Target temperature management following cardiac arrest: a systematic review and Bayesian meta-analysis

Background Temperature control with target temperature management (TTM) after cardiac arrest has been endorsed by expert societies and adopted in international clinical practice guidelines but recent evidence challenges the use of hypothermic TTM. Methods Systematic review and Bayesian meta-analysis of clinical trials on adult survivors from cardiac arrest undergoing TTM for at least 12 h comparing TTM versus no TTM or with a separation > 2 °C between intervention and control groups using the PubMed/MEDLINE, EMBASE, CENTRAL databases from inception to 1 September 2021 (PROSPERO CRD42021248140). All randomised and quasi-randomised controlled trials were considered. The risk ratio and 95% confidence interval for death (primary outcome) and unfavourable neurological recovery (secondary outcome) were captured using the original study definitions censored up to 180 days after cardiac arrest. Bias was assessed using the updated Cochrane risk-of-bias for randomised trials tool and certainty of evidence assessed using the Grading of Recommendation Assessment, Development and Evaluation methodology. A hierarchical robust Bayesian model-averaged meta-analysis was performed using both minimally informative and data-driven priors and reported by mean risk ratio (RR) and its 95% credible interval (95% CrI). Results In seven studies (three low bias, three intermediate bias, one high bias, very low to low certainty) recruiting 3792 patients the RR by TTM 32–34 °C was 0.95 [95% CrI 0.78—1.09] for death and RR 0.93 [95% CrI 0.84—1.02] for unfavourable neurological outcome. The posterior probability for no benefit (RR ≥ 1) by TTM 32–34 °C was 24% for death and 12% for unfavourable neurological outcome. The posterior probabilities for favourable treatment effects of TTM 32–34 °C were the highest for an absolute risk reduction of 2–4% for death (28–53% chance) and unfavourable neurological outcome (63–78% chance). Excluding four studies without active avoidance of fever in the control arm reduced the probability to achieve an absolute risk reduction > 2% for death or unfavourable neurological outcome to ≤ 50%. Conclusions The posterior probability distributions did not support the use of TTM at 32–34 °C compared to 36 °C also including active control of fever to reduce the risk of death and unfavourable neurological outcome at 90–180 days. Any likely benefit of hypothermic TTM is smaller than targeted in RCTs to date. Supplementary Information The online version contains supplementary material available at 10.1186/s13054-022-03935-z.


Item # Checklist item
Location where item is reported Describe any assumptions made about any missing or unclear information.
Study risk of bias assessment 11 Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process.
Lines 124-127 Effect measures 12 Specify for each outcome the effect measure(s) (e.g. risk ratio, mean difference) used in the synthesis or presentation of results. Lines 132-133 Synthesis methods 13a Describe the processes used to decide which studies were eligible for each synthesis (e.g. tabulating the study intervention characteristics and comparing against the planned groups for each synthesis (item #5)).
As per #5 and #11 13b Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions.
Lines 132-133 13c Describe any methods used to tabulate or visually display results of individual studies and syntheses. Table 1 13d Describe any methods used to synthesize results and provide a rationale for the choice(s). If meta-analysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used.
Lines 133-179, Additional File, Table 4 13e Describe any methods used to explore possible causes of heterogeneity among study results (e.g. subgroup analysis, metaregression).
Lines 140-143, 155-156, Additional File, Table 4 13f Describe any sensitivity analyses conducted to assess robustness of the synthesized results. Lines 174-178, Additional File, Table 6 Reporting bias assessment 14 Describe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases).

As per RoB2
Certainty assessment 15 Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome. Lines 157-159 RESULTS Study selection 16a Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram. Figure 1 16b Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded. Figure 1 Study characteristics 17 Cite each included study and present its characteristics. Table 1 Risk of bias in studies 18 Present assessments of risk of bias for each included study. Figure 2 Section and Topic

Item # Checklist item
Location where item is reported Results of individual studies 19 For all outcomes, present, for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimate and its precision (e.g. confidence/credible interval), ideally using structured tables or plots. Results of syntheses 20a For each synthesis, briefly summarise the characteristics and risk of bias among contributing studies.  20b Present results of all statistical syntheses conducted. If meta-analysis was done, present for each the summary estimate and its precision (e.g. confidence/credible interval) and measures of statistical heterogeneity. If comparing groups, describe the direction of the effect. 20d Present results of all sensitivity analyses conducted to assess the robustness of the synthesized results. Figure 3, Additional File, Figures 9 and 10, Table 6 Reporting biases 21 Present assessments of risk of bias due to missing results (arising from reporting biases) for each synthesis assessed. Figure 2 Certainty of evidence 22 Present assessments of certainty (or confidence) in the body of evidence for each outcome assessed. Additional File,

Figure 2. Sensitivity analysis: survival and shockable rhythm
Observed and estimated effects sizes on survival 90-180 days in patients with initial shockable (left graph) and non-shockable (right graph) rhythms. The observed effect sizes are displayed in black with the estimated effect size, i.e. the random effect estimate, displayed in grey. The overall effect size, risk ratio (RR), is represented by the mean and its 95% credible interval (95%CrI).

Figure 3. Sensitivity analysis: neurological outcome and shockable rhythm
Observed and estimated effects sizes on favourable neurological outcome 90-180 days in patients with initial shockable (left graph) and non-shockable (right graph) rhythms. The observed effect sizes are displayed in black with the estimated effect size, i.e. the random effect estimate, displayed in grey. The overall effect size, risk ratio (RR), is represented by the mean and its 95% credible interval (95%CrI).