Blood Pressure and OXygenation Targets After OHCA (BOX)

Blood Pressure and Oxygenation Targets in Post-resuscitation Care, a Randomized Clinical Trial

This study compares two blood pressure targets and two oxygenation targets in the post-resuscitation care of comatose out-of-hospital cardiac arrets patients. Using a novel method the blood pressure-intervention is double-blinded. The oxygenation-intervention is open-label. As a subordinate study, the patients will be randomized 1:1 to active fever-control with an automated feedback temperature control-device for 36 or 72 hours following return of spontaneous circulation.

Study Overview

• Status: Completed
• Conditions: Blood Pressure; Out-of-Hospital Cardiac Arrest; Hemodynamic Instability
• Intervention / Treatment: Other: Low normal MAP; Other: Low normal PaO2.; Other: High normal MAP; Other: High normal PaO2

Detailed Description

In comatose patients resuscitated from out of hospital cardiac arrest (OHCA), neurological injuries remain the leading cause of death. The in-hospital mortality is reported at 30-50%, and the total mortality, although improved substantially over the last decade, remain to be significant, in most countries at up to 90%. An adequate blood pressure must be maintained in the post-cardiac arrest patient i order to optimize neurological recovery and avoid further brain injury. Blood pressure targets in post-resuscitation guidelines are based on limited clinical evidence. Furthermore registry and clinical data suggest a u-shaped relationship of outcome with levels of oxygen supplementation. Blinded, randomized, clinical trials addressing specific blood pressure- or oxygenation-targets during the post-resuscitation care, have not been performed.

The current trial addresses strategies for neuroprotection using a 2-by-2 design of two different target blood pressure levels and two different oxygenation levels.

Intervention:

• 'Low-normal MAP' (appoximately 63 mmHg) vs. 'high-normal MAP' (approximately 77 mmHg) (double blind intervention) and
• Low-normal oxygenation (9-10 kPa) vs. high-normal oxygenation (13-14) kPa (open label).
• As a subordinate study, the patients will be randomized 1:1 to active fever-control with an automated feedback temperature control device for 72 hours or to 36 hours following return of spontaneous circulation.

Design: National collaborative, randomized clinical trial randomizing 800 comatose out-of-hospital cardiac arrest patients undergoing targeted temperature management (TTM) to the specified interventions.

The investigators have planned the following sub-studies:

Sub-study 1: Devopment and validation af a method for double blinded allocation to different blood pressure targets.

Hypothesis: It is possible to develop a method for double blinded allocation of patients to different blood pressure targets in clinical trials.

Sub-study 2: Assessment of different blood pressure targets and relation to renal function during TTM.

Hypothesis: Different blood presure goals will affect biomarkes of renal function after cardiac arrest.

Sub-study 3: To investigate the hemodynamic profil in relation to different blood pressure targets after cardiac arrest.

Hypothesis: Blood pressure and vassopressor-doses are related to hemodynamic parameters, such as systemic vaskular resistence index and cardiac index.

Sub-study 4: To investigate the hemodynamic profil in relation to different oxygenation targets after cardiac arrest.

Hypothesis: Lower oxygenation targets are related to higher pulmonary vascular resistance.

Sub-study 5: The prognostic value of automated videobased assessment of pupillary dilatation and reaction to light. Derivation and validation of relevant cut-off for introducing pupillomtry as part of the prognostication

INTERIM ANALYSIS There will be an independent DSMC arranging an independent statistician to conduct primarily a blinded interim analysis at time points of their choosing. The DSMC will be able to request unblinding of data coordinated by the data managing agency. An interim analysis is planned after inclusion of 200 and 400 patients.

For the BP intervention, a blinded interim analysis of vasorepressor need and recorded blood pressures is planned after 50 patients, to monitor blinding of treatment allocation and that a clinically relevant blood pressure separation between groups is achieved. Vasopressor needs in terms of vasopressor need in a variance component model is expected to differ. New sites will be monitored for these factors after inclusion of 50 patients.

EARLY STOPPING CRITERIA After an interim analysis the DSMC may suggest to the steering committee that the trial should be stopped early. No specific criteria to guide the DSMB will be put forward.

