Ketamine in Acute Brain Injury Patients.

In this study the effects of ketamine as an adjunct to an standard sedation regime in adult TBI patients will be investigated on the therapy intensity level and intracranial pressure. All patients will receive propofol for sedation to control ICP, to a maximum dose of 4 mg/kg/h. If the ICP is not controlled at the maximum dose of propofol, midazolam will be added, to a maximum dose of 0.3 mg/kg/h, as part of the current standard of care in the Participating Sites. All patients will receive remifentanil, fentanyl or sufentanil infusions for pain relief. The study medication (ketamine or placebo) will be started after randomization.

As part of the current standard of care in the Participating Sites, the decision for decompressive craniectomy and/or barbiturate coma will be taken after multidisciplinary consultation between the treating intensivist and neurosurgeon.

The decision to stop or reduce sedation, lies with the treating physician, based on the level of ICP control, the absence of clinical or radiological signs of deterioration of the neurologic state. In the case of barbiturate coma, the study drug will be discontinued. During and following decompressive craniectomy, the sedative regime (propofol/midazolam/study drug/ opioids) will be continued. In case of suspected or threatening Propofol-Related Infusion syndrome, propofol will be stopped and switched to midazolam. In case of hypertriglyceridemia \>200 mg/dL, propofol will be reduced and if necessary, midazolam will be associated to allow control of sedation. During surgical procedures related to the traumatic brain injury or not, the study drug will not be discontinued. The use of open label administration of ketamine is not allowed during the course of the trial, i.e until hospital discharge.

• Intracranial pressure (ICP) [Time frame: From date of randomization until study drug discontinuation or or date of death from any cause, whichever came first, assessed up to 6 months.]
• Duration of sedation [Time frame: defined as the start of the first infusion of either propofol, midazolam and/or dexmedetomidine to the cessation of the last uninterrupted infusion of either propofol, midazolam, opioids and/or dexmedetomidine, assessed up to 6 months.]
• Propofol [Time frame: From date of randomization until study drug discontinuation or date of death from any cause, whichever came first, assessed at ICU discharge, assessed up to 6 months.]
• Mechanical ventilation [Time frame: From date of randomization until study drug discontinuation or date of death from any cause, whichever came first, assessed up to 6 months.]
• Midazolam [Time frame: From date of randomization until study drug discontinuation or date of death from any cause, whichever came first, assessed up to 6 months.]
• ICU length of stay [Time frame: From ICU admission until ICU discharge (end of stay is defined as application for discharge in the hospital computer system, or death), assessed up to 6 months.]
• Hospital length of stay [Time frame: From admission to hospital until end of stay in hospital (dead or alive), assessed up to 6 months.]
• Richmond Agitation-Sedation scale (RASS) [Time frame: From date of randomization until study drug discontinuation or date of death from any cause, whichever came first, assessed up to 6 months.]
• Delirium [Time frame: From date of randomization until study drug discontinuation or date of death from any cause, whichever came first, assessed up to 6 months.]
• eGOS [Time frame: 6 months after the onset of TBI]
• ICU mortality [Time frame: From date of randomization until ICU discharge, assessed up to 6 months.]
• In-hospital mortality [Time frame: From date of randomization until hospital discharge, assessed up to 6 months.]