An ECG should be performed on presentation and at 6 hours
post-ingestion to detect QRS or QT interval prolongation. Further
serial ECGs are only necessary if an abnormality is noted.
MANAGEMENT
l Resuscitation is rarely required but the patient should be monitored
initially and for 6 hours if symptomatic because of the risk of QRS
or QT prolongation
l Manage anticholinergic delirium as outlined in Chapter 2.9:
l Manage seizures along conventional lines, as outlined in Chapter
l Hypotension usually responds to fluid administration. If not, an α1-
adrenergic agonist (noradrenaline) is second-line therapy
l In the rare event of ventricular dysrhythmias, intubate,
hyperventilate and give IV bolus sodium bicarbonate, as outlined in
Chapter 4.25: Sodium bicarbonate
Decontamination
l Activated charcoal is not routinely indicated because the onset of
SPECIFIC TOXINS
sedation occurs in the first few hours and simple supportive care
ensures a good outcome
Antidotes
l Physostigmine administration is considered in patients with severe
anticholinergic delirium not controlled with benzodiazepines (see
Chapter 4.22: Physostigmine). 163
TOXICOLOGY HANDBOOK
l Patients who remain asymptomatic and have a normal 12-lead
ECG at 6 hours may be discharged. Discharge should not occur at
night
l Patients with mild sedation or anticholinergic features but a
normal 12-lead ECG at 6 hours may be managed supportively in
a ward environment. They are fit for medical discharge when well,
l Patients with significant agitation or delirium, and those requiring
intubation, require admission to a high-dependency or intensive
care unit
l Ongoing cardiac monitoring is reserved for patients with abnormal
ECGs, until changes resolve.
HANDY TIPS
l Antihistamines may be abused for their anticholinergic
properties.
PITFALLS
l Failure to recognise anticholinergic delirium because of
concomitant sedative effects
l Failure to detect and relieve urinary retention. This
exacerbates agitation and prevents control with benzodiazepine
sedation.
CONTROVERSIES
l Role of physostigmine in the management of antihistamine-
induced anticholinergic delirium.
Presentations
Alkylamines
Brompheniramine 2 mg/5 mL in decongestant elixirs
Chlorpheniramine 0.5–6 mg/tablet or 5 mL of elixir in cold and flu formulations
Dexchlorpheniramine maleate 2 mg modified-release tablets (20, 40)
Dexchlorpheniramine maleate 6 mg modified-release tablets (20, 40)
Dexchlorpheniramine 2.5 mg/1 mL syrup (100 mL)
Ethanolamines
Dimenhydrinate 50 mg/hyoscine hydrobromide 0.2 mg/caffeine 20 mg tablets (10)
Diphenhydramine hydrochloride 50 mg capsules (10)
Diphenhydramine hydrochloride 50 mg tablets (10)
Diphenhydramine 2.5 mg/mL in cough syrup formulations
Doxylamine succinate 25 mg capsules (20)
Doxylamine succinate 6.25 mg per tablet in cold and flu preparations
SPECIFIC TOXINS
Doxylamine 5–6.25 mg per tablet with paracetamol–codeine combination analgesics

Phenothiazines
Pheniramine maleate 43.5 mg tablets (10, 50)
Promethazine hydrochloride 10 mg tablets (50)
Promethazine hydrochloride 25 mg tablets (50)
Promethazine hydrochloride 1 mg/1 mL elixir (100 mL)
Promethazine hydrochloride 25 mg/1 mL ampoules
Promethazine hydrochloride 50 mg/2 mL ampoules
Promethazine hydrochloride in cold and flu formulations and analgesics (e.g. Pain Stop)
Trimeprazine 7.5 mg/5 mL syrup (100 mL)
164 Trimeprazine 6 mg/1 mL syrup (100 mL)
16
Others
4
Cyproheptadine tablets 4 mg (50, 100)

TOXICOLOGY HANDBOOK
References
Burns MJ, Linden CH, Graudins A et al. A comparison of physostigmine and
benzodiazepines for the treatment of anticholinergic poisoning. Annals of Emergency
Medicine 2000; 35(4):374–381.
Clark RF, Vance MV. Massive diphenhydramine poisoning resulting in a wide-complex
tachycardia: successful treatment with sodium bicarbonate. Annals of Emergency
Medicine 1992; 21:318–321.
3.14 ARSENIC
Arsenic is a metal found in elemental, inorganic and organic forms. The
inorganic and organic forms exist as trivalent (arsenite) and pentavalent
(arsenate) forms. Most commercially available arsenic-containing
products are produced from arsenic trioxide, one of the more toxic
trivalent inorganic compounds. Acute ingestion, usually in the context
of deliberate self-poisoning, is followed by severe gastroenteritis with a
characteristic sequential life-threatening multiple organ failure. Subacute
exposures occur from industrial accidents, food contamination and
ingestion of arsenic-containing herbal medicines. Chronic intoxication
usually follows long-term drinking of contaminated artesian water. The
organic arsenoids found in seafood are non-toxic.
RISK ASSESSMENT
l Acute or subacute ingestion of inorganic arsenic leads to a dose-
dependent sequential pattern of multiple organ failure:
— Ingestion of >1 mg/kg is potentially lethal
— Ingestion of <0.05 mg/kg may cause mild self-limiting
gastrointestinal symptoms but does not cause systemic toxicity
l Chronic arsenic intoxication usually occurs secondary to long-term
(>10 years) drinking of contaminated artesian water
l Children: Any ingestion of arsenic insecticide should be regarded
as potentially lethal.
Toxic mechanism
Arsenic binds to numerous cellular enzymes, interferes with cellular respiration and
-
inhibits DNA replication and repair. It binds to sulfhydryl (SH ) groups and substitutes for
phosphate in ATP. It produces reactive oxygen intermediates causing lipid peroxidation.
Toxicokinetics
SPECIFIC TOXINS
Absorption occurs via dermal, respiratory and gastrointestinal routes. Elimination half-
life is 3–5 days following acute ingestion. Arsenic initially distributes to kidneys and
liver. Following chronic ingestion, arsenic is distributed to liver, kidneys, lungs, nervous
system, spleen, hair and nails. Arsenic undergoes hepatic methylation and the metabolites
are excreted in the urine. A small amount of inorganic arsenic is excreted in the urine
unchanged. The organic arsenoids found in seafood are excreted unchanged.
CLINICAL FEATURES
Acute toxicity
l Following large ingestions there is rapid onset of severe watery 165
diarrhoea (‘choleroid’ or ‘rice water diarrhoea’), vomiting and
abdominal pain
l Gastrointestinal haemorrhage may occur
TOXICOLOGY HANDBOOK

l Encephalopathy, seizures, and cardiovascular collapse develop
within hours
l Hypersalivation is characteristic, as is a garlic odour
l Acute cardiomyopathy, ECG changes (prolonged QT) and cardiac
dysrhythmias are described
l Acute adult respiratory distress syndrome, renal failure and hepatic
injury follow
l Bone marrow depression develops within 24–72 hours in survivors,
reaching a nadir in 2–3 weeks
l Alopecia occurs in survivors of the initial phase
l Peripheral neuropathy may develop with a delay of 1–3 weeks.
It is an ascending predominantly motor neuropathy, may mimic
Guillain-Barré syndrome and may progress to respiratory failure
Subacute toxicity
l Initially manifests with gastrointestinal symptoms, leucopenia,
deranged liver function and haematuria
l Peripheral neuropathy develops after several weeks
Chronic toxicity
l Insidious onset over years of a multi-system disorder manifested
by constitutional symptoms, cutaneous lesions (hyperkeratosis of
palms and soles, hyperpigmentation), nail changes (Mees’ lines),
painful peripheral neuropathy (glove-stocking type distribution),
and malignancies of the skin or bladder.
INVESTIGATIONS
l Spot urinary arsenic (normal <30 microgram/L or 400 nmol/L)
— Helpful to confirm ingestion
— Levels after acute ingestion may be >1000 microgram/L
(13 500 nmol/L)
l 24–hour urinary arsenic excretion (normal <50 microgram/24 hours
or 675 nmol/24 hours)
— Better reflection of body burden
— May be one or two orders of magnitude higher than normal
following acute exposure
— 24-hour urine collection with speciation of non-toxic organic
and toxic inorganic forms is useful in assessing chronic
exposure
l Blood levels
SPECIFIC TOXINS

— Limited utility (may have a role in the assessment of acute
exposure in the anuric patient)
l Full blood count and coagulation profile
l Electrolytes
l Liver function tests
l Chest and abdominal x-rays (inorganic arsenic compounds are
radio-opaque).
166
16
MANAGEMENT
6

TOXICOLOGY HANDBOOK

l The immediate life threat in early acute arsenic poisoning is
hypovolaemia and shock secondary to profound gastrointestinal
fluid losses
l General supportive care measures and meticulous fluid
resuscitation is indicated, as outlined in Chapter 1.4: Supportive
care and monitoring
Decontamination
l Activated charcoal does not bind arsenic and is not indicated
l Cooperative patients who present following deliberate self-
poisoning with arsenic trioxide confirmed on abdominal x-ray
should undergo whole bowel irrigation with polyethylene glycol (see
Chapter 1.6: Gastrointestinal decontamination). Therapy may be
guided by monitoring arsenic transit on serial abdominal x-rays
Antidotes
l Chelation is indicated where there are objective clinical features
of acute arsenic intoxication, or where subacute intoxication is
diagnosed on the basis of history of exposure, clinical features and
elevated urinary arsenic concentration (usually >200 microgram/L
or 2700 nmol/L)
l Succimer is the agent of choice where oral administration is
available (see Chapter 4.28: Succimer)
l Dimercaprol (British Anti-Lewisite (BAL)) should be administered by
IM injection where oral administration is not feasible because of GI
symptoms (see Chapter 4.7: Dimercaprol)
l 2,3-dimercaptopropane-1-sulfonic acid (DMPS) is not readily
available in Australasia but is suitable for IV or PO administration
and is preferred to dimercaprol for parenteral administration if
available.

l Chronic intoxication can be managed on an outpatient basis
l Patients who are clinically well without gastrointestinal symptoms
at 12 hours following acute ingestion of arsenic are not poisoned
and may be discharged
SPECIFIC TOXINS
l Patients in whom clinical features develop following acute ingestion
of inorganic arsenic require admission for observation, aggressive
supportive care and chelation.
HANDY TIPS
l Chelation therapy of acute arsenic intoxication is not delayed
pending confirmatory levels
l Discovery of elevated arsenic levels in an asymptomatic patient
undergoing a ‘heavy metal screen’ usually reflects increased
excretion of non-toxic organic arsenic compounds contained in 167
seafood
l Patients should be instructed to avoid eating seafood or seaweed
TOXICOLOGY HANDBOOK
for 3–4 days prior to 24-hour urinary arsenic level
l Cutting or burning pine impregnated with copper chrome arsenate
preservative may cause symptoms of mucosal irritation from
smoke or sawdust but does not cause arsenic poisoning. Elevated
arsenic levels are associated with long-term occupational or
domestic exposure to this compound.
PITFALLS
l Ordering ‘heavy metal screens’ on patients with non-specific
symptoms without exposure assessment—these are rarely
clinically useful.
CONTROVERSIES
l There is no evidence to support any treatment intervention
for chronic arsenic poisoning, although vitamin and mineral
supplements and antioxidant therapy have been recommended.
Prevention of exposure is the priority
l Analysis of hair for metals is frequently subject to artefacts and is
not recommended
l Relative efficacy of various chelating agents.
Presentations
Inorganic: Found naturally in ground water in some regions. Used in the production of
semiconductors, glass, pesticides and wood preservatives. Used medically to induce
remission in acute promyleocytic leukaemia. Found in many traditional and herbal
remedies.
Organic: Found predominantly in fish and shellfish as non-toxic arsenobetaine and
arsenocholine
References
Graeme KA, Pollack CK. Heavy metal toxicity: arsenic and mercury. Journal of Emergency
Medicine 1998; 16(1):45–46.
Ratnaike RN. Acute and chronic arsenic toxicity. Postgraduate Medical Journal 2003; 79:
391–396.
Xu Y, Wang Y, Zheng Q. Clinical manifestations and arsenic methylation after a rare
subacute arsenic poisoning accident. Toxicological Sciences 2008; 103(2):278–284.
3.15 BETA-BLOCKERS
Atenolol, Bisoprolol, Carvedilol, Esmolol, Metoprolol, Oxprenolol, Pindolol,
Propranolol, Sotalol
SPECIFIC TOXINS
Beta-blocker overdose, other than with propranolol or sotalol, usually

results in little or no toxicity and does not require specific care. In
contrast, propranolol or sotalol overdose may be life threatening.
RISK ASSESSMENT
l Toxicity does not correlate well with ingested dose
l The following factors increase risk of severe toxicity:
— Ingestion of propanolol/sotalol
168 — Underlying heart or lung disease
— Co-ingestion/regular treatment with calcium channel blocker or
16
digoxin
8
— Advanced age
TOXICOLOGY HANDBOOK
l The threshold dose for severe toxicity from propranolol may be as

little as 1 g
l Toxicity usually manifests within the first few hours, with the
exception of overdose with controlled-release preparations or sotalol
l PR interval prolongation even in the absence of bradycardia is an
early sign of toxicity
l Children: There is risk of toxicity following ingestion of any dose
of propranolol or sotalol. Ingestion of one or two tablets of other
agents does not cause significant toxicity.
Toxic mechanism
Competitive antagonists at beta1 and beta2 receptors. Excessive beta-adrenergic
blockade leads to decreased intracellular cAMP concentration and resultant blunting of
the metabolic, chronotropic and inotropic effects of catecholamines. Propranolol also has
Na+-blocking effects (class I effects) leading to QRS widening and ventricular arrhythmias
and, being lipid soluble, enters the CNS where it exerts direct toxicity. Sotalol also blocks
cardiac K+ channels interfering with cardiac repolarisation and leading to QT prolongation.
Toxicokinetics
Rapidly absorbed from GIT with peak serum concentrations occurring from 1 to 3 hours post-
ingestion. Rapidly distributed with a variable volume of distribution depending on the agent.
Propranolol is distinguished from other agents by being extremely lipophilic. Metabolism and
elimination vary with the different agents. Propranolol undergoes extensive hepatic metabolism
with an elimination half-life of 12 hours but this may be prolonged following overdose.
CLINICAL FEATURES
Occur within 4 hours with the onset of beta-blockade manifested by a
fall in heart rate to around 60 beats/minute. More severe manifestations
may also occur during this period following propranolol overdose or
where there are other factors predisposing to severe effects.
Cardiovascular
l Hypotension and bradycardia
l Bradyarrhythmias observed include sinus bradycardia, 1st to 3rd
degree heart block, junctional or ventricular bradycardia
l QRS widening is observed following propranolol overdose and the
magnitude is a predictor of ventricular arrhythmias
l QT prolongation is observed following sotalol overdose
Central nervous system
l Delirium, coma and seizures (propranolol)
Other
l Bronchospasm, pulmonary oedema
l Hyperkalaemia
l Hypo/hyperglycaemia.
SPECIFIC TOXINS
INVESTIGATIONS
l EUC
MANAGEMENT 169
l Acute beta-blocker poisoning is a potentially life-threatening
emergency managed in an area equipped for cardiorespiratory
TOXICOLOGY HANDBOOK
monitoring and resuscitation.
l Resuscitation is most likely to be required following propranolol
overdose. Prompt intubation and ventilation and administration
of sodium bicarbonate are necessary to control ventricular
arrhythmias (propanolol overdose is managed as a tricyclic
antidepressant overdose)
l Immediate life-threats and treatment options include:
— Bradycardia and hypotension
– Atropine 0.01–0.03 mg/kg IV (temporising measure)
– Isoprenaline: 4 microgram/minute IV infusion
– Adrenaline (peripheral vasodilation-beta2)
– High-dose insulin (see Chapter 4.15: Insulin (high
dose))
— Wide QRS
– Sodium bicarbonate 1–2 mEq/kg boluses over 1–2 min
— Torsades de pointes (QT prolongation from sotalol)
– Isoprenaline
– Magnesium
– Overdrive pacing
l Close clinical observation and continuous ECG monitoring is
mandatory for at least 4 hours
l Invasive monitoring of haemodynamic parameters is very useful in
sick patients
Decontamination
l Activated charcoal may be administered to patients who present
within 2 hours but caution should be exercised following propranolol
overdose because of the risk of imminent coma and seizures
Antidotes
l None available.

l Patients who remain asymptomatic and have a normal ECG at
6 hours following the overdose may be medically cleared
l Patients with clinical or ECG manifestations of toxicity
require admission to an intensive care or high-dependency
unit.
SPECIFIC TOXINS
HANDY TIPS
l Approach management of a propranolol overdose more like a
tricyclic antidepressant or other Na-channel blocker overdose
rather than a beta-blocker overdose
CONTROVERSIES
l Glucagon (see Chapter 4.12: Glucagon) has been regarded
as a specific antidote to beta-blocker poisoning but it offers no
170 advantages over standard inotropes and chronotropes. It can also
be very difficult to source sufficient stocks and its use in beta-
17
0
blocker poisoning is largely abandoned

l Precise indications for high-dose insulin therapy (see Chapter
TOXICOLOGY HANDBOOK

4.15: Insulin (high dose)) are as yet undefined but it is increasingly
instituted early in the management of propranolol toxicity with
haemodynamic compromise
l The role of intravenous lipid emulsion in propranolol poisoning is
as yet undefined. It may be considered in life-threatening toxicity
where response to other interventions is inadequate (see Chapter
4.16: Intravenous lipid emulsion).
Presentations
Atenolol 50 mg tablets (30) Metoprolol succinate controlled-release
Bisoprolol fumarate 2.5 mg tablets (28) 190 mg tablets (30)
Bisoprolol fumarate 5 mg tablets (28) Oxprenolol hydrochloride 20 mg tablets
Bisoprolol fumarate 10 mg tablets (28) (100)
Carvedilol 3.125 mg tablets (30) Oxprenolol hydrochloride 40 mg tablets
Carvedilol 6.25 mg tablets (60) (100)
Carvedilol 12.5 mg tablets (60) Pindolol 5 mg tablets (100)
Carvedilol 25 mg tablets (60) Pindolol 15 mg tablets (50)
Esmolol hydrochloride 100 mg/10 mL Propranolol hydrochloride 10 mg tablets
ampoules (100)
Metoprolol tartrate 50 mg tablets (100) Propranolol hydrochloride 40 mg tablets
Metoprolol tartrate 100 mg tablets (60) (100)
Metoprolol tartrate 5 mg/5 mL Propranolol hydrochloride 160 mg tablets
ampoules (50)
Metoprolol succinate controlled-release Sotalol hydrochloride 80 mg tablets (60)
23.75 mg tablets (15) Sotalol hydrochloride 160 mg tablets (60)
Metoprolol succinate controlled-release Sotalol hydrochloride 40 mg/4 mL
47.5 mg tablets (30) ampoules
Metoprolol succinate controlled-release
95 mg tablets (30)
References
Love J, Howell JM, Litovitz TL et al. Acute beta-blocker overdose: Factors associated
with the development of cardiovascular morbidity. Journal of Toxicology-Clinical
Toxicology 2000; 38:275–281.
Reith DM, Dawson AH, Epid D et al. Relative toxicity of beta-blockers in overdose. Journal
of Toxicology-Clinical Toxicology 1996; 34:273–278.
Taboulet P, Cariou A, Berdeaux A et al. Pathophysiology and management of self-poisoning
with beta-blockers. Journal of Toxicology-Clinical Toxicology 1993; 31:531–551.
3.16 BACLOFEN
Large overdoses are characterised by rapid onset of delirium, respiratory
SPECIFIC TOXINS
depression, coma and seizures and are potentially lethal without timely
institution of good supportive care.
RISK ASSESSMENT
l Ingestions >200 mg in adults are expected to cause significant
CNS effects, including delirium, respiratory depression, coma and
seizures
l Ingestions of smaller doses cause relatively mild symptoms
l Good supportive care should result in a favourable outcome in all
171
cases.
Toxic mechanism
TOXICOLOGY HANDBOOK
Baclofen is a synthetic derivative of GABA. At therapeutic doses, it acts principally on
spinal GABAB receptors. It is also mediates pre- and post-synaptic inhibition, causing
paradoxical seizures in overdose, and withdrawal syndromes.
Toxicokinetics
Baclofen is rapidly and completely absorbed following oral administration. Peak serum
concentrations are achieved within 2 hours. It readily penetrates the blood–brain barrier. Its
volume of distribution is 0.7 L/kg and it is primarily excreted unchanged in the urine. About
15% is metabolised by the liver. The mean elimination half-life is 3.5 hours.
CLINICAL FEATURES
l Clinical features of intoxication develop within 2 hours of overdose
and include:
— Central nervous system
– Delirium
– Respiratory depression
– Profound and prolonged coma
– Seizures
— Cardiovascular
– Sinus bradycardia
– Hypertension
– 1st degree heart block and QT prolongation (rare)
l Delirium is most evident just prior to the onset of coma or upon
awakening
l Following large ingestions, coma may be profound. The patient
may appear brain dead with fixed dilated pupils, absent brainstem
(doll’s eyes, oculocephalic and corneal) reflexes and profound
hypotonia
l The duration of coma is usually between 24 and 48 hours.
INVESTIGATIONS
MANAGEMENT
l Baclofen poisoning is a potentially life-threatening emergency managed
in an area equipped for cardiorespiratory monitoring and resuscitation
l Respiratory depression and coma necessitate advanced airway
management with early intubation and ventilation
l Level of consciousness should be closely monitored during the first
few hours
l Seizures, should they occur, are managed with titrated doses of IV
SPECIFIC TOXINS
diazepam
l Hypotension usually responds to fluid boluses. Inotropes are not
usually required
Decontamination
l Activated charcoal is avoided in the patient with an unprotected
airway due to the risk of imminent coma and seizures
172
Antidotes
17
2
l None available.
TOXICOLOGY HANDBOOK

l Following baclofen overdose, all patients are closely observed for
at least 4 hours
l Patients who are asymptomatic at 4 hours following ingestion may
be discharged. Discharge should never occur at night
l Those manifesting minor CNS features such as delirium, require
medical admission for ongoing supportive care until all clinical
features resolve
l Patients with significant CNS depression require intubation and are
admitted to an intensive care unit.
HANDY TIPS
l Baclofen overdose should be considered in any patient with access
to this agent who presents with coma. It is not detected on routine
drug screening
l Baclofen is sometimes administered by continuous intrathecal infusion
via a reservoir and pump system. Pump malfunctions resulting in even
small intrathecal boluses can produce profound coma
l Baclofen withdrawal syndrome occurs between 24 and 48
hours post cessation of baclofen and is manifested by seizures,
hallucinations, dyskinesia and visual disturbances.
CONTROVERSIES
l Management of intrathecal overdose is controversial. Current
recommendations, in addition to standard resuscitation measures,
include:
— Emptying reservoir
— Lumbar puncture and removal of 30–50 mL of CSF.
Presentations
Baclofen 10 mg tablets (100)
Baclofen 25 mg tablets (100)
Reference
Leung NY, Whyte IM, Isbister GK. Baclofen overdose: Defining the spectrum of toxicity.
Emergency Medicine Australasia 2006; 18:77–82.
3.17 BARBITURATES
Pentobarbitone, Phenobarbitone, Primidone, Thiopentone
SPECIFIC TOXINS
Barbiturate overdose is an uncommon presentation, but can cause
profound and prolonged coma mimicking brain death. It is potentially
lethal but recognition of the diagnosis and timely appropriate
interventions will assure a good outcome.
RISK ASSESSMENT
l Ingestion of >8 mg/kg is expected to produce toxic neurological
symptoms in the non-tolerant individual. Multiples of this dose are
expected to produce profound prolonged coma 173
l Self-administration of thiopentone or pentobarbitone (often by medical
or veterinary professionals) by the intravenous route is likely to be
lethal unless the mechanics of administration are such that the rapid
TOXICOLOGY HANDBOOK
onset of coma prevents administration of all of the intended dose
l Children: Most barbiturate toxicity in children occurs in the context
of therapeutic administration. Acute ingestion of >8 mg/kg of
phenobarbitone or >40 mg/kg of primidone would be expected to
produce neurological symptoms and requires medical assessment.
Toxic mechanism
Barbiturates cause CNS depression by enhancing gamma-amino butyric acid (GABA)
mediated inhibitory neurotransmission. They bind to the GABAA receptor complex and
increase the duration of chloride channel opening (in contradistinction to benzodiazepines,
which increase the frequency of opening). They also antagonise the effect of the
excitatory neurotransmitter glutamate by causing receptor blockade in the CNS. Inhibition
of medullary cardiorespiratory centres and hypothalamic autonomic nuclei results in
hypotension, hypothermia and respiratory arrest.
Toxicokinetics
All barbiturates are well absorbed from the gastrointestinal tract but only some agents
are clinically effective after oral administration. Because of their rapid redistribution
from the CNS and large volumes of distribution, the highly lipid soluble ‘short-acting’
barbiturates (thiopentone and pentobarbitone) are only useful medically if given by
intravenous administration. In contrast, the less lipid-soluble ‘long-acting’ barbiturates
such as phenobarbitone and primidone are distributed more slowly to the CNS, have
slower redistribution from the CNS, slower onset of clinical effect and smaller volumes of
distribution, of around 0.9 L/kg. For these reasons, they are suitable for oral administration.
All barbiturates are metabolised by saturable hepatic microsomal pathways. Primidone is
first metabolised to two active metabolites, phenobarbitone and phenylethylmalonamide
(PEMA). Phenobarbitone undergoes both enterohepatic and enteroenteric recirculation.
Approximately 25–50% of an ingested dose of phenobarbitone is excreted unchanged
in the urine. The elimination half-life of phenobarbitone is long with considerable inter-
individual variation (35–140 hours) and, as a result of saturable kinetics, may be prolonged
even further after overdose.
CLINICAL FEATURES
l Barbiturate toxicity may develop with therapeutic administration
of phenobarbitone or primidone. Symptoms are mild and
neurological in nature; they resolve with cessation of
administration
l Barbiturate overdose is characterised by profound, prolonged
and potentially fatal depression of the central nervous and
cardiovascular systems
l Onset of toxicity is within seconds to minutes of intravenous
overdose of thiopentone or pentobarbitone or within 1–2 hours of
ingestion of phenobarbitone or primidone
– Ataxia, lethargy, slurred speech, drowsiness, vertigo and
SPECIFIC TOXINS
nystagmus are followed by coma, hypotonia, hypothermia

and respiratory arrest at higher doses
– Profound coma with complete loss of neurologic function
can develop. Clinical features mimic brain death with
absent pupillary responses, vestibulo-ocular reflexes and
deep tendon reflexes
– Profound respiratory depression occurs, with Cheyne-
Stokes respiration progressing to apnoea
174 — Cardiovascular system
– Tachycardia is frequently observed
17
– In very large ingestions, hypotension occurs as a result

4
of depression of medullary vasomotor nuclei as well

TOXICOLOGY HANDBOOK
as peripheral vasodilatation and direct myocardial

depression
— Other
– Hypothermia
– Reduced bowel sounds
– Skin bullae over pressure areas can occur (‘barbiturate
blisters’) but are not specific for barbiturate toxicity.
INVESTIGATIONS
l Serum barbiturate levels
— Phenobarbitone assays are readily available in most locations.
Other barbiturate assays can be obtained at specialised
centres
— CNS depression correlates well with serum phenobarbitone
(see Table 3.17.1)
— Levels are useful to confirm ingestion and serial levels are
essential in the management of the comatose patient with
barbiturate poisoning. They allow monitoring of clinical
progress and are used to guide the use of enhanced
elimination techniques
— A phenobarbitone level of >100 mg/L (>430 micromol/L)
prompts consideration of haemodialysis
— Serum levels are not usually helpful in the absence of coma
TABLE 3.17.1 Correlation of serum phenobarbitone levels and
clinical features
Level Clinical features
15–25 mg/L (65–108 micromol/L) Usual therapeutic range
30–80 mg/L (130–350 micromol/L) Increasing sedation
>80 mg/L (>345 micromol/L) Coma requiring intubation
l Other investigations may be required to exclude alternative causes

of coma
SPECIFIC TOXINS
— Note: the electroencephalogram (EEG) in barbiturate coma may
demonstrate profound suppression of activity to the point of
mimicking brain death.
MANAGEMENT
l Allpatients are managed in an area equipped for cardiopulmonary
monitoring and resuscitation
l Attention to airway, breathing and circulation are paramount. These 175
l The need for intubation is anticipated and performed early in the
TOXICOLOGY HANDBOOK
patient with a declining level of consciousness
Decontamination
l Activated charcoal 50 g is administered via a nasogastric tube
to the unconscious patient only after the airway is secured by
endotracheal intubation
l The pharmacokinetics of phenobarbitone render it suitable for
enhanced elimination techniques. The aim of instituting these
interventions is to reduce duration of coma and length of ventilation
in intensive care, which might otherwise amount to days or weeks
l Multiple-dose activated charcoal (MDAC) substantially increases
the rate of elimination of phenobarbitone by interrupting
enterohepatic and enteroenteric circulation (see Chapter 1.7:
Enhanced elimination for details on performing this intervention).
It is indicated in the intubated comatose patient as long as bowel
sounds remain present
l Haemodialysis, haemoperfusion and haemodiafiltration efficiently
remove phenobarbitone. These invasive interventions are indicated
for the patient with markedly elevated levels (>100 mg/L, >430
micromol/L) or where levels are rising or have plateaued despite
MDAC, or where continued MDAC is not feasible due to ileus
Antidotes
l None available.
l All children suspected of ingesting >8 mg/kg of phenobarbitone
or >40 mg/kg of primidone must be referred to hospital for
assessment and observation. They may be discharged home if
they remain asymptomatic 6 hours post-ingestion
l Adult patients who deliberately self-poison with phenobarbitone
or primidone should be observed in a closely monitored setting
for at least 6 hours. If they do not develop neurological signs or
symptoms during that time then further observation is not required
l Patients who develop clinical evidence of toxicity require admission
for ongoing observation and serial barbiturate levels. Significant
CNS depression prompts endotracheal intubation and intensive
care admission.
SPECIFIC TOXINS
HANDY TIPS
l Consider barbiturate poisoning in the patient with profound coma
of unknown origin and hypotonia. Have a high index of suspicion if
the patient has a medical or veterinary background, or has a history
of epilepsy.
PITFALLS
176 l Failure to consider the diagnosis of barbiturate toxicity. Along
with carbamazepine and valproate poisoning, it is an unusual but
17
eminently treatable cause of coma.

6
TOXICOLOGY HANDBOOK
CONTROVERSIES
l Urinary alkalinisation has been shown to enhance elimination of
phenobarbitone but it is inferior to MDAC and not recommended
l Although MDAC effectively enhances phenobarbitone elimination,
it has not been shown to reduce duration of coma or length of stay
in intensive care
l The indications for, method and timing of haemodialysis are
not clearly defined. The decision involves clinical judgment of
the patient’s clinical course and a risk–benefit analysis of the
procedure.
Presentations
Pentobarbitone sodium: available as a veterinary preparation (used to euthanase animals)
Phenobarbitone 15 mg/5 mL elixir (100 mL)
Phenobarbitone 30 mg tablets (200)
Phenobarbitone sodium 200 mg/1 mL ampoules
Primidone 250 mg tablets (200)
Thiopentone sodium 500 mg ampoules for reconstitution
References
Ebid A-HIM, Abdel-Rahman HM. Pharmacokinetics of phenobarbital during certain
enhanced elimination modalities to evaluate their clinical efficacy in management of
drug overdose. Therapeutic Drug Monitoring 2001; 23(3):209–216.
Frenia ML, Schauben JL, Wears RL et al. Multiple-dose activated charcoal compared
to urinary alkalinization for the enhancement of phenobarbital elimination. Clinical
Toxicology 1996; 34(2):169–175.
Pond SM, Olson KR, Osteroloh JD et al. Randomized study of the treatment of
Phenobarbital overdose with repeated doses of activated charcoal. Journal of the
American Medical Association 1984; 251(23):3104–3108.
3.18 BENZODIAZEPINES
Alprazolam, Bromazepam, Clobazam, Clonazepam, Diazepam,
Flunitrazepam, Midazolam, Nitrazepam, Oxazepam, Temazepam,
Triazolam
Also covers the non-benzodiazepine sedative-hypnotics: Zolpidem,
Zopiclone
Benzodiazepines are involved in up to one-third of deliberate self-
poisonings. An excellent prognosis is expected with supportive care of
CNS depression. Flumazenil is a useful diagnostic and therapeutic tool in
carefully selected cases.
SPECIFIC TOXINS
RISK ASSESSMENT
l Isolated benzodiazepine overdose usually causes only mild
sedation, irrespective of the dose ingested, and can be easily
managed with simple supportive care
l Alprazolam overdose is associated with greater degree of
CNS depression and is more likely to require intubation and
ventilation
l Zolpidem and zopiclone rarely cause severe CNS or respiratory
depression when taken alone 177
l Co-ingestion of other CNS depressants (e.g. alcohol, opioids,
antidepressants) increases the risk of complications, prolonged
length of stay and death
TOXICOLOGY HANDBOOK
l The elderly and patients with cardiorespiratory co-morbidities may
suffer greater complications
l Children: Ingestion of one or two benzodiazepines usually
manifests as mild sedation and ataxia within 2 hours.
Toxic mechanism
Benzodiazepines act by enhancing gamma-amino butyric acid (GABA) mediated
neurotransmission. They bind to the GABAA receptor complex and increase the
frequency of chloride channel opening. Zolpidem and zopiclone are non-benzodiazepine
sedative-hypnotics that also act at the GABAA receptor complex.
Toxicokinetics
Benzodiazepines are rapidly absorbed orally. Most are highly protein bound and have
volumes of distribution that vary from 0.5 to 4 L/kg. Benzodiazepines undergo hepatic
metabolism. Many have active metabolites. For example, diazepam is metabolised to
N-desmethyldiazepam, oxazepam and temazepam, and alprazolam is metabolised to
1- and 4-hydroxyalprazolam. Duration of effect following overdose depends on CNS
tolerance and redistribution, rather than rate of elimination. Clinical features of intoxication
are poorly correlated to serum benzodiazepine levels.
CLINICAL FEATURES
l Onset of symptoms occurs within 1–2 hours. Ataxia, lethargy,
slurred speech and drowsiness are followed by decreased
responsiveness. Profound coma is rare. Apnoea is a complication
of airway obstruction.
l In very large ingestions hypothermia, bradycardia and hypotension
may occur. Resolution of CNS depression usually occurs within 12
hours. More prolonged coma is common in the elderly.
INVESTIGATIONS
l 12-lead ECG, BSL and paracetamol level.
MANAGEMENT
priorities can usually be managed along conventional lines, as
outlined in Chapter 1.2: Resuscitation
l Monitor for urinary retention and place an indwelling catheter as
required
SPECIFIC TOXINS
Decontamination
l Activated charcoal is not indicated because the onset of sedation
occurs in the first few hours and simple supportive care ensures a
good outcome
178 Antidotes
l Flumazenil is a competitive benzodiazepine antagonist with a
17
limited role in benzodiazepine overdose. Its indications include:

8
— Management of airway and breathing when resources are not

TOXICOLOGY HANDBOOK
available to safely intubate and ventilate the patient

— Diagnostic tool to avoid further investigation
— Reversal of conscious sedation
l For further information on the indications, contraindications and
administration see Chapter 4.9: Flumazenil.

l Paediatric patients following accidental exposure may be
observed at home. If significant ataxia or drowsiness occurs,
referral to hospital for supportive care, usually overnight, is
appropriate
l Patients with mild sedation are managed supportively in a ward
environment. They may be discharged when clinically well.
Discharge should not occur at night
l Patients with significant CNS depression requiring intubation or
flumazenil infusion are admitted to a high-dependency or intensive
care unit (rare).
HANDY TIPS
l Profound coma, tachycardia or 12-lead ECG changes suggest a
co-ingested agent and the need to revise the risk assessment
l Flumazenil may be life saving in selected patients when the airway
and breathing cannot be controlled by other means.
PITFALLS
l Administration of flumazenil when contraindicated because of the
risk of seizures.
Presentations
Alprazolam 0.25 mg tablets (50) Flunitrazepam 1 mg tablets (30)
Alprazolam 0.5 mg tablets (50) Lorazepam 1 mg tablets (50)
Alprazolam 1 mg tablets (50) Lorazepam 2.5 mg tablets (50)
Alprazolam 2 mg tablets (50) Midazolam 5 mg/1 mL ampoules
Bromazepam 3 mg tablets (30) Midazolam 5 mg/5 mL ampoules
Bromazepam 6 mg tablets (30) Midazolam 15 mg/3 mL ampoules
Clobazam 10 mg tabletss (50) Midazolam 50 mg/10 mL ampoules
Clonazepam 0.5 mg tablets (100) Nitrazepam 5 mg tablets (25, 30, 50)
Clonazepam 2 mg tablets (100) Oxazepam 15 mg tablets (25, 50, 90)
Clonazepam 2.5 mg/1 mL liquid Oxazepam 30 mg tablets (25, 50)
Clonazepam 1 mg/1 mL ampoules Temazepam 10 mg tablets (25, 50)
Diazepam 2 mg tablets (30, 50, 90) Triazolam 0.125 mg tablets (50)
Diazepam 5 mg tablets (30, 50) Zolpidem 10 mg tablets (7, 20)
SPECIFIC TOXINS
Diazepam 10 mg/10 mL liquid (100 mL) Zopiclone 7.5 mg tablets (10, 30)
Diazepam for injection 10 mg/2 mL
ampoules
References
Buckley NA, Dawson AH, Whyte IM. Relative toxicity of benzodiazepines in overdose.
British Medical Journal 1995; 310:219–221.
Garnier R, Guerault E, Muzard D et al. Acute zolpidem poisoning—analysis of 344 cases.
Journal of Toxicology-Clinical Toxicology 1994; 32(4):391–394.
Isbister GK, O’Regan L, Sibbritt D et al. Alprazolam is relatively more toxic than other 179
benzodiazepines in overdose. British Journal of Clinical Pharmacology 2004; 58(1):
88–95.
TOXICOLOGY HANDBOOK
3.19 BENZTROPINE
Frequently prescribed to patients on antipsychotics to ameliorate
dyskinesias, this is a potent anticholinergic agent in overdose.
RISK ASSESSMENT
l Any overdose of this agent is likely to precipitate anticholinergic
symptoms and require medical care
l Anticholinergic syndrome can also occur with excessive
therapeutic doses.
Toxicokinetics
There is little information on the pharmacokinetics of benztropine and even less on its
toxicokinetics. It appears to be well absorbed following oral administration. The onset of
therapeutic action is between 1 and 2 hours following oral administration. Metabolism is
probably hepatic with metabolites excreted in the urine.
Toxic mechanism
A synthetic drug containing the active tropine component of atropine and the
diphenylmethyl portion of diphenhydramine (antihistamine). It acts as an anticholinergic,
antihistaminergic and dopamine reuptake inhibitor.
CLINICAL FEATURES
l The clinical features are those of the anticholinergic syndrome (see
Chapter 2.9: Anticholinergic syndrome) and include: delirium,
mydriasis, blurred vision, sinus tachycardia, warm flushed dry skin,
urinary retention and ileus
l The maximal effects are normally observed within 6 hours and may
persist for a period from 12 hours to 5 days.
INVESTIGATIONS
l Other tests including EUC, CT head and lumbar puncture are
indicated if necessary to exclude important alternative diagnoses
such as intracranial infection.
MANAGEMENT
SPECIFIC TOXINS
l Management is supportive and consists principally of sedation with

benzodiazepines, intravenous fluids and insertion of an indwelling
urinary catheter
l Control of delirium can be challenging. Physical restraints are
sometimes necessary
l Once adequate sedation is attained, one-to-one nursing in a calm,
closely monitored environment is essential to ensure patient safety
l For a more detailed description of the management of
180 anticholinergic syndrome see Chapter 2.9: Anticholinergic
syndrome
18
0
Decontamination
l Activated charcoal may be useful if administered within 2 hours of
TOXICOLOGY HANDBOOK

ingestion
l It is of little value, not to mention technically challenging, once
delirium is established
Antidote
l Physostigmine is considered in cases where the delirium is
not easily controlled with benzodiazepines (see Chapter 4.22:
Physostigmine).

l Once initial control of delirium is attained, admission to a high-
dependency area with one-to-one nursing in a calm, reassuring
environment is essential. Staff should be aware that the delirium
might persist several days.
HANDY TIPS
l Insert an indwelling urinary catheter as soon as possible. Urinary
retention is almost universal in anticholinergic delirium and, if not
relieved, will exacerbate the patient’s agitation
l Excessive doses of benztropine, like other anticholinergic agents,
are sometimes consumed for recreational purposes.
PITFALLS
l Failure to distinguish anticholinergic delirium from psychosis or
antisocial personality disorder.
CONTROVERSIES
l The role of physostigmine: early use of this drug in severe
benztropine-induced anticholinergic delirium is increasingly
favoured.
Presentations
Benztropine mesylate 2 mg tablets (60)
Benztropine mesylate 2 mg/2 mL ampoules
3.20 BUPROPION
SPECIFIC TOXINS
This antidepressant agent is now used to suppress nicotine craving and
is only available as an extended-release preparation. There is a high risk
of seizures following an overdose of any amount and potential for life-
threatening cardiotoxicity occurs with very high doses. Supportive care
and adequate benzodiazepine sedation usually ensure a good outcome.
RISK ASSESSMENT
l High risk of seizures following overdose of any amount
l The first seizure is usually delayed 2–8 hours following ingestion
181
but may be delayed up to 24 hours
l Risk of seizures is increased if there is a preexistent lowered
seizure threshold or co-ingestion of other centrally acting
TOXICOLOGY HANDBOOK
sympathomimetic or serotonergic agents
l Severe cardiotoxicity, haemodynamic instability and cardiac deaths
have occurred at doses >9 g
l Children: Any child suspected of ingesting >10 mg/kg requires
assessment and observation in hospital.
TABLE 3.20.1 Dose-related risk assessment: Bupropion
Dose Effect
Any dose Seizures, tachycardia, hypertension, tremors,

agitation, hallucinations, GI symptoms
> 4.5 g Seizure risk of 50% and first seizure usually within
8 hours of ingestion
>9 g Seizures universal. Risk of cardiovascular

complications, including haemodynamic instability,
prolonged QRS and QT intervals and ventricular
arrhythmias. Fatal without good supportive care
Toxic mechanism
Bupropion is a monocyclic antidepressant that suppresses nicotine craving by an
unknown mechanism. It increases the levels of CNS excitatory neuroamines by inhibiting
noradrenaline and dopamine reuptake. Also causes minimal serotonin reuptake inhibition
and moderate anticholinergic effects.
Toxicokinetics
Well absorbed orally with peak plasma levels occurring within 2–3 hours. Relatively large volume
of distribution (19.8–47 L/kg). Metabolised to active metabolites, which are renally excreted.
CLINICAL FEATURES
l Clinical features develop progressively over 8 hours and include
tachycardia, hypertension, tremors, GI disturbance, agitation,
hallucinations, altered mental state and seizures
l First seizure, heralded by neurological symptoms, usually occurs
during this period but may be delayed up to 24 hours post-
ingestion
l Cardiovascular effects and ECG manifestations, including shock,
QRS widening and tachydysrhythmias, are reported after massive
overdose and manifest within 6 hours.
SPECIFIC TOXINS
INVESTIGATIONS
l Serial ECGs
— Perform a 12-lead ECG on all patients at presentation and at
182 6 hours post-ingestion
— For ingestions >4.5 g, 12-lead ECGs should be reviewed every
18
2 hours (or if symptoms occur).

2
TOXICOLOGY HANDBOOK
MANAGEMENT
l Bupropion overdose is a life-threatening emergency and is
resuscitation
l Early intubation and ventilation is indicated when the history and
clinical progression suggest ingestion of >9 g
— Seizures: give IV diazepam 5–10 mg and repeat if necessary as
— Broad-complex tachycardias: manage aggressively with
intubation, ventilation and administration of sodium
bicarbonate 1–2 mmol/kg repeated every 1–2 minutes to
achieve serum alkalinisation as described in Chapter 4.25:
Sodium bicarbonate
l Control agitation and tachycardia with titrated doses of IV
diazepam: give 2.5–5 mg every 2–5 minutes until gentle sedation
achieved
l Continue close monitoring for at least 12 hours following ingestions
of >9 g
Chapter 1.4: Supportive care and monitoring.
Decontamination
l Activated charcoal or other attempts at decontamination are
generally contraindicated because of the high risk of seizures
l If >9 g is ingested and there is any evidence of toxicity, give
activated charcoal 50 g via the nasogastric tube following
Antidotes
l None available.

l Because of the risk of seizures following bupropion overdose, all
patients are observed with IV access in place for a minimum of
24 hours and until symptom-free
l Patients who are clinically well at 24 hours following ingestion do
not require further medical observation. Discharge should never
occur at night
l Patients with cardiotoxicity or seizures are admitted for monitoring
SPECIFIC TOXINS

and supportive care until all clinical features of toxicity, including
sinus tachycardia, resolve
l Admission to ICU is indicated following massive ingestions (>9 g)
and for patients manifesting signs of significant cardiotoxicity.
HANDY TIPS
l It is useful to give early prophylactic doses of IV benzodiazepines
in order to prevent seizures. The dose is titrated to achieve a calm
patient and a fall in the pulse rate towards 100/minute. 183
PITFALLS
l Failure to anticipate and prepare for delayed onset of symptoms
TOXICOLOGY HANDBOOK

and seizures
l Failure to administer benzodiazepines early and in sufficient dose
l Administration of activated charcoal or initiation of whole bowel
irrigation shortly before onset of seizures or cardiovascular
toxicity.
CONTROVERSIES
l The role of whole bowel irrigation (WBI): patients who present
early after massive ingestion of bupropion would appear to be
candidates for WBI. However the risk of seizures occurring during
the procedure is such that it is contraindicated
l Intravenous lipid emulsion has been advocated in the management
of severe bupropion toxicity but its role is as yet undefined.
Presentations
Bupropion hydrochloride 150 mg sustained-release tablets (30, 90)
References
Balit CR, Lynch CN, Isbister GK. Bupropion poisoning: a case series. Medical Journal of
Australia 2003; 178:61–63.
Morazin F, Lumbroso A, Harry P. Cardiogenic shock and status epilepticus after massive
bupropion overdose. Clinical Toxicology 2007; 45(7):794–797.
Shepherd G, Veliz LI, Keys DC. Intentional bupropion overdoses. Journal of Emergency
Medicine 2004; 27(2):147–151.
Spiller HA, Bosic GM, Beuhler M et al. Unintentional ingestion of bupropion in children.
Starr P, Klein-Schwartz W, Spiller H et al. Incidence and onset of delayed seizures after
overdose of extended-release bupropion. American Journal of Emergency Medicine
2009; 27:911–915.
3.21 BUTTON BATTERIES
Ingestion of button batteries is almost exclusively a paediatric problem.
The majority pass through the gastrointestinal (GI) tract easily and without
complication. Larger batteries may lodge in the oesophagus, causing
significant complications.
RISK ASSESSMENT
l Ingested batteries of diameter <15 mm almost never lodge in the
oesophagus and rarely cause significant complications
l Ingested batteries >15 mm diameter (and usually >20 mm) may
lodge in the oesophagus and cause severe local injury, including
SPECIFIC TOXINS
mucosal burns and strictures, oesophageal perforation, tracheo-

oesophageal fistula and haemorrhage
l Local injury may also occur after insertion of batteries into the aural
or nasal cavities
l Button batteries may contain manganese, silver, mercury, lithium
or zinc but the quantities available for absorption are insufficient to
cause systemic heavy metal toxicity.
184 Mechanism of injury

Local injury from ingested button batteries occurs as a result of direct pressure necrosis
18
and leakage of alkali. Mucosal burns and strictures, oesophageal perforation, tracheo-
4
oesophageal fistula and haemorrhage can develop. Elevated mercury levels are described
TOXICOLOGY HANDBOOK
after ingestion of mercuric oxide-containing batteries but severe toxicity is not reported.
CLINICAL FEATURES
l he majority of patients are asymptomatic initially. They may
T
present to hospital because ingestion was witnessed or suspected
by parents or carers, or only after signs and symptoms of
oesophageal obstruction or injury develop
l The most frequent symptoms of oesophageal lodgement are
dysphagia and pain, although this may be delayed for several days.
Many children also develop non-specific symptoms of cough or
respiratory distress, irritability or fever if diagnosis is delayed.
INVESTIGATIONS
l istory of possible button battery ingestion mandates plain
H
anteroposterior (together with a lateral if an object is identified
above the diaphragm) x-ray of the chest and abdomen to localise
the object and guide further management
l Mercury and other heavy metal levels are not required routinely.
MANAGEMENT
Resuscitation and supportive care
l Resuscitation is rarely needed following acute ingestion unless
airway obstruction occurs.
l Delayed presentation may require resuscitation along standard
protocols for cardiovascular collapse secondary to haemorrhage
or sepsis from oesophageal perforation, or for respiratory distress
from tracheo-oesophageal fistula
Decontamination
l A button battery lodged in the oesophagus requires endoscopic
removal, ideally within 6 hours of ingestion
l Endoscopy allows both removal of the battery and examination for
local complications to guide further management. The presence of
a mucosal burn prompts further investigation to exclude perforation
l A button battery located beyond the oesophagus in an
asymptomatic child can be allowed to pass naturally
l Batteries lodged in the nose or ears should be removed urgently.

l atients with a battery lodged in the oesophagus are referred for
P
urgent upper GI endoscopy and removal, ideally within 6 hours of
SPECIFIC TOXINS
ingestion
l Patients in whom the battery has passed beyond the pylorus are
unlikely to develop complications and can be discharged with
advice to observe and return if symptoms develop. Repeat x-ray is
only required if symptoms of perforation occur.
HANDY TIPS
l atteries typically have a ‘double density’ shape on anteroposterior
B
view, and a ‘stepped’ appearance on lateral view radiography
l A high index of suspicion is required for investigation of small
185
children when a history of ingestion is not available.
TOXICOLOGY HANDBOOK
PITFALLS
l ailure to perform an x-ray
F
l Mistaking a button battery for a coin on x-ray. Batteries have a
distinctive appearance and lateral x-ray may help to identify the object
l Delayed referral for endoscopic removal.
CONTROVERSIES
l iming of endoscopy. Removal of oesophageal button batteries is
T
recommended within 6 hours of ingestion; however, mucosal burns
have been documented as early as 4 hours after ingestion and
oesophageal perforation within 6 hours
l Management of button batteries located in the stomach. Some
authors recommend repeat x-ray at 48 hours when a larger button
battery (>15 mm) is initially seen in the stomach, with endoscopic
retrieval if it has not passed through the pylorus by this time.
Smaller batteries can usually be managed expectantly at home
without repeat imaging.
Sources
Button batteries are commonly found in watches, cameras, electronic games and hearing
aids. More recently manufactured devices tend to have smaller button batteries.
References
Alvi A, Bereliani A, Zahtz GD. Miniature disc battery in the nose: A dangerous foreign body.
Clinical Paediatics 1997; 36(7):427–429.
Sheikh A. Button battery ingestions in children. Paediatric Emergency Care 1993; 9(4):224–229.
Yardeni D, Yardeni H, Coran AG et al. Severe esophageal damage due to button battery
ingestion: can it be prevented? Paediatric Surgery International 2004; 20:496–501.
3.22 CALCIUM CHANNEL BLOCKERS
Amlodipine, Diltiazem, Felodipine, Lercanidipine, Nifedipine, Nimodipine,
Verapamil
Verapamil and diltiazem commonly cause cardiovascular collapse
following overdose and this may be delayed 4–16 hours after ingestion of
the extended-release (XR) preparations. The other agents are not usually
associated with severe toxicity.
RISK ASSESSMENT
l Ingestion of as little as 2–3 times the normal therapeutic dose of
SPECIFIC TOXINS
verapamil or diltiazem XR preparations can cause severe toxicity in

susceptible individuals
l All deliberate self-poisonings are regarded as potentially serious
l Ingestion of >10 tablets of verapamil or diltiazem XR preparations
in an adult is likely to cause life-threatening toxicity
l Onset of effects is up to 2 hours following ingestion of standard
preparations and 16 hours following XR preparations
l The other calcium channel blockers (CCBs) do not usually cause
life-threatening toxicity, irrespective of dose
186 l Co-ingestion of other cardiotoxic medications (e.g. beta-blockers
or digoxin) significantly increases the risk of serious toxicity
18
6
l Advanced age and co-morbidities (e.g. cardiac disease) increase

the risk of significant toxicity
TOXICOLOGY HANDBOOK
l Children: Ingestion of 2 or more tablets of any strength of XR

verapamil or diltiazem is potentially lethal. All children suspected
of ingesting any quantity of XR preparations should be assessed
in hospital. Children who are suspected of ingesting >2 tablets of
other preparations should also be assessed in hospital.
Toxic mechanism
Calcium channel blockers prevent the opening of L-type calcium channels, resulting in
decreased calcium influx. This leads to vascular smooth muscle relaxation, slowing of
cardiac conduction and reduced force of cardiac contraction. Verapamil and diltiazem
cause central cardiac effects and peripheral vasodilatation. The dihydropyridines chiefly
cause the latter. Hypotension results from severe peripheral vasodilation, bradycardia and
decreased contractility, associated with hyperglycaemia and lactic acidosis.
Toxicokinetics
Calcium channel blockers are well absorbed, with peak levels occurring within 1–2
hours (standard preparations) and 6–12 hours for XR preparations. However, in overdose
peak levels may not occur until 6 hours for standard preparations and 22 hours for XR
preparations. They have high volumes of distribution (e.g. verapamil 3–7 L /kg) and are
protein bound, but free levels often increase in overdose. Calcium channel blockers
undergo hepatic metabolism. There is a high first-pass effect after absorption, giving
bioavailability of approximately 40%. This may increase in overdose due to saturation of
hepatic metabolism. Verapamil is metabolised to an active metabolite norverapamil, and
diltiazem is metabolised to diacetyldiltiazem, which has vasodilator activity.
CLINICAL FEATURES
Following ingestion of standard preparations, onset of symptoms may
occur within 1–2 hours. In XR preparations, onset of significant toxicity
may be delayed 12–16 hours with peak effects beyond 24 hours.
l Cardiovascular
— Bradycardia, first-degree heart block and hypotension (e.g.
SBP 95 mmHg) are early signs
— Progression to refractory shock and death
— Myocardial ischaemia, stroke or non-occlusive mesenteric
ischaemia may occur
— Seizures and coma are rare
— Coma usually indicates a co-ingested agent
l Metabolic
— Hyperglycaemia and lactic acidosis occur in severe
intoxication.
SPECIFIC TOXINS
INVESTIGATIONS
— Perform a 12-lead ECG at presentation and 8 hours post-
ingestion. Additional ECGs should be performed if there are
abnormal vital signs, and at 12, 18 and 24 hours following
ingestion of XR products 187
— First, second and third degree heart block may occur
l EUC
l Serum calcium
TOXICOLOGY HANDBOOK
l Serum lactate and arterial blood gases
l Chest x-ray
l Pulmonary artery capillary wedge pressure, cardiac output,
systemic resistance.
MANAGEMENT
Key objectives in the management of CCB poisoning are early
identification of patients at risk, initiation of appropriate monitoring,
consideration of gastrointestinal decontamination and referral to a
facility capable of advanced resuscitation and intensive care.
l Acute CCB overdose is a time-critical emergency managed in an
area equipped for cardiorespiratory monitoring and resuscitation
l Hypotension (SBP <90 mmHg) refractory to initial fluid resuscitation
indicates the onset of significant toxicity and the need for a
planned approach to resuscitation. Failure to achieve sustained
cardiovascular stability at each step requires the rapid initiation of the
next step
l Potential early life-threats that require immediate intervention
include:
— Hypotension
— Cardiac dysrhythmia
— Cardiac arrest
l Although mentation and airway protective reflexes are usually
preserved until cardiac arrest is imminent, early controlled
intubation and ventilation is recommended where life-threatening
toxicity is anticipated
l arly invasive blood pressure monitoring is advised for evolving
E
shock. Inotropic and vasopressor therapy is best guided by
pulmonary artery catheter measurements
l Graduated approach to hypotension:
— Fluid resuscitation: give 10–20 mL/kg isotonic crystalloid
— Calcium: (see Chapter 4.2: Calcium)
– Give 60 mL calcium gluconate 10% (0.6–1.0 mL/kg in
children) or calcium chloride 10% 20 mL (0.2 mL/kg) IV
over 15 minutes
– Although unlikely to be definitive treatment, calcium
boluses can produce a temporary increase in heart rate
and blood pressure and may be repeated up to three times
while other therapies are started
– Commence an infusion to maintain calcium level above 2.0
SPECIFIC TOXINS
mEq/L
l Atropine
— Administer 0.6 mg every 2 minutes up to 3 mg
l Catecholamine infusion
— Titrate infusion of dopamine, adrenaline and/or
noradrenaline
l High-dose insulin (see Chapter 4.15: Insulin (high dose))
l Sodium bicarbonate
188 — Administer 50–100 mEq sodium bicarbonate (0.5–1.0 mEq/kg
in children) for metabolic acidosis
18
8
l Cardiac pacing
— Ventricular pacing should be used to bypass AV block and
TOXICOLOGY HANDBOOK
rates should not exceed 60 beats/minute. Electrical capture

is often difficult to achieve, and may not be associated with
improved perfusion
l Cardiopulmonary bypass and intra-aortic balloon pump have been
successfully used as extraordinary manoeuvres
Decontamination
l Activated charcoal
— Administer to cooperative patients who present within 1 hour
of ingestion of standard preparations and 4 hours for XR
preparations
— Administer to all intubated patients
l Whole bowel irrigation (see Chapter 1.6: Gastrointestinal
decontamination)
— Commence after dose of activated charcoal in cooperative
adult patients without evidence of established toxicity and who
present within 4 hours of deliberate self-poisoning with >10
tablets of verapamil XR or diltiazem XR
Antidotes
l As discussed in Resuscitation, supportive care and monitoring
above
— Calcium (see Chapter 4.2: Calcium)
— Atropine (see Chapter 4.1: Atropine)
— High-dose insulin therapy (see Chapter 4.15: Insulin (high
dose)).
l atients who are clinically well with normal vital signs and 12-
P
lead ECG at 4 hours following standard preparations or 16 hours
following XR preparations may be discharged. Discharge should
not occur at night
l Patients with manifestations of intoxication are referred to an
HANDY TIPS
l nce significant toxicity has manifested (e.g. SBP <90 mmHg
O
following 20 mL/kg fluid bolus), do not delay endotracheal
intubation.
SPECIFIC TOXINS
PITFALLS
l ailure to anticipate potential for delayed onset of severe toxicity
F
following ingestion of XR preparations
l Failure to initiate aggressive decontamination (activated charcoal
followed by whole bowel irrigation) in patients that present early
following life-threatening overdose of XR diltiazem or verapamil.
CONTROVERSIES
l he indications for high-dose insulin therapy are evolving. This
T 189
therapy appears to be effective and is increasingly instituted
earlier and in preference to standard inotropic agents to manage
cardiovascular toxicity
TOXICOLOGY HANDBOOK
l The role of intravenous lipid emulsion in CCB poisoning is as yet
undefined. It may be considered in life-threatening toxicity where
response to other interventions is inadequate (see Chapter 4.16:
Intravenous lipid emulsion).
Presentations Amlodipine besylate 10 mg/atorvastatin

Benzothiazepines: 40 mg tablets (30)
Diltiazem 60 mg tablets (90) Amlodipine besylate 10 mg/atorvastatin
Diltiazem extended-release capsules 80 mg tablets (30)
180 mg (30) Felodipine extended-release tablets
Diltiazem extended-release capsules 2.5 mg (30)
Diltiazem extended-release capsules 5 mg (30)
Dihydropyridines: 10 mg (30)
Amlodipine besylate 5 mg tablets (30) Felodipine 2.5 mg/ramipril 2.5 mg
Amlodipine besylate 10 mg tablets (30) modified-release tablets (30)
Amlodipine besylate 5 mg/atorvastatin Lercanidipine hydrochloride 10 mg tablets
10 mg tablets (30) (30)
Amlodipine besylate 5 mg/atorvastatin Lercanidipine hydrochloride 20 mg tablets
20 mg tablets (30) (30)
Amlodipine besylate 5 mg/atorvastatin Lercanidipine hydrochloride 10 mg/
40 mg tablets (30) enalapril maleate 10 mg tablets (30)
Amlodipine besylate 5 mg/atorvastatin Lercanidipine hydrochloride 10 mg/
80 mg tablets (30) enalapril maleate 20 mg tablets (30)
Amlodipine besylate 10 mg/atorvastatin Nifedipine 10 mg tablets (60)
10 mg tablets (30) Nifedipine 20 mg tablets (60)
Amlodipine besylate 10 mg/atorvastatin Nifedipine controlled-release tablets
20 mg tablets (30) 20 mg (30)
Nifedipine controlled-release tablets 30 Verapamil hydrochloride sustained-release
mg (30) tablets 180 mg (30)
Nifedipine controlled-release tablets 60 Verapamil hydrochloride sustained-release
mg (30) tablets 240 mg (30)
Nimodipine 30 mg tablets (100) Verapamil hydrochloride 5 mg/2 mL
Nimodipine 10 g/50 mL ampoules ampoules
Phenylalkylamines: Verapamil hydrochloride 180 mg/
Verapamil hydrochloride immediate- trandolapril 2 mg sustained-release
release tablets 40 mg (100) tablets (28)
Verapamil hydrochloride immediate- Verapamil hydrochloride 240 mg/
release tablets 80 mg (100) trandolapril 4 mg sustained-release
Verapamil hydrochloride immediate- tablets (28)
release tablets 120 mg (100)
Verapamil hydrochloride immediate-
release tablets 160 mg (60)
SPECIFIC TOXINS
Verapamil hydrochloride sustained-release

capsules 160 mg (30)
References
Buckley N, Dawson A, Whyte I. Calcium channel blockers. Medicine 2007; 35(11):134–139.
DeWitt CR, Waksman JC. Pharmacology, pathophysiology and management of calcium
channel blocker and β-blocker toxicity. Toxicological Reviews 2004; 23(4): 223–238.
Mégarbane B, Karyo S, Baud FJ. The role of insulin and glucose (hyperinsulinaemia/
euglycaemia) therapy in acute calcium channel antagonist and β-blocker toxicity.
190 Toxicological Reviews 2004; 23(4): 215–222.
Olsen KR, Erdman AR, Woolf AD et al. Calcium channel blocker ingestion: an evidence-
19
based guideline for out-of-hospital management. Clinical Toxicology 2005; 43:797–822.

0
Yuan TH, Kerns WP, Tomaszewski CA et al. Insulin-glucose as an adjunctive therapy for
TOXICOLOGY HANDBOOK
severe calcium channel antagonist poisoning. Clinical Toxicology 1999; 37(4): 463–474.
3.23 CANNABINOIDS (marijuana)

Delta-9-tetrahydrocannabinol, delta-8-tetrahydrocannabinol, cannabinol,
cannabidiol
Slang terms include hashish, dope, marijuana, ganja, grass, pot and weed.
Marijuana is the most widely used recreational illicit drug in Australasia. It
is a psychoactive drug that can cause unpleasant but benign symptoms in
adults. Cannabis ingestion by children leads to significant CNS depression.
RISK ASSESSMENT
l here are no reports of death directly attributed to recreational use
T
of marijuana
l Adults may experience unpleasant symptoms in a dose-dependent
manner
l Low-dose effects: 50 microgram/kg (3–4 mg) are associated with
mild sedation, disinhibition, mild disorientation and euphoria
l High-dose effects: 250 microgram/kg (15 mg) associated with
tachycardia, postural hypotension, CNS depression, anxiety and
perceptual disturbances even psychotic symptoms
l Co-ingestion of other CNS depressants has an additive effect
l Chronic use leads to long-term neuropsychiatric sequelae and a
withdrawal syndrome is described in habitually heavy users
l Children: Ingestion may lead to life-threatening coma in a child.
Toxic mechanism
Marijuana is a psychoactive drug with central sympathomimetic and antiemetic properties.
It acts on cannabinoid receptors in the central and peripheral nervous system (CB1)
and on immune cells (CB2). It has been shown to augment dopamine release. Delta-9-
tetrahydrocannabinoid (THC) is the most potent component.
Toxicokinetics
Rapidly and completely absorbed by inhalation. Bioavailability is reduced if ingested.
Cannabinoids are highly protein bound, lipid soluble and have large volumes of distribution
(10 L/kg). They undergo hepatic metabolism to form active and inactive metabolites that
are excreted in the urine. Elimination half-life of the metabolites is several days.
CLINICAL FEATURES
Patients may present with symptoms of acute intoxication, psychiatric
SPECIFIC TOXINS
sequelae or withdrawal. In adults, acute symptoms last up to 4 hours
following inhalation and up to 8 hours following ingestion. Clinical
features of intoxication include:
— Ataxia, incoordination, impaired judgment
— Sedation
— CNS depression
— Coma in children can last up to 36 hours
l Cardiovascular
— Tachycardia 191
— Orthostatic hypotension
— Syncope
l Psychiatric
TOXICOLOGY HANDBOOK

— Euphoria and relaxation
— Agitation
— Anxiety and panic attacks
— Time distortion, hallucinations, delusions
— Acute psychosis
l Respiratory complications (rare)
— Pneumothorax
— Pneumomediastinum
Chronic cannabis users may also present repeatedly to emergency
departments with cannabinoid hyperemesis syndrome. This syndrome
is characterised by repeated episodes of vomiting separated by weeks
or months and difficult to control. There is a high incidence of repeated
therapeutic showering or bathing in hot water to achieve temporary
control of symptoms. The diagnosis should only be made after alternative
aetiologies are excluded. The vomiting resolves with abstinence.
INVESTIGATIONS
l Serum or urine cannabinoid levels are not readily available and do
not assist acute management. They are sometimes performed for
forensic indications
l A single cannabis cigarette is associated with peak blood THC
levels of 50–129 microgram/L at 15 minutes. 11-carboxy-THC,
a metabolite of THC, reaches peak concentrations of 15–54
microgram/L in 2.4 hours
l pot blood levels of 11-carboxy-THC greater than 40 microgram/L
S
indicate chronic consumption
l Urine screening tests may be positive for 1–3 days after acute use,
or 10 days to 4 weeks after chronic use
l Passive smoking of cannabis may give positive results after an
acute exposure for several days on some screening tests.
l False positive urine screens occur.
MANAGEMENT
l Cannabis intoxication is benign and self-limiting
l Tachycardia and hypotension are managed with fluids and
sedation as appropriate
SPECIFIC TOXINS
l Treat severe agitation with IV diazepam 5 mg every 2–5 minutes

until sedation is achieved. Once sedated, the patient should be
rousable to voice but calm. Large doses are often necessary
l Adult patients with mild dysphoria or agitation are given oral
diazepam 5 mg and reassured
l Cannabinoid hyperemesis syndrome sufferers may require
intravenous fluids and antiemetics
Decontamination
192 l Not clinically useful
19
2

TOXICOLOGY HANDBOOK
Antidotes
l None available.

l hildren who may have ingested marijuana should be observed in
C
hospital for 4 hours. If they do not develop symptoms during that
period they may then be safely discharged
l Patients with intoxication adequately controlled with
benzodiazepine sedation may be managed supportively
in a ward environment. They may be discharged when
asymptomatic. Patients with cannabinoid hyperemesis
syndrome frequently require short admissions for intravenous
fluids and antiemetic therapy. They should be counselled
and supported to achieve and maintain abstinence following
discharge.
HANDY TIPS
l annabis poisoning is not life threatening and acute toxicity is
C
very low
l Profound coma or 12-lead ECG changes suggest a co-ingested
agent and the need to revise the risk assessment.
PITFALLS
l ailure to anticipate the potential in paediatric ingestions for rapid
F
onset of coma, hypotonia, abnormal movements, tachycardia and
bradycardia lasting 24–36 hours.
CONTROVERSIES
l annabis impairs coordination, cognition and behaviour in a dose-
C
dependent manner; however, the impairment of driving ability and
correlation with blood or urine cannabinoid levels has not been
established.
Presentations
Any part or extract of the hemp plant (Cannabis sativa) can be dried or converted to a resin
extract.
References
Allen JH, de Moore GM, Heddle R et al. Cannabinoid hyperemesis: cyclical hyperemesis in
association with chronic cannabis abuse. Gut 2004; 53:1566–1570.
SPECIFIC TOXINS
Hall W, Solowij N. Adverse effects of cannabis. Lancet 1998: 352:1611–1615.
Reece AS. Chronic toxicology of cannabis. Clinical Toxicology 2009; 47(6):517–524.
Sydney S, Beck JE, Tekawa IE et al. Marijuana use and mortality. American Journal of
Public Health 1997; 87:585–590.
3.24 CARBAMAZEPINE
Deliberate self-poisoning with this anticonvulsant agent results
in predictable dose-dependent CNS and anticholinergic effects. 193
Management is primarily supportive with the selected use of enhanced
elimination techniques.
TOXICOLOGY HANDBOOK
RISK ASSESSMENT
l linical features are dose dependent (see Table 3.24.1) but
C
onset varies depending on whether preparation is immediate or
controlled release.
TABLE 3.24.1 Dose-related risk assessment: Carbamazepine
Dose Effect
20–50 mg/kg Mild–moderate CNS and anticholinergic effects
>50 mg/kg Fluctuating mental status with intermittent

agitation and risk of progression to coma
within the first 12 hours
Risk of hypotension and cardiotoxicity with
extreme doses
l ollowing larger overdoses, anticholinergic effects may be

F
prominent prior to development of coma
l Following massive ingestions, coma is anticipated to last several
days, secondary to ongoing absorption, slow elimination and the
presence of an active metabolite
l Pregnancy: Carbamazepine is teratogenic. Overdose in the first

trimester warrants referral for further antenatal assessment
l Children: One 400 mg tablet is enough to cause significant
intoxication in a toddler and suspected ingestion of this dose or
greater warrants observation in hospital for 8 hours.
Toxic mechanism
Carbamazepine is structurally similar to the tricyclic antidepressant, imipramine. It inhibits
inactivated sodium channels, thus preventing further action potentials. It also blocks
noradrenaline reuptake and is an antagonist at muscarinic, nicotinic and N-methyl-D-
aspartate central adenosine receptors.
Toxicokinetics
Carbamazepine is slowly and erratically absorbed. Following large overdoses, ileus
secondary to anticholinergic effects may result in ongoing absorption for several days.
Carbamazepine has a small volume of distribution (0.8–1.2 L/kg) and undergoes hepatic
metabolism by cytochrome P450 3A4 to form an active metabolite (carbamazepine
10,11-epoxide). This is metabolised to inactive metabolites that are excreted in the urine.
CLINICAL FEATURES
SPECIFIC TOXINS
Clinical features of intoxication are usually evident within 4 hours of

ingestion, but may not reach their most severe extent until 8–12 hours,
particularly with controlled-release preparations. Ongoing erratic
absorption for several days frequently complicates large overdoses
producing a fluctuating clinical course.
l Mild–moderate CNS effects include nystagmus, dysarthria, ataxia,
sedation, delirium, mydriasis, ophthalmoplegia and myoclonus
l Anticholinergic effects, such as urinary retention, tachycardia and
dry mouth, are common in the early stages
194 l Coma requiring intubation and ventilation may be delayed until
19
8–12 hours post-ingestion. A fluctuating mental status with

4
intermittent agitation may also occur

l Large overdoses may be complicated by seizures, hypotension
TOXICOLOGY HANDBOOK

and cardiac conduction abnormalities. Cardiac dysrhythmias
(VT, VF, asystole) are associated with massive overdoses.
INVESTIGATIONS
l Serum carbamazepine levels (see Table 3.24.2)
Useful to confirm the diagnosis
In mild–moderate intoxication management is guided by clinical
features, so repeated levels are not required
In cases with coma, monitoring of carbamazepine levels every
6 hours is essential to monitor the patient’s clinical course
TABLE 3.24.2 Correlation of serum levels and clinical features:

Carbamazepine
Carbamazepine level Clinical features
8–12 mg/L (34–51 micromol/L) Therapeutic range
>12 mg/L (51 micromol/L) Nystagmus and ataxia
>20 mg/L (85 micromol/L) CNS and anticholinergic effects
>40 mg/L (170 micromol/L) Coma, seizures and cardiac
conduction abnormalities
Ingestions >50 mg/kg may be associated with evidence
of sodium channel blockade (1st degree heart block and
increased QRS duration). A repeat ECG should be examined
at the onset of significant intoxication, and every 12 hours
thereafter. Abnormalities prompt more frequent ECG evaluation.
MANAGEMENT
l In the rare event of ventricular dysrhythmias, resuscitation should
include the use of IV bolus sodium bicarbonate, as outlined in
SPECIFIC TOXINS
Chapter 4.25: Sodium bicarbonate
l Basic resuscitative measures ensure the survival of the vast majority
of patients. General supportive care measures are indicated, as
outlined in Chapter 1.4: Supportive care and monitoring
l Seizures and agitated delirium may be managed with
benzodiazepines as outlined in Chapter 2.6: Approach to
seizures and Chapter 2.7: Delirium and agitation
Decontamination
l Activated charcoal is considered for ingestions <50 mg/kg or larger 195
ingestions of controlled-release preparations that present very
early and asymptomatic
l If CNS toxicity is already evident, activated charcoal is only
TOXICOLOGY HANDBOOK

administered after the patient is intubated
l Methods of enhanced elimination are frequently considered in severe
carbamazepine intoxication but their effect on outcome has not been
studied in controlled trials (see Chapter 1.7: Enhanced elimination)
l Multiple-dose activated charcoal is indicated in intubated patients.
It is ceased immediately if bowel sounds disappear
l Extracorporeal elimination techniques are useful in severe
intoxication. Haemodialysis or haemodiafiltration remove
carbamazepine effectively when serum levels are markedly
elevated. Indications include prolonged coma with rising serum
levels after 48 hours or haemodynamic instability
Antidotes
l None available.

l hildren suspected of ingesting 20 mg/kg mg of carbamazepine
C
should be observed in hospital for at least 8 hours and overnight
l Patients who are clinically well without sedation or anticholinergic
effects at 8 hours following ingestion do not require further
monitoring or investigation
l Patients with nystagmus, ataxia, drowsiness and anticholinergic
effects are managed supportively in a ward environment after an
initial 8-hour period of observation in the emergency department
l Patients with coma requiring intubation or seizures require
admission to the intensive care unit.
HANDY TIPS
l In suspected paediatric ingestion, an undetectable serum
carbamazepine level any time after the first hour excludes ingestion
and allows immediate discharge.
PITFALLS
l ailure to appreciate the potential for delayed onset of toxicity
F
l Failure to detect urinary retention and place an indwelling urinary
catheter.
CONTROVERSIES
l he indications for multiple-dose activated charcoal and
T
extracorporeal elimination. The decision remains one of clinical
SPECIFIC TOXINS
judgment involving a risk–benefit analysis.
Presentations
Carbamazepine tablets 100 mg (200)
Carbamazepine tablets 200 mg (200)
Carbamazepine controlled-release tablets 200 mg (200)
Carbamazepine controlled-release tablets 400 mg (200)
Carbamazepine suspension 20 mg/mL (300 mL)
196
References
19
Apfelbaum JD, Carabati EM, Kerns WP II. Cardiovascular effects of carbamazepine

6
toxicity. Annals of Emergency Medicine 1995; 25:631–635.

Hojer J, Malmlund HO, Berg A. Clinical features in 28 consecutive cases of laboratory
TOXICOLOGY HANDBOOK
confirmed massive poisoning with carbamazepine alone. Journal of Toxicology-

Jones AL, Proudfoot AT. Features and management of poisoning with modern drugs used
to treat epilepsy. Quarterly Journal of Medicine 1998; 91:325–332.
Spiller HA. Management of carbamazepine overdose. Pediatric Emergency Care 2001;
17(6):452–456.
Tapolyai M, Campbell M, Dailey K et al. Hemodialysis is as effective as hemoperfusion for
drug removal in carbamazepine poisoning. Nephron 2002; 90(2):213–215.
3.25 CARBON MONOXIDE

Carbon monoxide is a common cause of poisoning death. Acute effects
are secondary to tissue hypoxia. Delayed neurological sequelae are
secondary to an incompletely understood cascade of endovascular
oxidative injury and inflammation.
RISK ASSESSMENT
l arbon monoxide poisoning deaths almost always occur pre-
C
hospital. For those who arrive at hospital, survival is ensured and
risk assessment attempts to identify those at risk of long-term
neuropsychological sequelae
l Acute deliberate self-poisoning by car exhaust fumes usually
involves exposure to high concentrations of CO for a limited
duration and lower risk of long-term sequelae
l Accidental occupational or domestic exposure often involves
exposure to lower concentrations of CO for a prolonged duration
and higher risk of long-term sequelae
l Other high-risk features include:
— Significant loss of consciousness or coma
— Persistent neurological dysfunction (e.g. confusion)
— Abnormal cerebellar examination
— Metabolic acidosis
— Myocardial ischaemia
— Age over 55 years
l Outcome is poorly correlated with carboxyhaemoglobin level
l Pregnancy: Fetal haemoglobin binds CO more avidly, rendering

the fetus more susceptible to injury.
Toxic mechanism
Carbon monoxide has 210 times the affinity for haemoglobin than oxygen. Binding
SPECIFIC TOXINS
therefore renders haemoglobin oxygen transport less effective. Hypoxia results. In addition,
CO binds to intracellular cytochromes. Carbon monoxide also initiates endothelial oxidative
injury, lipid peroxidation and an inflammatory cascade. This process is probably responsible
for the delayed neurological sequelae.
Toxicokinetics
Elimination half-life is determined by the dissolved oxygen tension of the blood and varies
as follows:
l Room air: 240 min
l 100% oxygen: 90 min 197
l 100% oxygen at three atmospheres: 23 min.
CLINICAL FEATURES
TOXICOLOGY HANDBOOK
Following acute exposure, most patients present with headache,
nausea and varying degrees of altered mentation, which rapidly resolve
with oxygen therapy. A history of transient loss of consciousness is
common. Potential symptoms include:
— Headache, nausea, dizziness
— Confusion, poor concentration, mini mental status examination
(MMSE) errors
— Incoordination and ataxia
— Seizures and coma
l Cardiovascular
— Tachycardia and hypertension
— Ischaemic ECG changes
— Hypotension
— Dysrhythmias
— Acute myocardial infarction
l Respiratory
— Non-cardiogenic pulmonary oedema
l Metabolic
— Lactic acidosis
— Rhabdomyolysis
— Hyperglycaemia
l Other
— Disseminated intravascular coagulation
— Bullae, alopecia, sweat gland necrosis
Persistent neurological sequelae are usually evident from the time of
poisoning and seen in up to 30% of survivors at 1 month. Neuropsychiatric
sequelae persist in 6–10% at 12 months. Symptoms are non-specific and
include personality changes, poor concentration, dementia, psychosis,
parkinsonism, ataxia, peripheral neuropathy and hearing loss.
INVESTIGATIONS
l Carboxyhaemoglobin level (COHb)
— Confirms the diagnosis and can be loosely correlated to
symptoms when measured shortly after the termination of
exposure
SPECIFIC TOXINS
TABLE 3.25.1 Correlation of COHb levels and clinical features
Level Clinical features
<10% Background level in a smoker
10% Usually asymptomatic, slight headache

198 20% Dizziness, nausea, dyspnoea, throbbing headache
19
8
30% Vertigo, ataxia, visual disturbance

TOXICOLOGY HANDBOOK
40% Confusion, coma, seizures, syncope
50% Cardiovascular and respiratory failure, arrhythmias,

seizures and death
l erum lactate
S
l Full blood count
l EUC
l Troponin
l β-HCG
l Mini mental status examination (MMSE)
l Cranial CT or MRI brain
— May demonstrate cerebral oedema, cerebral atrophy, basal
ganglia injury or cortical demyelination in severe cases
l Neuropsychiatric testing
— May be indicated at 3–12 months to investigate persistent or
delayed neurological symptoms.
MANAGEMENT
l Administration of high-flow supplemental oxygen as soon as
possible
G
l Close clinical and physiological monitoring is indicated in
symptomatic patients
Decontamination
l Remove from exposure and apply supplemental oxygen
l Elimination of CO is enhanced by
— Normobaric oxygen
– All patients should receive 100% oxygen or high-flow oxygen
via a non-rebreather mask until all symptoms have resolved
– Pregnant patients receive 100% oxygen for 24 hours while
SPECIFIC TOXINS
fetal wellbeing is assessed
— Hyperbaric oxygen (HBO)
– May be indicated in patients with one or more of the risk
factors listed above but indications and effectiveness are
controversial (see Controversies below)
– All pregnant patients should be considered for HBO
Antidotes
l None available.
199
l ll symptomatic patients immediately receive supplemental oxygen
A
and are referred to hospital for evaluation
TOXICOLOGY HANDBOOK
l Continue oxygen in hospital until all symptoms resolve
l Patients with persistent symptoms of end-organ ischaemia are
managed in a high-dependency or intensive care setting
l Arrange follow-up at 1–2 months to assess general
neuropsychiatric function.
HANDY TIPS
l he patient who presents following accidental occupational or
T
domestic poisoning represents an index case. Investigation of the
source and other potential victims is indicated.
PITFALLS
l ailure to diagnose accidental occupational or domestic poisoning in
F
patients who present with headache or other non-specific symptoms
l Failure to perform a detailed neurological examination and MMSE.
CONTROVERSIES
l he duration of normobaric oxygen treatment
T
l The indications for and effectiveness of HBO. Randomised
controlled trials give conflicting evidence. While HBO cannot be
routinely recommended, there may be a small group of patients
with severe poisoning for whom there is some (unproven) benefit.
Clinical judgment and consideration of local logistics is required.
Sources
Incomplete combustion of hydrocarbon fuels
Methylene chloride (dichloromethane) is a solvent metabolised to CO in vivo.
References
Buckley NA, Isbister GK, Stokes B et al. Hyperbaric oxygen for carbon monoxide
poisoning: A systematic review and critical analysis of the evidence. Toxicological
Reviews 2005: 24(2):75–92.
Juurlink DN, Buckley NA, Stanbrook MB et al. Hyperbaric oxygen for carbon
monoxide poisoning. Cochrane Database of Systematic Reviews 2005;1: CD002041.
pub2.
Scheinkestel CD, Bailey M, Myles PS et al. Hyperbaric or normobaric oxygen for acute
carbon monoxide posioning: a randomised controlled clinical trial. Medical Journal of
Australia 1999; 170:203–210.
Weaver LK, Hopkins RO, Chan KJ et al. Hyperbaric oxygen for acute carbon monoxide
poisoning. New England Journal of Medicine 2002; 347(14):1057–1067.
SPECIFIC TOXINS
3.26 CHLOROQUINE AND HYDROXYCHLOROQUINE

These quinolone-related drugs are the most toxic of the antimalarials when
taken in overdose. Hydroxychloroquine is also used to treat systemic lupus
and rheumatoid arthritis. Overdose produces rapid onset of hypotension,
CNS depression, cardiac conduction defects and hypokalaemia.
Chloroquine is a leading cause of pharmaceutical overdose mortality in
many countries where malaria is endemic. Management is supportive.
200
RISK ASSESSMENT
20
0
l Ingestion of >10 mg/kg of chloroquine is potentially toxic

l Serious toxicity and increasing mortality is expected with ingested
TOXICOLOGY HANDBOOK
doses >30 mg/kg

l Ingestion of >5 g of chloroquine in adults is usually fatal without
intervention
l The dose-related risk assessment is less well-defined for
hydroxychloroquine, but appears to be similar to chloroquine
l Children: Ingestion of even one tablet is regarded as potentially
lethal in a child less than 6 years of age.
Toxic mechanism
These drugs have a direct toxic effect on the CNS via effects on voltage-dependent Na+
channels. CNS toxicity is compounded by cerebral hypoperfusion from cardiovascular
effects. Cardiovascular manifestations are related to blocking of multiple inward and outward
membrane currents. Hypotension and cardiogenic shock are due to a direct cardiodepressant
effect. Hypokalaemia is believed to be due to a transport-dependent mechanism.
Toxicokinetics
Both agents have similar toxicokinetics. Absorption after ingestion is rapid and complete. They
are extensively tissue bound and have Vd of >50 L/kg. They are partially metabolised and have
prolonged half-lives of several weeks. More than 50% of chloroquine is excreted unchanged.
CLINICAL FEATURES
Onset of symptoms occurs within 1–2 hours
Clinical features include:
l Non specific symptoms of dizziness, nausea and vomiting
l Cardiovascular
— Rapid onset of hypotension
— Cardiac conduction defects (QRS widening, QT prolongation)
— Cardiac arrest
— Depressed conscious state
— Seizures
l Metabolic
— Hypokalaemia due to intracellular shift of potassium.
INVESTIGATIONS
l EUC
— Detect and monitor hypokalaemia
SPECIFIC TOXINS
l Serial ECGs
— Detect and monitor QRS and QT prolongation
— Sinus arrest, varying degrees of heart block
l Specific levels are not routinely available and do not assist in
management. They may be useful retrospectively to confirm the
diagnosis.
MANAGEMENT
Resuscitation, supportive care and monitoring 201
l Chloroquine or hydroxychloroquine overdose is a life-
threatening emergency and is managed in an area equipped for
TOXICOLOGY HANDBOOK
— Coma: prompt intubation and ventilation is indicated at the
first sign of a depressed conscious state
— Broad complex tachycardias: Manage broad complex
tachycardias aggressively with intubation, ventilation and
serum alkalinisation. Give sodium bicarbonate 1–2 mmol/kg IV
for QRS prolongation. Aim for a pH of 7.5–7.55 (see Chapter
4.25 Sodium bicarbonate)
— Hypotension: initially treat with fluid resuscitation but
vasopressors are often required and adrenaline by titrated IV
infusion is the first-line agent
— Seizures are controlled with intravenous benzodiazepines
l Ensure normokalaemia. Hypokalaemia should be anticipated, but
avoid aggressive replacement, as total body potassium is not
depleted
l High dose diazepam (0.5 mg/kg IV bolus then an infusion of
1 mg/kg IV over 24 hours) post-intubation has been advocated. Its
protective mechanism is unclear
Decontamination
l Administration of activated charcoal is withheld until the airway is
protected
Antidote
l None available.
l ll children suspected of ingesting even one chloroquine or
A
hydroxychloroquine tablet must be assessed and observed in hospital
l Patients who are asymptomatic at 6 hours following ingestion may
be discharged. Discharge should never occur at night
l Patients with signs of cardiotoxicity or seizures are admitted for
observation and supportive care until all clinical features of toxicity
including sinus tachycardia resolve
l Admission to ICU is indicated following massive ingestions (>30 mg/kg)
and for patients manifesting signs of significant cardiotoxicity.
HANDY TIPS
l nticipate catastrophic deterioration in any patient presenting early
A
SPECIFIC TOXINS
following chloroquine overdose. Intubate and hyperventilate at the

first sign of cardiotoxicity or clinical deterioration
l Avoid over-enthusiastic correction of hypokalaemia as total body
potassium is not depleted and excessive administration can lead to
life-threatening hyperkalaemia as toxicity resolves.
CONTROVERSIES
l he mechanism of action of high-dose diazepam infusion in
T
chloroquine and hydroxychloroquine toxicity is unclear and its
202 efficacy is unproven.
20
2
Presentations
TOXICOLOGY HANDBOOK
Chloroquine phosphate 155 mg tablets (no longer available in Australia)

Hydroxychloroquine sulfate 200 mg tablets (100)
References
Clemessy JL, Favier C, Borron SW et al. Hypokalaemia related to acute chloroquine
ingestion. Lancet 1995; 346(8979):877–880.
Clemessy J-L, Taboulet P, Hoffman JR et al. Treatment of acute chloroquine poisoning: a
5-year experience. Critical Care Medicine 1996; 24:1189–1195.
Marquardt K, Albertson TE. The treatment of hydroxychloroquine overdose. Journal of
Emergency Medicine 2005; 28(4): 437–443.
Riou B, Barriot P, Rimailho A et al. Treatment of severe chloroquine poisoning. New
England Journal of Medicine 1988; 318:1–6.
Smith ER, Klein-Schwartz W. Are 1-2 dangerous? Chloroquine and hydroxychloroquine
exposure in toddlers. Journal of Emergency Medicine 2005; 28 (4):437–443.
3.27 CHLORAL HYDRATE

Chloral hydrate is still available for use as a sedative in children
undergoing procedures. It was withdrawn as a sedative-hypnotic for
adults because of its narrow therapeutic index. In overdose it causes
rapid onset of CNS depression and cardiac dysrhythmias and these are
frequently lethal without intervention.
RISK ASSESSMENT
l Ingestion of >100 mg/kg, twice the upper limit of therapeutic
dosing, is associated with high risk of coma and life-threatening
cardiac dysrhythmias.
Toxic mechanism
Chloral hydrate has a direct irritant action on mucosal surfaces. The mechanism of
action of the toxic metabolite, trichloroethanol (TCE), on the CNS and cardiovascular
system is unclear. Cardiac dysrhythmias are thought to be caused by sensitisation
of the myocardium to circulating catecholamines. Chloral hydrate also decreases
myocardial contractility and shortens the refractory period, which enhances
cardiotoxicity.
Toxicokinetics
Chloral hydrate is rapidly absorbed following oral administration. It is then rapidly
converted to the active metabolite, TCE, by hepatic alcohol dehydrogenase. TCE is
conjugated with glucuronic acid and excreted in the urine and to a limited extent in the
bile. Chloral hydrate has an elimination half-life of only 4–5 minutes whereas TCE has
an elimination half-life of 8–12 hours after therapeutic doses and up to 35 hours after
SPECIFIC TOXINS
overdose.
CLINICAL FEATURES
Chloral hydrate overdose is characterised by rapid (<30 min) onset
of life-threatening CNS and cardiovascular toxicity. Gastrointestinal
effects and hypothermia complete the clinical profile.
— Drowsiness, lightheadedness and ataxia may rapidly progress
to coma and respiratory depression
203
l Cardiovascular
— Cardiac dysrhythmias:
– Multifocal premature ventricular ectopics
TOXICOLOGY HANDBOOK
– Atrial fibrillation
– Supraventricular tachycardia
– Ventricular tachycardia
– Ventricular fibrillation
– Torsades de pointes
– Asystole
— Hypotension
l Hypothermia
l Gastrointestinal
— Corrosive injury may be associated with gastro-oesophageal
necrosis and even perforation
— Permanent stricture formation is a potential sequela.
INVESTIGATIONS
l Serial 12-lead ECGs are essential to monitor the effects on clinical
conduction and response to therapy
l Other investigations may be useful to exclude alternative
aetiologies when the diagnosis is in doubt
l TCE levels can be measured and correlate with toxicity, but
are never available in a clinically useful time frame. They may
be useful to retrospectively confirm the diagnosis in forensic
cases
l Gastroscopy may be indicated after a large ingestion to assess
mucosal damage and potential for stricture formation.
MANAGEMENT
l The patient is initially managed in an area equipped for
l Attention to airway, breathing and circulation are paramount and
managed along conventional lines, as outlined in Chapter 1.2:
Resuscitation
l Immediate endotracheal intubation and ventilation is indicated at
the first signs of progressive CNS or cardiovascular toxicity
l Beta-blockers are indicated for chloral hydrate-induced cardiac
tachydysrhythmias. Administer propranolol 0.5–1 mg or metoprolol
5 mg (0.1 mg/kg in children) by slow IV injection and repeat after
5 minutes if response inadequate. An esmolol infusion is prepared
SPECIFIC TOXINS
at a concentration of 10 mg/mL in 5% dextrose and commenced at

rate of 0.05 mg/kg/minute (20 mL/hour in 70-kg adult) and titrated
to response
l Hypotension is managed with IV fluids. Give 10–20 mL/kg of IV
crystalloid as an initial response (see Chapter 2.5: Hypotension)
l Catecholamines are contraindicated for hypotension as they are
dysrhythmogenic in chloral hydrate toxicity
204 l Corrosive effects of oral chloral hydrate, especially in large
20
ingestions, may warrant evaluation with upper gastrointestinal

4
endoscopy within 24 hours

TOXICOLOGY HANDBOOK
Decontamination
l Activated charcoal may be given once the airway is secured
with endotracheal intubation, but never takes precedence over
resuscitation and supportive care measures
l TCE elimination can be enhanced with haemodialysis, but patients
are usually stabilised by the measures described above, rendering
this intervention unnecessary
Antidotes
l Not clinically useful.

