Efficacy of Ketamine, Propofol, and Ketamine-Propofol Combination for Rapid Sequence Induction in Patients at Risk of Aspiration: A Randomized Controlled Trial

The primary objective of this study is to compare the **efficacies** of ketamine alone and a ketamine-propofol combination against standard doses of propofol in achieving successful tracheal intubation on the first attempt without severe hemodynamic hypotension in patients at risk of aspiration of gastric contents in the operating room. This is clinically relevant as it aims to identify the most effective hypnotic drug regimen for rapid sequence induction, potentially improving patient safety and outcomes during surgical procedures.

Secondary objectives include:

• Comparing the efficacy of ketamine and/or the ketamine-propofol combination to standard doses of propofol in preventing postoperative complications.
• Assessing the tolerance of ketamine and/or the ketamine-propofol combination compared to standard doses of propofol.

The clinical trial focuses on patients undergoing **rapid sequence induction** in the operating room, specifically comparing the efficacies of ketamine alone and a ketamine-propofol combination against standard doses of propofol. The study population includes both **female** and **male** participants aged between 18 and 80 years. Participants are required to have at least one risk factor for aspiration of gastric contents, such as a preoperative fasting period of less than 6 hours, recent vomiting, or a history of gastroesophageal reflux. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Selection criteria include the necessity for orotracheal intubation during general anesthesia, with informed consent obtained from the patient or their next of kin. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the efficacy and safety of **ketamine** alone and in combination with **propofol** compared to standard doses of propofol for rapid sequence induction in the operating room. This is a 3-arm, randomized, open-label trial with blinded evaluation of the primary outcome. The trial aims to achieve successful tracheal intubation on the first attempt without severe hemodynamic hypotension in patients at risk of aspiration of gastric contents. The study is categorized as a Phase III trial and is considered low-intervention, as the investigational medicinal products are used in accordance with their marketing authorization, posing minimal additional risk to participants.

The trial will commence with a screening visit to assess eligibility based on criteria such as age between 18 and 80 years, presence of at least one risk factor for aspiration, and requirement for orotracheal intubation during general anesthesia. Participants will be randomly assigned to one of the three study groups. The primary endpoint is the proportion of patients with successful intubation at the first attempt without post-induction hypotension, defined by a mean arterial pressure ≤ 60 mmHg within 10 minutes after the start of the hypnotic injection. Secondary endpoints include rates of arterial hypotension, tracheal intubation success, and various postoperative complications.

The trial is expected to start recruitment on March 10, 2025, and conclude by March 8, 2027. Participants will be involved in the study for a maximum treatment period of one day, with follow-up assessments conducted up to seven days post-procedure to monitor for any major cardiovascular complications or mortality. Conditions that may lead to early termination from the study include withdrawal of consent or any adverse events that compromise participant safety. The study will ensure that all procedures adhere to ethical standards and regulatory requirements, maintaining the integrity and scientific validity of the trial outcomes.

The clinical trial involves the administration of **ketamine**, a chemical active substance, as an experimental medication. Ketamine is provided in the form of a **solution for injection** and is administered via **intravenous injection**. The dosing regimen for ketamine is set at a maximum daily dose of 2 mg/kg, with the same maximum total dose amount, over a treatment period of one day. The trial aims to evaluate the efficacy of ketamine in achieving successful tracheal intubation without severe hemodynamic hypotension in patients at risk of aspiration of gastric contents in the operating room.

In addition to ketamine, the trial also includes the administration of **propofol**, another chemical active substance, which serves as a comparator treatment. Propofol is provided in the form of an **emulsion for injection/infusion** and is also administered via **intravenous injection**. Similar to ketamine, the dosing regimen for propofol is set at a maximum daily dose of 2 mg/kg, with the same maximum total dose amount, over a treatment period of one day. The trial seeks to compare the efficacy of propofol alone and in combination with ketamine to achieve the primary outcome of successful tracheal intubation on the first attempt.

Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the treatment protocol. The trial is designed as a 3-arm randomized study with open-label administration and blinded evaluation of the primary outcome, focusing on the best hypnotic drug choice for rapid sequence induction in the operating room.

Efficacy in this clinical trial will be assessed by evaluating the primary and secondary endpoints related to the use of **ketamine** and **propofol** during rapid sequence induction in the operating room. The primary endpoint is a composite outcome measuring the proportion of patients achieving successful tracheal intubation on the first attempt without experiencing post-induction hypotension, defined as a mean arterial pressure of ≤ 60 mmHg within 10 minutes after the start of the hypnotic injection.

Secondary endpoints will include separate analyses of the components of the primary outcome, such as rates of arterial hypotension episodes and rates of successful tracheal intubation at the first attempt. Additional secondary endpoints will assess the efficacy of **ketamine** and the **ketamine-propofol** combination compared to standard doses of **propofol** in preventing postoperative complications. These will be measured within 10 minutes after the start of the hypnotic injection and will include intubation quality score (IDS-3), Cormack-Lehane score, POGO score, time to tracheal intubation, heart rate, SpO2, arterial pressure, rates of pulmonary aspiration, minimal SpO2 values, and rates of vasopressor use.

Further secondary endpoints will evaluate the tolerance of **ketamine** and the **ketamine-propofol** combination compared to **propofol**. These will be assessed in the recovery room and up to day 7 post-operation, including postoperative Nu-DESC score changes, need for sedative therapy, rates of major cardiovascular complications, and mortality rates at day 7. The efficacy parameters will be collected and analyzed using validated scales and measurements at specified timepoints, ensuring a comprehensive evaluation of the trial's objectives.