ACCOUNTABILITY PROCEDURE FOR MISSING DATA/POPULATION FOR ANALYSIS Trial sites will be asked to complete all CRFs and other forms if missing data is found in the electronic database. Missing data will be reported in the publications. More than 5% missing data will result in multiple imputation with the creation of 5-10 imputed datasets to be analysed separately and the aggregated into one estimate of intervention effect on the primary and secondary outcomes. Analyses will be performed according to the modified intention to treat principle with patients lost to follow up included in the denominator.

SUBGROUP ANALYSIS AND DESIGN VARIABLES Subgroups will be analysed according to pre-defined design variables: over or under median age, shockable rhythm, gender, the presence of shock at admission, diagnosed AMI and time from arrest to ROSC. Difference in intervention effect estimates according to subgroup will be declared exclusively based on a statistically significant test of interaction.

DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION The principal investigator and the site investigators will permit monitoring, audits, review of ethical committees and regulatory authorities direct access to source data and documentation, blinded to treatment allocation.

DATA HANDLING AND RECORD KEEPING Individual patient data will be handled as ordinary chart records and will be kept according to the legislation (e.g. data protection agencies) of the countries of each health system. The study database will be stored for 15 years and anonymised if requested by the relevant authorities.

Danish legislation regarding the respect for patients physical and mental integrity and rights will be respected, Approval for storing data relevant to the trial, including potentially sensitive information has been approved by the relevant authorities.

QUALITY CONTROL AND QUALITY ASSURANCE A monitoring plan will be published before start of the trial. The monitoring will include: inclusion and absence of exclusion criteria, consent obtained in all patients.

All trial sites will be provided with sufficient information to participate in the trial. The site investigator will be responsible for that all relevant data is entered into the electronic CRFs. The CRFs will be constructed in order to assure data quality with predefined values and ranges on all data entries.

STATISTICAL METHODS The combined primary outcome will be reported as proportional hazard of experiencing one of two endpoints (death or poor neurological status at hospital discharge), differences tested with a log rank test. Other proportions are expected to be normally distributed; therefore a t-test is applied. Survival analyses are performed using proportional hazard models, survival is adjusted for site.

Furthermore pre-specified analysis of interaction for design variables: sex, age (median), time to ROSC (median), shockable rhythm, STEMI, pre-existing hypertension, pre-existing chronic obstructive pulmonary disease.

SIGNIFICANCE A two-sided significance level of 0.05 will be applied to all endpoints. No adjustment for the factorial design is made, as no interaction is expected.

SAMPLE SIZE ESTIMATION Sample size estimation is based on blinded BP target allocation and on the assumption that no interaction of the two interventions exist.

The combined primary outcome is time to death or hospital discharge in a state of CPC 3 or 4. The investigators are planning a study with 400 subjects in each group, an accrual interval of 48 months, and additional follow-up after the accrual interval of 3 months. Prior data indicate the 6 months mortality is 33% overall. Assuming a mortality of 28% in the superior group compared to 38% in the inferior groups the investigators will need to include 732 patients in total or 846 patients in total to achieve a power of 0.8 and 0.9 respectively. The Type I error probability associated with this test of the null hypothesis that the experimental and control survival curves are equal is 0.05.

Loss of final measurement is expected but from the experience from previous trial the number of missing follow-up assessments is small (<5%) and will not result in an increase of the number of patients needed.

• Study Type: Interventional
• Enrollment (Actual): 802
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Odense, Denmark, 5000
    • Depart med Cardiothoracic Intensive Care, Odense University Hospital
  • København Ø
    • Copenhagen, København Ø, Denmark, 2100
      • Department of Cardiology, Copenhagen University Hospital, Rigshospitalet

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age ≥18 years
2. OHCA of presumed cardiac cause
3. Sustained ROSC
4. Unconsciousness (GCS <8) (patients not able to obey verbal commands) after sustained ROSC

Exclusion Criteria:

