Hypothermia for traumatic head injury

  • Review
  • Intervention

Authors


Abstract

Background

Hypothermia has been used in the treatment of head injury for many years. Encouraging results from small trials and laboratory studies led to renewed interest in the area and some larger trials.

Objectives

To estimate the effect of mild hypothermia for traumatic head injury on mortality and long-term functional outcome complications.

Search strategy

We searched the Injuries Group Specialised Register, Current Controlled Trials MetaRegister of trials, Zetoc, Web of Knowledge; Science Citation Index [expanded], CENTRAL, MEDLINE and EMBASE. We handsearched conference proceedings and checked reference lists of relevant articles. The search was updated on 23 May 2008.

Selection criteria

Randomised controlled trials of hypothermia to a maximum of 35ºC for at least 12 hours versus control in patients with any closed traumatic head injury requiring hospitalisation. Two authors independently assessed all trials.

Data collection and analysis

Data on death, Glasgow Outcome Scale and pneumonia were sought and extracted, either from published material or by contacting the investigators. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each trial on an intention-to-treat basis.

Main results

We found 22 trials with a total of 1409 randomised patients. Twenty trials involving 1382 patients reported deaths. There were fewer deaths in patients treated with hypothermia than in the control group (OR 0.76, 95% CI 0.60 to 0.97). Eight trials with good allocation concealment showed a non-significant reduction in the likelihood of death for patients treated with hypothermia (OR 0.96, 95% CI 0.68 to 1.35). Twenty trials involving 1382 patients reported data on unfavourable outcomes (death, vegetative state or severe disability). Patients treated with hypothermia were less likely to have an unfavourable outcome than those in the control group (OR 0.69, 95% CI 0.55 to 0.86). Eight trials with good allocation concealment showed a non-significant reduction in the likelihood of unfavourable outcome for patients treated with hypothermia (OR 0.79, 95% CI 0.57 to 1.08). Hypothermia treatment was associated with an increase in odds of pneumonia but this increase was not statistically significant for trials with good allocation concealment (3 trials, 69 patients, OR 1.06, 95% CI 0.38 to 2.97).

Authors' conclusions

Hypothermia may be effective in reducing death and unfavourable outcomes for traumatic head injured patients, but significant benefit was only found in low quality trials. Low quality trials have a tendency to overestimate the treatment effect. The high quality trials found some statistically non-significant benefit of hypothermia which could be due to the play of chance. Hypothermia may increase the risk of pneumonia. Due to uncertainties in its effects, hypothermia should only be given to patients taking part in a randomised controlled trial with good allocation concealment.

Plain language summary

Hypothermia (body temperature cooling) for traumatic head injury

Twenty-two randomised controlled trials involving 1409 patients with traumatic head injury were included in this review. In each trial, the patients were randomly divided into two groups: one group remained at normal body temperature, and the other group was cooled to a maximum of 35 degrees Celsius for at least 12 hours. Cooling could be of the whole body (e.g. with a blanket with circulating cold water), or just the head (e.g. with a helmet with circulating cold water). Information on death, disability, and pneumonia was evaluated for each trial.

The review authors found that fewer people died or became severely disabled if they were treated with hypothermia, but this finding may be due to the play of chance. It was also found that patients given hypothermia were more likely to develop pneumonia, and some patients died from pneumonia, but the increased risk of pneumonia could also be due to the play of chance.

Some of the trials included in the review were of low methodological quality. Low quality trials have a tendency to overestimate the effect of a treatment. In this review, the lower quality trials showed hypothermia treatment to be effective in reducing death and disability among head injured patients. However, the good quality trials showed less benefit for hypothermia treatment and a lower chance of pneumonia.

The review authors conclude that hypothermia might reduce death and disability in traumatic head injured patients, but it may also increase the risk of pneumonia. These effects may be due to the play of chance. Due to uncertainties in its effects, hypothermia should only be given to patients taking part in good quality randomised controlled trials.

Background

Traumatic head injury is a major cause of death and disability amongst a predominantly young population, with an estimated ten million people experiencing severe head injury worldwide every year (Alexander 1992). There is, however, a significant lack of evidence about effective therapies in the acute care of these patients. A long-term effort to review the literature and produce management guidelines by the American Association of Neurological Surgeons (Bullock 1996; Kirkpatrick 1997) could only make four definitive statements about treatment effectiveness that were supported by strong evidence from randomised studies.

Mild to moderate hypothermia has been used in the treatment of head injury for over 50 years (Fay 1945). Although there were several promising experimental studies (Laskowski 1960; Clasen 1968) and case series (Sedzimir 1959; Shapiro 1974), no controlled clinical studies were performed and the therapy fell from favour. In the last decade, however, several investigators have reported encouraging results of Phase II and III randomised clinical trials (Clifton 1995; Marion 1997; Shiozaki 1993), corroborated by consistent findings of high levels of cerebral protection associated with systemic cooling in well validated laboratory models of global ischaemia (Busto 1987). The early trials were small, single-centre investigations, which were sufficiently promising to lead on to larger, multi-centre trials.

Whilst the mechanism of action of such temperature control therapy was originally thought to be primarily a reduction in cerebral metabolic rate (Bering 1961), there is now evidence that mild hypothermia might also influence the excessive post-traumatic release of excitatory neurotransmitters (Busto 1989), and attenuate the opening of the blood-brain barrier (Smith 1996). The main risks associated with induced systemic hypothermia are an increased risk of sepsis and pneumonia, coagulation abnormalities, and possible myocardial ischaemia and atrial fibrillation (Schubert 1995).

Objectives

To determine whether the use of mild hypothermia in the treatment of traumatic head injury:

  • reduces the risk of death (either during the treatment period or at the end of follow-up);

  • reduces the proportion of patients who at final follow-up are either dead, in a vegetative state, or severely disabled;

  • increases the risk of pneumonia.

Methods

Criteria for considering studies for this review

Types of studies

A search was conducted for all randomised controlled trials of mild hypothermia versus control.

Types of participants

Patients with any closed traumatic head injury requiring hospitalisation.

Types of interventions

Therapeutic cooling, either locally or systemically, by means of a fluid-filled cooling blanket, a 'bear-hugger' air-cooling device, ice water lavage, any combination of the above, or other methods, to a target temperature of at most 35ºC for a period of at least 12 consecutive hours. Cooling could begin immediately upon admission to the intensive therapy unit or be deferred until ICP becomes uncontrollable by conventional management.

