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. 2020 Jan 17;8(1):3.
doi: 10.1186/s40635-019-0291-9.

Meta-analysis of targeted temperature management in animal models of cardiac arrest

Hilmer Olai  1 , Gustav Thornéus  1 , Hannah Watson  2   3 , Malcolm Macleod  4 , Jonathan Rhodes  5 , Hans Friberg  6 , Niklas Nielsen  7 , Tobias Cronberg  8 , Tomas Deierborg  9
Affiliations

Meta-analysis of targeted temperature management in animal models of cardiac arrest

Hilmer Olai et al. Intensive Care Med Exp. .

Abstract

Background: Targeted temperature management (TTM) of 32 to 34 °C has been the standard treatment for out-of-hospital cardiac arrest since clinical trials in 2002 indicated benefit on survival and neurological outcome. In 2013, a clinical trial showed no difference in outcome between TTM of 33 °C and TTM of 36 °C. In this meta-analysis, we investigate the evidence for TTM in animal models of cardiac arrest.

Methods: We searched PubMed and EMBASE for adult animal studies using TTM as a treatment in different models of cardiac arrest or global brain ischemia which reported neurobehavioural outcome, brain histology or mortality. We used a random effects model to calculate estimates of efficacy and assessed risk of bias using an adapted eight-item version of the Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CAMARADES) quality checklist. We also used a scoring system based on the recommendations of the Stroke Treatment Academic Industry Roundtable (STAIR), to assess the scope of testing in the field. Included studies which investigated a post-ischemic induction of TTM had their treatment regimens characterized with regard to depth, duration and time to treatment and scored against the modified STAIR criteria.

Results: The initial and updated search generated 17809 studies after duplicate removal. One hundred eighty-one studies met the inclusion criteria, including data from 1,787, 6,495 and 2,945 animals for neurobehavioural, histological and mortality outcomes, respectively. TTM was favoured compared to control for all outcomes. TTM was beneficial using short and prolonged cooling, deep and moderate temperature reduction, and early and delayed time to treatment. Median [IQR] study quality was 4 [3 to 6]. Eighteen studies checked seven or more of the eight CAMARADES quality items. There was no clear correlation between study quality and efficacy for any outcome. STAIR analysis identified 102 studies investigating post-ischemic induction of TTM, comprising 147 different treatment regimens of TTM. Only 2 and 8 out of 147 regimens investigated comorbid and gyrencephalic animals, respectively.

Conclusions: TTM is beneficial under most experimental conditions in animal models of cardiac arrest or global brain ischemia. However, research on gyrencephalic species and especially comorbid animals is uncommon and a possible translational gap. Also, low study quality suggests risk of bias within studies. Future animal research should focus on mimicking the clinical scenario and employ similar rigour in trial design to that of modern clinical trials.

Keywords: Animals; Cardiac arrest; Global ischemia; Hypothermia; Meta-analysis; Targeted temperature management.

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Conflict of interest statement

JR has received fees for lectures and consultancy work from Bard Medical. HF is a medical advisor of QuickCool and has received lecture fees from Bard Medical.

Figures

Fig. 1
Fig. 1
PRISMA flow diagram
Fig. 2
Fig. 2
Funnel plot and Trim and Fill analysis of neurobehavioural outcome. Open circles are missing studies according to Trim and Fill-analysis. Estimate of efficacy with missing studies included: 0.76 SMD [95% CI 0.59 to 0.93]. Efficacy without missing studies: 0.93 SMD [95% CI 0.79 to 1.08]. Standardized mean difference = SMD. Standard error = SE. Confidence interval = CI
Fig. 3
Fig. 3
Number of study quality checklist items scored and point estimates of SMD with 95% confidence intervals (CI) for neurobehavioural outcome. Low numerical checklist score on x axis indicates higher risk of bias. Shaded area is the 95% CI of the global estimate. Thickness of bar reflects number of contributing comparisons. Score ranging from a minimum of 0 to a maximum of 8. SMD = standardized mean difference
Fig. 4
Fig. 4
Forest plot for neurobehavioural outcome (SMD) and 95% confidence intervals (CI) for select subgroups. Shaded area is the 95% CI of the global estimate. Percentage in parentheses is meta-analytic weight. “Unknown” categories are omitted. Right column brackets are 95% CI’s. *p < 0.0031, #p < 0.01 and n.s (not significant) denote between-group differences for the groups covered by the vertical line. Corresponding forest plots for histological and mortality outcomes are in supplement. SMD = standardized mean difference
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