Although, in the past years, an increasing use of ketamine in Traumatic Brain injury (TBI) has been reported as an adjunct to other sedatives, there is no evidence from randomized clinical trial to support this practice. The BIKe (Brain Injury and Ketamine) study is a double-blind placebo controlled randomized multicenter clinical trial to examine the safety and feasibility of using ketamine as an adjunct to a standard sedative strategy in TBI 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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
SUPPORTIVE_CARE
Masking
DOUBLE
Enrollment
100
Racemic ketamine® will be administered by continuous infusion in a prefilled 50 ml syringe at a concentration of 50 mg/ml, undiluted. The ketamine dose is 1 mg/kg/h, to a maximum dose of 120 mg/hour, which corresponds to an infusion rate of 0.02 ml/kg/h to a maximum rate of 2.4 ml/h.
Placebo (NaCl 0.9%) will be provided in the same type syringes and administered at the same infusion rate as the IMP (0.02 ml/kg/h to a maximum rate of 2.4 ml/h).
Imelda Bonheiden
Bonheiden, Belgium
RECRUITINGAZ Sint-Jan
Bruges, Belgium
RECRUITINGJessa Ziekenhuis
Hasselt, Belgium
Change in therapeutic intensity of intracranial pressure (ICP) reducing measures, assessed by the TIL score (Therapy Intensity Level)
The primary efficacy endpoint will be the reduction in daily Therapy Intensity Level (TIL) score, based on the highest score in each item per day until study drug discontinuation (calculated every day on the available data at 7:00 AM). Scales for TIL score range from 0 (minimum) to 38 (maximum). Higher scores are related to worse outcome.
Time frame: From date of randomization (and start study drug) until study drug discontinuation or date of death from any cause, whichever came first, assessed up to 6 months.
Intracranial pressure (ICP)
The average of hourly validated intracranial pressure (mmHg) measurements per 24 hours
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
Total duration of the first period of sedative treatments (propofol, midazolam and/or dexmedetomidine)
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
Total dose of propofol in mg per 24 hours
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
Total duration of mechanical ventilation, defined as all types of ventilation where positive end expiratory pressure is applied, expressed in cm H2O (5 cm H2O minimum).
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.
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UZLeuven
Leuven, Belgium
RECRUITINGCHR de la Citadelle Liège
Liège, Belgium
RECRUITINGCHU de Liège
Liège, Belgium
RECRUITINGAZ Delta
Roeselare, Belgium
RECRUITINGAZ Turnhout
Turnhout, Belgium
RECRUITINGMidazolam
Total dose of midazolam in mg per 24 hours
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
Length of stay (number of days) in ICU
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
Length of stay in hospital (days)
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)
Average daily RASS. Scale ranges from +4 (combative) until -5 (Unarousable).
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
Number of delirium-free days, assessed 3 times per day with the Intensive Care Delirium Screening Checklist (ICDSC) or Confusion Assessment Method for the ICU (CAM-ICU delirium scale).
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
extended Glasgow Outcome Scale (eGOS)
Time frame: 6 months after the onset of TBI
ICU mortality
Mortality during ICU stay
Time frame: From date of randomization until ICU discharge, assessed up to 6 months.
In-hospital mortality
Mortality during hospital stay
Time frame: From date of randomization until hospital discharge, assessed up to 6 months.
Barbiturate coma incidence
The incidence of barbiturate coma
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.
Barbiturate coma duration
The duration of barbiturate coma
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.
Decompressive craniectomy
The incidence of decompressive craniectomy
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, assessed up to 6 months.
Propofol Infusion Syndrome (PRIS)
Incidence of PRIS documented and diagnosed by the attending physician and defined as: * Cardiac manifestations, not explained by a coronary ischemic event: * Acute refractory bradycardia leading to asystole, or * ECG: widening of QRS-complex, or Brugada-syndrome-like patterns (particularly Type 1: Coved-type ST-segment elevation \>2mm in \>1 of V1-V3 followed by a negative T-wave), or ventricular tachy-arrhythmias * Combined with one or more of the following: * Unexplained metabolic acidosis (base deficit \> 10 mmol/L) * Rhabdomyolysis (Creatinine kinase at least five times the upper limit of normal) * Hyperlipidaemia (triglyceride levels \> 150 mg/dl) * Enlarged or fatty liver, apparent on CT or echography * All occurring in patients receiving propofol for \> 24h * Diagnosed by the attending physician
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.