Aspirin and Nonsteroidal Agents

Key Concepts

In the overdose setting, salicylates are profoundly toxic and can be fatal. Salicylate overdose requires vigilant assessment and treatment. The other nonsteroidal antiinflammatory drugs (NSAIDs) generally have self-limited toxicity and respond to supportive measures. There is no specific antidote for any of these drugs.
Salicylism should be considered in the differential diagnosis of altered mental status, particularly in the elderly.
Acidemia signifies loss of respiratory compensation and acceleration of toxicity.
The Done nomogram is no longer used and is not recommended in the evaluation and treatment of salicylate toxicity.
Salicylate concentrations and blood gas draws should occur every 2 hours until the serum salicylate level is less than 30 mg/dL and is steadily declining at least 10% between assays in the absence of measures to enhance elimination.
Potassium stores are rapidly depleted in patients with salicylate intoxication and should be repleted with a goal serum level of 4.5 to 5.0 mEq/L (4.5–5.0 mmol/L).
When possible, mechanical ventilation should be avoided in cases of severe salicylate poisoning. Acidosis may rapidly worsen due to loss of adequate ventilation during the intubation procedure, and it is difficult to maintain ventilation at the level of physiologic hyperventilation.
If intubation is necessary, a bolus of sodium bicarbonate (50 to 100 mEq) should be given before intubation and post-intubation; minute ventilation should be increased to match pre-intubation respiratory compensation.
Enhanced elimination through urinary alkalinization with an intravenous sodium bicarbonate drip should be initiated in acute toxicity with a serum level >30 mg/dL.
Consultation with nephrology and preparation for emergent hemodialysis should occur if the salicylate concentration is above 80 mg/dL or is rising rapidly.
Hemodialysis is recommended for signs of pulmonary or cerebral edema, coma, seizures, hepatic failure, renal failure, circulatory collapse, or refractory metabolic acidosis along with acute serum levels greater than 100 mg/dL and chronic levels over 40 mg/dL.
Altered mental status in the setting of salicylate toxicity warrants IV dextrose supplementation.
Most NSAID overdoses are asymptomatic or cause only minor gastrointestinal symptoms.
Ibuprofen, along with other propionic acid derivatives, has been associated with sporadic cases of aseptic meningitis.
The management of NSAID overdose is supportive, and there is no specific antidote. Hemodialysis is reserved for patients with massive overdose (>400–500 mg/kg) and pH <7.1.
Patients who have ingested a pyrazolone or fenamate require observation for possible seizures for 8 to 12 hours following ingestion.

Aspirin

Principles of Toxicity

Overview

Aspirin, or acetylsalicylic acid, is widely consumed for its analgesic, antiinflammatory, and antiplatelet effects. Although its therapeutic use is ubiquitous, salicylate toxicity is not a benign condition and causes a complex set of life-threatening metabolic derangements with significant morbidity and mortality.

Epidemiology

In 2017, twenty-three deaths were reported to United States Poison Control Centers due to aspirin alone. This is consistent with reports to Poison Control Centers of twenty to thirty deaths per year for the past decades. One analysis identified salicylate toxicity as the most common preventable death due to poisoning that reached medical attention, suggesting an opportunity to impact mortality through proper management. Elderly patients with chronic medical problems and young patients diagnosed with an acute illness are particularly at risk for delay in diagnosis with consequent severe adverse clinical effects. In addition, increasing age has been identified as an independent predictor of severe outcomes and has been associated with lower peak levels in fatal cases. ^,

Salicylate-Containing Products

Aspirin is the most common salicylate-containing product. Other potential sources of salicylate toxicity include topical salicylates, analgesic balms, oil of wintergreen, willow bark, Alka Seltzer®, and bismuth subsalicylate. Ingestion of oil of wintergreen is of particular concern given that 1 mL of 98% solution contains the equivalent of 1.4 grams of aspirin.

Pathophysiology

Salts of salicylic acid are rapidly absorbed intact from the gastrointestinal (GI) tract with appreciable serum concentrations typically occurring within 30 minutes after ingestion of a therapeutic dose with peak levels delayed from 2 to 4 hours. Large ingestions frequently slow gastric emptying. Aspirin, particularly enteric-coated preparations, tends to form concretions or bezoars in the stomach. These properties often result in prolonged absorption with rising serum levels for 12 hours or more.

In the intestinal wall, liver, and red blood cells, aspirin is hydrolyzed to free salicylic acid, which reversibly binds to albumin. Free salicylate is eliminated by renal excretion. At therapeutic salicylate concentrations, elimination follows first-order kinetics. Once serum salicylate concentrations are greater than 30 mg/dL, elimination follows zero-order kinetics. The metabolic pathways become saturated, and the pH-sensitive urinary excretion of salicylic acid determines the half-life, prolonging significantly (up to 15 to 30 hours) with large overdoses.

