WikiTox

Overview

Salicylates are readily available and used as analgesics, antipyretics, and anti-inflammatory agents. Poisoning can result from acute overdose, chronic excessive use, or accidental ingestion.

Salicylate poisoning is relatively uncommon, as for many indications, NSAIDs have become the preferred agents. Most cases seen in hospitals are therefore a result of intentional overdose. The most common form available is aspirin (acetyl salicylate), but other available formulations include oil of wintergreen (methyl salicylate), analgesic and teething gels (choline salicylate) and topical preparations (salicylic acid).

Severe toxicity may result in mixed acid–base disorders, hyperventilation, CNS effects, and multi-organ failure. Treatment involves decontamination, serial monitoring of acid-base status and in more significant cases enhanced elimination techniques.

Mechanism Of Toxic Effects

The major feature of salicylate toxicity is uncoupling of oxidative phosphorylation which leads to:

Increased metabolic rate and heat production.
Increased oxygen consumption and CO2 formation.
Stimulation of the respiratory centre causing respiratory alkalosis and compensatory increased renal excretion of bicarbonate.
Increased glucose utilization.

The effects of toxicity are often exacerbated by accumulation of organic acid metabolites, starvation and dehydration-induced ketosis and lactic acidosis.

Other effects include:

Hypokaleamia due to increased renal excretion and intracellular shift.
Competitive inhibition of synthesis of vitamin K dependent clotting factors.

Risk Assessment

Acute toxicity is dose dependent, with the table below detailing the expected toxicity based on the aspirin dose ingested.

Other salicylates should be converted to aspirin equivalents. Methyl salicylate has an aspirin-dose-conversion factor of 1.4, meaning that as little as 4mL of oil of wintergreen (98% methyl salicylate) can cause severe toxicity in a small child.

Ingested aspirin dose	Toxic effects
<150mg/kg	Mild toxicity
150 to 300 mg/kg	Mild/moderate toxicity. Respiratory alkalosis with metabolic acidosis in more severe cases
300 to 500 mg/kg	Severe toxicity. Respiratory alkalosis, metabolic acidosis and CNS effects
>500mg/kg	Potentially fatal

Chronic toxicity may present following ingestion of more than 100mg/kg of aspirin per day, especially in the elderly or renally impaired patients.

Kinetics In Overdose

Absorption

Acetylsalicylic acid is a weak acid with a pKA of 3.5 and is rapidly absorbed and hydrolysed to salicylic acid and acetic acid. It is better absorbed from the acid environment of the stomach than from the alkaline small intestine.

Tablet dissolution may be extremely slow and in overdose pharmacobezoars (large tablet aggregates) may form which may lead to greatly delayed absorption.

Distribution

Salicylates are bound to albumin. The extent of protein binding is concentration dependent (and falls with higher blood concentrations). This, and the effect of acidosis decreasing ionisation, means that the volume of distribution increases markedly in overdose as does CNS penetration and adverse effects.

Metabolism

At therapeutic levels, salicylates undergo hepatic conjugation. In overdose, metabolic pathways become saturated, shifting elimination toward zero-order kinetics.

Elimination

Renal excretion is a major route of elimination. Alkalinisation increases ionised salicylate in urine, enhancing renal clearance. Elimination half-life increases from 2–3 h (therapeutic) to >20 h in overdose.

Clinical Effects

Gastrointestinal: nausea/vomiting, epigastric pain
CNS: tinnitus, dizziness and in severe toxicity agitation, seizures , coma
Metabolic: respiratory alkalosis (early), high anion gap metabolic acidosis (later and with more severe toxicity), hypokalaemia, hypoglycaemia, hyperthermia.
Haematological: mild coagulation abnormalities, antiplatelet effects
Other: acute kidney injury, non-cardiogenic pulmonary oedema

Chronic toxicity is rare and often misdiagnosed due to its insidious onset. It is mostly commonly seen in the elderly with clinical effects including delirium, dizziness, dehydration, fever, unexplained metabolic acidosis and coagulopathy.

Investigations

Serum salicylate concentrations: Serial measures every 4-6 hours to determine peak concentration, guide initiation of treatment, exclude ongoing absorption and monitor effectiveness of elimination efforts.
Bloods gas: Perform in all patients on presentation and every 4-6 hours whilst salicylate levels are being trended. Increase to every 2 hours during urinary alkalinisation.
Serum electrolyte and renal function
Dipstick urine: On fresh urine sample (ideally catheter tube sample) every 2 hours during urinary alkalinisation.

