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Acetaminophen Overdose with Altered Acetaminophen Pharmacokinetics and Hepatotoxicity Associated with Premature Cessation of Intravenous N-Acetylcysteine Therapy

at time of writing, Senior Fellow, Medical Toxicology, New York City Poison Control Center, New York, NY; Department of Emergency Medicine, School of Medicine, New York University, New York, NY; now, Assistant Professor, Emergency Medicine, School of Medicine, New York University

Mary Ann Howland, PharmD

Clinical Professor of Pharmacy, College of Pharmacy, St. John's University, New York, NY; Adjunct Professor of Emergency Medicine, School of Medicine, New York University; Consultant, New York City Poison Control Center; Consultant, Bellevue Hospital Center Emergency Department, New York, NY

Robert S Hoffman, MD

Associate Professor, Emergency Medicine and Medicine (Clinical Pharmacology), School of Medicine, New York University; Director, New York City Poison Control Center

Lewis S Nelson, MD

Associate Professor, Emergency Medicine, School of Medicine, New York University; Director, Medical Toxicology Fellowship Program and Associate Director, New York City Poison Control Center

Reprints: Dr. Smith, 455 First Ave., Room 123, New York, NY 10016, fax 212/447-8223, Silas.Smith{at}nyumc.org

OBJECTIVE: To report a case of erratic absorption, double peak serum concentrations, and hepatotoxicity following premature cessation of intravenous N-acetylcysteine (NAC) treatment in the setting of a massive acetaminophen overdose.

CASE SUMMARY: A 78-year-old man reportedly ingested approximately 96 immediate-release acetaminophen 500-mg tablets (48 g) over a one-hour period in an apparent suicide attempt. The acetaminophen concentration at 2.25 hours was 264 µg/mL. Intravenous NAC was initiated 5 hours postingestion. At 6.25 hours postingestion, the acetaminophen concentration was 281 µg/mL. Following administration of intravenous NAC for 21 hours, therapy was discontinued despite a residual acetaminophen concentration of 116 µg/mL. The patient experienced hepatotoxicity, coagulopathy, and renal injury. Pharmacokinetic analysis revealed significantly prolonged acetaminophen absorption and a second peak acetaminophen concentration of 228 µg/mL approximately 48 hours postingestion. Direct in-hospital monitoring of the patient made a second ingestion unlikely.

DISCUSSION: Acetaminophen overdose is usually effectively managed with NAC. Patients with massive ingestions may have altered absorption kinetics due to acetaminophen's solubility being exceeded, physiologically or chemically altered gastrointestinal emptying or motility, or other factors. These patients may benefit from gastrointestinal decontamination and prolonged NAC therapy.

CONCLUSIONS: In patients with massive acetaminophen ingestion, erratic absorption may occur, and toxic serum concentrations may persist beyond a standard 21-hour course of intravenous NAC therapy. Acetaminophen concentrations and aminotransferase levels should be evaluated at the completion of the intravenous NAC infusion to ensure complete elimination of acetaminophen and absence of hepatotoxicity and to exclude the need for prolonged treatment.

Key Words: acetaminophen, hepatotoxicity, N-acetylcysteine

Published Online, July 15, 2008. www.theannals.com, DOI 10.1345/aph.1K680