The initial physiologic effect of salicylates is direct stimulation of the medullary respiratory center. In addition, salicylic acid increases the sensitivity of the respiratory center to pH and partial pressure of carbon dioxide (P co ₂ ). Hyperventilation develops early, subsequently becoming a compensatory mechanism for metabolic acidosis. Prolonged high serum concentrations eventually depress the respiratory center. Respiratory alkalosis is compensated by the buffering capacity of the hemoglobin-oxyhemoglobin system, the exchange of intracellular hydrogen ions for extracellular cations, and the urinary excretion of bicarbonate. Loss of bicarbonate decreases buffering capacity and exacerbates the degree of metabolic acidosis ( Box 139.1 ).

BOX 139.1

Acid-Base Disturbance and Progression of Toxicity in Acute Salicylate Overdose

Early (0 to 4 hours; level 20 to 60 mg/dL): Respiratory alkalosis with alkalemia; gastrointestinal (GI) distress, mild to moderate hyperpnea, tinnitus, lethargy
Moderate (2 to 12 hours; level 50 to 90 mg/dL): Respiratory alkalosis and metabolic acidosis with alkalemia or neutral pH; severe hyperpnea, lethargy or agitation, hyperthermia
Severe (6 to 24 hours: level >80 mg/dL): Respiratory alkalosis or acidosis and metabolic acidosis with acidemia; severe hyperpnea, coma or acute delirium, hyperthermia, pulmonary or cerebral edema, seizure, cardiovascular collapse

Toxicity results primarily from salicylate interference with aerobic metabolism by uncoupling of mitochondrial oxidative phosphorylation. Inhibition of the Krebs cycle increases production of pyruvic acid and increases conversion to lactic acid. Increased lipid metabolism generates ketone bodies. Metabolic rate, temperature, tissue carbon dioxide, and oxygen consumption are increased. Tissue glycolysis predisposes to hypoglycemia, particularly in children. Inefficiency of anaerobic metabolism results in decreased production of adenosine triphosphate, with energy released as heat causing the hyperthermia frequently attributed to salicylate poisoning.

Only nonionized particles can cross the lipophilic cell membrane and accumulate in the brain and other tissues. Because salicylic acid has a p K _a of 3.5, the majority of salicylate is ionized and unable to enter tissue at the physiologic pH of 7.4. However, as serum pH decreases, more particles become un-ionized and cross the cell membrane and blood-brain barrier, markedly increasing the movement of salicylate into the tissues and central nervous system (CNS).

The rapid depletion of potassium stores in salicylate toxicity is caused by multiple factors. Immediate losses occur due to vomiting, which is secondary to stimulation of the medullary chemoreceptor trigger zone. In addition, increased renal excretion of sodium, bicarbonate, and potassium occurs as a compensatory response to the respiratory alkalosis, and salicylate-induced increased permeability of the renal tubules causes further loss of potassium. A final factor is inhibition of the active transport system, secondary to uncoupling of oxidative phosphorylation.

Salicylate-related decreases in renal blood flow or direct nephrotoxicity may cause acute nonoliguric renal failure. Drug-induced, inappropriate secretion of antidiuretic hormone may also affect renal function. The exact mechanism by which salicylates increase alveolar capillary membrane permeability is not clearly defined. Theories include inhibition of prostacyclin, changes in platelet-vessel interaction, and neurogenic influences.

In adults, risk factors for salicylate-induced pulmonary edema include age greater than 30 years old, long-term cigarette smoking, chronic salicylate ingestion, metabolic acidosis, neurologic symptoms, and serum salicylate concentration greater than 40 mg/dL. Risk factors in children include high serum salicylate levels (>80 mg/dL), large anion gap acidosis, decreased serum potassium concentration, and low pCO ₂ .

Salicylates severely affect the CNS in two ways. First, there is a poorly elucidated aspect of toxicity that ultimately results in cerebral edema. This pathway is presumably related to increased energy requirements, acidemia, and direct cellular toxicity. Second, the consumption of glucose in the brain may outpace the supply. This occurs even in the face of normal serum glucose. One or both of these mechanisms can cause altered mental status, seizures, and coma.

At moderate to high tissue burden, salicylates induce a classic finding of toxicity—tinnitus, or the sensation of ringing in the ears. This phenomenon is due to a combination of central and peripheral effects. Cochlear toxicity is thought to be the result of alterations in N -methyl-D-aspartate (NMDA) activity, decreased blood flow, and increased membrane permeability. Cochlear toxicity combines with hyperactivity in the auditory cortex to cause tonotopic shifts where upper and lower frequency sounds are perceived in the 10 to 20 hertz tinnitus range, and sounds within this range become hyperacute. Salicylate-induced hearing disturbance may take days to resolve after the tissue burden normalizes.

