Introduction
Background
The use of salicylates dates back 2500 years to when Hippocrates recommended the use of willow bark to relieve the pain of childbirth. Salicylic acid is the extract from willow bark that produces the analgesic effect. Today, salicylates are used in many over-the-counter and prescription medications for their analgesic, anti-inflammatory, and antipyretic properties. Aspirin (acetylsalicylic acid)–containing products are the most commonly found salicylates. Sources of salicylate poisoning include aspirin overdose and excessive topical application or ingestion of ointments that contain methyl salicylate (oil of wintergreen). Salicylate ingestion was a common cause of poisoning and death in children in the United States prior to the 1970s, when legislation was passed that required childproof packaging on medications. Despite the reduction of poisonings due to repackaging, salicylate toxicity remains a significant cause of morbidity and mortality.
Pathophysiology
Acid-base disturbances, electrolyte abnormalities, and central nervous system effects characterize salicylate poisoning. The wide range of toxic effects varies depending on the age of the patient and whether the ingestion is chronic or acute.
Metabolic effects
In salicylate toxicity, as salicylate levels increase, the acid-base disturbance progresses from respiratory alkalosis to mixed respiratory alkalosis and metabolic acidosis. In children, the progression to metabolic acidosis occurs more rapidly. Salicylates directly stimulate respiratory centers in the medulla, causing hyperventilation and, subsequently, respiratory alkalosis. Salicylates also cause the uncoupling of oxidative phosphorylation, which leads to decreased adenosine triphosphate production, increased oxygen consumption, increased carbon dioxide production, and increased heat production. Derangement in the Krebs cycle and in carbohydrate metabolism leads to an accumulation of organic acids, including pyruvate, lactate, and acetoacetate, causing metabolic acidosis.
Toxic levels of salicylates also displace large amounts of plasma bicarbonate, worsening the metabolic acidosis. The metabolic acidosis in salicylate poisoning is an anion gap acidosis, Na+ - (Cl- +HCO3 -) greater than 14 mEq/L. Other causes of anion gap metabolic acidosis that can be confused with or can coexist with salicylate toxicity include diabetic ketoacidosis, renal failure, lactic acidosis, and volatile alcohol overdose (methanol, ethylene glycol).
Fluid and electrolyte effects
Increased metabolic rate, pyrexia, tachypnea, and vomiting lead to fluid loss and dehydration. Compensation for respiratory alkalosis leads to increased renal excretion of bicarbonate and increased excretion of sodium and potassium. Because of significant water losses, hyponatremia might not be present; however, hypokalemia is prominent.
Central nervous system effects
Toxic effects in the CNS range from mild confusion to coma. The exact mechanism that produces CNS toxicity is not known, but the degree of CNS effects, as well as overall mortality, correlates with the concentration of salicylates in brain tissue. Acidemia increases the nonionized form of salicylates, allowing for movement across the blood-brain barrier and, therefore, increasing CNS toxicity.
Gastrointestinal effects
Salicylate ingestion can cause nausea, vomiting, and abdominal pain. Salicylate stimulation of medullary chemoreceptors and local irritation of the GI tract produce emesis. Upper GI ulceration and bleeding can occur. Gastrointestinal effects are much more prominent in acute ingestion.
Ototoxicity
Salicylate toxicity results in a reversible ototoxicity characterized by tinnitus, deafness, and dizziness.
Pulmonary effects
Noncardiogenic pulmonary edema is the most common cause of major morbidity and might be related to an increase in the permeability of pulmonary vasculature caused by salicylates. Acute respiratory distress syndrome is more prominent in chronic ingestions than in acute ingestions.
Hematological effects
Salicylates inhibit vitamin K–dependent synthesis of factors II, VII, IX, and X, leading to a prolonged prothrombin time. Salicylates prolong bleeding time by inhibiting a prostaglandin-initiated sequence required for platelet aggregation.
Hepatic effects
Dose-dependent hepatotoxicity can occur with salicylate poisoning. A small percentage of patients might develop hepatitis, but most develop an asymptomatic elevation of transaminases.
Renal effects
Acute renal failure has rarely been reported.
Mortality/Morbidity
Mortality rates vary with chronicity of exposure. Compared with acute toxicity, chronic toxicity carries higher morbidity and mortality rates and is more difficult to treat.
- Acute overdose - Mortality rate of less than 2%
- Chronic overdose - Mortality rate as high as 25%
Clinical
History
- Acute ingestion is associated with the following factors:
- History of suicide attempts involving teens and adults and of accidental ingestion by children
- Possible asymptomatic early presentation
- Nausea, vomiting, hematemesis
- Diaphoresis and fever
- Epigastric pain
- Tinnitus
- CNS effects generally presenting later in the toxicity course
- Chronic ingestion is associated with the following factors:
- Change in mental status in elderly patients, prompting medical evaluation
- Prominent CNS symptoms, including confusion, disorientation, hallucinations, lethargy, seizures, and coma
- The long-term treatment of children with inappropriate dosing of salicylates
Physical
- Vital signs
- Fever
- Increased respiratory rate
- Tachycardia
- Pulmonary manifestations
- Tachypnea
- Respiratory arrest
- Cardiovascular manifestations
- Dysrhythmias (premature ventricular contractions; ventricular tachycardia, fibrillation, or both)
- Hypotension and shock
- Gastrointestinal manifestations (more prominent in acute intoxication)
- Epigastric tenderness
- Emesis or hematemesis
- Neurologic manifestations
- Confusion, disorientation, hallucinations
- Lethargy
- Seizures
- Coma
Causes
- Accidental ingestion
- Suicide attempt
- Inappropriate dosing of salicylates in children and elderly people
More on Toxicity, Salicylate |
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| Follow-up: Toxicity, Salicylate |
| References |
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References
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Proudfoot AT. Toxicity of salicylates. Am J Med. Nov 14 1983;75(5A):99-103. [Medline].
Temple AR. Acute and chronic effects of aspirin toxicity and their treatment. Arch Intern Med. Feb 23 1981;141(3 Spec No):364-9. [Medline].
Wood DM, Dargan PI, Jones AL. Measuring plasma salicylate concentrations in all patients with drug overdose or altered consciousness: is it necessary?. Emerg Med J. Jun 2005;22(6):401-3. [Medline].
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Further Reading
Keywords
salicylate poisoning, salicylate toxicity, salicylate overdose, salicylic acid, analgesic toxicity, anti-inflammatory, antipyretic, electrolyte abnormality, acid-base disturbance, acute salicylate toxicity, chronic salicylate toxicity, acute salicylate overdose, chronic salicylate overdose, salicylate abuse, respiratory alkalosis, mixed respiratory alkalosis, metabolic acidosis, anion gap metabolic acidosis, dehydration, fever, hyperventilation, tachycardia, hematemesis, tinnitus, dysrhythmia, ventricular tachycardia, ventricular fibrillation, hypokalemia, hypoglycemia, urinary alkalinization, serum alkalinization, hemodialysis
