Clinical Drug Investigation

, Volume 37, Issue 5, pp 473–482 | Cite as

Effect of N-Acetylcysteine on Mortality and Liver Transplantation Rate in Non-Acetaminophen-Induced Acute Liver Failure: A Multicenter Study

  • Samar K. Darweesh
  • Mona F. Ibrahim
  • Mahmoud A. El-Tahawy
Original Research Article

Abstract

Introduction and Aim

Previous studies and systematic reviews have not provided conclusive evidence on the effect of N-acetylcysteine (NAC) in non-acetaminophen-induced acute liver failure (NAI-ALF). We aimed to study the value of intravenous NAC in reducing liver transplantation and mortality in NAI-ALF.

Patients and Methods

In a prospective, multicenter, observational study, acute liver failure patients without clinical or historical evidence of acetaminophen overdose were enrolled. NAC infusion (in empirical dose) was given as 150 mg/kg in 100 ml dextrose 5% over half an hour, then 70 mg/kg in 500 ml dextrose 5% over 4 h, then 70 mg/kg in 500 ml dextrose 5% over 16 h. Thereafter continuous infusion was administered over 24 h of 150 mg/kg in 500 ml dextrose 5% until up to two consecutive normal international normalized ratios (INRs) were obtained. Our endpoints were recovery, transplantation, or death. The primary outcome of the study was to assess reduction in mortality or liver transplantation. The secondary outcome was the evaluation of other clinical outcomes (length of ICU and hospital stays, organ system failure, and hepatic encephalopathy).

Results

The study included a total of 155 adults; the NAC group (n = 85) were given NAC between January 2011 to December 2013 and the control group (n = 70) were not given NAC and were included from files dating between 2010 and 2011. Both groups (before NAC) were comparable with regard to etiology, age, sex, smoking, presence of co-morbidities, encephalopathy, liver profile, and INR. The success rate (transplant-free survival) in the NAC group was 96.4%. While in the control group, 17 patients (23.3%) recovered and 53 (76.6%) did not recover, of these 37 (53.3%) had liver transplantation and 16 (23.3%) died (p < 0.01). The NAC group had significantly shorter hospital stays (p < 0.001), less encephalopathy (p = 0.02), and less bleeding (p < 0.01) than the control group. The control group reported a higher ICU admission (p = 0.01) rate and abnormal creatinine and electrolytes (p = 0.002, p < 0.01, respectively). Liver profile and INR (after NAC infusion) differed significantly between the two groups with regard to bilirubin (increased in controls, p = 0.02), AST and INR (decreased in NAC group, p < 0.001 for both), but the ALT decrease showed no statistical significance between the two groups.

Conclusions

When administered on admission, intravenous NAC caused a reduction in NAI-ALF mortality and need for transplantation. NAC decreased encephalopathy, hospital stay, ICU admission, and failure of other organs.

