Hypothermia for traumatic head injury

 

Characteristics of included studies [ordered by study ID]

Adelson 2005 HYPO1

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Methods	Multicentre, randomised, controlled trial.
Participants	Patients less than 13 years of age, with a Glasgow coma scale (GCS) score of ≤8.
Interventions	Hypothermia patients: Cooling to 32-33C within 6 hours of injury for 48 hours. Passively rewarmed by 1C every 3-4 hours. Normothermia patients: no intervention/not reported.
Outcomes	ICP CPP Mortality Infection Arrhythmia Coagulopathy Pneumonia
Notes
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Yes	'The investigators were blinded to the allocation. The statistician and data systems manager controlled the randomisation protocol and were blinded to the site.' Adelson 2008b

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Adelson 2005 HYPO2

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Methods	Single centre, randomised, controlled trial.
Participants	Patients less than 17 years of age, with a GCS score of ≤8.
Interventions	Hypothermia patients: Cooling to 32-33C for 48 hours. Passively rewarmed by 1C every 3-4 hours. Normothermia patients: no intervention/not reported.
Outcomes	ICP CPP Mortality Infection Arrhythmia Coagulopathy Pneumonia
Notes	The time between injury and randomisation was more than 6 hours. In some cases there was an unknown time of injury (e.g. child abuse).
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Yes	'The investigators were blinded to the allocation. The statistician and data systems manager controlled the randomisation protocol and were blinded to the site.' Adelson 2008b

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Aibiki 2000

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Methods	Randomised controlled trial. Four patients were excluded from the normothermic group after randomisation because of abdominal or chest injuries.
Participants	Patients aged 4 to 76, within 8 hours of traumatic brain injury. GCS score of ≤8 on admission to emergency room.
Interventions	Hypothermia patients: Cooling to 32-33C within 4 hours of injury for 3-4 days. Rewarming at 1C per day. Normothermia patients: maintained at 36-37C.
Outcomes	Death and Glasgow Outcome Scale (GOS) score at 6 months. Thromboxane A2 and prostaglandin I2 levels during study. Complications during treatment.
Notes	GOS assessed by "independent neurosurgeon who were not aware of the study". p.3904
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Unclear	'Patients were assigned randomly to each group.' p.3903 No mention of allocation concealment.

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Biswas 2002

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Methods	Randomised controlled trial.
Participants	Children up to 18 years old, with closed traumatic brain injury and a GCS score of ≤8.
Interventions	Hypothermia patients (n=10): cooled to 32 to 34 degrees Celsius for 48 hours, by cooling blanket placed underneath the body. Rewarming over a period of 12 hours. Control patients (n=11): rectal temperature was maintained between 36.5 and 37.5 degrees Celsius.
Outcomes	Death. GOS score at three, six and 12 months. ICP and CPP.
Notes	GOS score assessed blind to allocation. Analysis on an intention-to-treat basis. Two patients in the hypo group were lost to follow-up at the end of the study period. (2/10 lost to follow-up.) Five patients in the control group were lost to follow-up at the end of the study period. (5/11 lost to follow-up.)
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Unclear	Not described.

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Clifton 1992

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Methods	Randomised controlled trial.
Participants	Patients with GCS score of 4-8 with closed head injury but no major systemic injuries, in whom cooling could begin within 6 hours of injury.
Interventions	Hypothermia patients: cooling to 30-32C for 24 hours using cooling blankets and iced saline stomach lavage. Rewarming over a period of 24 hours. Control patients: No active temperature management.
Outcomes	Death and GOS score at 3 months. Complications during treatment phase.
Notes	GOS score was not assessed blind to treatment allocation.
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Yes	By 'sealed envelopes'.

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Clifton 1993

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Methods	Randomised controlled trial.
Participants	Patients age 16 to 60, GCS score of 4-7 with closed head injury but no major systemic injuries, in whom cooling could begin within 6 hours of injury.
Interventions	Hypothermia patients: cooling to 32-33C for 48 hours using cooling blankets. Rewarming over a period of 48 hours. Control patients: Cooling blankets were used to maintain body temperature at 37C for 80 hours.
Outcomes	Death and GOS score at 3 months. Complications during treatment period. ICP during treatment period.
Notes	GOS score assessed blind to treatment allocation.
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Yes	By 'sealed envelopes'.

