Critical Care Nephrology

and Acute Kidney Injury

Management of Poisonings and Intoxications

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1 2
Marc Ghannoum and Darren M. Roberts

Abstract
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Poisoning occurs after exposure to any of a number of substances, including medicines, which can result in
severe toxicity including death. The nephrologist may be involved in poisonings that cause kidney disease and
for targeted treatments. The overall approach to the poisoned patient involves the initial acute resuscitation
and performing a risk assessment, whereby the exposure is considered in terms of the anticipated severity and 1
Research Center,
in the context of the patient’s status and treatments that may be required. Time-critical interventions such as
CIUSSS du Nord-de-
gastrointestinal decontamination (e.g., activated charcoal) and antidotes are administered when indicated. l’ı̂le-de-Montréal,
The nephrologist is usually involved when elimination enhancement techniques are required, such as urine University of
alkalinization or extracorporeal treatments. There is increasing data to guide decision making for the use of Montreal, Montreal,
extracorporeal treatments in the poisoned patient. Principles to consider are clinical indications such as Quebec, Canada, and
Department of
whether severe toxicity is present, anticipated, and/or will persist and whether the poison will be significantly Nephrology and
removed by the extracorporeal treatment. Extracorporeal clearance is maximized for low–molecular weight Hypertension,
drugs that are water soluble with minimal protein binding (<80%) and low endogenous clearance and volume University Medical
of distribution. The dosage of some antidotes (e.g., N-acetylcysteine, ethanol, fomepizole) should be increased Center Utrecht and
to maintain therapeutic concentrations once the extracorporeal treatment is initiated. To maximize the effect Utrecht University,
Utrecht, The
of an extracorporeal treatment, blood and effluent flows should be optimized, the filter with the largest Netherlands
surface area selected, and duration tailored to remove enough poison to reduce toxicity. Intermittent 2
New South Wales
hemodialysis is recommended in most cases when an extracorporeal treatment is required because it is the Poisons Information
most efficient, and continuous kidney replacement therapy is prescribed in some circumstances, particularly if Centre, Sydney
Children’s Hospitals
intermittent hemodialysis is not readily available. Network, Westmead,
CJASN 18: 1210–1221, 2023. doi: https://doi.org/10.2215/CJN.0000000000000057 and Edith Collins
Centre, Drug Health
Services, Royal Prince
Alfred Hospital,
Introduction techniques. These decisions are largely made on a Sydney, New South
Poisonings are a major cause of morbidity and case-by-case basis, depending on the exposure, the Wales, Australia
mortality worldwide. Poisoning can occur from di- patient, and the manifestations. The evidence sup-
verse exposures including medicines, chemicals (e.g., porting specific treatments are often based on limited Correspondence:
household, industrial, pesticides), or natural toxins data such as case reports or theoretical rationale. Dr. Marc Ghannoum,
from animals (e.g., snakes, spiders) or plants. Further- Fortunately, clinical recommendations on the basis of Department of Verdun
Hospital, 4000 Lasalle
more, poisoning can be intentional or accidental data and expert consensus are increasingly available Boulevard, Verdun,
(including occupational) following acute, chronic, or to support decision making. Quebec H4G 2A3,
acute-on-chronic exposures. Each scenario potentially Canada. Email:
manifests differently, which in turn prompts different marcghannoum@
gmail.com
approaches to management. Resuscitation and Supportive Care
In 2020, there were over 2 million toxic exposures All poisonings, especially those that are acute and
reported to US poison control centers,1 with an esti- intentional, which can progress quickly, should be
mated 100,000 fatalities from drug overdose, represent- considered serious. Management commences with a
ing the leading cause of death in young adults.2 detailed assessment of the airway, breathing, circula-
Although poisonings are usually managed by critical tion, and neurological function. Initial interventions
care physicians and clinical/medical toxicologists, the are applied according to standard indications, in-
nephrologist also has a crucial role for selected cases. cluding endotracheal intubation, ventilatory support,
This relates to kidney disease being a risk factor for and administration of fluids, inotropes, or vasopres-
some poisonings and/or the utilization of elimination sors. Volume repletion is an important part of man-
enhancement techniques in toxicological management. agement to correct volume depletion because it
Rapid initiation of appropriate management re- improves hemodynamics and optimizes kidney func-
duces the severity and duration of poisoning. The tion and elimination of some drugs (e.g., lithium,
general approach to the poisoned patient necessitates dabigatran, baclofen, digoxin). Seizures and agitation
prompt resuscitation and stabilization and clinical are treated with titrated doses of benzodiazepines.
and laboratory evaluation. When appropriate, time- Severe poisoning commonly prompts admission
critical treatments include antidotes, gastrointestinal to the intensive care unit and continuous cardiac
decontamination, and enhanced elimination monitoring. This is indicated until peak effects are

