Benzodiazepine Antagonist in the Treatment of Human Hepatic Encephalopathy
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Recently it was suggested that hepatic encephalopathy (HE) is mediated by an increased GABA-ergic tone. The logical consequence of such a hypothesis is the use of antagonists of the GABA -benzodiazepine receptor for treatment of HE. The experience with these drugs in human HE is limited. In order to get an estimate of the efficacy of this type of drug in humans 20 consecutive episodes of HE in 17 patients with acute or chronic liver failure were treated with flumazenil. All patients entered into the study were encephalopathic for up to 120 hours and failed to respond to conventional therapy. After an observation period of 8 hours, 15 mg of flumazenil were infused intravenously over 3 hours. Before and after treatment patients were examined neurologically and the Glasgow coma scale was calculated. In addition, somatosensory evoked potentials were recorded. In 5 out of 11 episodes in 10 patients with fulminant hepatic failure and in 7 out of 9 episodes in 7 patients with cirrhosis an unequivocal amelioration of HE was observed. The response to treatment occurred very rapidly. After stopping treatment in 8 out of these 12 episodes HE worsened again after 2 to 4 hours. The favourable clinical response was also documented by improvement of somatosensory evoked potentials. In 5 of the 8 episodes not reacting to flumazenil patients had signs of increased intracranial pressure. These findings indicate that flumazenil may be valuable in treatment of acute HE occurring in fulminant hepatic failure or in decompensated cirrhosis.
Furthermore a patient with portal systemic encephalopathy refractory to standard therapy following extensive liver resection and construction of a portocaval shunt was treated with flumazenil 25 mg twice daily. Before treatment she was encephalopathic with 12 attacks of coma within 2 years. On treatment with flumazenil all signs of HE abated in spite of unrestricted dietary protein intake. After one year treatment with flumazenil was stopped. Two days later she became comamonths. Since reinstitution of flumazenil she is well for 16 months of follow up without any signs of HE. She does not require a protein restricted diet. The favourable response of this patient to treatment with flumazenil suggests that flumazenil may be also valuable in long term management of portal systemic encephalopathy.
KeywordsHepatic Encephalopathy Glasgow Coma Scale Fulminant Hepatic Failure Hepatic Coma Chronic Liver Failure
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- 4.Paul SM, Marangos PJ, Skolnick P. The benzodiazepine-GABA-chloride ionophore receptor complex. Common site of minor tranquillizer action. Biological Psych 1981, 16: 213–229.Google Scholar
- 7.Bansky G, Meier PJ, Ziegler WH. Reversal of hepatic coma by benzodiazepine antagonist (Ro 15–1788). Lancet 1985, I: 1324–1325.Google Scholar
- 8.Bansky G, Meier PJ, Riederer E, et al. Effect of a benzodiazepine antagonist in hepatic encephalopathy. Hepatology 1987; 7: 1103.Google Scholar
- 12.Grimm G, Lenz K, Kleinberger G, et al. Ro 15-1788 improves coma in 4 out of 5 patients with fulminant hepatic failure; verification by long latency auditory and somatosensory potentials. J Hepatol 1987; 4 (suppl 1): S 21.Google Scholar
- 13.Meier R, Gyr K. Treatment of hepatic encephalopathy (HE) with the benzodiazepine antagonist flumazenil: a pilot study. Eur J Anaesthesiology 1988; Suppl 2: 139–146.Google Scholar
- 16.Frontiers of Clinical Neuroscience, Vol. 3, Evoked Potentials. R.Q. Cracco, I. Bodis-Wolner (Eds.), Alan R. Liss, New York 1986.Google Scholar
- 18.Conn HO, Lieberthal M. The hepatic coma syndromes and lactulose. Williams & Wilkins, Baltimore, 1979, p. 6Google Scholar
- 21.Roncari G, Ziegler WH, Guentert TW. Pharmacokinetics of the new benzodiazepine antagonist Ro 15-1788 in man following intravenous and oral administration. Br J Clin Pharmac 1986; 22: 421–428.Google Scholar
- 22.Prischl F, Donner A, Grimm G, et al. Value of flumazenil in benzodiazepine self-poisoning. Med Toxicol 1988; 3: 334–339.Google Scholar
- 25.Pidoux B, Zylberberg Ph, Valla D, Opolon P: Etude electro-encephalographique de l’effet d’un antagoniste des benzodiazepines dans 1’encephalopathie hepatique. Neurophysiol. Clinique 1989; in press.Google Scholar
- 26.Van der Rijt CCD, Schalm SW, Meulstee J, Stijnen T: Flumazenil therapy for hepatic encephalopathy. 40th Annual Meeting of AASLD, Chicago 1989, Abstract # 85.Google Scholar