Salicylate poisoning

Salicylate toxicity is a medical emergency. In 2011 there were 30,000 cases of salicylate toxicity in the United States with 39 deaths ¹. 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 ². Salicylates and aspirin (acetylsalicylic acid) 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 ³. Salicylates are used as analgesic agents for the treatment of mild to moderate pain. Aspirin is most commonly used analgesic, antipyretic, anti-inflammatory and antiplatelet medication for the treatment of soft tissue and joint inflammation and vasculitides such as acute rheumatic fever and Kawasaki disease. Aspirin is also used to treat acute coronary syndrome. Low-dose aspirin helps to prevent thrombosis.

Acetylsalicylic acid (aspirin) 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. Insidious cases of salicylate intoxication may also occur, caused by either ingestion or topical absorption, most often in elderly patients with renal failure.

Prior to antibiotics, topical salicylates were widely used to treat scabies and impetigo, and toxicity associated with dermal absorption was common. One case series reported 13 deaths, 10 of them in children, substantiating the severe potential for toxicity associated with this route ⁴. A review of the literature of topical salicylates reported 17 documented cases of toxicity associated with underlying illnesses, days to diagnosis, and serum salicylate ⁵. Psoriasis is the main entity still treated with topical salicylates, and there are numerous case reports documenting toxicity ⁴. Another route of application is with sports creams used in massage therapy for muscle pain. Local skin necrosis and interstitial nephritis have also been associated with these creams ⁵.

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.

A high index of suspicion of salicylate toxicity is necessary, with prompt recognition of clinical signs and symptoms of salicylate poisoning, such as tinnitus, hyperventilation, tachycardia, and metabolic acidosis ⁶. Early treatment can prevent organ damage and death.

The severity of toxicity can generally be predicted from the amount of drug absorbed. Ingestion of less than 150 mg/kg is usually not associated with systemic toxicity; 150–300 mg/kg may produce mild to moderate symptoms of hyperpnea and neurologic disturbances (lethargy and/or excitability) ⁷. A dose of greater than 500 mg/kg of salicylate can result in severe hyperpnea, coma, and occasionally seizures ⁸.

About 20% of the salicylate is oxidized in the tissues and 70% is excreted by the kidneys ⁹. Because the hepatic enzymatic metabolism becomes saturated as salicylate levels increase, renal excretion becomes increasingly important as a means of elimination ¹⁰. Therefore, renal insufficiency or renal failure contributes to further accumulation of salicylate.

The treatment of acute salicylate intoxication consists of decreasing further absorption of salicylates, enhancing drug elimination, and correcting for acid-base, fluid, and electrolyte imbalances. No specific antidote is available for salicylates. Gastric lavage has not demonstrated to be better than charcoal alone at reducing toxicity in an evidence-based review ¹¹. Extra doses of activated charcoal may be needed to achieve the desired ration of 10:1 activated charcoal to salicylates. Repeated doses of activated charcoal may enhance elimination through enteroenteric recirculation ¹².

Prompt correction of systemic acidosis with sodium bicarbonate is critical to prevent further transfer of unbound salicylate into the central nervous system (CNS). Alkalization of the urine with sodium bicarbonate (2–3 mEq/kg loading dose intravenously, and 2 mEq/kg every 3–4 hours thereafter to maintain a urine pH above 8) will enhance urinary excretion of salicylate and reduce serum half-life ¹³. Overly vigorous fluid administration can lead to pulmonary edema or cerebral edema. Fluid or osmotic diuresis does not increase renal salicylate excretion more than urinary alkalization ¹⁰.

Hemodialysis is the most efficient method of removing salicylates from the blood. Dialysis is the treatment of choice in salicylate-intoxicated patients who have severe renal, hepatic, or cardiovascular disorders, uncorrectable acidosis, comatose, seizing, or are unresponsive to other methods of treatment ⁷.

Salicylate poisoning causes

Salicylates are widely available over the counter medications. Salicylates 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. Intentional ingestion or accidental overdose can cause severe metabolic derangements making treatment difficult. Salicylates can be compounded into formulations with other classes of medications including narcotics, antihistamines, and anticholinergic medications. This can further complicate management ¹⁴.

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.

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 ¹⁵.

Salicylate poisoning symptoms

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 emergency medical services personnel.

Nausea, vomiting, diaphoresis, and tinnitus ¹⁶ 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.

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.

Phases 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.
• Phase 2, paradoxical aciduria in the presence of continued respiratory alkalosis occurs 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.

Salicylate poisoning complications

Salicylate poisoning complications may include:

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

Salicylate poisoning diagnosis

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, arterial blood gas (ABG), liver function tests (LFTs), complete blood count (CBC), lactate, and coagulation studies should be obtained. An electrocardiogram (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. 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 blood urea nitrogen (BUN), creatinine, and lactate levels can occur. Worsening of the metabolic acidosis with an anion gap occurs at severe toxicity ¹⁷.

Salicylate poisoning treatment

Patients with salicylate toxicity are volume depleted due to hyperventilation, fever, and increased metabolic activity. Fluid resuscitation should utilize dextrose 5% with 3 amps of sodium bicarbonate. The dextrose will treat the central nervous system (CNS) hypoglycemia. The sodium bicarbonate 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 ¹⁸.

Patients with severe salicylate 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 ¹⁹.

Salicylate poisoning prognosis

Salicylate toxicity has a high morbidity and mortality. At least 1-2% of patients die from this agent. Data from the poison control centers reveal that at least 1/4 of the medication-related deaths are related to aspirin alone or in combination with other medications. The important fact is that salicylate toxicity can be treated if the diagnosis and treatment are done promptly. For the survivors, some residual neurological deficit may persist for a few years ²⁰.

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