Therapeutic hypothermia for head injury

Phil Alderson; David Signorini; Chirag Patil

doi:10.1002/14651858.CD001048.pub2

Therapeutic hypothermia for head injury

Contraer todo Desplegar todo

Referencias

References to studies included in this review

Ir a:

estudios excluidos
estudios a la espera de valoración
estudios en curso
otras referencias

Aibiki M, Maekawa S, Yokono S. Moderate hypothermia improves imbalances of thromboxane A2 and prostaglandin I2 production after traumatic brain injury in humans. Critical Care Medicine 2000;28(12):3902‐6.

Biswas AK, Bruce DA, Sklar FH, Bokovoy JL, Sommerauer JF. Treatment of acute traumatic brain injury in children with moderate hypothermia improves intracranial hypertension. Critical Care Medicine 2002;30(12):2742‐51.

Clifton GL, Allen S, Berry J, Koch SM. Systemic hypothermia in treatment of brain injury. Journal of Neurotrauma 1992;9:S487‐95.

Clifton GL. Hypothermia and hyperbaric oxygen as treatment modalities for severe head injury. New Horizons 1995;3:474‐8.

Clifton GL. Hypothermia in the management of patients with head injury. Abstracts of the 2nd International Neurotrauma Symposium. Glasgow, 1993; Vol. July 4‐9.

Google Scholar

Clifton GL. Systemic hypothermia in treatment of severe brain injury. Journal of Neurosurgical Anesthesiology 1995;7:152‐6.

Clifton GL. Systemic hypothermia in treatment of severe brain injury: A review and update. Journal of Neurotrauma 1995;12:923‐7.

Clifton GL, Allen S, Barrodale P, Plenger P, Berry J, Koch S, Fletcher J, Hayes RL, Choi SC. A phase II study of moderate hypothermia in severe brain injury. Journal of Neurotrauma 1993;10:263‐73.

Clifton GL. Hypothermia in Neurotrauma. Abstracts of the 3rd International Neurotrauma Symposium. Toronto, Canada, 1995:July 22‐27.

Google Scholar

Clifton GL, Miller ER, Choi SC, Levin HS, McCauley S, Smith KR, et al. Lack of effect of induction of hypothermia after acute brain injury. New England Journal of Medicine 2001;344(8):556‐63.

Hayashi N, Hirayama T, Udagawa A, Daimon W, Ohata M. Systemic Management of Cerebral Edema Based on a New Concept in Severe Head Injury Patients. Acta Neurochir 1994;60(supplement):541‐3.

Hayashi N, Shibuya T, Kinoshita K, Jo S, Azuhata T, Mera K, Tanjo K. The cerebral thermal dysregulation and hypothermia treatment in severe brain injury patients. Abstracts of the Tenth International Symposium on Intracranial Pressure and Neuromonitoring in Brain Injury. Williamsburg USA, 1997:May 25‐29.

Google Scholar

Hirayama T, Katayama Y, Kano T, Hayashi N, Tsubokawa T. Impact of Moderate Hypothermia on Therapies for Intracranial Pressure Control in Severe Traumatic Brain Injury. In: Nagai H, Ishii S, Maeda M editor(s). Intracranial Pressure IX. Tokyo: Springer‐Verlag, 1994:233‐236.

Google Scholar

Hirayama T, Katayama Y, Maeda T, Kawamata T, Tsubokawa T. Effects of moderate hypothermia on the evolution of cerebral contusion. Abstracts of the 3rd International Neurotrauma Symposium. Toronto, Canada, 1995:July 22‐27.

Google Scholar

Ishikura H, Yamagami K, Akahori M, Shoji Y, Fukui H, Tanaka T. Changes in Blood Platelet Count and Serum Thrombopoetin (TPO) level under Moderate Hypothermic Therapy in Traumatic Severe Closed Head Injury. Critical Care Medicine 1998;26(Supplement 1):A82.

