MD Notes

creation date: 2026-05-21 16:43
tags: Pathologies

Salicylate Toxicity

Background

Definitions

Salicylates are one of the oldest medication still used clinically. Aspirin in particular is still a widely used analgesic (less so now with better NSAIDs) and antiplatelet agent.

Salicylate toxicity, also referred to as salicylism, is a somewhat common cause of pediatric poisoning, although it has greatly declined since the 1980s following its association with Reye syndrome.

Pharmacology

Sources of salicylates

  • Acetylsalicylic acid (ASA, aspirin) - chewable tab, tab, cap, effervescent tab, delayed-release, enteric-coated
  • Methyl salicylate - favouring agent and massage oils
    • Oil of wintergreen: 7 g in 5 mL; other oils vary
  • Bismuth subsalicylate - OTC antidiarrheals (eg. Pepto-Bismol)
    • 8.7 mg salicylate per 1 mL
  • Magnesium salicylate - OTC NSAIDs (eg. Doan’s)
  • Salicylic acid - topical keratolytic agent and wart remover

Pharmacokinetics
Absorption

  • Rapidly absorbed in the jejunum; slightly in stomach and duodenum
  • Peak blood concentration within one hour for regular tabs or caps; 4-15 for delayed or enteric coated

Distribution

  • At therapeutic concentration, 90% of salicylate is albumin-bound
  • Overdose results in free salicylic acid that can cross blood-brain barrier and renal tubular epithelium; lowers pH

Metabolism

  • Half-life of 2-4 hours via liver metabolism
  • Major metabolite is salicyluric acid which is less toxic and more rapidly excreted
  • At high concentrations, liver enzymes become saturated and rate of metabolism drops (zero-order)

Elimination

  • Excreted through the kidney

Toxic Doses & Mechanism of Toxicity

Toxic doses

  • <150 mg/kg: no/minimal symptoms
  • 150-300 mg/kg: mild to moderate toxicity
  • 301-500 mg/kg: severe toxicity

  • 500 mg/kg: potentially lethal; generally adult = 20g, child = 3g

A toxic serum salicylate concentration corresponds to 2.2-3.6 mmol/L.

Mechanism
Salicylates at toxic levels cause the following:

  • Interferes with cellular metabolism (incl. uncoupling oxphos) leading to metabolic acidosis, hyperthermia, fluid losses
  • Depletes glycogen stores and inhibits gluconeogenesis
  • Causes catabolic state leading to accumulation of organic acids and ketoacids
  • Activates respiratory centres of medulla leading to tachypnea, hyperventilation, respiratory alkalosis, and bicarbonate elimination
  • Stimulates chemoreceptors causing nausea vomiting
  • Inhibits cyclooxygenase (prostaglandins and platelet function)
  • Irritates gastric mucosa
  • Affects cochlear hair cells causing tinnitus and hearing changes
  • Inactivates CNS cardiorespiratory centres in severe cases

Clinical Presentation

Signs & Symptoms

Mild or early toxicity manifests as:

  • Tinnitus
  • Nausea ± vomiting
  • Serum salicylate: 2.2-3.6 mmol/L

Moderate toxicity:

  • Mild hyperthermia
  • Tachycardia
  • Hyperpnea
  • Vomiting
  • Diaphoresis
  • Serum salicylate: 3.6-6.5 mmol/L

Severe or late toxicity:

  • Altered mental status
  • Cerebral or pulmonary edema
  • Clinical deterioration
  • Serum salicylate: >6.5 mmol/L (acute) or >4.3 mmol/L (chronic)
  • Blood pH < 7.3, urine pH <5

Acid-base derangements are seen with salicylate toxicity:

  • Respiratory alkalosis (hyperventilation induced)
  • Mixed respiratory alkalosis-metabolic acidosis (elevated anion gap from accumulation of organic acids)

History & Physical Exam

History should include:

  • Amount of aspirin ingested (# of tablets and dose of each)
  • Was patient taking aspirin regularly (chronic use vs. acute single overdose)
  • Other possible sources of salicylates

Physical exam should include:

  • Respiratory exam
  • Skin for diaphoresis and hypovolemia
  • Mental status

Diagnosis

Criteria

Diagnosis is confirmed by a supratherapeutic serum salicylate concentration (>2.2 mmol/L).

A presumed diagnosis is often made based on characteristic findings and acid-base derangements as elevation in serum salicylate can lag for several hours.

A Done nomogram was historically used for severity but has since been deemed inadequate.

