HYdrocortisone and VAsopressin in Post-RESuscitation Syndrome

Phase 3RecruitingNCT04591990

Assistance Publique - Hôpitaux de Paris380 enrolled

Overview

The primary objective is to demonstrate the superiority of arginine-vasopressin (AVP) and hydrocortisone compared with norepinephrine regarding day-30 survival and neurological recovery in post-cardiac arrest patients with hemodynamic failure.

For patients successfully resuscitated who got restoration of spontaneous circulation (ROSC) after cardiopulmonary resuscitation (CPR), the course is usually marked by a post-resuscitation syndrome including multiple organ failures of various intensity and anoxic brain damage. The cardiocirculatory failure usually dominates the clinical picture, and it often leads to multiorgan failure. This hemodynamic failure is multifactorial, including at various levels vasoplegia, myocardial dysfunction, endotoxin release and adrenal dysfunction and is at least partly related to a hormonal defect that could be counteracted by hormonal supplementation. Such a substitutive opotherapy by hydrocortisone and AVP could improve hemodynamic failure and decrease overall mortality in this setting. This trial is a superiority multicentric trial and patients will be randomized in a 1:1:1:1 ratio using an electronic CRF. Investigational medicinal products: \- Arginin-vasopressin or AVP (REVERPLEG) The solution for infusion is prepared by diluting 40 I.U. REVERPLEG® with sodium chloride 9 mg/ml (0.9%) solution. The total volume after dilution should be 50 ml (equivalent to 0.8 I.U. AVP per ml). AVP will be administered according to mean arterial pressure to target a 65mmHg blood pressure for max 3 days. \- HYDROCORTISONE HEMISUCCINATE Vials with lyophilisate (100mg hydrocortisone) are provided by SERB laboratory. Hydrocortisone hemisuccinate will be administered as a 50mg intravenous bolus every 6 hours after an initial dose of 100mg, for 7 consecutive days. Stop of treatment by hydrocortisone will be performed without tapering. Comparator treatment: placebos. 17 ICU centers in France will participate to this study targetting 380 patient's enrollment in the study.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

380

Conditions

Postresuscitation Syndrome

Interventions

Administration of AVPDRUG

Administration of AVP

Administration of placebo AVPDRUG

Administration of placebo AVP

Administration of placebo hydrocortisoneDRUG

Administration of placebo hydrocortisone

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Adult patients (\>18y) * Cardiac arrest (in-hospital or out-of-hospital) with sustained ROSC (\> 30 minutes) admitted to the ICU * Post-resuscitation shock defined as arterial hypotension (SAP \< 90 mmHg or MAP \< 65 mmHg) unresponsive to adequate fluid loading, which occurred within the first 24 hours after ROSC and requiring norepinephrine/epinephrine continuous infusion at a dose greater or equal to 0.2µg/kg/min for at least 3 hours * A maximal delay between the start of norepinephrine infusion and randomization of 9 hours * Informed written consent of the patient or a legally authorized close relative. Exclusion Criteria: * Evidence for a traumatic or a neurological cause of cardiac arrest * Shock due to uncontrolled haemorrhage * Previously known adrenal insufficiency * Limitation of life-sustaining therapies * Ongoing treatment by any steroids, whatever the dose * Ongoing extra-corporeal circulatory assistance * Gastrointestinal bleeding in the past 6 weeks * Pregnant or breastfeeding women * Participation in another interventional study involving human participants or being in the exclusion period at the end of a previous study involving human participants, if applicable * Hypersensitivity to arginin-vasopressin and to its excipients * Hypersensitivity to hydrocortisone and to its excipients * Legal protection (i.e. incompetence to provide consent, guardianship, curator or incarceration) * No affiliation with the French health care system.

Locations (14)

Intensive care unit, CHU Amiens- Picardie

Amiens, France

RECRUITING

Intensive care unit, CHU Angers

Angers, France

Outcomes

Primary Outcomes

Neurological outcome

The primary endpoint will be the good neurological outcome at day-30. This will be evaluated using the Glasgow Outcome Scale (GOS, addendum 18.5.1) dichotomized as follow: good neurological outcome for categories 4 and 5 and poor neurological outcome or death for categories 3, 2 and 1. The GOS will be obtained at day-30 from an in-hospital visit if the patient is still hospitalized or from telephone contact with patients, relatives or general practitioners.

Time frame: at day-30

Secondary Outcomes

All-cause mortality

Vital status at day-30.

Time frame: at day-30

Mortality attributed to irreversible hemodynamic failure

Time to irreversible cardiovascular failure defined as death in pharmacologically uncontrollable hypotension (mean arterial blood pressure \< 60 mmHg) despite maximal ICU care, or withdrawal of care based on same, as previously defined (Witten L, Resuscitation 2019).

Time frame: at day-30

Mortality attributed to neurological withdrawal of care

Time to neurological withdrawal of care. Withdrawal of care will be based on expectations of a poor neurological recovery based on most recent guidelines (Sandroni C, ICM 2015).

Time frame: at day-30

Mortality attributed to comorbid withdrawal of care

Time to comorbid withdrawal of care. Comorbid withdrawal of care or refusal of life-sustaining therapy based on the expectation of a poor quality of life. This may be related to a preexisting or newly discovered terminal illness or other serious medical condition (e.g. dementia or cancer).

Time frame: at day-30

Day-30 brain death

Time to brain death (according to French legislation)

Central Contacts

Guillaume GERI, MD, PhD

CONTACT

+33 (0) 6 69 24 22 47 dr.guillaume.geri@gmail.com

Alain Cariou, MD, PhD

CONTACT

+33 (0)1 58 41 25 01 alain.cariou@aphp.fr

Data from ClinicalTrials.gov

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