Google Scholar

Jiang JY, Yu MK, Zhu C. Effect of long‐term mild hypothermia therapy in patients with severe traumatic brain injury: 1‐year follow‐up review of 87 cases. Journal of Neurosurgery 2000;93:546‐9.

Jiang JY, Zhu C. The mild hypothermia significantly decreases mortality of severe traumatic brain injured patients. Abstracts of the International Conference on Recent Advances in Neurotraumatology, Riccione, Italy, Sept 8‐11 1996.. 1996.

Google Scholar

Clark RSB, Kochanek PM, Obrist WD, Wong HR, Billiar TR, Wisniewski SR, Marion DW. Cerebrospinal fluid and plasma nitrite and nitrate concentrations after head injury in humans. Critical Care Medicine 1996;24:1243‐51.

Darby JM, Marion DW, Peitzman A, Carlier P, Obrist WD. Pulmonary complications in brain‐injured patients treated with hypothermia. Anesthesiology 1992;77:A295.

Marion DW, Carlier P. Moderate therapeutic hypothermia improves outcome following severe traumatic brain injury. Abstracts of the 3rd International Neurotrauma Symposium. Toronto, Canada, 1995:July 22‐27.

Google Scholar

Marion DW, Obrist WD, Carlier PM, Penrod LE, Darby JM. The use of moderate therapeutic hypothermia for patients with severe head injuries: a preliminary report. Journal of Neurosurgery 1993;79:354‐62.

Marion DW, Palmer AM, DeKosky ST, Kochanek PM, Carlier PM. Effect of moderate hypothermia on neurochemical mediators of secondary brain injury. Journal of Neurosurgery 1995;82:344A.

Google Scholar

Marion DW, Penrod LE, Kelsey SF, Obrist WD, Kochanek PM, Palmer AM, Wisniewski SR, DeKosky ST. Treatment of traumatic brain injury with moderate hypothermia. Abstracts of the Tenth International Symposium on Intracranial Pressure and Neuromonitoring in Brain Injury. Williamsburg USA, 1997:May 25‐29.

Google Scholar

Marion DW, Penrod LE, Kelsey SF, Obrist WD, Kochanek PM, Palmer AM, Wisniewski SR, DeKosky ST. Treatment of traumatic brain injury with moderate hypothermia. New England Journal of Medicine 1997;336:540‐6.

Resnick DK, Marion DW, Darby JM. The effect of hypothermia on the incidence of delayed traumatic intracerebral hemorrhage. Neurosurgery 1994;34:252‐6.

Meissner W, Fritz H, Dohrn B, Specht M, Reinhart K. Influence of Hypothermia on Cytokine Concentrations in Head Injured Patients. Critical Care Medicine 1998;26(Supplement 1):A82.

Meissner W, Fritz H, Dohm B, Krapp C, Reinhart K. Hormonal and haemodynamic consequences of moderate hypothermia in head injured patients. Neurosciences 2003:102‐3.

Google Scholar

Meissner W, Krapp C, Kauf E, Dohrn B, Reinhart K. Thyroid hormone response to moderate hypothermia in severe brain injury. Intensive Care Medicine 2003;29:44‐8.

Shiozaki T, Sugimoto H, Taneda M, Yoshida H, Iwai A, Yoshioka T, Sugimoto T. Effect of mild hypothermia on uncontrollable intracranial hypertension after severe head injury. Journal of Neurosurgery 1993;79:363‐8.

Shiozaki T, Kato A, Taneda M, Hayakata T, Hashiguchi N, Tanaka H. Little benefit from mild hypothermia therapy for severely head injured patients with low intracranial pressue. Journal of Neurosurgery 1999;91:185‐91.

Shiozaki T, Hayakata T, Taneda M, Nakajima Y, Hashiguchi N, Fujimi S, et al. A multicenter prospective randomized controlled trial of the efficacy of mild hypothermia for severely head injured patients with low intracranial pressue. Journal of Neurosurgery 2001;94:50‐4.

