TTM: Targeted Temperature Management at 33°C vs 36°C (2013)

“In unconscious survivors of out-of-hospital cardiac arrest of presumed cardiac cause, hypothermia at a targeted temperature of 33°C did not confer a benefit as compared with a targeted temperature of 36°C.”

— The TTM Trial Investigators

1. Publication Details

  • Trial Title: Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest.
  • Citation: Nielsen N, Wetterslev J, Cronberg T, et al; for the TTM Trial Investigators. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med. 2013;369(23):2197-2206. doi:10.1056/NEJMoa1310519.
  • Published: December 5, 2013, in The New England Journal of Medicine.
  • Author: Niklas Nielsen, M.D., Ph.D.
  • Funding: European Union, Swedish Heart–Lung Foundation, and others.

2. Keywords

Cardiac Arrest, Out-of-Hospital Cardiac Arrest, Targeted Temperature Management, Therapeutic Hypothermia, Normothermia, Anoxic Brain Injury, Coma.

3. The Clinical Question

In adult patients who are unconscious after an out-of-hospital cardiac arrest of presumed cardiac cause (Population), does targeted temperature management at 33°C (Intervention) compared to targeted temperature management at 36°C (Comparison) reduce all-cause mortality at the end of the trial (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Two small trials in 2002 suggested a benefit from inducing therapeutic hypothermia (32-34°C) after cardiac arrest, and this became the international standard of care. However, the optimal temperature target was unknown.
  • Knowledge Gap: It was unclear if the benefit seen in earlier trials was due to the induction of hypothermia itself or simply the prevention of fever. It was also unknown if a less aggressive temperature target (36°C, i.e., strict normothermia) could provide the same benefit with fewer side effects compared to the colder target of 33°C.
  • Proposed Hypothesis: The authors hypothesized that a targeted temperature of 33°C would be superior to a targeted temperature of 36°C in improving survival and neurologic function.

5. Study Design and Methods

  • Design: A prospective, multicenter, international, randomized, parallel-group, open-label trial with blinded outcome assessment.
  • Setting: 36 intensive care units (ICUs) in Europe and Australia.
  • Trial Period: Enrollment from November 2010 to January 2013.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) who remained unconscious (GCS <8) after an out-of-hospital cardiac arrest of presumed cardiac cause, with a sustained return of spontaneous circulation (ROSC).
    • Exclusion Criteria: Unwitnessed arrest with asystole, time from ROSC to screening >240 minutes, or pregnancy.
  • Intervention: Targeted temperature management at 33°C. Patients were cooled to and maintained at 33°C for 28 hours, followed by controlled rewarming.
  • Control: Targeted temperature management at 36°C. Patients were maintained at 36°C for 28 hours, followed by a period of fever prevention.
  • Management Common to Both Groups: Both groups received active temperature management with cooling devices. All patients were managed with a strict, standardized protocol for sedation and neurological prognostication.
  • Power and Sample Size: The trial was powered to detect a 20% relative risk reduction in all-cause mortality, requiring 900 patients.
  • Outcomes:
    • Primary Outcome: All-cause mortality at the end of the trial (maximum follow-up of 25 months).
    • Secondary Outcomes: A composite of all-cause mortality or poor neurological function (defined as Cerebral Performance Category [CPC] of 3-5) at 6 months.

6. Key Results

  • Enrollment and Baseline: 939 patients were included in the final analysis (473 in the 33°C group, 466 in the 36°C group). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in all-cause mortality between the 33°C and 36°C groups (50% vs 48%; P=0.51).
  • Secondary Outcomes: There was no significant difference in the composite outcome of death or poor neurological function at 6 months (54% in the 33°C group vs 52% in the 36°C group; P=0.78).
  • Adverse Events: The rates of adverse events, including pneumonia, bleeding, and arrhythmias, were similar between the two groups.

