Background
Traumatic head injury is a major cause of death and disability amongst a predominantly young population. An estimated ten million people worldwide experience severe head injury every year (Langlois 2006). There is, however, a significant lack of evidence about effective therapies in the acute care of head injured patients, especially children (Adelson 2003). A long-term effort to review the literature and produce management guidelines by the American Association of Neurological Surgeons (Bullock 1996; Kirkpatrick 1997, Bullock 2007) could only make four definitive statements about treatment effectiveness that were supported by strong evidence from randomised studies. These recommendations included guidance on the management of blood pressure and oxygenation, intracranial pressure, hyperventilation, and nutrition of head injured patients.
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. During the 1990s several investigators 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 to larger, multi-centre trials.
Originally it was thought that the primary mechanism of action of temperature control therapy was 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
We searched 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 have begun immediately upon admission to the intensive therapy unit or be deferred until intracranial pressure (ICP) became 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
The searches were not restricted by language, date or publication status.
Electronic searches
We searched the following electronic databases:
- Cochrane Injuries Group Specialised Register (12 Jan 2009);
- CENTRAL (The Cochrane Library Issue 1, 2009);
- MEDLINE (1950 to March 2009);
- PubMed (searched 6 April 2009);
- EMBASE (1980 to week 14, March 2009);
- ISI Web of Science: Science Citation Index Expanded (SCI-EXPANDED) 1970 to April 2009 and Conference Proceedings Citation Index-Science (CPCI-S) 1990 to 7 April 2009;
- Controlled Trials metaRegister of trials (mRCT) http://www.controlled-trials.com/mrct/ (12 January 2009);
- Zetoc (12 January 2009).
The latest search strategies are listed in Appendix 1. The original search strategy from the first version of the review is in Appendix 2.
Searching other resources
In addition, we checked the reference lists of all relevant trials and review articles, and contacted leading investigators in the field for information about any other published, unpublished or ongoing trials.
Data collection and analysis
Selection of studies
Two authors screened the search results (ES and IR). We then retrieved the full text of relevant records. We independently compared the trial design with the inclusion criteria for this review. Disagreements were resolved by discussion.
Data extraction and management
We extracted the following information 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 entered into Review Manager (RevMan) by ES; IR checked for accuracy. We contacted trial report authors for additional information or clarification.
There were a number of trials where it was not possible to determine the method of randomisation or allocation concealment from the trial report. We sought to contact the trial report authors, but were unable to reach them in some cases. These trials have been excluded from the review, and can be identified in the Characteristics of excluded studies table.
Assessment of risk of bias in included studies
We assessed the quality of allocation concealment 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
We calculated Mantel-Haenzel odds ratios (ORs) and 95% confidence intervals (CIs) for death, unfavourable outcomes and pneumonia 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 risk ratio 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
Subgroup analysis and investigation of heterogeneity
We performed subgroup analyses 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 ongoing studies.
Results of the search
We identified a total of 23 randomised controlled trials that met the inclusion criteria.
Included studies
The 23 included randomised controlled trials involved 1614 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. Fifteen trials reported Glasgow Outcome Scale (GOS) scores specifically at three, six or 12 months post-injury. Eleven trials reported the occurrence of pneumonia.
Risk of bias in included studies
Allocation
Adequate allocation concealment is an important dimension of trial quality.
Nine trials had a reasonable standard of allocation concealment (Adelson 2005 HYPO1; Adelson 2005 HYPO2; Clifton 1992; Clifton 1993; Clifton 2001; Harris 2009; Hutchison 2008; Marion 1997; 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 scores in the treatment and control groups (Ishikura 1998; Meissner 2003a) and had unclear allocation concealment.
Figure 1 and Figure 2 show the proportion of trials that were judged by the review authors to have had adequate allocation concealment.
 | Figure 1. Methodological quality graph: review authors' judgements on whether there was allocation concealment, presented as percentages across all included studies. |
 | Figure 2. Methodological quality summary: review authors' judgements on whether there was allocation concealment for each included study. |
Effects of interventions
Death at final follow-up
Twenty-one trials involving 1587 patients reported deaths. Patients treated with hypothermia were somewhat less likely to die than those in the control group, but the reduction was not significant (OR 0.85, 95% CI 0.68 to 1.06). There was no evidence of statistical heterogeneity between trials (Chi² = 21.91, df = 19 (P = 0.29); I² = 13%).