1210 Copyright © 2023 by the American Society of Nephrology www.cjasn.org Vol 18 September, 2023
 CJASN 18: 1210–1221 September, 2023
anticipated (which may be problematic to ascertain if
there is ongoing absorption of the poison) and until
recovery. In the absence of clinical toxicity, medical
clearance of the patient may be considered after a mini-
mum observation period. Intentional poisonings often
require mental health input.
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Risk Assessment
The toxicological risk assessment is a cognitive process
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performed by the clinician to predict the clinical course
for a specific exposure. It guides the triaging of patients and
initiation of therapy and is conducted concurrently with
resuscitation and supportive care.3 Components of the risk
assessment include identifying the poison (what?), the
exposure (how much?), the duration (how long?), patient
factors (who?), and timing (when?). Some poisonings
manifest with shared clinical characteristics, referred to
as a toxidrome (e.g., serotonin toxicity, sympathomimetic,
cholinergic, opioid, and anticholinergic), and may help
identify a poison when clinical information is lacking.4
Investigations are essential to the toxicological risk assess-
ment, in particular an electrocardiogram, blood gas, rou-
tine blood chemistry including kidney function, and drug
assays, as appropriate.
This information is interpreted with knowledge of the
poisoning being treated. For example, the onset of poison-
ing is usually rapid (e.g., within 2–4 hours) after acute
intentional poisoning, but there are exceptions including
ingestion of a sustained-release xenobiotic or one that is
metabolized to a more toxic compound (e.g., acetamino-
phen, methanol) or cellular poisons (e.g., bromoxynil,
salicylate, 2,4-dinitrophenol). Certain acute exposures are
associated with more severe outcomes. Here, risk may be
predicted on the basis of the dose (e.g., .400 mg/kg
valproic acid5), symptoms (e.g., coma in carbamazepine
poisoning6), blood or plasma concentration (e.g., salicylate
concentration .100 mg/dl or .7.2 mmol/L7), or other
laboratory tests (e.g., lactate concentration .15 mmol/L in
metformin poisoning8).
Chronic poisoning (e.g., over weeks) may be associated
with persistent toxicity, due to intercurrent illness with AKI
or drug-drug interactions, which cause accumulation of a
therapeutic drug over time. Here, clinical toxicity may be
severe (e.g., neurotoxicity including confusion and seizures
from lithium or complete heart block from digoxin) despite
relatively lower plasma concentrations than are observed
after acute poisoning.
The risk assessment is adjusted according to new in-
formation from history and/or investigations and clinical
progression. Advice by a clinical/medical toxicologist or
Poison Control Center is invaluable and recommended in
most cases.
Gastrointestinal Decontamination
Gastrointestinal decontamination is a time-critical inter-
vention that has the potential to reduce the severity and
duration of poisoning by decreasing the amount of the
poison that is absorbed. Activated charcoal is most com-
monly used for gastrointestinal decontamination, at a usual
dose of 50 g in adults. Activated charcoal should be initiated
Poisonings and Intoxications, Ghannoum and Roberts 1211
within approximately 2 hours of ingestion, but there are
notable exceptions including extended-release medications
(e.g., diltiazem, theophylline) and enteric-coated medicines
(e.g., valproic acid). A second dose of activated charcoal
may be given 2–4 hours later in the case of large exposures,
in particular when the drug concentration is seen to
increase after the first dose (e.g., acetaminophen, valproic
acid, salicylates). Activated charcoal is not effective for
acids or alkali, alcohols (including ethylene glycol and
methanol), ions, or metals such as lithium and iron.
Whole bowel irrigation involves the enteral administra-
tion of a large volume (1 L/h) of an isotonic solution such
as polyethylene glycol (macrogol) until the rectal effluent is
clear. Indications include exposures that are nonresponsive
to activated charcoal, extended-release formulations,
“body packers,” or a highly toxic exposure.
Care is required when giving gastrointestinal decontam-
ination to patients at risk of aspiration, including due to
vomiting, depressed conscious state, or seizures. In such
cases, once the patient has been intubated for airway
protection, decontamination is usually administered
using a nasogastric or orogastric tube. Other forms or
gastrointestinal decontamination such as gastric lavage
and forced emesis are almost never recommended, as they
are of low efficacy given that most patients present many
hours after poisoning and poorly tolerated. Lavage
requires a large bore orogastric tube, thereby requiring
intubation. Electrolyte and water imbalances have been
reported and both delay the time to administration of the
more effective activated charcoal.
Antidotes
Antidotes are direct or indirect agonists or antagonists
to the effect of a poison, including through actions at a
receptor (e.g., naloxone for opioids), inhibitors of metab-
olism (e.g., fomepizole for methanol), and binding for
inactivation (e.g., chelators, antivenoms). Indications vary
depending on the specific poison, but they are usually
administered in the context of demonstrated toxicity
and/or a confirmed high drug concentration (e.g., N-ace-
tylcysteine for acetaminophen). The antidote dosage
varies depending on the poisoning exposure and is
titrated to clinical response or the results of investiga-
tions. A list of the more commonly used antidotes is
provided in Table 1.
There are specific considerations relevant to nephrolo-
gists when prescribing antidotes. These include antidote
removal by extracorporeal treatments, which prompts dose
up-titration (e.g., ethanol or fomepizole), antidote accumu-
lation in patients with advanced kidney disease, which
prompts dose down-titration (e.g., EDTA), and persistent
or recurrent toxicity in patients with advanced kidney
disease requiring repeated doses of antidotes (e.g., dabiga-
tran,9 digoxin10).
Enhanced Elimination
Elimination enhancement modalities can be divided
between corporeal treatments, which augment physiolog-
ical process, and extracorporeal treatments, which require
an artificial device located outside the body. 1 1
 1212 CJASN

