Intravenous N-acetylcysteine in pediatric patients with nonacetaminophen acute liver failure

A placebo-controlled clinical trial

Robert H. Squires, Anil Dhawan, Estella Alonso, Michael R. Narkewicz, Benjamin L. Shneider, Norberto Rodriguez-Baez, Dominic Dell Olio, Saul Karpen, John Bucuvalas, Steven Lobritto, Elizabeth Rand, Philip Rosenthal, Simon Horslen, Vicky Ng, Girish Subbarao, Nanda Kerkar, David Rudnick, M. James Lopez, Kathleen Schwarz, Rene Romero & 5 others Scott Elisofon, Edward Doo, Patricia R. Robuck, Sharon Lawlor, Steven H. Belle

Research output: Contribution to journalArticle

66 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1542-1549
Number of pages8
JournalHepatology
Volume57
Issue number4
DOIs
StatePublished - Apr 2013

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Acute Liver Failure
Controlled Clinical Trials
Acetylcysteine
Placebos
Pediatrics
Hepatic Encephalopathy
Survival
Liver Transplantation
Intensive Care Units
Length of Stay
Glucose
Water
Intravenous Infusions
Registries
Transplantation
Parturition

ASJC Scopus subject areas

  • Hepatology

Cite this

Squires, R. H., Dhawan, A., Alonso, E., Narkewicz, M. R., Shneider, B. L., Rodriguez-Baez, N., ... Belle, S. H. (2013). Intravenous N-acetylcysteine in pediatric patients with nonacetaminophen acute liver failure: A placebo-controlled clinical trial. Hepatology, 57(4), 1542-1549. https://doi.org/10.1002/hep.26001

Intravenous N-acetylcysteine in pediatric patients with nonacetaminophen acute liver failure : A placebo-controlled clinical trial. / Squires, Robert H.; Dhawan, Anil; Alonso, Estella; Narkewicz, Michael R.; Shneider, Benjamin L.; Rodriguez-Baez, Norberto; Olio, Dominic Dell; Karpen, Saul; Bucuvalas, John; Lobritto, Steven; Rand, Elizabeth; Rosenthal, Philip; Horslen, Simon; Ng, Vicky; Subbarao, Girish; Kerkar, Nanda; Rudnick, David; Lopez, M. James; Schwarz, Kathleen; Romero, Rene; Elisofon, Scott; Doo, Edward; Robuck, Patricia R.; Lawlor, Sharon; Belle, Steven H.

In: Hepatology, Vol. 57, No. 4, 04.2013, p. 1542-1549.

Research output: Contribution to journalArticle

Squires, RH, Dhawan, A, Alonso, E, Narkewicz, MR, Shneider, BL, Rodriguez-Baez, N, Olio, DD, Karpen, S, Bucuvalas, J, Lobritto, S, Rand, E, Rosenthal, P, Horslen, S, Ng, V, Subbarao, G, Kerkar, N, Rudnick, D, Lopez, MJ, Schwarz, K, Romero, R, Elisofon, S, Doo, E, Robuck, PR, Lawlor, S & Belle, SH 2013, 'Intravenous N-acetylcysteine in pediatric patients with nonacetaminophen acute liver failure: A placebo-controlled clinical trial', Hepatology, vol. 57, no. 4, pp. 1542-1549. https://doi.org/10.1002/hep.26001
Squires, Robert H. ; Dhawan, Anil ; Alonso, Estella ; Narkewicz, Michael R. ; Shneider, Benjamin L. ; Rodriguez-Baez, Norberto ; Olio, Dominic Dell ; Karpen, Saul ; Bucuvalas, John ; Lobritto, Steven ; Rand, Elizabeth ; Rosenthal, Philip ; Horslen, Simon ; Ng, Vicky ; Subbarao, Girish ; Kerkar, Nanda ; Rudnick, David ; Lopez, M. James ; Schwarz, Kathleen ; Romero, Rene ; Elisofon, Scott ; Doo, Edward ; Robuck, Patricia R. ; Lawlor, Sharon ; Belle, Steven H. / Intravenous N-acetylcysteine in pediatric patients with nonacetaminophen acute liver failure : A placebo-controlled clinical trial. In: Hepatology. 2013 ; Vol. 57, No. 4. pp. 1542-1549.
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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.",
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T2 - A placebo-controlled clinical trial

AU - Squires, Robert H.

AU - Dhawan, Anil

AU - Alonso, Estella

AU - Narkewicz, Michael R.

AU - Shneider, Benjamin L.

AU - Rodriguez-Baez, Norberto

AU - Olio, Dominic Dell

AU - Karpen, Saul

AU - Bucuvalas, John

AU - Lobritto, Steven

AU - Rand, Elizabeth

AU - Rosenthal, Philip

AU - Horslen, Simon

AU - Ng, Vicky

AU - Subbarao, Girish

AU - Kerkar, Nanda

AU - Rudnick, David

AU - Lopez, M. James

AU - Schwarz, Kathleen

AU - Romero, Rene

AU - Elisofon, Scott

AU - Doo, Edward

AU - Robuck, Patricia R.

AU - Lawlor, Sharon

AU - Belle, Steven H.

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N2 - 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.

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