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DOI: 10.1055/s-0038-1672180
Neurocritical Care Management of Hepatic Encephalopathy and Coma in Liver Failure
Publication History
Publication Date:
28 November 2018 (online)
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Abstract
Hepatic encephalopathy (HE) is a severe complication of liver disease, describing a spectrum of neurological and psychiatric abnormalities ranging from subclinical alterations to coma. HE is the leading cause for hospital readmission, intensive care treatment, and mortality in patients with chronic liver disease. The complex and multifaceted pathogenesis is not yet fully understood, but hypotheses focus on ammonia and systemic inflammation, which are the main targets for currently available therapies in clinical practice. Nevertheless, the remaining high clinical relevance and healthcare burden of this syndrome underlines the emergence for further unraveling the full spectrum of pathomechanisms, as this provides the basis for the development of novel, highly targeted therapies. In this review, the most recent literature about current and future therapies for HE, relevant for intensive care management, will be discussed.
* Both authors share equal authorship.
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References
- 1 Vilstrup H, Amodio P, Bajaj J. , et al. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology 2014; 60 (02) 715-735
- 2 Stepanova M, Mishra A, Venkatesan C, Younossi ZM. In-hospital mortality and economic burden associated with hepatic encephalopathy in the United States from 2005 to 2009. Clin Gastroenterol Hepatol 2012; 10 (09) 1034-41.e1
- 3 Poordad FF. Review article: the burden of hepatic encephalopathy. Aliment Pharmacol Ther 2007; 25 (Suppl. 01) 3-9
- 4 Kaplan PW, Rossetti AO. EEG patterns and imaging correlations in encephalopathy: encephalopathy part II. J Clin Neurophysiol 2011; 28 (03) 233-251
- 5 D'Amico G, Morabito A, Pagliaro L, Marubini E. Survival and prognostic indicators in compensated and decompensated cirrhosis. Dig Dis Sci 1986; 31 (05) 468-475
- 6 Ding A, Lee A, Callender M, Loughrey M, Quah SP, Dinsmore WW. Hepatic encephalopathy as an unusual late complication of transjugular intrahepatic portosystemic shunt insertion for non-cirrhotic portal hypertension caused by nodular regenerative hyperplasia in an HIV-positive patient on highly active antiretroviral therapy. Int J STD AIDS 2010; 21 (01) 71-72
- 7 Ito T, Ikeda N, Watanabe A. , et al. Obliteration of portal systemic shunts as therapy for hepatic encephalopathy in patients with non-cirrhotic portal hypertension. Gastroenterol Jpn 1992; 27 (06) 759-764
- 8 Bajaj JS, Reddy KR, Tandon P. , et al; North American Consortium for the Study of End-Stage Liver Disease. The 3-month readmission rate remains unacceptably high in a large North American cohort of patients with cirrhosis. Hepatology 2016; 64 (01) 200-208
- 9 Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT. Hepatic encephalopathy--definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology 2002; 35 (03) 716-721
- 10 Amodio P, Montagnese S, Gatta A, Morgan MY. Characteristics of minimal hepatic encephalopathy. Metab Brain Dis 2004; 19 (3-4): 253-267
- 11 McCrea M, Cordoba J, Vessey G, Blei AT, Randolph C. Neuropsychological characterization and detection of subclinical hepatic encephalopathy. Arch Neurol 1996; 53 (08) 758-763
- 12 Wiltfang J, Nolte W, Weissenborn K, Kornhuber J, Rüther E. Psychiatric aspects of portal-systemic encephalopathy. Metab Brain Dis 1998; 13 (04) 379-389
- 13 Weissenborn K. Diagnosis of encephalopathy. Digestion 1998; 59 (Suppl. 02) 22-24
- 14 Cadranel JF, Lebiez E, Di Martino V. , et al. Focal neurological signs in hepatic encephalopathy in cirrhotic patients: an underestimated entity?. Am J Gastroenterol 2001; 96 (02) 515-518
- 15 Weissenborn K, Bokemeyer M, Krause J, Ennen J, Ahl B. Neurological and neuropsychiatric syndromes associated with liver disease. AIDS 2005; 19 (Suppl. 03) S93-S98
