Evaluation of Goal-Directed Low Oxygen Concentration Versus Fixed Oxygen Concentration During Anesthesia in Patients Undergoing Surgery: A Randomized Controlled Trial

The primary objective of this study is to evaluate whether there is an improvement in postoperative **arterial oxygen partial pressure (PaO2)** following the use of goal-directed low oxygen concentration during anesthesia, as opposed to the routine use of fixed oxygen concentrations. This is clinically relevant as optimizing oxygen levels during anesthesia could potentially enhance patient outcomes by improving oxygenation post-surgery.

Secondary objectives include assessing:

• Improvement in oxygen transport, measured as the diffusion capacity for carbon monoxide (DLCO), after goal-directed low oxygen concentration during anesthesia.
• Enhancement in vital capacity and postoperative recovery with goal-directed low oxygen concentration.
• Differences in changes in arterial carbon dioxide partial pressure (PaCO2) and arterial oxygen partial pressure (PaO2) on postoperative day 1 and after 3 months, based on randomization.
• Variations in surgical site infections, postoperative recovery, and hospital length of stay concerning randomization.
• The impact of background variables such as age, sex, BMI, type of surgery, duration of surgery, and type of anesthesia on outcomes.

The clinical trial involves **adults** over the age of 18 who are scheduled for abdominal surgery under **general anesthesia**. The study population includes both male and female participants, with no specific vulnerable populations selected. Participants are required to fall under the American Society of Anesthesia (ASA) Class 1-3, indicating they are generally healthy or have mild systemic disease. The trial does not specify the total number of participants, as the sponsor has not provided this information. Participants must have given written consent to partake in the trial. The study does not highlight any specific lifestyle considerations such as diet or physical activity. The trial population was selected based on their scheduled surgeries in the Departments of Surgery, Urology, and Gynecology, with procedures expected to last more than two hours.

The clinical trial is designed as a **randomized**, single-blind, controlled, multicenter study, focusing on the effects of goal-directed low oxygen concentration during anesthesia compared to a fixed oxygen concentration. The primary objective is to assess the improvement in postoperative arterial oxygen partial pressure (**PaO2**) following surgery under general anesthesia. The trial is categorized as a Phase IV study and is not considered low intervention. The trial is expected to commence recruitment on January 1, 2025, and conclude by December 31, 2026.

Participants will be adults over 18 years of age, scheduled for abdominal surgery lasting more than two hours, and classified under the American Society of Anesthesia (ASA) Class 1-3. Written consent is required for participation. The study will involve several visits, beginning with an inclusion (screening) visit to confirm eligibility based on the inclusion criteria. Follow-up visits will occur on postoperative day 2, where the primary endpoint, PaO2, will be measured. Secondary endpoints include changes in diffusion capacity for carbon monoxide, vital capacity, and PaO2 and PaCO2 levels, assessed on day 2 and after three months. Additional follow-up will monitor surgical site infections, postoperative recovery, and hospital length of stay.

The expected duration of participant involvement is approximately three months, with conditions for early termination including withdrawal of consent or any adverse events that compromise participant safety. The study will utilize **nitrous oxide** and **oxygen** administered as an inhalation gas, with a maximum daily and total dose of 100% for a treatment period of one day. The trial will not involve pediatric formulations or orphan drug designations. The study aims to provide valuable insights into optimizing oxygen concentration during anesthesia to enhance postoperative outcomes.

The clinical trial involves the administration of an **experimental medication** composed of a combination of **nitrous oxide** and **oxygen**. The pharmaceutical form of this medication is designated as PHF763, and it is administered as an **inhalation gas**. The dosage is expressed in percentage terms, with a maximum daily dose and total dose amounting to 100% each. The treatment period is limited to a maximum of one day. The active substances, **nitrous oxide** and **oxygen**, are both of chemical origin. **Nitrous oxide** is also known by synonyms such as nitrogen dioxide, dinitrogenii oxidum, nitrogen monoxide, and laughing gas. **Oxygen** is alternatively referred to as oxygenium. The ATC code for this combination is V03AN01, classified under the category of oxygen.

In addition to the experimental medication, the study employs a **comparator treatment** involving the routine use of fixed oxygen concentrations. This standard-of-care therapy serves as a control to evaluate the efficacy of the goal-directed low oxygen concentration approach during anesthesia. The trial is designed to assess improvements in postoperative arterial oxygen partial pressure (PaO2) when using the experimental treatment compared to the fixed oxygen concentration method. Participant compliance with the dosing schedule is monitored to ensure adherence to the treatment protocol.

Efficacy in this clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoint is the improvement in postoperative **arterial oxygen partial pressure (PaO2)**, measured on postoperative day 2 compared to the day before surgery. To ensure accurate measurement, supplemental oxygen will be ceased before blood sampling, if possible, for 30 minutes or longer.

Secondary endpoints include changes in diffusion capacity for carbon monoxide, vital capacity (VC), and PaO2 and PaCO2 on day 2 and after 3 months compared to baseline. Additional secondary endpoints are the incidence of surgical site infections within 30 days of surgery, postoperative recovery assessed using the Postoperative Recovery Profile at discharge and after 3 months, and hospital length of stay. The effect of background variables such as age, sex, height, weight, body mass index (BMI), type of surgery, duration of surgery, and type of anesthesia on outcomes will also be analyzed.