At therapeutic dosing, salicylates increase bleeding risk via irreversible inhibition of platelet cyclooxygenase (COX). In overdose, vitamin K epoxide reductase is inhibited in a manner similar to warfarin. This acquired coagulopathy prolongs prothrombin time measurements and is associated with a substantial risk of clinically significant bleeding.

Physiologic changes of aging predispose elderly patients to toxicity from chronic therapeutic ingestion. Decreased liver blood flow limits biotransformation of salicylate, and decreased renal function reduces salicylate clearance. Chronic ingestion decreases albumin binding, increasing the free salicylate that can enter the cell, and allows salicylates more time to pass through the blood-brain barrier. Therefore, a patient with chronic salicylate toxicity and a serum concentration of 40 mg/dL may be more ill than a patient with an acute ingestion and serum concentration of 80 mg/dL.

Clinical Features

Salicylate toxicity initially generates gastrointestinal (GI) distress followed by tachypnea with an accompanying respiratory alkalosis, tinnitus, and hearing disturbances due to concentration-dependent reversible ototoxicity, diaphoresis, and an evolving anion gap acidosis. As the toxicity progresses, hyperthermia, coagulopathy, cerebral and pulmonary edema, cardiovascular collapse, and, ultimately, death occur. Chronic poisoning may be more subtle, manifesting as a waxing and waning combination of the above manifestations of toxicity.

Differential Diagnoses

Salicylism mimics sepsis, CNS infection, withdrawal syndromes, and alcoholic or diabetic ketoacidosis. This is especially true in chronic toxicity given that the serum salicylate concentration is relatively low. Thus, the severity of poisoning is often not recognized or not fully appreciated. In addition, co-ingestion is common, so evaluation for other toxic exposures is warranted. Other pain relievers and fever reducers such as acetaminophen and ibuprofen are often confused with aspirin by patients. Other toxins that cause a metabolic acidosis with an elevated anion gap include colchicine, iron, isoniazid, methanol, ethylene glycol, metformin, and cyanide. Other toxins that can cause tinnitus include aminoglycosides, loop diuretics, opioids, methotrexate, cisplatin, and antimalarial agents containing quinine.

Diagnostic Testing

The serum salicylate concentration, acid-base status, serum potassium, and glucose are key diagnostic studies. Be mindful of the laboratory units of measurement when interpreting salicylate levels. Serum salicylate concentrations are reported as mg/dL, mg/L, or mmol/L by various labs but are listed in mg/dL in this text. The Done nomogram, historically used for aspirin toxicity, should not be used to determine prognosis or treatment of the salicylate-poisoned patient.

Measure an initial salicylate concentration on arrival with a second sample obtained 2 hours later. A low initial salicylate level may be deceptive as early salicylate levels have not been shown to predict severity of outcome. Obtain concentrations every 2 hours to monitor for continued absorption, which may be prolonged. Serum salicylate levels should be repeated every 2 hours until three consecutive levels are less than 30 mg/dL and are declining by at least 10% to 20% on each measurement while the patient is no longer undergoing therapy to enhance elimination. In one series, 3.5% of cases demonstrated peak serum levels greater than 30 mg/dl despite a nondetectable initial level with the longest interval from ingestion to detection of 225 minutes. Thus, given sufficient clinical suspicion, continue to obtain salicylate levels up to 4 hours post-ingestion even if the initial level is undetectable.

Acid-base status can change quickly, and monitoring of pH every 2 hours is important to guide treatment. Use early and frequent arterial or venous blood gas determinations in symptomatic patients to rapidly assess acid-base and compensatory status. Developing acidemia portends severe disease. The pH begins to drop when the patient is unable to compensate for acidemia. Lactic acid accumulates, and serum bicarbonate is consumed. A serum lactate greater than 2.25 mmol/L is a predictor of severe outcome. When serum pH is less than 7.4 and both P co ₂ and bicarbonate level are low, hemodynamic instability rapidly develops.

A metabolic panel is necessary to guide electrolyte replacement (with a focus on serum potassium) and to assess renal function and glucose metabolism. However, anion gap determination on a metabolic panel is not a substitute for obtaining a salicylate level or measuring the pH. Measurement of protime/INR will assist in guiding vitamin K therapy in the setting of coagulopathy. A serum acetaminophen concentration should also be obtained to screen for ingestion of this common, clinically occult analgesic overdose.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here