- 16 Garcia-Martinez R, Rovira A, Alonso J. , et al. Hepatic encephalopathy is associated with posttransplant cognitive function and brain volume. Liver Transpl 2011; 17 (01) 38-46
- 17 Bajaj JS, Schubert CM, Heuman DM. , et al. Persistence of cognitive impairment after resolution of overt hepatic encephalopathy. Gastroenterology 2010; 138 (07) 2332-2340
- 18 Rikkers L, Jenko P, Rudman D, Freides D. Subclinical hepatic encephalopathy: detection, prevalence, and relationship to nitrogen metabolism. Gastroenterology 1978; 75 (03) 462-469
- 19 Del Piccolo F, Sacerdoti D, Amodio P. , et al. Central nervous system alterations in liver cirrhosis: the role of portal-systemic shunt and portal hypoperfusion. Metab Brain Dis 2002; 17 (04) 347-358
- 20 Riggio O, Ridola L, Pasquale C. , et al. Evidence of persistent cognitive impairment after resolution of overt hepatic encephalopathy. Clin Gastroenterol Hepatol 2011; 9 (02) 181-183
- 21 Saunders JB, Walters JR, Davies AP, Paton A. A 20-year prospective study of cirrhosis. Br Med J (Clin Res Ed) 1981; 282 (6260): 263-266
- 22 Romero-Gómez M, Boza F, García-Valdecasas MS, García E, Aguilar-Reina J. Subclinical hepatic encephalopathy predicts the development of overt hepatic encephalopathy. Am J Gastroenterol 2001; 96 (09) 2718-2723
- 23 Jepsen P, Ott P, Andersen PK, Sørensen HT, Vilstrup H. Clinical course of alcoholic liver cirrhosis: a Danish population-based cohort study. Hepatology 2010; 51 (05) 1675-1682
- 24 Coltorti M, Del Vecchio-Blanco C, Caporaso N, Gallo C, Castellano L. ; National Project on Liver Cirrhosis Group. Liver cirrhosis in Italy. A multicentre study on presenting modalities and the impact on health care resources. Ital J Gastroenterol 1991; 23 (01) 42-48
- 25 Amodio P, Del Piccolo F, Pettenò E. , et al. Prevalence and prognostic value of quantified electroencephalogram (EEG) alterations in cirrhotic patients. J Hepatol 2001; 35 (01) 37-45
- 26 Bustamante J, Rimola A, Ventura PJ. , et al. Prognostic significance of hepatic encephalopathy in patients with cirrhosis. J Hepatol 1999; 30 (05) 890-895
- 27 Hartmann IJ, Groeneweg M, Quero JC. , et al. The prognostic significance of subclinical hepatic encephalopathy. Am J Gastroenterol 2000; 95 (08) 2029-2034
- 28 Gentilini P, Laffi G, La Villa G. , et al. Long course and prognostic factors of virus-induced cirrhosis of the liver. Am J Gastroenterol 1997; 92 (01) 66-72
- 29 Benvegnù L, Gios M, Boccato S, Alberti A. Natural history of compensated viral cirrhosis: a prospective study on the incidence and hierarchy of major complications. Gut 2004; 53 (05) 744-749
- 30 Watson H, Jepsen P, Wong F, Ginès P, Córdoba J, Vilstrup H. Satavaptan treatment for ascites in patients with cirrhosis: a meta-analysis of effect on hepatic encephalopathy development. Metab Brain Dis 2013; 28 (02) 301-305
- 31 Sharma BC, Sharma P, Agrawal A, Sarin SK. Secondary prophylaxis of hepatic encephalopathy: an open-label randomized controlled trial of lactulose versus placebo. Gastroenterology 2009; 137 (03) 885-891 , 891.e1
- 32 Moreau R, Jalan R, Gines P. , et al; CANONIC Study Investigators of the EASL–CLIF Consortium. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology 2013; 144 (07) 1426-1437 , 1437.e1–1437.e9
- 33 Cordoba J, Ventura-Cots M, Simón-Talero M. , et al; 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; 60 (02) 275-281
- 34 Wendon J, Cordoba J, Dhawan A. , et al; European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu; Clinical practice guidelines panel; Panel members; EASL Governing Board representative. EASL Clinical Practical Guidelines on the management of acute (fulminant) liver failure. J Hepatol 2017; 66 (05) 1047-1081
- 35 Ware AJ, D'Agostino AN, Combes B. Cerebral edema: a major complication of massive hepatic necrosis. Gastroenterology 1971; 61 (06) 877-884
- 36 Canalese J, Gimson AE, Davis C, Mellon PJ, Davis M, Williams R. Controlled trial of dexamethasone and mannitol for the cerebral oedema of fulminant hepatic failure. Gut 1982; 23 (07) 625-629
- 37 Bernal W, Hyyrylainen A, Gera A. , et al. Lessons from look-back in acute liver failure? A single centre experience of 3300 patients. J Hepatol 2013; 59 (01) 74-80
