Article Identification

  • Article Title: Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest
  • Citation: Nielsen NJ, Wetterslev J, Cronberg T, et al. N Engl J Med. 2013;369(23):2197-2206.
  • DOI/PMID: DOI: 10.1056/NEJMoa1310519 | PMID: 24237006

Quick Reference Summary

  • The TTM trial randomized 939 unconscious adults post-OHCA to targeted temperature management at either 33°C or 36°C.
  • No significant difference was observed in all-cause mortality (50% vs. 48%, HR 1.06, P=0.51) or poor neurologic outcomes at 180 days between the two temperature targets.

Core Clinical Question

Does targeted temperature management at 33°C versus 36°C improve all-cause mortality and neurologic outcomes in unconscious adults after out-of-hospital cardiac arrest of presumed cardiac cause?

Background

  • Disease Overview:
    • Out-of-hospital cardiac arrest (OHCA) survivors often face high mortality rates and significant neurologic deficits.
  • Prior Data:
    • Bernard et al. (2002) and The Hypothermia after Cardiac Arrest Study Group (2002) demonstrated improved neurologic outcomes and survival with therapeutic hypothermia (32°C to 34°C) in OHCA patients with shockable rhythms.
    • Holzer et al. (2002) supported mild therapeutic hypothermia's neuroprotective effects post-OHCA.
  • Current Standard of Care:
    • International guidelines recommend therapeutic hypothermia or targeted temperature management (TTM) to prevent fever in comatose OHCA survivors.
  • Knowledge Gaps Addressed by the Study:
    • Optimal target temperature within the hypothermic range (33°C vs. 36°C) is unclear.
    • Limited evidence on the benefits of deeper hypothermia over controlled normothermia.
  • Study Rationale:
    • To determine whether a lower target temperature (33°C) offers additional benefits over a slightly higher target (36°C) in improving survival and neurologic outcomes.

Methods Summary

  • Study design: International, multicenter, randomized clinical trial.
  • Setting and time period: 36 ICUs across Europe and Australia from November 2010 to January 2013.
  • Population characteristics: 939 unconscious adults post-OHCA of presumed cardiac cause.
  • Inclusion/exclusion criteria: Adults ≥18 years, unconscious on admission, more than 20 minutes of spontaneous circulation post-resuscitation. Exclusions included prolonged downtime (>240 minutes), unwitnessed arrest with asystole, acute intracranial hemorrhage, and hypothermia (<30°C).
  • Intervention details: Randomized to TTM at 33°C or 36°C for 36 hours, followed by gradual rewarming.
  • Control/comparison group details: Active temperature management at the assigned target temperature aimed at preventing fever.
  • Primary and secondary outcomes:
    • Primary: All-cause mortality through trial end.
    • Secondary: Composite of poor neurologic function or death at 180 days (CPC and modified Rankin scale).
  • Basic statistical analysis approach: Modified intention-to-treat, Kaplan–Meier survival curves, Cox regression adjusted for prognostic factors.
  • Sample size calculations: 950 patients to detect a 20% reduction in hazard ratio with 90% power.
  • Ethics and funding information: Approved by ethics committees per Declaration of Helsinki. Funded by the Swedish Heart–Lung Foundation and others. Conflicts of interest declared.

Detailed Results

  • Participant flow and demographics:
    • Enrolled: 950; Analyzed: 939 (473 at 33°C, 466 at 36°C).
    • Baseline characteristics were similar across groups.
  • Primary outcome results:
    • All-cause mortality: 50% (33°C) vs. 48% (36°C) (HR 1.06; 95% CI, 0.89–1.28; P=0.51).
  • Secondary outcome results:
    • CPC 3-5 or death at 180 days: 54% (33°C) vs. 52% (36°C) (RR 1.02; 95% CI, 0.88–1.16; P=0.78).
    • Modified Rankin scale 4-6: 52% (33°C) vs. 52% (36°C) (RR 1.01; 95% CI, 0.89–1.14; P=0.87).
  • Subgroup analyses:
    • No significant differences across predefined subgroups.
  • Adverse events/safety data:
    • Serious adverse events: 93% (33°C) vs. 90% (36°C) (RR 1.03; 95% CI, 1.00–1.08; P=0.09).
    • Higher hypokalemia in 33°C group (19% vs. 13%, P<0.05).
Outcome Intervention Group (33°C) Control Group (36°C) Difference (95% CI) P-value
Primary Outcome: Deaths at end of trial 235/473 (50%) 225/466 (48%) HR 1.06 (0.89–1.28) 0.51
Secondary Outcomes
CPC of 3–5 251/469 (54%) 242/464 (52%) RR 1.02 (0.88–1.16) 0.78
Modified Rankin scale 4–6 245/469 (52%) 239/464 (52%) RR 1.01 (0.89–1.14) 0.87
Deaths at 180 days 226/473 (48%) 220/466 (47%) RR 1.01 (0.87–1.15) 0.92