Types of outcome measures

Primary outcomes
  • All-cause mortality at the end of the follow-up period.

  • Unfavourable outcome at the end of the follow-up period.

Unfavourable outcome was defined as a Glasgow Outcome Scale score of 'severe disability', 'persistent vegetative state', or 'death'; or an equivalent measure if a Glasgow Outcome Score was not presented.

Secondary outcomes
  • The frequency of pneumonia.

Search methods for identification of studies

None of the searches were restricted by language, date or publication status.

Electronic searches

For the initial version of the review we searched The Cochrane Injuries Group's Specialised Register in May 1998 for any relevant randomised trials relating to temperature control using the search terms: hypotherm* OR normotherm* OR cool* OR cold* OR temperature.

The search strategy for the register is primarily an electronic search of both MEDLINE and CENTRAL, supplemented by various hand-searching activities listed in the Group details. This was supplemented by a comprehensive EMBASE search, also performed in May 1998, to identify all potential RCTs involving human head injury and temperature control from 1980 onwards. Titles and abstracts from this search were reviewed by David Signorini for possibly relevant trial reports, and the appropriate articles retrieved. The original search strategies can be obtained by contacting the Trials Search Co-ordinator of the Cochrane Injuries Group.

Searches have since been carried out in October 2003, November 2005 and May 2008. The latest search strategies are listed in full in Appendix 1.

Searching other resources

The searches were supplemented by further handsearching of conference proceedings and abstracts as follows:

  • International Conference on Recent Advances in Neurotraumatology, Italy 1996

  • 2nd International Neurotrauma Symposium, Glasgow 1993

  • 3rd International Neurotrauma Symposium, Toronto 1995

  • 4th International Neurotrauma Symposium, Seoul 1997

  • 27th Meeting of the Society for Critical Care Medicine, USA 1998

  • 10th International Symposium on Intracranial Pressure, USA 1997

In addition, reference lists of all relevant trials and review articles were checked, and leading investigators in the field were contacted for information about any other published or unpublished trials which may have been overlooked.

Data collection and analysis

Selection of studies

The results of the search were screened by ES and IR. The full text of relevant records were obtained. Both authors independently compared the trial design with the inclusion criteria for this review. Disagreements were resolved by discussion.

Data extraction and management

The following information was extracted from each trial: method of allocation concealment, blinding of outcome assessment, number of randomised patients, death or severe disability at various times during follow up, treatment duration, duration of follow up, loss to follow up, and number of patients with pneumonia during the treatment period. This information was extracted and entered into Review Manager (RevMan) by ES; IR checked for accuracy. Trial report authors were contacted for additional information or clarification.

Assessment of risk of bias in included studies

Quality of allocation concealment was assessed by the review authors on the following scale (Higgins 2008):

  • Yes: low risk of bias (e.g. sequentially numbered, sealed, opaque envelopes)

  • No: high risk of bias (e.g. day of the week)

  • Unclear: unclear or unknown risk of bias (method not stated).

Data synthesis

Mantel-Haenzel odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for death, pneumonia, and unfavourable outcomes for each trial on an intention-to-treat basis. The odds ratio was chosen because of the large variation in baseline event rates between the trials (mortality in the control groups ranges from 0% to 82%), implying that the relative risk would not be a good summary measure. Also, the Mantel-Haenzel approach was used because of the inaccuracy of Peto's approximation when the estimated treatment effect is large, as it was in several of the trials considered. Heterogeneity of treatment effect between trials was assessed using a standard chi-square test, I2, and if appropriate, a weighted estimate of the typical treatment effect across all studies was calculated.

Subgroup analysis and investigation of heterogeneity

Subgroup analyses were performed to determine whether the treatment effect varies with: a) trial quality (quality of allocation concealment), b) duration of hypothermia, and c) length of follow-up.

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting assessment; Characteristics of ongoing studies.

Results of the search

A total of 22 randomised controlled trials were identified that met the inclusion criteria.

Included studies

The 22 included randomised controlled trials involved 1409 randomised patients. All trials except two (Ishikura 1998, Meissner 2003a) reported the number of deaths in the intervention and control groups at final follow-up. Fourteen trials reported GOS scores specifically at three, six or 12 months post-injury. The occurrence of pneumonia was reported in ten trials.

Risk of bias in included studies

Allocation

Adequate allocation concealment is an important dimension of trial quality.

Eight trials had a reasonable standard of allocation concealment (Adelson 2005 HYPO1; Adelson 2005 HYPO2; Clifton 1992; Clifton 1993; Clifton 2001; Marion 1997; Meissner 1998; Qiu 2007). Twelve trials had unclear allocation concealment (e.g. 'by lot') (Aibiki 2000; Biswas 2002; Hashiguchi 2003; Hirayama 1994; Jiang 2000; Meissner 2003b; Shiozaki 1993; Shiozaki 1999; Shiozaki 2001; Smrcka 2005; Yan 2001; Zhang 2000). Two trials did not present mortality or GOS data in the treatment and control groups (Ishikura 1998; Meissner 2003a) and had unclear allocation concealment.

Effects of interventions

Death at final follow-up

Analysis 1.1

Twenty trials involving 1382 patients reported deaths. Patients treated with hypothermia were less likely to die than those in the control group (OR 0.76, 95% CI 0.60 to 0.97). There was no evidence of statistical heterogeneity between trials (Chi² = 15.53, df = 18 (P = 0.63); I² = 0%).

Death at final follow-up stratified by trial quality

Analysis 1.2

Concealed allocation was reported in 8 studies involving 686 patients. Hypothermia treatment was associated with a statistically non-significant reduction in death compared with the control group (OR 0.96, 95% CI 0.68 to 1.35). There was no evidence of statistical heterogeneity between trials (Chi² = 1.01, df = 7 (P = 0.99); I² = 0%).

Non-concealed allocation, or 'unclear' concealment according to Higgins 2008, was reported in 12 studies involving 696 patients. Patients treated with hypothermia were less likely to die than those in the control group (OR 0.62, 95% CI 0.44 to 0.86). There was no evidence of statistical heterogeneity between trials (Chi² = 11.14, df = 10 (P = 0.35); I² = 10%).