- 38 Oketani M, Ido A, Nakayama N. , et al; Intractable Hepato-Biliary Diseases Study Group of Japan. Etiology and prognosis of fulminant hepatitis and late-onset hepatic failure in Japan: summary of the annual nationwide survey between 2004 and 2009. Hepatol Res 2013; 43 (02) 97-105
- 39 Bernal W, Wendon J. Acute liver failure. N Engl J Med 2013; 369 (26) 2525-2534
- 40 Bajaj JS, Wade JB, Sanyal AJ. Spectrum of neurocognitive impairment in cirrhosis: implications for the assessment of hepatic encephalopathy. Hepatology 2009; 50 (06) 2014-2021
- 41 Montagnese S, Amodio P, Morgan MY. Methods for diagnosing hepatic encephalopathy in patients with cirrhosis: a multidimensional approach. Metab Brain Dis 2004; 19 (3-4): 281-312
- 42 Lockwood AH. Blood ammonia levels and hepatic encephalopathy. Metab Brain Dis 2004; 19 (3-4): 345-349
- 43 Rolando N, Wade J, Davalos M, Wendon J, Philpott-Howard J, Williams R. The systemic inflammatory response syndrome in acute liver failure. Hepatology 2000; 32 (4, Pt 1): 734-739
- 44 Bernal W, Hall C, Karvellas CJ, Auzinger G, Sizer E, Wendon J. Arterial ammonia and clinical risk factors for encephalopathy and intracranial hypertension in acute liver failure. Hepatology 2007; 46 (06) 1844-1852
- 45 Clemmesen JO, Larsen FS, Kondrup J, Hansen BA, Ott P. Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration. Hepatology 1999; 29 (03) 648-653
- 46 Bhatia V, Singh R, Acharya SK. Predictive value of arterial ammonia for complications and outcome in acute liver failure. Gut 2006; 55 (01) 98-104
- 47 Kramer L, Tribl B, Gendo A. , et al. Partial pressure of ammonia versus ammonia in hepatic encephalopathy. Hepatology 2000; 31 (01) 30-34
- 48 Drolz A, Jäger B, Wewalka M. , et al. Clinical impact of arterial ammonia levels in ICU patients with different liver diseases. Intensive Care Med 2013; 39 (07) 1227-1237
- 49 Ong JP, Aggarwal A, Krieger D. , et al. Correlation between ammonia levels and the severity of hepatic encephalopathy. Am J Med 2003; 114 (03) 188-193
- 50 Montagnese S, Schiff S, Amodio P. Quick diagnosis of hepatic encephalopathy: fact or fiction?. Hepatology 2015; 61 (01) 405-406
- 51 Rama Rao KV, Norenberg MD. Brain energy metabolism and mitochondrial dysfunction in acute and chronic hepatic encephalopathy. Neurochem Int 2012; 60 (07) 697-706
- 52 Bosoi CR, Rose CF. Oxidative stress: a systemic factor implicated in the pathogenesis of hepatic encephalopathy. Metab Brain Dis 2013; 28 (02) 175-178
- 53 Jalan R, Bernuau J. Induction of cerebral hyperemia by ammonia plus endotoxin: does hyperammonemia unlock the blood-brain barrier?. J Hepatol 2007; 47 (02) 168-171
- 54 Wright G, Vairappan B, Stadlbauer V, Mookerjee RP, Davies NA, Jalan R. Reduction in hyperammonaemia by ornithine phenylacetate prevents lipopolysaccharide-induced brain edema and coma in cirrhotic rats. Liver Int 2012; 32 (03) 410-419
- 55 Shawcross DL, Davies NA, Williams R, Jalan R. Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. J Hepatol 2004; 40 (02) 247-254
- 56 Wright G, Davies NA, Shawcross DL. , et al. Endotoxemia produces coma and brain swelling in bile duct ligated rats. Hepatology 2007; 45 (06) 1517-1526
- 57 Pedersen HR, Ring-Larsen H, Olsen NV, Larsen FS. Hyperammonemia acts synergistically with lipopolysaccharide in inducing changes in cerebral hemodynamics in rats anaesthetised with pentobarbital. J Hepatol 2007; 47 (02) 245-252
- 58 Vaquero J, Chung C, Blei AT. Cerebral blood flow in acute liver failure: a finding in search of a mechanism. Metab Brain Dis 2004; 19 (3-4): 177-194
- 59 Cichoż-Lach H, Michalak A. Current pathogenetic aspects of hepatic encephalopathy and noncirrhotic hyperammonemic encephalopathy. World J Gastroenterol 2013; 19 (01) 26-34
- 60 Ciećko-Michalska I, Szczepanek M, Słowik A, Mach T. Pathogenesis of hepatic encephalopathy. Gastroenterol Res Pract 2012; 2012: 642108
- 61 Romero-Gómez M. Role of phosphate-activated glutaminase in the pathogenesis of hepatic encephalopathy. Metab Brain Dis 2005; 20 (04) 319-325