Ionized poisons are less easily reabsorbed through kidney

Table 1. Examples of poisons for which antidotes are tubules and more readily eliminated in urine. The efficacy of
recommended
urine alkalinization depends on the relative contribution of
Poison Antidote kidney clearance to the total body clearance of the poison;
e.g., if ,1% of the ingested poison is excreted unchanged in
Acetaminophen N-acetylcysteinea the urine, even a ten-fold increase in kidney elimination will
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(paracetamol)
Anticholinergic drugs Physostigmine for significant delirium have no clinically significant effect.12 Criteria that determine
Anticholinesterase Atropine and possibly pralidoxime whether a poison is amenable to urine alkalinization are (1) it
insecticides or obidoxime
Benzodiazepines Flumazenil (rarely required) is eliminated unchanged by the kidneys, (2) smaller volume
b-adrenergic antagonists Adrenaline, insulin-dextrose infusion of distribution (VD) (see below), (3) lower protein binding,
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Calcium channel blockers Calcium, insulin-dextrose infusion

Carbon monoxide Oxygen and (4) a weak acid (pKa between 3 and 7). Urine alkalin-
Cyanide Hydroxocobalamin and/or thiosulfate ization is most often used to enhance the excretion of
Dabigatran Idarucizumab
Digoxin Digoxin Fab antitoxin, atropine salicylates but can also be used for chlorpropamide, pheno-
Envenomation Antivenom barbital, herbicides (e.g., 2,4-dichlorophenoxyacetic acid
(e.g., snake, spider)
Ethylene glycol/methanol Ethanol or fomepizolea [2,4-D], 4-chloro-2-methylphenoxyacetic acid, mecoprop),
Iron Deferoxamine fluoride, and methotrexate (Table 2).12
Isoniazid Pyridoxinea
Lead Ca,Na2-EDTA or succimer (DMSA)
Target urine pH should be 7.5–8.5 while maintaining a
Methotrexate Folinic acid, glucarpidase blood pH #7.55. Sodium bicarbonate (100 mmol) is
Opioids Naloxone
Poison-induced Methylene blue
administered as a bolus, followed by 100–150 mmol/L in
methemoglobinemia 5% dextrose in water at a rate of up to 200 ml/h. Serum
(e.g., dapsone,
alkyl nitrite)
potassium should be $4 mmol/L before buffer adminis-
Salicylates Bicarbonate tration. In the setting of hypokalemia, potassium is reab-
Sulfonylureas Octreotide, glucose sorbed in the collecting duct in exchange for a proton, so
Tricyclic antidepressants Bicarbonate
Valproic acid L-carnitinea urine cannot be readily alkalinized. Furthermore, alkalin-
Warfarin Vitamin K ization induces kaliuresis, which may lead to dangerous
hypokalemia and subsequent dysrhythmias. Serum potas-
DMSA, dimercaptosuccinic acid.
a
The dose of the antidote must be adjusted during extra- sium and ionized calcium must be closely monitored and
corporeal treatment. corrected accordingly. Other potential complications in-
clude hypernatremia, pulmonary, and cerebral edema.
Carbonic anhydrase inhibitors are contraindicated for
urine alkalinization of poisons as they can worsen meta-
Extracorporeal treatments and urine alkalinization are
bolic acidemia and exacerbate toxicity, as in the case, for
increasingly used (Figure 1). Nephrologists are frequently
example, of a salicylate poisoning where acidemia can
consulted for input at this stage.
accelerate salicylate entry in the central nervous system.

Corporeal Treatments Fecal Elimination Enhancement

Urine Alkalinization Multiple doses of activated charcoal (MDAC) enhance
Increasing urine pH can either increase solubility of the the elimination of certain poisons by interrupting their
poison or the proportion of a weak acid that is ionized. enterohepatic circulation or by promoting passive back

100,000

10,000
Technique performed per
100,000 exposures

Single-dose activated charcoal

1000 Whole bowel irrigation
Gastric lavage
Ipecac
Multiple-dose activated charcoal
100
Alkalinization
Extracorporeal treatment

