Impact of Early Optimization of Brain Oxygenation on Neurological Outcome After Severe Traumatic Brain Injury (OXY-TC)

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.

Study Overview

• Status: Completed
• Conditions: Brain Injuries, Traumatic
• Intervention / Treatment: Other: No PbtO2 probes; Device: PbtO2 probes

• Study Type: Interventional
• Enrollment (Actual): 320
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Angers, France
    • CHU Angers
  • Annecy, France
    • General Hospital of Annecy
  • Besançon, France
    • University Hospital Besancon
  • Bordeaux, France
    • University Hospital of Bordeaux
  • Caen, France
    • CHU Caen
  • Clermont-Ferrand, France
    • University Hospital of Clermont-Ferrand
  • Dijon, France
    • University Hospital of Dijon
  • Grenoble, France
    • Grenoble University Hospital
  • Le Kremlin Bicetre, France
    • University Hospital of Kremlin-Bicetre
  • Lille, France
    • University Hospital of Lille
  • Lyon, France
    • University Hospital of Lyon
  • Marseille, France
    • University Hospital of Marseille-Nord
  • Marseille, France
    • University Hospital of Marseille-Timone
  • Montpellier, France
    • University Hospital of Montpellier
  • Nancy, France
    • University Hospital Of Nancy
  • Nice, France
    • University Hospital of Nice
  • Nimes, France
    • University Hospital of Nîmes
  • Paris, France
    • University Hospital of Paris-Salpetriere
  • Poitiers, France
    • University Hospital of Poitiers
  • Rennes, France
    • University Hospital of Rennes
  • Rouen, France
    • University Hospital of Rouen
  • Saint Pierre, France
    • University Hospital Sud Réunion
  • Saint-Etienne, France
    • University Hospital of St-Etienne
  • Strasbourg, France
    • University Hospital of Strasbourg
  • Toulon, France
    • hôpital d'Instruction des Armées
  • Toulouse, France
    • University Hospital of Toulouse

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	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

Other Outcome Measures

Outcome Measure	Time Frame
Ancillary outcome : Volume of cerebral lesions with abnormal MD values, i.e., decreased or increased MD values, using diffusion tensor MR imaging	at day 6-10 following initiation of cerebral monitoring after severe TBI

Collaborators and Investigators

• Sponsor: University Hospital, Grenoble
• Investigators: Principal Investigator: Jean-Francois Payen, MD, PhD, University Hospital, Grenoble

Publications and helpful links

General Publications

• 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. Erratum In: J Neurotrauma. 2008 Mar;25(3):276-8. multiple author names added.
• 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.
• Oddo M, Levine JM, Mackenzie L, Frangos S, Feihl F, Kasner SE, Katsnelson M, Pukenas B, Macmurtrie E, Maloney-Wilensky E, Kofke WA, LeRoux PD. Brain hypoxia is associated with short-term outcome after severe traumatic brain injury independently of intracranial hypertension and low cerebral perfusion pressure. Neurosurgery. 2011 Nov;69(5):1037-45; discussion 1045. doi: 10.1227/NEU.0b013e3182287ca7.
• 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.
• 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.
• 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.
• Mistral T, Roca P, Maggia C, Tucholka A, Forbes F, Doyle S, Krainik A, Galanaud D, Schmitt E, Kremer S, Kastler A, Troprès 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2016
• Primary Completion (Actual): October 17, 2021
• Study Completion (Actual): April 1, 2022

Study Registration Dates

• First Submitted: April 15, 2016
• First Submitted That Met QC Criteria: April 26, 2016
• First Posted (Estimate): April 28, 2016

Study Record Updates

• Last Update Posted (Actual): May 18, 2022
• Last Update Submitted That Met QC Criteria: May 17, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Brain Injuries; Wounds and Injuries; Brain Injuries, Traumatic; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Dopamine Agonists; Dopamine Agents; 3,4,4a,10b-tetrahydro-4-propyl-2H,5H-(1)benzopyrano(4,3-b)-1,4-oxazin-9-ol
• Other Study ID Numbers: 38RC14.039