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This study analyses the effect of intravenous branched chain amino acids (BCAA) on overt HE in patients with ACLF. The investigators plan to study the efficacy of combining intravenous BCAA with lactulose versus lactulose alone in the medical management of overt HE in patients with ACLF and its impact on overall survival and improvement in grade of HE.
Acute on chronic liver failure (ACLF) is a distinct clinical entity in the spectrum of chronic liver disease associated with high short term mortality. Hepatic encephalopathy (HE) is commonly seen in patients with ACLF and its treatment mainly involves non-absorbable disaccharides (lactulose/lactitol).Treatment of HE in ACLF is based on extrapolation of data available from cirrhotic patients. No studies have compared different treatment options for HE in patients with ACLF.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| IV BCAA + Lactulose | Experimental | IV Branched Chain Amino Acids - 500mL once daily for 3 days plus Lactulose |
|
| Lactulose alone | Active Comparator | Oral Lactulose alone |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Branched chain amino acid | Drug | Intravenous branched chain amino acids will be given for 3 days to patients in experimental arm |
|
| Measure | Description | Time Frame |
|---|---|---|
| Improvement of Survival | All cause Mortality assessment | At day day 28 |
| Improvement of encephalopathy by ≥ 1 grade | Improvement in hepatic encephalopathy | 72 hours |
| Measure | Description | Time Frame |
|---|---|---|
| Reduction in level of ammonia | 48 and 72 hours | |
| Reduction of consciousness recovery time among survivors | 30 days | |
| Prolongation of time to death among non-survivors |
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Inclusion Criteria:
Exclusion Criteria:
As the study was carried out during the peak of the COVID-19, patients who developed COVID-19 after randomization were excluded from the analysis as they were shifted to dedicated COVID-19 ICU's.
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| Name | Affiliation | Role |
|---|---|---|
| Madhumita Premkumar, MD, DM | Post Graduate Institute of Medical Education and Research, Chandigarh | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| PGIMER | Chandigarh | 160012 | India |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 21163546 | Background | Shawcross DL, Sharifi Y, Canavan JB, Yeoman AD, Abeles RD, Taylor NJ, Auzinger G, Bernal W, Wendon JA. Infection and systemic inflammation, not ammonia, are associated with Grade 3/4 hepatic encephalopathy, but not mortality in cirrhosis. J Hepatol. 2011 Apr;54(4):640-9. doi: 10.1016/j.jhep.2010.07.045. Epub 2010 Dec 1. | |
| 9504517 |
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| ID | Term |
|---|---|
| D006501 | Hepatic Encephalopathy |
| D065290 | Acute-On-Chronic Liver Failure |
| ID | Term |
|---|---|
| D017093 | Liver Failure |
| D048550 | Hepatic Insufficiency |
| D008107 | Liver Diseases |
| D004066 | Digestive System Diseases |
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| ID | Term |
|---|---|
| D000597 | Amino Acids, Branched-Chain |
| D007792 | Lactulose |
| ID | Term |
|---|---|
| D000596 | Amino Acids |
| D000602 | Amino Acids, Peptides, and Proteins |
| D004187 | Disaccharides |
| D009844 | Oligosaccharides |
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Prospective interventional cohort study
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| Lactulose | Drug | Oral lactulose will be given to patients in both arms |
|
| 30 days |
| Prevention/reduction of cerebral edema based on optic nerve sheath diameter | 72 hours |
| Donovan JP, Schafer DF, Shaw BW Jr, Sorrell MF. Cerebral oedema and increased intracranial pressure in chronic liver disease. Lancet. 1998 Mar 7;351(9104):719-21. doi: 10.1016/S0140-6736(97)07373-X. |
| 17006913 | Background | Albrecht J, Norenberg MD. Glutamine: a Trojan horse in ammonia neurotoxicity. Hepatology. 2006 Oct;44(4):788-94. doi: 10.1002/hep.21357. |
| 31966 | Background | Norenberg MD, Martinez-Hernandez A. Fine structural localization of glutamine synthetase in astrocytes of rat brain. Brain Res. 1979 Feb 2;161(2):303-10. doi: 10.1016/0006-8993(79)90071-4. |
| 10733001 | Background | Albrecht J, Dolinska M, Hilgier W, Lipkowski AW, Nowacki J. Modulation of glutamine uptake and phosphate-activated glutaminase activity in rat brain mitochondria by amino acids and their synthetic analogues. Neurochem Int. 2000 Apr;36(4-5):341-7. doi: 10.1016/s0197-0186(99)00142-4. |
| 10336125 | Background | Laake JH, Takumi Y, Eidet J, Torgner IA, Roberg B, Kvamme E, Ottersen OP. Postembedding immunogold labelling reveals subcellular localization and pathway-specific enrichment of phosphate activated glutaminase in rat cerebellum. Neuroscience. 1999;88(4):1137-51. doi: 10.1016/s0306-4522(98)00298-x. |
| 24128414 | Background | Cordoba J, Ventura-Cots M, Simon-Talero M, Amoros A, Pavesi M, Vilstrup H, Angeli P, Domenicali M, Gines P, Bernardi M, Arroyo V; CANONIC Study Investigators of EASL-CLIF Consortium. Characteristics, risk factors, and mortality of cirrhotic patients hospitalized for hepatic encephalopathy with and without acute-on-chronic liver failure (ACLF). J Hepatol. 2014 Feb;60(2):275-81. doi: 10.1016/j.jhep.2013.10.004. Epub 2013 Oct 12. |
| 818729 | Result | Fischer JE, Rosen HM, Ebeid AM, James JH, Keane JM, Soeters PB. The effect of normalization of plasma amino acids on hepatic encephalopathy in man. Surgery. 1976 Jul;80(1):77-91. |
| 30568347 | Result | Dam G, Aamann L, Vistrup H, Gluud LL. The role of Branched Chain Amino Acids in the treatment of hepatic Encephalopathy. J Clin Exp Hepatol. 2018 Dec;8(4):448-451. doi: 10.1016/j.jceh.2018.06.004. Epub 2018 Jun 27. |
| 6749458 | Result | Rossi-Fanelli F, Riggio O, Cangiano C, Cascino A, De Conciliis D, Merli M, Stortoni M, Giunchi G. Branched-chain amino acids vs lactulose in the treatment of hepatic coma: a controlled study. Dig Dis Sci. 1982 Oct;27(10):929-35. doi: 10.1007/BF01316578. |
| 25715177 | Result | Gluud LL, Dam G, Les I, Cordoba J, Marchesini G, Borre M, Aagaard NK, Vilstrup H. Branched-chain amino acids for people with hepatic encephalopathy. Cochrane Database Syst Rev. 2015 Feb 25;(2):CD001939. doi: 10.1002/14651858.CD001939.pub2. |
| 37975059 | Derived | Mehtani R, Premkumar M, Garg S, Kajal K, Kulkarni AV, Duseja AK, Dhiman RK, De A, Verma N, Taneja S, Rathi S, Singh V, Chakma J, Soni SL, Kakkar A, Kapila AT, Ahuja CK, Divyaveer S, Praharaj D. Intravenous BCAA Infusion Does Not Lead to a Sustained Recovery From Overt HE in ACLF - An Open Label Randomized Clinical Trial. J Clin Exp Hepatol. 2023 Nov-Dec;13(6):977-988. doi: 10.1016/j.jceh.2023.05.015. Epub 2023 Jun 1. |
| D001928 |
| Brain Diseases, Metabolic |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D017114 | Liver Failure, Acute |
| D011134 |
| Polysaccharides |
| D002241 | Carbohydrates |
| D000073893 | Sugars |