Yan Y, Tang W. Changes of evoked potentials and evaluation of mild hypothermia for treatment of severe brain injury. Chinese Journal of Traumatology 2001;4:8‐13.

Zhang K, Wang JX. Comparative study on mild hypothermia in patients with severe head injury and the most severe head injury. Inner Mongolia Medical Journal 2000;32:4‐6.

Google Scholar

References to studies excluded from this review

Ir a:

estudios incluidos
estudios a la espera de valoración
estudios en curso
otras referencias

Gentilello LM, Jurkovich GJ, Stark MS, Hassantash SA, O'Keefe GE. Is hypothermia in the victim of major trauma protective or harmful?. Annals of Surgery 1997;226:439‐49.

Nara I, Shiogai T, Saruta K, Hara M, Saito I. Comparative effects of hypothermia, barbituates, and osmotherapy for cerebral oxygen metabolism, intracranial pressure and cerebral perfusion pressure in patients with severe head injury. Abstracts of the Tenth International Symposium on Intracranial Pressure and Neuromonitoring in Brain Injury. Williamsburg USA, 1997:May 25‐29.

Google Scholar

Nordby HK, Nesbakken R. The effect of high‐dose barbituate eecompression after severe head Injury: a controlled clinical trial. Acta Neurochirurgica 1984;72:157‐66.

Yamagami K, Iwase M, Matsubara M, Matsuo N, Tanaka T. Nitric oxide production and arginine consumption in traumatic brain injury are correlated with severity. Abstracts of the 26th Meeting of the Society for Critical Care Medicine. Critical Care Medicine. 1997; Vol. 25, issue supplement 1:A72.

Google Scholar

References to studies awaiting assessment

Ir a:

estudios incluidos
estudios excluidos
estudios en curso
otras referencias

Shen JH, Shen MW. Application of mild hypothermia in treatment of severe brain injury. Heibel Med J 2000;6:498‐500.

Google Scholar

References to ongoing studies

Ir a:

estudios incluidos
estudios excluidos
estudios a la espera de valoración
otras referencias

National Acute Brain Injury Study: Hypothermia II (NABISH II). Ongoing study Run‐in period 21st October 2002 to 21st April 2003.

Randomisation begins after run‐in period..

Additional references

Ir a:

estudios incluidos
estudios excluidos
estudios a la espera de valoración
estudios en curso

Alexander E. Global Spine and Head Injury Prevention Project (SHIP). Surgical Neurology 1992;38:478‐9.

Bering EA. Effect of body temperature change on cerebral oxygen consumption of the intact monkey. American Journal of Physiology 1961;200:417‐19.

Bullock R, Chesnut RM, Clifton G, Ghajar J, Marion DW, Narayan RK, et al. Guidelines for the management of severe head injury. Journal of Neurotrauma 1996;13:639‐734.

Google Scholar

Busto R, Dietrich WD, Globus MY, Valdes I, Scheinberg P, Ginsberg MD. Small differences in intra‐ischemic brain temperature critically determine the extent of ischemic neuronal injury. Journal of Cerebral Blood Flow Metabolism 1987;7:729‐38.

Busto R, Globus MY, Dietrich WD, Martinez E, Valdes I, Ginsberg MD. Effect of mild hypothermia on ischemia‐induced release of neuro‐transmitters and free fatty acids in rat brain. Stroke 1989;20:904‐10.

Clasen RA, Pandolfi S, Russell J, Stuart D, Hass GM. Hypothermia and hypotension in experimental cerebral edema. Archives of Neurology 1968;19:472‐86.

Clifton GL. Systemic Hypothermia in Treatment of Severe Brain Injury : A Review and Update 1995. Journal of Neurotrauma 1995;12:923‐7.

Fay T. Observations on generalized refrigeration in cases of severe cerebral trauma. Assoc Res Nerv Ment Dis Proc 1945;24:611‐19.

