TAME: Therapeutic Mild Hypercapnia after Cardiac Arrest (2022)

“Among patients who were comatose after out-of-hospital cardiac arrest, targeted therapeutic mild hypercapnia did not lead to better neurologic outcomes at 6 months than targeted normocapnia.”

— The TAME Cardiac Arrest Trial Investigators

1. Publication Details

  • Trial Title: Targeted Therapeutic Mild Hypercapnia after Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial.
  • Citation: The TAME Cardiac Arrest Trial Investigators. Targeted Therapeutic Mild Hypercapnia after Out-of-Hospital Cardiac Arrest. N Engl J Med. 2022;387(16):1465-1475. doi:10.1056/NEJMoa2208158.
  • Published: October 20, 2022, in The New England Journal of Medicine.
  • Author: The TAME Cardiac Arrest Trial Investigators.
  • Funding: National Health and Medical Research Council of Australia; Health Research Council of New Zealand, and others.

2. Keywords

Cardiac Arrest, Post-Cardiac Arrest Syndrome, Therapeutic Hypothermia, Hypercapnia, Carbon Dioxide, Neurological Outcome.

3. The Clinical Question

In comatose adult patients successfully resuscitated from out-of-hospital cardiac arrest (Population), does targeted therapeutic mild hypercapnia (PaCO2 50-55 mmHg) (Intervention) compared to targeted normocapnia (PaCO2 35-45 mmHg) (Comparison) improve favorable neurological outcome at 6 months (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Brain injury after cardiac arrest is a major cause of death and disability. Mild hypercapnia (a slightly elevated level of carbon dioxide in the blood) was thought to be potentially neuroprotective by increasing cerebral blood flow and reducing neuronal injury.
  • Knowledge Gap: While small, preliminary studies suggested a potential benefit, there was no large-scale, high-quality randomized trial to determine if intentionally targeting mild hypercapnia was safe and effective in improving outcomes for post-cardiac arrest patients.
  • Proposed Hypothesis: The authors hypothesized that targeted therapeutic mild hypercapnia would result in a higher percentage of patients with a favorable neurological outcome at 6 months compared to targeted normocapnia.

5. Study Design and Methods

  • Design: An international, multicenter, randomized, controlled, parallel-group trial.
  • Setting: 63 intensive care units in 17 countries.
  • Trial Period: Enrollment from December 2017 to August 2021.
  • Population:
    • Inclusion Criteria: Adults (≥18 years) who were comatose and admitted to the ICU after resuscitation from an out-of-hospital cardiac arrest of presumed cardiac or unknown cause.
    • Exclusion Criteria: Patients with known severe chronic obstructive pulmonary disease, severe asthma, or suspected intracranial bleeding.
  • Intervention: Mild Hypercapnia Group: Ventilation was adjusted to target a partial pressure of arterial carbon dioxide (PaCO2) of 50 to 55 mmHg for 24 hours after randomization.
  • Control: Normocapnia Group: Ventilation was adjusted to target a PaCO2 of 35 to 45 mmHg for 24 hours.
  • Management Common to Both Groups: All patients were managed with targeted temperature management (36°C) and other aspects of post-cardiac arrest care according to international guidelines.

6. Key Results

  • Enrollment and Baseline: 1700 patients were randomized, with 1648 included in the final analysis (826 in the hypercapnia group, 822 in the normocapnia 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 favorable neurological outcome at 6 months (defined as a score of 5 on the Glasgow Outcome Scale–Extended). A favorable outcome occurred in 43.5% of patients in the hypercapnia group and 44.6% in the normocapnia group.
  • Secondary Outcomes: There were no significant differences between the groups in 6-month mortality or any other secondary outcomes.
  • Adverse Events: The incidence of adverse events was similar in 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 mixed-effects logistic regression model.
  • Key Statistic(s) Reported:
    • Primary Outcome (Favorable Neurologic Outcome): Relative Risk (RR) 0.98 (95% CI, 0.87 to 1.11; P=0.76).
  • Interpretation of Key Statistic(s):
    • Relative Risk (RR):
      • Formula: Conceptually, RR = (Risk in Intervention Group) / (Risk in Control Group).
      • Calculation: The paper reports the RR as 0.98.
      • Clinical Meaning: A relative risk of 0.98 means the likelihood of a favorable outcome was 2% lower in the hypercapnia group, a difference that is clinically and statistically negligible.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The reported 95% CI was 0.87 to 1.11.
      • Clinical Meaning: The 95% CI ranged from a 13% harm to an 11% benefit and confidently crossed 1.0. This indicates that the result is consistent with no effect and that any small difference observed is likely due to chance.
    • P-value:
      • Calculation: The reported p-value was 0.76.
      • Clinical Meaning: The p-value of 0.76 is very high, far above the 0.05 threshold, confirming the lack of a statistically significant difference between the two strategies.
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Intervention Group) – (Risk in Control Group).
      • Calculation: ARR = 43.5% – 44.6% = -1.1%.
      • Clinical Meaning: There was a 1.1% absolute increase in unfavorable outcomes in the hypercapnia group, a small and non-significant difference.

