The widespread availability of aspirin or acetylsalicylic acid in prescription and over-the-counter preparations can lead to both accidental and intentional toxicity. Morbidity and mortality increase significantly when the condition is not rapidly identified, if there is a delay to starting treatment, or if poisoned patients are not treated aggressively.

In additional to aspirin oral preparations, numerous forms of salicylate are available as karyolitic agents, liniments, flavoring agents, and combination products. These products may contain salicylate, methyl salicylate, or acetylsalicylic acid, but regardless of the product, all formulations are rapidly converted to salicylate once ingested.¹ Five mL of oil of wintergreen contains 7 g of aspirin and can be deadly to a toddler. Liniments and products used in hot vaporizers have high concentrations of methyl salicylate, and an ingestion of 5 to 10 mL can be lethal for an infant or a toddler.² Even though salicylate is poorly absorbed after ingestion of bismuth subsalicylate (Peptobismol^®), significant exposures can occur from massive ingestions, such as in patients with human immunodeficiency virus/acquired immunodeficiency syndrome taking this medication for chronic diarrhea.³

After ingestion of therapeutic doses in standard tablet formulation, absorption is variable and dependent on dosage form, presence of food, and gastric pH, with peak salicylate levels usually occurring in 1 to 2 hours. In overdose, peak serum salicylate concentrations may not be reached for hours. Enteric-coated aspirin exhibits erratic absorption in therapeutic doses, and peak levels may be delayed for hours after an overdose.⁴ Salicylate itself impairs gastric emptying, which may account for delayed absorption in some cases⁵ and create the potential for gastric bezoar formation, which can provide an additional source of ongoing absorption.⁶ Ingestion of methyl salicylate or other liquid formulations may have much more rapid absorption and achieve peak levels more rapidly.

After absorption, aspirin is hydrolyzed to salicylic acid (salicylate) and is distributed throughout body tissues with 50% to 80% being bound to serum proteins. As salicylate concentrations increase and saturate protein-binding sites, free (unbound) concentrations of salicylate increase. In solution, salicylate exists in equilibrium between the ionized and nonionized state; only the unbound, nonionized salicylate can readily cross cell membranes. At physiologic pH (7.40), almost all salicylate is ionized, but acidemia will increase the nonionized fraction, enabling more salicylate to cross cell membranes and, importantly, substantially increasing brain salicylate concentration.⁷ Patients with identical total salicylate serum concentrations may vary greatly in their degree of toxicity depending on their tissue burden, plasma protein concentrations, pH, and other factors.

Salicylate undergoes hepatic metabolism; however, this process rapidly becomes saturated even within the therapeutic ranges of drug use and changes to zero order kinetics; a set amount of salicylate is eliminated per unit of time.⁸ Increased fraction of unbound salicylate also enhances renal clearance, making the kidney the major route of elimination during toxicity. Nonionized salicylate can be resorbed by renal tubules. Serum alkalinization can be used to keep salicylate in the plasma compartment and out of tissues, and urinary alkalinization can be used to enhance renal elimination. If the urine pH is above 7.5, more salicylate molecules in the urine will be ionized compared with the renal tubular cell pH of 7.4, and reabsorption across the urinary tubule will be reduced. This pH difference will also enhance secretion of nonionized salicylate down the concentration gradient.

Salicylate toxicity affects many physiologic systems (Table 189-1).

Salicylate directly stimulates the medullary respiratory center to produce tachypnea, hyperpnea, and respiratory alkalosis.⁹ As toxicity worsens, inhibition of metabolism produces an acidosis that overwhelms the alkalosis. Classically the acid-base disturbance associated with salicylate poisoning is mixed: early respiratory alkalosis, followed by an elevated anion gap metabolic acidosis, and possibly late respiratory acidosis. Co-ingestion or administration of CNS depressants may blunt this initial respiratory stimulation. Salicylate stimulates skeletal muscle metabolism, which causes an increase in oxygen consumption and carbon dioxide production. Neurologic toxicity may impair ventilation so that it is unable to keep pace with increased carbon dioxide production, leading to respiratory acidosis—usually a late and ominous finding. Decreased ventilation can also be related to co-ingestions or iatrogenic medication.

