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

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.

Targeted temperature management after cardiac arrest. A systematic review and meta-analysis of animal studies

“…We are aware of one other systematic review and meta-analysis on this topic, which partly overlaps with our aim of the study. Olai and colleagues 18 applied more broad eligibility criteria including models of global and local brain ischaemia without cardiac arrest, target temperatures below 32 C, induced pre-arrest, intra-arrest as well as post-arrest, TTM by cardiopulmonary bypass systems, and brain histology as outcome parameter. While this may be a comprehensive approach, comparability to the clinical cardiac arrest studies may be difficult.…”

“…Numerous animal studies on the efficacy of cooling exist, and previous reviews have either summarised articles concerning intra-arrest hypothermia, 17 or assessed the pooled efficacy of pre-arrest, intra-arrest, and post-arrest hypothermia and hypothermia in various brain ischaemia models. 18 However, no systematic review has either analysed the pooled effects of TTM in a clinically relevant cardiac arrest model with post-arrest induction of mild hypothermia, or has examined multiple effect modifiers in a metaregression analysis.…”

Which Target Temperature for Post-Anoxic Brain Injury? A Systematic Review from “Real Life” Studies

“…The only therapeutic intervention that has shown some benefits to mitigate the sequelae of HIBI is the use of targeted temperature management (TTM); at this moment, three randomized clinical trials (RCTs) have demonstrated a significant improvement in the proportion of patients with favorable neurological outcome when cooling at 33 °C for 24 h was compared to no temperature control or normothermia [ 5 , 6 , 7 ]. Nevertheless, although TTM remains still recommended into international guidelines [ 8 ], the level of evidence supporting its use remains low (because of several methodological bias present into initial trials [ 5 , 6 ]), many concerns on clinically relevant effectiveness have been raised also for experimental studies [ 9 ] and a large trial has been recently completed (NCT03114033) and will eventually provide a definitive answer on the role of TTM in this setting.…”

Targeted Temperature Management Suppresses Hypoxia-Inducible Factor-1α and Vascular Endothelial Growth Factor Expression in a Pig Model of Cardiac Arrest

“…Therapeutic hypothermia or hypothermic targeted temperature management (HTTM, 32–36 °C) has emerged as a proven strategy to minimize secondary brain damage in survivors of CA and has become the recommended treatment by the American Heart Association [ 4 ]. Hypothermia protects against CA- and resuscitation-induced brain injury and improves neurological outcome in CA patients and animals [ 5 , 6 ]; these effects are multifactorial and may involve in the inhibition of inflammatory reactions, decrease in oxidative stress, attenuation of blood–brain barrier disruption, and inhibition of early brain edema [ 7 – 9 ]. However, the precise mechanism of this protection is largely unknown.…”