title: Intravenous N-acetylcysteine in pediatric patients with nonacetaminophen acute liver failure: a placebo-controlled clinical trial.
abstract: N-acetylcysteine (NAC) was found to improve transplantation-free survival in only those adults with nonacetaminophen (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 intensive care unit (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.
  
  
  CONCLUSIONS
  NAC did not improve 1-year survival in non-APAP PALF. One-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.
authors.affiliation: Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA 15224, USA. squiresr@upmc.edu
authors.forename: Robert H
authors.initials: RH
authors.lastname: Squires
authors.forename: Anil
authors.initials: A
authors.lastname: Dhawan
authors.forename: Estella
authors.initials: E
authors.lastname: Alonso
authors.forename: Michael R
authors.initials: MR
authors.lastname: Narkewicz
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Shneider
authors.forename: Norberto
authors.initials: N
authors.lastname: Rodriguez-Baez
authors.forename: Dominic Dell
authors.initials: DD
authors.lastname: Olio
authors.forename: Saul
authors.initials: S
authors.lastname: Karpen
authors.forename: John
authors.initials: J
authors.lastname: Bucuvalas
authors.forename: Steven
authors.initials: S
authors.lastname: Lobritto
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Rand
authors.forename: Philip
authors.initials: P
authors.lastname: Rosenthal
authors.forename: Simon
authors.initials: S
authors.lastname: Horslen
authors.forename: Vicky
authors.initials: V
authors.lastname: Ng
authors.forename: Girish
authors.initials: G
authors.lastname: Subbarao
authors.forename: Nanda
authors.initials: N
authors.lastname: Kerkar
authors.forename: David
authors.initials: D
authors.lastname: Rudnick
authors.forename: M James
authors.initials: MJ
authors.lastname: Lopez
authors.forename: Kathleen
authors.initials: K
authors.lastname: Schwarz
authors.forename: Rene
authors.initials: R
authors.lastname: Romero
authors.forename: Scott
authors.initials: S
authors.lastname: Elisofon
authors.forename: Edward
authors.initials: E
authors.lastname: Doo
authors.forename: Patricia R
authors.initials: PR
authors.lastname: Robuck
authors.forename: Sharon
authors.initials: S
authors.lastname: Lawlor
authors.forename: Steven H
authors.initials: SH
authors.lastname: Belle
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage* / Q000627:therapeutic use*; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004311:Double-Blind Method; D005260:Female; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000627:therapeutic use; D006501:Hepatic Encephalopathy / Q000188:drug therapy / Q000401:mortality; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007262:Infusions, Intravenous; D017114:Liver Failure, Acute / Q000188:drug therapy* / Q000401:mortality*; D016031:Liver Transplantation; D008297:Male; D012720:Severity of Illness Index; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D016166:Free Radical Scavengers; D000111:Acetylcysteine