Death at final follow-up stratified by trial quality
Nine trials involving 891 patients used good allocation concealment methods. Hypothermia treatment was associated with no decrease in the likelihood of death, which was statistically non-significant compared with the control group (OR 1.11, 95% CI 0.82 to 1.51). There was no evidence of statistical heterogeneity between trials (Chi² = 4.33, df = 8 (P = 0.83); I² = 0%).
Twelve trials involving 696 patients did not conceal allocation, or used 'unclear' concealment methods according to Higgins 2008. 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
Twenty-one trials involving 1587 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 0.77, 95% CI 0.62 to 0.94). There was some evidence of statistical heterogeneity between trials (Chi² = 38.20, df = 20 (P = 0.008); I² = 48%).
Unfavourable outcome stratified by trial quality
Nine trials involving 891 patients used good allocation concealment methods. Hypothermia treatment was associated with a statistically non-significant small reduction in unfavourable outcome compared with the control group (OR 0.93, 95% CI 0.70 to 1.23). There was no statistical heterogeneity between trials (Chi² = 9.77, df = 8 (P = 0.28); I² = 18%).
Twelve trials involving 696 patients did not conceal allocation, or used 'unclear' concealment methods according to Higgins 2008. 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
Fourteen trials reported deaths or severe disability according to the duration of treatment.
Four trials involving 321 patients treated the hypothermia group for 24 hours. There was a slight, non-significant, increase in the likelihood of unfavourable outcome for patients given hypothermia (OR 1.03, 95% CI 0.65 to 1.65). There was some statistical heterogeneity between trials (Chi² = 7.86, df = 3 (P = 0.05); I² = 62%).
Ten trials involving 683 patients treated the hypothermia group for 48 hours. Hypothermia treatment was associated with a very slight, 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
Fifteen trials reported Glasgow Outcome Scale (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 unfavourable outcome 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%).
Nine trials involving 839 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, but the reduction was not significant (OR 0.76, 95% CI 0.57 to 1.01). There was significant statistical heterogeneity between trials (Chi² = 27.77, df = 8 (P = 0.0005); I² = 71%).
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
Eleven trials involving 559 patients reported pneumonia cases. Patients treated with hypothermia were somewhat more likely to have pneumonia than those in the control group, but the increase was not significant (OR 1.35, 95% confidence interval 0.95 to 1.91).
Pneumonia was stratified by trial quality:
Four trials with good allocation concealment involving 306 patients reported pneumonia cases. Hypothermia treatment was associated with a statistically non-significant decrease in pneumonia (OR 0.84, 95% confidence interval 0.52 to 1.35). There was no statistical heterogeneity between trials (Chi² = 1.47, df = 3 (P = 0.69); 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
There is no evidence that hypothermia is beneficial in the treatment of head injury. 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 no decrease in the likelihood of death with hypothermia, but this finding was not statistically significant. Some of the findings in this review are therefore contradictory, and this is probably due to the inclusion of data from low quality trials. Most of the positive and negative effects of hypothermia found may be due to the play of chance.
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.
In trials with good allocation concealment, patients receiving hypothermia were slightly more likely to die, but this may be due to the play of chance. There was a non-significant reduction in pneumonia 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.
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.
A broader review by Polderman 2008 summarises the findings of some of the trials included in this review.
P. David Adelson describes how paediatric patients may respond to hypothermia treatment differently than adult patients (Adelson 2009).
Authors' conclusions
Implications for practice There is no evidence that hypothermia is beneficial in the treatment of head injury. 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 no decrease in the likelihood of death with hypothermia, but this finding was not statistically significant and could be due to the play of chance. Hypothermia should not be used except in the context of a high quality 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, 2008 and 2009.
- Odette Harris and Monique Surles for providing additional data for the Harris 2009 trial.
