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Toxicity, Salicylate
Updated: Feb 12, 2008
Introduction
Background
Salicylates are ubiquitous agents found in hundreds of over-the-counter (OTC) medications and in numerous prescription drugs. Salicylic acid and its derivatives are active ingredients in a wide variety of readily available topical preparations used for the treatment of pain, warts, and acne. Pepto-Bismol, a common antidiarrheal agent, contains 131 mg of salicylate per tablespoon.
Salicylate ingestion continues to be a common cause of poisoning in children and adolescents. The prevalence of aspirin-containing analgesic products makes these agents, found in virtually every household, common sources of both accidental and suicidal ingestion.
Salicylate ingestion is one of the most common methods of drug exposure; however, the incidence of salicylate poisoning in children has declined because of reliance on alternative analgesics and the use of child-resistant containers. Repackaging has decreased children's accessibility to lethal amounts, and salicylate's association with Reye syndrome has significantly decreased its use.
Still, more than 10,000 tons of aspirin are consumed in the United States each year. Salicylate intoxication persists as an important cause of morbidity and mortality. Aspirin or aspirin-equivalent preparations (in milligrams) include children's aspirin (80-mg tablets with 36 tablets per bottle), adult aspirin (325-mg tablets), methyl salicylate (eg, oil of wintergreen) (98% salicylate), and Pepto-Bismol (236 mg of nonaspirin salicylate per 15 mL). Ingestion of topical products containing salicylates, such as Ben-Gay, salicylic acid (keratolytic), and oil of wintergreen or methyl salicylate, can cause severe salicylate toxicity. One teaspoon of 98% methyl salicylate contains 7000 mg of salicylate, the equivalent of nearly 90 baby aspirin and more than 4 times the potentially toxic dose for a child who weighs 10 kg. A comprehensive review of the existing medical literature on methyl salicylate poisoning has determined that it is a relatively common source of pediatric exposures.1
The prevalence of alternative medicines and popularity of herbs and traditional medicine formulae are increasing in North America. Many of these medicines may contain salicylate. Therefore, consider salicylate poisoning when topical herbal medicinal oil is involved.
Percy Medicine contains bismuth subsalicylate as the active ingredient and is used as a constipation reliever. A case of neonatal salicylate poisoning due to administration of this medicine as a colic reliever has been reported.2 It is available OTC, and parents should be educated that salicylate-containing products are not routinely recommended for children aged 1 year or younger.
Pathophysiology
After ingestion, acetylsalicylic acid is rapidly converted to salicylic acid, its active moiety. Salicylic acid is readily absorbed in the stomach and small bowel. At therapeutic doses, salicylic acid is metabolized by the liver and eliminated in 2-3 hours. Salicylate poisoning is manifested clinically by disturbances of several organ systems, including the CNS and the cardiovascular, pulmonary, hepatic, renal, and metabolic systems. Salicylates directly or indirectly affect most organ systems in the body by uncoupling oxidative phosphorylation, inhibiting Krebs cycle enzymes, and inhibiting amino acid synthesis.
Acid-base status
Salicylates stimulate the respiratory center, leading to hyperventilation and respiratory alkalosis. Salicylates also interfere with the Krebs cycle, limit production of ATP, and increase lactate production, leading to ketosis and a wide anion-gap metabolic acidosis. Adult patients with acute poisoning usually present with a mixed respiratory alkalosis and metabolic acidosis. However, respiratory alkalosis may be transient in children such that metabolic acidosis may occur early in the course. Patients with mixed acid-base disturbances have been found to have normal anion-gap metabolic acidosis; therefore, normal anion-gap acidosis does not exclude salicylate.
Salicylates are weak acids that may produce metabolic acidosis through various mechanisms. In toxic concentrations, salicylates interfere with energy production by uncoupling oxidative phosphorylation and may produce renal insufficiency that causes accumulation of phosphoric and sulfuric acids. The metabolism of fatty acids is likewise increased in patients with salicylate toxicity, generating ketone body formation. These processes all contribute to the development of an elevated anion gap metabolic acidosis in patients with salicylate poisoning.
Respiratory system effects
Salicylates cause both direct and indirect stimulation of respiration. A salicylate level of 35 mg/dL or higher causes increases in both rate (tachypnea) and depth (hyperpnea). Salicylate poisoning may cause noncardiogenic pulmonary edema (NCPE) in a few patients. Although the exact etiology is not known, hypoxia is considered a major factor.
