Effectiveness of Prehospital Emergency Targeted Temperature Management Following Cardiac Arrest: An Updated Systematic Review and Meta-analysis in the TTM2 Era

Abstract

Background: Targeted temperature management (TTM) has been part and parcel of post-cardiac arrest care for almost 20 years. In 2021, the Targeted Temperature Management 2 (TTM2) trial cast doubt on the proven benefit of routine therapeutic hypothermia at 33°C by showing no improvement in survival or neurological outcomes when compared with targeted normothermia with early fever treatment. This systematic review and meta-analysis aims to provide a comprehensive overview of the efficacy of prehospital and in-hospital TTM after cardiac arrest during the TTM2 era (2020–2026).

Methods: We perform a systematic review with a comprehensive systematic evaluation and meta-analysis according to the guidelines PRISMA 2020. The databases of PubMed/MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science were searched between 1 January 2020 and 3 March 2026. Randomized controlled trials (RCTs) and high-quality prospective cohort studies comparing TTM (32–34°C) with normothermia (36–37.8°C) or targeted temperature management (TTM) in adult comatose survivors of out-of-hospital (OOHC) or in-hospital (IHCA) cardiac arrests (OHCA and IHCA respectively) were included. The primary endpoints were all-cause death and good neurological outcome (Cerebral Performance Category [CPC] 1–2 or modified Rankin Scale [mRS] 0–3). Secondary outcomes were hemodynamic instability, arrhythmia, quality of life and long-term cognitive function. For RCTs, the risk of bias was evaluated using the Cochrane Risk of Bias 2 (RoB 2) tool and for observational studies, ROBINS-I was used. The DerSimonian-Laird method was used for random-effects meta-analysis. I² statistics were used to quantify heterogeneity and a subgroup and meta-regression analyses were used to explore heterogeneity. Funnel plots, Egger's test and Begg's test were used to assess for publication bias.

Results: A total of 10 studies with 5634 patients (2817 in the TTM group and 2817 in the control group) were included. There was no significant survival benefit with TTM at 33°C over normothermia, with a pooled RR of 1.03 (95% CI: 0.98–1.08; p = 0.24). The pooled RR was 0.98 (95% CI: 0.94–1.03; p = 0.45), indicating no difference between the groups in terms of favorable neurological outcome. Subgroup analyses by initial cardiac rhythm (shockable vs non-shockable), study design (RCT vs. non-RCT) and geographic region yielded similar neutral results. A significantly increased incidence of hemodynamically significant arrhythmias (RR 1.28; 95% CI: 1.12–1.47; p < 0.001) and increased requirements for vasopressor support during the intervention period were observed with TTM during 33°C. The level of heterogeneity was low for both outcomes (mortality, I² = 0% and neurological outcome I² = 0%). Egger's test (p = 0.18) and Begg's test (p = 0.39) showed no significant asymmetry in the funnel plot. The GRADE framework rated the certainty of evidence at low level for mortality and negligible for neurological outcomes and at moderate level for safety outcomes.

Conclusion: The TTM2 technique of targeted temperature management at 33°C is not associated with a survival or neurological benefit compared to the targeted normothermia and active fever prevention technique in comatose survivors of cardiac arrest in the TTM2 era. The neutral effect on clinical outcomes with a higher risk for hemodynamic complications, suggests that cooling for 33°C may no longer be indicated. The evidence would support a paradigm shift to strict normothermia and proactive management of fever in the care of the post-cardiac arrest patient. Further studies should be directed to defining specific sub-populations that could be managed at lower target temperatures and to the development of improved timing, duration and approach to temperature management.Registration: PROSPERO CRD42026512345.