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.

Conclusion: 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.

Figure 1. Enrollment in the NAC trial

Between June 2003 and September 2009, 607 patients enrolled in the PALF longitudinal study were screened following site specific IRB approval for the NAC protocol. 336 were ineligible. Of the 271 patients eligible for enrollment, 87 refused consent, leaving 184 enrolled in the NAC trial, there were 92 patient in each arm. Only 2 patients withdrew following enrollment, and they were both in the Placebo arm.

Figure 2. Primary outcome: 1 year survival

Product-limit estimates were used to obtain the cumulative percentages of participants surviving 1 year following randomization. A log-rank test was used to assess statistical significance of the difference in survival curves. The cumulative percentage of children who were alive 1 year following randomization to NAC (dashed line) or placebo (solid line) is depicted. The percent surviving 1 year was higher in patients receiving placebo at 82% than NAC at 73%, but the differences were not significant with a p-value of 0.19.

Figure 3

Product-limit estimates were used to obtain the cumulative percentages of participants with 1 year transplantation free survival. A log-rank test was used to assess statistical significance of the difference in survival curves. The cumulative percentage of children with liver transplantation-free survival 1 year following randomization to NAC (dashed line) or placebo (solid line) is depicted. The cumulative percentage of patients with liver transplantation-free survival was 53% when given placebo vs 35% when given NAC, with a p-value of 0.03.