Keeping cool in acute liver failure: Rationale for the use of mild hypothermia
2005; Elsevier BV; Volume: 43; Issue: 6 Linguagem: Inglês
10.1016/j.jhep.2005.05.039
ISSN1600-0641
AutoresJavier Vaquero, Christopher F. Rose, Roger F. Butterworth,
Tópico(s)Climate Change and Health Impacts
ResumoEncephalopathy, brain edema and intracranial hypertension are neurological complications responsible for substantial morbidity/mortality in patients with acute liver failure (ALF), where, aside from liver transplantation, there is currently a paucity of effective therapies. Mirroring its cerebro-protective effects in other clinical conditions, the induction of mild hypothermia may provide a potential therapeutic approach to the management of ALF. A solid mechanistic rationale for the use of mild hypothermia is provided by clinical and experimental studies showing its beneficial effects in relation to many of the key factors that determine the development of brain edema and intracranial hypertension in ALF, namely the delivery of ammonia to the brain, the disturbances of brain organic osmolytes and brain extracellular amino acids, cerebro-vascular haemodynamics, brain glucose metabolism, inflammation, subclinical seizure activity and alterations of gene expression. Initial uncontrolled clinical studies of mild hypothermia in patients with ALF suggest that it is an effective, feasible and safe approach. Randomized controlled clinical trials are now needed to adequately assess its efficacy, safety, clinical impact on global outcomes and to provide the guidelines for its use in ALF. Encephalopathy, brain edema and intracranial hypertension are neurological complications responsible for substantial morbidity/mortality in patients with acute liver failure (ALF), where, aside from liver transplantation, there is currently a paucity of effective therapies. Mirroring its cerebro-protective effects in other clinical conditions, the induction of mild hypothermia may provide a potential therapeutic approach to the management of ALF. A solid mechanistic rationale for the use of mild hypothermia is provided by clinical and experimental studies showing its beneficial effects in relation to many of the key factors that determine the development of brain edema and intracranial hypertension in ALF, namely the delivery of ammonia to the brain, the disturbances of brain organic osmolytes and brain extracellular amino acids, cerebro-vascular haemodynamics, brain glucose metabolism, inflammation, subclinical seizure activity and alterations of gene expression. Initial uncontrolled clinical studies of mild hypothermia in patients with ALF suggest that it is an effective, feasible and safe approach. Randomized controlled clinical trials are now needed to adequately assess its efficacy, safety, clinical impact on global outcomes and to provide the guidelines for its use in ALF. Hepatic encephalopathy and brain edema leading to intracranial hypertension are two major complications in patients with acute liver failure (ALF). Whereas the former defines the syndrome of ALF, the development of high intracranial pressure (ICP) is associated with high mortality [[1]Ware A.J. D'Agostino A.N. Combes B. Cerebral edema: a major complication of massive hepatic necrosis.Gastroenterology. 1971; 61: 877-884PubMed Google Scholar]. The current view embraces both entities as parts of the same spectrum of alterations, and recognizes central pathophysiologic roles for ammonia and astrocyte swelling (Fig. 1) [[2]Butterworth R.F. Molecular neurobiology of acute liver failure.Semin Liver Dis. 2003; 23: 251-258Crossref PubMed Scopus (23) Google Scholar]. Risk factors for developing intracranial hypertension and brain herniation include a short interval between the onset of jaundice and brain dysfunction, worsening of encephalopathy, and arterial ammonia concentrations >150 mM [3O'Grady J.G. Schalm S.W. Williams R. 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In the studies reviewed here, hypothermia was induced by cooling the whole body, as selective brain cooling is difficult in adults [[5]Mellergard P. Changes in human intracerebral temperature in response to different methods of brain cooling.Neurosurgery. 