Evaluation of Hydrocortisone and Argipressin Efficacy on 30-Day Survival and Neurological Outcomes in Post-Resuscitation Syndrome with Hemodynamic Failure

The primary objective of this study is to demonstrate the superiority of **arginine vasopressin** (AVP) and **hydrocortisone** compared with placebo in terms of day-30 survival and neurological recovery in adult cardiac arrest patients with sustained return of spontaneous circulation (ROSC) and hemodynamic failure due to post-resuscitation syndrome. This is clinically relevant as it aims to improve outcomes in a critical patient population by potentially enhancing survival rates and neurological function, which are significant challenges in post-cardiac arrest care.

Secondary objectives include evaluating: - Day-30 all-cause mortality and mortality attributed to irreversible hemodynamic failure, neurological withdrawal of care, comorbid withdrawal of care, recurrent cardiac arrest, and other causes. - Day-30 brain death and neurological recovery. - Brain damage assessment. - Number of days between inclusion and day-30 without catecholamines, norepinephrine, AVP, and inotropic support. - Number of patients successfully weaned from vasopressor support at days 3, 5, and 7. - Incidence of new-onset atrial fibrillation between inclusion and day-30. - Left ventricular systolic function assessed at days 1, 2, 3, and 7. - Number of days free of mechanical ventilation and renal replacement therapy between inclusion and day-30. - Incidence of acute kidney injury at days 7 and 30. - Safety related to AVP use, including acute coronary syndrome, mesenteric ischemia, digital ischemia, and diabetes insipidus at AVP weaning. - Safety related to hydrocortisone use, including gastrointestinal bleeding up to day-30 and episodes of hyperglycemia up to day 7. - Intensive care unit (ICU) and hospital length of stay.

The clinical trial involves **adult cardiac arrest patients** with sustained return of spontaneous circulation (ROSC) and hemodynamic failure due to post-resuscitation syndrome. The study population includes both male and female participants aged 18 years and older. The trial focuses on individuals who have experienced cardiac arrest, either in-hospital or out-of-hospital, with sustained ROSC for more than 30 minutes and are admitted to the intensive care unit (ICU). Participants are required to have post-resuscitation shock characterized by arterial hypotension unresponsive to adequate fluid loading, necessitating continuous infusion of norepinephrine tartrate or epinephrine at a dose of at least 0.2 μg/kg/min for a minimum of 3 hours. The trial population was selected based on these criteria, and the maximal delay between the start of norepinephrine infusion and randomization is 9 hours. The sponsor has not provided information regarding the total number of participants. The study includes a vulnerable population, and informed written consent is obtained from a legally authorized close relative or through an emergency procedure.

The clinical trial is designed to evaluate the efficacy of **hydrocortisone** and **argipressin** in adult patients experiencing post-resuscitation syndrome following cardiac arrest. This study is a randomized, double-blind, controlled trial, aiming to demonstrate the superiority of the treatment combination over placebo in terms of day-30 survival and neurological recovery. The trial is expected to span approximately four years, with an estimated recruitment start date of July 18, 2021, and an anticipated end date of August 18, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), sustained return of spontaneous circulation (ROSC) post-cardiac arrest, and hemodynamic failure unresponsive to fluid loading. Following randomization, participants will receive either the active treatment or placebo. The treatment period will last up to seven days, with the maximum daily doses of **hydrocortisone** and **argipressin** being 200 mg and 43.2 IU, respectively.

Follow-up visits will be conducted to monitor the participants' health status and treatment response. These visits will include assessments of vital status, neurological outcomes, and other secondary endpoints such as the Glasgow Outcome Scale, time to recurrent cardiac arrest, and the incidence of adverse events like atrial fibrillation or mesenteric ischemia. The end-of-study visit will occur at day-30, where the primary endpoint of good neurological outcome will be evaluated.

Participant involvement is expected to last for the duration of the treatment period and follow-up, totaling approximately 30 days. Conditions that may lead to early termination from the study include withdrawal of consent, occurrence of serious adverse events, or any medical condition that, in the investigator's opinion, warrants discontinuation of the study treatment. The trial will adhere to rigorous ethical standards, ensuring informed consent is obtained from legally authorized representatives when necessary.

The clinical trial involves the administration of several treatments, including **Sodium Chloride**, which is utilized as a **solution for infusion**. This experimental medication is administered via **intravenous infusion**. The maximum daily dose is 54 ml, with a total maximum dose of 162 ml over a treatment period of up to 3 days. The solution is chemically derived and is used in the trial to maintain blinding.

**Hydrocortisone Upjohn 100 mg** is another experimental treatment used in the trial. It is provided as a **solution for injection** and is administered through **intravenous bolus use**. The maximum daily dose is 200 mg, with a total maximum dose of 1400 mg over a treatment period of up to 7 days. This medication is chemically synthesized and is part of the trial to evaluate its efficacy in combination with other treatments.

The trial also includes a **placebo** for hydrocortisone, which is used to maintain blinding and assess the efficacy of the active treatment. The placebo is designed to mimic the appearance and administration route of the active hydrocortisone treatment but contains no active substance.

Additionally, **Reverpleg 40 U.I./2 ml**, containing **Argipressin**, is used as a **solution for infusion**. This treatment is administered via **intravenous infusion**. The maximum daily dose is 43.2 IU, with a total maximum dose of 129.6 IU over a treatment period of up to 3 days. Argipressin is a protein-derived substance, also known as **arginine vasopressin**, and is included in the trial to assess its potential benefits in post-resuscitation syndrome.

Efficacy in the clinical trial titled "HYVAPRESS. HYdrocortisone and VAsopressine in Post-RESuscitation Syndrome" will be assessed using both primary and secondary endpoints. The primary endpoint is the evaluation of a good neurological outcome at day-30, which will be measured using the **Glasgow Outcome Scale (GOS)**. This scale will categorize outcomes as good (categories 4 and 5) or poor, including death (categories 3, 2, and 1). The GOS will be obtained through an in-hospital visit if the patient remains hospitalized or via telephone contact with patients, relatives, or general practitioners.

Secondary endpoints include various measures such as vital status at day-30, time to day-30 caused by irreversible cardiovascular failure, and time to brain death according to French legislation. Additional assessments involve the **Neuron-specific enolase (NSE)** blood level measured at 48 and 72 hours post-cardiac arrest, the number of days between inclusion and day-30 without catecholamines, norepinephrine, AVP, or inotropic support, and the proportion of patients with new onset atrial fibrillation at day-30. Left ventricular ejection fraction will be evaluated using echocardiography at specified time points, and the KDIGO classification will be assessed at day-7 and day-30. Other parameters include the proportion of patients with acute coronary syndrome, mesenteric ischemia, digital ischemia, central diabetes insipidus, gastrointestinal bleeding, and hyperglycemia occurrence. The length of ICU and hospital stays will also be recorded.