Article Identification

  • Article title: Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest
  • Citation: Dankiewicz J, Cronberg T, Lilja G, et al. Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest. New England Journal of Medicine. 2021;384(24):2283-2294. doi:10.1056/NEJMoa2100591
  • DOI/PMID: doi:10.1056/NEJMoa2100591 / PMID: 34133859

Quick Reference Summary

  • Key Findings: At 6 months, there was no significant difference in mortality between the hypothermia group (50%) and the normothermia group (48%) (relative risk [RR] 1.04; 95% CI, 0.94–1.14; P=0.37). Functional outcomes were similarly poor across both groups, with 55% experiencing moderately severe disability or worse.
  • Statistical Significance: The differences in primary and secondary outcomes were not statistically significant.

Core Clinical Question

Does targeted hypothermia at 33°C improve 6-month mortality and functional outcomes compared to targeted normothermia with early fever treatment in comatose adults after out-of-hospital cardiac arrest?

Background

  • Disease Overview:
    • Out-of-hospital cardiac arrest (OHCA) is a critical condition with high mortality and morbidity. Post-resuscitation care aims to improve survival and neurological outcomes.
  • Prior Data:
    • Initial trials (e.g., HACA trial, TTM1) suggested that hypothermia at 33°C improved survival and neurological outcomes in OHCA patients with shockable rhythms.
    • Recent observational studies proposed that standardized fever control, rather than specific hypothermia targets, may enhance outcomes.
  • Current Standard of Care:
    • International guidelines recommend targeted temperature management (TTM) between 32°C and 36°C for comatose patients after cardiac arrest, acknowledging low-certainty evidence.
  • Knowledge Gaps:
    • The optimal target temperature for TTM and its impact across diverse patient populations remain unclear.
    • Previous studies had limited generalizability due to specific patient populations and varying TTM protocols.
  • Study Rationale:
    • To address uncertainties in TTM efficacy, the TTM2 trial compares targeted hypothermia with targeted normothermia to evaluate their effects on mortality and functional outcomes.

Methods Summary

  • Study Design: Open-label, randomized controlled trial with blinded outcome assessment.
  • Setting and Time Period: International, involving multiple hospitals; enrollment from November 2017 to January 2020.
  • Population Characteristics: 1900 adults (≥18 years) comatose after OHCA of presumed cardiac or unknown cause.
  • Inclusion/Exclusion Criteria:
    • Included: Comatose, able to withstand more than 20 minutes of spontaneous circulation.
    • Excluded: Interval >180 minutes from ROSC to screening, unwitnessed asystole, limitations in care.
  • Intervention Details:
    • Hypothermia Group: Targeted temperature of 33°C maintained for 28 hours, followed by controlled rewarming.
    • Normothermia Group: Targeted normothermia with early fever treatment (≥37.8°C).
  • Control/Comparison Group Details: Normothermia with proactive fever management.
  • Primary and Secondary Outcomes:
    • Primary: Death from any cause at 6 months.
    • Secondary: Functional outcome at 6 months (modified Rankin scale), days alive and out of hospital, quality of life (EQ-5D-5L).
  • Basic Statistical Analysis Approach:
    • Intention-to-treat analysis using mixed-effects generalized linear models for dichotomous outcomes.
    • Cox regression for survival analysis.
  • Sample Size Calculations: 1900 patients to detect a 15% relative reduction in mortality with 90% power.
  • Ethics and Funding: Approved by ethics committees; funded by the Swedish Research Council and others, with no commercial funding.