10

1
1985 1990 1995 2000 2005 2010 2015 2020
Year

Figure 1. Trends in the use of elimination enhancement techniques in the United States.
 CJASN 18: 1210–1221 September, 2023
Table 2. Poisons whose elimination may be enhanced by corporeal techniques
Multiple-Dose
Urine Alkalinization
Activated Charcoal
Chlorophenoxy herbicides Carbamazepine
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(2,4-D, MCPA, MCPP) Colchicine
Chlorpropamide Dapsone
Diflusinal Digoxin
Fluoride Phenobarbital
Methotrexate Phenytoin
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Phenobarbital Quinine
Salicylates Salicylates
Theophylline
Yellow oleander
Amanita phalloides
2,4-D, 2,4-dichlorophenoxyacetic acid; MCPA, 4-chloro-2-methylphenoxyacetic acid; MCPP, methylchlorophenoxypropionic
acid (Mecoprop).
diffusion from the intestinal capillaries to the gut lumen, a
process often referred to as gut dialysis. Typical dosage
is 25 g of activated charcoal every 2 hours until clinical or
biochemical end points are achieved. Present guidelines
recommend MDAC for poisoning due to carbamazepine,
dapsone, phenobarbital, quinine, and theophylline.13,14 In
addition, MDAC may be of benefit in poisonings due to
colchicine, Amanita phalloides, salicylates, cardiac glyco-
sides,15 or phenytoin.16 Ion exchange resins may adsorb
poisons from the gut capillaries into the lumen. For
example, sodium polystyrene sulfonate, historically
used for treating hyperkalemia, can also reduce the
lithium half-life.17 Prussian blue binds radiocesium and
thallium in the bowel lumen and enhances their fecal
elimination (Table 2).18
Forced Diuresis
Administration of large volumes of isotonic fluids with
or without loop diuretics is rarely used today to enhance
elimination of poisons due to low efficacy and the risk of
complications, including pulmonary edema and electrolyte
abnormalities.
Extracorporeal Treatments
Recommendations
Over the past decade, evidence-based consensus rec-
ommendations for the use of extracorporeal treatments
for managing poisoning have been published by the
EXtracorporeal TReatments In Poisoning (EXTRIP)
workgroup, a large multinational multidisciplinary group
(Table 3, http://www.extrip-workgroup.org/).6,7,19–35
These guidelines are based on principles described in
this article and were derived from systematic reviews of
the literature, using accepted, robust, and reproducible
methodology. The goal of the guidelines was to stan-
dardize management of specific complex poisonings and
propose directions for future research.36
Decision Making in the Absence of Recommendations
Clinical decision making for extracorporeal treatments in
the context of poisonings for which EXTRIP recommenda-
tions are not available is informed by understanding the
Poisonings and Intoxications, Ghannoum and Roberts 1213
Sodium
Prussian Blue
Polystyrene Sulfonate
Lithium Radiocesium
Potassium Thallium
risk assessment (see above), clinical effects and time course
of the poisoning, other treatments available, expected risk
versus benefit of extracorporeal treatments, the poison’s
physicochemical characteristics and pharmacokinetics, and
available extracorporeal treatments, as summarized in
Figure 2. In each case, decision making occurs on a case-
by-case basis. For example, AKI may be an indication for
extracorporeal treatments in some poisonings (e.g., metfor-
min, baclofen), but not others.
A. Clinical toxicology of the poison
The risk assessment should first predict that the poisoning
is severe (see above). Extracorporeal treatments are less
likely to be needed if less invasive treatments, such as an-
tidotes (Table 1) or corporeal treatments for enhanced
elimination (Table 2), are available. If toxicity is expected to
be prolonged despite these treatments, an extracorporeal
treatment can be considered.
B. Expected clinical impact of extracorporeal treatments
The clinician must anticipate which benefits are expected
from the extracorporeal treatment and weigh these benefits
against its risks and costs. For example, hemodialysis (HD)
will reduce the likelihood of mortality after a massive in-
gestion of salicylates or methanol. The advantages of ex-
tracorporeal treatments in those circumstances would
largely outweigh costs and complications of the procedure.
In contrast, HD may only marginally reduce the duration of
mechanical ventilation in baclofen poisoning while poten-
tially increasing the risk of withdrawal.30 Risks of extra-
corporeal treatments include those associated with catheter
insertion and bleeding from anticoagulation and antidote
removal (e.g., N-acetylcysteine, ethanol, fomepizole, and
pyridoxine). Costs of a single dialysis, including equipment
and nursing/physician fees, are usually minor compared
with the cost of a day in the intensive care unit and can
reduce the duration over which costly antidotes are needed
(e.g., fomepizole for methanol poisoning).37
C. Characteristics of poisons that influence their removal by
extracorporeal treatments
In the absence of any clinical outcome data from extra-
corporeal treatment, at a minimum, enhanced elimination
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1214
Table 3. EXtracorporeal TReatments In Poisoning recommendations

CJASN
Indications Choice of
Cessation of
Poison Extracorporeal Other Considerations
Extracorporeal Treatment
Clinical and Laboratory Poison Concentration Treatment