1. Conscious patients (obeying verbal commands)
2. Females of childbearing potential (unless a negative HCG test can rule out pregnancy within the inclusion window)
3. In-hospital cardiac arrest (IHCA)
4. 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).
5. Known bleeding diathesis (medically induced coagulopathy (e.g. warfarin, NOAC, clopidogrel) does not exclude the patient).
6. Suspected or confirmed acute intracranial bleeding
7. Suspected or confirmed acute stroke
8. Unwitnessed asystole
9. Known limitations in therapy and Do Not Resuscitate-order
10. Known disease making 180 days survival unlikely
11. Known pre-arrest CPC 3 or 4
12. >4 hours (240 minutes) from ROSC to screening
13. Systolic blood pressure <80 mm Hg in spite of fluid loading/vasopressor and/or inotropic medication/intra-aortic balloon pump/axial flow device
14. Temperature on admission <30°C.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Low normal MAP and low normal PaO2; MAP 63 mmHg and PaO2 9-10 kPa during targeted temperature management (36 hours) after OHCA.	Other: Low normal MAP; The patients are randomized to recieve a Phillips M1006B blood pressure measuring module, offset by +10 %. All patients will target a MAP of 70, but due to the offset module, the patients will target an actual blood pressure of 63 mmHg.; Other Names: Mean arterial blood pressure at 63 mmHg.; Other: Low normal PaO2.; The patients are randomized to a PaO2 target of 9-10 kPa (open-label).; Other Names: PaO2 at 9-10 kPa.
Active Comparator: High normal MAP and low normal PaO2; MAP 77 mmHg and PaO2 9-10 kPa during targeted temperature management (36 hours) after OHCA.	Other: Low normal PaO2.; The patients are randomized to a PaO2 target of 9-10 kPa (open-label).; Other Names: PaO2 at 9-10 kPa.; Other: High normal MAP; The patients are randomized to recieve a Phillips M1006B blood pressure measuring module, offset by -10 %. All patients will target a MAP of 70, but due to the offset module, the patients will target an actual blood pressure of 77mmHg.; Other Names: Mean arterial blood pressure at 77 mmHg .
Active Comparator: Low normal MAP and high normal PaO2; MAP 63 mmHg and PaO2 13-14 kPa during targeted temperature management (36 hours) after OHCA.	Other: Low normal MAP; The patients are randomized to recieve a Phillips M1006B blood pressure measuring module, offset by +10 %. All patients will target a MAP of 70, but due to the offset module, the patients will target an actual blood pressure of 63 mmHg.; Other Names: Mean arterial blood pressure at 63 mmHg.; Other: High normal PaO2; The patients are randomized to a PaO2 target of 13-14 kPa (open-label).; Other Names: PaO2 at 13-14 kPa.
Active Comparator: High normal MAP and high normal PaO2; MAP 77 mmHg and PaO2 13-14 kPa during targeted temperature management (36 hours) after OHCA.	Other: Low normal PaO2.; The patients are randomized to a PaO2 target of 9-10 kPa (open-label).; Other Names: PaO2 at 9-10 kPa.; Other: High normal MAP; The patients are randomized to recieve a Phillips M1006B blood pressure measuring module, offset by -10 %. All patients will target a MAP of 70, but due to the offset module, the patients will target an actual blood pressure of 77mmHg.; Other Names: Mean arterial blood pressure at 77 mmHg .

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause mortality or severe anoxic brain injury	Death from any cause or discharge from hospital in Cerebral Performance Category 3 or 4	3 months after OHCA.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Renal replacement therapy	Time to Renal replacement therapy.	3 months
Time to death	Time to death	180 days
Neuron-Specific Enolase	Neuron-Specific Enolase level at 48 hours	48 hours
MOCA-score	Assesed at three months (lowest score allocated to patients not available for follow-up).	3 months
Modified Ranking Scale	Modified Ranking Scale.	3 months
NT-pro-BNP	NT-pro-BNP at three months (Highest value allocated to patients not available for follow-up).	3 months
eGFR	Last available measurement of eGFR with 3 month of follow-up	3 months
LVEF	Last available measurement of LVEF with 3 month of follow-up	3 months
Vasopressor use	Daily cumulated vasopressor requirement in the first week of the ICU stay.	First week after cardiac arrest
Renal function	Assesed by creatinine-clearence at 48 and 96 hours after OHCA.	96 hours

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vital status at 180 days post cardiac arrest	Vital status at 180 days post cardiac arrest	180 days post cardiac arrest
CPC category at 180 days post cardiac arrest	CPC category at 180 days post cardiac arrest	180 days post cardiac arrest