7. Medical Statistics

  • Analysis Principle: An intention-to-treat analysis was performed.
  • Statistical Tests Used: The primary outcome was analyzed using a Cox proportional-hazards model.
  • Primary Outcome Analysis: Time to death from any cause was compared between the two groups.
  • Key Statistic(s) Reported: Hazard Ratio (HR) for death with 33°C: 1.06 (95% CI, 0.89 to 1.28; P=0.51).
  • Interpretation of Key Statistic(s):
    • Hazard Ratio (HR):
      • Formula: Conceptually, HR represents the instantaneous risk of death in the intervention group relative to the control group.
      • Calculation: The paper reports the HR as 1.06.
      • Clinical Meaning: An HR of 1.06 means there was a 6% higher hazard of death at any given time in the 33°C group compared to the 36°C group, a difference that is not statistically significant.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The reported 95% CI was 0.89 to 1.28.
      • Clinical Meaning: Since this confidence interval widely crosses the line of no effect (1.0), it provides a precise estimate that there is no significant difference between the two temperature targets. The true effect is likely somewhere between an 11% benefit and a 28% harm.
    • P-value:
      • Calculation: The reported p-value was 0.51.
      • Clinical Meaning: The p-value of 0.51 is far above the 0.05 threshold, confirming that the observed difference is very likely due to chance. A result is conventionally considered statistically significant if the p-value is less than 0.05.
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group).
      • Calculation: ARR = 48% – 50% = -2%. This is an absolute risk increase of 2%.
      • Clinical Meaning: The intervention was associated with a non-significant 2% absolute increase in the risk of death.
    • Number Needed to Treat (NNT): Not applicable, as the intervention showed no benefit.
  • Subgroup Analyses: There was no benefit from targeting 33°C in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: This was a large, international, multicenter, randomized trial with blinded outcome assessment, providing high-quality evidence.
  • Methodological Rigor: The use of a strict protocol for sedation and, crucially, for neurological prognostication, minimized the risk of a self-fulfilling prophecy where comatose patients might have had life support withdrawn prematurely.
  • Active Control Group: The comparison was between two active temperature management strategies, both of which involved fever prevention.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was open-label for clinicians, which is a potential source of bias, though this is mitigated by the objective primary outcome and blinded outcome assessment.
  • External Validity (Generalizability): The findings apply to out-of-hospital cardiac arrest of presumed cardiac cause and may not be generalizable to in-hospital arrest or arrests from non-cardiac causes.
  • Other: The trial did not include a “no temperature control” group, so it could not determine if fever prevention itself was the key intervention.

10. Conclusion of the Authors

“In unconscious survivors of out-of-hospital cardiac arrest, targeted temperature management at 33°C did not confer a benefit as compared with a targeted temperature of 36°C.”

11. To Summarize

  • Impact on Current Practice: The TTM trial was a landmark study that fundamentally changed the understanding of post-cardiac arrest care. It demonstrated that the key intervention was likely the active prevention of fever, rather than the induction of hypothermia itself. This led to a major shift in international guidelines, allowing for a higher temperature target (36°C), which is easier to achieve and maintain.
  • Specific Recommendations:
    • Patient Selection: For adult patients who are comatose after an out-of-hospital cardiac arrest.
    • Actionable Intervention: A strategy of targeted temperature management aiming for a temperature of 36°C (i.e., strict fever prevention) is an appropriate standard of care.
    • Expected Benefit: No difference in survival or neurological outcome compared to a colder target of 33°C.
  • What This Trial Does NOT Mean: This trial does NOT mean that temperature management is unimportant. Both groups received active temperature control. The results strongly support the importance of actively preventing fever.
  • Implementation Caveats: Maintaining a target of 36°C still requires active monitoring and often the use of cooling devices to prevent fever.

12. Context and Related Studies

  • Building on Previous Evidence: The TTM trial was designed to clarify the findings of the original HACA (2002)and Bernard (2002) trials. It provided a much larger and more methodologically robust comparison of different temperature targets.
  • Influence on Subsequent Research: The results of the TTM trial were a major impetus for the even larger TTM2 trial (2021), which was designed to answer the final question: is any level of cooling (33°C) better than just preventing fever (targeted normothermia)? TTM2 confirmed the findings of TTM, showing no benefit for hypothermia.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: After this trial, the main unresolved question was whether active temperature control to prevent fever was superior to no temperature control at all.
  • Future Directions: This trial, along with its successor TTM2, has largely settled the debate on temperature targets. Future research is focused on other aspects of post-cardiac arrest care, such as optimizing hemodynamics and ventilation.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The question was of fundamental importance, re-evaluating the specific target of a widely adopted and resource-intensive standard of care.
  • Methods: The large, international RCT design with blinded outcome assessment was methodologically superb. The rigorous standardization of co-interventions, especially neuroprognostication, was a critical strength that increased the validity of the findings.
  • Results: The trial had a clear and robustly neutral result for its primary and secondary outcomes.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair interpretation of the data. The results are highly applicable to global critical care practice and provided a strong evidence base to support the use of a higher, less aggressive temperature target (36°C) for post-cardiac arrest care.

16. Disclaimer and Contact

This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.

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