HYdrocortisone and VAsopressin in Post-RESuscitation Syndrome

Official title

HYdrocortisone and VAsopressin in Post-REsuscitation Syndrome

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.

Detailed description

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.

Interventions

• Drug Administration of AVP
  Administration of AVP
• Drug Administration of placebo AVP
  Administration of placebo AVP
• Drug Administration of placebo hydrocortisone
  Administration of placebo hydrocortisone
• Drug Administration of hydrocortisone
  Administration of hydrocortisone

Primary outcome measures

• Neurological outcome [Time frame: at day-30]

Secondary outcome measures (9)

• All-cause mortality [Time frame: at day-30]
• Mortality attributed to irreversible hemodynamic failure [Time frame: at day-30]
• Mortality attributed to neurological withdrawal of care [Time frame: at day-30]
• Mortality attributed to comorbid withdrawal of care [Time frame: at day-30]
• Day-30 brain death [Time frame: at day-30]
• mortality attributed to recurrent cardiac arrest [Time frame: at day-30]
• Other causes [Time frame: at day-30]
• Neurological recovery at day-30 [Time frame: at day-30]
• Brain damage [Time frame: at 48 hours and at 72hours]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Factorial

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

France · 14 centers

• Intensive care unit, CHU Amiens- Picardie — Amiens
• Intensive care unit, CHU Angers — Angers
• Intensive care unit, CHI Robert Ballanger — Aulnay-sous-Bois
• Medical Intensive Care Unit, Ambroise Paré hospital, APHP — Boulogne-Billancourt
• Intensive care unit, CH public du Cotentin — Cherbourg
• Intensive care unit, CHU Dijon — Dijon
• Intensive care unit, Hospices civils de Lyon — Lyon
• Intensive care unit, Hôpital Jacques Cartier — Massy
• … and 6 more centers

Publications

• Witten L, Gardner R, Holmberg MJ, Wiberg S, Moskowitz A, Mehta S, Grossestreuer AV, Yankama T, Donnino MW, Berg KM. Reasons for death in patients successfully resuscitated from out-of-hospital and in-hospital cardiac arrest. Resuscitation. 2019 Mar;136:93-99. doi: 10.1016/j.resuscitation.2019.01.031. Epub 2019 Jan 30. PMID 30710595
• Geri G, Lascarrou JB, Levy B, Asfar P, Muller G, Legriel S, Ricome S, Cour M, Klouche K, Sauneuf B, Quenot JP, Bougouin W, Cariou A; HYVAPRESS investigators. Hydrocortisone and arginine vasopressin in post-resuscitation shock: the HYVAPRESS trial. Resusc Plus. 2025 May 19;24:100982. doi: 10.1016/j.resplu.2025.100982. eCollection 2025 Jul. PMID 40503090

Identifiers

NCT: NCT04591990 · APHP200033 · 2020-001620-33

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