Evaluation of Prolonged Hydrocortisone and Fludrocortisone Therapy in Intermediate/High-Risk Cardiac Surgery Patients: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to demonstrate the efficacy of prolonged **corticosteroid therapy** for 5 days, using Hydrocortisone and Fludrocortisone, compared to placebo in patients at intermediate to high risk undergoing scheduled cardiac surgery. This is clinically relevant as it aims to improve outcomes in a population vulnerable to complications during cardiac procedures.

Secondary objectives include comparing between both groups:

• The occurrence of major cardiovascular events within 7 days post-surgery, including postoperative atrial fibrillation, cerebrovascular accident, and myocardial infarction.
• The cumulative norepinephrine levels within 7 days of surgery.
• The side effects observed 7 days after surgery.
• The mortality rate at 28 days post-surgery.

The clinical trial involves participants undergoing **cardiac surgery** who are at intermediate to high risk, as defined by a Euroscore II greater than 4%. The study population includes both male and female subjects over the age of 18, with no specific mention of vulnerable populations being included. Participants are required to be admitted for scheduled cardiac surgery and must provide signed informed consent. The trial aims to assess the efficacy of prolonged corticosteroid therapy, specifically Hydrocortisone and Fludrocortisone, compared to a placebo. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of prolonged **corticosteroid** therapy in patients undergoing scheduled cardiac surgery who are at intermediate or high risk. This study is a prospective, multicenter, randomized, controlled, double-blind, placebo-controlled trial. The trial aims to compare the effects of a combination of **hydrocortisone** and **fludrocortisone** administered over a period of five days against a placebo. The primary endpoint is a composite measure of the occurrence of acute renal failure, postoperative pulmonary complications, or the use of noradrenaline within seven days post-surgery. Secondary endpoints include major cardiac events, stroke, total noradrenaline usage, specific side effects such as hypernatremia and hyperglycemia, and mortality at 28 days.

Participants will be involved in the study for a maximum of five days of treatment, with follow-up assessments extending to 28 days post-surgery. The trial is expected to commence recruitment on March 15, 2025, and conclude by April 15, 2028. The inclusion criteria require participants to be over 18 years of age, at intermediate or high risk as defined by a Euroscore II greater than 4%, and scheduled for cardiac surgery involving extracorporeal circulation. Informed consent is mandatory for participation. There are no specified exclusion criteria provided.

The sequence of study visits includes an initial screening visit to confirm eligibility based on the inclusion criteria. Following this, participants will undergo the treatment phase, which involves the administration of the study drugs or placebo. Follow-up visits will be conducted to monitor the primary and secondary endpoints, with the final visit occurring 28 days post-surgery to assess mortality and any long-term effects. Participants may be withdrawn from the study if they experience adverse effects that necessitate discontinuation of the treatment or if they withdraw consent. The study is structured to ensure rigorous monitoring and data collection to support the evaluation of the trial's objectives.

The clinical trial involves the administration of **HYDROCORTISONE**, a chemical active substance, formulated as a solution for injection/infusion. The maximum daily dose is 200 mg, with a total maximum dose of 1000 mg over a treatment period of 5 days. The route of administration is via infusion. This medication is used as part of the experimental treatment to evaluate the efficacy of prolonged corticosteroid therapy in patients undergoing scheduled cardiac surgery.

**FLUDROCORTISONE** is another experimental medication used in this trial. It is a chemical active substance provided in tablet form. The maximum daily dose is 50 µg, with a total maximum dose of 250 µg over a 5-day treatment period. The administration route is oral. This medication is combined with hydrocortisone to assess the therapeutic benefits of corticosteroid therapy in the specified patient population.

As a comparator treatment, **SODIUM CHLORIDE** is utilized as a placebo. It is a chemical substance available as an irrigation solution. The maximum daily dose is 200 mg, with a total maximum dose of 1000 mg over the course of 5 days. The administration is conducted via infusion. This placebo is used to maintain the double-blind nature of the study.

**CELLULOSE, MICROCRYSTALLINE** serves as an additional placebo in the trial. It is a polymer active substance provided in oral powder form. The maximum daily dose is 50 µg, with a total maximum dose of 250 µg over a 5-day period. The route of administration is oral. This placebo is used to ensure the integrity of the study's blinding process.

Efficacy in this clinical trial will be assessed by evaluating both primary and secondary endpoints. The primary endpoint is a composite measure that includes the occurrence of one of the following events within 7 days post-surgery: **Acute Renal Failure (ARF)**, postoperative pulmonary complications (PPC), or the use of noradrenaline. These events will be monitored and recorded to determine the effectiveness of the prolonged corticosteroid therapy, which includes **Hydrocortisone** and **Fludrocortisone**, compared to a placebo in intermediate/high-risk patients undergoing scheduled cardiac surgery.

Secondary endpoints will provide additional insights into the efficacy of the treatment. These include the incidence of major cardiac events (MCE), stroke confirmed by brain imaging, and the total quantity of noradrenaline administered from admission to intensive care until day 7 post-surgery. Furthermore, side effects such as hypernatremia, hyperglycemia requiring insulin therapy, and infections like urinary tract infection, postoperative pneumonitis, and mediastinitis will be documented. Mortality at 28 days, defined as death from any cause from the date of surgery up to and including day 28, will also be assessed.