Salicylate affects both central and peripheral glucose homeostasis. Although salicylate causes mobilization of glycogen stores, resulting in hyperglycemia, it is also a potent inhibitor of gluconeogenesis. Therefore, normoglycemia is the most common finding, hyperglycemia can occur, and hypoglycemia is a rare possibility during toxicity.¹⁰ Animal studies demonstrate that toxic doses of salicylate produce a profound decrease in brain glucose concentration despite normal serum glucose concentrations.^7,11 This suggests that a patient may be relatively neuroglucopenic even if the blood glucose is normal.

Salicylate can cause corrosive injury of the GI tract with abdominal pain, nausea, and vomiting and occasional hematemesis. This can all lead to volume loss, metabolic alkalosis, and hypokalemia. Gastric perforation has been reported after significant aspirin ingestion.¹² Salicylate-induced acute lung injury (noncardiogenic pulmonary edema) has been observed in humans. Antiplatelet activity is a well-known, often desired effect of aspirin (but not other salicylate products), but hemorrhage is a rare complication of acute, single, massive overdose. Large doses of all salicylates may cause significant hypoprothrombinemia resulting from inhibition of vitamin K–dependent functions.¹³

Salicylate ototoxicity is common, and tinnitus often occurs with levels >20 milligrams/dL (1.4 millimol/L). Although classically described as tinnitus or “ringing in the ears,” in practice most patients will describe decreased sounds or that their hearing is “muffled.” The exact mechanism causing this is unknown, and hearing effects are not permanent. Cardiac arrhythmias are a rare complication of salicylate poisoning.¹⁴

Clinical manifestations of salicylate toxicity depend on the dose ingested, duration of exposure, age, and comorbidities of the patient.^7,15 In children and the elderly, end-organ toxicity can be seen with smaller doses and lower serum levels following an acute overdose. Chronic toxicity can produce insidious and severe neurologic changes that do not correlate well with dose or serum salicylate level. Patients with even a mild toxicity can become critically and severely ill if acidemia or dehydration develops.

INTOXICATION IN CHILDREN

In general, when the duration of salicylate intoxication is between 12 to 24 hours, metabolic acidosis and acidemia (pH <7.35) occur primarily in children <4 years old, and nearly all children <1 year old have acidosis. Young children can have a respiratory alkalosis, but this is often transient and missed because of their smaller ventilatory reserves.¹⁶ In older children (>4 years old), the acid-base disturbance is usually a mixed disturbance with respiratory alkalosis, increased anion gap metabolic acidosis, and alkalemia (pH >7.45).

Chronic or “therapeutic” (repeated dose) pediatric salicylate poisonings are more serious and are associated with a higher mortality than acute salicylism.^7,15,17 Often, several days may elapse between the initial salicylate administration and the onset of symptoms. There is frequently a coincidental illness that prompted salicylate administration, and children usually appear more ill than those with acute intoxication. The presenting features are usually fever, hyperventilation, and altered mental status with volume depletion, acidosis, and severe hypokalemia.¹⁵ Young children are prone to hyperpyrexia, which indicates a worse prognosis.¹⁷ Renal failure may be a significant complication, but pulmonary edema is unusual in the pediatric population.^15,17 Chronic salicylism is often mistaken for an infectious process, and the resultant delay in diagnosis may account for the more severe clinical picture.

The diagnosis may be delayed if a history of salicylate ingestion is not available. The differential diagnosis includes diabetic ketoacidosis, sepsis, iron intoxication, and toxic alcohol poisoning.

INTOXICATION IN ADULTS

Acute salicylate intoxication in adults is often due to intentional ingestion. The typical clinical presentation includes nausea, vomiting, tinnitus, hearing loss, sweating, and hyperventilation. Patients with tinnitus or hearing loss following an acute ingestion usually have an elevated serum salicylate value.¹⁸

Most adult patients with acute salicylate overdose have a mixed acid-base disturbance of alkalemia with respiratory alkalosis and metabolic acidosis. As toxicity progresses, acidosis worsens. CNS dysfunction manifests as agitation, lethargy, confusion, seizure, or coma. CNS dysfunction leading to cerebral edema is an ominous development and a sign of severe toxicity, requiring rapid and aggressive treatment.^7,19 Despite treatment and decreasing serum salicylate levels, patients may worsen and die from progressive neurologic impairment, possibly because of increasing CNS salicylate levels.