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Clifton 2001

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Methods	Randomised controlled trial.
Participants	Patients aged 16 to 65 with a non-penetrating head injury and a GCS score of 3 to 8 after resuscitation.
Interventions	Hypothermia patients: cooling to 32.5-34C for 48 hours using ice, cold gastric lavage, unwarmed ventilator gases, and then temperature control pads. Rewarming at rate of up to 0.5C in 2 hours. Control: Body temperature maintained at 37C.
Outcomes	Death and GOS score at 6 months. ICP monitored during treatment. Nine neurobehavioural and neuropsychological scales at 6 months.
Notes	GOS score was assessed blind to treatment allocation. Outcome data missing for 7 patients, and not presented for 17 patients whose entry details were incomplete.
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Yes	Allocation concealment unclear, but report states that "only the study biostatistician was aware of each patient's treatment group assignment". p557

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Harris 2009

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Methods	Randomised controlled trial.
Participants	Patients over 18 years of age with a Glasgow coma scale score of ≤8, who required an ICP monitor and Foley catheter as part of routine treatment.
Interventions	Hypothermia patients (n= 12): the 'Discrete Cerebral Hypothermia System cooling cap' was used to reduce cerebral temperature to a target 33 degrees Celsius for 24 hours. 'Using heating blankets, patients' core body temperatures were kept above 36 degrees Celsius to avoid systemic hypothermia' p.3. Control patients (n= 13): Patients did not receive a cooling cap, and remained at normal body temperature.
Outcomes	Death, ICP, FIM, and GOS score at days 1, 2, 3, 4, 14, 21, 28 and 1 month (or at hospital discharge, if sooner than one month).
Notes	Cooling was begun within 48 hours of hospital admission.
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Yes	'After informed consent was obtained, all study patients were blindly randomized in a 1:1 ratio to the treatment or control group; patients in the treatment group received the cooling cap and the controls did not. The randomization was determined by the Department of Biostatistics using computer-generated random numbers. These numbers were assigned to each patient based on their order in the study and GCS score on initial assessment (severe [5-8] vs critical [3-4]), to allow for block randomization and to provide an initial balance in severity between the 2 groups.' p.3

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Hashiguchi 2003

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Methods	Randomised controlled trial. Allocation method not stated.
Participants	Participants age 10 years or older, with a GCS score of ≤8, 'who required continuous infusion of barbiturates to control intracranial hypertension.' p.1055
Interventions	Hypothermia patients (n=9): intracranial temperature in the lateral ventricle was maintained at 33.5 to 34.5 degrees Celsius for 48 hours, by water circulating blankets above and below the body. Rewarming over a period of 3 days, by 1 degree Celsius each day. Control patients (n=8): intracranial temperature was maintained between 36.5 and 37.5 degrees Celsius for 5 days, by water circulating blankets above and below the body. Barbiturates were given to both groups at 6 to 8 mg/kg/h for the first 48 hours, then at 2 mg/kg/h for 3 days.
Outcomes
Notes
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Unclear	Not described.

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Hirayama 1994

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Methods	Randomised controlled trial. Allocation method not stated.
Participants	Patients age 18 to 81, GCS 3-7 with closed head injury. Hypothermia started within 6 hours of injury.
Interventions	Hypothermia patients: cooling to 32-33C for 48 hours using cooling blankets. Rewarming over a period of 48 hours. Control patients: Not stated.
Outcomes	Death and GOS score at 3 months. ICP during treatment period.
Notes	Blinding of outcome assessment not stated.
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Unclear	Not described.