l ll suspected paediatric ingestions and adult deliberate self-
A
poisonings require immediate assessment and observation in hospital
l All patients should be closely observed with cardiac monitoring in
place for at least 2 hours and until recovery is complete
l Development of CNS depression requiring intubation, cardiac
dysrhythmias or hypotension are indications for admission to an
HANDY TIPS
l orsades de pointes has been treated with IV magnesium
T
and overdrive pacing but rarely responds; beta-blockade is
indicated
l Consider haemodialysis in patients with refractory cardiac
dysrhythmias and haemodynamic instability.
PITFALLS
l xacerbation of ventricular dysrhythmias by the administration of
E
catecholamines during resuscitation
l Failure to administer beta-blockers to the patient with ventricular
dysrhythmias.
CONTROVERSIES
l he administration of beta-blockers is based on the premise
T
that ventricular dysrhythmias arise as a result of sensitisation of
the myocardium to circulating catecholamines. Their efficacy is
supported by clinical experience and multiple favourable case
reports, but has not been evaluated in clinical trials
l Flumazenil is reported to reverse the CNS depression of chloral
SPECIFIC TOXINS

hydrate, but its administration is not recommended. Given the life-
threatening nature of the cardiovascular toxicity, early definitive control
of airway and ventilation with endotracheal intubation is preferred.
Presentations
Chloral hydrate 1 g/10 mL syrup (200 mL)
References
Graham SR, Day RO, Lee R et al. Overdose with chloral hydrate: A pharmacological and 205
therapeutic review. Medical Journal of Australia 1988; 149:686–688.
Pershad J, Palmisano P, Nichols M. Chloral hydrate: the good and the bad. Pediatric
Emergency Care 1999; 15:432–435.
Sing K, Erickson T, Amitai Y et al. Chloral hydrate toxicity from oral and intravenous
TOXICOLOGY HANDBOOK
administration. Journal of Toxicology-Clinical Toxicology 1996; 34:101–106.
Zahedi A, Grant MH, Wong DT. Successful treatment of chloral hydrate cardiac toxicity
with propranolol. American Journal of Emergency Medicine 1999; 17(5):490–491.
3.28 CLONIDINE
Clonidine overdose produces varying degrees of CNS depression and mild
cardiovascular effects. Classically, intoxication manifests clinically with
the triad of drowsiness, miosis and bradycardia. Treatment is supportive.
RISK ASSESSMENT
l linical effects correlate poorly with ingested dose. Significant
C
CNS depression may occur with doses >20 microgram/kg, but
large doses are sometimes tolerated with minor effects
l Onset of clinical features is rapid, usually within 2 hours of
ingestion and always within 6 hours
l Children: Ingestion of 2 tablets is potentially lethal without
supportive care
— >10 microgram/kg: Bradycardia and hypotension
— >20 microgram/kg: Respiratory depression or apnoea.
Toxic mechanism
Clonidine is a centrally acting α2-adrenergic agonist used in the management of
hypertension, migraine, withdrawal states, menopause and pain control. It acts as a
sympathoplegic agent, decreasing central nervous sympathetic outflow. It also increases
endothelial nitric oxide levels and decreases renin activity.
Toxicokinetics
Clonidine is rapidly and completely absorbed with peak concentration and therapeutic
effects occurring within 1–3 hours. Clonidine has a large volume of distribution of 3–6 L/kg.
It is metabolised in the liver, but half the ingested dose is eliminated unchanged in the
urine. Elimination half-life is 6–24 hours. Protein binding is approximately 20–40%.
CLINICAL FEATURES
l nset of toxicity is rapid. Transient early hypertension (not usually
O
clinically significant) is reported in 20–50% of cases
l Lethargy, miosis, slurred speech and ataxia usually occur within
2 hours, and always within 6 hours. The patient can frequently be
roused with a stimulus, only to become deeply somnolent again
when not disturbed
l Severe intoxication is associated with coma, bradycardia and
SPECIFIC TOXINS
hypotension. Sinus bradycardia (rate sometimes as low as 30/minute)

is common and is frequently present without hypotension or signs of
decreased end-organ perfusion. Heart block is reported
l Hypothermia, respiratory depression and apnoea are reported, but
uncommon
l Symptoms resolve within 24 hours.
INVESTIGATIONS
206 Screening tests in deliberate self-poisoning
20

TOXICOLOGY HANDBOOK
l Serial ECGs.
MANAGEMENT
l Intubation and ventilation is only required in the most severe
intoxications
l Bradycardia is common but specific management (e.g. atropine,
catecholamine infusion or pacing) is rarely required and only if
there is hypotension or evidence of decreased end-organ perfusion
l Give 10–20 mL/kg of normal saline IV to patients with symptomatic
hypotension
Decontamination
l Oral activated charcoal is contraindicated because of the risk of
subsequent CNS depression
Antidote
l Naloxone inconsistently provides transient reversal of the CNS and
respiratory depression associated with clonidine intoxication
l A trial of administration may be warranted as a temporising
measure if airway or breathing is compromised, but definitive care
with intubation and ventilation is more reliable
l dminister repeated doses of 0.1 mg IV every 30–60 seconds while
A
supporting airway and ventilation, until adequate spontaneous
respiration is re-established. Alternatively, 0.4 mg IM or SC can be
administered if IV access cannot be established
l For further information on the indications, contraindications and
administration see Chapter 4.19: Naloxone.

l aediatric patients should be observed in hospital following
P
potential accidental exposure
l Patients who are clinically well without symptoms at 4 hours
following ingestion may be discharged. Discharge should never
occur at night
SPECIFIC TOXINS
l Patients with mild symptoms may be managed supportively in a
ward environment. Discharge is appropriate when the patient is
clinically well, ambulant, passing urine, eating and drinking
l Patients with significant CNS depression requiring intubation
require admission to an intensive care unit.
HANDY TIPS
l onsider the diagnosis of clonidine ingestion in any small child
C
who presents with lethargy, bradycardia and miosis
207
l Bradycardia is frequently asymptomatic and specific management
is not required
l Adults who overdose on clonidine are frequently opioid dependent
TOXICOLOGY HANDBOOK
and use clonidine to ameliorate symptoms of opioid withdrawal—
avoid naloxone in these patients, as it will exacerbate opioid
withdrawal.
PITFALLS
l ailure to recognise the potential lethality of accidental paediatric
F
ingestion of clonidine
l Failure to recognise respiratory depression in children, especially at
night
l Iatrogenic anticholinergic delirium from excessive doses of atropine
administered in response to bradycardia.
CONTROVERSIES
l Role of naloxone.
Presentations
Clonidine 100 microgram tablets (100)
Clonidine 150 microgram tablets (100)
Clonidine 150 microgram/mL 1 mL ampoules
References
Erickson SJ, Duncan A. Clonidine poisoning—an emerging problem: epidemiology, clinical
features, management and preventative strategies. Journal of Paediatrics and Child
Health 1998; 34(3):280–282.
Fiser DH, Moss MM, Walker W. Critical care for clonidine poisoning in toddlers. Critical
Care Medicine 1990; 18(10):1124–1128.
Seger DL. Clonidine toxicity revisited. Journal of Toxicology-Clinical Toxicology 2002;
40:145–155.
3.29 CLOZAPINE
Deliberate self-poisoning with this atypical antipsychotic agent is unusual
because its use is restricted and closely supervised. Care is supportive.
RISK ASSESSMENT
l clear dose-response is not defined, but most poisonings follow a
A
relatively benign course
l Coma requiring intubation is uncommon when clozapine is taken
alone. It is more likely to develop in patients who do not normally
take clozapine
l Children: Ingestion of a single tablet usually results in
SPECIFIC TOXINS
symptoms and prompts referral to hospital for assessment and

observation. Ingestion of >2.5 mg/kg is associated with sedation,
hypersalivation, tachycardia, ataxia and agitation. Extrapyramidal
effects may be seen in the following days.
Toxic mechanism
Clozapine is a tricyclic dibenzodiazepine atypical antipsychotic. It is an antagonist at
mesolimbic dopamine (D1 and D2), serotonin (5HT) and peripheral alpha (α1) receptors.
Compared to other antipsychotic agents in its class, it is a potent antagonist at muscarinic
208 (M1), histamine (H1) and gamma-aminobutyric acid (GABA) receptors.
20
Toxicokinetics
8
Clozapine is rapidly absorbed following oral administration. It is highly protein bound and
TOXICOLOGY HANDBOOK
has a moderate volume of distribution 0.5–3 L/kg. Clozapine is metabolised in the liver by
oxidation (cytochrome P450 1A2, 2D6) to metabolites that are excreted in the urine and
faeces. A significant first-pass effect occurs.
CLINICAL FEATURES
l nset of intoxication is rapid, occurring within 4 hours of ingestion
O
l Lethargy, confusion, sedation, tachycardia and orthostatic
hypotension are common
l Anticholinergic effects, such as agitation, ileus or urinary retention,
often occur
l Mydriasis and miosis are both described
l Hypersalivation is characteristic
l Seizures occur in approximately 5–10% of patients
l Extrapyramidal effects are more common in children
l Coma requiring intubation is uncommon
l QT prolongation is uncommon
l Toxicity usually resolves within 24 hours.
INVESTIGATIONS
Specific investigations as required
l Serial ECGs
— Patients should have a 12-lead ECG at presentation and at
6 hours. If normal, ECG monitoring may cease. If there is
prolongation of the QT >450 ms, monitoring should continue
until the patient is clinically well and ECG changes have
resolved. Torsades de pointes has not been reported.
MANAGEMENT
l Basic resuscitative measures ensure a good outcome in the vast
l Treat seizures with benzodiazepines, as outlined in Chapter 2.6:
Approach to seizures
SPECIFIC TOXINS
Decontamination
l Clozapine is rapidly absorbed and characterised by a benign
clinical course; activated charcoal is not indicated
Antidotes
l None available.
209
l atients who are clinically well at 6 hours following ingestion are fit
P
TOXICOLOGY HANDBOOK
for medical discharge
l Patients who manifest clinical features of intoxication require
admission for appropriate supportive care
l Parents of small children who have ingested clozapine are advised that
abnormal (extrapyramidal) movements might occur up to 7 days later.
HANDY TIPS
l onsider the diagnosis of clozapine overdose in a sedated patient
C
with features of anticholinergic poisoning but small pupils and
hypersalivation
l Therapeutic use of clozapine is associated with agranulocytosis
and myocarditis. These are not clinical features of acute poisoning.
PITFALLS
l Failure to recognise and correct urinary retention.
Presentations
Clozapine 25 mg tablets (28, 100) Clozapine 100 mg tablets (28, 100)
Clozapine 50 mg tablets (100) Clozapine 200 mg tablets (100)
References
Burns MJ. The pharmacology and toxicology of atypical antipsychotic agents. Clinical
Toxicology 2001: 39(1);1–14.
Isbister GK, Balit CR, Kilham HA. Antipsychotic poisoning in young children: A systematic
review. Drug Safety 2005; 26(11):1029–1044.
Reith D, Monteleone JP, Whyte IM et al. Features and toxicokinetics of clozapine in
overdose. Therapeutic Drug Monitoring 1998; 20(1):92–97.
Trenton A, Currier G, Zwemer F. Fatalities associated with therapeutic use and overdose of
atypical antipsychotics. CNS Drugs 2003; 17(5):307–324.
3.30 COCAINE
Cocaine has powerful sympathomimetic and local anaesthetic properties.
It is potentially lethal in overdose if severe hyperthermia, hypertension,
myocardial ischaemia or pro-arrhythmic effects occur.
RISK ASSESSMENT
l Ingestions of >1 g are potentially lethal
l The toxic dose is highly variable and small doses, particularly in
non-tolerant patients, may result in significant intoxication
l The presence of hyperthermia, headache, cardiac conduction
abnormalities, focal neurological signs or chest pain heralds
SPECIFIC TOXINS
potentially life-threatening complications
TABLE 3.30.1 Dose-related risk assessment: Cocaine

Dose Effect
1–3 mg/kg Safe local anaesthetic dose
20–30 mg Usual dose in a line of cocaine to be snorted
1g Potentially lethal
210
l Pregnancy: Cocaine is teratogenic and associated with an
21
increased incidence of miscarriage and fetal demise

l Lactation: Cocaine is excreted in breast milk and can result in
TOXICOLOGY HANDBOOK
infant intoxication
l Children: Ingestion is potentially lethal.
Toxic mechanism
Toxicity results from sympathomimetic, vasospastic and sodium channel blocking (local
anaesthetic) effects. Sympathomimetic effects are due to blockade of presynaptic
catecholamine reuptake and can result in vascular dissection, intracranial haemorrhage
and acute cardiomyopathy. Vasospasm and endothelial fissuring result in acute coronary
syndrome. Blockade of myocardial fast sodium channels may result in ventricular
dysrhythmias, as occur in tricyclic antidepressant cardiotoxicity. Central nervous system
excitation may result in psychomotor acceleration, seizures and hyperthermia.
Toxicokinetics
Well-absorbed through the mucous membranes of nasopharynx, pulmonary alveolar tree
and gastrointestinal tract. Peak concentrations achieved fastest with IV and inhalational
administration. Bioavailability depends on route (intranasal 25–80%; smoked 60–70%).
Highly lipid soluble, with a volume of distribution of 2 L/kg. Cocaine is rapidly metabolised
by liver and plasma cholinesterases to water-soluble metabolites. Only 1% of the drug
appears unchanged in the urine. Metabolites may persist in the blood and urine for up to
36 hours. Clinical duration of effect is approximately 60 minutes, with biological half-lives
being reported between 0.5 and 1.5 hours.
CLINICAL FEATURES
Patients may present with symptoms of acute intoxication, medical
complications of abuse or psychiatric sequelae. The onset of cocaine
intoxication is rapid, with major clinical manifestations occurring within
the first hour and usually lasting several hours. They include:
— Euphoria
— Anxiety, dysphoria, agitation and aggression
— Paranoid psychosis with visual and tactile hallucinations
— Hyperthermia, rigidity and myoclonic movements
— Seizures
l Cardiovascular
— Tachycardia and hypertension may be severe
— Arrhythmias and cardiac conduction abnormalities
— Acute coronary syndromes: vasospastic and/or coronary
thrombotic
— QT prolongation
— Acute pulmonary oedema
l Peripheral sympathomimetic
— Hyperthermia
— Muscle fasciculations
— Mydriasis, sweating and tremor
SPECIFIC TOXINS
l Clinical features associated with the following medical
complications:
— Hyperthermia-induced rhabdomyolysis, renal failure and
cerebral oedema
— Aortic and carotid dissection
— Subarachnoid and intracerebral haemorrhage
— Ischaemic colitis
— Pneumothorax
— Pneumomediastinum. 211
INVESTIGATIONS
TOXICOLOGY HANDBOOK
l EUC
— Detect renal failure and hyponatraemia
l ECG, CK and troponin
— Detect myocardial ischaemia, infarction, acute coronary
syndrome, QT prolongation and rhabdomyolysis
— A Brugada-type pattern of ECG changes (RBBB with ST
elevation in leads V1, V2 and V3) can occur in cocaine
intoxication
— Overall, the sensitivity of ECG for detecting myocardial
infarction is lower in cocaine users
l Chest x-ray
— Detect aortic dissection or pulmonary aspiration
l CT head
— Detect intracranial haemorrhage
l Note: Decreased mental status or focal neurological signs prompts
exclusion of hypoglycaemia, aortic dissection or intracranial
haemorrhage
l Note: Serum or urine cocaine levels are not readily available and do
not assist acute management.
MANAGEMENT
l Cocaine intoxication is a life-threatening emergency and is
resuscitation
— Cardiac dysrhythmias including ventricular tachycardia
— Hypertension
— Hyperthermia
— Seizures
— Severe agitation
l Ventricular tachycardia is treated with an IV bolus of 50–100
mmol sodium bicarbonate. Ventricular dysrhythmias refractory to
bicarbonate and defibrillation are treated with lignocaine 1.5 mg/kg
IV followed by an infusion of 2 mg/minute
l Acute coronary syndromes are treated by standard therapies,
with the exception of beta-blockers. This includes aspirin and
nitroglycerin. Thrombolytics are contraindicated in the presence of
severe hypertension, seizures, intracerebral haemorrhage or aortic
SPECIFIC TOXINS
dissection
l Urgent coronary angiography is indicated in the setting of ST
elevation that persists after nitroglycerin and calcium antagonists
l Sinus tachycardia and hypertension are treated with titrated
parenteral benzodiazepines
l Supraventricular tachycardia refractory to benzodiazepine sedation
is treated with verapamil 5 mg IV or adenosine 6–12 mg IV.
Cardioversion is indicated if unstable
212 l Hypertension refractory to benzodiazepine sedation, consider:
— Phentolamine 1 mg IV repeated every 5 minutes
21
2
— Titrated vasodilator infusion (sodium nitroprusside or glyceryl

trinitrate)
TOXICOLOGY HANDBOOK
— Note: Beta-adrenergic blockers are contraindicated

l Seizures and agitated delirium are managed with 5 mg diazepam
as an IV bolus every 2–5 minutes, repeated until seizures stop
or gentle sedation is achieved (See Chapter 2.6: Approach to
seizures and Chapter 2.7: Delirium and agitation.)
l Hyperthermia:
— Temperature >38.5°C is an indication for continuous core-
resuscitation
— Temperature >39.5°C requires rapid external cooling to
prevent multiple organ failure and neurological injury. Paralysis,
intubation and ventilation may be required
Decontamination
l Gastrointestinal decontamination with activated charcoal is not
indicated except in the specific instance of cocaine body packers
as discussed in Chapter 2.17: Body packers and stuffers
l Not clinically indicated
Antidotes
l None available.

C
for 4 hours. If they do not develop symptoms during that period
they may then be safely discharged
l atients whose intoxication is adequately controlled with
P
benzodiazepine sedation and have a normal blood pressure and
They are discharged when clinically well
l Patients with significant alteration of conscious state, hyperthermia
or ongoing chest pain are admitted to a high-dependency or
intensive care unit
l Cocaine body packers or stuffers must undergo gastrointestinal
decontamination under medical supervision.
HANDY TIPS
l arly control of agitation with IV benzodiazepine sedation calms
E
the patient, improves tachycardia, hypertension and hyperthermia,
SPECIFIC TOXINS
and is safe
l Administration of beta-adrenergic blockers is contraindicated in the
management of cocaine intoxication because it causes unopposed
alpha-receptor stimulation
l Ongoing chest pain or headache requires further investigation
l Acute coronary syndrome is managed according to normal
protocols. CT brain should be performed prior to anticoagulation or
angiography if headache is a feature.
213
PITFALLS
l ailure to recognise and treat hyperthermia
F
l Failure to adequately sedate the agitated patient with cocaine
TOXICOLOGY HANDBOOK
intoxication
l Administration of beta-blockers.
CONTROVERSIES
l espite theoretical concerns, intravenous lignocaine does not
D
appear to cause cardiovascular or CNS toxicity when used to treat
dysrhythmias in cocaine toxicity
l Indications for coronary angiography and thrombolytic therapy in
cocaine-associated chest pain with ECG abnormalities.
Presentations
Prescription medications
Cocaine eye drops 15 mL bottles
Illicit cocaine derivatives
Cocaine hydrochloride powder or paste: processed from the alkaloid extracted from
coca leaves, it cannot be smoked as it decomposes at high temperatures
Cocaine base (crack cocaine) or free-base: created by combining cocaine
hydrochloride with an alkaline substance to render it heat stable.
References
Afonso L, Mohammad T, Thatai D. Crack whips the heart: a review of the cardiovascular
toxicity of cocaine. American Journal of Cardiology 2007; 100(6):1040–1043.
Hatsukami DK, Fischman MW. Crack cocaine and cocaine hydrochloride. Are the
differences myth or reality? Journal of the American Medical Association 1996;
276:1580–1588.
Lange RA, Hillis LD. Cardiovascular complications of cocaine use. New England Journal of
Medicine 2001; 345(5):351–358.
Shih RD, Hollander JE, Burstein JL et al. Clinical safety of lidocaine in patients with cocaine-
associated myocardial infarction. Annals of Emergency Medicine 1995; 26:702–706.
3.31 COLCHICINE
Colchicine overdose is uncommon but potentially lethal. Toxicity is
characterised by severe gastroenteritis followed by multi-system
organ failure. Aggressive decontamination and supportive care are the
cornerstones of management.
RISK ASSESSMENT
l ny intentional ingestion of colchicine is considered potentially
A
lethal. The doses outlined in Table 3.31.1 are useful in predicting
outcome, although fatalities are reported with acute ingestion of as
little as 0.2 mg/kg
SPECIFIC TOXINS
TABLE 3.31.1 Dose-related risk assessment: Colchicine
Dose Effect
<0.5 mg/kg Gastrointestinal symptoms
0.5–0.8 mg/kg Systemic toxicity including bone marrow

depression
214 10% mortality
21
4
>0.8 mg/kg Severe poisoning involving cardiovascular

collapse, coagulopathy, acute renal
TOXICOLOGY HANDBOOK
failure.
Approaching 100% mortality
l Children: Ingestion of one or two colchicine tablets is not

problematic. Larger ingestions may cause severe gastrointestinal
symptoms and any symptomatic child should be assessed in
hospital.
Toxic mechanism
Colchicine is a naturally occurring alkaloid. It is found in certain plants, including the
autumn crocus (Colchicum autumnale) and glory lily (Gloriosa superba). It is used in the
treatment of acute gout and has also been advocated in familial Mediterranean fever. It
binds tubulin and prevents microtubule formation, thus inhibiting mitosis, as well as other
essential intracellular processes. Following overdose, tissues with high cellular turnover
(GIT, bone marrow) are preferentially affected.
Toxicokinetics
Colchicine is rapidly absorbed, with peak levels occurring from 0.5 to 2 hours post-
ingestion. Bioavailability is only 40% as a result of extensive first-pass metabolism.
It is extensively tissue bound with a volume of distribution of 2 L/kg. Elimination is
by hepatic metabolism, with an elimination half-life of up to 30 hours following
overdose.
CLINICAL FEATURES
Colchicine overdose usually presents with severe gastroenteritis
followed by onset of multi-organ toxicity (if more than 0.5 mg/kg is
ingested) in the second 24 hours (see Table 3.31.2).
TABLE 3.31.2 Clinical progression of severe colchicine toxicity
Time Effect
2–24 hours Nausea, vomiting, diarrhoea, abdominal pain. Severe
GI fluid losses can result in haemodynamic
instability. Peripheral leucocytosis commonly
seen on blood film
2–7 days Bone marrow suppression and pancytopenia,
rhabdomyolysis, renal failure, progressive metabolic
acidosis, respiratory insufficiency, ARDS, cardiac
arrhythmias and risk of sudden cardiac death
>7 days Rebound leucocytosis and transient alopecia.
SPECIFIC TOXINS
Complete recovery is expected in patients who
survive to this stage
INVESTIGATIONS
l Specific colchicine levels are not routinely available 215
l Appropriate laboratory and radiological investigations are used to
identify and monitor fluid, electrolyte and acid–base status, and
development of organ toxicity as outlined above.
TOXICOLOGY HANDBOOK
MANAGEMENT
l Patients may present in hypovolaemic shock due to massive
GI fluid losses. They require resuscitation with large volumes of
intravenous crystalloid solutions
l Aggressive supportive care in an intensive care environment offers
the best chance of survival in severe colchicine poisoning. This
includes meticulous management of fluid, electrolyte and acid–
base status, and infectious complications
l Early respiratory insufficiency and cardiac arrest is anticipated; airway
protection and ventilatory assistance are implemented as necessary
l Close clinical, physiological and laboratory monitoring is indicated
l Patients with severe toxicity require invasive monitoring
Decontamination
l Administer activated charcoal 50 g (1 g/kg in children) as soon as
possible to any patient who has potentially ingested >0.5 mg/kg
of colchicine, because prevention of absorption of even a small
amount may be life saving
l Multiple-dose oral activated charcoal may enhance elimination, but
is technically difficult in the vomiting patient. It has not been shown
to affect outcome and is not routinely recommended
Antidotes
l Colchicine-specific antibodies were used successfully in a single
case of colchicine overdose, but are not currently available.
l ll adult cases of deliberate self-poisoning are admitted for
A
observation
l Patients who do not develop gastrointestinal symptoms within
24 hours of ingestion are medically cleared
l Patients with significant toxicity require admission to an intensive
care unit.
HANDY TIPS
l dmit ALL colchicine overdoses. Arrange early transfer to intensive
A
care if more than 0.5 mg/kg is ingested or any symptoms develop.
PITFALLS
SPECIFIC TOXINS
l ailure to identify ingestion of colchicine at presentation

F
l Failure to anticipate the severity of colchicine poisoning.
CONTROVERSIES
l tility of granulocyte colony stimulating factor (GCSF) in the
U
treatment of severe leucopenia.
Presentations
216 Colchicine 500 microgram tablets (100)
21
6
References
Harris R, Gillet M. Colchicine poisoning—overview and new directions. Emergency
TOXICOLOGY HANDBOOK
Medicine 1998; 10:161–167.

Jayaprakash V, Ansell G, Galler D. Colchicine overdose: the devil is in the detail.
New Zealand Medical Journal 2007; 120(1248):81–88.
3.32 CORROSIVES
Alkalis: Ammonia, Potassium hydroxide, Sodium hydroxide, Sodium
hypochlorite
Acids: Hydrochloric acid, Sulfuric acid
Other: Glyphosate, Paraquat, Phenols, Potassium permanganate,
Mercuric chloride, Zinc chloride
Ingestion of corrosive agents causes injury to the upper airway and
gastrointestinal tract. Upper airway injury is a life-threatening emergency.
Endoscopy stratifies the risk for delayed sequelae in symptomatic
patients.
RISK ASSESSMENT
l eliberate or unintentional ingestion of concentrated sulfuric acid
D
(H2SO4), sodium hydroxide (NaOH) solutions and solid preparations
are associated with severe corrosive injury to the pharynx, upper
airway, oesophagus and stomach. These agents are not associated
with systemic toxicity
l Stridor, dyspnoea, dysphonia or throat pain indicate airway injury
and an immediate threat to life
l Significant gastro-oesophageal injury is indicated by any two of the
following: stridor, drooling or vomiting
l Ingestion of >60 mL of concentrated hydrochloric acid (HCl) leads
to severe injury to the stomach and duodenum with necrosis and
perforation, rapid onset of severe multi-organ failure and is usually fatal
l Ingestion of <150 mL household bleach containing dilute sodium
hypochlorite does not cause significant corrosive injury
l The absence of lip or oral burns does not exclude significant
gastro-oesophageal injury
l The following corrosive agents are also associated with severe
systemic toxicity: glyphosate, mercuric chloride, paraquat,
potassium permanganate, zinc (see Chapter 3.38: Glyphosate and
Chapter 3.61: Paraquat)
l Children: Unintentional ingestion of household drain and oven cleaners
or automatic dishwashing powders can cause severe corrosive
SPECIFIC TOXINS
injury. Unintentional ingestion of household bleach is usually benign.
Ingested button batteries may cause local corrosive injury if they
lodge in the oesophagus (see Chapter 3.21: Button batteries).
Toxic mechanism
Corrosive agents cause direct chemical injury to tissues. The extent of injury is dependent
on pH, concentration and volume ingested. Alkaline agents cause liquefactive necrosis,
resulting in deep and progressive mucosal damage. Acids cause protein denaturation and
coagulative necrosis.
217
CLINICAL FEATURES
l ollowing corrosive ingestion, patients may experience immediate
F
pain in the mouth and throat, drooling, odynophagia, vomiting and
TOXICOLOGY HANDBOOK
abdominal pain
l Laryngeal oedema may cause rapidly progressive stridor,
hoarseness and respiratory distress
l Oesophageal perforation and mediastinitis are associated with chest
pain, dyspnoea, fever, subcutaneous emphysema and a pleural rub
l Thirty per cent of patients with grade IIB or III injury (see below) will
develop oesophageal strictures
l Grade II and III injuries are associated with oesophageal carcinoma
40–50 years later
l Perforation of the stomach or small intestine produces clinical
features of peritonitis
l Gastrointestinal tract perforation is complicated by septic shock
and multi-organ failure
l Patients who ingest large amounts of concentrated acids usually
present in shock with profound metabolic acidosis and progress
to multi-organ failure and death despite laparotomy and surgical
debridement of necrotic tissue.
INVESTIGATIONS
l Endoscopy
— Endoscopy is performed in all patients with persistent vomiting,
oral burns, drooling or abdominal pain to define the extent
of injury and define the risk for immediate (perforation) and
delayed sequelae (stricture)
— Endoscopic grading
Grade 0 Normal
Grade I Mucosal oedema and hyperaemia
Grade IIA Superficial ulcers, bleeding and exudates
Grade IIB Deep focal or circumferential ulcers
Grade IIIA Focal necrosis
Grade IIIB Extensive necrosis
l Chest and abdominal x-rays
— Assist in diagnosis of perforation.
MANAGEMENT
l Symptomatic corrosive ingestion is a time-critical emergency
SPECIFIC TOXINS
managed in an area equipped for resuscitation

l The early potential life threat is rapid onset of upper airway oedema
and compromise
l Early endotracheal intubation or surgical airway may be required
l Do not insert a nasogastric tube until after endoscopy
l Administer analgesia as required
l The patient remains nil by mouth until the extent of injury is defined
218 by endoscopy
l Urgent surgical intervention is required if there is evidence of full
21
thickness necrosis or perforation

l Urgent surgical intervention may be indicated prior to endoscopy
TOXICOLOGY HANDBOOK
for acid ingestion

l Broad-spectrum antibiotics are not indicated unless there is
evidence of perforation
Decontamination
l The mouth may be rinsed with water as an immediate first aid
measure
l Do not induce vomiting
l Do not administer fluids
l Do not administer activated charcoal
l Do not attempt pH neutralisation
Antidotes
l None available.

l atients who are asymptomatic and tolerating oral fluids at 4 hours
P
post-ingestion are medically clear for discharge
l Symptomatic patients remain nil by mouth and are admitted for
observation and endoscopy within 24 hours. Further management
and disposition is directed by endoscopic findings
l Patients with airway compromise require intensive care admission
once the airway is controlled
l Patient with haemodynamic instability or evidence of
gastrointestinal perforation require urgent surgical intervention and
subsequent intensive care admission.
HANDY TIPS
l igns and symptoms correlate poorly with the extent of gastro-
S
oesophageal injury
l Stridor, dysphonia or dysphagia indicate the potential for imminent
airway compromise
l Absence of oral and lip burns does not exclude significant gastro-
oesophageal injury.
PITFALLS
l Failure to perform endoscopy within 24 hours of injury.
CONTROVERSIES
l here is no evidence that corticosteroids prevent oesophageal
T
SPECIFIC TOXINS

stricture formation following corrosive injury from alkali ingestion,
and they may increase mortality following grade III injury.
Sources
Ammonia—anti-rust products, jewellery and metal cleaners
Hydrochloric acid—metal cleaners
Sodium hydroxide—button batteries, detergents, drain and oven cleaners
Sodium hypochlorite—bleaches and household cleaners
Sulfuric acid—automotive batteries, drain cleaners
219
References
Munoz EM, Garcia-Domingo MI, Santiago JR et al. Massive necrosis of the
gastrointestinal tract after ingestion of hydrochloric acid. European Journal of
TOXICOLOGY HANDBOOK
Surgery 2001; 67:195–198.
Pelclová D, Navrátil T. Do corticosteroids prevent oesophageal stricture after corrosive
ingestion? Toxicological Reviews 2005; 24(2):125–129.
Zargar SA, Kochhar R, Nagi B et al. Ingestion of corrosive alkalis: Spectrum of injury to
upper gastrointestinal tract and natural history. American Journal of Gastroenterology
1992; 87(3):337–341.
3.33 CYANIDE
Acute cyanide intoxication is rare but dramatic and lethal. Rapid removal
from the source, attention to the principles of critical care and timely
administration of an antidote in selected cases provides the best
opportunity for survival.
RISK ASSESSMENT
l cute cyanide exposure, whether by ingestion of cyanide salts or
A
inhalation of hydrogen cyanide gas, is potentially rapidly lethal.
Death is likely to occur before arrival at hospital
l Patients who arrive alive at hospital following inhalational exposure
survive with supportive care
l Although potentially lethal, amygdalin (cyanogenic-containing plant
material, usually seeds) is rarely ingested in a dose sufficient to
cause serious poisoning
l Chronic occupational intoxication leads to non-specific symptoms
such as headache and fatigue
l Children: Unintentional ingestion of cyanide is potentially lethal.
Toxic mechanism
Cyanide acts at several sites. It binds to the ferric ion (Fe3+) of cytochrome oxidase and
inhibits oxidative metabolism, leading to lactic acidosis. It stimulates release of biogenic
amines, resulting in pulmonary and coronary vasoconstriction. In the CNS, cyanide
triggers neurotransmitter release, particularly N-methyl-D-aspartate (NMDA), which leads
to seizures.
Toxicokinetics
Cyanide is rapidly absorbed and taken up into cells. It has a volume of distribution of
1.5 L/kg and is protein bound. The metabolism of cyanide is not fully understood. The
main mechanism is thought to involve hepatic transfer of sulfane sulfur to cyanide, forming
thiocyanate, which is non-toxic and excreted in the urine. This reaction is catalysed by the
enzyme rhodanese. Cyanide elimination half-life is 2–3 hours.
SPECIFIC TOXINS
CLINICAL FEATURES
l cute inhalation of hydrogen cyanide gas leads to loss of
A
consciousness within seconds to minutes
l Symptoms develop within 30–60 minutes of ingestion of cyanide salts
l Early features include nausea, vomiting, headache, dyspnoea,
tachypnoea, hypertension, tachycardia, agitation, collapse and
seizures.
l Progressive features include hypotension, bradycardia, confusion,
tetany, drowsiness, respiratory depression and coma
220 l Delayed neurological toxicity, usually parkinsonism, may be
22
observed weeks to months after surviving a serious acute

0
poisoning.
TOXICOLOGY HANDBOOK
INVESTIGATIONS
l EUC
l Arterial blood gases and serum lactate
— Serum lactate strongly correlates with severity of intoxication
— In smoke inhalation victims without severe burns, the
sensitivity, specificity, and positive predictive value of a serum
lactate >10 mmol/L for cyanide levels >40 micromol/L
(0.1 mg/dL) are 87%, 94% and 95% respectively
l Cyanide levels
— These do not aid acute management but confirm diagnosis in
retrospect
— Take blood before antidotes are commenced (use a heparinised
tube).
TABLE 3.33.1 Correlation of blood levels and clinical effects:

Cyanide
Level Effect
>20 micromol/L (0.05 mg/dL) Symptomatic
>40 micromol/L (0.1 mg/dL) Potentially toxic
>100 micromol/L (0.26 mg/dL) Lethal

MANAGEMENT
l Cyanide poisoning poses multiple immediate threats to life: coma,
seizures, shock and profound lactic acidosis
l Immediate intubation and ventilation with 100% oxygen is
indicated in severe poisoning
l Resuscitation proceeds along conventional lines, as outlined in
Decontamination
l Removal from the source of hydrogen cyanide gas exposure is
vital
SPECIFIC TOXINS
l Remove clothes and wash skin with soap and water. Clothing
should be bagged
l Cyanide is rapidly absorbed and the onset of symptoms occurs
within minutes. Resuscitation takes priority over decontamination.
Activated charcoal is contraindicated until the airway has been
secured by endotracheal intubation
221
Antidotes
l In a patient with suspected cyanide poisoning and serious clinical
effects (altered mental status, seizures, hypotension, significant
TOXICOLOGY HANDBOOK
metabolic acidosis), administer a cyanide antidote
l The available antidotes are hydroxocobalamin, thiosulfate and
dicobalt edetate (see Chapter 4.5: Dicobalt edetate, Chapter
4.14: Hydroxocobalamin and Chapter 4.27: Sodium thiosulfate
for administration details)
l Under most circumstances, hydroxocobalamin is the preferred
antidote if available.

l atients who are clinically well at 4 hours may be discharged
P
l Patients managed supportively who show rapid clinical
improvement, with normal mental status and vital signs, may be
managed in a ward environment
l Patients with objective evidence of cyanide intoxication require
aggressive supportive care, intubation and ventilation and
consideration for antidote treatment
l Patients with severe cyanide intoxication and cardiovascular
instability require management in an intensive care setting.
HANDY TIPS
l onsider the diagnosis of cyanide poisoning where a sustained
C
lactic acidosis is noted in the patient presenting following sudden
collapse
l Despite the presence of effective antidotes, early aggressive
supportive care alone may be sufficient to achieve a good outcome
in some cases
l The decision to give antidote must be made before cyanide levels
are available.
PITFALLS
l ailure to recognise cyanide intoxication
F
l Inability to immediately access cyanide antidotes.
CONTROVERSIES
l he relative comparative efficacy between the antidotes for
T
cyanide poisoning in humans is not established.
Sources
Industrial
Cyanide salts are used in metallurgy and ore extraction
Hydrogen cyanide is a fumigant (aeroplanes, buildings, ships)
Nitriles that yield cyanide are used in manufacture of plastics and synthetic fibres
Non-industrial
Cyanide is the product of combustion of natural substances and synthetic material and
SPECIFIC TOXINS
therefore commonly produced in fires

Natural
Amygdalin (apple, apricot and peach pips)
Foodstuffs (almonds, cabbage, spinach, tapioca, white lima beans)
Iatrogenic
Chemical warfare agent
Sodium nitroprusside therapy
References
Baud FJ, Barriot P, Toffis V et al. Elevated blood cyanide levels in victims of smoke
222 inhalation. New England Journal of Medicine 1991; 325:1761–1766.
22
Braitberg G, Vanderpyl MMJ. Treatment of cyanide poisoning in Australasia. Emergency

2
Medicine 2000; 12(3):232–240.

Hall A, Saiers J, Baud F. Which cyanide antidote? Critical Reviews in Toxicology 2009;
TOXICOLOGY HANDBOOK
39(7):541–552.
Meredith TJ, Jacobsen D, Haines JA et al. IPCS/CEC evaluation of antidotes series.
Volume 2. Antidotes for poisoning by cyanide. Cambridge University Press 1993. Also
available online at http://www.inchem.org/documents/antidote/antidote/ant02.htm,
accessed 16 May 2010.
3.34 DIGOXIN: ACUTE OVERDOSE

See also 3.35: Digoxin: Chronic poisoning
Acute digoxin toxicity manifests with early onset of vomiting and
hyperkalaemia and can progress to life-threatening cardiac dysrhythmias
and cardiovascular collapse. Cardiovascular complications are refractory
to conventional resuscitation measures. Digoxin immune Fab is a highly
effective antidote.
RISK ASSESSMENT
l cute digoxin intoxication occurs if more than 10 times the daily
A
defined dose is ingested
l Potentially lethal digoxin intoxication is predicted by:
— Dose ingested >10 mg (adult) or >4 mg (child)
— Serum digoxin level >15 nmol/L (12 ng/mL) at any time
— Serum potassium >5.5 mmol/L
l Potentially lethal natural cardiac glycoside intoxication can occur
following ingestion of certain plants or plant parts, or of concoctions
or teas brewed using glycoside-containing plants or toad skins
l Children: Ingestion of up to 75 microgram/kg is safe and does not
require hospital observation or treatment unless symptoms develop.
Toxic mechanism
Digoxin inhibits the membrane Na+-K+ ATPase pump, leading to a reduced sodium
gradient and reduced calcium extrusion from the cell. This results in increased
concentrations of intracellular calcium (enhanced automaticity, positive inotropic effect)
and extracellular potassium. Digoxin also enhances vagal tone, resulting in decreased
sinoatrial and atrioventricular node (AV), conduction velocities.
Toxicokinetics
Digoxin is well absorbed after oral administration, with bioavailability 60–80%. Peak effects
usually occur after 6 hours. Its volume of distribution is large (5–10 L/kg) and increased in
the elderly and obese. Digoxin undergoes minimal hepatic metabolism and is eliminated
unchanged by the kidneys. The elimination half-life is 30–40 hours and prolonged further in
renal impairment.
SPECIFIC TOXINS
CLINICAL FEATURES
Nausea and vomiting are early clinical features of acute digoxin poisoning
and develop within 2–4 hours of ingestion. Peak serum digoxin levels are
reached at approximately 6 hours and death secondary to cardiovascular
collapse may follow at 8–12 hours. Specific clinical features include:
l Gastrointestinal
— Nausea, vomiting and abdominal pain
l Cardiovascular
— Bradycardias 223
– First, second or third degree AV block
– AF with ventricular response <60
— Increased automaticity
TOXICOLOGY HANDBOOK
– Ventricular ectopic beats or bigeminy
– Supraventricular tachycardia with AV block
— Hypotension
— Lethargy
— Confusion and delirium
l Note: Acute natural cardiac glycoside intoxication has similar
clinical features. However, onset may be more rapid if liquid
preparations are ingested.
INVESTIGATIONS
l Serum digoxin levels
— Confirm poisoning
— Provide indication for antibody treatment
— Perform level 4 hours post-ingestion and then every 2 hours
until definitive treatment or toxicity resolving
l EUC
— Hyperkalaemia of any magnitude is an important early sign of
severe digoxin toxicity
— Assess renal function
— Essential to monitor progression or resolution of
cardiotoxicity.
MANAGEMENT
l Acute digoxin poisoning is a potentially life-threatening emergency
resuscitation. Cardiac monitoring must be continued until reversal
of toxicity with digoxin immune Fab
l Potential early life threats that require immediate intervention include:
— Hypotension
— Cardiac arrest
l In cardiac arrest, standard resuscitation measures are futile.
Advanced cardiac life support is initiated while 20 ampoules
(or as many as are available) of digoxin immune Fab are
SPECIFIC TOXINS
sourced and administered. This may be life saving. Attempts at

resuscitation should continue for at least 30 minutes after the
administration of digoxin immune Fab
l If digoxin immune Fab is not immediately available, temporising
measures are instituted to deal with imminent life threats:
— Hyperkalaemia
– Administer sodium bicarbonate 100 mEq IV bolus
(1 mEq/kg in children)
– Give insulin 10 units and 50 mL 50% dextrose
224
simultaneously as an IV bolus (0.1 units/kg insulin and
22
5 mL/kg 10% dextrose in children)

4
– Note: Calcium is contraindicated

TOXICOLOGY HANDBOOK
— Atrioventricular block
– Give atropine 0.6 mg IV bolus. Repeat until desired clinical
effect is achieved to a maximum of 1.8 mg (20 microgram/
kg/dose in children)
– External pacing is rarely effective
— Ventricular tachydysrhythmias
– Administer lignocaine 1 mg/kg (max 100 mg) IV over 2 minutes
Decontamination
l Oral activated charcoal should be offered to cooperative adults
who present within the first hour following overdose. Activated
charcoal alone is unlikely to be life saving. Administration may be
problematic due to persistent vomiting
Antidote
l Digoxin immune Fab is the definitive treatment for acute digoxin
poisoning. It is indicated whenever potentially life-threatening
toxicity is predicted or present:
— Cardiac arrest
— Life-threatening cardiac dysrhythmia
— Ingested dose >10 mg (adult) or >4 mg (child)
— Serum digoxin level >15 nmol/mL (12 ng/mL)
— Serum potassium >5 mmol/L
l Digoxin immune Fab dosing is empirical or based on the dose
of digoxin known to be ingested (see Chapter 4.6: Digoxin
immune Fab).
l atients with falling serial serum digoxin levels, normal serum
P
potassium, no gastrointestinal symptoms and no evidence of
cardiotoxicity at 6 hours do not require further medical care or
observation
l Patients who have received digoxin immune Fab, have normal
serum potassium, manifest no significant cardiac dysrhythmia and
remain clinically well over the next 6 hours do not require further
medical care or observation.
HANDY TIPS
l arly accurate risk assessment allows administration of digoxin
E
SPECIFIC TOXINS
immune Fab before life-threatening toxicity develops
l If digoxin immune Fab is not immediately available, it is usually
quicker and safer to arrange for it to be transported to the patient
rather than for the patient to be transported to a hospital with
antidote stocks
l Serum K >5.5 mmol/L predicts 100% mortality without digoxin
immune Fab
l Calcium is contraindicated in the treatment of digoxin or cardiac
glycoside-induced hyperkalaemia
l Digoxin is sometimes co-ingested with other cardiotropic 225
medications, such as calcium channel blockers. The aetiology
of bradycardia or AV block may not be clear. Therapeutic trial of
digoxin immune Fab may assist risk assessment
TOXICOLOGY HANDBOOK
l Do not repeat digoxin levels following administration of digoxin
immune Fab; most laboratories measure both bound and unbound
digoxin, resulting in alarmingly high serum levels that are of no
clinical relevance
l Serum digoxin levels are an unreliable indication of dose following
ingestion of natural cardiac glycosides.
PITFALLS
l ailure to stock sufficient digoxin immune Fab. In a large
F
overdose, antidote needs to be gathered from all available
sources.
CONTROVERSIES
l ultiple-dose activated charcoal may be associated with improved
M
outcomes in plant glycoside poisoning, particularly where digoxin
immune Fab is not immediately available.
Presentations
Digoxin 62.5 microgram tablets (200)
Digoxin 250 microgram tablets (100)
Digoxin 50 microgram/mL elixir (60 mL)
Digoxin 50 microgram/2 mL ampoules
Digoxin 500 microgram/2 mL ampoules
Note: Natural sources of cardiac glycosides with similar toxicity:
l lants: foxglove, lily of the valley, oleander, rhododendron
P
l Animals: toad (Bufo spp.) venom and body parts—used in some traditional
Chinese medicines
References
Antman EM, Wenger TL, Butler VP et al. Treatment of 150 cases of life-threatening digitalis
intoxication with digoxin-specific Fab antibody fragments: final report of a multicenter
study. Circulation 1990; 81(6):1744–1752.
Bateman DN. Digoxin-specific antibody fragments: how much and when? Toxicological
Reviews 2004: 23(3):135–143.
De Silva HA, Fonseka MM, Pathmeswaran A et al. Multiple-dose activated charcoal
for treatment of yellow oleander poisoning: a single-blind, randomised, placebo-
controlled trial. Lancet 2003; 361:1935–1938.
Eddleston M, Rajapakse S, Rajakanthan et al. Anti-digoxin Fab fragments in cardiotoxicity
induced by ingestion of yellow oleander: a randomised controlled trial. Lancet 2000;
355(9208):967–972.
Woolf AD, Wenger T, Smith TW et al. The use of digoxin-specific Fab fragments for
severe digitalis intoxication in children. New England Journal of Medicine 1992;
SPECIFIC TOXINS
326:1739–1744.
3.35 DIGOXIN: CHRONIC POISONING

See also 3.34: Digoxin: Acute overdose
Chronic digoxin poisoning is an underdiagnosed condition that carries
significant morbidity and mortality. Digoxin has a narrow therapeutic index
226 and intoxication commonly develops in elderly patients with multiple co-
22
morbidities. Use of digoxin immune Fab reduces mortality and may reduce
6
hospital length of stay and cost of care.

TOXICOLOGY HANDBOOK
RISK ASSESSMENT
l hronic digoxin poisoning, although variable in severity, is a life-
C
threatening condition
l Untreated, mortality within a week is 15–30%
l The probability of digoxin intoxication is predicted by considering
serum digoxin level and clinical features (see Table 3.35.1)
TABLE 3.35.1 Probability of digoxin toxicity
Serum digoxin level Serum digoxin

1.5 ng/mL level 2.5 ng/mL
Clinical features (1.9 nmol/L) (3.2 nmol/L)
Bradycardia only 10% 50%
GI symptoms only 25% 60%
GI symptoms and 60% 90%

bradycardia
Automaticity alone 70% 90%
Automaticity plus >80% 100%

any other feature
dapted from Abad-Santos F, Carca AJ, Ibanez C et al. Digoxin level
A
and clinical manifestations as determinants in the diagnosis of digoxin
toxicity. Therapeutic Drug Monitoring 2000; 22(2): 163–168.
Toxic mechanism
Digoxin inhibits the membrane Na+-K+ ATPase pump, which in turn leads to increased
intracellular calcium (enhanced automaticity, positive inotropic effect) and increased
extracellular potassium. Digoxin also enhances vagal tone leading to a decrease in
sinoatrial and atrioventicular (AV) node conduction velocity.
Toxicokinetics
Digoxin is well absorbed after oral administration, with bioavailability 60–80%. Peak
effects usually occur after 6 hours. Its volume of distribution is large (5–10 L/kg) and
increased in the elderly and obese. Digoxin undergoes minimal hepatic metabolism and
is eliminated unchanged by the kidneys. The elimination half-life is 30–40 hours and
prolonged further in renal impairment.
CLINICAL FEATURES
SPECIFIC TOXINS
The clinical manifestations of chronic digoxin toxicity are non-
specific. Digoxin intoxication commonly develops in elderly patients
in the context of intercurrent illness, particularly where this leads to
impaired renal function and digoxin elimination. It is often difficult to
determine whether the unwell patient with an elevated serum digoxin
level has digoxin toxicity or another cause for the observed clinical
features.
Onset is insidious over days or weeks. Clinical features include:
l Cardiovascular 227
— Bradycardias
– First, second or third degree AV block
– AF with ventricular response <60/minute
TOXICOLOGY HANDBOOK
— Increased automaticity
– Ventricular ectopic beats or bigeminy
– Supraventricular tachycardia with AV block
— Hypotension
— Syncope
l Gastrointestinal
— Nausea, vomiting, abdominal pain
— Often less obvious than in acute toxicity
— Lethargy
— Confusion and delirium
l Visual
— Decreased visual acuity
— Aberration of colour vision (chromatopsia)
— Yellow haloes (xanthopsia).
INVESTIGATIONS
l Serum digoxin level
— The diagnosis of chronic digoxin intoxication is based on a
steady state level 6 or more hours after the last dose
— Serum digoxin levels near the therapeutic range of
0.5–1.0 ng/mL (0.6–1.3 nmol/L), correlate poorly with severity
of intoxication (see Table 3.35.1)
l Other investigations
— EUC
— Investigations as indicated to assess intercurrent illnesses.
MANAGEMENT
l Chronic digoxin poisoning is a potentially life-threatening
monitoring and resuscitation. Cardiac monitoring continues until
reversal of toxicity with digoxin immune Fab
l Potential early life threats that require immediate intervention
include:
— Hypotension
SPECIFIC TOXINS
— Cardiac dysrhythmias
— Cardiac arrest
l In cardiac arrest, standard resuscitation measures are futile.
Advanced cardiac life support is initiated while 5 ampoules (or as
many as are available) of digoxin immune Fab are sourced and
administered. This may be life saving. Attempts at resuscitation
should continue for at least 30 minutes after the administration of
digoxin immune Fab
l If digoxin immune Fab is not immediately available, temporising
228 measures are instituted to deal with imminent life threats.
— Hyperkalaemia
22
8
– Administer sodium bicarbonate 100 mEq IV bolus

(1 mEq/kg in children)
TOXICOLOGY HANDBOOK
– Give insulin 10 units and 50 mL 50% dextrose

simultaneously as an IV bolus (0.1 units/kg insulin and
5 mL/kg 10% dextrose in children)
– Note: Calcium is contraindicated
— Atrioventricular block
– Give atropine 0.6 mg IV bolus. Repeat until desired clinical
effect is achieved to a maximum of 1.8 mg (20 microgram/
kg/dose in children)
– External pacing is rarely effective
— Ventricular tachydysrhythmias
– Administer lignocaine 1 mg/kg (max 100 mg) IV over
2 minutes
l Discontinue digoxin
l Correct hypovolaemia if present
l Correct hypokalaemia if present
l Assess and manage contributing intercurrent illnesses
Decontamination
l Not indicated
Antidote
l Digoxin immune Fab is indicated whenever clinical features of
digoxin intoxication are associated with an elevated steady-state
serum digoxin level. A dose of 1–2 ampoules is usually sufficient
to reverse all features of toxicity within 12 hours (see Chapter 4.6:
Digoxin immune Fab).
l If significant cardiac dysrhythmias do not occur over a 6-hour
observation period following treatment with digoxin immune Fab,
further cardiac monitoring is not indicated
l The vast majority of patients with chronic digoxin poisoning require
admission to hospital for management of intercurrent illnesses,
even after treatment with digoxin immune Fab.
HANDY TIPS
l onsider the diagnosis of chronic digoxin intoxication in any
C
patient on digoxin who presents with collapse, hypotension,
bradycardia, dysrhythmia, gastrointestinal complaints, altered
mental status or general deterioration
SPECIFIC TOXINS
l Early treatment with digoxin immune Fab decreases mortality
l Early treatment with digoxin immune Fab is cost-effective because
it eliminates the need for prolonged cardiac monitoring and
decreases hospital length of stay
l In the absence of a serum digoxin level, patients with suspected
chronic digoxin intoxication are safely treated with an initial empiric
dose of 2 ampoules of digoxin-immune Fab
l If cardiac dysrhythmia or hypotension continue 12 hours after a
definitive dose of digoxin immune Fab, an alternative cause is 229
likely.
PITFALLS
TOXICOLOGY HANDBOOK
l ailure to appreciate the life-threatening nature of chronic digoxin
F
poisoning
l Failure to treat with digoxin immune Fab because of
underestimation of potential mortality and concerns about cost.
CONTROVERSIES
l recise indications for digoxin immune Fab. The threshold for
P
treatment continues to be lowered as clinical experience accumulates
and it is now generally considered that all cases should be treated.
Presentations
Digoxin 62.5 microgram tablets (200) Digoxin 50 microgram/2 mL ampoules
Digoxin 250 microgram tablets (100) Digoxin 500 microgram/2 mL ampoules
Digoxin 50 microgram/mL elixir (60 mL)
References
Abad-Santos F, Carca AJ, Ibanez C et al. Digoxin level and clinical manifestations as
determinants in the diagnosis of digoxin toxicity. Therapeutic Drug Monitoring 2000;
22(2):163–168.
DiDomenico RJ, Walton SM, Sanoski CA et al. Analysis of the use of digoxin immune fab
for the treatment of non-life-threatening digoxin toxicity. Journal of Cardiovascular
Pharmacology and Therapeutics 2000; 5(2):77–85.
Lapostolle F, Borron SW, Verdier C et al. Digoxin-specific Fab fragments as in single first-
line therapy in digitalis poisoning. Critical Care Medicine 2008; 36:3014–3018.
Marik PE, Fromm L. A case series of hospitalised patients with elevated digoxin levels.
American Journal of Medicine 1998; 105(2):110–115.
3.36 DIPHENOXYLATE-ATROPINE
This combination drug causes delayed onset of opioid and anticholinergic
effects when ingested by children, even in small amounts.
RISK ASSESSMENT
l dults are much less susceptible than children to toxic effects
A
l Large ingestions have the potential to cause opioid or
anticholinergic poisoning
l Children:
— Fatalities are reported after repetitive or incorrect dosing
SPECIFIC TOXINS
— Acute ingestion of six or more tablets is associated with

potentially lethal opioid poisoning
— Acute ingestion of one tablet does not cause significant
symptoms and does not require hospital referral
— Acute ingestion of between one and six tablets may cause
opioid and/or anticholinergic poisoning and should be
assessed and observed in hospital.
Toxic mechanism
230 Combination synthetic opioid (diphenoxylate) and anticholinergic (atropine) preparation
used as adjunctive therapy for acute and chronic diarrhoea. Atropine is added to
23
0
discourage abuse of this medication. Diphenoxylate and difenoxine are opioid agonists.
Atropine is a competitive antagonist of acetylcholine at muscarinic receptors.
TOXICOLOGY HANDBOOK
Toxicokinetics
Diphenoxylate is rapidly and well absorbed following oral administration. It is rapidly
metabolised to difenoxine, a compound that is 5 times more active than diphenoxylate
and undergoes enterohepatic circulation. Diphenoxylate has a volume of distribution of
3.8 L/kg and an elimination half-life of 2.5 hours. Difenoxine has an elimination half-life
of 12 hours. Peak plasma concentrations of both diphenoxylate and difenoxine occur at
2 hours. Atropine is rapidly absorbed following oral administration, with peak plasma levels
occurring at 2 hours. It has a volume of distribution of 2.6 L/kg and an elimination half-life
of 2.4–12.8 hours. The co-administration of atropine in this compound preparation may
slow the absorption of diphenoxylate.
CLINICAL FEATURES
The clinical features are those of opioid intoxication and anticholinergic
poisoning
l Opioid intoxication
— Decreased level of consciousness
— Respiratory depression
— Miosis
— Note: Opioid effects usually manifest within the first few hours,
but may recur after a period of apparent improvement for up to
12–24 hours
l Anticholinergic poisoning
— Delirium, agitation
— Tachycardia, dry skin
— Urinary retention
l Note: Not all patients develop anticholinergic effects. If these do
occur, they may precede or be obscured by the opioid effects.
Occasionally, the anticholinergic effects may predominate.
INVESTIGATIONS
Management of diphenoxylate intoxication is determined
by clinical features. Investigations are performed to assess
potential complications as dictated by the individual risk
assessment.

l Exclude alternate diagnoses and assess complications.
MANAGEMENT
SPECIFIC TOXINS
l Attention to airway, breathing and circulation is paramount.
These priorities are managed along conventional lines, as
Decontamination 231
l Consider administration of oral activated charcoal to the
cooperative alert patient who presents within 2 hours.
Decontamination is not necessary to ensure a favourable
TOXICOLOGY HANDBOOK
outcome, but may reduce naloxone requirement and length
of stay
Antidotes
l Naloxone is indicated to reverse clinical manifestations of opioid
intoxication. Repeated doses or an infusion may be necessary
(see Chapter 4.19: Naloxone).

l hildren who may have ingested no more than one tablet can be
C
observed at home
l Children who may have ingested two or more tablets should be
observed in hospital for a minimum of 12 hours. Discharge should
not occur at night
l Adults are observed for at least 8 hours following deliberate self-
poisoning
l Symptomatic patients require admission until clinical
manifestations resolve. This may take up to 48 hours.
PITFALLS
l Premature discharge.
Presentations
Diphenoxylate hydrochloride 2.5 mg/atropine sulfate 25 microgram tablets (8, 20, 100)
References
McCarron MM, Chalhower KR, Thompson GA. Diphenoxylate-atropine (Lomotil) overdose
in children: an update (report of 8 cases and review of the literature). Pediatrics 1991;
87(5):694–700.
Thomas TJ, Pauze D, Love JN. Are one or two dangerous? Diphenoxylate-atropine
exposure in toddlers. Journal of Emergency Medicine 2008; 34(1):71–75.
3.37 GAMMA-HYDROXYBUTYRATE (GHB)

Slang terms: Cherry meth, Easy lay, Fantasy, G, G caps, Georgia homeboy,
GHB, Ghbers, Grievous bodily harm, G-riffik, Liquid E, Liquid X, Scoop,
SPECIFIC TOXINS
Soap, Somatomax, Water.

When taken in excessive doses, this illicit drug causes rapid onset of
CNS and respiratory depression, myoclonic jerking and bradycardia.
Management of intoxication is supportive. The duration of toxic effects
is short, with complete recovery occurring within 4–6 hours. Gamma-
butyrolactone is a precursor drug that is rapidly metabolised to GHB and
causes identical toxicity.
232 RISK ASSESSMENT

23
l HB is frequently distributed at a strength of 1 g/mL, but dose

G
2
estimation is virtually impossible because concentration varies

widely and is almost never known
TOXICOLOGY HANDBOOK
l Overdose usually occurs because the concentration supplied

was higher than anticipated by the recreational user or the user is
unfamiliar with the drug
l Standard recreational doses are 30–40 mg/kg. Twice the standard
dose is capable of causing coma
l Overdose is life-threatening without timely support of airway and
ventilation
l Maximal toxicity is usually evident by the time of arrival at the
emergency department
l Co-ingestion of ethanol or other CNS depressants increases the
risk of respiratory depression, apnoea and death
l Children: Any ingestion may be associated with rapid onset of
coma and is regarded as potentially fatal.
Toxic mechanism
GHB is a short-chain carboxylic acid that occurs naturally in the brain. It is
a breakdown product of gamma-aminobutyric acid (GABA) and may be a
neurotransmitter itself. The mechanism of action is unclear. Hypotheses include
agonist activity at GABAB receptors, activity at specific GHB receptors, dopaminergic
modulation, increased acetylcholine and serotonin levels, and interaction with
endogenous opioids.
Toxicokinetics
GHB is rapidly absorbed following oral administration. The presence of food reduces
bioavailability. It has variable distribution. Gamma-butyrolactone (GBL) is rapidly
transformed in the liver to GHB. 1,4-butanediol (BD) is metabolised rapidly to GHB by
alcohol dehydrogenase. GHB is rapidly oxidised to carbon dioxide and water with zero
order kinetics. Elimination is complete within 4–6 hours.
CLINICAL FEATURES
Standard recreational doses produce rapid onset of euphoria and
drowsiness, as well as enhanced sexual desire, performance and orgasm.
In overdose, a brief period of euphoria is followed by rapid onset of
coma. The patient can be roused with an external stimulus, only to
become deeply somnolent again when not disturbed. Sudden recovery
of consciousness occurs, usually within 2–3 hours. Recovery is
characterised by a short period of agitation or delirium, and vomiting.
Complete recovery is expected within 6 hours.
Deaths are reported and occur from airway obstruction, pulmonary
aspiration or respiratory arrest.
Typical clinical features observed following overdose include:
SPECIFIC TOXINS
— Coma
— Agitation and delirium
— Miosis
— Myoclonic movements may be noted in rare cases, sometimes
mimicking generalised seizures
l Respiratory
— Airway obstruction
— Cheyne-Stokes-type breathing
233
l General
— Vomiting
— Bradycardia
TOXICOLOGY HANDBOOK
— Sweating
Tolerance to GHB develops with regular use and a withdrawal
syndrome is described. This usually occurs with bodybuilders who take
GHB because it is believed to stimulate secretion of growth hormone.
Tolerance and withdrawal do not develop with recreational users.
INVESTIGATIONS
l Rarely required, except to exclude alternative diagnoses for coma
l Blood and urine GHB levels are not readily available, do not correlate
with toxic symptoms and do not assist management. Serum and
urine levels may be useful retrospectively in forensic cases; however,
GHB is rapidly cleared from the blood and may not be detected in
samples taken later in the clinical course. It is detectable somewhat
longer in the urine, but not reliably after 12 hours.
MANAGEMENT
l Acute GHB intoxication is a potentially life-threatening emergency
resuscitation. Basic resuscitative measures ensure the survival of
the vast majority of patients
— Coma
— Loss of airway protective reflexes
l ttention to airway, breathing and circulation are paramount. These
A
l Bradycardia is common. Specific management (e.g.
atropine, catecholamine infusion or pacing) is only required
if there is hypotension or evidence of decreased end-organ
perfusion
l Myoclonic movements do not require specific management. If
seizures are suspected, they should be managed as outlined in
Chapter 2.6: Approach to seizures
SPECIFIC TOXINS
Decontamination
l Activated charcoal is not indicated because absorption and onset
of CNS depression occurs rapidly
Antidotes
l None available.
234
23

4
l atients who are clinically well 2 hours following ingestion may be

P
discharged. Discharge should not occur at night
TOXICOLOGY HANDBOOK
l Patients with mild symptoms are managed supportively in a ward

environment. They are fit for medical discharge when ambulant,
passing urine, eating and drinking
l Patients with significant CNS depression requiring intubation are
admitted to an intensive care unit. Short-term ventilation in the ED
is an alternative when the diagnosis is certain.
HANDY TIPS
l he resolution of coma may be abrupt. Care is required as patients
T
may be agitated and forcefully extubate themselves
l The diagnosis of GHB intoxication is frequently made in retrospect.
It should be suspected in any young person found collapsed in
a nightclub, although alternative diagnoses, particularly alcohol
intoxication, are more likely
l Standard urine toxicological screens do not detect GHB.
PITFALLS
l oma lasting greater than 6 hours indicates an alternative
C
diagnosis (e.g. co-ingested agent or complication) and should
prompt further investigation.
CONTROVERSIES
l hysostigmine has been advocated in the management of
P
GHB poisoning. There is no evidence to suggest that the use of
physostigmine confers any additional benefits over supportive
measures alone.
Presentation and Sources
GHB is a white crystalline powder. It is usually distributed dissolved in water to
form a clear colourless liquid. It may be ingested directly or added to drinks.
The concentration is often 1 g/mL but this is extremely variable
Precursors are found in several household solvents:
l Gamma-butyrolactone (GBL) is an oily liquid
l 1,4-butanediol (BD) is a water soluble liquid.
References
Allen L, Alsalim W. Gammahydroxybutyrate overdose and physostigmine. Emergency
Medicine Journal 2006; 23(4):300–301.
Chin RL, Sporer KA, Cullison B et al. Clinical course of gamma-hydroxybutyrate overdose.
Annals of Emergency Medicine 1998; 31:716–722.
Traub SJ, Nelson LS, Hoffman RS. Physostigmine as treatment for gamma hydroxybutyrate
SPECIFIC TOXINS
toxicity: A review. Journal of Toxicology-Clinical Toxicology 2002; 40(6):781–787.
3.38 GLYPHOSATE
Glyphosate is a widely used herbicide. Severe toxicity occurs as result
of deliberate ingestion of a concentrated formulation. It manifests with
gastrointestinal corrosive symptoms and, in large ingestions, severe
metabolic acidosis and cardiovascular collapse can occur.
235
RISK ASSESSMENT
l Ingestion of concentrated formulations poses the greatest risk
l Dose is frequently difficult to quantify but correlates to severity (see
TOXICOLOGY HANDBOOK
Table 3.38.1)
l Acute corrosive injury to the upper airways poses an immediate
potential threat to life
l Tachycardia, abnormal chest x-ray, metabolic acidosis, hyperkalaemia,
and rising creatinine are associated with poor prognosis
l Diluted glyphosate solutions pose little risk when ingested, with
toxicity confined to minor gastrointestinal irritation
l Cutaneous exposures cause skin irritation, but do not cause
systemic toxicity
TABLE 3.38.1 Dose-related risk assessment: Glyphosate

Dose Effect
<50 mL Asymptomatic or minor gastrointestinal
concentrate symptoms
50–150 mL Gastrointestinal symptoms only
concentrate
>150 mL Severe gastrointestinal symptoms. Risk of early upper
concentrate airways swelling. May develop multi-system toxicity,
especially metabolic acidosis and hypotension
>300 mL Potentially fatal. Death usually from refractory shock
concentrate
l Children: Minor ingestions do not need hospital assessment

unless symptoms develop.
Toxic mechanism
Glyphosate is a phosphonoglycine compound structurally similar to glycine. It does
not inhibit cholinesterase enzymes. Toxicity is thought to be predominantly due to
the surfactant rather than glyphosate per se. The mechanism of toxicity may involve
uncoupling of mitochondrial oxidative phosphorylation. Surfactant appears to cause
significant direct myocardial depression and hypotension.
Toxicokinetics
Glyphosate is poorly absorbed following dermal and oral exposure. It is not metabolised,
but eliminated unchanged by the kidneys. Prolonged elimination half-life occurs in renal
impairment.
CLINICAL FEATURES
l Gastrointestinal
— Gastrointestinal irritation occurs early following ingestion
SPECIFIC TOXINS
— Nausea, vomiting, diarrhoea, abdominal pain

— Oropharyngeal and oesophageal erosions
l Cardiovascular
— Myocardial depression
— Hypotension
l Respiratory
— Upper respiratory tract irritation and drooling
— Aspiration pneumonitis
236 — Non-cardiogenic pulmonary oedema has been reported
l Patients may develop hepatic and renal dysfunction
23
6
l Multi-organ dysfunction secondary to myocardial depression and

systemic acidosis can also occur.
TOXICOLOGY HANDBOOK
INVESTIGATIONS
l Glyphosate levels are not readily available and not clinically
useful
l EUC, LFTs
— Detect and monitor hepatic and renal dysfunction
l Arterial blood gas, venous lactate
— Detect and monitor metabolic acidosis
l Chest x-ray
— Detect aspiration pneumonitis, pulmonary oedema.
MANAGEMENT
l Manage the patient in an area equipped for cardiorespiratory
l Intubate and ventilate if any evidence of airway compromise from
oropharyngeal corrosive injury
l Treat hypotension initially with volume replacement. Give a bolus of
10–20 mL/kg of crystalloid solution IV. Those patients unresponsive
to fluid challenge are likely to require invasive monitoring and
vasopressor therapy
Decontamination
l Not indicated and technically difficult due to vomiting
l Haemodialysis enhances the elimination of glyphosate, but is not
generally indicated. It is supportive in severe refractory shock and
worsening metabolic acidosis
Antidotes
l None available.

l atients who are clinically well after 4 hours of observation may be
P
l Patients with objective evidence of glyphosate intoxication are
admitted to an area with resources and staff available to monitor
fluid balance and observe for potential cardiorespiratory compromise
SPECIFIC TOXINS
l A patient known to have ingested >150 mL is admitted to a high-
dependency or intensive unit in anticipation of multiple organ
effects within 24 hours
l Adult patients with dermal occupational exposure do not require
referral to hospital unless they are symptomatic.
HANDY TIPS
l Intubate early if stridor develops.
237
PITFALLS
l ailure to appreciate potential for cardiovascular compromise
F
following large ingestions
TOXICOLOGY HANDBOOK
l Confusion between glyphosate and organophosphate poisoning.
These are two distinct clinical entities.
CONTROVERSIES
l Utility of haemodialysis in severe glyphosate poisoning.
Presentation and Sources

Numerous glyphosate formulations are available.
Concentrated preparations are usually 36–50% glyphosate while ready-to-use
diluted preparations are approximately 10%.
All preparations also contain polyoxyethyleneamine surfactant.
References
Bradberry SM, Proudfoot AT, Vale JA. Glyphosate poisoning. Toxicological Reviews 2004;
23(3):159–167.
Lee CH, Shih CP, Hsu KH et al. The early prognostic features of glyphosate-surfactant
intoxication. American Journal of Emergency Medicine 2008; 26:275–281.
Lee HL, Chen KW, Chi CH et al. Clinical presentations and prognostic factors of
glyphosate-surfactant herbicide intoxication: a review of 131 cases. Academic
Emergency Medicine 2000; 7(8):906–910.
3.39 HYDROCARBONS
Aliphatic: Essential oils (includes eucalyptus oil), Kerosene, Petroleum
distillates, Turpentine
Aromatic: Benzene, Toluene, Xylene
Halogenated: Carbon tetrachloride, Methylene chloride,
Tetrachloroethylene, Trichloroethylene
See also Chapter 2.16: Solvent abuse, dependence and withdrawal
Hydrocarbons, whether ingested or inhaled, can cause rapid onset of CNS

depression, seizures and (rarely) cardiac dysrhythmias. Aspiration can
lead to chemical pneumonitis. Other end-organ effects are uncommon
and usually associated with long-term occupational exposure.
RISK ASSESSMENT
l he major risks following acute ingestion are early CNS depression
T
and seizures. For most petroleum distillates, more than 1–2 mL/kg
is required to cause significant systemic toxicity
l Ingestion of as little as 10 mL of eucalyptus oil may lead to CNS
depression and seizures, always within 1–2 hours
SPECIFIC TOXINS
l Ingestion may be complicated by aspiration, resulting in a

pneumonitis that evolves over hours
l Large or prolonged inhalational exposure may also produce
asphyxia
l High-viscosity compounds (motor oil, petroleum jelly) have very low
risk of systemic toxicity or chemical pneumonitis
l Children:
— There is a small risk of pulmonary aspiration and chemical
238 pneumonitis following ingestion of any hydrocarbon
— Ingestion of 5 mL of eucalyptus oil or other essential oils is
23
associated with the rapid onset of coma.

8
TOXICOLOGY HANDBOOK
Toxic mechanism
Disruption of lung surfactant produces a chemical pneumonitis. The mechanism of CNS
depression is unclear. Dysrhythmias are secondary to myocardial sensitisation to endogenous
catecholamines. Mechanisms of negative inotropic effects are unclear. Chlorinated
hydrocarbons (carbon tetrachloride) are metabolised to produce a hepatotoxic metabolite.
Toxicokinetics
The hydrocarbons of concern are volatile. Absorption following inhalational exposure is
determined by concentration, duration of exposure and minute ventilation. Absorption
following ingestion is inversely related to the molecular weight of the hydrocarbon. Minimal
absorption occurs following dermal exposure. Distribution to the CNS is determined by
lipid solubility. Most hydrocarbons are eliminated unchanged through expired air. Some
compounds produce metabolites that are excreted in the bile or urine.
CLINICAL FEATURES
l Respiratory
— Immediate coughing and gagging indicates aspiration
— The development of chemical pneumonitis is heralded by wheeze,
tachypnoea, hypoxia, haemoptysis and pulmonary oedema. In
mild cases, pulmonary signs may be delayed 4–6 hours. Features
typically worsen over 24–72 hours and resolve over 5–7 days
l Cardiovascular
— Dysrhythmias occur early in poisoning (pre-hospital)
l Neurological
— Profound CNS depression, coma and seizures may occur with
massive acute exposures. Onset is within 2 hours
— Chronic toluene abuse results in ataxia, dementia, and
peripheral neuropathy (See Chapter 2.16: Solvent abuse,
dependence and withdrawal)
l Gastrointestinal
l Other
— Chemical phlebitis and local tissue injury occur following IV or
SC injection
— High-pressure injection injuries can produce extensive tissue
injury involving tendons and deep structures
— Hepatic and renal injury occur in carbon tetrachloride (CCl4)
poisoning
— Toluene is nephrotoxic
— Benzene is associated with haemolysis and leukaemia.
INVESTIGATIONS
SPECIFIC TOXINS
l Serial ECGs and continuous cardiac monitoring if ectopy or
bigeminy are noted at initial assessment
l FBC, EUC, LFTs, arterial blood gases
l Chest x-ray: Radiographic changes lag behind clinical features of
pneumonitis
l Chronic toluene abuse leads to a renal tubular acidosis characterised
by hypokalaemic hyperchloraemic non-anion gap metabolic acidosis. 239
MANAGEMENT
TOXICOLOGY HANDBOOK
l In the event of ventricular dysrhythmias (VT, VF):
— Commence advanced cardiac life support
— Intubate, hyperventilate and correct hypoxia
— Administer propranolol 1 mg IV or metoprolol 5 mg IV (0.1 mg/
kg in children)
— Correct hypokalaemia and hypomagnesaemia
— Withhold catecholamine inotropes if possible
l Manage seizures along conventional lines, as outlined in
l Chemical pneumonitis is managed supportively with supplemental
oxygen and bronchodilators. Non-invasive ventilation or intubation
and ventilation is required in severe cases. Corticosteroids and
prophylactic antibiotics are not indicated
l Fever is common following significant aspiration with pneumonitis.
Withhold antibiotics until there is objective evidence of pulmonary
sepsis
Decontamination
l Remove patient from the exposure, remove clothing and wash skin
l Activated charcoal does not bind hydrocarbons
l Gastrointestinal decontamination of any kind is contraindicated
following ingestion because induction of vomiting increases the risk
of hydrocarbon aspiration
Antidotes
l None available.

l hildren suspected of ingesting small amounts of hydrocarbons
C
may be observed at home providing they remain asymptomatic.
Any respiratory symptoms beyond an initial cough mandates
hospital assessment and observation
l Patients who are clinically well without cough, dyspnoea, wheeze
or any alteration in vital signs (including pulse oximetry) at 6 hours
are fit for medical discharge
SPECIFIC TOXINS
l Patients with any symptoms or alteration in vital signs are admitted

for observation and supportive care
l Patients with high-pressure injection injuries require surgical
referral for urgent debridement.
HANDY TIPS
l Coughing or gagging following ingestion suggests aspiration.
240 PITFALLS
l ailure to recognise dry cough as a symptom of evolving
F
24
0
pneumonitis.
TOXICOLOGY HANDBOOK
CONTROVERSIES
l echanisms of myocardial toxicity
M
l Chronic occupational solvent encephalopathy.
Sources
Most commercial hydrocarbon products are mixtures. Hydrocarbons are organic compounds
derived from many sources, including petroleum, plant oils and animal fats. They are widely
used in both commercial and household settings as fuel, lubricants, paint thinners and solvents.
References
Flanagan RJ, Ruprah M, Meredith TJ et al. An introduction to the toxicology of volatile
substances. Drug Safety 1990; 5(5):359–383.
Tibballs J. Clinical effects and management of eucalyptus oil ingestion in infants and
young children. Medical Journal of Australia 1995; 163(4):177–180.
3.40 HYDROFLUORIC ACID

Hydrofluoric acid (HF) is found in car wheel cleaners, rust removing solutions,
and in preparations for glass etching and other industrial processes.
Exposure may be dermal, inhalational, ocular or oral. Accidental dermal
exposure is common. Toxicity ranges from minor dermal injury to life-
threatening systemic complications. Ingestion of HF is potentially lethal.
RISK ASSESSMENT
l ny dermal exposure may lead to delayed severe pain and tissue injury
A
l Inhalational exposure can lead to pulmonary injury
l ystemic life-threatening fluorosis is associated with ingestion or
S
extensive dermal exposures:
— Dermal exposure with 100% HF solution to 2.5% body surface
area (BSA)
— Dermal exposure with 70% HF to 8% BSA
— Dermal exposure with 23% HF to 11% BSA
— Ingestion of ≥100 mL of low-concentration HF (6%) by an adult
— Ingestion of any volume of higher concentrations of HF
l Children: Any ingestion of a HF-containing product is potentially lethal.
Toxic mechanism
Fluoride ions bind directly with calcium and magnesium, as well as interfering with cellular
potassium channels to cause cell dysfunction and death. Systemic toxicity and ventricular
SPECIFIC TOXINS
dysrhythmias are secondary to hypocalcaemia, hyperkalaemia, hypomagnesaemia and
acidosis.
Toxicokinetics
Hydrofluoric acid is readily absorbed after ingestion or dermal contact. It penetrates
deeply into tissues to release fluoride ions.
CLINICAL FEATURES
l Dermal exposure
— Skin contact with HF in concentrations <50% is not
immediately painful and may go unnoticed for several hours 241
— Gradual onset of severe deep unremitting pain develops at the
contact site over hours without obvious erythema or blistering
— Pallor and blanching appear after several hours
TOXICOLOGY HANDBOOK
— Blistering or tissue loss is delayed many hours or days
— Pain usually lasts less than 24–36 hours
— Very large exposures result in systemic fluorosis
l Inhalational exposure
— Immediate onset of mucosal irritation followed by delayed
onset of dyspnoea, cough and wheeze
— Non-cardiac pulmonary oedema occurs in severe cases
l Ingestion
— Low concentrations (<20%) are minimally corrosive to the
gastrointestinal tract
— Patients may experience vomiting, mild throat pain, dysphagia
and abdominal pain
— Cardiac arrest from systemic fluorosis may occur without
warning 30 minutes to 6 hours post-ingestion
l Systemic effects (fluorosis)
— Hypocalcaemia and hypomagnesaemia manifest as tetany and
QT prolongation
— Ventricular arrhythmias and cardiac arrest.
INVESTIGATIONS
l Serial ECGs
— Indicated in all patients with potential systemic HF poisoning
every 2 hours until cardiac monitoring ceases
— Degree of QT prolongation is a useful marker of hypocalcaemia
l Serum or ionised calcium
— Measure at presentation and at 4 hours in all patients with
potential systemic HF poisoning until cardiac monitoring ceases
l Endoscopy
— May be indicated to assess the extent of corrosive injury, but
only once the patient is stable.
MANAGEMENT
l Systemic HF poisoning is a time-critical emergency and the patient
at risk of this complication is managed in an area equipped for
cardiopulmonary monitoring and resuscitation
l Intravenous calcium is drawn up and available at the bedside
l In the event of ventricular dysrhythmias:
SPECIFIC TOXINS

— Commence advanced cardiac life support
— Intubate and hyperventilate
— Administer calcium gluconate 10% 60 mL (0.6–1.0 mL/kg in
children) or calcium chloride 10% 20 mL (0.2 mL/kg) IV and
repeat every 5 minutes until return of spontaneous circulation.
Large doses are required and ongoing administration to
maintain serum calcium concentrations may be necessary
— Administer sodium bicarbonate 100 mEq IV (3 mEq/kg in children)
242 — Administer magnesium sulfate 10 mmol IV (0.05 mmol/kg in
children)
24
2
— Beware drug extravasation

TOXICOLOGY HANDBOOK

l Administer oral and parenteral analgesia as required
l Continuous cardiac monitoring is only indicated if there is potential
for systemic fluorosis
Decontamination
l Dermal exposure
— Remove clothing
— Irrigate thoroughly with water
l Ingestion
— Do not induce vomiting
l Ocular exposure
— Irrigate thoroughly with water or saline
Antidotes
l Calcium (see Chapter 4.2: Calcium)
— Calcium chloride or calcium gluconate is given by IV infusion
as described above to correct systemic hypocalcaemia
— Calcium gluconate gel is indicated for all symptomatic patients
following dermal exposure. Administer repeatedly to all
affected areas until pain resolves
— If pain is refractory, calcium gluconate is administered by either
subcutaneous infiltration, regional intravenous infusion or intra-
arterial infusion as described in Chapter 4.2: Calcium
— W ARNING: Do not give calcium chloride by SC injection, regional
IV infusion or arterial infusion as it will cause tissue damage.
l inor skin exposure to low-concentration preparations may be
M
managed in the outpatient setting with calcium gluconate gel
l Patients are instructed to return if pain is not controlled with
repeated applications of gel
l Patients who require calcium administration by regional
intravenous or intra-arterial infusion are not discharged until pain is
controlled with simple analgesia
l All patients at risk of systemic HF poisoning are admitted to an area
capable of detecting and treating cardiovascular collapse. Cardiac
monitoring is continued for at least 8 hours post ingestion or
12 hours after extensive dermal exposure and until serum calcium
and 12-lead ECG are normal without calcium administration.
SPECIFIC TOXINS
HANDY TIPS
l nset of pain is delayed after dermal HF exposure; the less
O
concentrated the product, the greater delay
l Patients often present with pain in the evening or night after using
a HF product during the previous day
l Pain is out of proportion to local signs and frequently requires
parenteral opioids until calcium can be effectively delivered
l Local anaesthetic techniques are contraindicated, as relief of pain
243
is used as an end point to determine adequacy of calcium delivery
l If not available, 2.5% calcium gluconate gel may be made by
mixing:
TOXICOLOGY HANDBOOK
— 10 mL calcium gluconate for injection and 30 mL of lubricant jelly
or
— 3.5 g calcium gluconate powder in 150 mL of lubricant jelly
l Do not use calcium gluconate to irrigate after ocular exposures—
use normal saline or water.
PITFALLS
l ailure to appreciate the severity of dermal injury due to lack of
F
local signs
l Administration of calcium chloride by subcutaneous injection,
intravenous regional or intra-arterial routes.
CONTROVERSIES
l he role of prophylactic calcium infusion in patients at risk of
T
systemic HF poisoning.
Presentations
Exists in two forms, aqueous and anhydrous:
Aqueous HF is available in a wide range of concentrations up to 40%
Anhydrous form is more concentrated (>50%) and used in industry
Products for domestic use typically contain 5–12% aqueous HF.
References
Kao W, Dart RC, Kuffner E et al. Ingestion of concentrated hydrofluoric acid: an insidious
and potentially fatal poisoning. Annals of Emergency Medicine 1999; 34(1):35–41.
Kirkpatrick JR, Burd DAR. An algorithmic approach to the treatment of hydrofluoric acid
burns. Burns 1995; 21:495–499.
Kirkpatrick JR, Enion DS, Burd DAR. Hydrofluoric acid burns: a review. Burns 1995;
21:483–493.
3.41 HYDROGEN PEROXIDE
Hydrogen peroxide (H2O2) is an oxidising agent with a wide range of
domestic and industrial applications. Ingestion of concentrated solution
can cause serious toxicity and death due to corrosive effects, and from
gas embolism caused by release of oxygen gas.
RISK ASSESSMENT
l Ingestion of small volumes (<30 mL) of 3% H2O2 causes mild
gastrointestinal irritation only
l Ingestion of larger volumes of 3% H2O2 causes a more significant
gastrointestinal injury and may result in gas embolism
SPECIFIC TOXINS
l Ingestion of concentrated H2O2 solutions (>10%) causes potentially

life-threatening corrosive injury to the airway and gastrointestinal
tract, and life-threatening venous and arterial gas embolism
l Exposure of the eye to concentrated H2O2 solutions (>10%) causes
permanent corneal injury
l Exposure of the skin to concentrated H2O2 solutions (>10%)
causes local injury
l Gas embolism can also arise where H2O2 solutions are used
medically to irrigate closed body cavities.
244
l Children: Minor exposures to domestic products containing 3%
24
H2O2 are unlikely to cause significant injury. Any exposure to

concentrated H2O2 solutions (>10%) or where symptoms develop
TOXICOLOGY HANDBOOK
is of concern and warrants hospital assessment.
Toxic mechanism
Hydrogen peroxide causes toxicity by three mechanisms: direct corrosive injury, oxygen
gas formation and lipid peroxidation. Hydrogen peroxide is corrosive and exposure can
cause local tissue damage to the skin, mucosal membranes or cornea. Metabolism of
ingested H2O2 liberates large quantities of oxygen. Once the amount of oxygen produced
exceeds its maximal solubility in the blood, oxygen bubbles form and venous or arterial
gas embolism may occur. Rapid accumulation of oxygen in closed body cavities can
cause mechanical distension and complications such as rupture of a hollow viscus.
Intravascular foaming may occur and can seriously impede left ventricular output. Direct
cytotoxic effects from lipid peroxidation are also thought to occur.
Toxicokinetics
Following ingestion, H2O2 is readily absorbed through the stomach mucosa and into the
portal venous system. It is then rapidly metabolised, predominantly by catalases within
red cells, to yield oxygen and water; 30 mL of 35% H2O2 solution liberates almost 3.5 L of
oxygen at standard temperature and pressure.
CLINICAL FEATURES
l Ingestion
— Clinical features of corrosive injury include nausea, vomiting,
haematemesis and foaming at the mouth
— More severe corrosive injury is manifested by blistering of the
mouth and oropharynx, laryngospasm, stridor, cyanosis and
respiratory arrest
— Tachycardia, lethargy, confusion, coma, convulsions and
cardiac arrest and sudden death within minutes may occur with
larger ingestions of concentrated H2O2 (>10%) solutions
— P ainful gastric distension and belching may occur secondary to
liberation of large volumes of gas in the stomach
— Cerebral oxygen gas embolism manifests with progressive
neurological disturbance
l Inhalation
— Usually produces little more than coughing and transient
dyspnoea
— Highly concentrated solutions can produce severe irritation.
Coughing and dyspnoea can progress to shock, coma,
seizures and pulmonary oedema
l Dermal
— Inflammation, blistering and skin necrosis can occur, usually
following exposure to concentrated solutions. Subcutaneous
emphysema may be detected.
SPECIFIC TOXINS
l Ocular
— Exposure of the cornea to 3% H2O2 solution produces
immediate onset of stinging, irritation, lacrimation and blurred
vision
— Subepithelial corneal and conjunctival bubbles may be
observed
— Exposure to concentrated solutions may produce corneal
ulceration and even perforation
— Transient injury is reported after insertion of soft contact lenses 245
stored in 3% H2O2 solution without neutralisation.
INVESTIGATIONS
TOXICOLOGY HANDBOOK
l EUC, FBE, ABGs
l Chest and abdominal x-rays may demonstrate perforation or
oxygen gas embolism
l Chest x-ray is also indicated if there is evidence of pulmonary
irritation following inhalational exposure
l Cerebral CT or MRI scanning is indicated if CNS effects develop
and will demonstrate cerebral gas embolism and infarction
l Upper gastrointestinal endoscopy is considered if there is
persistent vomiting, haematemesis, significant oral burns,
abdominal pain, dysphagia or stridor and the patient has ingested
a solution of >10% concentration.
MANAGEMENT
l Early aggressive airway management is critical to the survival
of the patient who has ingested concentrated H2O2 solution.
Endotracheal intubation or, rarely, tracheostomy may be required
for life-threatening laryngeal oedema
l High-flow oxygen via a tight-fitting mask is administered to all
patients
l Hyperbaric oxygen therapy is of value in treating cerebral gas
embolism if suspected
l lose cardiorespiratory monitoring is essential for any patient at
C
risk of gas embolism
l Passage of a nasogastric tube may relieve the pain of gaseous
gastric distension
Decontamination
l Gastrointestinal decontamination is not indicated due to the rapid
decomposition of H2O2
l Immediate eye irrigation with copious amounts of water or
saline for at least 15 minutes is indicated after ophthalmic
exposure
l Clothing should be removed and the exposed skin washed with
SPECIFIC TOXINS
copious amounts of water following dermal exposure

l Not useful
Antidote
l None available.