Google Scholar

Kirkpatrick PJ. On guidelines for the management of severe head injury. Journal of Neurology, Neurosurgery and Psychiatry 1997;62:109‐11.

Laskowski EJ, Klato I, Baldwin M. Experimental sutdy on the effects of hypothermia on local brain injury. Neurology 1960;10:499‐505.

McIntyre L, Fergusson D, Hebert P, Moher D, Hutchison J. Prolonged therapeutic hypothermia after traumatic brain injury in adults. A systematic review. Journal of the American Medical Association 2003;289:2992‐9.

Schubert A. Side effects of mild hypothermia. Journal of Neurosurgical Anesthesiology 1995;7:139‐47.

Schulz, KF, Chalmers, I, Hayes, RJ, Altman, DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. Journal of the American Medical Association 1995;273(5):408‐12.

Sedzimir CB. Therapeutic hypothermia in cases of head injury. Journal of Neurosurgery 1959;16:407‐14.

Shapiro HM, Wyte SR, Loeser J. Barbiturate‐augmented hypothermia for reduction of persistent intracranial hypertension. Journal of Neurosurgery 1974;40:90‐100.

Smith SL, Hall ED. Mild pre‐ and posttraumatic hypothermia attenuates blood‐brain barrier damage following controlled cortical impact injury in the rat. Journal of Neurotrauma 1996;13:1‐9.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Ir a:

estudios excluidos
estudios en curso

Aibiki 2000

Methods	Randomised controlled trial. Allocation concealment unclear. Four patients excluded from the normothermic group after randomisation because of abdominal or chest injuries.
Participants	Patients aged 4 to 76 with traumatic brain injury and Glasgow coma scale from 3 to 8.
Interventions	Hypothermia patients: Cooling to 32‐33C within 4 hours on injury for 3‐4 days. Rewarming at 1C per day. Normothermia patients: maintained at 36‐37C.
Outcomes	Death and GOS 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".
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Biswas 2002

Methods	Randomised controlled trial. Allocation concealment
Participants	Twenty‐one children up to 18 years old, with closed traumatic brain injury and a GCS of 8 or less.
Interventions	Hypothermia patients (n=10?): cooled to 32 to 34 degress celsius for 48 hours. 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 at three, six and 12 months. ICP and CPP.
Notes	GOS assessed blind to allocation. Analysis on an intention‐to‐treat basis.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	D ‐ Not used

Clifton 1992

Methods	Randomised controlled trial. Allocation by 'sealed envelopes'.
Participants	Patients with GCS 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 at 3 months. Complications during treatment phase.
Notes	GOS not assessed blind to treatment allocation.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Clifton 1993

Methods	Randomised controlled trial. Allocation by 'sealed envelopes'.
Participants	Patients age 16 to 60, GCS 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 at 3 months. Complications during treatment period. ICP during treatment period.
Notes	GOS assessed blind to treatment allocation.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Clifton 2001

Methods	Randomised controlled trial. Allocation concealment unclear, but report states that "only the study biostatistician was aware of each patient's treatment group assignment". Outcome data missing for 7 patients, and not presented for 17 patients whose entry details were incomplete.
Participants	Patients aged 16 to 65 with a non‐penetrating head injury and a Glasgow coma scale 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 at 6 months. ICP monitored during treatment. Nine neurobehavioural and neuropsychological scales at 6 months..
Notes	GOS assessed blind to treatment allocation.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Hirayama 1994

Methods	Randomised controlled trial. Allocation method not stated.
Participants	Patients age 18 to 81, GCS 3‐7 with closed head 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 at 3 months. ICP during treatment period.
Notes	Blinding of outcome assessment not stated.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Ishikura 1998

Methods	Randomised controlled trial. Allocation by 'random sampling'.
Participants	Patients with GCS 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*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Jiang 2000

