Salicylate toxicity

Salicylate toxicity or poisoning, also known as aspirin poisoning, is the acute or chronic poisoning with a salicylate such as aspirin.

Salicylates are rapidly absorbed through the gastric mucosa with peak blood levels typically occurring within one hour after ingestion, but may be reached more slowly with enteric-coated and extended release preparations.

After absorption 90% of the salycilate molecules are protein bound. 

Salicylates are metabolized in the liver to salicyluric acid, which is then excreted through the kidney. 

Overdose and toxicity lead to peak levels that are higher and occur later which may saturated hepatic detoxification mechanisms, increasing the level of non-protein bound molecules in the circulation and prolonging half-life from 2 to 4 hours to up to 30 hours. 

Unbound molecules are excreted through the kidneys, but are rapidly reabsorbrd through the epithelium and renal collecting tubule, which exacerbates toxicity.

The classic symptoms are ringing in the ears, nausea, abdominal pain, and a fast breathing rate.

Early on, symptoms may be subtle, while larger doses may result in fever.

Complications can include swelling of the brain or lungs, seizures, low blood sugar, or cardiac arrest.

Symptoms: Ringing in the ears, nausea, abdominal pain, fast breathing rate.

Complications:  Swelling of the brain or lungs, seizures, low blood sugar, cardiac arrest.


Early: Slightly elevated blood aspirin levels ~ 2.2 mmol/L (30 mg/dL, 300 mg/L), respiratory alkalosis

Late: Metabolic acidosis

Differential diagnosis

Sepsis, heart attack, agitation.


Child-resistant packaging, low number of pills per package


~1% risk of death


> 20,000 per year in US.

Salycilate toxicity is usually due to aspirin, but other possible causes include oil of wintergreen and bismuth subsalicylate.

Excess doses can be either on purpose or accidental.

Small amounts of oil of wintergreen can be toxic.

Diagnosis is generally based on repeated blood tests measuring aspirin levels and blood gases.

In overdose maximum blood levels may not occur for more than 12 hours.

Efforts to prevent poisoning include child-resistant packaging and a lower number of pills per package.

Treatment may include activated charcoal, intravenous sodium bicarbonate with dextrose and potassium chloride, and dialysis.

Giving dextrose may be useful even if the blood sugar is normal.

Dialysis is recommended in those with kidney failure, decreased level of consciousness, blood pH less than 7.2, or high blood salicylate levels.

If a person requires intubation, a fast respiratory rate may be required.

About 1% of those with an acute overdose die, while chronic overdoses may have severe outcomes.

Older people are at higher risks of toxicity for any given dose.

Salicylate toxicity has potentially serious consequences, sometimes leading to significant morbidity and death. 

Patients with mild intoxication frequently have nausea and vomiting, abdominal pain, lethargy, ringing in the ears, and dizziness. 

More significant signs and symptoms occur in more severe poisonings and include high body temperature, fast breathing rate, respiratory alkalosis, metabolic acidosis, low blood potassium, low blood glucose, hallucinations, confusion, seizure, cerebral edema, and coma. 

The most common cause of death following an aspirin overdose is cardiopulmonary arrest usually due to pulmonary edema.

High doses of salicylate can cause salicylate-induced tinnitus.[8]

The severity of toxicity depends on the amount of aspirin taken.

SeverityMild (150 mg/kg)

Moderate (150–300 mg/kg)

Severe (300–500 mg/kg)


Nausea, vomiting, ringing in the ears, headache, confusion, hyperventilation, tachycardia, fever, delirium, hallucinations, seizures, coma, respiratory arrest.

High levels of salicylates stimulate peripheral chemoreceptors and the central respiratory centers in the medulla causing increased ventilation and a respiratory alkalosis.

The increased pH secondary to hyperventilation with respiratory alkalosis causes an increase in lipolysis and ketogenesis which causes the production of lactate and organic keto-acids: accumulation of these organic acids can cause an acidosis with an increased anion-gap as well as a decreased buffering capacity of the body.

Salicylate toxicity uncouples oxidative phosphorylation and a decrease in citric acid cycle activity in the mitochondria.

As a result there is a decrease in aerobic production of adenosine triphosphate (ATP) is accompanied by an increase in anaerobic production of ATP through glycolysis which leads to glycogen depletion and hypoglycemia.

The inefficient ATP production through anaerobic metabolism causes the body to shift to a catabolic predominant mode for energy production with increased oxygen consumption, increased heat production, sweating, liver glycogen utilization and increased carbon dioxide production.

This increased catabolism accompanied by hyperventilation can lead to severe insensible water losses, dehydration and hypernatremia.

Acute aspirin or salicylates overdose or poisoning can cause initial respiratory alkalosis, followed by  metabolic acidosis.

 The acid-base, fluid, and electrolyte abnormalities observed in salicylate toxicity can be grouped into three broad phases:

Phase I is characterized by hyperventilation resulting from direct respiratory center stimulation, leading to respiratory alkalosis and compensatory alkaluria. 

In phase 1 potassium and sodium bicarbonate are excreted in the urine. 

Phase 1 may last as long as 12 hours.

Phase II is characterized by paradoxic aciduria in the presence of continued respiratory alkalosis occurs when sufficient potassium has been lost from the kidneys. 