Authors' Conclusions

  • The TTM trial demonstrated that targeting 33°C did not confer a survival or neurologic benefit over targeting 36°C in unconscious OHCA survivors of presumed cardiac cause.
  • Both temperature management strategies were similarly safe, though deeper hypothermia was associated with more hypokalemia.
  • Decisions regarding target temperature should consider the lack of additional benefit with lower temperatures and balance potential side effects.

Critical Analysis

A. Strengths

  • Methodological strengths:
    • Large, international multicenter randomized design enhances the robustness of findings.
    • Comprehensive follow-up period of 180 days ensures long-term outcome assessment.
    • Blinded outcome assessment minimizes bias in primary and secondary outcomes.
  • Internal validity:
    • High adherence to protocol with minimal loss to follow-up (939/950 included in analysis).
    • Adjustment for known prognostic factors in statistical analysis.
  • External validity:
    • Diverse patient population across multiple countries increases generalizability.
    • Inclusion of patients with both shockable and non-shockable rhythms reflects real-world scenarios.

B. Limitations

  • Study design limitations or biases:
    • Inability to blind clinical staff to temperature assignments could introduce performance bias, although outcome assessors remained blinded.
  • Generalizability issues:
    • Exclusion of patients with prolonged downtime and specific initial rhythms may limit applicability to all OHCA populations.
  • Statistical limitations:
    • Primary endpoint was all-cause mortality, which may not capture nuanced neurologic outcomes fully.
  • Missing data handling or loss to follow-up:
    • Minimal loss to follow-up strengthens results; however, lack of detailed data on sedation practices could influence outcomes.

Literature Review

Literature Review: Targeted Temperature Management After Cardiac Arrest

Introduction

The Targeted Temperature Management (TTM) trial by Nielsen et al. (2013) critically evaluated the efficacy of two different temperature targets, 33°C vs. 36°C, in unconscious adults after out-of-hospital cardiac arrest (OHCA). The study's findings, indicating no significant difference in all-cause mortality or neurologic outcomes between the two temperature targets, have profound implications for clinical practice. This literature review contextualizes the TTM trial within the broader spectrum of research, guidelines, and subsequent studies, elucidating its position in the evolving landscape of post-cardiac arrest care.

A. Positioning the Current Study in Existing Evidence

Key Previous Studies:

  • Bernard et al. (2002) and The Hypothermia after Cardiac Arrest Study Group (2002):
    • These seminal trials established the foundation for therapeutic hypothermia.
    • Demonstrated improved neurologic outcomes and reduced mortality in OHCA patients with shockable rhythms treated at 32°C to 34°C.
  • Holzer et al. (2002):
    • Reinforced the neuroprotective benefits of mild hypothermia in OHCA survivors.
    • Influenced initial guidelines advocating for lower temperature targets.
  • Dankiewicz et al. (2021) - TTM2 Trial:
    • Expanded upon Nielsen's findings by comparing 33°C vs. normothermia (actively preventing fever above 37.8°C).
    • Similar to TTM, TTM2 found no significant differences in mortality or neurologic outcomes, further challenging the superiority of deeper hypothermia.
  • Additional Studies:
    • Kim et al. (2022): In the KORHN-PRO registry, no significant difference in good neurological outcomes or survival at six months between 33°C and 36°C.
    • Johnson et al. (2020): A retrospective cohort study suggested higher odds of neurologically intact survival at discharge with 33°C, but lacked the robustness of randomized trials.
    • Bray et al. (2017): A before-and-after study indicated challenges in achieving target temperatures and a trend towards worsened outcomes post-temperature shift to 36°C.

Methodological Quality Comparison:

  • Nielsen et al. (2013): High-quality randomized controlled trial (RCT) with robust sample size and multicenter design.
  • TTM2 (Dankiewicz et al., 2021): Larger RCT, reinforcing Nielsen's findings.
  • Retrospective Studies (e.g., Johnson et al., 2020): Provide valuable real-world insights but are subject to confounding factors.

