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N Engl J Med. 2015 Dec 17;373(25):2403-12. doi: 10.1056/NEJMoa1507581. Epub 2015 Oct 7.

Hypothermia for Intracranial Hypertension after Traumatic Brain Injury.

Collaborators (154)

Noble D, Galt S, Taylor J, Addison J, Wallis C, Paterson R, Harris G, Mullan B, Quinn V, Bannon L, Gordon A, Templeton M, Wilson R, Thomas E, McMillan H, Tantam K, Gratrix A, Smith N, Martinson V, Barrera-Groba C, Littlejohn I, Spurling G, Hopkins P, Casboult S, Hadfield D, McKinlay J, Beardow Z, Elliot S, Jain R, Bellini A, McCluskey T, Harvey D, Chikhani M, Bolland A, Waldmann C, Jacques N, Prowse H, Turnbull D, Eapen G, Birchall K, Verma V, Creary T, Niebrzegowska E, Owen T, Baldwin J, Williams A, Thompson C, Salt R, Cartlidge D, Vincent A, Calder V, Scott C, Ferris P, Roberts J, Evans T, Burgess N, Della Torre V, Mellinghoff J, Stotz M, Hauer V, Ochelli-Okpue A, McMahon C, Tweedie I, Murray L, Bassford C, Ward G, McCauley M, Wise M, Palmer N, Cole J, Damas F, Xavier N, Dulière GL, Simoens G, Biston P, Joosten A, Simon M, Antoine A, Zieppen B, Bulpa P, Dive A, Bouhon S, Taccone F, Vincent JL, Durand D, Spapen H, Troubleyn J, Van Malderen C, Toome V, Sillaots P, Koger I, Stuttmann R, Jakubetz J, Langer S, Michalia M, Clouva-Molyvdas PM, Vassiliadis I, Nanas S, Douka L, Dimopolous S, Pneumatikos I, Dragoumanis C, Kouliatsis G, Nakos G, Kostanti E, Zakynthinos E, Makris D, Palli E, Koukoulitsios G, Tsikritsaki K, Kalogeromitros A, Nagy E, Lampiri C, Valtoy M, Barzo P, Kis D, Fulop B, Gupta D, Bindra A, Breen D, Barry J, Neau E, Spoto M, Fusilli N, Malossini S, Antonelli M, Caricato A, Tersali A, Seabra F, Aragão I, Antunes R, Petrikov S, Titova J, Solodov A, Al-Jabbary A, Deeb A, Richi H, del Campo MM, Casado JM, Pérez EB, Pérez AZ, Diez MA, Echeverri SO, Blesa A, Romero F, Sanchez M, van der Jagt M, Haitsma I, van Duijn D, Dennesen P, Koole M, Krishnareddy K, Hegazi M, Sharma BS.

Author information

From the Centre for Clinical Brain Sciences (P.J.D.A.), Department of Anaesthesia, Critical Care, and Pain Medicine (H.L.S., B.A.H., C.G.B., J.K.J.R.), and Centre for Population Health Sciences (A.R., G.D.M.), University of Edinburgh, and Critical Care, Western General Hospital, NHS Lothian (B.A.H., J.K.J.R.) - all in Edinburgh.



In patients with traumatic brain injury, hypothermia can reduce intracranial hypertension. The benefit of hypothermia on functional outcome is unclear.


We randomly assigned adults with an intracranial pressure of more than 20 mm Hg despite stage 1 treatments (including mechanical ventilation and sedation management) to standard care (control group) or hypothermia (32 to 35°C) plus standard care. In the control group, stage 2 treatments (e.g., osmotherapy) were added as needed to control intracranial pressure. In the hypothermia group, stage 2 treatments were added only if hypothermia failed to control intracranial pressure. In both groups, stage 3 treatments (barbiturates and decompressive craniectomy) were used if all stage 2 treatments failed to control intracranial pressure. The primary outcome was the score on the Extended Glasgow Outcome Scale (GOS-E; range, 1 to 8, with lower scores indicating a worse functional outcome) at 6 months. The treatment effect was estimated with ordinal logistic regression adjusted for prespecified prognostic factors and expressed as a common odds ratio (with an odds ratio <1.0 favoring hypothermia).


We enrolled 387 patients at 47 centers in 18 countries from November 2009 through October 2014, at which time recruitment was suspended owing to safety concerns. Stage 3 treatments were required to control intracranial pressure in 54% of the patients in the control group and in 44% of the patients in the hypothermia group. The adjusted common odds ratio for the GOS-E score was 1.53 (95% confidence interval, 1.02 to 2.30; P=0.04), indicating a worse outcome in the hypothermia group than in the control group. A favorable outcome (GOS-E score of 5 to 8, indicating moderate disability or good recovery) occurred in 26% of the patients in the hypothermia group and in 37% of the patients in the control group (P=0.03).


In patients with an intracranial pressure of more than 20 mm Hg after traumatic brain injury, therapeutic hypothermia plus standard care to reduce intracranial pressure did not result in outcomes better than those with standard care alone. (Funded by the National Institute for Health Research Health Technology Assessment program; Current Controlled Trials number, ISRCTN34555414.).

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