TTM 48: 24 vs 48 Hours of TTM after Cardiac Arrest (2017) - ESBICM® | Educational Society of Bedside Intensive Care Medicine

TTM 48: 24 vs 48 Hours of TTM after Cardiac Arrest (2017)

“Among adults with comatose out-of-hospital cardiac arrest, targeted temperature management for 48 hours did not improve 6-month neurologic outcomes compared with targeted temperature management for 24 hours.”

— The TTM 48 Investigators

1. Publication Details

Trial Title: Duration of Targeted Temperature Management After Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial.
Citation: Kirkegaard H, Søreide E, de Haas I, et al; for the TTM 48 Trial Investigators. Duration of Targeted Temperature Management After Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial. JAMA. 2017;318(4):341-350. doi:10.1001/jama.2017.8818.
Published: July 25, 2017, in The Journal of the American Medical Association (JAMA).
Author: Hans Kirkegaard, M.D., Ph.D.
Funding: The Danish Council for Independent Research and others.

2. Keywords

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

3. The Clinical Question

In adult patients who are comatose after an out-of-hospital cardiac arrest (Population), does a longer duration of targeted temperature management at 33°C (48 hours) (Intervention) compared to a standard duration (24 hours) (Comparison) improve neurological outcome at 6 months (Outcome)?

4. Background and Rationale

Existing Knowledge: Targeted temperature management (TTM) at 32-36°C for at least 24 hours was the standard of care for comatose survivors of cardiac arrest. The neuroprotective effects of hypothermia are thought to be time-dependent.
Knowledge Gap: Animal studies suggested that a longer duration of hypothermia might provide additional neuroprotection. However, the optimal duration of TTM in humans was unknown, and it was unclear if extending the duration would improve outcomes or simply increase the risk of complications.
Proposed Hypothesis: The authors hypothesized that a 48-hour duration of TTM at 33°C would be superior to a 24-hour duration in improving 6-month neurological outcomes.

5. Study Design and Methods

Design: A prospective, multicenter, international, randomized, parallel-group, open-label trial with blinded outcome assessment.
Setting: 10 intensive care units (ICUs) in 6 European countries.
Trial Period: Enrollment from June 2013 to June 2016.
Population:
- Inclusion Criteria: Adult patients (≥18 years) who remained unconscious 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 for a duration of 48 hours.
Control: Targeted temperature management at 33°C for a duration of 24 hours.
Management Common to Both Groups: Both groups were cooled to 33°C. After the assigned duration, patients were rewarmed at a controlled rate of 0.33°C per hour. All patients were managed with a standardized sedation protocol.
Power and Sample Size: The trial was powered to detect a 12% absolute difference in the primary outcome, requiring 350 patients.
Outcomes:
- Primary Outcome: Neurological outcome at 6 months, defined by the Cerebral Performance Category (CPC) scale, dichotomized as good (CPC 1-2) or poor (CPC 3-5).
- Secondary Outcomes: Included 6-month mortality, distribution of CPC scores, and adverse events.

6. Key Results

Enrollment and Baseline: 355 patients were randomized (176 to the 48-hour group, 179 to the 24-hour group). The groups were well-matched at baseline.
Trial Status: The trial was completed as planned.
Primary Outcome: There was no significant difference in the rate of poor neurological outcome (CPC 3-5) at 6 months between the 48-hour and 24-hour groups (35% vs 34%; P=0.87).
Secondary Outcomes: There was no significant difference in 6-month mortality (27% in the 48-hour group vs 26% in the 24-hour group).
Adverse Events: The total duration of mechanical ventilation and ICU stay was significantly longer in the 48-hour group. The incidence of other adverse events was similar.