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Hutchison 2008

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Methods	Randomised controlled trial.
Participants	Patients age 1-17 years, with a recent traumatic brain injury (within 8 hours) and a GCS score of ≤8.
Interventions	Hypothermia patients: cooling to 32-33C for 24 hours with surface cooling. Rewarming at a rate of 0.5C every 2 hours. Control patients: temperature was maintained at 36.5 to 37.5C.
Outcomes	Unfavourable outcome at 6 months post-injury. Pediatric Cerebral Performance Category scale at pre-injury, and at 1, 3 and 12 months post-injury.
Notes	'Overall, 20 out of the 225 patients (9%) were lost to follow-up at 6 months -- 6 out of 108 patients (6%) in the hypothermia group and 14 of 117 (12%) in the normothermia group.' p.2451
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Yes	'...a study physician randomly assigned the patient to a treatment group with the use of a central telephone-based system that was available 24 hours a day. The randomization, prepared by an independent statistician, was blocked in groups of four (participating centers were unaware of the block size) and included two stratification variables: center and age (less than 7 years of age and 7 years of age or more).' p.2448

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Ishikura 1998

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Methods	Randomised controlled trial. Allocation by 'random sampling'.
Participants	Patients with GCS score of 3-8 with closed head injury.
Interventions	'Moderate hypothermia' without any details.
Outcomes	Thrombopoetin levels during treatment. Deaths in hypothermia arm only.
Notes	Abstract only.
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Unclear	'11 patients with severe closed head injuries were divided into two groups by random sampling.' No information provided on allocation concealment.

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Jiang 2000

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Methods	Randomised controlled trial. Allocation method not clear.
Participants	Patients with mean age of 41 years, and GCS score of 3-8.
Interventions	Hypothermia patients: 'Mild hypothermia' induced using cooling blankets until ICP within 'normal range' for 24 hours. Control patients: Temperature maintained between 37-38C for 14 days.
Outcomes	Death and GOS score at 12 months. Complications.
Notes	Assessment by MD blinded to treatment allocation.
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Unclear	Not described.

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Marion 1997

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Methods	Randomised controlled trial. Allocation by 'sealed envelopes'.
Participants	Patients age 16 to 75, GCS score of 3-7 with closed head injury, in whom cooling could begin within 6 hours of injury.
Interventions	Hypothermia patients: Cooling to 32-33C for 24 hours using cooling blankets and nasogastric lavage. Rewarming over a period of 12 hours. Control patients: Active management of temperature to 37-38.5C during five day treatment period.
Outcomes	Death and GOS score at 3, 6 and 12 months. ICP and CPP values during treatment phase. Complications for subset.
Notes	GOS score assessment by psychiatrist blinded to treatment allocation.
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Yes	'Using a block-randomization scheme, we assigned patients with a Glasgow coma score of 3 or 4 to a treatment group separately from those with a score of 5 to 7 by choosing among equal numbers of sealed envelopes containing the group assignments.' p.540

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Meissner 2003a

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Methods	Randomised controlled trial.
Participants	Patients with severe blunt head injury. Intervention was started within 8 hours of injury.
Interventions	Hypothermia patients: Cooling to 32-33C for 48 hours. Control patients: Temperature maintained at 36-37C.
Outcomes	Heart rate. Mean blood pressure. Plasma cortisol.
Notes	Primary outcome of study was moderate hypothermia on the cardiovascular and cortisol response in severe head injury. No mortality data reported.
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Unclear	Not described.

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Meissner 2003b

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Methods	Randomised controlled trial.
Participants	Patients aged 18 or older, with severe closed head injury with a GCS score of ≤9. The intervention was started within 8 hours of injury.
Interventions	Hypothermia patients: Cooling to 32-33C for 24-48 hours. Cooling was by water blankets and forced air. Control patients: Temperature maintained at 36-37C.
Outcomes	TSH TT4 FT4 TT3 FT3 RT3
Notes	This study examined thyroid hormone response in relation to therapeutic hypothermia.
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Unclear	Not described.

