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Dosage of N-Acetyl Cysteine in Acute Liver Failure Not Related to Acetaminophen

Published:January 09, 2022DOI:https://doi.org/10.1016/j.jceh.2022.01.002
      We thank Dr Saurabh for his interest in the article INASL-Consensus Statement on Acute Liver Failure (Part-2)-Management of Acute Liver Failure
      • Anand A.C.
      • Nandi B.
      • Acharya S.K.
      • et al.
      Indian National Association for the Study of Liver Consensus statement on acute liver failure (Part-2): management of acute liver failure.
      and for pointing out the printing error.
      The use of N-acetyl cysteine (NAC), a glutathione precursor, was initially introduced in the 1970s for the treatment of acetaminophen-induced ALF, and its safety/efficacy is well established in this fatal condition.
      • Chughlay M.F.
      • Kramer N.
      • Spearman C.W.
      • Werfalli M.
      • Cohen K.
      N-acetylcysteine for non-paracetamol drug-induced liver injury: a systematic review.
      ,
      • Mumtaz K.
      • Azam Z.
      • Hamid S.
      • et al.
      Role of N-acetylcysteine in adults with non-acetaminophen-induced acute liver failure in a center without the facility of liver transplantation.
      NAC has also been shown to provide beneficial effect in non-Acetaminophen ALF (NA-ALF).
      • Lee W.M.
      • Stravitz R.T.
      • Larson A.M.
      Introduction to the revised American Association for the Study of Liver Diseases position paper on acute liver failure 2011.
      Various prospective studies and meta-analyses have also shown a beneficial effect of NAC in improving overall survival (OS), transplant-free survival (TFS) or even post-transplant survival (PTS).
      • Lee W.M.
      • Hynan L.S.
      • Rossaro L.
      • et al.
      Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure.
      A few studies have, however, failed to show significant improvement in overall survival when compared to placebo.
      • Chughlay M.F.
      • Kramer N.
      • Spearman C.W.
      • Werfalli M.
      • Cohen K.
      N-acetylcysteine for non-paracetamol drug-induced liver injury: a systematic review.
      ,
      • Hu J.
      • Zhang Q.
      • Ren X.
      • Sun Z.
      • Quan Q.
      Efficacy and safety of acetylcysteine in “non-acetaminophen” acute liver failure: a meta-analysis of prospective clinical trials.
      In a recent meta-analysis of seven studies, the use of NAC was associated with improvement in OS, TFS, and PTS in patients with NA-ALF.
      • Walayat S.
      • Shoaib H.
      • Asghar M.
      • Kim M.
      • Dhillon S.
      Role of N-acetylcysteine in non-acetaminophen-related acute liver failure: an updated meta-analysis and systematic review.
      There was a significant reduction in the duration of hospital stay. In this meta-analysis, the most common etiology of ALF was acute viral hepatitis. It was concluded that NAC should be used in all patients with NA-ALF especially in nontransplant centers and for optimal outcomes it is preferable to initiate treatment in the early stages of ALF.
      NAC is available as Intravenous (200 mg/mL, 10 mL ampoule) and oral liquid formulation (10% and 20%) of NAC.
      World Health Organization
      Model List of Essential Medicines – 22nd List.
      Traditionally dosage protocol for NAC for acetaminophen-induced ALF includes a 21-h intravenous protocol, which includes (a) 150 mg/kg of NAC 20% in 200 mL 5% dextrose over 60 min followed by (b) 12.5 mg/kg/hour in 500 mL 5% dextrose for 4 h and then (C) 6.25 mg/kg/hour in 1000 mL 5% dextrose for 16 h). Instead of 5% dextrose, 0.9% normal saline can also be used.
      • Kama A.
      • Yılmaz S.
      • Yaka E.
      • et al.
      Comparison of short-term infusion regimens of N-acetylcysteine plus intravenous fluids, sodium bicarbonate plus intravenous fluids, and intravenous fluids alone for prevention of contrast-induced nephropathy in the emergency department.
      For children less than 12 years a body weight of more than 20 kg, the recommended volumes of 5% dextrose are 100 mL, 250 mL, and 500 mL for three dosages, respectively. In children with a body weight of less than 20 kg, the diluting volumes of 5% dextrose at 3 mL/kg, 7 mL/kg, and 14 mL/kg, respectively, have been used. At the end of 21 h infusion, it has been suggested that infusion be continued till encephalopathy resolves and INR normalizes.
      • Ershad M.
      • Naji A.
      • Vearrier D.
      N acetylcysteine.
      In the older studies, NAC has been used either by intravenous route or orally in patients with NA-ALF. The intravenous route has been preferred by many.
      • Sales I.
      • Dzierba A.L.
      • Smithburger P.L.
      • Rowe D.
      • Kane-Gill S.L.
