Salicylate (Aspirin) Toxicity

Salicylates

• The use of salicylates dates back more than 3500 years, when the bark of the willow tree was recognized to possess analgesic and anti-pyretic properties.¹
• Salicylates are found in several prescription and over-the-counter medicinal preparations.²
  • Aspirin (acetylsalicylic acid) is a commonly used analgesic and antiplatelet therapy. It is available as chewable tablets, regular tablets, and capsules, and enteric-coated formulations.
  • Methyl salicylate is used as a flavoring agent and a common ingredient in liniments and ointments for the relief of musculoskeletal pain. Oil of Wintergreen contains 98-100% methyl salicylate. One milliliter of a 98% solution contains approximately 1,400 mg of salicylate.¹
  • Bismuth subsalicylate is a common ingredient in over-the-counter antidiarrheal agents (e.g., Pepto-Bismol, Kaopectate).
  • Magnesium salicylate is found in over-the-counter non-steroidal anti-inflammatory drugs.
  • Salicylic acid is used as a topical keratolytic agent and wart remover.

Salicylate Toxicity

• The widespread availability, ease of access, and frequent coingestion of multiple salicylate-containing agents, combined with the nonlinear pharmacokinetic properties of salicylate, result in salicylate poisoning being a common occurrence.¹
• Salicylate toxicity most commonly results from intentional overdose (acute) or therapeutic misadventure (chronic), with an estimated incidence of thousands of cases annually in the United States, though exact numbers vary by region and reporting method.¹
• Acute toxicity is more frequent in young adults with psychiatric histories, while chronic toxicity is seen in older adults using salicylates for pain or cardiovascular prevention.¹
• A common scenario for chronic toxicity is the simultaneous use of an oral salicylate-containing drug, topical application of a methyl salicylate–containing cream along with a heating pad, and home remedies containing herbs and spices enriched with salicylate.¹

Clinical Presentation

• Early symptoms include tinnitus, vertigo, nausea, vomiting, and hyperpnea (Table 1). Severe toxicity manifests as fever, sweating, confusion, seizures, cerebral edema, noncardiogenic pulmonary edema, and cardiovascular collapse. Chronic toxicity may present with subtle central nervous system symptoms and metabolic derangements at lower serum levels.¹

Pathophysiology

• Toxicity results from direct stimulation of the respiratory center (causing hyperventilation and respiratory alkalosis), uncoupling of oxidative phosphorylation (leading to metabolic acidosis, hyperthermia, and increased glucose demand), and fluid/electrolyte losses.¹
• Toxic levels of salicylate directly stimulate the respiratory center of the medulla, causing an increase in the rate and depth of respiration, which leads to the development of respiratory alkalosis.
• Salicylates also uncouple oxidative phosphorylation and inhibit citric acid cycle dehydrogenases, resulting in a shift in metabolism toward glycolysis for energy production. A compensatory increase in body catabolism is characterized by increased oxygen consumption, increased heat production (resulting in hyperpyrexia, diaphoresis, and dehydration), depletion of liver glycogen, and enhanced metabolic production of carbon dioxide.
• Acid-base disturbances are common.²
  • Initial respiratory alkalosis results from the stimulation of the respiratory center, leading to tachypnea and hyperpnea.
  • Elevated anion-gap metabolic acidosis is common from the accumulation of organic acids (lactic acids from uncoupling of oxidative phosphorylation and ketoacids from increased catabolism).
  • Most adults develop a mixed respiratory alkalosis as the net effect of these acid-base derangements.
• Salicylate poisoning also causes fluid losses from vomiting, insensible losses from the elevated metabolic rate (i.e., hyperthermia, diaphoresis), and osmotic diuresis (from organic aciduria and solute excretion).²
• Mental status changes (agitation, confusion, restlessness, seizures, etc.) result from direct central nervous system toxicity, cerebral edema, and neuroglycopenia.²

Diagnosis

• The diagnosis of acute intoxication is generally straightforward, but chronic salicylate poisoning can be difficult to diagnose because there is no clear history of excess ingestion, and the classic symptoms and signs tend to be milder or absent.¹
• The diagnosis is clinical, supported by measurements of plasma salicylate levels, serial arterial blood gases (ABGs), and electrolyte levels.
• Acid-base disturbances are common (see above). Severity correlates more closely with clinical findings than with serum levels, especially in chronic cases.¹

Treatment

• There is no specific antidote for salicylate poisoning.^1,3 Good supportive care is critical.
• Early consultation with a toxicologist is recommended.

