BOX TRIAL
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BOX trial cardiac arrest oxygenation blood pressure
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BOX trial cardiac arrest results oxygenation blood pressure targets
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PMID: 36027564
Reading Article
PMID: 36027567
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https://rebelem.com/the-box-trial-bp-o2-targets-in-comatose-…
The BOX Trial
The BOX trial (Blood Pressure and OXygenation Targets after Out-of-Hospital Cardiac Arrest) was a landmark 2x2 factorial randomized controlled trial published simultaneously in two papers in the New England Journal of Medicine in October 2022. It was conducted at two Danish centers (Rigshospitalet and Odense University Hospital) and funded by the Novo Nordisk Foundation.
Background / Rationale
After return of spontaneous circulation (ROSC) from cardiac arrest, two physiological targets are commonly manipulated in the ICU:
- Oxygenation - Hypoxemia is clearly harmful, but whether targeting high-normal (liberal) vs. low-normal (restrictive) PaO2 matters was unknown.
- Blood pressure - Hypoperfusion is harmful, and impaired cerebral autoregulation post-arrest raises the question of whether a higher MAP improves cerebral perfusion and outcomes.
Trial Design
| Feature | Details |
|---|---|
| Design | Double-blind, 2x2 factorial RCT |
| Population | Comatose adults resuscitated after out-of-hospital cardiac arrest (OHCA) of presumed cardiac cause |
| Setting | 2 tertiary Danish ICUs |
| Registration | NCT03141099 |
| N | 789 patients |
| Blinding | BP arm: invasive BP monitors were recalibrated so clinicians targeted 70 mmHg while the true target differed (clever blinding approach) |
Inclusion: Comatose adult OHCA survivors of presumed cardiac cause, achieving ROSC and admitted to ICU
Exclusion: Non-cardiac arrest cause, ROSC not achieved, obvious non-cardiac etiology
The Two Randomizations
1. Oxygenation Arm (Paper 1 - Schmidt et al., PMID 36027567)
| Group | PaO2 Target |
|---|---|
| Restrictive (normoxia) | 9-10 kPa (68-75 mmHg) |
| Liberal (hyperoxia) | 13-14 kPa (98-105 mmHg) |
Primary outcome: Composite of death or hospital discharge with severe disability/coma (CPC 3-4) within 90 days
Results:
- Restrictive group: 126/394 patients (32.0%) reached primary endpoint
- Liberal group: 134/395 patients (33.9%) reached primary endpoint
- HR 0.95 (95% CI 0.75-1.21), P = 0.69 - No significant difference
- 90-day mortality: 28.7% vs. 31.1%
- Neuron-specific enolase at 48h: 17 vs. 18 μg/L (similar)
- Conclusion: Restrictive and liberal oxygenation strategies produced similar outcomes
2. Blood Pressure Arm (Paper 2 - Kjaergaard et al., PMID 36027564)
| Group | MAP Target |
|---|---|
| Higher MAP | 77 mmHg |
| Lower MAP | 63 mmHg |
Primary outcome: Same composite (death or CPC 3-4 within 90 days)
Results:
- Higher MAP group: 133/393 patients (34%) reached primary endpoint
- Lower MAP group: 127/396 patients (32%) reached primary endpoint
- HR 1.08 (95% CI 0.84-1.37), P = 0.56 - No significant difference
- 90-day mortality: 31% vs. 29%
- Median CPC: 1 in both groups; median mRS: 1 in both groups
- Conclusion: A higher MAP target of 77 vs. 63 mmHg did not reduce death or severe disability
Key Take-Home Points
- Neither a higher MAP target nor liberal oxygenation provided benefit in post-cardiac arrest comatose patients over standard/lower targets.
- The trial was adequately powered and well-designed (double-blind, factorial). It genuinely tested two clinically important questions simultaneously.
- The blinding methodology for the BP arm (recalibrated monitors) was innovative.
- The population was relatively favorable - ~85% shockable rhythm, ~87% bystander CPR, predominantly male (~80%), mean age ~63 years.
- Clinical implication: There is no strong evidence to drive MAP >63 mmHg or to use liberal oxygen in post-ROSC comatose patients. Targeting normoxia (PaO2 ~68-75 mmHg / SpO2 94-98%) and MAP ~63 mmHg appears reasonable.
Limitations
- Single-country (Denmark) - limits generalizability
- ~85% shockable rhythms - results may not apply to non-shockable arrest
- Did not address timing, duration of targets, or patients with pre-existing hypertension separately (a higher "personalized" MAP might still matter in those patients)
- The population was well-managed overall (high bystander CPR rate, short ROSC times) - a "best case" scenario
Subsequent Work
A 2024 sub-analysis (Meyer et al., PMC10785348) examined combined effects of both interventions and found no interaction - neither strategy alone nor in combination improved outcomes. A 2025 sex-specific analysis (PMID 40838912) explored whether results differed by sex, and a 2024 substudy validated quantitative pupillometry thresholds using the BOX cohort.
References:
- Schmidt et al. NEJM 2022 - Oxygen Targets (PMID 36027567)
- Kjaergaard et al. NEJM 2022 - Blood-Pressure Targets (PMID 36027564)
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