BOX: BP and Oxygen Targets in Comatose Survivors of Cardiac Arrest (2022)

“Among adult patients who were comatose after out-of-hospital cardiac arrest, targeting a mean arterial pressure of 63 mm Hg was not significantly different from targeting a mean arterial pressure of 77 mm Hg with respect to the risk of death or severe disability or coma at 90 days.”

  • The BOX Trial Investigators

1. Publication Details

  • Trial Title: Blood-Pressure and Oxygenation Targets in Comatose Survivors of Out-of-Hospital Cardiac Arrest
  • Citation: Kjaergaard J, Møller JE, Schmidt H, et al. Blood-Pressure and Oxygenation Targets in Comatose Survivors of Out-of-Hospital Cardiac Arrest. N Engl J Med. 2022;387(16):1456-1466. DOI: 10.1056/NEJMoa2208686
  • Published: October 20, 2022, in The New England Journal of Medicine
  • Author: Jesper Kjaergaard, M.D., D.M.Sc.
  • Funding: The Novo Nordisk Foundation.

2. Keywords

  • Cardiac Arrest, Post-Cardiac Arrest Care, Blood Pressure, Oxygenation, Targeted Temperature Management, Randomized Controlled Trial

3. The Clinical Question

  • In comatose adult survivors of out-of-hospital cardiac arrest (Population), does targeting a lower mean arterial pressure (MAP) and a restrictive oxygen target (Intervention) compared to a higher MAP and a liberal oxygen target (Comparison) affect the composite outcome of death or severe disability at 90 days (Outcome)?

4. Background and Rationale

  • Existing Knowledge: After successful resuscitation from cardiac arrest, secondary brain injury from hypotension and hypoxia is a major concern. However, the optimal blood pressure and oxygenation targets to prevent this injury were unknown. While avoiding hypotension seemed logical, aggressively targeting a high MAP could increase cardiac afterload and vasopressor requirements. Similarly, while avoiding hypoxia is critical, hyperoxia could also be harmful.
  • Knowledge Gap: There was no high-quality evidence from large randomized trials to guide clinicians on the specific MAP and oxygenation targets in the post-cardiac arrest period.
  • Proposed Hypothesis: The authors hypothesized that targeting a lower MAP would be non-inferior to a higher MAP target, and that a restrictive oxygenation strategy would be superior to a liberal strategy.

5. Study Design and Methods

  • Design: A multicenter, 2×2 factorial, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: 2 large university hospitals in Denmark.
  • Trial Period: Enrollment ran from February 2017 to December 2021.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) who were comatose (GCS < 9) after resuscitation from an out-of-hospital cardiac arrest of presumed cardiac cause.
    • Exclusion Criteria: Included unwitnessed asystole, known pregnancy, and suspected stroke or intracranial hemorrhage.
  • Intervention: Patients were randomized in a factorial design to one of four groups:
  • Blood Pressure: Lower MAP target (63 mm Hg) vs. Higher MAP target (77 mm Hg).
  • Oxygenation: Restrictive oxygen target (PaO2 9-10 kPa or 68-75 mm Hg) vs. Liberal oxygen target (PaO2 13-14 kPa or 98-105 mm Hg).
  • Control: The control groups were the higher MAP target and the liberal oxygen target.
  • Management Common to Both Groups: All patients were managed with targeted temperature management at 36°C and other standard post-cardiac arrest care.
  • Power and Sample Size: The authors calculated that a sample size of 800 patients would provide 80% power to detect a 10% absolute difference in the primary outcome for each of the two interventions. (Power is a study’s ability to find a real difference between treatments if one truly exists; 80% is the standard accepted level for clinical trials).
  • Outcomes:
    • Primary Outcome: A composite of death from any cause or discharge to a state of severe disability or coma (Cerebral Performance Category 3 or 4) at 90 days.
    • Secondary Outcomes: Included mortality at 90 days, and scores on cognitive and quality-of-life assessments.