Collaborators and Investigators

• Sponsor: Jesper Kjaergaard
• Collaborators: Odense University Hospital
• Investigators: Principal Investigator: Jesper Kjaergaard, Md, DMSc, Rigshospitalet, Denmark

Publications and helpful links

General Publications

• Hassager C, Schmidt H, Moller JE, Grand J, Molstrom S, Beske RP, Boesgaard S, Borregaard B, Bekker-Jensen D, Dahl JS, Frydland MS, Hofsten DE, Isse YA, Josiassen J, Lind Jorgensen VR, Kondziella D, Lindholm MG, Moser E, Nyholm BC, Obling LER, Sarkisian L, Sondergaard FT, Thomsen JH, Thune JJ, Veno S, Wiberg SC, Winther-Jensen M, Meyer MAS, Kjaergaard J. Duration of Device-Based Fever Prevention after Cardiac Arrest. N Engl J Med. 2022 Nov 6. doi: 10.1056/NEJMoa2212528. Online ahead of print.
• Schmidt H, Kjaergaard J, Hassager C, Molstrom S, Grand J, Borregaard B, Roelsgaard Obling LE, Veno S, Sarkisian L, Mamaev D, Jensen LO, Nyholm B, Hofsten DE, Josiassen J, Thomsen JH, Thune JJ, Lindholm MG, Stengaard Meyer MA, Winther-Jensen M, Sorensen M, Frydland M, Beske RP, Frikke-Schmidt R, Wiberg S, Boesgaard S, Lind Jorgensen V, Moller JE. Oxygen Targets in Comatose Survivors of Cardiac Arrest. N Engl J Med. 2022 Oct 20;387(16):1467-1476. doi: 10.1056/NEJMoa2208686. Epub 2022 Aug 27.
• Kjaergaard J, Moller JE, Schmidt H, Grand J, Molstrom S, Borregaard B, Veno S, Sarkisian L, Mamaev D, Jensen LO, Nyholm B, Hofsten DE, Josiassen J, Thomsen JH, Thune JJ, Obling LER, Lindholm MG, Frydland M, Meyer MAS, Winther-Jensen M, Beske RP, Frikke-Schmidt R, Wiberg S, Boesgaard S, Madsen SA, Jorgensen VL, Hassager C. Blood-Pressure Targets in Comatose Survivors of Cardiac Arrest. N Engl J Med. 2022 Oct 20;387(16):1456-1466. doi: 10.1056/NEJMoa2208687. Epub 2022 Aug 27.
• Kjaergaard J, Schmidt H, Moller JE, Hassager C. The "Blood pressure and oxygenation targets in post resuscitation care, a randomized clinical trial": design and statistical analysis plan. Trials. 2022 Feb 24;23(1):177. doi: 10.1186/s13063-022-06101-6.
• Grand J, Hassager C, Schmidt H, Møller JE, Mølstrøm S, Nyholm B, Kjaergaard J. Hemodynamic evaluation by serial right heart catheterizations after cardiac arrest; protocol of a sub-study from the Blood Pressure and Oxygenation Targets after Out-of-Hospital Cardiac Arrest-trial (BOX). Resusc Plus. 2021 Dec 10;8:100188. doi: 10.1016/j.resplu.2021.100188. eCollection 2021 Dec. Erratum in: Resusc Plus. 2022 Mar 17;9:100198.

Study record dates

Study Major Dates

• Study Start (Actual): March 10, 2017
• Primary Completion (Actual): December 15, 2021
• Study Completion (Actual): March 15, 2022

Study Registration Dates

• First Submitted: April 30, 2017
• First Submitted That Met QC Criteria: May 3, 2017
• First Posted (Actual): May 4, 2017

Study Record Updates

• Last Update Posted (Actual): June 30, 2022
• Last Update Submitted That Met QC Criteria: June 28, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Keywords: Hemodynamic; OHCA; TTM; post-rescusitation care; Blood pressure targets; Oxygenation targets
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Arrest; Out-of-Hospital Cardiac Arrest
• Other Study ID Numbers: H-16033436

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Will be shared by a case-by-case agreement

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No