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

Abstract

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.

Hypothermia vs Normothermia in Patients With Cardiac Arrest and Nonshockable Rhythm

“…In this individual patient data meta-analysis of the TTM2 and HYPERION trials, hypothermia at 33 °C was not associated with improved survival or functional outcomes at 3 to 6 months for adult OHCA patients with an initial nonshockable rhythm when compared with targeted normothermia. Our study, along with recent systematic reviews that used traditional and bayesian meta-analyses, [17][18][19] suggests that the current type of temperature control used to induce and maintain hypothermia (ie, target of 33 °C; duration of the intervention of 24 to 40 hours; associated sedation), which has been used over the past 2 decades, does not provide the intended benefit, as shown in landmark trials. 2,3 Of note, the TTM2 and HYPERION studies are not comparable with previous trials, 2,3 as study cohorts were larger, more heterogenous (ie, different initial rhythms or different causes of arrest), and with a more rigorous methodological structure (ie, lower risk of bias).…”

“…These differences prevented drawing more definitive conclusions regarding the association of hypothermia with measured outcomes in other subgroups of patients. [17][18][19] Our analysis had enhanced statistical power (ie, combination of raw data resulting in larger sample sizes and increased statistical power), improved data quality (ie, verification and standardization of data across studies), the possibility to assess time-to-event outcomes (ie, time to death), flexibility in modeling (ie, adjust for potential confounders at the individual patient level), and detailed subgroup analyses for a better understanding of treatment effect heterogeneity. As such, this individual patient meta-analysis provides the best available evidence regarding the use of hypothermia in the management of OHCA patients with an initial nonshockable rhythm.…”

Temperature Control After Cardiac Arrest: A Narrative Review

“…While guidelines recommend a target temperature of 32–37.5 °C for at least 24 h after ROSC, there is no set temperature that has been proven to show more benefit over another, and the selection tends to be patient-dependent. A recent Bayesian meta-analysis determined that temperature control at 32–34 °C as compared to temperatures over 36 °C did not lead to more positive neurological outcomes [ 68 ]. Furthermore, a network meta-analysis indicated that hypothermia at 31–36 °C compared to normothermia at 37–37.8 °C did not lead to increased survival rates or better outcomes, and was associated with a greater risk of developing arrhythmias [ 14 ].…”

Optimal oxygen and mean arterial blood pressure targets after cardiac arrest

“…Given outcome rate from ICU care of OHCA patients is generally in line in the range of 50–60%, this would translate into an absolute difference of 12–18% (equalling a number needed to treat of between 5 and 9). This may be an unrealistic effect size compared to other post-cardiac arrest interventions, such as targeted temperature management [ 11 ]. Observational data do suggest that the optimal MAP target in a patient with impaired cerebral autoregulation could be as high as 85–90 mmHg [ 12 ].…”