Cooling the patient with acute liver failure

Abstract

Acute liver failure (ALF) is a rare disease, with an estimate of 2000 cases per year in the United States. However, it is a worldwide problem, affecting previously healthy individuals and placing great demands on the provision of intensive care. Although multiorgan failure is increasingly recognized as the cause of death, brain edema and intracranial hypertension are unique complications of the syndrome, especially in patients with hyperacute liver failure, in whom less than a week elapse between the onset of symptoms and the development of hepatic encephalopathy. In this issue of Gastroenterology, Jalan et al.1Jalan R. Olde Damink S.W.M. Deutz N.E.P. Hayes P.C. Lee A. Moderate hypothermia in patients with acute liver failure and uncontrolled intracranial hypertension.Gastroenterology. 2004; 127: 1338-1346Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar show that moderate hypothermia (33°C) was able to control the elevated intracranial pressure (ICP) in 14 patients with ALF and intracranial hypertension who had failed standard medical therapy, allowing the performance of emergency liver transplantation. Such surgery can be lifesaving but the decision to operate can be quite challenging.2Bernal W. Wendon J. Liver transplantation in adults with acute liver failure.J Hepatol. 2004; 40: 192-197Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar Uncertainty is not the case in the patients treated by Jalan et al.,1Jalan R. Olde Damink S.W.M. Deutz N.E.P. Hayes P.C. Lee A. Moderate hypothermia in patients with acute liver failure and uncontrolled intracranial hypertension.Gastroenterology. 2004; 127: 1338-1346Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar in whom death could be expected within a short period of time. Although this series expands on an earlier report from this group,3Jalan R. Damink S.W. Deutz N.E. Lee A. Hayes P.C. Moderate hypothermia for uncontrolled intracranial hypertension in acute liver failure.Lancet. 1999; 354: 1164-1168Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar additional insight into the mechanisms responsible for the benefits of hypothermia are provided. At a time when bioartificial liver support systems have not fulfilled their promise,4Demetriou A.A. Brown Jr, R.S. Busuttil R.W. Fair J. McGuire B.M. Rosenthal P. Am Esch II, J.S. Lerut J. Nyberg S.L. Salizzoni M. Fagan E.A. de Hemptinne B. Broelsch C.E. Muraca M. Salmeron J.M. Rabkin J.M. Metselaar H.J. Pratt D. De La Mata M. McChesney L.P. Everson G.T. Lavin P.T. Stevens A.C. Pitkin Z. Solomon B.A. Prospective, randomized, multicenter, controlled trial of a bioartificial liver in treating acute liver failure.Ann Surg. 2004; 239: 660-667Crossref PubMed Scopus (522) Google Scholar the possibility that a relatively simple and inexpensive measure could bridge patients with ALF to emergency transplantation is particularly attractive. Hypothermia is used in several other critical conditions associated with an elevated ICP; it has been recommended as standard of care after resuscitation from an out-of-hospital cardiac arrest.5Nolan J.P. Morley P.T. Vanden Hoek T.L. Hickey R.W. Kloeck W.G. Billi J. Bottiger B.W. Morley P.T. Nolan J.P. Okada K. Reyes C. Shuster M. Steen P.A. Weil M.H. Wenzel V. Hickey R.W. Carli P. Vanden Hoek T.L. Atkins D. International Liaison Committee on ResuscitationTherapeutic hypothermia after cardiac arrest an advisory statement by the advanced life support task force of the International Liaison Committee on Resuscitation.Circulation. 2003; 108: 118-121Crossref PubMed Scopus (604) Google Scholar However, the potential use in ALF is not a simple extrapolation from the practice of other disciplines—it is the result of laboratory and clinical investigations that during the past 20 years have provided insight into the pathogenesis of brain edema. Three major elements need to be considered; they are all affected by hypothermia to a varying extent. Hyperammonemia is linked to osmotic changes in brain. This relationship was highlighted in a study where arterial ammonia levels >200 μg/dL were associated with the development of brain herniation.6Clemmesen J.O. Larsen F.S. Kondrup J. Hansen B.A. Ott P. Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration.Hepatology. 