Acetaminophen Metabolic acidemia, coma .1000 mg/L (6620 mmol/L) HD.CKRT Clinical improvement Dose of NAC should be at least doubled
(paracetamol) during HD
Baclofen Coma requiring mechanical ventilation Not specified HD Clinical improvement Not recommended if normal
AND impaired kidney function kidney function
Barbiturates Coma, mechanical ventilation, shock Increasing or persisting HD.HP/CKRT Clinical improvement Coadminister MDAC
(long acting) (not specified)
ß-Adrenergic Atenolol and sotalol only: refractory Not specified HD Clinical improvement
antagonists bradycardia with hypotension AND
impaired kidney function
Calcium Not indicated
channel blockers
Carbamazepine Refractory seizures, life-threatening Increasing or persistently HD.CKRT/HP Clinical improvement OR Coadminister MDAC
dysrhythmias, prolonged coma, elevated (not specified) [carbamazepine]
respiratory depression requiring ,10 mg/L (42 mmol/L)
mechanical ventilation, despite MDAC
Chloroquine/ Not indicated
hydroxychloroquine/
quinine
Ethylene glycol Shock, coma, seizures, anion gap .23 .310 mg/dl (50 mmol/L) if HD.CKRT Anion gap ,18 mmol/L, normalization ECTR may not be required if normal
mmol/L,a impaired kidney function antidote used of acid-base parameters, [ethylene kidney function and fomepizole used
.62 mg/dl (10 mmol/L) glycol] ,25 mg/dl (10 mmol/L) The dose of ethanol and fomepizole
if no antidote used must be adjusted during ECTR
Gabapentin/pregabalin Coma requiring mechanical ventilation Not specified HD Clinical improvement Not recommended if normal
AND impaired kidney function kidney function
Isoniazid If standard dose pyridoxine cannot be Not specified HD
administered, if there are
refractory seizures
Lithium Decreased LOC, seizures, dysrhythmias, .5.0 mEq/Lb HD.CKRT Clinical improvement OR Consider CKRT after HD because of
impaired kidney function Expected time to [Li] ,1.0 mEq/L rebound concentrations post-HD
reduce the [Li] to
,1.0 mEq/L .36 h
Metformin Shock, failure of standard supportive Not specified HD.CKRT [Lactate] ,3 mmol/L AND pH .7.35 Repeat sessions using HD or CKRT
measures, decreased LOC, Closely monitor lactate and pH for
[lactate] .20 mmol/L, pH ,7.0 additional ECTR courses
Methanol Coma, seizures, new vision deficits, .70 mg/dl (21.8 mmol/L) HD.CKRT Clinical improvement AND ECTR may not be required if normal
pH #7.15, anion gap .24 mmol/La if fomepizole used [methanol] ,20 mg/dl (6.2 mmol/L) kidney function and fomepizole used
.60 mg/dl (18.7 mmol/L) The dose of ethanol and fomepizole
if ethanol used must be adjusted during ECTR
Folic acid should be continued
during ECTR
Phenytoin Severe poisoning, such as prolonged coma Not specified HD.HP Clinical improvement Listed indications are suggestions only;
or ataxia effectiveness of ECTR is uncertain
Methotrexate Not indicated; possible (rare) exception is rapid initiation immediately after
a large intravenous exposure (e.g., dosing error), when there is still a large
burden in blood, before it has fully distributed to tissues
Salicylates Altered mental status, ARDS, impaired .100 mg/dl (7.2 mmol/L) HD.HP.CKRT Clinical improvement AND ET may be used in children,
kidney function, pH #7.20 [salicylate] ,20 mg/dl (1.4 mmol/L) coadminister MDAC
Thallium Significant exposure, severe poisoning .1 mg/L (4.6 mmol/L) HD.HP or CKRT [Thallium] ,0.1 mg/L (0.5 mmol/L)
Theophylline Seizures, life-threatening dysrhythmias, .100 mg/L (555 mmol/L) in HD.HP.CKRT Clinical improvement OR Coadminister MDAC
shock, clinical deterioration despite acute exposure) [theophylline] ,15 mg/L (83 mmol/L)
optimal care, GI decontamination .60 mg/L (333 mmol/L) in
cannot be administered chronic poisoning
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CJASN 18: 1210–1221 September, 2023

Table 3. (Continued)
Indications Choice of
Cessation of
Poison Extracorporeal Other Considerations
Extracorporeal Treatment
Clinical and Laboratory Poison Concentration Treatment

Tricyclic antidepressants Not indicated

Valproic acid Cerebral edema, coma, shock, acute .1300 mg/L (9000 mmol/L) HD.CKRT/HP Clinical improvement OR [valproic Consider another dose of activated
hyperammonemia, pH #7.10, acid] ,100 mg/L (700 mmol/L) charcoal if valproate concentrations
respiratory depression continue to rise after the first dose

HD, hemodialysis; CKRT, continuous KRT; NAC, N-acetylcysteine; HP, hemoperfusion; MDAC, multiple doses of activated charcoal; ECTR, extracorporeal treatment; LOC, level of
consciousness; ARDS, acute respiratory distress syndrome; ET, exchange transfusion; GI, gastrointestinal.
a
The anion gap is calculated by (Na1 1 K1) 2 (Cl2 1 HCO32)
b
The lithium concentration frequently exceeds this value for acute poisonings, with favorable outcomes without extracorporeal treatment in the context of normal kidney function, in
particular if the patient is naive to lithium.

Poisonings and Intoxications, Ghannoum and Roberts

1215
 1216 CJASN

Risk assessment: is the exposure to the poison causing or likely to cause clinical toxicity No
(e.g., salicylate ingestion >500 mg/kg, seizures associated with lithium poisoning)?

Yes
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Alternative treatments: is toxicity expected to be reversed or prevented with supportive

Yes
care, antidotes, gastrointestinal decontamination, and/or corporeal methods to enhance
elimination (e.g., rapid reversal of opioid-induced coma with naloxone)?

No ECTR
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not indicated
Toxicokinetic factors: does the poison have an endogenous clearance >5 ml/kg/min or a Yes
volume of distribution >2–3 L/kg (e.g., amitriptyline, verapamil)?

No

Risk–benefit balance: are the benefits of ECTR expected to outweigh its risks and costs No
(e.g., reduction of mechanical ventilation from 5 days to 1 day in carbamazepine poisoning)?

Yes

What percentage of the poison is protein bound at the current concentration?