Unfavourable outcome at final follow-up

Analysis 1.3

Twenty trials involving 1382 patients reported death or severe disability. Patients treated with hypothermia were less likely to have an unfavourable outcome than those in the control group (OR 0.69, 95% CI 0.55 to 0.86). There was some evidence of statistical heterogeneity between trials (Chi² = 30.71, df = 19 (P = 0.04); I² = 38%).

Unfavourable outcome stratified by trial quality

Analysis 1.4

Concealed allocation was reported in 8 studies involving 686 patients. Hypothermia treatment was associated with a statistically non-significant reduction in death compared with the control group (OR 0.79, 95% CI 0.57 to 1.08). There was no statistical heterogeneity between trials (Chi² = 4.79, df = 7 (P = 0.69); I² = 0%).

Non-concealed allocation, or 'unclear' concealment according to Higgins 2008, was reported in 12 studies involving 696 patients. Patients treated with hypothermia were less likely to have an unfavourable outcome than those in the control group (OR 0.60, 95% CI 0.44 to 0.82). There was some statistical heterogeneity between trials (Chi² = 24.64, df = 11 (P = 0.01); I² = 55%).

Unfavourable outcome stratified by treatment duration

Analysis 1.5

Twelve trials reported deaths or severe disability according to the duration of treatment.

Two trials involving 91 patients treated patients in the hypothermia group for 24 hours. Patients in the hypothermia group were less likely to have an unfavourable outcome than those in the control group (OR 0.38, 95% CI 0.16 to 0.90). There was no statistical heterogeneity between these two trials (Chi² = 0.00, df = 1 (P = 0.99); I² = 0%).

Ten trials involving 683 patients treated patients in the hypothermia group for 48 hours. Hypothermia treatment was associated with a statistically non-significant reduction in unfavourable outcome compared with the control group (OR 0.96, 95% CI 0.70 to 1.31). There was no statistical heterogeneity between trials (Chi² = 12.13, df = 9 (P = 0.21); I² = 26%).

Unfavourable outcome at various times during follow-up

Analysis 1.6

Fourteen trials reported GOS scores at three, six or 12 months post-injury. Some trials reported GOS scores at more than one time point.

Six trials involving 271 patients reported GOS scores at three months post-intervention. Hypothermia treatment was associated with a statistically non-significant reduction in death compared with the control group (OR 0.85, 95% CI 0.52 to 1.39). There was some statistical heterogeneity between trials (Chi² = 10.29, df = 5 (P = 0.07); I² = 51%).

Eight trials involving 634 patients reported GOS scores at six months post-intervention. Patients treated with hypothermia were less likely to have an unfavourable outcome than those in the control group (OR 0.62, 95% CI 0.45 to 0.86). There was significant statistical heterogeneity between trials (Chi² = 21.55, df = 7 (P = 0.003); I² = 68%).

Four trials involving 262 patients reported GOS scores at 12 months post-intervention. Patients treated with hypothermia were less likely to have an unfavourable outcome than those in the control group (OR 0.52, 95% CI 0.31 to 0.87). There was no statistical heterogeneity between trials (Chi² = 3.62, df = 3 (P = 0.31); I² = 17%).

Pneumonia during the treatment period

Analysis 1.7

Ten trials involving 322 patients reported pneumonia cases. Patients treated with hypothermia were more likely to have pneumonia than those in the control group (OR 2.06, 95% confidence interval 1.28 to 3.30).

Pneumonia was stratified by trial quality:

Three trials with good allocation concealment involving 69 patients reported pneumonia cases. Hypothermia treatment was associated with a statistically non-significant increase in pneumonia (OR 1.06, 95% confidence interval 0.38 to 2.97). There was no statistical heterogeneity between trials (Chi² = 0.55, df = 2 (P = 0.76); I² = 0%).

Seven trials with non-concealed allocation involving 253 patients reported pneumonia cases. Patients treated with hypothermia were more likely to have pneumonia than those in the control group (OR 2.47, 95% confidence interval 1.44 to 4.23). There was no statistical heterogeneity between trials (Chi² = 9.34, df = 5 (P = 0.10); I² = 46%).

Discussion

Summary of main results

Hypothermia may be effective in reducing death and unfavourable outcomes for traumatic head injured patients, but significant benefit was only found in low quality trials. The high quality trials found some statistically non-significant benefit of hypothermia which could be due to the play of chance. Hypothermia may increase the risk of pneumonia. Due to uncertainties in its effects, hypothermia should only be given to patients taking part in a randomised controlled trial with good allocation concealment.

Quality of the evidence

Numerous trials of hypothermia treatment have been conducted in recent years. The majority of trials found were of low quality, with unclear allocation concealment. These low quality trials may overestimate the effectiveness of hypothermia treatment versus control.

Trials with good allocation concealment showed a smaller treatment effect which may be due to the play of chance. The increased incidence of pneumonia was not statistically significant in trials with good allocation concealment.

Potential biases in the review process

This systematic review addresses a focused research question using predefined inclusion criteria and methodology to select and appraise eligible studies.

As with all systematic reviews, the possibility of publication bias should be considered as a potential threat to validity. However, in light of our extensive and sensitive searching we believe that the risk of such a bias affecting the results is minimal.

The majority of trials found or included in the review were of low methodological quality. An additional ten trials with unclear methods of randomisation or allocation concealment were identified, and are awaiting assessment until clarification is obtained from the trial report authors.

Agreements and disagreements with other studies or reviews

The conclusions of this review are broadly consistent with those of Peterson 2008. The majority of trials identified for this review and Peterson 2008 were of low methodological quality. Both reviews found there may be an increased likelihood of pneumonia with hypothermia.

Authors' conclusions

Implications for practice

Hypothermia may be effective in reducing death and unfavourable outcomes for traumatic head injured patients, but significant benefit was only found in low quality trials. Low quality trials have a tendency to overestimate the treatment effect. The high quality trials found some statistically non-significant benefit of hypothermia which could be due to the play of chance. Hypothermia may increase the risk of pneumonia. Due to uncertainties in its effects, hypothermia should only be given to patients taking part in a randomised controlled trial with good allocation concealment.

Implications for research

More high quality randomised controlled trials are needed to determine the benefit of hypothermia for traumatic head injury.

Acknowledgements

Thanks to:

  • Brenda Thomas (Stroke Review Group) for help and advice with the original EMBASE search strategy.