Treatment

Supportive care

Airway and breathing

Severe aspirin overdose may cause an altered level of consciousness which may impair airway or breathing and require intubation.

Minute ventilation in these patients is often very high, which helps compensate for the associated metabolic acidosis. If intubating a patient for aspirin toxicity, aim to maintain their minute ventilation to avoid precipitous worsening of acidosis.

Circulation

First-line treatment for hypotension should by intravenous fluid resuscitation. For patients with normal blood pressure, aim to maintain hydration by maintenance fluid provision. Ensure a normal potassium and glucose concentration are maintained by addition of these to the maintenance fluids based on serial measurements.

Hypoglycaemia

Monitor patient for hypoglycaemia and treat with intravenous dextrose if this occurs.

Seizures

In salicylate poisoining, intracellular glucose may be low despite normal bloods glucose concentration. Treat all patients presumptively with intravenous glucose bolus. If seizures persist or are recurrent treat along standard lines, starting with an intravenous benzodiazepine.

Decontamination

Aspirin absorption can be prolonged and erratic meaning that gastrointestinal decontamination may be effective for many hours following ingestion. For those ingestion >150mg/kg of aspirin (or equivalent) who are alert, co-operative and able to protect their airway , offer activated charcoal up to six hours post ingestion. In intubated patients, charcoal can be given anytime post ingestion.

Give: 50g Activated Charcoal (Child: 1g/kg, max 50g)

A second dose of activated charcoal should be offered 4 hour after the initial dose, if serum salicylate concentrations continue to rise.

Enhanced elimination

Urinary alkalinisation

Urinary alkalinisation increases the rate of salicylate renal clearance and can be used with the aim to reduce peak levels and speed clearance of salicylate from the serum. Indications for starting urinary alkalinization are:

Respiratory alkalosis (pCO2<30mmHg)
Metabolic acidosis
Serum salicylate concentration >500mg/L

Give: sodium bicarbonate 8.4% 1 mL/kg up to 100 mL (1 mmol/kg up to 100 mmol) intravenously over 30 to 60 minutes, as an initial dose

Followed by

sodium bicarbonate 25 mmol/hour (child: 0.5 mmol/kg /hour up to 25 mmol/hour) by intravenous infusion. To administer 25 mmol/hour of sodium bicarbonate , add 150 mL of sodium bicarbonate 8.4% to 850 mL glucose 5% and infuse at a rate of 166 mL/hour.

During urinary alkalinization monitor serum pH every 2 hours, if the serum pH exceeds 7.5 , pause the infusion and monitor the pH until it improves then restart the infusion (do not re-bolus). Measure urinary pH every 2 hours, aiming for a pH 7.5 -8.0 and a urine output of 2ml/kg/hr.

Note: the most common reason for failing to reach the desired alkalinity in the urine is hypokalaemia . Maintain a normal serum potassium concentration by oral and intravenous supplementation as required.

Continue urinary alkalinization until:

Serum salicylate concentration is <300mmol/L and falling
Acid-base disturbances have resolved
The patient is asymptomatic

Dialysis

Haemodialysis is effective at removing salicylate from the body, but is rarely needed as most patients respond well to decontamination, urinary alkalinization and supportive cares.

If considering dialysis for salicylate toxicity, consult with a clinical toxicologist. The indications for dialysis for salicylate toxicity are not well defined but may include:

Altered level of consciousness
Pulmonary oedema or acute kidney injury
Rising serum salicylate concentrations despite adequate decontamination and urinary alkalinization
Serum salicylate concentrations >1000mg/L
Worsening metabolic acidosis despite or electrolyte disturbances despite other interventions

Antidotes

There are no specific antidotes for the treatment of salicylate ingestion

Observation And Disposition

Discharge patients who have ingested <150mg/kg of aspirin (or equivalent) if they remain asymptomatic for at least 6 hours post ingestion.

Patients who have ingested >150mg/kg of aspirin (or equivalent) should be admitted for serial salicylate and acid base levels. Patients can be discharged when their salicylate concentration is <300mmol/L and falling, their acid base status is normal and they are clinically well.

Educational Resources

Video: Aspirin Overdose- not quite like the textbooks - A/Prof Katherine Isoardi - TAPNA ASM 2021

Video: Salicylate Toxicology, does it need up update? - A/Prof Katherine Isoardi - TAPNA ASM 2022

Salicylate Toxicity

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