DESCRIPTION

Salicylates include a variety of medications used for their analgesic and antiinflammatory effects.

FORMS AND USES

• The product packaging should be checked to determine whether a main ingredient is aspirin or acetaminophen and whether narcotics, decongestants, or barbiturates are present.
• Salicylates are available in a variety of forms for oral and topical use.
• Numerous brands contain aspirin alone, whereas others are combination products.
• Analgesic/antipyretic agents, such as aspirin [acetylsalicylic acid (ASA)], provide temporary relief of mild to moderate pain and reduce fever.
• Antiinflammatory agents (ASA, magnesium salicylate, salsalate, sulfasalazine) provide long-term maintenance in rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, inflammatory bowel disease, and other diseases.
• Antiplatelet agents reduce deaths from myocardial infarction or unstable angina, and reduce transient ischemic attacks and stroke.
• Gastrointestinal agents (bismuth, subsalicylate, Pepto Bismol) are used to treat diarrhea and indigestion.
• Topical wart removers may contain 17% salicylate.
• Liniments and vaporizers contain high concentrations of methyl salicylate (up to 30%) in additives; oil of wintergreen is 100% methyl salicylate.
• The maximum recommended dosage for analgesic, antipyretic, and antiinflammatory indications is 4 g per day in divided doses (650 mg every 4 hours or 1 g every 6 hours), although some conditions are treated with larger amounts under a physician's supervision.

TOXIC DOSE

• An acute single ingestion of more than 150 mg/kg often causes toxicity, and the patient should be examined in a health-care facility.
• Chronic ingestion of more than 100 mg/kg/day may cause toxicity.
• One teaspoon (5 ml) of oil of wintergreen contains 1.4 g of salicylate and is a potentially lethal dose in a child who weighs less than 10 kg.

PATHOPHYSIOLOGY

• Aspirin (ASA) is hydrolyzed to salicylic acid (salicylate).
• Salicylate stimulates the medullary respiratory center, producing hyperventilation and respiratory alkalosis.
• Salicylate also uncouples oxidative phosphor-ylation at the cellular level, resulting in fever and decreased adenosine triphosphate production.
• Elevated lactic acid levels contribute to metabolic acidosis.
• Acidosis promotes the formation of the unionized form of salicylate, which readily penetrates the brain.
• Concentration of salicylate in the brain is directly correlated with lethality in animals.

EPIDEMIOLOGY

• Poisoning is common.
• Toxic effects following exposure are typically mild to moderate.
• Death occurs in patients who are inadequately treated or in whom the diagnosis is missed (usually the elderly with an underlying medical disease and chronic salicylate intoxication).

CAUSES

• Poisoning is usually caused by a suicidal ingestion.
• Chronic ingestion from therapeutic misadventure is also common.
• Child neglect should be considered if the patient is less than 1 year of age; suicide attempt in patients over 6 years of age.

RISK FACTORS

• Children between 4 and 12 years of age who ingest aspirin during a febrile illness may be at risk for Reye's syndrome.
• Elderly patients with underlying medical conditions have a 25% to 30% mortality rate from chronic salicylate when toxicity develops.

DRUG AND DISEASE INTERACTIONS

Acetazolamide increases salicylate toxicity by promoting CNS penetration.

PREGNANCY AND LACTATION

• US FDA Pregnancy Category C. The drug exerts animal teratogenic or embryocidal effects, but there are no controlled studies in women, or no studies are available in either animals or women.
• Therapeutic doses of aspirin during the first trimester of pregnancy and during breastfeeding are safe.
• Increased incidence of intracranial hemorrhage and premature closure of the ductus arteriosus in premature infants are associated with maternal ingestion of aspirin within 1 week of delivery.

Section Outline:

• DESCRIPTION
• FORMS AND USES
• TOXIC DOSE
• PATHOPHYSIOLOGY
• EPIDEMIOLOGY
• CAUSES
• RISK FACTORS
• DRUG AND DISEASE INTERACTIONS
• PREGNANCY AND LACTATION

DIFFERENTIAL DIAGNOSIS

• Toxicants causing increased anion gap metabolic acidosis include methanol, ethylene glycol, iron, metformin, lactic acidosis from any cause, and isoniazid (see SECTION II, Anion Gap Acidosis chapter).
• Nontoxic conditions causing metabolic acidosis include hypoxia or hypotension induced by any cause.

SIGNS AND SYMPTOMS

• Acute intoxication usually begins with nausea, vomiting, tinnitus, hearing loss, and respiratory alkalosis and may progress to severe toxicity over several hours.
• Chronic intoxication is insidious and often presents with altered mental status with a history consistent with volume depletion (anorexia, vomiting), perhaps in the setting of subacute pain such as toothache for several days.
• Either acute or chronic ingestion may result in dehydration, hypotension, hepatotoxicity, noncardiogenic pulmonary edema, lethargy, agitation, and seizures.

