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Published in: Hepatology International 4/2020

01-07-2020 | Hepatic Encephalopathy | Original Article

Utility of N-acetylcysteine in ischemic hepatitis in cirrhotics with acute variceal bleed: a randomized controlled trial

Authors: Rakhi Maiwall, Awinash Kumar, Ajeet Singh Bhadoria, Ankur Jindal, Guresh Kumar, Ankit Bhardwaj, Jaswinder Singh Maras, Manoj Kumar Sharma, Barjesh Chandra Sharma, Shiv Kumar Sarin

Published in: Hepatology International | Issue 4/2020

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Abstract

Background and aims

Ischemic hepatitis (IH) following acute variceal bleed (AVB) carries an ominous prognosis. N-Acetylcysteine (NAC), a potent anti-oxidant, may prevent IH by improving tissue oxygen delivery and improving hepatic hypoxia.

Methods

Consecutive cirrhotics with AVB were prospectively randomized to receive either standard of care (SOC) plus NAC intravenously for 72 h(at 150 mg/kg/h for 1 h followed by 12.5 mg/kg/h for 4 h, followed by 6.25 mg/kg for 67 h) (Group A, n = 107) or SOC alone (Group B, n = 107).

Results

Baseline characteristics were comparable. IH developed more frequently in Gr.B 25(23%) than A-15(14%); p = 0.08). Incidence of IH increased with severity of liver disease. Binary logistic regression analysis showed reduced incidence of IH in Gr.A than B [odds ratio (OR) 0.33, 0.11–0.93] patients after controlling for other significant factors. The incidence of acute kidney injury (AKI) was also reduced in Gr.A [OR 0.34, 0.15–0.75]. Development of IH was significantly associated with increased deaths due to liver failure at 6 weeks [subdistribution hazard ratio (SHR) 21.6, 7.4–62.8]. On multivariate competing risk analysis, significantly lower deaths due to liver failure (SHR 0.33, 0.11–0.97) were noted in Gr.A than B.

Conclusions

One in five patients with acute variceal bleed develops ischemic hepatitis which is associated with worse outcomes. NAC therapy averts deaths due to liver failure by preventing IH and reduces AKI and is, therefore, recommended for cirrhotics with acute variceal bleed.

