A study which took 8 years to complete (2001-2009) and involved more than 20 pediatric liver transplant centers has shown that N-acetylcysteine (NAC) is NOT effective for nonacetaminophen acute liver failure in the pediatric population (Hepatology 2013; 57: 1542-49).
Eligible patients were drawn from a registry of pediatric acute liver failure (PALF) patients. Among 607 who were enrolled in the registry, 271 were eligible for the NAC trial and 184 of these patients (families) agreed to participate. The most common reasons for patients to be ineligible for the study included acetaminophen toxicity, previous NAC treatment, sepsis, and “reason unknown.”
The design of the study was doubly masked with patients stratified by age and hepatic encephalopathy. Patients either received intravenous NAC (150 mg/kg/d) or D5W for up to 7 consecutive days.
- No significant difference in 1-year survival: 73% of NAC patients and 82% of placebo patients
- NAC patients had lower 1-year liver transplant free survival (p = 0.03): 35% in NAC group compared to 53% of placebo patients.
The study did have several limitations. Despite the lengthy enrollment period, the absolute number of patients was only 92 in each group. In addition, there were differences in the diagnoses in both groups and the ages of the groups, though these were unlikely to change the results. With regard to diagnoses, both groups had ~60% with an indeterminate reason for PALF. However, the NAC group had an increased number with metabolic diseases (14% compared with 5% in placebo group); the most common metabolic disease was Wilson’s disease (7 in NAC group and 3 in placebo group). The NAC group had a median age of 3.7 years compared with 4.5 years for the placebo group.
Another limitation was in testing for acetaminophen-cysteine adducts (A-CA) which can be used as a marker of acetaminophen exposure. This was performed retrospectively in 84 of the participants. A-CA was positive in 9 (six from placebo and three from treatment arm). Again, this was unlikely to change the results as there were no statistical differences in clinical features of those who were tested for A-CA compared with those who were not.
In some ways, the results are surprising due to prospective studies in adults showing benefit of NAC in ALF and a previous retrospective uncontrolled pediatric study suggesting efficacy in PALF. Ultimately, this study proves again that pediatric patients are not “small adults” and highlights the need for prospective pediatric drug trials.
NAC works for acetaminophen-induced ALF but is not helpful for other causes of PALF.
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