      Use of acetylcysteine for non-acetaminophen-induced acute liver failure.
      A systemic review comparing oral and intravenous NAC showed a similar level of hepatotoxicity in rats with acetaminophen overdose, and the route of dosing did not make much difference.
      • Walayat S.
      • Shoaib H.
      • Asghar M.
      • Kim M.
      • Dhillon S.
      Role of N-acetylcysteine in non-acetaminophen-related acute liver failure: an updated meta-analysis and systematic review.
      One fears that oral NAC may have impaired absorption in, poor tolerance (due to nausea and vomiting), delayed gastric emptying and intestinal failure in the setting of ALF.
      • Sales I.
      • Dzierba A.L.
      • Smithburger P.L.
      • Rowe D.
      • Kane-Gill S.L.
      Use of acetylcysteine for non-acetaminophen-induced acute liver failure.
      A prospective study that included the sick patients with ALF failed to show any significant benefit (in terms of OS and duration of hospital stay) using NAC by oral route.
      • Mumtaz K.
      • Azam Z.
      • Hamid S.
      • et al.
      Role of N-acetylcysteine in adults with non-acetaminophen-induced acute liver failure in a center without the facility of liver transplantation.
      Therefore intravenous administration of NAC was preferred over the oral route by the INASL consensus document. INASL has recommended the dosage used by most of the studies.
      • Lee W.M.
      • Hynan L.S.
      • Rossaro L.
      • et al.
      Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure.
      ,
      • Darweesh S.K.
      • Ibrahim M.F.
      • El-Tahawy M.A.
      Effect of N-acetylcysteine on mortality and liver transplantation rate in non-acetaminophen-induced acute liver failure: a multicenter study.
      ,
      • Nabi T.
      • Nabi S.
      • Rafiq N.
      • Shah A.
      Role of N-acetylcysteine treatment in non-acetaminophen-induced acute liver failure: a prospective study.
      The safety and tolerability of NAC is well established and minor adverse events reported include allergic reactions (Bronchospasm, rash), cardiac arrhythmias and peripheral edema.
      • Walayat S.
      • Shoaib H.
      • Asghar M.
      • Kim M.
      • Dhillon S.
      Role of N-acetylcysteine in non-acetaminophen-related acute liver failure: an updated meta-analysis and systematic review.
      A summary of these studies have been provided in Table 1.
      • Anand A.C.
      • Nandi B.
      • Acharya S.K.
      • et al.
      Indian National Association for the Study of Liver Consensus statement on acute liver failure (Part-2): management of acute liver failure.
      ,
      • Mumtaz K.
      • Azam Z.
      • Hamid S.
      • et al.
      Role of N-acetylcysteine in adults with non-acetaminophen-induced acute liver failure in a center without the facility of liver transplantation.
      ,
      • Lee W.M.
      • Hynan L.S.
      • Rossaro L.
      • et al.
      Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure.
      ,
      • Darweesh S.K.
      • Ibrahim M.F.
      • El-Tahawy M.A.
      Effect of N-acetylcysteine on mortality and liver transplantation rate in non-acetaminophen-induced acute liver failure: a multicenter study.
      • Nabi T.
      • Nabi S.
      • Rafiq N.
      • Shah A.
      Role of N-acetylcysteine treatment in non-acetaminophen-induced acute liver failure: a prospective study.
      • Kortsalioudaki C.
      • Taylor R.M.
      • Cheeseman P.
      • Bansal S.
      • Mieli-Vergani G.
      • Dhawan A.
      Safety and efficacy of N-acetylcysteine in children with non-acetaminophen-induced acute liver failure.
      • Kumarasena R.S.
      • Mananjala Senanayake S.
      • Sivaraman K.
      • et al.
      Intravenous N-acetylcysteine in dengue-associated acute liver failure.
      • Sotelo N.
      • Durazo M.
      • Gonzalez A.
      • Dhanakotti N.
      Early treatment with N-acetylcysteine in children with acute liver failure secondary to hepatitis A.
      • Parkash A.
      • Asghar M.
      • Haider N.
      Non-acetaminophen induced acute liver failure of viral etiology: treatment with and without N-acetylcysteine; comparing the length of hospital stay and survival status in children at the tertiary care hospital.
      Table 1Various Dosage Schedules for the Use of NAC for Non-acetaminophen Acute Liver Failure.
      Study referenceEtiology of ALFNAC regimen usedRoute of administration
      Kortsalioudaki et al, 2008
      • Kortsalioudaki C.
      • Taylor R.M.
      • Cheeseman P.
      • Bansal S.
      • Mieli-Vergani G.
      • Dhawan A.
      Safety and efficacy of N-acetylcysteine in children with non-acetaminophen-induced acute liver failure.
      Infective/AIH/Metabolic/DILI/Indeterminate100 mg/kg/24 h infusion until normalization of INR, death or LT.

