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BOXing out oxygen and blood pressure targets

Presented by
Prof. Jacob Eifer Møller & Dr Jesper Kjaergaard, Copenhagen University Rigshospitalet, Denmark
ESC 2022
In dual back-to-back presentations from the 2-by-2 factorial BOX trial, both of which were simultaneously published in the New England Journal of Medicine, researchers conclusively showed that outcomes of comatose patients after an out-of-hospital cardiac arrest (OHCA) are not affected by shifting targets of oxygenation or blood-pressure.

BOX (NCT03141099) enrolled 789 comatose patients who had been admitted to hospital after resuscitated cardiac arrest and had a sustained return to spontaneous circulation [1–4]. All participants received temperature control at 36°C with mechanical ventilation for at least 24 hours, prior to return to normothermia. BOX was a double-blind, randomised trial with a 2-by-2 factorial design, in which the researchers evaluated a mean arterial blood-pressure target of 63 mmHg as compared with 77 mmHg; patients were also assigned to different oxygen targets. The primary outcome in both arms was a composite of all-cause death or hospital discharge with severe disability or coma (Cerebral Performance Category [CPC] of 3 or 4), whichever came first within 90 days of randomisation.

Prof. Jacob Eifer Møller (Copenhagen University Rigshospitalet, Denmark), presented the first part, the BOX trial’s oxygen analysis. Participants were randomised to receive either a restrictive target (partial pressure of arterial oxygen [PaO2] of 68–75 mmHg) or a liberal target (PaO2 98–105 mmHg) of oxygenation.

Prof. Møller provided the rationale: “There are translational data and some observational data that suggest that a lot of oxygen may harm the brain,” while other studies have shown “of course, that if you give too little oxygen that can be harmful as well. We wanted to know what is best.”

The trial results showed that there was no difference between the low or high PaO2 groups (32.0% vs 33.9%; HR 0.95; 95% CI 0.75–1.21). BOX was “very conclusive” on this question, said Prof. Møller. “There was absolutely no signal of difference between these groups, and it was very stable in all subgroup analyses and also for the secondary endpoints. So even though it’s neutral, it’s a very consistent signal in this study.” All-cause mortality at 90 days was also not affected by liberal versus restrictive PaO2 targets (31.1% vs 28.7%; not significant).
Blood pressure

The second part of BOX, interrogating the role of blood pressure in OHCA outcomes, was presented by Dr Jesper Kjaergaard (Copenhagen University Rigshospitalet, Denmark). It was hypothesised that a higher mean arterial blood pressure target of 77 mmHg may improve cerebral perfusion. In BOX, the blood pressure comparison was double-blinded due to tweaking the internal calibration of the blood pressure machines, which displayed values 10% above or 10% below the true measurements. Thus, while the study’s stated goal for mean target blood pressure was 70 mmHg, in reality participants were randomised to targets of 63 or 77 mmHg, and the data showed that indeed a 10.5 mmHg difference between the 2 arms was achieved (95% CI 9.9–11.2 mmHg; P<0.0001). The higher blood pressure target was obtained using vasopressors and noradrenaline.

However, again, BOX showed there was no impact on the proportion of patients who died or left the hospital with a CPC of 3 or 4, within 90 days, for those with a target of 73 mmHg compared with a target of 63 mmHg (34% vs 32%; HR 1.08; 95% CI 0.84–1.37). Likewise, all-cause mortality at 90 days was similar between the blood pressure targets (31% vs 29%; HR 1.13; 95% CI 0.88–1.46).

Across both parts of BOX, results were similar across all subgroups, with no interaction between the oxygen and blood pressure targets.

  1. Møller JE, et al. BOX - Oxygen therapy in comatose OHCA patients. Hot Line Session 2, ESC Congress 2022, Barcelona, Spain, 26–29 August.
  2. Kjaergaard J, et al. Blood pressure targets in comatose survivors of cardiac arrest. Hot Line Session 2, ESC Congress 2022, Barcelona, Spain, 26–29 August.
  3. Schmidt H, et al. N Engl J Med. 2022 Aug 27. doi: 10.1056/NEJMoa2208686.
  4. Kjaergaard J, et al. N Engl J Med. 2022 Aug 27. doi: 10.1056/NEJMoa2208687.


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