>95% <80% 80–95%

Therapeutic What is the molecular weight Hemoperfusion

plasma exchange of the poison?

<10,000 Da 10–25,000 Da 25–50,000 Da >50,000 Da

Intermittent Hemofiltration HCO/MCO hemodialysis Therapeutic
hemodialysis Hemoperfusion plasma exchange

Figure 2. Schematic approach to extracorporeal treatment. ECTR, extracorporeal treatment; HCO, high cutoff filter; MCO, middle cut-
off filter.

should be potentially significant based on properties of the
poison (Table 5).
Molecular Weight
A poison can be removed by an extracorporeal treat-
ment only if it can pass through the pores of the
membrane. Most encountered poisons have a molecular
weight ,2000 Da. Typically, membranes used for in-
termittent HD have a molecular cutoff of 10,000 Da,
whereas membranes used for hemofiltration can remove
poisons with a molecular weight up to 50,000 Da. Poisons
with very high molecular weights (.100,000 Da, e.g.,
monoclonal antibodies) can only be removed by tech-
niques such as exchange transfusion or therapeutic
plasma exchange.
Protein Binding
The size of a poison-protein complex (.66,000 Da if
bound to albumin) surpasses the pore size of most
membranes used for HD or continuous KRT (CKRT).
Generally, a poison is not considered removable by
HD or hemofiltration if the protein binding is over 80%,
but there are exceptions: (1) some poisons (salicylates,
valproic acid) are highly protein bound at therapeutic
concentrations, but at toxic concentrations, protein-binding
sites are saturated, leading to a larger percentage of poison
in unbound form; (2) some poisons have a high dissocia-
tion quotient (phenytoin), meaning they do not bind tightly
to albumin, and once unbound poison is removed, bound
poison quickly dissociates from serum proteins, replenish-
ing the pool of removable poison; and (3) certain disease
states such as hypoalbuminemia or CKD can influence
the percentage of poison that is bound and/or reduce
protein-binding sites.
Endogenous Clearance
An extracorporeal treatment must contribute substan-
tially to total clearance of that poison. If liver clearance
exceeds 1000 ml/min, extracorporeal clearance (which
cannot realistically exceed 200 ml/min) will be inconse-
quential to increase total clearance. In poisons that are
predominantly eliminated by kidneys, the presence of AKI
will increase the relative contribution of extracorporeal
clearance to total clearance, as illustrated in Figure 3.
For example, the endogenous metformin clearance is
600 ml/min; assuming a clearance of metformin using
 CJASN 18: 1210–1221 September, 2023
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Liver Kidney
clearance clearance
Metformin
<5 mL/min 600 mL/min
(normal kidney function)
WnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 09/26/2023
Metformin
<5 mL/min <10 mL/min
(kidney failure)
Lidocaine
900 mL/min
(normal kidney function)
Lidocaine
500 mL/min
(kidney failure)
Methanol
<10 mL/min <10 mL/min
(if fomepizole used)
Figure 3. Examples of the contribution of extracorporeal clearance to total clearance. Dialyzability is assessed according to alternative
criteria 1 in Table 7 of the EXTRIP methods document.36 CKRT, continuous KRT; HD, hemodialysis.
CKRT of 50 ml/min, CKRT will contribute at most 10% of
total clearance, whereas it will contribute almost com-
pletely to total clearance in patients with anuric AKI. By
contrast, HD will contribute little to total clearance regard-
less of kidney function for lidocaine elimination, because of
extensive liver metabolism, whereas HD will greatly
contribute to overall methanol clearance once a patient
receives fomepizole.
Volume of Distribution
The VD of a poison is an apparent volume that quantifies
the extent to which it distributes throughout the body.
Extracorporeal treatments remove poisons most effectively
from the intravascular space and total body water. The
higher a poison’s VD, the more that it resides outside the
blood compartment, so extracorporeal removal relies on
redistribution kinetics, such as observed with digoxin,
calcium channel blockers, or tricyclic antidepressants. In
selected cases, extracorporeal treatments may be used
quickly after a large exposure to a very toxic poison that
has a high VD (e.g., thallium or methotrexate), when there is
still a large burden in blood, before it has fully distributed
to tissues19; this timeframe is poorly defined because of
pharmacokinetic and physicochemical properties of the
drug but may be within approximately 4 hours
postexposure.
D. Available extracorporeal treatments
Numerous extracorporeal treatments are available to
facilitate removal of poisons. As soon as the risk assess-
ment suggests that a patient may require an extracorpo-
real treatment, prompt communication with a dialysis
unit, preemptive transfer, and even insertion of a dialysis
catheter may be required to minimize treatment delays,
even if the patient does not yet meet criteria for blood
purification. Table 4 summarizes the various extracorpo-
real treatments available for poison removal and their
Poisonings and Intoxications, Ghannoum and Roberts 1217
Extracorporeal Contribution of extracorporeal
clearance clearance to total clearance
50 mL/min (CKRT) 8% (= slightly dialyzable)
50 mL/min (CKRT) >75% (= dialyzable)
50 mL/min (HD) 5% (= slightly dialyzable)
50 mL/min (HD) 9% (= slightly dialyzable)
120 mL/min (HD) >75% (= dialyzable)
differences, which impact decision-making. In each case,
parameters of the extracorporeal treatment are prescribed
to maximize poison clearance (see operational character-
istics in Table 5). In rare cases, e.g., refractory metformin-
induced lactic acidemia, two distinct extracorporeal de-
vices may be used at the same time to increase clearance
(Table 5), whereby a parallel circuit is more effective
than a series circuit.
Hemodialysis
During HD, poison is removed from the blood by
diffusion, across a semipermeable membrane, passively
down a concentration gradient. Older conventional dialysis
membranes had a molecular cutoff of approximately
1000 Da (larger xenobiotics could be removed from
filtration/back-filtration within the dialyzer), compared
with .10,000 Da for modern synthetic high-flux mem-
branes.38 This is exemplified by the increase in vancomycin
(1449 Da) clearance over the years, from 10 ml/min with
cuprophane membranes39 to .100 ml/min today with
polysulfone membranes.40 In poisoning, a filter with the
largest surface area and maximal blood and dialysate flow
rates should be used unless a contraindication is present
(e.g., concern for disequilibrium syndrome, as can be seen
in severe azotemia) (Table 5).41 HD has other major
advantages such as fluid removal (although rarely re-
quired in that setting), correction of metabolic abnormal-
ities, replacement of kidney function, and highest
achievable clearance among all extracorporeal treatments.
Because of its prevalent use for the treatment of AKI and
kidney failure, HD is the most available extracorporeal
treatment and is also the least expensive and the quickest
to implement.37 Some care is required to the prescription
of the dialysate, as poisoned patients may not share
metabolic disturbances as patients with AKI. For example,
phosphate may be added to the dialysate of a patient who
has a low-to-normal serum phosphate concentration, and
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1218
CJASN
Table 4. Summary of extracorporeal treatments and their differences