Methods	Randomised controlled trial. Allocation method not clear. stated.
Participants	Patients with mean age of 41 years, GCS 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 at 12 months. Complications.
Notes	Assesment by MD blinded to treatment allocation.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Marion 1997

Methods	Randomised controlled trial. Allocation by 'sealed envelopes'.
Participants	Patients age 16 to 75, GCS 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 at 3, 6 and 12 months. ICP and CPP values during treatment phase. Complications for subset.
Notes	GOS assessment by psychiatrist blinded to treatment allocation.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Meissner 1998

Methods	Randomised controlled trial. Allocation by 'sealed envelopes'.
Participants	Patients with severe blunt head injury, in whom cooling could begin within 8 hours of injury.
Interventions	Hypothermia patients: Cooling to 32‐33C for 48 hours. Control patients: Temperature maintained at 36‐37C.
Outcomes	Death. Infections.
Notes	GOS assessed at 6 months by non‐blinded assessor, but not yet available.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Meissner 2003a

Methods
Participants
Interventions
Outcomes
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	D ‐ Not used

Meissner 2003b

Methods
Participants
Interventions
Outcomes
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	D ‐ Not used

Shiozaki 1993

Methods	Randomised controlled trial. Allocation 'by lot'.
Participants	Patients age 10 or over, GCS 8 or less with head injury, in whom ICP could not be controlled by high‐dose barbituate therapy.
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 at 6 months. Complications during treatment. ICP and CPP values during treatment period for hypothermic arm only.
Notes	GOS assessed blind to treatment allocation.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Shiozaki 1999

Methods	Randomised controlled trial. Allocation concealment not clear. No loss to follow up.
Participants	Patients with traumatic brain injury, a Glasgow coma scale of 8 or less, and ICP under 20mmHg on treatment with hyperventilation, barbiturates and fluid restriction.
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 at 6 months. Complications.
Notes	Blinding of outcome assessment not stated.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Shiozaki 2001

Methods	Randomised controlled trial. Allocation concealment not clear. No loss to follow up.
Participants	Patients with traumatic brain injury, a Glasgow coma scale of 8 or less, and ICP of under 25mmHg with other therapies.
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 at 3 months. Complications
Notes	Blinding of outcome assessment not stated.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Yan 2001

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 of 3 to 8 on initial assesment.
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*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Zhang 2000

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 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*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Characteristics of excluded studies [ordered by study ID]

Ir a:

estudios incluidos
estudios en curso

Study	Reason for exclusion
Gentilello 1997	Randomized trial of rewarming therapy after accidental hypothermia in trauma.
Nara 1997	Unable to find sufficient information on study design.
Nordby 1984	Not a randomised comparison, and hypothermia confounded with barbituate therapy
Yamagami 1997	Not a randomised study; hypothermia group GCS 4‐6, normothermia group GCS 8‐10.

Characteristics of ongoing studies [ordered by study ID]

Ir a:

estudios incluidos
estudios excluidos

Clifton 2002

Trial name or title	National Acute Brain Injury Study: Hypothermia II (NABISH II)
Methods
Participants	Patients aged 16 to 45 years inclusive who have a closed head injury, present to the Emergency Dept. with a Glasgow Coma Score between 3‐8, have a body temperature (bladder or rectal) of 35 degrees Celsius or less, and with 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 signes. 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	Run‐in period 21st October 2002 to 21st April 2003. Randomisation begins after run‐in period.
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 [email protected] 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 [email protected]
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 Cincinnatti, University of Mississippi at Jackson.