1999; 29: 648-653Crossref PubMed Scopus (517) Google Scholar In the current study, Jalan et al.1Jalan R. Olde Damink S.W.M. Deutz N.E.P. Hayes P.C. Lee A. Moderate hypothermia in patients with acute liver failure and uncontrolled intracranial hypertension.Gastroenterology. 2004; 127: 1338-1346Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar reports that moderate hypothermia is associated with a decrease in arterial ammonia levels. The mechanism for this effect has not been elucidated but, on a theoretical basis, could imply effects on the splanchnic release of ammonia, which is increased in ALF.7Clemmesen J.O. Kondrup J. Ott P. Splanchnic and leg exchange of amino acids and ammonia in acute liver failure.Gastroenterology. 2000; 118: 1131-1139Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar More on hypothermia and the liver is discussed later. Once in brain, ammonia is detoxified in cortical astrocytes to form glutamine, a reaction catalyzed by glutamine synthetase. Glutamine levels increase several-fold in the brain, as assessed by magnetic resonance spectroscopy in human ALF.8McConnell J.R. Antonson D.L. Ong C.S. Chu W.K. Fox I.J. Heffron T.G. Langnas A.N. Shaw Jr, B.W. Proton spectroscopy of brain glutamine in acute liver failure.Hepatology. 1995; 22: 69-74Crossref PubMed Google Scholar Like other amino acids, such as taurine, or polyols, such as myo-inositol, glutamine is also an organic osmolyte. Astrocyte swelling occurs as a result of the increase in intracellular osmolarity induced by glutamine, a process that activates compensatory mechanisms, including a reduction in the levels of myoinositol and taurine.9Cordoba J. Gottstein J. Blei A.T. Glutamine, myo-inositol, and organic brain osmolytes after portocaval anastomosis in the rat: implications for ammonia-induced brain edema.Hepatology. 1996; 24: 919-923PubMed Google Scholar Mild hypothermia (35°C) in a rat model of ALF prevented the development of brain edema and was associated with unchanged levels of myoinositol and taurine.10Zwingmann C. Chatauret N. Rose C. Leibfritz D. Butterworth R.F. Selective alterations of brain osmolytes in acute liver failure protective effect of mild hypothermia.Brain Res. 2004; 999: 118-123Crossref PubMed Scopus (50) Google Scholar Although not directly measured, it can be surmised that hypothermia decreased the extent of astrocyte swelling. An ammonia infusion to rats with portacaval anastomosis results in a predictable increase in brain water, a rise prevented by the application of temperatures of 33°C and 35°C.11Cordoba J. Crespin J. Gottstein J. Blei A.T. Mild hypothermia modifies ammonia-induced brain edema in rats after portacaval anastomosis.Gastroenterology. 1999; 116: 686-693Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar The development of brain edema was associated with cerebral hyperermia, and the increase in cerebral blood flow was prevented by both mild and moderate hypothermia. In the current study, an increase in cerebral blood flow was also noted in human ALF and application of therapeutic hypothermia (once brain edema and intracranial hypertension occurred) normalized this hemodynamic abnormality. So is the increase in cerebral blood flow cause or consequence of the process that leads to brain edema? A pathogenic role for cerebral hyperemia was suggested via pharmacologic manipulations of cerebral blood flow, whose reduction induced by indomethacin12Chung C. Gottstein J. Blei A.T. Indomethacin prevents the development of experimental ammonia-induced brain edema in rats after portacaval anastomosis.Hepatology. 2001; 34: 249-254Crossref PubMed Scopus (84) Google Scholar or increase as a result of vasopressin13Chung C. Vaquero J. Gottstein J. Blei A.T. Vasopressin accelerates experimental ammonia-induced brain edema in rats after portacaval anastomosis.J Hepatol. 2003; 39: 193-199Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar prevented or accelerated the development of brain edema, respectively. This animal experience with indomethacin and vasopressin has been reproduced in humans with ALF.14Tofteng F. Larsen F.S. 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: 798-804Crossref PubMed Google Scholar, 15Shawcross D.L. Davies N.A. Mookerjee R.P. Hayes P.C. Williams R. Lee A. Jalan R. Worsening of cerebral hyperemia by the administration of terlipressin in acute liver failure with severe encephalopathy.Hepatology. 