CASE STUDIES

SALICYLATES
Dr. Mokhtar A. Alhrani
(M.B.B.S - M.Sc. - MD)
 Case Study
A 24-year-old male presents to the Emergency Department after swallowing
“a bottle” of pills. He states that this was done in an attempt to kill himself. He is
vomiting and is moderately ill-appearing.
History of Present illness
• The patient states that he ingested the entire contents of the bottle;
• He refuses to identify them.
• He states he ingested them two or three hours ago.
• He states that he only took one type of medication.
 Case Study
Review of Systems Physical Examination
General: Negative Vitals: BP 123/76 HR 117
RR 26 T 100.4
Neck: Negative
Pulmonary: Negative (100.4-32/1.8= 38)
Cardiac: Negative General: Moderately ill-appearing
Gastrointestinal: Nausea and Vomiting HEENT: Pupils midrange and reactive.

Urogenital: Negative Chest: Clear to auscultation bilaterally

Musculoskeletal: Negative Cardiovascular: Tachycardic without murmurs rubs
or gallops
Neurologic: Negative Abdomen: Soft and nontender with normal
bowel sounds Occult blood in stool
Rheumatologic: Negative Rectal: Trace guaiac positive brown stool
Endocrine: Negative Neurologic: Alert and oriented
 Case Study
Lab Test Value Normal Range Units Lab Test Value Normal Range Units
WBC 14.5 4-10 K/mL Na 143 134-142 meq/L
Hgb 14.2 F: 11.5-16.4 g/dL K 3.2 3.5-5.0 meq/L
M: 13.5-18.0 Cl 107 98-108 meq/L
Hct 42.6 F: 36-48 % HCO3 18 18-27 meq/L
M: 40-54 BUN 11 9-25 mg/dL
Plt 243 150-450 K/mL Cr 0.6 0.8-1.3 mg/dL
Glu 143 60-100 mg/dL
(fasting)

• Urinalysis: • ECG: Normal sinus rhythm, normal

Dip: 2+ ketones QRS and QTc intervals, no ischemia
Micro: No RBC, no WBC
• Urine Tox Screen: Negative •CXR: No infiltrates or effusions
(Includes, barbiturates, opiates, cocaine, PCP, marijuana )
 Case Study Q1 of 5
Based on the history, physical examination, and laboratory values,
what is your working diagnosis?

A. Aspirin overdose with resultant toxicity

B. Acetaminophen overdose with resultant toxicity
C. Amphetamine overdose with resultant toxicity
D. Multivitamin overdose with resultant toxicity
 Case Study
Several aspects of the patient’s presentation suggest salicylate poisoning.

Nausea and vomiting are seen in several ingestions, including salicylates.

The patient’s low-grade fever may be due to aspirin’s ability to uncouple
oxidative phosphorylation. The elevated respiratory rate is due to
aspirin’s action on the medulla, stimulating the respiratory center. The
mild metabolic acidosis may be due to many factors: aspirin itself is a
weak acid, aspirin may produce a mild lactic acidosis, and aspirin
frequently causes ketonemia (as seen in the patients urinalysis).
 Extensive application of topical preparations containing methyl salicylate result in
poisoning particularly in children.

Salicylates After 30 minutes of contact time, only 1.5% to 2.0% of a dose is absorbed, and even after
10 hours of contact with the methyl salicylate, only 12% to 20% of the salicylate is
systemically absorbed. Heat, occlusive dressings, young age, inflammation, certain body
Sources: areas with enhanced absorption, and psoriasis may increase topical salicylate absorption.

❑ Aspirin
❑ Pepto Bismol (Bismuth subsalicylate): the salicylate in Bismuth subsalicylate is almost completely
bioavailable, Pepto-Bismol contains 8.7 mg salicylate /mL (261 -525 mg salicylate/ 30 mL). It is used to
treat diarrhea, and as prophylaxis for travelers diarrhea. (101-262 mg /chewable table)

❑ Topical Salicylates
 Salicylic Acid (keratolytic)
 Methyl Salicylate: rubefacients used for the local treatment of musculoskeletal pain & inflammation
- 98% in Oil of wintergreen: One teaspoon contains 7000 mg of Salicylate (1.4 gm/ml)
- 30% in many products e.g. BENGAY pain relieving cream (camphor, menthol, methyl
salicylate)
Salicylates
Sources:
 Case Study Q2 of 5
You establish a working diagnosis of aspirin toxicity in the setting of a
suicidal attempt. Which of the following is NOT indicated at this time?