246 l inor unintentional exposures to 3% solutions in either children
M
or adults do not require hospital evaluation unless persistent
24
6
symptoms develop
l Any patient who has ingested or inhaled concentrated (>10%)
TOXICOLOGY HANDBOOK
hydrogen peroxide, or has ongoing symptoms, is admitted for

close observation and monitoring
l Those patients with evidence of corrosive injury to the airway
or gastrointestinal tract require admission for definitive
management
l Patients in whom arterial or venous gas embolism is suspected
should be referred for consideration of hyperbaric oxygen
therapy
l Patients with eye exposures and any signs or symptoms of
corneal injury should be referred for formal ophthalmological
evaluation.
PITFALLS
l remature discharge of a patient with vague neurological signs or
P
symptoms; this may indicate cerebral gas embolism.
CONTROVERSIES
l orticosteroids have been recommended for laryngeal and
C
pulmonary oedema, but their value is unproven.
Presentations
Solutions ranging in concentration from 3% to 90% are used in various applications:
Household products (mostly 3% H2O2): disinfectants, bleaches, fabric stain removers,
contact lens disinfectants, hair dyes, tooth-whitening products
Industrial products: bleaching agent in paper industry
Medical products: wound irrigation solutions, sterilising solutions for ophthalmic and
endoscopic instruments
References
Moon JM, Chun BJ, Min YI. Haemorrhagic gastritis and gas embolism after ingestion of
3% hydrogen peroxide. Journal of Emergency Medicine 2006; 30(4):403-406.
Papafragkou S, Gasparyam A, Batista R et al. Treatment of portal venous gas embolism
with hyperbaric oxygen after accidental ingestion of hydrogen peroxide: a case report
and review of the literature. Journal of Emergency Medicine 2009 Oct 19 [Epub ahead
of print].
Watt BE, Proudfoot AT, Vale JA. Hydrogen peroxide poisoning. Toxicological Reviews
2004; 23:51–57.
3.42 INSULIN
SPECIFIC TOXINS
Deliberate self-administered insulin overdose causes profound and
prolonged hypoglycaemia that may result in life-threatening seizures,
coma and permanent neurological injury.
RISK ASSESSMENT
l eliberate self-poisoning with insulin by subcutaneous injection
D
causes life-threatening persistent hypoglycaemia with the risk of
permanent neurological injury if not treated aggressively
l Hypoglycaemia may last for days; patients require prolonged 247
periods of close monitoring and treatment
l The severity and duration of hypoglycaemia is unpredictable, is not
dependent on the insulin preparation administered and correlates
TOXICOLOGY HANDBOOK
poorly with the dose injected
l Poor outcome is associated with delayed presentation with
established hypoglycaemic coma. The prognosis is excellent with
early effective glucose replenishment.
Toxic mechanism
Insulin is released from the beta pancreatic islet cells at a low basal rate, which increases
in response to various stimuli. Exogenous insulin is used for the treatment of type 1 and
type 2 diabetes mellitus, severe hyperkalaemia and calcium channel blocker overdose.
Insulin stimulates the transfer of glucose, potassium, phosphate and magnesium into cells.
It promotes synthesis and storage of glycogen, protein and triglycerides.
Toxicokinetics
In overdose, the pharmacokinetic properties of insulin change. The duration of action is
extended (days) and does not depend on the type of insulin preparation used. Instead,
it is determined by the slow and erratic release from subcutaneous adipose tissue at the
injection site, in addition to the prolonged clearance of the absorbed insulin. Endogenous
insulin is degraded by the liver (60%) and kidneys (40%).
CLINICAL FEATURES
l he clinical features are those of hypoglycaemia. They usually
T
manifest within 2 hours after administration:
l Autonomic symptoms
— Diaphoresis
— Tachycardia and palpitations
— Agitation and tremor
— Confusion and visual disturbances
— Seizures
— Hemiplegia
— Coma
l The hyperinsulinaemic state commonly persists for >3 days
l Persistent, untreated hypoglycaemia may cause permanent
neurologic injury and death.
INVESTIGATIONS
l Serial blood glucose levels
— Perform every 15 minutes during the resuscitation phase and
SPECIFIC TOXINS
every 1–2 hours during glucose infusion

l EUC, serum phosphate and magnesium
— Detect and monitor hypokalaemia, hypophosphataemia and
hypomagnesaemia associated with insulin excess
l Insulin levels
— Insulin levels are elevated, but do not predict the magnitude or
duration of glucose administration and are not clinically useful
— Insulin and C-peptide levels are helpful in the extremely rare
248 circumstance where it is necessary to exclude an endogenous
hyperinsulinaemic state.
24
8
MANAGEMENT
TOXICOLOGY HANDBOOK

l Insulin overdose is a life-threatening emergency and the patient
should be managed in an area capable of detecting and managing
hypoglycaemia with close clinical and physiological monitoring
l If symptoms of hypoglycaemia occur or serum glucose is <4.0 mmol/L
(bedside or laboratory value) administer concentrated IV glucose:
— A dult
50 mL bolus of 50% glucose IV
Repeat if no immediate clinical improvement
— C hild
5 mL/kg bolus of 10% glucose IV
Repeat if no immediate clinical improvement
l Hyperinsulinaemia as manifested by hypoglycaemia requiring
ongoing exogenous glucose administration. Infusion concentration
and rate is titrated to maintain serum glucose at or just above the
normal range
l Commence a 10% glucose infusion at 100 mL/hour and monitor
bedside BSL frequently
l Any further episodes of symptomatic hypoglycaemia are treated
with an IV bolus of concentrated glucose
l If the above infusion fails to maintain normoglycaemia, obtain
central venous access and commence a titrated infusion of
25% or 50% glucose to maintain normoglycaemia (or mild
hyperglycaemia)
l Infusion rates of up to around 150 mL/hour of 50% dextrose may
be required for many (frequently 3–7) days
l Manage asymptomatic hypoglycaemia by increasing the rate of
infusion without bolus therapy
l onitor serum potassium and supplement as required
M
(e.g. 20 mmol/hour)
Decontamination
Antidote
l Glucose as outlined in Chapter 4.13: Glucose.

l atients who are clinically well with normal serum glucose levels
P
SPECIFIC TOXINS
at 6 hours following exposure have not administered a significant
insulin dose and do not require further medical care
l Confirmed significant deliberate self-poisoning with insulin
requires admission to an intensive care or high-dependency unit
for several days of ongoing exogenous IV glucose administration
via a central line and careful monitoring of blood glucose and
serum potassium levels.
HANDY TIPS 249

l nticipate the need for large ongoing glucose requirement and
A
insert a central line early so that 50% glucose infusion may
commence
TOXICOLOGY HANDBOOK
l Diabetic patients have a diminished counter-regulatory hormonal
response to hypoglycaemia and may require increased glucose
replacement
l Withdrawal of glucose infusion should be gradual and should not
take place at night
l Monitor patients for 4–6 hours after glucose cessation
l Excessively prolonged glucose infusions can stimulate
endogenous insulin secretion in non-diabetic patients, resulting
in hyperinsulinaemic state and difficulty withdrawing the glucose
infusion
l Consider the diagnosis of deliberate insulin overdose in
the diabetic patient with unexplained severe and recurrent
hypoglycaemia or the non-diabetic patient who presents with
profound hypoglycaemia
l Glucagon is not indicated in the hospital management of
hypoglycaemia.
PITFALLS
l ailure to anticipate ongoing glucose requirement after initial
F
hypoglycaemia in a patient with deliberate self-poisoning
l Attempts to manage with an infusion of 5% glucose solution
l O ver-enthusiastic attempts at early weaning of glucose
infusion.
CONTROVERSIES
l xcision of the insulin injection site has been described, but such
E
an invasive procedure is not justified.
Presentations
Actrapid preparations (insulin neutral) Humulin 30/70 injection 1000 IU /10 mL
Actrapid 300 IU/3 mL cartridges vials
Actrapid 1000 IU/10 mL vials Hypurin isophane (NPH)
Apidra preparations (insulin glulisine) preparations (insulin isophane
Apidra 300 IU/3 mL cartridges (bovine))
Apidra 1000 IU/10 mL vials Hypurin isophane (NPH) 1000 IU/10 mL
Humalog preparations (insulin lispro) vials
Humalog injection 300 IU/3 mL Hypurin neutral preparations (insulin
cartridges neutral (bovine))
Humalog injection 1000 mL/10 mL vials Hypurin neutral 1000 IU/10 mL vials
Humalog Mix 25 preparations Lantus preparations (insulin glargine)
(insulin lispro 25%, insulin Lantus injection 300 IU/3 mL cartridges
protamine 75%) Lantus injection 1000 IU/10 mL vials
SPECIFIC TOXINS
Humalog Mix 25 300 IU/3 mL Levemir FlexPen preparations (insulin

cartridges detemir)
Humalog Mix 25 1000 IU/10 mL vials Levemir FlexPen 300 IU/3 mL cartridges
Humalog Mix 50 preparations Mixtard preparations (insulin neutral,
(insulin lispro 50%, insulin insulin isophane)
protamine 75%) Mixtard 30/70 300 IU/3 mL cartridges
Humalog Mix 50 300 IU/3 mL cartridges Mixtard 50/50 300 IU/3 mL cartridges
Humalog Mix 50 1000 IU/3 mL vials NovoMix 30 preparations (insulin
Humulin R preparations (insulin aspart 30%, insulin aspart
neutral) protamine 70%)
250 Humulin 300 IU/ 3 mL cartridges Novomix 30 300 IU/3 mL cartridges
Humulin 1000 IU/10 mL vials Novomix 30 300 IU /1 mL penfill
25
Humulin NPH preparations (insulin cartridges

0
isophane) NovoRapid preparations (insulin

TOXICOLOGY HANDBOOK
Humulin NPH injection 300 IU/1 mL, 3 mL aspart)

cartridges NovoRapid 300 IU/3 mL cartridges
Humulin NPH injection 1000 IU /10 mL vials NovoRapid 1000 IU/10 mL vials
Humulin 30/70 preparations Protaphane preparations (insulin
(insulin neutral 30%, insulin isophane)
isophane 70%) Protaphane 1000 IU /10 mL
Humulin 30/70 injection 300 IU /3 mL Protaphane 300 IU/3 mL
cartridges
References
Haskell RJ, Stapczynski JS. Duration of hypoglycaemia and need for intravenous glucose
following intentional overdoses of insulin. Annals of Emergency Medicine 1984;
13:505–511.
Megarbane B, Deye N, Bloch V et al. Intentional overdose with insulin: prognostic factors
and toxicokinetic/toxicodynamic profiles. Critical Care 2007; 11(5):R115.
3.43 IRON
Ferrous chloride, Ferrous fumarate, Ferrous gluconate, Ferrous
phosphate, Ferrous sulfate, Iron amino acid chelates
Iron poisoning is characterised by both local gastrointestinal and
dose-related systemic toxicity. Toxicity is determined by the quantity
of elemental iron ingested. Most acute overdoses produce minor or
moderate gastrointestinal effects only. In large overdoses, systemic
toxicity can be prevented by early gastrointestinal decontamination and/or
administration of desferrioxamine.
RISK ASSESSMENT
l Iron overdose is potentially lethal
l Risk assessment is based on the ingested dose of elemental iron
(see Table 3.43.1) and the observed evolving clinical features (see
Table 3.43.2)
l The amount of elemental iron in a ferrous or ferric salt is calculated
as follows:
Ferric chloride dose divided by 3.5
Ferrous chloride dose divided by 4
Ferrous fumarate dose divided by 3
Ferrous gluconate dose divided by 9
Ferrous sulfate (dried) dose divided by 3.3
Ferrous sulfate (heptahydrate) dose divided by 5
SPECIFIC TOXINS
l Refinement of the initial risk assessment can be achieved by:
Abdominal x-ray to confirm or quantify ingestion
An iron level at 4–6 hours post-ingestion
l Patients presenting with established systemic iron toxicity
have a poor prognosis and may not respond to medical
therapy
TABLE 3.43.1 Dose-related risk assessment: Iron

251
Elemental iron dose Effect
<20 mg/kg Asymptomatic
TOXICOLOGY HANDBOOK
20–60 mg/kg Gastrointestinal symptoms
>60–120 mg/kg Systemic toxicity anticipated
>120 mg/kg Potentially lethal
l Children: The dose ingested is usually trivial (<60 mg/kg).
Toxic mechanism
Local: Direct corrosive effect on the gastrointestinal (GI) mucosa manifests with symptoms
ranging from vomiting and diarrhoea to haematemesis and melaena. Large GI fluid losses
may contribute to significant hypovolaemia. Systemic toxicity does not occur in the
absence of GI symptoms.
Systemic: Iron acts as a direct cellular toxin via poorly understood mechanisms.
The chief target organs are the cardiovascular system and the liver. CNS toxicity is
secondary to cardiovascular instability and metabolic derangements. Severe metabolic
acidosis is observed following large overdoses and attributed to lactic acid formation
and the liberation of hydrogen ions from the hydration of free ferric ions in the plasma.
Coagulopathy is frequently observed and attributed to interference with the coagulation
cascade.
Toxicokinetics
Absorption of iron from the GI tract is normally finely regulated according to the
requirements of the body. In overdose these mechanisms are overwhelmed and the
bioavailability of iron increases significantly. Absorbed iron shifts intracellularly over a
period of hours. Elimination is minimal under normal conditions.
TABLE 3.43.2 Classical stages of severe iron poisoning
Time
post-ingestion Clinical features
0–6 hours Direct corrosive effect on GI tract characterised by

vomiting, diarrhoea and abdominal pain. Fluid losses
may be sufficient to cause hypovolaemic shock
6–12 hours Progressive increase in iron absorption and distribution.

Some resolution of symptoms may be observed, giving
false hope of recovery
SPECIFIC TOXINS
12–48 hours Disruption of cellular metabolism manifested as shock

from vasodilatation and third-space losses, anion gap
metabolic acidosis and hepatorenal failure
2–5 days Acute hepatic failure with jaundice, coma, hypoglycaemia,

coagulopathy and elevated aminotransferases. This
phase is rare, but has a high mortality
2–6 weeks Delayed sequelae, including cirrhotic liver disease and GI

252 fibrosis/strictures
25
2
TOXICOLOGY HANDBOOK
CLINICAL FEATURES
Iron toxicity is classically described as having five stages (see
Table 3.43.2), although this is an over-simplification. Not all patients
experience all stages and the duration of each stage is imprecise and
they usually overlap. Iron toxicity is more accurately conceptualised
as two overlapping stages with a pathophysiological basis:
gastrointestinal and systemic toxicity.
INVESTIGATIONS
l Serum iron concentration:
— Iron levels usually peak at 4–6 hours following ingestion.
Following this there is rapid intracellular migration of iron. A
clear correlation between iron levels and clinical toxicity is not
established, but peak levels >90 micromol/L (500 microgram/
dL) are thought to be predictive of systemic toxicity
l Arterial or venous blood gas
— An anion gap metabolic acidosis is a useful marker of systemic
toxicity
l Abdominal x-ray
— Useful in confirming ingestion, and planning and monitoring
decontamination
l Note: Hyperglycaemia and elevated white cell counts are frequently
observed in iron poisoning, but do not correlate with toxicity.
MANAGEMENT
l An early priority is the restoration of adequate circulating volume.
Give boluses of 10–20 mL/kg of crystalloid and assess response
l Ongoing fluid replacement is essential in the face of continuing
gastrointestinal and third-space losses
Decontamination
l Iron is not adsorbed to activated charcoal
l Whole bowel irrigation (WBI) is the decontamination method of
choice and recommended for ingestions >60 mg/kg confirmed on
x-ray (see Chapter 1.6: Gastrointestinal decontamination)
l Surgical or endoscopic removal may be considered in potentially
SPECIFIC TOXINS
lethal ingestions if WBI fails or is impractical
Antidotes
l Desferrioxamine chelation therapy is indicated if systemic toxicity
(shock, metabolic acidosis, altered mental status) is present or
predicted by a serum iron level >90 micromol/L (500 microg/dL)
at 4–6 hours post ingestion. For further details see Chapter 4.4:
Desferrioxamine. 253

l hildren thought to have ingested <40 mg/kg may be managed at
C
TOXICOLOGY HANDBOOK
home provided they remain asymptomatic. Larger or symptomatic
ingestions are evaluated in hospital. The child who remains
asymptomatic at 6 hours and has an abdominal x-ray negative for
iron may be safely discharged
l All adults who have deliberately self-poisoned with iron are
evaluated in hospital. If the history suggests ingestion of <60
mg/kg of iron and they remain asymptomatic at 6 hours, further
medical observation is unnecessary
l Symptomatic patients requiring intravenous fluid therapy or WBI
require admission to hospital
l Those presenting with established systemic iron toxicity or requiring
intravenous chelation therapy are admitted to intensive care.
HANDY TIPS
l here serum iron levels are not readily available, a fall in serum
W
bicarbonate concentration is a good surrogate marker of systemic
iron poisoning and, in conjunction with worsening clinical features,
would justify desferrioxamine administration
l Iron supplements are readily accessible to pregnant women and
so frequently taken in overdose. The fetus is relatively protected
unless maternal cardiovascular instability develops. Therapy is
directed towards care of the mother and does not differ from the
care of the non-pregnant patient.
PITFALLS
l ver-treatment of trivial ingestions
O
l Failure to perform initial risk assessment thus leading to delays in
therapy and irreversible toxicity following large overdoses
l ailure to recognise systemic iron toxicity in the patient who
F
presents late with minimal elevation in serum iron level.
CONTROVERSIES
l hreshold serum iron level that mandates chelation with
T
desferrioxamine
l Duration and endpoints for desferrioxamine therapy.
Presentations
There are numerous over-the-counter vitamin preparations containing relatively small
amounts of elemental iron, usually iron amino acid chelates, ferrous phosphate or ferrous
fumarate. The important preparations containing large amounts of elemental iron are:
Ferrous sulfate 325 mg (105 mg elemental iron) slow-release tablets (30)
Ferrous sulfate 250 mg (80 mg elemental iron)/folic acid 300 mg combination
SPECIFIC TOXINS
controlled-release tablets (30)
References
Chyka PA, Butler AY. Assessment of acute iron poisoning by laboratory and clinical
observations. American Journal of Emergency Medicine 1993: 11(2):99–103.
Pearn J, Nixon J, Ansford A et al. Accidental poisoning in childhood: five year urban
population study with 15 year analysis of fatality. British Medical Journal 1984; 288:44–46.
Singhi SC, Baranwal AK, Jayashree M. Acute iron poisoning: Clinical picture, intensive
care needs and outcome. Indian Pediatrics 2003: 40(12):1177–1182.
254 Tenenbein M. Benefits of parenteral deferoxamine for acute iron poisoning. Journal of
Toxicology-Clinical Toxicology 1996; 34(5):485–489.
25
4
TOXICOLOGY HANDBOOK
3.44 ISONIAZID
Isoniazid overdose is rare but potentially fatal. Severe poisoning presents
with rapid onset of seizures, coma and severe metabolic acidosis.
Pyridoxine is the specific antidote.
RISK ASSESSMENT
l oxicity is of rapid onset, occurring within 30 min to 2 hours of
T
ingestion and follows a predictable dose-response (see Table 3.44.1).
TABLE 3.44.1 Dose-related risk assessment: Isoniazid
Dose Effect
>1.5 g (20 mg/kg) May develop symptoms
>3 g (40 mg/kg) Seizures, metabolic acidosis and coma
>10 g (130 mg/kg) Uniformly fatal without intervention
Toxic mechanism
Isoniazid is structurally related to pyridoxine, nicotinic acid and NAD. Toxicity results from
a deficiency of the active form of pyridoxine, pyridoxine 5-phosphate (P5P). Isoniazid
interferes with the enzyme responsible for the conversion of pyridoxine to P5P, pyridoxine
phosphokinase, binds to and inactivates P5P and enhances urinary excretion of P5P.
Because P5P is an essential co-factor for the conversion of glutamic acid to GABA in
the CNS, an acute GABA deficiency manifesting as status seizures develops. The severe
lactic acidosis is due to the status seizures and direct inhibition of conversion of lactate to
pyruvate.
Toxicokinetics
Absorption following oral administration is rapid and complete. Peak serum levels
occur within 1–2 hours. Volume of distribution is 0.6 L /kg. Isoniazid undergoes hepatic
metabolism by either acetylation to form acetyl-isoniazid, or hydrolysis by cytochrome
p450 to form hydrazine derivatives. Some drug is excreted unchanged in the urine.
There are ‘fast’ and ‘slow’ acetylators such that the elimination half-life varies from 1 to
4 hours.
CLINICAL FEATURES
SPECIFIC TOXINS
l Initial symptoms are light-headedness, blurred vision, photophobia,
nausea and vomiting
l Physical examination may reveal tachycardia, dilated pupils,
slurred speech, ataxia and hyperreflexia
l If a sufficient dose is ingested, patients rapidly develop confusion,
depressed level of consciousness, coma, status seizures, severe
lactic acidosis and death
l Seizures are typically generalised tonic–clonic. They may
resolve spontaneously but then recur promptly. Complications 255
of prolonged status seizures, including hyperpyrexia, pulmonary
aspiration and rhabdomyolysis, may be observed.
TOXICOLOGY HANDBOOK
INVESTIGATIONS
l Arterial blood gas
— Severe anion gap metabolic acidosis with a high serum lactate
is a major feature of isoniazid overdose. The pH may range
from 6.8 to 7.3
l Isoniazid levels
— Not routinely available, difficult to interpret and do not aid
in acute management. They may be useful to confirm the
diagnosis retrospectively.
MANAGEMENT
l Isoniazid overdose is a medical emergency and managed
in an area equipped for cardiorespiratory monitoring and
resuscitation
l Aggressive supportive care of airway, breathing and circulation
is paramount until seizures are controlled and adequate doses of
pyridoxine administered
l The patient presenting unconscious or with seizures undergoes
prompt rapid sequence induction of anaesthesia, intubation and
ventilation
l Seizures are controlled with high-dose intravenous diazepam while
supplies of pyridoxine are secured and administered
l EEG monitoring if available is useful in the intubated patient
Decontamination
l Activated charcoal is only given once the airway is secured
with endotracheal intubation and never takes precedence over
resuscitation and supportive care
l Haemodialysis effectively removes isoniazid, but the time course of
the poisoning is such that this intervention is not clinically useful
Antidotes
l Urgent administration of IV pyridoxine is indicated if coma or
seizures develop (See Chapter 4.24: Pyridoxine)
l Give 1 g for each gram of isoniazid ingested
l If the ingested dose is unknown, give 5 g of pyridoxine and review
SPECIFIC TOXINS
response.

l symptomatic patients can be observed for 6 hours and
A
discharged if no symptoms develop and no treatment is given
l All patients who develop neurological toxicity should be admitted
to an intensive care or high-dependency unit
l Any patient who develops seizures is intubated and managed in
intensive care.
256
25
6
HANDY TIPS
l lways consider isoniazid overdose in the differential diagnosis of
A
TOXICOLOGY HANDBOOK
status epilepticus, particularly if the patient or household member

has a history of tuberculosis
l Rapidly ascertain location of all available pyridoxine when
confronted with a possible isoniazid overdose.
PITFALLS
l Inability to secure adequate doses of IV pyridoxine.
CONTROVERSIES
l alue of prophylactic administration of pyridoxine to patients with a
V
history of ingestion of >1.5 g of isoniazid.
Presentations
Isoniazid 100 mg tablets (100)
Reference
Alvarez FG, Guntupalli KK. Isoniazid overdose: four case reports and review of the
literature. Intensive Care Medicine 1995; 21(8):641–644.
3.45 LEAD
Acute lead intoxication is usually due to ingestion. It is rare, but potentially
life threatening. Chronic environmental lead exposure remains a major
public health issue in some regions and occupations. Evaluation of
patients with possible lead exposure requires a detailed risk assessment.
RISK ASSESSMENT
l cute or subacute severe lead intoxication occurs in the context
A
of ingestion or inhalational occupational exposure to lead. It is
associated with encephalopathy, cerebral oedema and death
l Chronic occupational or environmental exposure usually leads to
a vague multi-system disorder with the potential for permanent
neurological and neuropsychological sequelae
l Risk of long-term neurological sequelae loosely correlates to blood
lead level (see Table 3.45.1)
l Pregnancy: Major malformations are reported in children born to
mothers with elevated lead levels
l Children: Childhood exposure to lead is neurotoxic and associated
SPECIFIC TOXINS
with impaired intellectual development. There appears to be
no threshold below which lead is not deleterious during early
childhood development.
Toxic mechanism
Lead has no physiological function. It has toxic effects through interference with
intracellular functions, including maintenance of cell wall integrity, haem synthesis,
neurotransmitter systems and steroid production. Major target organs affected by lead are
the nervous system, kidneys, reproductive and haematopoietic systems.
257
Toxicokinetics
Absorption is via oral, topical and inhaled routes. Absorption from lead foreign bodies such
as shotgun pellets lodged in joints or other body cavities also occurs. Oral absorption
TOXICOLOGY HANDBOOK
is greater in children than adults (bioavailability 50% and 20% respectively). Lead
bioavailability is increased with high-fat, low-calcium diets. Fumes from lead smelting, or
inhaled lead dust, are rapidly absorbed by the lungs. Dermal absorption of organic lead
compounds through intact skin can occur. Lead is absorbed and bound by red cells, then
distributed widely throughout the body. The bony skeleton acts as a major lead store.
Other sites of deposition are the CNS, kidneys and spleen. Bone stores can remobilise
decades after exposure has ceased, resulting in persistently high levels for months to
years. Lead easily crosses the placenta and significant fetal transfer can occur. Urinary
excretion is the predominant elimination pathway.
CLINICAL FEATURES
l Acute
— Acute ingestion of lead leads to abdominal pain, nausea,
vomiting, haemolytic anaemia and hepatitis
— Cerebral oedema, encephalopathy, seizures and coma are
preterminal conditions
— Clinical effects generally correlate with levels although there is
wide inter-individual variation (see Table 3.45.1)
l Chronic
— Vague constitutional symptoms and multi-system effects
include impaired concentration, anorexia, vague abdominal
pain, emotional lability, weight loss, arthralgia and impaired
coordination
— Subclinical impairment of higher centre functions, including IQ.
INVESTIGATIONS
TABLE 3.45.1 Blood lead level and clinical effects
Blood lead level Effects
<10 microgram/dL Minor dose-dependent reduction in IQ

(0.48 micromol/L) in young children as lead levels increase
towards 10 microgram/dL
>10 microgram/dL Subtle developmental, learning, motor and

(0.48 micromol/L) intellectual abnormalities in children
>30 microgram/dL Non-specific constitutional symptoms

(1.4 micromol/L) such as abdominal pain, malaise,
headaches, hypertension and insomnia
SPECIFIC TOXINS
Subclinical impairment of peripheral nerve

conduction and psychometric testing
may occur
Clinically overt peripheral neuropathies
involving ulnar and radial nerves (wrist
drop) are classical but rare
Renal injury in the form of a chronic
interstitial nephritis or Fanconi’s
258 syndrome may occur
Decreased fertility reported in both sexes
25
8
>100 microgram/dL Severe gastrointestinal symptoms,

TOXICOLOGY HANDBOOK
(4.8 micromol/L) encephalopathy, seizures and coma

l Whole blood lead level
— Most useful indicator of lead exposure
l FBC
— Normochromic, normocytic anaemia with basophilic stippling
of erythrocytes is classical but rarely seen
l EUC, LFTs
l Free erythrocyte protoporphyrin (FEP)
— FEP is a surrogate measure of total body burden of lead, but has
low sensitivity at levels below 25 microgram/dL (1.2 micromol/L)
— FEP is elevated in chronic lead intoxication due to the inhibition
of haemoglobin synthesis
l Abdominal x-ray
— Assists identification of ingested lead foreign bodies
l Nerve conduction and psychomotor testing
— May be useful in chronic exposures to demonstrate objective
evidence of lead neurotoxicity.
MANAGEMENT
l Acute resuscitation is rarely required
l In cases of acute lead-induced encephalopathy, management of
airway, breathing and circulation are managed along conventional
lines, as outlined in Chapter 1.2: Resuscitation
l Administer mannitol 1 g/kg and dexamethasone 10 mg (0.15 mg/kg
in children) if cerebral oedema is present
l eizures are treated with benzodiazepines, as outlined in
S
Decontamination
l Lead foreign body ingestion
— Endoscopic retrieval if located above the gastro-oesophageal
junction
— If beyond the gastro-oesophageal junction and the patient
is asymptomatic, commence a high-residue diet plus oral
polyethylene glycol to drink at home. Repeat abdominal x-rays
every 24 hours to ensure passage of the foreign body within
72 hours
SPECIFIC TOXINS
— If the foreign body is still present at 72 hours, admit
the patient for formal whole bowel irrigation with
polyethylene glycol (see Chapter 1.6: Gastrointestinal
decontamination)
l Shrapnel or bullets adjacent to synovial tissue:
— Surgical excision if feasible is indicated in the patient with
symptoms or rising lead levels
l Not clinically useful 259
Antidotes
l Chelation therapy is indicated in symptomatic lead poisoning or if
TOXICOLOGY HANDBOOK

long-term neurological injury is anticipated
l Sodium calcium edetate (EDTA), an intravenous chelator,
is indicated for acute lead-induced encephalopathy or the
symptomatic patient with blood level >100 microgram/dL
(4.8 micromol/L). For administration see Chapter 4.26: Sodium
calcium edetate
l Succimer (DMSA), an oral chelator, is used in symptomatic patients
without encephalopathy and asymptomatic patients with blood
lead levels >60 microgram/dL (2.9 micromol/L) for adults or >45
microgram/dL (2.17 micromol/L) for children. For administration
see Chapter 4.28: Succimer.
HANDY TIPS
l iagnosis of chronic lead intoxication identifies an index case.
D
Other family members or colleagues should be screened and all
potential exposures considered
l Lead levels <25 microgram/dL (1.2 micromol/L) are usually
asymptomatic. However, any level >10 microg/L (0.48 micromol/L)
mandates strenuous efforts to identify the source and prevent
further exposure, especially in children
l Lead intoxication is a notifiable disease in most jurisdictions.
PITFALLS
l sing dicobalt edetate (antidote for cyanide) instead of sodium
U
calcium edetate (EDTA)
l Failure to identify source of lead exposure in chronic poisoning,
and prevent further exposure.
CONTROVERSIES
l hresholds for chelation in pregnant women, children and
T
asymptomatic adults remain controversial and are constantly under
review
l Value of chelation therapy for children with mild–moderate elevated
lead levels (<45 microgram/dL or 2.17 micromol/L). This intervention
does not appear to lead to improved neuropsychological outcomes.
Sources
Smelting and metal recycling
Atmospheric lead due to leaded petrol
Occupations and hobbies (e.g. soldering metal, lead galvanising and painting, jewellery,
stained glass, radiator repairs, battery recycling, plumbing, injection moulding of
SPECIFIC TOXINS
plastics, sports shooting)

Lead paint used in housing prior to 1960s (tastes sweet and attractive to children)
Soil contamination—often idiopathic
Fishing sinkers
Antique toys painted with lead paint
Pottery glazes
Lead powder medications available in many developing countries
Make-up (especially from India and Pakistan)
Retained bullets near synovial joints
260
References
26
Canfield RL, Henderson CR, Cory-Slechta DA et al. Intellectual impairment in children

0
with blood lead concentrations below 10 microg per deciliter. New England Journal of
TOXICOLOGY HANDBOOK
Medicine 2003; 348(16):1517—1526.

Dietrick Kn, Ware JH, Salganik M et al. Effect of chelation therapy on neuropsychological
and behavioural development of lead-exposed children after school entry. Pediatrics
2004; 114:19—26.
Keogh JP, Boyer LV. Lead. In: Sullivan JB, Krieger GR, eds. Clinical Environmental
Health and Toxic Exposures. 2nd edn. Lippincott Williams & Wilkins, Philadelphia,
2001:879—889.
Toxicological profile for Lead, ATSDR (Agency for Toxic Substances and Disease Registry).
Available online at: http://www.atsdr.cdc.gov/toxprofiles/tp13.pdf; accessed 6 April 2010.
3.46 LITHIUM: ACUTE OVERDOSE

See also 3.47: Lithium: Chronic poisoning
Acute lithium overdose frequently produces acute gastrointestinal
symptoms, including nausea, vomiting, abdominal pain and diarrhoea.
Provided adequate urinary lithium excretion is maintained, significant
neurotoxicity of the type observed with chronic lithium intoxication rarely
develops.
RISK ASSESSMENT
l In the setting of normal renal function, acute ingestion of <25 g is
benign, causing no more than minor gastrointestinal (GI) symptoms
l Acute ingestion of >25 g may cause more significant GI symptoms
but rarely leads to significant neurotoxicity, provided that good
supportive care is instituted so as to avoid dehydration, sodium
depletion or renal impairment
l cute or chronic impairment of renal function, dehydration or
A
sodium depletion significantly impairs urinary lithium excretion.
Under these conditions, lithium absorbed following acute overdose
is preferentially redistributed to tissue compartments, including
the CNS, rather than excreted, thus enhancing the potential for
delayed onset of neurotoxicity
l Patients who present late with established neurotoxicity have a risk
assessment similar to that of chronic lithium toxicity (see Chapter
3.47: Lithium: Chronic poisoning)
l Children: Minor paediatric ingestions do not cause toxicity and do
not require hospital assessment unless symptoms develop.
Toxic mechanism
SPECIFIC TOXINS
Lithium is a monovalent cation primarily used in the management of bipolar disorder. Like
most metal salts, lithium carbonate acts as a direct irritant to the GI tract. Once absorbed,
lithium ions substitute for sodium and potassium ions and are thought to modulate
intracellular second messengers. They may also affect neurotransmitter (including
serotonin) production and release.
Toxicokinetics
Standard-release lithium carbonate preparations are normally completely absorbed within
6 hours of ingestion and peak serum lithium levels occur within 4 hours. Absorption may
be prolonged following overdose, with peak levels delayed up to 12 hours with slow-
release preparations. Lithium is slowly redistributed from the intravascular compartment 261
to tissue compartments, including the CNS, with a steady-state volume of distribution
of 0.7–0.9 L/kg. Elimination is almost entirely by the kidney. Clearance is dependent on
glomerular filtration and reduced in water- or sodium-depleted states. Elimination half-life
TOXICOLOGY HANDBOOK
is 24 hours at steady state.
CLINICAL FEATURES
l mall acute overdoses are often asymptomatic
S
l Following larger ingestions, symptoms of acute gastroenteritis
occur early and include nausea, vomiting, abdominal pain and
diarrhoea
l Significant fluid losses may occur
l Neurological symptoms, if they develop, are delayed, reflecting
slow redistribution into the CNS. The earliest and most frequent
neurological sign is tremor. Neurotoxic symptoms rarely progress
beyond tremor provided adequate lithium excretion is maintained
l Patients occasionally present late with established neurotoxicity
(see Chapter 3.47 Lithium: Chronic poisoning for description)
l Minor ST-T wave changes may be observed on the 12-lead ECG.
INVESTIGATIONS
Specific investigations as indicated:
l EUC
— Detect and monitor renal impairment
l Serum lithium levels
— Useful to confirm ingestion and, following larger overdoses,
monitor progress and determine safety of medical discharge
— Peak levels >5 mmol/L occurring at 4–8 hours post ingestion
are not unusual following acute overdose.
MANAGEMENT
l The patient who presents late with severe GI symptoms requires
fluid resuscitation. Give normal saline 10–20 mL/kg IV and
reassess.
l Maintain adequate hydration and sodium repletion with
intravenous normal saline if necessary. Urine output is ideally
>1 mL/kg/hour
l Monitor fluid and electrolyte status, renal function, serum lithium
and clinical features of neurotoxicity
l Continuous cardiac monitoring is not required in the absence of
co-ingestants
SPECIFIC TOXINS
Decontamination
l Activated charcoal does not effectively adsorb lithium and is not
indicated
l Elimination of lithium can be enhanced with haemodialysis;
however, in the patient with normal renal function whose
hydration and sodium repletion are ensured, this relatively minor
enhancement of elimination is not clinically useful
262 l Haemodialysis is reserved for patients with established renal
failure, particularly those who present late with clinical features of
26
2
lithium neurotoxicity
TOXICOLOGY HANDBOOK
Antidotes
l None available.

l atients with no clinical evidence of neurotoxicity and a serum
P
lithium level <2.5 mmol/L and falling do not require further medical
care or monitoring.
HANDY TIPS
l oma in the context of acute deliberate self-poisoning is never
C
due to lithium. It is always due to a co-ingestant or is of non-
toxicological aetiology
l Patients on long-term lithium therapy do not have a significantly
increased risk of developing neurotoxicity following acute lithium
overdose. The approach to management does not require
modification.
PITFALLS
l ailure to distinguish between acute lithium overdose and chronic
F
lithium toxicity. These represent distinct clinical entities.
CONTROVERSIES
l hole bowel irrigation has been advocated following overdose
W
of sustained-release preparations. The value of this intervention
is unproven and provides no theoretical benefit over meticulous
supportive care in patients with normal renal function.
Presentations
Lithium carbonate 250 mg standard-release tablets (200)
Lithium carbonate 450 mg slow-release tablets (100)
References
Jaeger A, Saunder P, Kopferschmidt J et al. When should dialysis be performed in lithium
poisoning? A kinetic study in 14 cases of lithium poisoning. Clinical Toxicology 1993;
31:429–427.
Waring WS. Management of lithium toxicity. Toxicology Reviews 2006; 25(4):221–230.
3.47 LITHIUM: CHRONIC POISONING
SPECIFIC TOXINS
See also 3.46: Lithium: Acute overdose
Lithium neurotoxicity develops in patients on lithium therapy when renal
lithium excretion is impaired for any reason.
RISK ASSESSMENT
l onsider lithium intoxication in any patient on lithium therapy who
C
presents with neurological signs or symptoms
l Significant obtundation or seizure activity is an indication of severe 263
toxicity that carries a risk of permanent neurological sequelae
l Serum lithium concentrations correlate poorly with clinical features
of toxicity.
TOXICOLOGY HANDBOOK
Toxic mechanism
Lithium ions substitute for sodium and potassium ions and are thought to modulate
intracellular second messengers. They may also affect neurotransmitter (including
serotonin) production and release.
Toxicokinetics
Lithium is well absorbed following oral administration with peak serum levels within 4 hours
of administration of a standard-release preparation. Lithium is slowly redistributed from
the intravascular compartment to tissue compartments, including the CNS, with a steady-
state volume of distribution of 0.7–0.9 L/kg. Elimination is almost entirely by the kidney.
Clearance is dependent on glomerular filtration and reduced in water- or sodium-depleted
states. Elimination half-life is about 24 hours at steady state under normal conditions.
CLINICAL FEATURES
l he clinical features are principally neurological. The following
T
classification by Hansen and Amdisen is widely used:
Grade 1 (mild)
— Tremor, hyperreflexia, agitation, muscle weakness, ataxia
Grade 2 (moderate)
— Stupor, rigidity, hypertonia, hypotension
Grade 3 (severe)
— Coma, convulsions, myoclonus
l Gastrointestinal symptoms are not prominent with chronic toxicity
l Clinical features frequently include those of the underlying
precipitating illness
l The most common causes of impaired lithium excretion are
impaired renal function, diabetes insipidus, sodium depletion,
dehydration and drug interactions
l rugs that may impair lithium excretion include non-steroidal anti-
D
inflammatory drugs, angiotensin converting enzyme inhibitors,
selective serotonin reuptake inhibitors, thiazide diuretics and
topiramate
l Nephrogenic diabetes insipidus and hypothyroidism are associated
with lithium therapy. They may contribute to the development of
toxicity and complicate the clinical presentation.
INVESTIGATIONS
l Serum lithium level
— Essential to confirm the diagnosis, but the level does not
correlate well with CSF levels and clinical severity
— Serial levels are useful in monitoring the progress of a patient
SPECIFIC TOXINS
receiving supportive care or haemodialysis

l EUC
l Thyroid function tests.
MANAGEMENT
l Acute resuscitation is unlikely to be necessary except in cases of
extreme neurotoxicity with coma and seizures
264 l Careful attention to correcting any water and sodium deficits and
restoring renal function is essential to maximise lithium excretion
26
4
l Lithium and any drugs that may impair lithium excretion are ceased
l Renal function, urine output, electrolytes and serum lithium levels
TOXICOLOGY HANDBOOK
are closely monitored

Decontamination
l No role in chronic toxicity
l Haemodialysis enhances the elimination of lithium. It is considered
in the patient with neurological dysfunction and a serum lithium
level >2.5 mmol/L. It is most likely to be useful in the presence
of established renal impairment. Prolonged and repeated
haemodialysis sessions may be necessary to eliminate lithium
Antidotes
l None available.

l atients with chronic lithium toxicity always require admission.
P
Resolution of neurological symptoms may be very slow (weeks)
and sometimes incomplete.
HANDY TIPS
l onsider the diagnosis of chronic lithium toxicity in any individual
C
on lithium who presents unwell, particularly if there is evidence of
neurological dysfunction
l Lithium neurotoxicity may persist long after serum lithium returns to
therapeutic range.
PITFALLS
l Failure to check a lithium level in the unwell patient on lithium therapy.
CONTROVERSIES
l he indications for haemodialysis are unproven and have not been
T
evaluated in clinical trials. Most patients can be managed without
dialysis provided they receive adequate fluid and electrolyte
resuscitation and normal renal function is rapidly re-established
l Continuous arterio- or venovenous haemofiltration has been
proposed as an alternative to haemodialysis for enhancement of
lithium elimination. Although lower clearances are achieved with
these methods, they are often easier to institute and may minimise
rapid transcellular fluid and electrolyte shifts. At the moment they
can only be recommended if haemodialysis is not available.
Presentations
SPECIFIC TOXINS
Lithium carbonate 250 mg standard-release tablets (200)
Lithium carbonate 450 mg slow-release tablets (100)
References
Hansen HE, Amdisen A. Lithium intoxication. Quarterly Journal of Medicine 1978; 47:
123–144.
Oakley P, Whyte IM, Carter GL. Lithium toxicity: an iatrogenic problem in susceptible
individuals. Australian and New Zealand Journal of Psychiatry 2001; 35:833–840.
Waring WS. Management of lithium toxicity. Toxicology Reviews 2006; 25(4):221–230.
265
3.48 LOCAL ANAESTHETIC AGENTS
TOXICOLOGY HANDBOOK
Amethocaine, Articaine, Benzocaine, Bupivacaine, Levobupivacaine,
Lignocaine, Mepivacaine, Prilocaine, Ropivacaine
Local anaesthetic (LA) toxicity is nearly always the result of a therapeutic
error. It occurs because of incorrect dose, route of administration or
technique. Care for this potentially life-threatening toxicity is primarily
supportive, although use of intravenous lipid emulsion plays an important
role in management of severe cases.
RISK ASSESSMENT
l ost cases of LA toxicity arise from inadvertent intravascular
M
administration rather than gross overdose
l Clinical manifestations correspond to the concentration achieved in
the systemic circulation
l Onset of clinical manifestations is rapid
l Maximal recommended doses for agents are listed in Table 3.48.1
but toxicity can occur when lower doses are administered by direct
intravenous or intra-arterial injection. Larger doses can be safely
given in some circumstances when co-administered with adrenaline
l Methaemoglobinaemia is not dose-related, but is more likely to
complicate administration of benzocaine, lignocaine or prilocaine
l Children: Although paediatric fatalities are reported following
ingestion of lignocaine-containing local and topical anaesthetic
preparations, ingested doses <6 mg/kg are safe. Children are more
likely to develop methaemoglobinaemia after LA administration,
including topical administration.
TABLE 3.48.1 Maximal dose of selected local anaesthetic agents
Local anaesthetic Maximal dose (mg/kg)
Bupivacaine 1–2.5
Lignocaine 4–5
Mepivacaine 4–5
Prilocaine 5–7
Ropivacaine 2.5–3
Toxic mechanism
SPECIFIC TOXINS
The LA agents bind reversibly to sodium channels and act on peripheral nerves to
inhibit the sodium flux necessary to initiate and propagate action potentials. Local
anaesthetic agents, especially benzocaine, lignocaine and prilocaine, may also cause
methaemoglobinaemia.
Toxicokinetics
The amide LAs are usually administered topically or by injection into skin and
subcutaneous tissues, intravenous regional injection, epidural and intrathecal routes.
Systemic toxic effects correspond to peak concentrations achieved in the systemic
266 circulation and these are influenced by multiple factors, including total dose, rate
of administration, route and location of administration, presence of tourniquets and
26
local blood flow. Toxicity is rare following ingestion because of extensive first-pass
6
metabolism. Some preparations contain adrenaline to cause vasoconstriction and

slow the movement of the LA agent away from the site of administration. The amide
TOXICOLOGY HANDBOOK
LAs have small volumes of distribution and are eliminated by hepatic metabolism,
with elimination half-lives around 2 hours for most agents, but somewhat longer for
bupivacaine.
CLINICAL FEATURES
l arliest symptoms of LA toxicity are neurologic and include
E
tinnitus, dizziness, anxiety, confusion and perioral numbness
l More severe toxicity is characterised by:
— C NS effects: Seizures, coma
— C ardiovascular effects: Bradycardia, hypotension, atrial
and ventricular dysrhythmias, cardiovascular collapse
and asystole
— R espiratory effects: Respiratory depression, apnoea
l CNS toxicity normally manifests before cardiovascular toxicity,
except following massive intravenous overdose where cardiac
arrest may be the first clinical manifestation of toxicity
l Bupivacaine is particularly cardiotoxic due to prolonged binding to
myocardial tissue
l Methaemoglobinaemia is not dose-related. It manifests initially as
blue discolouration of the mucous membranes, but may progress
to CNS and cardiovascular manifestations of cellular hypoxia,
culminating in death as methaemoglobin concentrations rise above
70%.
INVESTIGATIONS
l EUC, ABGs, methaemoglobin concentration
l Serial ECGs
— May reveal evidence of Na+ channel blockade (prolongation PR
and QRS intervals, large terminal R wave in aVR).
MANAGEMENT
Chapter 1.2: Resuscitation. Immediate intubation and ventilation
is indicated if there is evidence of cardiovascular toxicity
l Ventricular dysrhythmias are treated with sodium bicarbonate
100 mEq (2 mEq/kg in children) IV repeated every 1–2 minutes
until restoration of perfusing rhythm (see Chapter 4.25: Sodium
bicarbonate)
SPECIFIC TOXINS
l Seizures are treated with benzodiazepines, as described in
l Hypotension should be treated with administration of
intravenous crystalloid 20 mL/kg followed by inotropic support if
necessary
Decontamination
l Not indicated
Enhanced elimination 267

Antidotes
TOXICOLOGY HANDBOOK
l Sodium bicarbonate for ventricular dysrhythmias secondary to Na+
channel blockade as described above
l Intravenous lipid emulsion is indicated in cardiac arrest refractory
to standard resuscitation protocols. For details on administration
see Chapter 4.16: Intravenous lipid emulsion
l Methylene blue is the specific antidote for methaemoglobinaemia
and is administered to all symptomatic patients. For details on
administration see Chapter 4.17: Methylene blue.

l hildren who ingest lignocaine-containing teething gels and other
C
topical preparations do not require hospital assessment unless
>6 mg/kg may have been ingested or symptoms develop
l Local anaesthetic toxicity usually occurs in a hospital or clinic
setting. Once resuscitated, the patient should be managed in a
high-dependency or intensive care setting until toxicity resolves.
HANDY TIPS
l he development of any neurological symptoms during or shortly
T
after administration of a LA prompts close observation in an area
equipped for cardiorespiratory monitoring and resuscitation.
CONTROVERSIES
l lthough currently recommended for cardiac arrest refractory
A
to standard resuscitation attempts, it may be appropriate to
trial intravenous lipid emulsion in any patient with evidence of
significant CNS or cardiovascular manifestations of LA toxicity.
Presentations
Amethocaine HCl 0.5% eye drops Lignocaine HCL 20 mg/mL; adrenaline
Amethocaine HCl 1% eye drops 12.5 microgram/mL cartridges (2.2 mL)
Articaine HCl 40 mg/mL; adrenaline acid Lignocaine HCl 2% pre-filled syringe
tartrate 1:100 000 vials (1.7 mL, 2.2 (5 mL)
mL) Lignocaine HCl 3%; cetrimol 0.5% gel
Benzocaine topical oropharyngeal and (25 g)
otic preparations Lignocaine HCl 2%; cetrimol 0.25% spray
Bupivacaine HCl 0.25% ampoules (20 mL) (125 mL)
Bupivacaine HCl 0.5% ampoules (10 mL, Lignocaine HCl 1%; cetrimol 1%;
20 mL) chlorhexidine 0.2% cream (50 g)
Bupivacaine HCl 5 mg/mL; adrenaline 12.5 Lignocaine 5 mg/1 mL (5 mL)
microgram/mL cartridges (2.2 mL) Lignocaine 10 mg/1 mL (2 mL, 5 mL)
Bupivacaine HCL 0.5% ampoules (4 mL) Lignocaine 20 mg/1 mL (2 mL 20 mL)
SPECIFIC TOXINS
Bupivacaine HCl 1.25 mg; fentanyl citrate Lignocaine HCl 20 mg/1 mL; adrenaline
5 microgram/mL ampoules (20 mL, 1:80 000 ampoules (5 mL)
200 mL) Lignocaine HCl 10 mg/1 mL; adrenaline
Bupivacaine HCl 1.25 mg/1 mL polybags 1:100 000 ampoules (5 mL)
(100 mL, 200 mL) Lignocaine HCl 5 mg/1 mL; adrenaline
Bupivacaine HCl 2.5 mg/1 mL ampoules 1:200 000 ampoules (20 mL)
(20 mL) Lignocaine HCl 10 mg/1 mL; adrenaline
Bupivacaine HCl 2.5 mg/1 mL polybags 1:200 000 ampoules (20 mL)
(100 mL) Lignocaine HCl 20 mg/1 mL; adrenaline
Bupivacaine HCl 2.5 mg/1 mL; adrenaline 1:200 000 ampoules (20 mL)
268 2.5 microgram/mL vials (20 mL) Lignocaine 10 mg/0.1 mL pump spray
Bupivacaine HCl 3.75 mg/1 mL ampoules (50 mL)
26
(20 mL) Lignocaine 100 mg/1 g ointment (15 g)

8
Bupivacaine 5 mg/1 mL ampoules (10 mL, Lignocaine 20 mg/1 mL viscous solution

TOXICOLOGY HANDBOOK
20 mL) (200 mL)

Bupivacaine 5 mg/1 mL; adrenaline Lignocaine 40 mg/1 mL topical solution
5 microgram/mL vials (20 mL) (30 mL)
Bupivacaine HCl 1.25 mg; fentanyl citrate Lignocaine 2% gel (30 g)
5 microgram/mL ampoules (20 mL) Lignocaine HCl 20 mg/1 mL cartridges
Bupivacaine HCl 1.25 mg; fentanyl citrate (2.2 mL)
5 microgram/mL polybags (200 mL) Lignocaine 20 mg/1 mL; adrenaline
Levobupivacaine 25 mg/10 mL vials 1:80 000 cartridges (2.2 mL)
Levobupivacaine 50 mg/10 mL vials Lignocaine 20 mg/1 mL; adrenaline
Levobupivacaine 75 mg/10 mL vials 1:100 000 cartridges (2.2 mL)
Levobupivacaine 62.5 mg/100 mL Lignocaine 5 g/100 g gel (50 g)
polybag Mepivacaine 2% cartridges (2.2 mL)
Levobupivacaine 125 mg/100 mL Mepivacaine 3%; adrenaline 1:100 000
polybag cartridges (1.8 mL, 2.2 mL)
Levobupivacaine 125 mg/200 mL polybag Prilocaine HCl 0.5% vials (50 mL)
Levobupivacaine 250 mg/200 mL polybag Prilocaine HCl 2% ampoules (5 mL)
Lignocaine HCL 50 mg/1 mL; Prilocaine HCl 40 mg/1 mL cartridges
phenylephrine HCl 5 mg/mL nasal (2.2 mL)
spray (15 mL, 50 mL) Prilocaine HCl 30 mg/1 mL; adrenaline
Lignocaine/prilocaine eutectic mixture 5% 1:300 000 cartridges (2.2 mL)
cream (5 g, 30 g) Prilocaine HCl 30 mg/1 mL; felypressin
Lignocaine/prilocaine eutectic mixture 5% 0.03 IU/mL cartridges (2.2 mL)
patches (1 g) Ropivacaine HCl 2 mg/1 mL ampoules
Lignocaine HCL 2% gel (10 g, 20 g) (10 mL, 20 mL)
Lignocaine HCl 2% gel urethral syringes Ropivacaine HCl 2 mg/1 mL polybags
(10 g) (100 mL, 200 mL)
Lignocaine HCL 20 mg; chlorhexidine Ropivacaine HCl 7.5 mg/1 mL ampoules
0.5 mg urethral syringes (10 mL) (10 mL, 20 mL)
Lignocaine HCl 1% ampoules (5 mL, Ropivacaine HCl 7.5 mg/1 mL polybags
20 mL) (100 mL, 200 mL)
Lignocaine HCl 2% ampoules (5 mL, Ropivacaine HCl 10 mg/1 mL ampoules
20 mL) (10 mL, 20 mL)
References
Balit CR, Lynch AM, Gilmore SP et al. Lignocaine and chlorhexidine toxicity in children
resulting from mouthpaint ingestion: a bottling problem. Journal of Paediatrics and
Child Health 2006; 42(6):350–353.
Curtis LA, Dolan TS, Seibert HE. Are one or two dangerous? Lidocaine and topical
anesthetics exposure in children. Journal of Emergency Medicine 2009; 37:32–39.
Felice KL, Schumann HM. Intravenous lipid emulsion for local anesthetic toxicity: a review
of the literature. Journal of Medical Toxicology 2008; 4(3):184–191.
Weinberg G. Lipid rescue resuscitation from local anaesthetic cardiac toxicity.
Toxicological Reviews 2006; 25(3):139–145.
3.49 MERCURY
SPECIFIC TOXINS
Elemental mercury, Inorganic mercury, Organic mercury
Mercury intoxication is now rare. Most exposures come from consumption
of seafood. Accidental ingestion of elemental thermometer mercury or
amalgam mercury present minimal risk. Occupational exposures and
deliberate self-poisoning with mercury may cause serious morbidity or
mortality.
RISK ASSESSMENT
269
l Benign presentations
— Accidental ingestion of elemental mercury (e.g. from a broken
thermometer) in a normal intact gastrointestinal tract
TOXICOLOGY HANDBOOK
— Incidental discovery of elevated mercury levels in an
asymptomatic patient undergoing a ‘heavy metal screen’
— Concern about dental amalgams
l Potentially serious presentations
— Inhalation of mercury aerosol (after vacuuming or prolonged
stasis) or vapour (heating of elemental mercury). Pneumonitis,
acute non-cardiac pulmonary oedema and neurological injury
may occur
— Ingestion of inorganic mercury salts, leading to haemorrhagic
gastroenteritis, acute renal failure and shock. Potential lethal
dose is 30–50 mg/kg
— Exposure to organic mercury compounds by ingestion,
inhalation or dermal application, leading to neurological injury
l Undefined risk
— Injection of elemental mercury SC or IV, leading to mercuric
pulmonary emboli. This creates depots from which distribution
of mercury to the brain may occur over the long term
— Intentional ingestion of merbromin (Mercurochrome) is
associated with high mercury levels, although long-term
sequelae are not reported
l Children: Minor unintentional ingestion or skin exposure to
elemental mercury or Mercurochrome antiseptic solution does not
warrant medical assessment, observation or investigation.
Toxic mechanism
Mercury is a metal with no natural cellular function. It binds to sulfhydryl (SH-) groups
at multiple intracellular sites, causing inhibition of enzymes and disruption of cellular
membranes.
Toxicokinetics
There is minimal absorption of elemental mercury from an intact gastrointestinal (GI)
tract. In contrast, elemental mercury is well absorbed from the respiratory tract when
inhaled as either an aerosol (produced when it is vacuumed) or vapour (produced
when it is heated). About 10% of a dose of inorganic mercury is absorbed following
ingestion. Inorganic mercury is also significantly absorbed when applied to skin or
mucous membranes. Organic mercury is readily absorbed from both the GI tract and
via inhalation. Absorption also occurs across disrupted skin. Mercury has a large
volume of distribution and is deposited in the kidneys, liver, spleen and CNS. The high
lipid solubility of elemental and organic mercury compounds favours distribution to the
CNS. Mercuric ions are excreted by the kidney and across the GI tract into faeces. The
elimination half-life of elemental mercury and inorganic mercury is 30–60 days. Organic
mercury is eliminated primarily in the faeces and undergoes enterohepatic circulation.
Half-life is approximately 70 days.
SPECIFIC TOXINS
CLINICAL FEATURES
l Acute exposure to elemental mercury
Acute intoxication develops following inhalation of vaporised or
aerosolised mercury. Within a few hours there is the abrupt onset of
headache, nausea, vomiting, chills, fever, salivation, metallic taste,
visual disturbances, dyspnoea and dry cough. Respiratory failure
secondary to interstitial pneumonitis may occur over the following
days.
270 l Acute exposure to inorganic mercury salts
Acute ingestion causes severe haemorrhagic gastroenteritis within
27
hours. The patient experiences severe local oropharyngeal pain, a

0
metallic taste, nausea, vomiting and diarrhoea. Grey discolouration

TOXICOLOGY HANDBOOK
of the mucous membranes may be noted. Massive fluid loss

leading to hypotension, shock and acute tubular necrosis follows.
l Acute exposure to organic mercury
Acute manifestations include GI symptoms, tremor, respiratory
distress and dermatitis, renal tubular dysfunction and ECG (ST
segment) changes. Delayed neurotoxicity develops weeks or
months after initial exposure and is usually permanent. It is most
severe in children who have suffered prenatal exposure. Organic
mercury is excreted in breast milk and can produce toxicity in
infants. Delayed neurological sequelae include:
— Psychological: poor concentration, short-and long-term
memory loss, emotional lability, depression and coma
— Cerebellar: ataxia, incoordination and dysdiadochokinesis
— Sensory: glove-stocking paraesthesia of distal limbs,
tunnel vision, deafness, scanning speech with slurring and
dysphagia
— Motor: spasticity, tremor, weakness and paralysis.
l Chronic mercury toxicity
Chronic exposure to elemental mercury vapour or inorganic
mercury salts leads to the insidious onset of a multi-system
disorder with prominent neuropsychiatric symptoms:
— Neurological: tremor, neurasthenia (fatigue, depression,
headaches, hypersensitivity, lack of concentration, general
weakness), erethism (blushing and intense shyness), emotional
lability, insomnia, delirium, mixed sensorimotor neuropathy,
ataxia, tunnel vision, anosmia
— Gastrointestinal: metallic taste, burning pain in the mouth,
gingivostomatitis, loose teeth, nausea, hypersalivation
— R enal dysfunction: Proximal tubular atrophy with mercuric
deposits within the renal interstitium and macrophages
— Acrodynia (usually children): erythematous, oedematous,
hyperkeratotic indurated rash of the palms, soles and face. It
often progresses to desquamation and ulceration.
INVESTIGATIONS
l Whole blood mercury level (normal: <20 microgram/L (100 nmol/L))
— Level >200 microgram/L (1000 nmol/L) is associated with
symptoms
SPECIFIC TOXINS
— Level may be >500 microgram/L (2500 nmol/L) following acute
inorganic mercury exposure
— Confirms recent exposure but does not reflect total body burden
l Urine mercury level: (normal: <10 microgram/L (5 nmol/L)
— Level >100 microgram/L (500 nmol/L) is associated with
neuropsychiatric disturbance
l X-rays
— Elemental mercury is radio-opaque and x-rays confirm
ingestion, subcutaneous or intravenous injection. 271
— Intravenous injection produces multiple mercuric pulmonary
emboli and a characteristic ‘milky way’ appearance on chest
x-ray
TOXICOLOGY HANDBOOK
l Endoscopy
— May be indicated to assess corrosive GI injury.
MANAGEMENT
l Accidental oral or skin exposure to elemental mercury does not
require medical assessment or management
l Following other acute exposure, attention to airway, breathing and
circulation are paramount. These priorities are managed along
conventional lines, as outlined in Chapter 1.2: Resuscitation
l Inhalational exposure to mercury vapour requires close clinical and
physiological monitoring and general supportive care measures, as
l Ingestion of inorganic mercury requires aggressive fluid resuscitation
and general supportive care measures for multiple organ failure
l Exposure to organic mercury requires general supportive care
measures, as outlined in Chapter 1.4: Supportive care and
monitoring
Decontamination
l Decontamination is aimed at preventing further exposure to
mercury
— Environmental
– Seek advice regarding mercury spills
– Avoid vacuuming
– Discard contaminated carpets or surfaces
— Individual
– Elemental mercury
Remove contaminated clothing
Remove mercury from skin
Administration of oral polyethylene glycol solution
enhances removal from the GI tract following deliberate
ingestion of massive volumes
Surgical excision of subcutaneous mercury depots or
residues following SC injection should be undertaken
where feasible
— Organic mercury compounds
– Administer activated charcoal
l Not clinically useful for elemental or inorganic mercury toxicity
l Administration of polythiol resin may interrupt enterohepatic
SPECIFIC TOXINS
circulation of organic mercury compounds

Antidotes
l Chelation therapy with dimercaprol, penicillamine or succimer
(see Chapter 4.7: Dimercaprol, Chapter 4.21: Penicillamine and
Chapter 4.28: Succimer)
— Chelation therapy is indicated when there are objective clinical
features of mercury intoxication or if markedly elevated urine
or blood mercury levels indicate potential for significant
272 morbidity
— Chelation is only useful once further exposure to mercury is
27
2
terminated by decontamination of the environment or individual

— Note: Dimercaprol is only used for inorganic mercury salt
TOXICOLOGY HANDBOOK
exposure.

l atients exposed to mercury vapour or aerosol are counselled
P
regarding appropriate measures to cease exposure and clean up
remnant environmental contamination
l Symptomatic patients require admission for further management
l Patients with potential ingestion of inorganic or organic mercury
require admission for observation and aggressive management
should clinical features develop.
HANDY TIPS
l imercaprol is contraindicated following elemental mercury
D
exposure, as there is concern that it increases distribution of
mercury to the brain.
PITFALLS
l rdering ‘heavy metal screens’ on patients with non-specific
O
symptoms without exposure assessment—these are rarely
clinically useful.
CONTROVERSIES
l he indications for chelation therapy. Dimercaprol does not
T
reduce symptoms of organic mercury intoxication. Succimer
reduces mercury levels but has not been shown to alter
prognosis
l alue of long-term chelation therapy following IV or SC injection of
V
mercury if decontamination cannot be adequately achieved
l The literature does not support the routine replacement of mercury
dental amalgams.
Sources
Elemental mercury (Hg0): dental amalgam, thermometers, barometers, manufacture of
chlorine and caustic soda, paints, pigments and gold mining
Inorganic mercury (mercuric acetate, mercuric arsenate, mercuric bromide, mercuric
chloride, mercuric potassium cyanide, mercuric sulfide): disinfectants, fireworks
and explosives, processing of fur and leather, waterproofing and antifouling paints,
photographic plates, batteries
Organic mercury (alkoxyalkyl mercury, alkyl mercury, methyl mercury): embalming
fluid, fungicides, pesticides, wood preservatives, seafood
SPECIFIC TOXINS
Merbromin
References
Brownawall AM, Berent S, Brent RL et al. The potential adverse effects of dental amalgam.
Clarkson TW, Magos L, Myers GJ. The toxicology of mercury: current exposures and
clinical manifestations. New England Journal of Medicine 2003; 349:1731–1737.
Kales SN, Goldman RH. Mercury exposure: current concepts, controversies, and a
clinic’s experience. Journal of Occupational and Environmental Medicine 2002;
44:143–154.
273
3.50 METFORMIN
TOXICOLOGY HANDBOOK
Metformin can produce life-threatening lactic acidosis. This may occur
in patients on therapeutic doses who develop renal failure or, less
commonly, following large acute ingestions. Early recognition and
haemodialysis are life saving.
RISK ASSESSMENT
l actic acidosis in a patient on therapeutic metformin usually
L
occurs in the context of acute renal failure or severe sepsis and is
associated with a mortality exceeding 50%
l Metformin overdose is usually benign, but severe lactic acidosis is
reported. The threshold dose of concern remains undefined but is
thought to be >10 g
l Lactic acidosis is more likely to develop following acute overdose if
there is preexisting impairment of renal function or if cardiovascular
toxicity of co-ingestants results in impaired renal perfusion
l The prognosis for severe lactic acidosis from metformin overdose
remains good provided there is early recognition and institution of
haemodialysis
l Children: Unintentional ingestion of up to 1700 mg is benign and
does not require hospital assessment.
Toxic mechanism
Metformin inhibits gluconeogenesis, reduces hepatic glucose output and stimulates
peripheral glucose uptake. The chief agent of toxicity is lactate. Metformin can produce a
type B (non-aerobic) lactic acidosis, possibly by changing the intracellular redox potential
and increasing cellular production, and by inhibiting hepatic uptake of lactate.
Toxicokinetics
Metformin is rapidly and well absorbed following oral administration, with peak levels
occurring at 2 hours. It is not metabolised and elimination is entirely dependent on renal
excretion.
CLINICAL FEATURES
l cute metformin overdose is usually asymptomatic
A
l Lactic acidosis, if it develops, manifests some hours following the
overdose, with worsening non-specific features including altered
sensorium, nausea, vomiting, diarrhoea, dyspnoea, tachycardia,
hypotension and cool peripheries
l Lactic acidosis may progress to coma, shock and death
l Hypoglycaemia, if it develops at all, is usually minor and easily
SPECIFIC TOXINS
corrected by dextrose administration

l Patients who develop lactic acidosis on therapeutic metformin
present unwell with a history of progressively worsening clinical
features as described above. There is nearly always co-existing
acute renal failure and/or sepsis.
INVESTIGATIONS
274
27
4
l Electrolytes, renal function tests, arterial blood gases, serum

lactate
TOXICOLOGY HANDBOOK
— Confirm diagnosis of lactic acidosis

— Indicated in any unwell patient on metformin and any patient
with clinical deterioration following metformin overdose.
MANAGEMENT
l General supportive care measures, as outlined in Chapter 1.4:
Supportive care and monitoring ensure a good outcome in the
l Administration of sodium bicarbonate to control severe acidosis
(see Chapter 4.25: Sodium bicarbonate) and control of
hyperkalaemia help stabilise the severely unwell patient while
awaiting haemodialysis
Decontamination
l Administer oral activated charcoal to the co-operative patient who
presents within 2 hours of deliberately self-poisoning with >10 g of
metformin
l Haemodialysis not only rapidly corrects acidosis, but also removes
metformin, thus preventing further lactate production. It is urgently
indicated in:
— Any unwell patient with lactic acidosis from therapeutic
administration
— W orsening lactic acidosis following acute overdose where
signs of clinical instability are present or emerging
l Haemodialysis may need to be prolonged >15 hours
Antidotes
l None available.

l hildren who acutely ingest up to 1700 mg of metformin may be
C
safely observed at home
l Deliberate self-poisoning with >10 g of metformin mandates
observation for at least 8 hours. Patients who remain well with a
normal bicarbonate at the end of that period may be medically
cleared
SPECIFIC TOXINS
l Patients who present with or develop lactic acidosis require
critical care admission, monitoring and assessment for urgent
haemodialysis.
HANDY TIPS
l onsider the diagnosis of lactic acidosis when confronted with any
C
unwell patient on metformin or any patient who becomes unwell
following acute self-poisoning with metformin.
275
PITFALLS
l reating metformin overdose as a sulfonylurea overdose—they are
T
both antidiabetic medications but belong to different classes and
TOXICOLOGY HANDBOOK
have different toxicities and risk assessments
l Failure to consider the diagnosis of metformin-induced lactic
acidosis.
CONTROVERSIES
l recise indications for initiating haemodialysis in metformin-related
P
lactic acidosis following overdose. It is probably safe to tolerate
lactates of up to 10 mmol/L, provided the patient has normal renal
function and a stable cardiovascular system
l Relative efficacy of various haemodialysis methods. Both
intermittent and continuous haemodialysis techniques have been
used successfully.
Presentations
Metformin hydrochloride 500 mg tablets (100)
References
Guo PYF, Storsley LJ, Finkle SN. Severe lactic acidosis treated with prolonged
haemodialysis: Recovery after massive overdose of metformin. Seminars in Dialysis
2006; 19(1):80–83.
Seidowsky A, Nseir S, Houdret N et al. Metformin-associated lactic acidosis: A prognostic
and therapeutic study. Critical Care Medicine 2009; 37(7):2191–2196.
Spiller HA, Weber JA, Winter ML et al. Multicenter case series of pediatric metformin
ingestion. Annals of Pharmacotherapy 2000; 34:1385–1358.
Teale KFH, Devine A, Stewart H et al. The management of metformin overdose.
Anaesthesia 1998; 53:698–701.
3.51 METHOTREXATE
The toxic effects of this antimetabolite are employed therapeutically in the
treatment of a variety of neoplastic conditions, psoriasis and rheumatoid
arthritis. Toxicity is not described following acute overdose, but severe
toxicity occurs following repeated supratherapeutic dosing. Folinic acid is
used as an antidote in selected cases.
RISK ASSESSMENT
l Acute overdose
— Toxicity is not described following acute deliberate self-
poisoning (single ingestion)
SPECIFIC TOXINS
— Methotrexate levels taken following acute overdose suggest

that toxic levels are not attained where less than 500 mg is
ingested (5 mg/kg in children) (see Table 3.51.1 and Table
3.51.2)
l Repeated supratherapeutic ingestion
— Associated with potentially lethal bone marrow suppression
— Toxicity may develop if the weekly therapeutic oral dose is
taken on as few as 3 consecutive days
— Patients with renal impairment and the malnourished are
276 more susceptible to methotrexate-induced bone marrow
27
suppression
6
l Intrathecal overdose
— Potentially lethal
TOXICOLOGY HANDBOOK
l Children: Toxicity is not reported after acute ingestion, but single

ingestion suspected to be >2.5 mg/kg warrants referral to hospital
for assessment including a methotrexate level.
Toxic mechanism
Methotrexate is a structural analogue of folate. It acts by competitive inhibition of
dihydrofolate reductase and thymidylate synthetase, resulting in decreased DNA and
RNA synthesis, and hence decreased cell replication. Methotrexate toxicity is related to
inhibition of dividing cells (e.g. gastrointestinal tract, bone marrow, hair). Renal and hepatic
injuries are also noted.
Toxicokinetics
Intestinal absorption of orally administered methotrexate is saturable. Peak levels occur
at 1–2 hours post ingestion. The volume of distribution is 0.4–0.8 L/kg, with 50% protein
binding. Up to 80% is excreted by the kidney unchanged. Hepatic metabolism creates
a nephrotoxic metabolite (7-hydroxymethotrexate), which accumulates at high doses.
Elimination half-life increases with dose, accounting for the accumulation and severe
toxicity seen with inadvertent daily dosing.
TABLE 3.51.1 Dose-related risk assessment: Acute methotrexate

overdose
Single dose <500 mg (5 mg/kg in Toxic levels unlikely

children)
Single dose >500 mg (5 mg/kg in Toxic levels possible

children)
CLINICAL FEATURES
l ost patients remain asymptomatic after acute ingestion
M
l Following repeated supratherapeutic ingestion, patients
present with clinical features and complications of
gastrointestinal, bone marrow, hepatic and renal injury.
Stomatitis is an early sign. Nausea, vomiting and diarrhoea are
common. Pallor and fatigue indicate anaemia, which reaches a
nadir at 7–14 days.
INVESTIGATIONS
SPECIFIC TOXINS
l Methotrexate level and renal function
— Following acute single overdose, a timed methotrexate level
and renal function tests determine the need for folinic acid
rescue
— If folinic acid is indicated, follow-up methotrexate levels
determine the duration of therapy
l EUC, FBC, liver function tests.
277
MANAGEMENT
TOXICOLOGY HANDBOOK
In patients presenting with established methotrexate toxicity
managed along conventional lines, as outlined in Chapter 1.2:
Resuscitation
l Supportive care includes meticulous fluid resuscitation,
management of sepsis, and administration of granulocyte colony
stimulation factor (G-CSF)
In patients presenting following acute overdose

l Ingestion <500 mg (5 mg/kg in children)
— Ensure adequate hydration
— Check renal function and methotrexate level at 6 or more hours
post ingestion
l Ingestion >500 mg (5 mg/kg in children)
— Administer activated charcoal
— Ensure adequate hydration
— Commence folinic acid
— Check renal function and methotrexate level at 6 or more hours
post ingestion
l If renal function is normal and the serum methotrexate level is
below thresholds for toxicity (see Table 3.51.2), further folinic
acid is not indicated and the patient may be medically
cleared if otherwise well. A follow-up FBC is recommended at
7 days
l Folinic acid is indicated if a methotrexate level cannot be obtained
within 24 hours, the patient is symptomatic, renal function is
abnormal or the methotrexate level is above the threshold for
toxicity.
TABLE 3.51.2 Threshold blood levels for toxicity following a
single acute overdose of methotrexate
Time since ingestion Methotrexate level (micromol/L)
6 hours 5
12 hours 1
24 hours 0.1
Decontamination
l Oral activated charcoal 50 g (1 g/kg in children) is indicated in
cooperative patients who present within 2 hours of acute overdose
SPECIFIC TOXINS
of >5 mg/kg
l Not clinically useful in the management of acute oral overdose in
patients with normal renal function
Antidotes
l Folinic acid (Leucovorin) is indicated in patients at potential risk of
methotrexate toxicity (see above). Administer folinic acid 15 mg
278 PO, IM or IV every 6 hours. For a single acute methotrexate
overdose, therapy may be ceased when methotrexate level is
27
8
confirmed to be below threshold for toxicity (see Table 3.51.2)

It is otherwise continued until the serum methotrexate is
TOXICOLOGY HANDBOOK
<0.05 micromol/L
l With chronic toxicity, therapy should be continued for at least 3
days and until the serum methotrexate is <0.05 micromol/L
l Refer to Chapter 4.10: Folinic acid for further detail on
administration and therapeutic end points.

l hildren who ingest <2.5 mg/kg do not require referral to
C
hospital
l Most patients with acute oral overdose can be medically cleared
by 24 hours, provided a methotrexate level can be obtained within
that time frame
l Patients who require folinic acid are admitted to complete
therapy and for monitoring of blood counts and methotrexate
levels
l Patients with established methotrexate toxicity are admitted for
supportive care and monitoring and folinic acid therapy.
HANDY TIPS
l ethotrexate levels are not available in all hospitals. A result can
M
usually be obtained within 24 hours by sending blood (rather than
the patient) elsewhere.
PITFALLS
l ailure to recognise the potential lethality of repeated
F
supratherapeutic dosing
l Administration of folic acid instead of folinic acid as an antidote.
CONTROVERSIES
l isk assessment and management plans for acute methotrexate
R
overdose have been extrapolated from experience with therapeutic
parenteral dosing. Poor outcomes associated with acute overdose
are not described
l The management plan outlined is based on consideration of
methotrexate pharmacokinetics and a small prospective case
series published only in abstract form
l The thresholds for risk of toxicity following repeated
supratherapeutic dosing are not well established.
Presentations
Methotrexate 2.5 mg tablets (30) Methotrexate 500 mg/5 mL vials
SPECIFIC TOXINS
Methotrexate 10 mg tablets (50) Methotrexate 500 mg/20 mL vials
Methotrexate 5 mg/2 mL vials Methotrexate 1000 mg/10 mL vials
Methotrexate 50 mg/2 mL vials Methotrexate 5000 mg/50 mL vials
Methotrexate 100 mg/4 mL vials
References
Balit C, Daly FFS, Little M et al. Acute methotrexate overdose (abstract). Clinical
Toxicology 2006; 44(4):411–412.
Lovecchio F, Katz K, Watts D et al. Four-year experience with methotrexate exposures.
Journal of Medical Toxicology 2008; 4(3):149–150. 279
3.52 MIRTAZAPINE
TOXICOLOGY HANDBOOK
Deliberate self-poisoning with this novel tetracyclic antidepressant usually
follows a benign course, with mild CNS depression and tachycardia the
most frequently reported clinical features. Care is supportive.
RISK ASSESSMENT
l irtazapine overdose is associated with relatively minor clinical
M
effects, even after large ingestions
l Children: Accidental ingestion of up to 100 mg is not associated
with significant symptoms. Referral to hospital is not required
unless symptoms occur.
Toxic mechanism
Mirtazapine is a centrally acting alpha2-adrenergic antagonist that enhances release of
serotonin and noradrenaline. It is also acts as an antagonist at serotonin (5-HT2, 5-HT3)
and histamine (H1) receptors.
Toxicokinetics
Mirtazapine is rapidly absorbed following oral administration. It is 85% protein bound and
has a very large volume of distribution (>100 L/kg). It undergoes hepatic metabolism by
cytochrome P450 (2D6 and 3A4) and metabolites are excreted in the urine. A significant
first-pass effect occurs. Elimination half-life is 20–40 hours.
CLINICAL FEATURES
l any patients remain asymptomatic. If symptoms occur, onset is
M
within the first 4 hours
l Mild tachycardia, drowsiness, confusion and miosis may occur.
INVESTIGATIONS
l 12-lead ECG, BSL and paracetamol level.
MANAGEMENT
l Intubation for airway control is rarely necessary
Decontamination
SPECIFIC TOXINS

Antidotes
l None available.

l atients who are asymptomatic with normal 12-lead ECG and vital
P
signs at 4 hours post ingestion are fit for medical discharge
l Patients with mild sedation are managed supportively in a ward
280 environment. They are fit for medical discharge when clinically well,
ambulant, passing urine, eating and drinking.
28
0
HANDY TIPS
TOXICOLOGY HANDBOOK
l oma, seizures or significant alteration in vital signs prompts

C
consideration of alternative diagnoses and revision of the risk
assessment.
Presentations
Mirtazapine 15 mg tablets (30)
References
Kelly CA, Dhuan N, Laing WJ et al. Comparative toxicity of citalopram and the newer
antidepressants after overdose. Journal of Toxicology-Clinical Toxicology 2004;
42(1):67–71.
Timmer CJ, Ad Sitsen JM, Delbressine LP. Clinical pharmacokinetics of mirtazapine. Drug
Disposition 2000; 38(6):461–474.
3.53 MONOAMINE OXIDASE INHIBITORS (MAOIs)

Irreversible non-selective (MAO-A+B): Phenelzine, Tranylcypromine;
Irreversible selective (MAO-B): Selegiline; Reversible selective (MAO-A):
Moclobemide
Irreversible non-selective MAO inhibitors are associated with potentially
lethal serotonin toxicity in overdose, significant adverse reactions and
a withdrawal syndrome. Isolated overdose of the newer reversible and
selective agents is associated with a benign clinical course unless there
is co-ingestion of other serotonergic agents. In these cases, the clinical
course may be complicated by severe serotonin syndrome.
RISK ASSESSMENT
l verdose of moclobemide alone causes minor symptoms only,
O
irrespective of dose
— Non-life-threatening serotonin syndrome occurs in <5%
— QTc prolongation >500 ms may occur with ingestions >3 g but
torsades de pointes is not reported
l Co-ingestion of moclobemide with other serotonergic agents
is associated with a high risk of severe serotonin syndrome,
irrespective of dose (see Chapter 2.8: Serotonin syndrome)
l Phenelzine and tranylcypromine are associated with
dose-dependent, potentially lethal serotonin and sympathomimetic
toxicity. Symptoms are delayed and prolonged:
— D ose-related risk assessment
SPECIFIC TOXINS
Phenelzine
– >2 mg/kg associated with toxicity
– 4–6 mg/kg potentially fatal
Tranylcypromine
– >1 mg/kg associated with toxicity
– 170 mg has caused a fatality
l Children: Potential ingestion of 1–2 phenelzine or tranylcypromine
tablets may be associated with toxicity and referral to hospital for
assessment and observation is indicated. Isolated ingestion of 281
moclobemide is benign and referral to hospital is not indicated.
Toxic mechanism
TOXICOLOGY HANDBOOK
MAOIs inhibit monoamine oxidase (A and B) in a selective or non-selective, reversible
or irreversible manner. MAO-A metabolises serotonin, noradrenaline and dopamine.
MAO-B metabolises phenylethylamine and benzylamine at central and peripheral synaptic
sites. Irreversible blockade requires new enzyme synthesis over days to re-establish
enzymatic function. Irreversible non-selective agents in overdose lead to an accumulation
of serotonin, adrenaline, noradrenaline, dopamine and phenylethylamine, resulting in
serotonin and sympathomimetic toxicity that can persist for days.
Toxicokinetics
All MAOIs are well absorbed after oral administration and reach peak levels within
2–3 hours. There is considerable first-pass metabolism (e.g. moclobemide bioavailability
60–80%). They have moderate volumes of distribution (moclobemide 1.2 L/kg). These
agents undergo hepatic metabolism to metabolites that are excreted in the urine.
Phenelzine, tranylcypromine and selegiline have active metabolites.
CLINICAL FEATURES
l Moclobemide overdose (no co-ingestions)
— Minor symptoms only
— Nausea, anxiety and tachycardia may occur
— Serotonin syndrome is rare
l Moclobemide overdose in combination with another serotonergic
agent
— Serotonin syndrome frequently develops within 6–12 hours (see
Chapter 2.8: Serotonin syndrome)
l Phenelzine or tranylcypromine overdose
— Patients are usually asymptomatic for the first 6–12 hours
— Onset of toxicity is heralded by restlessness, agitation, tachycardia,
involuntary movements, grimacing, clonus and hyperreflexia
— A rapid decline in conscious state follows
— M uscle rigidity develops, leading to respiratory compromise,
hypoxia, respiratory acidosis, hyperthermia and rhabdomyolysis
— Autonomic instability is demonstrated by swings from
hypertension to hypotension
— Disseminated intravascular coagulation (DIC) and multiple
organ failure may occur
— Even with optimal supportive care, intoxication may last several
days
l Classically described MAOI adverse reactions
— Serotonin syndrome
— Tyramine reaction: after the ingestion of a tyramine-containing
food (e.g. cheese) patients complain of severe occipital
headache, associated with pronounced hypertension,
sweating, agitation, mydriasis and sometimes chest pain.
SPECIFIC TOXINS
Complications of acute hypertensive crises include:

– Intracranial haemorrhage
– Rhabdomyolysis
– Acute renal failure
– DIC.
INVESTIGATIONS
282 l 12-lead ECG, BSL and paracetamol level
28
2
l Serial ECGs (moclobemide)

— Mild QT prolongation is described following moclobemide
TOXICOLOGY HANDBOOK
overdose. A 12-lead ECG is reviewed at presentation and at

6 hours. If the QTc is >500 ms, further monitoring is indicated
l EUC, FBC, CK, troponin, arterial blood gases, chest x-ray, cranial
CT scan, EEG.
MANAGEMENT
l A basic level of supportive care and monitoring is sufficient for pure
moclobemide overdose
l Serotonin syndrome and severe sympathomimetic toxicity are
potentially life-threatening emergencies and managed in an area
equipped for cardiorespiratory monitoring and resuscitation
l Attention to airway, breathing and circulation are paramount (see
Chapter 1.2: Resuscitation)
l Hypertension and tachycardia are usually controlled with titrated
IV benzodiazepines. Severe hypertension (including tyramine
reactions) may require parenteral vasodilator therapy. Caution is
required, as the onset of autonomic instability may rapidly produce
hypotension. Consider:
— Titrated vasodilator infusion (sodium nitroprusside, glyceryl
trinitrate)
— α -antagonism (phentolamine 2–3 mg increments every
10–15 minutes until control achieved)
— Note: Beta-adrenergic blockers are contraindicated as
unopposed α-agonist stimulation may result
l Seizures and agitated delirium may be managed with
benzodiazepines, as outlined in Chapter 2.6: Approach to
seizures and Chapter 2.7: Delirium and agitation
l Hyperthermia resulting from MAOI toxicity requires aggressive therapy
— Temperature >38.5°C is an indication for continuous core-
resuscitation
— Temperature >39.5°C requires rapid treatment to prevent
multiple organ failure and neurological injury. Paralysis,
intubation and ventilation are indicated
l Life-threatening serotonin syndrome requires specific care,
including paralysis and intubation and ventilation to avoid fatalities
(see Chapter 2.8: Serotonin syndrome)
SPECIFIC TOXINS
Decontamination
l Moclobemide overdose has a good prognosis with standard
supportive care. Decontamination is not indicated
l Patients who are alert and cooperative and who have ingested
>1 mg/kg of tranylcypromine or >2 mg/kg of phenelzine are given
50 g oral activated charcoal if they present within 2 hours. Activated
charcoal is contraindicated in the symptomatic patient due to the
potential for imminent deterioration of conscious state and seizures
Antidotes
l A trial of cyproheptadine is indicated in patients with symptoms
TOXICOLOGY HANDBOOK

consistent with mild–moderate serotonin syndrome refractory to
benzodiazepines (see Chapter 4.3: Cyproheptadine).

l atients who are clinically well without features of serotonin toxicity
P
at 12 hours may be discharged. Discharge should not occur at night
l Patients with symptomatic moclobemide overdose are managed
supportively in a ward environment following a period of 6 hours
close observation. When the patient is clinically well, ambulant,
passing urine, eating and drinking, discharge may occur
l Patients with severe serotonin syndrome or phenelzine/
tranylcypromine overdose usually require management in an
HANDY TIPS
l yperthermia in the setting of MAOI toxicity requires rapid and
H
aggressive therapy.
PITFALLS
l ailure to recognise and treat hyperthermia
F
l Failure to observe a patient for a sufficient period of time following
deliberate self-poisoning with phenelzine or tranylcypromine,
or following moclobemide overdose in combination with other
serotonergically active agents.
CONTROVERSIES
l he role of specific serotonin antagonists in the management of
T
MAOI toxicity.
Presentations
Moclobemide 150 mg tablets (60) Selegiline hydrochloride 5 mg tablets (100)
Moclobemide 300 mg tablets (60) Tranylcypromine sulfate 10 mg tablets (50)
Phenelzine sulfate 15 mg tablets (100)
References
Downes MA, Whyte IM, Isbister GK. QTc abnormalities in deliberate self-poisoning with
moclobemide. Internal Medicine Journal 2005; 35:388–391.
Isbister GK, Hackett LP, Dawson AH et al. Moclobemide poisoning: toxicokinetics and
occurrence of serotonin toxicity. British Journal of Clinical Pharmacology 2003;
56(4):441–450.
Kaplan RF, Feinglass NG, Webster W. Phenelzine overdose treated with dantrolene
sodium. Journal of the American Medical Association 1986; 255:642–644.
Mills KC. Monoamine oxidase inhibitor toxicity. Emergency Medicine 1993; 15:58–71.
SPECIFIC TOXINS
3.54 NON-STEROIDAL ANTI-INFLAMMATORY

DRUGS (NSAIDs)
Celecoxib, Diclofenac, Etoricoxib, Ibuprofen, Indomethacin, Ketoprofen,
Ketorolac, Mefenamic acid, Meloxicam, Naproxen, Parecoxib, Piroxicam,
Sulindac, Tiaprofenic acid
284 Overdose with any of the NSAIDs, unless the ingestion is massive, is
28
benign. Management is symptomatic and supportive. Ibuprofen accounts

4
for over two-thirds of NSAID deliberate self-poisoning cases.

