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Harris B, Andrews PJD, Murray GD, et al. Systematic Review of Head Cooling in Adults After Traumatic Brain Injury and Stroke. Southampton (UK): NIHR Journals Library; 2012 Nov. (Health Technology Assessment, No. 16.45.)

Cover of Systematic Review of Head Cooling in Adults After Traumatic Brain Injury and Stroke

Systematic Review of Head Cooling in Adults After Traumatic Brain Injury and Stroke.

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3Review methods

Differences between protocol and review

The review protocol can be found in Appendix 2. We had consultancy support from Brenda Thomas, Cochrane Stroke Group Trials Search Co-ordinator, and on her advice the outline search strategy in the protocol was considerably extended to include, for example, EMBASE classic, the British Library’s Electronic Table of Contents (Zetoc), British Nursing Index (BNI) and BNI Archive, and Web of Science conference proceedings. Had time allowed we would also have included additional country-specific databases in addition to those in the protocol (e.g. WanFang, Panteleimon, IndMED, KoreaMed), Web of Science cited reference search (forward search) and more hand-searching. The formal patent search was omitted owing to lack of time. Of the head-cooling reports in the review (see Figure 1, which corresponds to the results of stage 2, trial identification and selection in the protocol) only studies that could potentially have been RCTs were screened, assessed and had data extracted by two reviewers.

Criteria for considering studies for this review

Types of studies

Studies or case reports of any kind in adult humans after TBI and stroke, using any form of non-invasive head cooling were searched for. Studies of head cooling in cardiac arrest and neonatal HIE were also searched for to obtain information on temperature reduction (cardiac arrest) and adverse effects of cooling methods and devices (cardiac arrest and neonatal HIE).

Types of participants

All adults (aged ≥ 18 years) admitted to hospital with TBI, or ischaemic or haemorrhagic stroke, of any severity, and after resuscitation from cardiac arrest for the purposes of assessing efficacy of head cooling in reducing temperature. Studies of cooling in neonatal HIE were included only for information on adverse effects.

Types of intervention

Studies of any method of non-invasive head cooling of any duration given for the purposes of fever reduction, inducing normothermia or hypothermia, or reducing disability and mortality or reducing ICP were included. Studies in which head cooling was used solely during surgery or combined with another cooling intervention, excepting antipyretic drugs, such as paracetamol, were excluded.

Cooling intervention comparisons could include:

  1. no cooling intervention or standard care
  2. physical cooling interventions applied systemically or to parts of the body other than the head, for example tepid sponging, ice packs, cooling blankets, intravascular cooling catheters
  3. pharmacological cooling interventions, for example paracetamol, non-steroidal anti-inflammatory drugs, cyclo-oxygenase inhibitors, ethymisole.

Outcome measures

Primary outcomes

  1. Intracranial temperature (inside the skull and within the dura) or core trunk temperature (measured in an artery, the oesophagus, bladder or rectum). Comparisons could include temperature with and without head cooling, temperature at baseline compared with temperature at the end of cooling or the lowest temperature achieved.
  2. All-cause mortality by end of follow-up.
  3. Outcome assessed with a validated outcome score, i.e. Glasgow Outcome Scale (GOS),41 and acute, functional or outcome assessments listed on the Internet Stroke Center.42

Other outcomes

  1. Reduction in ICP.
  2. Improvement in biochemical markers of injury, for example lactate–pyruvate ratio, glutamate, cytokines.
  3. Improvement in cross-sectional imaging.
  4. Time from brain injury or onset of stroke to start of cooling, cooling rate (hourly temperature reduction), and time from injury to target temperature and from device application to achieving target temperature. These are indicators of the effectiveness of head-cooling methods and devices and their ease of use, for example how quickly and easily they can be applied.

Adverse effects

Complications actually or possibly attributable to the head-cooling intervention or the specific device, for example infections, prolonged clotting time and bleeding complications, scalp damage.

Search methods for identification of studies

Appendix 3 (search strategies) contains details of the searches and search terms. The searches were not restricted by publication status, date or language.

Electronic searches

Dates given are for the most recent search.

Major international medical bibliographical databases

MEDLINE 1950 to 12 March 2011.


EMBASE 1980 to 2011 Week 10.

EMBASE Classic 1947–79.

Cumulative Index of Nursing and Allied Health Literature (CINAHL) 1937 to April 6 2010.

British Nursing Index (BNI) and BNI Archive 1985 to May 2010.

Web of Science Conference Proceedings Citation Index-Science (CPCI-S) 1990 to 19 July 2010.

Zetoc Conference Proceedings (8 August 2010).

ProQuest Dissertations & Theses (PQDT) database (25 March 2011).

The Cochrane Library

Cochrane Central Register of Controlled Trials (CENTRAL) (2011 Issue 1).

Cochrane Database of Systematic Reviews (CDSR) (2011 Issue 3).

Database of Abstracts of Reviews of Effects (DARE) (2011 Issue 1).

Health Technology Assessment (HTA) database (2011 Issue 1).

NHS Economic Evaluation Database (NHS EED) (2011 Issue 1).

Cochrane specialised trials registers

Cochrane Injuries Group (14 June 2010).

Cochrane Stroke Group (5 May 2010).

Other trial registers (last update all registers 6 March 2011)

World Health Organization International Clinical Trials Registry Platform (WHO ICTR).

Current Controlled Trials: the meta-register of controlled trials and International Standard

Randomised Controlled Trial Number (ISRCTN) register.

National Research Register archive.

Stroke Trials Registry.

Country-specific databases

Informit Health Collection (includes Australasian Medical Index) (6 February 2011).

