Intravenous N-acetylcysteine in pediatric patients with nonacetaminophen acute liver failure: A placebo-controlled clinical trial

• Type of Material: Article
• Authors: Robert H. Squires, Children's Hospital of Pittsburgh of UPMC; Anil Dhawan, Kings College; Estella Alonso, Northwestern University; Michael R. Narkewicz, University of Colorado; Benjamin L. Shneider, Children's Hospital of Pittsburgh of UPMC; Norberto Rodriguez-Baez, University of Texas Southwestern Medical Center; Dominic Dell Olio, Birmingham Children’s Hospital; Saul Karpen, Emory University; John Bucuvalas, Cincinnati Children’s Hospital; Steven Lobritto, Columbia University; Elizabeth Rand, Children's Hospital of Philadelphia; Philip Rosenthal, University of California; Simon Horslen, University of Washington; Vicky Ng, Hospital for Sick Children; Girish Subbarao, University of Indiana; Nanda Kerkar, Mt. Sinai Medical Center; David Rudnick, Washington University; M. James Lopez, University of Michigan; Kathleen Schwarz, Johns Hopkins University; Rene Romero Jr., Emory University; Scott Elisofon, Children’s Hospital of Boston; Edward Doo, National Institutes of Health; Patricia R. Robuck, National Institutes of Health; Sharon Lawlor, University of Pittsburgh; Steven H. Belle, University of Pittsburgh
• Language: English
• Date: 2013-04
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 American Association for the Study of Liver Diseases
• Final Published Version (URL): http://onlinelibrary.wiley.com/doi/10.1002/hep.26001/abstract;jsessionid=CF85E75D8BF00A8BF90D99722038D700.f04t02
• Title of Journal or Parent Work: Hepatology
• ISSN: 0270-9139
• Volume: 57
• Issue: 4
• Start Page: 1542
• End Page: 1549
• Grant/Funding Information: This study was supported by NIH grant UO1-DK58369; and by M01-RR00069, M01-RR00037, and M01 RR08084 from the General Clinical Research Center Program of the National Center for Research Resources of the NIH.
• Keywords: liver transplantation; Child; multi-organ system failure; hepatic encephalopathy; treatment
• Research Categories: Health Sciences, Human Development; Biology, Physiology; Health Sciences, General

Abstract

N-acetylcysteine (NAC) was found to improve transplantation-free survival in only those adults with non-acetaminophen (non-APAP) acute liver failure (ALF) and grade 1–2 hepatic encephalopathy (HE). Because non-APAP ALF differs significantly between children and adults, the Pediatric Acute Liver Failure (PALF) Study Group evaluated NAC in non-APAP PALF. Children from birth through age 17 years with non-APAP ALF enrolled in the PALF registry were eligible to enter an adaptively allocated, doubly masked, placebo-controlled trial using a continuous intravenous infusion of NAC (150 mg/kg/day in 5% dextrose in water [D5W]) or placebo (D5W) for up to 7 days. The primary outcome was 1-year survival. Secondary outcomes included liver transplantation-free survival, liver transplantation (LTx), length of ICU and hospital stays, organ system failure and maximum HE score. A total of 184 participants were enrolled in the trial with 92 in each arm. The 1-year survival did not differ significantly (p=0.19) between the NAC (73%) and placebo (82%) treatment groups. The 1-year LTx-free survival was significantly lower (p=0.03) in those who received NAC (35%) than those who received placebo (53%), particularly, but not significantly so, among those less than 2 years old with HE grade 0–1 (NAC 25%; placebo 60%; p=0.0493). There were no significant differences between treatment arms for hospital or ICU length of stay, organ systems failing, or highest recorded grade of HE. Conclusion: NAC did not improve 1-year survival in non-APAP PALF. 1-year LTx-free survival was significantly lower with NAC, particularly among those < 2 years old. These results do not support broad use of NAC in non-APAP PALF and emphasizes the importance of conducting controlled pediatric drug trials, regardless of results in adults.