KetAmine and Recovery After Mechanical VentilAtion ( KARMA )

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

• Patients over 18 years of age
• 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)
• Need for unplanned invasive mechanical ventilation
• Need for continuous intravenous sedative agents (propofol, midazolam or dexmedetomidine) for more than 6 hours.
• Affiliation to a social security system (excluding "Aide Médicale d'Etat" [AME])

Exclusion criteria

• Refusal to participate in the study
• 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)
• Psychosis
• Status asthmaticus
• Current liver failure with Model for End-Stage Liver Disease (MELD) > 30
• Initiation of mechanical ventilation > 48 hours
• Expected lifespan < 24 hours
• Patients already receiving a continuous infusion of ketamine
• 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.
• Positive highly sensitive pregnancy test
• Persons deprived of liberty
• Persons on a protective judicial measure
• Breastfeeding
• Severe arterial hypertension (mean arterial pressure>130 mmHg) despite treatment
• Hypersensitivity to the active substances or any of the excipients
• Known contraindications to ketamine according to the SmPC (Severe heart failure, history of stroke, severe uncontrolled hypertension, severe aneurysmal disease, pheochromocytoma)