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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

Systematic review of randomized controlled trials of therapeutic hypothermia as a neuroprotectant in post cardiac arrest patients

KW Cheung, RS Green, and KD Magee.

Review published: 2006.

CRD summary

The authors concluded that the induction of mild hypothermia reduces in-hospital mortality and improves neurological outcomes in comatose survivors of cardiac arrest, but more information about adverse events is required. Overall, this was a well-conducted review and the authors' conclusions are likely to be reliable.

Authors' objectives

To evaluate the effects of mild induced hypothermia in comatose survivors of cardiac arrest.

Searching

The Cochrane Controlled Trials Register (Issue 4, 2005), MEDLINE, EMBASE, CINAHL and Web of Science were searched from inception to November 2005 using the reported terms. The reference lists

of primary studies and review articles were screened, and authors of primary studies and researchers in the field were contacted for details of additional studies. No language or publication restrictions were applied.

Study selection

Study designs of evaluations included in the review

Randomised controlled trials (RCTs) and quasi-RCTs were eligible for inclusion in the review.

Specific interventions included in the review

Studies that compared mild induced hypothermia (32 to 34 degrees C) with normothermia within 24 hours of the patient's presentation were eligible for inclusion. Where reported, the included studies used different methods of cooling, including cooling mattress (plus ice packs if required), ice packs and

cooling helmet. The duration of cooling ranged from no time after mild hypothermia was reached to 3 days.

Participants included in the review

Studies of adults (aged older than 18 years) who had a primary cardiac arrest and were comatose (Glasgow Coma Scale <8) following return of spontaneous circulation (ROSC) were eligible

for inclusion. Where reported, patients in the included studies presented with ventricular fibrillation, pulseless ventricular tachycardia, asystole or pulseless electrical activity. The median time from collapse to ROSC ranged from 21 to 34 minutes.

Outcomes assessed in the review

Studies that assessed neurological outcomes or mortality were eligible for inclusion. In the review, a 'good' neurological outcome was defined as no disability or mild to moderate disability, while a 'poor' neurological outcome was defined as more severe degrees of disability. The review also assessed

adverse effects. The included studies used different scales to assess neurological outcomes: Glasgow-Pittsburgh Cerebral Performance, Glasgow Outcome Scale and classification based on discharge destination.

How were decisions on the relevance of primary studies made?

One reviewer screened titles and abstracts and selected potentially relevant studies. Two reviewers then independently selected the studies from retrieved full reports. Any disagreements on inclusion were resolved through discussion with a third author.

Assessment of study quality

Two reviewers independently assessed validity using the Cochrane allocation concealment approach and the 0- to 5-point Jadad scale (randomisation, blinding and description of withdrawals).

Data extraction

The data were extracted by one reviewer and double-entered into Review Manager software. The numbers of patients in each treatment group with events of interest were presented. Relative

risks (RRs) with 95% confidence intervals (CIs) were calculated for dichotomous data, while mean differences and standardised mean differences with 95% CIs were calculated for continuous data.

Methods of synthesis

How were the studies combined?

Pooled RRs and 95% CIs were calculated for dichotomous data, while pooled weighted mean difference or standardised mean differences with 95% CIs were calculated for continuous data.

Where 5 or fewer studies were pooled and no significant heterogeneity was found (p<0.10), a fixed-effect model was used. The number-needed-to-treat with induced mild hypothermia to prevent one in-hospital death (with 95% CI) was calculated. Funnel plots were used to assess publication bias.

How were differences between studies investigated?

Statistical heterogeneity was assessed using the Breslow-Day chi-squared test and the I-squared statistic. Studies scoring at least 3 on the Jadad scale were compared with studies scoring

less than 3.

Results of the review

Four RCTs (n=436) were included.

Two studies scored 3 on the Jadad scale; both of these showed adequate concealment of treatment allocation. The other 2 studies scored 1 on the Jadad scale; one of these had uncertain

concealment of treatment allocation and the other clearly inadequate concealment of treatment allocation.

Induction of mild hypothermia was associated with a significant reduction in in-hospital mortality compared with normothermia (RR 0.75, 95% CI: 0.62, 0.92; based on 3 studies); there was no

evidence of heterogeneity (I-squared 0%; p=0.56). Seven patients (95% CI: 4, 25) needed to be induced with mild hypothermia to prevent one in-hospital death.

Induction of mild hypothermia was associated with a significantly reduced risk of poor neurological outcome compared with normothermia (RR 0.74, 95% CI: 0.62, 0.84; based on 4 studies);

moderate heterogeneity was found (I-squared 51%; p=0.11). Five patients (95% CI: 4, 10) needed to be induced with mild hypothermia to prevent one poor neurological outcome.

The results were similar when restricted to the 2 studies that scored 3 on the Jadad scale.

Treatment-limiting adverse events were not consistently reported. Three studies assessed bleeding and fatal or long-lasting arrhythmias, and two assessed sepsis and haemodynamic instability. There were no statistically significant differences in adverse events between mild hypothermia and normothermia.

The funnel plot was asymmetrical, suggesting the absence of small negative studies and the possibility of publication bias.

Authors' conclusions

The induction of mild hypothermia reduced in-hospital mortality and improved neurological outcomes in comatose survivors of cardiac arrest, but more information about adverse events is required.

CRD commentary

The review addressed a clear question that was defined in terms of the participants, intervention, outcomes and study design. Several relevant sources were searched and attempts were made to

minimise publication and language bias. The potential for publication bias was assessed but was of limited value given the small number of studies. Methods were used to minimise reviewer error and bias in the validity assessment, but not all parts of the study selection and data extraction processes were performed in duplicate; this might have led to reviewer error and bias. Validity was assessed using established criteria.

Statistical heterogeneity was assessed and the studies appear to have been appropriately pooled. Sensitivity analyses were undertaken to examine the robustness of the results. Overall,

this was a well-conducted review and the authors' conclusions are likely to be reliable.

Implications of the review for practice and research

Practice: The authors did not state any implications for practice.

Research: The authors stated that further research is needed to identify patient groups that will benefit from mild hypothermia and to measure treatment-limiting adverse events such as sepsis and haemorrhage.

Bibliographic details

Cheung K W, Green R S, Magee K D. Systematic review of randomized controlled trials of therapeutic hypothermia as a neuroprotectant in post cardiac arrest patients. Canadian Journal of Emergency Medicine 2006; 8(5): 329-337. [PubMed: 17338844]

PubMedID

17338844

Indexing Status

Subject indexing assigned by NLM

MeSH

Adult; Brain Injuries /prevention & control; Chi-Square Distribution; Heart Arrest /complications /mortality; Humans; Hypothermia, Induced; Randomized Controlled Trials as Topic

AccessionNumber

12006009032

Date bibliographic record published

10/09/2007

Date abstract record published

09/08/2008

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.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

PMID: 17338844

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