Data and analyses
- Top of page
- Background
- Objectives
- Methods
- Results
- Discussion
- Authors' conclusions
- Acknowledgements
- Data and analyses
- Appendices
- What's new
- History
- Contributions of authors
- Declarations of interest
- Sources of support
- Differences between protocol and review
- Index terms
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Appendices
Appendix 1. Latest search strategy
Injuries Group's Specialised Register (searched 12 January 2009)
((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 2009, Issue 1)
#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 March week 4, 2009)
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 6 April 2009 (last 90 days)
#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 (week 14) March 2009
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 12 January 2009)
((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*)
ISI Web of Science: Science Citation Index Expanded (SCI-EXPANDED) 1970 to April 2009 and Conference Proceedings Citation Index- Science (CPCI-S) 1990 to 7 April 2009.
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 12 January 2009)
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*
Appendix 2. Original search strategy
For the initial version of the review the following search was done:
The Specialist Trials Register for the Injuries Group was searched 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 as follows, to identify all potential RCTs involving human head injury and temperature control from 1980 onwards :
001 exp head injury/
002 pneumocephalus/
003 cerebrospinal fluid/
004 otorrhea/
005 exp skull fracture/
006 exp spine fracture/
007 Cerebrospinal Fluid Rhinorrhea/
008 exp asphyxia/
009 exp spine injury/
010 helmet/
011 brain protection/
012 brain edema/
013 exp brain hemorrhage/
014 brain hypoxia/
015 coma/
016 persistent vegetative state/
017 Traumatic Epilepsy/
018 or/1-17
019 (head or brain or cerebr$ or skull or crani$ or spin$).tw.
020 (wound$ or injur$ or trauma$ or oedema$ or edema$).tw.
021 damage$.tw.
022 20 or 21
023 19 and 22
024 18 or 23
025 human/
026 "888".tg.
027 25 or 26
028 Nonhuman/
029 "777".tg.
030 28 or 29
031 27 and 30
032 30 not 31
033 clinical trial/
034 Multicenter Study/
035 phase 2 clinical trial/
036 phase 3 clinical trial/
037 Phase 4 Clinical Trial/
038 Randomized Controlled Trial/
039 controlled study/
040 meta analysis/
041 crossover procedure/
042 double blind procedure/
043 Single Blind Procedure/
044 randomization/
045 Major Clinical Study/
046 placebo/
047 drug comparison/
048 clinical study/
049 "0197".tg.
050 "0150".tg.
051 "03738".dc.
052 (clin$ adj25 trial$).tw.
053 ((singl$ or doubl$ or tripl$ or trebl$) adj25 (blind$ or mask$)).tw.
054 placebo$.tw.
055 random$.tw.
056 control$.tw.
057 or/33-56
058 24 not 32
059 Induced Hypothermia/
060 Profound Induced Hypothermia/
061 exp temperature/
062 exp low temperature procedures/
063 cold/
064 cold air/
065 cold exposure/
066 (hypotherm$ or normotherm$ or cool$ or cold$ or temperature$).tw.
067 or/59-66
068 58 and 67
069 68 and 57
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
What's new
Last assessed as up-to-date: 6 April 2009.
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History
Protocol first published: Issue 2, 1999
Review first published: Issue 2, 1999
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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. ES and 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.
Karen Blackhall performed the search for the January 2009 update. ES and IR assessed trial eligibility and applied the selection criteria. ES extracted the data, and IR checked the extracted data 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.
In April 2009, Karen Blackhall updated the search for trials. ES and IR assessed trial eligibility and applied the selection criteria. ES and IR re-assessed all previously included trials against the inclusion criteria. All authors agreed that the Meissner 1998 study should be excluded. ES updated the text of the review. IR and PA checked the final manuscript of the update.
Emma Sydenham included data from the Harris 2009 trial for the July 2009 update. IR and PA checked the extracted data. All authors approved the manuscript for publication.
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.
Index terms
Medical Subject Headings (MeSH)
*Hypothermia, Induced [adverse effects; mortality]; Craniocerebral Trauma [mortality; *therapy]; Randomized Controlled Trials as Topic
MeSH check words
Humans
* Indicates the major publication for the study