A. Salicylate level
B. Acetaminophen level
C. ABGs
D. Head CT
 Case Study
The Case Continued

The indicated laboratory tests return as follows:

Salicylate Level: 72 mg/dL (therapeutic: 10-30 mg/dL)

Acetaminophen Level: Undetectable
Arterial Blood Gas: 7.57/26/98/20
Salicylates
PKs: Absorption:
 Acetylsalicylic acid is a weak acid with a pKa of 3.5
 During and after ingestion, all salicylate products are converted rapidly to salicylate.
 It is better absorbed from the acid environment of the stomach than from the alkaline
small intestine. The pK of aspirin (3.5) and the majority is nonionized (ie, acetylsalicylic
a

acid) in the strongly acidic stomach (pH 1–2).Although absorption of acetylsalicylate is

less efficient in the small bowel because of its higher pH, it is substantial and rapid
due to the large surface area of the small intestine increases the solubility of
acetylsalicylate.
 Liquid salicylate preparations (e.g., methyl salicylate, salicylic acid, pediatric aspirin
products) undergo more rapid absorption than solid products.
 Toxic and fatal amounts of salicylate can be absorbed across the skin after the use of
salicylic acid containing keratolytic agents.
Salicylates
PKs: Absorption:
 Salicylate impairs gastric emptying, and gastric bezoars have formed in patients
with chronic ingestion of enteric-coated aspirin tablets.
 Causes of delayed absorption:
- Enteric-coated or extended-release aspirin tablets
- Bezoars formation
- Salicylate induced pylorospsam
- Pyloric stenosis or Gastric outlet obstruction
 Salicylates: PKs & TKs:
 The plasma half-life of acetylsalicylate: Elimination:
- 15-20 minutes (Rapidly hydrolyzed to salicylic acid) - mainly hepatic at low salicylate
concentrations
 The apparent half-life for salicylate:
- mainly renal at upper therapeutic and
- 2 to 3 hours at antiplatelet doses
toxic serum salicylate concentrations
- up to 12 hours at anti-inflammatory doses
- >30% of an ingested salicylate dose is
- as long as 18-36 hours at toxic concentrations eliminated in alkaline urine and as little as
 Salicylates are distributed bound to albumin: 2% in acidic urine
- 90% at therapeutic concentrations ↑ unbound fraction:
- < 75% at toxic concentrations (saturation of protein High serum salicylate concentrations
binding sites) Hypoalbuminemia
- Only unbound, unionized salicylate readily crosses
cell membranes (↑ salicylate’s apparent Vd). ↑ un-ionized fraction:
Acidosis (decrease in pH)
A decrease in pH can result in a movement of salicylate from the blood into the tissue, raising the tissue levels of
salicylate and worsening systemic toxicity, while serum salicylate concentrations decline. A drop in pH of only 0.25
(e.g., 7.45–7.2) almost doubles the amount of un-ionized drug capable of diffusing into the tissue.

Upon chronic Use:

