1 A single-arm clinical trial of a 48-hour intravenous N-acetylcysteine protocol for treatment of acetaminophen poisoning K. HEARD, 1,2 B. H. RUMACK, 2,3 J. L. GREEN, 1,4 B. BUCHER-BARTELSON, 1,5 S. HEARD, 1 A. C. BRONSTEIN, 1,2 and R. C. DART 1,2 1 Rocky Mountain Poison and Drug Center, Denver, CO, USA 2 Department of Emergency Medicine, University of Colorado School of Medicine, Aurora, CO, USA 3 Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA 4 Vanderbilt University School of Nursing, Nashville, TN, USA 5 University of Colorado School of Public Health, Aurora, CO, USA Introduction. Acetylcysteine prevents hepatic injury when administered soon after acetaminophen overdose. The most commonly used treatment protocols are a 72-hour oral and a 21-hour intravenous (IV) protocol. Between 1984 and 1994, 409 patients were enrolled in a study to describe the outcomes of patients who were treated using a 48-hour IV protocol. In 1991, an interim analysis reported the first 223 patients. The objective of this manuscript is to report the rates of hepatotoxicity and adverse events occurring during a 48-hour IV acetylcysteine protocol in the entire 409 patient cohort. Methods. This was a multicenter, single-arm, open-label clinical trial enrolling patients who presented with a toxic serum acetaminophen concentration within 24 h of acute acetaminophen ingestion. Patients were treated with 140 mg/kg loading dose followed by 70 mg/kg every 4 h for 12 doses. Serum aminotransferase activities were measured every 8 h during the protocol, and adverse events were recorded. The primary outcome was the percentage of subjects who developed hepatotoxicity defined as a peak serum aminotransferase greater than 1000 IU/L. Results. Four hundred and nine patients were enrolled, and 309 met inclusion for the outcome analysis. The overall percentage of patients developing hepatotoxicity was 18.1%, and 3.4% of patients treated within 10 h developed hepatotoxicity. One acetaminophen-related death occurred in a patient treated at 22 h. Adverse events occurred in 28.9% of enrolled subjects; the most common adverse events were nausea, vomiting, and flushing, and no events were rated as serious by the investigator. Conclusions. Acetaminophen-overdosed patients treated with IV acetylcysteine administered as 140 mg/kg loading dose followed by 70 mg/kg every 4 h for 12 doses had a low rate of hepatotoxicity and few adverse events. This protocol delivers a higher dose of acetylcysteine which may be useful in selected cases involving very large overdoses. Keywords: Acetylcysteine; Acetaminophen; Liver injury; Antidote; Poisoning Introduction In the United States, acetaminophen overdose is one of the most common pharmaceutical overdoses resulting in hospitalization. 1 Acetylcysteine therapy for acetaminophen overdose is associated with a very high rate of survival and significant hepatic injury is uncommon when treatment is started within 10 h of exposure. 2–4 For almost 30 years, the only approved protocol in the United States required 72 h of oral treatment. However, in 2004, an intravenous (IV) formulation was approved using a 20-hour protocol 5 first described by Prescott et al. 6 Several recent cases have suggested that some patients will develop hepatic injury or even hepatic failure despite early treatment with the 20-hour protocol. 7–9 One possible reason for these treatment failures is the acetylcysteine dose administered using the 20-hour protocol is not sufficient in the setting of a massive ingestion (  40 gm); pharmacoki- netic modeling suggests that a higher-dose IV protocol may be needed to prevent hepatic injury in massive over- dose cases. 10,11 Several protocols have been reported, such as doubling the final infusion rate, 7 basing the dose on the serum acetaminophen concentrations, 10 and repeating the IV protocol. 9 However, the efficacy and safety of these higher dose protocols is not known. In 1984, a clinical trial was initiated to evaluate a 48-hour intravenous acetylcysteine protocol. This protocol provided a much higher total acetylcysteine dose than the 21-hour protocol. A report including the first 223 patients enrolled in this study was published in 1991. 12 However, an additional 186 subjects were enrolled subsequent to this publication but never described as the support for the study ended prior to Clinical Toxicology (2014), Early Online: 1–7 Copyright © 2014 Informa Healthcare USA, Inc. ISSN: 1556-3650 print / 1556-9519 online DOI: 10.3109/15563650.2014.902955 ORIGINAL ARTICLE Received 28 October 2013; accepted 2 March 2014. Address correspondence to Kennon Heard, Rocky Mountain Poison and Drug Center, 777 Bannock ST mc 0180, Denver, CO 80204, USA. Tel:  303-389-1264. E-mail: Kennon.heard@rmpdc.org Clinical Toxicology Downloaded from informahealthcare.com by 71.229.180.242 on 04/13/14 For personal use only.