Vital Signs

Hyperventilation, tachycardia, fever, and hypotension may occur in moderate to severe overdose.

HEENT

• Tinnitus and transient hearing loss are common.
• Mucosal burns may occur from ingestion of topical wart removers (due to acid in product).

Cardiovascular

• Hypotension and shock are signs of severe poisoning.
• Malignant dysrhythmia may occur abruptly during severe toxicity.

Pulmonary

Tachypnea and hyperventilation are common; noncardiogenic pulmonary edema and respiratory failure occur in severe cases.

Gastrointestinal

• Nausea and vomiting are common.
• Aspirin bezoars may form after large ingestion or chronic ingestion of enteric-coated preparations, leading to prolonged absorption.
• Gastric stasis from pylorospasm, gastrointestinal bleeding, viscus perforation, and pancreatitis may occur.

Hepatic

Hepatic injury may occur in severe cases.

Renal

Proteinuria and acute renal insufficiency may develop.

Fluids and Electrolytes

• After acute ingestion, respiratory alkalosis develops initially, which may be followed by metabolic acidosis as the patient deteriorates.
• In small children, alkalosis may not occur and metabolic acidosis may be an early presenting sign.
• Dehydration and hypokalemia are common.
• Syndrome of inappropriate antidiuretic hormone may develop.
• Respiratory acidosis indicates severe toxicity or possibly coingestion of a CNS depressant.

Musculoskeletal

Rhabdomyolysis is a rare complication of severe poisoning.

Neurologic

In severe poisoning, lethargy, agitation, confusion, coma, seizures, cerebral edema, encephalopathy, asterixis, and focal neurologic findings may develop.

Endocrine

Hyperglycemia or hypoglycemia may occur.

Hematologic

Prolonged prothrombin time/partial thromboplastin time, disseminated intravascular coagulation, and inhibition of platelet aggregation are seen.

PROCEDURES AND LABORATORY TESTS

Essential Tests

Serial Serum Salicylate Levels

• Single acute ingestion
  • Serum salicylate levels should be obtained every 2 hours for the first 4 to 8 hours to assess the rate of rise and absolute value of salicylate concentrations.
  • Then levels should be obtained every 4 to 6 hours until sustained decline in levels is observed.
  • Mild toxicity is associated with levels higher than 30 mg/dl.
  • Hemodialysis is usually initiated for salicylate levels over 90 to 100 mg/dl, respiratory acidosis, or signs of end-organ damage (e.g., persistent hypotension, pulmonary edema, altered mental status, seizure).
• Chronic ingestion. A single level should be performed to screen for chronic intoxication. It is interpreted in the context of clinical signs. Interpretation of levels is as follows:
  • Serious effects develop at salicylate levels lower than for acute ingestion.
  • In the elderly, toxicity can occur at "therapeutic" levels, and seizures and death have occurred at a serum level of 35 mg/dl.
  • Hemodialysis is often initiated for salicylate level greater than 50 mg/dl, respiratory acidosis, or signs of end-organ damage (e.g., pulmonary edema, altered mental status, or seizure).
• Diflunisal (Dolobid) may induce a false-positive salicylate level.

Serum Electrolytes, Glucose, BUN, and Creatinine

• Metabolic acidosis is common.
• Serial serum bicarbonate levels are used to assess acid-base status.
• Hyper- or hypoglycemia may develop.
• Elevated BUN and creatinine may develop.

Recommended Tests

• Arterial blood gases
  • These are used to follow oxygenation and respiratory compensation for metabolic acidosis.
  • Rising pCO₂ indicates respiratory failure and the need for endotracheal intubation as well as hemodialysis.
• ECG and serum acetaminophen level in an overdose setting are used to evaluate occult ingestion.
• Serum calcium is measured; hypocalcemia has been associated with aggressive bicarbonate therapy.
• Chest radiography in symptomatic patients can assess noncardiogenic pulmonary edema.
• Abdominal radiography may detect sustained-release or enteric-coated tablets.

Not Recommended Tests

Use of the Done nomogram is not recommended.

Section Outline:

• DIFFERENTIAL DIAGNOSIS
• SIGNS AND SYMPTOMS
  • Vital Signs
  • HEENT
  • Cardiovascular
  • Pulmonary
  • Gastrointestinal
  • Hepatic
  • Renal
  • Fluids and Electrolytes
  • Musculoskeletal
  • Neurologic
  • Endocrine
  • Hematologic
• PROCEDURES AND LABORATORY TESTS
  • Essential Tests
  • Recommended Tests
  • Not Recommended Tests

• Treatment should focus on gastrointestinal decontamination, enhancement of renal excretion of salicylate, and deciding when hemodialysis is indicated.
• Treatment decisions should be based on signs of toxicity and the salicylate level.
• The salicylate level alone should not determine course of therapy.
• The dose and time of exposure must be determined for all substances involved.

