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Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase-II: A Phase II Randomized Trial*

Okonkwo, David O. MD, PhD1; Shutter, Lori A. MD1; Moore, Carol MA2; Temkin, Nancy R. PhD3; Puccio, Ava M. RN, PhD1; Madden, Christopher J. MD4; Andaluz, Norberto MD5; Chesnut, Randall M. MD3; Bullock, M. Ross MD, PhD6; Grant, Gerald A. MD, FACS7; McGregor, John MD8; Weaver, Michael PhD9; Jallo, Jack MD, PhD10; LeRoux, Peter D. MD, FACS11; Moberg, Dick MSE12; Barber, Jason MS3; Lazaridis, Christos MD13; Diaz-Arrastia, Ramon R. MD, PhD14

doi: 10.1097/CCM.0000000000002619
Neurologic Critical Care

Objectives: A relationship between reduced brain tissue oxygenation and poor outcome following severe traumatic brain injury has been reported in observational studies. We designed a Phase II trial to assess whether a neurocritical care management protocol could improve brain tissue oxygenation levels in patients with severe traumatic brain injury and the feasibility of a Phase III efficacy study.

Design: Randomized prospective clinical trial.

Setting: Ten ICUs in the United States.

Patients: One hundred nineteen severe traumatic brain injury patients.

Interventions: Patients were randomized to treatment protocol based on intracranial pressure plus brain tissue oxygenation monitoring versus intracranial pressure monitoring alone. Brain tissue oxygenation data were recorded in the intracranial pressure –only group in blinded fashion. Tiered interventions in each arm were specified and impact on intracranial pressure and brain tissue oxygenation measured. Monitors were removed if values were normal for 48 hours consecutively, or after 5 days. Outcome was measured at 6 months using the Glasgow Outcome Scale–Extended.

Measurements and Main Results: A management protocol based on brain tissue oxygenation and intracranial pressure monitoring reduced the proportion of time with brain tissue hypoxia after severe traumatic brain injury (0.45 in intracranial pressure–only group and 0.16 in intracranial pressure plus brain tissue oxygenation group; p < 0.0001). Intracranial pressure control was similar in both groups. Safety and feasibility of the tiered treatment protocol were confirmed. There were no procedure-related complications. Treatment of secondary injury after severe traumatic brain injury based on brain tissue oxygenation and intracranial pressure values was consistent with reduced mortality and increased proportions of patients with good recovery compared with intracranial pressure–only management; however, the study was not powered for clinical efficacy.

Conclusions: Management of severe traumatic brain injury informed by multimodal intracranial pressure and brain tissue oxygenation monitoring reduced brain tissue hypoxia with a trend toward lower mortality and more favorable outcomes than intracranial pressure–only treatment. A Phase III randomized trial to assess impact on neurologic outcome of intracranial pressure plus brain tissue oxygenation–directed treatment of severe traumatic brain injury is warranted.

Supplemental Digital Content is available in the text.

1University of Pittsburgh School of Medicine, Pittsburgh, PA.

2Uniformed Services University of the Health Sciences, Bethesda, MD.

3University of Washington, Seattle, WA.

4UT Southwestern Medical Center, Dallas, TX.

5University of Cincinnati College of Medicine, Cincinnati, OH.

6University of Miami, Miller School of Medicine, Miami, FL.

7Stanford University, Stanford, CA.

8Ohio State University College of Medicine, Columbus, OH.

9Temple University, Philadelphia, PA.

10Thomas Jefferson University, Philadelphia, PA.

11Lankenau Medical Center, Wynnewood, PA.

12Moberg Research, Ambler, PA.

13Baylor St. Luke’s Medical Center, Houston, TX.

14Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.

*See also p. 1961.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Supported, in part, by the National Institutes of Neurological Disorders and Stroke (R01 NS061860).

Drs. Okonkwo, Shutter, Moore, Temkin, Puccio, Madden, Chesnut, McGregor, Weaver, LeRoux, and Diaz-Arrastia received support for article research from the National Institutes of Health (NIH). Dr. Okonkwo disclosed off-label product use of intracranial pressure monitors and brain tissue oxygenation monitors (Integra LifeSciences, Plainsboro, NJ). Dr. Shutter’s institution received funding from the NIH; she received funding from legal firms for expert testimony on cases not related to this study; and she disclosed that her spouse was briefly an independent contractor for medical sales with Raumedic, who makes a medical device that measures brain tissue oxygen. The Raumedic device was not used in this study (total compensation was $3,500). Drs. Temkin’s and Barber’s institution received funding from the NIH/National Institute of Neurological Disorders and Stroke. Dr. Temkin disclosed that her salary through her institution comes primarily from grants and contracts with various U.S. federal agencies; and she received funding from various pharmaceutical companies and academic institutions (data and safety monitoring boards and statistical consulting) and from reviewing grants for various federal agencies and for nonprofits. Dr. Chesnut disclosed that he holds the Integra Endowed Professorship in Neurotrauma at the University of Washington, which was established in total, with no further contributions, prior to the origin of this work. Dr. Grant received funding from honorarium for talk about brain oxygen monitoring from Integra Life Sciences in 2016, 2 years after completion of Brain Oxygen Optimization in Severe TBI Phase-II trial. Dr. McGregor’s institution received funding from the NIH. Dr. LeRoux’s institution received funding from the NIH; he received other support from consulting for Integra and Codman; he receives research funding from Integra Lifesciences; and he is a consultant for Integra Lifesciences, Codman, Depuy-Synthes, and Neurologica and a member of the scientific advisory board of Cerebrotech and Edge Therapeutics. Mr. Moberg’s institution received funding from the NIH; he disclosed that he is the founder, CEO, and shareholder of a company that provided data collection equipment and expertise for the project; and he has a proprietary interest in Moberg ICU Solutions, which manufactures the data collection device used in the study Dr. Diaz-Arrastia’s institution received funding from the NIH. The remaining authors have disclosed that they do not have any potential conflicts of interest.

For information regarding this article, E-mail: okonkwodo@upmc.edu

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