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Qiu 2007

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Methods	Randomised, controlled, double-blind trial.
Participants	Patients 18-65 years old with traumatic brain injury with a Glasgow Coma Scale score of ≤8.
Interventions	Hypothermia patients: Cooling to 33-35C for 4 days after craniotomy, using a cooling blanket and cooling head cap with circulating water at 4C. 'Natural' rewarming. Normothermia patients: cooling not used.
Outcomes	Mortality. ICP. Serum superoxide dismutase level. Glasgow Outcome Scale score at 1 year post-intervention.
Notes
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Yes	'Allocation and randomization was concealed so that the study investigators were not aware to which group the patient would be assigned, and the allocation sequence was protected until assignment.' p.230

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Shiozaki 1993

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Methods	Randomised controlled trial.
Participants	Patients age 10 or over, with a GCS score of ≤8 with head injury, who 'required continuous infusion of barbiturates to control intracranial hypertension'. p.363
Interventions	Hypothermia patients: cooling to 33.5-34.5C using water-circulating cooling blankets for a minimum of 48 hours and until ICP was below 20 mmHg for 24 hours. Rewarming over a period of 24 hours. Control patients: No active temperature management.
Outcomes	Death and GOS score at 6 months. Pneumonia. Complications during treatment. ICP and CPP values during treatment period for hypothermic arm only.
Notes	GOS score assessed blind to treatment allocation.
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Unclear	Not described.

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Shiozaki 1999

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Methods	Randomised controlled trial. Allocation concealment not clear. No loss to follow up.
Participants	Patients age 10 and above with traumatic brain injury, a Glasgow coma scale score of ≤8, and 'who required continuous infusion of barbiturate medication to control intracranial hypertension.' p.185
Interventions	Hypothermia patients: cooling to 33.5-34.5C for 48 hours, using water circulating blankets. Rewarming at 1C per day. Normothermia patients: maintained at 36.5-37.5C.
Outcomes	Death and GOS score at 6 months. Complications.
Notes	Blinding of outcome assessment not stated.
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Unclear	Not described.

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Shiozaki 2001

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Methods	Randomised controlled trial. Allocation concealment not clear. No loss to follow up.
Participants	Patients with traumatic brain injury, a Glasgow coma scale score of ≤8, and 'in whom ICP was maintained below 25mmHg by conventional therapies'. p.50
Interventions	Hypothermia patients: Cooling to 33.5-34.5C for 48 hours, using cooling blankets and gastric lavage. Rewarming at 1C per day. Normothermia patients: maintained at 36.5-37.5C.
Outcomes	Death and GOS score at 3 months. Complications.
Notes	Blinding of outcome assessment not stated.
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Unclear	Not described.

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Smrcka 2005

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Methods	Randomised controlled trial - randomisation method not described. No loss to follow up described.
Participants	Patients with traumatic brain injury with a Glasgow Coma Scale score of ≤8, who were up to age 61 years of age.
Interventions	Hypothermia (n=37): surface cooling to 34C for 72 hours. Temperature measured in urinary bladder. Passive rewarming. Normothermia (n=35): cooling not used.
Outcomes	ICP CPP SvjO2 (jugular bulb oxygen saturation) GOS
Notes
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Unclear	Not described.

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Yan 2001

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Methods	Randomised controlled trial. Allocation concealment not described. No loss to follow up described.
Participants	Patients with traumatic brain injury within 10 hours of injury and a Glasgow Coma Scale score of 3 to 8 on initial assessment.
Interventions	Hypothermia patients: Cooling to 32-34C for 3-5 days, using a cooling bed and, in some, ice blocks. 'Natural' rewarming. Normothermia patients: cooling not used.
Outcomes	Death, follow up period unclear. Neuroelectrophysiological measurements.
Notes	Blinding of outcome assessment not stated.
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Unclear	Not described.

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Zhang 2000

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Methods	Randomised controlled trial. Allocation concealment not described. No loss to follow up mentioned.
Participants	Patients aged under 65 with traumatic brain injury and a Glasgow Coma Scale score of 3-8 on admission to hospital.
Interventions	Hypothermia patients: Cooling to 32-33C for 3-8 days. Normothermia patients: temperature not stated.
Outcomes	Death, follow up period unclear.
Notes	Blinding of outcome assessment not stated.
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Unclear	Not described.