DIRECTING PATIENT COURSE

The health-care provider should call the poison control center when:

• Altered mental status, seizure, respiratory acidosis, or hypoxia are present or dialysis is planned.
• Toxic effects are not consistent with salicylate poisoning.
• Coingestant, drug interaction, or underlying disease presents an unusual challenge.

The patient should be referred to a health-care facility when:

• Attempted suicide or homicide is possible.
• Patient or caregiver seems unreliable.
• Toxic effects are present.
• Coingestant, drug interaction, or underlying disease presents an unusual challenge.

Admission Considerations

Inpatient management is warranted for patients with a rising salicylate level or signs of end-organ damage (e.g., altered mental status, seizure, acidosis, or pulmonary edema).

DECONTAMINATION

Out of Hospital

Emesis should be induced with ipecac within 1 hour of ingestion for alert pediatric or adult patients if health-care evaluation will be delayed.

In Hospital

• Gastric lavage should be performed in pediatric (tube size 24-32 French) or adult (tube size 36-42 French) patients presenting within 1 hour of a large ingestion or if serious effects are present.
• Sustained-release formulations may be too large to be effectively removed by gastric lavage.
• One dose of activated charcoal (1-2 g/kg) is administered without a cathartic if a substantial ingestion has occurred; activated charcoal (0.5-1 g/kg) may be repeated every 4 to 6 hours for an additional one to two doses, provide bowel sounds are present.

ANTIDOTES

There is no specific antidote for salicylate poisoning.

ADJUNCTIVE TREATMENT

Endotracheal Intubation and Mechanical Ventilation

• Indications
  • Altered mental status with inability to protect airway
  • Rising pCO₂ level
• Method of administration
  • Patient should be intubated in the standard manner.
  • Ventilator setting should maintain the patient's previous minute volume, which is usually increased markedly.
  • Settings should not be adjusted to produce pCO₂ of 40 mm Hg, which would probably produce relative respiratory acidosis and potentially worsen the patient's condition rapidly.

Hemodialysis

• Indications
  • Clinical worsening, respiratory acidosis, particularly in conjunction with rising salicylate level despite gastrointestinal decontamination and urinary alkalinization
  • Evidence of end-organ damage (persistent or recurrent hypotension, altered mental status, seizure, respiratory acidosis, noncardiogenic pulmonary edema, refractory metabolic acidosis)
  • Oliguric renal failure
  • Elderly patients with chronic salicylate ingestion and worsening clinical status
    • These patients have a high rate of mortality.
    • Early hemodialysis may be life saving.
• Method of administration
  • Hemodialysis is terminated when clinical improvement, decline in the serum salicylate level approaching the therapeutic range, and correction of acid-base disturbances are achieved.

Whole-Bowel Irrigation

• Indications
  • Large ingestion of enteric-coated or sustained-release tablet formulations
  • Rising salicylate level despite gastrointestinal decontamination
• Contraindications
  • Gastrointestinal ileus, perforation, bleeding, or obstruction
• Method of administration
  • Adolescents and adults are administered a polyethylene glycol solution (Golytely, Colyte) at 2 L/h orally until rectal effluent is clear.
  • The pediatric dose is 20 ml/kg/h orally until rectal effluent is clear.
• Adverse effects include vomiting, especially with rapid administration, and abdominal cramping.

Urinary Alkalinization

• Indications
  • Symptomatic patients (tachypnea, tinnitus, recurrent vomiting) with history of salicylate ingestion should undergo empiric urinary alkalinization while awaiting initial salicylate level.
  • Most patients with salicylate level of over 30 mg/dl should receive urinary alkalization while being further evaluated.
  • All patients in whom hemodialysis is planned should receive urinary alkalization.
• Contraindications
  • Encephalopathy, cerebral edema, renal failure, pulmonary edema, arterial pH higher than 7.55, serum sodium greater than 150 mEq/L
• Method of administration
  • Adults are administered one to two ampules of sodium bicarbonate (44 or 50 mEq per ampule) by intravenous push. Three ampules of sodium bicarbonate are then mixed in 1 L of D5W and infused at 200 ml/h. The rate should be increased within clinically reasonable boundaries to produce urinary pH higher than 7.5. Urinary pH should be monitored hourly.
  • Pediatric patients are administered sodium bicarbonate 1 to 2 mEq/kg by intravenous push. One to two ampules of sodium bicarbonate (44 or 50 mEq per ampule) are mixed in 1 L of D5W and infused at a rate within clinically reasonable boundaries starting at 1.5 to 2.0 times the maintenance rate and then adjusted to maintain the urinary pH above 7.5.
  • When determining infusion rate, the influence on underlying medical conditions, such as congestive heart failure, myocardial ischemia, and renal insufficiency, should be considered.
  • Urinary alkalinization continues until the patient has demonstrated clinical improvement with documented serial decline in serum salicylate levels toward the therapeutic range and correction of acid-base disturbances.
  • Supplemental potassium is administered if serum level is less than 4.0 mEq/L.
• Adverse effects include pulmonary edema, metabolic alkalosis (rare), and hypernatremia (rare).