Extracorporeal Molecular Weight Protein Maximal Clearance Relative

Predominant Process Complications Advantages or Other Comments
Treatment Cutoff (Da) Binding Cutoff (ml/min) Cost

Intermittent HD Diffusion ,10,000 for regular ,80% 240 1 1 Allows correction of uremia and
dialyzersa acid-base and
,45,000 for middle electrolyte disorders
cutoff dialyzers
,60,000 for high
cutoff dialyzers
Intermittent Convection ,50,000 ,80% 240 11 1 Allows correction of uremia and
hemofiltration acid-base and
electrolyte disorders
Hemoperfusion Adsorption ,50,000 for charcoal ,95% 200 11 111 Saturation of cartridge requires
cartridges changes every 2 h
,60,000 for Cytosorb
Continuous KRT Convection and/ ,10,000–50,000 ,80% 80 11 1 May include diffusion and/or
or diffusion convection correction of uremia
and acid-base and
electrolyte disorders
Therapeutic Centrifugation/ ,300,000 if filtration used None 50 111 111
plasma exchange separation, filtration
ELAD Diffusion, adsorption ,250,000 for Prometheus ,95% 50 1111 11 Liver replacement support
,60,000 for MARS
Peritoneal dialysis Diffusion ,15,000 ,80%–90% 20 11 11 Technically easier in neonates
Does not require
extracorporeal circuit
Exchange Centrifugation/ None None 10 11 11 Technically easier in neonates
transfusion separation, filtration Correction of hemolysis

