Dr. Cayley is assistant professor in the Eau Claire Family Medicine Residency Program, University of Wisconsin School of Medicine, in Eau Claire, and a reviewer for DynaMed. Dr. Alper is medical director of clinical reference products for EBSCO Publishing, in Ipswich, Mass., and editor-in-chief of DynaMed (www.dynamicmedical.com), a database of comprehensive updated summaries covering nearly 2,000 clinical topics.

Description
• Accidental or intentional overdose of OTC analgesic that is generally safe when taken in recommended doses

ICD-9 codes
• 965.4 poisoning by aromatic analgesics, not elsewhere classified
• 995.2 unspecified adverse effect of drug, medicinal, and biologic substance
• E850.4 accidental poisoning by aromatic analgesics, not elsewhere classified


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Incidence/prevalence
• Second-most common poisoning after alcohol
• Acute acetaminophen ingestion has 0.02% incidence.
• Most common cause of acute liver failure (40%-50%)

Pathogenesis and complications
• Minimum toxic single dose is 7.5 g in adults and >150 mg/kg in children.
• Peak levels occur three to four hours after acute ingestion, hepatotoxicity 12-24 hours later.
• With saturation of sulfate and glucuronide conjugation and depletion of hepatic glutathione, reactive metabolites covalently bind hepatocytes and cause cell lysis.
• Same reaction occurs in kidneys.

Symptoms
• Frequently presents as a suicide gesture by teenagers, young adults, and women; patient may have told others about overdose.
• Acetaminophen is commonly believed to be a safe drug, and intentional ingestions may be ignored or overlooked by family or friends.
• Occasionally nausea, vomiting, diaphoresis, pallor, but even severely poisoned patients can be asymptomatic, and symptoms are rare prior to onset of hepatic failure.
• Symptoms related to hepatotoxicity may develop over one to five days: anorexia, nausea, vomiting, malaise, abdominal pain, pallor, diaphoresis, jaundice, confusion, stupor, coagulation defects, hypoglycemia, encephalopathy, renal failure, cardiomyopathy.
• Chronic alcohol use or acute binge drinking may contribute to toxicity.

Physical exam
• Abnormal findings rare prior to onset of hepatic failure
• Right upper quadrant tenderness or mild hepatomegaly may occur with hepatic damage.

Diagnosis and testing
• Based on history and acetaminophen levels
• Use DynaMed Acetaminophen Overdose Curve (www.ebscohost.com/dynamed/overdoseCurves.php [accessed June 8, 2007]) to determine toxicity based on serum acetaminophen levels and time post ingestion.
• Consider repeated serum acetaminophen concentrations if extended-release preparations ingested.
• Liver enzymes and coagulation profiles are useful as baseline tests if liver toxicity subsequently develops.
• Abnormal renal function tests may occur in minority of patients with acetaminophen poisoning.
• Arterial lactate levels predict mortality.

Treatment
• Use DynaMed Acetaminophen Overdose Curve to determine need for treatment based on serum
acetaminophen level and time since ingestion.
• No treatment if presumed ingested dose <100 mg/kg or if blood tests show nontoxic acetaminophen level.
• Hospitalize if serum level in toxic range (150-200 µg/mL at four hours post ingestion), treat with IV fluids (5% dextrose in half-strength normal saline at 150 mL/hr) plus N-acetylcysteine orally (Mucomyst, generic) or IV (Acetadote).
• Consult hepatologist if liver failure.

Medications
• Activated charcoal recommended but clinical benefitis unclear.
• N-acetylcysteine (started within eight hours of ingestion)
— Oral formulation (Mucomyst, generic)
◊ Given as 140 mg/kg p.o. loading dose, then 70 mg/kg p.o. every four hours for 68 hours (17 doses)
◊ Cost for 70-kg patient about $275 for Mucomyst, $200 for generic
— IV formulation (Acetadote)◊ Given as 150 mg/kg over 15 minutes, then 50 mg/kg over four hours, then 100 mg/kg over 16 hours
◊ Cost for 70-kg patient about $474, or $45-$62 if using oral solution for IV delivery
• Discontinue if nontoxic level.

Prognosis
• Treatment most effective if started within eight hours of ingestion but may be effective if started within 24 hours.
• Recovery occurs over days.
• Liver histology returns to normal within three months; complete recovery if patient survives.
• 27% mortality reported with acetaminophen-induced acute liver failure

Follow-up
• Monitoring young children at home appears safe for exposures up to 200 mg/kg.
• Monitor if extended-release formulation of acetaminophen was ingested.
• Check liver function tests and chemistries daily for four days if toxic exposure.
• Normal prothrombin time, aspartate aminotransferase, and alanine aminotransferase 48 hours after ingestion associated with very low risk of hepatotoxicity

References available at (www.dynamicmedical.com).