1992; 31: 671-677Crossref PubMed Google Scholar]. The modern clinical use of hypothermia commenced in 1950, when Bigelow demonstrated its neuro-protective properties during cardiac surgery [6Bigelow W.G. Lindsay W.K. Greenwood W.F. Hypothermia; its possible role in cardiac surgery: an investigation of factors governing survival in dogs at low body temperatures.Ann Surg. 1950; 132: 849-866Crossref PubMed Google Scholar, 7Bigelow W.G. Callaghan J.C. Hopps J.A. General hypothermia for experimental intracardiac surgery; the use of electrophrenic respirations, an artificial pacemaker for cardiac standstill, and radio-frequency rewarming in general hypothermia.Trans Meet Am Surg Assoc Am Surg Assoc. 1950; 68: 211-219PubMed Google Scholar]. This hallmark discovery allowed the performance of open-heart surgical procedures without the neurological sequellae of brain ischemia, and prompted the investigation of hypothermia in other conditions. In addition to cardiac surgery, hypothermia is now used during some neurosurgical procedures, mainly those involving aneurysms [[8]Pemberton P.L. Dinsmore J. The use of hypothermia as a method of neuroprotection during neurosurgical procedures and after traumatic brain injury: a survey of clinical practice in great Britain and Ireland.Anaesthesia. 2003; 58: 370-373Crossref PubMed Google Scholar]. Cardiac arrest and traumatic brain injury are two conditions, where hypothermia is also used. The American Heart Association includes hypothermia in the treatment of unconscious adult patients with spontaneous circulation after out-of-hospital cardiac arrest [[9]Nolan J.P. Morley P.T. Vanden Hoek T.L. Hickey R.W. Kloeck W.G. 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Hypothermia; its possible role in cardiac surgery: an investigation of factors governing survival in dogs at low body temperatures.Ann Surg. 1950; 132: 849-866Crossref PubMed Google Scholar, 32Rosomoff H.L. Holaday D.A. Cerebral blood flow and cerebral oxygen consumption during hypothermia.Am J Physiol. 1954; 179: 85-88PubMed Google Scholar]. Accordingly, induction of hypothermia during brain ischemia decreases the histological damage in several experimental models [15Busto R. Dietrich W.D. Globus M.Y. Valdes I. Scheinberg P. Ginsberg M.D. Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury.J Cereb Blood Flow Metab. 1987; 7: 729-738Crossref PubMed Google Scholar, 33Welsh F.A. Sims R.E. Harris V.A. Mild hypothermia prevents ischemic injury in gerbil hippocampus.J Cereb Blood Flow Metab. 1990; 10: 557-563Crossref PubMed Google Scholar, 34Minamisawa H. Smith M.L. Siesjo B.K. 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Ginsberg M.D. Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury.J Cereb Blood Flow Metab. 1987; 7: 729-738Crossref PubMed Google Scholar, 43Natale J.A. D'Alecy L.G. Protection from cerebral ischemia by brain cooling without reduced lactate accumulation in dogs.Stroke. 1989; 20: 770-777Crossref PubMed Google Scholar]. These observations suggest that hypothermia affects other steps in addition to the disturbance of energy metabolism. The alteration of cellular ionic homeostasis plays a major role in brain ischemia and neurotrauma. Due to energy failure, the energy-dependent membrane ionic pumps, the voltage-dependent ion channels and others become progressively altered, and result in disturbance of ionic homeostasis, which ultimately leads to cell swelling, activation of proteolysis, lipid degradation, mitochondrial dysfunction and free radical generation. A release of excitatory neurotransmitters worsens further this scenario, e.g. via the influx of sodium and/or calcium after the binding of glutamate to NMDA receptors. Hypothermia may influence several steps of this cascade of events. For example, it may have a 'membrane-stabilizing' effect, improving the altered permeability to ions [[44]Katsura K. Minamisawa H. Ekholm A. Folbergrova J. Siesjo B.K. Changes of labile metabolites during anoxia in moderately hypo- and hyperthermic rats: correlation to membrane fluxes of K+.Brain Res. 1992; 590: 6-12Crossref PubMed Google Scholar]. Hypothermia also prevents the extracellular increase of brain excitatory neurotransmitters in brain ischemia [45Busto R. Globus M.Y. Dietrich W.D. Martinez E. Valdes I. Ginsberg M.D. Effect of mild hypothermia on ischemia-induced release of neurotransmitters and free fatty acids in rat brain.Stroke. 1989; 20: 904-910Crossref PubMed Google Scholar, 46Winfree C.J. Baker C.J. Connolly Jr, E.S. Fiore A.J. 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