- 62 Lachmann V, Görg B, Bidmon HJ, Keitel V, Häussinger D. Precipitants of hepatic encephalopathy induce rapid astrocyte swelling in an oxidative stress dependent manner. Arch Biochem Biophys 2013; 536 (02) 143-151
- 63 Görg B, Schliess F, Häussinger D. Osmotic and oxidative/nitrosative stress in ammonia toxicity and hepatic encephalopathy. Arch Biochem Biophys 2013; 536 (02) 158-163
- 64 Lemberg A, Fernández MA. Hepatic encephalopathy, ammonia, glutamate, glutamine and oxidative stress. Ann Hepatol 2009; 8 (02) 95-102
- 65 Görg B, Qvartskhava N, Bidmon HJ. , et al. Oxidative stress markers in the brain of patients with cirrhosis and hepatic encephalopathy. Hepatology 2010; 52 (01) 256-265
- 66 Häussinger D, Görg B. Interaction of oxidative stress, astrocyte swelling and cerebral ammonia toxicity. Curr Opin Clin Nutr Metab Care 2010; 13 (01) 87-92
- 67 Bruck R, Aeed H, Shirin H. , et al. The hydroxyl radical scavengers dimethylsulfoxide and dimethylthiourea protect rats against thioacetamide-induced fulminant hepatic failure. J Hepatol 1999; 31 (01) 27-38
- 68 Guerrini VH. Effect of antioxidants on ammonia induced CNS-renal pathobiology in sheep. Free Radic Res 1994; 21 (01) 35-43
- 69 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) 1852-1857
- 70 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 (04) 277-285
- 71 Wendon JA, Harrison PM, Keays R, Williams R. Cerebral blood flow and metabolism in fulminant liver failure. Hepatology 1994; 19 (06) 1407-1413
- 72 Butterworth RF. Pathophysiology of hepatic encephalopathy: a new look at ammonia. Metab Brain Dis 2002; 17 (04) 221-227
- 73 Lai JC, Cooper AJ. Brain alpha-ketoglutarate dehydrogenase complex: kinetic properties, regional distribution, and effects of inhibitors. J Neurochem 1986; 47 (05) 1376-1386
- 74 Shawcross DL, Sharifi Y, Canavan JB. , et al. Infection and systemic inflammation, not ammonia, are associated with Grade 3/4 hepatic encephalopathy, but not mortality in cirrhosis. J Hepatol 2011; 54 (04) 640-649
- 75 Hung TH, Lay CJ, Chang CM, Tsai JJ, Tsai CC, Tsai CC. The effect of infections on the mortality of cirrhotic patients with hepatic encephalopathy. Epidemiol Infect 2013; 141 (12) 2671-2678
- 76 Odeh M, Sabo E, Srugo I, Oliven A. Relationship between tumor necrosis factor-alpha and ammonia in patients with hepatic encephalopathy due to chronic liver failure. Ann Med 2005; 37 (08) 603-612
- 77 Goral V, Atayan Y, Kaplan A. The relation between pathogenesis of liver cirrhosis, hepatic encephalopathy and serum cytokine levels: what is the role of tumor necrosis factor α?. Hepatogastroenterology 2011; 58 (107-108): 943-948
- 78 Jiang W, Desjardins P, Butterworth RF. Direct evidence for central proinflammatory mechanisms in rats with experimental acute liver failure: protective effect of hypothermia. J Cereb Blood Flow Metab 2009; 29 (05) 944-952
- 79 Jiang W, Desjardins P, Butterworth RF. Cerebral inflammation contributes to encephalopathy and brain edema in acute liver failure: protective effect of minocycline. J Neurochem 2009; 109 (02) 485-493
- 80 Prakash R, Mullen KD. Mechanisms, diagnosis and management of hepatic encephalopathy. Nat Rev Gastroenterol Hepatol 2010; 7 (09) 515-525
- 81 Wright G, Shawcross D, Olde Damink SW, Jalan R. Brain cytokine flux in acute liver failure and its relationship with intracranial hypertension. Metab Brain Dis 2007; 22 (3-4): 375-388
- 82 Milewski K, Oria M. What we know: the inflammatory basis of hepatic encephalopathy. Metab Brain Dis 2016; 31 (06) 1239-1247
- 83 Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH. Mechanisms underlying inflammation in neurodegeneration. Cell 2010; 140 (06) 918-934
- 84 McCoy MK, Tansey MG. TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease. J Neuroinflammation 2008; 5: 45
- 85 Gupta A, Dhiman RK, Kumari S. , et al. Role of small intestinal bacterial overgrowth and delayed gastrointestinal transit time in cirrhotic patients with minimal hepatic encephalopathy. J Hepatol 2010; 53 (05) 849-855
- 86 Hakansson A, Molin G. Gut microbiota and inflammation. Nutrients 2011; 3 (06) 637-682