Phase II may begin within hours and may last 12–24 hours.

Phase III is characterized by dehydration, hypokalemia, and progressive metabolic acidosis. 

Phase III may begin 4–6 hours after ingestion in a young infant or 24 hours or more after ingestion in an adolescent or adult.


The acutely toxic dose of aspirin is generally considered greater than 150 mg per kg of body mass.

The diagnosis of poisoning usually involves measurement of plasma salicylate, the active metabolite of aspirin.

Moderate toxicity occurs at doses up to 300 mg/kg, severe toxicity occurs between 300 and 500 mg/kg, and a potentially lethal dose is greater than 500 mg/kg.

Chronic toxicity may occur following doses of 100 mg/kg per day for two or more days.

Evaluation includes monitoring electrolytes and solutes, liver and kidney function, urinalysis, and complete blood count,  along with frequent checking of salicylate and blood sugar levels. 

Arterial blood gas assessments typically find respiratory alkalosis early in the course of the overdose due to hyperstimulation of the respiratory center, and may be the only finding in a mild overdose. 

An anion-gap metabolic acidosis occurs later in the course of the overdose, especially if it is a moderate to severe overdose, due to the increase in protons, acidic contents, in the blood.

Plasma salicylate levels generally range from 30–100 mg/L (3–10 mg/dL) after usual therapeutic doses, 50–300 mg/L in patients taking high doses, and 700–1400 mg/L following acute overdose.

Plasma levels should be assessed four hours after ingestion and then every two hours after that to allow calculation of the maximum level, which can then be used as a guide to the degree of toxicity expected.


There is no antidote for salicylate poisoning.

Initial treatment of an overdose involves maintaining an adequate airway and adequate circulation followed by gastric decontamination by administering activated charcoal.

Activated charcoal adsorbs the salicylate in the gastrointestinal tract.

Inducing vomiting with syrup of ipecac is not a recommended strategy.

Repeated doses of activated charcoal may be beneficial in cases of salicylate poisoning, especially with enteric coated and extended release salicylic acid formulations which are able to remain in the gastrointestinal tract for long periods of time.

Repeated doses of activated charcoal are also useful to re-adsorb salicylates in the GI tract that may have desorbed from the previous administration of activated charcoal.

Using activated charcoal is most useful if given within 2 hours of initial ingestion.

Contraindications to the use of activated charcoal include:  altered mental status with the risk of aspiration, GI bleeding or poor gastric motility.

The use of the laxative polyethylene glycol can be useful to induce the gastrointestinal elimination of salicylates.

Alkalinization of the urine and plasma with sodium bicarbonate fluids, is an effective method to increase the clearance of salicylates from the body.

Alkalinization of the urine traps salicylates in renal tubules in their ionized form and then readily excreted in the urine:  increases urinary salicylate excretion by 18 fold.

Alkalinization of the plasma decreases the soluble form of salicylates facilitating movement out of the central nervous system.

Oral sodium bicarbonate alkalinization is contraindicated in salicylate toxicity as it can cause dissociation of salicylate tablets in the GI tract and subsequent increased absorption.

Intravenous fluids containing dextrose such as dextrose 5% in water (D5W) are recommended to keep a urinary output between 1 and 1.5 millilitres per kilogram per hour.

Sodium bicarbonate is given if there is a significant aspirin overdose regardless of the serum pH, as it enhances elimination of aspirin in the urine. 

It is given until a urine pH between 7.5 and 8.0 is achieved.

Hemodialysis can enhance the removal of salicylate from the blood, usually in those who are severely poisoned. 

Examples of severe poisoning include people with high salicylate blood levels: 7.25 mmol/L (100 mg/dL) in acute ingestions or 40 mg/dL in chronic ingestions.

Patients with severe salicylate toxicity have significant neurotoxicity (agitation, coma, convulsions), kidney failure, pulmonary edema, or cardiovascular instability.

Dialysis restores electrolyte and acid-base abnormalities while removing salicylate.

Salicylic acid has a small size low molecular mass, low volume of distribution, has low tissue binding and is largely free at toxic levels in the body; all of which make it easily removable by hemodialysis.

Indication for dialysis:

Salicylate level higher than 90 mg/dL

Severe acid base imbalance

Severe cardiac toxicity

Acute respiratory distress syndrome

Cerebral involvement/ neurological signs and symptoms

Rising serum salicylate level despite alkalinization/multidose activated charcoal, or people in which standard approaches to treatment ave failed

Unable to tolerate fluids with fluid overload

Acute salicylate toxicity usually occurs after an intentional ingestion.

Often younger adults with a history of psychiatric disease or previous overdose are involved.

With chronic toxicity, it occurs in older adults who experience inadvertent overdose while ingesting salicylates therapeutically over longer periods of time.

Salycilate are in oral medications, foods, herbs, supplements, and topical products, such as liniments and ointments.

1 teaspoon of some of products contains up to 7 g of salycilate, which is equivalent to the amount of 21 full dose tablets of the acetylsalicylic acid. 

Aspirin poisoning has been cited as a possible driver of the high mortality rate during the 1918 flu pandemic, which killed 50 to 100 million people.

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