6. Key Results

  • Enrollment and Baseline: 789 patients were randomized. The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome:
    • Blood Pressure: There was no significant difference in the primary outcome. The primary outcome occurred in 133 of 393 patients (34%) in the low-MAP group and in 127 of 396 patients (32%) in the high-MAP group (p=0.56).
    • Oxygenation: There was no significant difference in the primary outcome. The primary outcome occurred in 127 of 395 patients (32%) in the restrictive-oxygen group and in 133 of 394 patients (34%) in the liberal-oxygen group (p=0.59).
  • Secondary Outcomes: There were no significant differences in 90-day mortality or any of the other secondary outcomes for either intervention.
  • Adverse Events: The incidence of serious adverse events was similar in all groups.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of patients who met the composite endpoint between the intervention groups.
  • Key Statistic(s) Reported: The key statistics were the absolute rates of the primary outcome and the associated P-values.
  • Interpretation of Key Statistic(s):
    • P-value: The p-values for both the blood pressure (p=0.56) and oxygenation (p=0.59) comparisons were much higher than the 0.05 threshold, indicating that the results were not statistically significant and very likely due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures: As the trial was neutral, ARR and NNT are not applicable.
  • Subgroup Analyses: No significant differences were found in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, factorial design was a major strength, allowing two important clinical questions to be answered efficiently and with a low risk of bias.
  • Generalizability: The inclusion of a broad population of comatose survivors of out-of-hospital cardiac arrest increases the applicability of the findings.
  • Statistical Power: The study was large and adequately powered to detect a clinically meaningful difference if one existed.
  • Patient-Centered Outcomes: The primary outcome was a composite of death and severe disability, which is a robust and patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was unblinded, which introduces a risk of performance bias.
  • External Validity (Generalizability): The study was conducted in two high-performing academic centers in Denmark, and the results may not be fully generalizable to all healthcare systems.
  • Other: The separation between the groups for both MAP and PaO2 was modest, which may have made it more difficult to detect a true difference in outcomes.

10. Conclusion of the Authors

  • Among comatose adult survivors of out-of-hospital cardiac arrest, targeting a lower MAP (63 mm Hg) or a restrictive oxygen target (PaO2 of 9-10 kPa) did not lead to significantly better or worse outcomes at 90 days compared to targeting a higher MAP (77 mm Hg) or a liberal oxygen target.

11. To Summarize

  • Impact on Current Practice: This large, high-quality trial provides strong evidence that there is no benefit to aggressively targeting a high MAP or a high PaO2 in the post-cardiac arrest period. It supports a more conservative and individualized approach.
  • Specific Recommendations:
    • Patient Selection: For adult patients who are comatose after an out-of-hospital cardiac arrest.
    • Actionable Intervention: The results suggest that targeting a MAP of 63 mm Hg and a PaO2 of 9-10 kPa (68-75 mm Hg) is a safe and acceptable strategy.
  • What This Trial Does NOT Mean: This trial does NOT mean that hypotension or hypoxia are acceptable. It only suggests that targeting “supranormal” blood pressure or oxygen levels is not beneficial.
  • Implementation Caveats: The findings support the current practice of avoiding both hypotension and significant hyperoxia in the post-cardiac arrest period.

12. Context and Related Studies

  • Building on Previous Evidence: The BOX trial (2022) was the first large RCT to simultaneously investigate both blood pressure and oxygenation targets in this population, addressing a major evidence gap.
  • Influence on Subsequent Research: The definitive neutral findings of this trial will be highly influential in shaping future post-cardiac arrest care guidelines, likely leading to recommendations for more conservative targets.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The optimal targets in patients with chronic hypertension or other specific comorbidities remain an area of investigation.
  • Future Directions: Future research may focus on using more advanced monitoring to guide hemodynamic and oxygenation goals in a more personalized manner.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing two very common and important clinical questions in post-cardiac arrest care.
  • Methods: The multicenter, factorial RCT design was a major strength. The main methodological weakness is the lack of blinding.
  • Results: The study reported clear neutral findings for both of its primary comparisons, with confidence intervals that included the null value.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair reflection of the data. The high external validity of this pragmatic trial means its findings are broadly applicable to the care of comatose survivors of out-of-hospital cardiac arrest.

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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