Salicylates Toxicity

Etiology

Salicylates are widely available over the counter medications. They are commonly used for their analgesic, antipyretic, and anti-thrombotic properties. Toxicity can occur due to acute ingestion or from chronic ingestions that result in an increased serum concentration. Salicylates can be compounded into formulations with other classes of medications including narcotics, antihistamines, and anticholinergic medications. This can complicate management.[3][4]

Epidemiology

In 2011 there were 30,000 cases of salicylate toxicity in the United States with 39 deaths. Overall the mortality was less than 0.01%; however, this increased to 15% for patients with severe toxicity. Complications increased when the diagnosis was not made upon initial evaluation.[5][6]

Pathophysiology

Salicylate poisoning causes a variety of metabolic disorders. Direct stimulation of the cerebral medulla causes hyperventilation and respiratory alkalosis. As it is metabolized, it causes an uncoupling of oxidative phosphorylation in the mitochondria. Lactate levels then increase due to the increase in anaerobic metabolism. The lactic acid along with a slight contribution from the salicylate metabolites result in metabolic acidosis. Hyperventilation worsens in an attempt to compensate for the metabolic acidosis. Eventually, the patient fatigues and is no longer able to compensate via hyperventilation, and metabolic acidosis prevails. This results in hemodynamic instability and end-organ damage.[7]

Toxicokinetics

The ionization constant of aspirin is 3, which makes it is more readily absorbed in acidic environments such as the stomach. A variety of factors can affect absorption. The formulation of the salicylate (extended vs. immediate release) being one. Food in the stomach at the time of ingestion can delay absorption. Aspirin has the propensity to form bezoars which will delay absorption. Aspirin can cause pyloric sphincter spasms, which increases the amount of time in the stomach allowing for more absorption.  Absorption continues in the small intestine.

The liver metabolizes salicylates by first-order elimination, and the inactive metabolites are then excreted in the urine. With increased salicylate levels, these pathways become saturated resulting in zero order elimination. Elimination is further delayed in patients with underlying renal and liver disease.

Dermal salicylate preparations have been shown to reach the bloodstream. However, the serum concentrations do not reach toxic levels. Theoretically, this may occur in children or patients with compromised skin, such as due to burns or psoriasis.

History and Physical

If the patient can provide history, there are several important pieces of information to obtain. These include time of ingestion, amount ingested, as well as formulation. The later is important as it may affect the rate of absorption. It is also critical to determine if there were any other substances ingested as this may complicate treatment and increase mortality. Finally, determine whether this was accidental or intentional. This information should be corroborated by family, friends, or EMS personnel.

In an acute salicylate overdose, the onset of symptoms will occur within 3 to 8 hours. The severity of symptoms is dependent on the amount ingested. For mild ingestions (salicylate levels 40 to 80 mg/dL) nausea, vomiting, and generalized abdominal pain are common. Tachypnea is usually present. Headaches and dizziness may also occur. The classic finding of tinnitus may also be present. However, this can occur at lower, non-toxic levels.

Patients with moderate salicylate toxicity (80 to 100 mg/dL) will experience more severe neurological symptoms. These can include confusion, slurred speech, and hallucinations. Tachypnea is more pronounced and is accompanied by tachycardia and orthostatic hypotension. Expect these symptoms 6 to 18 hours after ingestion.

Salicylate levels greater than 100 mg/dL are considered severe toxicity and occur 12 to 24 hours after ingestion. Damage to the basement membranes will cause cerebral and pulmonary edema. Patients may become obtunded and develop seizures. Hypoventilation may replace hyperventilation, which is concerning for impending respiratory failure. Endotracheal intubation, while not ideal for the metabolic disorders, may be necessary for airway protection. Hypotension due to acidosis and hypovolemia is possible. Cardiac dysrhythmias may occur. Sinus tachycardia is the most common. Cardiac arrest may also occur with asystole being the most common rhythm.

