BOX Trial: Blood Pressure

Blood-Pressure Targets in Comatose Survivors of Cardiac Arrest

Kjaergaard et al | New England Journal of Medicine| August 2022

DOI: 10.1056/NEJMoa2208687

Clinical Question

In patients with return of spontaneous circulation (ROSC) after cardiac arrest does a higher MAP target (> 77mmHg) compared to a standard target  (>63mmHg) reduce death or survival at discharge with a poor neurological status?


  • Manipulation of mean arterial pressure is a central intervention in the ICU to maintain adequate organ perfusion.
  • Following cardiac arrest cerebral autoregulation may be impaired and therefore be dependent on adequate perfusion pressure
  • Maintenance of higher MAP is likely to require higher doses of vasopressor which may be associated with complications


  • Two-centre, double blind, parallel-group randomised clinical trial
  • Blinding was achieved by altering the calibration of the invasive blood pressure monitor such that in the intervention group the true blood pressure was 10% higher than the target of 70mmHg and in the control arm the value was 10% lower.
  • 2* 2 factorial design (patients also randomised to restrictive or liberal oxygenation – results reported separately)
  • Web based randomisation with varying block sizes, stratified by randomisation site
  •  Further subordinate randomisation to one of two cooling devices for 24 hours (Surface vs Intravascular)
  • 800 patients provided between 80 and 90% power to detect a 10% absolute reduction in the primary outcome (a composite of death or discharge from hospital up to ay 90 with a cerebral performance score of 3-4). This was based on a predicted mortality of 38%


  • Conducted in 2 Tertiary Danish ICUs between March 2017 to December 2021


Inclusion Criteria

  • Out of hospital cardiac arrest of presumed cardiac cause
  • Sustained ROSC > 20mins
  • Unconscious (GCS < 9)


Exclusion Criteria

  • Females of childbearing potential (unless a negative HCG test can rule out pregnancy within the inclusion window)
  • In-hospital cardiac arrest (IHCA)
  • OHCA of presumed non-cardiac cause, e.g., after trauma or dissection/rupture of major artery OR cardiac arrest caused by initial hypoxia (i.e., drowning, suffocation, hanging)
  • Suspected or confirmed acute intracranial bleeding
  • Suspected or confirmed acute stroke
  • Unwitnessed asystole
  • Known limitations in therapy and Do Not Resuscitate-order
  • Known disease making 180 days survival unlikely
  • >4hours (240min)from ROSC to screening
  • Systolic blood pressure < 80 mmHg despite fluid loading/vasopressor and/or inotropic medication intra-aortic balloon pump/axial flow device
  • Temperature on admission<30°C


  • 1196 patients assessed for eligibility
    • 188 not meeting inclusion criteria.
      • Younger than 18 years of age = 9
      • OHCA on non-cardiac origin, n=47
      • ROSC not sustained > 20 minutes, n=17
    • 206 with an exclusion criteria
    • 802 randomised
      • 403 High target BP group, 9 withdrew consent  ITT population of 393
      • 399 Low target BP group 3 withdrew consent  ITT population of 396


Baseline characteristics

High BP target vs Low BP target  – very similar between the two groups

  • Mean age: 63 vs 62
  • Male: 80% vs 81%
  • Cardiovascular history
    • Hypertension 45% vs 47%
    • Diabetes 12% vs 16%
    • Myocardial infarction 24% vs 20%
    • Atrial Fibrillation 17% vs 15%
    • Heart failure 17% vs 18%
    • COPD 8% vs 8%
    • Stroke 6% vs 9%
  • Cardiac Arrest Details
    • Shockable rhythm 86% vs 84%
    • Witnessed arrest 86% vs 84%
    • Bystander CPR 88% vs 87%
    • Time to ROSC 21 vs 21 minutes
    • Time from arrest to randomisation 150 vs 154 minutes
  • Finding and procedures on arrival to hospital
    • ST Elevation on ECG 44% vs 47%
    • Coronary angiogram performed 93% vs 90%
    • pH 7.21 vs 7.22
    • Lactate 6.1 vs 5.6


    • Higher MAP target
      • Target MAP of 77mmHg for duration of invasive blood pressure monitoring


    • Standard MAP target
      • Target MAP of 63mmHg for duration of invasive blood pressure monitoring.

In both groups

  • Protocolised recommendations for achieving MAP with fluids followed by Noradrenaline and then Dopamine.
  • Targeted temperature management at 36oC for 24 hours
  • Standardised neurological assessment


  • No significant difference across any outcomes


  • No difference across any pre-specified subgroups for 90 day all-cause mortality
    • Age > 64 HR 1.05 (95% CI 0.77-1.44)
    • Hypertension HR 1.15 (95% CI 0.81-1.62)
    • Renal Impairment HR 0.95 (95% CI 0.39-2.30)
    • COPD HR 0.48 (95% CI 0.23-0.99)
    • Shockable rhythm HR 1.11 (95% CI 0.85-1.45)

Adverse Events

  • Number of moderate and severe bleeding events was not different between groups
  • Number of units of packed red blood cells transfused during VA-ECMO was higher in the moderate hypothermia group
  • Number of nosocomial infections was not different between groups

Authors’ Conclusions

In comatose survivors of out of hospital cardiac arrest a mean arterial blood pressure of 77 mm Hg as compared with 63 mm Hg did not result in a significant difference in the percent- age of patients who died or had severe disability or coma 


  • Innovative design allowing for double blinding in a haemodynamics trial.
  • Good treatment separation between groups (BP 10mmHg and Noradrenaline dose 0.038mcg/kg/min)
  • Event rate consistent with predicted reducing risk of type 2 error.
  • Well-designed, multi-centre study performed in the emergency setting
  • Minimal loss to follow up
  • Standardised protocol for temperature regulation
  • Similar baseline characteristics between groups


  • Study only performed in two centres in one country which limits generalisability.
  • Some may argue that the 10mmHg is not sufficient to difference in outcome
  • Large predicted effect size increases risk of type 2 error but no real signal in either direction
  • Use of dopamine as inotrope of choice may reduce generalisability
  • MOCA scores only available for 359 patients at 3 months making this data harder to interpret
  • Did not mandate sedation hold on initial assessment 

The Bottom Line

  • I will aim to maintain a mean arterial pressure of > 65mmHg for survivors of out of hospital as has been my current practice. It seems any value in this range is likely to be safe

External Links


Summary author: Alastair Brown

Summary date: 27th September 2022

Peer-review editor: David Slessor

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