Salicylate Toxicity: Practice Essentials, Etiology and Pathophysiology, Epidemiology (original) (raw)

Overview

Practice Essentials

Salicylates are ubiquitous agents found in hundreds of over-the-counter (OTC) medications and in numerous prescription drugs, making salicylate toxicity an important cause of morbidity and mortality. [1, 2, 3, 4]

Salicylates are used as analgesic agents for the treatment of mild to moderate pain. Aspirin is used as an antipyretic and as an anti-inflammatory agent for the treatment of soft tissue and joint inflammation and vasculitides such as acute rheumatic fever and Kawasaki disease. Aspirin is also used to treat acute coronary syndrome. Low-dose aspirin helps to prevent thrombosis.

Acetylsalicylic acid is colorless or white in crystalline, powder, or granular form. The chemical is odorless and is soluble in water. Salicylate is available for ingestion as tablets, capsules, and liquids. Salicylate is also available for topical application, in creams or lotions.

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 unintentional and suicidal ingestion.

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 annually in the United States. 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 non-aspirin salicylate per 15 mL).

Ingestion of topical products containing salicylates (eg, Ben-Gay, salicylic acid [keratolytic], oil of wintergreen or methyl salicylate), can cause severe salicylate toxicity. According to published sources, one teaspoon of 98% methyl salicylate contains as much as 7000 mg of salicylate, the equivalent of nearly 90 baby aspirins and more than 4 times the potentially toxic dose for a child who weighs 10 kg. [5, 6]

Salicylate toxicity has been reported with the topical use of salicylate-containing teething gels in infants. [7] Based on a literature review, Greene et al estimated the allowable daily intake of methyl salicylate to be 11 mg/kg/d. [8]

A comprehensive review of the existing medical literature on methyl salicylate poisoning has determined that it is a relatively common source of pediatric exposure. [9] In younger children, most of these exposures are accidental. In a study of 599 cases of salicylate exposure in children less than 6 years old, the majority of children with signs of salicylate toxicity (metabolic acidosis, tachypnea) were exposed to liquid preparations. [10] Intentional ingestions are much more common in adolescents.

The prevalence of alternative medicines and the 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 a constipation reliever. A case of neonatal salicylate poisoning due to the use of this medicine to relieve colic has been reported. [11] Percy Medicine is available OTC, and parents should be educated that salicylate-containing products are not routinely recommended for children aged 1 year or younger.

Although concentrations of salicylate persist following ingestion of aspirin tablets, it has been shown that salicylate concentrations typically decline following ingestion of salicylate as acetylsalicylic powder. In one study, salicylate concentrations increased or changed insignificantly in 50% of patients who had ingested tablets, but following powder ingestions, concentrations declined in 94% of cases. [12]

Phases and symptoms of salicylate toxicity

The acid-base, fluid, and electrolyte abnormalities seen with salicylate toxicity can be grouped into three phases. (See Presentation and Workup.)

Phase 1 of the toxicity is characterized by hyperventilation resulting from direct respiratory center stimulation, leading to respiratory alkalosis and compensatory alkaluria. Potassium and sodium bicarbonate are excreted in the urine. This phase may last as long as 12 hours.

In phase 2, paradoxical aciduria occurs when sufficient potassium has been lost from the kidneys in the presence of continued respiratory alkalosis. This phase may begin within hours and 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 or adult.

Nausea, vomiting, diaphoresis, and tinnitus [13] are the earliest signs and symptoms of salicylate toxicity. Other early symptoms and signs are vertigo, hyperventilation, tachycardia, and hyperactivity. As toxicity progresses, agitation, delirium, hallucinations, convulsions, lethargy, and stupor may occur. Hyperthermia is an indication of severe toxicity, especially in young children.

Treatment

A high index of suspicion of salicylate toxicity is necessary, with prompt recognition of clinical signs and symptoms of salicylate poisoning, such as tinnitus, hyperventilation, tachycardia, and metabolic acidosis. [3] Early treatment can prevent organ damage and death. Treatments include stabilizing the ABCs as necessary, limiting absorption, enhancing elimination, correcting metabolic abnormalities, and providing supportive care. No specific antidote is available for salicylates. No specific antidote is available for salicylate toxicity. However, alkalinization of the urine and serum with sodium bicarbonate is crucial to management. [14]

Etiology and 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 central nervous system (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

The toxic effects of salicylates are complex. Respiratory centers are directly stimulated, causing hyperventilation that results in primary respiratory alkalosis. Salicylates also cause an inhibition of the citric acid cycle and an uncoupling of oxidative phosphorylation and may produce kidney insufficiency that causes the accumulation of phosphoric and sulfuric acids. The metabolism of fatty acids is likewise increased, generating ketone body formation. These processes all contribute to the development of an elevated anion-gap metabolic acidosis. This combination of primary respiratory alkalosis and primary metabolic acidosis is characteristic of salicylate poisoning, especially in adults. It should make the clinician suspect the diagnosis when it is present. [14]

Catabolism occurs secondary to the inhibition of adenosine triphosphate (ATP) ̶ dependent reactions, with the following results:

Increased oxygen consumption
Increased carbon dioxide production
Accelerated activity of the glycolytic and lipolytic pathways
Depletion of hepatic glycogen
Hyperpyrexias

Adults with acute poisoning usually present with mixed respiratory alkalosis and metabolic acidosis. However, respiratory alkalosis may be transient in children, so metabolic acidosis may occur early in the course. Some 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 toxicity.