China National Knowledge Database (CNKI): China Academic Journals (CAJ) Medicine and Public Health (hygiene) database (14 January 2011).

Japan Science and Technology Agency (JST): J-EAST (16 August 2010), J-STAGE (5 February 2011), journal@rchive (4 February 2011).

Latin American Caribbean Health Sciences Literature (LILACS) (5 February 2011).

Russian Academy of Sciences Bibliographies (25 March 2011).

Web search engines

Scirus (7 March 2011).

Google Scholar (26 March 2011).

Searching other resources

Reference lists of relevant studies and reviews and of books on therapeutic hypothermia and the proceedings of hypothermia conferences were checked. Investigators and manufacturers of head-cooling equipment were contacted in writing.

Data collection and analysis

Selection of studies

Bridget Harris conducted the searches with advice and help from Brenda Thomas, Cochrane Stroke Group Trials Search Co-ordinator. All retrieved results were imported into Reference Manager (version 11, Thomson Reuters, CA, USA), de-duplicated, and titles and abstracts were screened by BH to remove anything that did not meet the review criteria with regard to study type, participants, intervention and outcome (details above). Where full review or further information to determine relevance was required the complete paper was obtained and screened by BH. This resulted in a final data set of studies that met the review criteria, with full text, where this existed, for detailed assessment regarding inclusion and exclusion for analysis. If there was more than one report of a study all were included in order to facilitate complete data extraction. The method for screening and assessing papers in languages other than English is detailed below. The study assessment and data collection form was piloted by BH and PA (Appendix 4 contains the final version used for the review). It includes the quality checklist we used to assess RCTs, which was developed by the Cochrane Renal Group.43 Trials were not included or excluded on the basis of an overall score on this checklist but according to whether they met the prespecified inclusion criteria for the review.

From the final data set any studies that purported to be RCTs were independently assessed for quality by BH and PA. Trials that had an adequate method of randomisation (see Appendix 4) were eligible for inclusion for formal analysis of the effect of head cooling on patient outcome. Trials in which the assessor of disability outcome was not blinded were excluded from the formal analysis as prespecified in the protocol. One of the reasons for this was because the intervention could not be blinded.

In addition to RCTs any studies, including proof of concept and case studies, that contained information on head-cooling devices and methods (presented in full in Appendix 7), their efficacy in reducing temperature, ease of use and adverse effects were included for descriptive reporting (as prespecified in the protocol). These studies were not formally assessed for quality and bias; they are described and the temperature data and adverse effects tabulated. It was considered that temperature, being a physical measure of a physiological variable, is less susceptible to interpretation and bias than, for example, functional outcome, and it was therefore reasonable to include information on the effect of head cooling on temperature, even if the studies were not randomised or controlled, because this provides some evidence of proof of concept (or otherwise).

Papers in languages other than English

A number of papers in foreign languages required full-text review: French (13), Italian (1), Slovakian (1), German (11), Japanese (3), Russian (8) and Chinese (26). Some of these had no, or an inadequate, English abstract so that it was not clear, for example, if the research was in humans or animals or whether head cooling or systemic cooling had been used without reading at least part of the paper. We had assistance from colleagues and friends with the requisite languages and used Google Translate ( to eliminate papers that were not relevant.

A Chinese-speaking intensive care doctor helped with the Chinese papers. She read them all, translated parts and went through them in detail with BH to assess quality and extract data. This did not highlight any that, on grounds of quality, warranted formal professional translation but we did have the study comparing head cooling with systemic cooling translated, as this was a particular comparison of interest with very few studies.44 Because the other Chinese studies were not formally translated in full it has been possible only to report the main points and reasons for exclusion Appendix 6 (see Characteristics of Excluded Studies) compared with some of the studies in English where we have reported in more detail, although this is sometimes simply because there was more detail to report (the Chinese papers were mostly short).

Papers on head cooling in neonatal HIE in languages other than English were not assessed because this was not the primary condition of interest and there are recent systematic reviews (see Appendix 5, References to studies in neonatal hypoxic–ischaemic encephalopathy), which were also consulted for information on adverse effects of head-cooling methods and devices, i.e. the reason why papers on neonatal HIE were of interest.

Data extraction

BH and PA independently extracted data from RCTs using a standard form (see Appendix 4). They were not blinded to authors, journal or results. Disagreements were resolved by discussion. BH extracted data from all other studies. Where multiple reports of a trial were available, discrepancies between the reports were noted. Where there was missing information attempts were made to contact investigators.

Assessment of risk of bias

Randomised controlled trials were assessed for adequacy of the randomisation and allocation concealment process, potential for selection bias after allocation and level of masking (blinding of treatment provider, patient, outcome assessor, investigators and analysers of the data) (see Appendix 4).

Data synthesis

We were unable to carry out the full analysis plan specified in the protocol (see Appendix 2) because there were insufficient good-quality RCTs to undertake formal outcome analysis.

Briefly, had there been suitable RCT data, the following analysis was planned. For temperature data the difference in means would have been calculated with 95% confidence intervals (CIs). If sufficient good-quality trials for a meta-analysis had been found then a weighted mean difference would have been calculated. Pooled relative risk and 95% CIs for all-cause mortality and good neurological outcome would have been calculated using a random-effects model. Statistical heterogeneity would have been assessed using the chi-squared test.

However, it was recognised in the protocol that, depending on what was found, description of results might be all that was possible and the available temperature data are tabulated as a descriptive record of the effect of head cooling. No attempt has been made to draw any statistical inference. Data on adverse effects are reported descriptively.

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© 2012, Crown Copyright.

Included under terms of UK Non-commercial Government License.

Bookshelf ID: NBK127498


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