Trial registration

Clinicaltrials.gov no: NCT 02015403.
Appendix
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Literature
1.
go back to reference Gitlin N, Serio KM. Ischemic hepatitis: widening horizons. Am J Gastroenterol 1992;87:831–836PubMed Gitlin N, Serio KM. Ischemic hepatitis: widening horizons. Am J Gastroenterol 1992;87:831–836PubMed
2.
go back to reference Seeto RK, Fenn B, Rockey DC. Ischemic hepatitis: clinical presentation and pathogenesis. Am J Med 2000;109:109–113CrossRef Seeto RK, Fenn B, Rockey DC. Ischemic hepatitis: clinical presentation and pathogenesis. Am J Med 2000;109:109–113CrossRef
3.
go back to reference Henrion J, Schapira M, Luwaert R, Colin L, Delannoy A, Heller FR. Hypoxic hepatitis: clinical and hemodynamic study in 142 consecutive cases. Medicine (Baltimore). 2003;82:392–406CrossRef Henrion J, Schapira M, Luwaert R, Colin L, Delannoy A, Heller FR. Hypoxic hepatitis: clinical and hemodynamic study in 142 consecutive cases. Medicine (Baltimore). 2003;82:392–406CrossRef
4.
go back to reference Henrion J, Colin L, Schmitz A, Schapira M, Heller FR. Ischemic hepatitis in cirrhosis. Rare but lethal. J Clin Gastroenterol 1993;16:35–39CrossRef Henrion J, Colin L, Schmitz A, Schapira M, Heller FR. Ischemic hepatitis in cirrhosis. Rare but lethal. J Clin Gastroenterol 1993;16:35–39CrossRef
5.
go back to reference Kamiyama T, Miyakawa H, Tajiri K,Marumo F, Sato C. Ischemic hepatitis in cirrhosis. Clinical features and prognostic implications. J Clin Gastroenterol 1996;22:126–130 Kamiyama T, Miyakawa H, Tajiri K,Marumo F, Sato C. Ischemic hepatitis in cirrhosis. Clinical features and prognostic implications. J Clin Gastroenterol 1996;22:126–130
6.
go back to reference Erecinska M, Silver IA. Tissue oxygen tension and brain sensitivity to hypoxia. Respir Physiol 2001;128:263–276CrossRef Erecinska M, Silver IA. Tissue oxygen tension and brain sensitivity to hypoxia. Respir Physiol 2001;128:263–276CrossRef
7.
go back to reference Hoppeler H, Vogt M. Muscle tissue adaptations to hypoxia. J Exp Biol 2001;204:3133–3139PubMed Hoppeler H, Vogt M. Muscle tissue adaptations to hypoxia. J Exp Biol 2001;204:3133–3139PubMed
8.
go back to reference Ciobanu AO, Gherasim L. Ischemic hepatitis—intercorrelated pathology. Maedica (Buchar) 2018;13(1):5–11CrossRef Ciobanu AO, Gherasim L. Ischemic hepatitis—intercorrelated pathology. Maedica (Buchar) 2018;13(1):5–11CrossRef
9.
go back to reference Schumacker PT, Chandel N, Agusti AG. Oxygen conformance of cellular respiration in hepatocytes. Am J Physiol 1993;265:L395–L402PubMed Schumacker PT, Chandel N, Agusti AG. Oxygen conformance of cellular respiration in hepatocytes. Am J Physiol 1993;265:L395–L402PubMed
10.
go back to reference Lautt WW. Mechanism and role of intrinsic regulation of hepatic arterial blood flow: hepatic arterial buffer response. Am J Physiol 1985;249:G549–G556PubMed Lautt WW. Mechanism and role of intrinsic regulation of hepatic arterial blood flow: hepatic arterial buffer response. Am J Physiol 1985;249:G549–G556PubMed
11.
go back to reference Richter S, Mucke I, Menqer MD, Vollmar B. Impact of intrinsic blood flow regulation in cirrhosis: maintenance of hepatic arterial buffer response. Am J Physiol Gastrointest Liver Physiol 2000;279:G454–G462CrossRef Richter S, Mucke I, Menqer MD, Vollmar B. Impact of intrinsic blood flow regulation in cirrhosis: maintenance of hepatic arterial buffer response. Am J Physiol Gastrointest Liver Physiol 2000;279:G454–G462CrossRef
12.
go back to reference Rank N, Michel C, Haertel C et al. N-acetylcysteine increases liver blood flow and improves liver function in septic shock patients: results of a prospective, randomized, double-blind study. Crit Care Med 2000;28 (12):3799–3807 Rank N, Michel C, Haertel C et al. N-acetylcysteine increases liver blood flow and improves liver function in septic shock patients: results of a prospective, randomized, double-blind study. Crit Care Med 2000;28 (12):3799–3807
13.
go back to reference 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. Hepatol Int 2009;3:563–570CrossRef 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. Hepatol Int 2009;3:563–570CrossRef
14.
go back to reference Sarin SK, Kumar A, Anqus PW, et al. Diagnosis and management of acute variceal bleeding: Asian Pacific Association for Study of the Liver recommendations. Hepatol Int 2011;5:607–624CrossRef Sarin SK, Kumar A, Anqus PW, et al. Diagnosis and management of acute variceal bleeding: Asian Pacific Association for Study of the Liver recommendations. Hepatol Int 2011;5:607–624CrossRef
15.
go back to reference de Franchis R, Baveno V Faculty. Revising consensus in portal hypertension: report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol 2010;53:762–728 de Franchis R, Baveno V Faculty. Revising consensus in portal hypertension: report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol 2010;53:762–728
16.