Respiratory system effects

Salicylates cause direct and indirect stimulation of respiration. A salicylate level of 35 mg/dL or higher causes increases in rate (tachypnea) and depth (hyperpnea) of respiration. Salicylate poisoning may rarely cause noncardiogenic pulmonary edema (NCPE) and acute lung injury in pediatric patients. It is more common in elderly patients with chronic salicylate toxicity. Although its exact etiology is not known, its consequence is severe hypoxia, necessitating treatment with high concentrations of oxygen. It also makes adequate hydration and sufficient administration of sodium bicarbonate difficult. Pulmonary edema has extremely high mortality in both children and adults; if present, hemodialysis should be considered as soon as possible. [14]

Glucose metabolism

Increased cellular metabolic activity due to uncoupling of oxidative phosphorylation may produce clinical hypoglycemia, although the serum glucose levels may sometimes be within the normal range. As intracellular glucose is depleted, the salicylate may produce discordance between plasma and cerebrospinal fluid (CSF) glucose levels, so symptoms of CNS hypoglycemia (eg, altered mental status) may occur even when blood glucose levels are within the reference range. [14]

Fluid and electrolyte effects

Salicylate poisoning may result in dehydration because of increased gastrointestinal (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. The initial manifestation of this is tinnitus, which helps differentiate salicylate toxicity from other diseases that cause acidosis, such as diabetic ketoacidosis, sepsis, theophylline poisoning, and alcoholic ketoacidosis. Significant ingestion can lead to hearing loss at serum levels of 30-45 mg/dL or higher. Other signs and symptoms of CNS toxicity include nausea, vomiting, hyperpnea, and lethargy.

CNS toxicity from salicylates is related to the amount of drug bound to CNS tissue. It is more common with chronic than acute toxicity. Acidosis worsens CNS toxicity by increasing the amount of salicylate that crosses the blood-brain barrier and increases CNS tissue levels. Severe toxicity can progress to disorientation, seizures, cerebral edema, hyperthermia, coma, cardiorespiratory depression, and, eventually, death.

In one case report of fatal acute acetylsalicylate toxicity in a 34-year-old oligophrenic woman, brain histopathology revealed acute white matter damage, with myelin disintegration and caspase-3 activation in glial cells. Only sparse changes in grey matter were noted. [15]

GI tract effects

Nausea and vomiting are the most common toxic effects. This can be caused by CNS toxicity or by direct damage to the gastric mucosa. Salicylates can disrupt the mucosal barrier and occasionally cause GI bleeding. [16] Large overdoses of salicylates can also cause spasms of the pyloric valve, decreased GI tract motility, and bezoar formation. These effects slow elimination and increase salicylate absorption from the GI tract.

Hepatic effects

Hepatitis can occur in children ingesting doses at or above 30.9 mg/dL. [17] Reye syndrome is another form of pediatric salicylate-induced hepatic disease. It is 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 formation of thromboxane A2.

Salicylates cause a dose-dependent inhibition of clotting factor II, VII, IX, and X activation. In a retrospective study, duration of elevated salicylate concentration and impaired kidney function were associated with coagulopathy. [18]

Musculoskeletal effects

Rhabdomyolysis can occur because of the dissipation of heat and energy resulting from oxidative phosphorylation uncoupling.

Epidemiology

Occurrence in the United States

According to the American Association of Poison Control Centers' National Poison Data System, 7160 single exposures to acetylsalicylic acid, alone or in combination with other drugs, were reported in 2022, along with 2625 single exposures to methyl salicylate. About 3004 of these exposures were intentional. Over 177 exposures resulted in major outcomes, and 18 fatal cases were noted. [1]

Generally, the degree of the toxicity is more severe in elderly individuals and infants, as well as in persons with coexisting morbidity or chronic intoxication.

Acid-base disturbances vary with age and severity of the intoxication. Infants rarely present with pure respiratory alkalosis. Respiratory alkalosis may not develop in an infant or it may be short-lived. The most common presentation for a child is metabolic acidosis.

Factors contributing to a decline in the incidence of pediatric salicylate intoxication include increased acetaminophen and ibuprofen use and child-resistant packaging.

Prognosis

A 16% morbidity rate and a 1% mortality rate have been reported in patients presenting with an acute salicylate overdose. The incidences of morbidity and mortality for patient with chronic intoxication are 30% and 25%, respectively. Early identification of salicylate poisoning and the expeditious institution of appropriate treatment can be lifesaving.

Categories of toxicities

The following four categories are helpful for assessing the potential severity and morbidity of an acute, single-event, non–enteric-coated salicylate ingestion:

Less than 150 mg/kg ingested - Spectrum ranges from no toxicity to mild toxicity
From 150-300 mg/kg ingested - Mild-to-moderate toxicity
From 301-500 mg/kg ingested - Serious toxicity
Greater than 500 mg/kg ingested - Potentially lethal toxicity

Patient Education

Advise patients and their families that the use or overuse of seemingly benign OTC medications is sometimes dangerous. The ready availability of aspirin and aspirin-containing products does not establish the safety of aspirin.

For patient education information, see Aspirin Poisoning and Poison Proofing Your Home.

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Author

Muhammad Waseem, MBBS, MS, FAAP, FACEP, FAHA Professor of Emergency Medicine and Clinical Pediatrics, Weill Cornell Medical College; Attending Physician, Departments of Emergency Medicine and Pediatrics, Lincoln Medical and Mental Health Center; Adjunct Professor of Emergency Medicine, Adjunct Professor of Pediatrics, St George's University School of Medicine, Grenada

Muhammad Waseem, MBBS, MS, FAAP, FACEP, FAHA is a member of the following medical societies: American Academy of Pediatrics, American Academy of Urgent Care Medicine, American College of Emergency Physicians, American Heart Association, American Medical Association, Association of Clinical Research Professionals, Public Responsibility in Medicine and Research, Society for Academic Emergency Medicine, Society for Simulation in Healthcare