Hypotension

• The patient is treated with 10 to 20 ml/kg 0.9% saline intravenously and placed in the Trendelenburg position.
• Further fluid therapy is guided by central pressure monitoring to avoid volume overload.
• If hypotension is unresponsive, a vasopressor is administered.

Not Recommended Therapies

Acetazolamide should not be administered to alkalinize urine because it acidifies serum and increases salicylate penetration into the CNS.

Section Outline:

• DIRECTING PATIENT COURSE
  • Admission Considerations
• DECONTAMINATION
  • Out of Hospital
  • In Hospital
• ANTIDOTES
• ADJUNCTIVE TREATMENT
  • Endotracheal Intubation and Mechanical Ventilation
  • Hemodialysis
  • Whole-Bowel Irrigation
  • Urinary Alkalinization
  • Hypotension
  • Not Recommended Therapies

PATIENT MONITORING

• Continuous respiratory and cardiac monitoring should be performed in symptomatic patients.
• Patients should be reassessed frequently for change in mental status and should have serial determinations of serum electrolyte and salicylate levels.
• Patients with rising salicylate levels, altered mental status, seizure, pulmonary edema, or respiratory acidosis should be monitored in an intensive care setting.

EXPECTED COURSE AND PROGNOSIS

• Acute intoxication typically begins within hours of ingestion and resolves within 24 to 48 hours depending on severity; a complete recovery is expected.
• Chronic intoxication may begin within days to weeks of salicylate ingestion and resolves over 48 to 72 hours once treatment is initiated.
• Permanent sequelae of hypoxia or cerebral edema may occur.

DISCHARGE CRITERIA/INSTRUCTIONS

• From the emergency department. Asymptomatic or minimally symptomatic patients may be discharged after gastrointestinal decontamination, observation for 4 to 6 hours, and a psychiatric evaluation, provided that serial serum salicylate levels decline significantlyand acid-base status is normal.
• From the hospital. Asymptomatic patients may be discharged after signs of toxicity resolve, serum electrolytes and renal function return to baseline, serial serum salicylate levels decline to 30 mg/dl, and a psychiatric evaluation is completed, if needed.

Section Outline:

• PATIENT MONITORING
• EXPECTED COURSE AND PROGNOSIS
• DISCHARGE CRITERIA/INSTRUCTIONS

DIAGNOSIS

• Use of the Done nomogram is not recommended.
  • The specific conditions under which the nomogram was developed rarely mimic clinical conditions, so its use is not appropriate in many situations.
  • Use of a 6-hour level often delays treatment of seriously ill patients.
• Use of salicylate concentration alone to guide therapy may lead to either overtreatment or undertreatment of seriously ill patients.
  • Serum salicylate levels should be followed until at least two consecutive measurements demonstrate significant decline.
  • Peak serum salicylate levels may be delayed from 10 to 60 hours with enteric-coated or sustained-release aspirin preparations.
• Methyl salicylate. Pure oil of wintergreen, a liquid formulation containing 100% methyl salicylate, is quickly absorbed in the gastrointestinal tract, resulting in rapid development of clinical salicylism.

TREATMENT

• Urinary alkalinization should be initiated empirically while awaiting initial serum salicylate levels if signs and symptoms consistent with salicylate toxicity are present.
• Ventilator settings of intubated and sedated patients should be adjusted (minute volume) to maintain pCO₂ at the patient's pCO₂ before intubation.

Section Outline:

• DIAGNOSIS
• TREATMENT

Poisoning by analgesics, antipyretics, and antirheumatics: salicylates.

See Also: SECTION II, Anion Gap Metabolic Acidosis and Hypotension chapters; and SECTION III, Sodium Bicarbonate chapter.

RECOMMENDED READING

Anderson RJ, Potts DE, Gabow PA. Unrecognized adult salicylate intoxication. Ann Intern Med 1976;85:745-748.

Gabow PA. How to avoid overlooking salicylate intoxication. J Crit Illness 1986;1:77-85.

Yip L, Jastremski MS, Dart RC. Salicylate intoxication. J Intens Care Med 1997;12:66-78.

Author: Luke Yip

Reviewer: Rivka S. Horowitz