A small increase in
dosage or a small
decrease in metabolism
or elimination results in
substantial increases in
serum salicylate
concentrations and the
risk of toxicity.
50% increase in daily
dose → 300% increase
in serum concentration
(geometrical increase).
The urinary clearance of salicylate can Un-ionized salicylate undergoes
increase more than 500% by raising urine pH reabsorption by renal tubules,
from 7.0 to 8.0 (ion trapping in the urine). prolonging elimination.
Salicylates
Precautions:
❑ Consider intentional Overdose (Suicidality) in the elderly.
❑ Salicylate Poisoning (especially chronic poisoning) has a high mortality and is easily
mis-diagnosed.
❑ Chronic Salicylate Toxicity is frequently missed:
 Symptoms and signs occur at lower Salicylate levels.
 Patients may present with: Encephalopathy, Coagulopathy (INR increased)
and Non-Cardiogenic Pulmonary Edema (NCPE).
Salicylates
Pathophysiology:
❑ Local corrosive injury to the GIT ❑ Enhances glycogenolysis
❑ CNS Stimulation: Stimulates respiratory ❑ Inhibits gluconeogenesis
center & CTZ.
❑ Increases glucose consumption
❑ Uncouples oxidative phosphorylation
❑ Enhances lipolysis
❑ Inhibits tricarboxylic acid cycle (Kreb’s cycle)
❑ Prevents activation of vitamin K-
dependent coagulation factors
❑ Inhibits platelet aggregation
(significant only with aspirin)
Salicylates
Pathophysiology:
❑Salicylates directly stimulate the respiratory center of the brain → ↑ RR
→ CO2 washout → primary respiratory alkalosis.
❑ Salicylate Toxicity uncouples mitochondrial oxidative phosphorylation → inhibition
of TCA cycle and ATP production:
 Results in shift to anaerobic metabolism → accumulation of lactic acid and
ketones → Lactic Acidosis (and HAGMA)
 Because chloride is falsely elevated in the presence of salicylates, a high anion gap may not always
be present.
 Compensatory Hyperventilation (triggered by Metabolic Acidosis) further
increases Tachypnea.
 Energy is released in the form of heat (Hyperthermia).
 Progressive Acid-Base Stages of Salicylate Poisoning
Early: Respiratory alkalosis, alkalemia, and alkaluria
Salicylates Intermediate: Respiratory alkalosis, metabolic acidosis, alkalemia, and aciduria
Late: Metabolic acidosis with either a respiratory alkalosis or respiratory
Pathophysiology: acidosis, acidemia, and aciduria

❑ Respiratory acidosis in salicylate overdose indicates grave prognosis and is seen in:
 Salicylate induced pulmonary edema

 CNS depression from mixed overdose

 Severe fatigue due to prolonged hyperventilation

 Clinical presentation is variable
and may not always correlate
Salicylates with serum salicylate levels.
Clinical Features:
Salicylate Toxicity Severity
Serum salicylate level Clinical features

Mild toxicity •Adults: 30–60 mg/dL •Tinnitus * typically develop within

•Children/elderly: 20–45 mg/dL •Nausea/vomiting 1 to 2 hrs of acute
ingestion. May be
•Lethargy delayed up to 24hrs
Moderate toxicity •Adults: 60–80 mg/dL •Tachypnea
•Children/elderly: 45–70 mg/dL •Diaphoresis

Severe toxicity •Adults: > 80 mg/dL •Coma (rare & late)

•Children/elderly: > 70 mg/dL •Seizures, Auditory hallucinations
* As CNS salicylate concentrations increase, tinnitus is rapidly followed by diminished auditory (e.g. musical)
acuity that sometimes leads to deafness •Pulmonary edema
•Renal failure
 Salicylates
Notes:
❑ Salicylates competitively inhibit synthesis of vitamin K dependent factors II, VII, IX and X reflected
in an increased INR.
 Despite coagulopathies and potential platelet dysfunction, hemorrhage remains a rare cause of
serious morbidity or mortality in patients with salicylate toxicity, with the exception of occasional
GI bleeding.
❑ Paratonia, extreme muscle rigidity, is reported in severe salicylate poisoning pre- and
postmortem, it was unresponsive to succinylcholine in a single case report. Decreased ATP
production, impaired glycolysis, increased lactate, and uncoupling of muscular oxidative
phosphorylation likely contribute to this phenomenon. This excess neuromuscular activity leads to
rhabdomyolysis acute tubular necrosis and, most concerning, hyperthermia, which is typically a
preterminal condition.
Salicylates
Diagnostics:
❑ABG
 Mixed respiratory alkalosis and increased anion gap metabolic acidosis in early stages
 Progresses to mixed metabolic acidosis-respiratory alkalosis

