Evaluation of Argipressin Versus Noradrenaline in Reducing Intraoperative Fluid Administration During Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy in Disseminated Cancer

The primary objective of this study is to evaluate whether low-dose **argipressin** reduces cumulative intraoperative fluid administration during cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) compared to the standard use of noradrenaline, while adhering to a standard goal-directed therapy (GDT) protocol. This is clinically relevant as managing fluid balance during such complex surgical procedures is crucial for optimizing patient outcomes and minimizing complications associated with fluid overload.

Secondary objectives include:

• Determining if low-dose argipressin decreases postoperative fluid overload compared to standard noradrenaline when using a standard GDT protocol.
• Assessing whether low-dose argipressin reduces postoperative complications and improves overall outcomes and recovery compared to standard noradrenaline under the same protocol.

The clinical trial involves participants diagnosed with **disseminated cancer** who are scheduled to undergo CRS-HIPEC surgery. The study population includes both male and female subjects, with an age range that spans from young adults to older adults. The trial does not involve a vulnerable population. The sponsor has not provided the total number of participants. Participants were selected based on their scheduled surgical procedure, and no specific lifestyle considerations such as diet or physical activity were highlighted. The trial aims to evaluate the effects of low-dose argipressin on intraoperative fluid administration compared to standard noradrenaline under a standard GDT protocol.

The clinical trial is designed to evaluate the efficacy of **argipressin** in reducing cumulative intraoperative fluid administration during cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) in patients with disseminated cancer. This study is a randomized, double-blind, controlled trial, ensuring that neither the participants nor the researchers know which treatment the participants are receiving, thus minimizing bias. The trial is categorized as a low-intervention study and is expected to span from December 2024 to November 2026, with the primary objective of comparing the effects of low-dose argipressin to standard noradrenaline under a standard goal-directed therapy (GDT) protocol.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility is confirmed based on the principal inclusion criterion of being scheduled for CRS-HIPEC. Follow-up visits will be conducted to monitor cumulative total intraoperative fluid administration, postoperative fluid balance, and signs of fluid overload, among other secondary endpoints. These visits will include assessments on postoperative days 0, 1, 3, and up to day 30 for major complications. The end-of-study visit will occur after the final assessment of the primary and secondary endpoints, including the evaluation of quality of recovery and 30-day mortality.

The expected length of participant involvement is approximately 30 days post-surgery, with the possibility of early termination if significant adverse events occur or if the participant withdraws consent. The trial will adhere to strict protocols to ensure the safety and well-being of participants, with regular monitoring and assessments to identify any potential complications or deviations from expected outcomes. The study aims to provide valuable insights into the management of fluid administration during complex surgical procedures in patients with disseminated cancer.

The clinical trial involves the administration of **Empressine**, a pharmaceutical product containing the active substance **argipressin**. Empressine is formulated as a **solution for infusion** and is provided as a concentrate for solution for infusion, with a concentration of 40 I.E./2ml. The product is manufactured by ORPHA-DEVEL HANDELS UND VERTRIEBS GMBH. The active substance, argipressin, also known as **arginine vasopressin**, is classified under the ATC code H01BA01, indicating its role as a vasopressin. The maximum daily dose of Empressine is 43.2 IU, with a total maximum dose of 432 IU over a treatment period not exceeding 10 days. The route of administration is via infusion, and the product is not formulated for pediatric use.

In this study, Empressine is being evaluated for its potential to decrease cumulative intraoperative fluid administration during cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). The trial aims to compare the effects of low-dose argipressin with standard noradrenaline when using a standard goal-directed therapy (GDT) protocol. The study does not involve any other experimental treatments, and the use of a placebo or comparator treatment is not specified. Participant compliance with the dosing schedule will be monitored to ensure adherence to the protocol.

Efficacy in the clinical trial titled "Decrease of intraoperative fluid administration in cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) with **vasopressin** (HiPRESS)" will be assessed using both primary and secondary endpoints. The primary endpoint is the cumulative total intraoperative fluid administration, measured in milliliters, at the end of the operation, which includes the amounts of crystalloids and blood products. Secondary endpoints include cumulative total intraoperative fluid administration measured in mL/kg/h, postoperative fluid balance in mL, fluid balance at day 1, and signs of fluid overload assessed by Point-of-care ultrasound (POCUS) at days 0, 1, and 3. Additional secondary endpoints are major complications rated by the Clavien Dindo score ≥2 up to postoperative day 30, abdominal complications up to day 30, pulmonary complications up to day 5, postoperative acute kidney injury as defined by the Kidney Disease Improving Global Outcomes (KDIGO) up to day 5, quality of recovery (QoR-15) at day 3, hospital and ICU length of stay, and 30-day mortality.