- 87 Chastre A, Bélanger M, Nguyen BN, Butterworth RF. Lipopolysaccharide precipitates hepatic encephalopathy and increases blood-brain barrier permeability in mice with acute liver failure. Liver Int 2014; 34 (03) 353-361
- 88 Rodrigo R, Cauli O, Gomez-Pinedo U. , et al. Hyperammonemia induces neuroinflammation that contributes to cognitive impairment in rats with hepatic encephalopathy. Gastroenterology 2010; 139 (02) 675-684
- 89 McPhail MJ, Patel NR, Taylor-Robinson SD. Brain imaging and hepatic encephalopathy. Clin Liver Dis 2012; 16 (01) 57-72
- 90 Rovira A, Mínguez B, Aymerich FX. , et al. Decreased white matter lesion volume and improved cognitive function after liver transplantation. Hepatology 2007; 46 (05) 1485-1490
- 91 Donovan JP, Schafer DF, Shaw Jr BW, Sorrell MF. Cerebral oedema and increased intracranial pressure in chronic liver disease. Lancet 1998; 351 (9104): 719-721
- 92 Joshi D, O'Grady J, Patel A. , et al. Cerebral oedema is rare in acute-on-chronic liver failure patients presenting with high-grade hepatic encephalopathy. Liver Int 2014; 34 (03) 362-366
- 93 Amodio P, Bemeur C, Butterworth R. , et al. The nutritional management of hepatic encephalopathy in patients with cirrhosis: International Society for Hepatic Encephalopathy and Nitrogen Metabolism Consensus. Hepatology 2013; 58 (01) 325-336
- 94 American Association for the Study of Liver Diseases; European Association for the Study of the Liver. Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases. J Hepatol 2014; 61 (03) 642-659
- 95 Krähenbühl L, Lang C, Lüdes S. , et al. Reduced hepatic glycogen stores in patients with liver cirrhosis. Liver Int 2003; 23 (02) 101-109
- 96 Kabadi UM. The association of hepatic glycogen depletion with hyperammonemia in cirrhosis. Hepatology 1987; 7 (05) 821-824
- 97 Gluud LL, Dam G, Les I. , et al. Branched-chain amino acids for people with hepatic encephalopathy. Cochrane Database Syst Rev 2017; 5: CD001939
- 98 Dam G, Keiding S, Munk OL. , et al. Branched-chain amino acids increase arterial blood ammonia in spite of enhanced intrinsic muscle ammonia metabolism in patients with cirrhosis and healthy subjects. Am J Physiol Gastrointest Liver Physiol 2011; 301 (02) G269-G277
- 99 Holecek M, Kandar R, Sispera L, Kovarik M. Acute hyperammonemia activates branched-chain amino acid catabolism and decreases their extracellular concentrations: different sensitivity of red and white muscle. Amino Acids 2011; 40 (02) 575-584
- 100 Holecek M. Three targets of branched-chain amino acid supplementation in the treatment of liver disease. Nutrition 2010; 26 (05) 482-490
- 101 Kimball SR, Jefferson LS. Regulation of global and specific mRNA translation by oral administration of branched-chain amino acids. Biochem Biophys Res Commun 2004; 313 (02) 423-427
- 102 Leenders M, van Loon LJ. Leucine as a pharmaconutrient to prevent and treat sarcopenia and type 2 diabetes. Nutr Rev 2011; 69 (11) 675-689
- 103 Als-Nielsen B, Gluud LL, Gluud C. Non-absorbable disaccharides for hepatic encephalopathy: systematic review of randomised trials. BMJ 2004; 328 (7447): 1046
- 104 Gluud LL, Vilstrup H, Morgan MY. Nonabsorbable disaccharides for hepatic encephalopathy: a systematic review and meta-analysis. Hepatology 2016; 64 (03) 908-922
- 105 Rahimi RS, Singal AG, Cuthbert JA, Rockey DC. Lactulose vs polyethylene glycol 3350--electrolyte solution for treatment of overt hepatic encephalopathy: the HELP randomized clinical trial. JAMA Intern Med 2014; 174 (11) 1727-1733
- 106 Kandiah PA, Olson JC, Subramanian RM. Emerging strategies for the treatment of patients with acute hepatic failure. Curr Opin Crit Care 2016; 22 (02) 142-151
- 107 Patidar KR, Bajaj JS. Covert and overt hepatic encephalopathy: diagnosis and management. Clin Gastroenterol Hepatol 2015; 13 (12) 2048-2061
- 108 Bass NM, Mullen KD, Sanyal A. , et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med 2010; 362 (12) 1071-1081
- 109 Patidar KR, Bajaj JS. Antibiotics for the treatment of hepatic encephalopathy. Metab Brain Dis 2013; 28 (02) 307-312
- 110 Kimer N, Krag A, Møller S, Bendtsen F, Gluud LL. Systematic review with meta-analysis: the effects of rifaximin in hepatic encephalopathy. Aliment Pharmacol Ther 2014; 40 (02) 123-132