2004; 39: 471-475Crossref PubMed Scopus (94) Google Scholar The mechanisms that lead to the rise in cerebral blood flow have been explored in the experimental animal. Specific and nonspecific inhibitors of neuronal nitric oxide synthase did not prevent the development of cerebral hyperemia.16Larsen F.S. Gottstein J. Blei A.T. Cerebral hyperemia and nitric oxide synthase in rats with ammonia-induced brain edema.J Hepatol. 2001; 34: 548-554Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar Recent preliminary studies in our laboratory suggest that zinc-protoporphyrin, an inhibitor of heme oxygenase, prevents the rise in cerebral blood flow and brain edema in the model of induced hyperammonemia.17Blei A.T. The pathophysiology of brain edema in Acute Liver Failure. An integrated view.Neurochem Int. 2004; (in press)Google Scholar Activation of heme oxygenase can occur as a result of oxidative stress, whose importance is increasingly recognized in experimental studies in this area,18Norenberg M.D. Oxidative and nitrosative stress in ammonia neurotoxicity.Hepatology. 2003; 37: 245-248Crossref PubMed Scopus (103) Google Scholar and will be discussed in the next segment. Whether the same mechanisms occur in human disease is yet unknown because other variables may affect cerebral hemodynamics, including the presence of infection. Cerebral hemodynamics are an important physiologic target for hypothermia. Ammonia delivery to brain is clearly reduced by mild hypothermia as the result of both a lower ammonia level and the normalization of cerebral blood flow. This effect was confirmed in the current study1Jalan R. Olde Damink S.W.M. Deutz N.E.P. Hayes P.C. Lee A. Moderate hypothermia in patients with acute liver failure and uncontrolled intracranial hypertension.Gastroenterology. 2004; 127: 1338-1346Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar where hypothermia reduced the extraction of brain ammonia and normalized the brain flux of ammonia. An increase in brain lactate is noted in rats with ALF as a result of hepatic devascularization, a rise that is also prevented by the application of mild hypothermia.19Chatauret N. Zwingmann C. Rose C. Leibfritz D. Butterworth R.F. Effects of hypothermia on brain glucose metabolism in acute liver failure a H/C-nuclear magnetic resonance study.Gastroenterology. 2003; 125: 815-824Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar Higher lactate levels may reflect anaerobic glycolysis in swollen astrocytes. This metabolic change may also underlie the genesis of oxygen-reactive species in isolated astrocytes exposed to ammonia.20Murthy C.R. Rama Rao K.V. Bai G. Norenberg M.D. Ammonia-induced production of free radicals in primary cultures of rat astrocytes.J Neurosci Res. 2001; 66: 282-288Crossref PubMed Scopus (252) Google Scholar Oxidative and nitrosative stress has been reported in such cells with nitration and phosphorylation of tyrosine protein residues.21Schliess F. Gorg B. Fischer R. Desjardins P. Bidmon H.J. Herrmann A. Butterworth R.F. Zilles K. Haussinger D. Ammonia induces MK-801-sensitive nitration and phosphorylation of protein tyrosine residues in rat astrocytes.FASEB J. 2002; 16: 739-741Crossref PubMed Scopus (246) Google Scholar Recent studies in isolated astrocytes suggest that glutamine itself may induce the production of reactive-oxygen species via the induction of the mitochondrial permeability transition.22Rama Rao K.V. Jayakumar A.R. Norenberg M.D. Induction of the mitochondrial permeability transition in cultured astrocytes by glutamine.Neurochem Int. 2003; 43: 517-523Crossref PubMed Scopus (78) Google Scholar The swollen astrocyte is a functionally altered cell. One of the main functions of astrocytes is the reuptake of the neurotransmitter glutamate released from presynaptic neurons. In experimental ALF, increased levels of brain glutamate have been noted by using brain microdialysis,23Michalak A. Rose C. Butterworth J. Butterworth R.F. Neuroactive amino acids and glutamate (NMDA) receptors in frontal cortex of rats with experimental acute liver failure.Hepatology. 