CRD summary

This well conducted review evaluated the use of therapeutic hypothermia as a neuroprotective strategy after severe traumatic brain injury in adults. Although therapeutic hypothermia might reduce the risks of death and poor neurological outcome, the authors' stated that there was insufficient evidence to recommend its routine use in clinical practice. The authors' were appropriately cautious in their conclusions.

Authors' objectives

To investigate the effects of depth, duration and rate of rewarming after discontinuation of hypothermia on mortality and neurological outcome in adults following traumatic brain injury (TBI).

Searching

A range of databases were searched: MEDLINE (from 1966 to September 2002), EMBASE, Current Contents (from 1993 to 2002) and the Cochrane Library. The search terms and dates were provided in the report. In addition, the bibliographies of identified studies and review articles were checked and corresponding authors of identified studies were contacted for additional unpublished and ongoing trials. Conference proceedings were also explored (further details were given in the report). There were no restrictions relating to language or publication status.

Study selection

Assessment of study quality

Methodological quality was assessed on the basis of two items: allocation concealment and blinding of the outcome assessment. The studies were considered high quality if allocation concealment was present and the outcome assessment was blinded; moderate quality if allocation concealment was unclear, but the outcome assessment was blinded; and low quality if allocation concealment was unclear and the outcome assessment was not blinded. Losses to follow up and/or missing outcome assessments were also documented for each included study. Two independent reviewers abstracted data on methodological quality and resolved any disagreements by consensus.

Data extraction

Two independent reviewers abstracted the data and resolved any disagreements by consensus. Data on the occurrence of all-cause mortality and poor neurological outcome were extracted from each individual study, and were used to derive a relative risk (RR). Additional data were extracted on the depth, duration of cooling and rate of rewarming.

Methods of synthesis

Results of the review

Twelve RCTs with a total of 1,069 participants were included.

Two studies were graded as high, three as moderate and five as low methodological quality.

Mortality.

Therapeutic hypothermia was associated with a significant reduction in the risk of death compared with normothermia (RR 0.81, 95% CI: 0.69, 0.98). The results were statistically homogeneous across the included studies (Q=8.12, P value not provided). Subgroup analyses found that hypothermia longer than 48 hours was associated with a statistically significant reduction in the risk of death (RR 0.70, 95% CI: 0.56, 0.87). However, none of the other subgroup analyses were statistically significant. Analyses exploring methodological quality did not detect any evidence of bias in the estimation of treatment effect for mortality. The reduction in the risk of death remained significant after the largest clinical trial was removed (RR 0.75, 95% CI: 0.62, 0.91). A funnel plot did not find any evidence of publication bias.

Neurological outcome.

Therapeutic hypothermia was associated with a significant reduction in the risk of poor neurological outcome (RR 0.78, 95% CI: 0.63, 0.98), but this effect was statistically heterogeneous (Q=16.05, P value not given). There remained a reduction in risk when hypothermia was induced for more than 48 hours (RR 0.65, 95% CI: 0.48, 0.89) or for 24 hours (RR 0.61, 95% CI: 0.39, 0.97), but not for 48 hours. Studies that included both induced hypothermia at 32 to 33 degrees C and rewarming within 24 hours after discontinuation of hypothermia were associated with a significant reduction in the risk of poor neurological outcome (RR 0.61, 95% CI: 0.45, 0.83 and RR 0.79, 95% CI: 0.63, 0.98, respectively). No other subgroup analyses had a statistically significant effect on neurological outcome. Analyses according to methodological quality did not show any evidence of bias in the treatment effects.

Authors' conclusions

Therapeutic hypothermia might reduce the risks of mortality and poor neurological outcome in adults with TBI. However, the authors added that the evidence was not yet sufficient to recommend the routine use of therapeutic hypothermia for TBI in clinical practice.

CRD commentary

The review had a well-defined question with clear inclusion criteria for the participants, interventions, outcomes and study designs. The searches were thorough and attempts were made to locate foreign language and unpublished material, thus limiting the potential for language or publication bias. Validity was assessed systematically and the effects of study quality on the results were explored. Details of the studies were supplied, as was information on the review process. Two reviewers were involved in extracting the data and assessing methodological quality, which serves to minimise potential bias. However, the potential for selection bias cannot be ruled out as it is unclear whether more than one reviewer was involved in selecting the studies for inclusion in the review.

The authors' decision to combine the studies statistically appears to have been appropriate given the a priori decision to explore clinical, methodological and statistical sources of heterogeneity and to assess potential effect modifiers. The authors discussed the potential impact of clinical heterogeneity and were cautious in their conclusions. This review points to the need for well-designed trials to confirm both the overall effects of hypothermia for TBI and any potential effect modifiers.

Implications of the review for practice and research

Practice: The authors stated that their results should not influence practice due to the small number of high-quality trials and the potential sources of heterogeneity that were not explored in this review.

Research: The authors stated that the results of the review should assist in the development of future clinical trials. In particular, they stated that it might be useful to conduct a trial that induces hypothermia to a target temperature of 32 to 33 degrees C, with a cooling duration of greater than 48 hours and a rewarming period of 24 hours or less, to potentially maximise treatment benefits.

Funding

Ontario Neurotrauma Foundation, grant number ONBO-00009; Canadian Neurotrauma Research Partnership through the Canadian Institutes of Health Research, grant number MCT50398.

Bibliographic details

McIntyre L A, Fergusson D A, Hebert P C, Moher D, Hutchison J S. Prolonged therapeutic hypothermia after traumatic brain injury in adults: a systematic review. JAMA 2003; 289(22): 2992-2999. [PubMed: 12799408]

Original Paper URL

http://jama.ama-assn.org/

Other publications of related interest

This additional published commentary may also be of interest. Shann F. Hypothermia for traumatic brain injury: how soon, how cold, and how long? Lancet 2003;362:1950-1.

Indexing Status

Subject indexing assigned by NLM

MeSH

Adult; Brain Injuries /therapy; Humans; Hypothermia, Induced; Randomized Controlled Trials as Topic; Treatment Outcome

AccessionNumber

12003008348

Database entry date

31/08/2004

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.