Patients suffering from chronic salicylate toxicity will experience similar symptoms as acute toxicity but at lower levels. Pediatric patients will progress from mild symptoms to severe symptoms more quickly than adults.

Evaluation

A salicylate level should be checked on all patients with a concern for salicylate toxicity. Serial levels are recommended as absorption is widely variable and will impact treatment. Acetaminophen levels should also be checked as confusion about what substance was ingested may occur. Electrolytes, including calcium and magnesium, ABG, LFTs, CBC, lactate, and coagulation studies should be obtained. An ECG to evaluate for dysrhythmias should be obtained. Consider a CT head if the patient has altered mental status. Serial ABGs and salicylate levels should be obtained until levels clearly begin to downtrend and pH stabilizes.

Lab results may be normal or reveal slight electrolyte abnormalities at mild salicylate levels. PA pure respiratory alkalosis may be noted due to tachypnea. At moderate levels, metabolic acidosis with respiratory alkalosis will be present. Leukocytosis and thrombocytopenia may be noted. Hypokalemia and hypercalcemia as well as an increased BUN, creatinine, and lactate levels can occur. Worsening of the metabolic acidosis with an anion gap occurs at severe toxicity.[4]

Treatment / Management

Patients with salicylate toxicity are volume depleted due to hyperventilation, fever, and increased metabolic activity. Fluid resuscitation should utilize D5 with 3 amps of sodium bicarbonate. The dextrose will treat the central nervous system (CNS) hypoglycemia. The sodium bicarb will help correct the metabolic acidosis. Potassium may be supplemented if hypokalemia is present. Goal urine output is 2 to 3 mL/kg per hour.[8][9](A1)

Patients with severe toxicity will eventually fatigue and be unable to maintain respiratory compensation for the metabolic acidosis. Mechanical ventilation, while not ideal, may be required. Consider a bolus of 1 to 2 mEq/kg of sodium bicarbonate at the time of intubation to temporize the patient’s pH until hyperventilation can be resumed on the ventilator. Mechanical ventilation will not be able to compensate for the metabolic acidosis as well. Arrangements for emergent hemodialysis should be arranged following intubation. Patients may also experience respiratory distress secondary to pulmonary edema following fluid resuscitation.

Following initial stabilization, attempts should be made to decrease the serum salicylate levels. Activated charcoal has been shown to decrease salicylate levels. However, no morbidity or mortality benefit has been shown. Gastric lavage may be considered if the patient presents after acute ingestion of enteric-coated aspirin. If there is any concern for aspiration, these options should be avoided. Whole bowel irrigation has shown no benefit and may increase absorption.

Fluid resuscitation and serum alkalization will increase salicylate elimination. Hemodialysis can also accomplish this. Indications for hemodialysis include severe acidosis or hypotension despite fluid resuscitation; salicylate levels are greater than 100 mg/dL, mechanical ventilation, or end-organ damage. Common signs of end-organ damage in salicylate toxicity include seizures, rhabdomyolysis, pulmonary edema, cerebral edema, and renal failure. Hemodialysis removes salicylates and lactate, which should improve the patient’s metabolic acidosis.

Seizures should be treated with benzodiazepines. Glucose should also be administered as CNS hypoglycemia may be present. Expect the patient’s metabolic acidosis to be worse following a seizure and consider administering a bicarbonate bolus.

Patients with minor ingestions and minimal symptoms may be discharged home if their salicylate levels are down trending and no metabolic derangements are present. Patients with rising salicylate levels and worsening serum pH require admission to the intensive care unit for further monitoring.[10](B3)

Differential Diagnosis

• Caffeine toxicity
• Ethylene glycol overdose
• Hydrocarbon toxicity
• Sepsis
• Drug withdrawal symptoms
• Iron toxicity
• Schizophrenia

Complications

• Respiratory Arrest
• Apnea
• Dyspnea
• Aspiration pneumonitis
• Deafness
• Tinnitus
• Asystole
• Hypotension
• Encephalopathy
• Seizures
• Coma