  • Ian Whittle, Kate Signorini, Elena Telaro, Yoichi Nagayama, Irene Kwan, Frank Del Vecchio, Lisa Xue and Cynthia To for help with manuscripts in languages other than English.

  • Reinhard Wentz and Irene Kwan of the Injuries Group for the original searches.

  • Katharine Ker of the Injuries Group for work on previous versions of the review.

  • Karen Blackhall, Trials Search Co-ordinator of the Cochrane Injuries Group for updating the searches in 2003, 2005 and 2008.

Data and analyses

Download statistical data

Comparison 1. Immediate hypothermia versus normothermia
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Death at final follow-up201382Odds Ratio (M-H, Fixed, 95% CI)0.76 [0.60, 0.97]
2 Death at final follow-up stratified by trial quality201382Odds Ratio (M-H, Fixed, 95% CI)0.76 [0.60, 0.97]
2.1 Concealed allocation8686Odds Ratio (M-H, Fixed, 95% CI)0.96 [0.68, 1.35]
2.2 Non-concealed allocation12696Odds Ratio (M-H, Fixed, 95% CI)0.62 [0.44, 0.86]
3 Unfavourable outcome at final follow-up201382Odds Ratio (M-H, Fixed, 95% CI)0.69 [0.55, 0.86]
4 Unfavourable outcome stratified by trial quality20 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
4.1 Concealed allocation8686Odds Ratio (M-H, Fixed, 95% CI)0.79 [0.57, 1.08]
4.2 Non-concealed allocation12696Odds Ratio (M-H, Fixed, 95% CI)0.60 [0.44, 0.82]
5 Unfavourable outcome stratified by treatment duration12 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
5.1 24 hours291Odds Ratio (M-H, Fixed, 95% CI)0.38 [0.16, 0.90]
5.2 48 hours10683Odds Ratio (M-H, Fixed, 95% CI)0.96 [0.70, 1.31]
6 Unfavourable outcome at various times during follow-up14 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
6.1 3 months6271Odds Ratio (M-H, Fixed, 95% CI)0.85 [0.52, 1.39]
6.2 6 months8634Odds Ratio (M-H, Fixed, 95% CI)0.62 [0.45, 0.86]
6.3 12 months4262Odds Ratio (M-H, Fixed, 95% CI)0.52 [0.31, 0.87]
7 Pneumonia during the treatment period10322Odds Ratio (M-H, Fixed, 95% CI)2.06 [1.28, 3.30]
7.1 Concealed allocation369Odds Ratio (M-H, Fixed, 95% CI)1.06 [0.38, 2.97]
7.2 Non-concealed allocation7253Odds Ratio (M-H, Fixed, 95% CI)2.47 [1.44, 4.23]
Analysis 1.1.

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

Analysis 1.2.

Comparison 1 Immediate hypothermia versus normothermia, Outcome 2 Death at final follow-up stratified by trial quality.

Analysis 1.2.1.

Analysis 1.2.1.

Comparison 1 Immediate hypothermia versus normothermia, Outcome 2 Death at final follow-up stratified by trial quality, Subgroup 1 Concealed allocation.

Analysis 1.2.2.

Analysis 1.2.2.

Comparison 1 Immediate hypothermia versus normothermia, Outcome 2 Death at final follow-up stratified by trial quality, Subgroup 2 Non-concealed allocation.

Analysis 1.3.

Comparison 1 Immediate hypothermia versus normothermia, Outcome 3 Unfavourable outcome at final follow-up.

Analysis 1.4.

Comparison 1 Immediate hypothermia versus normothermia, Outcome 4 Unfavourable outcome stratified by trial quality.

Analysis 1.4.1.

Analysis 1.4.1.

Comparison 1 Immediate hypothermia versus normothermia, Outcome 4 Unfavourable outcome stratified by trial quality, Subgroup 1 Concealed allocation.

Analysis 1.4.2.

Analysis 1.4.2.

Comparison 1 Immediate hypothermia versus normothermia, Outcome 4 Unfavourable outcome stratified by trial quality, Subgroup 2 Non-concealed allocation.

Analysis 1.5.

Comparison 1 Immediate hypothermia versus normothermia, Outcome 5 Unfavourable outcome stratified by treatment duration.

Analysis 1.5.1.

Analysis 1.5.1.

Comparison 1 Immediate hypothermia versus normothermia, Outcome 5 Unfavourable outcome stratified by treatment duration, Subgroup 1 24 hours.

Analysis 1.5.2.

Analysis 1.5.2.

Comparison 1 Immediate hypothermia versus normothermia, Outcome 5 Unfavourable outcome stratified by treatment duration, Subgroup 2 48 hours.

Analysis 1.6.

Comparison 1 Immediate hypothermia versus normothermia, Outcome 6 Unfavourable outcome at various times during follow-up.

Analysis 1.6.1.

Analysis 1.6.1.

Comparison 1 Immediate hypothermia versus normothermia, Outcome 6 Unfavourable outcome at various times during follow-up, Subgroup 1 3 months.

Analysis 1.6.2.

Analysis 1.6.2.

Comparison 1 Immediate hypothermia versus normothermia, Outcome 6 Unfavourable outcome at various times during follow-up, Subgroup 2 6 months.

Analysis 1.6.3.

Analysis 1.6.3.

Comparison 1 Immediate hypothermia versus normothermia, Outcome 6 Unfavourable outcome at various times during follow-up, Subgroup 3 12 months.

Analysis 1.7.

Comparison 1 Immediate hypothermia versus normothermia, Outcome 7 Pneumonia during the treatment period.

Analysis 1.7.1.

Analysis 1.7.1.

Comparison 1 Immediate hypothermia versus normothermia, Outcome 7 Pneumonia during the treatment period, Subgroup 1 Concealed allocation.

Analysis 1.7.2.

Analysis 1.7.2.

Comparison 1 Immediate hypothermia versus normothermia, Outcome 7 Pneumonia during the treatment period, Subgroup 2 Non-concealed allocation.