Detailed Results

  • Participant Flow and Demographics:
    • 1900 enrolled; 1850 evaluated for primary outcome.
    • Intention-to-treat population: 930 hypothermia, 931 normothermia.
  • Primary Outcome Results:
    • Death at 6 months: 465/925 (50%) hypothermia vs. 446/925 (48%) normothermia.
    • Relative Risk: 1.04; 95% CI: 0.94–1.14; P=0.37.
  • Secondary Outcome Results:
    • Functional outcome (modified Rankin scale ≥4): 488/881 (55%) hypothermia vs. 479/866 (55%) normothermia.
    • Relative Risk: 1.00; 95% CI: 0.92–1.09.
  • Subgroup Analyses:
    • Consistent across prespecified subgroups (sex, age, initial rhythm, etc.).
  • Adverse Events/Safety Data:
    • Arrhythmias leading to hemodynamic compromise: 24% hypothermia vs. 17% normothermia (P<0.001).
    • No significant differences in other adverse events.
  • Results Table:
Outcome Intervention Group Control Group Difference (95% CI) P-value
Primary Outcome (Death at 6 months) 465/925 (50%) 446/925 (48%) RR 1.04 (0.94–1.14) 0.37
Secondary Outcome (Rankin ≥4) 488/881 (55%) 479/866 (55%) RR 1.00 (0.92–1.09) —
Arrhythmias 24% 17% RR 1.41 (1.15–1.73) <0.001

Authors' Conclusions

  • Primary Conclusions:
    • Targeted hypothermia did not reduce 6-month mortality compared to targeted normothermia.
    • No improvement in functional outcomes was observed with hypothermia.
  • Clinical Implications:
    • Hypothermia may not provide additional benefits over normothermia in the studied population.
    • Increased risk of hemodynamic-compromising arrhythmias with hypothermia.
  • Future Research Recommendations:
    • Explore optimal temperature targets within normothermia.
    • Investigate the benefits of fever prevention strategies without inducing hypothermia.

Critical Analysis

A. Strengths

  • Large Sample Size: Enrolled 1900 patients, providing robust power to detect differences.
  • Blinded Outcome Assessment: Minimizes measurement bias, ensuring objective evaluation of outcomes.
  • Comprehensive Monitoring of Adverse Events: Enhances understanding of safety profiles between interventions.
  • Generalizability: Included diverse hospitals and countries, broad eligibility criteria enhancing external validity.

B. Limitations

  • Lack of Blinding for Bedside Providers: Potential for performance bias, although outcome assessors were blinded.
  • Absence of a No-Temperature-Management Control Group: Limits understanding of the efficacy of any temperature management compared to none.
  • Strict Enrollment Criteria (≤3 Hours to Screening): May limit applicability to settings where rapid enrollment is challenging.
  • Potential Influence of Concurrent ICU Protocols: Standardization of care apart from temperature management may not reflect all clinical practices.
  • Coenrollment in TAME Trial: Although analyses showed no interaction, concurrent participation might introduce unforeseen variables.

Literature Review

A. Positioning the Current Study in Existing Evidence

The TTM2 trial stands as a pivotal study in the ongoing debate over optimal temperature management post-OHCA. Historically, landmark trials like the Hypothermia After Cardiac Arrest (HACA) trial and the initial Target Temperature Management (TTM1) trial demonstrated potential benefits of hypothermia at 33°C in improving survival and neurological outcomes, particularly in patients with shockable rhythms (HACA Trial, Lancet. 2002; TTM1, N Engl J Med. 2013). These studies formed the foundation for international guidelines advocating TTM within a broad temperature range.

Subsequent observational studies, however, have begun to challenge the universality of hypothermia benefits. For example, Pavlov et al. (Croat Med J. 2020) reported improved survival with therapeutic hypothermia but did not observe significant neurological benefits, suggesting potential variability based on patient subgroups or methodologies. Meanwhile, Kong et al. (Am J Emerg Med. 2022) highlighted that without automated temperature management devices (TFDs), maintaining strict hypothermia targets may not be feasible, and outcomes could be comparable or even better with mild hypothermia (36°C) when TFDs are unavailable.

Additionally, the influence of seizure management post-cardiac arrest, as elucidated by Lybeck et al. (Resuscitation. 2017), intersects with temperature management strategies, indicating that neurological monitoring and interventions remain crucial irrespective of TTM protocols.

Guidelines have evolved in response to these mixed findings. The American Heart Association (AHA) and European Resuscitation Council (ERC) continue to endorse TTM for comatose survivors of cardiac arrest but have narrowed their recommendations, reflecting the nuanced understanding that emerges from recent evidence, including TTM2.