      Median duration of treatment-5 (1–77) days
      Intravenous
      Lee et al, 2009
      • Lee W.M.
      • Hynan L.S.
      • Rossaro L.
      • et al.
      Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure.
      DILI/AIH/HBV/Indeterminate150 mg/kg body weight followed by 12.5 mg/kg/hour over 4 h and then 6.25 mg/kg/hour over 16 h. Continued for remaining 67 hIntravenous
      Kumarasena et al, 2010
      • Kumarasena R.S.
      • Mananjala Senanayake S.
      • Sivaraman K.
      • et al.
      Intravenous N-acetylcysteine in dengue-associated acute liver failure.
      Dengue infection150 mg/kg body weight followed by 12.5 mg/kg/hour over 4 h and then 6.25 mg/kg/hour up to72 hIntravenous
      Mumtaz et al, 2009
      • Mumtaz K.
      • Azam Z.
      • Hamid S.
      • et al.
      Role of N-acetylcysteine in adults with non-acetaminophen-induced acute liver failure in a center without the facility of liver transplantation.
      Infective/DILI/AFLP140 mg/kg, followed by 70 mg/kg, for a total of 17 doses, 4 h apart starting within 6 h of admission.Oral
      Soteolo et al, 2009
      • Sotelo N.
      • Durazo M.
      • Gonzalez A.
      • Dhanakotti N.
      Early treatment with N-acetylcysteine in children with acute liver failure secondary to hepatitis A.
      HAV100 mg/kg every 4 h × 16 h, followed by 100 mg/kg every 6–8 h depending on clinical/laboratory improvementOral
      Parkash et al, 2016
      • Parkash A.
      • Asghar M.
      • Haider N.
      Non-acetaminophen induced acute liver failure of viral etiology: treatment with and without N-acetylcysteine; comparing the length of hospital stay and survival status in children at the tertiary care hospital.
      HAV/HEV/Non-A to E100 mg/kg/24 h continuous infusion till normalization of INR or death, median duration of treatment-15.5 daysIntravenous
      Darweesh et al 2017
      • Darweesh S.K.
      • Ibrahim M.F.
      • El-Tahawy M.A.
      Effect of N-acetylcysteine on mortality and liver transplantation rate in non-acetaminophen-induced acute liver failure: a multicenter study.
      Infective/DILI/Pregnancy related150 mg/kg infusion over 30 min followed by 70 mg/kg over 4 h, then 70 mg/kg over 16 h

      Afterwards 150 mg/kg/24 h till 2 INR reports are normal
      Intravenous
      Nabi et al, 2017
      • Nabi T.
      • Nabi S.
      • Rafiq N.
      • Shah A.
      Role of N-acetylcysteine treatment in non-acetaminophen-induced acute liver failure: a prospective study.
      Infective/DILI/AIH150 mg/kg body weight followed by 12.5 mg/kg/hour over 4 h and then 6.25 mg/kg/hour over 16 h, continued for remaining 67 hIntravenous
      INASL Consensus recommendation
      • Anand A.C.
      • Nandi B.
      • Acharya S.K.
      • et al.
      Indian National Association for the Study of Liver Consensus statement on acute liver failure (Part-2): management of acute liver failure.
      ALF all etiologies(a) 150 mg/kg body weight in 250 mL of 5% dextrose over 1 h followed by (b) 50 mg/kg over 4 h and then (c) 100 mg/kg over 16 h. The latter dose, i.e. 100 mg/kg over 16 h, may be repeated till encephalopathy and INR normalize.Intravenous
      Note: ALF, acute liver failure; NAC, N-acetyl cysteine; AIH, autoimmune hepatitis; DILI, drug-induced liver injury; HBV, hepatitis B virus; HAV, hepatitis A virus; AFLP, acute fatty liver of pregnancy.
      INASL consensus document for ALF, after due deliberation, recommended that NAC be administered intravenously in all patients with NA-ALF. The recommended regimen should read (a) 150 mg/kg body weight in 250 mL of 5% dextrose over 1 h followed by (b) 50 mg/kg over 4 h and then (c) 100 mg/kg over 16 h. The latter dose, i.e., 100 mg/kg over 16 h, may be repeated till encephalopathy and INR normalize. The time period of 16 h was wrongly printed as 6 h. We duly acknowledge this unintentional printing mistake, which may be corrected. An erratum has also been requested to be published in the upcoming issue of the journal.

      Conflicts of interest

      The authors who have taken part in this study declare that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

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