Invasive mechanical ventilation of critically ill patients in the intensive care unit (ICU) is associated with significant morbidity and mortality, as well as a severe prognosis in survivors, in terms of functional, psychological, and cognitive sequelae. During the initial phase, invasive mechanical ventilation aims to promote oxygenation and reduce respiratory effort, with most patients receiving continuous intravenous sedation comprising gamma-aminobutyric acid (GABA) agonists (propofol, midazolam), and opioids. This continuous intravenous sedation is associated with complications, particularly hemodynamic issues (e.g., hypotension, vasopressor dependency), and neurological concerns (e.g., coma, delayed awakening, withdrawal syndrome upon discontinuation of sedation) during the acute phase and is linked to prolonged mechanical ventilation and long-term neurocognitive sequelae.

The use of ketamine as an alternative sedative agent in ICU has garnered considerable attention in recent years. Ketamine has a rapid onset of action and a short duration of effect, potentially beneficial bronchodilatory effects, and minimal impact on hemodynamics or respiratory drive. It also provides effective analgesia. Due to its action on N-methyl-D-aspartate (NMDA) glutamatergic receptors, its mechanism of action differs from other commonly used agents such as propofol and benzodiazepines. Furthermore, emerging research suggests that ketamine may have anti-inflammatory/immunomodulatory and neuroprotective properties that could be advantageous in critically ill patients.

Recent observational studies utilizing low-dose ketamine have suggested an improvement in neurological complications in ICU (e.g., coma, delirium) while other authors have raised concerns about potential renal and hepatic toxicity associated with high doses of ketamine used for sedation. Despite its increasing use, there is currently a lack of high-quality data on the efficacy and safety of ketamine use for sedation in critically ill patients.

In this trial, we hypothesise that, critically ill patients requiring unplanned invasive mechanical ventilation, adjunctive treatment with low dose of ketamine will translate into better outcomes, with higher numbers of days alive outside of the hospital.

The study is a multicenter, randomised, double-blinded placebo-controlled superiority trial involving adult patients requiring unplanned mechanical ventilation, and sedation for more than 6 hours in the ICU. Patients will be randomised within 48 hours following initiation of mechanical ventilation adhering to a 1:1 allocation of ketamine or placebo.

Patients will be randomized to receive either intravenous ketamine or placebo as an adjunctive sedative agent during ICU stay for a maximum duration of 14 days.

Follow-up visits will be performed at day 3, day 14, ICU discharge, day 60, and day 90 after randomization.

The primary endpoint, "days alive and at home," will be assessed at day 60. The end of the research visit is the day 90 follow-up visit. If the patient has been discharged from the hospital, the day-90 visit will consist of telephone contact with the patient by a centralized research assistant and he also will complete the scales at D90.

Data collected by phone consist in Vital status, scales's results and Retrieval of Adverse Events if the patient has been discharged home or with the medical team of the healthcare structure if the patient has been discharged to another structure.

Phase III study Prospective, multicenter, superiority, double-blind, randomized controlled study with two arms (1:1).

The study includes a screening/baseline visit (V0), followed by daily assessments during the intervention period (V1 to V4), and post-discharge (V5) follow-up visits at Day 60 (V6) and Day 90 (V7).

At screening and baseline (within 48 hours prior to Day 1), eligibility is confirmed, and informed consent is obtained when possible. In cases where prior consent cannot be obtained, deferred consent procedures are applied in accordance with French legislation. Baseline data include medical history, comorbidities, concomitant treatments, clinical examination, and pregnancy testing when applicable.

Randomization is performed at Day 1 (V1). From Day 1 to Day 14 (V4), patients will be receive either intravenous ketamine or placebo as an adjunctive sedative agent during ICU stay for a maximum duration of 14 days.

Until ICU discharge (V5), patients undergo daily assessments including clinical examination, vital status, organ dysfunction (Sequential Organ Failure Assessment [SOFA] score), At Day 14 (V4), opioid and sedative consumption during the treatment period will be quantified.

At Day 60 (V6), ventilator-free days and vasopressor-free days will be assessed.

Duration of delirium and coma are assessed using the RASS/CAM-ICU, at V 4, during the first 14 days following randomization.

Biological monitoring includes daily measurement of serum creatinine and liver function parameters (ASAT, ALAT, gamma-GT, and bilirubin) to evaluate potential renal and hepatic toxicity. Adverse events are collected throughout the ICU stay, and assessed at Day 60 (V6) At ICU discharge (V5), a clinical evaluation and morbidity/mortality assessment are performed if the patient is still hospitalized.

The primary endpoint-the number of days alive and at home-is assessed at Day 60. Secondary outcomes, including mortality (all-cause deaths), are assessed at both Day 60 (V6) and Day 90(V7).

Inclusion Criteria :

1. Patients over 18 years of age
2. Signed informed consent or inclusion under the emergency provisions of the law (ArticleL1122 -1-3 of the PHC / modified by Order n°2016-800 of June 16 2016 - art. 2)
3. Need for unplanned invasive mechanical ventilation
4. Need for continuous intravenous sedative agents (propofol, midazolam or dexmedetomidine) for more than 6 hours.
5. Affiliation to a social security system (excluding "Aide Médicale d'Etat" [AME])

Exclusion Criteria

1. Refusal to participate in the study
2. Acute brain injuries (i.e. acute stroke, traumatic brain injury, cardiac arrest, brain infections) or conditions (status epilepticus or coma with suspected/confirmed intracranial hypertension at admission requiring deep sedation)
3. Psychosis
4. Status asthmaticus
5. Current liver failure with Model for End-Stage Liver Disease (MELD) > 30
6. Initiation of mechanical ventilation > 48 hours
7. Expected lifespan < 24 hours
8. Patients already receiving a continuous infusion of ketamine
9. Currently participating in another interventional clinical trial investigating sedation or protocols using Ketamine or another drug which may interact with Ketamine or which may have an impact on the evaluation of the trial's judgement criteria.
10. Positive highly sensitive pregnancy test
11. Persons deprived of liberty
12. Persons on a protective judicial measure
13. Breastfeeding
14. Severe arterial hypertension (mean arterial pressure>130 mmHg) despite treatment
15. Hypersensitivity to the active substances or any of the excipients
16. Known contraindications to ketamine according to the SmPC (Severe heart failure, history of stroke, severe uncontrolled hypertension, severe aneurysmal disease, pheochromocytoma)

Treatments will be conditioned and labelled by AGEPS according to a list provided by an independent person and assigning a treatment arm to each treatment number.

Patients, investigation site staff, persons performing the assessments, and data managers will remain blinded to the treatment codes from the time of randomization until database lock, using the following methods:

• Randomization and treatment numbers lists are kept strictly confidential until the time of unblinding, and will not be accessible by anyone involved in the study, with the exception of the independent, unblinded statistician approving the randomization scheme;
• The study will be kept blinded to patients, investigators and study personnel also during the entire study period;
• The identification of treatment will be concealed by the use of a matching placebo to the study product that will be provided in boxes identical in packaging, labelling and appearance.