Appendices

Appendix 1. Search strategy

Injuries Specialised Register (searched 21 May 2008)
((injur* or trauma* or lesion* or damage* or wound* or oedema* or edema* or fracture* or contusion* or concus* or commotion* or pressur*) and (head or crani* or capitis or brain* or forebrain* or skull* or hemisphere or intracran* or orbit*)) and (hypotherm* or normotherm* or cool* or cold* or temperature* or cryother* or cryogen* or cryotreat*)

CENTRAL (The Cochrane Library 2008, Issue 2)
#1MeSH descriptor Craniocerebral Trauma explode all trees
#2MeSH descriptor Cerebrovascular Trauma explode all trees
#3MeSH descriptor Brain Edema explode all trees
#4(brain or cerebral or intracranial) near3 (oedema or edema or swell*)
#5MeSH descriptor Glasgow Coma Scale explode all trees
#6MeSH descriptor Glasgow Outcome Scale explode all trees
#7MeSH descriptor Unconsciousness explode all trees
#8glasgow near3 (coma or outcome) near3 (score or scale)
#9(Unconscious* or coma* or concuss* or 'persistent vegetative state') near 3 (injur* or trauma* or damag* or wound* or fracture*)
#10"Rancho Los Amigos Scale"
#11(head or crani* or cerebr* or capitis or brain* or forebrain* or skull* or hemispher* or intra-cran* or inter-cran*) near3 (injur* or trauma* or damag* or wound* or fracture* or contusion*)
#12Diffuse near3 axonal near3 injur*
#13(head or crani* or cerebr* or brain* or intra-cran* or inter-cran*) near3 (haematoma* or hematoma* or haemorrhag* or hemorrhag* or bleed* or pressure)
#14(#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13)
#15MeSH descriptor Hypothermia, Induced explode all trees
#16MeSH descriptor Cryotherapy explode all trees
#17MeSH descriptor Body Temperature explode all trees
#18hypotherm* or normotherm* or cool* or cold* or temperature* or cryother* or cryogen* or cryotreat*
#19(#15 OR #16 OR #17 OR #18)
#20(#14 AND #19)
#21neonat*
#22(#20 AND NOT #21)

MEDLINE STRATEGY (1966 to May 2008)
1.exp Craniocerebral Trauma/
2.exp Brain Edema/
3.exp Glasgow Coma Scale/
4.exp Glasgow Outcome Scale/
5.exp Unconsciousness/
6.exp Cerebrovascular Trauma/
7.((head or crani$ or cerebr$ or capitis or brain$ or forebrain$ or skull$ or hemispher$ or intra-cran$ or inter-cran$) adj3 (injur$ or trauma$ or damag$ or wound$ or fracture$ or contusion$)).ab,ti.
8.((head or crani$ or cerebr$ or brain$ or intra-cran$ or inter-cran$) adj3 (haematoma$ or hematoma$ or haemorrhag$ or hemorrhag$ or bleed$ or pressure)).ti,ab.
9.(Glasgow adj3 (coma or outcome) adj3 (scale$ or score$)).ab,ti.
10."rancho los amigos scale".ti,ab.
11.("diffuse axonal injury" or "diffuse axonal injuries").ti,ab.
12.((brain or cerebral or intracranial) adj3 (oedema or edema or swell$)).ab,ti.
13.((unconscious$ or coma$ or concuss$ or 'persistent vegetative state') adj3 (injur$ or trauma$ or damag$ or wound$ or fracture$)).ti,ab.
14.or/1-13
15.(randomised or randomized or randomly or random order or random sequence or random allocation or randomly allocated or at random or controlled clinical trial$).tw,hw.
16.clinical trial.pt.
17.randomized controlled trial.pt.
18.15 or 16 or 17
19.exp models, animal/
20.exp Animals/
21.exp Animal Experimentation/
22.exp Disease Models, Animal/
23.exp Animals, Laboratory/
24.or/19-23
25.Humans/
26.24 not 25
27.18 not 26
28.14 and 27
29.exp Hypothermia, Induced/
30.exp Cryotherapy/
31.exp Body Temperature/
32.(hypotherm* or normotherm* or cool* or cold* or temperature* or cryother* or cryogen* or cryotreat*).ab,ti.
33.or/29-32
34.neonat*.ab,ti.
35.33 not 34
36.28 and 35
PUBMED Searched 21-05-08 (last 90 days)
7 records retrieved
#1Craniocerebral Trauma [mh] OR Brain Edema [mh] OR Glasgow Coma Scale [mh] OR Glasgow Outcome Scale [mh] OR Unconsciousness [mh] OR Cerebrovascular Trauma [mh] OR ((head or cranial or cerebral or brain* or intra-cranial or inter-cranial) AND (haematoma* or hematoma* or haemorrhag* or hemorrhage* or bleed* or pressure)) OR (Glasgow AND scale) OR ("diffuse axonal injury" OR "diffuse axonal injuries") or ("persistent vegetative state") OR ((unconscious* OR coma* OR concuss*) AND (injury* OR injuries OR trauma OR damage OR damaged OR wound* OR fracture* OR contusion* OR haematoma* OR hematoma* OR haemorrhag* OR hemorrhag* OR bleed* OR pressure))
#2(randomised OR randomized OR randomly OR random order OR random sequence OR random allocation OR randomly allocated OR at random OR randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized controlled trials [mh]) NOT ((models, animal[mh] OR Animals[mh] OR Animal Experimentation[mh] OR Disease Models, Animal[mh] OR Animals, Laboratory[mh]) NOT (Humans[mh]))
#31 and 2
#4("Hypothermia, Induced"[Mesh] OR "Cryotherapy"[Mesh]) OR "Body Temperature"[Mesh]
#5hypotherm* or normotherm* or cool* or cold* or temperature* or cryother* or cryogen* or cryotreat* Field: Title/Abstract
#64 or 5
#7Neonat* Field: Title/Abstract
#86 not 7
#93 and 8

