Impact of Early Optimization of Brain Oxygenation on Neurological Outcome After Severe Traumatic Brain Injury

Study Overview
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Brief Summary
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Post-traumatic brain hypoxia/ischemia develops hours after traumatic brain injury (TBI), and its intensity is directly related to the neurological outcome. The thresholds for irreversible tissue damage following TBI indicate a particular vulnerability of injured brain. Improving brain oxygenation after severe TBI is the focus of modern TBI management in the intensive care unit (ICU). The calculation of cerebral perfusion pressure (CPP), with CPP = mean arterial pressure (MAP) - intracranial pressure (ICP), has become the most used estimator of cerebral blow flow. To prevent ischemia due to elevated ICP, current international guidelines recommend maintaining CPP at 60-70 mmHg and ICP below 20 mmHg. However, episodes of brain hypoxia/ischemia, as assessed with brain tissue oxygen pressure (PbtO2) measurements, might occur despite optimization of CPP and ICP, and have been independently associated with poorer patient outcome. PbtO2 values lower than 15 mmHg for more than 30 minutes were shown to be an independent predictor of unfavorable outcome and death. The aggressive treatment of low PbtO2 was associated with improved outcome compared to standard ICP/CPP-directed therapy in cohort studies of severely head-injured patients. On the basis of these findings, it is hypothesized that an early optimization of brain oxygenation, together with keeping ICP and CPP within recommended values, could reduce the volume of vulnerable lesions following severe TBI and possibly improve neurological outcome.

Official Title
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Impact of Early Optimization of Brain Oxygenation on Neurological Outcome After Severe Traumatic Brain Injury

Conditions
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Brain Injuries, Traumatic

Intervention / Treatment
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* Device: PbtO2 probes
* Other: No PbtO2 probes


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 18 and 75 Severe non- penetrating TBI (GCS score 3-8) with motor Glasgow score between 1 and 5 Possible associated extracranial lesions, except tetraplegia Initiation of cerebral monitoring within the first 16 hours since primary traumaticinjury Indication of ICP monitoring on admission as part of the management Indication of continuous sedation/analgesia for more than 48 hours Under mechanical ventilation with stable conditions: PaO2//FiO2 over 150 and PaCO2 between 35 and 45 mmHg, mean arterial pressure over 70 mmHg Written informed consent from legal surrogate, patient's relative or investigator decision Affiliation to the French Social Security or affiliated to a social security system of EU member state, Norway, Lichtenstein, Iceland or Switzerland French-speaking or English-speaking patient Exclusion Criteria: Penetrating TBI GCS 3 with bilateral fixed dilated pupils Decompressive craniectomy and no repositioning of the bone flap after subdural hematoma evacuation surgery prior to enrolment Contraindication of ICP and/or PbtO2 monitoring, i.e., hemostasis disorders and brain tissue infection Persistent hemodynamic or respiratory instability despite treatments, i.e., mean arterial pressure < 70 mmHg, PaO2/FiO2 <150, PaCO2 <30 mmHg or >45 mmHg or lactate >5 mmol/l if available. Hypothermia <34°C at randomization Life expectancy < 24 hours Cardiac arrest at initial presentation Tetraplegia Neuropsychiatric co-morbidities that could interfere with 6 and 12-months assessment outcomes. Consent refusal Pregnancy Participation in another therapeutic study with written consent Inability to have a 6-months follow-up Ischemic stroke after carotid arterial dissection Incapacitated patients in accordance with article L 1121-5 to L1121-8 of the public health code.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: ICP Management<br> | Other: No PbtO2 probes<br>* ICP/CPP-directed therapy according to international recommendations<br>|
| Experimental: PbtO2 + ICP Management<br> | Device: PbtO2 probes<br>* PbtO2/ICP/CPP-directed therapy according to international recommendations<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neurological outcome according to the extended Glasgow Outcome Scale (GOSE) blind assessed |  | at 6 months post-trauma | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neurological outcome according to the extended Glasgow Outcome Scale (GOSE) and Disability Rating Scale |  | at 12 months post-trauma (GOSE) | 
| Disability Rating Scale (DRS) |  | at 6 and 12 months post-trauma | 
| Quality of life assessment: Functional Independence Measure (FIM) and Medical Outcomes Study Short-Form 12 (SF-12) |  | at 6 and 12 months post-trauma | 
| Mortality rate |  | at day 28 | 
| Therapeutic intensity as reflected by the number of level 2 and level 3 treatments to treat elevated ICP |  | during the first 5 days of the ICU stay | 
| Incidence of critical events as defined by: ICP >30 mmHg during 30 min at least ICP >40 mmHg during 5 min at least PbtO2 <10 mmHg during 30 min at least (PbtO2 group) |  | during the first 5 days of the ICU stay |