Work-up

Laboratory studies

  • Serum salicylate concentration
  • CBC
  • Serum electrolytes, magnesium, phosphate, and glucose
  • Serum creatinine and blood urea nitrogen
  • VBG
  • Serum lactate
  • Urinalysis and urine pH
  • Serum acetaminophen concentration (since many over-the-counter preparations contain both aspirin and acetaminophen)
  • Coagulation studies (PT and PTT)
  • Liver enzymes
  • Pregnancy test

Differential

Differential consist of other anion gap elevated metabolic acidosis:

  • Diabetic ketoacidosis
  • Sepsis, pneumonia, or SIRS
  • Iron intoxication
  • MUDPILES

Red Flags / Complications

Major complications include:

  • Respiratory arrest (more likely in pediatrics)
  • Aspiration pneumonitis
  • Deafness
  • TInnitus
  • Asystole
  • Hypotension
  • Encephalopathy, seizures, coma

In children, salicylate use is a major precipitating factor in the development of Reye syndrome. This is characterized by rapidly progressive encephalopathy with hepatic dysfunction:

  • Vomiting and confusion
  • Evolution to seizures and coma
  • Hepatomegaly

Management

General Management

Stabilization and supportive care
Standard ABCs should be assessed and stabilized. Note:

  • Intubation should be avoided as RSI can exacerbate acidosis (due to induction agents terminating salicylate-induced primary respiratory alkalosis); if necessary, treat acidosis prior or perform awake intubation with ketamine
  • Ventilator use requires high minute ventilation to mimic salicylate toxic breathing

Gastrointestinal decontamination
Patients who can protect their airway with an acute oral salicylate overdose should receive:

  • Single-dose (or initial) activated charcoal 1 g/kg PO (single max dose: 50g)

regardless of time from ingestion. Other decontamination therapies (whole bowel irrigation or lavage) is not routinely performed.

Laboratory monitoring
Continuous monitoring consist of:

  1. Serum salicylate and VBG q2h until concentration decreasing and acid-base is stable or improving for two consecutive measurements
  2. Serum salicylate q4h until concentration <2.2 mmol/L and patient is asymptomatic with normal resp rate and effort

Additional monitoring includes:

  • Hourly blood and urine pH, serum sodium and potassium for patients receiving alkalization
  • Serum or POCT glucose for altered mental status or hypoglycemic patients

Consultation
Involvement of medical toxicologist or poison centre to avoid errors.

Additional Therapy

Moderate to Severe Toxicity

Fluid repletion
Patients who are hypovolemic may require large amounts of fluids to achieve euvolemia.

  • Initial: 0.9% sodium chloride at 10-15 mL/kg/hr for 2-3 hrs
  • Then: 1.5-2 times maintenance rate titrated to maintain urine output of 1-2 mL/kg/hr

If the patient is clinical acute salicylate toxicity, sodium bicarbonate is administered, even prior to serum salicylate levels.

Note that if a patient is euvolemic, fluids are used cautiously to avoid pulmonary or cerebral edema.

Electrolyte repletion
Potassium is aggressively repleted unless serum potassium >5.5 mEq/L as potassium reabsorption in the kidneys interfere with urinary alkalinization (H pumps).

Magnesium is repleted if patient is receiving urinary alkalinization (magnesium sulfate 2g IV) prior to repleting potassium but otherwise is repleted as needed along with phosphate.

Supplemental glucose
Administered in patients with any neurologic deficit, regardless of serum glucose (due to decreased cerebral glucose concentrations).

  • Maintain glucose at high normal (5.6-7.8 mmol/L)
  • PO or IV bolus of dextrose (50-100 mL of 50% dextrose)

Additional doses of activated charcoal
Multi-dose AC is indicated for moderate-to-severe toxicity or large ingestion (>300 mg/kg).

  • 0.5 g/kg (max dose: 50g) q4h
  • 0.25 g/kg (max dose: 25g) q2h

Withhold dose if patient is vomiting, poor gastric motility, or GI bleed. Continue until clinical improvement or serum levels consistently decrease.

Serum and urine alkalinization
Alkalinization is recommended with a goal of urine pH >7.5 while keeping serum pH ≤7.55.

  • Sodium bicarbonate IV 1-2 mEq/kg (1-2 mL/kg of 8.4% NaHCO3)

Hemodialysis
Indications of hemodialysis, regardless of serum salicylate levels, are:

  • Altered mental status attributed to salicylate toxicity
  • Acidosis (blood pH <7.2, or 7.3 despite aggressive resuscitation)
  • Cerebral or pulmonary edema
  • Fluid overload that prevents bicarbonate infusion
  • Clinical deterioration despite care
  • Presence of AKI or CKD and unchanging serum salicylate concentration despite bicarbonate infusion

Laboratory indications, regardless of clinical findings, include:

  • Serum salicylate >7.2 mmol/L with normal kidney function
  • Serum salicylate >6.5 mmol/L with impaired kidney function
  • Serum salicylate >4.3 mmol/L in chronic toxicity

Mild Toxicity

In cases of mild toxicity, close monitoring is typically sufficient and additional therapies are not required. Monitoring is performed until there are two downtrending concentrations <2.2 mmol/L with signs/symptoms resolved.

References

Tools / Guidelines

Additional Reading