- 111 Sharma BC, Sharma P, Lunia MK, Srivastava S, Goyal R, Sarin SK. A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy. Am J Gastroenterol 2013; 108 (09) 1458-1463
- 112 Kircheis G, Nilius R, Held C. , et al. Therapeutic efficacy of L-ornithine-L-aspartate infusions in patients with cirrhosis and hepatic encephalopathy: results of a placebo-controlled, double-blind study. Hepatology 1997; 25 (06) 1351-1360
- 113 Bai M, Yang Z, Qi X, Fan D, Han G. l-ornithine-l-aspartate for hepatic encephalopathy in patients with cirrhosis: a meta-analysis of randomized controlled trials. J Gastroenterol Hepatol 2013; 28 (05) 783-792
- 114 Goh ET, Stokes CS, Sidhu SS, Vilstrup H, Gluud LL, Morgan MY. L-ornithine L-aspartate for prevention and treatment of hepatic encephalopathy in people with cirrhosis. Cochrane Database Syst Rev 2018; 5: CD012410
- 115 Bai M, He C, Yin Z. , et al. Randomised clinical trial: L-ornithine-L-aspartate reduces significantly the increase of venous ammonia concentration after TIPSS. Aliment Pharmacol Ther 2014; 40 (01) 63-71
- 116 Acharya SK, Bhatia V, Sreenivas V, Khanal S, Panda SK. Efficacy of L-ornithine L-aspartate in acute liver failure: a double-blind, randomized, placebo-controlled study. Gastroenterology 2009; 136 (07) 2159-2168
- 117 Rose C, Michalak A, Rao KV, Quack G, Kircheis G, Butterworth RF. L-ornithine-L-aspartate lowers plasma and cerebrospinal fluid ammonia and prevents brain edema in rats with acute liver failure. Hepatology 1999; 30 (03) 636-640
- 118 Garcia-Martinez R, Caraceni P, Bernardi M, Gines P, Arroyo V, Jalan R. Albumin: pathophysiologic basis of its role in the treatment of cirrhosis and its complications. Hepatology 2013; 58 (05) 1836-1846
- 119 Jalan R, Kapoor D. Reversal of diuretic-induced hepatic encephalopathy with infusion of albumin but not colloid. Clin Sci (Lond) 2004; 106 (05) 467-474
- 120 Simón-Talero M, García-Martínez R, Torrens M. , et al. Effects of intravenous albumin in patients with cirrhosis and episodic hepatic encephalopathy: a randomized double-blind study. J Hepatol 2013; 59 (06) 1184-1192
- 121 Freeman WD. Management of intracranial pressure. Continuum (Minneap Minn) 2015; 21 (5 Neurocritical Care): 1299-1323
- 122 Rajajee V, Fontana RJ, Courey AJ, Patil PG. Protocol based invasive intracranial pressure monitoring in acute liver failure: feasibility, safety and impact on management. Crit Care 2017; 21 (01) 178
- 123 Dmello D, Cruz-Flores S, Matuschak GM. Moderate hypothermia with intracranial pressure monitoring as a therapeutic paradigm for the management of acute liver failure: a systematic review. Intensive Care Med 2010; 36 (02) 210-213
- 124 Karvellas CJ, Fix OK, Battenhouse H, Durkalski V, Sanders C, Lee WM. ; U S Acute Liver Failure Study Group. Outcomes and complications of intracranial pressure monitoring in acute liver failure: a retrospective cohort study. Crit Care Med 2014; 42 (05) 1157-1167
- 125 Vaquero J, Fontana RJ, Larson AM. , et al. Complications and use of intracranial pressure monitoring in patients with acute liver failure and severe encephalopathy. Liver Transpl 2005; 11 (12) 1581-1589
- 126 Figaji AA, Zwane E, Fieggen AG, Siesjo P, Peter JC. Transcranial Doppler pulsatility index is not a reliable indicator of intracranial pressure in children with severe traumatic brain injury. Surg Neurol 2009; 72 (04) 389-394
- 127 O'Brien NF, Maa T, Reuter-Rice K. Noninvasive screening for intracranial hypertension in children with acute, severe traumatic brain injury. J Neurosurg Pediatr 2015; 16 (04) 420-425
- 128 Bellner J, Romner B, Reinstrup P, Kristiansson KA, Ryding E, Brandt L. Transcranial Doppler sonography pulsatility index (PI) reflects intracranial pressure (ICP). Surg Neurol 2004; 62 (01) 45-51 , discussion 51
- 129 Wakerley BR, Kusuma Y, Yeo LL. , et al. Usefulness of transcranial Doppler-derived cerebral hemodynamic parameters in the noninvasive assessment of intracranial pressure. J Neuroimaging 2015; 25 (01) 111-116
