toxicity of salicylate and acetylsalicylate (aspirin)

aspirin toxicity

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

Salicylate is used as an analgesic agent for the treatment of mild to moderate pain. Aspirin is used as an anti-inflammatory agent for the treatment of soft tissue and joint inflammation and vasculitides such as acute rheumatic fever and Kawasaki disease. The product is an antipyretic drug. 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 in the United States each year. 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 aspirins and more than 4 times the potentially toxic dose for a child who weighs 10 kg. Salicylate toxicity has been reported with the topical use of salicylate-containing teething gels in infants.^[1]

A comprehensive review of the existing medical literature on methyl salicylate poisoning has determined that it is a relatively common source of pediatric exposures.^[2] In younger children, most of these exposures are accidental. 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 used as a constipation reliever. A case of neonatal salicylate poisoning due to administration of this medicine as a colic reliever has been reported.^[3] It is available OTC, and parents should be educated that salicylate-containing products are not routinely recommended for children aged 1 year or younger.

Phases and symptoms of salicylate toxicity

The acid-base, fluid, and electrolyte abnormalities seen with salicylate toxicity can be grouped into phases

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, paradoxic aciduria in the presence of continued respiratory alkalosisoccurs 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 or adult.

Nausea, vomiting, diaphoresis, and tinnitus 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.

Other symptoms seen are.

• Mild poisoning causes nausea, vomiting, tinnitus, lethargy or dizziness.
• More severe poisoning causes dehydration, restlessness, sweating, warm extremities with bounding pulses, increased respiratory rate, hyperventilation and deafness.
• A degree of disturbance of acid-base balance is present in most cases.
• Hyperglycaemia, normoglycaemia or hypoglycaemia (all with intracellular glucose depletion) may occur.
• Uncommon features include haematemesis, hypokalaemia, hyponatraemia/hypernatraemia, hypocalcaemia, thrombocytopenia, abnormal blood coagulation (increased prothrombin ratio/INR), disseminated intravascular coagulation, acute kidney injury and non-cardiac pulmonary oedema.
• CNS: confusion, disorientation, coma and convulsions (less common in adults than in children).

Chronic salicylate poisoning^[2] 

• Chronic salicylate poisoning is more common in the elderly and requires lower levels of salicylate ingestion. Chronic salicylate toxicity often goes unrecognised.
• The onset of chronic salicylate poisoning may be insidious. An increasing amount of salicylate may be taken over several days to alleviate pain such as joint pain.
• Chronic salicylate poisoning may cause anxiety, tachypnoea, diffuse sweating, difficulty concentrating, confusion, hallucinations and even agitated delirium. Elderly individuals may present with a deterioration in functional status.
• Salicylate poisoning should be considered in the differential diagnosis of an adult patient with acid-base abnormalities of uncertain cause, especially when there are also neurological symptoms. 
• Delayed diagnosis results in increased morbidity and mortality, particularly in the elderly.

Investigations

• Plasma salicylate concentrations:^[1]
  
  • The severity of poisoning cannot be assessed from plasma salicylate concentrations alone and the clinical and biochemical features should also be considered.
  • Should be measured urgently for patients who are thought to have ingested more than 125 mg/kg of aspirin as well as those who have taken methyl salicylate or salicylamide.
  • The sample should be taken at least two hours (symptomatic patients) or four hours (asymptomatic patients) following ingestion, as it may take several hours for peak plasma concentrations to occur.
  • A repeat sample should be taken after a further two hours because of the possibility of continuing absorption. Measurements should be repeated every three hours until concentrations are falling.
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• Renal function and electrolytes, FBC, coagulation studies (raised INR/PTR), urinary pH, and blood glucose.
• Plasma potassium should be checked every three hours and plasma potassium levels maintained at between 4.0-4.5 mmol/L.
• Arterial blood gases (capillary gases or venous blood gases are alternatives in children): some degree of acid-base disturbance is present in most cases:
  • Adults and older children over the age of 4 years: mixed respiratory alkalosis and metabolic acidosis, with normal or high arterial pH.
  • Young children: metabolic acidosis is common.

Toxicity

The likelihood of toxicity can be gauged to a degree by:

• The ingested dose:^[1]
  • Greater than 125 mg/kg body weight: likely toxicity is mild.
  • Greater than 250 mg/kg body weight: likely toxicity is moderate.
  • Greater than 500 mg/kg body weight: likely toxicity is severe, possibly fatal.
• Salicylate concentration:
  • Severity of poisoning cannot be assessed from plasma salicylate concentrations alone but salicylate intoxication is usually associated with plasma concentrations greater than 350 mg/L (2.5 mmol/L). Most adult deaths occur in patients whose concentrations exceed 700 mg/L (5.1 mmol/L).
• Clinical grading:
  • Mild (nausea, vomiting, tinnitus).
  • Moderate (hyperventilation and confusion).
  • Serious (hallucinations, seizures, coma, cerebral oedema or pulmonary oedema).
• Acid-base staging:
  • Stage I: blood pH >7.4, urine pH >6.0 - respiratory alkalosis, increased urinary excretion of bicarbonate.
  • Stage II: blood pH >7.4, urine pH <6.0 - metabolic acidosis with compensating respiratory alkalosis, urinary hydrogen excretion, intracellular potassium depletion.
  • Stage III: blood pH <7.4, urine pH <6.0 - severe metabolic acidosis and hypokalaemia.

