A systematic review of therapeutic hypothermia for adult patients following traumatic brain injury

Samantha Crossley, Jenny Reid, Rachel McLatchie, Judith Hayton, Clair Clark, Margaret MacDougall, Peter J D Andrews, Samantha Crossley, Jenny Reid, Rachel McLatchie, Judith Hayton, Clair Clark, Margaret MacDougall, Peter J D Andrews

Abstract

Introduction: Research into therapeutic hypothermia following traumatic brain injury has been characterised by small trials of poor methodological quality, producing variable results. The Cochrane review, published in 2009, now requires updating. The aim of this systematic review is to assess the effectiveness of the application of therapeutic hypothermia to reduce death and disability when administered to adult patients who have been admitted to hospital following traumatic brain injury.

Methods: Two authors extracted data from each trial. Unless stated in the trial report, relative risks and 95% confidence intervals (CIs) were calculated for each trial. We considered P < 0 · 05 to be statistically significant. We combined data from all trials to estimate the pooled risk ratio (RR) with 95% confidence intervals for death, unfavourable outcome, and pneumonia. All statistical analyses were performed using RevMan 5.1 (Cochrane IMS, Oxford, UK) and Stata (Intercooled Version 12.0, StataCorp LP). Pooled RRs were calculated using the Mantel-Haenszel estimator. The random effects model of DerSimonian and Laird was used to estimate variances for the Mantel-Haenszel and inverse variance estimators.

Results: Twenty studies are included in the review, while 18 provided mortality data. When the results of 18 trials that evaluated mortality as one of the outcomes were statistically aggregated, therapeutic hypothermia was associated with a significant reduction in mortality and a significant reduction in poor outcome. There was a lack of statistical evidence for an association between use of therapeutic hypothermia and increased onset of new pneumonia.

Conclusions: In contrast to previous reviews, this systematic review found some evidence to suggest that therapeutic hypothermia may be of benefit in the treatment of traumatic brain injury. The majority of trials were of low quality, with unclear allocation concealment. Low quality trials may overestimate the effectiveness of hypothermia treatment versus standard care. There remains a need for more, high quality, randomised control trials of therapeutic hypothermia after traumatic brain injury.

Figures

Figure 1
Figure 1
Death at final follow-up. (a) In total 18 trials involving 1,839 patients reported deaths. When the results of the 18 randomised controlled trials (RCTs) were statistically aggregated, therapeutic hypothermia was associated with a significant reduction in mortality (relative risk (RR) = 1.31, 95% CI = 1.13, 1.52, P = 0.0004). (b) Trials assessed as having lower risk of bias: when the results of the 14 RCTs were statistically aggregated, therapeutic hypothermia was associated with a significant reduction in mortality (RR = 1.62, 95% CI = 1.30, 2.01, P <0.0001).
Figure 2
Figure 2
Poor outcome at final follow-up. (a) In total 20 trials involving 1,885 patients reported death, vegetative state, and long-term disability. When the results of 20 randomised controlled trials (RCTs) that evaluated poor outcome were statistically aggregated, therapeutic hypothermia was associated with a significant reduction in poor outcome (relative risk (RR) = 1.49, 95% CI = 1.27, 1.74, P <0.00001). (b) Trials assessed as lower risk of bias: 16 trials, involving 964 patients, and assessed as lower risk of bias (domain-based assessment) were included in this analysis. When the results of 16 RCTs that evaluated poor outcome were statistically aggregated, therapeutic hypothermia was associated with a significant reduction in poor outcome (RR = 1.67, 95% CI = 1.45, 1.92, P <0.00001).
Figure 3
Figure 3
Incidence of pneumonia during the course of treatment. (a) In total 12 trials involving 689 patients reported pneumonia in patients during the course of treatment. When the data from 12 randomised controlled trials (RCTs) were aggregated, therapeutic hypothermia had no effect on increasing onset of new pneumonia (relative risk (RR) = 0.81, 95% CI = 0.62, 1.05, P = 0.12). (b) Trials assessed as lower risk of bias: 9 trials, involving 504 patients, assessed as having lower risk of bias (domain-based assessment) were included in this analysis. When the data from the 9 RCTs that reported pneumonia were aggregated, therapeutic hypothermia had no effect on increasing onset of new pneumonia (RR = 0.87, 95% CI = 0.71, 1.07, P = 0.17).
Figure 4
Figure 4
Funnel plots to investigate evidence of bias. (4.1) Death. (a) Standard funnel plot. (b) Contour-enhanced funnel plot. (4.2) Poor outcome. (a) Standard funnel plot. (b) Contour-enhanced funnel plot. (4.3) Pneumonia; RR, relative risk (equivalently, risk ratio). (a) Standard funnel plot. (b) Contour-enhanced funnel plot.

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Source: PubMed

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