By Alexander E. Merkler, MD
Assistant Professor of Neurology, Weill Cornell Medical College
Dr. Merkler reports no financial relationships relevant to this field of study.
In a Phase II, single-blind, randomized, multicenter trial, the use of intraparenchymal brain tissue oxygenation monitoring reduced brain tissue hypoxia in patients with severe traumatic brain injury.
Okonkwo DO, Shutter LA, Moore C, et al. Brain oxygen optimization in severe traumatic brain injury phase-II: A phase II randomized trial. Crit Care Med 2017;45:1907-1914. doi: 10.1097/CCM.0000000000002619.
Traumatic brain injury (TBI) remains a significant public health burden and accounts for 30% of all injury-related deaths in Americans.1 In 2010, 25 million people sustained a TBI.1 Persons with TBI and a Glasgow Coma Scale score of 3-8 are considered to have severe TBI. Patients with severe TBI are at a high risk for mortality and long-term cognitive, motor, and psychological disability. Furthermore, the societal and economic toll of TBI is massive, approximately $76 billion in 2010.1 Therefore, further strategies are necessary to reduce secondary brain injury and improve long-term outcomes.
Prior studies in patients with severe TBI have focused on reduction of raised intracranial pressure (ICP) as a means to improve neurological outcomes. However, in a landmark randomized, controlled trial, Chesnut et al failed to show an improvement in mortality or neurological outcomes using targeted ICP reduction via ICP monitoring in patients with severe TBI.2 Nonetheless, ICP monitoring in patients with severe TBI remains a level IIB recommendation from the Brain Trauma Foundation’s: Guidelines for the Management of Severe TBI.3 Advanced cerebral monitoring, including brain tissue oxygenation (PbtO2), represents another physiological variable that may be targeted to reduce secondary brain injury and improve outcomes. Brain oxygenation is important to allow normal cellular metabolism; a decrease in brain oxygen delivery may lead to secondary brain injury and, as a consequence, poor neurological outcomes. Moreover, a decrease in PbtO2 may herald elevated ICP and, therefore, may serve as a more valuable therapeutic target. Indeed, prior observational studies suggest that PbtO2-guided therapy is associated with improved outcomes after severe TBI.4 Thus, Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase-II (BOOST II) was created as a Phase II clinical trial to assess both the feasibility and safety of early PbtO2-directed therapy in patients with severe TBI.
BOOST II was a two-arm, single-blind, prospective, randomized clinical trial performed at 10 Level 1 trauma centers. Patients with non-penetrating severe TBI were randomized to receive either ICP-only monitoring or ICP + PbtO2 monitoring. Both groups received intraparenchymal monitors, which had both ICP and PbtO2 monitoring capabilities. In the ICP-only group, a cover was placed over the PbtO2 monitor so that the treating physicians were blinded to the PbtO2 values. Treating physicians followed a stepwise treatment algorithm for elevated ICP (> 20 mmHg) in the ICP-only arm and elevated ICP or brain hypoxia (PbtO2 < 20 mmHg) in the ICP + PbtO2 monitoring arm. These algorithms used an explicit set of interventions that addressed isolated elevated ICP, isolated brain hypoxia, or simultaneous elevated ICP and brain hypoxia. Monitors were left in the brain until patients awoke from coma, when ICP and PbtO2 values were normal for > 48 hours, or when the monitors had been in place for five days. The primary outcome was the physiologic efficacy of PbtO2 monitoring, defined as the duration of time with brain hypoxia. Safety outcomes and six-month neurological outcomes also were recorded.
Of 119 patients, 62 were randomized to the ICP-only group and 57 to the ICP + PbtO2 group. Overall, the duration of brain hypoxia was significantly less in the ICP + PbtO2 group than the ICP-only group. Treatment of reduced PbtO2 decreased the absolute duration of brain hypoxia by 29%. There was no difference in the proportion of time with an elevated ICP. Intraparenchymal monitors were placed on average nine hours after brain injury, and there was no difference in serious adverse events between the two groups. There was no difference in six-month neurological outcomes between the two groups, although there was a trend toward improved outcomes in the ICP + PbtO2 intervention group.
COMMENTARY
This study showed that early PbtO2-directed therapy in patients with severe TBI is feasible and associated with a reduction in the amount overall time with brain hypoxia. As brain hypoxia is associated with loss of normal cellular metabolism and resultant tissue death, these findings suggest a possible interventional target to avoid secondary brain injury and improve neurological outcomes. On the other hand, there was no difference in the duration of time with elevated ICP, and although safety outcomes were no different in the treatment groups, there was no control group (without an intraparenchymal monitor) of management via imaging and clinical parameters alone (found to be equally as good as ICP-monitoring in the Chesnut et al randomized, controlled trial).2
Overall, severe TBI represents a devastating neurological disease in which novel strategies for preventing secondary brain injury and improving neurological outcomes are imminently needed. Prior randomized clinical trials in patients with severe TBI have failed to show improvement in neurological outcomes after various interventions, including decompressive craniectomy,5,6 induced hypothermia,7 or targeted ICP monitoring therapy.2 The promising results from BOOST-II suggest that PbtO2-targeted therapy reduces the duration of brain hypoxia. Further study of whether reduction of brain hypoxia results in improved neurological outcomes is necessary.
REFERENCES
- Centers for Disease Control and Prevention. Traumatic Brain Injury & Concussion. Severe TBI, 2016. Available at: https://www.cdc.gov/traumaticbraininjury/severe.html. Accessed Nov. 7, 2017.
- Chesnut RM, Temkin N, Carney N, et al. A trial of intracranial-pressure monitoring in traumatic brain injury. N Engl J Med 2012;367:2471-2481.
- Carney N, Totten AM, O'Reilly C, et al. Guidelines for the management of severe traumatic brain injury, fourth edition. Neurosurgery 2017;80:6-15.
- Nangunoori R, Maloney-Wilensky E, Stiefel M, et al. Brain tissue oxygen-based therapy and outcome after severe traumatic brain injury: A systematic literature review. Neurocrit Care 2012;17:131-138.
- Cooper DJ, Rosenfeld JV, Murray L, et al. Decompressive craniectomy in diffuse traumatic brain injury. N Engl J Med 2011;364:1493-1502.
- Hutchinson PJ, Kolias AG, Timofeev IS, et al. Trial of decompressive craniectomy for traumatic intracranial hypertension. N Engl J Med 2016;375:1119-1130.
- Clifton GL, Valadka A, Zygun D, et al. Very early hypothermia induction in patients with severe brain injury (the national acute brain injury study: Hypothermia II): A randomised trial. Lancet Neurol 2011;10:131-139.