Patient education

Advise patients and their families that 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.

Management^[1]

Treatment must be in hospital where plasma salicylate, pH and electrolytes can be measured. Absorption of aspirin may be slow and the plasma-salicylate concentration may continue to rise for several hours, requiring repeated measurement of plasma-salicylate concentration.

• General measures for poisoning.
• Consider oral activated charcoal (50 g for an adult, 1 g/kg for a child) if ingested more than 125 mg/kg body weight salicylate less than one hour previously.
• A second dose of charcoal may be required in patients whose plasma salicylate level continues to rise or who have taken enteric-coated preparations (absorption may be slower).
• Gastric lavage if the patient has ingested more than 500 mg/kg body weight salicylate within one hour.
• Aggressive rehydration.
• Have a low threshold to give glucose, as intracellular glucose depletion may not be reflected in the blood glucose level.
• Urinary alkalinisation:
  
  • Elimination of salicylate may be increased by alkalinisation of the urine.^[3] The optimum urine pH is 7.5-8.5.
  • If the salicylate concentration in an adult is above 500 mg/L (3.6 mmol/L): 225 mmol sodium bicarbonate (225 mL of 8.4% over 60 minutes or 1.5 L of 1.26% over two hours).
  • If the salicylate concentration in a child is above 350 mg/L (2.5 mmol/L): 1 mL/kg 8.4% bicarbonate diluted in 0.5L 5% dextrose or normal saline at 2-3 mL/kg/hour.
  • The urinary pH should be checked hourly. Further amounts of sodium bicarbonate (8.4%) may be required to maintain the urine pH at 7.5-8.5.
  • Urinary alkalinisation does not need to be delayed while awaiting haemodialysis but volume overload must be avoided in a patient who is oliguric.
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• The plasma salicylate concentration should be repeated 1- to 2-hourly to ensure that treatment has been effective.
• Hypokalaemia:
  • May make alkalinisation of the urine less effective and it is important to recheck the plasma potassium 1- to 2-hourly and to give potassium if the plasma potassium falls below 4.0 mmol/L.
  • Hypokalaemia should be corrected before giving sodium bicarbonate.
• Forced diuresis: should not be used, as it does not enhance salicylate excretion and may cause pulmonary oedema.
• Haemodialysis is the treatment of choice for severe poisoning and should be seriously considered in patients with:^[1]
  • Plasma concentrations greater than 700 mg/L (5.1 mmol/L)
  • Acute kidney injury
  • Congestive cardiac failure
  • Non-cardiogenic pulmonary oedema
  • Coma
  • Convulsions
  • CNS effects not resolved by correction of acidosis
  • Persistently high salicylate concentrations unresponsive to urinary alkalinisation
  • Severe metabolic acidosis (pH below 7.2)
• Patients aged under 10 years or over 70 years have increased risk of salicylate toxicity and may require dialysis at an earlier stage.
• Haemofiltration is much less efficient than haemodialysis or haemodiafiltration, but may be an alternative in hospitals without dialysis facilities, especially if transfer is likely to be delayed.
• Mechanical ventilation:^[4] 
  • Endotracheal intubation may be indicated for deteriorating mental status or acute lung injury and should be considered in those with significant, uncontrollable agitation.
  • Hyperventilation is not itself an indication for intubation.
  • Endotracheal intubation and mechanical ventilation can be associated with rapid worsening of clinical salicylate toxicity and increased mortality unless a normal or slightly alkalaemic blood pH is maintained by hyperventilation (causing a low pCO₂) and/or intravenous sodium bicarbonate.

Prevention

 

• Small retail pack size.^[5] 
• Measures to prevent accidental overdose by children - eg, safe storage, child-proof caps.

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Further reading & references

1. Toxbase®
2. Pearlman BL, Gambhir R; Salicylate intoxication: a clinical review. Postgrad Med. 2009 Jul;121(4):162-8. doi: 10.3810/pgm.2009.07.2041.
3. British National Formulary
4. Management priorities in salicylate poisoning; American College of Medical Toxicology, June 2013
5. Hawton K, Simkin S, Deeks J, et al; UK legislation on analgesic packs: before and after study of long term effect on poisonings. BMJ. 2004 Nov 6;329(7474):1076. Epub 2004 Oct 29.