TOXICOLOGY HANDBOOK
RISK ASSESSMENT
l verdose with these agents is generally benign, even following
O
large ingestions
Dose-related risk assessment is best defined for ibuprofen (see
Table 3.54.1)
l Massive overdose is associated with severe multi-system organ
dysfunction including shock, coma, seizure, acute renal failure and
metabolic acidosis. Fatalities are reported.
l Overdose with any amount of mefenamic acid is commonly
associated with self-limiting seizures
TABLE 3.54.1 Dose-related risk assessment: Ibuprofen

Dose Effect
<100 mg/kg Asymptomatic
100–300 mg/kg Mild GI and CNS symptoms
>300 mg/kg Risk of multi-system organ dysfunction
l Children: Significant symptoms usually are not observed until the

dose ingested exceeds 300 mg/kg of ibuprofen (or equivalent of other
NSAID). Minor unintentional ingestion of <100 mg/kg of ibuprofen
does not require referral to hospital for assessment or observation.
Toxic mechanism
NSAIDs exert their pharmacological effects through the competitive inhibition of
cyclooxygenase-1 and -2 and consequent blockade of prostaglandin synthesis. The NSAIDs
are directly irritant to the gastrointestinal tract. Prostaglandin inhibition leads to renal glomerular
vasoconstriction and mild reversible renal dysfunction. Bleeding time is prolonged due to
inhibition of thromboxane A2 production. The exact mechanism of the other effects is unclear.
Toxicokinetics
NSAIDs are rapidly absorbed following oral administration. Most are highly protein bound
and have small volumes of distribution. They undergo hepatic metabolism and metabolites
are excreted in the urine. Most agents have elimination half-lives of less than 4 hours
(naproxen and piroxicam have half-lives of 12 and 45 hours respectively).
CLINICAL FEATURES
l ollowing acute overdose, most patients are asymptomatic or
F
experience minor self-limiting gastrointestinal symptoms such as
nausea, vomiting and epigastric discomfort
l Minor CNS symptoms such as lethargy and drowsiness are
SPECIFIC TOXINS

sometimes observed
l Massive ibuprofen overdose can result in rapid onset of shock,
coma, seizures, acute renal failure and metabolic acidosis
l Self-limiting seizures commonly occur within hours of mefenamic
acid overdose.
INVESTIGATIONS
l 12-lead ECG, BSL and paracetamol level 285
l EUC, LFTs and FBC in symptomatic patients
TOXICOLOGY HANDBOOK
l An anion gap metabolic acidosis is commonly observed and not of
clinical importance. It usually resolves within 24–48 hours
l NSAID serum levels are not routinely available and do not assist in
management.
MANAGEMENT
l Seizures and agitated delirium are managed with benzodiazepines,
as outlined in Chapter 2.6: Approach to seizures and Chapter
2.7: Delirium and agitation
Decontamination
l Oral activated charcoal is contraindicated following mefenamic
overdose because of the risk of imminent seizures
Antidotes
l None available.

l hildren may be observed at home following possible unintentional
C
ingestion, unless symptoms occur
l dult patients following deliberate self- poisoning who are
A
asymptomatic with normal vital signs at 4 hours post ingestion are
fit for medical discharge
l Symptomatic patients with mild-to-moderate gastrointestinal
or CNS symptoms may be managed supportively in a ward
environment. They are fit for medical discharge when ambulant,
passing urine, eating and drinking
l Patients with significant CNS depression are admitted to an
intensive care unit for supportive care and monitoring.
HANDY TIPS
l Anticipate seizures following mefenamic acid overdose.
SPECIFIC TOXINS
PITFALLS
l ailure to anticipate the risk of multi-system organ dysfunction
F
following massive ingestion of these agents.
Preparations
Celecoxib 100 mg capsules (60)
Celecoxib 200 mg capsules (10, 30)
Diclofenac sodium 25 mg tablets (30, 100)
Diclofenac sodium 50 mg tablets (50)
286 Diclofenac sodium 12.5 mg suppositories (10)
Diclofenac sodium 25 mg suppositories (10)
28
Diclofenac sodium 50 mg suppositories (10)

6
Diclofenac sodium 100 mg suppositories (20, 40)

Diclofenac potassium 12.5 mg tablets (10, 20)
TOXICOLOGY HANDBOOK
Diclofenac potassium 25 mg tablets (10, 20, 30)

Diclofenac potassium 50 mg tablets (20)
Diclofenac sodium 50 mg/misoprostol 200 microgram tablets (60)
Etoricoxib 30 mg (30)
Ibuprofen 200 mg capsules (10, 20, 40, 90)
Ibuprofen 1500 mg/30 g gel
Ibuprofen 100 mg meltlets (12)
Ibuprofen 200 mg meltlets (6)
Ibuprofen 100 mg/5 mL suspension (100 mL, 200 mL)
Ibuprofen 200 mg/5 mL suspension (30 mL)
Ibuprofen 200 mg tablets (12, 16, 24, 48, 50, 96, 100)
Ibuprofen 400 mg tablets (30)
Ibuprofen lysine 342 mg tablets (12, 36)
Ibuprofen 200 mg/codeine phosphate 12.8 mg tablets (12, 24, 48, 96)
Ibuprofen 200 mg/pseudoephedrine hydrochloride 30 mg tablets (24)
Indomethacin 25 mg capsules (50, 90, 100)
Indomethacin 100 mg suppositories (20, 40)
Indomethacin sodium trihydrate 1 mg vials
Ketoprofen 100 mg sustained-release pellet capsules (100)
Ketoprofen 200 mg sustained-release pellet capsules (28)
Ketoprofen 100 mg suppositories (20)
Ketoprofen 7500 mg/30 g gel
Ketoprofen 15 000 mg/60 g gel
Ketorolac trometamol 10 mg tablets (20)
Ketorolac trometamol 10 mg/1 mL ampoules
Ketorolac trometamol 30 mg/1 mL ampoules
Mefenamic acid 250 mg capsules (20, 50)
Meloxicam 7.5 mg tablets (30)
Meloxicam 15 mg tablets (30)
Meloxicam 7.5 mg capsules (30)
Meloxicam 15 mg capsules (30)
Naproxen 250 mg tablets (50, 100)
Naproxen 500 mg tablets (50)
Naproxen 750 mg sustained-release tablets (28)
Naproxen 1000 mg sustained-release tablets (28)
Naproxen sodium 275 mg tablets (12, 20, 24)
Naproxen sodium 550 mg tablets (50)
Parecoxib sodium 40 mg vials and 2 mL diluent
Piroxicam 10 mg tablets (50)
Piroxicam 20 mg tablets (25)
Piroxicam 10 mg capsules (50)
Piroxicam 20 mg capsules (25)
SPECIFIC TOXINS
Piroxicam 125 mg/25 g gel
Piroxicam 250 mg/50 g gel
Sulindac 100 mg tablets (50, 100)
Sulindac 200 mg tablets (50)
Tiaprofenic acid 300 mg tablets (60)
References
Balali-Mood M, Critchley JA, Proudfoot AT et al. Mefenamic acid overdose. Lancet 1981;
1:1354–1356.
Hall AH, Smolinske SC, Conrad FL et al. Ibuprofen overdose: 126 cases. Annals of
Emergency Medicine 1986; 15:1308–1313. 287
Hall AH, Smolinske SC, Stover B et al. Ibuprofen overdose in adults. Journal of Toxicology-
McElwee NE, Veltri JC, Bradford DC et al. A prospective, population-based study of acute
TOXICOLOGY HANDBOOK
ibuprofen overdose: Complications are rare and routine serum levels not warranted.
Annals of Emergency Medicine 1990; 19(6):657–652.
3.55 OLANZAPINE
Deliberate self-poisoning with this second-generation atypical
antipsychotic agent is associated with sedation, delirium and coma in
ascending doses. Thorough supportive care ensures a good outcome.
RISK ASSESSMENT
l lanzapine overdose is associated with predictable
O
dose-dependent clinical features (see Table 3.55.1)
l Extrapyramidal effects are uncommon
l Co-ingestion of ethanol or other sedative-hypnotic agents
increases the risk of coma
l Children: The toxic dose is not clear. Ingestion of >0.5 mg/kg
may cause clinical features of intoxication including lethargy,
agitation, tachycardia and extrapyramidal effects. Referral
to hospital for monitoring and supportive care is warranted.
Delayed extrapyramidal effects may occur over the following
days.
Toxic mechanism
Olanzapine is an antagonist at dopamine (D2), serotonin (particularly 5HT2), histamine (H1),
muscarinic (M1) and peripheral alpha(α)-receptors.
TABLE 3.55.1 Dose-related risk assessment: Olanzapine
Dose (adult) Effect
<40 mg Therapeutic sedation and antipsychotic effects
40–100 mg Mild to moderate sedation with possible

anticholinergic effects
100–300 mg Sedation with intermittent marked agitation
>300 mg Increasing sedation progressing to coma likely to

require intubation
Hypotension secondary to peripheral alpha blockade
SPECIFIC TOXINS
Toxicokinetics
Olanzapine is well absorbed after oral or sublingual administration. The volume of
distribution is 10–20 L/kg. It undergoes hepatic metabolism by oxidative (cytochromes
P450 1A2 and 2D6) and conjugative (glucuronidation) pathways to inactive water-soluble
metabolites. There is a large first-pass effect after oral dosing.
288 CLINICAL FEATURES

l nset of clinical features of intoxication occurs within 2–4 hours
O
28
l Sedation, ataxia, miosis, orthostatic hypotension and tachycardia

8

are common
TOXICOLOGY HANDBOOK
l Fluctuating mental status with intermittent agitated delirium occurs

with moderate doses, usually lasting less than 24 hours. Urinary
retention frequently complicates this presentation
l Coma when it occurs following large ingestions lasts from 18 to 48 hours
l Non-specific ST-T wave changes occur in 15% of overdoses, but
clinically significant QT prolongation is rare
l Extrapyramidal effects are uncommon
l Seizures are rare.
INVESTIGATIONS
l Serial ECGs
— An ECG is performed at presentation and at 6 hours. If the ECG
is normal at that time, further ECG monitoring may be ceased
in the unintubated patient
— In the intubated patient, 12-lead ECGs are assessed for QT
prolongation every 4 hours until clinical improvement occurs.
MANAGEMENT
l Intubation and ventilation may be required if significant sedation
occurs
G
l Severe agitated delirium is managed, as outlined in Chapter 2.7:
Delirium and agitation
l Monitor for urinary retention and insert an indwelling urinary
catheter if required
Decontamination
l Oral activated charcoal is not indicated, because the onset of
sedation and coma occurs early and supportive care ensures a
good outcome
SPECIFIC TOXINS
Antidotes
l None available.

l ll paediatric patients are observed in hospital following possible
A
unintentional ingestion of >0.5 mg/kg. If they remain clinically well
without sedation at 4 hours following ingestion they can be safely
discharged. Parents are advised that abnormal (extrapyramidal) 289
movements sometimes occur up to 3 days after ingestion
l Patients with mild sedation, normal blood pressure and normal
TOXICOLOGY HANDBOOK
Medical discharge occurs when the patient is clinically well,
l Patients with significant agitation or delirium, and those requiring
intubation, require admission to a high-dependency or intensive
care unit, often for up to 48 hours.
HANDY TIPS
l enzodiazepines are first-line agents for the management of
B
olanzapine-induced agitated delirium. However, subsequent
fluctuations in mental status may mandate intubation and ventilation.
PITFALLS
l ndetected urinary retention contributes to agitation and is
U
managed with an indwelling catheter.
CONTROVERSIES
l he role of physostigmine in the management of agitated
T
delirium. It is not clear that the delirium is entirely of
anticholinergic origin.
Presentations
Olanzapine 2.5 mg tablets (28) Olanzapine 10 mg vials
Olanzapine 5 mg tablets (28) Olanzapine pamoate monohydrate
Olanzapine 7.5 mg tablets (28) 210 mg vials
Olanzapine 10 mg tablets (28) Olanzapine pamoate monohydrate
Olanzapine 5 mg wafers (28) 300 mg vials
Olanzapine 10 mg wafers (28)
References
Burns MJ. The pharmacology and toxicology of atypical antipsychotic agents. Journal of
Palenzona S, Meier PJ, Kupferschmidt H et al. Clinical picture of olanzapine poisoning
with special reference to fluctuating mental status. Journal of Toxicology-Clinical
Toxicology 2004; 42(1):27–32.
3.56 OPIOIDS
Buprenorphine, Codeine, Dextropropoxyphene, Fentanyl, Heroin,
SPECIFIC TOXINS
Hydromorphone, Methadone, Morphine, Oxycodone, Pethidine

Opioid intoxication causes CNS and respiratory depression. Death is due
to respiratory failure. Good supportive care ensures survival. The specific
antidote, naloxone, can assist the management of airway and breathing.
Some opioids possess unexpected toxic effects (e.g. dextropropoxyphene).
RISK ASSESSMENT
l ife-threatening CNS and respiratory depression frequently occur
L
290 just above the analgesic dose
29
l Opioid use by naive patients (no tolerance) or co-ingestion of other

0
CNS depressants (antidepressants, benzodiazepines, ethanol)

increases the severity of CNS depression and the likelihood of a
TOXICOLOGY HANDBOOK
fatal outcome without supportive care

l Certain agents have specific risk assessments based on particular
toxicities (see Table 3.56.1)
l Children: Opioid intoxication is the leading cause of death by
poisoning in children. Ingestion of a single opioid tablet or a
mouthful of methadone syrup can cause respiratory arrest. More
than 2 mg/kg of codeine may cause symptoms in children and
>5 mg/kg can cause respiratory arrest.
TABLE 3.56.1 Opioid risk assessment: Special cases
Drug Effect
Dextropropoxyphene 10 mg/kg likely to cause symptoms

20 mg/kg may cause CNS depression,
seizures and cardiac dysrhythmias (fast
sodium channel blocking effect)
Pethidine Repeated therapeutic doses are associated

with seizures
Implicated in serotonin syndrome
Toxic mechanism
Agonist activity at μ-receptors is responsible for euphoria, analgesia, physical
dependence, sedation and respiratory depression. Multiple other opioid actions
are responsible for side effects such as nausea and vomiting (dopamine receptors),
constipation (peripheral μ-receptors in the gut wall), pruritus (histamine release) and
seizures.
Toxicokinetics
Oral absorption of opioids is variable. Most, with the exception of controlled-release
preparations, are absorbed rapidly. Volumes of distribution are usually large (e.g. codeine
2.6 L/kg; methadone 3.6 L/kg; morphine 3.4 L/kg). Most undergo hepatic metabolism to
form metabolites that are excreted in the urine, some of which are active. Morphine, for
example, is one of three active metabolites of codeine.
CLINICAL FEATURES
l The classic opioid toxidrome consists of:
— CNS depression
— Respiratory depression (rate and depth of respirations)
— Miosis
SPECIFIC TOXINS
l The duration of effects depends on the pharmacokinetics of the
individual agent. Heroin intoxication is typically short (e.g. less
than 6 hours), while methadone intoxication may last more than
24 hours
l Death is caused by loss of airway protective reflexes and
apnoea
l Nausea and vomiting may occur, promoting pulmonary
aspiration
l Tachycardia may occur as a response to hypoxia and 291
hypercarbia
l Hypothermia, skin necrosis, compartment syndrome,
rhabdomyolysis and hypoxic brain injury may complicate
TOXICOLOGY HANDBOOK
prolonged non-lethal intoxication
l Dextropropoxyphene intoxication is also associated with seizures,
hypotension and ventricular dysrhythmias
l Pethidine is associated with serotonin syndrome.
INVESTIGATIONS
Specific investigations as indicated:
l Specific blood levels and urine screening do not assist clinical
management
l Specific investigations are only indicated to diagnose and assess
secondary complications.
MANAGEMENT
ensure the survival of the vast majority of patients
l These priorities are managed along conventional lines, as outlined
in Chapter 1.2: Resuscitation
l In the rare event of ventricular dysrhythmias in
dextropropoxyphene intoxication, resuscitation includes serum
alkalinisation by the administration of IV bolus sodium bicarbonate,
as outlined in Chapter 4.25: Sodium bicarbonate
Decontamination
l Opioid intoxication is associated with CNS and respiratory
depression, and vomiting. A good outcome is expected with
supportive care and, possibly, antidote administration. Therefore,
activated charcoal is not routinely indicated.
l Oral activated charcoal may reduce length of stay if administered
to patient presenting early after overdose with controlled-release
morphine tablets
Antidotes
l Respiratory and CNS depression can be reversed with titrated
SPECIFIC TOXINS
doses of naloxone (see Chapter 4.19: Naloxone).

l he period of observation required to detect CNS depression varies
T
with the opioid. For most oral preparations 4 hours is sufficient
l A patient who ingests controlled-release morphine must be
observed for at least 12 hours before medical clearance
l Following ingestion of standard preparations, patients with mild
sedation who have not required naloxone may be managed in a
292 ward environment after an initial observation period of 4 hours
29
l Any child who has potentially ingested an opioid (unless <2 mg/kg
2
of codeine) is admitted for 12 hours of close observation in an

area equipped and staffed to detect and manage respiratory
TOXICOLOGY HANDBOOK
depression. Discharge must not occur at night

l Patients with significant CNS depression requiring intubation or
naloxone infusion require admission to a high-dependency or
HANDY TIPS
l atients must be admitted to an area with staff and resources
P
capable of detecting respiratory depression
l Appraise staff of the features of opioid intoxication for which
the patient is being observed (CNS depression and decreased
respiratory rate)
l Respiratory depression can be delayed up to 12 hours following
controlled-release morphine overdose
l Respiratory rate should be measured while the patient is sleeping
or otherwise undisturbed.
PITFALLS
l ailure to recognise the potential lethality of unintentional
F
paediatric ingestion of opioids
l Failure to detect opioid-induced respiratory depression due to
inadequate observation (in-hospital deaths have occurred).
Presentations
Buprenorphine
Buprenorphine 5 mg transdermal patches
Buprenorphine 2 mg/naloxone 0.5 mg sublingual tablets (7, 28)
Buprenorphine 8 mg/naloxone 2 mg sublingual tablets (7, 28)
Buprenorphine 0.2 mg sublingual tablets (50)
Buprenorphine 0.4 mg sublingual tablets (7)
Buprenorphine 2 mg sublingual tablets (7)
Buprenorphine 8 mg sublingual tablets (7)
Buprenorphine injection 300 microgram/1 mL
Codeine
Codeine phosphate 30 mg tablets (20, 100)
Codeine phosphate 5 mg /1 mL (100 mL)
Codeine phosphate 19.2 mg/pseudoephedrine HCl 60 mg/ethanol 6%/10 mL (200 mL)
Codeine phosphate 15 mg/phenylephrine HCl 5 mg/pseudoephedrine HCl 45 mg/
guaifenesin 60 mg/ammonium chloride 200 mg/10 mL (200 mL)
Codeine phosphate 14.9 mg/pseudoephedrine HCl 60 mg/10 mL (200 mL)
Codeine phosphate 8 mg/aspirin 300 mg tablets (20, 50, 100)
SPECIFIC TOXINS
Codeine phosphate 8 mg/aspirin 250 mg tablets (24, 96)
Codeine phosphate 8 mg/aspirin 325 mg tablets (20, 50, 100)
Codeine phosphate 9.5 mg/aspirin 500 mg tablets (24)
Codeine phosphate 12.8 mg/ibuprofen 200 mg tablets (12, 24, 48)
Codeine phosphate 6 mg/paracetamol 500 mg/pseudoephedrine 30 mg tablets
(16, 24, 32, 48)
Codeine phosphate 9 mg/paracetamol 500 mg/pseudoephedrine 30 mg tablets
(24, 30, 48, 60)
Codeine phosphate 8 mg/paracetamol 500 mg/doxylamine succinate 5 mg tablets 293
(20, 24)
Codeine phosphate 9.6 mg/paracetamol 500 mg/doxylamine succinate 5.1 mg tablets (10, 20)
Codeine phosphate 10 mg/paracetamol 500 mg/doxylamine succinate 5.1 mg tablets (20)
TOXICOLOGY HANDBOOK
Codeine phosphate 10 mg/paracetamol 500 mg/doxylamine succinate 2 mg capsules (20)
Codeine phosphate 9.75 mg/paracetamol 450 mg/doxylamine succinate 5 mg tablets (20)
Codeine phosphate 9.75 mg/paracetamol 450 mg/doxylamine succinate 5 mg caplets (20)
Codeine phosphate 30 mg/paracetamol 450 mg/doxylamine succinate 5 mg tablets (20)
Codeine phosphate 10 mg/paracetamol 500 mg tablets (24, 48, 96)
Codeine phosphate 8 mg/paracetamol 500 mg tablets (12, 20, 24, 48, 50, 96, 100)
Codeine phosphate 30 mg/paracetamol 500 mg tablets (20, 50)
Codeine phosphate 9.6 mg/paracetamol 500 mg caplets (12, 20, 24, 40, 48)
Codeine phosphate 15 mg/paracetamol 500 mg caplets (12)
Codeine phosphate 15 mg/paracetamol 500 mg tablets (20, 50)
Codeine phosphate 5 mg/paracetamol 120 mg/5 mL (100 mL, 200 mL)
Codeine phosphate 5 mg/paracetamol 120 mg/promethazine 6.5 mg/5 mL (100, 200mL)
Dextropropoxyphene
Dextropropoxyphene 32.5 mg/paracetamol 325 mg capsules (20)
Dextropropoxyphene 32.5 mg/paracetamol 325 mg tablets (20)
Dextropropoxyphene 100 mg capsules (10)
Fentanyl
Fentanyl citrate 200 microgram lozenges (3)
Fentanyl 12 microgram/hour (2.1 mg) transdermal patches
Fentanyl 50 microgram/hour (5 mg) transdermal patches
Fentanyl 100 microgram/hour (10 mg) transdermal patches
Fentanyl citrate 100 microgram/2 mL transdermal ampoules
Fentanyl citrate 500 microgram/10 mL ampoules
Fentanyl citrate 1000 microgram/20 mL ampoules
Hydromorphone
Hydromorphone 2 mg tablets (20)
Hydromorphone 1 mg/mL (473 mL)
Hydromorphone 2 mg/1 mL ampoules
Hydromorphone 500 mg/50 mL vials
Methadone
Methadone hydrochloride 5 mg/mL (200 mL, 1000 mL)
Methadone hydrochloride 10 mg tablets (20)
Methadone hydrochloride 10 mg/1 mL ampoules
SPECIFIC TOXINS
Morphine
Morphine sulfate 10 mg tablets (20)
Morphine sulfate 5 mg controlled-release tablets (20)
Morphine sulfate 10 mg controlled-release tablets (20, 60)
294 Morphine sulfate 200 mg controlled-release tablets (20, 60)
29
Morphine sulfate 20 mg controlled-release granules for reconstitution (20)

4

TOXICOLOGY HANDBOOK

Morphine sulfate 30 mg modified-release capsules (10)
Morphine sulfate 10 mg sustained-release pellet capsules (20, 60)
Morphine sulfate 5 mg/1 mL ampoules
Morphine hydrochloride 1 mg/mL (200 mL)
Morphine hydrochloride 2 mg/1 mL (200 mL)
Morphine hydrochloride 5 mg/1 mL (200 mL)
Morphine hydrochloride 10 mg/1mL (200 mL)
Morphine tartrate 120 mg/1.5 mL ampoules
Morphine tartrate 400 mg/5 mL ampoules
Oxycodone
Oxycodone hydrochloride 5 mg capsules (20)
Oxycodone hydrochloride 5 mg tablets (20, 60)
Oxycodone hydrochloride 30 mg suppositories (12)
Oxycodone hydrochloride 5 mg/5 mL (250 mL)
Pethidine
Pethidine hydrochloride 50 mg/1 mL ampoules
Pethidine hydrochloride 75 mg/1.5 mL ampoules
Reference
Sachdeva DK, Stadnyk JM. Are one or two dangerous? Opioid exposure in toddlers.
3.57 ORGANOCHLORINES
SPECIFIC TOXINS
Aldrin, Chlordane, Dichlorodiphenyltrichloroethane (DDT), Dieldrin,
Endosulfan, Endrin, Ethylan, Heptachlor, Hexachlorobenzene, Isobenzan,
Lindane, Methoxychlor
Chlorinated pesticides are widely used in agriculture. Lindane is used
medically as a treatment for lice infestations. Acute ingestion or repeated
large dermal exposure causes neurological toxicity, including seizures and
coma. Rarely, ventricular dysrhythmias occur due to sensitisation of the
myocardium to catecholamines. Management is supportive.
295
RISK ASSESSMENT
l he risk assessment for lindane is relatively well documented
T
(see Table 3.57.1). There is a paucity of data regarding acute and
TOXICOLOGY HANDBOOK
chronic exposures to other organochlorines. As a general guide
endrin, aldrin, dieldrin and chlordane have the lowest LD50s in
animal models.
l Toxicity occurs in three main settings:
— Acute deliberate self-poisoning by ingestion: rapid onset of
neurological symptoms, seizures and coma
— Excessive dermal application or accidental ingestion of lindane:
agitation and seizures
— Occupational exposures via dermal or inhalational routes:
usually no acute symptoms
l Children: Ingestion is potentially life threatening. Topical lindane

used as a lice treatment can cause agitation and seizures,
particularly with repeat use or prolonged application.
TABLE 3.57.1 Dose-related risk assessment: Lindane
Effect
Children Ingestion of >50 mg (5 mL of 1% solution) causes

symptoms
Adult Estimated mean lethal ingested dose is 125 mg/kg

Dose required to induce toxicity from dermal
absorption not defined
Toxic mechanism
Lindane and the cyclodienes (aldrin, dieldrin, heptachlor, endrin, chlordane, endosulfan)
are non-competitive antagonists acting at the chlorine ion channel of GABAA receptors.
DDT acts by inhibiting sodium channel closure following depolarisation. Both mechanisms
are neuroexcitatory.
Toxicokinetics
These agents are rapidly absorbed following ingestion. The degree of dermal absorption
depends on the agent, concentration, solvent (usually hydrocarbon) and skin integrity.
Lindane and the cyclodienes are well absorbed across skin. Organochlorines are highly
lipid soluble and widely distributed to fat stores. Accumulation may occur with repeated
occupational exposure. Organochlorines undergo hepatic microsomal metabolism prior to
elimination in the urine. They have non-linear kinetics, due to slow redistribution from fat
stores. Elimination of some organochlorines may take weeks to months.
SPECIFIC TOXINS
CLINICAL FEATURES
l Principal clinical features of toxicity are:
— Anxiety, agitation and confusion
— Perioral paraesthesia, fasciculation and myoclonic movements
— Seizures. These are usually of short duration but may be
recurrent
— Sedation and coma
296 l Clinical features develop within 1–2 hours of acute ingestion and
over hours to days following excessive dermal application
29
6
l Hypotension, cardiac dysrhythmias and ventricular ectopy are rare

complications of severe intoxication
TOXICOLOGY HANDBOOK
l Hypoxaemia and acidosis contribute to myocardial sensitisation to

catecholamines
l Hepatitis and renal dysfunction are reported following acute
intoxication
l Vomiting and aspiration may be complicated by a severe chemical
pneumonitis from the hydrocarbon vehicle in which many of these
agents are formulated.
INVESTIGATIONS
— Hypoxaemia and acidosis
— Increased ventricular ectopy may herald the onset of ventricular
tachydysrhythmias
l EUC, liver function tests
— Hepatic and renal failure
l Serum and fat organochlorine levels
— Not readily available and do not assist management.
MANAGEMENT
l Organochlorine poisoning is a potentially life-threatening
l Potential life threats that require immediate intervention include:
— Coma (see Chapter 2.4: Coma)
— Seizures (see Chapter 2.6: Approach to seizures)
— Ventricular dysrhythmias
l Control agitation with carefully titrated doses of benzodiazepines
l Institute general supportive care, as outlined in Chapter 1.4:
Decontamination
l Resuscitation takes priority over decontamination and activated
charcoal is not indicated until the airway is secured by
l Following excessive dermal exposure, wash the skin with soap and
water
SPECIFIC TOXINS
Antidotes
l None available.

C
for 4 hours. If they do not develop symptoms during that period 297
they may then be safely discharged.
l Excessive dermal exposure only warrants referral to hospital if
symptoms occur
TOXICOLOGY HANDBOOK
l Patients with objective evidence of organochlorine intoxication
as evidenced by gastrointestinal or neurological symptoms are
managed in a hospital location capable of managing seizures.
Those that develop features of major intoxication (recurrent
seizures or coma) require admission to the intensive care unit for
ongoing supportive care
l Patients may be safely discharged once all symptoms resolve.
Follow-up is not necessary if asymptomatic.
HANDY TIPS
l he seizures associated with acute intoxication are usually rapid in
T
onset, short duration and controlled with benzodiazepines.
l Ventricular dysrhythmias associated with organochlorines are
rare and may respond to IV beta-blockers (e.g. metoprolol or
propranolol).
PITFALLS
l ailure to recognise the onset of acute toxicity, manifested by
F
vomiting, agitation or perioral paraesthesia.
CONTROVERSIES
l he chronic subclinical effect of the organochlorines, including
T
their carcinogenic potential.
Presentations
Most organochlorines are solid at room temperature and dissolved in hydrocarbon for
ease of application.
Industrial formulations:
Aldrin, Chlordane, Dichlorodiphenyltrichloroethane (DDT), Dieldrin, Endosulfan, Endrin,
Ethylan, Heptachlor, Hexachlorobenzene, Isobenzan, Lindane, Methoxychlor
Medical formulations:
Lindane 1% shampoo or lotion
References
Aks SE, Krantz A, Hryhorczuk DO et al. Acute accidental lindane ingestion in toddlers.
Annals of Emergency Medicine 1995; 26(5):647–651.
Baselt R. Disposition of toxic chemicals and drugs in man. 5th edn. Foster City, California:
Chemical Toxicology Institute; 2000.
CDC. Unintentional topical lindane ingestions—United States, 1998-2003. MMWR
Morbidity Mortality Weekly Report 2005; 54(21):533–535.
SPECIFIC TOXINS
3.58 ORGANOPHOSPHORUS AGENTS

(organophosphates and carbamates)
Organophosphates: Chlorpyrifos, Coumaphos, Diazinon, Dichlorvos,
Dimethoate, Fenthion, Malathion, Parathion, Trichlorfon
Carbamates: Aldicarb, Carbendazim, Carbendazole, Carbazine, Propoxur
Chemical nerve agents: Sarin (GB), Soman (GD), Tabun (GA), VX
298 Deliberate self-poisoning with organophosphate and carbamate insecticides
29
is responsible for more than 100 000 deaths worldwide each year. Although
8
agent-dependent variations in clinical features occur, these agents

generally cause death by respiratory failure. Attention to the principles of
TOXICOLOGY HANDBOOK
resuscitation and supportive care, together with use of antidotes (atropine

and pralidoxime), is essential to achieve a good outcome.
RISK ASSESSMENT
l eliberate self-poisoning by ingestion of organophosphates almost
D
always produces life-threatening toxicity
l Deliberate self-poisoning by ingestion of carbamates produces
similar serious toxicity, but is usually of shorter duration and less
likely to be life threatening
l Onset of clinical manifestations of poisoning may be delayed up to
12 hours with some agents
l Inadvertent or accidental occupational dermal or inhalation
exposure can cause toxicity but is rarely life threatening
l Significant secondary poisoning of staff (nosocomial poisoning)
does not occur
l Children: Any ingestion of organophosphates or carbamates is

potentially lethal.
Toxic mechanism
Organophosphates inhibit acetylcholinesterase (AChE) enzymes, and increase
acetylcholine (ACh) concentration at both muscarinic and nicotinic cholinergic receptors.
Clinical features are secondary to the widespread effects of increased ACh at CNS,
autonomic (parasympathetic and sympathetic) and skeletal muscle neuromuscular
synapses. Irreversible loss of an alkyl side chain and permanent binding of the
organophosphate (‘ageing’) prevents reactivation of AChE by the antidote, pralidoxime.
The time taken for ageing to occur depends on the individual agent. Ageing does not
occur with carbamates. Organophosphates and carbamates are frequently formulated with
hydrocarbon solvents (e.g. xylene). Inhalation of solvent fumes can produce headache
and dizziness but this does not indicate organophosphate poisoning. The insecticides
themselves have very low vapour pressures and are only inhaled when aerosolised.
Toxicokinetics
These agents are well absorbed after ingestion. Dermal and inhalational represent
important routes following occupational exposure. Agents generally have large volumes
of distribution and some accumulation in lipid stores. Carbamates are distributed less to
the CNS. Lipid solubility is a feature of the thioates. Thioates (e.g. malathion, parathion,
fenthion) act as indirect agents; they require metabolism to their active forms. Metabolism
of organophosphate compounds is primarily hydrolysis by serum HDL-bound esterase
enzymes (paraoxomases). Others undergo hepatic microsomal (cytochrome P450)
metabolism with excretion of inactive metabolites in the urine. Most carbamates are
metabolised in the liver by oxidation, hydrolysis or conjugation and then excreted in the urine.
SPECIFIC TOXINS
CLINICAL FEATURES
l iming of symptom onset depends on the agent, dose and route of
T
exposure. Symptoms may occur within minutes following ingestion
of some agents (e.g. dimethoate, chlorpyrifos) or be delayed by
many hours
l Dimethoate intoxication is characterised by the early onset of
coma, cardiovascular collapse and death within 24 hours
l Chlorpyrifos is associated with early cholinergic symptoms
l Fenthion is associated with few early symptoms but the late onset
(up to 2 days) of paralysis 299
l Typical clinical syndromes include:
Acute intoxication
TOXICOLOGY HANDBOOK
— Muscarinic effects
– Diarrhoea, urination, miosis, bronchorrhea, bronchospasm,
emesis, lacrimation, salivation (‘DUMBBELS’ mnemonic)
– Bradycardia and hypotension
— Nicotinic effects
– Fasciculation, tremor, weakness, respiratory muscle paralysis
– Tachycardia and hypertension
– Note: tachycardia is frequently present due to hypoxia and
hypotension
– Agitation, coma, seizures
— Respiratory
– Chemical pneumonitis if hydrocarbon solvent aspirated
– For further detail on the cholinergic syndrome, see Chapter
2.10: Cholinergic syndrome
Intermediate syndrome
— Delayed paralysis (2–4 days) is associated with
particular agents (e.g. fenthion, diazinon, malathion). The
pathophysiology is not understood. Hypotheses include
prolonged motor end-plate stimulation, delayed redistribution
from lipid stores and inadequate early pralidoxime dosing
Delayed
— Organophosphate-induced delayed neuropathy (OPIDN) is
rare and occurs 1–5 weeks post acute exposure to particular
agents (e.g. fenthion, chlorpyrifos, parathion). It is an ascending
sensorimotor polyneuropathy thought to be secondary to
ageing of axonal neuropathy target esterase (NTE)
Chronic organophosphate-induced neuropsychiatric disorder
— Long-term neuropsychiatric disorder, which may occur
following acute intoxication or chronic low-level exposure.
INVESTIGATIONS
l Red cell and plasma (butyryl-) cholinesterase activities
— The diagnosis and management of acute anticholinesterase
poisoning is primarily clinical, but measures of cholinesterase
activity can be useful in making a definitive diagnosis and to
monitor therapy
SPECIFIC TOXINS
— Significant clinical features generally occur at levels <25% of

normal activity
— Plasma cholinesterase activity is a sensitive biomarker of
anticholinesterase exposure, but has no relation to the severity
of the poisoning. It falls more rapidly and recovers more quickly
(4–6 weeks) than red cell cholinesterase activity. Once it starts
to increase, it suggests that the plasma concentration of the
anticholinesterse compound is negligible
300 — Red cell cholinesterase activity correlates better with severity of
anticholinesterase poisoning and takes longer to recover (120
30
days). It returns to normal following successful oxime therapy

0
and is used to monitor progress when oximes are withdrawn

TOXICOLOGY HANDBOOK
— The mixed cholinesterase test has been advocated as a

method to assess adequacy of therapy. It has not been
validated. Patient and control serum are mixed in a 50:50 ratio.
A plasma cholinesterase activity of the mixed sample that is
less than the mean of the two unmixed samples suggests the
patient’s plasma contains unbound organophosphate and
increased oxime administration is indicated.
MANAGEMENT
l Place the patient in an area equipped for cardiorespiratory
monitoring and resuscitation ensuring that it is well ventilated to
minimise complications of hydrocarbon vapour inhalation
— Coma (see Chapter 2.4: Coma)
— Hypotension (see Chapter 2.5: Hypotension)
— Seizures (see Chapter 2.6: Approach to seizures)
— Respiratory failure
l Resuscitation must not be delayed by external decontamination
procedures, which should proceed simultaneously. Staff should
use universal precautions. More sophisticated personal protective
equipment is not indicated.
l If there is miosis, excessive sweating, poor air entry, wheeze,
cough, bradycardia or hypotension, start escalating doses of
atropine (see below and Chapter 4.1: Atropine).
l Control agitation with carefully titrated doses of benzodiazepines
l Institute general supportive care, as outlined in Chapter 1.4:
Decontamination
l Remove clothes and wash skin with soap and water. Clothing
should be bagged
l Activated charcoal confers no benefit and is not indicated.
Antidotes
l Atropine
— Atropine in escalating doses is indicated to control significant
clinical features of cholinergic excess: excessive sweating,
reduced breath sounds, wheeze, cough, bradycardia or
hypotension
SPECIFIC TOXINS
— Administer 1.2 mg (50 microgram/kg in children) IV and
double the dose every 5 minutes until there is resolution of
bradycardia, drying of secretions and good air entry. Large
doses may be required. Continuing administration as repeat
bolus doses or an infusion is frequently required.
— Note: Atropine has no effect on the neuromuscular junction and
muscle weakness
— For more information on indications, administration and
therapeutic end points see Chapter 4.1: Atropine
l Pralidoxime 301
— Pralidoxime reverses neuromuscular blockade by reactivating
inhibited AChE before ageing occurs
— Indicated, in addition to atropine, in all patients with objective
TOXICOLOGY HANDBOOK
evidence of organophosphate intoxication
— Give 2 g IV then continue an infusion of 0.5 gram/hour for at
least 24 hours
— Pralidoxime is not necessary in carbamate intoxication
— For more information on indications, administration and
therapeutic end points see Chapter 4.23: Pralidoxime.

l ny adult patient who has deliberately self-poisoned with an
A
organophosphate or carbamate insecticide is admitted for a
minimum of 12 hours close observation. Discharge does not occur
at night
l Any child suspected of ingesting an organophosphate or
carbamate insecticide is admitted for a minimum of 12 hours close
observation. Discharge does not occur at night
l Patients with objective evidence of organophosphate or
carbamate intoxication requiring antidote administration are
admitted to an area with resources and staff available to detect
respiratory and neuromuscular complications and monitor
response to therapy
l Patients are observed for 24 hours after the cessation of oxime
therapy
l Follow-up is arranged to detect intermediate and delayed
syndromes
l Adult patients with potential occupational exposure do not
require referral to hospital unless they develop significant
symptoms.
PITFALLS
l ailure to appreciate the risk of life-threatening poisoning in the
F
patient who presents asymptomatic
l Failure to recognise the cholinergic syndrome
l Excessive concern about risks of nosocomial poisoning. This is not
documented following exposure to the organophosphate poisoned
patient and unwarranted concerns should not compromise patient
care. Universal precautions and management in a well-ventilated
room to reduce the strong smell of the hydrocarbon solvent are
appropriate.
CONTROVERSIES
l he value of pralidoxime in improving clinical outcome from
T
SPECIFIC TOXINS

organophosphate poisoning is disputed. Although pralidoxime
has been shown to reactivate red cell acetylcholinesterase in
organophosphate poisoned patients, it has not been shown to
improve survival or reduce the need for intubation
l The value of serum alkalinisation in organophosphate poisoning.
Presentations
These agents may be in both solid and liquid forms. They are frequently formulated with
302 organic solvents such as toluene, in varying concentrations.
30
2
References
Buckley NA, Eddleston M, Szinicz L. Oximes for acute organophosphate poisoning.
TOXICOLOGY HANDBOOK
Cochrane Database of Systematic Reviews 2006; 1.

Eddleston M, Eyer P, Worek F et al. Differences between organophosphorus
insecticides in human self-poisoning: a prospective cohort study. Lancet 2005;
366:1452–1459.
Eddleston M, Eyer P, Worek F et al. Pralidoxime in acute organophosphorus insecticide
poisoning: a randomised controlled trial. PLoS Medicine 2009; 6(6):e1000104.
Published online June 30 2009.
Eddleston M, Szinicz L, Eyer P et al. Oximes in acute organophosphorus pesticide
poisoning: a systematic review of clinical trials. Quarterly Journal of Medicine 2002;
95:275–283.
Little M, Murray L. Consensus statement: risk of nosocomial organophosphate poisoning
in emergency departments. Emergency Medicine Australasia 2004; 16:456–458.
Roberts DM, Aaron CK. Management of acute organophosphorus pesticide poisoning.
British Medical Journal 2007; 334(7594):629–634.
3.59 PARACETAMOL: ACUTE OVERDOSE

Acetaminophen; N-acetyl-p-aminophenol (APAP)
See also Chapter 3.60: Paracetamol: Repeated supratherapeutic ingestion

This chapter refers to a single or staggered ingestion of excessive
paracetamol over 8 hours or less. Provided that the time of ingestion
is well-defined, risk assessment and the decision to treat (or not) with
the antidote, N-acetylcysteine (NAC), is straightforward and guided by a
serum paracetamol level plotted on a nomogram. Where the nomogram
cannot be utilised, the decision to treat is based on serum paracetamol
and hepatic transaminase levels.
RISK ASSESSMENT
l ife-threatening hepatotoxicity is uncommon and fatalities are rare
L
l The threshold dose for paracetamol-induced hepatic injury in
adults is extremely variable but usually considered to be >150 mg/kg
(>10 g).
l The risk of hepatic injury following a single acute ingestion without
NAC is predicted by plotting a serum paracetamol level taken
4–15 hours later on the Prescott or Rumack-Matthew nomogram
(see Figure 3.59.1 for a modified version of this nomogram). The
probability of hepatotoxicity (defined as peak AST/ALT >1000 IU/L) is:
— 1–2% if 4-hour level is <1320 micromol/L (200 mg/L)
— 30% if 4-hour level is 1320–1980 micromol/L (200–300 mg/L)
— 90% if 4-hour level is >1980 micromol/L (300 mg/L)
SPECIFIC TOXINS
l The risk of hepatic injury with NAC is determined primarily by time
from overdose to commencement of NAC
— Survival is 100% where NAC is commenced within 8 hours
of ingestion (a small percentage of patients develop minor
elevation of hepatic transaminases)
— Benefit is reduced where NAC is commenced 8–24 hours
following ingestion
— Benefit is not established if NAC is commenced >24 hours
following ingestion except in fulminant hepatic failure, where IV 303
NAC decreases cerebral oedema, inotrope requirements and
mortality
l Risk assessment is problematic if the time of ingestion is unknown
TOXICOLOGY HANDBOOK
or staggered. The nomogram may still be able applied using time-
anchoring strategies (see Handy Tips below).
l Patients who present >8 hours after overdose with elevated
hepatic transaminases are assumed to have early
paracetamol-induced hepatotoxicity
l The patient who presents >24 hours following an overdose and has
normal hepatic transaminases and no detectable paracetamol has
little risk of developing clinically significant hepatotoxicity
l Models that predict the risk at presentation of developing
hepatotoxicity or fulminant hepatic failure have been developed by
Silvalotti and Schiødt respectively
l Children: There are no reports of death following single acute non-
intentional paracetamol exposure in children under 8 years of age.
Ingestion of <200 mg/kg as a single dose or over a period of
<8 hours does not warrant decontamination, referral to hospital,
serum paracetamol level, liver function tests, antidote treatment or
follow-up.
Toxic mechanism
Elevated production of N-acetylbenzoquinoneimine (NAPQI) following paracetamol
overdose leads to depletion of hepatic glutathione stores. Once glutathione levels reach
a critical threshold (30% of normal), NAPQI starts binding to other proteins, causing
hepatocyte injury. The hallmark of paracetamol-induced hepatic injury is centrilobular
necrosis.
Toxicokinetics
Paracetamol is well absorbed from the small intestine following oral administration; peak
levels usually occur within 1–2 hours for standard tablet or capsule preparations and
within 30 minutes for liquid preparations. The absorption kinetics following overdose of
30304
4
TOXICOLOGY HANDBOOK SPECIFIC TOXINS
FIGURE 3.59.1 Paracetamol treatment nomogram recommended for use in Australia and New Zealand
Blood
paracetamol
concentration Blood
paracetamol
(µmol/L) concentration
(mg/L)
Time (hours)
Daly FSS, Fountain JS, Murray L et al. Medical Journal of Australia 2008; 188:296–301.
extended-release preparations are poorly described. The volume of distribution is 0.9 L/kg.
Ninety per cent of paracetamol undergoes hepatic glucuronidation or sulfation.
These conjugates are excreted in the urine. Most of the remainder is oxidised by the
cytochrome P450 system to form NAPQI, a potentially toxic intermediate. Under normal
circumstances, NAPQI is immediately bound by intracellular glutathione and eliminated in
the urine as mercapturic adducts.
CLINICAL FEATURES
l part from early gastrointestinal upset, the clinical features are
A
those of progressive hepatic injury, which develops in a minority of
patients
l Transient coma is rare, but reported following massive paracetamol
ingestion
l The four classically described clinical phases of paracetamol
SPECIFIC TOXINS
hepatotoxicity are described in Table 3.59.1
TABLE 3.59.1 Clinical phases of acute paracetamol overdose
Phase 1 Patients are frequently asymptomatic but may

(<24 hours) have nausea and vomiting
Phase 2 Right upper quadrant tenderness is common. 305

(1–3 days) Hepatic transaminases (ALT/AST) rise rapidly
to a peak at 48–72 hours and may reach 15
000–20 000 IU/L. Hepatotoxicity is defined as
TOXICOLOGY HANDBOOK
an ALT or AST >1000 IU/L. In survivors, ALT/
AST rapidly return to baseline. Prothrombin
time and INR are at their most abnormal within
hours of peak AST/ALT. Hyperbilirubinaemia
also occurs and renal function may be
impaired
Phase 3 In very severe cases, hepatotoxicity

(3–4 days) progresses to fulminant hepatic failure with
coagulopathy, jaundice, encephalopathy and
multiple organ failure. Death may occur in this
phase. Non-survivors demonstrate metabolic
acidosis with elevated lactate despite
resuscitation, renal failure (serum creatinine
>300 micromol/L), worsening coagulopathy
(PT >100 seconds) and encephalopathy
Phase 4 Recovery phase during which hepatic

(4 days–2 weeks) structure and function return to normal
INVESTIGATIONS
l 12-lead ECG and BSL. The paracetamol level is not used as a
screening test following known deliberate self-poisoning with
paracetamol (see below).
l A recommended approach to initial investigations is outlined in
Table 3.59.2
TABLE 3.59.2 Recommended initial investigations according to time

from paracetamol ingestion to NAC treatment
Time after paracetamol ingestion
Test <8 hours 8–24 hours >24 hours
Serum At 4 hours or as At presentation At presentation

paracetamol soon thereafter
as possible
SPECIFIC TOXINS
Transaminases Not indicated At presentation At presentation

(ALT/AST) and at end of
20-hour NAC
infusion
INR/prothrombin Not indicated Not indicated At presentation

time
306 Creatinine and Not indicated Not indicated At presentation
urea
30
6
Glucose Not indicated Not indicated At presentation

TOXICOLOGY HANDBOOK
Arterial blood Not indicated Not indicated At presentation

gas
Adapted from Daly FSS, Fountain JS, Murray L et al. Medical Journal of Australia 2008;
188:296–301.
l Serum paracetamol
— If the time of ingestion is known, a timed paracetamol level is
taken at 4 or more hours to establish risk of hepatotoxicity and
need for treatment
— If NAC is commenced within 8 hours of a single acute
ingestion, the first serum paracetamol level is the only
investigation required
— Serum paracetamol levels at 4 hours and again 8 hours
after ingestion may be useful following ingestion of
extended-release paracetamol preparations
l Hepatic transaminases
— If NAC is commenced later than 8 hours, baseline and serial
hepatic transaminase levels are also taken to detect and
monitor hepatic injury. The magnitude of elevation of ALT or
AST is not, however, linked to outcome
l Coagulation studies
— Elevation of the INR is an important marker of hepatic
injury
l Platelet count, renal function and acid–base status
— Useful to assess and monitor clinical status and prognosis of
established hepatotoxicity.
MANAGEMENT
l Resuscitation is required only in the rare instances of coma
due to massive acute ingestion, and delayed presentation with
established hepatic failure. In such cases, urgent attention to
airway, breathing and circulation, plus correction of hypoglycaemia
are required
l G eneral supportive care and monitoring measures are
indicated, as outlined in Chapter 1.4: Supportive care and
monitoring
l Patients with rising hepatic aminotransferase levels and INR >2.5
should have 4-hourly recording of vital signs and bedside serum
glucose, and close monitoring of fluid balance
SPECIFIC TOXINS
Decontamination
l Oral activated charcoal is not life saving
— It may be offered to the cooperative adult who presents
within the first hour following overdose, in which case it may
sufficiently reduce the 4-hour paracetamol level to such a
degree that NAC will be unnecessary
— It is never justified following acute ingestion of paracetamol by
small children.
307
Antidotes
TOXICOLOGY HANDBOOK
l Intravenous NAC is indicated in all patients in whom the risk
assessment suggests potential for poor outcome and in patients
who present late with clinical or biochemical evidence of hepatic
injury
l Presentation <8 hours of defined time of ingestion
— The decision to initiate NAC is deferred until the result of a
paracetamol level taken at 4 hours or later is plotted on the
nomogram
l Presentation 8–24 hours following a defined time of ingestion
— NAC is initiated immediately and continued or ceased once a
paracetamol level is available and plotted on the nomogram
l Unknown time of ingestion
— If paracetamol is detectable, but the time of ingestion
unknown (this commonly occurs where coma or delirium
prevents history taking), NAC is commenced immediately.
It may be ceased later when history is available or if hepatic
transaminases are found to be normal at the end of the
20-hour NAC infusion
l Presentation >24-hours post ingestion
— NAC is only indicated if paracetamol is detectable or hepatic
transaminases are elevated. It is continued until hepatic
transaminases are falling and the patient is improving
clinically
l A management flow chart for acute paracetamol exposure with
known time of ingestion is shown in Figure 3.59.2
l Note: See Chapter 4.18: N-acetylcysteine for full details on
dosing and administration of NAC.
FIGURE 3.59.2 Management flow chart for acute paracetamol
exposure with known time of ingestion
<1 hour 1-8 hours >8 hours
Activated Measure serum Commence

charcoal* paracetamol NAC infusion
level within 4-8
hours of
ingestion Measure serum
paracetamol
level & ALT
SPECIFIC TOXINS
UNDER Plot serum Plot serum UNDER

nomogram paracetamol paracetamol treatment line
treatment line level on level on or >24 hrs post
nomogram nomogram OD
Medical
treatment not OVER OVER ALT normal
required nomogram nomogram
308 treatment line treatment line
30
8
Commence Continue NAC

TOXICOLOGY HANDBOOK
no yes
NAC infusion infusion
No further Measure ALT at STOP NAC

investigation end of NAC
required infusion
No further
treatment
yes ALT normal required
Continue NAC
no
and monitor
*Cooperative adult patients who have potentially ingested greater than 10 g or

200 mg/kg, whichever is less
Source: Daly FSS, Fountain JS, Murray L et al. Medical Journal of Australia 2008;
188:296–301.

l atients in whom NAC is commenced within 8 hours of ingestion
P
do not require further investigation or follow-up. They are fit for
medical discharge at the termination of the 20-hour infusion
l atients in whom NAC is commenced later than 8 hours
P
following ingestion (or unknown time of ingestion) have hepatic
transaminases tested at baseline and at the end of the
20-hour infusion. If they are normal at that time, NAC is ceased.
If abnormal, NAC continues at 100 mg/kg/16 hours and hepatic
transaminases are tested every 12–24 hours until falling. If hepatic
transaminases exceed 1000 IU/L, serial testing also includes INR,
renal function and platelet count
l In uncommon cases, rising INR and hepatic transaminases
herald fulminant hepatic failure and the need to transfer to a liver
transplant service. Arrangements for transfer to such a facility
should occur if any of the following high-risk criteria develop:
— INR >3.0 at 48 hours or >4.5 at any time
— Oliguria or creatinine >200 micromol/L
SPECIFIC TOXINS
— Acidosis with pH <7.3 after resuscitation
— Systolic hypotension with BP <80 mmHg
— Hypoglycaemia
— Severe thrombocytopenia
— Encephalopathy of any degree.
HANDY TIPS
l ime-anchoring strategies may be used to determine risk of
T
hepatotoxicity and need for NAC where time of ingestion is 309
uncertain. Plot the measured paracetamol level on the nomogram
line and determine the time before which the ingestion must have
taken place to be of concern. It should then be determined whether
TOXICOLOGY HANDBOOK
it is possible for the overdose to have occurred before that time
l If multiple ingestions have occurred over a few hours (e.g. at
1 pm, 3 pm and 4 pm) a worst-case scenario may be constructed.
A serum paracetamol level may be drawn and plotted on the
nomogram, assuming that the entire dose was taken at the earliest
time. If it is above the line, NAC is commenced.
PITFALLS
l ailure to commence NAC immediately in the patient who presents
F
more than 8 hours following a paracetamol overdose
l NAC dosing errors (see Chapter 4.18: N-acetylcysteine for advice
on safe charting of NAC infusions)
l Failure to check paracetamol units. Different units are used to
report paracetamol levels (micromol/L, mol/L and mg/L). Incorrect
plotting of level may lead to a potentially lethal error.
CONTROVERSIES
l hoice of nomogram. A number of nomograms are available in
C
Australasian hospitals. The Prescott nomogram uses a line extending
from 200 mg/L (1320 micromol/L) at 4 hours to 30 mg/L at 15 hours
using a semi-logarithmic scale. The Rumack-Matthew uses a line
extending from 150 mg/L at 4 hours to 37.5 mg/L at 12 hours using
a semi-logarithmic scale. The line is extrapolated to 6 mg/L at 24
hours. The choice of nomogram is usually based on local practice.
Appropriate use of the available nomogram by ensuring accurate
time of ingestion, appropriate interpretation of units and early NAC is
far more important than which nomogram or nomogram line is used
l lthough commonly done and clinically useful, extrapolation
A
of the treatment line from 15 to 24 hours has not been formally
validated
l Risk factors for paracetamol-induced liver injury. Some
authorities hypothesise that chronic alcoholism (ingestion of
>50 g/day), prolonged fasting and use of particular medications
(inducers of cytochrome P450 2E1 and 3A4; isoniazid,
rifampicin and carbamazepine) are likely to increase the risk of
hepatotoxicity. In these patient groups they recommend lowering
of the nomogram lines. Evidence to date does not support this
practice
l Risk assessment for extended-release preparations. In the
absence of good data, a safe approach is to start NAC
if >150 mg/kg of paracetamol is ingested and check serum
SPECIFIC TOXINS
paracetamol levels at 4 and 8 hours. If both levels fall below the

treatment line, NAC may be discontinued.
Presentations
Paracetamol 500 mg/metoclopramide 5 mg tablets (8, 10, 24)
Paracetamol 325 mg/dextropropoxyphene 32.5 mg capsules (20)
Paracetamol 325 mg/dextropropoxyphene 32.5 mg tablets (20)
Paracetamol 500 mg tablets (12, 24, 48, 50, 96, 100, 500)
310 Paracetamol 500 mg capsules (24, 48, 96)
31
Paracetamol 500 mg caplets (10, 12, 20, 24)

0
Paracetamol 500 mg gel cap tablets (12, 24, 48)

Paracetamol 250 mg soluble tablets (12)
TOXICOLOGY HANDBOOK
Paracetamol 500 mg soluble tablets (20)

Paracetamol 500 mg gel tablets (12, 24)
Paracetamol 120 mg chewable tablets (24)
Paracetamol 160 mg chewable tablets (24)
Paracetamol 665 mg modified-release tablets (96, 192)
Paracetamol 665 mg extended-release tablets (18, 36)
Paracetamol 1000 mg sachets (5, 10)
Paracetamol 500 mg sachets (10)
Paracetamol 125 mg suppositories (20)
Paracetamol 10 mg/1mL vials (50, 100 mL)
Paracetamol liquid 120 mg/5 mL (100, 200 mL)
Paracetamol liquid 240 mg/5 mL (100, 200 mL)
Paracetamol drops 100 mg/1 mL (20 mL)
Paracetamol 160 mg/pseudoephedrine 15 mg/chlorpheniramine 1 mg per 5 mL liquid
(100 mL, 200 mL)
Paracetamol 120 mg/pseudoephedrine 20 mg/dextromethorphan 7.5 mg per 5 mL liquid
(100, 200 mL)
Paracetamol 500 mg/pseudoephedrine 30 mg tablets (24)
Paracetamol 400 mg/pseudoephedrine 30 mg tablets (10, 30, 50)
Paracetamol 1000 mg/pseudoephedrine 60 mg sachets (10)
Paracetamol 500 mg/pseudoephedrine 30 mg/triprolidine 1.25 mg tablets (8, 16, 20, 24)
Paracetamol 500 mg/pseudoephedrine 30 mg/codeine phosphate 9 mg tablets (24, 30,
48, 60)
Paracetamol 500 mg/pseudoephedrine 30 mg/codeine phosphate 6 mg tablets (16, 24,
32, 48)
Paracetamol 500 mg/pseudoephedrine 30 mg/dextromethorphan 10 mg capsules
(18, 24)
Paracetamol 300 mg/pseudoephedrine 30 mg/dextromethorphan 10 mg capsules
(18, 24)
Paracetamol 300 mg/pseudoephedrine 30 mg/dextromethorphan 10 mg/doxylamine
6.25 mg capsules (6, 16, 20)
Paracetamol 500 mg/chlorpheniramine 2 mg/dextromethorphan 10 mg capsules (6)
Paracetamol 500 mg/pseudoephedrine 30 mg/dextromethorphan 15 mg tablets
(18, 24, 36)
Paracetamol 650 mg/pseudoephedrine 30 mg/dextromethorphan 15 mg/chlorpheniramine
4 mg sachets (10)
Paracetamol 325 mg/pseudoephedrine 30 mg/dextromethorphan 15 mg tablets
(18, 24, 48)
Paracetamol 325 mg/dextromethorphan 15 mg/chlorpheniramine 2 mg
tablets (6, 24)
Paracetamol 325 mg/pseudoephedrine 30 mg/dextromethorphan 15 mg/chlorpheniramine
2 mg tablets (24)
Paracetamol 500 mg/pseudoephedrine 30 mg/chlorpheniramine 2 mg tablets (6, 12, 24,
30, 60)
SPECIFIC TOXINS
Paracetamol 325 mg/pseudoephedrine 30 mg/chlorpheniramine 2 mg tablets
(10, 30, 50)
Paracetamol 500 mg/pseudoephedrine 30 mg/chlorpheniramine 2 mg/codeine phosphate
9.5 mg (24)
Paracetamol 500 mg/chlorpheniramine 2 mg tablets (24)
Paracetamol 500 mg/doxylamine succinate 5.1 mg/codeine phosphate 10 mg
tablets (20)
Paracetamol 500 mg/doxylamine succinate 5.1 mg/codeine phosphate 9.6 mg tablets
(10, 20)
Paracetamol 500 mg/doxylamine succinate 5 mg/ codeine phosphate 8 mg tablets
(20, 24) 311
Paracetamol 500 mg/doxylamine succinate 2 mg/ codeine phosphate 10 mg
capsules (20)
Paracetamol 450 mg/codeine phosphate 9.75 mg/doxylamine succinate 5 mg
TOXICOLOGY HANDBOOK
tablets (20)
Paracetamol 450 mg/codeine phosphate 9.75 mg/doxylamine succinate 5 mg
caplets (20)
Paracetamol 450 mg/codeine phosphate 30 mg/doxylamine succinate 5 mg
tablets (20)
Paracetamol 450 mg/orphenadrine citrate 35 mg tablets (100)
Paracetamol 500 mg/codeine phosphate 10 mg tablets (24, 48, 96)
Paracetamol 500 mg/codeine phosphate 8 mg tablets (12, 20, 24, 48, 50,
96, 100)
Paracetamol 500 mg/codeine phosphate 30 mg tablets (20, 50)
Paracetamol 500 mg/codeine phosphate 9.6 mg caplets (12, 20, 24, 40, 48)
Paracetamol 500 mg/codeine phosphate 15 mg caplets (12)
Paracetamol 500 mg/codeine phosphate 15 mg tablets (20, 50)
Paracetamol liquid 120 mg/codeine phosphate 5 mg per 5 mL (100, 200 mL)
Paracetamol liquid 120 mg/codeine phosphate 5 mg/promethazine 6.5 mg per 5 mL
(100, 200 mL
References
Daly FSS, Fountain JS, Murray L et al. Guidelines for the management of paracetamol
poisoning in Australia and New Zealand: explanation and elaboration. A consensus
statement from toxicologists consulting to the Australasian Poisons Information
Centres. Medical Journal of Australia 2008; 188:296–301.
O’Grady JG. Acute liver failure. Postgraduate Medical Journal 2005; 81:148–154.
Prescott LF. Paracetamol (acetaminophen). A Critical Bibliographic Review. 2nd edn.
London: Taylor and Francis; 2001.
Prescott LF, Illingworth RN, Critchley JA. Intravenous N-acetylcysteine: the treatment of
choice for paracetamol poisoning. British Medical Journal 1979; 2:1097.
Rumack BH. Acetaminophen hepatotoxicity: the first 35 years. Journal of Toxicology-
Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics 1975; 55:
871–876.
Schiødt FV, Bondesen S, Tygstrup N et al. Prediction of hepatic encephalopathy in
paracetamol overdose: a prospective and validated study. Scandinavian Journal of
Gastroenterology 1999; 34(7):723–728.
Silvalotti MCA, Yarema MC, Juurlink DN et al. A risk quantification instrument for acute
acetaminophen overdose patient treatment with N-acetyl cysteine. Annals of
3.60 PARACETAMOL: REPEATED SUPRATHERAPEUTIC

INGESTION
Acetaminophen, N-acetyl-p-aminophenol (APAP)
See also Chapter 3.59: Paracetamol: Acute overdose
SPECIFIC TOXINS
Repeated supratherapeutic ingestion of paracetamol refers to staggered

dosing with therapeutic intent of >4 g /day in adults or >60 mg/kg/day
in children. In adults, it usually occurs in the context of self-medication
for acute pain or exacerbations of chronic pain. In children, it is usually
a therapeutic error. Repeated supratherapeutic ingestion is responsible
for all deaths related to paracetamol in children less than 6 years of age
and up to 15% of those in adults. Standard nomograms do not apply.
The decision to treat is based on an estimation of dose in conjunction
312 with biochemical testing (serum paracetamol level and hepatic
31
aminotransferase levels).
2
TOXICOLOGY HANDBOOK
RISK ASSESSMENT
l he Rumack-Matthew and Prescott nomograms are not useful
T
l Risk assessment is based on dose history and biochemical
testing
l Adults (and children >6 years) are referred for biochemical risk
assessment if there is a history of ingestion of:
— 10 g or >200 mg/kg (whichever is less) over a single 24-hour
period
OR
— 6 g or 150 mg/kg/24 hours (whichever is less) for the preceding
48 hours or longer
l Patients who may be more susceptible to paracetamol poisoning
(e.g. alcoholism, isoniazid use or prolonged fasting) are referred for
biochemical risk assessment if they ingest >4 g or 100 mg/kg/24
hours
l Biochemical risk assessment is based on an untimed serum
paracetamol level and a hepatic transaminase level (ALT or AST) at
presentation:
— ALT or AST < 50 IU/L and paracetamol level <120 micromol/L
(<20 mg/L)
– Good prognosis
– No further investigation or treatment required, regardless of
reported dose
— ALT or AST >50 IU/L or paracetamol level >66 micromol/L
(>10 mg/L)
– Higher risk group
– Commence N-acetylcysteine (NAC) pending further
evaluation
l Children: Patients <6 years of age are referred for biochemical risk
assessment if there is a history of ingestion of:
— >200 mg/kg over a single 24-hour period
OR
— >150 mg/kg/24 hours for the preceding 48 hours
OR
— >100 mg/kg/24 hours for the preceding 72 hours.
Toxic mechanism
Supratherapeutic doses of paracetamol can result in depletion of hepatic glutathione
stores. Once glutathione levels are depleted to below 30% of normal, the same toxicity is
observed as following acute paracetamol overdose.
Toxicokinetics
SPECIFIC TOXINS
See Chapter 3.59: Paracetamol: Acute overdose.
CLINICAL FEATURES
l atients who go on to develop hepatic injury following
P
supratherapeutic paracetamol overdose encounter the same four
clinical phases as for acute paracetamol poisoning (see Table 3.59.1).
INVESTIGATIONS
l Serum paracetamol level and hepatic transaminase levels (ALT/AST) 313
— Determine the risk of hepatotoxicity and requirement for
NAC
l Liver function tests, urea and electrolytes, prothrombin time-INR,
TOXICOLOGY HANDBOOK

acid–base status and blood sugar
— Monitor the clinical course of those patients with hepatic injury
(see Chapter 3.59: Paracetamol: Acute overdose).
MANAGEMENT
l Resuscitative efforts are only required in the rare instance where
a patient presents late in established hepatic failure with jaundice,
altered conscious state and hypoglycaemia. In such cases, urgent
attention to airway, breathing and circulation, plus correction of
hypoglycaemia and coagulopathy are required
l General supportive care and monitoring measures are indicated, as
l Patients with worsening hepatic transaminase levels and INR >2.5
should have 4-hourly recording of vital signs and bedside serum
glucose, and close monitoring of fluid balance
Decontamination
Antidotes
l N-acetylcysteine is indicated immediately if there are clinical
features of hepatitis and a history of repeated supratherapeutic
ingestion of paracetamol. Otherwise it is commenced following
biochemical risk assessment (see above)
l Intravenous NAC is continued for at least 8 hours. Serum
ALT or AST measurement is repeated after that time. A rapid
rise in hepatic transaminase levels is consistent with evolving
paracetamol hepatic injury and NAC is continued at
100 mg/kg over 16 hours until the patient is clinically well
and the ALT and INR are falling. Falling or static serum
AST/ALT values suggest a resolving injury or alternative
diagnosis and NAC may be ceased
l Note: For a detailed description of NAC and its administration see
Chapter 4.18: N-acetylcysteine
l A management flow chart for repeated therapeutic ingestion of
paracetamol exposure is shown in Figure 3.60.1.
SPECIFIC TOXINS
FIGURE 3.60.1 Management flow chart for repeated supratherapeutic

paracetamol ingestion
no
Does the patient meet the No further management
criteria for repeated required
supratherapeutic ingestion?
yes
314 Measure serum paracetamol
31
level and ALT

4
Adults and Children 6+ years

• At least 10 g or 200 mg/kg
TOXICOLOGY HANDBOOK
(whichever is lower) over a

ALT normal ANY OTHER
single 24-hour period
and serum RESULT
• At least 6 g or 150 mg/kg paracetamol
(whichever is lower) per 24-hour level
period for the preceding 48 hours <120 µmol/L Commence
• More than 4 g/day or (20 mg/L) NAC infusion
100 mg/kg (whichever is less)
in patients with pre-disposing
risk factors No further Repeat serum
Children treatment paracetamol
• 200 mg/kg or more over a required level and ALT at
single 24-hour period 8 hours
• 150 mg/kg or more per 24-hour
period for the preceding 48 hours
ALT normal or
• 100 mg/kg or more per 24-hour yes
static
period for the preceding 72 hours
no
Continue NAC and check ALT

at 12-hourly intervals.
Other parameters are
measured as indicated
Source: Daly FSS, Fountain JS, Murray L et al. Medical Journal of Australia 2008;
188:296–301.
l atients with clinical or biochemical evidence of hepatotoxicity are
P
admitted for NAC infusion and monitoring of liver function. They
may be discharged if they remain well once transaminase levels are
falling. In the absence of other hepatic pathology, follow-up liver
function tests are not indicated
l Patients with fulminant hepatic failure require intensive care
admission and consideration for referral to a liver transplant service
(see Chapter 3.59: Paracetamol: Acute overdose for precise
referral criteria).
HANDY TIPS
l nquire about analgesic use in all patients presenting with severe
E
SPECIFIC TOXINS

dental, back or pelvic pain
l Minor elevations of ALT and AST (up to 300 IU/L) are common
and usually related to coexistent alcoholic or viral hepatitis. In the
absence of known previous values, NAC is started and continued
until it is demonstrated that hepatic aminotransferase levels are not
rising rapidly.
PITFALLS
l ailure to identify cases of repeated supratherapeutic ingestion of
F 315
paracetamol.
TOXICOLOGY HANDBOOK
CONTROVERSIES
l here are no published prospective studies of repeated
T
supratherapeutic ingestion of paracetamol in children and risk
assessment is controversial.
Presentations
See Chapter 3.59: Paracetamol: Acute overdose.
References
poisoning in Australia and New Zealand: explanation and elaboration. A consensus
statement from toxicologists consulting to the Australasian Poisons Information
Centres. Medical Journal of Australia 2008; 188:296–301.
Daly FSS, O’Malley GF, Heard K et al. Prospective evaluation of repeated supratherapeutic
acetaminophen (paracetamol) ingestion. Annals of Emergency Medicine 2004;
44(4):393–398.
Dart RC, Erdman AR, Olson KR et al. Acetaminophen poisoning: an evidence-based
consensus guideline for out-of-hospital management. Clinical Toxicology 2006;
44:1–18.
3.61 PARAQUAT
Paraquat is a widely used herbicide that is potentially lethal following
ingestion of as little as a mouthful. If the dose is insufficient to cause
fulminating multi-organ failure and death, severe gastrointestinal
corrosive injury and rapid onset of pulmonary fibrosis are common.
Immediate decontamination and avoidance of supplemental oxygen
therapy are the mainstays of treatment.
RISK ASSESSMENT
l eliberate self-poisoning with more than a mouthful is invariably
D
fatal
SPECIFIC TOXINS
l Accidental ingestions have better survival rates because they

generally involve a smaller dose. A mouthful may cause toxicity but
a taste or splash is unlikely to cause problems
l Dermal and inhalational exposures do not cause significant
intoxication
l Risk assessment can be refined using urinary and serum paraquat
assays (see below)
l Children: Ingestion of a teaspoonful (5 mL) may be fatal.
316
31
TABLE 3.61.1 Dose-related risk assessment: Paraquat

6
TOXICOLOGY HANDBOOK
Dose Effect
<30 mg/kg Mild to moderate gastrointestinal

<0.15 mL/kg of 20% solution effects with full recovery
<10 mL of 20% solution in a expected
70-kg patient
30–50 mg/kg Significant gastrointestinal

0.15–0.25 mL/kg of 20% corrosive injury followed by
solution multiple organ failure (including
10–18 mL of 20% solution in a renal and hepatic injury), then
70-kg patient pulmonary fibrosis several days
post ingestion
>50 mg/kg Fulminant multiple organ

>0.25 mL/kg of 20% solution failure and alveolitis resulting in
>18 mL of 20% solution in a progressive refractory hypoxia,
70-kg patient metabolic acidosis, renal and
hepatic injury and cardiovascular
collapse. Death occurs within
12 hours–7 days
Toxic mechanism
Paraquat is a water-soluble para-substituted quarternary bipyridyl cation herbicide. It is
a caustic agent specifically transported into pneumocytes, where it causes superoxide
production and depletes superoxide dismutase and NADPH. Oxygen free radicals
cause lipid peroxidation, further free radical production and damage to cell membrane
integrity.
Toxicokinetics
Absorption is rapid, but only a small percentage of the dose is absorbed (<5%). Peak
blood levels occur within 2–4 hours. Oral absorption is further reduced by the presence
of food in the stomach. Inhalational and dermal absorption via intact skin are minimal.
Prolonged exposure to concentrated solutions, or contact on broken skin, may rarely result
in systemic absorption. Distribution is rapid to highly vascular tissues such as kidney, liver,
heart, muscle and lungs. Paraquat is not metabolised and is predominantly excreted by
the kidneys. Biliary excretion is minor.
CLINICAL FEATURES
l atients may initially appear well but complain of oral burns.
P
Central tongue burns and vomiting are common. Corrosive injury
may be severe and oesophageal perforation is reported
l Following large ingestions, multiple organ effects become apparent
SPECIFIC TOXINS
within hours. Tachycardia and tachypnoea accompany metabolic
acidosis with elevated lactate and hypokalaemia. Cardiovascular
collapse and multi-system organ failure may lead to death within
24 hours in severe cases
l Patients with moderate ingestion may not develop systemic toxicity
during the first 48 hours but then go on to develop a delayed
progressive pulmonary injury characterised by pulmonary fibrosis.
The initial symptoms are of increasing dyspnoea and hypoxia,
which progresses until death occurs within days to weeks.
317
TABLE 3.61.2 Clinical progression: Paraquat
TOXICOLOGY HANDBOOK
Time Effect
Immediate Vomiting and symptoms of gastrointestinal injury
Hours Corrosive injury to lips and oral cavity. Metabolic acidosis

develops early in large ingestions
<48 hours Progressive acidosis, cardiovascular instability, renal

failure, hepatic injury and progressive hypoxaemia in large
ingestions
>48 hours Progressive pulmonary injury with rapid development of

pulmonary fibrosis
INVESTIGATIONS
l Regular oxygen saturations
— Detect developing hypoxia and determine oxygen
requirement
l Serial pulmonary function testing
— Detect developing alveolitis and pulmonary fibrosis
l Serial arterial blood gases
— Detect development and progress of acidosis and response to
treatment
l FBC, EUC, LFT
— Detect signs of multi-organ failure
l Chest x-ray
— Detect fibrosis and aspiration
l Urinary paraquat
— The qualitative (dithionite) colorimetric spot test can be
performed by most laboratories on urine, dialysate or gastric
fluids. It is reliable in the first 12 hours. Sodium dithionite
reduces paraquat; a positive test is based on reduction to a
blue cation. The reaction occurs within 1 minute
— A positive test demonstrates paraquat has been absorbed, but
does not indicate prognosis
l Serum paraquat levels
— Not readily available but invaluable in defining prognosis (see
SPECIFIC TOXINS
Figure 3.61.1)
— Ideally, samples should be collected 4–24 hours after
exposure.
FIGURE 3.61.1 Paraquat survival nomogram
5.5
Plasma levels of paraquat (microgram/mL)
318 5.0
31
8
4.0
TOXICOLOGY HANDBOOK
Percentages denote
3.0
the Probability of Survival
2.0
1.0
0
0 4 8 12 16 20 24 28
Hours after swallowing
Adapted from Hart TB, Nevitt A, Whitehead A. A new statistical approach to the
prognostic significance of plasma paraquat concentrations. Lancet 1984;
2(8413):1222–1223.
MANAGEMENT
l Paraquat intoxication is a time-critical emergency
l This is the only poisoning in which decontamination takes
priority over resuscitation or transport to hospital and ideally
decontamination occurs at the scene (see below)
l Patients are managed in an area equipped for cardiorespiratory
l In patients close to the lethal threshold dose, the aim of
management is to improve prognosis by reducing the dose
that reaches the lungs through early decontamination and
haemodialysis
l Immediate management of airway, breathing and circulation
is rarely required. However, stridor, dysphagia and dysphonia
indicate airway injury and potential imminent airway
compromise. Early intubation or surgical airway is indicated in
this setting
l Do not administer supplemental oxygen unless oxygen saturation
<90%. Oxygen administration is titrated to achieve saturation not
>91%
SPECIFIC TOXINS
Decontamination
l At the scene, administer food or soil to adsorb paraquat and
reduce gastrointestinal absorption
l Fuller’s earth is a clay soil adsorbent that has been traditionally
used, but is now often not readily available and offers no
advantage over activated charcoal
l In hospital administer 50 g of activated charcoal (1 g/kg in children)
PO immediately on arrival
319
l Haemodialysis is considered with the greatest urgency in patients
near the threshold lethal dose (from about a mouthful up to a
TOXICOLOGY HANDBOOK
0.25 mL/kg of 20% solution). It is not indicated for minor exposures
(splashes, lick or tastes) and will not prevent fatal outcome
following large deliberate self-poisoning ingestions
l Haemodialysis and haemoperfusion may remove paraquat if
performed early before distribution to tissues. The time beyond
which dialysis is of benefit (due to distribution of paraquat to
tissues) is uncertain. Maximal benefit is attained if performed within
2 hours
Antidotes
l None available
l Note: Many adjunct therapies have been proposed, including
corticosteroids, cyclophosphamide, N-acetylcysteine, vitamins C
and E, desferrioxamine, superoxide dismutase and nitrous oxide.
Studies to date are hypothesis generating and inconclusive.
Given their safety, it is reasonable to commence all patients on
N-acetylcysteine (see Chapter 4.18: N-acetylcysteine) and
vitamin C (10 mg/kg).

l atients who are clinically well without oral burns and a negative
P
dithionite test have not been exposed and may be discharged
l Adult patients with deliberate self-poisoning should be managed
in an intensive care setting. An early paraquat level is useful in
determining prognosis and utility of care
l Patients with a history of massive ingestion (e.g. >250 mL of 20%
paraquat) and early clinical features of intoxication have a hopeless
prognosis and are managed palliatively from the outset.
HANDY TIPS
l Immediate pre-hospital gastrointestinal decontamination with
anything that is available (food, dirt, charcoal) may be life saving.
PITFALLS
l ailure to advise carers to avoid oxygen unless there is profound
F
hypoxia.
CONTROVERSIES
l he efficacy and indications for haemodialysis and the time beyond
T
which it is unlikely to provide any benefit
l The role of immunosuppressive therapies such as
SPECIFIC TOXINS
methylprednisolone and cyclophosphamide is not established

l Predictive value of serum paraquat levels. They appear to be more
accurate at predicting death than survival.
Presentations
Paraquat alone: 6.4%, 20%, 24%, 25% w/v
Paraquat concentrate 36% has been discontinued but may still be accessible.
Paraquat–Diquat mixtures: 1.25% and 1.25%, 2.5% and 2.5%, 10% and 5%, 10% and
10%, 12.5% and 7.5%, 13.5% and 11.5%
320 Most products contain colouring (blue-green or red-brown) and stenching agents.
32
0
References
Dinis-Oliveira PJ, Duarte JA, Sanchez-Navarro A et al. Paraquat poisonings: mechanisms
TOXICOLOGY HANDBOOK
of lung toxicity, clinical features and treatment. Critical Reviews in Toxicology 2008;
38:13–71.
Eddleston M, Wilks MF, Buckley NA. Prospects for treatment of paraquat-induced lung
fibrosis with immunosuppressive drugs and the need for better prediction of outcome:
a systematic review. Quarterly Journal of Medicine. 2003; 96(11):809–824.
Senarathna L, Eddleston M, Wilks MF. Prediction of outcome after paraquat poisoning by
measurement of the plasma paraquat concentration. Quarterly Journal of Medicine
2009; 102:251–259.
3.62 PHENOTHIAZINES AND BUTYROPHENONES

(antipsychotic agents)
Phenothiazines: Chlorpromazine, Fluphenazine, Pericyazine,
Prochloperazine, Thioridazine, Trifluoperazine
Butyrophenones: Droperidol, Haloperidol
The antipsychotic (neuroleptic) agents cause CNS depression, orthostatic
hypotension and anticholinergic effects in overdose. Thioridazine, which
was associated with cardiac conduction abnormalities (increased QRS
and QT intervals) and higher rates of ventricular dysrhythmias, is now no
longer marketed.
RISK ASSESSMENT
l he antipsychotic agents cause dose-dependent CNS depression,
T
tachycardia, hypotension and anticholinergic effects
l Chlorpromazine can cause coma requiring intubation and
ventilation with ingestions >5 g
l ardiac dysrhythmias are very uncommon, with the exception of
C
thioridazine in large doses
l Seizures are uncommon after any dose
l Children: Lethargy, coma, agitation, tachycardia and
extrapyramidal effects may occur after small ingestions. Ingestion
of even one tablet warrants hospital observation. Delayed
extrapyramidal effects sometimes occur over the next few days.
Toxic mechanism
The major therapeutic action of the phenothiazines is mediated via central dopamine (D2)
antagonism. Their adverse effects are secondary to antagonist action at multiple other
receptor systems, including histaminic (H1), GABAA, muscarinic (M1), α1- and α2-adrenergic
and serotonergic (5HT) receptors. Cardiotoxicity is secondary to sodium and potassium
channel blocking effects. The butyrophenones are a separate class of drug, but have
SPECIFIC TOXINS
similar pharmacologic and pharmacokinetic properties.
Toxicokinetics
The antipsychotics are rapidly absorbed following oral administration at therapeutic
doses and undergo extensive first-pass metabolism. As a result, bioavailability is relatively
low and can be variable. Absorption may be slow and erratic following overdose.
Antipsychotics are lipid soluble with large volumes of distribution. They undergo extensive
hepatic metabolism by cytochrome P450 enzymes. Many have active metabolites
and prolonged elimination half-lives. Chlorpromazine has early, intermediate and late
elimination phases (2–3 hours, 11–15 hours and up to 60 days respectively).
321
CLINICAL FEATURES
l nset of clinical features of intoxication occurs within 2–4 hours of
O
TOXICOLOGY HANDBOOK
overdose
l Sedation, ataxia, orthostatic hypotension and tachycardia are common
l Fluctuating mental status with intermittent agitated delirium may
occur with moderate doses and usually lasts <24 hours
l Urinary retention is common
l Coma occurs following large ingestions of chlorpromazine and may
last from 18 to 48 hours
l Anticholinergic delirium may complicate recovery from coma
l QT prolongation and torsades de pointes were characteristic of
thioridiazine overdose but are not clinically significant with other
agents
l Seizures and extrapyramidal effects are uncommon.
INVESTIGATIONS
l If the 12-lead ECG is normal at 6 hours, further cardiac monitoring
is not required.
MANAGEMENT
l Manage agitated delirium as outlined in Chapter 2.7: Delirium and
agitation
G
Decontamination
l Activated charcoal is only administered after endotracheal
intubation. It is withheld prior to intubation due to the risk of
imminent coma. Activated charcoal is not indicated for patients
without coma, as good outcome is expected with supportive care
Antidotes
l None available.
SPECIFIC TOXINS

l hildren are referred for hospital evaluation and observation
C
following suspected unintentional ingestion of any amount
l Patients who are clinically well, with normal 12-lead ECG (or static
preexisting changes), normal mental status and normal vital signs
at 6 hours post ingestion may cease continuous cardiac monitoring
and are fit for medical discharge
l Patients with minor abnormalities of mental status or 12-lead ECG
322 at 6 hours post ingestion require ongoing careful observation, ECG
monitoring and reassessment of 12-lead ECGs, until there is clear
32
2
evidence of clinical improvement

l Patients requiring intubation and ventilation are admitted to
TOXICOLOGY HANDBOOK
intensive care. Anticholinergic delirium may predominate as coma

resolves, influencing decisions regarding safe extubation.
HANDY TIPS
l ypotension is usually secondary to peripheral vasodilatation and
H
responds well to infusion of IV crystalloid solution
l Significant cardiotoxicity is not observed with phenothiazine
overdose now that thioridiazine is no longer available.
Presentations
Chlorpromazine hydrochloride 10 mg tablets (100)
Chlorpromazine hydrochloride 10 mg/mL mixture (100 mL)
Chlorpromazine hydrochloride 25 mg/5 mL mixture (100 mL)
Chlorpromazine hydrochloride 50 mg/2 mL ampoules
Droperidol 2.5 mg/1 mL ampoules
Fluphenazine hydrochloride 0.5 mg/1 mL elixir (480 mL)
Fluphenazine decanoate 12.5 mg/0.5 mL ampoule
Fluphenazine decanoate 25 mg/1 mL ampoule
Fluphenazine decanoate 50 mg/2 mL ampoule
Haloperidol 0.5 mg tablets (100)
Haloperidol 2 mg/1 mL liquid (100 mL)
Haloperidol 5 mg/1 mL ampoules
Haloperidol decanoate 50 mg/1 mL ampoules (for depot injection)
Haloperidol decanoate 150 mg/3 mL ampoules (for depot injection)
Pericyazine 2.5 mg tablets (100)
Pericyazine 10 mg tablets (100)
Prochloperazine maleate 5 mg tablets (25)
Prochlorperazine maleate 25 mg suppositories (5)
Prochlorperazine mesylate 12.5 mg/1 mL ampoules
Trifluoperazine hydrochloride 1 mg tablets (100)
Trifluoperazine hydrochloride 15 mg capsules (50)
Trifluoperazine hydrochloride 1 mg/mL syrup (1000 mL)
References
James LP, Abel K, Wilkinson J et al. Phenothiazine, butyrophenone, and other
psychotropic medication poisonings in children and adolescents. Clinical Toxicology
SPECIFIC TOXINS
2000; 38(6):615–623.
Strachan EM, Kelly CA, Bateman DN. Electrocardiographic and cardiovascular changes
in thioridiazine and chlorpromazine poisoning. European Journal of Clinical
Pharmacology 2004; 60:541–545.
3.63 PHENYTOIN
Phenytoin intoxication results from either repeated supratherapeutic 323
dosing or acute overdose. Intoxication is usually benign and results in
dose-related ataxia and CNS depression. Falls represent the greatest
danger to the majority of patients. Care is supportive.
TOXICOLOGY HANDBOOK
RISK ASSESSMENT
l ose-dependent CNS effects, mainly cerebellar, occur following
D
acute oral overdose
l Coma and seizures are rare, even with massive doses
l Cardiovascular effects are not associated with ingestions of any dose
TABLE 3.63.1 Dose-related risk assessment: Phenytoin overdose
Dose Effect
10–15 mg/kg Standard therapeutic loading dose
>20 mg/kg Ataxia, dysarthria and nystagmus
>100 mg/kg Potential for coma and seizures
l Children: Ingestion of one or two 100 mg tablets is insufficient

to cause symptoms and does not require referral for medical
assessment or observation.
Toxic mechanism
Phenytoin blocks sodium channels and suppresses membrane post-tetanic potentiation
and hyperexcitability.
Toxicokinetics
Absorption is slow and erratic following oral overdose. Peak serum levels may be delayed
up to 24–48 hours. Volume of distribution is 0.6 L/kg and protein binding is high (90%).
Phenytoin undergoes hepatic hydroxylation (cytochrome P450 2C9) to form an inactive
metabolite. Metabolism is saturable (Michaelis-Menten kinetics) and plasma levels and
elimination half-life rise dramatically with small increases in daily dose. Elimination
half-lives in poisoned patients may vary from 24 to 230 hours. Cytochrome P450 2C9
exhibits genetic polymorphism and there is inter-individual variation in elimination rates.
CLINICAL FEATURES
l hronic toxicity usually presents with gradual onset of ataxia.
C
Dysarthria and nystagmus are also evident
l Mild gastrointestinal symptoms may occur within 2 hours of acute
overdose
l Onset of neurological toxicity develops slowly over hours following
acute overdose. Clinical features of toxicity include: slow horizontal
nystagmus, dysarthria, ataxia, tremor, vertical nystagmus,
drowsiness, involuntary movements and ophthalmoplegia
SPECIFIC TOXINS
l Neurological symptoms of toxicity typically resolve over 2–4 days

as serum levels slowly fall
l Coma, rigidity and seizures occur rarely and only after massive
overdose
l Hypernatraemia and hyperglycaemia resulting in non-ketotic
hyperosmolar coma are reported after massive ingestion
l Permanent cerebellar injury is rarely reported after prolonged and
severe intoxication
324 l Rapid IV administration of phenytoin (and propylene glycol
diluent) is associated with hypotension, bradycardia, ventricular
32
arrhythmias and asystole.

4
TOXICOLOGY HANDBOOK
INVESTIGATIONS
l Serum phenytoin levels
— Useful to confirm the diagnosis
— Correlate with clinical toxicity:
– Nystagmus is associated with levels >20 mg/L
(80 micromol/L)
– Severe ataxia is associated with levels of 30–40 mg/L
(130–160 micromol/L)
– Coma is associated with levels >50 mg/L (200 micromol/L)
— In mild to moderate intoxication, management is guided by
clinical features; repeated levels are not required
— Serial phenytoin levels are useful in severe intoxication to
monitor ongoing absorption and response to interventions.
MANAGEMENT
l General supportive care as outlined in Chapter 1.4: Supportive
care and monitoring ensure a good outcome in the majority of
patients
l Bed rails should be raised at all times and ambulation should be
initially only attempted with supervision
l CG monitoring is not necessary following oral phenytoin overdose
E
or for chronic phenytoin toxicity
Decontamination
l Give activated charcoal to the cooperative patient who presents
within 4 hours of acute oral overdose. This may reduce toxicity and
length of hospital stay
l Multiple-dose activated charcoal enhances elimination but there
is no evidence that outcome is improved; this intervention is not
routine
l Charcoal haemoperfusion and plasmapheresis have been used in
severe phenytoin intoxication and may enhance elimination, but are
SPECIFIC TOXINS
not routine
Antidotes
l None available.

l hildren may be observed at home following unintentional
C
exposures. Hospital assessment is only indicated if significant
ataxia or drowsiness develops
l Patients with nystagmus, ataxia or drowsiness are managed 325
supportively in a ward environment
l Patients with coma requiring intubation or seizures require
admission to the intensive care unit
TOXICOLOGY HANDBOOK
l Patients are medically fit for discharge as soon as they are able to
walk safely.
HANDY TIPS
l onsider the diagnosis of phenytoin toxicity in any patient on
C
chronic therapy who presents with difficulty walking
l It may take several days for phenytoin toxicity to resolve
l Coma is rare in isolated phenytoin overdose. Other causes should
be considered and excluded.
PITFALLS
l ailure to order a phenytoin level in the patient on chronic therapy
F
who presents with ataxia or non-specific symptoms
l Allowing a patient with phenytoin toxicity to fall during
unsupervised attempts at mobilisation.
CONTROVERSIES
l tility of techniques of enhanced elimination. These techniques
U
have not been demonstrated to provide any clinical benefit.
Presentations
Phenytoin sodium 30 mg tablets (200)
Phenytoin sodium 100 mg tablets (200)
Phenytoin 50 mg infatabs (200)
Phenytoin 30 mg/5 mL suspension (500 mL)
Phenytoin sodium 100 mg/2 mL ampoules (contain propylene glycol diluent)
Phenytoin sodium 250 mg/5 mL ampoules (contain propylene glycol diluent)
References
Anonymous. Position statement and practice guidelines on the use of multi-dose activated
charcoal in the treatment of acute poisoning. Journal of Toxicology-Clinical Toxicology
1999; 37(6):731–751.
Craig S. Phenytoin poisoning. Neurocritical Care 2005; 3(2):161–170.
Curtis DL, Piibe R, Ellenhorn MJ et al. Phenytoin toxicity: A review of 94 cases. Veterinary
and Human Toxicology 1989; 31(92):164–165.
Jones AL, Proudfoot AT. Features and management of poisoning with modern drugs used
to treat epilepsy. Quarterly Journal of Medicine 1998; 91:325–332.
Wyte CD, Berk WA. Severe oral phenytoin overdose does not cause cardiovascular
morbidity. Annals of Emergency Medicine 1991; 20(5):510–512.
3.64 POTASSIUM CHLORIDE

SPECIFIC TOXINS
Deliberate self-poisoning by ingestion of potassium chloride is rare

but can result in life-threatening hyperkalaemia and cardiac arrest. The
principal preparation of concern is slow-release potassium chloride,
which is available in bottles of 100 tablets without prescription. A
good outcome depends on early risk assessment, gastrointestinal
decontamination and haemodialysis where indicated.
326 RISK ASSESSMENT

l mall ingestions are usually benign in patients with normal renal
S
32
function
l Ingestion of >2.5 mmol/kg of potassium may theoretically
TOXICOLOGY HANDBOOK
temporarily overwhelm the capacity of the kidneys to excrete

potassium and lead to hyperkalaemia
l The lethal dose of KCl tablets (each containing 8 mmol KCl) in an
adult is not well defined
l Massive ingestion (>40 x 600 mg tablets) prompts early planning
for haemodialysis in case severe hyperkalaemia cannot be
controlled by other means
l Patients with renal impairment or cardiac disease may be at higher risk
l Abdominal x-ray assists risk assessment as slow-release
potassium tablets are radio-opaque
l Children: Ingestion of three 600 mg KCl tablets may cause

significant hyperkalaemia in a 10-kg toddler.
Toxic mechanism
Potassium is the principal intracellular cation. Hyperkalaemia interferes with electrical
conduction in both nerve and muscle and, if severe, causes cardiac arrest. Potassium
salts have a direct irritant effect on the gastrointestinal mucosa when ingested.
Toxicokinetics
Potassium is rapidly absorbed from the small intestine. It is distributed to the intracellular
compartment. Potassium is excreted in the urine (90–95%), faeces and sweat.
Hyperkalaemia develops when the rate of absorption from the gut exceeds the combined
rates of redistribution to the intracellular compartment and urinary excretion.
CLINICAL FEATURES
l ollowing overdose of potassium salts, GI symptoms including
F
abdominal pain, nausea and vomiting are common and occur early.
Ileus and mucosal perforation may occur
l s hyperkalaemia progresses (serum potassium 6–8 mmol/L),
A
lethargy, confusion, weakness, paraesthesia and hyporeflexia develop
l Paralysis and bradycardia herald cardiac arrest (serum K >8 mmol/L).
INVESTIGATIONS
l Serial 12-lead ECGs demonstrate a progression of abnormalities as
serum potassium rises: peaked T waves (plasma K >5.5–6.0 mmol/L),
PR prolongation, loss of P waves with atrial paralysis, widening of
QRS, QT prolongation, sine wave appearance and finally asystole
l EUC with serial potassium concentrations
SPECIFIC TOXINS

l Abdominal x–ray. Useful to confirm number of slow-release
potassium chloride tablets ingested. Serial x-rays also have a role
in monitoring success of decontamination.
MANAGEMENT
l Attention to airway, breathing and circulation are paramount. Refer
to Chapter 1.2: Resuscitation
l Initial efforts are directed at detecting a rising serum potassium and
327
acting to achieve temporary control while arrangements are made
for urgent haemodialysis
l Obtain an urgent serum potassium level and control hyperkalaemia
TOXICOLOGY HANDBOOK

aggressively:
— Calcium chloride 10 mL 10% (0.15 mL/kg in children) IV
through a running line
— Nebulised salbutamol 10–20 mg (in children 2.5 mg if <5 years
or 5 mg if >5 years)
— Dextrose 50 mL 50% and insulin 10 U IV (10 mL/kg 10%
dextrose and insulin 0.1 U/kg in children)
— Sodium bicarbonate 50–100 mmol slow IV (1 mmol/kg in
children)
Decontamination
l Activated charcoal does not bind potassium chloride and is not
indicated
l Slow-release potassium chloride tablets are amenable to removal
by whole bowel irrigation (WBI). However, decontamination cannot
be achieved rapidly enough to prevent lethal hyperkalaemia
following large overdoses. Institution of WBI must never delay
initiation of haemodialysis if it is indicated. The chief value of WBI
lies in completing decontamination once hyperkalaemia has been
controlled with haemodialysis
l Haemodialysis is the definitive treatment of hyperkalaemia following
massive potassium chloride overdose. Initiation of haemodialysis
provides immediate control of hyperkalaemia. Haemodialyis must
be started before hyperkalaemic cardiac arrest occurs
l lanning for haemodialysis begins at the risk assessment stage
P
and is indicated if:
— Ingested dose >40 x 600 mg KCl tablets confirmed on x-ray
— Renal impairment
— Cardiovascular instability
— Serum potassium >8.0 mmol/L
— Rapidly rising serum potassium
l Haemodialysis continues until decontamination of the
gastrointestinal tract with WBI is confirmed on x-ray
l Serum potassium is monitored closely after haemodialysis is
ceased. A rising potassium indicates incomplete decontamination,
ongoing absorption and the need to reinstitute haemodialysis
Antidotes
SPECIFIC TOXINS
l None. A number of pharmacological interventions are useful to

provide temporary control of hyperkalaemia (see above).

l atients demonstrating toxicity or having ingested a toxic dose are
P
managed in a high-dependency or intensive care area with dialysis
facilities
l Patients are medically fit for discharge once decontamination is
328 complete and serum potassium is stable off haemodialysis.
32
8
HANDY TIPS
l low-release potassium chloride tablets are radio-opaque
S
TOXICOLOGY HANDBOOK
l Massive potassium ingestion is potentially lethal. Measures to

reduce serum potassium do not constitute definitive care. They are
initiated only in an effort to provide sufficient time for the patient to
receive definitive care with haemodialysis
l Resonium A (cation exchange resin) 20–50g (0.5–1.0 g/kg in
children) binds only 1 mmol of potassium per gram. It is not useful
following massive slow-release potassium chloride overdose.
CONTROVERSIES
l Indications for haemodialysis and WBI.
Presentations
Potassium chloride 600 mg (8 mmol KCl) slow-release tablets (100)
Reference
Su M, Stork C, Ravuri S et al. Sustained-release potassium chloride overdose. Clinical
Toxicology 2001; 39(6):641–648.
3.65 QUETIAPINE
Quetiapine is a second-generation atypical antipsychotic agent.
Deliberate self-poisoning is associated with sedation, delirium, coma,
tachycardia and hypotension. It is currently a leading cause of toxic coma
requiring intensive care admission. Thorough supportive care ensures a
good outcome.
RISK ASSESSMENT
l uetiapine intoxication is associated with predictable dose-
Q
dependent CNS depression ranging from sedation to coma and a
characteristic brisk tachycardia (see Table 3.65.1)
l Mild hypotension is sometimes observed. It may be profound with
massive ingestion
l Minor QT prolongation may occur but there are no reports of
torsades de pointes
l C o-ingestion of ethanol or other sedative–hypnotic agents
increases the risk of coma and loss of airway protective
reflexes
l Children: Extrapolation from adult data and paediatric experience
SPECIFIC TOXINS
with other atypical antipsychotic agents suggests that sedation,
tachycardia and delirium may occur with ingestion of >100 mg.
TABLE 3.65.1 Dose-related risk assessment: Quetiapine
Dose Effect
<3 g Mild–moderate sedation and sinus tachycardia (frequently >120

beats/minute) 329
>3 g Increasing risk of CNS depression, coma and hypotension
Delirium and seizures may occur
TOXICOLOGY HANDBOOK
Toxic mechanism
Quetiapine is an antagonist at mesolimbic dopamine (D2), serotonin (particularly 5HT2A),
histaminic (H1), muscarinic (M1) and peripheral alpha (α1) receptors.
Toxicokinetics
Quetiapine is rapidly but incompletely absorbed. It is lipid soluble and highly
protein bound, with a large volume of distribution (10 L/kg). Quetiapine is almost
completely metabolised by hepatic cytochrome P450 3A4 to an active metabolite,
7-hydroxyquetiapine.
CLINICAL FEATURES
l nset of clinical features of intoxication occurs within 2–4 hours
O
and may last 24–72 hours
l Sedation and sinus tachycardia are common
l Coma, if it occurs, usually lasts from 18–48 hours
l Hypotension
l Clinically significant QT prolongation is rare and torsades de
pointes is not reported.
l Seizures occur in <5 % of cases.
INVESTIGATIONS
l Serial 12-lead ECG
l Sinus tachycardia is frequently seen
l n ECG should be performed at presentation and after 4 hours. If it
A
remains normal at that time, ECG monitoring is ceased in patients
not requiring intubation
l In intubated patients, 12-lead ECGs are assessed for QT
prolongation every 4 hours until clinical improvement occurs.
MANAGEMENT
l Hypotension should initially be treated with fluid administration.
SPECIFIC TOXINS

Give 10–20 mL/kg of IV crystalloid. If the response is inadequate,
commence an infusion of noradrenaline and titrate to response
l Severe agitated delirium is managed with titrated doses of intravenous
diazepam, as outlined in Chapter 2.7: Delirium and agitation.
Decontamination
l The onset of sedation and coma occurs in the first few hours.
Thorough supportive care ensures a good outcome. Therefore,
activated charcoal is not indicated unless the airway is first
330 protected by endotracheal intubation
33
0
TOXICOLOGY HANDBOOK
Antidotes
l None available.

l hildren are observed in hospital following unintentional ingestion
C
of >100 mg quetiapine or if any symptoms develop. If they remain
clinically well without sedation at 4 hours, they may be discharged.
Parents are advised that abnormal (extrapyramidal) movements
might occur up to 3 days after ingestion
l Patients who have ingested <3 g and are clinically well, not
sedated and have normal 12-lead ECG at 4 hours do not require
further medical assessment or monitoring
l Patients who have ingested >3 g, or manifest clinical features of
intoxication, require admission for appropriate supportive care.
HANDY TIPS
l inus tachycardia exceeding 120 beats/minute is usual. No specific
S
intervention is required
l Adrenaline infusion may paradoxically exacerbate the hypotension
of quetiapine toxicity. This is thought to be due to excessive
β2-mediated vasodilation. Noradrenaline is the preferred inotropic
agent and an excellent response is usually observed.
CONTROVERSIES
l he agitated delirium associated with quetiapine intoxication is
T
likely to be of central anticholinergic origin; however, the role of
physostigmine is yet to be determined.
Presentations
Quetiapine 25 mg tablets (60) Quetiapine 200 mg modified-release
Quetiapine 100 mg tablets (90) tablets (60)
Quetiapine 200 mg tablets (60) Quetiapine 300 mg modified-release
Quetiapine 300 mg tablets (60) tablets (60, 100)
Quetiapine 50 mg modified-release Quetiapine 400 mg modified-release
tablets (60) tablets (60)
Quetiapine 150 mg modified-release
tablets (60)
References
Balit CR, Isbister GK, Hackett LP. Quetiapine: A case series. Annals of Emergency
Medicine 2003; 42:751–758.
SPECIFIC TOXINS
Hawkins DJ, Unwin P. Paradoxical and severe hypotension in response to adrenaline infusion
in massive quetiapine overdose. Critical Care and Resuscitation 2008; 10(4):320–322.
Ngo A, Ciranni M, Olson KR. Acute quetiapine overdose in adults: A 5-year retrospective
case series. Annals of Emergency Medicine 2008; 52:541–547.
Tan HH, Hoppe J, Heard K. A systematic review of cardiovascular effects after atypical
antipsychotic medication overdose. American Journal of Emergency Medicine 2009;
27:607–616. 331
3.66 QUININE
TOXICOLOGY HANDBOOK
Quinine toxicity is characterised by ‘cinchonism’, consisting of nausea,
vomiting, tinnitus, vertigo and deafness. Larger overdoses may result in
life-threatening cardiotoxicity and severe, potentially permanent, visual
disturbance.
RISK ASSESSMENT
l ll cases of deliberate self-poisoning should be regarded as having
A
the potential to cause cardiotoxicity and delayed visual disturbance
l Ingestion of >1 g usually produces some degree of cinchonism
l Cardiotoxicity, CNS disturbances and blindness are more
commonly observed when the ingested dose is >5 g and almost
universal if >10 g
l Children: Ingestion of 600 mg (two tablets) by a child <6 years old
has the potential to cause life-threatening toxicity.
Toxic mechanism
Quinine is a class 1A antidysrhymthic with corresponding sodium channel and potassium
rectifier channel blocking functions. It results in prolongation of both the QRS and QT
intervals. In overdose, quinine is directly toxic to the retina. Quinine also stimulates
pancreatic insulin release in a manner similar to sulfonylureas.
Toxicokinetics
Quinine is rapidly absorbed from the small intestine with a bioavailability of approximately
70%. It is highly protein bound in adults but less so in children; this may explain the
relative vulnerability of the paediatric population. Elimination half-life may be prolonged
to >24 hours in overdose. Elimination is largely via hydroxylation with about 20% being
excreted unchanged in the urine. Quinine does not undergo enterohepatic circulation.
CLINICAL FEATURES
l Cinchonism
— Characterised by nausea, vomiting, alterations in hearing,
tinnitus, and vertigo
— Occurs early following overdose and resolves as blood quinine
concentration falls
l Cardiovascular
— Hypotension, sinus tachycardia, QRS widening and
prolongation of the QT and PR intervals
— Wide-complex tachycardia and torsades de pointes are
reported
— These effects usually occur relatively early (within 8 hours) and
resolve as blood quinine concentration falls
SPECIFIC TOXINS

— Drowsiness and confusion are observed with larger
ingestions
— Coma and seizures are rare
l Eyes
— Onset of visual disturbance is delayed and usually not apparent
until 6–8 hours post ingestion. It is often not detected until the
next morning when the patient wakes up
— Manifestations include blurring, disturbances in colour
332
perception, pupillary dilatation and visual field constriction.
33
Complete blindness develops in severe cases

2
— Recovery of visual disturbance usually occurs over days to

TOXICOLOGY HANDBOOK
weeks, although permanent residual deficits do occur. These

are more likely in patients who develop complete blindness
during the acute phase.
INVESTIGATIONS
l EUC, BSL, formal visual field mapping
l Quinine blood levels: These correlate well with toxicity (>10 mg/L
at 6 hours is associated with cardiovascular toxicity and visual
disturbance) but are not available in a clinically relevant time frame
and do not assist clinical decision making.
MANAGEMENT
— Coma
– Urgent intubation and ventilation is indicated
— Wide-complex tachydysrhythmias
– Immediate intubation and hyperventilation, and serum
alkalinisation with sodium bicarbonate is indicated
(see Chapter 4.25: Sodium bicarbonate for details on
administration)
— T orsades de pointes
– Correct hypoxia and hypokalaemia and administer
magnesium sulfate 10 mmol (0.05 mmol/kg in children)
IV over 15 minutes. If heart rate is <100 beats/minute
commence an isoprenaline infusion IV at 1–10 microgram/
min (0.05–2.0 microgram/kg/min in children) or overdrive
pacing to maintain heart rate at 100–120 beats/minute
— Seizures
– Control with titrated intravenous benzodiazepines, as
Chapter 1.4: Supportive care and monitoring. Intravenous fluids
and antiemetics are always required for the supportive care of
cinchonism. The blind patient will require particular assistance,
SPECIFIC TOXINS
potentially for days or weeks
Decontamination
l Administer 50 g activated charcoal to all overdose patients who are
awake and able to drink the charcoal slurry themselves. Antiemetics
may aid administration. If there is significant CNS depression or
seizures then activated charcoal is only administered by nasogastric
tube after the airway is secured by endotracheal intubation
l Multiple-dose activated charcoal is demonstrated to substantially
enhance the elimination of quinine. This intervention is indicated
in any patient who has ingested >5 g of quinine or who has any
TOXICOLOGY HANDBOOK
degree of visual disturbance
Antidotes
l None available.

l ll children who are suspected of ingesting 600 mg or more
A
of quinine must be observed and monitored for 6 hours
post ingestion
l All patients who deliberately self-poison with quinine should be
observed and monitored for at least 6 hours
l Patients who are asymptomatic and have a normal ECG at 6 hours
following ingestion are cleared for medical discharge
l Patients with symptoms or an abnormal ECG must be admitted for
ongoing observation and monitoring until symptoms resolve
l All patients with quinine toxicity must have careful assessment of
vision prior to medical clearance. Those patients with abnormal
vision or visual fields require ophthalmological review and follow-up
l Patients who develop coma, seizures, an abnormal ECG or cardiac
dysrhythmia during the initial 6 hours observation are admitted to
an intensive care unit
HANDY TIPS
l onsider quinine overdose in any patient with deliberate
C
self-poisoning who complains of visual disturbance
l Anticipate the onset of visual disturbance in any patient who has
ingested >5 g of quinine. The patient’s vision should be carefully
assessed the morning following admission.
PITFALLS
l ailure to warn the patient that visual disturbance may develop
F
6–8 hours later. It is very disturbing for the patient to awake the
following morning and unexpectedly discover themself to be
blind.
CONTROVERSIES
l It was previously believed that the visual disturbance was a
complication of retinal arterial vasospasm. Various interventions
including vasodilators, stellate ganglion blocks and hyperbaric
oxygen therapy were used in attempts to prevent blindness. It
now appears that the blindness occurs from direct retinal toxicity
and cannot be prevented by any of these interventions. Attempts
SPECIFIC TOXINS
at decontamination and enhanced elimination with multiple-dose

activated charcoal offer the best chance of minimising retinal
toxicity.
Presentations
Quinine bisulfate 300 mg (50)
Quinine sulfate 300 mg (50)
334 References
Boland ME, Roper SM, Henry JA. Complications of quinine poisoning. Lancet 1985;
33
4
1(8425):384–385.
Guly U, Driscoll P. The management of quinine-induced blindness. Archives of Emergency
TOXICOLOGY HANDBOOK
Medicine 1992; 9:317–322.

