Moderate-to-Severe Traumatic Brain Injury
Conditions
Brief summary
The goal of this clinical trial is to compare the effects of propofol, midazolam, and dexmedetomidine on intracranial pressure control and clinical outcomes in adults with moderate-to-severe traumatic brain injury undergoing urgent neurosurgical intervention. The main questions it aims to answer are: * Which sedative agent provides better control of intracranial pressure, assessed by optic nerve sheath diameter (ONSD), during the first 24 hours after neurosurgical intervention? * How do the three sedative agents compare in achieving target sedation depth, maintaining hemodynamic stability, and improving short-term clinical outcomes such as ICU mortality, duration of mechanical ventilation, and ICU length of stay? Participants will be randomly assigned to receive propofol, midazolam, or dexmedetomidine for 24 hours of continuous sedation. Clinical, hemodynamic, and neurological outcomes will be assessed and compared among the three study groups.
Detailed description
Traumatic brain injury (TBI) is a major cause of mortality and long-term disability worldwide. Prevention of secondary brain injury through optimal control of intracranial pressure (ICP) is a key component of intensive care management in patients with moderate-to-severe TBI. Sedative agents are routinely used to facilitate mechanical ventilation, reduce cerebral metabolic demand, and improve ICP control. However, uncertainty remains regarding the optimal sedative agent for this patient population. Propofol, midazolam, and dexmedetomidine are among the most commonly used sedatives in neurocritical care. Each agent has distinct pharmacological characteristics that may influence intracranial pressure, hemodynamic stability, neurological assessment, and clinical outcomes. Despite widespread use, direct comparative evidence between these agents remains limited. This prospective randomized clinical trial aims to compare the effects of propofol, midazolam, and dexmedetomidine on intracranial pressure control and clinical outcomes in adult patients with moderate-to-severe traumatic brain injury undergoing urgent neurosurgical intervention. Intracranial pressure will be assessed noninvasively using serial optic nerve sheath diameter (ONSD) measurements obtained by ocular ultrasonography during the first 24 hours of continuous sedation. Participants will be randomly assigned to receive one of the three sedative regimens according to a standardized protocol targeting a Richmond Agitation-Sedation Scale (RASS) score of -3 to -4. Standard neurocritical care management and analgesia protocols will be applied to all study groups. The study will evaluate the comparative effects of the three sedative agents on intracranial pressure control, sedation quality, hemodynamic stability, adverse events, secondary brain injury, and short-term clinical outcomes. The findings are expected to provide evidence to guide sedative selection in patients with moderate-to-severe traumatic brain injury, particularly in settings where invasive intracranial pressure monitoring is not routinely available.
Interventions
DRUGpropofol
Continuous intravenous propofol infusion initiated at 1 mg/kg/h and titrated within a range of 1-4 mg/kg/h to maintain a target Richmond Agitation-Sedation Scale (RASS) score of -3 to -4 during the 24-hour study intervention period.
DRUGmidazolam
Continuous intravenous midazolam infusion initiated at 0.03 mg/kg/h and titrated within a range of 0.02-0.1 mg/kg/h to maintain a target Richmond Agitation-Sedation Scale (RASS) score of -3 to -4 during the 24-hour study intervention period. An initial bolus dose of 0.05 mg/kg may be administered if rapid sedation is required.
DRUGDexmedetomidine
Continuous intravenous dexmedetomidine infusion initiated at 0.4 μg/kg/h and titrated within a range of 0.2-0.7 μg/kg/h to maintain a target Richmond Agitation-Sedation Scale (RASS) score of -3 to -4 during the 24-hour study intervention period. No loading dose will be administered.
Sponsors
Aswan University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
This is an open-label randomized trial. Treating clinicians and investigators are aware of treatment allocation. Outcome assessment is blinded; optic nerve sheath diameter (ONSD) measurements are performed by a blinded ultrasonographer, and radiological outcomes are evaluated by a blinded neuroradiologist who is unaware of treatment assignment.