References

  1. 1.
    Mumtaz K, Azam Z, Hamid S, Abid S, Memon S, Ali Shah H, Jafri W. Role of N-acetylcysteine in adults with non-acetaminophen induced acute liver failure in a center without the facility of liver transplantation. Hepatol Int. 2009;3:563–70. doi:10.1007/s12072-009-9151-0.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    O’Grady JG, Schalm SW, Williams R. Acute liver failure: redefining the syndromes. Lancet. 1993;342(8866):273–5.CrossRefPubMedGoogle Scholar
  3. 3.
    O’Grady JG, Williams R. Classification of acute liver failure. Lancet. 1993;342(8873):743.CrossRefPubMedGoogle Scholar
  4. 4.
    Smilkstein MJ, Bronstein AC, Linden C, Augenstein WL, Kulig KW, Rumack BH. Acetaminophen overdose: a 48-h intravenous N-acetylcysteine treatment protocol. Ann Emerg Med. 1991;20(10):1058–63.CrossRefPubMedGoogle Scholar
  5. 5.
    Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976–1985). N Engl J Med. 1988;319(24):1557–62.CrossRefPubMedGoogle Scholar
  6. 6.
    Burgunder JM, Varriale A, Lauterburg BH. Effect of N-acetylcysteine on plasma cysteine and glutathione following paracetamol administration. Eur J Clin Pharmacol. 1989;36(2):127–31.CrossRefPubMedGoogle Scholar
  7. 7.
    Zafarullah M, Li WQ, Sylvester J, Ahmad M. Molecular mechanisms of N-acetylcysteine actions. Cell Mol Life Sci. 2003;60(1):6–20.CrossRefPubMedGoogle Scholar
  8. 8.
    Harrison P, Wendon J, Williams R. Evidence of increased guanylate cyclase activation by acetylcysteine in fulminant hepatic failure. Hepatology. 1996;23(5):1067–72.CrossRefPubMedGoogle Scholar
  9. 9.
    Harrison PM, Wendon JA, Gimson AE, Alexander GJ, Williams R. Improvement by acetylcysteine of hemodynamics and oxygen transport in fulminant hepatic failure. N Engl J Med. 1991;324(26):1852–7.CrossRefPubMedGoogle Scholar
  10. 10.
    Ytrebo LM, Korvald C, Nedredal GI, Elvenes OP, Nielsen Grymyr OJ, Revhaug A. N-Acetylcysteine increases cerebral perfusion pressure in pigs with fulminant hepatic failure. Crit Care Med. 2001;29(10):1989–95.CrossRefPubMedGoogle Scholar
  11. 11.
    Peristeris P, Clark BD, Gatti S, Faggioni R, Mantovani A, Mengozzi M, et al. N-acetylcysteine and glutathione as inhibitors of tumor necrosis factor production. Cell Immunol. 1992;140:390–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Ben-Ari Z, Vaknin H, Tur-Kaspa R. N-Acetylcysteine in acute hepatic failure (non-paracetamol induced). Hepatogastroenterology. 2000;47(33):786–9.PubMedGoogle Scholar
  13. 13.
    Katoonizadeh A, Decaestecker J, Wilmer A, Aerts R, Verslype C, Vansteenbergen W, et al. MELD score to predict outcome in adult patients with non-acetaminophen-induced acute liver failure. Liver Int. 2007;27(3):329–34.CrossRefPubMedGoogle Scholar
  14. 14.
    Escorsell A, Mas A, de la Mata M. Acute liver failure in Spain: analysis of 267 cases. Liver Transpl. 2007;13(10):1389–95.CrossRefPubMedGoogle Scholar
  15. 15.
    Sklar GE, Subramaniam M. Acetylcysteine treatment for non-acetaminophen-induced acute liver failure. Ann Pharmacother. 2004;38(3):498–500 Epub 2004 Jan 12.CrossRefPubMedGoogle Scholar
  16. 16.
    Lee WM, Larson AM, Stravitz RT. AASLD Position Paper: The Management of Acute Liver Failure: Update 2011. http://www.aasld.org/practiceguidelines/ Documents/AcuteLiverFailureUpdate2011.pdf. Accessed Jan 2016.
  17. 17.
    Lee WM, Hynan LS, Rossaro L, Fontana RJ, Stravitz RT, Larson AM, et al. Acute Liver Failure Study Group. Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. Gastroenterology. 2009;137:856–86.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Sales I, Dzierba AL, Smithburger PL, Rowe D, Kane-Gill SL. Use of acetylcysteine for non-acetaminophen-induced acute liver failure. Ann Hepatol. 2013;12(1):6–10.PubMedGoogle Scholar
  19. 19.
    Bass S, Zook N. Intravenous acetylcysteine for indications other than acetaminophen overdose. Am J Health Syst Pharm. 2013;70(17):1496–501. doi:10.2146/ajhp120645.CrossRefPubMedGoogle Scholar
  20. 20.
    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. Clin Res Hepatol Gastroenterol. 2015;39(5):594–9. doi:10.1016/j.clinre.2015.01.003 Epub 2015 Feb 26.CrossRefPubMedGoogle Scholar
  21. 21.
    Chughlay MF, Kramer N, Spearman CW, Werfalli M, Cohen K. N-acetylcysteine for non-paracetamol drug-induced liver injury: a systematic review. Br J Clin Pharmacol. 2016;. doi:10.1111/bcp.12880 [Epub ahead of print].PubMedGoogle Scholar
  22. 22.
    Koch A, Trautwein C. N-acetylcysteine on its way to a broader application in patients with acute liver failure. Hepatology. 2010;51(1):338–40. doi:10.1002/hep.23484.CrossRefPubMedGoogle Scholar
  23. 23.
    Trey C, Davidson CS. The management of fulminant hepatic failure. Prog Liver Dis. 1970;3:282–98.PubMedGoogle Scholar
  24. 24.
    Zwingmann C, Bilodeau M. Metabolic insights into the hepato-protective role of N-acetylcysteine in mouse liver. Hepatology. 2006;43:454–63.CrossRefPubMedGoogle Scholar
  25. 25.
    Pitari G, Dupre S, Spirito A, Antonini G, Amicarelli F. Hypotaurine protection on cell damage by singlet oxygen. Adv Exp Med Biol. 2000;483:157–62.CrossRefPubMedGoogle Scholar
  26. 26.
    Jones AL. Mechanism of action and value of N-acetylcysteine in the treatment of early and late acetaminophen poisoning: a critical review. J Toxicol Clin Toxicol. 1998;36:277–85.CrossRefPubMedGoogle Scholar
  27. 27.
    Kortsalioudaki C, Taylor RM, Cheeseman P, Bansal S, Mieli-Vergani G, Dhawan A. Safety and efficacy of N-acetylcysteine in children with non-acetaminophen-induced acute liver failure. Liver Transpl. 2008;14(1):25–30.CrossRefPubMedGoogle Scholar
  28. 28.
    Gunduz H, Karabay O, Tamer A, Özaras R, Mert A, Tabak ÖF. N-acetylcysteine therapy in acute viral hepatitis. World J Gastroenterol. 2003;9(12):2698–700.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Squires RH, Dhawan A, Alonso E, Narkewicz MR, Shneider BL, Rodriguez-Baez N, et al. Intravenous N-acetylcysteine in pediatric patients with non-acetaminophen acute liver failure: a Placebo-Controlled Clinical Trial. Hepatology. 2013;57(4):1542–9. doi:10.1002/hep.26001.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Nguyen-Khac E, Thevenot T, Piquet MA, Benferhat S, Goria O, Chatelain D, Tramier B. Glucocorticoids plus N-acetylcysteine in severe alcoholic hepatitis. N Engl J Med. 2011;365:1781–9.CrossRefPubMedGoogle Scholar
  31. 31.
    Singh S, Hynan LS, Lee WM. Improvements in hepatic serological biomarkers are associated with clinical benefit of intravenous N-acetylcysteine in early stage non-acetaminophen acute liver failure. Dig Dis Sci. 2013;58(5):1397–402. doi:10.1007/s10620-012-2512-x.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  • Samar K. Darweesh
    • 1
  • Mona F. Ibrahim
    • 2
  • Mahmoud A. El-Tahawy
    • 3
  1. 1.Hepato-Gastroenterology and Tropical Medicine Department, Faculty of MedicineCairo UniversityCairoEgypt
  2. 2.Anesthesiology and ICU Department, Faculty of MedicineCairo UniversityCairoEgypt
  3. 3.Internal Medicine and Hepatology Department, National Liver InstituteMenoufya UniversityShibin El KomEgypt

Personalised recommendations