Guidelines and Consensus Statements:

  • ERC-ESICM Guidelines (Sandroni et al., 2022):
    • Recommend maintaining controlled temperature to prevent fever (>37.7°C) for at least 72 hours post-OHCA.
    • Do not mandate a specific target temperature within the 32°C to 36°C range, aligning with TTM and TTM2 findings.
  • ILCOR Recommendations (2020):
    • Support temperature control post-cardiac arrest but emphasize individualized patient care over rigid target temperatures.

Geographic and Population Differences:

  • Nielsen et al. (2013): International study across Europe and Australia, enhancing generalizability.
  • Other Trials (e.g., KORHN-PRO in Korea): Demonstrate consistent findings across diverse populations, reinforcing the broader applicability of results.

B. Comprehensive Synthesis of Findings

Alignment and Conflict with Recent Data:

  • TTM and TTM2 Trials: Both confirm that deeper hypothermia does not yield superior outcomes compared to controlled normothermia with fever prevention.
  • Retrospective Studies: Mixed results, with some suggesting benefits at 33°C, but methodologies limit definitive conclusions.

Strengths and Weaknesses of Referenced Studies:

  • TTM Trials: High internal validity; however, variations in sedation protocols and exclusion criteria may affect applicability.
  • Retrospective Cohorts: Offer insights into real-world implementation but lack randomization, increasing bias risk.

Clinical Applicability in Light of Guidelines:

  • Guidelines: Shift towards maintaining controlled normothermia, emphasizing fever prevention over specific hypothermic targets.
  • TTM Findings: Reinforce guidelines by demonstrating no added benefit from targeting 33°C.

Integration of Systematic Reviews and Meta-Analyses:

  • Arrich et al. (2012 Cochrane Review): Supports guidelines advocating temperature control without specific targets.
  • Logue et al. (2017 Meta-Analysis): Confirms that stricter temperature targets do not improve survival or neurologic outcomes.

Cost-Effectiveness and Resource Utilization:

  • Lower Target Temperatures: Require more intensive cooling and monitoring, potentially increasing healthcare costs without added benefits.
  • Normothermia: Simplifies management protocols, potentially reducing resource burden.

Ongoing Trials:

  • HYPERION Trial (Dankiewicz et al., 2016): Investigates longer duration of hypothermia (48 vs. 24 hours) at 33°C, aiming to refine understanding of temperature management durations.

C. Gaps and Future Directions

Unanswered Questions:

  • Identification of specific patient subgroups that might benefit from different temperature targets.
  • Optimal duration of temperature management post-OHCA.

Areas for Additional Research:

  • Biomarkers: Studies like Wiberg et al. (2017) exploring neuron-specific enolase (NSE) aim to refine prognostication for neurologic outcomes.
  • Complement System Activation: Research by Bro-Jeppesen et al. (2020) on MAp19 protein suggests potential avenues for understanding systemic inflammation post-OHCA.
  • Implementation Strategies: Ensuring adherence to temperature control protocols, as highlighted by Bray et al. (2017), remains crucial.

Conclusion of Literature Review:

The body of evidence, underscored by Nielsen et al. (2013) and reinforced by subsequent trials like TTM2, collectively indicate that targeting 36°C is as effective as 33°C for improving survival and neurologic outcomes in OHCA survivors. This paradigm shift towards normothermia is supported by evolving guidelines and extensive research, advocating for simplified temperature management protocols that prioritize fever prevention without the complexities and risks associated with deeper hypothermia.

Clinical Application

  • Implementing the TTM trial findings, clinicians should adopt a target temperature of 36°C for comatose OHCA survivors, aligning with current ERC-ESICM guidelines.
  • This approach is particularly applicable in diverse practice settings, including academic, community, and rural hospitals, where resources for deeper hypothermia may be limited.
  • Given that both temperature targets exhibit similar outcomes, facility protocols can streamline temperature management, focusing on preventing hyperthermia without the need for intensive cooling measures associated with 33°C targets.
  • This strategy not only aligns with the most up-to-date evidence but also optimizes resource utilization and reduces the risk of adverse events like hypokalemia.

How To Use This Info In Practice

Practitioners should adopt a target temperature of 36°C for TTM in comatose OHCA patients, integrating these findings with existing ERC-ESICM guidelines to ensure evidence-based, resource-efficient care that prioritizes fever prevention and minimizes risks associated with deeper hypothermia.