Salicylates

GENERAL PRINCIPLES

Salicylate toxicity may result from acute or chronic ingestion of acetylsalicylic acid (ASA). Toxicity is

usually mild after acute ingestions of lt;150 mg/kg, moderate after ingestions of 150-300 mg/kg, and generally severe with overdoses of 300-500 mg/kg.

• Toxicity from chronic ingestion is typically due to intake of gt;100 mg/kg/d over a period of several days and usually occurs in elderly patients with chronic underlying illness. Diagnosis is often delayed in this group of patients, and mortality is approximately 25%. Significant toxicity due to chronic ingestion may occur with blood concentrations lower than those associated with acute ingestions.

• Topical preparations containing methyl salicylate or oil of wintergreen can cause toxicity with excessive topical use or if ingested.

Pathophysiology

• At toxic doses, salicylates disrupt aerobic respiration in the mitochondria. They uncouple oxidative phosphorylation from ATP production by disrupting the proton gradient in the intermembrane space.

• The resultant impairment of aerobic respiration produces an elevated anion gap metabolic acidosis, impairs effective glucose utilization, and leads to widespread cellular metabolic failure.

The brain is particularly reliant on glucose as an energy source. Disruption of aerobic metabolism by salicylate poisoning leads to rapid depletion of central nervous system glucose through less effective anaerobic respiration.

• In the early stages of poisoning, salicylates directly stimulate the medullary respiratory centers, producing the characteristic early tachypnea and primary respiratory alkalosis. As poisoning progresses, metabolic acidosis worsens and the tachypnea becomes compensatory.

DIAGNOSIS

Clinical Presentation

• Patients with salicylate poisoning typically present with GI upset, tinnitus or hearing changes, tachypnea, tachycardia, and hyperpnea.

• Severe intoxication may produce lethargy, encephalopathy, coma, seizures, or hypoxemic respiratory failure (due to noncardiogenic pulmonary edema).

• Chronic salicylate poisoning, especially in elderly patients, may mimic sepsis, with tachycardia, tachypnea, alterations in mental status, and occasionally hyperthermia.

Diagnostic Testing

LABORATORIES

• Obtain a BMP.

î Acidosis with an elevated anion gap is an important indicator of salicylate poisoning.

î Some chloride analyzers may report spurious hyperchloremia in the presence of high salicylate concentrations, which falsely depresses the anion gap.

î Maintenance of eukalemia is critical for treatment (see below).

• Obtain a blood gas (either venous or arterial). The acid-base pattern will depend on the phase of poisoning.

O

#9632; Early, patients exhibit a primary respiratory alkalosis (due to direct stimulation of the medullary respiratory centers, as above).

#9632; Later, a mixed picture develops, with a combined primary respiratory alkalosis and primary

metabolic acidosis (the “classic” acid-base finding in salicylate poisoning).

#9632; Patients in extremis or patients with a co-ingestion of a respiratory depressant may develop a mixed metabolic and respiratory acidosis.

• Obtain a serum salicylate concentration.

î Salicylate concentrations gt;30 mg/dL are supratherapeutic and potentially toxic.

î Salicylate concentrations gt;70 mg/dL at any time represent moderate to severe intoxication.

î Salicylate concentrations gt;100 mg/dL are serious and often fatal.

î Enteric-coated aspirin may have delayed absorption and delayed peak concentration.

î Chronic salicylate poisoning can cause severe toxicity with lower serum salicylate concentrations.

O Be aware of units. Most hospitals report salicylate concentrations in mg/dL. However, some hospitals still report concentrations in mg/L, which has caused multiple interpretation errors.

• Frequent repetition of laboratory tests is critical—the toxicokinetics of salicylates are unpredictable and erratic, and patients' lab results and clinical condition can change rapidly.

Frequency of lab monitoring depends on the clinical condition—critically ill patients may require q2 hour monitoring of salicylate concentration, electrolytes, and blood gas, while mildly or moderately poisoned patients may have labs checked every 6-8 hours.

IMAGING

Salicylate is known to produce large concretions or bezoars in overdose. Theoretically, imaging by computed tomography or endoscopy might reveal the presence of a bezoar, but imaging is almost never required for diagnosis or management.

TREATMENT

Medications

• Administer AC to patients presenting shortly after acute overdose with no contraindications to AC. Repeated doses of AC, even many hours postingestion, may be useful in severe poisoning, especially in cases when salicylate concentrations fail to decline as expected (due to possible bezoar formation or pylorospasm leading to a prolonged absorption phase). ⁸

• In an acute overdose, most patients will be volume depleted due to GI volume losses and insensible losses from tachypnea and will benefit from intravenous crystalloid resuscitation. Caution should be used in patients with renal failure or congestive heart failure (CHF).

• Enhanced elimination via urinary alkalinization with sodium bicarbonate is indicated for symptomatic patients with salicylate blood concentrations gt;30 mg/dL.

î Initiate therapy with a bolus dose of ~1 mEq/kg sodium bicarbonate (typically about two standard 50 mEq ampules).

î Continue therapy with an infusion of sodium bicarbonate (150 mEq sodium bicarbonate in 1 L of 5% dextrose in water) at twice the maintenance rate.

î Monitor the success of urinary alkalinization by following the patient's clinical condition (target consistent improvement), salicylate concentrations (target consistent decline), and urine pH (target 7-8). Administer additional boluses of sodium bicarbonate and/or increase the infusion rate as needed to achieve these goals.

î Avoid excessive alkalemia.

î Aggressively replete potassium to a target of gt;4 mEq/L. Even relative hypokalemia will impair appropriate urinary alkalinization, and bicarbonate therapy will induce hypokalemia via transcellular shift.

î Use caution with urinary alkalinization in patients with significant renal impairment, heart failure with reduced ejection fraction, or volume overload.

î Sodium acetate may be substituted for sodium bicarbonate during a drug shortage. Sodium acetate cannot be administered as a rapid IV bolus but may be infused in place of sodium bicarbonate.

• Administer intravenous dextrose to patients with altered mental status, even if the peripheral blood glucose is normal. Salicylate poisoning causes profound depletion of glucose in the central nervous system.

• Administer parenteral benzodiazepines (or other directly GABAergic antiepileptics such as barbiturates or propofol) to patients with seizures. These patients should also receive intravenous dextrose as noted above.

Nonpharmacologic Therapies

• Avoid intubation and mechanical ventilation if possible. Even the brief period of sedation and apnea required for rapid-sequence intubation will significantly worsen acidosis and promote the movement of salicylate into target organs.

î The compensatory hyperpnea and tachypnea seen in severe salicylate poisoning often cannot be replicated by mechanical positive-pressure ventilation. Intubation and mechanical ventilation are associated with profound acidosis and death in salicylate-poisoned patients.

° If intubation is completely unavoidable (e.g., refractory hypoxemia, gross aspiration, profound respiratory fatigue), push sodium bicarbonate before and during intubation, maximize tidal volume and respiratory rate on the ventilator, and arrange for emergent hemodialysis (see below).

• Hemodialysis effectively clears salicylates and corrects acid-base deficits. It is indicated in salicylate poisoning in the following situations:

î Salicylate gt; 100 mg/dL, or gt;90 mg/dL in the presence of renal impairment

° Any degree of altered mental status

î New hypoxemia requiring supplemental oxygen

î Failure of standard therapy with elevated salicylate concentrations (gt;90 mg/dL, or gt;80 mg/dL with renal impairment) or pH lt; 7.20