Data and analyses

Open in table viewer

Comparison 1. Immediate hypothermia versus normothermia

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death at final follow‐up Show forest plot	13	1063	Odds Ratio (M‐H, Fixed, 95% CI)	0.80 [0.61, 1.04]
Open in figure viewer Analysis 1.1 Comparison 1 Immediate hypothermia versus normothermia, Outcome 1 Death at final follow‐up.
2 Death or severe disability at final follow‐up Show forest plot	9	746	Odds Ratio (M‐H, Fixed, 95% CI)	0.75 [0.56, 1.00]
Open in figure viewer Analysis 1.2 Comparison 1 Immediate hypothermia versus normothermia, Outcome 2 Death or severe disability at final follow‐up.
3 Death or severe disability stratified by quality Show forest plot	9		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.3 Comparison 1 Immediate hypothermia versus normothermia, Outcome 3 Death or severe disability stratified by quality.
3.1 Concealed allocation, blinded outcome assessment	3	494	Odds Ratio (M‐H, Fixed, 95% CI)	0.80 [0.56, 1.14]
3.2 Concealed allocation, non‐blinded outcome assessment	1	10	Odds Ratio (M‐H, Fixed, 95% CI)	0.38 [0.02, 6.35]
3.3 Non‐concealed allocation, blinded outcome assessment	2	113	Odds Ratio (M‐H, Fixed, 95% CI)	0.34 [0.16, 0.76]
3.4 Non‐concealed allocation, non‐blinded outcome assessment	3	129	Odds Ratio (M‐H, Fixed, 95% CI)	1.17 [0.58, 2.35]
4 Death or severe disability stratified by treatment duration Show forest plot	7		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.4 Comparison 1 Immediate hypothermia versus normothermia, Outcome 4 Death or severe disability stratified by treatment duration.
4.1 24 hours	2	91	Odds Ratio (M‐H, Fixed, 95% CI)	0.38 [0.16, 0.90]
4.2 48 hours	5	542	Odds Ratio (M‐H, Fixed, 95% CI)	0.97 [0.69, 1.36]
5 Death or severe disability at various times during follow‐up Show forest plot	9		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.5 Comparison 1 Immediate hypothermia versus normothermia, Outcome 5 Death or severe disability at various times during follow‐up.
5.1 3 months	5	250	Odds Ratio (M‐H, Fixed, 95% CI)	0.72 [0.43, 1.21]
5.2 6 months	4	492	Odds Ratio (M‐H, Fixed, 95% CI)	0.79 [0.55, 1.13]
5.3 12 months	2	168	Odds Ratio (M‐H, Fixed, 95% CI)	0.41 [0.22, 0.77]
6 Pneumonia during the treatment period Show forest plot	8	283	Odds Ratio (M‐H, Fixed, 95% CI)	1.95 [1.18, 3.23]
Open in figure viewer Analysis 1.6 Comparison 1 Immediate hypothermia versus normothermia, Outcome 6 Pneumonia during the treatment period.

Open in table viewer

Comparison 2. Deferred hypothermia versus normothermia

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death at final follow‐up Show forest plot	1	33	Odds Ratio (M‐H, Fixed, 95% CI)	0.21 [0.04, 1.05]
Open in figure viewer Analysis 2.1 Comparison 2 Deferred hypothermia versus normothermia, Outcome 1 Death at final follow‐up.
2 Death or severe disability at final follow‐up Show forest plot	1	33	Odds Ratio (M‐H, Fixed, 95% CI)	0.10 [0.01, 1.00]
Open in figure viewer Analysis 2.2 Comparison 2 Deferred hypothermia versus normothermia, Outcome 2 Death or severe disability at final follow‐up.
3 Death or severe disability at various times during follow‐up Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 2.3 Comparison 2 Deferred hypothermia versus normothermia, Outcome 3 Death or severe disability at various times during follow‐up.
3.1 3 months	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 6 months	1	33	Odds Ratio (M‐H, Fixed, 95% CI)	0.10 [0.01, 1.00]
3.3 12 months	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Death or severe disability stratified by quality Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 2.4 Comparison 2 Deferred hypothermia versus normothermia, Outcome 4 Death or severe disability stratified by quality.
4.1 Concealed allocation, blinded outcome assessment	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 Concealed allocation, non‐blinded outcome assessment	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.3 Non‐concealed allocation, blinded outcome assessment	1	33	Odds Ratio (M‐H, Fixed, 95% CI)	0.10 [0.01, 1.00]
4.4 Non‐concealed allocation, non‐blinded outcome assessment	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Death or severe disability stratified by treatment duration Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 2.5 Comparison 2 Deferred hypothermia versus normothermia, Outcome 5 Death or severe disability stratified by treatment duration.
5.1 24 hours	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.2 48 hours	1	33	Odds Ratio (M‐H, Fixed, 95% CI)	0.10 [0.01, 1.00]
6 Pneumonia during the treatment period Show forest plot	1	22	Odds Ratio (M‐H, Fixed, 95% CI)	1.13 [0.18, 6.93]
Open in figure viewer Analysis 2.6 Comparison 2 Deferred hypothermia versus normothermia, Outcome 6 Pneumonia during the treatment period.