Glucose metabolism
Increased cellular metabolic activity due to uncoupling of oxidative phosphorylation may produce clinical hypoglycemia, although the serum glucose levels are within reference range. As intracellular glucose is depleted, the salicylate may produce discordance between levels of plasma and cerebrospinal fluid (CSF) glucose.
Fluid and electrolyte effects
Salicylate poisoning may result in dehydration because of increased GI tract losses (vomiting) and insensible fluid losses (hyperpnea and hyperthermia). All patients with serious poisoning are more than 5-10% dehydrated. Renal clearance of salicylate is decreased by dehydration. Hypokalemia and hypocalcemia can occur as a result of primary respiratory alkalosis.
CNS effects
Salicylates are neurotoxic, which manifests as tinnitus, and ingestion can lead to hearing loss at doses of 20-45 mg/dL or higher. CNS toxicity is related to the amount of drug bound to CNS tissue. Other signs and symptoms include nausea, vomiting, hyperpnea, and lethargy, which can progress to disorientation, seizures, cerebral edema, hyperthermia, coma, and, eventually, death.
GI tract effects
Nausea and vomiting are the most common effects. Pylorospasm and decreased GI tract motility can occur with large doses.
Hepatic effects
Hepatitis can occur in children ingesting doses at or above 30.9 mg/dL.3 Reye syndrome is another form of pediatric salicylate-induced hepatic disease characterized by nausea, vomiting, hypoglycemia, elevated levels of liver enzymes and ammonia, fatty infiltration of the liver, increased intracranial pressure, and coma.
Hematologic effects
Hypoprothrombinemia and platelet dysfunction are the most common effects. Bleeding may also be promoted either by inhibition of vitamin K–dependent enzymes or by the formation of thromboxane A2.
Musculoskeletal effects
Rhabdomyolysis can occur because of dissipation of heat and energy resulting from oxidative phosphorylation uncoupling.
Clinical and laboratory manifestations
- Phase 1 of the toxicity is characterized by hyperventilation resulting from direct respiratory center stimulation, leading to respiratory alkalosis and compensatory alkaluria. Both potassium and sodium bicarbonate are excreted in the urine. This phase may last as long as 12 hours.
- In phase 2, paradoxic aciduria in the presence of continued respiratory alkalosis occurs when sufficient potassium has been lost from the kidneys. This phase may begin within hours and may last 12-24 hours.
- Phase 3 includes dehydration, hypokalemia, and progressive metabolic acidosis. This phase may begin 4-6 hours after ingestion in a young infant or 24 hours or more after ingestion in an adolescent.
Nausea, vomiting, diaphoresis, and tinnitus are the earliest signs and symptoms of salicylate toxicity. Other early effects include vertigo, hyperventilation, hyperactivity, agitation, delirium, hallucination, convulsion, lethargy, and stupor. Hyperthermia is an indication of severe toxicity.
Mortality/Morbidity
According to the Toxic Exposures Survey from the American Association of Poison Control Centers, 24% of analgesic-related deaths are due to aspirin alone or aspirin in combination with other drugs. Early identification of salicylate poisoning can be lifesaving.
Clinical
History
- When possible, elicit the following information:
- Type of salicylate
- Amount
- Approximate time of ingestion
- Possibility of long-term ingestion
- Potential co-ingestants
- Presence of other medical conditions (eg, cardiac, renal diseases)
- Treatment should not be withheld in symptomatic patients because of pending serum level tests. The presence of tinnitus is a clue for salicylate ingestion. Tachypnea, tachycardia, and elevated temperature can be detected by evaluating vital signs.
Causes
Salicylate toxicity continues to be seen in emergency department as a result of unintentional ingestion or suicide attempt. Prompt recognition of clinical signs and symptoms and a high index of suspicion can prevent organ damage and death.
Oral ingestion of a large amount of acetylsalicylate, given for treatment of ear pain, has resulted in severe metabolic derangements and death. Brain histopathology revealed sparse grey matter changes and acute white matter damage.4
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References
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Further Reading
Keywords
salicylate toxicity, salicylic toxicity, aspirin, oil of wintergreen, salicylic acid, salicylate toxicity, salicylate poisoning, salicylate intoxication, aspirin overdose, analgesic overdose, tinnitus, bedside ferric chloride testing, activated charcoal, methyl salicylate, Pepto-Bismol, Ben-Gay, respiratory alkalosis, ketosis, wide anion-gap metabolic acidosis, noncardiogenic pulmonary edema, hypoxia, dehydration, tinnitus, cerebral edema, hyperthermia, pylorospasm, hepatitis, Reye syndrome, hypoprothrombinemia, rhabdomyolysis
