BOX TRIAL
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BOX trial
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BOX trial cardiac arrest oxygenation blood pressure targets NEJM 2022
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https://rebelem.com/the-box-trial-bp-o2-targets-in-comatose-…
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PMID: 36027564
Reading Article
PMID: 36027567
Here is a full summary of the BOX Trial:
The BOX Trial
The BOX trial (ClinicalTrials.gov: NCT03141099, funded by the Novo Nordisk Foundation) was a landmark 2-by-2 factorial randomized controlled trial published simultaneously in the New England Journal of Medicine in October 2022. It enrolled comatose adults resuscitated after out-of-hospital cardiac arrest (OHCA) of presumed cardiac cause and simultaneously addressed two separate clinical questions.
Trial Design
| Feature | Detail |
|---|---|
| Design | Double-blind, 2x2 factorial RCT |
| Setting | Two centres (Denmark) |
| Population | Comatose adults post-ROSC from OHCA of cardiac cause |
| N | 789 patients total |
| Primary outcome | Composite of death OR hospital discharge with CPC 3-4 (severe disability/coma) within 90 days |
| Blinding | BP arm: calibration of invasive monitor was adjusted ±10% to blind staff; O2 arm: blinded by ventilator settings |
Paper 1 - Oxygen Targets (PMID: 36027567)
Schmidt H et al., NEJM 2022. DOI: 10.1056/NEJMoa2208686
Intervention
- Restrictive O2 target: PaO2 9-10 kPa (68-75 mmHg)
- Liberal O2 target: PaO2 13-14 kPa (98-105 mmHg)
Results
| Outcome | Restrictive (n=394) | Liberal (n=395) | HR (95% CI) | P |
|---|---|---|---|---|
| Primary outcome (death or CPC 3-4) | 126 (32.0%) | 134 (33.9%) | 0.95 (0.75-1.21) | 0.69 |
| Death at 90 days | 113 (28.7%) | 123 (31.1%) | - | NS |
| Median NSE at 48h | 17 µg/L | 18 µg/L | - | NS |
| Median CPC | 1 | 1 | - | NS |
| Median mRS | 2 | 1 | - | NS |
| Median MoCA | 27 | 27 | - | NS |
Conclusion: Restrictive vs liberal oxygenation resulted in similar rates of death or severe disability/coma at 90 days. Neither approach is superior.
Paper 2 - Blood Pressure Targets (PMID: 36027564)
Kjaergaard J et al., NEJM 2022. DOI: 10.1056/NEJMoa2208687
Intervention
- High MAP target: 77 mmHg (true pressure 10% higher than displayed 70 mmHg)
- Low MAP target: 63 mmHg (true pressure 10% lower than displayed 70 mmHg)
- Both groups: noradrenaline first-line, then dopamine; TTM at 36°C for 24h
Patient Characteristics
Both arms were well matched: mean age ~63, ~80% male, shockable rhythm ~85%, bystander CPR ~88%, time to ROSC ~21 min.
Results
| Outcome | High MAP (n=393) | Low MAP (n=396) | HR (95% CI) | P |
|---|---|---|---|---|
| Primary outcome (death or CPC 3-4) | 133 (34%) | 127 (32%) | 1.08 (0.84-1.37) | 0.56 |
| Death at 90 days | 122 (31%) | 114 (29%) | 1.13 (0.88-1.46) | NS |
| Median NSE at 48h | Similar | Similar | - | NS |
| Median CPC | 1 | 1 | - | NS |
| Adverse events | No significant difference | - | - | NS |
Conclusion: Targeting MAP 77 mmHg vs 63 mmHg post-cardiac arrest made no significant difference in death or severe neurological disability.
Key Takeaways
-
No benefit from higher MAP: Targeting MAP 77 vs 63 mmHg after ROSC did not improve survival or neurological outcome. This challenges the rationale of aggressive vasopressor use to achieve higher cerebral perfusion pressure post-arrest.
-
No benefit from liberal oxygen: Targeting higher PaO2 (normoxia-to-hyperoxia range) did not reduce death or disability compared to a more restrictive PaO2 target. This supports the shift away from routine hyperoxia in post-resuscitation care.
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Overall good outcomes: ~68-70% of patients survived without severe disability in both groups - reflecting the highly selected nature of the population (largely shockable rhythms, witnessed arrests, early bystander CPR).
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Clinical implication: Both a MAP of ~63 mmHg and restrictive oxygenation (PaO2 ~9-10 kPa) appear to be safe and adequate targets in the post-cardiac arrest care bundle. There is no need to drive higher BP or O2 values.
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Limitations: Single-country, two-centre study; predominantly shockable rhythms (limits generalizability to non-shockable arrest); blinding was more complex to maintain for the BP arm.
The BOX trial effectively provided Level 1 evidence against two common assumptions in post-resuscitation ICU care - that "higher is better" for both mean arterial pressure and oxygen delivery.
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