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Characteristics of excluded studies [ordered by study ID]

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Study	Reason for exclusion
Bayir 2009	Report on antioxidant status of paediatric patients treated with hypothermia. These patients have already been included in this review as part of the Adelson 2005 HYPO1 and Adelson 2005 HYPO2 trial.
Chen 2001	Unclear method of randomisation. Unable to confirm method of randomisation with trial report authors.
Chouhan 2006	Patients were not cooled for a minimum of 12 consecutive hours.
Fukuoka 2004	Quasi-randomised study design.
Gal 2002	Not a randomised study.
Gentilello 1997	Randomised trial of rewarming therapy after accidental hypothermia in trauma.
Guo 2004	Not a randomised trial.
Hayashi 2002	Not a randomised study.
Hayashi 2005	Not a randomised study.
Legros 1985	Not a randomised study.
Li 2008	Unclear if randomised trial. Unable to confirm method of randomisation with trial report authors.
Liu 2005	Patients who died within 72 hours of participating in the study were not included in the analysis.
Liu 2006	Patients were not cooled for a minimum of 12 consecutive hours.
Meissner 1998	No mention of method of randomisation.
Mrlian 2006	Not a randomised study.
Nara 1997	Unable to find sufficient information on study design.
Nordby 1984	Not a randomised comparison, and hypothermia confounded with barbiturate therapy.
Qiu 2005	Unclear if randomised trial. Unable to confirm method of randomisation with trial report authors.
Qiu 2006	Not a randomised study.
Schulman 2005	Patients in this study were excluded if they had evidence of acute brain injury and if they had previous traumatic brain injury.
Shen 2000	Not a randomised trial.
Wang 2005	Unclear if randomised trial. Unable to confirm method of randomisation with trial report authors.
Wang 2007	Unclear if randomised trial. Unable to confirm method of randomisation with trial report authors.
Wusi 2006	Not a randomised trial.
Xia 2005	Not a randomised trial.
Yamagami 1997	Not a randomised trial; hypothermia group GCS 4-6, normothermia group GCS 8-10.
Yan 2007	Unclear if randomised trial. Unable to confirm method of randomisation with trial report authors.
Zhi 2003	Unclear if randomised trial. Unable to confirm method of randomisation with trial report authors.

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Characteristics of ongoing studies [ordered by study ID]

Adelson 2007

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Trial name or title	Pediatric traumatic brain injury consortium: hypothermia.
Methods	Treatment, Randomized, Single Blind (outcome assessor), single group assignment, efficacy study.
Participants	TBI patients under 16 years of age, with a GCS </= 8.
Interventions	Patients in the treatment arm will be cooled to 32-33C for 48 hours and then slowly rewarmed.
Outcomes	To determine the effect of induced moderate hypothermia (32-33C) after severe TBI in children on mortality. To determine the effect of hypothermia after severe TBI in children on global function and neurocognitive outcomes in the areas of intellectual ability/development, memory and learning, and behaviour. To determine the effect of hypothermia after severe TBI in children of different age ranges (<6y and 6 to <16y) on mortality and 6- and 12-month functional and neurocognitive outcomes. To determine the effect of hypothermia after severe TBI in children on reducing intracranial hypertension and maintaining adequate cerebral perfusion pressure (CPP).
Starting date	November 2007
Contact information	David Adelson [phone] [e-mail] Danielle Brown [phone] [e-mail]
Notes	Phase III Clinical Trial. The sites participating in this trial are: Duke University, Durham, North Carolina; Johns Hopkins University, Baltimore, Maryland; Schneider Children’s Hospital, New Hyde Park, New York; Penn State University College of Medicine, Hershey, Pennsylvania; University of California, Davis, Sacramento, California; Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; University of Miami, Coral Gables, Florida; University of North Carolina, Chapel Hill, North Carolina; University of Pittsburgh, Pittsburgh, Pennsylvania; University of Tennessee, Memphis, Tennessee; University of Texas Southwestern, Dallas, Texas; University of Washington, Seattle, Washington.