❑Serum salicylate level: > 40 mg/dL Serum levels within 4 hours of ingestion may be falsely low.
❑BMP: hypokalemia, ↑ BUN, ↑ creatinine
 Salicylates are primarily excreted by the kidneys. High doses are nephrotoxic. Patients also tend to
be hypovolemic, which further contributes to renal failure. Diagnostics:
❑Toxicology screen: evaluate for concurrent ingestions ❑ CXR
 Because salicylate levels are not always elevated initially and do not necessarily correlate with
clinical presentation, a high index of suspicion should be maintained when caring for a patient with
symptoms of salicylate toxicity. Rapid treatment is essential!
Salicylates
Treatment:
❑ Initial Stabilization
❑ GI Decontamination:
- Oral/orogastric activated charcoal (MDAC)
- Whole Bowel Irrigation (enteric coated)

❑ Alkalinize blood and urine

❑ Hemodialysis
 Case Study
Treatment:

The first priority in treating aspirin-poisoned patients is to

secure the airway, breathing, and circulation (ABCs)

 Case Study Q3 of 5
When addressing the ABCs in an aspirin-poisoned patient, which of the
following interventions performed to secure the ABCs may lead to
abrupt and catastrophic deterioration?

A. Endotracheal intubation
B. High-flow supplemental oxygen
C. Crystalloid infusion for mild hypotension
D. Pressor support for hypotension refractory to appropriate
doses of crystalloid infusion
· Intubation is associated with a transient respiratory acidosis during induction. This
acidosis greatly increases salicylate toxicity.

· Salicylate poisoned patients who are breathing spontaneously generally have a

higher minute ventilation with a respiratory alkalosis, and thus a more favorable
acid-base status.
This is not to say that patients who are aspirin poisoned should never be intubated.
Intubation is indicated for patients who are:
Intubation is indicated for Initial assessment and airway management
patients who are unable to
protect their airway, or Evaluate the need for intubation but avoid intubation,
have objective signs of
respiratory failure (hypoxia if possible. If intubation is necessary:
despite a non-rebreathing  Administer bicarbonate prior to intubation
face mask or a respiratory  Maximize minute ventilation (e.g., at least 8–10 mL/kg/breath)
acidosis on the arterial
blood gas).

Indications for intubation in Intubating patients with salicylate toxicity is dangerous!

salicylate toxicity If intubation is required, extra care should be taken to
 Deteriorating mental state maximize minute ventilation, as there is a high risk of
 Seizures worsening acidosis and death.
 ARDS
 Hypoventilation
(e.g., hypercarbia)
 Case Study
Treatment Continued:

After the ABCs have been addressed, there are several other

basic therapeutic interventions which the clinician should perform.

 Case Study Q4 of 5
Which of the following is NOT an important intervention in the
treatment of salicylate poisoned patients?

A. Administration of supplemental glucose in the setting of altered

mental status, even if the serum blood sugar is normal
B. GI decontamination with syrup of ipecac to induce vomiting
C. GI decontamination with multiple-dose activated charcoal to
adsorb any aspirin remaining in the GI tract
D. Alkalinization of serum and urine with IV sodium bicarbonate
 Case Study
Therapy Continued

Alkalinization of Serum and Urine

How to alkalinize a salicylate-poisoned patient
Hypokalemia and Urinary Alkalinization
Use of Acetazolamide in Salicylate Poisoning
Advanced Therapy: Hemodialysis
Salicylates
Treatment:
❑Stabilization of vitals
 Almost all patients requiring admission for salicylate toxicity should be placed in an
intensive care unit setting. clinical deterioration that can be rapid. Patients who are
awake and alert can die within 6 h.
 With an emphasis on adequate oxygenation, IV fluids, IV glucose, and correction
of hypokalemia.
 Salicylates impair glucose utilization and cause symptoms of hypoglycemia even in
the presence of normal glucose levels.
 Tepid sponging should be done in patients with hyperthermia.
Salicylates
Treatment:
❑ Fluid resuscitation:
 Preferred fluids: LR and/or 5% dextrose
 Avoid normal saline, as it can aggravate acidosis.
 Add IV dextrose even if blood glucose is normal to prevent cerebral hypoglycemia.
Salicylates
Treatment:
❑ Alkalinize blood and urine: IV sodium bicarbonate:
Indications: any symptomatic patient, or if serum salicylates > 60 mg/dL

