Clinical trial NCT02754063: Impact of Early Optimization of Brain Oxygenation on Neurological Outcome After Severe Traumatic Brain Injury
Official title: Impact of Early Optimization of Brain Oxygenation on Neurological Outcome After Severe Traumatic Brain Injury
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Brain Injuries, Traumatic
Lead sponsor: University Hospital, Grenoble
Sponsor class: OTHER
First posted: 2016-04-28
Enrollment: 320
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Neurological outcome according to the extended Glasgow Outcome Scale (GOSE) blind assessed
timeFrame: at 6 months post-trauma
Secondary outcomes:
measure: Neurological outcome according to the extended Glasgow Outcome Scale (GOSE) and Disability Rating Scale
timeFrame: at 12 months post-trauma (GOSE)
measure: Disability Rating Scale (DRS)
timeFrame: at 6 and 12 months post-trauma
measure: Quality of life assessment: Functional Independence Measure (FIM) and Medical Outcomes Study Short-Form 12 (SF-12)
timeFrame: at 6 and 12 months post-trauma
measure: Mortality rate
timeFrame: at day 28
measure: Therapeutic intensity as reflected by the number of level 2 and level 3 treatments to treat elevated ICP
timeFrame: during the first 5 days of the ICU stay
measure: 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)
timeFrame: during the first 5 days of the ICU stay
Other outcomes:
measure: Ancillary outcome : Volume of cerebral lesions with abnormal MD values, i.e., decreased or increased MD values, using diffusion tensor MR imaging
timeFrame: at day 6-10 following initiation of cerebral monitoring after severe TBI
Locations:
city: Angers
country: France
facility: CHU Angers
city: Annecy
country: France
facility: General Hospital of Annecy
city: Besançon
country: France
facility: University Hospital Besançon
city: Bordeaux
country: France
facility: University Hospital of Bordeaux
city: Caen
country: France
facility: CHU CAEN
city: Clermont-Ferrand
country: France
facility: University Hospital of Clermont-Ferrand
city: Dijon
country: France
facility: University Hospital of Dijon
city: Grenoble
country: France
facility: Grenoble University Hospital
city: Le Kremlin Bicetre
country: France
facility: University Hospital of Kremlin-Bicetre
city: Lille
country: France
facility: University Hospital of Lille
city: Lyon
country: France
facility: University Hospital of Lyon
city: Marseille
country: France
facility: University Hospital of Marseille-Nord
city: Marseille
country: France
facility: University Hospital of Marseille-Timone
city: Montpellier
country: France
facility: University Hospital of Montpellier
city: Nancy
country: France
facility: University Hospital of Nancy
city: Nice
country: France
facility: University Hospital of Nice
city: Nimes
country: France
facility: University Hospital of Nimes
city: Paris
country: France
facility: University Hospital of Paris-Salpetriere
city: Poitiers
country: France
facility: University Hospital of Poitiers
city: Rennes
country: France
facility: University Hospital of Rennes
city: Rouen
country: France
facility: University Hospital of Rouen
city: Saint Pierre
country: France
facility: University Hospital Sud Réunion
city: Saint-Etienne
country: France
facility: University Hospital of St-Etienne
city: Strasbourg
country: France
facility: University Hospital of Strasbourg
city: Toulon
country: France
facility: Hôpital d'Instruction des Armées
city: Toulouse
country: France
facility: University Hospital of Toulouse
Study officials:
affiliation: University Hospital, Grenoble
name: Jean-François PAYEN, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Cunningham AS, Salvador R, Coles JP, Chatfield DA, Bradley PG, Johnston AJ, Steiner LA, Fryer TD, Aigbirhio FI, Smielewski P, Williams GB, Carpenter TA, Gillard JH, Pickard JD, Menon DK. Physiological thresholds for irreversible tissue damage in contusional regions following traumatic brain injury. Brain. 2005 Aug;128(Pt 8):1931-42. doi: 10.1093/brain/awh536. Epub 2005 May 11.
citation: Brain Trauma Foundation; American Association of Neurological Surgeons; Congress of Neurological Surgeons; Joint Section on Neurotrauma and Critical Care, AANS/CNS; Bratton SL, Chestnut RM, Ghajar J, McConnell Hammond FF, Harris OA, Hartl R, Manley GT, Nemecek A, Newell DW, Rosenthal G, Schouten J, Shutter L, Timmons SD, Ullman JS, Videtta W, Wilberger JE, Wright DW. Guidelines for the management of severe traumatic brain injury. IX. Cerebral perfusion thresholds. J Neurotrauma. 2007;24 Suppl 1:S59-64. doi: 10.1089/neu.2007.9987. No abstract available.
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citation: van den Brink WA, van Santbrink H, Steyerberg EW, Avezaat CJ, Suazo JA, Hogesteeger C, Jansen WJ, Kloos LM, Vermeulen J, Maas AI. Brain oxygen tension in severe head injury. Neurosurgery. 2000 Apr;46(4):868-76; discussion 876-8. doi: 10.1097/00006123-200004000-00018.
citation: Stiefel MF, Spiotta A, Gracias VH, Garuffe AM, Guillamondegui O, Maloney-Wilensky E, Bloom S, Grady MS, LeRoux PD. Reduced mortality rate in patients with severe traumatic brain injury treated with brain tissue oxygen monitoring. J Neurosurg. 2005 Nov;103(5):805-11. doi: 10.3171/jns.2005.103.5.0805.
citation: Narotam PK, Morrison JF, Nathoo N. Brain tissue oxygen monitoring in traumatic brain injury and major trauma: outcome analysis of a brain tissue oxygen-directed therapy. J Neurosurg. 2009 Oct;111(4):672-82. doi: 10.3171/2009.4.JNS081150.
citation: Mistral T, Roca P, Maggia C, Tucholka A, Forbes F, Doyle S, Krainik A, Galanaud D, Schmitt E, Kremer S, Kastler A, Tropres I, Barbier EL, Payen JF, Dojat M. Automated Quantification of Brain Lesion Volume From Post-trauma MR Diffusion-Weighted Images. Front Neurol. 2022 Feb 23;12:740603. doi: 10.3389/fneur.2021.740603. eCollection 2021.
citation: Payen JF, Richard M, Francony G, Audibert G, Barbier EL, Bruder N, Dahyot-Fizelier C, Geeraerts T, Gergele L, Puybasset L, Vigue B, Skaare K, Bosson JL, Bouzat P. Comparison of strategies for monitoring and treating patients at the early phase of severe traumatic brain injury: the multicentre randomised controlled OXY-TC trial study protocol. BMJ Open. 2020 Aug 20;10(8):e040550. doi: 10.1136/bmjopen-2020-040550.