REstrictive Versus LIberal Oxygen Strategy and Its Effect on Pulmonary Hypertension After Out-of-hospital Cardiac Arrest (RELIEPH-study)

Study Overview
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Brief Summary
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Background: For patients with out-of-hospital cardiac arrest (OHCA) at the intensive care unit (ICU), oxygen therapy plays an important role in post resuscitation care. During hospitalisation, a lot of these patients occur with pulmonary arterial hypertension (PAH). Currently a wide oxygen target is recommended but no evidence regarding optimal treatment targets to minimise the prevalence of PAH exists. Methods: The RELIEPH trial is a substudy within the BOX (Blood pressure and OXygenation targets in post resuscitation care) trial. It is a single-center, parallel-group randomised controlled clinical trial. 300 patients with OHCA hospitalised at the ICU are allocated to one of the two oxygenation interventions, either a restrictive- (9-10 kPa) or liberal (13-14 kPa) oxygen target both within the recommended range. The primary outcome is the fraction of time with pulmonary hypertension (mPAP >25 mmHg) out of total time with mechanical ventilation. Secondary outcomes are: length of ICU stay among survivors, lactate clearance, right ventricular failure, 30 days mortality and plasma brain natriuretic peptide (BNP) level 48 hours from randomisation. Discussion: This study hypothesises that a liberal target of oxygen reduces the time with PAH during mechanical ventilation compared to a restrictive oxygen target in patients with OHCA at the ICU. When completed, this study hopes to provide new knowledge regarding which oxygen target is beneficial for this group of patients.

Official Title
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REstrictive Versus LIberal Oxygen Strategy and Its Effect on Pulmonary Hypertension After Out-of-hospital Cardiac Arrest (RELIEPH-study): a Substudy Protocol for a Randomised Clinical Trial

Conditions
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Hypertension, Pulmonary Arterial, Out-Of-Hospital Cardiac Arrest, Intensive Care Unit, Oxygen Therapy, Mechanical Ventilation, Resuscitation

Intervention / Treatment
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* Other: Restrictive PaO2
* Other: Low normal MAP
* Other: Liberal PaO2
* Other: High normal MAP


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years OHCA of presumed cardiac cause Sustained ROSC Unconsciousness (Glasgow coma scale <8) after sustained ROSC Exclusion Criteria: Conscious patients (obeying verbal commands) Females of childbearing potential (unless a negative HCG test can rule out pregnancy within the inclusion window) In-hospital cardiac arrest 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). Known bleeding diathesis (medically induced coagulopathy (e.g. warfarin, NOAC, clopidogrel) does not exclude the patient) 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 Known pre-arrest cerebral performance category 3 or 4 >4 hours (240 minutes) from ROSC to screening Systolic blood pressure <80 mmHg in spite of fluid loading/vasopressor and/or inotropic medication/intra-aortic balloon pump/axial flow device Temperature on admission <30°C

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The RELIEPH trial is a substudy of the BOX trial, which is a multicenter, randomised clinical trial with a 2x2 factorial design. Patients are allocated 1:1:1:1 to two interventions, respectively high- or low mean arterial pressures (double blinded) and restrictive- or liberal oxygenation (open label). The RELIEPH trial focuses on the oxygen intervention and only has access to data from one trial site. This makes the RELIEPH trial a single-center, parallel-group randomised controlled trial with patients allocated 1:1 to the oxygen target interventions.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Restrictive PaO2 and low normal MAP<br>Patients receiving PaO2 9-10 kPa (68-75 mmHg) and MAP 63 mmHg during targeted temperature management (36 hours) after OHCA. | Other: Restrictive PaO2<br>* Patients are randomized to a PaO2 target of 9-10 kPa (open-label).<br>* Other names: PaO2 target at 9-10 kPa.;Other: Low normal MAP<br>* The patients are randomized to receive 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.<br>* Other names: Mean arterial blood pressure at 63 mmHg.;|
| Active Comparator: Restrictive PaO2 and high normal MAP<br>Patients receiving PaO2 9-10 kPa (68-75 mmHg) and MAP 77 mmHg during targeted temperature management (36 hours) after OHCA. | Other: Restrictive PaO2<br>* Patients are randomized to a PaO2 target of 9-10 kPa (open-label).<br>* Other names: PaO2 target at 9-10 kPa.;Other: High normal MAP<br>* The patients are randomized to receive 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.<br>* Other names: Mean arterial blood pressure at 77 mmHg.;|
| Active Comparator: Liberal PaO2 and low normal MAP<br>Patients receiving PaO2 13-14 kPa (98-105 mmHg) and MAP 63 mmHg during targeted temperature management (36 hours) after OHCA. | Other: Low normal MAP<br>* The patients are randomized to receive 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.<br>* Other names: Mean arterial blood pressure at 63 mmHg.;Other: Liberal PaO2<br>* Patients are randomized to a PaO2 target of 13-14 kPa (open-label).<br>* Other names: PaO2 target at 13-14 kPa.;|
| Active Comparator: Liberal PaO2 and high normal MAP<br>Patients receiving PaO2 13-14 kPa (98-105 mmHg) and MAP 77 mmHg during targeted temperature management (36 hours) after OHCA. | Other: Liberal PaO2<br>* Patients are randomized to a PaO2 target of 13-14 kPa (open-label).<br>* Other names: PaO2 target at 13-14 kPa.;Other: High normal MAP<br>* The patients are randomized to receive 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.<br>* Other names: Mean arterial blood pressure at 77 mmHg.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pulmonary hypertension | Fraction of time with pulmonary hypertension (mPAP >25 mmHg) out of total time with mechanical ventilation. | Up to 30 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Length of ICU stay. | Length of ICU stay among survivors. | Up to 8 weeks. | 
| Lactate clearance. | >30% reduction in lactate level. | 24 hours. | 
| Right ventricular failure. | Cardiac index <2 and central venous pressure >18 mmHg. | Up to 8 weeks. | 
| Mortality. | Dead or alive. | 30 days after ROSC. | 
| Plasma brain natriuretic peptide. | Plasma brain natriuretic peptide level. | 48 hours from randomisation. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Out-of-hospital cardiac arrest, Resuscitation, Intensive Care Unit, Mechanical ventilation, Pulmonary Hypertension, Oxygen