Huston M, Levinson M. Are one or two dangerous? Quinine and quinidine exposure in
toddlers. Journal of Emergency Medicine 2006; 31(4):395–401.
Langford NJ, Good AM, Laing WJ et al. Quinine intoxications reported to the Scottish
Poisons Information Bureau 1997–2002: A continuing problem. British Journal of
Clinical Pharmacology 2003; 56:576–578.
3.67 RISPERIDONE
Deliberate self-poisoning with this atypical antipsychotic agent is
associated with mild sedation, tachycardia and orthostatic hypotension.
Supportive care ensures a good outcome.
RISK ASSESSMENT
l he dose–effect profile is not well defined
T
l Mild clinical features of toxicity, including sedation, tachycardia
and orthostatic hypotension, are common following deliberate
self-poisoning with any dose
l Coma is uncommon when risperidone is taken alone
l Children: Ingestion of >1 mg is associated with clinical features

of toxicity including lethargy, sedation, tachycardia, postural
hypotension and extrapyramidal effects.
Toxic mechanism
Risperidone is an antagonist at mesolimbic dopamine (D2), serotonin (particularly 5HT2A),
alpha (α2) and peripheral alpha (α1) receptors. Compared with other antipsychotic agents in
its class, it has much lower affinity for histamine (H1) and muscarinic (M1) receptors.
Toxicokinetics
Risperidone is rapidly and well absorbed after oral administration. It is highly protein
bound and has a moderate volume of distribution (1.5 L/kg). Risperidone undergoes
hepatic metabolism by oxidation (cytochrome P450 2D6) to an active metabolite
(9-hydroxyrisperidone), which is eliminated by the kidneys. Renal impairment prolongs the
elimination half-life.
CLINICAL FEATURES
l he onset of clinical features of intoxication is rapid and usually
T
occurs within 4 hours
l Lethargy, confusion, mild sedation and tachycardia are common
l Mild hypertension or hypotension sometimes occurs
l Miosis and mydriasis are reported
l Extrapyramidal movements may be seen
SPECIFIC TOXINS
l QT prolongation may occur but torsades de pointes is not reported
l Anticholinergic features and coma are rare
l Clinical features resolve within 24 hours.
INVESTIGATIONS
l Serial ECGs 335
— Perform an ECG is at presentation and at 4 hours
— Sinus tachycardia is common.
— Prolongation of the QT interval is reported but is not sufficient in
TOXICOLOGY HANDBOOK
magnitude to pose a risk of torsades de pointes (see Figure 2.20.4).
MANAGEMENT
l Basic resuscitative measures ensure a good outcome in the vast
Decontamination
l Activated charcoal is not routinely indicated
Antidotes
l None available.

l ll symptomatic children and those thought to have ingested
A
>1 mg should be referred for hospital assessment and observation
l Patients who are clinically well, not sedated and have a normal
12-lead ECG at 4 hours may be medically cleared
l ymptomatic patients are admitted for supportive care until all
S
clinical features of toxicity resolve
l Cardiac monitoring is not indicated beyond 4 hours post ingestion
unless the QT interval is prolonged
l At discharge parents should be advised that abnormal
(extrapyramidal) movements might occur up to 3 days after
ingestion.
HANDY TIPS
l oma, seizures or significant alteration in vital signs prompt
C
consideration of alternative diagnoses and revision of the risk
assessment.
SPECIFIC TOXINS
PITFALLS
l ailure to warn parents of the possibility of delayed abnormal
F
(extrapyramidal) movements after unintentional paediatric
exposure.
Presentations
Risperidone 0.5 mg tablets (20, 60)
Risperidone 1 mg tablets (60)
336 Risperidone 3 mg tablets (60)
33
Risperidone 0.5 mg orally disintegrating tablets (28)

6
Risperidone 1 mg orally disintegrating tablets (28)

Risperidone 2 mg orally disintegrating tablets (28)
TOXICOLOGY HANDBOOK
Risperidone 1 mg/mL solution (30 mL, 100 mL)

Risperidone 25 mg extended-release microspheres with 2 mL solvent pre-filled syringe
Risperidone 37.5 mg extended-release microspheres with 2 mL solvent pre-filled syringe
Risperidone 50 mg extended-release microspheres with 2 mL solvent pre-filled syringe
References
Toxicology-Clinical Toxicology 2001;39(1):1–14.
Cobaugh DJ, Erdman AR, Booze LL et al. Atypical antipsychotic medication poisoning:
An evidence based consensus guideline for out-of-hospital management. Clinical
Toxicology 2007; 45(8):918–942.
Tan HH, Hoppe J, Heard K. A systematic review of cardiovascular effects after atypical
antipsychotic medication overdose. American Journal of Emergency Medicine 2009;
27:607–616.
3.68 SALICYLATES
Acetylsalicylic acid (aspirin), Methyl salicylate
Acute intoxication presents with classical symptoms of vomiting, tinnitus,
hyperventilation, respiratory alkalosis and metabolic acidosis. Severe
toxicity may result in coma and seizures. Chronic intoxication presents
with non-specific clinical features and the diagnosis is frequently
missed. Morbidity and mortality are greater in chronic intoxication.
Urinary alkalinisation and haemodialysis are highly effective methods of
enhancing elimination.
RISK ASSESSMENT
l he severity of clinical features following acute aspirin overdose is
T
dose-related (see Table 3.68.1) and progresses over hours
l Chronic poisoning has an increased risk of an adverse outcome
l In terms of the salicylate dose, 5 g of methyl salicylate is equivalent
to 7.5 g of acetylsalicylate (i.e. 1 mL of ‘oil of wintergreen’ is
equivalent to 1400 mg of aspirin)
TABLE 3.68.1 Dose-related risk assessment: Acute acetylsalicylic acid

(aspirin) overdose
Dose Effect
SPECIFIC TOXINS
<150 mg/kg Minimal symptoms
150–300 mg/kg Mild to moderate intoxication. Salicylism with

hyperpnoea, tinnitus, vomiting
>300 mg/kg Severe intoxication. Metabolic acidosis, altered

mental state, seizures
>500 mg/kg Potentially lethal

337
l Children: Rarely ingest a dose of aspirin sufficient to cause toxicity
TOXICOLOGY HANDBOOK
but small ingestions of methyl salicylate-containing products are
sufficient to cause severe toxicity, for example >5 mL of oil of
wintergreen may cause serious toxicity and even death in a child
<6 years of age.
Toxic mechanism
Salicylates cause irreversible inhibition of cyclo-oxygenase enzymes resulting in decreased
prostaglandin synthesis. Stimulation of the respiratory centre causes hyperventilation and
respiratory alkalosis. Uncoupling of oxidative phosphorylation results in accumulation of
lactic acid, contributing to metabolic acidosis. Promotion of fatty acid metabolism and
generation of ketone bodies also contributes to metabolic acidosis. Death is associated
with very high salicylate levels in the CNS.
Toxicokinetics
Salicylates are rapidly absorbed following oral administration and highly protein bound,
with a volume of distribution of 0.1–0.3 L/kg. Absorption may be delayed with enteric-
coated forms or if large tablet masses form within the stomach (‘bezoars’). In overdose,
protein binding is saturated and free salicylate increases. In acidaemia, more salicylate is
unionised, favouring movement into extravascular spaces, including the CNS. Salicylates
undergo hepatic metabolism. Kinetics change from first order to zero order in overdose,
as metabolic pathways become saturated. The elimination half-life of 2–4 hours in normal
therapeutic dosing is prolonged up to 24 hours following overdose. Urinary pH affects renal
elimination. High urinary pH promotes urinary salicylate excretion, as a greater proportion
of salicylate is ionised and unable to be reabsorbed across the renal tubular epithelium.
CLINICAL FEATURES
Acute salicylate intoxication
l Onset of clinical features is progressive over hours and severe
toxicity may not be evident until 6–12 hours following ingestion.
Deterioration may then be very rapid
l Gastrointestinal
— Nausea, vomiting
— Tinnitus, decreased hearing, vertigo
— CNS stimulation, agitation, seizures
— May progress to cerebral oedema and death
l Acid–base disturbance
— Respiratory alkalosis
— Elevated anion gap metabolic acidosis
— Actual acidaemia occurs late and indicates imminent demise
without intervention
l Other
— Hyperthermia, hyper/hypoglycaemia, hypokalaemia
Chronic salicylate intoxication
SPECIFIC TOXINS
l Difficult to diagnose clinically and often missed

l Most common in elderly patients
l Often presents with non-specific symptoms such as confusion,
delirium, dehydration, fever and unexplained metabolic acidosis
l Cerebral and pulmonary oedema are more common than in acute
poisoning.
INVESTIGATIONS
33

TOXICOLOGY HANDBOOK
l Salicylate level
— Therapeutic range is 1.1–2.2 mmol/L (15–30 mg/dL)
— Poor correlation between levels and severity of toxicity
— Serial levels every 2–4 hours are useful to identify ongoing or
delayed absorption from a tablet bezoar or slow-release
tablets
— Detect and monitor acid–base disturbances.
MANAGEMENT
l If intubation and ventilation are required for coma or respiratory
insufficiency, ensure controlled hyperventilation is implemented in
order to maintain respiratory alkalosis.
l Control seizures with intravenous benzodiazepines, as detailed in
l Ensure sufficient fluid replacement with intravenous crystalloid to
account for gastrointestinal and insensible losses
Decontamination
l Administer oral activated charcoal 50 g up to 8 hours following
acute overdose of >150 mg/kg. Following ingestion of >300 mg/kg,
administer activated charcoal 50 g via a nasogastric tube, after first
securing the airway if necessary. In either case, a second dose of
activated charcoal 50 g is indicated after 4 hours if serum salicylate
levels continue to rise.
l Urinary alkalinisation is indicated in patients with symptomatic
salicylate poisoning. Further details on the rationale and use of this
intervention are provided in Chapter 1.7: Enhanced elimination
and Chapter 4.25: Sodium bicarbonate
l Haemodialysis effectively removes salicylate but is rarely required
if early decontamination and urinary alkalinisation are implemented.
Consider this intervention in the following circumstances:
— Urinary alkalinisation not feasible
— Serum salicylate levels rising to >4.4 mmol/L (>60 mg/dL)
despite decontamination and urinary alkalinisation
— Severe toxicity as evidenced by altered mental status,
acidaemia or renal failure
— Very high serum salicylate levels:
SPECIFIC TOXINS
– Acute poisoning >7.2 mmol/L (>100 mg/dL)
– Chronic poisoning >4.4 mmol/L (>60 mg/dL)
— The threshold to dialyse is lower in the elderly (>60 mg/dL)
Antidotes
l None available.

l ll children suspected of ingesting methyl salicylate products
A 339
should be observed in hospital for signs of salicylate toxicity for at
least 6 hours
l All symptomatic patients require admission for careful monitoring
TOXICOLOGY HANDBOOK
and enhanced elimination techniques. Therapy is ceased when
salicylate level falls to within the normal range (1.1–2.2 mmol/L) and
the clinical features and acid–base abnormalities have resolved
l Patients with significant toxicity are admitted to an intensive care
or high-dependency unit.
HANDY TIPS
l rgent haemodialysis is indicated in any patient who requires
U
intubation for salicylate poisoning (but not if intubated because of
co-ingestants)
l Consider salicylate toxicity and order a serum salicylate level in any
elderly patient with altered mental status and metabolic acidosis.
PITFALLS
l ailure to appreciate the potential for ongoing delayed absorption
F
from the gastrointestinal tract
l Failure to maintain alkalaemia after intubation and ventilation,
leading to catastrophic clinical deterioration due to rapid
redistribution of salicylate to the CNS
l Failure to diagnose chronic aspirin poisoning
l Confusion between standard and SI units for salicylate
concentration.
Presentations
Aspirin 100 mg tablets (112)
Aspirin 300 mg tablets (24, 42, 60)
Aspirin 500 mg tablets (16, 120)
Methyl salicylate is found in oil of wintergreen (98% methyl salicylate) and various
products marketed for topical application, including certain Asian herbal remedies.
References
Davis JE. Are one or two dangerous? Methyl salicylate exposure in toddlers. Journal of
O’Malley GF. Management of the salicylate poisoned patient. Emergency Medicine Clinics
of North America 2007; 25(2):333–336.
Pearlman BL, Gambhir R. Salicylate intoxication: A clinical review. Postgraduate Medicine
2009; 121(4):162–168.
SPECIFIC TOXINS
3.69 SELECTIVE SEROTONIN REUPTAKE INHIBITORS

(SSRIs)
Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline
Deliberate self-poisoning with the selective serotonin reuptake inhibitors
(SSRIs) is common and usually follows a benign course. Serotonin
toxicity develops in a small minority. Among the SSRIs, citalopram and
340 escitalopram appear to be unique in their ability to cause dose-dependent
QT interval prolongation.
34
0
RISK ASSESSMENT
TOXICOLOGY HANDBOOK
l verdose with SSRIs is usually benign, irrespective of dose

O
l Mild symptoms of serotonin toxicity occur in less than 20% of
patients and usually last <12 hours
l Seizures occur in <4% of patients and are more likely with citalopram
l Ingestion of >600 mg citalopram is associated with QT
prolongation but torsades de pointes occurs rarely
l Co-ingestion of other serotonergic agents, such as monoamine
oxidase inhibitors, selective noradrenaline reuptake inhibitors
(venlafaxine, bupropion) or tramadol, greatly increases the risk of
severe serotonin syndrome
l Children: Unintentional paediatric ingestion of up to 3 tablets is benign
and referral to hospital is not required unless symptoms develop.
Toxic mechanism
The SSRIs enhance central serotonergic neurotransmission by inhibiting serotonin
reuptake. They have little affinity for adrenergic, dopaminergic, cholinergic, serotonergic or
histamine receptors.
Toxicokinetics
The SSRIs are rapidly absorbed following oral administration. They are protein bound and
have large volumes of distribution. They undergo hepatic metabolism to form less active and
water-soluble metabolites. Didesmethylcitalopram is the metabolite of citalopram thought to
be responsible for QT prolongation. Elimination half-lives are approximately 24 hours.
CLINICAL FEATURES
l any patients remain asymptomatic
M
l Minor symptoms usually begin within 4 hours and resolve within
12 hours
l ausea is common
N
l Mild serotonin syndrome occurs in less than 20% and manifests
as anxiety, tremor, tachycardia, bradycardia and mydriasis
(see Chapter 2.8: Serotonin syndrome). Severe serotonin
syndrome does not develop unless there is co-ingestion of other
serotonergically active drugs
l Seizures are uncommon and most strongly associated with
citalopram (incidence about 2%) and usually heralded by increased
anxiety, sweating, tremor, tachycardia and mydriasis. They are
short lived and easily controlled with benzodiazepines
l QT prolongation occurs after citalopram and escitalopram
overdose and is dose-dependent. There are rare reports of cardiac
dysrhythmias (wide-complex bradycardia and torsades de pointes)
following citalopram overdose.
SPECIFIC TOXINS
INVESTIGATIONS
— Dose-dependent prolongation of the QT interval is described in
citalopram intoxication, with 68% of patients having QTc 341
>440 ms and 12% >500 ms in one series. QT prolongation is
also described with escitalopram intoxication
— Following citalopram overdose of >600 mg, perform a 12-lead
TOXICOLOGY HANDBOOK
ECG at presentation and continue cardiac monitoring for at
least 8 hours post ingestion
— Monitoring should continue until any risk of torsades de
pointes, as predicted by plotting QT nomogram against heart
rate, resolves (see Figure 2.20.4)
— If >1000 mg citalopram is ingested, continue ECG monitoring
until 13 hours post ingestion, prior to a decision based on a
12-lead ECG performed at that time.
MANAGEMENT
l Attention to airway, breathing and circulation are paramount. Refer
to Chapter 1.2: Resuscitation
l Seizures and agitation are managed with benzodiazepines, as
outlined in Chapter 2.6: Approach to seizures and Chapter 2.7:
Delirium and agitation
l Management of serotonin syndrome is discussed in Chapter 2.8:
Serotonin syndrome
l Increasing anxiety, sweating, tremor, tachycardia and mydriasis
may herald the onset of seizures. Administer IV diazepam 5 mg
every 2–5 minutes until gentle sedation is achieved and the pulse
rate falls towards 100 beats/minute
l Continuous cardiac monitoring continues for 8 hours following
ingestion of >600 mg citalopram, and 13 hours following ingestion
of >1000 mg of citalopram. If the QT suggests no risk of torsades
de pointes at that time, monitoring may cease
Decontamination
l Alert and cooperative patients who have ingested >600 mg
citalopram may drink 50 g of activated charcoal if it can be
administered within 4 hours
l Overdose with other SSRIs has an excellent outcome with minimal
supportive care; activated charcoal is not indicated unless
warranted by co-ingestants
Antidotes
l None available.
SPECIFIC TOXINS

l aediatric patients may be observed at home following possible
P
unintentional exposure. If significant symptoms occur, referral to
hospital for supportive care is appropriate
l Patients are observed with cardiac monitoring in place for at least
8 hours after ingestion of >600 mg citalopram and 13 hours after
ingestion of >1000 mg of citalopram. Monitoring should continue if
significant abnormalities are detected (see Chapter 2.20: The 12-
lead ECG in toxicology)
342 l All other patients who deliberately self-poison with SSRIs are
34
observed for 6 hours. Asymptomatic patients with a normal ECG

2
are fit for medical discharge at the end of that time

l Patients with clinical features of SSRI intoxication require
TOXICOLOGY HANDBOOK

supportive care in a ward environment, usually for no more than
12–24 hours. They are fit for medical discharge as soon as clinical
features resolve.
l Patients who develop severe serotonin syndrome require
management in an intensive care unit.
HANDY TIPS
l oma indicates co-ingestion or complication and is not secondary
C
to SSRI intoxication
l Citalopram and escitalopram are unique among the SSRIs in
causing dose-dependent QT prolongation. Cardiac dysrhythmias
are rare, but activated charcoal and ECG monitoring are indicated
if >600 mg is ingested
l Although the thresholds for risk of significant QT prolongation
with escitalopram are less defined than with citalopram, a similar
approach to monitoring is suggested.
PITFALLS
l ailure to administer prophylactic benzodiazepines to patients with
F
increasing anxiety, sweating, tremor, tachycardia and mydriasis.
CONTROVERSIES
l ctivated charcoal reduces citalopram absorption and decreases
A
maximal QT prolongation. However, given that torsades de pointes
is extremely rare following citalopram overdose, the number
needed to treat with activated charcoal to prevent dysrhythmia is
not known.
Presentations
Citalopram hydrobromide 10 mg tablets (28)
Escitalopram oxalate 10 mg tablets (28)
Escitalopram oxalate 20 mg tablets (28)
Escitalopram oxalate 10 mg/mL oral solution (28 mL)
Fluvoxamine maleate 50 mg tablets (30)
Fluvoxamine maleate 100 mg tablets (30)
Fluoxetine hydrochloride 20 mg tablets (28)
Fluoxetine hydrochloride 20 mg capsules (28)
Paroxetine hydrochloride 20 mg tables (30)
Sertraline hydrochloride 50 mg tablets (30)
Sertraline hydrochloride 100 mg tablets (30)
SPECIFIC TOXINS
References
Hayes BD, Klein-Schwartz W, Clark RF et al. Comparison of toxicity of acute overdose
with citalopram and escitalopram. Journal of Emergency Medicine 2008; Dec 10
(Epub ahead of print).
Isbister GK, Bowe SJ, Dawson A et al. Relative toxicity of selective serotonin reuptake
inhibitors (SSRIs) in overdose. Clinical Toxicology 2004; 42(3):277–285.
Isbister GK, Friberg LE, Duffull SB. Application of pharmacokinetic-pharmacodynamic
modelling in the management of QT abnormalities after citalopram overdose. Intensive
Care Medicine 2006; 32(7):1060–1065.
Isbister GK, Friberg LE, Stokes B et al. Activated charcoal decreases QT prolongation after 343
citalopram overdose. Annals of Emergency Medicine 2008; 52(1):86–87.
Jimmink A, Caminada K, Hunfeld NG et al. Clinical toxicology of citalopram after acute
intoxication with the sole drug or in combination with other drugs: overview of 26
TOXICOLOGY HANDBOOK
cases. Therapeutic Drug Monitoring 2008; 30(3):365–371.
Van Gorp F, Whyte IM, Isbister GK. Clinical and ECG effects of escitalopram overdose.
Annals of Emergency Medicine 2009: 54(3):404–408.
3.70 STRYCHNINE
This heterocyclic ergot-type alkaloid is used as a rodenticide. Deliberate
self-poisoning by ingestion leads to the onset of generalised skeletal
muscle spasm within 30 minutes. Death from respiratory failure may follow
promptly. Paralysis, intubation and ventilation are life saving if instituted
before hypoxic neurological injury and multiple organ failure occurs.
RISK ASSESSMENT
l Ingestion of as little as 30–100 mg by an adult is potentially lethal
(i.e. 1 g of 0.03% powder). Death can occur within 30 minutes
l Any deliberate ingestion is likely to be rapidly lethal without early
intervention
l Sublethal doses lead to painful generalised muscle spasms and
stiffness precipitated by external stimuli
l Children: An accidental taste is potentially lethal in a small child.
Toxic mechanism
Strychnine is a competitive glycine antagonist at brainstem and spinal post-synaptic
receptors. Glycine antagonism results in loss of normal descending inhibitory motor tone
and the onset of skeletal muscle spasm. Ventilatory failure occurs secondary to severe
muscular spasm.
Toxicokinetics
Strychnin e is rapidly and completely absorbed following ingestion or inhalation. It is
not absorbed across intact skin. It has a large volume of distribution (13 L/kg). Up to
30% of the dose is excreted unchanged in the urine. The remainder undergoes hepatic
microsomal (cytochrome P450) metabolism to inactive metabolites. The elimination
half-life is 10–16 hours.
CLINICAL FEATURES
l nset of nausea, agitation, twitching and muscle spasms occurs
O
within minutes of ingestion
l Generalised painful muscle spasms of all voluntary muscles (risus
sardonicus, opisthotonos) precipitated by any external sensory
stimulus rapidly progress, in severe cases, to hyperthermia,
rhabdomyolysis, lactic acidosis and respiratory paralysis
SPECIFIC TOXINS
l Death is from ventilatory failure

l Loss of consciousness does not occur until secondary hypoxia
develops
l If the acute phase is survived, myoglobinuria, renal failure and
hypoxic brain injury may complicate recovery
l Muscle spasms and rigidity resolve within 24 hours if ventilation
and oxygenation are maintained.
344 INVESTIGATIONS
34
4

TOXICOLOGY HANDBOOK

l Serum strychnine levels are not readily available and do not assist
management. Serum and urine levels are useful to confirm the
diagnosis retrospectively especially in forensic cases
l EUC, CK, arterial blood gases, lactate and troponin.
MANAGEMENT
l Strychnine intoxication is a time-critical life-threatening
emergency
include:
— Generalised muscle rigidity
— Respiratory paralysis
l Prompt neuromuscular paralysis, intubation and ventilation are life
saving
l The patient is not unconscious and it is essential to ensure
adequate sedation
l Mild intoxication, manifested by minor muscular twitching without
generalised spasm or respiratory compromise, is managed with IV
diazepam 5 mg every 5–10 minutes, titrated to achieve reduction
of spasm
Decontamination
l Resuscitation takes priority over decontamination. Activated
charcoal is not indicated until the airway is secured
Antidotes
l None available.

l xposed patients who are clinically well without twitching or
E
muscle spasm at 4 hours post ingestion are not poisoned and
are cleared for medical discharge. Discharge should not occur
at night
l Patients with objective evidence of strychnine intoxication (muscle
spasm or twitching) are managed in an intensive care unit. The
patient is clear for medical discharge once muscle spasm and
SPECIFIC TOXINS
rigidity have resolved, provided secondary complications of spasm
or hypoxia do not complicate clinical progress.
HANDY TIPS
l atients with mild symptoms must be observed very carefully for
P
any signs of progression
l Muscle spasm heralds the imminent onset of lethal muscle
rigidity—prepare for immediate paralysis, intubation and
ventilation. 345
PITFALLS
TOXICOLOGY HANDBOOK
l ollowing deliberate self-poisoning, many patients do not reach
F
hospital alive
l Failure to institute prompt paralysis and intubation leading to
secondary complications, including hyperthermia, lactic acidosis,
rhabdomyolysis and hypoxic brain injury.
CONTROVERSIES
l orced diuresis, dialysis and urinary acidification have been
F
suggested, but are not recommended.
Presentations
Preparations available to the public contain 0.3% to 0.5% strychnine, but those used by
licensed exterminators may contain up to 5% strychnine. Strychnine has been added as
an adulterant to street drugs such as amphetamines, cocaine and heroin.
References
Edmunds M, Sheehan TM, Van’t Hoff W. Strychnine poisoning: clinical and toxicological
observations on a non-fatal case. Journal of Toxicology-Clinical Toxicology 1986;
24:245–255.
Makarovsky, Markel G, Hoffman A et al. Strychnine: a killer from the past. Israeli Medical
Association Journal 2008; 10(2):142–145.
Palatnick W, Meatherall R, Sitar D et al. Toxicokinetics of acute strychnine poisoning.
Journal of Toxicology-Clinical Toxicology 1997; 35:617–620.
3.71 SULFONYLUREAS
Glibenclamide, Gliclazide, Glimepiride, Glipizide
Acute sulfonylurea overdose results in profound and prolonged
hypoglycaemia with onset usually within 8 hours of ingestion.
Hypoglycaemia can also develop at therapeutic doses, particularly in
the setting of acquired or preexisting renal dysfunction. Although initial
control of hypoglycaemia requires administration of concentrated glucose
solutions, early administration of the specific antidote, octreotide, greatly
simplifies subsequent management.
RISK ASSESSMENT
SPECIFIC TOXINS
l cute poisoning with sulfonylureas can result in profound

A
hypoglycaemia
l Ingestion of just one tablet can produce hypoglycaemia in the non-
diabetic patient
l Sulfonylurea-induced hypoglycaemia is likely to be prolonged and
relapse is common following initial resolution that follows glucose
administration
l The hypoglycaemic response is more severe in the non-diabetic patient
346 l Onset of hypoglycaemia may be delayed up to 8 hours following
overdose (and even longer for modified-release preparations)
34
6
l There is a wide variation in the duration of hypoglycaemic effect

depending on the preparation and dose. It may be several days
TOXICOLOGY HANDBOOK
following large ingestions

l Children: Ingestion of one tablet of any sulfonylurea is sufficient
to cause profound, potentially fatal, hypoglycaemia in a child. The
diagnosis should be considered in any child who presents with
hypoglycaemia.
Toxic mechanism
The sulfonylureas are antidiabetic agents employed in the treatment of type 2 diabetes
mellitus. They stimulate endogenous insulin release from pancreatic beta cells through the
inhibition of K+ efflux. Overdose results in a hyperinsulinaemic state.
Toxicokinetics
Sulfonylureas are rapidly and completely absorbed, with peak serum levels occurring
within 4–6 hours. Volumes of distribution are variable, but mostly small. They are
metabolised in the liver to active and inactive metabolites, which undergo renal excretion.
Elimination half-life varies between agents and may be more prolonged following overdose.
CLINICAL FEATURES
l Autonomic and CNS manifestations of hypoglycaemia including:
— Sweating, tachycardia, and confusion
— Altered mental status progressing to coma.
INVESTIGATIONS
l 12-lead ECG and paracetamol level
l Serial blood glucose levels
l Insulin levels may have some application if available.
MANAGEMENT
l Administer concentrated IV glucose solutions as part of the initial
resuscitation of the already hypoglycaemic patient
l Give adults 50 mL of 50% glucose as an IV bolus and children
5 mL/kg of 10% glucose IV
l Maintain euglycaemia by continued administration of concentrated
glucose solution until octreotide can be started
l Blood sugar levels are monitored closely with bedside testing.
They should be checked at least hourly in the initial phase of
treatment. This frequency can be reduced in the stable patient on
octreotide
SPECIFIC TOXINS
Decontamination
l Oral activated charcoal can be given where the patient presents
within 1 hour of acute overdose, providing mental state permits.
Activated charcoal could be considered up to 4 hours following
ingestion of a modified-release preparation
Antidote
l Octreotide is the specific antidote for sulfonylurea-induced 347
hyperinsulinaemia. Give adults a 50 microgram IV bolus followed
by 25 microgram/hour continuous infusion for at least 24 hours.
Give children 1 microgram/kg IV followed by 1 microgram/kg/hour
TOXICOLOGY HANDBOOK
continuous infusion
l See Chapter 4.20: Octreotide for further details.

l ll children with suspected sulfonylurea ingestion require
A
observation in hospital and monitoring of blood sugar levels with
bedside testing for at least 8 hours
l All patients with definite or suspected sulfonylurea overdose
require observation for clinical features of hypoglycaemia and
monitoring of blood sugar levels with bedside testing for at least 8
hours from the time of the overdose
l Patients who remain asymptomatic, euglycaemic and clinically well
after 8 hours may be discharged
l Symptomatic patients with hypoglycaemia treated with IV glucose
and octreotide are admitted. They are medically fit for discharge
once they maintain euglycaemia on a normal diet for at least
6 hours from the time of discontinuation of octreotide
l The patient who develops hypoglycaemia on therapeutic doses
of a sulfonylurea requires admission for oral or IV glucose
administration, monitoring of the blood sugar level, treatment
of intercurrent medical conditions and re-evaluation of diabetic
therapy.
HANDY TIPS
l arly institution of octreotide therapy can completely avoid the
E
need for hypertonic dextrose infusions and central venous
access
l o not ignore blood glucose level <4 mmol/L following
D
sulfonylurea overdose. It heralds the onset of profound
hypoglycaemia
l Documentation of hypoglycaemia is essential to confirm the
diagnosis of sulfonylurea overdose. Do not give concentrated
glucose or start octreotide until hypoglycaemia occurs.
PITFALLS
l ecurrent administration of concentrated glucose boluses
R
stimulates endogenous insulin release and leads to rebound
hypoglycaemia. Supplies of octreotide should be procured as soon
as hypoglycaemia occurs in the setting of an acute overdose
l Failure to admit a patient on therapeutic sulfonylurea who presents
SPECIFIC TOXINS
with hypoglycaemia
l Failure to observe suspected paediatric ingestions that present
early while still euglycaemic.
CONTROVERSIES
l he observation period required for suspected ingestion of
T
modified-release preparations is unknown. Onset of hypoglycaemia
could be delayed up to 48 hours
l Optimal dose and route for administration of octreotide is yet to
348 be established. A safe approach is suggested in Chapter 4.20:
34
Octreotide
8
l The role of insulin assays in monitoring response to octreotide

therapy.
TOXICOLOGY HANDBOOK
Presentations
Glibenclamide 5 mg tablets (100)
Glibenclamide 1.25 mg /Metformin 250 mg tablets (90)
Glibenclamide 2.5 mg /Metformin 500 mg tablets (90)
Glibenclamide 5 mg/Metformin 500 mg tablets (90)
Gliclazide 80 mg tablets (100)
Gliclazide 30 mg modified-release tablets (100)
Glimepiride 1 mg tablets (30)
Glipizide 5 mg tablets (100)
References
Harrigan RA, Nathan MS, Beattie P. Oral agents for the treatment of type 2 diabetes
mellitus: pharmacology, toxicity and treatment. Annals of Emergency Medicine 2001;
38:68–78.
Spiller HA, Villalobos D, Krenzelok EP et al. Prospective multicenter study of sulfonylurea
ingestion in children. Journal of Pediatrics 1997; 131:141–146.
3.72 THEOPHYLLINE
Theophylline has an extremely narrow therapeutic index and both acute
overdose and chronic toxicity are potentially life threatening. Aggressive
supportive care and early accurate risk assessment to determine the need
for dialysis ensure a favourable outcome.
RISK ASSESSMENT
l ll acute theophylline overdoses develop clinical features of toxicity
A
l Ingestion of >50 mg/kg is expected to lead to life-threatening
toxicity, manifested by tachyarrhythmias and seizures (see Table
3.72.1)
TABLE 3.72.1 Dose-related risk assessment: Acute theophylline

overdose
Dose Effect
5–10 mg/kg Therapeutic loading dose
SPECIFIC TOXINS
>10 mg/kg Potential for toxicity
>50 mg/kg Life-threatening
l atients with chronic toxicity have a poor prognosis. This is

P
frequently compounded by failure to make the diagnosis or
appreciate the severity of the condition
l Elderly patients with coexisting medical illnesses tolerate
theophylline toxicity poorly and are more likely to have a poor
349
outcome
l Serum theophylline levels, when available, further refine risk
assessment (see Investigations below).
TOXICOLOGY HANDBOOK
l Children: Ingestion of even one 200 mg modified-release tablet will
produce toxicity in a 10-kg child. Ingestion of multiple tablets can
be life threatening.
Toxic mechanism
Multiple toxic mechanisms have been proposed for theophylline, including competitive
antagonism of adenosine, altered intracellular calcium transport and inhibition of
phosphodiesterase leading to elevated intracellular cAMP concentrations.
Toxicokinetics
Theophylline is well absorbed after oral administration. Absorption is delayed with
modified-release preparations and peak levels may not occur until up to 15 hours
following ingestion. It is rapidly distributed with a small volume of distribution (0.5 L/
kg). Metabolism is via the cytochrome P450 system to active and inactive metabolites.
Metabolism is variable and saturable. Elimination half-life may be greatly prolonged in
severe intoxication.
Aminophylline is a water-soluble complex of theophylline molecules suitable for
intravenous administration. It rapidly dissociates in vivo to release theophylline.
CLINICAL FEATURES
l arly manifestations of toxicity in acute overdose include anxiety,
E
vomiting, tremor and tachycardia
l Severe poisoning is associated with:
— Cardiac dysrhythmias:
– Supraventricular tachycardia
– Atrial fibrillation and flutter
— Refractory hypotension
— Seizures
— M etabolic abnormalities:
– Hypokalaemia (severe, refractory)
– Hypophosphataemia, hypomagnesaemia
– Hyperglycaemia
– Metabolic acidosis
l Cardiac dysrhythmias and seizures occur late and indicate an
extremely poor prognosis
l Chronic toxicity usually develops in elderly or infant patients and
generally presents with vomiting and tachycardia. The metabolic
effects are less pronounced than for acute overdose, but seizures
and dysrhythmias occur frequently and at lower serum theophylline
concentrations.
SPECIFIC TOXINS
INVESTIGATIONS
l Serial serum theophylline levels:
— Extremely useful in predicting the risk of life-threatening toxicity
— In acute overdose, levels correlate well with clinical severity
(see Table 3.72.2) and are repeated every 2–4 hours until falling
350 — Levels >330 micromol/L (60 mg/L) may be associated with
severe toxicity in elderly patients
35
— In chronic intoxication, severe toxicity can occur at levels >220

0
micromol/L (40 mg/L).

TOXICOLOGY HANDBOOK
TABLE 3.72.2 Correlation of serum levels and toxicity: Acute

theophylline overdose
Level (micromol/L) Level (mg/L) Toxicity
55–110 10–20 Therapeutic

110–220 20–40 Minor toxicity
220–440 40–80 Moderate toxicity
>440 >80 Severe toxicity
>550 >100 Usually fatal without
urgent intervention
MANAGEMENT
l Theophylline poisoning is a life-threatening emergency that is managed
in an area equipped for cardiorespiratory monitoring and resuscitation
l Potential immediate life-threats include:
— Hypotension
— Seizures
— Ventricular and supraventricular tachycardia (SVT)
l Aggressive resuscitation and control of seizures is required in severe
theophylline toxicity. The patient who presents with established
severe toxicity has an extremely poor prognosis. Supportive care
measures do not ensure survival and are instituted in an effort to
allow sufficient time for definitive treatment with haemodialysis
l ypotension usually responds to fluid administration, although
H
a noradrenaline infusion may be needed in resistant cases. Give
10–20 mL/kg of IV crystalloid solution as an initial response (see
Chapter 2.5: Hypotension)
l Treat seizures with benzodiazepines, as outlined in Chapter 2.6:
Approach to seizures
l Supraventricular tachycardia is controlled with beta-blockade using
carefully titrated doses of propranolol or metoprolol, or an esmolol
infusion. Beware bronchospasm in susceptible individuals (asthmatics).
Administer propranolol 0.5–1 mg or metoprolol 5 mg (0.1 mg/kg in
children) by slow IV injection and repeat after 5 minutes if response
inadequate. An esmolol infusion is prepared at a concentration of
10 mg/mL in 5% dextrose and commenced at rate of 0.05 mg/kg/
minute (20 mL/hour in 70-kg adult) and titrated to response
SPECIFIC TOXINS
l Metabolic disturbances do not generally require specific therapy,
although severe hypokalaemia, if present, should be corrected with
potassium supplementation
Decontamination
l Oral activated charcoal is indicated following acute overdose even
if presentation is delayed. Aggressive control of vomiting with
antiemetics, such as ondansetron 4 mg IV or tropisetron 2 mg IV,
is usually necessary for success in the unintubated patient
351
l Haemodialysis is the definitive life-saving intervention in severe
theophylline poisoning and highly effective in achieving good
TOXICOLOGY HANDBOOK
clinical outcome if commenced early
l Arrangements for urgent haemodialysis are made as soon as
potentially life-threatening theophylline toxicity is anticipated.
Commonly accepted indications are:
— Serum theophylline >550 micromol/L (100 mg/L) in the setting
of acute overdose
— Serum theophylline >330 micromol/L (60 mg/L) in the setting of
chronic toxicity
— Clinical manifestations of severe toxicity: arrhythmia,
hypotension or seizures
l Multiple-dose activated charcoal enhances the elimination of
activated charcoal, but use of this modality delays effective
treatment with haemodialysis
Antidotes
l None available.

l atients who have acutely ingested theophylline syrup and are
P
asymptomatic at 6 hours may be medically cleared
l Overdose of modified-release tablets requires observation for
12 hours although serial levels may hasten medical clearance
l All symptomatic patients are admitted to a monitored environment
for close observation and serial theophylline levels. If the initial risk
assessment, subsequent clinical progress or theophylline levels
indicate potential for severe toxicity, retrieval to a facility with an
intensive care unit capable of emergency haemodialysis is undertaken
as soon as possible, preferably before clinical deterioration.
HANDY TIPS
l atients at risk of death should be identified and dialysed before
P
clinical deterioration
l Most theophylline overdoses are of sustained-release preparations
and clinical deterioration is delayed many hours
l Cardiac dysrhythmias (including SVT), hypotension or seizures are
predictive of poor outcome in both acute and chronic toxicity. Any
one of these clinical features mandates urgent haemodialysis.
PITFALLS
l ailure to identify high-risk cases early based on dosing history.
F
This delays arrangements for haemodialysis until patient is clinically
unstable
SPECIFIC TOXINS
l Failure to closely observe and follow theophylline levels.
CONTROVERSIES
l eta-blocker use in asthmatic patients with theophylline toxicity. If
B
beta-blockers are used, short-acting agents such as esmolol given
by titrated infusion are preferred
l Charcoal haemoperfusion is described as the modality of choice
for enhancing theophylline elimination. However, the technique is
352 not widely available and standard haemodialysis is effective and
usually able to be implemented more quickly.
35
2
Presentations
TOXICOLOGY HANDBOOK
Aminophylline 250 mg/10 mL ampoules

Theophylline 200 mg modified-release tablets (100)
Theophylline 133 mg/25 mL syrup (500 mL)
References
Minton NA, Henry JA. Treatment of theophylline overdose. American Journal of Emergency
Medicine 1996; 14:606–612.
Shannon M. Life-threatening events after theophylline overdose: a 10-year prospective
analysis. Archives of Internal Medicine 1999; 159:989–994.
3.73 THYROXINE
Overdose of thyroxine is rarely sufficient to produce significant symptoms
of hyperthyroidism. When these do occur, they are mild, delayed in onset
and may last up to 2 weeks. They can usually be successfully managed in
the outpatient setting.
RISK ASSESSMENT
l he majority of patients with acute thyroxine overdose remain
T
asymptomatic or experience only mild to moderate symptoms of
hyperthyroidism some 2–7 days later
l Symptoms are not expected unless >10 mg of thyroxine is
ingested
l The elderly and patients with cardiovascular co-morbidities are at
increased risk of complications should hyperthyroid symptoms occur
l evere toxicity is more likely to occur following chronic abuse of
S
thyroid hormones
l Children: Ingestion of up to 5 mg is associated with minimal
symptoms. Clinically significant thyrotoxicosis is not reported after
unintentional paediatric ingestion of thyroxine.
Toxic mechanism
Thyroxine (T4) is converted to triiodothyronine (T3) in the liver and kidney. T3 binds to the
nucleus and influences multiple metabolic processes (cardiovascular, metabolic, growth
and development).
Toxicokinetics
Oral bioavailability is high (80%) with a maximal absorption at 2 hours post ingestion.
Onset of the hormonal effect is delayed and maximal effects are not attained until 1–3
SPECIFIC TOXINS
weeks. Thyroxine is extensively distributed and bound completely to proteins. The
elimination half-life is 6–7 days after therapeutic dosing and is shortened to a mean of
3 days following overdose.
CLINICAL FEATURES
l ollowing acute ingestion, most patients remain asymptomatic
F
l Where symptoms do develop, they are not usually apparent until
>24 hours following the ingestion but may then last more than
1 week
l Signs and symptoms when they do occur are those of adrenergic 353
stimulation and include fever, agitation, sweating, tachycardia,
hypertension, headache, diarrhoea and vomiting
l Chronic ingestion of excessive thyroxine causes severe illness
TOXICOLOGY HANDBOOK
characterised by angina pectoris, myocardial infarction,
myocarditis, ventricular and atrial dysrhythmias, left ventricular
hypertrophy, thyrotoxicosis and thyroid storm.
INVESTIGATIONS
l Thyroid function tests after overdose usually show marked elevation
of thyroxine concentration that is without clinical correlate. They
do not assist in management following either accidental paediatric
ingestion or deliberate self-poisoning and are not indicated.
MANAGEMENT
l Resuscitation measures are rarely required
l Beta-blockers rapidly control the sympathomimetic symptoms of
thyroid excess. In symptomatic patients with no contraindications
to beta-blockade, administer oral propranolol 10–40 mg (0.2–0.5
mg/kg in children) every 6 hours
l If beta-blockers are contraindicated, calcium channel blockers are
a suitable alternative. Administer diltiazem 60–180 mg (1–3 mg/kg
in children) every 8 hours
l Close clinical and physiological monitoring is indicated for patients
with severe symptoms.
Decontamination
l Give oral activated charcoal 50 g to cooperative patients who
present within 1 hour of ingesting >10 mg of thyroxine
l Oral activated charcoal is not indicated in children following
unintentional ingestion
Antidotes
l None available.

l hildren suspected of ingesting up to 5 mg of thyroxine may be
C
SPECIFIC TOXINS
observed at home provided they remain asymptomatic

l Adult patients with acute deliberate self-poisoning rarely require
immediate management. Disposition occurs as dictated by the
medical and psychiatric condition, with advice to report symptoms
of thyroid toxicity. If these occur, supportive therapy with beta-
blockers is indicated, usually for a period of 1 week. Thyroxine may
be restarted after a week if indicated.
HANDY TIPS
354
l any patients remain asymptomatic. If symptoms occur, onset is
M
35
usually delayed >24 hours post ingestion.

4
TOXICOLOGY HANDBOOK
PITFALLS
l nnecessary admission for prolonged medical observation
U
l Failure to anticipate or recognise the delayed onset of symptoms
following large overdoses.
Presentations
Thyroxine 50 microgram tablets (40, 200)
References
Lewander WJ, Lacouture PG, Silva JE et al. Acute thyroxine ingestion in pediatric patients.
Pediatrics 1989; 84:262–265.
Litovitz TL, White JD. Levothyroxine ingestions in children: An analysis of 78 cases.
American Journal of Emergency Medicine 1985; 3:297–300.
Shilo L, Kovatz S, Hadari R et al. Massive thyroid hormone overdose: Clinical
manifestations and management. Israeli Medical Association Journal 2002; 4:
298–289.
Tunget CL, Clark RF, Turchen SG et al. Raising the decontamination level for
thyroid hormone ingestions. American Journal of Emergency Medicine 1995;
13:9–13.
3.74 TRAMADOL
Tramadol is a centrally acting synthetic analgesic. In overdose, it
frequently causes delayed-onset seizures. It may also cause mild sedation
and respiratory depression.
RISK ASSESSMENT
l pioid effects (sedation and respiratory depression) are usually
O
mild and rarely require intervention
l The major potential risk is seizures and these are usually delayed
in onset (>6 hours). Seizures should be anticipated in patients who
ingest >1.5 g tramadol
l Serotonin syndrome may develop if there is co-ingestion of other
serotonergically active agents
l Children: CNS depression and seizures can occur with ingestion of
>10 mg/kg.
Toxic mechanism
Tramadol is a weak partial agonist at μ opioid receptors. It also inhibits serotonin and
SPECIFIC TOXINS
noradrenaline reuptake in the CNS. The toxic effects in overdose seem to be primarily a
result of the inhibition of CNS serotonin and noradrenaline reuptake.
Toxicokinetics
Tramadol is well absorbed orally and peak levels occur at 1–3 hours after ingestion of
standard preparations and 3–5 hours after ingestion of extended-release preparations.
Peak levels may be further delayed after overdose. The volume of distribution
is 2–3 L/kg. It is extensively metabolised in the liver and one of the metabolites,
O-desmethyltramadol, is pharmacologically active. Elimination is in the urine with
elimination half-lives of 5–7 hours for the parent drug and 6–8 hours for the active
metabolite. 355
CLINICAL FEATURES
l pioid agonist effects are not prominent and consist of mild
O
TOXICOLOGY HANDBOOK
sedation, mild respiratory depression and miosis
l Coma requiring intubation is unusual except in the presence of co-
ingestants, especially ethanol or benzodiazepines
l Serotonergic and noradrenergic effects are more prominent and
may include tachycardia, agitation, mydriasis and seizures
l Seizures are the most serious clinical effect. They are delayed
in onset (usually >6 hours after overdose of the sustained-
release preparation), of short duration and easily controlled with
benzodiazepines
l Serotonin syndrome may develop, especially if there is co-
ingestion of other serotonergically active drugs (see Chapter 2.8:
Serotonin syndrome).
INVESTIGATIONS
l Specific investigations are only indicated to diagnose and assess
secondary complications.
MANAGEMENT
l eizures are treated with titrated doses of IV benzodiazepines, as
S
outlined in Chapter 2.6: Approach to seizures
l Increasing agitation, tachycardia, tremor and myoclonic jerks
herald onset of seizures and these symptoms are controlled with
titrated IV doses of diazepam: give 5 mg every 2–5 minutes until
gentle sedation is achieved and the heart rate falls towards 100
beats/minute
l Serotonin syndrome, if it develops, should be identified and
managed as described in Chapter 2.8: Serotonin syndrome
Decontamination
l Administration of oral activated charcoal 50 g is considered in
SPECIFIC TOXINS
the patient who is alert and cooperative and presents within

2 hours of ingestion of >1.5 g of a sustained-release tramadol
preparation
l The potential for seizures must be considered when making a risk–
benefit analysis of the value of administering activated charcoal
l In the patient who is intubated, activated charcoal may be safely
administered via a nasogastric tube
356 l Not clinically useful
35
Antidotes
6
l Naloxone may reverse CNS and respiratory depression secondary

TOXICOLOGY HANDBOOK
to μ opioid agonist activity (see Chapter 4.19: Naloxone).

However, this is rarely a clinically significant problem with pure
tramadol overdose and naloxone is rarely useful.

l hildren suspected of ingesting >10 mg/kg of sustained-release
C
tramadol must be assessed and observed in hospital for at least
12 hours. Discharge should not occur at night
l Because of the risk of seizures, all adult patients who have
ingested >1.5 g must be observed with IV access in place for a
minimum of 12 hours and until symptom free
l Patients who are significantly sedated or require benzodiazepine
administration for seizure or symptom control should be admitted
for continued observation and supportive care until symptom free.
Discharge should not occur at night
l Patients who require intubation for coma or severe serotonin
syndrome are admitted to intensive care.
HANDY TIPS
l rophylactic administration of intravenous benzodiazepines
P
to patients with clinical features of toxicity such as agitation,
tachycardia, tremor or myoclonic jerking will usually prevent
seizures.
PITFALLS
l ailure to anticipate and prepare for delayed symptoms or seizures
F
l Administration of activated charcoal shortly before onset of
seizures.
Presentations
Tramadol hydrochloride 50 mg capsules (20)
Tramadol hydrochloride 50 mg sustained-release tablets (20)
Tramadol hydrochloride 100 mg sustained-release tablets (10, 20)
Tramadol hydrochloride 200 mg sustained-release tablets (10, 20)
Tramadol hydrochloride 100 mg/1 mL oral drops (10 mL)
Tramadol 100 mg/2 mL ampoules
References
Persson H, Sjöberg G. Acute toxicity of tramadol: analyses of 287 cases (abstract). Clinical
Toxicology 2008; 46:398.
Sachdeva DK, Stadnyk JM. Are one or two dangerous? Opioid exposure in toddlers.
SPECIFIC TOXINS
Shadnia S, Soltaninejad K, Heyardi K et al. Tramadol intoxication: a review of 114 cases.
Human and Experimental Toxicology 2008; 27:201–205.
Spiller HA, Gorman SE, Villalobos D et al. Prospective multicenter evaluation of tramadol
exposure. Journal of Toxicology-Clinical Toxicology 1997; 35(4):361–364.
3.75 TRICYCLIC ANTIDEPRESSANTS (TCAs)

357
Amitriptyline, Clomipramine, Dothiepin, Doxepin, Imipramine,
Nortriptyline, Trimipramine
Tricyclic antidepressant (TCA) poisoning remains a major cause of
TOXICOLOGY HANDBOOK
morbidity and mortality. Deliberate self-poisoning may lead to the
rapid onset of CNS and cardiovascular toxicity. Prompt intubation,
hyperventilation and sodium bicarbonate administration at the first
evidence of severe toxicity are life saving.
RISK ASSESSMENT
l Ingestion of >10 mg/kg is potentially life threatening (see Table
3.75.1)
l Onset of severe toxicity usually occurs within 2 hours of ingestion
l Seizures and myoclonus are more common with dothiepin
TABLE 3.75.1 : Dose-related risk assessments: Tricyclic

antidepressants
Dose Effect
<5 mg/kg Minimal symptoms
5–10 mg/kg Drowsiness and mild anticholinergic effects

Major toxicity not expected
>10 mg/kg Potential for all major effects (coma, hypotension,

seizures, cardiac dysrhythmias) to occur within
2–4 hours of ingestion
Anticholinergic effects likely but often masked by coma
>30 mg/kg Severe toxicity with pH-dependent cardiotoxicity

and coma expected to last >24 hours
l Children: Ingestion of >10 mg/kg of amitriptyline, dothiepin,
doxepin or trimipramine tablets is potentially lethal in a 10-kg
toddler. Any child who is suspected of ingesting >5 mg/kg is
referred to hospital for 6 hours observation.
Toxic mechanism
TCAs are noradrenaline and serotonin reuptake inhibitors and GABAA receptor-blockers.
Myocardial toxicity is chiefly due to blockade of inactivated fast sodium channels. Other
toxic effects are mediated by blockade at muscarinic (M1), histaminic (H1) and peripheral
post-synaptic α1-adrenergic receptors. TCAs cause reversible inhibition of potassium
channels and direct myocardial depression unrelated to conduction abnormalities.
Toxicokinetics
TCAs are rapidly absorbed following oral administration, with peak levels occurring within
SPECIFIC TOXINS
2 hours. TCAs are highly bound to plasma and tissue proteins and have large volumes of
distribution (5–20 L/kg). TCAs undergo hepatic metabolism by oxidation (cytochrome P450
2D6) to active metabolites. Some enterohepatic circulation occurs.
CLINICAL FEATURES
l evere toxicity is characterised by rapid deterioration in clinical
S
status within 1–2 hours of ingestion. Patients may present alert and
orientated, only to rapidly develop coma, seizures, hypotension
and cardiac dysrhythmias
358 l Central nervous system
— Sedation and coma usually precede cardiovascular signs
35
8
— Seizures
— Delirium secondary to anticholinergic effects is often obscured
TOXICOLOGY HANDBOOK
by coma
l Cardiovascular
— Sinus tachycardia and mild elevation of blood pressure
— Hypotension due to alpha blocking effects and impaired
contractility
— Broad-complex tachydysrhythmias
— Broad-complex bradycardia occurs pre-arrest
l Anticholinergic effects
— Can occur on presentation or may be delayed and prolonged
— Agitation, restlessness, delirium
— Mydriasis
— Dry, warm, flushed skin
— Tachycardia, urinary retention, ileus
— Myoclonic jerks.
INVESTIGATIONS
l Serial ECGs
— Vital tool in the management of TCA intoxication
— Diagnostic features include:
– Prolongation of PR and QRS intervals
– Large terminal R wave in aVR
– Increased R/S ratio (>0.7) in aVR
– QT prolongation is also noted secondary to potassium
channel blockade
– See Appendix 2 for examples of ECGs in TCA poisoning
— Q RS widening reflects degree of fast sodium channel blockade
— QRS >100 ms is predictive of seizures
— QRS >160 ms is predictive of ventricular tachycardia.
MANAGEMENT
l Acute TCA poisoning is a potentially life-threatening emergency
resuscitation
l Close clinical and physiological monitoring is mandatory for at least
6 hours post ingestion
l Cardiac monitoring is continued until resolution of toxicity
l Potential early life-threats that require immediate intervention
SPECIFIC TOXINS
include:
— Coma
— Respiratory acidosis
— Seizures
— Cardiac arrest
l At the onset of CNS depression (e.g. GCS <12), prompt intubation
and hyperventilation are indicated
l Ventricular dysrhythmias
— Cardioversion and defibrillation are unlikely to be effective
359
— Administer sodium bicarbonate 100 mmol (2 mmol/kg) IV
repeated every 1–2 minutes until restoration of perfusing
TOXICOLOGY HANDBOOK
rhythm (see Chapter 4.25: Sodium bicarbonate for further
details)
— Lignocaine (1.5 mg/kg) IV is third-line therapy when pH is
established at >7.5
— Type Ia antiarrhythmic agents (e.g. procainamide), amiodarone
and beta-blockers are contraindicated
l Hypotension is treated with IV crystalloid solutions (10–20 mL/
kg), sodium bicarbonate 100 mmol (2 mmol/kg) and adrenaline or
noradrenaline infusion (see Chapter 2.5: Hypotension)
l Seizures are managed with benzodiazepines, as outlined in
l Intubated patients are hyperventilated to maintain serum pH 7.50–
7.55.
Decontamination
l Activated charcoal is not indicated for ingestions <10 mg/kg, as
good outcome is expected with supportive care
l In patients with significant ingestions, activated charcoal is
indicated, but should never be administered until after the airway is
secured by endotracheal intubation and only after dealing with all
resuscitation priorities
Antidotes
l Sodium bicarbonate as above and see Chapter 4.25: Sodium
bicarbonate.
l atients who are clinically well, with normal 12-lead ECG (or
P
static preexisting changes), normal mental status, no hypotension
and no seizures at 6 hours post ingestion do not require further
cardiac monitoring or observation and are medically fit for
discharge
l Patients with minor abnormalities of mental status or 12-lead ECG
at 6 hours post ingestion require ongoing careful observation, ECG
monitoring and reassessment of 12-lead ECGs, until there is clear
evidence of clinical improvement.
l Patients requiring intubation and ventilation are admitted to an
SPECIFIC TOXINS
HANDY TIPS
l esuscitation efforts do not cease until the patient has
R
been intubated, and treated with sodium bicarbonate and
hyperventilation to achieve a serum pH of 7.50–7.55. Numerous
reports describe survival with good neurological outcome following
prolonged cardiac arrest and CPR (up to hours).
l Onset of coma may be abrupt and followed by rapid decline and
arrest if rapid intubation, hyperventilation and sodium bicarbonate
360 are not undertaken. These interventions are sufficient to ensure
survival of all patients who arrive alive at hospital and most of
36
those who arrive shortly after arrest.

0
TOXICOLOGY HANDBOOK
PITFALLS
l Insufficient doses of sodium bicarbonate when attempting
resuscitation of severe TCA poisoning.
CONTROVERSIES
l alue and indications for prophylactic serum alkalinisation
V
l Relative efficacy of hyperventilation versus sodium bicarbonate
l Efficacy of hypertonic saline.
Presentations
Amitriptyline hydrochloride 10 mg tablets (50)
Clomipramine hydrochloride 25 mg tablets (50)
Dothiepin hydrochloride 25 mg capsules (50)
Dothiepin hydrochloride 75 mg tablets (30)
Doxepin hydrochloride 10 mg capsules (50)
Doxepin hydrochloride 25 mg capsules (50)
Doxepin hydrochloride 50 mg tablets (50)
Imipramine hydrochloride 10 mg tablets (50)
Imipramine hydrochloride 25 mg tablets (50)
Nortriptyline hydrochloride 10 mg tablets (50)
Nortriptyline hydrochloride 25 mg tablets (50)
Trimipramine maleate 25 mg tablets (50)
Trimipramine maleate 50 mg capsules (50)
References
Bateman ND. Tricyclic antidepressant poisoning: central nervous system effects and
management. Toxicological Reviews 2005; 24(3):181–186.
Bradberry SM, Thanacoody HKR, Watt BE et al. Management of the cardiovascular
complications of tricyclic antidepressant toxicity: role of sodium bicarbonate.
Heard K, Cain BS, Dart RC et al. Tricyclic antidepressants directly depress human
myocardial mechanical function independent of effects on the conduction system.
Academic Emergency Medicine 2001; 8(12):1122–1127.
Liebelt EL, Francis PD, Woolf AD. ECG lead aVR versus QRS interval in predicting seizures
and arrhythmias in acute tricyclic antidepressant toxicity. Annals of Emergency
Medicine 1995; 26(2):195–201.
3.76 VALPROIC ACID (sodium valproate)

Most valproate overdoses result in CNS depression and are managed
SPECIFIC TOXINS
successfully with supportive care. Large overdoses can cause multi-system
organ failure and death. Death is preventable with early haemodialysis.
RISK ASSESSMENT
l ose-dependent CNS depression may be delayed up to 12 hours
D
(see Table 3.76.1)
l Increasingly severe multi-system organ effects occur as doses rise
above 400 mg/kg
l Ingestion of >1 g/kg is potentially lethal
361
TABLE 3.76.1 Dose-related risk assessment: Valproic acid
TOXICOLOGY HANDBOOK
Dose Effect
<200 mg/kg Asymptomatic, or mild drowsiness and ataxia

only
200–400 mg/kg Variable CNS depression; airway control rarely

required
400–1000 mg/kg Significant CNS depression likely

Coma requiring intubation may be delayed up
to 12 hours after ingestion
As doses increase within this range, more
severe multi-system toxicity is observed
>1000 mg/kg Potentially lethal with profound prolonged

coma and multiple organ toxicity, including
cerebral oedema, hypotension, lactic
acidosis, hypoglycaemia, hyperammonaemia,
hypernatraemia, hypocalcaemia and bone
marrow suppression
l Children: Unintentional ingestions of <200 mg/kg may be observed

at home. Referral to hospital for assessment is indicated if more
than this amount may have been ingested, or if symptoms develop.
Toxic mechanism
Valproate increases levels of gamma-aminobutyric acid (GABA), a central inhibitory
neurotransmitter. In large doses, it interferes with numerous mitochondrial metabolic pathways.
Toxicokinetics
Valproate is usually well absorbed following oral administration, but absorption may be
slow and erratic following overdose. Peak levels may be delayed up to 18 hours. Valproate
is highly protein bound and has a very small volume of distribution (0.1–0.2 L/kg).
Valproate undergoes hepatic metabolism to produce multiple active metabolites.
CLINICAL FEATURES
l he patient frequently presents relatively asymptomatic, even after
T
large ingestions
l Progressive deterioration in conscious state is paralleled closely by
rising serum levels (see below)
l Following large ingestions, coma is accompanied by:
— Metabolic abnormalities (anion gap metabolic acidosis,
hypoglycaemia, hypernatraemia, hypocalcaemia and
SPECIFIC TOXINS
hyperammonaemia)
— Other evidence of systemic toxicity, including hypotension,
renal impairment and bone marrow depression
l In very severe poisoning, cerebral oedema, prolonged coma,
cardiovascular instability and death occur
l In severe poisoning, coma and manifestations of toxicity may persist
for several days after serum valproate levels return to normal.
INVESTIGATIONS
36

2

TOXICOLOGY HANDBOOK
l Serial valproate levels: Confirm poisoning; refine risk assessment

and guide therapy. Serum valproate levels correlate well with the
degree of CNS depression and the risk of developing multi-system
toxicity (see Table 3.76.2)
l If CNS depression develops, or ingestion >400 mg/kg is suspected,
serum valproate levels are repeated every 4–6 hours until they
decrease
l In the comatose patient, valproate levels are essential to
determining the risk of life-threatening multi-system valproate
toxicity and need for haemodialysis
l Serial EUC, acid–base status and full blood counts are followed in
all comatose patients to detect and manage multi-system toxicity.
TABLE 3.76.2 Correlation of clinical effects with serum valproate
level
Serum valproate Clinical effects
<3500 micromol/L Not usually associated with multiple organ

(<500 mg/L) effects
>3500 micromol/L Usually manifest coma and may have other

(>500 mg/L) organ effects
>7000 micromol/L Frequently develop life-threatening multiple

(>1000 mg/L) organ effects
>14 000 micromol/L Death expected without urgent

(>2000 mg/L) haemodialysis
MANAGEMENT
l All patients are managed in an area equipped for cardiopulmonary
Decontamination
SPECIFIC TOXINS
l Oral activated charcoal is not indicated in patients who have
ingested <400 mg/kg
l In larger ingestions activated charcoal 50 g is administered via the
nasogastric tube after securing the airway with endotracheal intubation,
as outlined in Chapter 1.6: Gastrointestinal decontamination
l A repeat dose of activated charcoal at 3–4 hours may reduce
absorption and peak serum levels, and is recommended in
intubated patients with preserved bowel sounds and rising
valproate levels
363
l Haemodialysis removes valproic acid efficiently and is indicated
whenever life-threatening systemic toxicity is anticipated:
TOXICOLOGY HANDBOOK
— Ingestion of >1000 mg/kg with serum level >7000 micromol/L
(1000 mg/L)
— Serum level >10 400 micromol/L (1500 mg/L) at any time
— Severe valproic acid poisoning with lactic acidosis or
cardiovascular instability
l Haemodialysis is ideally performed before multi-system organ
dysfunction is evident
Antidotes
l None available.

l atients who ingest <200 mg/kg are observed in a ward
P
environment for 8 hours. They are fit for medical discharge after
that time as soon as they are alert and ambulant
l Those who ingest larger amounts are observed closely for
deteriorating conscious state. If coma develops, the patient is
intubated and ventilated and admitted to an intensive care unit.
HANDY TIPS
l fter large ingestions, absorption is slow and erratic. Coma may be
A
delayed for up to 8–12 hours
l Consider valproic acid overdose in any patient with unexplained
coma, particularly where there is hypernatraemia, hypocalcaemia
or lactic acidosis
l The valproate level taken on arrival may be within normal therapeutic
range, even following a life-threatening ingestion—always repeat the
level if there is any decline in the level of consciousness
l rgent valproate levels are essential in the comatose patient to
U
stratify risk and the need for haemodialysis
l Continuous veno-venous haemofiltration and haemodiafiltration
do not appear to be as effective as haemodialysis in removing
valproate, but are acceptable alternatives if more readily
available.
PITFALLS
l alsely low levels have been reported from laboratory equipment
F
not calibrated for levels exceeding 3000 micromol/L (450 mg/L).
CONTROVERSIES
l hole bowel irrigation (WBI) has been advocated in large valproic
W
SPECIFIC TOXINS
acid ingestions (>1 g/kg) if the patient presents within 4 hours.

Progressive CNS depression renders the procedure difficult and
hazardous. In the intubated patient, WBI may be not feasible;
early haemodialysis is highly effective and a more appropriate
intervention in this life-threatening situation
l Carnitine has been suggested as an antidote for valproate-induced
mitochondrial effects. These recommendations are based on case
reports and extrapolation from treatment of children with selected
inborn errors of metabolism. Carnitine is not recommended at this
364 time
36
l The benefit of haemodialysis has not been validated with controlled

4
trials.
TOXICOLOGY HANDBOOK
Presentations
Sodium valproate 100 mg tablets (100)
Sodium valproate 200 mg enteric-coated tablets (100, 200)
Sodium valproate 500 mg enteric-coated tablets (100, 200)
Sodium valproate 200 mg/5 mL liquid (300 mL)
Sodium valproate 400 mg and 4 mL solvent vials
References
Isbister GK, Balit CR, Whyte IM et al. Valproate overdose: a comparative cohort study of
self-poisonings. British Journal of Clinical Pharmacology 2003; 55:398–404.
Spiller HA, Krenzelok EP, Klein-Schwartz W et al. Multicenter case series of valproic acid
ingestion: serum concentrations and toxicity. Clinical Toxicology 2000; 38(7):755–760.
Sztajnkrycer MD. Valproic acid toxicity: Overview and management. Journal of Toxicology-
Thanacoody RH. Extracorporeal elimination in acute valproic acid poisoning. Clinical
Toxicology 2009; 47(7):609–616.
3.77 VENLAFAXINE AND DESVENLAFAXINE

Venlafaxine and desvenlafaxine are potent selective serotonin and
noradrenaline reuptake inhibitors. Venlafaxine overdose is potentially life
threatening; it frequently causes seizures and in very large ingestions,
cardiovascular toxicity. Supportive care and adequate benzodiazepine
sedation usually ensure a good outcome. There is less clinical experience
with desvenlafaxine, but it is likely that the clinical features of overdose
are similar to those of venlafaxine.
RISK ASSESSMENT
l 4% of patients have seizures but the incidence is dose dependent
1
(see Table 3.77.1)
l Onset of seizures may be delayed up to 16 hours following overdose
l Preexistent seizure disorder may increase the probability of
seizures
l There is a high risk of serotonin syndrome if other serotonergic
agents are co-ingested (see Table 2.8.2), irrespective of the dose
of venlafaxine
l Massive ingestion (>7 g) is associated with cardiovascular effects
l Children: Accidental ingestion of up to 2–3 tablets is not
associated with significant symptoms. Referral to hospital is not
SPECIFIC TOXINS
required unless symptoms occur.
TABLE 3.77.1 Dose-related risk assessment: Venlafaxine
Dose Effect
<1.5 g Risk of seizures <5%
<3 g Risk of seizures 10%
>3 g Risk of seizures >30%

365
>4.5 g Risk of seizures approaches 100%

Hypotension
TOXICOLOGY HANDBOOK
Minor QRS and QT prolongation on 12-lead ECG
>7 g Hypotension and cardiac dysrhythmias
Toxic mechanism
Venlafaxine and its metabolite O-desmethylvenlafaxine (desvenlafaxine) are potent
selective serotonin and noradrenaline reuptake inhibitors (SNRIs). They also exhibit rate-
dependent sodium channel blocking activity. They have only weak dopamine reuptake
activity and no activity at muscarinic, histamine (H1), or α1-adrenegic receptors. They do
not inhibit monoamine oxidase (MAO).
Toxicokinetics
Venlafaxine is well absorbed and undergoes extensive first pass metabolism, resulting in
bioavailability of only 50%. All currently available preparations are modified-release and
peak plasma levels occur at 6–8 hours. The volume of distribution of venlafaxine is 5–7
L/kg. The apparent elimination half-life following therapeutic doses of modified-release
preparations is 15 hours.
Desvenlafaxine is also well absorbed, but does not undergo extensive first-pass
metabolism and has a bioavailability of 80%. The volume of distribution is 3–4 L/kg. Up to
45% of an ingested dose is excreted unchanged in the urine, with the rest predominantly
undergoing glucuronide conjugation. The elimination half-life is approximately 11 hours.
CLINICAL FEATURES
l nset of significant clinical features of toxicity may be delayed up
O
to 6–12 hours following overdose
l Dysphoria, anxiety, mydriasis, sweating, tremor, clonus,
tachycardia (up to 160 beats/minute) and hypertension are
common, and may herald the onset of seizures
l eizures are generalised, short duration and terminated with
S
benzodiazepines. The first seizure may be delayed up to 16 hours
l Coma is not a feature of venlafaxine intoxication
l Although some clinical features of intoxication may be serotonergic
in origin, severe serotonin syndrome develops only where there is
co-ingestion of other serotonergically active drugs, especially MAO
inhibitors
l Hypotension occurs following very large ingestions and again,
onset may be delayed up to 12 hours
l Minor dose-dependent QRS and QT prolongation may occur
with venlafaxine intoxication but is unlikely to be associated with
dysrhythmias, except perhaps following massive overdose
l Rhabdomyolysis, occasionally severe, is reported infrequently
following large overdose of venlafaxine
SPECIFIC TOXINS
l Venlafaxine intoxication usually resolves within 24 hours.
INVESTIGATIONS
l Serial ECGs
366 — Perform a 12-lead ECG on all patients at presentation and
6 hours post ingestion, repeat at 12 hours if >4.5 g ingested
36
l Creatine kinase
6

— Detect and monitor rhabdomyolysis.
TOXICOLOGY HANDBOOK
MANAGEMENT
l Venlafaxine overdose is a life-threatening emergency and managed in
an area equipped for cardiorespiratory monitoring and resuscitation
l Early intubation and ventilation is indicated when the history and
clinical progression suggest ingestion of >7g
— Seizures: treat with benzodiazepines, as outlined in Chapter
— Broad complex tachydysrhythmias: manage aggressively
with intubation, hyperventilation and administration of sodium
bicarbonate 1–2 mmol/kg repeated every 1–2 minutes to
achieve serum alkalinisation, as described in Chapter 4.25:
Sodium bicarbonate
l Increasing agitation, tachycardia and tremor herald onset of
seizures and are controlled with titrated doses of IV diazepam: give
5 mg every 2–5 minutes until gentle sedation is achieved and the
heart rate falls towards 100 beats/minute
l Hyperthermia is a feature of severe serotonin syndrome and must
be immediately controlled. Temperature >38.5°C is an indication
for continuous core-temperature monitoring, benzodiazepine
sedation and fluid resuscitation. Temperature >39.5°C requires
rapid treatment to prevent multiple organ failure and neurological
injury. Paralysis, intubation and ventilation are indicated, as
described in Chapter 2.8: Serotonin syndrome
l General supportive care measures as outlined in Chapter 1.4:
Supportive care and monitoring are indicated
Decontamination
l Activated charcoal is administered to patients who are alert and
cooperative and present within 2 hours following ingestion of
>4.5 g of venlafaxine or desvenlafaxine
l Activated charcoal is contraindicated in the awake patient with
more delayed presentation or symptoms, due to the risk of seizures
l If >7 g venlafaxine is ingested and seizures, hypotension or
altered mental status occur, give activated charcoal 50 g via the
nasogastric tube only after endotracheal intubation
Antidotes
SPECIFIC TOXINS
l None available.

l ecause of the risk of seizures following venlafaxine or
B
desvenlafaxine overdose, all patients must be observed with IV
access in place for a minimum of 16 hours and until symptom free
l For ingestions <4.5 g, cardiac monitoring is not required after the
first 6 hours, provided the ECG demonstrates normal QRS and QT
intervals at that time
l Patients who ingest >4.5 g require cardiac monitoring and serial 367
ECGs for a period of 12 hours post ingestion. ECG monitoring may
then cease if there is no evidence of QRS or QT prolongation
l Patients with severe venlafaxine intoxication or serotonin syndrome
TOXICOLOGY HANDBOOK
require management in an intensive care unit.
HANDY TIPS
l arly prophylactic doses of intravenous benzodiazepines will
E
usually prevent seizures. The dose is titrated to achieve a calm
patient and a fall in the pulse rate towards 100 beats/minute
l Coma is not secondary to venlafaxine intoxication and indicates
co-ingestion or complication.
PITFALLS
l ailure to anticipate and prepare for delayed onset of symptoms
F
and seizures
l Failure to administer benzodiazepines early and in sufficient dose
l Administration of activated charcoal or initiation of whole bowel
irrigation (WBI) shortly before onset of seizures or cardiovascular
toxicity.
CONTROVERSIES
l oth single-dose oral activated charcoal and WBI reduce venlafaxine
B
absorption, with the combination of both treatments producing the
greatest reduction in maximal venlafaxine concentrations. However,
the risk of seizures occurring following delayed administration of
activated charcoal or during WBI means that a risk–benefit analysis
does not clearly favour these interventions
l There is little clinical experience with desvenlafaxine overdose
and it is not yet known whether the seizure risk is the same.
A similar management approach is advised until further clinical
data becomes available.
Presentations
Desvenlafaxine succinate 50 mg (7, 28)
Desvenlafaxine succinate 100 mg (28)
Venlafaxine modified-release tablets 37.5 mg (28)
Venlafaxine modified-release tablets 75 mg (28)
Venlafaxine modified-release tablets 150 mg (28)
References
Howell C, Wilson AD, Waring WS. Cardiovascular toxicity due to venlafaxine poisoning in
adults: a review of 235 consecutive cases. British Journal of Clinical Pharmacology
2007; 64(2):192–197.
Isbister GK. Electrocardiogram changes and arrhythmias in venlafaxine overdose. British
Journal of Clinical Pharmacology 2009; 67(5):572–576.
Kumar VV, Oscarsson S, Friberg LE et al. The effect of decontamination procedures on the
SPECIFIC TOXINS
pharmacokinetics of venlafaxine in overdose. Clinical Pharmacology and Therapeutics

2009; 27:911–915.
Whyte IM, Dawson AH, Buckley NA. Relative toxicity of venlafaxine and selective serotonin
reuptake inhibitors in overdose compared to tricyclic antidepressants. Quarterly
Journal of Medicine 2003; 96(5):369–374.
3.78 WARFARIN
368
Over-anticoagulation is a frequent complication of warfarin therapy.
36
Deliberate self-poisoning with warfarin occurs in patients with or without

8
a requirement to maintain therapeutic anticoagulation. All patients

TOXICOLOGY HANDBOOK
are usually asymptomatic at presentation. The approach to therapy

is determined by both the magnitude of over-anticoagulation and the
indication (or not) for therapeutic anticoagulation. Patients with active
bleeding require urgent combination reversal therapy. Vitamin K is the
specific antidote.
RISK ASSESSMENT
l herapeutic over-anticoagulation presents as an asymptomatic
T
patient with an elevated INR or with active bleeding; the risk of
bleeding increases progressively as the INR rises above 5
l In patients not on therapeutic warfarin who overdose:
— Acute ingestion <0.5 mg/kg is unlikely to cause a clinically
significant increase in INR
— Acute ingestion >2 mg/kg can produce a significant increase in
INR within 72 hours
l Active bleeding constitutes an emergency and requires urgent
combination therapy (see below)
l Children: Single acute unintentional ingestion of <0.5 mg/kg does

not present a risk of significant anticoagulation and does not
require investigation or treatment.
Toxic mechanism
Warfarin inhibits vitamin K metabolism, leading to depletion of the active reduced form.
Vitamin K is a cofactor required for the synthesis of coagulation factors II, VII, IX, and X
(plus proteins C and S). The observed 8–12 hour delay before anticoagulation that occurs
is secondary to the half-lives of existing vitamin K-dependent coagulation factors (6, 24,
40 and 60 hours for factors VII, IX, X and II respectively). Peak effects are observed by 72
hours. Toxicity renders patients coagulopathic and vulnerable to haemorrhage.
Toxicokinetics
Warfarin is rapidly absorbed with 100% bioavailability. It has a small volume of
distribution (0.2 L/kg) and is 99% protein bound. Warfarin is metabolised in the liver
(cytochrome P450) to form metabolites that undergo enterohepatic recirculation.
Warfarin and its metabolites are excreted in urine and faeces with an elimination half-life
of 35 hours.
CLINICAL FEATURES
l ver-anticoagulated patients are usually asymptomatic
O
l Severe coagulopathy may manifest as bruising, petechial or
purpural rashes, gingival bleeding, epistaxis, gastrointestinal
bleeding or haematuria.
SPECIFIC TOXINS
INVESTIGATIONS
l anagement of warfarin-induced coagulopathy is based on
M
measurement of INR.
l Other investigations are performed to assess
potential complications as dictated by the individual risk
assessment
369
l INR
— In patients not previously anticoagulated, the INR is
TOXICOLOGY HANDBOOK
normal for the first 6 hours after accidental or deliberate
overdose and a normal INR at 48 hours excludes warfarin
overdose
— In patients with excessive anticoagulation, but a therapeutic
requirement, the INR is measured at presentation and at
6 hourly intervals thereafter.
MANAGEMENT
l In patients with evidence of haemorrhage, attention to airway,
breathing and circulation are paramount. These priorities can
usually be managed along conventional lines, as outlined in
l If there is active uncontrolled haemorrhage, administer
prothrombin complex concentrate (25–50 IU/kg), fresh frozen
plasma (150–300 mL or 10–15 mL/kg) if prothrombin complex
concentrate is unavailable and vitamin K 5–10 mg IV
Decontamination
l Following deliberate self-poisoning in cooperative patients on
therapeutic anticoagulation, administer 50 g oral activated charcoal
if they present within 1 hour of ingestion
l Activated charcoal is not indicated in other patients
Antidotes
l Vitamin K is administered prophylactically to patients who have
ingested a potentially anticoagulating dose of warfarin but have no
therapeutic requirement for anticoagulation. This obviates the need
for repetitive coagulation testing. In patients with a therapeutic
requirement for anticoagulation, vitamin K dose is carefully titrated
in an effort to maintain an INR in the optimal therapeutic range (see
Chapter 4.29: Vitamin K)
l Accepted guidelines for management of therapeutic over-
anticoagulation, including vitamin K administration, are shown in
Appendix 5: Therapeutic over-warfarinisation.

SPECIFIC TOXINS
l hildren who ingest <0.5 mg/kg do not required medical

C
assessment or observation
l Children who ingest >0.5 mg/kg are given 10 mg vitamin K PO
and discharged. They do not require INRs or follow-up
l Patients with no therapeutic requirement for anticoagulation are
treated with 10–20 mg of oral vitamin K and medically cleared.
Follow-up INR is indicated at 48 hours
l Patients with a therapeutic requirement for anticoagulation are
admitted and receive titrated vitamin K doses, as discussed in
370 Chapter 4.29: Vitamin K
l Therapeutic over-anticoagulation is managed on an outpatient
37
basis, unless there is active bleeding or an INR >9.

TOXICOLOGY HANDBOOK
HANDY TIPS
l arfarin levels may be useful in cases where paediatric
W
non-accidental injury or occult poisoning is suspected.
PITFALLS
l ailure to carefully titrate vitamin K dose in patients requiring
F
therapeutic anticoagulation.
Presentations
Warfarin 1 mg tablets (50)
References
Baker RI, Coughlin PB, Gallus AS et al. The Warfarin Reversal Consensus
Group Warfarin reversal: consensus guidelines, on behalf of the Australasian
Society of Thrombosis and Haemostasis. Medical Journal of Australia 2004:
181(9):494–497.
Isbister GK, Hackett LP, Whyte, IM. Intentional warfarin overdose. Therapeutic Drug
Monitoring 2003; 25(6):715–722.
CHAPTER 4
ANTIDOTES
4.1 Atropine 372

4.2 Calcium 373
4.3 Cyproheptadine 376
4.4 Desferrioxamine 377
4.5 Dicobalt edetate 379
4.6 Digoxin immune Fab 381
4.7 Dimercaprol 383
4.8 Ethanol 385
4.9 Flumazenil 387
4.10 Folinic acid 389
4.11 Fomepizole 391
4.12 Glucagon 392
4.13 Glucose 394
4.14 Hydroxocobalamin 396
4.15 Insulin (high-dose) 398
4.16 Intravenous lipid emulsion 400
4.17 Methylene blue 401
4.18 N-acetylcysteine 403
4.19 Naloxone 406
4.20 Octreotide 408
4.21 Penicillamine 410
4.22 Physostigmine 411
4.23 Pralidoxime 413
4.24 Pyridoxine 415
4.25 Sodium bicarbonate 417
4.26 Sodium calcium edetate 420
4.27 Sodium thiosulfate 422
4.28 Succimer 424
4.29 Vitamin K 426
4.1 ATROPINE
Atropine is a competitive muscarinic antagonist, used to treat drug-
induced bradycardia and poisoning by acetylcholinesterase inhibitors.
Presentations
Atropine sulfate 0.6 mg/mL ampoules
Atropine sulfate 1.2 mg/mL ampoules
TOXICOLOGICAL INDICATIONS
l Poisoning by agents that impair AV conduction such as cardiac
glycosides, beta-blockers and calcium channel blockers
l Organophosphate and carbamate poisoning.
CONTRAINDICATIONS
l Relativecontraindications include:
— Closed angle glaucoma
— Obstructive disease of the gastrointestinal tract
ANTIDOTES
— Obstructive uropathy.
Mechanism of action
Atropine is a competitive antagonist of acetylcholine at muscarinic receptors. It
reverses the excessive parasympathetic stimulation that results from inhibition of
acetylcholinesterase. It does not act at nicotinic receptors.
372 Pharmacokinetics
37
Atropine has a poor oral bioavailability and undergoes hepatic metabolism with an
2
elimination half-life of 2–4 hours. It crosses the blood–brain and placental barriers. About
50% is excreted unchanged in urine.
TOXICOLOGY HANDBOOK
ADMINISTRATION
l Place the patient in a monitored area where equipment, drugs and
personnel are available to provide full resuscitative care
Organophosphate and carbamate poisoning
l Administer an initial IV bolus of 1.2 mg
l Further doses are given every 2–3 minutes, doubling the dose each
time until drying of respiratory secretions is achieved
l Very large doses (up to 100 mg) may be required in severe
cases and ongoing atropine administration by infusion may be
necessary
Bradycardia caused by drug-induced AV conduction blockade
l Administer an IV bolus of 0.6 mg
l Repeat doses of 0.6 mg are given as required up to a maximum of
1.8 mg.
THERAPEUTIC END POINTS

l Drying of respiratory secretions in organophosphate poisoning
l Note: The development of anticholinergic features indicates
excessive dosing.
ADVERSE DRUG REACTIONS AND THEIR MANAGEMENT

l Excessive atropine administration manifests with clinical features of
anticholinergic poisoning, including delirium, tachycardia, mydriasis
and urinary retention
— No further atropine should be administered while features of
anticholinergic poisoning are present
— Benzodiazepine sedation may be necessary to control delirium
and an indwelling urinary catheter should be inserted because
of the risk of retention.
Pregnancy: No restriction on use
Paediatric: Initial paediatric dose is 20 microgram/kg.
HANDY TIPS
l Very large doses of atropine may be required to treat
organophosphate poisoning—anticipate this need and procure
sufficient stocks as soon as possible.
PITFALLS
l Failureto administer sufficient doses of atropine in
organophosphate or carbamate poisoning
ANTIDOTES
l Administration of excessive atropine leading to iatrogenic
anticholinergic poisoning.
References
Bardin PG, Van Eeden SF. Organophosphate poisoning: grading the severity and
comparing treatment between atropine and glycopyrrolate. Critical Care Medicine
1990; 18(9):956–960. 373
Eddleston M, Buckley NA, Eyer P et al. Management of acute organophosphorus pesticide
poisoning. Lancet 2008; 371:597–607.
TOXICOLOGY HANDBOOK
4.2 CALCIUM
Calcium is a cation that is essential for normal organ (including muscle
and nerve tissue) and cell function.
Presentations
Calcium gluconate 1 g/10 mL vials (0.22 mmol calcium ions/mL)
Calcium gluconate 5 g/50 mL vials (0.22 mmol calcium ions/mL)
Calcium chloride 0.74 g/5 mL ampoules (1.01 mmol calcium ions/mL)
Calcium chloride 1 g/10 mL ampoules (0.68 mmol calcium ions/mL)
Calcium chloride 1 g/10 mL single-use syringe (0.68 mmol calcium ions/mL)
l Calcium channel blocker poisoning
l Hydrofluoric acid skin exposure
l Hypocalcaemia of systemic fluorosis secondary to ingestion of, or
extensive skin exposure to, hydrofluoric acid
l Hypocalcaemia secondary to ethylene glycol poisoning
l Iatrogenic hypermagnesaemia
l Hyperkalaemia.
CONTRAINDICATIONS
l Hypercalcaemia
l Digoxin toxicity.
Mechanism of action
Calcium acts as a physiological antagonist to the effects of hyperkalaemia and
hypermagnesaemia on the cardiac conducting system and skeletal muscle. Administration
of calcium in hypocalcaemic states restores or maintains ionised calcium at a
concentration sufficient to prevent cardiac dysrhythmias. In hydrofluoric acid poisoning,
calcium ions bind to fluoride ions and prevent further tissue penetration and injury.
Elevation of the ionised calcium concentration may help overcome the deleterious effects
of calcium channel blocker poisoning.
Pharmacokinetics
Ninety-nine per cent of the body’s calcium is contained within bone. Of the calcium in
plasma, about half is ionised and physiologically active while the other half is bound to
albumin. Plasma calcium concentration is maintained at close to 2.5 mmol/L by a number
of hormonal homeostatic mechanisms.
ADMINISTRATION
l Cardiac monitoring is mandatory during infusion of calcium salts
ANTIDOTES
Hypocalcaemia/hyperkalaemia/hypermagnesaemia
l Administer 0.5–1 g (5–10 mL) of calcium chloride or 1–2 g
(10–20 mL) of calcium gluconate IV over 5–10 minutes. Repeat
every 10–15 minutes as required
l Further administration of calcium salts is guided by serum calcium
concentrations, which should not exceed the normal range
374 Calcium channel blocker poisoning
l Give 2 g (20 mL) of calcium chloride IV or 6 g (60 mL) of calcium
37
gluconate IV over 5–10 minutes. This dose may be repeated every

4
20 minutes for up to three doses.

TOXICOLOGY HANDBOOK
l Commence patients who respond to calcium on a continuous

infusion of 1 g/hour of calcium chloride
l Serum calcium concentrations are monitored during an infusion.
An ionised serum calcium concentration of 2 mmol/L has been
suggested as optimal
Hydrofluoric acid skin exposure
l Topical 2.5% calcium gel
— Minor burns
— For burns to hand, put gel in glove and place hand in glove
l Local injection of calcium gluconate 1 g/10 mL
— Consider if topical application fails to stop pain
— Inject 0.5 mL/cm2 depots intradermally and subcutaneously
using a 25 G needle to achieve local tissue infiltration
— Not suitable for finger exposures
— Do not inject calcium chloride, as this can cause tissue
injury
l Bier’s block (forearm regional intravenous injection)
— Consider for large HF exposures to fingers, hand or forearm or
if gel application to these regions has failed
— Insert intravenous line proximally in affected forearm
— Dilute 1 g (10 mL) calcium gluconate in 40 mL of normal
saline
— Inject diluted calcium gluconate solution intravenously with
pneumatic tourniquet inflated (Bier’s block technique)
— Release cuff after 20 minutes
l Intraarterial infusion
— Insert arterial line into radial, brachial or femoral artery of
affected limb
— Dilute 1g (10 mL) of calcium gluconate in 40 mL of normal saline
— Infuse diluted calcium gluconate solution over 4 hours and
repeat as necessary
Hydrofluoric acid inhalation injury
l Give nebulised 2.5% calcium gluconate solution.

l Hypocalcaemia/hypermagnesaemia/hyperkalaemia: normalisation
of serum calcium
l Calcium channel blocker poisoning: haemodynamic improvement
l Hydrofluoric acid skin exposure: resolution of pain.

l Transient hypercalcaemia manifested by tetany and seizures
— Interrupt calcium salt administration and check serum calcium
concentration
ANTIDOTES
l Vasodilatation, hypotension, dysrhythmias, syncope or cardiac
arrest due to over-rapid administration
— Interrupt calcium salt administration
— Institute advanced cardiac life support as appropriate
l Local tissue damage from extravasation of calcium chloride.
SPECIFIC CONSIDERATIONS 375

Paediatric: Paediatric dose for hypocalcaemia or calcium channel
blocker poisoning is 1.0 mL/kg 10% calcium gluconate solution over
TOXICOLOGY HANDBOOK
5–10 minutes and repeated after 10–15 minutes if necessary.
HANDY TIPS
l QT duration and clinical features of hypocalcaemia may be a
more useful guide to calcium requirements than serum calcium
concentrations
l Calcium gluconate can safely be given via a peripheral line whereas
calcium chloride is best given via a central line because of the risk
of tissue damage from extravasation
l 2.5% calcium gluconate gel for treatment of skin exposure to
hydrofluoric acid can be prepared by mixing 10 mL of 10% calcium
gluconate solution with 30 mL lubricant gel (e.g. K-Y jelly) or by
mixing 3.5 g calcium gluconate powder in 150 mL of lubricant gel
l Do not use calcium salt solution to irrigate the eye after ocular
hydrofluoric acid exposure as it may cause corrosive injury
l Pain refractory to calcium administration in late-presentation
hydrofluoric acid burns may indicate established tissue damage
rather than therapeutic failure
l Very large doses of calcium chloride may be required to maintain
eucalcaemia following hydrofluoric acid ingestion.
CONTROVERSIES
l Efficacyand optimal dosing of calcium salts in calcium channel
blocker poisoning
l Most effective route of administration of calcium salts for
hydrofluoric acid skin exposures.
References
Albertson TE, Dawson AH, de Latorre F et al. TOX-ACLS: toxicologic-oriented advanced
cardiac life support. Annals of Emergency Medicine 2001; 37:S78–S90.
Graudins A, Burns MJ, Aaron CK. Regional intravenous infusion of calcium gluconate for
hydrofluoric acid burns of the upper extremity. Annals of Emergency Medicine 1997;
30:604–607.
Vance MV, Curry SC, Kunkel DB et al. Digital hydrofluoric acid burns: treatment with
intraarterial calcium infusion. Annals of Emergency Medicine 1986; 15:890–896.
4.3 CYPROHEPTADINE
Cyproheptadine is a histamine and serotonin antagonist with
anticholinergic properties. It has been advocated for control of symptoms
in mild to moderate serotonin syndrome.
Presentations
Cyproheptadine 4 mg tablets (50, 100)
ANTIDOTES
TOXICOLOGICAL INDICATION
l Mild to moderate serotonin syndrome.
CONTRAINDICATIONS
l Known hypersensitivity
376 l Acute asthma
37
l Closed angle glaucoma

6
l Bladder neck obstruction, including prostatism.