1996; 24: 908-913Crossref PubMed Google Scholar a rise that underlies changes in glutamatergic neurotransmission seen in liver failure. The reuptake of glutamate is impaired as a result of the decreased activity of astrocytic glutamate transporters, especially GLUT-1.24Knecht K. Michalak A. Rose C. Rothstein J.D. Butterworth R.F. Decreased glutamate transporter (GLT-1) expression in frontal cortex of rats with acute liver failure.Neurosci Lett. 1997; 229: 201-203Crossref PubMed Scopus (152) Google Scholar Mild hypothermia normalizes extracellular brain glutamate levels in rats with ALF.25Rose C. Michalak A. Pannunzio M. Chatauret N. Rambaldi A. Butterworth R.F. Mild hypothermia delays the onset of coma and prevents brain edema and extracellular brain glutamate accumulation in rats with acute liver failure.Hepatology. 2000; 31: 872-877Crossref PubMed Scopus (108) Google Scholar In summary, mild hypothermia exerts potential beneficial effects at multiple levels of the chain of events that lead to brain edema in ALF. Most of the experimental studies hereby reviewed focus on ammonia’s effects on the brain. However, in most cases of human ALF, the development of infection precedes the worsening of encephalopathy.26Vaquero J. Polson J. Chung C. Helenowski I. Schiodt F.V. Reisch J. Lee W.M. Blei A.T. Infection and the progression of hepatic encephalopathy in acute liver failure.Gastroenterology. 2003; 125: 755-764Abstract Full Text Full Text PDF PubMed Scopus (298) Google Scholar The contribution of endotoxin and/or circulating cytokines to the development of brain edema has not been examined. By measuring levels in the arterial circulation and the brain venous effluent, Jalan et al.1Jalan R. Olde Damink S.W.M. Deutz N.E.P. Hayes P.C. Lee A. Moderate hypothermia in patients with acute liver failure and uncontrolled intracranial hypertension.Gastroenterology. 2004; 127: 1338-1346Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar noted a reduced efflux of cytokines from brain in patients with ALF as a result of mild hypothermia. This is an original and a very interesting observation that raises the possibility of an intracerebral production of cytokines. The observation should be taken back to the laboratory to model the potential synergism among ammonia, endotoxin, and cytokines. Is the use of mild hypothermia applicable to all patients with ALF? The lack of therapeutic options in cases with uncontrolled intracranial hypertension, such as reported in this issue, suggests that, at the present time, it should be reserved for such individuals. The total permissible length of treatment with hypothermia for ALF is unknown because trials in other conditions have examined effects over 24 hours. Hypothermia is associated with side effects, including the development of infection, coagulation abnormalities, and cardiac rhythm disturbances, events that are already present in ALF. Only a well-designed clinical trial can answer the exact role of hypothermia in this condition, one that encompasses candidates for emergency liver transplantation and subjects in whom the procedure is not performed. If the potential effects of hypothermia on the brain of patients with ALF were not convincing enough, recent studies suggest an effect of mild cooling on the degree of liver injury. FAS-mediated hepatocyte apoptosis is decreased after exposure of liver cells to 32°C.27Fu T. Blei A.I. Takamura N. Lin T. Guo D. Li H. O’Gorman M.R. Soriano H.E. Hypothermia inhibits Fas-mediated apoptosis of primary mouse hepatocytes in culture.Cell transplantation. 2004; (in press)PubMed Google Scholar In a preliminary study, acetaminophen-induced liver injury in mice was decreased at temperatures of 35°C.28Vaquero J. Belanger M. Cote J. Butterworth R.F. Mild hypothermia attenuates acetaminophen-induced hepatic necrosis in mice therapeutic implications (abstr).Hepatology. 2004; 40: 220AGoogle Scholar Protective effects of hypothermia in ischemia reperfusion of the liver are well described.29Kato A. Singh S. McLeish K.R. Edwards M.J. Lentsch A.B. Mechanisms of hypothermic protection against ischemic liver injury in mice.Am J Physiol Gastrointest Liver Physiol. 2002; 282: G608-616PubMed Google Scholar If hypothermia in ALF would be able to ameliorate liver injury and control the neurologic repercussions of this condition, a simple, relatively inexpensive approach would become available for the management of ALF. Adoption of such an approach would also be a reaffirmation of the importance of clinical investigation. Interactions between bench and bedside have been keenly successful in unraveling the pathogenesis of brain edema during 2 decades of work. The potential therapeutic role of mild hypothermia is an outgrowth of this interaction.