- 130 Murphy N, Auzinger G, Bernel W, Wendon J. The effect of hypertonic sodium chloride on intracranial pressure in patients with acute liver failure. Hepatology 2004; 39 (02) 464-470
- 131 Curley G, Kavanagh BP, Laffey JG. Hypocapnia and the injured brain: more harm than benefit. Crit Care Med 2010; 38 (05) 1348-1359
- 132 Ede RJ, Gimson AE, Bihari D, Williams R. Controlled hyperventilation in the prevention of cerebral oedema in fulminant hepatic failure. J Hepatol 1986; 2 (01) 43-51
- 133 Bernal W, Murphy N, Brown S. , et al. A multicentre randomized controlled trial of moderate hypothermia to prevent intracranial hypertension in acute liver failure. J Hepatol 2016; 65 (02) 273-279
- 134 Slack AJ, Auzinger G, Willars C. , et al. Ammonia clearance with haemofiltration in adults with liver disease. Liver Int 2014; 34 (01) 42-48
- 135 McPhail MJ, Kriese S, Heneghan MA. Current management of acute liver failure. Curr Opin Gastroenterol 2015; 31 (03) 209-214
- 136 Larsen FS, Schmidt LE, Bernsmeier C. , et al. High-volume plasma exchange in patients with acute liver failure: an open randomised controlled trial. J Hepatol 2016; 64 (01) 69-78
- 137 Chen JJ, Huang JR, Yang Q. , et al. Plasma exchange-centered artificial liver support system in hepatitis B virus-related acute-on-chronic liver failure: a nationwide prospective multicenter study in China. Hepatobiliary Pancreat Dis Int 2016; 15 (03) 275-281
- 138 Yue-Meng W, Yang LH, Yang JH, Xu Y, Yang J, Song GB. The effect of plasma exchange on entecavir-treated chronic hepatitis B patients with hepatic de-compensation and acute-on-chronic liver failure. Hepatol Int 2016; 10 (03) 462-469
- 139 Wan YM, Li YH, Xu ZY. , et al. Therapeutic plasma exchange versus double plasma molecular absorption system in hepatitis B virus-infected acute-on-chronic liver failure treated by entercavir: a prospective study. J Clin Apher 2017; 32 (06) 453-461
- 140 Qin G, Shao JG, Wang B. , et al. Artificial liver support system improves short- and long-term outcomes of patients with HBV-associated acute-on-chronic liver failure: a single-center experience. Medicine (Baltimore) 2014; 93 (28) e338
- 141 Bañares R, Nevens F, Larsen FS. , et al; RELIEF Study Group. Extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute-on-chronic liver failure: the RELIEF trial. Hepatology 2013; 57 (03) 1153-1162
- 142 Saliba F, Camus C, Durand F. , et al. Albumin dialysis with a noncell artificial liver support device in patients with acute liver failure: a randomized, controlled trial. Ann Intern Med 2013; 159 (08) 522-531
- 143 Rose C, Jalan R. Is minimal hepatic encephalopathy completely reversible following liver transplantation?. Liver Transpl 2004; 10 (01) 84-87
- 144 Frederick RT. Extent of reversibility of hepatic encephalopathy following liver transplantation. Clin Liver Dis 2012; 16 (01) 147-158
- 145 O'Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989; 97 (02) 439-445
- 146 Bailey B, Amre DK, Gaudreault P. Fulminant hepatic failure secondary to acetaminophen poisoning: a systematic review and meta-analysis of prognostic criteria determining the need for liver transplantation. Crit Care Med 2003; 31 (01) 299-305
- 147 Artru F, Louvet A, Ruiz I. , et al. Liver transplantation in the most severely ill cirrhotic patients: a multicenter study in acute-on-chronic liver failure grade 3. J Hepatol 2017; 67 (04) 708-715
- 148 Laleman W, Simon-Talero M, Maleux G. , et al; EASL-CLIF-Consortium. Embolization of large spontaneous portosystemic shunts for refractory hepatic encephalopathy: a multicenter survey on safety and efficacy. Hepatology 2013; 57 (06) 2448-2457
- 149 An J, Kim KW, Han S, Lee J, Lim YS. Improvement in survival associated with embolisation of spontaneous portosystemic shunt in patients with recurrent hepatic encephalopathy. Aliment Pharmacol Ther 2014; 39 (12) 1418-1426
- 150 Lee EW, Saab S, Kaldas F. , et al. Coil-assisted retrograde transvenous obliteration (CARTO): an alternative treatment option for refractory hepatic encephalopathy. Am J Gastroenterol 2018
- 151 Riggio O, Nardelli S, Moscucci F, Pasquale C, Ridola L, Merli M. Hepatic encephalopathy after transjugular intrahepatic portosystemic shunt. Clin Liver Dis 2012; 16 (01) 133-146
