title: A multicentre randomized controlled trial of moderate hypothermia to prevent intracranial hypertension in acute liver failure.
abstract: Animal models and human case series of acute liver failure (ALF) suggest moderate hypothermia (MH) to have protective effects against cerebral oedema (CO) development and intracranial hypertension (ICH). However, the optimum temperature for patient management is unknown. In a prospective randomized controlled trial we investigated if maintenance of MH prevented development of ICH in ALF patients at high risk of the complication.
  
  
  
  Patients with ALF, high-grade encephalopathy and intracranial pressure (ICP) monitoring in specialist intensive care units were randomized by sealed envelope to targeted temperature management (TTM) groups of 34°C (MH) or 36°C (control) for a period of 72h. Investigators were not blinded to group assignment. The primary outcome was a sustained elevation in ICP >25mmHg, with secondary outcomes the occurrence of predefined serious adverse effects, magnitude of ICP elevations and cerebral and all-cause hospital mortality (with or without transplantation).
  
  
  
  Forty-six patients were randomized, of whom forty-three were studied. There was no significant difference between the TTM groups in the primary outcome during the study period (35% vs. 27%, p=0.56), for the MH (n=17) or control (n=26) groups respectively, relative risk 1.31 (95% CI 0.53-3.2). Groups had similar incidence of adverse events and overall mortality (41% vs. 46%, p=0.75).
  
  
  
  In patients with ALF at high risk of ICH, MH at 33-34°C did not confer a benefit above management at 36°C in prevention of ICH or in overall survival. This study did not confirm advantage of its prophylactic use. (ISRCTN registration number 74268282; no funding.)
  
  
  
  Studies in animals with acute liver failure (ALF) have suggested that cooling (hypothermia) could prevent or limit the development of brain swelling, a dangerous complication of the condition. There is limited data on its effects in humans. In a randomized controlled trial in severely ill patients with ALF we compared the effects of different temperatures and found no benefit on improving survival or preventing brain swelling by controlling temperature at 33-34°C against 36°C.
authors.affiliation: Liver Intensive Care Unit, Institute of Liver Studies, Kings College Hospital, Denmark Hill, London SE5 9RS, United Kingdom. Electronic address: william.bernal@kcl.ac.uk.
authors.forename: William
authors.initials: W
authors.lastname: Bernal
authors.affiliation: Department of Anaesthesia and Critical Care, University Hospital Birmingham, Birmingham B15 2GW, United Kingdom.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Murphy
authors.affiliation: Liver Intensive Care Unit, Institute of Liver Studies, Kings College Hospital, Denmark Hill, London SE5 9RS, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Brown
authors.affiliation: Department of Anaesthesia and Critical Care, University Hospital Birmingham, Birmingham B15 2GW, United Kingdom.
authors.forename: Tony
authors.initials: T
authors.lastname: Whitehouse
authors.affiliation: Department of Hepatology, Rigshospitalet, University Hospital Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark.
authors.forename: Peter Nissen
authors.initials: PN
authors.lastname: Bjerring
authors.affiliation: Department of Neurosurgery, Rigshospitalet, University Hospital Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark.
authors.forename: John
authors.initials: J
authors.lastname: Hauerberg
authors.affiliation: Department of Anaesthesia, Rigshospitalet, University Hospital Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark.
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Frederiksen
authors.affiliation: Liver Intensive Care Unit, Institute of Liver Studies, Kings College Hospital, Denmark Hill, London SE5 9RS, United Kingdom.
authors.forename: Georg
authors.initials: G
authors.lastname: Auzinger
authors.affiliation: Liver Intensive Care Unit, Institute of Liver Studies, Kings College Hospital, Denmark Hill, London SE5 9RS, United Kingdom.
authors.forename: Julia
authors.initials: J
authors.lastname: Wendon
authors.affiliation: Department of Hepatology, Rigshospitalet, University Hospital Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark.
authors.forename: Fin Stolze
authors.initials: FS
authors.lastname: Larsen
mesh_terms: D000818:Animals; D006801:Humans; D007036:Hypothermia, Induced; D019586:Intracranial Hypertension; D017114:Liver Failure, Acute; D011446:Prospective Studies
keywords: Acute liver failure; Cerebral oedema; Encephalopathy; Hypothermia; Randomized controlled trial; Transplantation