Best hypnotic drug choice for rapid sequence induction in the operating room: study protocol for a 3-arm superiority open-labeled randomized controlled trial with blinded evaluation of the primary outcome (the HyPnotiKs study).

BACKGROUND: Propofol is the most frequently used hypnotic during rapid sequence induction in patients at risk of pulmonary aspiration of gastric contents worldwide. Its most common side effect is to induce hypotension due to dose-dependent vasoplegia. Ketamine is an alternative with pharmacological hemodynamic stability but a higher risk of postoperative delirium. Ketofol, an equimolar combination of these two hypnotics, has recently been proposed in this setting. The objective of this study is to demonstrate the superiority of ketamine (or ketofol) compared to propofol, in association with a neuromuscular blocking agent, for achieving tracheal intubation without hypotension in patients undergoing surgery under general anesthesia and at risk of pulmonary aspiration of gastric contents.

METHODS: The HyPnotiKs study is a multicenter, open-labeled, superiority, randomized controlled trial comparing ketamine (2 mg/kg), propofol (2 mg/kg), and ketofol (1 mg/kg each) for rapid sequence induction in 1218 adult surgical patients requiring tracheal intubation during general anesthesia. Enrollment started in April 2025 in 20 French anesthesia units. The expected date of the final follow-up is May 2027. The primary outcome is the proportion of successful tracheal intubation at the first attempt and without major hypotension. A hierarchical procedure is planned to compare the three arms. Intention-to-treat principle will be applied.

DISCUSSION: The HyPnotiKs study protocol has been approved by the ethics committee of the Comité de Protection des Personnes Sud Méditerranée V and will be carried out in accordance with the principles of the Declaration of Helsinki and the Good Clinical Practice guidelines. The results of this study will be disseminated through presentations at scientific conferences and publications in peer-reviewed journals. The HyPnotiKs study is the first randomized controlled trial powered to investigate whether ketamine, ketofol, or propofol is the hypnotic of first choice for rapid sequence induction of anesthesia in patients with a full stomach, considering successful tracheal intubation without hypotension.

TRIAL REGISTRATION: ClinicalTrials.gov NCT06733129. Registered on December 2024.