- 152 Jalan R, Dabos K, Redhead DN, Lee A, Hayes PC. Elevation of intracranial pressure following transjugular intrahepatic portosystemic stent-shunt for variceal haemorrhage. J Hepatol 1997; 27 (05) 928-933
- 153 Jalan R, Olde Damink SW, Ter Steege JC. , et al. Acute endotoxemia following transjugular intrahepatic stent-shunt insertion is associated with systemic and cerebral vasodilatation with increased whole body nitric oxide production in critically ill cirrhotic patients. J Hepatol 2011; 54 (02) 265-271
- 154 Riggio O, Ridola L, Angeloni S. , et al. Clinical efficacy of transjugular intrahepatic portosystemic shunt created with covered stents with different diameters: results of a randomized controlled trial. J Hepatol 2010; 53 (02) 267-272
- 155 Rowley MW, Choi M, Chen S, Hirsch K, Seetharam AB. Refractory hepatic encephalopathy after elective transjugular intrahepatic portosystemic shunt: risk factors and outcomes with revision. Cardiovasc Intervent Radiol 2018 Doi: 10.1007/s00270-018-1992-2
- 156 Ventura-Cots M, Arranz JA, Simón-Talero M. , et al. Safety of ornithine phenylacetate in cirrhotic decompensated patients: an open-label, dose-escalating, single-cohort study. J Clin Gastroenterol 2013; 47 (10) 881-887
- 157 Rockey DC, Vierling JM, Mantry P. , et al; HALT-HE Study Group. Randomized, double-blind, controlled study of glycerol phenylbutyrate in hepatic encephalopathy. Hepatology 2014; 59 (03) 1073-1083
- 158 Agrawal A, Sharma BC, Sharma P, Sarin SK. Secondary prophylaxis of hepatic encephalopathy in cirrhosis: an open-label, randomized controlled trial of lactulose, probiotics, and no therapy. Am J Gastroenterol 2012; 107 (07) 1043-1050
- 159 Bajaj JS, Saeian K, Christensen KM. , et al. Probiotic yogurt for the treatment of minimal hepatic encephalopathy. Am J Gastroenterol 2008; 103 (07) 1707-1715
- 160 Mittal VV, Sharma BC, Sharma P, Sarin SK. A randomized controlled trial comparing lactulose, probiotics, and L-ornithine L-aspartate in treatment of minimal hepatic encephalopathy. Eur J Gastroenterol Hepatol 2011; 23 (08) 725-732
- 161 Shukla S, Shukla A, Mehboob S, Guha S. Meta-analysis: the effects of gut flora modulation using prebiotics, probiotics and synbiotics on minimal hepatic encephalopathy. Aliment Pharmacol Ther 2011; 33 (06) 662-671
- 162 Khoruts A, Dicksved J, Jansson JK, Sadowsky MJ. Changes in the composition of the human fecal microbiome after bacteriotherapy for recurrent Clostridium difficile-associated diarrhea. J Clin Gastroenterol 2010; 44 (05) 354-360
- 163 Shen TC, Albenberg L, Bittinger K. , et al. Engineering the gut microbiota to treat hyperammonemia. J Clin Invest 2015; 125 (07) 2841-2850
- 164 Wang WW, Zhang Y, Huang XB, You N, Zheng L, Li J. Fecal microbiota transplantation prevents hepatic encephalopathy in rats with carbon tetrachloride-induced acute hepatic dysfunction. World J Gastroenterol 2017; 23 (38) 6983-6994
- 165 Erceg S, Monfort P, Hernández-Viadel M, Rodrigo R, Montoliu C, Felipo V. Oral administration of sildenafil restores learning ability in rats with hyperammonemia and with portacaval shunts. Hepatology 2005; 41 (02) 299-306
- 166 Agusti A, Hernández-Rabaza V, Balzano T. , et al. Sildenafil reduces neuroinflammation in cerebellum, restores GABAergic tone, and improves motor in-coordination in rats with hepatic encephalopathy. CNS Neurosci Ther 2017; 23 (05) 386-394
- 167 Hernandez-Rabaza V, Agusti A, Cabrera-Pastor A. , et al. Sildenafil reduces neuroinflammation and restores spatial learning in rats with hepatic encephalopathy: underlying mechanisms. J Neuroinflammation 2015; 12: 195
- 168 Tofteng F, Larsen FS. The effect of indomethacin on intracranial pressure, cerebral perfusion and extracellular lactate and glutamate concentrations in patients with fulminant hepatic failure. J Cereb Blood Flow Metab 2004; 24 (07) 798-804
- 169 Romero-Gómez M, Montagnese S, Jalan R. Hepatic encephalopathy in patients with acute decompensation of cirrhosis and acute-on-chronic liver failure. J Hepatol 2015; 62 (02) 437-447