TOXICOLOGY HANDBOOK
Mechanism of action
Cyproheptadine acts as a competitive antagonist at histamine H1 and serotonin
5HT1a and 5HT2 receptors. It exerts centrally mediated hormonal effects, such as the
inhibition of adrenocorticotrophic hormone (ACTH), probably secondary to serotonin
antagonism. It also has moderate local anaesthetic action and mild peripheral
anticholinergic action.
Pharmacokinetics
Cyproheptadine is well absorbed following oral administration, with peak plasma levels
observed after 1–3 hours. Elimination is primarily by hepatic glucuronidation with urinary
excretion of metabolites.
ADMINISTRATION
l Administer an initial dose of 8 mg orally and observe for clinical
response
l If a response is observed, continue treatment with 8 mg every
8 hours for 24 hours
l Therapy should not be required beyond 24 hours, provided agents
that may precipitate serotonin syndrome are withheld
l A longer duration of therapy may be required to treat serotonin
syndrome associated with an irreversible MAO inhibitor.

l Resolution or amelioration of the clinical features associated with
serotonin syndrome within 1–2 hours of the initial dose.
l Insignificant adverse effects at therapeutic doses.
Paediatric: Paediatric dose is not well established. For 7–14-year-olds
an initial dose of 4 mg followed by 4 mg every 8 hours for 24 hours is
suggested.
HANDY TIPS
l Cyproheptadine is not a life-saving antidote. It may ameliorate the
symptoms of mild to moderate serotonin syndrome, but a good
outcome will be achieved in these cases with simple supportive
care including mild benzodiazepine sedation
l Cyproheptadine is not useful in the management of severe
serotonin syndrome. Early intubation and neuromuscular paralysis
is the key to achieving a good outcome in this circumstance.
ANTIDOTES
PITFALLS
l Failure to assess clinical response to initial dose
l Reliance on cyproheptadine to the detriment of good supportive
care in the management of serotonin syndrome.
Reference 377
Graudins A, Stearman A, Chan B. Treatment of the serotonin syndrome with
cyproheptadine. Journal of Emergency Medicine 1998; 16(4):615–619.
TOXICOLOGY HANDBOOK
4.4 DESFERRIOXAMINE
An effective iron chelator that is used to treat systemic iron toxicity or
prevent the development of systemic toxicity following acute iron overdose.
Presentations
Desferrioxamine mesylate 500 mg vials (powder for reconstitution)
Desferrioxamine mesylate 2 g vials (powder for reconstitution)
l Acute iron poisoning
— Established systemic iron toxicity with clinical features of severe
gastroenteritis, shock, metabolic acidosis and altered mental state
— Significant risk of systemic iron toxicity, as predicted by serum
iron levels >90 micromol/L or 500 microgram/dL at 4–6 hours
post ingestion
l Chronic iron overload.
CONTRAINDICATIONS
l None.
Mechanism of action
Desferrioxamine (DFO) binds avidly with free ferric ion in the plasma to form ferrioxamine.
This stable complex is highly water-soluble and is readily excreted in the urine.
DFO is able to remove iron bound to transferrin and haemosiderin, but not from outside
the intravascular compartment. 1000 mg of DFO is able to bind 85 mg of ferric iron.
Pharmacokinetics
The volume of distribution is 1 L/kg and it does not substantially enter tissue
compartments. Steady-state concentrations are achieved at 6–12 hours during
intravenous infusion. DFO undergoes hepatic metabolism, producing multiple metabolites,
one of which is responsible for the drug’s toxic effects. Some drug is excreted unchanged
in the urine. The elimination half-life is 3 hours but substantially increased in renal failure.
Ferrioxamine has a smaller volume of distribution than DFO, is not metabolised, but
excreted unchanged in the urine, and is dialysable.
ADMINISTRATION
l Cardiac monitoring is mandatory during DFO administration
l Reconstitute 500 mg of powder with 5 mL sterile water and dilute
in 100 mL normal saline or 5% dextrose
l Commence IV infusion at an initial dose of 15 mg/kg/hour
l Reduce the infusion rate if hypotension develops
l The rate may be increased in life-threatening toxicity up to
ANTIDOTES
40 mg/kg/hour, providing significant hypotension does not

supervene
l Continue the infusion until therapeutic end points have been
achieved, but avoid infusions prolonged >24 hours.

378 l Patient clinically stable
l Serum iron <60 micromol/L (350 microgram/dL).
37
8

TOXICOLOGY HANDBOOK
l Hypersensitivity reactions
l Hypotension, especially withrapid or high-dose IV infusion
— Reduce infusion rate if hypotension occurs
l ARDS may develop with prolonged infusions (>24 hours)
l Toxic retinopathy
l Secondary infections including Yersinia sepsis and mucormycosis:
ferrioxamine complex acts as a siderophore promoting growth of
these organisms.
Pregnancy: There is no evidence of human teratogenicity with DFO,
and although it is not known if DFO crosses the placenta, it should
never be withheld in the treatment of pregnant patients with severe iron
poisoning
Paediatric: Administration and dose as for adults.
HANDY TIPS
l DFO is ideally administered before iron moves intracellularly and
systemic toxicity develops
l Intramuscular DFO administration is not indicated in acute iron
poisoning
l Although urine may change to the classical vin rosé colour
during DFO administration, this is an unreliable sign of effective
chelation
l Six hours of DFO chelation is usually sufficient and it is extremely
rare to require therapy beyond 24 hours.
PITFALLS
l Administration of DFO when not clinically indicated
l Excessive duration of DFO administration.
CONTROVERSIES
l There are no controlled trials or dose–response studies
to support the efficacy of DFO chelation for human iron
poisoning
l The optimal indications, dose, route of administration and end
points for therapy are not well defined.
References
Howland MA. Risks of parenteral deferoxamine for acute iron poisoning. Journal of
ANTIDOTES
Tenenbein M. Benefits of parenteral deferoxamine for acute iron poisoning. Journal of
4.5 DICOBALT EDETATE

379
Cobalt edetate, Cobalt EDTA, Cobalt tetracemate
This agent was developed as a cyanide antidote based on the known
ability of cobalt to form stable complexes with cyanide. The severe direct
TOXICOLOGY HANDBOOK
toxic effects that occur when it is administered to a patient without
cyanide poisoning limit the use of this agent.
Presentations
Dicobalt edetate 300 mg/20 mL ampoules
l Unequivocal acute cyanide poisoning.
CONTRAINDICATIONS
l Suspected cyanide poisoning without definite signs of poisoning,
such as impairment or loss of consciousness.
Pharmacodynamics
Dicobalt edetate is an inorganic cobalt salt. At least one of the cobalt atoms is available
to bind cyanide. One mole of cobalt binds six moles of cyanide to form stable complexes.
Cobalt cyanides are much less toxic than free cyanide.
Pharmacokinetics
Dicobalt edetate is able to cross the blood–brain barrier. The cyanide–cobalt complex is
excreted in the urine.
ADMINISTRATION
l This antidote is only administered to critically ill patients in a
monitored area where equipment, drugs and personnel are
available to provide full resuscitative care. Cardiac monitoring is
mandatory
l Administer 300 mg (1 ampoule) IV over 1 minute, followed
immediately with 50 mL of 50% dextrose IV to protect against
toxicity
l A repeat second or third dose of 1 ampoule is given if an
immediate clinical response is not observed.

l Improvement in conscious state
l Haemodynamic stability
l Improvement in metabolic acidosis.
ADVERSE DRUG REACTIONS

l Significant adverse reactions have been reported, usually when
it is inappropriately administered in the absence of cyanide
poisoning
l These reactions are due to direct toxicity of the cobalt salt
ANTIDOTES

and include convulsions, oedema of the face, larynx and
neck, chest pain, dyspnoea, hypotension, vomiting and urticarial
rashes.
Pregnancy: Safety in pregnancy is not confirmed. Administration
380 should not be withheld if indicated
38
Paediatric: Paediatric dose is 7.5 mg/kg IV (maximum dose 300 mg).

0
TOXICOLOGY HANDBOOK
HANDY TIPS
l Never give dicobalt edetate to a patient without clinical features
of definite severe cyanide poisoning including impaired level of
consciousness
l The occurrence of adverse outcomes is minimised by adhering to
strict clinical criteria for giving the antidote.
PITFALLS
l Administration of dicobalt edetate to a patient without cyanide
poisoning or one displaying only minor clinical manifestations of
cyanide poisoning
l Inadvertent or mistaken administration of sodium calcium edetate
(EDTA), an antidote used in the treatment of lead poisoning.
CONTROVERSIES
l The relative efficacy of dicobalt edetate as an antidote for cyanide
poisoning in humans has not been established.
References
Hall A, Saiers J, Baud F. Which cyanide antidote? Critical Reviews in Toxicology 2009;
39(7):541–552.
Meredith TJ, Jacobsen D, Haines JA, Berger J-C. IPCS/CEC evaluation of antidotes series.
available at http://www.inchem.org/documents/antidote/ant02.htm#
SubSectionNumber:5.12.2, accessed13 April 2010.
4.6 DIGOXIN IMMUNE FAB
These antibody fragments promptly and safely reverse the toxicity of
digoxin and other cardiac glycosides.
Presentations
Digoxin-specific immune antigen binding fragments as lyophilised powder 38 mg ampoules
Cardiac glycoside poisoning where there is an imminent threat to life
or where the risk assessment suggests such a threat is an absolute
indication for immediate administration of digoxin immune Fab.
Administration is also indicated in any patient whose manifestations of
digoxin toxicity are sufficient to warrant inpatient care. More specifically:
l Acute digoxin overdose
— Cardiac arrest
ANTIDOTES
— Ingested dose >10 mg (adult) or >4 mg (child)
— Serum digoxin level >15 nmol/L (12 ng/mL)
— Serum potassium >5 mmol/L
l Chronic digoxin poisoning
— Cardiac arrest
— Cardiac dysrhythmia or increased automaticity not likely to be
tolerated for a prolonged period 381
— Moderate–severe gastrointestinal symptoms
— Any symptoms in presence of impaired renal function
l Other cardiac glycoside poisoning
TOXICOLOGY HANDBOOK

— Oleander
— Bufotoxin (cane toad).
CONTRAINDICATIONS
l None.
Mechanism of action
Digoxin immune Fab is created by papain cleaving of IgG molecules raised in sheep against
digoxin bound to albumin. 40 mg (one ampoule) of Fab binds 0.5 mg of digoxin. Digoxin
immune Fab binds directly to the free intravascular and interstitial digoxin with much greater
affinity than the Na/K ATPase receptor. A concentration gradient is created and intracellular
digoxin dissociates from tissues and moves to the intravascular space where binding to
immune Fab continues.
Pharmacokinetics
The elimination half-life of Fab fragments is about 12 hours and predominantly non-renal.
Digoxin bound to Fab fragments is excreted in the urine, with an elimination half-life of
16–30 hours.
ADMINISTRATION
personnel are available to provide full resuscitative care. Cardiac
monitoring is mandatory during antidote administration and until
toxicity is reversed
l Calculate the dose required (see below), dilute in 100 mL normal
saline and administer over 30 minutes
l Dose is calculated on the presumption that one ampoule of Fab
binds 0.5 mg of digoxin.
CALCULATION OF DOSE
l Acute digoxin overdose
— Known digoxin dose
– Number of ampoules = Ingested dose (mg) x 0.8
(bioavailability) x 2
— Unknown digoxin dose
– Commence empiric dosing with 5 ampoules if the patient is
haemodynamically stable or 10 ampoules if unstable
– Give repeat doses of 5 ampoules every 30 minutes until
reversal of digoxin toxicity is achieved
l Chronic digoxin poisoning
— Number of ampoules
serum digoxin (ng/ml) ´ body weight (kg)
=
100
ANTIDOTES
— Alternatively, commence empiric dosing with 2 ampoules and

observe for clinical response. If there is no reversal of digoxin
toxicity after 30 minutes, give a further 2 ampoules
l Other cardiac glycoside poisoning
— If the patient is stable, commence with an empiric dose of
5 ampoules and repeat every 30 minutes until reversal of
382 toxicity is observed
38
— Large doses may be required before a clinical response is

2
achieved. Up to 30 ampoules have been used to successfully

reverse severe yellow oleander poisoning.
TOXICOLOGY HANDBOOK
DURATION OF TREATMENT
l A single dose given over 30 minutes is usually sufficient
l Following an adequate dose, a response is normally apparent by
20 minutes and maximal by 4 hours.

l Restoration of normal cardiac rhythm and conduction
l Resolution of gastrointestinal symptoms.

This is an extremely safe antidote—adverse effects of any kind occur in less
than 5% of cases. Adverse effects include:
l Hypokalaemia
l Allergy (extremely rare)
l Exacerbation of underlying cardiac failure
l Loss of rate control of preexisting atrial fibrillation.
Paediatric: No restriction on use.
HANDY TIPS
l In cardiac arrest thought to be due to digoxin poisoning, give
high-dose digoxin immune Fab (20 ampoules if available) by
rapid intravenous injection, while continuing cardiopulmonary
resuscitation
l Digoxin levels following treatment may appear very high. This is
because most serum digoxin assays measure both free and Fab-
bound digoxin. Some laboratories are able to assay free digoxin
l Hyperkalaemia due to acute digoxin poisoning is treated with Fab,
not intravenous calcium, as digoxin causes elevation in intracellular
myocardial calcium levels
l It is not necessary to bind the total body digoxin load to control
toxicity. The administration of less than the calculated dose of
digoxin immune Fab may still be sufficient
l Administration of digoxin immune Fab to patients with non-life
threatening chronic digoxin toxicity is shown to significantly reduce
length-of-stay in hospital.
PITFALLS
l Unavailabilityof sufficient digoxin immune Fab to treat life-
threatening poisoning
ANTIDOTES
l Withholding digoxin immune Fab from patients with chronic digoxin
poisoning because of concerns about expense of the antidote. The risk
of death and cost of prolonged unnecessary admission to a monitored
bed greatly exceed the cost of 2 ampoules of digoxin immune Fab.
CONTROVERSIES
l Itmay be pharmacokinetically more appropriate to give smaller
initial doses of digoxin immune Fab and follow up with repeat 383
doses or an infusion
l The dose of digoxin immune Fab is not well defined in poisoning by
other cardiac glycosides, such as those contained in oleander.
TOXICOLOGY HANDBOOK
References
Bateman DN. Digoxin-specific antibody fragments: how much and when? Toxicological
Reviews 2004; 23(3):135–143.
Di Domenico R, Walton S, Sanoski CA et al. Analysis of the use of digoxin Fab for
the treatment of non life threatening digoxin toxicity. Journal of Cardiovascular
Pharmacology and Therapeutics 2000; 5(2):77–85.
Eddleston M, Rajapakse S, Rajakanthan et al. Anti-digoxin Fab fragments in cardiotoxicity
induced by ingestion of yellow oleander: a randomised controlled trial. Lancet 2000;
355(9208):967–972.
Lapostolle F, Borron SW, Verdier C et al. Digoxin-specific Fab fragments as single first-line
therapy in digitalis poisoning. Critical Care Medicine 2008; 36:3014–3018.
Woolf AD, Wenger T, Smith TW et al. The use of digoxin-specific Fab fragments for
severe digitalis intoxication in children. New England Journal of Medicine 1992;
326:1739–1744.
4.7 DIMERCAPROL
British antilewisite, 2,3-dimercaptopropanol
This rarely used intramuscular chelator is the most toxic of all chelating
agents and is reserved for the treatment of severe poisoning from lead,
inorganic arsenic and mercury.
Presentations
Dimercaprol 300 mg, benzyl benzoate 600 mg, peanut oil 2100 mg/3 mL ampoules
l Arsenic poisoning
l Inorganic mercury poisoning
l Gold intoxication
l Severe lead poisoning or lead encephalopathy (adjunct to EDTA)
l Other heavy metal poisoning
— Dimercaprol has been used to chelate bismuth, antimony,
chromium, nickel, tungsten and zinc, but clinical experience is
limited.
CONTRAINDICATIONS
l Peanut allergy
l G6PD deficiency.
Pharmacodynamics
ANTIDOTES
Dimercaprol binds metal ions to form stable dimercaptides, which can then be excreted in
the urine.
Pharmacokinetics
Dimercaprol is not absorbed orally. In fact, because it is formulated in peanut oil, it is
only suitable for IM administration. Blood concentrations peak about 30 minutes after
IM administration and distribution occurs rapidly. It is metabolised predominantly by
384 glucuronic conjugation and the metabolites are excreted in the urine. Dimercaprol–metal
conjugates are removed by dialysis.
38
4
ADMINISTRATION
TOXICOLOGY HANDBOOK
l Therapy is always commenced in an intensive care setting due to

severity of underlying condition and adverse effects
l Alkalinise the urine prior to commencing therapy in order to reduce
risk of nephrotoxicity (prevents dissociation of dimercaprol–metal
conjugates in the urine)
Severe inorganic arsenic or mercury poisoning
l Give 3 mg/kg IM every 4 hours for 48 hours
then
l Give 3 mg/kg IM every 12 hours for 7–10 days depending on
clinical response
Lead encephalopathy
l Commence dimercaprol 4 hours before commencing EDTA
l Give 4 mg/kg every 4 hours for 5 days
l See Chapter 4.26: Sodium calcium edetate for further
information.

Dimercaprol is associated with an extremely high incidence (about
50%) of adverse effects at therapeutic dose. These include:
l Pain and sterile abscess formation at injection sites
l Fever (especially children) and myalgia
l Chest pain, hypertension and tachycardia
l Headache, nausea and vomiting
l Peripheral paraesthesias; burning sensation of lips, mouth, throat
and eyes
l Lacrimation, rhinorrhoea and excessive salivation
l Risk of intravascular haemolysis in patients with G6PD
deficiency
l Nephrotoxicity secondary to the dissociation of dimercaprol–metal
complexes in acid urine
l Hypertensive encephalopathy at supratherapeutic doses
Unfortunately, many of these adverse effects may need to be tolerated
in view of the severity of the underlying intoxication and lack of
alternative viable chelating agents.
For life-threatening adverse effects, subsequent doses should be
reduced.
Pregnancy: Safety not established. Administration should not be
withheld if clinically indicated
Lactation: Safety not established
Paediatric: Dose and administration as for adults.
ANTIDOTES
HANDY TIPS
l Never give intravenously
l Dimercaprol is most effective when administered shortly after the
exposure
l Never give more than 4 mg/kg as a single dose due to high
incidence of adverse effects
l If the patient is well enough, chelation with the orally-active
385
analogue of dimercaprol (succimer) is always preferable.
PITFALLS
TOXICOLOGY HANDBOOK
l Failure to access supplies promptly—dimercaprol is difficult to
obtain and stocked by relatively few hospitals.
CONTROVERSIES
l Dosing regimens are usually historical and clinical efficacy is poorly
established.
References
Gold H. BAL (British anti-lewisite). American Journal of Medicine 1948; 4:1.
Vilensky JA, Redman K. British anti-lewisite (dimercaprol): An amazing history. Annals of
Emergency Medicine 2003; 41:378–383.
4.8 ETHANOL
Competitively blocks the formation of toxic metabolites in toxic
alcohol ingestions by having a higher affinity for the enzyme alcohol
dehydrogenase (ADH). Its chief application is in methanol and ethylene
glycol ingestions, although it has been used with other toxic alcohols.
Ethanol is now regarded as the second choice antidote in those countries
with access to the specific ADH blocker, fomepizole.
Presentations
Pure ethanol 20 mL ampoule (pharmaceutical grade)
Commercial alcoholic beverages with alcohol content from 5% to 70%
l Methanol poisoning (confirmed or suspected)
l Ethylene glycol poisoning (confirmed or suspected).
CONTRAINDICATIONS
l Recent ingestion of disulfiram (or drugs that may cause a
disulfiram-like reaction).
Mechanism of action
Alcohol dehydrogenase has a much higher affinity (up to 20x) for ethanol than for ethylene
glycol or methanol. Alcohol competitively inhibits the conversion of these other alcohols
to their toxic metabolites by blocking the receptor sites of ADH. Inhibition is virtually
complete at ethanol concentrations greater than 100 mg/dL (22 mmol/L).
Pharmacokinetics
Ethanol is rapidly absorbed after oral administration and distributed throughout the
total body water. It rapidly crosses both the placenta and the blood–brain barrier.
Elimination is principally by enzymatic oxidation in the liver in a two-step process
involving alcohol dehydrogenase and aldehyde dehydrogenase. Metabolic capacity is
ANTIDOTES
saturated at relatively low concentrations. The rate of metabolism is extremely variable

between individuals.
ADMINISTRATION
l Therapy should be commenced in a monitored area with personnel
and equipment available to monitor mental status and blood or
386 breath alcohol levels every 2 hours
38
l Ethanol may be administered by the oral, nasogastric or

6
intravenous route to maintain a blood ethanol concentration of

100–150 mg/dL (22–44 mmol/L)
TOXICOLOGY HANDBOOK
Oral or nasogastric administration

l Loading dose: 1.8 mL/kg of 43% ethanol, or 3 x 40 mL shots of
vodka in a 70-kg adult
l Note: Omit the loading dose of ethanol in the already ethanol-
intoxicated patient
l Maintenance: 0.2–0.4 mL/kg/hour of 43% ethanol, or 40-mL shot
each hour
Intravenous administration
l Loading dose: 8 mL/kg of 10% ethanol
l Maintenance infusion rate: 1–2 mL/kg/hour of 10% ethanol
l Note: A 10% ethanol solution is prepared by adding 100 mL of
100% ethanol to 900 mL of 5% dextrose in water
l Remember: The required maintenance dose is extremely
variable. The doses outlined above are a guide only and must be
adjusted to maintain blood alcohol concentrations in the desired
range
l Continue maintenance ethanol therapy until the toxic alcohol
poisoning has been definitively treated with haemodialysis.

l Local phlebitis from intravenous solutions
l Ethanol intoxication
l Reduce rate of ethanol administration if blood
ethanol
concentration exceeds 150 mg/dL (44 mmol/L)
l Hypoglycaemia in children.
Pregnancy: Ethanol and the toxic alcohols readily cross the placenta.
There is no contraindication to ethanol administration in the pregnant
woman with toxic alcohol poisoning
Paediatric: There is no contraindication to ethanol administration in
the child with toxic alcohol poisoning, but the child should be carefully
monitored for hypoglycaemia.
HANDY TIPS
l Ethanol for intravenous therapy is difficult to procure—alcoholic
spirits suitable for oral administration are ubiquitous
l Administration of ethanol may be delayed in the patient who
already has a high ethanol level
l Breath ethanol estimations may be substituted for repeated blood
ethanol levels during maintenance therapy.
PITFALLS
l Delay in starting therapy
ANTIDOTES

l Failure to monitor blood ethanol levels closely resulting in sub- or
supratherapeutic concentrations.
CONTROVERSIES
l Relative merits of fomepizole over ethanol in the management of
toxic alcohol poisoning
l Clinical efficacy of ethanol in the treatment of poisoning with other 387
toxic alcohols, including glycol ethers, diethylene glycol, triethylene
glycol, propylene glycol and butanediol
l Necessity to continue to maintain ethanol levels after
TOXICOLOGY HANDBOOK

commencement of haemodialysis.
References
Barceloux DG, Krenzelok EK, Olson K et al. American Academy of Clinical Toxicology
Practice Guidelines on the Treatment of Ethylene Glycol Poisoning. Journal of
Lepik KJ, Levy AR, Sobolev BG et al. Adverse drug events associated with the antidotes
for methanol and ethylene glycol poisoning: a comparison of ethanol and fomepizole.
4.9 FLUMAZENIL
Competitive benzodiazepine antagonist with a limited role in the
management of benzodiazepine poisoning.
Presentations
Flumazenil 0.5 mg/5 mL ampoules
l Benzodiazepine overdose
— Accidental paediatric ingestion with compromised airway and
breathing
— Deliberate self-poisoning with compromised airway and
breathing, and equipment and skills to intubate and ventilate
not readily available (rare)
— Note: Isolated benzodiazepine overdose rarely causes CNS
depression sufficient to warrant intervention
l To confirm diagnosis of benzodiazepine intoxication
— Useful if it avoids invasive or expensive further investigation to
exclude alternative diagnoses
l Reversal of benzodiazepine conscious sedation.
CONTRAINDICATIONS
l Known seizure disorder
l Known or suspected co-ingestion of pro-convulsant drugs
l Known benzodiazepine dependence
l QRS prolongation on ECG (suggests co-ingestion of tricyclic
antidepressant).
Mechanism of action
Flumazenil is a 1,4-imidazobenzodiazepine structurally similar to midazolam. It acts as a
competitive antagonist at the benzodiazepine receptor sites in the CNS. Binding inhibits
benzodiazepine activity at the GABA-benzodiazepine complex and reverses the CNS
ANTIDOTES
effects of benzodiazepines.
Pharmacokinetics
Flumazenil has a volume of distribution of 1 L/kg at steady state. It undergoes rapid
and extensive hepatic metabolism to inactive metabolites. Elimination half-life is 40–80
minutes. These pharmacokinetic properties are unaltered following benzodiazepine
overdose.
388
ADMINISTRATION
38
8
l Flumazenil should only be administered in an environment

where equipment and personnel are available to manage a
TOXICOLOGY HANDBOOK
seizure
l Give an initial dose of 0.1–0.2 mg IV and repeat every minute until
reversal of sedation is achieved
l Maximal response should be observed with a dose not exceeding
2 mg
l Re-sedation is expected and normally occurs at around
90 minutes. If necessary, repeated doses may be given to maintain
adequate reversal of benzodiazepine sedation. Occasionally a
flumazenil infusion may be of value
l Note: Patients must be observed for re-sedation for several hours
following the last dose of flumazenil.

Benzodiazepine withdrawal syndrome
l Manifests as agitation, tachycardia and seizures
l Mild benzodiazepine withdrawal will be short-lived
and does not
require specific management
l Severe withdrawal syndrome requires administration of
benzodiazepines in titrated doses
Seizures
l Most commonly occur in patients with benzodiazepine
dependence, co-ingestion of pro-convulsant drugs or an
underlying seizure disorder
l Withhold further flumazenil
l Repeated or prolonged seizures require administration of
benzodiazepines in titrated doses.
Paediatric: Give 0.01–0.02 mg/kg repeated every minute as necessary.
Flumazenil administration is extremely safe in children who have ingested
benzodiazepines, as they unlikely to be benzodiazepine-dependent.
HANDY TIPS
l Flumazenil may be life-saving if personnel and equipment for
definitive airway control are not available.
PITFALLS
l Unnecessary administration to patients with mild benzodiazepine
poisoning
l Administration when contraindicated due to risk of seizures
l Failure to observe for re-sedation.
ANTIDOTES
References
Ngo AS, Anthony CR, Samuel M et al. Should a benzodiazepine antagonist be used in
unconscious patients presenting to the emergency department? Resuscitation 2007;
74(1):27–37.
Seger D. Flumazenil: treatment or toxin. Journal of Toxicology-Clinical Toxicology 2004;
42(2):209–216.
The Flumazenil in Benzodiazepine Intoxication Multicenter Study Group. Treatment of
benzodiazepine overdose with flumazenil. Clinical Therapeutics 1992; 14:978–995. 389
4.10 FOLINIC ACID
TOXICOLOGY HANDBOOK
Leucovorin, 5-formyltetrahydrofolic acid
This agent is the active form of folic acid. It is routinely used for ‘folinic
acid rescue therapy’ following administration of high-doses of parenteral
methotrexate in oncologic practice. Its applications in clinical toxicology
are rather more limited.
Presentations
Calcium folinate 15 mg tablets (10)
Calcium folinate 15 mg/2 mL ampoules
Calcium folinate 50 mg/5 mL plastic vials
Calcium folinate 100 mg/10 mL plastic vials
l Supratherapeutic methotrexate ingestion
— This usually occurs in the context of accidental daily dosing of
methotrexate rather than the usual weekly dosing
— Folinic acid therapy is indicated if:
– Clinical features of methotrexate toxicity are evident
or
– The weekly dose has been administered daily for more than
3 consecutive days
l Single acute oral methotrexate overdose
— Methotrexate toxicity has never been reported in this scenario
— Folinic acid should be given empirically, if more than 500 mg
(5 mg/kg in children) is ingested, until methotrexate levels are
available to more fully assess risk of toxicity
— If less than 500 mg of methotrexate is ingested, consider
folinic acid when methotrexate levels are not available within
24 hours
l Adjunct treatment for methanol poisoning
l Massive pyrimethamine and trimethoprim poisoning.
CONTRAINDICATIONS
l Known hypersensitivity.
Mechanism of action
Folinic acid is the reduced biologically active form of folic acid and is essential for DNA/
RNA synthesis. Methotrexate acts as an antimetabolite, preventing the reduction of folic
acid to folinic acid, by inhibiting dihydrofolate reductase. Administration of exogenous
folinic acid bypasses this inhibition and restores DNA/RNA synthesis. Folates also
enhance the elimination of formate in methanol poisoning.
ANTIDOTES
Pharmacokinetics
Oral bioavailability of folinic acid is almost 100% after a 15-mg dose, but falls with higher
doses. The active isomer has a volume of distribution of 13.6 L and an elimination half-
life of 35 minutes. Elimination is predominantly by metabolism to an active metabolite,
5-methyl tetrahydrofolate, which has a volume of distribution of 40 L and an elimination
half-life of over 400 minutes.
390 ADMINISTRATION
Methotrexate overdose
39
0
l Give 15 mg PO, IM or IV every 6 hours

l For single acute methotrexate overdose, therapy may be ceased
TOXICOLOGY HANDBOOK
when methotrexate level is confirmed to be below the threshold for

toxicity (see Table 3.51.2) for an acute single overdose.
It is otherwise continued for at least 3 days or until the serum
methotrexate is <0.05 micromol/L
l With chronic toxicity, therapy should be continued for at least
3 days and until the serum methotrexate is <0.05 micromol/L
Methanol poisoning
l Give 2 mg/kg IV every 6 hours
l Continue until poisoning definitively treated.

l Anaphylaxis (rare)
l Seizures (rare)
l Hypercalcaemia with rapid IV administration
(>160 mg/minute).
Paediatric: Dosing for oral methotrexate overdose is not determined
for children.
HANDY TIPS
l Folinic acid administration can usually be avoided following acute
single methotrexate overdose, provided a methotrexate level can
be obtained within 24 hours.
PITFALLS
l Administration of folic acid instead of folinic acid (folic acid is not
an effective antidote for methotrexate toxicity).
CONTROVERSIES
l The indications (if any) for folinic acid administration following
single acute overdose of methotrexate
l The value of adjunctive treatment with folinic acid in methanol
poisoning.
4.11 FOMEPIZOLE
Alcohol dehydrogenase inhibitor used in management of methanol and
ethylene glycol poisoning. It is not currently available in either Australia
or New Zealand.
ANTIDOTES
Presentations
Fomepizole 1.5 g/1.5 mL ampoules
Fomepizole sulfate 160 mg/20 mL ampoules (equivalent to 100 mg of fomepizole per
20 mL ampoule)
l Methanol poisoning (confirmed or suspected)
l Ethylene glycol poisoning (confirmed or suspected) 391
l Note: May be used alone or in combination with haemodialysis.
TOXICOLOGY HANDBOOK
CONTRAINDICATIONS
l Known hypersensitivity (not yet reported)
Mechanism of action
Fomepizole is a potent competitive inhibitor of alcohol dehydrogenase. It blocks the first stage
in the metabolism of methanol and ethylene glycol to their respective toxic metabolites. The
toxic alcohols are then excreted unchanged in the urine.
Pharmacokinetics
Fomepizole has a small volume of distribution (0.7 L/kg). It undergoes hepatic metabolism
to form an inactive metabolite, 4-carboxypyrazole. Metabolism is saturable at therapeutic
doses. Fomepizole induces its own metabolism when administered for more than
48 hours, and is dialysable.
ADMINISTRATION
l Loading dose: 15 mg/kg in 100 mL of normal saline or 5% dextrose
IV over 30 minutes
l Maintenance dose: 10 mg/kg in 100 mL of normal saline or 5%
dextrose IV over 30 minutes every 12 hours for 48 hours
l Note: If administration for more than 48 hours is required, increase
to 15 mg/kg every 12 hours to compensate for induction of
metabolism
l Monitoring of fomepizole concentrations is not necessary
l If haemodialysis is undertaken, fomepizole should be given every
4 hours rather than every 12 hours or, alternatively, as a
continuous infusion at 1 mg/kg/hour for the entire duration of
haemodialysis.
l Treatment continues until ethylene glycol or methanol levels are
<30 mg/dL.

l The adverse effect profile is benign. The most common adverse
effect is burning at the infusion site. Minor symptoms such as
headache, nausea or dizziness may occur.
Pregnancy: Safety not established. Ethanol should be considered as
an alternative
CONTROVERSIES
l The appropriate threshold concentration of ethylene glycol or
methanol at which an alcohol dehydrogenase inhibitor should
ANTIDOTES
be started is not established. The currently recommended

concentration of 20 mg/dL is undoubtedly conservative
l The superiority of fomepizole over ethanol as an alcohol
dehydrogenase inhibitor. Potential advantages of fomepizole
include ease of administration, more predictable pharmacokinetics,
improved adverse effect profile, easier monitoring of therapy
392 and potentially reduced need for haemodialysis. The principal
disadvantages are availability and higher cost
39
2
l It remains unclear as to when use of fomepizole might obviate the

need for haemodialysis in methanol poisoning.
TOXICOLOGY HANDBOOK
References
Barceloux DG, Krenzelok EK, Olson K et al. American Academy of Clinical Toxicology
Practice Guidelines on the Treatment of Ethylene Glycol Poisoning. Journal of
Toxicology-Clinical Toxicology 1999; 37:537–560.
Brent J. Fomepizole for ethylene glycol and methanol poisoning. New England Journal of
Medicine 2009; 360:2216–2223.
Brent J, McMartin K, Phillips SP et al. Fomepizole for the treatment of ethylene glycol
poisoning. New England Journal of Medicine 1999; 340:832–838.
Brent J, McMartin K, Phillips SP et al. Fomepizole for the treatment of methanol poisoning.
New England Journal of Medicine 2001; 344:424–429.
Lepik KJ, Levy AR, Sobolev BG et al. Adverse drug events associated with the antidotes
for methanol and ethylene glycol poisoning: a comparison of ethanol and fomepizole.
4.12 GLUCAGON
Polypeptide hormone secreted by the alpha-cells of the pancreas.
Supra-physiological doses have previously been advocated in the
management of beta-blocker and calcium channel blocker poisoning, but
this practice is now largely abandoned.
Presentations
Glucagon hydrochloride 1 mg lyophilised powder/1 mL solvent in pre-filled syringes
Glucagon hydrochloride 1 mg lyophilised powder/1 mL solvent vials
l There are no clear indications for the use of glucagon in the
management of beta-blocker or calcium channel blocker poisoning.
Mechanism of action
Glucagon has positive inotropic and chronotropic effects similar to those of
β-adrenergic agonists. These are at least in part due to binding to specific
intracellular glucagon receptors that leads to activation of cardiac adenylate
cyclase and increased cAMP concentrations.
Pharmacokinetics
Glucagon has a volume of distribution of only 0.25 L/kg. It is rapidly metabolised
in the plasma, liver and kidney, with an elimination half-life of 8–18 minutes.
ADMINISTRATION
l Place the patient in a monitored area where equipment and
personnel are available to closely monitor haemodynamic
parameters and gauge clinical response
ANTIDOTES
l Give an initial bolus dose of 5 mg IV. If no response, repeat after
5 minutes
l If a clinical response is observed after the initial bolus dosing,
commence an IV infusion of 2–5 mg/hour in 5% dextrose
l Note: When preparing an infusion, reconstitute the glucagon with
sterile water for injection rather than the phenol-containing diluent
l Continue the infusion until it can be safely withdrawn without
haemodynamic deterioration. 393
TOXICOLOGY HANDBOOK
l Haemodynamic improvement.

l Dose-dependent nausea and vomiting
l Hyperglycaemia
l Hypokalaemia.
HANDY TIPS
l If there is no clinical response to an initial dose of 10 mg of
glucagon, further administration of this drug is futile and should be
abandoned.
PITFALLS
l Administration of glucagon to patients who are asymptomatic
following beta-blocker overdose
l Administration of glucagon as first-line treatment for beta-blocker
or calcium channel blocker poisoning
l Inadequate stocks of glucagon within the treating hospital to allow
administration of recommended doses
l Failure to administer adequate doses.
CONTROVERSIES
l The role of glucagon as an antidote for beta-blocker and calcium
channel blocker poisoning is not established. Its use is currently
unsupported by any clinical trials in humans.
Reference
Bailey B. Glucagon in beta-blocker and calcium channel blocker overdoses:
a systematic review. Journal of Toxicology-Clinical Toxicology 2003; 41(5):
595–602.
4.13 GLUCOSE
Symptomatic hypoglycaemia resulting from toxic exposures must be
immediately corrected by administration of glucose. In all but the mildest
of cases this is achieved with an intravenous bolus of hypertonic glucose
solution.
ANTIDOTES
Presentations
Glucose 50 g/1000 mL (5% solution) IV infusion packs
Glucose 12.5 g/50 mL (25% solution) IV infusion packs
394 Glucose 250 g/500 mL (50% solution) IV infusion packs
39

4
Glucose 25 g/50 mL (50% solution) single-use syringes

Glucose 100 mg/10 mL (10% solution) ampoules
TOXICOLOGY HANDBOOK
Glucose 5 g/100 mL (5% solution) vials

Glucose 5 g/10 mL (50% solution) ampoules
Glucose 25 g/50 mL (50% solution) vials
Glucose 12.5 g/200 mL (5% solution) IV infusion packs
l Correction of hypoglycaemia
— Ethanol ingestion in children
— Insulin overdose
— Propranolol overdose
— Quinine overdose
— Salicylate poisoning
— Sulfonylurea poisoning
— Valproate overdose
l Combined with high-dose insulin to maintain euglycaemia (see
Chapter 4.15: Insulin (high-dose))
— Beta-blocker poisoning
— Calcium channel poisoning
— Hyperkalaemia
— Local anaesthetic poisoning.
CONTRAINDICATIONS
l No absolute contraindications.
Mechanism of action
Parenteral administration of glucose solutions rapidly corrects hypoglycaemia. However,
the effect will be of relatively short duration in hyperinsulinaemic states. When insulin
therapy is used therapeutically to control hyperkalaemia or in the management of calcium
channel and beta-blocker toxicity, concomitant administration of dextrose is required to
maintain euglycaemia.
Pharmacokinetics
Under normal conditions, blood glucose concentration is maintained within a relatively
narrow range by a variety of homeostatic mechanisms. Toxic hypoglycaemia is usually a
result of a hyperinsulinaemic state.
ADMINISTRATION
personnel are available to frequently monitor blood sugar levels
and observe for clinical features of hypoglycaemia
l Initial correction of symptomatic hypoglycaemia
— Adult: Initial bolus of 50 mL of 50% glucose IV. Repeat if no
ANTIDOTES
immediate clinical improvement
— Child: 5 mL/kg bolus of 10% glucose IV. Repeat if no
immediate clinical improvement
l Deliberate self-poisoning with insulin
— Ongoing glucose infusion will be necessary, as the glucose
requirement may be massive. The infusion rate is titrated to
maintain euglycaemia or mild hyperglycaemia
— Infusion of concentrated solutions (20% or 50%) via a central 395
line is usually necessary to avoid excessive fluid administration
and severe phlebitis
l Deliberate self-poisoning with sulfonylureas
TOXICOLOGY HANDBOOK

— Patients require infusion of large volumes of concentrated
glucose solution, until such time as the hyperinsulinaemic state
is controlled by administration of octreotide (see Chapter 4.20:
Octreotide)
l Hypoglycaemia from other causes
— Usually have a much lower ongoing glucose requirement e.g.
chronic sulfonylurea poisoning
— Oral supplementation may suffice, but admission to
hospital for careful monitoring of glucose requirement is
essential.

l Euglycaemia or mild hyperglycaemia.

l Hyperglycaemia
l Hyperosmolality
l Hypokalaemia with large doses in hyperinsulinaemic state
l Local thrombophlebitis from extravasation
l Rebound hypoglycaemia due to further stimulation of insulin
secretion (especially in sulfonylurea overdose)
— Rebound hypoglycaemia mandates further boluses of
concentrated glucose solution IV.
HANDY TIPS
l Anticipate the need for large ongoing dextrose requirement
following deliberate self-poisoning with insulin and insert a central
line to commence 50% glucose solution
l Start octreotide after initial correction of hypoglycaemia in a patient
with sulfonylurea overdose
l Serum potassium replacement is necessary with glucose
infusions.
PITFALLS
l Failure to anticipate ongoing glucose requirement in patient with
deliberate self-poisoning with insulin
l Failure to start octreotide after initial treatment with
ANTIDOTES
glucose in the patient with deliberate self-poisoning with a

sulfonylurea.
4.14 HYDROXOCOBALAMIN
396 Vitamin B12a
39
Hydroxocobalamin is a vitamin B12 (cyanocobalamin) precursor. In high

6
doses, it is an effective chelator of cyanide.

TOXICOLOGY HANDBOOK
Presentations
Kits containing 2 vials of hydroxocobalamin 2.5 g as lyophilised powder and 2 vials of 100
mL normal saline for reconstitution (Cyanokit®)
Hydroxocobalamin chloride 1 mg/mL ampoules
l Known cyanide poisoning with serious clinical effects (altered
mental status, seizures, hypotension, significant lactic acidosis in
context of relatively normal oxygen saturation)
l Suspected cyanide poisoning with serious clinical effects
— It is the preferred cyanide antidote in this situation because of
its relatively benign adverse effects even if administered to a
patient without cyanide poisoning.
CONTRAINDICATIONS
Mechanism of action
Hydroxocobalamin has a complex molecular structure with a cobalt ion bound to a
hydroxyl group at its centre. Like other cobalt-containing compounds, it has a high affinity
for cyanide. Cyanide binds to the central cobalt ion and displaces the hydroxyl group,
forming cyanocobalamin, which is relatively non-toxic even in high concentrations and
is excreted in the urine. Hydroxocobalamin prevents circulating cyanide from entering
tissues and binding to cytochrome oxidase and also promotes reactivation of inhibited
cytochrome oxidase by removing cyanide.
Pharmacokinetics
Hydroxocobalamin has a small volume of distribution of 0.1–0.5 L/kg. It is largely excreted
unchanged in the urine with an elimination half-life from 1.5 to 26 hours. Cyanocobalamin
is also excreted in the urine, with an elimination half-life of approximately 9 hours in
cyanide-poisoned patients treated with hydroxocobalamin.
ADMINISTRATION
l Reconstitute hydroxocobalamin 2.5 g (1 ampoule) with 100 mL
normal saline provided in the kit. Administer reconstituted solution
IV over 15 minutes
l Repeat process with second vial in the kit to give a total dose of
5g
l This dose should be sufficient to bind 100 mg of cyanide; however,
if the ingested dose is known to be greater than this, a larger initial
dose could be administered
l If there is no improvement within 15 minutes, repeat administration
of hydroxocobalamin or administration of sodium thiosulfate should
ANTIDOTES
be considered.

397
l Minor hypertension, bradycardia and tachycardia have been
TOXICOLOGY HANDBOOK
occasionally reported; none required treatment and all resolved
within 48 hours
l Orange-red discolouration of the skin, mucous membranes, urine,
plasma and other bodily fluids occurs and lasts for 12–48 hours,
but is not consequential
l Acute allergic reactions have not been reported following single
high-dose therapy in poisoned patients.
Paediatric: The paediatric dose has not been determined, but it is
reasonable to commence with 50 mg/kg.
HANDY TIPS
l Only the Cyanokit® provides a dose of hydroxocobalamin
sufficient to treat cyanide poisoning. It is expensive, not widely
available and only available in Australia if imported under the
Special Access Scheme. The alternate preparation, used to treat
pernicious anaemia, contains only 1 mg of hydroxocobalamin.
5000 ampoules and a volume of 5 L would be necessary to obtain
the dose necessary to treat one case of cyanide poisoning
l Hydroxocobalamin 5 g IV should be given to patients in cardiac
arrest from cyanide poisoning while resuscitation efforts continue
l Failure to improve after the first dose of hydroxocobalamin prompts
reconsideration of the diagnosis in suspected cyanide poisoning
l Hydroxocobalamin and sodium thiosulfate must not be mixed in
the same infusion, as hydroxocobalamin complexes will result
l The discolouration of bodily fluids that occurs may interfere with
laboratory analyses that use colorimetric methods, including
liver enzymes, bilirubin, creatinine, creatine kinase, phosphorus,
glucose, magnesium and iron. Falsely high or falsely low results
may be obtained, but are rarely of clinical significance.
PITFALLS
l Failure to stock the appropriate preparations
l Failure to administer an adequate dose.
CONTROVERSIES
l This expensive antidote (approximately A$2000 per pack of
2 ampoules) is rarely required but must be immediately available if it
is to be useful. It is only appropriate to stock in locations where there
is a risk of being confronted with a case of cyanide poisoning
l Relative efficacy of hydroxocobalamin compared with other
ANTIDOTES
cyanide antidotes
l It has previously been advocated that administration of
hydroxocobalamin should be followed by administration of sodium
thiosulfate 12.5g (50mL of 25% solution) IV over 10 minutes. This is
probably unnecessary.
398 References
Borron SW, Baud FJ, Megarbane B et al. Hydroxocobalamin for severe acute cyanide
39
poisoning by ingestion or inhalation. American Journal of Emergency Medicine 2007;

8
25:551–518.
TOXICOLOGY HANDBOOK
Hall AH, Dart R, Bogdan G. Sodium thiosulfate or hydroxocobalamin for empiric treatment
of cyanide poisoning? Annals of Emergency Medicine 2007; 49:806–813.
SubSectionNumber:5.12.2, accessed14 April 2010.
4.15 INSULIN (high-dose)

High-dose insulin therapy is a novel therapeutic intervention that
produces a significant inotropic response in severe calcium channel
blocker overdose.
l Calcium channel blocker (CCB) poisoning with haemodynamic
compromise.
CONTRAINDICATIONS
l None.
Mechanism of action
Insulin has a well-established inotropic effect in the failing heart. It is thought to be due
to its ability to increase lactate oxidation while at the same time completely eliminating
myocardial fatty acid oxidation. This metabolic profile optimises heart function under
stress conditions. Glucose is given simultaneously with insulin to maintain
euglycaemia.
ADMINISTRATION
l This antidote is only administered to critically ill patients fully
monitored in an intensive care setting. Careful attention to blood
sugar and serum potassium concentrations must be maintained
during therapy
l Commence therapy by administering:
— Glucose 25 g (50 mL of 50% solution) IV bolus
then
— Short-acting insulin 1 IU/kg IV bolus
l Continue therapy with:
— Glucose 25 g/hour IV infusion
— Short-acting insulin 0.5 IU/kg/hour IV infusion
l The glucose infusion is titrated to maintain euglycaemia
l The insulin infusion may be increased to 1 IU/kg/hour if required
l The combined infusions should continue for as long as the patient
ANTIDOTES
has cardiovascular instability.

l Therapy is weaned as cardiovascular toxicity resolves.

l Hypoglycaemia: Dextrose infusion is titrated to maintain 399
euglycaemia
l Hypokalaemia: Potassium supplementation may be required.
TOXICOLOGY HANDBOOK
HANDY TIPS
l High-dose insulin therapy should be started as soon as
haemodynamic compromise manifests rather than waiting for poor
response to other measures
l Peak inotropic response is usually observed within 1 hour of
initiation of therapy.
PITFALLS
l Failure to initiate therapy sufficiently early in life-threatening CCB
toxicity.
CONTROVERSIES
l This therapy has also been recommended in severe beta-
blocker poisoning, but clinical data to support its use are currently
lacking.
References
Lheureux PE, Zahir S, Gris M et al. Bench-to-bedside review: Hyperinsulinaemia/
euglycaemia therapy in the management of overdose of calcium-channel blockers.
Critical Care 2006; 10:212.
Megarbane B, Karyo S, Baud FJ. The role of insulin and glucose (hyperinsulinaemia/
euglycaemia) therapy in acute calcium channel antagonist and beta-blocker
poisoning. Toxicological Reviews 2004; 23(4):215–222.
Yuan TH, Kerns WP, Tomaszewski CA et al. Insulin-glucose as adjunctive therapy
for severe calcium channel antagonist poisoning. Journal of Toxicology-Clinical
Toxicology 1999; 37(4):463–474.
4.16 INTRAVENOUS LIPID EMULSION

Intravenous lipid emulsion (IVLE) is a sterile emulsion of soyabean oil
in water, used in parenteral nutrition. It is a novel antidote that requires
further study, but may have a role to play in the resuscitation of patients
with refractory cardiac arrest induced by local anaesthetics or other
lipophilic agents.
Presentations
Intravenous lipid emulsion 10%, 500 mL
ANTIDOTES

l Local anaesthetic-induced cardiovascular collapse, resistant to
standard resuscitation protocols
400 l May be considered as a rescue therapy for refractory cardiac
arrest in the context of acute poisoning with other highly lipid
40
0
soluble agents, including propranolol, tricyclic antidepressants and

verapamil.
TOXICOLOGY HANDBOOK
CONTRAINDICATIONS
l Inadequate standard resuscitative efforts.
Mechanism of action
Proposed mechanisms include introduction of an intravascular lipid phase that extracts
agent from tissue binding sites, increased myocardial ATP synthesis due to reversal of
inhibition of fatty acid delivery to mitochondria, and restoration of myocyte function by
activation of calcium and potassium channels and increase in intracellular calcium.
ADMINISTRATION
l Continue standard resuscitation protocols during administration
l Give 1–1.5 mL/kg IVLE 20% as IV bolus over 1 minute
l Repeat bolus once or twice at 3–5 minute intervals if required
then
l Infuse IVLE 0.25 mL/kg/minute until haemodynamic stability is
restored
l Increase to 0.5 mL/kg/minute if hypotension persists
l Increasing the total dose above 8 mL/kg is unlikely to be beneficial.

l Return of spontaneous circulation with stabilisation of
haemodynamic parameters. Infusion may be restarted if
hypotension recurs on cessation.
l Immediate: Allergy and anaphylaxis
l Pulmonary hypertension, acute lung injury and haematuria have
been described; however, the relative contribution of IVLE is
unknown. Management is supportive.
Paediatric: There are no reports of paediatric administration, but
administration should not be withheld if clinically indicated.
HANDY TIPS
l A suitable dosing regimen of IVLE 20% for resuscitating a 70-kg
adult would be an IV bolus of 100 mL followed by an infusion of
400 mL over 20 minutes while continuing advanced life support.
If no response, repeat boluses twice more while giving further
ANTIDOTES
adrenaline. If hypotension persists, increase infusion rate to
400 mL over 10 minutes.
CONTROVERSIES
l Optimum dose and dosing regimen of IVLE are yet to be
established
l Short-and long-term adverse effects of IVLE require further
401
study
l Role of IVLE in poisoning other than that by local anaesthetic
agents requires further study.
TOXICOLOGY HANDBOOK
References
Felice KL, Schumann HM. Intravenous lipid emulsion for local anaesthetic toxicity:
a review of the literature. Journal of Medical Toxicology 2008; 4(3):184–191.
The Association of Anaesthetists of Great Britain and Ireland. Guidelines for the
management of severe local anaesthetic toxicity. August 2007; Available online at:
http://www.aagbi.org.
Turner-Lawrence DE, Kerns W. Intravenous fat emulsion: a potential novel antidote.
Journal of Medical Toxicology 2008; 4(2):109–114.
Weinberg G. Lipid rescue resuscitation from local anaesthetic cardiac toxicity.
4.17 METHYLENE BLUE

Methylene blue is the treatment of choice for symptomatic drug-induced
methaemoglobinaemia.
Presentations
Methylene blue trihydrate 50 mg/5 mL ampoules
l Symptomatic drug-induced methaemoglobinaemia (signs of
hypoxaemia with chest pain, dyspnoea or confusion)
l Consider in asymptomatic patients with methaemoglobin (MetHb)
levels >20%.
CONTRAINDICATIONS
l G6PD deficiency: lack of NADPH in this condition causes
methylene blue to be ineffective, as it cannot be reduced to
leucomethylene blue. Haemolysis may also occur
l Renal impairment: dose needs to be adjusted
l Methaemoglobinaemia reductase deficiency
l Nitrite-induced methaemoglobinaemia following the treatment of
cyanide poisoning
l Hypersensitivity.
Mechanism of action
Methylene blue dramatically increases the natural rate of reduction of MetHb to
haemoglobin. Methylene blue is reduced to leucomethylene blue by methaemoglobin
reductase in the presence of NADPH. Leucomethylene blue then reduces MetHb to
haemoglobin.
Pharmacokinetics
Methylene blue is rapidly reduced to leucomethylene blue, which is then largely excreted
in the urine as a salt complex.
ANTIDOTES
ADMINISTRATION
l Administer 1–2 mg/kg (0.1–0.2 mL/kg of 1% solution) IV slowly over
5 minutes. Follow with a normal saline flush to minimise venous
irritation
l MetHb levels should be measured hourly until a consistent fall is
402 documented
l Methaemoglobinaemia usually responds to a single dose.
40
However, a further dose of 1–2 mg/kg may be repeated after

30–60 minutes if the initial response is inadequate
TOXICOLOGY HANDBOOK
l In rare instances, such as dapsone poisoning, when

methaemoglobin formation may continue for days, repeat dosing
every 6–8 hours may be necessary for several days.

l Resolution of symptoms of hypoxaemia
l Response is confirmed by repeat MetHb estimations.

l Local pain and irritation commonly occur at site of administration
and extravasation can result in local tissue necrosis
l Common non-specific adverse effects include headache, dizziness
restlessness, nausea, vomiting, chest discomfort and shortness of
breath
l Blue staining of mucous membranes (may mimic cyanosis) and urine
l Methylene blue may paradoxically cause methaemoglobinaemia
when given in high doses (>7 mg/kg) secondary to a direct
oxidative effect on haemoglobin
l Acute haemolytic anaemia may occur in G6PD-deficient individuals
and with very large doses of methylene blue (>15 mg/kg).
Pregnancy: No restrictions on use
Lactation: No restrictions on use
Paediatric: Initial paediatric dose is 1 mg/kg.
HANDY TIPS
l Patients with preexisting conditions that interfere with
oxygenation, such as anaemia or coronary artery disease, may
require methylene blue administration at MetHb concentrations as
low as 10%
l Pulse oximetry is unreliable, as MetHb and methylene blue interfere
with the readings
l Replacement of the blue discolouration of methaemoglobinaemia
with that of methylene blue means that this clinical sign is an
unreliable guide to response to therapy
l Consider the following problems if MetHb levels are not falling after
2 doses of methylene blue:
— Massive ongoing exposure to oxidising agent
— Sulfhaemoglobinaemia (e.g. by sulfonamides)
— G6PD deficiency
— Methaemoglobin reductase deficiency
— Abnormal haemoglobin
— Excessive methylene blue
ANTIDOTES
l If methylene blue fails to control methaemoglobinaemia, consider
exchange transfusion or hyperbaric oxygen therapy.
CONTROVERSIES
l Whether a certain MetHb concentration mandates methylene
blue treatment. Most clinicians continue to monitor asymptomatic
patients with elevated levels even >20% and do not treat unless 403
symptoms of hypoxaemia develop.
Reference
TOXICOLOGY HANDBOOK
Clifton J, Leiken JB. Methylene blue. American Journal of Therapeutics 2003; 10:289–91.
4.18 N-ACETYLCYSTEINE
N-acetylcysteine (NAC) is the most widely used sulfhydryl donor in the
treatment of paracetamol poisoning. Standard therapy consists of a series
of three infusions given over 20 hours. It is almost completely protective
against paracetamol-induced hepatotoxicity when administered within
8 hours of an overdose. Adverse effects are limited to mild anaphylactoid
reactions.
Presentations
2 g/10 mL ampoules
l Acute paracetamol overdose
l Repeated supratherapeutic paracetamol ingestion
l Paracetamol-induced fulminant hepatic failure
l Note: NAC is indicated in the above situations where there is
judged to be a risk of hepatotoxicity. Risk assessment is based
on dose ingested, serum paracetamol and hepatic transaminase
levels, and is discussed in detail in Chapter 3.59: Paracetamol:
Acute overdose
l NAC has been investigated for use in poisonings by a variety of
other agents, including chemotherapeutic agents, paraquat, carbon
tetrachloride, chloroform, acrylonitrile, cyclophosphamide and
amanita mushrooms
l Prevention of contrast-induced nephrotoxicity.
CONTRAINDICATIONS
l None.
Mechanism of action
NAC prevents N-acetyl-p-benzoquinoneimine (NAPQI)-induced hepatotoxicity when given
within 8 hours of an acute paracetamol overdose. It ameliorates the clinical course of
toxicity when given after that time or following repeated supratherapeutic ingestion. Four
possible mechanisms may contribute to this action:
1 Increased glutathione availability
2 Direct binding to NAPQI
3 Provision of inorganic sulfate
4 Reduction of NAPQI back to paracetamol
ANTIDOTES
The antioxidant properties of NAC may offer benefit in a number of other poisonings in
which oxidative stress is an important toxic mechanism and may also explain its beneficial
effects in liver failure of any cause.
Pharmacokinetics
NAC metabolism is complex, with a variety of sulfur-containing compounds being
produced. Plasma half-life following IV administration is 6 hours and 30% is eliminated
404 unchanged in the urine.
40
4
ADMINISTRATION
TOXICOLOGY HANDBOOK
l Patients are carefully monitored for anaphylactoid reaction during

and after the initial dose of NAC. Cardiac monitoring is not required
after that time
l Give 150 mg/kg NAC diluted in 200 mL of 5% dextrose IV over
15 minutes
followed by
l 50 mg/kg NAC diluted in 500 mL of 5% dextrose IV over 4
hours
followed by
l 100 mg/kg NAC diluted in 1000 mL of 5% dextrose IV over
16 hours
l The standard treatment duration is 20 hours; however, it may
be interrupted before this time where risk of hepatotoxicity is
excluded
l The infusion may be continued beyond 20 hours in patients
with late presentation, repeated supratherapeutic ingestion or
biochemical evidence of hepatotoxicity. Repeat the final dose
of 100 mg/kg NAC diluted in 1000 mL of 5% dextrose IV over
16 hours until such time as transaminases begin to fall and the
patient is improving clinically.

l Absent or resolving hepatotoxicity as determined by
transaminases.
l Mild anaphylactoid reactions (incidence of 10–50%), including mild
hypotension, mild flushing, rash and angioedema
l These usually occur during or shortly after the initial dose and can
be treated with promethazine 12.5 mg IV
l The infusion need only be ceased if the reaction is severe, in which
case it may be restarted as soon as the reaction is settling.
Pregnancy: NAC crosses the placenta. When indicated, it is beneficial
for both mother and fetus.
Paediatric: The dose of NAC is the same as for adults. However it
should be infused in smaller volumes of 5% dextrose:
l Children <20 kg body weight:
— 150 mg/kg in 3 mL/kg of 5% dextrose over 15 minutes
followed by
— 50 mg/kg in 7 mL/kg of 5% dextrose over 4 hours
followed by
ANTIDOTES
followed by
l Children >20 kg body weight:
— 150 mg/kg in 100 mL of 5% dextrose over 15 minutes
followed by
— 50 mg/kg in 250 mL of 5% dextrose over 4 hours 405
followed by
— 50 mg/kg in 250 mL of 5% dextrose over 8 hours
followed by
TOXICOLOGY HANDBOOK
— 50 mg/kg in 250 mL of 5% dextrose over 8 hours.
HANDY TIPS
l Always chart NAC infusions using the chart supplied in the
package insert, which describes NAC volume rather than
milligrams. This practice reduces the chance of a dosing error.
PITFALLS
l Failure to initiate NAC empirically in the patient who presents more
than 8 hours following a paracetamol overdose of >200 mg/kg
l Failure to warn patient and staff of the high likelihood of a mild
anaphylactoid reaction occurring early in treatment.
CONTROVERSIES
l The practice of giving the initial dose of NAC over 60 minutes
rather than 15 minutes does not appear to significantly reduce the
incidence of anaphylactoid reactions
l The value of NAC in patients who present more than 24 hours post
overdose with elevated transaminases, but who are otherwise well.
References
poisoning in Australia and New Zealand—explanation and elaboration. A consensus
statement from clinical toxicologists consulting to the Australasian poisons
information centres. Medical Journal of Australia 2008; 188:296–301.
Kerr F, Dawson A, Whyte IM et al. The Australasian Clinical Toxicology Investigators
Collaboration randomized trial of different loading infusion rates of N-acetylcysteine.
Prescott LF, Illingworth RN, Critchley JA. Intravenous N-acetylcysteine: the treatment of
choice for paracetamol poisoning. British Medical Journal 1979; 2:1097.
4.19 NALOXONE
This opioid antagonist is a useful adjunct in the management of opioid
intoxication.
Presentations
Naloxone hydrochloride 400 microgram/1 mL ampoules
Naloxone hydrochloride 800 microgram/2 mL pre-filled syringe (‘mini-jet’)
Naloxone hydrochloride 2 mg/5 mL pre-filled syringe (‘mini-jet’)
l Reversal of CNS and respiratory depression caused by opioid
ANTIDOTES
intoxication
l Empiric treatment for coma thought to be secondary to opioids.
CONTRAINDICATIONS
l Avoid in the opioid-dependent individual unless:
— Significant respiratory depression (respiratory rate <8)
406 or
— Significant CNS depression (GCS <12).
40
6
Mechanism of action
TOXICOLOGY HANDBOOK
Naloxone is a pure competitive opioid antagonist at mu, kappa, and delta receptors. It
reverses opioid effects, including sedation and respiratory depression.
Pharmacokinetics
Naloxone has poor oral bioavailability with extensive first-pass effect. It is well absorbed
after IM, SC or endotracheal administration. Distribution and onset of action are rapid after
IV or IM administration. It is metabolised by the liver, with an elimination half-life of 60 to
90 minutes. Duration of effect also depends on dose and rate of elimination of agonist, but
is usually from 20 to 90 minutes.
ADMINISTRATION
personnel are available to provide full resuscitative care. Carefully
monitor respiratory rate, GCS and oxygen saturation in an effort to
detect re-sedation
l Treatment dose is extremely variable and depends on the amount
and type of agonist present
l Give an initial bolus dose of 100 micrograms IV or 400 micrograms
IM or SC if IV access cannot be established. Larger initial doses
may safely be used where the patient is not opioid dependent
l Repeated doses of 100 micrograms IV every 30–60 seconds
may be given until adequate spontaneous respiration is re-
established
l Doses >400 micrograms are rarely required following heroin
overdose; however, larger doses may be required in overdose from
partial opioid antagonists
l Duration of treatment is extremely variable and dependent on the
absorption and elimination kinetics of the ingested competing
agonist. Clinically significant re-sedation is extremely unusual
following heroin overdose. However, following overdose with
controlled-release morphine tablets or methadone, re-sedation is
expected and a naloxone infusion may be necessary
l Commence the naloxone infusion rate at 2/3 of the initial dose
required/hour. Administration of 100 microgram/hour can be
obtained by diluting 2 mg of naloxone in 100 mL normal saline and
running at 5 mL/hour
l Monitor the patient for evidence of opioid withdrawal and titrate the
infusion according to clinical response.

l In the non-opioid dependent individual, naloxone may be given in a
dose sufficient to achieve and maintain a normal mental status
l In the opioid-dependent individual, naloxone dose should be
sufficient to permit maintenance of an adequate airway, respiratory
ANTIDOTES
rate and a patient who is rousable (GCS 13–14), but not achieve full
reversal
l All patients given naloxone should be observed for re-sedation for
at least 2 hours after the last dose.

l In non-opioid dependent individuals, naloxone is without significant 407
adverse effects, even in very large doses
l In opioid-tolerant patients, dose-dependent production of a
withdrawal syndrome occurs. This can include severe agitation and
TOXICOLOGY HANDBOOK
aggression and should be avoided
l If a withdrawal syndrome is inadvertently produced, immediately
cease further administration of naloxone. Physical and chemical
control of the disturbed patient may be necessary if reassurance
fails. Avoid long-acting chemical sedation as the duration of
naloxone-induced withdrawal is short (usually <90 minutes).
withheld if clinically indicated. Maternal opioid dependence is associated
with fetal opioid dependence. Naloxone crosses the placenta and
precipitation of opioid withdrawal in the mother will be associated with
precipitation of opioid withdrawal in the fetus and should be avoided
Paediatric: Naloxone can usually be given with impunity to suspected
cases of paediatric opioid intoxication, as children are unlikely to
be opioid-dependent. Give a 400-microgram bolus IV to exclude or
confirm the diagnosis of opioid intoxication.
HANDY TIPS
l Do not completely reverse opioid intoxication in opioid-dependent
patients, as withdrawal will render assessment and management
more difficult
l IV administration is superior to IM or SC as it allows titration of dose
l Anticipate the need for ongoing naloxone administration following
overdose of methadone or controlled-release oral morphine
l Monitor patients on naloxone infusion for both re-sedation and
withdrawal and adjust the rate of infusion accordingly.
PITFALLS
l Production of severe acute withdrawal syndrome in opioid-
dependent patients
l Failure to detect and correct re-sedation following initial response
to naloxone
l Inadequate naloxone dose following partial agonist overdose.
CONTROVERSIES
l Intranasal or nebulised naloxone may be useful, but these
routes of administration are not yet validated and cannot be
recommended
l Naloxone has been advocated in the management of clonidine,
alcohol, benzodiazepine and sodium valproate intoxication. It does
not appear to be clinically useful in these situations.
ANTIDOTES
References
Ashton H, Hassan Z. Best evidence topic report: Intranasal naloxone in suspected opioid
overdose. Emergency Medicine Journal 2006; 23:221–223.
Clarke SFJ, Dargan PI and Jones AL. Naloxone in opioid poisoning: walking the tightrope.
Emergency Medicine Journal 2005; 22:612–616.
408
4.20 OCTREOTIDE
40
8
TOXICOLOGY HANDBOOK
Long-acting synthetic octapeptide analogue of somatostatin useful in the

control of sulfonylurea-induced hypoglycaemia
Presentations
Octreotide 0.05 mg/1 mL ampoules
l Drug-induced hyperinsulinaemic states resulting in persistent
hypoglycaemia (blood glucose <4 mmol/L) including:
— Intentional sulfonylurea overdose
— Therapeutic sulfonylurea-induced hypoglycaemia
— Quinine-induced hypoglycaemia.
CONTRAINDICATIONS
l None.
Mechanism of action
Octreotide powerfully suppresses endogenous insulin release from pancreatic islet cells.
Pharmacokinetics
Octreotide has a bioavailability following SC administration of 100%. Peak levels are
achieved within 30 minutes, but are only half those achieved following IV administration.
About 30% is excreted unchanged by the kidney, with an elimination half-life of
90 minutes.
ADMINISTRATION
personnel are available to frequently monitor blood sugar levels
and observe for clinical features of hypoglycaemia
l Administer an initial bolus of 50 micrograms IV
l Commence a continuous infusion at 25 microgram/hour by diluting
500 micrograms of octreotide in 500 mL of normal saline and
running at 25 mL/hour
l An alternative to IV infusion is 100 micrograms SC or IM every
6 hours. Breakthrough hypoglycaemia may occur between doses
l Normoglycaemia without dextrose supplementation is usually
maintained on the octreotide infusion. If hypoglycaemia recurs, it
should be corrected with 50% dextrose and the infusion rate doubled.

l Normoglycaemia must be maintained for 6 hours off octreotide and
on a normal diet before the patient is medically cleared.
ANTIDOTES
l Minor nausea only.
Paediatric: The optimal dose in children is unknown. Given the 409
absence of significant adverse effects, commence therapy with an
initial bolus of 1 microgram/kg IV or SC followed by an intravenous
infusion of 1 microgram/kg/hour.
TOXICOLOGY HANDBOOK
HANDY TIPS
l Initiation of therapy with a bolus of 100 micrograms SC is useful
in stabilising a patient in a remote location prior to transfer to the
place of definitive care. This dose may be brought in by a retrieval
team if unavailable on site
l If plasma insulin levels are available they can usefully assist in the
withdrawal of octreotide. A plasma insulin level in the normal range
at 6 hours after cessation of the octreotide infusion allows the
patient to be medically cleared.
PITFALLS
l Failure to start therapy when hypoglycaemia first develops
following sulfonylurea overdose.
CONTROVERSIES
l Intravenous versus subcutaneous administration and optimal
dosing regimens
l Role of octreotide in the management of therapeutic sulfonylurea-
induced hypoglycaemia.
References
Boyle PJ, Justice K, Krentz AJ et al. Octreotide reverses hyperinsulinemia and prevents
hypoglycaemia induced by sulfonylurea overdoses. Journal of Clinical Endocrinology
and Metabolism 1993; 77:752–756.
Fasano CJ, O’Malley G, Dominici P et al. Comparison of octreotide and standard
therapy versus standard therapy alone for the treatment of sulfonylurea-induced
hypoglycemia. Annals of Emergency Medicine 2008; 51:400–406.
McLaughlin SA, Crandall CS, McKinney PE. Octreotide: an antidote for sulfonylurea
induced hypoglycaemia. Annals of Emergency Medicine 2000; 36:133–138.
4.21 PENICILLAMINE
Potent oral chelating agent for a broad range of heavy metals. Agent
of choice in very few scenarios due to poor side-effect profile and the
existence of better tolerated and more efficacious agents.
Presentations
Penicillamine 125 mg tablets (100)
Penicillamine 250 mg tablets (100)
ANTIDOTES
l Copper toxicity (Wilson’s disease)

l Second-line drug for chelation of other heavy metals, including
arsenic, iron, lead, mercury and zinc.
CONTRAINDICATIONS
l Penicillin allergy
410 l Pregnancy
41
l Renal failure (unable to excrete chelates).

0
Mechanism of action
TOXICOLOGY HANDBOOK
Penicillamine is an orally administered chelating agent. It is a penicillin derivative

without antibiotic activity. It binds to various heavy metals with varying degrees
of efficacy. The penicillamine–metal chelate is soluble and eliminated by renal
excretion.
Pharmacokinetics
Penicillamine is well absorbed following oral administration, with peak concentrations
occurring within hours. It is distributed throughout the body water. Elimination is urinary
mainly as sulfide conjugates. Elimination half-life is up to 90 hours.
ADMINISTRATION
l Administer 4–7 mg/kg orally four times a day
l Maximum adult daily dose is 2 g
l Monitor closely for adverse effects:
— Second weekly full blood count and urinalysis
— Weekly urine and/or blood testing for target heavy metal
l Commencing therapy in the lower dose range may minimise
adverse effects
l Duration of therapy depends upon ability to tolerate the antidote
and the rate of elimination of the target metal. Months of therapy
may be required.

l Blood metal concentrations in desired range.
l Drug reactions are multiple and frequent, especially in the higher
dose range. They are commonly responsible for cessation of
therapy and include:
— Cutaneous hypersensitivity: erythematous skin reactions
— Systemic hypersensitivity: fever, proteinuria, haematuria,
erythema multiforme
— Haematological: bone marrow hypoplasia with varying degrees
of thrombocytopenia, leucopenia and fatal agranulocytosis
— Neurological: myasthenia gravis, peripheral neuropathy
— Nephrotoxicity: nephrotic syndrome, glomerulonephritis
— Other: Goodpasture’s syndrome, hepatotoxicity, pancreatitis
l Therapy should be ceased if significant cutaneous reactions,
abnormal urinalysis or falling white cell or platelet counts occur.
Pregnancy: This drug is teratogenic and is avoided in pregnancy
Paediatrics: Dose as for adults. Lower doses will minimise adverse
ANTIDOTES
effects.
HANDY TIPS
l Should only be prescribed by clinicians experienced with its use
and adverse effects.
CONTROVERSIES 411
l Lower dose regimens may achieve comparable clinical efficacy
with improved adverse effect profile.
TOXICOLOGY HANDBOOK
References
Liebelt EL, Shannon MW. Oral chelators for childhood lead poisoning. Pediatric Annals
1994; 23(11):616–619, 623–626.
Shannon MW, Townsend MK. Adverse effects of reduced-dose d-penicillamine in children
with mild-to-moderate lead poisoning. Annals of Pharmacotherapy. 2000; 34(1):15–18.
4.22 PHYSOSTIGMINE
A reversible acetylcholinesterase inhibitor useful in the treatment of
central anticholinergic delirium.
Presentations
Physostigmine 1 mg/2 mL ampoules
l Central antimuscarinic manifestations (agitated delirium) not easily
controlled with benzodiazepine sedation
l Isolated anticholinergic agent poisoning (i.e. atropine, benztropine).
CONTRAINDICATIONS
l Bradyarrhythmias
l Intraventricular block (QRS >100 ms)
l AV block
l Bronchospasm.
Mechanism of action
Physostigmine is a carbamate with a tertiary amine structure. It produces reversible
inhibition of acetylcholinesterase and accumulation of acetylcholine. The increased
concentration of acetylcholine overcomes the post-synaptic muscarinic receptor blockade
produced by anticholinergic agents.
Pharmacokinetics
Physostigmine is very poorly absorbed after oral administration. It is able to cross the
blood–brain barrier. It is rapidly metabolised by cholinesterase, with an elimination half-life
of about 20 minutes.
ADMINISTRATION
l Confirm absence of conduction defects on 12-lead ECG
l Administer 0.5–1 mg as a slow IV push over 5 minutes and repeat
every 10 minutes until the desired clinical effect is observed
l It is rare for a total dose of more than 4 mg to be required
l The duration of action of physostigmine is much shorter than most
ANTIDOTES
cases of anticholinergic delirium, and delirium may reoccur 1–4

hours following initial clinical response. Further carefully titrated
doses may then be given.

l Resolution of delirium.
412
41

2
l Excessive doses of physostigmine produce clinical features of

cholinergic stimulation including:
TOXICOLOGY HANDBOOK
— Seizures, usually seen following rapid administration

— Bradycardia, variable degrees of heart block
— Bronchospasm, bronchorrhoea, nausea, vomiting and
diarrhoea
l The cholinergic manifestations of physostigmine overdose
should be managed with good supportive care and, if necessary,
administration of titrated doses of atropine until there is resolution
of bradycardia and drying of respiratory secretions
l Physostigmine may also prolong the effect of succinylcholine or
inhibit the action of non-depolarising neuromuscular blockers.
Pregnancy: Safety not established. Alternative agents should be
considered.
Paediatric: Initial paediatric dose is 0.02 mg/kg to a maximum of
0.5 mg.
HANDY TIPS
l Although the duration of action of physostigmine is relatively short
(about 2 hours), repeat doses are not always required after initial
reversal of delirium
l Use of physostigmine may prevent the need to administer massive
doses of benzodiazepine to the delirious patient and thus reduce
the likelihood of excessive sedation and pulmonary aspiration
l Consider physostigmine in the management of anticholinergic
delirium that persists in the recovering tricyclic antidepressant
overdose patient
l Do not give physostigmine as an intravenous infusion—it is likely to
precipitate a cholinergic crisis.
PITFALLS
l Inadequate or excessive doses of physostigmine. This can usually
be avoided by careful titration of dose to clinical effect.
CONTROVERSIES
l Physostigmine fell out of favour in the treatment of anticholinergic
poisoning in the 1970s following a number of reports of
bradyarrhythmias and asystole. It is likely that the risk was
overestimated
l Relative value of benzodiazepines and physostigmine in the
management of anticholinergic delirium. Benzodiazepines are
useful in achieving sedation but will not reverse delirium
ANTIDOTES
l Physostigmine has been advocated in the management of gamma-
hydroxybutyrate (GHB) overdose, but its clinical utility in this
situation is unproven and unlikely to improve outcome beyond that
which is assured by good supportive care.
References
Burns MJ, Linden CH, Graudins A et al. A comparison of physostigmine and 413
benzodiazepines for the treatment of anticholinergic poisoning. Annals of Emergency
Medicine 2000; 35:374–381.
Suchard JR. Assessing physostigmine’s contraindication in cyclic antidepressant
TOXICOLOGY HANDBOOK
ingestions. Journal of Emergency Medicine 2003; 25(2):185–191.
4.23 PRALIDOXIME
This is the oxime commonly used in Australasia to reactivate
acetylcholinesterase inhibition caused by organophosphates (OPs).
PRESENTATION
Pralidoxime iodide 500 mg/20 mL vials
l Organophosphate poisoning
— Therapy should start in any symptomatic patient with definite
or suspected poisoning as soon as immediate resuscitation
and adequate atropinisation are achieved
l Carbamate poisoning
— Although not strictly indicated, it should not be withheld in
severe poisoning or if there is any doubt regarding the nature of
the agent
l Nerve agent poisoning.
CONTRAINDICATIONS
l Hypersensitivity.
Mechanism of action
Pralidoxime reactivates acetylcholinesterase that has been inhibited by binding to OP or
carbamate pesticides. It is only effective if given before irreversible binding or ‘ageing’
takes place. Re-establishment of enzymatic function rapidly reverses the nicotinic and
muscarinic effects of OP poisoning. Atropine is usually administered prior to pralidoxime
and the effect at muscarinic receptors is synergistic. Atropine is not effective at nicotinic
receptors. An improvement in muscle strength is usually observed within 10–40 minutes of
administration.
Pharmacokinetics
Following IV administration, pralidoxime has a volume of distribution of 0.8 L/kg. Over
80% of an administered dose is excreted unchanged by the kidney with an elimination
half-life of 75 minutes. These volumes of distribution and elimination half-lives increase
in poisoned patients and during continuous IV infusions. An infusion of 500 mg/hour
achieves levels of >4 microgram/mL (postulated target concentration) within 15 minutes
and maintains them for the duration of the infusion.
ADMINISTRATION
l The patient with confirmed organophosphate poisoning has
ANTIDOTES
a life-threatening illness and is managed in an intensive care

environment with full monitoring and resuscitation facilities
available
l Administer the initial dose of 2 g pralidoxime in 100 mL of normal
saline IV over 15 minutes
then
l Commence pralidoxime infusion at 500 mg/hour (pralidoxime 6 g in
414
500 mL of normal saline at 42 mL/hour)
41
l Higher infusion rates are rarely indicated, but may be considered if

4

clinical response is poor
TOXICOLOGY HANDBOOK
l The infusion may be discontinued after 24 hours provided the

patient is clinically well; the time of cessation is within daylight
hours and the patient remains under close observation for a further
24 hours. If clinical evidence of OP poisoning recurs, the infusion is
recommenced for a further 24 hours
l When facilities are available to perform rapid red cell
anticholinesterase activity assays, these should be done before the
infusion is ceased and then repeated after 4–6 hours. If activity is
maintained, pralidoxime is no longer required and the infusion can
be ceased
l Note: For severe poisoning with some OPs, many days of therapy
are required.

l Usually minimal or mild
l Non-specific adverse effects include nausea, headache, dizziness,
drowsiness, blurred vision and hyperventilation
l Rapid administration can cause tachycardia, laryngospasm,
muscle rigidity, hypertension and transient neuromuscular
blockade.
Paediatric: Children are treated with an initial dose of 25–50 mg/kg
followed by an infusion of 10–20 mg/kg/hour.
HANDY TIPS
l Administration beyond 24 hours after OP ingestion may be
ineffective, but a therapeutic trial should still be attempted
l Poisoning from certain OPs may be less responsive to pralidoxime
than others.
PITFALLS
l Failure to administer an appropriate dose
l Inadequate duration of treatment
l Late initiation of treatment.
CONTROVERSIES
l The value of pralidoxime in improving clinical outcome from OP
poisoning is disputed. Although pralidoxime has been shown to
ANTIDOTES
reactivate red cell acetylcholinesterase in OP-poisoned patients,
it has not been shown to improve survival or reduce the need for
intubation
l Optimal dosing and duration of pralidoxime is not
established. It almost certainly varies with different OPs
l The role of pralidoxime in carbamate poisoning.
415
References
Buckley NA, Eddleston M, Szinicz L. Oximes for acute organophosphate
pesticide poisoning. Cochrane Database of Systematic Reviews 2005(1):
CD005085.
TOXICOLOGY HANDBOOK
Eddleston M, Eyer P, Worek F et al. Pralidoxime in acute organophosphorus
insecticide poisoning—a randomised controlled trial. PLoS Medicine 2009 June;
6(6):e1000104.
4.24 PYRIDOXINE
Vitamin B6
Intravenous pyridoxine is used in high doses to control the metabolic
acidosis and seizures associated with isoniazid overdose and poisoning
from other hydrazine compounds.
Presentations
Pyridoxine hydrochloride 50 mg/mL vials
l Seizures induced by hydrazine compounds (includes isoniazid,
Gyromitra mushrooms and hydrazine, a component of jet and
rocket fuels)
l Adjunct in the treatment of ethylene glycol toxicity.
CONTRAINDICATIONS
Mechanism of action
The active form of pyridoxine, pyridoxal 5-phosphate (P5P), is known as vitamin
B6. It is an important cofactor in over 100 enzymatic reactions involving amino acid
metabolism. P5P is an essential coenzyme in the conversion of L-glutamic acid
to GABA. The hydrazines, including isoniazid, inhibit the formation of P5P, bind to
and inactivate existing P5P, and enhance elimination of P5P, thereby producing a
state of GABA depletion leading to CNS excitation and seizures. Large doses of
pyridoxine overcome this inhibition and restore normal GABA concentration and
activity.
Pharmacokinetics
Pyridoxine has an oral bioavailability of about 50% and a volume of distribution of
0.6 L/kg. It is rapidly metabolised at extrahepatic sites to the active phosphate ester and
other compounds.
ADMINISTRATION
l EEG monitoring is mandatory during pyridoxine administration if
ANTIDOTES
the patient is intubated and paralysed

l Isoniazid overdose
— Administer an initial dose of 1 g pyridoxine for each gram of
isoniazid ingested up to a maximum dose of 5 g (70 mg/kg in
children)
— Give this dose as a slow IV infusion at 0.5 g/minute until
416 seizures stop or infusion is complete. The remainder of the
dose may then be infused over 4 hours
41
— If the ingested dose of isoniazid is unknown, give 5 g of

6
pyridoxine empirically
TOXICOLOGY HANDBOOK
— Benzodiazepines are given concomitantly, as they have a

synergistic effect
l Hydrazine or monomethylhydrazine poisoning
— Administer an initial bolus of 25 mg/kg intravenously
l Ethylene glycol poisoning
— Give 50 mg IV every 6 hours.

l Control of seizures.

l Chronic high oral pyridoxine dosing is associated with peripheral
neuropathy, but this does not occur with acute dosing for isoniazid
overdose.
HANDY TIPS
l Pyridoxine is only available in 50 mg vials. Large numbers of
these will need to be procured to treat a single case of isoniazid
poisoning. If the recommended dose cannot be immediately
obtained, all available pyridoxine, together with high-dose
benzodiazepines, should be administered as an interim measure
l Always administer benzodiazepines in addition to pyridoxine
because of the likely synergistic effect.
PITFALLS
l Failure to administer benzodiazepines concurrently.
CONTROVERSIES
l Human experience with pyridoxine in isoniazid poisoning is
confined to case reports. It may be that severe isoniazid toxicity
can be successfully managed using supportive care and high-dose
benzodiazepine therapy alone
l Utility of pyridoxine in ethylene glycol poisoning.
Reference
Lheureux P, Penaloza A, Gris M. Pyridoxine in clinical toxicology: a review. European
Journal of Emergency Medicine 2005; 12:78–85.
ANTIDOTES
4.25 SODIUM BICARBONATE
Hyperosmolar sodium bicarbonate solutions are widely used in clinical
toxicology, both as an antidote to drugs that impair fast sodium channel
417
function and as an alkalinising agent to manipulate drug distribution and
excretion.
Presentations
TOXICOLOGY HANDBOOK
Sodium bicarbonate 50 mmol/50 mL single-use pre-filled syringe
Sodium bicarbonate 100 mmol/100 mL vial
l Cardiotoxicity secondary to fast sodium channel blockade
— Tricyclic antidepressants
— Bupropion
— Chloroquine/hydroxychloroquine
— Dextropropoxyphene
— Propranolol
— Type 1a and 1c antiarrhythmics
– Flecainide, quinidine, quinine
l Prevention of redistribution of drug to the CNS
— Severe salicylate poisoning
l Immediate correction of profound life-threatening metabolic
acidosis
— Cyanide poisoning
— Isoniazid overdose
— Toxic alcohol poisoning
– Ethylene glycol, methanol and other toxic alcohols
l Enhanced urinary drug elimination
— Salicylate intoxication (any symptomatic patient)
— Phenobarbitone intoxication
l Increased urinary solubility
— Methotrexate toxicity
— Drug-induced rhabdomyolysis.
CONTRAINDICATIONS
l Acute pulmonary oedema
l Hypokalaemia
l Metabolic or respiratory alkalosis
l Poorly controlled congestive cardiac failure
l Renal failure
l Severe hypernatraemia.
Mechanism of action
Administration of hypertonic sodium bicarbonate provides both a sodium and a bicarbonate
load. The bicarbonate load increases plasma bicarbonate concentration, buffers excess
hydrogen ion concentration and raises serum pH. Administration of a sufficient bicarbonate
load also results in urinary bicarbonate excretion and an alkaline urine pH. These properties
allow sodium bicarbonate to be used with benefit in a number of situations in clinical
toxicology.
Elevation of serum pH
l Improved fast sodium channel function
ANTIDOTES
— A number of drugs cause cardiotoxicity by impairing sodium flux

through the fast sodium channels of the cardiac conducting system
during depolarisation
— Raising the serum pH improves fast sodium channel function and
mitigates this toxic effect. Any increase from baseline pH is beneficial
but the effect is maximal at pH 7.50–7.55
— The sodium load provided by sodium bicarbonate administration
418 has a separate but additive positive effect on sodium channel
function
41
l Alteration of drug distribution

8

— Elevation of serum pH can reduce the proportion of drug in unionised
TOXICOLOGY HANDBOOK
form, reduce its ability to cross cell membranes and hence reduce the
proportion of drug that distributes to tissue compartments (especially
the CNS)
l Immediate correction of severe life-threatening metabolic acidosis
— Profound metabolic acidosis has negative effects on cardiovascular
function and may be life-threatening at pH approaching 6.7, irrespective
of the underlying toxic cause
Alkalinisation of urine
l ‘Ion trapping’ and enhanced urinary elimination
— An alkaline urinary pH can result in some drugs being predominantly
in an ionised form and unable to be reabsorbed across the tubular
epithelium
l Increased solubility
— An alkaline urinary pH promotes water solubility of some drugs and of
myoglobin, thus preventing tubular precipitation and secondary renal
injury in addition to promoting urinary excretion.
Pharmacokinetics
Sodium bicarbonate (NaHCO3) dissociates in water to provide sodium (Na+) and
bicarbonate (HCO3–) ions. Sodium is the principal cation in the extracellular fluid.
Bicarbonate is a normal constituent of body fluids and plasma concentration is regulated.
Under normal conditions, very little bicarbonate is excreted in the urine. Bicarbonate
combines with hydrogen ions to form carbonic acid, which dissociates to form H2O and
CO2.
ADMINISTRATION
Cardiotoxicity secondary to fast sodium channel blockade
l Resuscitation from severe cardiotoxicity (cardiac arrest,
ventricular arrhythmias and hypotension)
— Sodium bicarbonate administration occurs in concert with
advanced cardiac life-support, including establishment of an
airway, hyperventilation and administration of IV fluid boluses
— Give repeated boluses of 2 mmol/kg IV until cardiovascular
stability is achieved
— Following clinical stabilisation, further administration of
sodium bicarbonate is guided by repeated blood gas
estimations
l Maintenance of serum alkalinisation in severe cardiotoxicity
— Should be considered following resuscitation in the presence of
ventricular arrhythmias, hypotension, or a markedly wide QRS
complex (>140 ms)
— Commence an infusion of 100 mmol sodium bicarbonate
diluted in 1000 mL normal saline at 250 mL/hour
ANTIDOTES
— Check ABGs hourly and maintain serum pH in range of 7.50–7.55
— Cease infusion following resolution of cardiovascular toxicity as
determined by clinical and ECG criteria
— Note: in practice it is far easier and safer, and of comparable
efficacy, to maintain serum alkalinisation with hyperventilation
in the intubated patient
Prevention of redistribution of salicylate to CNS 419
— The pH must be maintained above 7.4 at all times
— The salicylate-poisoned patient with severe metabolic acidosis
is critically ill and usually intubated, and serum pH may be
TOXICOLOGY HANDBOOK
maintained >7.4 by hyperventilation
— Give sodium bicarbonate 2 mmol/kg IV bolus in an unwell
unintubated patient with salicylate poisoning
— Then intubate, hyperventilate and recheck ABGs
— Serum alkalinisation is maintained until definitive care with
haemodialysis
Urinary alkalinisation
— Correct hypokalaemia if present
— Given 1–2 mmol/kg sodium bicarbonate IV bolus
— Commence infusion of 100 mmol sodium bicarbonate in 1000
mL 5% dextrose at 250 mL/hour
— 20 mmol of KCl may be added to infusion to maintain
normokalaemia
— Monitor serum bicarbonate and potassium at least every
4 hours
— Regularly dipstick urine and aim for urinary pH >7.5
— Continue until clinical and laboratory evidence of toxicity is
resolving.

l Alkalosis (serum pH >7.6 is detrimental to cardiovascular function)
l Hypernatraemia and hyperosmolarity
l Fluid overload and acute pulmonary oedema
l Hypokalaemia
l Local tissue inflammation secondary to extravasation.
Lactation: No restriction on use
Paediatric: Doses are the same as for adults on mmol/kg basis.
Reduced fluid volumes should be used in children.
HANDY TIPS
l Rapid correction of acidosis by administration of sufficient doses of
sodium bicarbonate is an essential component of the resuscitation
of a patient with severe tricyclic antidepressant poisoning
l The frail elderly patient or patient with underlying cardiac disease
may not tolerate the fluid and osmotic load associated with sodium
bicarbonate administration.
PITFALLS
l Insufficient doses of sodium bicarbonate when attempting
resuscitation of severe tricyclic antidepressant poisoning
ANTIDOTES
l Failure to correct hypokalaemia when attempting urinary

alkalinisation
l Failure to recognise and rapidly treat acidaemia in the patient with
severe salicylate poisoning.
CONTROVERSIES
l Utility and indications for urinary alkalinisation in toxic rhabdomyolysis
420
l Value and indications for prophylactic serum alkalinisation in
42
tricyclic antidepressant poisoning

0
l Relative efficacy of hyperventilation versus administration of sodium

TOXICOLOGY HANDBOOK
bicarbonate in the management of tricyclic antidepressant toxicity

l Precise mechanism by which urinary alkalinisation enhances
salicylate elimination.
References
Bradberry SM, Thanacoody HK, Watt BE et al. Management of the cardiovascular
complications of tricyclic antidepressant poisoning: role of sodium bicarbonate.
Proudfoot AT, Krenzelok EP, Brent J et al. Does urine alkalinization increase salicylate
elimination? If so, why? Toxicological Reviews 2003; 22(3):129–136.
4.26 SODIUM CALCIUM EDETATE

Calcium disodium versenate, Calcium disodium edetate, Calcium
disodium ethylenediaminetetraacetic acid (EDTA)
An intravenous heavy metal chelating agent primarily used in the
treatment of severe lead poisoning, including lead encephalopathy.
Presentations
Sodium calcium edetate 1 g/5 mL ampoules
l Lead encephalopathy
l Severely symptomatic lead poisoning without encephalopathy
l Asymptomatic or mildly symptomatic lead poisoning (lead level >70
microgram/dL or 6.72 micromol/L)
l Second-line chelating agent when succimer is either not available
or not tolerated by the patient
l Other heavy metal poisoning (efficacy unknown).
CONTRAINDICATIONS
l Relative contraindication: anuric renal failure.
Mechanism of action
EDTA binds to divalent and trivalent metals, the calcium component of EDTA is displaced
and a stable water-soluble chelate is formed, which is readily excreted in the urine.
Pharmacokinetics
Absorption of EDTA is incomplete following oral administration and this antidote is
only administered by the intravenous route. The volume of distribution is small and
approximates that of the extracellular fluid compartment. It is not metabolised. Excretion is
urinary and largely dependent on the glomerular filtration rate. With normal renal function,
ANTIDOTES
the elimination half-life is 20–60 minutes.
ADMINISTRATION
l Lead encephalopathy
— This patient is critically unwell and managed in intensive care
— Commence dimercaprol (BAL) at 4 mg/kg IM every 4 hours and
continue for 5 days (see Chapter 4.7: Dimercaprol) 421
— Dilute EDTA 50–75 mg/kg in 500 mL of normal saline or 5%
dextrose and infuse over 24 hours starting 4 hours after first
dose of dimercaprol
TOXICOLOGY HANDBOOK
l Symptomatic lead poisoning without encephalopathy
— This patient is unwell and managed in a high-dependency
environment
— Commence dimercaprol (BAL) at 3 mg/kg IM every 4 hours and
continue for 5 days (see Chapter 4.7: Dimercaprol)
— Dilute EDTA 25–50 mg/kg in 500 mL of normal saline or 5%
dextrose and infuse over 24 hours starting 4 hours after first
dose of dimercaprol
l EDTA therapy is usually continued for a maximum of 5 days.
Therapy is then interrupted for 2 to 4 days to allow
redistribution of the lead prior to consideration of a further 5-day
course
l In the setting of encephalopathy, EDTA (and dimercaprol) should
be continued until the patient is clinically stable
l Once clinically improved, chelation may be switched to oral
succimer if tolerated.

