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Abstract
BackgroundTargeted 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.MethodsWe 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.ResultsThe 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.ConclusionsTTM 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.
Highlights
Animal research has shown that body temperature may have an effect on the extent of brain damage following global ischemia [1,2,3,4,5]
temperature management (TTM) is beneficial under most experimental conditions in animal models of cardiac arrest or global brain ischemia
Future animal research should focus on mimicking the clinical scenario and employ similar rigour in trial design to that of modern clinical trials
Summary
Animal research has shown that body temperature may have an effect on the extent of brain damage following global ischemia [1,2,3,4,5]. In 2002, two randomized clinical trials (RCT) testing the effects of hypothermia in patients with out-of-hospital cardiac arrest (OHCA) with ventricular fibrillation were published [11, 12] They showed improved neurological function [11, 12] and increased survival [11] in patients cooled to 32 to 34 °C for 12 to 24 h compared to patients with no temperature control. A recently published RCT, in patients with OHCA and in-hospital cardiac arrest with nonshockable rhythms, compared a controlled temperature of 33 °C to a controlled temperature of 37 °C and found that survival with good neurological outcome was higher with the lower temperature of 33 °C, while overall mortality was similar between the groups [27]. In this meta-analysis, we investigate the evidence for TTM in animal models of cardiac arrest
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