Plasma Salicylate Concentration

• An initial and subsequent plasma salicylate should be determined and interpreted in the patient’s clinical context.^2,3
• Seum salicylate levels should be checked every two hours until it is declining.² The patient’s overall clinical condition, not the salicylate concentration, should guide management.³
• Clinical deterioration, even in the setting of a declining serum concentration, is ominous, suggesting an increasing central nervous system salicylate concentration.³

Acid-Base and Volume Status

• ABGs should be repeated every two hours until the patient’s acid-base status is stable or improving.²
• Acidemia should be avoided.³
• Alkalinization is indicated in all symptomatic patients.1 A bolus of IV sodium bicarbonate (1-2 mEq/kg) may be administered, followed by maintenance therapy. A commonly used IV solution consists of 1 L of D5W to which three 50-mL ampoules of 7.5 or 8.4% sodium bicarbonate and 30-40 mEq or potassium chloride are added.³
• Electrolyte abnormalities, such as hypokalemia and hypocalcemia, should be corrected.²
• Supplemental glucose should be administered in patients with altered mental status.²
• Hypovolemia is often underappreciated and should be aggressively corrected as hypovolemia worsens salicylate toxicity.³ Isotonic crystalloids can be administered at a rate of 10-20 mL/kg/h for the first 2 hours and subsequently adjusted to maintain a urine output of 1-1.5 mL/kg/h.¹

Gastrointestinal Decontamination

• Administration of activated charcoal or even whole bowel irrigation may be considered in specific cases, especially those with early presentation after ingestion or rising salicylate levels.³
• Activated charcoal (1-2 g/kg or a maximum of 100 g in adults) is most effective if administered within 2 hours after salicylate ingestion.¹
• Whole bowel irrigation with polyethylene glycol may be considered when rising salicylate levels do not respond to activated charcoal, or when the ingestion of an enteric-coated or sustained-release formulation is suspected.¹

Airway Protection and Respiratory Status

• Hyperventilation alone is not an indication for endotracheal intubation.³
• Endotracheal intubation may be indicated in patients with deteriorating mental status, hypoventilation, or uncontrollable agitation.
• However, endotracheal intubation may be associated with rapid worsening of salicylate toxicity unless a normal or slightly alkalemic pH and low PaCO₂ are maintained via hyperventilation. Acidemia enhances the movement of salicylate into the tissues, precipitating a clinical deterioration.
• Intravenous sodium bicarbonate is often administered at the time of intubation to maintain a blood pH of 7.45-7.5.
• Sedation or paralysis can lead to retention of carbon dioxide and respiratory acidosis.
• In an agitated patient, avoid applying physical restraints or administering sedatives since it may worsen the metabolic acidosis by impairing respiratory alkalosis.²

Enhanced Elimination

• Diuresis should be induced with large volumes of isotonic sodium bicarbonate-containing intravenous fluids.³
• Forced diuresis should be avoided due to the risk of pulmonary edema.¹
• Urine alkalinization to a pH of 7.5 to 8.0 increases the urinary excretion of salicylates tenfold.
• Hemodialysis is the most efficient way to remove salicylate from the body and may be lifesaving for some patients.1 Indications for hemodialysis include the following:³
  • Significant alteration in mental status, cerebral edema, or seizures
  • Acute lung injury or respiratory failure
  • Refractory or profound acidemia
  • Refractory or profound electrolyte abnormalities
  • Deteriorating clinical status in the setting of delayed or inadequate urine alkalinization
  • Rising salicylate levels despite administration of sodium bicarbonate
  • Serum salicylate levels greater than 100 mg/dL in acute ingestion or greater than 60 mg/dL in chronic ingestion