EMBASE 1980 to May 2008
1.exp Brain Injury/
2.exp Brain Edema/
3.exp Glasgow Coma Scale/
4.exp Glasgow Outcome Scale/
5.exp Rancho Los Amigos Scale/
6.exp Unconsciousness/
7.((brain or cerebral or intracranial) adj3 (oedema or edema or swell$)).ab,ti.
8.((head or crani$ or cerebr$ or capitis or brain$ or forebrain$ or skull$ or hemispher$ or intra-cran$ or inter-cran$) adj3 (injur$ or trauma$ or damag$ or wound$ or fracture$ or contusion$)).ab,ti.
9.(Glasgow adj3 (coma or outcome) adj3 (scale$ or score$)).ab,ti.
10.Rancho Los Amigos Scale.ab,ti.
11.((unconscious$ or coma$ or concuss$ or 'persistent vegetative state') adj3 (injur$ or trauma$ or damag$ or wound$ or fracture$)).ti,ab.
12.Diffuse axonal injur$.ab,ti.
13.((head or crani$ or cerebr$ or brain$ or intra-cran$ or inter-cran$) adj3 (haematoma$ or hematoma$ or haemorrhag$ or hemorrhag$ or bleed$ or pressure)).ab,ti.
14.or/1-13
15.exp animal model/
16.Animal Experiment/
17.exp ANIMAL/
18.exp Experimental Animal/
19.15 or 16 or 17 or 18
20.Human/
21.19 not 20
22.(randomised or randomized or randomly or random order or random sequence or random allocation or randomly allocated or at random or controlled clinical trial$).tw,hw.
23.exp clinical trial/
24.22 or 23
25.24 not 21
26.14 and 25
27.exp INDUCED HYPOTHERMIA/
28.exp PROFOUND INDUCED HYPOTHERMIA/
29.exp CRYOTHERAPY/
30.exp Body Temperature/
31.(hypotherm* or normotherm* or cool* or cold* or temperature* or cryother* or cryogen* or cryotreat*).ab,ti.
32.27 or 28 or 29 or 30 or 31
33.neonat*.ab,ti.
34.32 not 33
35.26 and 34

Controlled Trials metaRegister of trials (mRCT) http://www.controlled-trials.com/mrct/ (Searched 22 May 2008)
((injur* or trauma* or damage*) and (head or crani* or brain* or forebrain* or intracran*)) and (hypotherm* or normotherm* or cool* or cold* or temperature* or cryother*)

WEB OF SCIENCE; Science Citation Index (searched 22 May 2008)
1.Topic=((injur* or trauma* or lesion* or damage* or wound* or oedema* or edema* or fracture* or contusion* or concus* or commotion* or pressur*) AND (head or crani* or capitis or brain* or forebrain* or skull* or hemisphere or intracran* or orbit*)) AND Topic=(hypotherm* or normotherm* or cool* or cold* or temperature* or cryother* or cryogen* or cryotreat*) NOT Topic=(neonat*)
2.Topic=(randomised OR randomized OR randomly OR random order OR random sequence OR random allocation OR randomly allocated OR at random OR randomized controlled trial OR controlled clinical trial OR randomized controlled trials OR controlled trial OR clinical trial) NOT Topic=(animal model* OR Animals OR Animal Experiment* OR Laboratory animals* or animal disease model*)
3.1 and 2

ZETOC (searched 22 May 2008)
Hypotherm* head injur* trial*
Hypotherm* head injur* random*
Hypotherm* head injur* control*

Hypotherm* brain injur* trial*
Hypotherm* brain injur* random*
Hypotherm* brain injur* control*

Hypotherm* head trauma* trial*
Hypotherm* head trauma* random*
Hypotherm* head trauma* control*

Hypotherm* brain trauma* trial*
Hypotherm* brain trauma* random*
Hypotherm* brain trauma* control*

What's new

DateEventDescription
31 October 2008New citation required and conclusions have changed

Eight new trials are included in this update. The results of the review have been amended accordingly.

One trial currently in 'studies awaiting assessment' (Hutchison 2008) was identified after the search was completed for this update. Data from this trial will be included in the review for issue 2, 2009.

The title has been changed from 'Therapeutic hypothermia for head injury' to 'Hypothermia for traumatic head injury'.

The authors of the review have changed.

History

Protocol first published: Issue 2, 1999
Review first published: Issue 2, 1999

DateEventDescription
9 July 2008Amended

The version of this review published in July 2008 mistakenly included three additional trials in the table of included studies and references sections.

Data from these three studies were not included in the review. The text of the review is the same as the 28 July 2004 update.

14 May 2008AmendedConverted to new review format.
28 July 2004New search has been performed

Substantive amendment. New studies found and included or excluded.

Two more trials have been included, and one added to the awaiting assessment list as we have not been able to obtain a copy of the trial.
Conclusions have been reviewed and compared to those found in a review of the topic in JAMA.

12 November 2001New search has been performedFour studies were included, which were published since the original version of this review.
Quantitative synthesis of the incidence of pulmonary infections was conducted in the 2001 update.

Contributions of authors

David Signorini wrote the protocol, performed the searches and reviewed the titles and abstracts, extracted the data, performed the analyses and wrote the draft of the review. Phil Alderson (PA) reviewed the manuscripts of potential trials, extracted the data and edited the draft review.

For the 2001 update, the Injuries Group performed the search and screened studies. PA and Chirag Gadkary assessed eligibility, extracted data, performed the analysis and redrafted the text.

For the 2004 update, the Injuries Group performed the search and screened studies. PA and the Injuries Group extracted data, and PA performed the analysis and rewrote the text.

For the 2008 update, the search was carried out by Karen Blackhall of the Cochrane Injuries Group. Emma Sydenham (ES) and Ian Roberts (IR) assessed trial eligibility and applied the selection criteria. ES extracted data, and IR checked for accuracy. ES updated the text of the review. IR and ES performed the analysis and edited the manuscript. PA checked the final manuscript of the update.

Declarations of interest

None known.

Sources of support

Internal sources

  • DFS was supported by MRC project grant G9604637, UK.

  • NHS R&D Programme, UK.

External sources

  • CG was supported by the Doris Duke Research Fellowship, USA.

Differences between protocol and review

The 2008 update of this review evaluated study quality by allocation concealment only. The incidence of pneumonia was also stratified by study quality.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Adelson 2005 HYPO1

MethodsMulticentre, randomised, controlled trial.
ParticipantsPatients less than 13 years of age, with a GOS of 8 or less.
InterventionsHypothermia 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.
OutcomesICP
CPP
Mortality
Infection
Arrhythmia
Coagulopathy
Pneumonia
Notes 
Risk of bias
ItemAuthors' judgementDescription
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

Adelson 2005 HYPO2

MethodsSingle centre, randomised, controlled trial.
ParticipantsPatients less than 17 years of age, with a GOS of 8 or less.
InterventionsHypothermia patients: Cooling to 32-33C for 48 hours. Passively rewarmed by 1C every 3-4 hours.
Normothermia patients: no intervention/not reported.
OutcomesICP
CPP
Mortality
Infection
Arrhythmia
Coagulopathy
Pneumonia
NotesThe 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
ItemAuthors' judgementDescription
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

Aibiki 2000

MethodsRandomised controlled trial.
Four patients were excluded from the normothermic group after randomisation because of abdominal or chest injuries.
ParticipantsPatients aged 4 to 76, within 8 hours of traumatic brain injury. Glasgow coma scale score of 8 or less on admission to emergency room.
InterventionsHypothermia 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.
OutcomesDeath and GOS at 6 months.
Thromboxane A2 and prostaglandin I2 levels during study. Complications during treatment.
NotesGOS assessed by "independent neurosurgeon who were not aware of the study". p.3904
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?Unclear'Patients were assigned randomly to each group.' p.3903 No mention of allocation concealment.