Analysis 1.1

Comparison 1 Immediate hypothermia versus normothermia, Outcome 1 Death at final follow‐up.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.2

Comparison 1 Immediate hypothermia versus normothermia, Outcome 2 Death or severe disability at final follow‐up.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.3

Comparison 1 Immediate hypothermia versus normothermia, Outcome 3 Death or severe disability stratified by quality.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.4

Comparison 1 Immediate hypothermia versus normothermia, Outcome 4 Death or severe disability stratified by treatment duration.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.5

Comparison 1 Immediate hypothermia versus normothermia, Outcome 5 Death or severe disability at various times during follow‐up.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.6

Comparison 1 Immediate hypothermia versus normothermia, Outcome 6 Pneumonia during the treatment period.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.1

Comparison 2 Deferred hypothermia versus normothermia, Outcome 1 Death at final follow‐up.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.2

Comparison 2 Deferred hypothermia versus normothermia, Outcome 2 Death or severe disability at final follow‐up.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.3

Comparison 2 Deferred hypothermia versus normothermia, Outcome 3 Death or severe disability at various times during follow‐up.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.4

Comparison 2 Deferred hypothermia versus normothermia, Outcome 4 Death or severe disability stratified by quality.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.5

Comparison 2 Deferred hypothermia versus normothermia, Outcome 5 Death or severe disability stratified by treatment duration.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.6

Comparison 2 Deferred hypothermia versus normothermia, Outcome 6 Pneumonia during the treatment period.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1. Immediate hypothermia versus normothermia

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death at final follow‐up Show forest plot	13	1063	Odds Ratio (M‐H, Fixed, 95% CI)	0.80 [0.61, 1.04]

2 Death or severe disability at final follow‐up Show forest plot	9	746	Odds Ratio (M‐H, Fixed, 95% CI)	0.75 [0.56, 1.00]

3 Death or severe disability stratified by quality Show forest plot	9		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Concealed allocation, blinded outcome assessment	3	494	Odds Ratio (M‐H, Fixed, 95% CI)	0.80 [0.56, 1.14]
3.2 Concealed allocation, non‐blinded outcome assessment	1	10	Odds Ratio (M‐H, Fixed, 95% CI)	0.38 [0.02, 6.35]
3.3 Non‐concealed allocation, blinded outcome assessment	2	113	Odds Ratio (M‐H, Fixed, 95% CI)	0.34 [0.16, 0.76]
3.4 Non‐concealed allocation, non‐blinded outcome assessment	3	129	Odds Ratio (M‐H, Fixed, 95% CI)	1.17 [0.58, 2.35]
4 Death or severe disability stratified by treatment duration Show forest plot	7		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 24 hours	2	91	Odds Ratio (M‐H, Fixed, 95% CI)	0.38 [0.16, 0.90]
4.2 48 hours	5	542	Odds Ratio (M‐H, Fixed, 95% CI)	0.97 [0.69, 1.36]
5 Death or severe disability at various times during follow‐up Show forest plot	9		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.1 3 months	5	250	Odds Ratio (M‐H, Fixed, 95% CI)	0.72 [0.43, 1.21]
5.2 6 months	4	492	Odds Ratio (M‐H, Fixed, 95% CI)	0.79 [0.55, 1.13]
5.3 12 months	2	168	Odds Ratio (M‐H, Fixed, 95% CI)	0.41 [0.22, 0.77]
6 Pneumonia during the treatment period Show forest plot	8	283	Odds Ratio (M‐H, Fixed, 95% CI)	1.95 [1.18, 3.23]