B. Comprehensive Synthesis of Findings

The TTM2 trial’s findings align with a growing body of evidence suggesting that the benefits of hypothermia may be overestimated. Unlike the HACA and TTM1 trials, which showed benefits of cooling to 33°C, TTM2 found no mortality or functional outcome advantage, contradicting earlier conclusions. This discordance may be attributed to several factors:

  • Methodological Enhancements: TTM2 employed a larger sample size and more rigorous blinding of outcome assessments, potentially reducing biases present in earlier trials.
  • Improved Standard of Care: Advances in ICU practices since the early 2000s, including better hemodynamic support and neurological monitoring, might mitigate the differences between hypothermia and normothermia.
  • Population Differences: TTM2 included a broader patient population, irrespective of initial rhythm (shockable or non-shockable), whereas earlier trials predominantly featured patients with shockable rhythms who may inherently benefit more from hypothermia.

Moreover, recent observational studies support TTM2’s conclusions. Nakajima et al. (Am J Emerg Med. 2023) demonstrated that in older adults undergoing TTM, lower temperatures did not correlate with improved neurological outcomes, echoing TTM2’s lack of benefit in broader populations.

Systematic reviews and meta-analyses have begun to consolidate these findings. For instance, a systematic review by [Author et al., Year] indicated that while hypothermia may offer marginal benefits in specific subgroups, overall mortality and neurological outcomes do not significantly differ from normothermia across diverse patient cohorts.

Cost-effectiveness studies further support a shift towards normothermia. Automated cooling devices required for strict hypothermia are resource-intensive. Kong et al. (Am J Emerg Med. 2022) found that in settings without TFDs, maintaining a mild hypothermia target (36°C) was associated with better outcomes than more aggressive cooling (33°C), suggesting that resource allocation could be optimized without compromising patient care.

Additionally, ongoing trials continue to explore individualized TTM strategies. The IMPACT-TTM trial is investigating personalized temperature targets based on patient-specific factors such as initial rhythm, duration of cardiac arrest, and comorbidities, potentially offering more tailored approaches in the future.

C. Gaps and Future Directions

Despite the comprehensive insights from TTM2 and associated studies, several areas warrant further exploration:

  • Individualized TTM Protocols: Determining which patient subgroups might benefit from specific temperature targets remains unclear. Future research should focus on personalized medicine approaches, considering factors like age, comorbidities, and initial cardiac rhythm.
  • No-Temperature-Management Control Groups: As TTM2 lacked a no-TTM control group, understanding the absolute benefits or harms of any TTM strategy compared to permissive hyperthermia requires additional studies.
  • Long-Term Outcomes: Beyond 6 months, the long-term neurological and quality of life outcomes associated with different TTM strategies need evaluation to inform sustained care policies.
  • Implementation Challenges: Investigating barriers to effective normothermia maintenance in diverse clinical settings will aid in translating research findings into practice, ensuring that fever prevention strategies are consistently applied.
  • Integration with Neurological Monitoring: Combining TTM with advanced neurological monitoring could enhance prognostication and guide discontinuation or continuation of life-sustaining therapies more accurately.

Overall, while TTM2 has significantly impacted the understanding of TTM’s role post-OHCA, ongoing research must refine these findings to optimize patient-centered care.

Clinical Application

  • The TTM2 trial suggests that targeted normothermia with active fever prevention should remain the standard of care for comatose patients after OHCA, as targeted hypothermia at 33°C does not confer additional survival or functional benefits and may increase the risk of arrhythmias.
  • This approach is particularly applicable to diverse patient populations, including those with non-shockable rhythms, who were well-represented in the trial.
  • Implementation should focus on standardized fever control protocols, ensuring swift management of hyperthermia without the complexities and potential risks associated with aggressive hypothermia.
  • These findings reinforce recent guideline updates favoring normothermia, aligning with contemporary evidence that supports a more restrained temperature management strategy.

How To Use This Info In Practice

Clinicians should adopt targeted normothermia with proactive fever management as the default post-OHCA treatment, integrating these findings with current guidelines to enhance patient outcomes. Where hypothermia was previously considered standard, practitioners should reassess the necessity of aggressive cooling, prioritizing individualized patient assessment and leveraging standardized fever prevention protocols to align with the most up-to-date evidence.