l Local pain and thrombophlebitis due to rapid IV administration.
Local phlebitis may be minimised by:
— Infusing dilute solution (<0.5%)
— Giving infusion over >4 hours
l General systemic
— Malaise, fatigue, thirst, chills, fever, myalgias, dermatitis,
headache, anorexia, urinary frequency, sneezing, nasal
congestion, lacrimation, glycosuria, hypotension, transaminase
elevations and ECG changes
l Nephrotoxicity secondary to the dissociation of EDTA-metal
complexes in acid urine. The risk of nephrotoxicity during therapy
is reduced by:
— Ensuring adequate hydration and urine flow of 1–2 mL/kg/hour
— Limit daily dose to 2 g (1 g in children)
— Continuous therapy for no longer than 5 days
— Daily monitoring of renal function.
Paediatric: The doses of EDTA are the same for children, but may be
diluted in a smaller volume of fluid. Oral succimer is preferred as a
chelation agent whenever possible.
ANTIDOTES
HANDY TIPS
l The asymptomatic patient or minimally symptomatic patient, able
to tolerate oral therapy, should be treated with oral succimer rather
than EDTA.
PITFALLS
l Inadvertent or mistaken administration of dicobalt edetate, an
422
antidote used in the treatment of cyanide poisoning.
42
2
CONTROVERSIES
TOXICOLOGY HANDBOOK
l EDTA may cause redistribution of lead from the soft tissues to the
CNS. For this reason EDTA is not given as sole therapy for lead
toxicity with levels >70 microgram/dL
l Ability of EDTA chelation to reverse the neurobehavioural effects of
lead poisoning is unknown
l Utility of diagnostic EDTA chelation lead mobilisation test to
evaluate total body lead burden.
References
Bradberry S, Vale A. A comparison of sodium calcium edetate (edetate calcium disodium)
and succimer (DMSA) in the treatment of inorganic lead poisoning. Clinical Toxicology
2009; 47:841–858.
Treatment guidelines for lead exposure in children: Committee on Drugs. Pediatrics 1995;
96: 155–160.
4.27 SODIUM THIOSULFATE

Sodium thiosulfate enhances the endogenous cyanide detoxification
capacity of the body. It is suitable to use alone in the treatment of mild
to moderately severe cases of cyanide poisoning, but should be used in
conjunction with other antidotes in severe cyanide toxicity.
Presentations
Sodium thiosulfate 12.5 g/50 mL vial
l Reasonable suspicion of cyanide poisoning
l May also be useful in poisoning from other agents including:
— Chlorate
— Cisplatin
— Bromate
— Bromine
— Iodine
— Mustard gas
— Nitrogen mustard.
CONTRAINDICATIONS
l None: sodium thiosulfate has little toxicity at the recommended
doses.
Mechanism of action
The major route for detoxification of cyanide is by conversion to thiocyanate. This
ANTIDOTES
conversion is catalysed by the enzyme rhodanese. The capacity of rhodanese is limited
by the availability of suitable sulfur donors. Sodium thiosulfate acts as a sulfur donor for
rhodanese and greatly enhances the endogenous cyanide elimination capacity of the
body.
Pharmacokinetics
Thiosulfate is rapidly distributed throughout the extracellular space following intravenous
injection. Distribution into the brain is limited. Most is eliminated unchanged by renal
excretion, with an elimination half-life of 0.5–3 hours. A small amount is oxidised to sulfate 423
via a two-step hepatic process.
TOXICOLOGY HANDBOOK
ADMINISTRATION
l Administer 12.5 g sodium thiosulfate (50 mL of 25% solution) IV
over 10 minutes or 200 mg/kg IV over 10 minutes
l Repeat after 30 minutes if clinical features of cyanide toxicity
persist.


l Adverse effects are mild and of minor importance compared with
the risks associated with cyanide poisoning
l Rapid injection may be associated with nausea and vomiting
l Other minor adverse effects associated with thiocyanate
production are hypotension, nausea, headache, abdominal pain
and disorientation.
Paediatric: The recommended dose of 400 mg/kg is relatively higher
than for adults.
HANDY TIPS
l Collect blood for cyanide level before antidote administration
l The combination of sodium thiosulfate, oxygen and supportive
therapy is probably sufficient to treat mild to moderately severe
cases of cyanide toxicity
l Sodium thiosulfate is valuable in doubtful cases of poisoning,
such as smoke inhalation, where it may have both therapeutic and
diagnostic value
l In severe poisoning sodium thiosulfate should be given together
with other antidotes, with which it acts synergistically.
CONTROVERSIES
l There are no clinical trials that assess the efficacy of thiosulfate in
humans. It has a relatively slow onset of action and should probably
be regarded as a second-line antidote for acute cyanide poisoning.
ANTIDOTES
References
Hall AH, Dart R, Bogdan G. Sodium thiosulfate or hydroxocobalamin for empiric treatment
of cyanide poisoning? Annals of Emergency Medicine 2007; 49:806–813.
424 SubSectionNumber:5.12.2, accessed 15 April 2010.
42
4
4.28 SUCCIMER
TOXICOLOGY HANDBOOK
2,3-Dimercaptosuccinic acid (DMSA)

This orally active metal chelator is used to treat lead and other heavy
metal poisoning.
Presentations
Succimer 100 mg tablets (100), obtained under special access scheme in Australia
l Adultlead poisoning
— Symptomatic
— Asymptomatic with blood lead level >60 microgram/dL (>2.9
micromol/L)
l Paediatric lead poisoning
— Symptomatic
— Asymptomatic with blood lead level >45 microgram/dL (2.17
micromol/L)
— Has been used to chelate mercury, arsenic, bismuth, antimony
and copper, but clinical experience is limited.
CONTRAINDICATIONS
l Known hypersensitivity
l Ongoing heavy metal exposure.
Mechanism of action
Succimer is a water-soluble analogue of dimercaprol, which binds to heavy metal ions via
sulfhydryl groups. The succimer–metal complexes can then be excreted in the urine.
Pharmacokinetics
Following oral administration, succimer is rapidly absorbed and undergoes rapid
metabolism. Metabolites and some unchanged drug are excreted in the urine.
ADMINISTRATION
l Lead poisoning
— May be administered on an outpatient basis
— Give 10 mg/kg orally 3 times per day for 5 days
then
— Give 10 mg/kg orally 2 times per day for 14 days
— Blood lead levels are followed after completion of this initial
course
— Further courses are indicated if blood levels rebound in the
absence of continued lead exposure
ANTIDOTES
— For more severe poisoning, succimer may be used after initial
chelation with parenteral agent (sodium calcium edetate)
(see Chapter 4.26: Sodium calcium edetate)
— In the absence of any guidelines, administration is the same as
for lead poisoning.
425
l Hypersensitivity reactions
l Gastrointestinal upset is very common with this foul-smelling drug
TOXICOLOGY HANDBOOK
— Symptomatic care for gastrointestinal symptoms
— Converting to parenteral therapy may occasionally be
necessary
l Transient liver function test abnormalities (occurs in up to 60% of
patients)
l Reversible neutropenia (rare).
Pregnancy: Safety not established. Consideration is given to chelation
therapy at lower blood levels because of the susceptibility of the fetal
central nervous system to lead
Paediatric: The doses for succimer are the same. It is generally
accepted that the blood lead level threshold for chelation is lower in
children than adults.
HANDY TIPS
l The asymptomatic patient or minimally symptomatic patient, able
to tolerate oral therapy, should be treated with oral succimer rather
than sodium calcium edetate
l Succimer can be given on an outpatient basis to compliant patients.
PITFALLS
l Itmay be difficult to obtain succimer—it is only available in
Australia under the special access scheme.
CONTROVERSIES
l The threshold blood level for succimer chelation in children is
extremely controversial. Although relatively low blood lead levels
may have an adverse effect on neurodevelopment, the evidence
to date does not suggest that chelation therapy improves
outcome.
References
Bradberry S, Vale A. Dimercaptosuccinic acid (succimer; DMSA) in inorganic lead
poisoning. Clinical Toxicology 2009; 47; 617–631.
Dietrich KN, Ware HH, Salganik M et al. Effect of chelation on the neuropsychological and
behavioral development of lead-exposed children after school entry. Pediatrics 2004;
114:19–26.
Treatment guidelines for lead exposure in children: Committee on Drugs. Pediatrics 1995;
96: 155–160.
ANTIDOTES
4.29 VITAMIN K
Phytomenadione, Phytonadione, Vitamin K1
An essential cofactor in the synthesis of clotting factors II, VII, IX and X.
It is used for the reversal of coumadin-induced coagulopathy.
426 Presentations
42
Phytomenadione 10 mg tablets (100)

6
Phytomenadione 2 mg/0.2 mL ampoules

Phytomenadione 10 mg/1 mL ampoules
TOXICOLOGY HANDBOOK
l Significant coumadin-induced coagulopathy:
— Therapeutic over-warfarinisation
— Intentional warfarin overdose
— Ingestion of long-acting anticoagulant rodenticides (e.g.
brodifacoum).
CONTRAINDICATIONS
Mechanism of action
Phytomenadione is a synthetic fat-soluble analogue of naturally-occurring vitamin K1,
an essential cofactor in the synthesis of clotting factors II, VII, IX and X. The coumadin
anticoagulants inhibit vitamin K1 2,3-epoxide reductase, thus preventing the formation of
vitamin K hydroxyquinone, the active form of vitamin K. This leads to impaired formation
of clotting factors. Administration of high doses of vitamin K is able to overcome this effect
and restore normal levels of clotting factors.
Pharmacokinetics
Oral bioavailability is variable and dependent on bile salts, but is usually about 50%. It is
rapidly metabolised by the liver, with an elimination half-life of about 2 hours. The increase
in blood coagulation factors is delayed 6–12 hours after an oral dose and 3–6 hours after
an IV dose.
ADMINISTRATION
The approach and dosing of Vitamin K varies according to the clinical
indication and relative need to maintain anticoagulation.
Therapeutic over-warfarinisation
l See Appendix 5: Therapeutic over-warfarinisation
Warfarin overdose
l No therapeutic requirement for warfarin anticoagulation (patient
took someone else’s warfarin)
— Single dose 10–20 mg vitamin K PO or IV
— INR can be checked at 48 hours as an outpatient
l Therapeutic requirement for warfarin anticoagulation
— Closely monitor INR (at least every 6 hours)
— Give vitamin K 0.5–2 mg IV if INR >5
— Continue close monitoring of INR
— Give repeat doses of vitamin K 0.5–2 mg IV if INR remains or
returns to >5
— Start heparin if INR falls <2 and absolute indication for
anticoagulation (mechanical heart valve)
ANTIDOTES
Ingestion of long-acting anticoagulant rodenticide
l Very large doses of oral vitamin K (10–50 mg up to 4 times a day)
are required for a period of weeks to months if anticoagulation
develops
l Initial daily dose is variable and determined under close medical
supervision with repeated INR estimations
l Close medical supervision is also necessary during treatment to 427
ensure compliance and safe withdrawal of vitamin K
l Note: Active bleeding or high-risk of active bleeding (INR >9)
requires immediate reversal of anticoagulation by administration
TOXICOLOGY HANDBOOK
of prothrombin complex concentrate and fresh frozen plasma,
in addition to vitamin K administration to achieve sustained
reversal.

l Minor facial flushing, chest tightness, dyspnoea or dizziness with IV
administration
l Anaphylaxis following IV administration (rare)
l Warfarin resistance and over-correction of anticoagulation
– Manage with heparinisation until warfarin resistance has
resolved and therapy can be re-established.
Paediatric: Treat suspected paediatric ingestion of warfarin tablets
(>0.5 mg/kg) empirically with a single dose of vitamin K solution 5 mg
PO. This obviates the need for repeated blood tests.
HANDY TIPS
l Never give vitamin K by the intramuscular route
l When giving vitamin K for warfarin reversal it is preferable to
give the injectable formulation orally rather than use tablets.
This formulation is well absorbed orally and allows more flexible
dosing
l Single unintentional acute ingestion of an anticoagulant
rodenticide by a child does not involve a sufficient dose to cause
anticoagulation. Neither medical assessment nor vitamin K therapy
is necessary.
PITFALLS
l Administration of excessive doses of vitamin K in patients with
an absolute indication for anticoagulation. The resulting warfarin
resistance necessitates prolonged heparin administration prior to
successful reintroduction of warfarin therapy
l Administration of vitamin K prior to demonstration of anticoagulant
effectinadultswhoself-poisonwithlong-actinganticoagulantrodenticides.
CONTROVERSIES
l The threshold INR for vitamin K administration following
therapeutic over-warfarinisation or warfarin overdose.
References
ANTIDOTES
Baker RI, Coughlin PB, Gallus AS et al. Warfarin reversal: consensus guidelines, on behalf
of the Australasian Society of Thrombosis and Haemostasis. Medical Journal of
Australia 2004; 181(9):492–497.
Bruno GR, Howland MA, McMeeding et al. Long-acting anticoagulant overdose:
brodifacoum kinetics and optimal vitamin K dosing. Annals of Emergency Medicine
2000; 36(3):262–267.
Dentali F, Ageno W, Crowther M. Treatment of coumarin-associated coagulopathy: a
428 systematic review and proposed treatment algorithms. Journal of Thrombosis and
Haemostasis 2006; 4:1853–1863.
42
8
Isbister GK, Hackett LP and Whyte IM. Intentional warfarin overdose. Therapeutic Drug
Monitoring 2003; 25(6):715–722.
TOXICOLOGY HANDBOOK
CHAPTER 5
ENVENOMINGS
5.1 lack snake

B 430
5.2 Brown snake 433
5.3 Death adder 436
5.4 Tiger snake 439
5.5 Taipan 442
5.6 Sea snake 445
5.7 Australian scorpions 447
5.8 Bluebottle jellyfish (Physalia species) 449
5.9 Stonefish 450
5.10 Box jellyfish (Chironex fleckeri) 452
5.11 Irukandji syndrome 454
5.12 Blue-ringed octopus 457
5.13 Redback spider 459
5.14 Funnel-web (big black) spider 461
5.15 White-tailed spider 463
5.16 Ticks 465
5.1 BLACK SNAKE Distribution of mulga snakes
l Pseudechis australis: mulga or king Perth Hills

brown snake Upper
l Pseudechis butleri: Butler’s or yellow- Swan Moree
bellied black snake
l Pseudechis colletti: Collett’s snake
l Pseudechis guttatus: blue-bellied or
spotted black snake
l Pseudechis papuanus: Papuan black
snake
l Pseudechis porphyriacus: red-bellied or
common black snake
Kalgoorlie
Mulga snakes are large aggressive Mildura
snakes found throughout inland and NOT Eyre
northern Australia. They usually inflict Peninsula Orange
a large bite, produce a significant
amount of venom and are potentially
ENVENOMINGS
lethal. Envenoming by the Collett’s

snake is rare, has only been reported
in snake handlers and has features of Distribution of red-bellied
black snakes
envenoming similar to mulga snakes.
Red-bellied black snakes are found Big Tableland
along the south-eastern coastal areas to Mt Elliot Proserpine to
and the envenoming is not usually lethal, Eungella
even without treatment.
430
43
0
TOXINS
Mulga snake venom contains Bourke
TOXICOLOGY HANDBOOK
myotoxins, neurotoxins and

anticoagulant toxins. It has no
procoagulant toxins. Red-bellied
and blue-bellied black snake
venoms have less potent toxins,
which cause minor myolysis Wilcannia
only. Gladstone
CLINICAL PRESENTATION AND COURSE

Mulga snake, Collett’s snake, Butler’s snake and Papuan
black snake
l These snakes characteristically inflict a large, painful bite leading
to extensive local tissue swelling. Regional lymphadenitis occurs in
60% of cases
l S ystemic features of headache, abdominal pain, nausea,
vomiting or diarrhoea occur in almost all envenomed patients
within a short time of the bite. Generalised myalgia and muscle
weakness develop within 6 hours of envenoming and last
several days in untreated patients. Features of mild paralysis,
such as blurred vision, ptosis or diplopia, occur in 15% of
envenomings
l yoglobinuria and renal failure may occur secondary to
M
rhabdomyolysis. Clinical features of anticoagulation, such as
bleeding gums, are rare
Red-bellied and blue-bellied black snakes
l Bites by the red-bellied or blue-bellied black snake usually cause
local pain and discomfort, but patients rarely develop systemic
features of envenoming. Minor myolysis may occur, but features of
paralysis or coagulopathy do not
l Minor, but unpleasant, long-term neurological sequelae, such as
anosmia and areas of numbness, paraesthesia or pain in the region
of the bite site, are reported.
MANAGEMENT
See Chapter 2.1: Approach to snakebite for a guide to the principles
of snakebite management.
Pre-hospital
l Apply a pressure immobilisation bandage (PIB)
l Transport to a hospital capable of providing definitive care
ENVENOMINGS
Hospital
esuscitation and supportive care
R
l Black snake envenoming is rarely an immediate life-threatening
emergency. However, patients should still be managed in an area
capable of cardiorespiratory monitoring and resuscitation
l Watch for evidence of rhabdomyolysis and deteriorating renal
function
Antivenom
431
l Systemic envenoming by black snakes is defined by
gastrointestinal symptoms refractory to supportive care, or
objective evidence of evolving rhabdomyolysis (e.g. CK rise above
TOXICOLOGY HANDBOOK
5000 IU/L). It is treated with an initial dose of 1 ampoule of either
monovalent Black Snake or Tiger Snake Antivenom
l CSL monovalent Black Snake Antivenom (see Chapter 6.1) is the
definitive treatment of systemic envenoming by mulga, Collett’s,
Butler’s and Papuan black snakes
l CSL monovalent Tiger Snake Antivenom or CSL monovalent Black
Snake Antivenom (see Chapters 6.1 and 6.4) is used to treat
envenoming by red-bellied and blue-bellied black snakes.
INVESTIGATIONS
l he diagnosis of envenoming is based on the correlation of history,
T
clinical features and laboratory data
l Routine laboratory investigations following snakebite include: FBC,
EUC, CK and coagulation profile (INR, APTT, fibrinogen, d-dimer)
at presentation and at intervals thereafter (see Chapter 2.1:
Approach to snakebite)
l CK is usually abnormal at the time of presentation if envenoming
has occurred. However, it may not become grossly abnormal
(>1000 IU/L) for many hours. CK levels are repeated every 6 hours
if the patient is symptomatic. If the patient is asymptomatic with
mild elevation of CK or APTT recheck every 12 hours
l he anticoagulant coagulopathy of black snake envenoming is
T
characterised by:
— Elevated APTT and INR (usually mild)
— Normal fibrinogen
— Normal d-dimer and fibrin degradation products
— Normal platelet count
l The Snake Venom Detection Kit (SVDK) is not used to diagnose
envenoming. Instead, it is used to determine the correct
monovalent antivenom if one or more snake types could be
responsible for the observed clinical features.
l levation of the CK may also be observed in taipan and tiger snake
E
envenoming
l In contrast to the venom-induced consumptive coagulopathy
(VICC) observed in brown, taipan and tiger snake envenoming,
the abnormalities of APTT and INR in black snake envenoming are
usually mild and the fibrinogen level normal
l Death adders may cause a painful bite. Presentation may include
early clinical features of a symmetrical descending flaccid paralysis
ENVENOMINGS
(e.g. ptosis or diplopia), but rhabdomyolysis and coagulation

defects do not occur.

l ll patients must be admitted for observation to a hospital capable of
A
providing definitive care (see Chapter 2.1: Approach to snakebite)
l Patients who have no clinical features and no laboratory evidence
432 of rhabdomyolysis at 12 hours are not envenomed and may be
43
2
l Envenomed patients may be discharged following antivenom

administration if they are clinically well, their coagulation studies
TOXICOLOGY HANDBOOK
and CK are improving, and there is no evidence of clinically

significant renal failure.
HANDY TIPS
l he mulga snake is sometimes referred to as the king brown
T
snake, however it is not a brown snake and envenoming will not
resolve with Brown Snake Antivenom
l Envenoming by the red-bellied black snake or blue-bellied black
snake is usually mild and rarely requires antivenom. If antivenom is
indicated, Tiger Snake Antivenom may be used as an alternative to
Black Snake Antivenom
l Envenoming by an Australian snake, associated with local
pain, headache, nausea and vomiting, and a mild anticoagulant
coagulopathy (increased APTT but normal fibrinogen), is highly
suggestive of black snake envenoming.
PITFALLS
l ailure to recognise that snakebite may have occurred, institute
F
early PIB or to manage the patient in a hospital setting for an
appropriate duration
l Inaccurate snake identification
l Misinterpretation of a SVDK result
l Administration of antivenom to a patient who is not envenomed.
CONTROVERSIES
l he point at which slowly evolving rhabdomyolysis is treated with
T
antivenom. Antivenom prevents progression of muscle injury,
but does not reverse injury that has already occurred. Most
experienced clinicians treat with antivenom if CK exceeds 5000
IU/L. A much lower threshold is used if the patient is symptomatic
l The indications for antivenom administration following red-bellied
black snake envenoming and the antivenom of choice (Tiger or
Black Snake Antivenom).
References
Currie BJ. Snakebite in tropical Australia: a prospective study in the “Top End” of the
Northern Territory. Medical Journal of Australia 2004; 181:693–697.
White J. Snakebite and spiderbite management guidelines for South Australia 2005.
Adelaide: Department of Health; South Australia.
5.2 BROWN SNAKE Distribution of brown snakes
ENVENOMINGS
l Pseudonaja affinis: dugite
l Pseudonaja guttata: spotted brown
snake
l Pseudonaja inframacula: peninsula
brown snake
l Pseudonaja ingrami: Ingram’s brown
snake
l Pseudonaja mengendi: western brown 433
snake or gwardar
l Pseudonaja modesta: ringed brown Rottnest
snake Island
TOXICOLOGY HANDBOOK
l Pseudonaja nuchalis: tropical brown
snake
l Pseudonaja textilis: eastern brown snake
Brown snake envenoming is the most common cause of death from
snakebite in Australia. The most important manifestation of severe
envenoming is venom-induced consumptive coagulopathy (VICC).
TOXINS
The venom contains procoagulants, cardiotoxins and a potent
presynaptic neurotoxin (textilotoxin).

l atients may present asymptomatic with no obvious bite site
P
l Non-specific features of envenoming include headache, nausea,
vomiting and abdominal pain
l Systemic envenoming may be heralded by pre-syncope or sudden
collapse
l Early death occurs rarely, probably secondary to direct
cardiotoxicity
l The hallmark of brown snake envenoming is VICC. This develops soon
after the bite and may manifest clinically as bleeding gums, persistent
haemorrhage at venesection sites or intracerebral haemorrhage
l hrombotic microangiopathy, characterised by thrombocytopenia,
T
microangiopathic haemolytic anaemia (MAHA) and acute renal
failure occur in about 10% of brown snake envenomings. Oliguria
may be present from the time of envenoming
l Rhabdomyolysis does not occur and significant neurotoxicity
is rare, despite the presence of a neurotoxin in the venom. Mild
diplopia and ptosis are observed occasionally.
MANAGEMENT
Pre-hospital
Hospital
l Brown snake envenoming is a potentially life-threatening
emergency and patients should be managed in an area capable of
ENVENOMINGS

include:
— Hypotension
— VICC with uncontrolled haemorrhage
l In cardiac arrest secondary to brown snake envenoming, undiluted
antivenom, administered as a rapid IV push may be life saving
434 Antivenom
l CSL Brown Snake Antivenom (see Chapter 6.2) is the definitive
43
treatment of envenoming. A dose of 2 ampoules (2 x 1000 units) is

4
indicated for systemic envenoming, as evidenced by collapse or

TOXICOLOGY HANDBOOK
objective evidence of coagulopathy.
INVESTIGATIONS
T
l Envenoming is diagnosed if there is a history of collapse, objective
clinical evidence of VICC, or laboratory abnormalities consistent
with brown snake envenoming during 12 hours of observation
l VICC is characterised by:
— Elevated INR (at least >3 but usually unrecordable)
— Undetectable fibrinogen
— Elevated d-dimer (10 x normal) and fibrin degradation products
l Recovery from VICC (INR returning to <2) usually occurs between
10 and 20 hours after the bite
l Thrombocytopenia may develop
l Watch for deteriorating renal function and evidence of MAHA,
indicated by raised lactate dehydrogenase (LDH) and fragmented
red blood cells on blood film
l he Snake Venom Detection Kit (SVDK) is not used to diagnose
T
l iger snake and brown snake envenoming may be
T
indistinguishable, early in the course, as both feature VICC.
However, in tiger snake envenoming, paralysis and
rhabdomyolysis evolve over the ensuing hours
l Taipan envenoming also features VICC, but it is usually
associated with early paralysis and rhabdomyolysis
l Black snake envenoming is associated with a mild
anticoagulant coagulopathy, normal fibrinogen levels and
myolysis (raised CK).

l ll patients must be admitted for observation to a hospital capable
A
of providing definitive care (see Chapter 2.1: Approach to
ENVENOMINGS
snakebite)
l Patients with no clinical features and no laboratory evidence
of coagulopathy at 12 hours are not envenomed and may be
l Envenomed patients should be monitored for a further 24 hours
following antivenom. This timeframe allows laboratory confirmation
of recovery from VICC and determination of whether they are
developing renal failure or microangiopathic haemolytic anaemia.
The patient is fit for discharge at the end of that time if they are 435
clinically well, the INR has returned to <2, and renal function and
blood counts remain stable
l Patients who develop thrombotic microangiopathy require a
TOXICOLOGY HANDBOOK
more prolonged admission for management of acute renal failure
and MAHA. Up to 8 weeks of dialysis may be required until renal
function recovers.
HANDY TIPS
l he majority of patients bitten by brown snakes do not become
T
envenomed
l In the early stages, brown snake envenoming may be
indistinguishable from tiger snake envenoming
l Early collapse after a brown snake bite is virtually pathognomonic
of envenoming
l All patients should be managed in a hospital equipped with
sufficient antivenom stocks (2 ampoules) to definitively treat
potential envenoming.
PITFALLS
F
l Misinterpretation of a SVDK result.
CONTROVERSIES
l ecent evidence suggests that administration of antivenom does
R
not hasten recovery from VICC. It may, however, reverse or prevent
other manifestations of envenoming
l Administration of clotting factors (fresh frozen plasma or
cryoprecipitate) after antivenom administration is associated with
earlier recovery from VICC. Randomised controlled clinical trials
are currently being conducted to determine the efficacy and safety
of clotting factor replacement after venom neutralisation in VICC
l Plasmapheresis has been used to treat thrombotic
microangiopathy, but its role remains undefined.
References
Brown SG, Caruso N, Borland M et al. Clotting factor replacement and recovery from
35(9):1532–1538.
Isbister GK, Duffull SB, Brown SGA. Failure of antivenom to improve recovery in Australian
snakebite coagulopathy. Quarterly Journal of Medicine 2009; 102(8):563–568.
Isbister GK, Little M, Cull G et al. Thrombotic microangiopathy from Australian brown
snake (Pseudonaja) envenoming. Internal Medicine Journal 2007; 37(8): 523–528.
ENVENOMINGS
Sutherland SK, Tibballs J. Australian animal toxins: the creatures, their toxins and care of
the poisoned patient. South Melbourne: Oxford University Press; 2001.
5.3 DEATH ADDER Distribution of death adders
436 l Acanthophis antarcticus: common death

43
adder
6
l Acanthophis hawkei: Barkly Tableland

death adder
TOXICOLOGY HANDBOOK
l Acanthophis laevis: smooth scale death

adder (PNG)
l Acanthophis praelongus: northern death
adder
l Acanthophis pyrrhus: desert death
adder Mundaring
l Acanthophis rugosus: rough scale death
Esperance
adder (PNG)
l Acanthophis wellsi: Pilbara death adder NOT Victoria or
Tasmania
Death adders are found throughout most
of mainland Australia and Papua New
Guinea, but both bites and envenoming
are uncommon. Prior to mechanical ventilation and antivenom mortality
was approximately 50%.
TOXIN
The venom contains a post-synaptic neurotoxin.

l ain or stinging at the bite site is common; however, puncture
P
wounds may not be apparent
l ystemic envenoming is characterised by a progressive
S
symmetrical descending flaccid paralysis, which usually manifests
within 6 hours. Early signs include ptosis, blurred vision, diplopia
and difficulty swallowing. If left untreated, generalised paralysis,
respiratory failure and secondary hypoxic cardiac arrest ensue.
With the institution of advanced airway support, paralysis resolves
spontaneously after 1–2 days
l Coagulopathy, rhabdomyolysis and renal failure are not features of
death adder envenoming.
MANAGEMENT
See Chapter 2.1: Approach to snakebite for a general guide to the
principles of snakebite management
Pre-hospital
Hospital
ENVENOMINGS
l Death adder envenoming is a potentially life-threatening emergency
and patients are managed in an area capable of cardiorespiratory
include:
— Descending flaccid paralysis with respiratory failure
— Hypotension
l If respiratory failure is present and antivenom is not immediately
available, provision of an airway and mechanical ventilation are life 437
saving
Antivenom
TOXICOLOGY HANDBOOK
l CSL monovalent Death Adder Antivenom (see Chapter 6.3) is
the definitive treatment of envenoming. Systemic envenoming,
with objective evidence of paralysis, is treated with an initial dose
of 1 ampoule (6000 units). A single dose is sufficient to reverse
paralysis in most cases.
INVESTIGATIONS
l he diagnosis of envenoming is based on the correlation
T
of history, clinical features and laboratory data
l Routine laboratory investigations following snakebite include:
FBC, EUC, CK and coagulation profile (INR, APTT, fibrinogen,
d-dimer) at presentation and at intervals thereafter (see Chapter
2.1: Approach to snakebite). These investigations are normal in
death adder envenoming
l Spirometry or peak flow measurements provide a surrogate
method of monitoring respiratory muscle strength and respiratory
function
l The Snake Venom Detection Kit (SVDK) is not used to
diagnose envenoming. Instead, it is used to determine
the correct monovalent antivenom if one or more
snake types could be responsible for the observed clinical
features.
l nvenoming by tiger, taipan and (rarely) brown snakes is
E
associated with neurotoxic paralysis. However, envenoming
by these snakes is usually associated with venom-induced
consumptive coagulopathy (VICC).

A
snakebite)
l Patients who are not envenomed will have no clinical features of
paralysis at 24 hours and may be discharged. Discharge should not
occur at night
l Envenomed patients may be discharged if they have complete
reversal of paralysis and remain clinically well for 24 hours
following antivenom administration.
HANDY TIPS
l eath adders are quiet and nocturnal. A common scenario is that
D
ENVENOMINGS
the victim is bitten on the ankle after treading on the snake while
walking outside with bare feet at dusk. The victim may feel little
more than a sting and not see the snake
l A painful bite site associated with a symmetrical descending
flaccid paralysis, but normal blood tests is characteristic of death
adder envenoming
l Basic resuscitation with maintenance of airway and breathing is life
saving
438 l In the absence of monovalent Death Adder Antivenom, 1 ampoule
43
of CSL Polyvalent Antivenom contains 6000 units of Death Adder

8
Antivenom and may be administered as an alternative

l In the absence of antivenom, neurotoxicity may be reversed by
TOXICOLOGY HANDBOOK

administration of neostigmine.
PITFALLS
F
l Administration of antivenom to a non-envenomed patient
l Failure to detect early neurotoxicity: ptosis, double vision and
falling FEV1.
CONTROVERSIES
l he role of neostigmine as an alternative to antivenom
T
treatment.
References
Currie BJ. Snakebite in tropical Australia: a prospective study in the “Top End” of the
Northern Territory. Medical Journal of Australia 2004; 181:693–697.
Lalloo DG, Trevett AJ, Black J et al. Neurotoxicity, anticoagulant activity and evidence of
rhabdomyolysis in patients bitten by death adders (Acanthopis sp.) in southern Papua
New Guinea. Quarterly Journal of Medicine 1996; 89:25–35.
Little M, Pereira P. Successful treatment of presumed death adder neurotoxicity using
anticholinesterases. Emergency Medicine 2000; 12:241–245.
5.4 TIGER SNAKE Distribution of tiger snakes
l Austrelaps labialis: pygmy copperhead Maryborough Sound

l Austrelaps superbus: common Fraser Island
copperhead Cooktown
l Hoplocephalus bitorquatus: Moore
River
pale-headed snake
l Hoplocephalus bungaroides: Bunya
broad-headed snake Point Mountains
Malcolm
l Hoplocephalus stephensi: Stephen’s
banded snake Orange
l Notechis ater: western or black tiger
snake Garden Eyre
ENVENOMINGS
l Notechis scutatus: and Peninsula
common or eastern tiger snake Carnac
Islands
l Tropidechis carinatus: rough-scaled NOT Kangaroo Bass
snake Rottnest Island Strait
Island Islands
Tiger snakes are widespread throughout
southern Australia and are the second
most common cause of snakebite death in Australia. They coexist with
brown snakes in most areas and early clinical features of envenoming 439
are very similar. Tiger snakes are the only venomous snakes in
Tasmania.
TOXICOLOGY HANDBOOK
TOXINS
Tiger snake venom contains pre- and post-synaptic neurotoxins,
procoagulants and myolysins. Envenoming is classically associated
with a venom-induced consumptive coagulopathy (VICC),
rhabdomyolysis and gradual onset paralysis.

l ot all patients who are bitten become envenomed, but serious
N
envenoming may develop in patients without an obvious bite site
l Local pain is reported in about half of all envenomings
vomiting and abdominal pain. These symptoms are usually present
on presentation to hospital
l Systemic envenoming may be heralded by collapse and, rarely,
early death secondary to cardiac arrest
l VICC occurs rapidly and may manifest as bleeding gums,
persistent haemorrhage at venesection sites or intracerebral
haemorrhage. The coagulopathy resolves spontaneously within
10–20 hours
l Paralysis is usually apparent within 1–2 hours of the bite, but is
slow in onset and progresses over many hours. The earliest clinical
features of neurotoxicity are diplopia and ptosis
l habdomyolysis is a late feature of envenoming and may be
R
massive. It is manifest by myalgia and myoglobinuria, and may
progress to cause renal failure
l Envenoming by the rough-scaled snake is similar to that of tiger
snakes
l Copperhead snakes have neurotoxins and myolysins, but
envenoming is usually mild and coagulopathy uncommon
l Hoplocephalus species produce VICC, but not significant paralysis
or rhabdomyolysis.
MANAGEMENT
Pre-hospital
Hospital
l Tiger snake envenoming is a potentially life-threatening emergency
ENVENOMINGS

— Paralysis with respiratory failure
— Hypotension
l In cardiac arrest secondary to tiger snake envenoming, undiluted
440 antivenom, administered as a rapid IV push may be life saving
44
Antivenom
0
l CSL Tiger Snake Antivenom (see Chapter 6.4) is the definitive

treatment of envenoming. Systemic envenoming, as evidenced by
TOXICOLOGY HANDBOOK
collapse or objective evidence of coagulopathy, is treated with a

dose of 2 ampoules (2 x 3000 units)
l Note: Tiger Snake Antivenom does not reverse established
paralysis but does halt progression.
INVESTIGATIONS
T
l Envenoming is diagnosed if there is a history of collapse, objective
clinical evidence of coagulopathy, or laboratory abnormalities
consistent with tiger snake envenoming during 12 hours of
observation
T
l iger snake and brown snake envenoming may be indistinguishable,
T
early in the course, as both feature VICC. Significant paralysis or
rhabdomyolysis is rare in brown snake envenoming
l Taipan envenoming also features VICC, but the onset of
neurotoxicity and rhabdomyolysis is usually more rapid
l Black snake envenoming is associated with rhabdomyolysis, but
only a mild anticoagulant coagulopathy with normal fibrinogen
levels
l Death adder envenoming is associated with a symmetrical
descending flaccid paralysis, which is gradual in onset. It is not
associated with coagulopathy, rhabdomyolysis or renal failure.
ENVENOMINGS
A
snakebite)
l Patients who are not envenomed will not have clinical features of
paralysis or laboratory evidence of coagulopathy at 12 hours and
may be discharged. Discharge should not occur at night
administration if they are clinically well, their coagulation studies
are improving (INR <2), and there is no evidence of clinically 441
significant renal failure.
HANDY TIPS
TOXICOLOGY HANDBOOK
l iger snake envenoming should be considered in the differential
T
diagnosis of collapse, paralysis or defibrinating coagulopathy
l In the early stages, tiger snake envenoming may be
indistinguishable from brown snake envenoming.
PITFALLS
F
l Administering antivenom to a patient who is not envenomed.
CONTROVERSIES
R
of clotting factor replacement after venom neutralisation in VICC.
References
Brown SG, Caruso N, Borland M et al. Clotting factor replacement and recovery from
35(9):1532–1538.
Gan M, O’Leary MA, Brown SG et al. Envenoming by the rough-scaled snake (Tropidectis
carinatus): a series of confirmed cases. Medical Journal of Australia 2009; 191(3):
183–186.
Isbister GK, Duffull SB, Brown SGA. Failure of antivenom to improve recovery in
Australian snakebite coagulopathy. Quarterly Journal of Medicine 2009; 102(8):
563–568.
Scop J, Little M, Jelinek GA et al. 16 years of severe tiger snake (Notechis) envenoming in
Perth, Western Australia. Anaesthesia and Intensive Care 2009; 37:613–618.
5.5 TAIPAN Distribution of taipans

ENVENOMINGS
Coastal taipan
l Oxyuranus microlepidotus: inland (Oxyuranus scutellatus)
taipan, small-scaled or fierce snake Mitchell
l Oxyuranus scutellatus canni: Papuan Plateau
taipan Koolan
l Oxyuranus scutellatus: coastal
Island
taipan Birdum
l Oxyuranus temporalis Normanton
442 Taipan envenoming is rare and is
44
usually lethal without antivenom

2
treatment. It is characterised by rapid (Oxyuranus

onset of venom-induced consumptive
TOXICOLOGY HANDBOOK
temporalis)
coagulopathy (VICC), neurotoxicity and Coober
Pedy
rhabdomyolysis. The Papuan taipan is Maclean
the most medically important snake in Inland taipan
(Oxyuranus microlepidotus)
Papua New Guinea.
TOXINS
Taipan venom contains potent pre- and post-synaptic neurotoxins
(paralysis), myotoxins (rhabdomyolysis) and procoagulants (activators
of factor VII and prothrombin).

l ite sites have minimal or no symptoms, puncture marks are often
B
not apparent and patients may not recognise that they have been
bitten
l Non-specific features of envenoming include headache, nausea
and vomiting
l Systemic envenoming may be heralded by collapse within a
few minutes of the bite and paralysis is usually apparent within
1–2 hours
l Clinical features of VICC include bleeding gums, persistent
haemorrhage at venesection sites or intracerebral haemorrhage
l habdomyolysis manifests by myalgia and myoglobinuria, and may
R
progress to cause renal failure
l Thrombotic microangiopathy characterised by thrombocytopenia,
microangiopathic haemolytic anaemia (MAHA) and acute renal
failure is a rare complication.
MANAGEMENT
See Chapter 2.1: Approach to snakebite for a general guide to the
principles of snakebite management.
Pre-hospital
Hospital
l Taipan envenoming is a time-critical and life-threatening
emergency and patients are managed in an area capable of
include:
ENVENOMINGS
— Hypotension
— Rapid onset paralysis with secondary respiratory failure
— Seizures
l In cardiac arrest, undiluted antivenom, administered as a rapid IV
push, may be life saving
Antivenom
l CSL Taipan Antivenom (see Chapter 6.5) is the definitive treatment 443
of envenoming by taipans. Systemic envenoming, as evidenced
by collapse or objective evidence of paralysis or coagulopathy, is
treated with an initial dose of 1 ampoule (12 000 units)
TOXICOLOGY HANDBOOK
l Note: If monovalent Taipan Antivenom is not immediately available,
each ampoule of CSL Polyvalent Antivenom contains 12 000 units
of Taipan Antivenom and may be administered as a substitute
l Note: Taipan Antivenom does not reverse established paralysis,
but does halt the progression.
INVESTIGATIONS
T
l Watch for deteriorating renal function and evidence of MAHA,
indicated by raised lactate dehydrogenase (LDH) and fragmented
red blood cells on blood film
T
envenoming. It is used to determine the correct monovalent
antivenom if one or more snake types could be responsible for the
observed clinical features.
l rown snakes are found in the same geographic areas as taipans.
B
Brown snake envenoming may also cause VICC, but significant
paralysis and rhabdomyolysis are rare
l Snakes from the tiger snake group coexist with taipans in some areas
of Queensland. The clinical features of envenoming by this group
are similar to taipan envenoming, but the onset of neurotoxicity and
rhabdomyolysis is more gradual (over several hours)
l Black snake envenoming is associated with rhabdomyolysis and a
mild anticoagulant coagulopathy with normal fibrinogen levels
l Death adder envenoming is associated with a symmetrical
descending flaccid paralysis, but is not associated with
coagulopathy, rhabdomyolysis or renal failure.
ENVENOMINGS

A
l Patients without clinical features of paralysis or laboratory evidence
of coagulopathy or rhabdomyolysis at 12 hours are not envenomed
and may be discharged. Discharge should not occur at night
l Envenomed patients can be discharged following antivenom
administration if they are clinically well, neurological findings are
444 mild and stable, their coagulation studies are improving (INR <2) and
CK is falling, and there is no evidence of significant renal failure.
44
4
HANDY TIPS
TOXICOLOGY HANDBOOK
l aipan envenoming should be considered in the differential

T
diagnosis of patients in tropical Australia who present with
collapse, paralysis or a defibrinating coagulopathy
l VICC occurs in taipan, brown and tiger snake envenoming.
PITFALLS
F
l Administration of antivenom to a non-envenomed patient.
CONTROVERSIES
R
of clotting factor replacement after venom neutralisation in VICC.
References
Sutherland SK, Tibballs J. Australian animal toxins: the creatures, their toxins and
care of the poisoned patient. South Melbourne: Oxford University Press;
2001.
Trevett AJ, Lalloo DG, Nwokolo NC et al. The efficacy of antivenom in the treatment of
bites by the Papuan taipan (Oxyuranus scutellatus canni). Transactions of the Royal
Society of Tropical Medicine and Hygiene 1995; 89:322–325.
Williams D, Bal B. Papuan Taipan (Oxyuranus scutellatus canni) envenomation in rural
Papua New Guinea. Annals of Australasian College of Tropical Medicine 2003;
4(1):6–9.
5.6 SEA SNAKE Distribution of sea snakes
At least 30 species of sea snakes are

Sydney
found around the coast of northern
Australia. They belong to the family
Hydrophiidae, and are closely
related to the venomous Australian
ENVENOMINGS
terrestrial snakes (Elapidae). They
are inquisitive, but rarely aggressive
and bites are most likely to occur
when they are handled, for example,
when they are manually removed from
fishing nets.
Esperance
TOXINS 445
Sea snake venom contains post-
synaptic neurotoxins (paralysis)
and myotoxins (rhabdomyolysis).
TOXICOLOGY HANDBOOK
l ost bites are very small, superficial, relatively painless and not
M
associated with local swelling or lymphadenitis
l Non-specific features of envenoming include headache, nausea
and vomiting
l Systemic envenoming is characterised by symmetrical
descending flaccid paralysis, which usually manifests within
6 hours. Early signs include ptosis, blurred vision, diplopia
and difficulty swallowing. If left untreated generalised
paralysis, respiratory failure and secondary hypoxic cardiac
arrest ensue
l Rhabdomyolysis manifests as myalgia and myoglobinuria
and may progress to cause renal failure.
MANAGEMENT
Pre-hospital
Hospital
l Sea snake envenoming is a time-critical life-threatening emergency
include:
— Rapid onset paralysis with secondary respiratory failure
— Hypotension
l If respiratory failure occurs and antivenom is not immediately
available, provision of an airway and mechanical ventilation is life
saving
Antivenom
l CSL Sea Snake Antivenom (see Chapter 6.6) is the definitive
treatment of envenoming. Systemic envenoming, as evidenced by
objective evidence of paralysis or rhabdomyolysis, is treated with
an initial dose of 1 ampoule (1000 units). This is usually sufficient to
reverse paralysis
l CSL Tiger Snake Antivenom (see Chapter 6.4) is also effective
ENVENOMINGS
in the treatment of envenoming by sea snakes. The initial dose is

3 ampoules (3 x 3000 units)
l If neither Sea Snake nor Tiger Snake Antivenoms are available,
or supplies have been exhausted, 3 ampoules of Polyvalent
Antivenom may be used as a substitute.
INVESTIGATIONS
T
446 clinical features and laboratory data
44

6

TOXICOLOGY HANDBOOK
l CK is usually abnormal at the time of presentation if envenoming
has occurred. However, it may not become grossly abnormal
(>1000 IU/L) for many hours. CK levels are repeated every 6 hours
if the patient is symptomatic. If the patient is asymptomatic with
mild elevation of CK or APTT, recheck every 12 hours
l The Snake Venom Detection Kit (SVDK) does not reliably detect
sea snake venoms.
l iger snake and taipan envenoming also cause paralysis and
T
rhabdomyolysis that evolve over a similar time course. However,
they are also associated with VICC, which does not occur in sea
snake envenoming
l Black snake envenoming by the mulga snake is associated
with rhabdomyolysis and rarely mild clinical features of
neurotoxicity. A mild anticoagulant coagulopathy with normal
fibrinogen is also commonly seen, which is absent in sea snake
envenoming
l Death adder envenoming is associated with a postsynaptic
reversible symmetrical descending flaccid paralysis. However,
rhabdomyolysis does not occur.
A
l Patients who do not display clinical features of paralysis or laboratory
evidence of rhabdomyolysis at 12 hours are not envenomed and may
be discharged. Discharge should not occur at night
administration if they are clinically well, their CK levels are improving
and there is no evidence of clinically significant renal failure.
HANDY TIPS
l iger Snake Antivenom or Polyvalent Antivenom may be
T
substituted if Sea Snake Antivenom is not available
l Three ampoules of Tiger Snake Antivenom are equivalent to one
ampoule of Sea Snake Antivenom
l Snake bite at sea, on the beach or in estuarine waters may be from
a terrestrial snake.
PITFALLS
ENVENOMINGS
F
early PIB or manage the patient in a hospital setting for an
l Misinterpretation of a SVDK result. The CSL Snake Venom
Detection Kit does not reliably detect sea snake venom.
References 447
White J. CSL Antivenom handbook 2001. Parkville, Victoria: CSL Ltd.
5.7 AUSTRALIAN SCORPIONS TOXICOLOGY HANDBOOK
l Bothruiridae
l Buthidae
l Urodacidae
Little is known about scorpion stings in Australia, but evidence suggests
that symptoms are usually limited to temporary pain at the sting site and
occasional minor non-specific systemic symptoms. This is in contrast to
some scorpion stings elsewhere in the world, which are associated with
life-threatening envenoming.
TOXINS
Venom contains excitatory neurotoxins.

l ymptoms are usually confined to the site of the sting
S
l Severe local pain is common and usually lasts 6–12 hours, but
may persist for up to 24 hours. Additional local symptoms include
erythema, tenderness, mild swelling, numbness and paraesthesia
l ystemic effects occur in a small minority of patients (10%).
S
They are mild, non-specific and self-limiting and include nausea,
headache and malaise.
MANAGEMENT
Pre-hospital
l Reassure the patient, apply an ice pack and give simple oral
analgesia such as paracetamol
l Do not apply a pressure immobilisation bandage (PIB)
l Patients do not require referral to hospital unless local
symptoms are refractory to simple analgesia or the diagnosis
is in doubt
Hospital
l Scorpion stings are not life threatening and resuscitation is not
required
l Pain refractory to simple first aid and oral analgesia requires IV
opioid analgesia (e.g. morphine 0.1 mg/kg up to 5 mg, repeated
every 10 minutes until appropriate analgesia is achieved)
ENVENOMINGS
Antivenom
l None available.
INVESTIGATIONS
l There are no confirmatory laboratory studies.
448 DIFFERENTIAL DIAGNOSIS

l edback spider envenoming is characteristically associated
R
44
with local pain, sweating and piloerection. Systemic features

8
include pain at proximal sites, generalised sweating and

TOXICOLOGY HANDBOOK
dysphoria
l Funnel-web spider envenoming is potentially lethal. It is associated
with a painful bite, sweating, agitation, piloerection, cardiovascular
abnormalities and neurological changes
l Non-specific spider bites are associated with bite site pain and
mild systemic symptoms, such as nausea, headache, malaise or
vomiting. Significant cardiovascular, autonomic or neurological
features do not occur
l Hymenoptera (bees, wasps, ants) also cause a painful sting
l Centipedes cause a painful bite.

l atients do not require hospital assessment unless pain is
P
not controlled with simple analgesia or systemic symptoms
develop.
HANDY TIPS
l The smallest scorpions cause the most painful stings.
Reference
Isbister GK, Volschenk ES, Balit CR et al. Australian scorpion stings: a prospective study
of definitive stings. Toxicon 2003; 41:877–883.
5.8 BLUEBOTTLE JELLYFISH (Physalia species)
The bluebottle jellyfish is responsible for thousands of stings on
Australian beaches each year. Clinical features include intense local pain
and dermal erythema. Hot water immersion provides safe symptomatic
relief. Unlike Physalia stings in other parts of the world, major systemic
envenoming does not occur.
TOXINS
The toxins are contained within nematocysts on the tentacles and
released on contact. A complex mixture of glycoproteins, they are yet
to be well characterised.

l tings are associated with immediate burning pain, typically lasting
S
up to 2 hours, and linear or elliptical erythematous welts
l Non-specific systemic symptoms, such as nausea, headache or
malaise, may occur.
ENVENOMINGS
MANAGEMENT
l tings are mild, self-limiting and respond to first aid measures
S
l Reassure the patient
l Place under a hot shower for 20 minutes (ideal temperature 45°C).
The shower should be hot but not scalding or uncomfortable
l Administer simple oral analgesics such as paracetamol
l Do not apply a pressure immobilisation bandage (PIB) or vinegar,
449
as this may worsen local symptoms
l Transport to hospital is not usually required
Antivenom
TOXICOLOGY HANDBOOK
l None available.
INVESTIGATIONS
l he diagnosis is clinical, based on a high index of suspicion and
T
correlation of history and characteristic features.
l ain associated with irukandji syndrome is usually delayed, severe
P
and generalised. Significant linear dermal markings or welts are not
seen
l Envenoming by the box jellyfish (Chironex fleckeri) is associated
with immediate pain and obvious dermal markings (large welts).
Tentacles may be seen adherent to the skin.

l Most patients do not require any care beyond first aid.
HANDY TIPS
l Ice packs were previously recommended as first aid for stings.
The superiority of hot water has now been conclusively
demonstrated.
References
Loten C, Stokes B, Worsley D et al. A randomised controlled trial of hot water (45°C)
immersion versus ice packs for pain relief in bluebottle stings. Medical Journal of
Australia 2006; 184(7):329–333.
Tibballs J. Australian venomous jellyfish, envenomation syndromes, toxins and therapy.
Toxicon 2006; 48:830–59.
5.9 STONEFISH Distribution of stonefish species
l Synanceia trachynis
Brisbane
l Synanceia verrucosa
Stonefish are extremely well camouflaged
reef fish found in the waters of northern
Australia. Their dorsal spines contain
venom, which is injected when external
pressure is applied.
ENVENOMINGS
TOXINS
The venom contains pre- and post-
Geraldton
synaptic neurotoxins, vascular
permeability factors, tissue necrosis
factors (hyaluronidase) and a
vasodilator (stonustoxin). Some
venom components may be denatured by heat.
450 CLINICAL PRESENTATION AND COURSE

45
l Immediate severe pain at the sting site

0
l Local swelling, bruising and puncture marks. A remnant of the

spine(s) may be left in the wound
TOXICOLOGY HANDBOOK
l Systemic envenoming is rare and there are no reports of deaths in

Australia
l Non-specific features of envenoming include nausea, vomiting,
dizziness and dyspnoea
l Cardiovascular signs, such as hypotension, bradycardia, collapse,
pulmonary oedema and cyanosis, are rarely reported.
MANAGEMENT
Pre-hospital
l Reassure the patient, and give simple oral analgesia such as
paracetamol
l Immerse both limbs in hot water. The unaffected limb is immersed
to ensure the water temperature is tolerable and so prevent burns
l Transport all patients with significant pain refractory to first aid or,
if systemic symptoms, to a medical facility
Hospital
l Stonefish envenoming is very painful, but rarely life threatening
l Treatment is essentially supportive
l Continue hot water immersion
l ive IV morphine 0.1 mg/kg (up to 5 mg), repeated every
G
10 minutes until patient is comfortable
l Consider regional anaesthesia (e.g. foot block or wrist block) with a
long-acting local anaesthetic agent (e.g. ropivacaine)
Antivenom
l CSL Stonefish Antivenom (see Chapter 6.8) is used in the
treatment of severe pain refractory to first aid, IV opioid analgesia
and regional block and/or systemic envenoming
l Give 1 ampoule (2000 units) for every two spine puncture wounds
(to a maximum of 3 ampoules), undiluted by IM injection or diluted
in 100 mL normal saline IV over 20 minutes.
INVESTIGATIONS
l lain x-ray or ultrasound examination may assist detection of a
P
retained foreign body.
l ther fish stings
O
l Stingray injury.
ENVENOMINGS


l atients without clinical features of systemic envenoming at
P
2 hours do not require further medical observation
l Patients treated with opioid analgesia or antivenom may be
discharged when they have been asymptomatic for a period of
4 hours
l Prior to discharge patients should be warned of the signs of 451
secondary infection.
HANDY TIPS
TOXICOLOGY HANDBOOK
l eware retained foreign bodies and marine infection
B
l Hot water should not be used following local anaesthetic infiltration
because of the risk of thermal burn.
PITFALLS
l Failure to administer antivenom when indicated.
CONTROVERSIES
l It is not known whether stonefish antivenom is more efficacious by
the IV or IM route
l Indications for antibiotics.
References
Lee JYL, Teoh LC, Leo SPM. Stonefish envenomation of the hand—a local marine hazard.
A series of 8 cases and review of the literature. Annals of the Academy of Medicine
Singapore 2004; 33:515–520.
Little M. Stonefish (Synaneceia species) sting. Emergency Medicine 1990;
2(4):5.
Ngo SYA, Ong SHJ, Ponampalam R. Stonefish envenomation presenting to a Singapore
hospital. Singapore Medical Journal 2009; 50:506–509.
Sutherland SK. Antivenom use in Australia. Medical Journal of Australia 1992; 157:
734–739.
5.10 BOX JELLYFISH Distribution of box jellyfish
(Chironex fleckeri)
Broome Gladstone
The box jellyfish is found in tropical Aus-
tralian waters. Most stings are benign
and respond to supportive measures.
Severe envenoming has been associ-
ated with at least 70 deaths in Australia,
the last 12 being children. Deaths occur
within 5 minutes of the sting, probably
secondary to direct cardiac toxicity.
TOXINS
The specific venom components
are still being identified. The lethal
component appears to affect
calcium channels. Pore formation on cell membranes is associated
with a rapid rise in cytosolic calcium levels in myocytes. There are also
ENVENOMINGS
haemolytic and dermatonecrotic components.

l tings are associated with immediate severe pain, typically lasting
S
up to 8 hours, and linear welts, which characteristically occur in a
crosshatched pattern
l In 25–30% of cases the jellyfish tentacles are still adherent
452 l Systemic envenoming is heralded by collapse or sudden death
within a few minutes of the sting
45
2
l Cardiovascular effects include hypertension, hypotension,

tachycardia, impaired cardiac contraction and arrhythmias
TOXICOLOGY HANDBOOK
l Delayed hypersensitivity reactions occur in at least 50% of

patients and manifest as pruritic erythema at the original sting site,
7–14 days after the sting.
MANAGEMENT
Pre-hospital
l If cardiac arrest occurs, it will happen on the beach. Immediate and
prolonged cardiopulmonary resuscitation is indicated
l Reassure the conscious patient, apply an ice pack and give simple
oral analgesia such as paracetamol
l Apply generous volumes of vinegar (acetic acid) to all visible sting
sites to inactivate undischarged nematocysts (sting cells)
l Do not apply a pressure immobilisation bandage (PIB) as this may
promote systemic envenoming
l Transport all patients with pain refractory to first aid or, if systemic
symptoms, to a medical facility
Hospital
l Rarely, box jellyfish envenoming is a life-threatening emergency
l Patients should be managed in an area equipped for
l otential early life threats that require immediate intervention
P
include:
— Cardiac arrest
— Hypotension or hypertension
— Cardiac arrhythmia
l In cardiac arrest, undiluted antivenom, administered as a rapid
IV push may be life saving. All immediately available box jellyfish
antivenom (up to 6 ampoules) should be given. Intravenous
magnesium (10 mmol) should be given if no response to antivenom
l Give titrated morphine (0.1 mg/kg IV up to 5 mg every 10 minutes)
to patients with pain refractory to first aid
Antivenom
l CSL Box Jellyfish Antivenom (see Chapter 6.9) is the definitive
treatment of envenoming by box jellyfish
l Give 6 ampoules (6 x 20 000 units) as an IV push in
cardiorespiratory arrest
l Give 3 ampoules (3 x 20 000 units) IV diluted in 100 mL normal
saline over 20 minutes to all patients with systemic envenoming
as evidenced by collapse, hypotension or significant cardiac
ENVENOMINGS
arrhythmia. The patient is observed closely for response to
treatment and ongoing features of envenoming prompt a further
dose of antivenom (up to 3 ampoules)
l Give 1 ampoule (20 000 units) for pain refractory to IV opioid
analgesia.
INVESTIGATIONS
l erform a 12-lead ECG to look for evidence of tachycardia, sinus
P
arrhythmia, ventricular ectopic beats, bigeminy and bundle branch 453
blocks
l Laboratory investigations are indicated to exclude alternative
diagnoses and assess complications in those patients who present
TOXICOLOGY HANDBOOK
following collapse or cardiovascular instability
l In the haemodynamically unstable patient, and check FBC, EUC,
CK and troponin and perform chest x-ray.
l luebottle stings (Physalia spp.) are also associated with
B
immediate pain and dermal markings. Pain usually resolves within
1 hour and systemic symptoms are extremely rare
l Pain associated with irukandji syndrome is usually delayed, severe
and generalised. Significant linear dermal markings or welts are not
seen
l Decompression illness may lead to severe pain and collapse
shortly after a diver has surfaced. Local pain and welts are not
seen.

l atients without clinical features of systemic envenoming or local
P
pain at 2 hours do not require further medical observation
l Patients with severe pain who require opioid analgesia or
antivenom are discharged when asymptomatic for 6 hours
l Envenomed patients treated with antivenom are also discharged
when asymptomatic for 6 hours.
HANDY TIPS
l eassurance is important. Despite its reputation, the vast majority
R
of box jellyfish stings require only first aid
l Survival from cardiac arrest on the beach due to box jellyfish
envenoming has been reported following prompt and prolonged
CPR
l Patients who die, do so at the scene of the sting. If they are alive
on arrival at hospital they will survive
l A steroid or antihistamine cream may provide symptomatic relief if
a delayed hypersensitivity rash occurs
l Immediate pain after a jellyfish sting, occurring in shallow tropical
waters between November and April, associated with linear welts
with a cross-hatched pattern, is pathognomonic of Chironex
fleckeri sting.
PITFALLS
l ailure to commence immediate CPR when cardiac arrest occurs
F
on the beach
l Administration of antivenom when not indicated.
ENVENOMINGS
CONTROVERSIES
l ressure immobilisation bandaging for box jellyfish stings has now
P
been abandoned because direct pressure over tentacles leads to
increased venom release from nematocysts
l Ice is currently recommended as appropriate first aid. It is possible
that heat is more effective
l Efficacy and role of CSL Box Jellyfish Antivenom.
454
45
References
4
Currie BJ, Jacups S. Prospective study of Chironex fleckeri and other box jellyfish stings
in the “Top End” of Australia’s Northern Territory. Medical Journal of Australia 2005;
TOXICOLOGY HANDBOOK
183:161–166.
Currie BJ. Marine antivenoms. Journal of Toxicology-Clinical Toxicology 2003; 41:301–308.
Tibballs J. Australian venomous jellyfish, envenomation syndromes, toxins and therapy.
Toxicon 2006; 48:830–859.
5.11 IRUKANDJI SYNDROME Distribution of irukandji and

related jellyfish
Irukandji syndrome is a distressing
envenoming secondary to the sting Moreton
of Carukia barnesi and other, as yet Bay
unidentified, jellyfish found in coastal Exmouth
waters of tropical Australia. It has also
been reported in Hawaii, the Caribbean,
Asia and Papua New Guinea. In a small
number of cases, life-threatening
hypertension and pulmonary oedema
may develop. Two fatalities have been
attributed to this condition in Australia.
Management is symptomatic and
supportive. Antivenom has not yet been
developed.
TOXINS
Venom composition and actions have not been fully characterised. It is
thought to induce massive catecholamine release.

l he initial sting is usually not felt and there is a short delay to the
T
onset of systemic symptoms. Local signs, such as welts or dermal
markings, are minimal or absent
l Multiple systemic symptoms develop from 30 to 120 minutes after
contact with the jellyfish. These include a sense of impending
doom, agitation, dysphoria, vomiting, generalised sweating and
severe pain in the back, limbs or abdomen. Hypertension and
tachycardia are common
l Symptoms usually settle within 12 hours
l Severe envenoming manifests within 4 hours, with ongoing
significant opioid requirements. These patients are at risk of toxic
cardiomyopathy, cardiogenic shock and pulmonary oedema and
may require intubation and mechanical ventilation
l Intracerebral haemorrhage occurred in two patients within
ENVENOMINGS

3–4 hours of the sting, presumably due to uncontrolled
hypertension.
MANAGEMENT
Pre-hospital
l Apply generous volumes of vinegar to all visible sting sites to
inactivate all undischarged nematocysts (sting cells)
l Do not apply a pressure immobilisation bandage (PIB) 455
l Transport all patients with pain refractory to first aid or, if systemic
symptoms, to a medical facility
TOXICOLOGY HANDBOOK
Hospital
Resuscitation and supportive care.
l This is a potentially life-threatening emergency. Patients should be
resuscitation
include:
— Severe hypertension
— Pulmonary oedema
l Administer IV fentanyl (0.5–1.0 microgram/kg/dose) repeated
every 10 minutes until appropriate analgesia is achieved. Large
doses may be required (e.g. 200–300 micrograms). Note: If
fentanyl is not available, give morphine 0.05–0.1 mg/kg IV in
titrated doses
l Treat nausea with IV promethazine (25 mg; 0.5 mg/kg in
children)
l Control hypertension refractory to opioid analgesia with an
intravenous infusion of glyceryl trinitrate (GTN 50 mg in 100 mL
starting at 6 mL/minute; 1–4 microgram/kg/minute in children)
titrated to achieve a systolic blood pressure <160 mmHg
Antivenom
l None available.
INVESTIGATIONS
l aboratory investigations are indicated to exclude alternative
L
diagnoses and to assess complications in those patients who
present following collapse or cardiovascular instability
l Perform a 12-lead ECG to look for evidence of tachycardia,
ischaemia and non-specific T wave conduction abnormalities
l Perform a chest x-ray in patients with ongoing opioid requirements
or clinical evidence of pulmonary oedema
l In the haemodynamically unstable patient check FBC, EUC, ECG,
troponin and CK every 8 hours
l Echocardiography is indicated in patients with raised troponin,
pulmonary oedema or hypotension requiring inotropic support.
l nvenoming by the box jellyfish (Chironex fleckeri) is associated
E
with immediate pain and obvious dermal markings (large welts).
Tentacles may be seen adherent to the skin
l Bluebottle stings (Physalia spp.) are associated with immediate
pain and dermal markings. The pain usually resolves within 1 hour
ENVENOMINGS
and systemic symptoms are extremely rare

l Decompression illness may lead to generalised pain or collapse
shortly after a diver has surfaced. Welts are not seen
l Redback spider envenoming (Latrodectus hasselti) causes bite
site pain and sweating, followed by more generalised pain,
sweating and dysphoria. It is associated with contact with a
spider on land.
456
45
l atients without features of systemic envenoming at 2 hours

P
6

do not have irukandji syndrome and do not require medical
TOXICOLOGY HANDBOOK
observation
l Patients with severe pain who require opioid analgesia may be
discharged when they are clinically well and pain-free for a period
of 6 hours.
HANDY TIPS
l linical features of envenoming occur after the patient has left the
C
water, so they may be unaware they have been stung
l Irukandji syndrome should be considered in any patient presenting
with clinical features during or shortly after swimming in tropical
coastal Australian waters
l Clinical features of dysphoria, severe generalised pain, sweating,
hypertension and pulmonary oedema, in the absence of major
dermal findings, are pathognomonic of irukandji syndrome
l Patient-controlled analgesia may be useful if there is ongoing
opioid requirement.
PITFALLS
l ailure to recognise the potential for irukandji syndrome or
F
administer adequate opioid analgesia
l Failure to consider the potential for development of
cardiomyopathy.
CONTROVERSIES
l agnesium IV has been advocated for control of pain refractory
M
to opioid administration. This practice is as yet unsupported by
clinical trials
l The role of benzodiazepines in the management of symptoms
presumed due to catecholamine release
l The agent of choice to manage hypertension and tachycardia.
References
Barnes JH. Cause and effect in Irukandji stingings. Medical Journal of Australia 1964;
1:897–904.
Huynh TT, Seymour J, Pereira P et al. Severity of Irukandji syndrome and nematocyst
identification from skin scrapings. Medical Journal of Australia 2003; 178:38–41.
Little M, Mulcahy RF. A year’s experience of “Irukandji” jellyfish envenomation in far north
Queensland. Medical Journal of Australia 1998; 169:638–641.
Little M, Pereira P, Carrette T et al. Jellyfish responsible for irukandji syndrome. Quarterly
Macrocanis CJ, Hall NJ, Mein JK. Irukandji syndrome in northern Western Australia: an
emerging health problem. Medical Journal of Australia 2004; 181(11/12):699–702.
Nickson CP, Waugh EB, Jacups SP et al. Irukandji syndrome case series from Australia’s
ENVENOMINGS
tropical Northern Territory. Annals of Emergency Medicine 2009; 54(3):395–403.
5.12 BLUE-RINGED OCTOPUS

l Hapalochlaena lunulate: northern or greater blue-ringed octopus
l Hapalochlaena maculosa: southern or lesser blue-ringed octopus
This small octopus is found in shallow coastal waters around Australia.
They are not aggressive and bites usually occur when humans ‘play’ with 457
this animal. Envenoming causes rapid paralysis. Timely support of airway
and ventilation ensures a good outcome.
TOXICOLOGY HANDBOOK
TOXINS
Tetrodotoxin (maculotoxin in Hapalochlaena maculosa) is a potent
sodium channel blocking neurotoxin. Venom is introduced from the
beak under the body of the octopus, not from the tentacles.

l he bite may not be painful
T
l Local symptoms are minimal or absent
l Systemic envenoming is characterised by a rapidly progressive
symmetrical descending flaccid paralysis, which usually manifests
within minutes
l Early signs include ptosis, blurred vision, diplopia and difficulty
swallowing. If left untreated, generalised paralysis, respiratory
failure and secondary hypoxic cardiac arrest ensue
l With the institution of advanced airway support, paralysis resolves
spontaneously within 24 hours.
MANAGEMENT
Pre-hospital
l Commence expired air respiration (EAR) if required
Hospital
l Blue-ringed octopus envenoming is potentially life threatening.
Patients should be managed in an area equipped for
include:
— Descending flaccid paralysis with respiratory failure
— Hypotension
l If respiratory failure is present, provision of an airway and
mechanical ventilation is life saving
Antivenom
l None available.
INVESTIGATIONS
l aboratory investigations are indicated to exclude alternative
L
diagnoses and assess complications
l Spirometry or peak flow measurements are useful to monitor
respiratory function.
ENVENOMINGS
l nvenoming by the box jellyfish (Chironex fleckeri) is associated
E
with collapse on the beach and sudden death following a sting.
However, there is immediate severe pain and obvious dermal
markings (large welts). Tentacles may be seen adherent to
the skin
l Puffer fish also contain tetrodotoxin and ingestion of these fish can
458
lead to flaccid paralysis. The history usually permits this diagnosis
45
to be easily distinguished from blue-ringed octopus bite.

8
TOXICOLOGY HANDBOOK

l atients who are not envenomed will have no clinical features of
P
paralysis at 6 hours and may be discharged. Discharge should not
occur at night
l Envenomed patients with paralysis require ventilatory support and
admission to intensive care.
HANDY TIPS
l ollapse with paralysis, on or near the beach, shortly after a minor
C
bite is pathognomonic of blue-ringed octopus envenoming.
PITFALLS
l ailure to appreciate the importance of close observation during
F
the first few hours
l Failure to appreciate that the paralysed patient is fully aware unless
sedated.
References
Sutherland SK, Lane WR. Toxins and mode of envenomation of the common ringed or
blue-banded octopus. Medical Journal of Australia 1969; 1:893–898.
5.13 REDBACK SPIDER Distribution of redback spiders
l Latrodectus hasselti: redback

spider (Australia)
l Latrodectus katipo: katipo spider
(New Zealand)
Redback spider bite is the most common
envenoming in Australia, with 5000–10 000
human bites occurring annually. Clinical
features can be distressing and refractory
to symptomatic treatment, but are not life
threatening.
TOXINS
Venom of the Latrodectus genus
contains alpha-latrotoxin. This
toxin acts pre-synaptically to open cation channels (including calcium
channels) and stimulate the release of multiple motor endplate
ENVENOMINGS
neurotransmitters.

l edback spider bites are not immediately painful
R
l Intense local pain develops 5–10 minutes after the bite and is
followed by sweating and piloerection within an hour. Puncture
marks are not always evident and erythema, if present, is
usually mild
459
l Systemic envenoming occurs in a significant minority of patients.
Pain typically radiates proximally from the bite site to become
regional then general (e.g. pelvic, back, abdominal, chest or
TOXICOLOGY HANDBOOK
shoulder pain). Autonomic features include severe sweating, which
may be regional (e.g. both legs) or generalised, mild hypertension
and tachycardia
vomiting and dysphoria
l Untreated, systemic envenoming may follow a fluctuating course
lasting 1–4 days. Rarely, patients may feel unwell for up to 1 week.
Very rarely, untreated patients report ongoing local symptoms that
last weeks or months.
MANAGEMENT
Pre-hospital
l Reassure the patient, apply an ice pack and give simple oral
l Refer to hospital if the patient has local symptoms refractory to
simple analgesia, clinical features of systemic envenoming or the
diagnosis is in doubt
Hospital
l Redback spider envenoming is not life threatening and
resuscitation is not required
Antivenom
l CSL Redback Spider Antivenom (see Chapter 6.10) is the definitive
treatment of envenoming by spiders of the Latrodectus genus.
l Give an initial 2 ampoules (2 x 500 units) IV or IM to all patients
with systemic latrodectism or local symptoms unrelieved by simple
analgesia
l Give a further dose of 2 ampoules if symptoms are unrelieved after
2 hours.
INVESTIGATIONS
l Laboratory investigations do not assist in diagnosis or management.
l unnel-web spider envenoming is potentially lethal. It is associated
F
with immediate bite site pain, visible fang marks and the abrupt
onset, within minutes, of a severe clinical syndrome characterised
by sweating, agitation, piloerection, cardiovascular and
neurological changes
l Envenoming by Steatoda species (cupboard spider or brown house
ENVENOMINGS
spider) closely resembles redback spider envenoming

l Non-specific spider bites are associated with bite site pain and
mild systemic symptoms, such as nausea, headache, malaise or
l Latrodectism has been mistaken for conditions such as acute
surgical abdomen, acute myocardial infarction and thoracic aortic
dissection.
460
46

0
l atients without clinical features of systemic envenoming or local

P
pain do not require referral for medical evaluation
TOXICOLOGY HANDBOOK
l Envenomed patients treated with antivenom are discharged when

asymptomatic and advised to return if symptoms recur.
HANDY TIPS
l he triad of local pain, sweating and piloerection increasing over
T
the first hour are pathognomic of redback spider bite
l Symmetrical profuse sweating and pain in both legs following a
bite to one lower limb is also characteristic of latrodectism
l Consider the diagnosis in any child with abrupt onset of
inconsolable crying, acute abdomen or priapism.
PITFALLS
l ailure to consider the diagnosis when spider bite is not witnessed
F
l Failure to administer antivenom to children or pregnant women
when indicated.
CONTROVERSIES
l he value of antivenom administration in the management of
T
latrodectism is being questioned. A randomised controlled
trial comparing IV with IM antivenom failed to demonstrate any
difference in pain scores at 2 hours. Antivenom is measurable in
serum following IV but not IM administration. This suggests the
possibility that antivenom by any route may not provide any benefit
over placebo. A placebo-controlled randomised controlled trial of
antivenom is underway.
References
Isbister GK, Brown SGA, Miller M et al. A randomised controlled trial of intramuscular
versus intravenous antivenom for latrodectism—the RAVE study. Quarterly Journal of
Medicine 2008; 101:557–565.
Isbister GK, Gray MR. Latrodectism: A prospective cohort study of bites by formally
identified redback spiders. Medical Journal of Australia 2003; 179:88–91.
Isbister GK, O’Leary MA, Miller M et al. A comparison of serum antivenom concentrations
after intravenous and intramuscular administration of redback (widow) spider
antivenom. British Journal of Clinical Pharmacology 2008; 65:138–143.
Isbister GK, Sibbritt D. Developing a decision tree algorithm for the diagnosis of suspected
spider bites. Emergency Medicine Australia 2006; 16:161–166.
5.14 FUNNEL-WEB Distribution of funnel-web spiders

(BIG BLACK) SPIDER
ENVENOMINGS
Mountain region
l Atrax robustus: Sydney funnel-web near Mossman
spider Gladstone
l Hadronyche cerberea: southern tree
funnel-web spider
l Hadronyche formidabilis: northern tree
funnel-web spider
l Hadronyche infensa: Toowoomba or
Darling Downs funnel-web spider 461
l Hadronyche species 14: Port
Macquarie funnel-web spider
l Hadronyche versuta: Blue Mountains
TOXICOLOGY HANDBOOK
funnel-web spider
The funnel-web spiders (FWS) comprise Tamworth
Albury
40 species in two genera (Atrax
and Hadronyche). These potentially
lethal spiders look very similar to other medically less significant big
black spiders, including the trap door spiders (families Idiopidae and
Nemesiidae) and mouse spiders (Actinopididae). For this reason it is
important to have a clinical approach to bite by a big black spider within
the distribution of the FWS.
TOXINS
Both genera of FWS produce venom that contains potent neurotoxins.
Robustoxin (Atrax sp.) and versutoxin (Hadronyche sp.) prevent
inactivation of sodium channels, leading to a massive increase in
autonomic activity and neuromuscular excitation.

l he patient often gives a history of witnessed painful bite by a big
T
black spider with large fangs
l Local pain at the bite site is severe and fang marks are often
visible
l ocal erythema and swelling are not features of FWS bite
L
l Severe systemic envenoming, if it occurs, develops rapidly, usually
within 30 minutes and almost always within 2 hours. Clinical
features include:
— General: agitation, vomiting, headache and abdominal pain
— Autonomic: sweating, salivation, piloerection and
lacrimation
— Cardiovascular: hypertension, tachycardia, hypotension,
bradycardia and pulmonary oedema
— Neurological: muscular fasciculation, oral paraesthesia, muscle
spasm and coma
l In young children, the first indication of envenoming may be
sudden severe illness with inconsolable crying, salivation, vomiting
or collapse.
MANAGEMENT
Pre-hospital
(antivenom, resuscitation facilities and medical staff)
ENVENOMINGS
Hospital
l Funnel-web spider envenoming is potentially life threatening.
Patients are managed in an area equipped for cardiorespiratory
include:
462 — Respiratory failure
46
— Hypotension or hypertension
2
— Pulmonary oedema
— Coma
TOXICOLOGY HANDBOOK
l In cardiac arrest, undiluted antivenom, administered as a rapid

IV push may be life saving. All immediately available funnel-web
antivenom (at least 4 ampoules) should be given
l Atropine may help decrease secretions until antivenom can be
administered
Antivenom
l CSL Funnel-web Spider Antivenom (see Chapter 6.11) is the
definitive treatment of envenoming by FWS
l Give an initial dose of 2 ampoules (2 x 125 units) to all patients with
systemic envenoming as evidenced by neurological, autonomic or
cardiovascular features
l The patient is observed for response to treatment. Ongoing
features of envenoming prompt administration of a further dose of
2 ampoules of antivenom
l An initial dose of 4 ampoules may be indicated in the severely
envenomed patient.
INVESTIGATIONS
l aboratory investigations are indicated to exclude
L
alternative diagnoses and to assess complications in severe
envenoming.
l edback spider envenoming is characterised by a triad of local
R
pain, sweating and piloerection. Systemic features include
generalised pain, sweating and dysphoria. Lethal envenoming with
coma, fasciculation or pulmonary oedema does not occur
l Bites by the other big black spiders (trap door and mouse spiders)
may be associated with significant bite site pain but only mild
systemic symptoms, such as nausea, headache, malaise or
l Scorpion stings cause local pain and paraesthesia without
evidence of systemic envenoming.

l atients without clinical features of systemic envenoming at
P
4 hours do not require further medical management
l Envenomed patients treated with antivenom are discharged if
clinically well for 12 hours. Do not discharge at night.
ENVENOMINGS
HANDY TIPS
l ig black spider bite in New South Wales or southern Queensland
B
is assumed to be by a FWS until proven otherwise
l Removal of the pressure immobilisation bandage only occurs when
the patient is located in an area equipped for cardiorespiratory
resuscitation with adequate supplies of FWS Antivenom
l A painful bite by a big black spider, with abrupt onset of sweating,
agitation, piloerection, coma and fasciculations is pathognomonic 463
of FWS envenoming.
PITFALLS
TOXICOLOGY HANDBOOK
l ailure to consider the diagnosis when spider bite is not witnessed
F
l Failure to anticipate the abrupt onset of life-threatening
envenoming and that delayed envenoming may occur following the
release of pressure immobilisation bandage
l Removal of PIB prior to availability of antivenom and resuscitation
facilities.
References
Isbister GK, Gray MR, Balit CR et al. Funnel-web spider bite; A systematic review of
recorded clinical cases. Medical Journal of Australia 2005; 182:407–411.
Isbister GK, Sibbritt D. Developing a decision tree algorithm for the diagnosis of suspected
spider bites. Emergency Medicine Australasia 2006; 16:161–166.
Nicholson GM, Graudins A, Wilson HI et al. Arachnid toxinology in Australia: From clinical
toxicology to potential applications. Toxicon 2006; 48:872–898.
Rosengren D, White J, Raven R et al. First report of a funnel-web spider envenoming
syndrome in Brisbane. Emergency Medicine Australasia 2008; 20:164–166.
5.15 WHITE-TAILED SPIDER

l Lampona cylindrata
l Lampona murina
The white-tailed spider is ubiquitous throughout Australia and previously
believed to cause necrotic arachnidism, a syndrome of progressive
cutaneous injury from spider venom. This association has now been refuted.
TOXINS
The venom of Lampona cylindrata has been extensively studied. No
cytotoxic effects have been noted.

l ainful bite
P
l Three local reactions to bites from Lampona species are reported:
— Severe local pain of <2 hours duration
— Local pain and a red mark lasting <24 hours.
— A persistent and painful red lesion, which does not break down
or ulcerate, and may last 5–12 days
l Mild, non-specific features of envenoming include nausea,
vomiting, malaise and headache
l Delayed pruritus occurs in up to 20% of cases
l No ulcers, necrotic lesions or infections were identified in a
prospective study of 130 Lampona bites, where the spider was
ENVENOMINGS
caught and formally identified by an arachnidologist.
MANAGEMENT
l eassure the patient, apply an ice pack and give simple oral
R
l Referral to hospital is not indicated.
464
INVESTIGATIONS
46
4
l Investigations are required only in an attempt to establish an

alternative diagnosis for a chronic skin lesion. These might include
TOXICOLOGY HANDBOOK
skin biopsy and microbiological investigations.
l If a necrotic cutaneous lesion is present, a causal association with
a spider bite is a diagnosis of exclusion
l The differential diagnoses of a chronic skin ulcer include:
— Infections (staphylococcal, streptococcal, herpes simplex,
herpes zoster, gonococcal, mycobacterial, fungal)
— Diabetic ulcers
— Pyoderma gangrenosum
— Squamous cell carcinoma
— Erythema nodosum
— Chemical burn
— Lymphatoid papulosis
— Localised vasculitis
— Factitious injury
— Traumatic.

l atients with an idiopathic non-specific chronic cutaneous ulcer
P
may be discharged to the care of their general practitioner for
further investigation or referred to a dermatologist as appropriate.
PITFALLS
l ttribution of causation of a chronic ulcer to spider bite in Australia
A
without extensive investigation to exclude alternative diagnosis.
References
Isbister GK, Gray MR. White-tailed spider bite: a prospective series of 130 definite bites by
the Lampona species. Medical Journal of Australia 2003; 179:199–202.
Swanson DL, Vetter RS. Bites of the brown recluse spiders and suspected necrotic
arachnidism. New England Journal of Medicine 2005; 352:700–707.
5.16 TICKS Distribution of Ixodes hylocyclus
l Ixodes cornuatus Cairns

l Ixodes hirsti
l Ixodes holocyclus
Ticks are arachnids that attach to other
animals at various stages of their life cycles
and obtain blood for nourishment. There
ENVENOMINGS
are 70 tick species found in Australia, but
only the three Ixodes species listed above
cause paralysis. Tick paralysis in humans is
almost exclusively associated with Ixodes
holocyclus, distributed in a narrow eastern Bairnsdale
coastal strip extending from far north
Queensland to Victoria.
TOXINS 465
The salivary glands of ticks excrete multiple haemostatic and anti-
inflammatory agents to facilitate attachment and feeding. These include,
in the case of the adult female Ixodes holocyclus, a protein neurotoxin
TOXICOLOGY HANDBOOK
known as holocyclotoxin. It is thought to act at the presynaptic region of
the neuromuscular junction and inhibit release of acetylcholine.

l ick paralysis, although rare, is the most feared complication of
T
tick bite. It usually occurs in children under 3 years of age, but has
been reported in adults
l Tick paralysis presents as a non-specific prodrome that includes
drowsiness and unsteadiness of gait. This may be followed by a
progressive ascending symmetrical flaccid paralysis that can take
days to develop. Cranial nerves are frequently involved leading to
ocular paralysis, ptosis and facial paralysis
l Paralysis may progress for up to 48 hours after the tick is removed
or falls off
l Death, if it occurs, is from respiratory paralysis
l Recovery in survivors is slow and it may take several weeks before
strength returns to normal
l Non-paralytic complications of tick bite include local itching and
swelling, hypersensitivity reactions, and local granuloma formation
due to retention of mouth parts
l A number of human infections are transmitted by ticks, but these
are outside the scope of this book.
MANAGEMENT
Pre-hospital
l The diagnosis of tick paralysis is rarely considered in the pre-
hospital phase. Respiration should be supported if necessary
Hospital
l Tick paralysis is potentially life threatening, the major threat being
respiratory failure
l Patients should be managed in an area equipped for
l If respiratory failure develops, provision of an airway and
mechanical ventilation is life saving
l If mechanical ventilation is required, it is likely to be required for
days to weeks
Tick removal
l The tick should be located and removed as soon as practicable
l When the diagnosis of tick paralysis is considered, a careful search
for ticks should include the scalp, behind the ears, inside the
ENVENOMINGS
auditory canal, the nose, perineum and natal cleft

l When located, the tick is carefully removed with every attempt
made to remove all of the tick mouth parts attached to the skin.
The tick should be grasped as close to the skin as possible using
fine forceps, veterinary tick removers or a loop of dental floss or
suture material. Once grasped the tick is then removed by applying
gentle outward traction
466 Antivenom
l CSL Tick Antivenom is no longer available for human use.
46
INVESTIGATIONS
TOXICOLOGY HANDBOOK
l ick paralysis is a clinical diagnosis. Investigations are directed

T
at excluding alternative diagnoses
l Nerve conduction studies, if performed, are abnormal with reduced
amplitude of compound motor action potentials but normal
conduction velocities. Sensory nerve studies are normal.
l his history of tick bite is frequently not available. The major
T
differential diagnosis of ascending flaccid paralysis is Guillain-
Barré syndrome. Location of an engorged paralysis tick by careful
searching will confirm the diagnosis of tick paralysis. Ocular signs
are not a feature of Guillain-Barré syndrome
l Infant botulism produces a similar clinical picture, but usually
occurs in the first few months of life, whereas tick paralysis usually
occurs in older more mobile children
l Ascending paralysis also occurs after snake and blue-ringed
octopus envenoming, but the progression in those cases is always
much more rapid than that seen in tick paralysis.

l ll patients must be admitted for close, sequential neurological
A
observation
l ischarge should not occur until sustained neurological
D
improvement is documented
l Patients requiring ventilatory support should be managed in an
intensive care unit. Several days to 1 week of ventilation followed
by several weeks of convalescence can be anticipated.
HANDY TIPS
l onsider the diagnosis of tick paralysis in any young child who
C
develops weakness or difficulty walking and resides on or has
recently visited the east coast of Australia.
l Consideration of the diagnosis should always prompt a careful
search for an attached tick
l The attached tick will usually be located on the head, frequently in
the scalp above the hairline or behind the ears
l More than one tick may be attached
l Weakness can be expected to progress for up to 48 hours after
removal of the tick.
PITFALLS
ENVENOMINGS
l ailure to admit the symptomatic child to hospital for continued
F
observation after removal of the tick.
CONTROVERSIES
l anufacture of CSL Tick Antivenom was recently discontinued
M
due to questionable efficacy, high incidence of adverse effects and
limited demand
l It has been suggested that forcible removal of a live tick will cause
release of further toxin. It has been advocated that the tick should 467
be killed using a pyrethrin-based insecticide prior to removal but
the value of this practice is unsubstantiated.
TOXICOLOGY HANDBOOK
Reference
Grattan-Smith PJ, Morris JG, Johnston HM et al. Clinical and neurophysiological features
of tick paralysis. Brain 1997; 120:1975–1987.

CHAPTER 6
ANTIVENOMS
6.1 SL Black Snake Antivenom

C 470
6.2 CSL Brown Snake Antivenom 471
6.3 CSL Death Adder Antivenom 473
6.4 CSL Tiger Snake Antivenom 475
6.5 CSL Taipan Antivenom 477
6.6 CSL Sea Snake Antivenom 479
6.7 CSL Polyvalent Snake Antivenom 481
6.8 CSL Stonefish Antivenom 482
6.9 CSL Box Jellyfish Antivenom 484
6.10 CSL Redback Spider Antivenom 486
6.11 CSL Funnel-web Spider Antivenom 488
6.1 CSL BLACK SNAKE ANTIVENOM
This equine IgG Fab is the definitive treatment of envenoming by black
snakes in Australia and Papua New Guinea. These include the mulga
snake (Pseudechis australis), Butler’s mulga snake (Pseudechis butleri),
Collett’s snake (Pseudechis colletti), Papuan black snake (Pseudechis
papuanus), red-bellied black snake (Pseudechis porphyriacus) and blue-
bellied black snake (Pseudechis guttatus).
PRESENTATION
18 000 unit (43–50 mL) ampoules
INDICATIONS
evidence of systemic envenoming (see Chapter 5.1: Black
l Clinical
Snake)
l Laboratory evidence of anticoagulant coagulopathy or
rhabdomyolysis (CK >5000 IU/L).
CONTRAINDICATIONS
l No absolute contraindications
l There is an increased risk of anaphylaxisin patients who have
been previously treated with antivenom or who have a known or
ANTIVENOMS
suspected equine sera allergy.
ADMINISTRATION
l Placethe patient in a monitored area where equipment, drugs and
personnel are available to manage an allergic reaction
l Administer 1 ampoule diluted in 500 mL of normal saline IV over 20
minutes
470 l Pre-medication with adrenaline is unnecessary
47
l Re-check the coagulation profile and CK 12 hours after antivenom

0
administration.
TOXICOLOGY HANDBOOK

l Resolution of systemic features of envenoming, including non-
specific symptoms such as headache, abdominal pain and vomiting
l Improving laboratory values that indicate a resolving coagulopathy
and falling CK.
ADVERSE DRUG REACTIONS AND MANAGEMENT

Acute allergic or anaphylactic reaction
l Incidence approximately 10%
l Usually mild and manifested by erythema or urticaria. Severe cases
manifest with hypotension
l Immediately cease antivenom infusion
l Give oxygen, IV fluids and administer IM adrenaline 0.01 mg/kg
(max 0.5 mg) to lateral thigh (see Appendix 6 for full management
description)
l Recommence antivenom infusion cautiously when clinical
manifestations of anaphylaxis are controlled
l Note: Rarely, ongoing administration of adrenaline by titrated
infusion may be necessary to complete antivenom administration
Serum sickness
l This relatively benign and self-limiting complication may occur
5–10 days after antivenom
l Manifestations include fever, rash, arthralgia and myalgia
l Oral steroids (e.g. prednisolone 50 mg/day in adults or 1–2 mg/kg/day
in children for 5 days) ameliorate symptoms
l Note: All patients should be warned about this potential
complication prior to discharge.
Paediatric: Give standard adult dose in 10 mL/kg of normal saline.
PITFALLS
l Withholding antivenom from the envenomed child or pregnant
woman because of concerns about the potential adverse reactions
l Administration of antivenom to a patient who is not envenomed.
CONTROVERSIES
l Tiger Snake Antivenom has been recommended as an alternative
to Black Snake Antivenom in the treatment of envenoming by the
ANTIVENOMS
red-bellied or blue-bellied black snake
l Antivenom doses currently recommended are based on clinical
experience and consensus. Recommendations may change as
l Although recommended by CSL, routine adrenaline pre-treatment
is not indicated.
471
References
Isbister GK, Brown SG, MacDonald E et al. Current use of Australian snake antivenoms
and frequency of immediate-type hypersensitivity reactions and anaphylaxis. Medical
Journal of Australia 2008; 188:473–476. TOXICOLOGY HANDBOOK
6.2 CSL BROWN SNAKE ANTIVENOM

This equine IgG Fab is the definitive treatment of envenoming by brown
snakes in Australia. These include the eastern brown snake (Pseudonaja
textilis), western brown snake or gwardar (Pseudonaja mengendi), dugite
(Pseudonaja affinis) and other Pseudonaja species.
PRESENTATION
1000 unit (4.5–9 mL) ampoules
INDICATIONS
l Clinicalevidence of systemic envenoming (see Chapter 5.2:
Brown snake)
l Laboratory evidence of venom-induced consumptive coagulopathy
(VICC).
CONTRAINDICATIONS
l There is an increased risk of anaphylaxis in patients who have
ADMINISTRATION
l Administer 2 ampoules diluted in 500 mL of normal saline IV over
20 minutes
l Pre-medication with adrenaline is unnecessary
l Note: Antivenom may be given as a rapid IV push if the patient is
unstable or in cardiac arrest.

l Resolution of systemic features of envenoming.