Biswas 2002

MethodsRandomised controlled trial.
ParticipantsChildren up to 18 years old, with closed traumatic brain injury and a GCS of 8 or less.
InterventionsHypothermia 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.
OutcomesDeath.
GOS at three, six and 12 months.
ICP and CPP.
Notes

GOS assessed blind to allocation.
Analysis on an intention-to-treat basis.

Two patients in the hypo group were lost to follow-up and 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
ItemAuthors' judgementDescription
Allocation concealment?UnclearNot described.

Clifton 1992

MethodsRandomised controlled trial.
ParticipantsPatients with GCS 4-8 with closed head injury but no major systemic injuries, in whom cooling could begin within 6 hours of injury.
InterventionsHypothermia 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.
OutcomesDeath and GOS at 3 months.
Complications during treatment phase.
NotesGOS was not assessed blind to treatment allocation.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesBy 'sealed envelopes'.

Clifton 1993

MethodsRandomised controlled trial.
ParticipantsPatients 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.
InterventionsHypothermia 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.
OutcomesDeath and GOS at 3 months.
Complications during treatment period.
ICP during treatment period.
NotesGOS assessed blind to treatment allocation.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesBy 'sealed envelopes'.

Clifton 2001

MethodsRandomised controlled trial.
ParticipantsPatients aged 16 to 65 with a non-penetrating head injury and a Glasgow coma scale of 3 to 8 after resuscitation.
InterventionsHypothermia 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.
OutcomesDeath and GOS at 6 months.
ICP monitored during treatment.
Nine neurobehavioural and neuropsychological scales at 6 months.
NotesGOS 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
ItemAuthors' judgementDescription
Allocation concealment?YesAllocation concealment unclear, but report states that "only the study biostatistician was aware of each patient's treatment group assignment".

Hashiguchi 2003

MethodsRandomised controlled trial. Allocation method not stated.
ParticipantsParticipants age 10 years or older, with a GCS of 8 or less, '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
ItemAuthors' judgementDescription
Allocation concealment?UnclearNot described.

Hirayama 1994

MethodsRandomised controlled trial. Allocation method not stated.
ParticipantsPatients age 18 to 81, GCS 3-7 with closed head injury. Hypothermia started within 6 hours of injury.
InterventionsHypothermia patients: cooling to 32-33C for 48 hours using cooling blankets. Rewarming over a period of 48 hours.
Control patients: Not stated.
OutcomesDeath and GOS at 3 months.
ICP during treatment period.
NotesBlinding of outcome assessment not stated.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearNot described.

Ishikura 1998

MethodsRandomised controlled trial. Allocation by 'random sampling'.
ParticipantsPatients with GCS 3-8 with closed head injury.
Interventions'Moderate hypothermia' without any details.
OutcomesThrombopoetin levels during treatment.
Deaths in hypothermia arm only.
NotesAbstract only.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?Unclear'11 patients with severe closed head injuries were divided into two groups by random sampling.' No information provided on allocation concealment.

Jiang 2000

MethodsRandomised controlled trial. Allocation method not clear.
ParticipantsPatients with mean age of 41 years, GCS 3-8.
InterventionsHypothermia 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.
OutcomesDeath and GOS at 12 months.
Complications.
NotesAssessment by MD blinded to treatment allocation.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearNot described.

Marion 1997

MethodsRandomised controlled trial. Allocation by 'sealed envelopes'.
ParticipantsPatients age 16 to 75, GCS 3-7 with closed head injury, in whom cooling could begin within 6 hours of injury.
InterventionsHypothermia 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.
OutcomesDeath and GOS at 3, 6 and 12 months.
ICP and CPP values during treatment phase.
Complications for subset.
NotesGOS assessment by psychiatrist blinded to treatment allocation.
Risk of bias
ItemAuthors' judgementDescription
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

Meissner 1998

MethodsRandomised controlled trial.
ParticipantsPatients with severe blunt head injury, in whom cooling could begin within 8 hours of injury.
InterventionsHypothermia patients: Cooling to 32-33C for 48 hours.
Control patients: Temperature maintained at 36-37C.
OutcomesDeath.
Infections.
NotesGOS assessed at 6 months by non-blinded assessor, but not yet available.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesBy 'sealed envelopes'.

Meissner 2003a

MethodsRandomised controlled trial.
ParticipantsPatients with severe blunt head injury. Intervention was started within 8 hours of injury.
InterventionsHypothermia patients: Cooling to 32-33C for 48 hours.
Control patients: Temperature maintained at 36-37C.
OutcomesHeart 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
ItemAuthors' judgementDescription
Allocation concealment?UnclearNot described.

Meissner 2003b

MethodsRandomised controlled trial.
ParticipantsPatients aged 18 or older, with severe closed head injury with a GCS <=9. Intervention was started within 8 hours of injury.
InterventionsHypothermia patients: Cooling to 32-33C for 24-48 hours. Cooling was by water blankets and forced air.
Control patients: Temperature maintained at 36-37C.
OutcomesTSH
TT4
FT4
TT3
FT3
RT3
NotesThis study examined thyroid hormone response in relation to therapeutic hypothermia.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearNot described.

Qiu 2007

MethodsRandomised, controlled, double-blind trial.
ParticipantsPatients 18-65 years old with traumatic brain injury with a Glasgow Coma Scale score of 8 or less.
InterventionsHypothermia 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.
OutcomesMortality.
ICP.
Serum superoxide dismutase level.
Glasgow Outcome Scale at 1 year post-intervention.
Notes 
Risk of bias
ItemAuthors' judgementDescription
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

Shiozaki 1993

MethodsRandomised controlled trial.
ParticipantsPatients age 10 or over, GCS 8 or less with head injury, who 'required continuous infusion of barbiturates to control intracranial hypertension'. p.363
InterventionsHypothermia 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.
OutcomesDeath and GOS at 6 months.
Pneumonia.
Complications during treatment.
ICP and CPP values during treatment period for hypothermic arm only.
NotesGOS assessed blind to treatment allocation.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearNot described.