All extracorporeal treatments above are less likely to be useful for poisons that have a high volume of distribution or a high endogenous clearance (Table 5). HD, hemodialysis; ELAD,
extracorporeal liver assist device; MARS, Molecular Adsorbent Recirculating System.
a
Clearance of higher molecular weight solutes during hemodialysis is mainly induced by adsorption and nondiffusive solute flux with filtration and back filtration.
 CJASN 18: 1210–1221 September, 2023
Table 5. Factors that will enhance poison clearance during
hemodialysis
Poison characteristics
Molecular weight: ,10,000 Da
Protein binding: ,80% at clinically relevant concentrations
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Endogenous clearance: ,200 ml/min
VD: ,1–2 L/kg body weight
Operational characteristics of the extracorporeal treatment
Larger surface area of dialysis membrane
High blood and dialysate flows
WnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 09/26/2023
Increased ultrafiltration rate (with replacement solution)
Increased duration of treatment
Reduced recirculation from vascular access
Two distinct extracorporeal circuits in parallel
VD, volume of distribution.
the bicarbonate concentration should be reduced in an
alkalemic patient.
Hemoperfusion
During hemoperfusion, poison is removed from the blood
when it passes through a charcoal or resin cartridge onto
which the poison is adsorbed.42 Compared with diffusion,
adsorption is not as limited regarding the molecular weight
or protein binding of the poison. However, hemoperfusion
has several disadvantages over HD: (1) The circuit requires
more generous systemic anticoagulation than dialysis;
(2) maximal blood flow is limited to 350 ml/min because
of risk of hemolysis43; (3) hemoperfusion also adsorbs
platelets, white blood cells, calcium, and glucose44,45;
(4) hemoperfusion cartridges cost several-fold more than
standard hemodialyzers; (5) cartridges need to be replaced
every 2 hours because of saturation and loss of efficiency;
(6) hemoperfusion does not correct electrolyte and acid-base
disturbances and cannot remove fluid; (7) hemoperfusion
cartridges are seldom available46; and (8) hemoperfusion
does not adsorb alcohols or many metals. For these reasons,
HD is generally preferred in most settings where hemo-
perfusion is also indicated.42 These considerations are
reflected by recent trends in the choice of extracorporeal
treatment for poisonings (Figure 1).46–48 The only hemo-
perfusion column available in the United States is the
Gambro Adsorba 300c, a coated activated charcoal car-
tridge.42 Recently, CytoSorb, a hemoadsorption device
containing polymer beads, has shown promise in removing
inflammatory mediators for patients with sepsis. However,
the data for removing protein-bound poisons re-
main unclear.49
Hemofiltration
During hemofiltration, solute and solvent in the blood
are removed by convection or solvent drag and replaced
by a physiological solution. Hemofiltration has similar
advantages to HD but can eliminate larger poisons, up to
50,000 Da.41,50
Continuous Techniques
Continuous techniques, such as CKRTs, are popular in the
critical care setting to manage fluid overload and AKI. They
usually combine diffusion and convection, albeit at lower
effluent and blood flow. Their benefit is mainly that they can
Poisonings and Intoxications, Ghannoum and Roberts 1219
be performed continuously, hence reducing the rate of net
ultrafiltration, which is a concern in hemodynamically
precarious patients; however, fluid removal is rarely re-
quired in poisoned patients. CKRT also reduces the rebound
in poison concentration seen after HD because of redistri-
bution from tissues to blood, although this phenomenon
may not be clinically important in poisoned patients. In
general, high-efficiency HD or hemofiltration is preferred to
CKRT because they maximize poison clearance. However,
in some centers, CKRT may be quicker to institute than HD
because of staffing and patient disposition issues, in which
case CKRT is a reasonable modality to trial.
Peritoneal Dialysis
Peritoneal dialysis (PD) has a limited role in acute poison-
ing as the maximum achievable clearance is ,20 ml/min (one
tenth of the clearance achievable by HD).51 An advantage of
PD is that it is technically more easily feasible in resource-
limited regions and in neonates.
Therapeutic Plasma Exchange
Therapeutic plasma exchange separates plasma and
blood cells by filtration or centrifugation, which is then
replaced by a solution that usually contains albumin or
fresh frozen plasma. Poison clearance during therapeutic
plasma exchange is limited to 50 ml/min.51 The advan-
tage of therapeutic plasma exchange over HD is in the
removal of highly protein-bound (.95%) or very large
poisons over the accepted cutoffs for hemoperfusion or
hemofiltration (.50,000 Da). Complications specific to
therapeutic plasma exchange include hypocalcemia and
hypersensitivity reactions.52
Exchange Transfusion
During exchange transfusion, whole blood or red blood
cells are removed by apheresis and replaced with blood
products. Exchange transfusion is simpler to perform in
infants because it does not require an extracorporeal
circuit, although achievable poison clearance is very low
(,10 ml/min).
Extracorporeal Liver Assist Devices
Extracorporeal liver assist devices, often referred as
albumin dialysis, are infrequently used nowadays to
support liver function in fulminant hepatitis or severe
cirrhosis, often as a bridge to transplantation. There are
three different major types: Single-pass albumin dialysis
is a technique similar to HD on to which albumin is added
to the dialysate. The Molecular Adsorbents Recirculation
System is identical to single-pass albumin dialysis, but the
discarded albumin-enhanced dialysate is recycled after
going through a dialysis filter, a resin, and a charcoal
cartridge. The Prometheus system combines albumin ad-
sorption with HD after selective filtration of the albumin
fraction through a polysulfone filter. These techniques have
very limited availability, are expensive, and have not
shown any benefit over therapeutic plasma exchange or
hemoperfusion at removing protein-bound poisons.
If a high-efficiency extracorporeal treatment is needed, a
single 6-hour session usually suffices for most poisonings,
but a longer duration may be required if the molar
concentration in blood is high (e.g., for toxic alcohols). After
extracorporeal treatment, serial poison concentrations
 1220 CJASN
and clinical status should be monitored for a period long
enough to account for rebound, redistribution, or ongoing
absorption. The catheter should remain in place until the
physician is convinced that additional sessions are
unnecessary.
In conclusion, general supportive care is sufficient to
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manage most poisoned patients. Some patients are treated
with decontamination, antidotes, and corporeal methods
for enhanced elimination. In a smaller selection of cases,
extracorporeal blood purification, usually consisting of
WnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 09/26/2023
HD, can help reduce the exposure of a patient to the toxic
effects of a poison, which decreases the duration and/or
severity of poisoning. An understanding of poison toxico-
kinetics can help a clinician discern what are the timely
conditions and circumstances when extracorporeal treat-
ments are most likely to be beneficial.
Disclosures
Both M. Ghannoum and D.M. Roberts are EXTRIP chairs.
M. Ghannoum reports employment with Government of Quebec.
D.M. Roberts’s partner is employed in a business support role by a
pharmaceutical company. This has no relationship to the manu-
script under consideration or any of D.M. Roberts’s work.
Funding
None.
Author Contributions
M. Ghannoum and D.M. Roberts conceptualized the study; were
responsible for resources and investigation; wrote the original
draft; and reviewed and edited the manuscript.
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Published Online Ahead of Print: January 13, 2023