Therapeutic Hypothermia for Acute Liver Failure: Toward a Randomized, Controlled Trial in Patients with Advanced Hepatic Encephalopathy

Abstract

Acute liver failure (ALF), the abrupt loss of liver function in a patient without previous liver disease, remains a highly mortal condition. Patients with ALF often succumb to their liver injury after the development of cerebral edema, resulting in intracranial hypertension and brain herniation. While the management of cerebral edema in ALF always includes the administration of osmotically active agents, osmotherapy often reduces intracranial pressure (ICP) insufficiently, such that herniation may be delayed but not prevented. Therapeutic hypothermia, the intentional reduction of body core temperature, has been increasingly used to treat cerebral edema in patients with traumatic and hypoxic brain injury. Data in animal models of ALF also suggest that hypothermia is effective in the prevention and treatment of cerebral edema, and case reports in humans have suggested that hypothermia is an effective bridge to orthotopic liver transplantation. A randomized, controlled trial comparing the management of ALF patients under normothermic and hypothermic conditions is a logical extension of these preliminary observations. Herein, we consider the many difficulties which will be encountered in the design of such a trial in patients with ALF at high risk of developing cerebral edema.

Potential targeted therapies for the inflammatory pathogenesis of hepatic encephalopathy

“…Meanwhile, several novel and potential therapeutic agents, including N-acetylcysteine (NAC), hypothermia, minocycline, nonsteroidal anti-inflammatory drugs (NSAIDs), tumour necrosis factor-alpha (TNF-␣) antagonists and p38 inhibitors, have been shown to ameliorate systemic inflammation and neuroinflammation, improve or reverse neuropsychiatric manifestations, and prevent the onset and progression of HE in patients and/or animal models with ALF or CLF (Table 1, Figs. 1 and 2) [8][9][10][11][12][13][14]. These results point to the therapeutic potential of decreasing inflammation in the treatment of HE, and translating these results to the clinic might provide novel and promising therapeutic approaches for patients with HE secondary to ALF or CLF.…”

“…Similarly, in ALF patients with increased ICP, the reduction of ICP via moderate hypothermia was accompanied by a decrease in the arterial concentrations and cerebral production of TNF-␣, IL-1␤ and IL-6 [39]. Furthermore, a randomized controlled trial has demonstrated that moderate hypothermia consistently attenuated the development of cerebral oedema and increased ICP, and delayed the progression of HE in patients with ALF [9]. However, a multi-centre retrospective cohort analysis of moderate hypothermia in ALF revealed that moderate hypothermia did not appear to consistently improve 21-days and transplant-free survival in ALF patients with grade III and IV HE, which indicates that prospective trials are needed to clarify the utility of moderate hypothermia in ALF patients with HE [40].…”

“…Recently, several experimental animal studies have indicated that modulation of inflammation could be a mechanism of action for moderate hypothermia, and the initial clinical studies indicate that it is an effective, feasible and safe therapeutic modality in patients with HE due to ALF [9,39].…”

Treatment of Brain Edema in Acute Liver Failure

“…Rewarming should always proceed slowly to minimize the risk of complications, including rebound brain edema. Rewarming rates averaging 1°C every 12 h have been proposed to be most prudent [41].…”

The Rise of Glutaminase in End-Stage Liver Diseases

“…It has been shown that in chronic liver failure there is a low grade brain edema (Andrade, Lucena et al 2005) that is resolved after transplantation. In comatose patients, moderate hypothermia using cooling blankets to depress energy consumption in the brain seems to be the only relatively effective palliative therapy, but it is expensive, difficult to implement, and not routinely available (Stravitz, Lee et al 2008;Albrecht 2010).…”