Comparison 1. Immediate hypothermia versus normothermia

Ir a la tabla de la revisión

Comparison 2. Deferred hypothermia versus normothermia

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death at final follow‐up Show forest plot	1	33	Odds Ratio (M‐H, Fixed, 95% CI)	0.21 [0.04, 1.05]

2 Death or severe disability at final follow‐up Show forest plot	1	33	Odds Ratio (M‐H, Fixed, 95% CI)	0.10 [0.01, 1.00]

3 Death or severe disability at various times during follow‐up Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 3 months	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 6 months	1	33	Odds Ratio (M‐H, Fixed, 95% CI)	0.10 [0.01, 1.00]
3.3 12 months	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Death or severe disability stratified by quality Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 Concealed allocation, blinded outcome assessment	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 Concealed allocation, non‐blinded outcome assessment	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.3 Non‐concealed allocation, blinded outcome assessment	1	33	Odds Ratio (M‐H, Fixed, 95% CI)	0.10 [0.01, 1.00]
4.4 Non‐concealed allocation, non‐blinded outcome assessment	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Death or severe disability stratified by treatment duration Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.1 24 hours	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.2 48 hours	1	33	Odds Ratio (M‐H, Fixed, 95% CI)	0.10 [0.01, 1.00]
6 Pneumonia during the treatment period Show forest plot	1	22	Odds Ratio (M‐H, Fixed, 95% CI)	1.13 [0.18, 6.93]

Comparison 2. Deferred hypothermia versus normothermia

Ir a la tabla de la revisión

	Idioma de la Revisión Cochrane Escoja su idioma de preferencia para las revisiones Cochrane y otros contenidos. Las secciones sin una traducción aparecerán en inglés.

	Idioma de la web Escoja su idioma de preferencia para la web de la Biblioteca Cochrane.

Idioma de la Revisión Cochrane

Idioma de la web

Referencias

References to studies included in this review

Aibiki 2000 {published data only}

Biswas 2002 {published data only}

Clifton 1992 {published and unpublished data}

Clifton 1993 {published data only}

Clifton 2001 {published data only}

Hirayama 1994 {published data only}

Ishikura 1998 {published data only}

Jiang 2000 {published data only}

Marion 1997 {published data only}

Meissner 1998 {published and unpublished data}

Meissner 2003a {published data only}

Meissner 2003b {published data only}

Shiozaki 1993 {published and unpublished data}

Shiozaki 1999 {published data only}

Shiozaki 2001 {published data only}

Yan 2001 {published data only}

Zhang 2000 {published data only}

References to studies excluded from this review

Gentilello 1997 {published data only}

Nara 1997 {published data only}

Nordby 1984 {published data only}

Yamagami 1997 {published data only}

References to studies awaiting assessment

Shen 2000 {published data only}

References to ongoing studies

Clifton 2002 {unpublished data only}

Additional references

Alexander 1992

Bering 1961

Bullock 1996

Busto 1987

Busto 1989

Clasen 1968

Clifton 1995

Fay 1945

Kirkpatrick 1997

Laskowski 1960

McIntyre 2003

Schubert 1995

Schulz 1995

Sedzimir 1959

Shapiro 1974

Smith 1996

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

Characteristics of ongoing studies [ordered by study ID]

Data and analyses

Copiar o descargar referencia

Idioma de la Revisión Cochrane

Idioma de la web

Instituciones a las que se accedió previamente

Usuarios institucionales

Instituciones a las que se accedió previamente

Otras opciones de acceso