7. Medical Statistics

Analysis Principle: An intention-to-treat analysis was performed.
Statistical Tests Used: The primary outcome was analyzed using a logistic regression model.
Primary Outcome Analysis: The proportion of patients with a poor neurological outcome (CPC 3-5) at 6 months was compared between the two groups.
Key Statistic(s) Reported: Risk Ratio (RR) for poor neurological outcome with 48-hour TTM: 1.03 (95% CI, 0.75 to 1.40; P=0.87).
Interpretation of Key Statistic(s):
- Relative Risk (RR):
  - Formula: Conceptually, RR = (Risk of poor outcome in 48h group) / (Risk of poor outcome in 24h group).
  - Calculation: The paper reports the RR as 1.03.
  - Clinical Meaning: An RR of 1.03 means there was a 3% higher relative risk of a poor neurological outcome in the 48-hour group compared to the 24-hour 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 0.75 to 1.40.
  - Clinical Meaning: Since this confidence interval is wide and crosses the line of no effect (1.0), it indicates that there is no significant difference between the two durations. The true effect is likely somewhere between a 25% benefit and a 40% harm.
- P-value:
  - Calculation: The reported p-value was 0.87.
  - Clinical Meaning: The p-value of 0.87 is far above the 0.05 threshold, confirming that the observed result 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 = 34% – 35% = -1%. This is an absolute risk increase of 1%.
  - Clinical Meaning: The intervention was associated with a non-significant 1% absolute increase in the risk of a poor neurological outcome.
- Number Needed to Treat (NNT): Not applicable, as the intervention showed no benefit.
Subgroup Analyses: No significant benefit was found in any of the pre-specified subgroups.

8. Strengths of the Study

Study Design and Conduct: This was a multicenter, randomized trial with blinded outcome assessment that addressed a specific and important clinical question.
Methodological Rigor: The use of standardized protocols for temperature management, rewarming, and sedation increased the internal validity of the trial.

9. Limitations and Weaknesses

Internal Validity (Bias): The study was open-label for clinicians, which could introduce performance bias.
External Validity (Generalizability): The trial was smaller than the major TTM trials and may have been underpowered to detect a smaller difference in outcomes.
Other: The trial specifically tested a 33°C target, and the results may not apply to other temperature targets (e.g., 36°C).

10. Conclusion of the Authors

11. To Summarize

Impact on Current Practice: This trial provided important evidence that extending the duration of hypothermia from 24 to 48 hours does not improve neurological outcomes and leads to a longer ICU stay. It reinforced the standard practice of a 24-hour duration for TTM.
Specific Recommendations:
- Patient Selection: For adult patients who are comatose after an out-of-hospital cardiac arrest and are being treated with TTM.
- Actionable Intervention: A duration of 24 hours for targeted temperature management is the appropriate standard of care.
- Expected Benefit: No benefit from extending TTM to 48 hours. A 24-hour duration results in a shorter ICU stay and duration of mechanical ventilation.
What This Trial Does NOT Mean: This trial does not question the practice of TTM itself, but rather addresses the optimal duration.
Implementation Caveats: The findings provide a clear recommendation against a specific intervention (prolonged TTM).

12. Context and Related Studies

Building on Previous Evidence: This trial was designed to test the hypothesis, generated from animal studies, that a longer duration of cooling might be more effective. It provided clinical trial evidence to refine the TTM protocol established by earlier studies like HACA (2002) and TTM (2013).
Influence on Subsequent Research: This trial, along with the larger TTM and TTM2 trials, has helped to precisely define the parameters of post-cardiac arrest temperature management, allowing research to focus on other aspects of care.

13. Unresolved Questions & Future Directions

Unresolved Questions: Is there any specific subgroup of patients who might benefit from a longer duration of TTM?
Future Directions: The focus of post-cardiac arrest care research has largely moved on from the duration of TTM to other interventions aimed at improving neurological recovery.

14. External Links

Original Article: Duration of Targeted Temperature Management After Out-of-Hospital Cardiac Arrest

15. Framework for Critical Appraisal

Clinical Question: The question was clinically relevant, addressing a specific parameter of a standard ICU intervention to see if it could be optimized.
Methods: The multicenter RCT design with blinded outcome assessment was methodologically sound.
Results: The trial had a clear and robustly neutral result for its primary and secondary outcomes. The finding of increased resource utilization (longer ICU stay) with the 48-hour strategy further strengthened the conclusion.
Conclusions and Applicability: The authors’ conclusion is a direct and fair interpretation of the data. The results are highly applicable to ICUs practicing TTM and provide a strong evidence-based recommendation to maintain a standard duration of 24 hours.

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.