Effect of Adjuvant Ketamine on Recovery from Critical Illness in Adult Patients Requiring Unplanned Invasive Mechanical Ventilation: A Multicenter Randomized Controlled Trial

The primary objective is to evaluate recovery from critical illness in patients requiring unplanned invasive mechanical ventilation within the intensive care unit. This study is classified under Therapy.

Secondary objectives include:

• Assessment of encephalopathy, specifically the duration of coma or delirium, within the first 14 days after randomization.
• Measurement of the number of days patients remain alive and free from mechanical ventilation within 60 days.
• Evaluation of the duration of shock, defined by the requirement for vasopressors or inotropes, within 60 days.
• Assessment of mortality at 60 and 90 days.
• Monitoring of renal toxicity and liver toxicity within 60 days.
• Exploratory assessment of opioid and sedative consumption, pain, sedation status, and hallucination events during the first 14 days.
• Evaluation of neuropsychological sequelae, including anxiety and depression, as well as post-traumatic stress disorder at day 90.

The sponsor did not provide information regarding the total number of participants. The study population consists of adult patients, including both males and females, admitted to the intensive care unit. The cohort is composed of individuals requiring unplanned invasive mechanical ventilation and the administration of continuous intravenous sedative agents, such as propofol, midazolam, or dexmedetomidine, for a duration exceeding 6 hours. Eligible participants must be over 18 years of age and possess affiliation to a social security system. The population includes vulnerable individuals.

This multicenter, double-blind, randomized controlled trial is designed to evaluate recovery from critical illness in adult patients requiring unplanned invasive mechanical ventilation. Participants will be randomized to receive either an infusion of ketamine hydrochloride or a sodium chloride placebo. The primary objective is to assess the number of days patients are alive and at home at 60 days following the initiation of the study drug or placebo. Secondary endpoints include ventilation-free days, vasopressor-free days, mortality, encephalopathy, and various measures of renal toxicity, liver toxicity, and psychological outcomes such as post-traumatic stress disorder. The study involves a screening process to identify eligible patients, followed by the treatment period and subsequent follow-up assessments to collect data at 14, 60, and 90 days. The estimated duration of the study, including recruitment, is from September 2026 to December 2028.

The experimental treatment consists of ketamine hydrochloride, provided as ketamine Renaudine in a solution for injection. This substance is administered via infusion at a dosage of 14.4 mg/kg.

The comparator treatment is a placebo consisting of sodium chloride, which is administered via infusion.

The primary efficacy endpoint is the number of days patients are alive and spent at home at 60 days following the initiation of the study drug or placebo. This parameter will be collected by an independent research assistant blinded to the randomization groups. Secondary endpoints include:

• The number of days alive and free of encephalopathy, characterized by coma or delirium as measured by the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU), during the 14 days following randomization.
• The number of ventilation-free days at 60 days.
• The number of vasopressor-free days, defined as days spent alive without norepinephrine or inotropes infusion during the ICU stay, at 60 days.
• Mortality, determined by the prevalence of all-cause deaths at 60 and 90 days.
• Renal toxicity, defined by the proportion of patients reaching a KDIGO stage ≥2 at 60 days.
• Liver toxicity, defined by the peak bilirubin and alkaline phosphatase levels during the first 60 days.
• Quantification of opioid and sedative consumption during the first 14 days of treatment.
• Mean daily pain scores measured via the Behavioral Pain Scale (BPS) and sedation scores via the Richmond Agitation-Sedation Scale (RASS) during the first 14 days.
• Cumulative incidence of hallucination events during the 14 days after randomization.