go back to reference Tapper EB, Sengupta N, Bonder A. The incidence and outcomes of ischemic hepatitis: a systematic review with meta-analysis. Am J Med 2015;128(12):1314–1321CrossRef Tapper EB, Sengupta N, Bonder A. The incidence and outcomes of ischemic hepatitis: a systematic review with meta-analysis. Am J Med 2015;128(12):1314–1321CrossRef
17.
go back to reference Sohrabpour AA, Mohamadnejad M, Malekzadeh R. Review article: the reversibility of cirrhosis. Aliment Pharmacol Ther 2012;36(9):824–832CrossRef Sohrabpour AA, Mohamadnejad M, Malekzadeh R. Review article: the reversibility of cirrhosis. Aliment Pharmacol Ther 2012;36(9):824–832CrossRef
18.
go back to reference Heimbach JK. Overview of the updated AASLD guidelines for the management of HCC. Gastroenterol Hepatol (N Y) 2017;13(12):751–753 Heimbach JK. Overview of the updated AASLD guidelines for the management of HCC. Gastroenterol Hepatol (N Y) 2017;13(12):751–753
19.
go back to reference Riordan S, Williams R. Treatment of hepatic encephalopathy. N Engl J Med 1997;337:473–479CrossRef Riordan S, Williams R. Treatment of hepatic encephalopathy. N Engl J Med 1997;337:473–479CrossRef
20.
go back to reference Nadim MK, Kellum JA, Davenport A, et al. Hepatorenal syndrome: the 8th International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2012;16:R23CrossRef Nadim MK, Kellum JA, Davenport A, et al. Hepatorenal syndrome: the 8th International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2012;16:R23CrossRef
22.
go back to reference Rimola A, García-Tsao G, Navasa M, Piddock LJ, Planas R, Bernard B, et al. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club. J Hepatol 2000;32:142–153CrossRef Rimola A, García-Tsao G, Navasa M, Piddock LJ, Planas R, Bernard B, et al. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club. J Hepatol 2000;32:142–153CrossRef
23.
go back to reference Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007;44:S27–S72 Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007;44:S27–S72
24.
go back to reference Hooton TM, Bardley SF, Cardenas DD, Colgan R, Geerlings SE, Rice JC, et al. Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 International Clinical Practice Guidelines from the Infectious Diseases Society of America. Clin Infect Dis 2010;50:625–663CrossRef Hooton TM, Bardley SF, Cardenas DD, Colgan R, Geerlings SE, Rice JC, et al. Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 International Clinical Practice Guidelines from the Infectious Diseases Society of America. Clin Infect Dis 2010;50:625–663CrossRef
25.
go back to reference Stevens DL, Bisno AL, Chambers HF, Everett ED, Dellinger P, Goldstein EJ, et al. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis 2005;41:1373–1406CrossRef Stevens DL, Bisno AL, Chambers HF, Everett ED, Dellinger P, Goldstein EJ, et al. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis 2005;41:1373–1406CrossRef
26.
go back to reference Doig GS, Simpson F. Randomization and allocation concealment: a practical guide for researchers. J Crit Care 2005;20(2):187–191CrossRef Doig GS, Simpson F. Randomization and allocation concealment: a practical guide for researchers. J Crit Care 2005;20(2):187–191CrossRef
27.
go back to reference Amitrano L, Guardascione MA, Martino R, Manguso F, Menchise A, Balzano A. Hypoxic hepatitis occurring in cirrhosis after variceal bleeding: still a lethal disease. J Clin Gastroenterol 2012;46:608–612CrossRef Amitrano L, Guardascione MA, Martino R, Manguso F, Menchise A, Balzano A. Hypoxic hepatitis occurring in cirrhosis after variceal bleeding: still a lethal disease. J Clin Gastroenterol 2012;46:608–612CrossRef
28.
go back to reference Lee S, Saxinger L, Ma M, Prado V, Fernández J, et al. Bacterial infections in acute variceal hemorrhage despite antibiotics-a multicenter study of predictors and clinical impact. United European Gastroenterol J 2017;5(8):1090–1099 Lee S, Saxinger L, Ma M, Prado V, Fernández J, et al. Bacterial infections in acute variceal hemorrhage despite antibiotics-a multicenter study of predictors and clinical impact. United European Gastroenterol J 2017;5(8):1090–1099
29.
go back to reference Moitinho E, Escorsell A, Bandi JC, et al. Prognostic value of earlymeasurements of portal pressure in acute variceal bleeding. Gastroenterology 1999;117:626–631CrossRef Moitinho E, Escorsell A, Bandi JC, et al. Prognostic value of earlymeasurements of portal pressure in acute variceal bleeding. Gastroenterology 1999;117:626–631CrossRef
Metadata
Title
Utility of N-acetylcysteine in ischemic hepatitis in cirrhotics with acute variceal bleed: a randomized controlled trial
Authors
Rakhi Maiwall
Awinash Kumar
Ajeet Singh Bhadoria
Ankur Jindal
Guresh Kumar
Ankit Bhardwaj
Jaswinder Singh Maras
Manoj Kumar Sharma
Barjesh Chandra Sharma
Shiv Kumar Sarin
Publication date
01-07-2020
Publisher
Springer India
Published in
Hepatology International / Issue 4/2020
Print ISSN: 1936-0533
Electronic ISSN: 1936-0541
DOI
https://doi.org/10.1007/s12072-020-10013-5

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