8. Strengths of the Study

  • Large and Rigorous: This was a large, international, multicenter, randomized trial with excellent methodological quality, including concealed allocation and blinded outcome assessment.
  • High Adherence: There was good separation in PaCO2 levels between the two groups, indicating that the intervention was successfully implemented.
  • Patient-Centered Outcome: The primary outcome of 6-month neurological function is a highly relevant and patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): No major limitations to internal validity. The lack of blinding of clinicians to the intervention is inherent to the study design but is unlikely to have biased the objective primary outcome.
  • External Validity (Generalizability): The trial population was predominantly male and of European ancestry, which may limit generalizability to other populations.

10. Conclusion of the Authors

“In this randomized trial involving comatose adults who had been resuscitated from out-of-hospital cardiac arrest, targeted therapeutic mild hypercapnia for 24 hours did not lead to a higher percentage of patients with a favorable neurologic outcome at 6 months than targeted normocapnia.”

11. To Summarize

  • Impact on Current Practice: This was a major, practice-changing “negative” trial. It definitively showed that the strategy of intentionally inducing mild hypercapnia provides no benefit to post-cardiac arrest patients. It put an end to the clinical equipoise on this topic and reinforced that targeting normocapnia (normal CO2 levels) should remain the standard of care.
  • Specific Recommendations:
    • Patient Selection: For comatose adult survivors of out-of-hospital cardiac arrest.
    • Actionable Intervention: Do not intentionally target mild hypercapnia. The goal of ventilation should be to maintain a normal PaCO2 (normocapnia).
    • Expected Benefit: No benefit from hypercapnia; therefore, the recommendation is to avoid it.
  • What This Trial Does NOT Mean: This trial does not mean that hypocapnia (low CO2) is safe; hypocapnia is known to be harmful as it can reduce cerebral blood flow. The trial confirms that the target should be normocapnia.

12. Context and Related Studies

  • Building on Previous Evidence: The TAME trial was designed to provide a definitive answer to a question raised by promising but inconclusive preclinical data and small pilot studies in humans.
  • Influence on Subsequent Research: As a large, well-conducted negative trial, TAME has effectively closed this line of inquiry. It allows the research community to refocus efforts and resources on other potentially neuroprotective strategies after cardiac arrest. It complements the TTM2 trial, which showed no benefit of targeting a lower temperature (33°C) over 36°C.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: Are there other ventilation strategies that could be neuroprotective? What is the optimal management of oxygenation (as opposed to carbon dioxide) after cardiac arrest?
  • Future Directions: The focus of post-cardiac arrest research continues to be on finding effective neuroprotective interventions, optimizing hemodynamics, and better predicting which patients will have a meaningful recovery.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The question was highly relevant, testing a plausible and relatively simple intervention to address the devastating problem of post-cardiac arrest brain injury.
  • Methods: The study’s design was of the highest quality—a large, international, multicenter RCT with robust methodology.
  • Results: The trial had a clear and unambiguous negative result for its primary, patient-centered outcome. The confidence intervals convincingly excluded any meaningful clinical benefit.
  • Conclusions and Applicability: The authors’ conclusion is a direct and definitive interpretation of the data. The results are highly applicable to ICUs worldwide and firmly establish that targeting normocapnia should remain the standard of 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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