Keeping cool in acute liver failure: Rationale for the use of mild hypothermia

Abstract

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.

Arterial ammonia and clinical risk factors for encephalopathy and intracranial hypertension in acute liver failure

“…11,23,24 In ALF as in other critical illness, MOF is associated with high circulating levels of proinflammatory cytokines and other modulators of vascular function; [25][26][27] the effects of these agents on cerebral endothelial and vascular function could be important factors in the pathogenesis of ICH. 5,28,29 The observation of an increased incidence of ICH in the young was reported in the original description of this complication. 30 Although we confirmed this observation, we found no association between age and the development of HE.…”

“…[4][5][6] The net result of these changes is a marked alteration in cerebral function and astrocytic swelling. [5][6][7] Recent studies reporting circulating ammonia concentrations in patients with ALF have found levels higher than those seen in patients with HE accompanying chronic liver disease (CLD). 2,3,8,9 The magnitude of the elevation of ammonia, particularly if it is above 150 mol/L, has been reported to be related to an increased risk of major cerebral complications, including reduced consciousness level, seizures, cerebral herniation (CH), and death.…”

“…[1][2][3] Experimental studies have demonstrated ammonia-induced changes in neurotransmitter synthesis and release, neuronal oxidative stress, impaired mitochondrial function, and osmotic disturbances resulting from astrocytic metabolism of ammonia to glutamine. [4][5][6] The net result of these changes is a marked alteration in cerebral function and astrocytic swelling. [5][6][7] Recent studies reporting circulating ammonia concentrations in patients with ALF have found levels higher than those seen in patients with HE accompanying chronic liver disease (CLD).…”

Finasteride improves motor, EEG, and cellular changes in rat brain in thioacetamide-induced hepatic encephalopathy

“…Motor and EEG changes were followed within 24 h after administration of the last dose of TAA. Because hypothermia may be a side effect of TAA treatment, that may protect the development of HE in acute liver failure (46,57); rectal temperature was monitored during the same period.…”

Therapeutic Hypothermia for Acute Neurological Injuries

“…Hepatic encephalopathy and brain edema leading to intracranial hypertension are 2 major complications in patients with acute liver failure [135]. It is estimated that 20% of patients with acute liver failure die from increased ICP while awaiting transplantation.…”