Shiozaki 1999

MethodsRandomised controlled trial. Allocation concealment not clear.
No loss to follow up.
ParticipantsPatients age 10 and above with traumatic brain injury, a Glasgow coma scale of 8 or less, and 'who required continuous infusion of barbiturate medication to control intracranial hypertension.' p.185
InterventionsHypothermia 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.
OutcomesDeath and GOS at 6 months.
Complications.
NotesBlinding of outcome assessment not stated.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearNot described.

Shiozaki 2001

MethodsRandomised controlled trial.
Allocation concealment not clear.
No loss to follow up.
ParticipantsPatients with traumatic brain injury, a Glasgow coma scale of 8 or less, and 'in whom ICP was maintained below 25mmHg by conventional therapies'. p.50
InterventionsHypothermia 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.
OutcomesDeath and GOS at 3 months.
Complications
NotesBlinding of outcome assessment not stated.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearNot described.

Smrcka 2005

MethodsRandomised controlled trial - randomisation method not described.
No loss to follow up described.
ParticipantsPatients with traumatic brain injury with a Glasgow Coma Scale score of 8 or less, 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.

OutcomesICP
CPP
SvjO2 (jugular bulb oxygen saturation)
GOS
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearNot described.

Yan 2001

MethodsRandomised controlled trial.
Allocation concealment not described.
No loss to follow up described.
ParticipantsPatients with traumatic brain injury within 10 hours of injury and a Glasgow Coma Scale of 3 to 8 on initial assessment.
InterventionsHypothermia 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.
OutcomesDeath, follow up period unclear.
Neuroelectrophysiological measurements.
NotesBlinding of outcome assessment not stated.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearNot described.

Zhang 2000

MethodsRandomised controlled trial.
Allocation concealment not described. No loss to follow up mentioned.
ParticipantsPatients aged under 65 with traumatic brain injury and a Glasgow Coma Scale of 3-8 on admission to hospital.
InterventionsHypothermia patients: Cooling to 32-33C for 3-8 days.
Normothermia patients: temperature not stated.
OutcomesDeath, follow up period unclear.
NotesBlinding of outcome assessment not stated.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearNot described.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Chouhan 2006Patients were not cooled for a minimum of 12 consecutive hours.
Fukuoka 2004Quasi-randomised study design.
Gentilello 1997Randomised trial of rewarming therapy after accidental hypothermia in trauma.
Hayashi 2002Not a randomised study.
Hayashi 2005Not a randomised study.
Legros 1985Not a randomised study.
Liu 2005Patients who died within 72 hours of participating in the study were not included in the analysis.
Liu 2006Patients were not cooled for a minimum of 12 consecutive hours.
Nara 1997Unable to find sufficient information on study design.
Nordby 1984Not a randomised comparison, and hypothermia confounded with barbituate therapy.
Schulman 2005Patients to this study were excluded if they had evidence of acute brain injury and if they had previous traumatic brain injury.
Shen 2000Not a randomised trial.
Wusi 2006Not a randomised trial.
Yamagami 1997Not a randomised trial; hypothermia group GCS 4-6, normothermia group GCS 8-10.

Characteristics of studies awaiting assessment [ordered by study ID]

Chen 2001

Methods 
Participants 
Interventions 
Outcomes 
NotesAwaiting clarification from authors about method of randomisation and allocation concealment.

Guo 2004

Methods 
Participants 
Interventions 
Outcomes 
NotesAwaiting clarification from authors about method of randomisation and allocation concealment.

Hutchison 2008

Methods 
Participants 
Interventions 
Outcomes 
NotesData to be included in this review for issue 2, 2009.

Mrlian 2006

Methods 
Participants 
Interventions 
Outcomes 
NotesAwaiting clarification from authors about method of randomisation and allocation concealment.

Qiu 2005

Methods 
Participants 
Interventions 
Outcomes 
NotesAwaiting clarification from authors about method of randomisation and allocation concealment.

Qiu 2006

Methods 
Participants 
Interventions 
Outcomes 
NotesAwaiting clarification from authors about method of randomisation and allocation concealment.

Wang 2005

Methods 
Participants 
Interventions 
Outcomes 
NotesAwaiting clarification from authors about method of randomisation and allocation concealment.

Wang 2007

Methods 
Participants 
Interventions 
Outcomes 
NotesAwaiting clarification from authors about method of randomisation and allocation concealment.

Xia 2005

Methods 
Participants 
Interventions 
Outcomes 
NotesAwaiting clarification from authors about method of randomisation and allocation concealment.

Yan 2007

Methods 
Participants 
Interventions 
Outcomes 
NotesAwaiting clarification from authors about method of randomisation and allocation concealment.

Zhi 2003

Methods 
Participants 
Interventions 
Outcomes 
NotesAwaiting clarification from authors about method of randomisation and allocation concealment.

Characteristics of ongoing studies [ordered by study ID]

Adelson 2007

Trial name or titlePediatric traumatic brain injury consortium: hypothermia.
MethodsTreatment, Randomized, Single Blind (outcome assessor), single group assignment, efficacy study.
ParticipantsTBI patients under 16 years of age, with a GCS </= 8.
InterventionsPatients 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 months 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 dateNovember 2007
Contact information

P. David Adelson +1(412)692-6347 david.adelson@chp.edu

S. Danielle Brown +1(412)692-8794 brownds2@upmc.edu

NotesPhase III Clinical Trial.

Clifton 2002

Trial name or titleNational Acute Brain Injury Study: Hypothermia II (NABISH II)
MethodsRandomized, prospective, multi-center trial. Hypothermia for 48 hours, begun within 6 hours of severe brain injury.
ParticipantsPatients aged 16 to 45 years inclusive who have a closed head injury, present to the Emergency Department with a Glasgow Coma 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.
InterventionsThe 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.
OutcomesMortality 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 date4/1/02 - 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
guy.l.clifton@uth.tmc.edu

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
Emmy.R.Miller@uth.tmc.edu

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.

Ancillary