Intervention model description
Participants will be randomly assigned in a 1:1:1 ratio to one of three parallel treatment groups receiving continuous sedation for 24 hours following urgent neurosurgical intervention for moderate-to-severe traumatic brain injury. Group A will receive propofol initiated at 1 mg/kg/h and titrated within a range of 1-4 mg/kg/h to maintain a target Richmond Agitation-Sedation Scale (RASS) score of -3 to -4. Group B will receive midazolam initiated at 0.03 mg/kg/h and titrated within a range of 0.02-0.1 mg/kg/h to maintain the target RASS score. An initial bolus dose of 0.05 mg/kg may be administered if rapid sedation is required. Group C will receive dexmedetomidine initiated at 0.4 μg/kg/h and titrated within a range of 0.2-0.7 μg/kg/h to maintain the target RASS score. Participants will remain in their assigned treatment group throughout the intervention period, and outcomes will be compared between groups. The trial uses a prospective randomized parallel-group design with blinded
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥18 years * Moderate to severe traumatic brain injury with post-resuscitation Glasgow Coma Scale (GCS) ≤12 * Undergone urgent neurosurgical intervention (craniotomy, craniectomy, or ICP monitor placement) within 24 hours of injury * Admitted to ICU and expected to require continuous sedation * Hemodynamically stable or stabilized (defined as MAP ≥65 mmHg with vasopressor requirement ≤0.1 mcg/kg/min norepinephrine equivalent) * Informed consent obtained from legally authorized representative
Exclusion criteria
* The Relative refusal to participate in the research. * Known allergy or contraindication to propofol, midazolam, or dexmedetomidine * Pre-existing neurological disorders (epilepsy, prior stroke, brain tumors, dementia) that may interfere with outcome assessment * Severe hepatic dysfunction (Child-Pugh Class C) or acute liver failure * Severe renal dysfunction (eGFR \<30 mL/min/1.73m² or requiring renal replacement therapy) * Pregnancy or breastfeeding * Hemodynamic instability requiring norepinephrine \>0.1 mcg/kg/min or equivalent vasopressor support * Heart rate \<50 bpm or second/third-degree AV block without pacemaker (relative contraindication for dexmedetomidine) * Clinical determination of brain death or expected survival \<24 hours * Enrollment in another interventional trial * Severe polytrauma requiring ongoing surgical interventions that would interfere with protocol adherence
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Intracranial Pressure Control Assessed by Optic Nerve Sheath Diameter (ONSD) | Baseline, 6 hours, 12 hours, and 24 hours after initiation of sedation | Intracranial pressure control will be evaluated using serial optic nerve sheath diameter (ONSD) measurements obtained by ocular ultrasonography. The primary outcome will be the mean ONSD over the 24-hour intervention period, analyzed as a continuous measure of intracranial pressure control. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Time at Target Sedation Level | 24 hours after initiation of sedation | Percentage of assessment time during which patients maintained the target Richmond Agitation-Sedation Scale (RASS) score of -3 to -4. The Richmond Agitation-Sedation Scale ranges from +4 (combative) to -5 (unarousable). Higher scores indicate greater agitation, whereas lower scores indicate deeper sedation. The target sedation level for this study is RASS -3 to -4. |
| Mean Richmond Agitation-Sedation Scale (RASS) Score | 24 hours after initiation of sedation | Mean Richmond Agitation-Sedation Scale (RASS) score during the 24-hour intervention period. The RASS ranges from +4 (combative) to -5 (unarousable), with target sedation defined as -3 to -4. |
| Need for Rescue Sedation | 24 hours after initiation of sedation | Proportion of patients requiring rescue sedation due to failure to achieve target sedation despite maximum protocol dose. |
| Time to Achieve Target Sedation | 24 hours after initiation of sedation | Time from initiation of study sedative infusion until achievement of target Richmond Agitation-Sedation Scale (RASS) score (-3 to -4).The RASS ranges from +4 (combative) to -5 (unarousable) |
| Incidence of Hypotension | 24 hours after initiation of study sedation | Incidence of hypotension, defined as mean arterial pressure (MAP) \<65 mmHg or cerebral perfusion pressure (CPP) \<60 mmHg. |
| Vasopressor Requirements | 24 hours after initiation of study sedation. | Vasopressor requirements assessed by the proportion of patients requiring vasopressor support. |
| Incidence of Bradycardia. | 24 hours after initiation of study sedation. | Percentage of participants who develop bradycardia, defined as a sustained heart rate \<50 beats per minute (bpm). |
| Percentage of Participants Who Developed Secondary Brain Injury ✅ | Baseline and 24 hours after initiation of study sedation. | Secondary brain injury will be assessed by the presence of new or progressive findings on brain computed tomography (CT) compared with baseline imaging, including new intracranial hemorrhage, progression of cerebral edema (defined as \>25% increase in midline shift or worsening basal cistern effacement), new cerebral infarction, or transtentorial or uncal herniation. Brain CT scans will be reviewed by a blinded neuroradiologist. |
| Duration of Mechanical Ventilation | From initiation of mechanical ventilation until successful extubation, assessed for up to 30 days. | Duration of invasive mechanical ventilation, measured as the number of days from initiation of mechanical ventilation until successful liberation from ventilatory support. |
| Time to Neurological Awakening | From discontinuation of study sedation until achievement of a Glasgow Coma Scale motor score of ≥5, assessed for up to 30 days. | Time from discontinuation of study sedation to achievement of a Glasgow Coma Scale (GCS) motor score of ≥5. The Glasgow Coma Scale motor component ranges from 1 (no motor response) to 6 (obeys commands), with higher scores indicating better neurological function. |
| ICU Mortality | From ICU admission until ICU discharge, assessed for up to 30 days. | Death from any cause during the ICU stay following urgent neurosurgical intervention for traumatic brain injury. |
Countries
Egypt
Contacts
CONTACTMohamed Abdelhamed, M.Sc
STUDY_CHAIRAhmed Elsaied Aly, Ph.D.
Sohag University
Outcome results
None listed