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Beca 2006

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Trial name or title	Pilot Study of Early and Prolonged Hypothermia in Severe Traumatic Brain Injury in Children.
Methods	International, multi-centre, randomised controlled trial, safety/efficacy study.
Participants	Children of both genders age 1 to 16. The patients must have a severe traumatic brain injury as defined by a GCS ≤8 and an abnormal CT scan (intracranial haemorrhage, cerebral oedema or diffuse axonal injury) or a motor score ≤3 and a normal CT scan. The patients must be mechanically ventilated.
Interventions	Patients will be randomised within 6 hours of injury. Patients will be stratified by 1) centre and 2) Glasgow Coma Score. Half the patients will be cooled to 32-33 degrees Celsius for 72 hours and then slowly rewarmed. The other patients will have their body temperature maintained at 36-37 degrees Celsius.
Outcomes	Paediatric Cerebral Performance Category (PCPC) at 6 and 12 months after injury; neuropsychological outcomes at 6 and 12 months after injury, intracranial pressure/cerebral perfusion pressure; duration of mechanical ventilation; intensive care and hospital length of stay; adverse effects.
Starting date	November 2006
Contact information	John Beca [phone] [e-mail] Laura Whelan [phone] [e-mail]
Notes	The sites participating in this trial are: in Australia -- Royal Alexandra Hospital for Children, New South Wales; Sydney Children's Hospital, New South Wales; Queensland Paediatric Intensive Care Services, Queensland; Women's and Children's Hospital, South Australia; Royal Children's Hospital, Victoria; Princess Margaret Hospital, Western Australia; and in New Zealand -- Starship Children's Hospital, Auckland.

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Clifton 2002

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Trial name or title	National Acute Brain Injury Study: Hypothermia II (NABISH II).
Methods	Randomized, prospective, multi-center trial. Hypothermia for 48 hours, begun within 6 hours of severe brain injury.
Participants	Patients aged 16 to 45 years inclusive who have a closed head injury, present to the Emergency Department with a Glasgow Coma Scale score between 3-8, have a body temperature (bladder or rectal) of 35 degrees Celsius or less at admission, and an Abbreviated Injury Score (AIS) of 4 or less for the rest of the body.
Interventions	The patients will be randomly allocated to either the hypothermia group or the normothermia group. A cooling suit will be used to cool the hypothermia patients down to a body temperature of 33 degrees Celsius. This temperature of 33 degrees will be maintained in the hypothermia patients for 48 hours. After 48 hours, the study nurses will gradually re-warm the hypothermia patients no faster than one degree every four hours. This takes at least 16 hours sometimes longer depending upon the stability of the patient's vital signs. The control group - normothermia will be allowed to re-warm gradually upon arrival to the hospital with no medical intervention to raise or lower the body temperature.
Outcomes	Mortality and GOS. ICP and complications. Outcomes will be measured 6 months post injury by Harvey Levin, MD at Baylor College of Medicine. The personnel conducting outcome measurements will be blinded to the patient's assigned treatment protocol (whether hypothermia or normothermia).
Starting date	4/1/02 - 6/30/08
Contact information	Guy L. Clifton, MD Chairman Neurosurgery Dept., University of Texas Medical School 6431 Fannin St., Suite 7.148 Houston, TX 77030 713-500-6135 [e-mail] Emmy R. Miller, RN, PhD, Co-investigator NABISH II Associate Professor of Neurosurgery University of Texas Medical School, Houston, TX 6431 Fannin St., Suite 7.148 Houston, TX 77030 713-500-6145 [e-mail]
Notes	There are other study sites participating in NABISH II. They are: University of Pittsburgh, Duke University, University of California at Los Angeles, University of California at Sacramento, University of California at San Francisco, University of Virginia at Fairfax, University of Cincinnati, University of Mississippi at Jackson. Preliminary publication and description of treatment protocol: Clifton 2009.

