The BOX Trial: BP Targets after ROSC

The patient in cardiac arrest, now has return of spontaneous circulation (ROSC). High fives all around, but our work isn’t over yet. This next ROSC phase of the resuscitation now begins and it’s critical to get this right, to maximise patient survival to hospital discharge. In this literature review we look at Blood Pressure Targets during the ROSC phase to maximise the chances of neurologically intact survival.

Following an arrest, this physiological autoregulation of blood pressure (BP), controlling brain perfusion, may be disrupted resulting in lower levels of perfusion for a given blood pressure. What BP targets should we be aiming for? Is a high Mean Arterial Pressure (MAP) better for patients post cardiac arrest, or is there no difference? There is currently little evidence on BP targets.

In this study, they wanted to test,  if a higher mean arterial blood pressure (MAP) ( 77mmHg vs 63 mm Hg) was superior in preventing death or severe anoxic brain injury in comatose survivors of out-of hospital cardiac arrest (OHCA).

The Paper: Kjaergaard J et al. Blood-Pressure Targets in Comatose Survivors of Cardiac Arrest. NEJM 387;16 2022 pp 1456-1466

What They Did

The BOX trial (Blood Pressure and Oxygenation Targets in Post Resuscitation Care) was a dual-center, randomized trial with a 2-by-2 factorial design. Comatose patients post ROSC from OHCA in ICU, were assigned(double-blind) to one of two BP targets (a double-blind intervention).

N= 789

Inclusion Criteria included:

• Patients ≥18 years of age, resuscitated after an OHCA with a presumed cardiac cause.
• ROSC with no chest compressions for >20 minutes
• Comatose

Exclusion Criteria included:

• Unwitnessed asystole
• Suspected acute intracranial bleeding
• Stroke
• Others included
  • In hospital cardiac arrest
  • Do-not resuscitate orders
  • Temperature <30^oC

Clinical staff, investigators, patients, and outcome assessors were blinded to the assigned blood-pressure targets. Patients were randomised before invasive monitoring occurred. Invasive BP monitoring used modules where the internal calibration was modified to show a BP that was either 10% higher or 10% lower than the actual BP, depending on the assigned target. This allowed half of the patients to have a MAP of 63 mm Hg and half to have a MAP of 77 mm Hg.

The protocol aimed to achieve a MAP of 70 mm Hg in three-stages:

1. Volume resuscitation to a central venous pressure(CVP) of 10 mm Hg,
2. Noradrenaline infusion, and if required
3. A dopamine infusion for a maximal dose of 10 μg per kilogram of body weight per minute

Primary outcome:

“Death from any cause or discharge from the hospital with a Cerebral Performance Category (CPC) of 3 or 4, indicating severe disability or a coma or vegetative state, within 90 days after randomization”

Secondary outcomes:

• Death from any cause within 90 days,
• Time to renal-replacement therapy,
• Neuron-specific enolase levels at 48 hours after randomization,
• Montreal Cognitive Assessment score at 3 months,
  • Score of > 26 is normal
• Modified Rankin scale score at 3 months,
  • 0 indicating no symptoms,
  • 1 no clinically significant disability,
  • 2 slight disability,
  • 3 moderate disability,
  • 4 moderately severe disability,
  • 5 severe disability, and 6 death
• CPC at 3 months.

Adverse events recorded included:

• Bleeding,
• Infection,
• Arrhythmia,
• Electrolyte or metabolic abnormalities,
• Acute kidney injury with renal-replacement therapy

What They Found

There was no significant difference between the two BP groups in survival or discharge of patients with a poor neurologic outcome within 90 days.

At 90 days:

• 133 patients (34%) in the high BP group and 127 patients (32%) in the low BP group had been discharged from the hospital with a CPC of 3 or 4 or had died
• 24 patients (3%) had been discharged from the hospital with a CPC of 3 or 4
  • 11 in the high BP group and 13 in the low BP group.
• 122 of 393 patients (31%) in the high BP group and 114 of 396 patients (29%) in the low BP group died within 90 days
• Renal-replacement therapy was initiated within the first 5 days in 41 patients (10%) in the high BP group and 40 patients (10%) in the low BP group
• The higher BP target was not associated with an increased risk of adverse events.

My Take on This

What was good about the Study

• Good Sample size
• Well designed
• Tested Specified BP points
• Randomised and ‘Blinded’

Limitations

• The trial was conducted in two tertiary ICUs centers, affecting how widely we can apply the results to other ICUs and to the emergency department.
• The mean BP difference between the two groups was only 10.7 mm Hg making these findings difficult to extrapolate to higher or lower BPs.
• I would think that 10mmHg is too small a difference. It would be important to test higher MAPs.
  • The authors state that “Our results do not suggest a benefit of a higher blood-pressure target in the subgroup of patients with known hypertension”. Logically we may expect that patients with pre-existing hypertension, may do better with higher MAPs, although we have no evidence for this. Also, it is sometimes difficult from the emergency department point of view to ascertain all those facts on patient arrival.
• Dopamine was the drug added to Noradrenaline to raise blood pressure. It is not a drug I would regularly use, in fact, not at all.

Will it change my practice?

Not greatly. I must admit that I tend to aim for a slightly higher MAP in ROSC post cardiac arrest patients, which stems from my concern over the loss of autoregulation and the potential for lower brain perfusion with MAPs that would have resulted in adequate perfusion prior to autoregulation loss. Due to this fact this study won’t change my practice. What it does is tell me that a higher MAP, is not necessarily associated with adverse events.

I would like to see a study that aims for for a higher difference in MAP ie., 20mm Hg.