 Recommended as a first-line treatment for patients with moderately severe salicylate

poisoning who do not meet the criteria for HD.
 It is also recommended for salicylate-poisoned patients who require HD while
preparations are being made to perform HD.
 Clinically suspected cases of salicylism until a salicylate concentration and
simultaneously obtained blood pH are available to guide treatment.
 Alkalinization of Urine LILAC
Preparation & dosing:
 Sodium bicarbonate 100-150 mEq (2-3 ampules)
 Dissolve in 1 liter D5W → 0.1 0.15 mEq/ml
 Add 20-40 mEq KCL
 Adult dose: 200-400 ml/hour (i.e. 20-40 mEq/hour)
 Don't exceed 1 mEq/kg/hour; Typically given over 2-3 hours
 Titrate to alkalinization (Targets):
Normokalemia must be maintained in order for
- Serum pH (7.40 -7.55) alkalinization to occur:
▪ Correct hypokalemia before beginning the infusion.
- Urine pH at 7.5 – 8.0 ▪ Supplement potassium during the infusion.
- Urine output at 2-5 ml/kg/hour ▪ Monitor urinary pH and potassium level every 1–2 hours

- Serum potassium: 4–4.5 mEq/L (Monitor serum potassium closely)

Effects of Urinary Alkalinization

Tissues pH 6.8 Plasma pH 7.1 Urine pH 6.5

HA HA HA

H+ + A- H+ + A- H+ + A-

Temple AR. Acute and chronic effects of aspirin toxicity and their treatment. Arch Intern Med 1981;141:367
Effects of Urinary Alkalinization
After Alkalinization

Tissues pH 6.8 Plasma pH 7.4 Urine pH 8

HA HA HA

H+ + A- H+ + A- H+ + A-

Temple AR. Acute and chronic effects of aspirin toxicity and their treatment. Arch Intern Med 1981;141:367
 Case Study Q5 of 5
Despite administration of activated charcoal, aggressive fluid replacement,
serum alkalinization and potassium repletion, the patient is not improving. His
respiratory status is unchanged, but he now seems slightly confused. A repeat
blood gas indicates no significant change in his acid-base status. A repeat
salicylate level is 89 mg/dl. What is the MOST APPROPRIATE next step?
A. Administer an additional dose of activated charcoal
B. Repeat the urine toxicology screen, to see if the first test was
“false-negative” for opiates
C. Perform endotracheal intubation
D. Call nephrology for emergent hemodialysis
Salicylates
Treatment:
❑Hemodialysis
Acute management checklist for salicylate toxicity:
• Establish IV access, Fluid resuscitation with LR and/or D5W (avoid normal saline)
• Assess the severity of intoxication (see salicylate toxicity severity).
• Consult ICU, nephrology, and toxicology.
• Avoid intubation if possible, but secure the airway if necessary (see indications for intubation).
• Assess the need for hemodialysis (see indications for hemodialysis in salicylate toxicity).
• Start alkalization of serum and urine.
• Avoid and correct hypoglycemia and hypokalemia.
• Check toxicology screen for concurrent ingestions.
• Evaluate for suicidal ideation.
• Order repeat labs (BMP, glucose, salicylate levels) every 2 hours.
• Admit to the ICU.
Acetaminophen (APAP)

• Mechanism of injury:
o NAPQI (toxic APAP metabolite) deplete
glutathione stores→ hepatotoxicity.
• Sx:
o Depressed patient with OD/suicide
o 0-24hrs: Nausea, Vomiting
o 24-48hrs: RUQ pain, ↑ liver enzymes
o 48-96hrs: jaundice, encephalopathy
o 96hrs: Fulminant hepatic failure

• Treatment:
o N-Acetylcysteine: IV or Oral
▪ Regenerate glutathione