ANTIVENOMS

description)
472 l Note: Rarely, ongoing administration of adrenaline by titrated
infusion may be necessary to complete antivenom
47
2
administration
Serum sickness
TOXICOLOGY HANDBOOK

l Oral steroids (e.g. prednisolone 50 mg/day or 1–2 mg/kg/day in
children for 5 days) ameliorate symptoms
PITFALLS
woman because of concerns about the potential adverse
reactions
l Administration of antivenom to a patient who has not been
envenomed.
CONTROVERSIES
l Recent evidence suggests that administration of antivenom does
earlier recovery from VICC. Randomised controlled clinical trials are
currently being conducted to determine the efficacy and safety of
clotting factor replacement after venom neutralisation in VICC
is not indicated.
References
35(9):1532–1538.
Journal of Australia 2008; 188:473–476.
ANTIVENOMS
6.3 CSL DEATH ADDER ANTIVENOM

This equine IgG Fab is the definitive treatment of envenoming by the death 473
adder (Acanthophis spp.) in Australia and Papua New Guinea.
PRESENTATION TOXICOLOGY HANDBOOK

6000 unit (25 mL) ampoules
INDICATIONS
l Clinicalevidence of systemic envenoming, characterised by
progressive paralysis and the absence of coagulopathy (see
Chapter 5.3: Death adder).
CONTRAINDICATIONS
ADMINISTRATION
l Placethe patient in a monitored area where equipment, drugs and
minutes
l Observe the patient clinically and monitor serial spirometry/peak
flow measurements. A further dose of 1 ampoule is indicated only if
clinical deterioration occurs.


description)
Serum sickness
ANTIVENOMS

474 SPECIFIC CONSIDERATIONS

47

4

TOXICOLOGY HANDBOOK
HANDY TIPS
l If Death Adder Antivenom is not available, 1 ampoule of Polyvalent
Antivenom may be substituted
l If no antivenom is available, patients should be managed with
supportive care. Providing airway and ventilation are supported,
survival rates are high, with the symptoms of neurotoxicity
resolving within 36–48 hours.
PITFALLS
envenomed.
CONTROVERSIES
l Relative efficacy of neostigmine as an alternative to antivenom
is not indicated.
References
6.4 CSL TIGER SNAKE ANTIVENOM

This equine IgG Fab is the definitive treatment of envenoming by tiger
snakes in Australia. These include the common tiger snake (Notechis
scutatus), western tiger snake (Notechis ater), Stephen’s banded snake
(Hoplocephalus stephensi ), pale-headed snake (Hoplocephalus bitorquatus),
broad-headed snake (Hoplocephalus bungaroides), rough-scaled snake
(Tropidechis carinatus) and copperhead snakes (Austrelaps spp.).
PRESENTATION
ANTIVENOMS
3000 unit (9–12 mL) ampoules
INDICATIONS
l Clinicalor laboratory evidence of systemic envenoming (see
Chapter 5.4: Tiger snake)
l Tiger snake and rough-scaled snake: venom-induced consumptive
coagulopathy (VICC), neurotoxicity, and rhabdomyolysis
l Copperhead: paralysis and occasionally rhabdomyolysis
l Pale-headed and broad-headed snake: VICC but not paralysis or
475
rhabdomyolysis
l Small-eyed snake: rhabdomyolysis.
TOXICOLOGY HANDBOOK
CONTRAINDICATIONS
ADMINISTRATION
20 minutes
l Note: Antivenom can be given as a rapid IV push if the patient is
haemodynamically unstable or in cardiac arrest.

l Resolution of systemic features of envenoming
l Note: Although Tiger Snake Antivenom halts the progression of
paralysis, established neurotoxicity is not reversed by antivenom.
description)
Serum sickness
ANTIVENOMS
HANDY TIPS
l If the correct choice of monovalent antivenom cannot be assured
based on geography or SVDK testing, neutralising doses of both
476
Brown and Tiger Snake Antivenom should be given.
47
6
PITFALLS
TOXICOLOGY HANDBOOK

envenomed.
CONTROVERSIES
is not indicated.
References
35(9):1532–1538.
Isbister GK, Tankel AS, White J et al. High rate of immediate systemic hypersensitivity
reactions to tiger snake antivenom. Medical Journal of Australia 2006; 184(8):
419–420.
6.5 CSL TAIPAN ANTIVENOM

This equine IgG Fab is the definitive treatment of envenoming by taipans
in Australia and Papua New Guinea. These include the coastal taipan
(Oxyuranus scutellatus), the Papuan taipan (Oxyuranus scutellatus canni )
and the small-scaled or fierce snake (Oxyuranus microlepidotus).
ANTIVENOMS
PRESENTATION
12 000 unit (43–50 mL) ampoules
INDICATIONS
l History,clinical features and laboratory evidence of envenoming
(see Chapter 5.5: Taipan)
l Taipan envenoming is characterised by pre-synaptic neurotoxicity,
venom-induced consumptive coagulopathy (VICC) and
477
rhabdomyolysis.
CONTRAINDICATIONS
l No absolute contraindications TOXICOLOGY HANDBOOK
ADMINISTRATION
minutes
l A repeat dose of 1 ampoule is given if there is clinical deterioration

l Note: Taipan Antivenom halts the progression of paralysis.
Established neurotoxicity is not reversed by antivenom.
description)
Serum sickness
ANTIVENOMS
HANDY TIPS
l Taipan Antivenom does not reverse established paralysis. Instead,
it halts the progression of paralysis
478
l One ampoule of Polyvalent Antivenom may substitute for one
47
ampoule of Taipan Antivenom.

8
TOXICOLOGY HANDBOOK
PITFALLS
l Administration of antivenom to a patient who has not been envenomed.
CONTROVERSIES
is not indicated.
References
35(9):1532–1538.
snakebite coagulopathy. Quarterly Journal of Medicine 2009; 102:563–568.
6.6 CSL SEA SNAKE ANTIVENOM

This equine IgG Fab is the definitive treatment of envenoming by all
species of sea snake (Family Hydrophiidae) found in Australian waters.
PRESENTATION
1000 unit (15–35mL) ampoules.
INDICATIONS
l Clinicalevidence of systemic envenoming with development of
ANTIVENOMS
paralysis and respiratory failure (neurotoxicity) (see Chapter 5.6:
Sea snake)
l Laboratory evidence of rhabdomyolysis within 6 hours of the bite.
CONTRAINDICATIONS
been previously treated with antivenom or who have a known or 479
ADMINISTRATION TOXICOLOGY HANDBOOK

l Administer 1 ampoule diluted in 500 mL of normal saline IV over
20 minutes.
Note: in the presence of progressive neurological deterioration,
3 ampoules of antivenom should be administered
l A single dose is sufficient to reverse paralysis in most cases.
Following the initial dose, the patient is observed clinically and
spirometry/peak flow measurements monitored. Any progression of
paralysis warrants treatment with further antivenom
l Repeat doses of 1 ampoule are given until therapeutic end point is
achieved (see below)
unstable or in cardiac arrest.

l Resolutionof systemic features of envenoming (paralysis and
rhabdomyolysis).
description)
Serum sickness
ANTIVENOMS
HANDY TIPS
l IfSea Snake Antivenom is unavailable, Tiger Snake Antivenom is
480 an effective alternative.
l Three ampoules of Tiger Snake Antivenom are equivalent to one
48
ampoule of Sea Snake Antivenom.

TOXICOLOGY HANDBOOK
PITFALLS
l Failureto give repeat doses of antivenom following an absent,
incomplete or transient response to the initial dose
reactions
envenomed.
CONTROVERSIES
is not indicated.
Reference
6.7 CSL POLYVALENT SNAKE ANTIVENOM
This equine IgG Fab is used in the treatment of envenoming by snakes
in Australia and Papua New Guinea. It contains antibodies to the
eastern brown snake (Pseudonaja textilis), mulga snake (Pseudechis
australis), common tiger snake (Notechis scutatus), common death adder
(Acanthophis antarcticus) and the coastal taipan (Oxyuranus scutellatus).
PRESENTATIONS
40 000 unit (~50 mL) ampoules containing:
1000 units Brown Snake Antivenom
3000 units Tiger Snake Antivenom
6000 units Death Adder Antivenom
12 000 units Taipan Antivenom
18 000 units Black Snake Antivenom
INDICATIONS
l Clinicalor laboratory evidence of snake envenoming in Australia
or Papua New Guinea when the correct monovalent antivenom
cannot be identified or is not available
l Note: Polyvalent Antivenom is not required in Tasmania (Tiger
Snake Antivenom is recommended) or in Victoria and south-west
ANTIVENOMS
Western Australia (a combination of Brown Snake Antivenom and
Tiger Snake Antivenom is recommended).
CONTRAINDICATIONS
suspected equine sera allergy. 481
ADMINISTRATION

TOXICOLOGY HANDBOOK
minutes


description)
Serum sickness
HANDY TIPS
l A patient envenomed by an unknown snake may usually be
appropriately treated with 1 or 2 (rarely 3) monovalent antivenoms
dependent on geography, clinical features and laboratory
investigations. This is less expensive and carries a lower risk of
ANTIVENOMS
adverse reaction than use of Polyvalent Antivenom.
PITFALLS
envenomed.
482
48
CONTROVERSIES
2

TOXICOLOGY HANDBOOK

is not indicated.
References
6.8 CSL STONEFISH ANTIVENOM

This equine IgG Fab is the definitive treatment of envenoming by stonefish
(Synanceia trachynis and Synanceia verrucosa) from Australian waters.
It may also have a role in the treatment of bullrout (Notesthes robusta)
stings.
PRESENTATION
2000 unit (1.5–3 mL) ampoules
INDICATIONS
l Severe localised pain unrelieved by intravenous opioids
l Clinical evidence of systemic envenoming, such as cardiac
failure.
CONTRAINDICATIONS
ADMINISTRATION
l Administer 1 ampoule for every two spine puncture wounds (to a
maximum of 3 ampoules) undiluted by IM injection
l Alternatively the antivenom may be diluted in 100 mL normal saline
and administered intravenously over 20 minutes
ANTIVENOMS
l Repeat doses of 1 ampoule are given until therapeutic end point is
haemodynamically unstable, or in cardiac arrest.

l Resolution of local and systemic features of envenoming. 483

Acute allergic or anaphylactic reaction TOXICOLOGY HANDBOOK
(max 0.5 mg) to lateral thigh (See Appendix 6 for full management
description)
l Note: Rarely, ongoing administration of adrenaline by
titrated infusion may be necessary to complete antivenom
administration
Serum sickness
Pregnancy: Pregnancy is not a contraindication to either opioid
analgesia or antivenom
PITFALLS
l Failureto give repeat doses of antivenom following an absent,
reactions
envenomed.
CONTROVERSIES
l Relative efficacy of IM versus IV route of administration.
References
ANTIVENOMS
6.9 CSL BOX JELLYFISH ANTIVENOM

This ovine IgG Fab is available for treatment of envenoming by box
jellyfish (Chironex fleckeri ) found in Australian waters. Its clinical utility is
questionable.
484
PRESENTATION
48
4
20 000 unit (1.5–4 mL) ampoule

TOXICOLOGY HANDBOOK
INDICATIONS
l Clinical features of systemic envenoming, such as cardiovascular
instability and cardiac arrest (see Chapter 5.10: Box jellyfish)
l Local pain refractory to IV opioid analgesia.
CONTRAINDICATIONS
suspected ovine sera allergy.
ADMINISTRATION
l In patients with pain refractory to IV opioid analgesia, administer
1 ampoule diluted in 100 mL of normal saline IV over 20 minutes.
Further doses of 1 ampoule may be given, to a total of 3 ampoules,
if pain persists
20 minutes in patients with haemodynamic compromise. Repeat
doses of 3 ampoules are given until therapeutic end point is
l Note: Six ampoules may be given as a rapid IV push if the patient
is in cardiac arrest.

l Resolution of severe local pain.

description)
ANTIVENOMS
Serum sickness
485
Pregnancy: No restriction on use TOXICOLOGY HANDBOOK
HANDY TIPS
l Most patients suffering local envenoming by box jellyfish do not
develop systemic features. Local pain usually settles with ice and
simple analgesia and antivenom is not required
l CSL Box Jellyfish Antivenom is not effective in irukandji syndrome
or for stings by other jellyfish.
PITFALLS
l Administration of antivenom to patients without clinical features of
systemic envenoming.
CONTROVERSIES
l Although antivenom is demonstrated to bind well to venom in
vitro, it does not appear to prevent venom-induced cardiovascular
collapse in vivo. This suggests that the venom acts very rapidly
on the cardiovascular system and before it can be bound by
antivenom. If correct, this means that antivenom is of limited
clinical value
l Although commonly advocated in patients with severe pain, there
is only anecdotal evidence to support the use of antivenom for
analgesia
l Antivenom is sometimes administered by the IM route, but this
route is almost certainly ineffective.
References
Winter KL, Isbister GK, Jacoby T et al. An in vivo comparison of the efficacy of CSL box
jellyfish antivenom with antibodies raised against nematocyst-derived Chironex
fleckeri venom. Toxicology Letters 2009; 187:94–98.
6.10 CSL REDBACK SPIDER ANTIVENOM

This equine IgG Fab is used in the treatment of envenoming by the
Australian redback spider (Latrodectus hasselti ). It may also be useful in
the treatment of envenoming due to Steatoda spp. and Latrodectus spp.
elsewhere in the world.
ANTIVENOMS
PRESENTATION
500 unit (1–1.5 mL) ampoules
INDICATIONS
l Local pain refractory to simple analgesia
l Clinical features of systemic envenoming(latrodectism) (see
486 Chapter 5.13: Redback spider)
48
l Therapeutic trial may be warranted when the diagnosis is

6
uncertain.
TOXICOLOGY HANDBOOK
CONTRAINDICATIONS
l There is an increased risk of allergicreaction in patients who have
ADMINISTRATION
20 minutes
l Repeat dose of 2 ampoules after 2 hours if clinical features of
envenoming fail to resolve
l Intramuscular injection of undiluted antivenom is an equally
effective alternative.

l Resolution of local and systemic features of envenoming.
l Acute hypersensitivity reactions occur in less than 5% of cases
following IV administration of diluted antivenom and less than 0.5%
of cases following IM administration
l The reactions are usually mild in nature
l Give oxygen, IV fluids and consider administration of IM adrenaline
0.01mg/kg (max 0.5mg) to lateral thigh (see Appendix 6 for full
management description)
Serum sickness
l This relatively benign and self-limiting complication occurs 5–10 days
after antivenom in about 10% of cases
l Oral steroids (e.g. prednisolone 50 mg/day in adults or 1–2 mg/kg/day
in children for 5 days) ameliorate symptoms
ANTIVENOMS
Pregnancy: Pregnancy is not a contraindication for antivenom
treatment. Antivenom administration has successfully reversed
premature labour caused by redback spider envenoming
Lactation: No restrictions on use
487
HANDY TIPS
l Redback antivenom may be used as a diagnostic (and therapeutic)
tool in patients who present with clinical features of envenoming,
but no history of bite. TOXICOLOGY HANDBOOK
PITFALLS
woman due to concerns about the potential adverse reactions.
Children receive the same dose of antivenom as adults, but dilution
may need to be adjusted to a suitable volume
l Administration of antivenom to a non-envenomed patient.
CONTROVERSIES
l Both the relative efficacy of IV versus IM route of administration
and the efficacy of redback antivenom itself are currently being
questioned. Antivenom is measurable in serum following IV
but not IM administration. However, a randomised controlled
trial comparing IV with IM antivenom failed to demonstrate any
difference in pain scores at 2 hours. This raises the possibility that
antivenom by any route may not provide benefit over placebo. A
placebo-controlled randomised controlled trial of antivenom is
underway.
References
Isbister GK, Brown SGA, Miller M et al. A randomised controlled trial of intramuscular
versus intravenous antivenom for latrodectism—the RAVE study. Quarterly Journal of
Medicine 2008; 101:557–565.
Isbister GK, O’Leary MA, Miller M et al. A comparison of serum antivenom concentrations
after intravenous and intramuscular administration of redback (widow) spider
antivenom. British Journal of Clinical Pharmacology 2008; 65:138–143.
Isbister GK. Safety of i.v. administration of redback spider antivenom. Internal Medicine
Journal 2007; 37:820–822.
6.11 CSL FUNNEL-WEB SPIDER ANTIVENOM

This lapine IgG Fab is the definitive treatment of envenoming by
funnel-web spiders (Atrax spp. and Hadronyche spp.). It may also be
useful in treating envenoming by mouse spiders (Missulena bradleyi ).
PRESENTATION
125 units per ampoule of freeze-dried antivenom
INDICATIONS
ANTIVENOMS
l Clinicalfeatures of systemic envenoming

l Usually these features are dramatic and sudden in onset and
commence with perioral tingling, tongue fasciculation, salivation,
sweating and lacrimation. They may progress to muscle twitching,
tachycardia and hypertension, pulmonary oedema and death.
CONTRAINDICATIONS
488 l No specific contraindications
48
8

suspected lapine sera allergy.
TOXICOLOGY HANDBOOK
ADMINISTRATION
l Reconstitute the freeze-dried antivenom in 10 mL of sterile water
20 minutes.
Note: In the severely envenomed patient, the recommended initial
dose is 4 ampoules
l Repeat doses of 2 ampoules are given every 2 hours until clinical
features of envenoming resolve.

l Resolution of local and systemic features of envenoming.

(max 0.5 mg) to lateral thigh (See Appendix 6 for full management
description)
Serum sickness
PITFALLS
ANTIVENOMS
l Failure
to give repeat doses of antivenom following an absent,
l Inadequate initial dose with life-threatening envenoming
woman due to concerns about the potential adverse reactions
envenomed.
489
Reference
TOXICOLOGY HANDBOOK

TOXICOLOGY HANDBOOK
APPENDICES
Appendix 1: Poisons information telephone numbers 492

Appendix 2: Example ECGs 493
Appendix 3: Conversion factors and therapeutic
ranges for important toxins 498
Appendix 4: Alcohol pathways 499
Appendix 5: Theraupeutic over-warfarinisation 500
Appendix 6: Management of allergic reactions
to antivenoms 502
APPENDIX 1: P
OISONS INFORMATION TELEPHONE
NUMBERS
Australia 13 11 26
New Zealand 0800 764 766/0800 POISON
United Kingdom 0870 6006266
United States of America 1 800 2221222

APPENDICES
492
49
2
TOXICOLOGY HANDBOOK
APPENDIX 2: EXAMPLE ECGs
APPENDIX 2A TCA cardiotoxicity (early)
APPENDICES
493
TOXICOLOGY HANDBOOK
APPENDIX 2B TCA cardiotoxicity (deterioration)
APPENDICES
49494
4
TOXICOLOGY HANDBOOK
APPENDIX 2C TCA cardiotoxicity (post-alkalinisation)
APPENDICES
495
TOXICOLOGY HANDBOOK
APPENDIX 2D Acute digoxin overdose
APPENDICES
49496
6
TOXICOLOGY HANDBOOK
APPENDIX 2E QT prolongation and torsades de pointes
APPENDICES
497
TOXICOLOGY HANDBOOK
49498
8
TOXICOLOGY HANDBOOK APPENDICES
APPENDIX 3: CONVERSION FACTORS AND

l
l To convert from conventional units to SI units, multiply by

Conventional SI
factor
To convert from SI units to conventional units, divide by conversion
conversion factor
Therapeutic Conversion Therapeutic
Drug range Units factor range Units
Carbamazepine 4–12 mg/L 4.25 17–51 micromol/L
IMPORTANT TOXINS
THERAPEUTIC RANGES FOR
Digoxin 0.8–2.0 ng/mL 1.281 1.1–2.6 nmol/L
Ethanol N/A mg/dL 0.217 N/A mmol/L
Ethylene glycol N/A mg/L 16.11 N/A micromol/L
Iron 80–180 microgram/dL 0.179 14–32 micromol/L
Lead <10 microgram/dL 0.0483 <0.48 micromol/L
Paracetamol 10–30 microgram/mL 6.62 66–199 micromol/L
Phenobarbitone 15–40 mg/L 4.31 65–172 micromol/L
Phenytoin 10–20 microgram/mL 3.96 40–79 micromol/L
Salicylate 15–30 mg/dL 0.0724 1.1–2.2 mmol/L
Theophylline 5–15 microgram/mL 5.55 28–83 micromol/L
Valproic acid 50–120 mg/L 6.94 347–833 micromol/L

APPENDIX 4: ALCOHOL PATHWAYS
Pathways of Alcohol Metabolism
Ethanol Ethylene Glycol
Ethanol Ethylene glycol

ADH NAD ADH NAD
NADH NADH
Acetaldehyde Glycoaldehyde
ALDH ALDH
Acetate Glycolic acid

Mg++
Thiamine Pyridoxine
APPENDICES
Acetyl CoA Alpha hydroxy- Glyoxylic acid Glycine
beta-ketoadipate
Thiamine Thiamine
CO2 + H2O Oxalic acid
Methanol Isopropanol 499
Methanol Isopropyl alcohol
TOXICOLOGY HANDBOOK
ADH NAD
NADH ADH
Formaldehyde Acetone
ALDH
Formic Acid
ADH: Alcohol dehydrogenase
Folate
ALDH: Aldehyde dehydrogenase
CO2 + H2O
APPENDIX 5: THERAPEUTIC OVER-WARFARINISATION
Guidelines for the management of an elevated international normalised
ratio (INR) in adult patients with or without bleeding
Clinical setting Action

INR higher than the l Lower the dose or omit the next dose of
therapeutic range warfarin. Resume therapy at a lower dose
but <5.0; bleeding when the INR approaches therapeutic
absent range
l If the INR is only minimally above
therapeutic range (up to 10%), dose
reduction may not be necessary
INR 5.0–9.0*, l Cease warfarin therapy; consider reasons

bleeding absent for elevated INR and patient-specific
factors
l If bleeding risk is high, give vitamin K1
APPENDICES
(1.0–2.0 mg orally or 0.5–1.0 mg

intravenously)
l Measure INR within 24 hours†, resume
warfarin at a reduced dose once INR is in
therapeutic range
INR >9.0; bleeding l Where there is a low risk of bleeding, cease

500 absent warfarin therapy, give 2.5–5.0 mg vitamin
50
K1 orally or 1.0 mg intravenously. Measure

0
INR in 6–12 hours, resume warfarin therapy

at a reduced dose once INR <5.0
TOXICOLOGY HANDBOOK
l Where there is high risk of bleeding‡, cease

warfarin therapy, give 1.0 mg vitamin K1
intravenously. Consider Prothrombinex-
HT (25–50 IU/kg) and fresh-frozen plasma
(150–300 mL), measure INR in 6–12 hours,
resume warfarin therapy at a reduced dose
once INR <5.0
Any clinically l Cease warfarin therapy, give
significant bleeding 5.0–10.0 mg vitamin K1 intravenously, as
where warfarin- well as Prothrombinex-HT (25–50 IU/kg)
induced coagulopathy and fresh-frozen plasma (150–300 mL),
is considered a assess patient continuously until INR
contributing factor <5.0, and bleeding stops§
OR
l If fresh-frozen plasma is unavailable, cease
warfarin therapy, give 5.0–10.0 mg vitamin
K1 intravenously, and Prothrombinex-HT
(25–50 IU/kg), assess patient continuously
until INR <5.0, and bleeding stops
OR
l If Prothrombinex-HT is unavailable, cease
warfarin therapy, give 5.0–10.0 mg vitamin
K1 intravenously, and 10–15 mL/kg
of fresh-frozen plasma, assess patient
continuously until INR <5.0, and bleeding
stops
APPENDICES
*Bleeding risk increases exponentially from INR 5 to 9; INR ≥6 should be monitored
closely.
†Vitamin K effect on INR can be expected within 6–12 hours.
‡Examples of patients in whom the bleeding risk would be expected to be high include
those with active gastrointestinal disorders (such as peptic ulcer or inflammatory
bowel disease), those receiving concomitant antiplatelet therapy, those who
underwent a major surgical procedure within the preceding 2 weeks, and those with
a low platelet count. 501
§In all situations carefully reassess the need for ongoing warfarin therapy.
Reproduced from Baker RI, Coughlin PB, Gallus AS et al. Warfarin reversal: consensus
TOXICOLOGY HANDBOOK
guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis.
Medical Journal of Australia 2004; 181(9):492–497.
APPENDIX 6: M
ANAGEMENT OF ALLERGIC REACTIONS
TO ANTIVENOMS
1 MANAGEMENT OF ACUTE SEVERE ALLERGIC REACTION OR ANAPHYLAXIS
Initial management
l Call for assistance
l Administer adrenaline IM (lateral thigh) 0.01 mg/kg up to 0.5 mg
l Lie flat/elevate legs if tolerated
l Administer high-flow oxygen, airway/ventilation support if
needed
l Intravenous normal saline bolus 20 mL/kg if hypotensive
Inadequate response or further deterioration

l Commence IV adrenaline infusion (1 mg of adrenaline in
100 mL normal saline and commence at 0.5–1 mL/kg/hour
then titrate to response)
OR
l Repeat IM adrenaline 0.01 mg/kg up to 0.5 mg every
APPENDICES
3–5 minutes as needed

l If persistent hypotension, repeat normal saline boluses
10–20 mL/kg up to 50 mL/kg over 30 minutes
l If severe bradycardia, administer atropine IV 0.02 mg/kg
l If bronchospasm, administer continuous salbutamol nebulisers
and hydrocortisone IV 5 mg/kg
502 l If upper airway obstruction, administer adrenaline nebulised 5 mg
in 5 mL.
50
2
Infusion of antivenom is recommenced cautiously as soon as

clinical manifestations of anaphylaxis are controlled. Rarely,
TOXICOLOGY HANDBOOK
ongoing administration of adrenaline by titrated infusion may be

necessary to complete antivenom administration.
2 MANAGEMENT OF SERUM SICKNESS

This is a benign and self-limiting condition, but responds well to a
short course of oral steroids (e.g. oral prednisolone 50 mg for
5 days).
Adapted from Brown SG, Mullins RJ, Gold MS. Anaphylaxis diagnosis and management.
Medical Journal of Australia 2006; 185(5):283–289.
TOXICOLOGY HANDBOOK
INDEX
Page numbers followed by ‘f’ denote figures, by ‘t’ denote tables and by ‘b’ denote boxes.
A risk assessment for, 10–12

ACE inhibitors. See angiotensin supportive care/monitoring for,
converting enzyme inhibitors 13–14
acetaminophen, 302, 312 adrenaline, 60, 145, 169, 188, 268,
acetazolamide, 111t 359, 502
acetone, 108t agitation, 62–66
acetylcholine, 76t agents/syndromes requiring specific
acetylcholine agonists, 76t interventions in, 65t
amphetamines and, 150
INDEX
acetylcholinesterase inhibitors, 76t

acetylsalicylic acid, 336, 337, 337t anticholinergic syndrome and, 75
acidaemia, 6t cannabinoids and, 191
acid-base disorders, 109–113 complications of, 63t
504 anion-gap acidosis, 110t conditions mimicking/contributing
low anion gap, 111t to, 64t
50
4
acidosis, 6t, 7t. See also metabolic management of, 64–66, 75, 192,
TOXICOLOGY HANDBOOK
acidosis; respiratory acidosis 212, 330

acids, 6t, 216. See also specific acids toxicological causes of, 63t
acromelic, 47t airway, breathing, circulation, 4–5,
activated charcoal and, 22t 6–9t
ackee fruit, 53 airway injury, 6t
aconite, 51t, 52, 53 alcohol. See also specific alcohols
acromelic acids, 47t agitation/delirium from, 63t
activated charcoal. See also anion-gap acidosis and, 110t
gastrointestinal decontamination osmolarity and, 108–109
agents poorly bound to, 22t pathways of metabolism, 499
body packers/stuffers and, 105, 106 toxic, 142–144
multiple-dose, 25–26, 175 alcohol abuse/dependence, 85
for plant poisoning, 54 clinical features of, 89–90
single-dose, 21–22 co-morbidities, 90
actrapid, 250 complications of, 86t
acute coronary syndrome, 9t management of, 90–92
acute poisoning pathophysiology of, 89
antidotes for, 29 screening/brief interventions for,
approach, 2–29 85–86, 89
in children, 120–125 alcohol dehydrogenase, 385, 386, 391
definition/description, 2 alcohol use disorders identification test
in elderly, 126 (AUDIT), 86, 87–88b, 89
enhanced elimination for, 24–29 alcohol withdrawal, 89
gastrointestinal decontamination for, alcohol withdrawal score (AWS),
17–24 91, 92b
investigations for, 15–17 alcoholic ketoacidosis, 90, 110t
medical disposition, 30–33 aldicarb, 76t, 298
morbidity/mortality from, 13 aldrin, 295, 296, 298
alert-verbal-pain-unresponsive system angiotensin, 154
(AVPU), 5 angiotensin converting enzyme
aliphatic hydrocarbons, 100, 100t, 237 inhibitors (ACE inhibitors),
alkalis, 6t, 216 152–154
activated charcoal and, 22t anion-gap
alkoxalkyl mercury, 273 acidosis, 110t, 139
alkyl mercury, 273 low, 111t
allergic contact dermatitis, 54 anticholinergic syndrome, 52, 63t,
alprazolam, 177, 179 70t, 72–75
amantadine, 73t, 115t agents causing, 73t
amatoxins, 46t agitation/delirium and, 63t, 75,
INDEX
amethocaine, 265, 268 160–161, 162–163
aminophylline, 351 benztropine and, 179–180
amiodarone, 7t, 359 clinical features of, 72, 73t, 74
children and, 145 differential diagnosis of, 74t
clinical features, 145 management of, 74–75 505
disposition/follow-up, 146 anticoagulant rodenticides
investigations, 145 children and, 123, 155
TOXICOLOGY HANDBOOK
management, 145–146 clinical features, 155
risk assessment, 144–145 disposition/follow-up, 155–156
amisulpride, 116t investigations, 155
clinical features, 147 management, 155–156
disposition/follow-up, 148 presentations, 156
investigations, 147 risk assessment, 154–155
management, 147–148 vitamin K and, 426–428
risk assessment, 146, 147t anticoagulation therapy, 9t
amitriptyline, 115t, 116t, 357, 358, 360 anticonvulsants. See also specific
amlodipine, 186, 189 anticonvulsants
ammonia, 216, 219 anticholinergic syndrome and, 73t
ammonium chloride, 111t, 293 clinical features, 157–158
amphetamines, 8t, 9t, 16, 148, 345. coma from, 158, 159
See also specific amphetamines disposition/follow-up, 158
body packing/stuffing, 104–106 investigations, 158
children and, 122t, 149 management, 158
clinical features, 149–150 presentations, 159
disposition/follow-up, 151 risk assessment, 157
investigations, 16, 150 antidotes. See also antivenom;
long-term effects, 93, 93t chelation; specific antidotes
management, 150–151 acute poisoning and, 29
presentations/sources of, 152 anticholinergic syndrome and, 75
risk assessment, 149 for arsenic, 166–167
seizures from, 5, 61, 61t for benzodiazepines, 178, 387–389
serotonin syndrome and, 69t body packers, 106
withdrawal, 93–94 for calcium channel blockers, 374
amygdalin, 52, 219 for carbamates, 372, 413–415
angel’s trumpet, 52 children and, 125
antidotes (Continued) sedating, 162–164
cholinergic syndrome and, 79 clinical features, 162
for clonidine, 206–207 disposition/follow-up, 163
coma and administration of, 59 investigations, 162
for cyanide, 54, 221, 396–398, management, 162–163
422–424 presentations, 164
delirium/agitation and, 66 risk assessment, 162
emergency administration of, 10 antimuscarinic agents. See
ethanol as, 135, 141, 143, 385–387 anticholinergic syndrome
administration, 386 antiplatelet therapy, 9t
adverse reaction, 386 antipsychotics, 65. See also specific
drugs
INDEX
pregnancy/children and, 387

for hydrofluoric acid, 374–375 anticholinergic syndrome and, 73t
for isoniazid, 254, 256 atypical, 66
for lead, 259 potassium efflux blockade and, 116t
506 medical disposition and, 33 antivenom
for methaemoglobinaemia, 267 allergic reactions to, 502
50
6
for methotrexate, 278 black snakes, 431, 470–471

TOXICOLOGY HANDBOOK
mushroom poisoning, 49 box jellyfish, 453

NMS and, 83–84 brown snakes, 434, 471–473
for organophosphates, 301, 372, death adder, 437, 473–475
413–415 determining type required, 41–42
for paracetamol, 306–307, 313–314 funnel-web spider, 462, 488–489
for plant poisoning, 54 jellyfish, 484–486
in resuscitation, emergency polyvalent, 41, 42t, 43, 438, 443,
administration of, 10 446, 447, 474, 478, 481–482
serotonin syndrome and, 71–72 redback spider, 460, 486–487
for sulfonylureas, 347 sea snake, 446, 479–480
for warfarin, 370 stonefish, 451, 482–484
antidysrhythmic agents. See also taipan, 443, 477–478
quinine tick, 466
fast sodium channel blockade and, tiger snake, 431, 440, 446, 471,
115t 475–476
potassium efflux blockade and, 116t APAP. See N-acetyl-p-aminophenol
antihistamines, 73t. See also specific apidra, 250
antihistamines arasan, 76t
anticholinergic syndrome and, aromatic hydrocarbons, 100, 100t, 237
161, 163 arsenic, 22t, 23t, 383–384, 410, 424
non-sedating, 159–161 antidotes for, 166–167
clinical features, 160 children and, 165
disposition/follow-up, 161 clinical features, 165
investigations, 160 disposition/follow-up, 167
management, 160–161 investigations, 165–166
presentations, 161 management, 166–167
risk assessment, 160 presentations/sources of, 167
potassium efflux blockade and, 116t risk assessment, 164–165
articaine, 265, 268 management, 172
aspirin, 212, 293, 336, 337, 337t, presentations, 173
339–340 risk assessment, 171
astemizole, 116t bagging, 101
asystole, 8t barbiturates, 16, 159. See also specific
atenolol, 168, 170 barbiturates
atorvastatin, 189 children and, 173
atropine, 6t, 9t, 52, 59t, 73t, 96t. clinical features, 174
See also diphenoxylate-atropine dependence/withdrawal, 97
administration, 372 disposition/follow-up, 176
adverse reactions, 372–373 investigations, 16, 174–175
INDEX
allergic reaction to antivenoms and, management, 175
502 presentations, 176
beta-blocker overdose management risk assessment, 173
and, 169 seizure correction with, 5, 62
calcium channel blocker overdose belladonna alkaloids, 51t, 52 507
management and, 188 benzene, 237, 239
cholinergic syndrome and, 49, 78, 79 benzocaine, 265, 266, 268
TOXICOLOGY HANDBOOK
clonidine overdose management benzodiazepines, 4t, 8t, 9t, 16, 53,
and, 206 161, 163. See also specific
digoxin poisoning and, 224, 228 benzodiazepines
funnel-web spider bites and, 462 amphetamine management and,
GHB management and, 234 149–151
hypotension management and, 60 anticholinergic syndrome and, 74,
indications/contraindications, 372 75, 180
mushroom poisoning and, 49 antidote for, 178, 387–389
organophosphorus agents and, 10, children and, 177
298, 300–301 cholinergic syndrome and, 78
physostigmine poisoning and, clinical features, 177
411–412 cocaine management and, 212–213
atypical antipsychotics, 66. See also delirium/agitation and, 63t, 65, 75
specific drugs dependence/withdrawal, 97–99, 388
agitation/delirium from, 63t disposition/follow-up, 178
anticholinergic syndrome and, 73t investigations, 16, 178
AUDIT. See alcohol use disorders management, 178
identification test MAOI management with, 282–283
autumn crocus, 52 NMS and, 83, 84
AVPU. See alert-verbal-pain- physostigmine as alternative to,
unresponsive system 411–413
AWS. See alcohol withdrawal score presentations, 179
pyridoxine administration and,
B 416–417
baclofen, 97, 98 risk assessment, 177
clinical features, 171 seizure management with, 5, 61, 62,
disposition/follow-up, 172 64, 135, 150, 212, 333, 341, 351
investigations, 172 serotonin syndrome and, 69, 71
benzodiazepines (Continued) blue-ringed octopus, 457–458
solvent abuse/dependence treatment body packing/stuffing, 23t, 104–106
and, 102 clinical presentation of, 104
venlafaxine/desvenlafaxine definitions, 104
management and, 364, 365–366 management of, 105–106
benzothiazepines, 189 box jellyfish, 449, 452–454, 456, 458
benztropine, 73t, 74, 411 bradycardia, 8t, 9t
clinical features, 179–180 British anti-lewisite (BAL), 167, 383.
disposition/follow-up, 180 See also dimercaprol
investigations, 180 brodifacoum, 154, 156, 426
management, 180 bromadiolone, 154
INDEX
presentations, 181 bromazepam, 177, 179

risk assessment, 179 bromocriptine, 65t, 83–84
benzyl alcohol, 142, 144 brompheniramine, 73t, 162, 164
benzyl penicillin (penicillin G), 49 brown snake, 37t, 40, 436, 481
508 beta2-agonists, 112t antivenom, 434, 471–473
beta-adrenergic blockers, 212, 213, 282 clinical presentation/course,
50
8
beta-blockers, 5, 7t, 8t, 9t, 13. See also 433–434

TOXICOLOGY HANDBOOK
specific drugs differential diagnosis, 435

children and, 168 disposition/follow-up, 435
chloral hydrate management and, distribution of, 433
204–205 investigations, 434–435
clinical features, 168–169 management, 434
disposition/follow-up, 170 toxins, 433
glucagon and management of, bupivacaine, 115t, 265, 266t, 268
392–394 buprenorphine, 95, 96, 290,
investigations, 169 292–293
management, 169–170 bupropion, 5, 61, 69t, 116t, 340, 417
presentations, 170 agitation/delirium from, 63t
risk assessment, 168 children and, 181
thyroid excess and, 353 clinical features, 182
bethanechol, 76t disposition/follow-up, 183
big black spider. See funnel-web spider investigations, 182
biotin deficiency, 112t management, 182–183
bisoprolol, 168, 170 presentations, 183
black snake, 38t, 433 risk assessment, 181–182, 181t
antivenom, 431, 470–471 butler’s snake, 430–431, 470
clinical presentation/course, button batteries, 184–185
430–431 butyrophenones
differential diagnosis, 432 children and, 321
distribution of, 430 disposition/follow-up, 322
investigations, 431–432 investigations, 321
management, 431 management, 321–322
toxins, 430 presentations, 322–323
bluebottle jellyfish, 449, 453, 456 risk assessment, 320–321
C captopril, 152, 154
CAGE questions, 86, 89b carbachol, 76t
calcium, 7t, 9t, 60, 188 carbamates, 6t, 76t, 123t, 298
administration, 374–375 antidote administration, 372–373,
adverse reactions, 375 413–415
as antidote, 242–243 children and, 123t, 298
indications/contraindications, 373 clinical features, 299–300
calcium channel blockers, 8t, 9t, 13, disposition/follow-up, 301
116, 168 investigations, 300
antidote administration, 374 management, 300–301
children and, 122t, 186 risk assessment, 298
INDEX
clinical features, 186–187 carbamazepine, 17t, 28, 59t, 157, 159
disposition/follow-up, 189 anticholinergic syndrome and,
ECG features, 116 73t, 74
glucagon and management of, children and, 193
392–394 clinical features, 194, 194t 509
high-dose insulin and management conversion factors, 498
disposition/follow-up, 195
TOXICOLOGY HANDBOOK
of, 398–399
hypotension management and, 60 fast sodium channel blockade and,
investigations, 187 115t
management, 187–188 investigations, 194–195
presentations, 189–190 management, 195
risk assessment, 186 MDAC and, 25t
self-poisoning with, 12, 13 pregnancy and, 193
thyroid excess and, 353 presentations, 196
calcium chloride, 242, 327 risk assessment, 193, 193t
calcium folinate, 389 carbazine, 298
calcium gluconate, 242 carbendazim, 298
calcium oxalate, 50, 133, 134 carbendazole, 298
calcium salts, 9t carbon monoxide, 110t, 112t, 119
camphor, 123t clinical features, 197–198, 198t
cannabidiol, 190 disposition/follow-up, 199
cannabinoid hyperemesis syndrome, investigations, 198, 198t
191, 192 management, 198–199
cannabinoids, 16 pregnancy and, 197
agitation/delirium from, 63t, 191 risk assessment, 196–197
body packing/stuffing, 104 sources of, 199
children and, 190 carbon tetrachloride, 100t, 237, 239,
clinical features, 191 404
disposition/follow-up, 192 cardiac conduction defects, 9t
investigations, 16, 191–192 cardiac glycosides, 51t, 52, 53, 54, 56,
management, 106, 192 372. See also digoxin
presentations/sources of, 193 cardiopulmonary resuscitation (CPR), 4
risk assessment, 190 cardiotropic medications, 60
withdrawal, 98 carvedilol, 168, 170
cannabinol, 190 castor bean seeds, 50, 53
catecholamines, 7, 101, 102, 295 digoxin and, 123, 222
calcium channel blocker diphenoxylate-atropine and, 230
management and, 188 ethanol and, 387
chloral hydrate management and, 204 ethylene glycol and, 133
GHB management and, 234 flumazenil and, 389
celecoxib, 284, 286 funnel-web spider bites and, 462
central nervous system (CNS) gamma-hydroxybutyrate and, 232
coma and, 55, 57 glyphosate and, 235
opioids and, 290 hydrocarbons and, 123t, 238
toxin action on, 57 hydrofluoric acid and, 241
cetirizine, 159, 161 hydrogen peroxide and, 244
INDEX
cetrimol, 268 lead and, 257

chelation, 166, 167, 253, 259, 272, lithium and, 261
420–422, 424–426. See also local anesthetics and, 265
specific chelating agents MAOIs and, 281
510 chemical nerve agents, 76t, 298, 413. mercury and, 269
See also organophosphates metformin and, 273
51
0
cherry meth. See gamma- methanol and, 139

TOXICOLOGY HANDBOOK
hydroxybutyrate methotrexate and, 276

children mirtazapine and, 279
ACE inhibitors and, 152 mushroom poisoning and, 44
amiodarone and, 145 NAC and, 405
amphetamines and, 122t, 149 naloxone and, 407
anticoagulant rodenticides and, non-toxic household exposures, 121t
123, 155 octreotide and, 409
arsenic and, 165 olanzapine and, 287
barbiturates and, 173 opioids and, 122t, 290
benzodiazepines and, 177 organochlorines and, 295, 295t
beta-blockers and, 168 organophosphates and, 78, 123t, 298
bupropion and, 181 paracetamol and, 123, 303
button batteries and, 184–185 paraquat and, 316
butyrophenones and, 321 phenothiazines and, 321
calcium channel blockers and, phenytoin and, 323
122t, 186 plant poisonings and, 50
cannabinoids and, 190 poisoning in
carbamates and, 123t, 298 agents involved in, 121t
carbamazepine and, 193 management of, 120–125, 124t
chloral hydrate and, 202 non-pharmaceuticals, 123t
chloroquine/hydroxychloroquine pharmaceuticals, 122t
and, 200, 202 potassium chloride and, 326
clonidine and, 205 pralidoxime and, 415
clozapine and, 208 quetiapine and, 329
cocaine and, 210 risperidone and, 334
colchicine and, 214 salicylates and, 337
corrosives and, 217 strychnine and, 343
cyanide and, 219 sulfonylureas and, 122t, 346
TCAs and, 122t, 358 clonazepam, 5, 177, 179
theophylline and, 122t, 349 clonidine, 96t
thyroxine and, 353 children and, 205
toxic alcohols and, 142 clinical features, 206
tramadol, 355 disposition/follow-up, 207
valproic acid and, 361 investigations, 206
venlafaxine/desvenlafaxine and, 365 management, 206–207
warfarin and, 368 presentations, 207
chloral hydrate, 7t, 97 risk assessment, 205
children and, 202 clozapine
INDEX
investigations, 203 disposition/follow-up, 209
management, 204 investigations, 208
presentations, 205 management, 209
risk assessment, 202 presentations, 209 511
chlordane, 295, 296, 298 risk assessment, 208
chlorhexidine, 268 CNS. See central nervous system
TOXICOLOGY HANDBOOK
chloroquine, 5, 7t, 61, 61t, 115t, 116t, coagulopathy. See venom-induced
122t, 417 consumptive coagulopathy
children and, 200, 202 cocaine, 7t, 8t, 9t, 16, 345
clinical features, 200–201 body packing/stuffing, 104–106
disposition/follow-up, 202 children and, 210
investigations, 201 clinical features, 210–211
management, 201 disposition/follow-up, 212–213
presentations, 202 fast sodium channel blockade
risk assessment, 200 and, 115t
chlorphacinone, 154 investigations, 16, 211
chlorpheniramine, 73t, 162, 164, management, 211–212
310, 311 pregnancy/lactation and, 210
chlorpromazine, 71, 73t, 75, 116t, presentations, 213
320–322 risk assessment, 210, 210t
chlorpyrifos, 76t, 298, 299 codeine, 164, 286, 290–293, 310, 311
cholestyramine, 111t colchicine, 51t, 52, 53, 60, 123
cholinergic crisis, 6t children and, 214
cholinergic syndrome, 44, 45t, 76–79, clinical features, 214, 215t
299 disposition/follow-up, 216
agents causing, 76t investigations, 215
atropine and, 49, 78, 79 management, 215
clinical features of, 77, 77t presentations, 216
differential diagnosis of, 78t risk assessment, 214, 214t
management of, 77–79 Collett’s snake, 430–431
cinchonism, 331–333 coma
citalopram, 69t, 116t, 340–343 agents requiring specific intervention
clobazam, 177, 179 and, 59t
clomipramine, 357, 360 anticonvulsants and, 158, 159
coma (Continued) cyproheptadine, 65t, 71, 73t, 162, 164,
causes of, 55, 56t 283, 377
complications of, 58 administration, 376
management of, 55, 57–59 indications/contraindications, 376
communication, in patient retrieval, 33
coniine, 51t, 52 D
contact dermatitis, 54 dantrolene, 83, 84
conversion factors, 498 dapsone, 25t, 26, 402
copperhead snakes, 439, 440, 475. DDT. See
See also tiger snake dichlorodiphenyltrichloroethane
coprine, 44, 45t death adders, 37t, 40, 432, 481
INDEX
corrosives antivenom, 437, 473–475

children and, 217 clinical presentation/course,
clinical features, 217 436–437
disposition/follow-up, 218 differential diagnosis, 438
512 investigations, 217–218 disposition/follow-up, 438
management, 218 distribution, 436
51
2
risk assessment, 216–217 investigations, 437

TOXICOLOGY HANDBOOK
sources of, 219 management, 437

corticosteroids, 121t, 219, 239, 246, toxin, 436
319 dehydration, 90
coumadin, 426 delirium, 62–66. See also agitation;
coumafos, 76t anticholinergic syndrome
coumaphos, 298 agents/syndromes requiring specific
CPR. See cardiopulmonary interventions in, 65t
resuscitation anticholinergic syndrome and, 75,
crack cocaine, 213 161, 163
cryoprecipitate, 43 diagnostic features of, 62t
cyanide, 52, 110t, 112t, 417 duty of care in, 63
antidotes for, 54, 221, 379–380, management of, 64–66
396–398, 422–424 toxicological causes of, 63t
children and, 219 delirium tremens
clinical features, 220, 220t alcohol abuse/dependence and, 90
disposition/follow-up, 221 management of, 91
investigations, 220, 220t delta-8-tetrahydrocannabinol, 190
management, 221 delta-9-tetrahydrocannabinol, 190
risk assessment, 219 dementia, agents used in, 76t
sources, 222 dermal exposures, plant poisoning, 54
cyanogenic glycosides, 51t desferrioxamine (DFO), 250, 253–254,
cycloate, 76t 319, 379
cyclobenzaprine, 73t administration, 378
cyclodienes, 296 adverse reactions, 378
cyclopentolate, 73t indications/contraindications, 377
cyclopeptide hepatotoxic poisoning, 44, pregnancy and, 378
46t, 48–49 desipramine, 115t, 116t
cyclophosphamide, 319–320 desloratadine, 159, 161
desvenlafaxine, 364 diazinon, 76t, 298, 299
children and, 365 dichlorodiphenyltrichloroethane
clinical features, 365–366 (DDT), 295, 296, 298
disposition/follow-up, 367 dichloromethane, 199
investigations, 365 dichlorvos, 298
management, 366–367 diclofenac, 284, 286
presentations, 368 dicobalt edetate, 221, 259
risk assessment, 365 administration, 379–380
detoxification, for opioid dependence/ adverse reactions, 380
withdrawal, 96–97 indications/contraindications, 379
dexamphetamine, 148, 152 dieldrin, 295, 296, 298
INDEX
dexchlorpheniramine, 73t, 162, 164 diethylene glycol, 142, 144
dextromethorphan, 69t, 73t, 310, 311 difenacoum, 154
dextropropoxyphene, 115t, 122t, 290, digoxin, 8t, 9t, 10, 17t, 52, 53, 60, 168
290t, 291, 293, 310, 417 acute overdose
dextrose clinical features, 223 513
coma management and, 57 disposition/follow-up, 225
euglycaemia maintenance with, 53 ECG, 496
TOXICOLOGY HANDBOOK
hyperkalaemia control and, 327 investigations, 124, 223
hypoglycaemia correction with, 5 management, 224
insulin combined with, for risk assessment, 222
hypotension, 8t, 9t children and, 123, 222
octreotides and, 9t chronic poisoning, 126
DFO. See desferrioxamine clinical features, 227
diabetes insipidus, lithium and, 264 disposition/follow-up, 229
diabetic ketoacidosis, 110t investigations, 227–228
diazepam, 177, 179 management, 228
agitation management and, 75, 192, risk assessment, 226, 226t
212, 330 conversion factors, 498
chloroquine/hydroxychloroquine presentations, 225, 229
overdose management and, 201 serum levels of, 53
delirium management with, 65, digoxin immune Fab, 8t, 9t, 10, 33, 54,
212, 330 60, 224, 225, 228–229, 383
delirium tremens and, 91 administration, 381–382
NMS management and, 83, 84 adverse reactions, 382
opioid withdrawal management dose calculation, 382
and, 96t indications, 381
pregnancy and, 119 dihydropyridines, 186, 189–190
propylene glycol as diluent in, 108t diltiazem, 23t, 115t, 122t, 186, 188,
seizure correction with, 5, 62, 189, 353
150, 172, 182, 212, 255, 341, dimenhydrinate, 73t, 162, 164
356, 366 dimercaprol, 167, 272, 383, 421, 425
serotonin syndrome management administration, 384
and, 69 adverse reactions, 384–385
strychnine poisoning management indications/contraindications, 384
and, 344 pregnancy/lactation and, 385
2,3-dimercaptopropane-1-sulfonic acid doxylamine, 73t, 162, 164, 293, 311
(DMPS), 167 droperidol, 65–66, 73t, 116t, 150,
2,3-dimercaptopropanol, 383 320, 322
dimethoate, 76t, 298, 299 drugs of abuse
2,5-dimethoxy-4-iodophenethylamine screening tests for, 16–17
(2C-I), 63t serotonin syndrome and, 69t
dimethyltryptamine (DMT), 63t
diphacinone, 154 E
diphenhydramine, 73t, 115t, 116t, 162, easy lay. See gamma-hydroxybutyrate
164, 179 ecstasy. See 3,4-methylenedioxy
diphenoxylate, 96t, 122t methamphetamine
INDEX
diphenoxylate-atropine, 96t, 104, 122t, ECT. See electroconvulsive therapy

230–231 ectopy, ventricular, 7t
dipropylene glycol, 142 edrophonium, 76t
diquat, 320 EEG. See electroencephalogram
514 disopyramide, 115t, 116t EGBE. See ethylene glycol monobutyl
disposition, medical. See also specific ether
51
4
toxins EGME. See ethylene glycol monoethyl

TOXICOLOGY HANDBOOK
acute poisoning and, 30–33 ether

alcohol abuse/dependence and, elderly
91–92 pharmacodynamics in, 126
antidotes and, 33 poisoning in, 126
body packers, 105 electrocardiogram (ECG), 15–16, 15t
children and, 125 analysis of, 117–118
communication in, 33 digoxin and, 496
EOU and, 30 electropathophysiology, 113,
mushroom poisoning, 49 116–117
NMS and, 84 myocardial action potential, 114t
patient retrieval, 31–33, 32t normal parameters, 114t
planning in, 32–33 QT prolongation/torsades de pointes,
plant poisoning and, 54 497
psychosocial assessment and, 33 toxicology uses for, 113–118
risk assessment and, 30 tricyclic antidepressants and, 115t,
sedative-hypnotic dependence/ 117, 493–495
withdrawal, 99 electroconvulsive therapy (ECT), 83, 84
serotonin syndrome and, 72 electroencephalogram (EEG), NMS
transport in, 32 on, 81
disulfiram, 48, 386 emergency observation unit (EOU)
DMPS. See 2,3-dimercaptopropane-1- admission criteria for, 14, 31
sulfonic acid design features for, 31
DMSA. See succimer disposition and, 30
donepezil, 76t duration of observation periods in, 13
dopamine, 60, 188, 191, 208 toxicology patients in, 30–31
dope. See cannabinoids emesis, induced, 19–20
dothiepin, 115t, 122t, 357, 358, 360 enalapril, 152, 154, 189
doxepin, 116t, 357, 360 encainide, 115t, 116t
endosulfan, 295, 296, 298 pathways of metabolism, 499
endrin, 295, 296, 298 risk assessment, 133
enhanced elimination, 24–29 sources of, 136
anticholinergic syndrome and, 75 ethylene glycol monobutyl ether
children and, 125 (EGBE), 142–144
cholinergic syndrome and, 79 ethylene glycol monoethyl ether
coma and, 59 (EGME), 142–144
delirium/agitation and, 66 etoricoxib, 284, 286
extracorporeal techniques of, 28–29 exchange transfusion, 28
indications for, 24 extracorporeal techniques of enhanced
MDAC, 25–26 elimination, 28–29
INDEX
mushroom poisoning, 48–49
techniques for, 25t F
urinary alkalinisation, 27–28 fantasy. See gamma-hydroxybutyrate
entero-hepatic circulation interruption, fast Na+ channel blockade, 7t
25 agents associated with, 115t 515
EOU. See emergency observation unit felodipine, 186, 189
epinephrine, 60
TOXICOLOGY HANDBOOK
fentanyl, 69t, 268, 290, 293–294
erythromycin, 116t fenthion, 76t, 298, 299
escitalopram, 69t, 116t, 340–343 fexofenadine, 159, 161
esmolol, 168, 170, 204, 351, 352 fibrillation, 7t
essential oils, 237 flecainide, 7t, 115t, 116t, 417
ethanol, 17t, 22t, 59t, 89, 108t, 112t, 293 flocoumafen, 154
as antidote, 135, 141, 143, 385–387 flumazenil, 177, 178
administration, 386 administration, 388
adverse reaction, 386 adverse reactions, 388
pregnancy/children and, 387 children and, 389
clinical features, 130, 131t indications/contraindications,
conversion factors, 498 387–388
disposition/follow-up, 132 flunitrazepam, 177, 179
indications/contraindications, 386 fluoxetine, 69t, 340, 343
investigations, 131 fluphenazine, 73t, 320, 322
management, 131–132 fluvoxamine, 69t, 340, 343
pathways of metabolism, 499 folinic acid, 140, 276–278,
risk assessment, 130 389–391
sources of, 132–133 fomepizole, 59t, 135, 141, 143–144,
ethers, 100, 100t 385, 387
ethylan, 295, 298 administration, 391
ethylene glycol, 6t, 17t, 22t, 28, 57, adverse reactions, 392
59t, 107, 108t, 110t, 386, 391, 417 indications/contraindications,
children and, 133 391
clinical features, 133–134 fosinopril, 152, 154
conversion factors, 498 foxglove, 52, 225
disposition/follow-up, 135–136 FRAMES, 89, 89b
investigations for, 134 funnel-web spider, 448, 460, 461–463,
management, 134–135 488–489
G glory lily, 52
G. See gamma-hydroxybutyrate glucagon, 170, 249, 392–394
G caps. See gamma-hydroxybutyrate glucose, 396
GA. See tabun administration, 395
gabapentin, 157, 159 adverse reactions, 395
galantamine, 76t indications/contraindications, 394
gamma-hydroxybutyrate (GHB), 97–99 glycerol, 108t
children and, 232 glyceryl trinitrate (GTN), 9t, 71, 83,
clinical features, 233 150, 212, 282, 455
disposition/follow-up, 234 glycine, 108t
investigations, 233 glycopyrrolate, 73t
INDEX
management, 233–234 glyphosate, 6t, 216, 217

presentations, 235 children and, 235
risk assessment, 232 clinical features, 236
ganja. See cannabinoids disposition/follow-up, 237
516 gastric lavage, 20–21 investigations, 236
gastroenteritis, mushroom poisoning management, 236–237
51
6
and, 44 presentation/sources, 237

TOXICOLOGY HANDBOOK
gastrointestinal decontamination, risk assessment, 235, 235t

17–24 grass. See cannabinoids
anticholinergic syndrome and, 75 grievous bodily harm. See gamma-
body packers, 106 hydroxybutyrate
children and, 124–125 G-riffik. See gamma-hydroxybutyrate
cholinergic syndrome and, 79 GTN. See glyceryl trinitrate
gastric lavage, 20–21 guaifenesin, 293
induced emesis, 19–20 gyromitrin, 44, 46t
methods of, 18t
mushroom poisoning, 48 H
plant poisoning and, 54 haemodiafiltration, 175
risk-benefit analysis for, 17t, 18, 18t haemodialysis, 8t, 9t, 28, 59t, 175, 264,
single-dose activated charcoal, 274–275
21–22 haemoperfusion, 28, 175
whole bowel irrigation, 22–24 halogenated hydrocarbons, 100, 100t,
gastrointestinal dialysis, 25 237
GB. See sarin haloperidol, 65–66, 73t, 75, 81, 116t,
GCS. See Glasgow Coma Scale 320, 322
GD. See soman hashish. See cannabinoids
Georgia homeboy. See gamma- hemlock, poison, 52
hydroxybutyrate henbane, 52
GHB. See gamma-hydroxybutyrate heptachlor, 295, 296, 298
Ghbers. See gamma-hydroxybutyrate heroin, 94, 96, 290–291, 345,
Glasgow Coma Scale (GCS), 5, 57 406–407
glibenclamide, 122t, 346, 348 body packing/stuffing, 104–106
gliclazide, 122t, 346, 348 hexachlorobenzene, 295, 298
glimepiride, 122t, 346, 348 high-dose insulin therapy, 60, 169, 170,
glipizide, 122t, 346, 348 188, 398–399
homatropine, 73t presentations, 202
huffing, 101 risk assessment, 200
Humalog, 250 hyoscine, 96
Humulin, 250 hyoscine-scopolamine, 73t
hydrocarbons, 22t, 237. See also hyoscyamine, 52, 73t
solvent abuse/dependence/ hyperbaric oxygen (HBO), 199, 245
withdrawal hyperinsulinaemia, 9t
children and, 123t, 238 hyperkalaemia, 9t
clinical features, 238–239 hyperlactataemia, causes of, 112t
disposition/follow-up, 240 hypersensitivity, plant poisoning, 54
investigations, 239 hypertension, 8t
INDEX
management, 239–240 hyperthermia, 5, 10
risk assessment, 238 hyperventilation, coma management
sources of, 240 and, 57
hydrochloric acid, 216, 217, 219 hypocalcaemia, 7t
hydrocortisone, 502 hypoglycaemia, 9t 517
hydrofluoric acid, 7t delirium/agitation and, 64
antidote administration, 374–375 detecting/correcting, 5
TOXICOLOGY HANDBOOK
children and, 241 in resuscitation, 5
clinical features, 241 hypoglycin A, 51t, 52
disposition/follow-up, 243 hypotension, 8t, 9t, 59–60
investigations, 241–242 hypothermia, 5, 10
management, 242 hypothyroidism, lithium and, 264
presentations, 243 hypoventilation, 6t
risk assessment, 240–241 hypoxaemia, 7t
hydrogen peroxide hypoxia, 7t
children and, 244 Hypurin isophane, 250
clinical features, 244–245
disposition/follow-up, 246 I
investigations, 245 ibotenic acid, 44, 45t
management, 245–246 ibuprofen, 96t, 284, 284t, 285, 286, 293
presentations, 246 ice. See methamphetamine
risk assessment, 244 imipramine, 115t, 116t, 357, 360
hydromorphone, 290, 294 indomethacin, 284, 286
hydroxocobalamin (Vitamin B12a), 54, induced emesis, 19–20
221, 396–398 inotropic agents, 60
administration, 396 insulin, 5, 327
adverse reactions, 397 digoxin overdose and, 224, 228
indications/contraindications, 396 high-dose, 60, 169, 170, 188
hydroxychloroquine, 115t, 116t, administration, 399
122t, 417 adverse reactions, 399
children and, 200, 202 indications, 398
clinical features, 200–201 hyperkalaemia control and, 327
disposition/follow-up, 202 overdose
investigations, 201 clinical features, 247–248
management, 201 disposition/follow-up, 249
insulin (Continued) isopropanol, 100, 100t
investigations, 248 clinical features, 137
management, 248–249 investigations, 137
risk assessment, 247 management, 137–138
presentations, 250 pathways of metabolism, 499
insulin-dextrose therapy, 8t, 9t, 327 risk assessment, 136–137
intravenous lipid emulsion (IVLE), sources of, 138
170, 265, 267 isopropyl alcohol, 22t, 108t
administration, 400 IVLE. See intravenous lipid emulsion
adverse reactions, 400
indications/contraindications, 400 K
INDEX
investigations, 15–17, 15t, 16t, 17t. See kerosene, 100, 123t, 237
also specific toxins ketamine, 63t
alcohol abuse/dependence and, 91 ketoprofen, 284, 286
anticholinergic syndrome and, 75 ketorolac, 284, 286
518 body packers, 106
children and, 124
51
L
8
cholinergic syndrome and, 79 lactation

TOXICOLOGY HANDBOOK
coma and, 58–59 cocaine and, 210

delirium/agitation, 66 dimercaprol and, 385
mushroom poisoning, 48 poisoning and, 119–120
NMS, 83 lactic acidosis, 110t, 273–275
plant poisoning, 53 laetrile, 52
screening tests, 15–16, 15t, 17t lamotrigine, 157, 159
serotonin syndrome, 71 lantus, 250
iron, 17t, 22t, 23t, 60, 110t, 119, 123 lead, 22t, 23t, 256, 383–384, 410,
conversion factors, 498 420–422, 424–426
overdose, 250 children and, 257
clinical features, 252 clinical features, 257
disposition/follow-up, 253 conversion factors, 498
investigations, 252 investigations, 257–258, 258t
risk assessment, 251, 251t pregnancy and, 119, 257
stages of, 252t risk assessment, 257
presentations, 254 sources of, 260
Irukandji syndrome, 449, 453, 454–457 lectins, 53
isobenzan, 295, 298 lercanidipine, 186, 189
isoniazid, 5, 9t, 44, 49, 59t, 62, 110t, leucovorin (folinic acid), 278, 389
310, 312, 415–417 Levemir FlexPen, 250
clinical features, 255 levetiracetam, 157, 159
disposition/follow-up, 256 levobupivacaine, 265, 268
investigations, 255 levocetirizine, 159, 161
management, 255–256 lignocaine, 7t, 212, 213, 224, 228, 265,
presentations, 256 266t, 267, 268, 358
risk assessment, 254, 254t lily of the valley, 225
isoprenaline, 145, 160, 169, 333 lindane, 295, 295t, 296, 298
Liquid E. See gamma-hydroxybutyrate MDAC. See multiple-dose activated
Liquid X. See gamma-hydroxybutyrate charcoal
lisinopril, 152, 154 MDMA. See 3,4- methylenedioxymeth
lithium, 17t, 22t, 28, 69t, 111t amphetamine
acute overdose meclizine, 73t
clinical features, 261 mefenamic acid, 284–286
disposition/follow-up, 262 meloxicam, 284, 287
investigations, 261 mental status, 11
management, 262 mepivacaine, 265, 266t, 268
risk assessment, 260–261 merbromin, 269, 273
children and, 261 mercuric acetate, 273
INDEX
chronic poisoning, 28, 126 mercuric bromide, 273
clinical features, 263–264 mercuric chloride, 216, 217, 273
investigations, 264 mercuric potassium cyanide, 273
management, 264 mercuric sulfide, 273
risk assessment, 263 Mercurochrome. See merbromin 519
presentations, 263, 265 mercury, 22t, 121t, 184, 383, 384,
local anesthetics, 7t, 8t. See also 410, 424
TOXICOLOGY HANDBOOK
specific anesthetics children and, 269
children and, 265 clinical features, 270–271
clinical features, 266 disposition/follow-up, 272
disposition/follow-up, 267 investigations, 271
fast sodium channel blockade management, 271–272
and, 115t risk assessment, 269
investigations, 266–267 sources of, 273
management, 267 mescaline, 52
presentations, 268 metabolic acidosis, 59
risk assessment, 265 causes of, 111t
loratadine, 116t, 159, 161 coma and, 57
lorazepam, 5, 179 ibuprofen and, 285
love drug. See non-anion gap, 111t
3,4-methylenedioxyamphetamine metabolic alkalosis, causes of, 111t
LSD. See lysergic acid diethylamide metformin, 25t, 109, 110t, 112t, 122t
lysergic acid, 52 children and, 273
lysergic acid diethylamide (LSD), 44 clinical features, 274
disposition/follow-up, 275
M investigations, 274
macrolides, 116t lactic acidosis from, 28
magnesium, 169 management, 274–275
magnesium sulfate, 333 presentations, 275
malathion, 76t, 298, 299 risk assessment, 273
malignant hyperthermia, 70t methadone, 94–96, 290, 294, 407
mannitol, 108t, 258 children and, 122t
MAOI. See monoamine oxidase methaemoglobinaemia, 26, 267
inhibitor methamphetamine, 93, 148, 152
marijuana. See cannabinoids children and, 122t
methanol, 6t, 17t, 22t, 28, 57, 58, 59t, MOF. See multiple organ failure
108t, 110t, 385, 386, 417 monitoring. See supportive care and
children and, 139 monitoring
clinical features, 139 monoamine oxidase inhibitor (MAOI),
disposition/follow-up, 141 68, 69t, 280. See also specific drugs
investigations, 139–140 agitation/delirium from, 63t
management, 140–141 children and, 281
pathways of metabolism, 499 clinical features, 281–282
risk assessment, 138–139 disposition/follow-up, 283
sources of, 141 investigations, 282
methotrexate, 17t, 389–391, 417 management, 282–283
INDEX
children and, 276 presentations, 284

clinical features, 277 risk assessment, 281
disposition/follow-up, 278 SSRI co-ingestion with, 68, 340
investigations, 277 monomethylhydrazine, 44, 49, 416
520 management, 277–278 morphine, 290–292, 294, 407, 448,
presentations, 279 451, 453, 455
52
0
risk assessment, 276, 276t morphine sulfate, 122t

TOXICOLOGY HANDBOOK
toxicity threshold, 278, 278t mothballs, 123t

methoxychlor, 295, 298 motion sickness agents, 73t
methyl mercury, 273 mucosal exposures, plant poisoning, 54
methyl salicylate, 336, 337, 339, 340 mulga snake, 430–431, 470, 481
methylene blue, 267, 403 multiple organ failure (MOF), 7t
administration, 402 multiple-dose activated charcoal
adverse reactions, 402 (MDAC), 25–26, 175
indications/contraindications, 401–402 muscarine, 44, 45t
methylene chloride, 199, 237 muscarinic agents, 76t
3,4-methylenedioxyamphetamine muscimol, 44, 45t
(MDA), 148 muscle relaxants, anticholinergic
3,4-methylenedioxymethamphetamine syndrome and, 73t
(MDMA/ecstasy), 69t, 104, 122t, mushroom poisoning
148–150, 152 anticholinergic syndrome and, 73t
methylphenydate, 148, 152 cholinergic syndrome and, 76t
metoclopramide, 23, 96t, 310 clinical features of, 48
metoprolol, 168, 170, 204, 239, 297, 351 clinical syndromes of, 45–47t
mianserin, 116t management of, 48–49
midazolam, 5, 177, 179 risk assessment for, 44
milk-alkali syndrome, 111t species/toxins in, 44, 45–47t, 48
mini mental status examination myasthenia gravis, agents used in, 76t
(MMSE), 197, 198 myocardial action potential, 114t
mirtazapine, 279–280
mixed hydrocarbons, 100 N
mixtard, 250 NAC. See N-acetylcysteine
MMSE. See mini mental status N-acetylcysteine (NAC), 15, 49, 120
examination administration, 404
moclobemide, 69t, 116t, 280–284 adverse reactions, 405
children and, 405 norepinephrine, 60
indications, 403–404 normobaric oxygen, 199
paracetamol overdose and, 302–303, nortriptyline, 115t, 116t, 357, 360
306–307, 308f, 312–314 NovoMix, 250
paraquat overdose and, 319 NovoRapid, 250
N-acetyl-p-aminophenol (APAP), NSAIDs. See non-steroidal
302, 312 anti-inflammatory drugs
NaHCO3, 7t
naloxone, 6t, 10, 57, 106, 154, O
206–207, 231, 290, 292, 293, octreotide, 9t, 346–348, 395
356, 408 administration, 409
INDEX
administration, 406–407 children and, 409
adverse reactions, 407 indications, 408
indications/contraindications, 406 olanzapine, 66, 71, 73t, 116t
pregnancy/children and, 407 agitation/delirium from, 63t
naltrexone, 95–97 children and, 287 521
naphthalene, 123t clinical features, 288
naproxen, 284–285, 287 disposition/follow-up, 289
TOXICOLOGY HANDBOOK
neostigmine, 76t, 438, 474 investigation, 288
nerve agents, 6t, 76t management, 288–289
neuroleptic malignant syndrome presentation, 289
(NMS), 70t, 80–84 risk assessment, 287, 288t
clinical features of, 80, 80t oleander, 225
complications of, 82 ophthalmic exposures, plant
diagnostic criteria for, 80–81, 81t poisoning, 54
differential diagnosis of, 82 OPIDN. See organophosphate-induced
management of, 82–84 delayed neuropathy
neuroleptic medications, 80 opioid replacement therapy, 96
nicotine, 51t, 52, 63t, 76t opioids, 6t, 10, 11. See also specific
nifedipine, 186, 189–190 drugs
nimodipine, 186, 190 body packers and, 104, 106
nitrazepam, 177, 179 children and, 122t, 230, 290
nitroglycerin, 212 clinical features, 291
nitroprusside, 71, 83, 150, 222, 282 coma from, 55
nitrous oxide, 100t, 319 dependence/withdrawal, 94–97
NMS. See neuroleptic malignant clinical features of, 94–95
syndrome co-morbidities, 95
non-steroidal anti-inflammatory drugs management of, 95–97
(NSAIDs) naloxone and, 406–408
clinical features, 285 pathophysiology, 94
disposition/follow-up, 285–286 disposition/follow-up, 292
investigations, 285 investigations, 16, 291
preparations, 286–287 presentations, 292–295
risk assessment, 284, 284t risk assessment, 290, 290t
noradrenaline, 60, 188, 330, 351, 359 orellanine, 47t
organochlorines, 7t NAC and management of overdose
children and, 295, 295t of, 302–303, 306–307, 308f,
clinical features, 296 312–314
disposition/follow-up, 297 pregnancy and, 119–120
investigations, 296 presentations, 310–311
management, 296–297 repeated supratherapeutic ingestion
presentations, 297–298 clinical features, 313
risk assessment, 295, 295t disposition/follow-up, 315
organophosphate-induced delayed investigations, 313
neuropathy (OPIDN), 299 management, 313–314, 314f
organophosphates, 6t, 10, 11, 59t, 76t risk assessment, 312–313
INDEX
antidote administration, 301, screening tests for, 15–16, 17t

372–373, 413–415 serum levels of, 15–16, 15t, 17t
children and, 78, 123t, 298 paradichlorobenzene, 123t
clinical features, 299–300 paraldehyde, 97, 110t
522 disposition/follow-up, 301 paraquat, 6t, 7t, 216, 217
investigations, 300 children and, 123t, 316
52
2
management, 300–301 clinical features, 317, 317t

TOXICOLOGY HANDBOOK
presentations, 302 investigations, 317–318, 318f

risk assessment, 298 management, 318–319
self-poisoning with, 78 presentations, 320
organophosphorus agents. See risk assessment, 316, 316t
carbamates; organophosphates parathion, 298, 299
orphenadrine, 73t, 311 parecoxib, 284, 287
osmolality, 107–109 paroxetine, 69t, 340, 343
osmolar gap, 107–109, 108t patient history, mental status and, 11
ethylene glycol and, 134 patient retrieval, 31–33, 32t
oxazepam, 177, 179 patient transport, 32
oxcarbazepine, 157, 159 snakebite and, 39–40
oxprenolol, 168, 170 penicillamine, 272
oxybutynin, 73t administration, 410
oxycodone, 122t, 290, 294 adverse reactions, 411
oxygen, 199. See also hyperbaric indications/contraindications, 410
oxygen pregnancy and, 411
penicillin G, 49
P pentobarbitone, 173, 174, 176
pancreatitis, 90 pericyazine, 320, 322–323
paracetamol, 75, 96t, 110t, 164, 293 perindopril, 152, 154
acute overdose, 302 pethidine, 69t, 290, 290t, 291, 295
clinical features, 305, 306t petroleum distillates, 237
disposition/follow-up, 308–309 phallotoxins, 46t
investigations, 305, 307t phencyclidine, 63t
management, 305–307, 308f phenelzine, 69t, 280, 281,
risk assessment, 303, 304f 283, 284
children and, 123, 303 phenformin, 110t
conversion factors, 498 pheniramine, 73t, 162, 164
phenobarbitone, 17t, 28, 59t, 157, management of, 53–54
173–176, 175t, 417 risk assessment for, 50
conversion factors, 498 plasma, fresh frozen, 43, 501
management, 321–322 plasmapheresis, 28
MDAC and, 25t, 26 Poisons Information Centres (PIC),
phenols, 216 3, 12
phenothiazines, 115t, 164 telephone numbers, 492
children and, 321 polyethylene glycol electrolyte solution
clinical features, 321 (PEG-ELS), 22–23, 166
disposition/follow-up, 322 polyvalent antivenom, 481–482
investigations, 321 death adder antivenom in, 438
INDEX
presentations, 322–323 indications for, 42t
risk assessment, 320–321 sea snake antivenom and, 446
phentolamine, 150, 212, 282 taipan antivenom in, 443
phenylalkylamines, 190 pot. See cannabinoids
phenytoin, 5, 61, 108t, 157 potassium, 22t 523
children and, 323 potassium chloride, 23t
TOXICOLOGY HANDBOOK
conversion factors, 498 clinical features, 326–327
disposition/follow-up, 325 disposition/follow-up, 328
investigations, 324 investigations, 327
management, 324–325 management, 327–328
presentations, 325 presentations, 328
risk assessment, 323, 323t risk assessment, 326
physostigmine, 54, 75, 76t, 161, 163, potassium efflux blockade, 116t
180–181, 234, 413 potassium hydroxide, 216
administration, 412 potassium permanganate, 216, 217
adverse reactions, 412 potassium salts, 28
indications/contraindications, 411 pralidoxime, 59t, 79, 298, 299, 301, 302
phytomenadione, 426 administration, 414
phytonadione, 426 children and, 415
PIB. See pressure-immobilisation indications/contraindications, 413
bandaging prednisolone, 42, 471, 472, 474,
PIC. See Poisons Information Centres 476, 478, 480, 482, 483,
pilocarpine, 76t 489, 502
pindolol, 168, 170 pregabalin, 157, 159
pink oleander, 52 pregnancy
piroxicam, 284, 285, 287 carbamazepine and, 193
planning, medical disposition and, carbon monoxide and, 197
32–33 cocaine and, 210
plant poisoning desferrioxamine and, 378
anticholinergic syndrome and, diazepam and, 119
73t, 74 dimercaprol and, 385
clinical features of, 53 ethanol and, 387
exposure to, 50 lead and, 119, 257
important toxins in, 50, 51t, 52–53 naloxone and, 407
pregnancy (Continued) quinidine, 115t, 116t, 417
penicillamine and, 411 quinine, 5, 7t, 25t, 26, 115t, 116t, 417
poisoning during, 119–120 clinical features, 332
succimer and, 425 disposition/follow-up, 333
valproic acid and, 119 investigations, 332
pressure-immobilisation bandaging management, 332–333
(PIB), 39 presentations, 334
prilocaine, 265, 266t, 268 risk assessment, 331
primidone, 173, 174, 176
procainamide, 7t, 115t, 116t, 358 R
prochlorperazine, 96t, 320, 323 ramipril, 152, 154, 189
INDEX
promethazine, 73t, 162, 164, 293, 311, redback spider, 448, 456, 459–461,
405, 455 463, 486–487
propoxur, 298 reperfusion therapy, 9t
propoxyphene, 115t respiratory acidosis, 57
524 propranolol, 7t, 115t, 122t, 168–170, causes of, 112t
170, 204, 239, 297, 351, 353, 394, respiratory alkalosis, causes of, 112t
52
4
400, 417 respiratory failure, 6t

TOXICOLOGY HANDBOOK
propylene glycol, 108t, 110t, 111t, resuscitation, 2, 4–10, 4t, 6–9t

142, 144 airway, breathing, circulation, 4–5
Protaphane, 250 alcohol abuse/dependence and, 91
Prothrombinex-HT, 155, 500, 501 anticholinergic syndrome and, 74
pseudoephedrine, 161, 286, 293, body packers, 105
310, 311 body temperature and, 10
psilocybin, 44, 45t children and, 120
psychosocial assessment, medical cholinergic syndrome and, 77–78
disposition and, 33 coma and, 55, 57
psychotropic alkaloids, 51t, 52 delirium/agitation and, 64
puffer fish, 458 emergency antidote administration
pyridostigmine, 76t in, 10
pyridoxine, 9t, 49, 59t, 254–256, 417 hyper-/hypothermia in, 5, 10
administration, 416 mushroom poisoning and, 48
adverse reactions, 416 NMS and, 82–83
indications/contraindications, 415 patient retrieval and, 32
seizure correction with, 5, 49, 62 plant poisoning and, 53
seizure detection/correction in, 5
Q serotonin syndrome and, 69, 71
quetiapine, 73t, 116t, 328 snakebite and, 40
children and, 329 rhododendron, 225
clinical features, 329 ricin, 51t, 53
disposition/follow-up, 330 risk assessment, 2, 3t. See also specific
investigations, 329–330 toxins
management, 330 anticholinergic syndrome and, 74
presentations, 331 body packers, 105
risk assessment, 329, 329t children and, 121–124
quinapril, 152, 154 cholinergic syndrome and, 78
coma and, 57–58 sedative-hypnotic dependence/
delirium/agitation and, 64 withdrawal
geographic area and, 11 agents causing, 97
medical disposition and, 30 clinical features of, 98
mushroom poisoning, 44 co-morbidities, 98
patient mental status in, 11 disposition, 99
plant poisoning, 50 management of, 98–99
poisons information centre in, 12 pathophysiology of, 97
serotonin syndrome, 71 seizures
for snakebite, 36, 39 approach to, 61–62
steps for, 11t cocaine and, 212
INDEX
time factors in, 11–12 delirium and, 64
timing of, 10 detecting/correcting, 5
risperidone, 334–336 flumazenil and, 388
rivastigmine, 76t isoniazid and, 9t
ropivacaine, 115t, 265, 266t, 268, 451 management of, 62 525
monomethylhydrazine poisoning
S and, 49
TOXICOLOGY HANDBOOK
salbutamol, 327, 502 in resuscitation, 5
salicylates, 5, 6t, 25, 27, 28, 57, 59t, 60, toxicological causes of, 61t
336, 417, 419 selective noradrenaline reuptake
anion-gap acidosis and, 110t inhibitors, 340
children and, 337 selective serotonin reuptake inhibitor
clinical features, 337–338 (SSRI), 68, 69t
conversion factors, 498 clinical features, 340–341
disposition/follow-up, 339 disposition/follow-up, 342
investigations, 338 investigations, 341
management, 338–339 management, 341–342
pregnancy and, 119 MAOI co-ingestion with, 68, 340
presentations, 339–340 other serotonergic agents and, 340
risk assessment, 337, 337t presentations, 343
serum levels of, 15t, 16, 17t risk assessment, 340
sarin (GB), 76t, 298 selegiline, 280, 284
scoop. See gamma-hydroxybutyrate serotonin and noradrenaline reuptake
scopolamine, 52, 73t inhibitors (SNRIs), 69t, 363
scorpions, 447–448, 463 serotonin antagonists, 71–72
screening tests, 15–16, 15t, 17t serotonin syndrome, 66–72, 280–283,
sea snakes, 38t 340
antivenom, 446, 479–480 agents causing, 68, 69t
clinical presentation/course, 445 clinical features of, 67, 67t
differential diagnosis, 446 diagnosis of, 67–68, 68f
disposition/follow-up, 447 differential diagnosis of, 69, 70t
distribution, 445 management of, 69, 71–72
investigations, 446 pethidine and, 291
management, 445–446 tramadol and, 355, 356
toxins, 445 sertraline, 69t, 340, 343
serum glucose, 5 sodium calcium edetate (EDTA), 259
serum pH, 7t administration, 421
serum sickness, 471, 478, 480, 482, 502 adverse reactions, 421–422
silibinin, 49 indications/contraindications,
single-dose activated charcoal, 21–22 420–421
Snake Venom Detection Kit (SVDK), sodium hydroxide, 216, 219
39, 41t, 43t, 432, 435, 437, sodium hypochlorite, 216, 217, 219
441, 446 sodium thiosulfate, 397, 398, 422–424
snakebite solvent abuse/dependence/withdrawal
adjuvant therapy for, 42–43 clinical features, 101–102
assessment of, 41t inhalational agents, 100t
INDEX
complications of, 43 management of, 102–103

evidence of envenoming, 40–41 mechanism of toxicity, 101
first aid for, 39 modes of abuse, 101
hospital management of, 40–43 physiochemical properties, 101
526 monovalent antivenom for, 41–42 during pregnancy/lactation, 103
patient transport and, 39–40 withdrawal, 103
52
6
polyvalent antivenom for, 42t soman (GD), 76t, 298

TOXICOLOGY HANDBOOK
pre-hospital care for, 39–40 Somatomax. See gamma-

risk assessment for, 36, 39 hydroxybutyrate
treatment approach to, 36t sotalol, 116t, 168, 169, 170
snakes speed. See methamphetamine
black, 38t, 430–433 SSRI. See selective serotonin reuptake
brown, 37t, 40, 433–436, 481 inhibitor
Butler’s, 430–431, 470 status epilepticus, delirium and, 64
Collett’s, 430–431 stonefish, 450–451, 482–484
copperhead, 439, 440 strychnine
death adders, 37t, 40, 432, 436–438 children and, 343
mulga, 430–431, 470, 481 clinical features, 344
sea snakes, 38t, 445-47 disposition/follow-up, 345
taipan, 38t, 40, 442-44, 481 investigations, 344
tiger, 37t, 40, 439–441, 481 management, 344–345
sniffing, 101 presentations, 345
snorting, solvents, 101 risk assessment, 343
SNRI. See serotonin and noradrenaline substance abuse, psychiatric definitions
reuptake inhibitors of, 85b
soap. See gamma-hydroxybutyrate succimer (DMSA), 166, 259, 272, 385,
sodium bicarbonate, 135, 140, 169, 421, 422, 426
188, 224, 228, 267, 291, 327, 358, administration, 425
365, 420 adverse reactions, 425
administration, 419 indications/contraindications, 424
adverse reactions, 419 pregnancy and, 425
indications/contraindications, sulfonylureas, 9t
417–418 children and, 122t, 346
mechanism of action, 418 clinical features, 346
tricyclic antidepressants and, 10 disposition/follow-up, 347
investigations, 346 tetrachloroethylene, 237
management, 347 tetracyclic antidepressants, 279
presentations, 348 theophylline, 8t, 9t, 17t, 25t, 26, 28, 60,
risk assessment, 346 63t, 122t, 348
sulfuric acid, 216, 219 children and, 122t, 349
sulindac, 284, 287 clinical features, 349–350
superoxide dismutase, 319 conversion factors, 498
supportive care and monitoring disposition/follow-up, 351
acute poisoning and, 13–14, 14t investigations, 350, 350t
alcohol abuse/dependence and, 91 management, 350–351
anticholinergic syndrome and, 74–75 presentations, 352
INDEX
body packers, 105 risk assessment, 349, 349t
children and, 124 therapeutic over-warfarinisation,
cholinergic syndrome and, 78–79 500–501
coma and, 58 thiamine
delirium/agitation and, 65–66 alcohol and, 91, 132 527
mushroom poisoning, 48 deficiency, 112t
NMS, 83 thioates, 299
TOXICOLOGY HANDBOOK
opioid dependence/withdrawal thiopentone, 173, 176
and, 97 thioridazine, 73t, 115t, 116t, 320, 321
plant poisoning and, 53 thiram, 76t
serotonin syndrome, 71 thyroxine
supraventricular tachycardia, 8t children and, 353
SVDK. See Snake Venom Detection Kit clinical features, 353
syrup of ipecac, 19–20 disposition/follow-up, 354
investigations, 353
T management, 353–354
tabun (GA), 76t, 298 presentations, 354
tachycardia, 8t risk assessment, 352–353
supraventricular, 8t tiagabine, 157, 159
ventricular, 7t tiaprofenic acid, 284, 287
tacrine, 76t ticks, 465–467
taipan, 38t, 40, 481 tiger snake, 37t, 40, 481
antivenom, 443, 477–478 antivenom, 431, 440, 446, 471,
clinical presentation/course, 442–443 475–476
differential diagnosis, 444 clinical presentation/course, 439–440
disposition/follow-up, 444 differential diagnosis, 441
distribution, 442 disposition/follow-up, 441
investigations, 443–444 distribution, 439
management, 443 investigations, 440–441
toxins, 442 management, 440
taxine, 51t, 53 toxins, 439
TCA. See tricyclic antidepressants toluene, 100, 100t, 102, 103, 110t, 237,
temazepam, 177, 179 238, 239, 302
terbucarb, 76t topiramate, 111t, 157–159, 264
terfenadine, 116t torsades de pointes, 169
toxic alcohols tropicamide, 73t
clinical features, 142 tryptophan, serotonin syndrome
disposition/follow-up, 144 and, 69t
investigations, 142–143 turpentine, 237
management, 143–144 2C-I, 63t
risk assessment, 142
sources of, 144 U
toxicology management guidelines, 2 urinary alkalinisation, 27–28, 419
tramadol, 5, 61, 69t, 340, 354
children and, 355 V
clinical features, 355 valproic acid, 5, 13, 17t, 28, 58, 59t,
INDEX
disposition/follow-up, 356 157, 159, 176

investigations, 355 children and, 361
management, 355–356 clinical features, 362
presentations, 357 conversion factors, 498
528 risk assessment, 355 disposition/follow-up, 363
trandolapril, 152, 154, 190 investigations, 362, 362t
52
8
tranylcypromine, 280, 281, 283, 284 management, 363

TOXICOLOGY HANDBOOK
triazolam, 177, 179 pregnancy and, 119

trichlorfon, 298 presentations, 364
trichloroethylene, 237 risk assessment, 361, 361t
tricyclic antidepressants (TCA), 7t, Vaughan Williams type Ia
10, 13, 15, 417. See also specific antiarrhythmics, 7t
drugs venlafaxine, 5, 61, 69t, 340, 364
anticholinergic syndrome and, 73t agitation/delirium from, 63t
children and, 122t, 358 children and, 365
clinical features, 358 clinical features, 365–366
coma from, 57 disposition/follow-up, 367
disposition/follow-up, 360 investigations, 366
ECG and, 113, 115t, 117 management, 366–367
fast sodium channel blockade and, presentations, 368
115t, 417 risk assessment, 365, 365t
investigations, 358–359 venom-induced consumptive
management, 359 coagulopathy (VICC), 40, 43, 434,
potassium efflux blockade and, 439, 440, 441, 442, 444
116t ventricular ectopy, 7t
presentations, 360 ventricular fibrillation, 7t
risk assessment, 357–358, 357t ventricular tachycardia, 7t
screening tests for, 16 verapamil, 23t, 122t, 186, 188, 190
self-poisoning with, 11–12 VICC. See venom-induced
serotonin syndrome and, 69t consumptive coagulopathy
triethylene glycol, 142 vigabatrin, 157, 158, 159
trifluoperazine, 73t, 320, 323 virotoxins, 46t
trimeprazine, 73t, 164 vitamin B12a, 396–398
trimipramine, 357, 360 vitamin C, 319
triprolidine, 310 vitamin E, 319
vitamin K, 155–156, 368–370, white-tailed spider, 463–465
426–428, 501 whole bowel irrigation, 22–24, 183,
VX, 76t, 298 327, 364, 367
potentially useful situations for, 23t
W
warfarin, 154 X
children and, 368 XTC. See 3,4-methylenedioxymeth
clinical features, 369 amphetamine
disposition/follow-up, 370 xylene, 100, 100t, 237
investigations, 369
management, 369–370 Y
INDEX
presentations, 370 yellow oleander, 50, 52
risk assessment, 368 yew trees, 51t, 53
therapeutic over-warfarinisation,
500–501 Z
vitamin K and, 426–428 zinc chloride, 216, 217 529
water. See gamma-hydroxybutyrate zolpidem, 63t, 97, 177, 179
TOXICOLOGY HANDBOOK
weed. See cannabinoids zopiclone, 97, 177
Wernicke’s encephalopathy, 90

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Sydney Edinburgh London New York Philadelphia St Louis Toronto

Elsevier Australia. ACN 001 002 357

This edition © 2011 Elsevier Australia

National Library of Australia Cataloguing-in-Publication Data

Title: Toxicology handbook / Lindsay Murray ... [et al.].

Edition: 2nd ed.

ISBN: 9780729539395 (pbk.)

Notes: Includes index.

Subjects: Toxicology--Australia--Handbooks, manuals, etc. Toxicology--Oceania--Handbooks,

Other Authors/Contributors: Murray, Lindsay.

Dewey Number: 571.95

Publisher: Sophie Kaliniecki

CHAPTER 1 APPROACH TO THE POISONED PATIENT

CHAPTER 2 SPECIFIC CONSIDERATIONS

CHAPTER 3 SPECIFIC TOXINS

3.28 Clonidine 205

3.37 Gamma-hydroxybutyrate (GHB) 232

3.38 Glyphosate 235

6.5 CSL Taipan Antivenom 477

Appendix 2: Example ECGs 493

Poisoning is a common emergency department presentation, and the third

Professor Anthony FT Brown MB ChB, FRCP, FRCS(Ed), FACEM, FCEM

Lindsay Murray Kerry Hoggett

likely clinical course and potential complications for the individual at

that particular presentation. Risk assessment should wherever possible be

use to ambulance and emergency paramedic personnel and staff of general

suffering from exacerbation of very significant underlying psychiatric,

in a patient with cardiac arrest, resuscitation should continue until

expert advice can be obtained. Cardiopulmonary bypass has been used

AIRWAY, BREATHING AND CIRCULATION

APPROACH TO THE POISONED PATIENT

DETECT AND CORRECT SEIZURES 5

Toxic seizures are generalised, and can usually be controlled with

DETECT AND CORRECT HYPOGLYCAEMIA

DETECT AND CORRECT HYPER-/HYPOTHERMIA

Life-threat Mechanism Agent(s) Comments

Airway compromise Corrosive injury to l Alkalis l Stridor,dysphagia and dysphonia indicate

Hypoventilation Opioid mu receptor l Opioids l Prompt administration of naloxone may obviate

Ventricular Hypocalcaemia l Hydrofluoricacid l Defibrillation alone unlikely to be efficacious

Ventricular Fast Na+ channel l Chloroquine l Cardioversion or defibrillation unlikely to be

Ventricular ectopy/ Halogen-induced l Chloral hydrate l Cardioversion or defibrillation unlikely to be

TOXICOLOGY HANDBOOK APPROACH TO THE POISONED PATIENT

Life-threat Mechanism Agent(s) Comments

Refractory Various l Beta-blockers l High-dose insulin–dextrose therapy

Tachycardia Central and l Amphetamines l Beta-blockers contraindicated

Supraventricular Adenosine l Theophylline l Urgent haemodialysis indicated

Hypertension Central and l Amphetamines l Beta-blockers contraindicated

Asystole Na+/K+ ATPase l Digoxin l Usual resuscitation interventions futile

Acute coronary Central and l Amphetamines l Beta-blockers contraindicated

Hyperkalaemia Na+/K+ ATPase l Digoxin l Calcium salts are contraindicated

Hypoglycaemia Hyperinsulinaemia l Sulfonylureas l Difficult

Seizures Adenosine l Theophylline l Urgent haemodialysis indicated

TOXICOLOGY HANDBOOK APPROACH TO THE POISONED PATIENT

management is an indication for continuous core-temperature monitoring.

Administration of antidotes is sometimes indicated during the

resuscitation phase of management. As with all drugs, antidotes have

1.3 RISK ASSESSMENT

Distinct cognitive step

The five key components of the history and examination required to

patients can be identified on clinical grounds at 6 hours post-ingestion.

few hours, early communication and disposition planning may begin.

ROLE OF THE POISONS INFORMATION CENTRE

3.28 Clonidine 205

3.37 Gamma-hydroxybutyrate (GHB) 232

3.38 Glyphosate 235

6.5 CSL Taipan Antivenom 477

Appendix 2: Example ECGs 493

Airway compromise Corrosive injury to l Alkalis l Stridor,dysphagia and dysphonia indicate

Hypoventilation Opioid mu receptor l Opioids l Prompt administration of naloxone may obviate

Ventricular Hypocalcaemia l Hydrofluoricacid l Defibrillation alone unlikely to be efficacious

Ventricular Fast Na+ channel l Chloroquine l Cardioversion or defibrillation unlikely to be

Ventricular ectopy/ Halogen-induced l Chloral hydrate l Cardioversion or defibrillation unlikely to be

Refractory Various l Beta-blockers l High-dose insulin–dextrose therapy

Tachycardia Central and l Amphetamines l Beta-blockers contraindicated

Supraventricular Adenosine l Theophylline l Urgent haemodialysis indicated

Hypertension Central and l Amphetamines l Beta-blockers contraindicated

Asystole Na+/K+ ATPase l Digoxin l Usual resuscitation interventions futile

Acute coronary Central and l Amphetamines l Beta-blockers contraindicated

Hyperkalaemia Na+/K+ ATPase l Digoxin l Calcium salts are contraindicated

Hypoglycaemia Hyperinsulinaemia l Sulfonylureas l Difficult

Seizures Adenosine l Theophylline l Urgent haemodialysis indicated

TABLE 1.4.1 Supportive care measures

TABLE 1.5.1 Screening tests

TABLE 1.5.2 Indications for other investigations

TABLE 1.6.1 Methods of gastrointestinal decontamination

l Induced emesis (syrup of ipecac)

TABLE 1.6.2 Gastrointestinal decontamination: risk–benefit analysis

TABLE 1.6.3 Agents poorly bound to activated charcoal

l Iron overdose >60 mg/kg

l Regularly dipstick urine and aim for urinary pH >7.5

TABLE 1.9.1 Principles of retrieval of the poisoned patient

l Risk assessment is vital

2.1 pproach to snakebite

TABLE 2.1.1 Treatment approach to snakebite

TABLE 2.1.2 Clinical effects of Australian Elapidae snakes—cont’d

l Establish intravenous access

l Given the low prevalence of severe anaphylactic and anaphylactoid