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Maekawa 2002

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Trial name or title	Therapeutic Strategy for Severe Head Trauma Patients With Mild Hypothermia and Estimation of Medical Expenses in Japan.
Methods	Randomized controlled trial with parallel assignment, safety/efficacy study. Hypothermia to 32-34 degrees Celsius for 72 hours, initiated within 6 hours of injury.
Participants	Patients age 15 to 69 years, of both genders, with a closed head injury and a Glasgow Coma Scale score of 4-8.
Interventions	Patients will be randomized into two groups. The mild hypothermia group will be kept at 32-34 degrees Celsius for 72 hours, initiated within six hours of injury. Patients in the control group will have their body temperature maintained at 35.5 to 37 degrees Celsius for 72 hours. The Glasgow Outcome Scale score at six months after injury, and the total medical expenses of the two groups will be evaluated.
Outcomes	Neurological outcomes including GOS score and neuropsychological performance at 6 months after injury, total medical expenses, physiological data, and laboratory data.
Starting date	December 2002
Contact information	Yamaguchi University Hospital University Hospital Medical Information Network (UMIN, Japan) Japan Clinical Research Support Unit (J-CRSU) Tsuyoshi Maekawa, MD, PhD [phone] [e-mail] Susumu Yamashita, MD [phone] [e-mail]
Notes	Contact: Susumu Yamashita, MD

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Comparison 1. Immediate hypothermia versus normothermia

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Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

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 1 Death at final follow-up

21

1587

Odds Ratio (M-H, Fixed, 95% CI)

0.85 [0.68, 1.06]

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 2 Death at final follow-up stratified by trial quality

21

1587

Odds Ratio (M-H, Fixed, 95% CI)

0.85 [0.68, 1.06]

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2.1 Concealed allocation

9

891

Odds Ratio (M-H, Fixed, 95% CI)

1.11 [0.82, 1.51]

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2.2 Non-concealed allocation

12

696

Odds Ratio (M-H, Fixed, 95% CI)

0.62 [0.44, 0.86]

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 3 Unfavourable outcome at final follow-up

21

1587

Odds Ratio (M-H, Fixed, 95% CI)

0.77 [0.62, 0.94]

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 4 Unfavourable outcome stratified by trial quality

21

Odds Ratio (M-H, Fixed, 95% CI)

Subtotals only

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4.1 Concealed allocation

9

891

Odds Ratio (M-H, Fixed, 95% CI)

0.93 [0.70, 1.23]

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4.2 Non-concealed allocation

12

696

Odds Ratio (M-H, Fixed, 95% CI)

0.60 [0.44, 0.82]

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 5 Unfavourable outcome stratified by treatment duration

14

Odds Ratio (M-H, Fixed, 95% CI)

Subtotals only

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5.1 24 hours

4

321

Odds Ratio (M-H, Fixed, 95% CI)

1.03 [0.65, 1.65]

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5.2 48 hours

10

683

Odds Ratio (M-H, Fixed, 95% CI)

0.96 [0.70, 1.31]

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 6 Unfavourable outcome at various times during follow-up

15

Odds Ratio (M-H, Fixed, 95% CI)

Subtotals only

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6.1 3 months

6

271

Odds Ratio (M-H, Fixed, 95% CI)

0.85 [0.52, 1.39]

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6.2 6 months

9

839

Odds Ratio (M-H, Fixed, 95% CI)

0.76 [0.57, 1.01]

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6.3 12 months

4

262

Odds Ratio (M-H, Fixed, 95% CI)

0.52 [0.31, 0.87]

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 7 Pneumonia during the treatment period

11

559

Odds Ratio (M-H, Fixed, 95% CI)

1.35 [0.95, 1.91]

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7.1 Concealed allocation

4

306

Odds Ratio (M-H, Fixed, 95% CI)

0.84 [0.52, 1.35]

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7.2 Non-concealed allocation

7

253

Odds Ratio (M-H, Fixed, 95% CI)

2.47 [1.44, 4.23]

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