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Brain Hypoxia and Ischemia After Traumatic Brain Injury: Is Oxygen the Right Metabolic Target?

Brain Hypoxia and Ischemia After Traumatic Brain Injury: Is Oxygen the Right Metabolic Target? Traumatic brain injury (TBI) is an important critical neurologic illness that requires neurocritical care. Traumatic brain injury is an active disease process in which primarily injured tissue manifests as brain hemorrhage and subsequent edema, which can lead to elevated intracranial pressure (ICP). For many years, secondary brain ischemia that resulted from elevated ICP, and a resultant reduction in cerebral perfusion, have been of concern. This concern has led to a number of investigations using brain positron emission tomography and parenchymal brain tissue oxygen monitoring. These investigations have resulted in several reproducible findings. First, cerebral blood flow (CBF) is reduced within and surrounding brain contusions.1 Second, cerebral oxidative metabolism is reduced heterogeneously across the brain and even within normal-appearing brain regions.1 Third, ischemic tissue volume ranges from 5% to 10% of the brain volume after TBI.2 Fourth, nonischemic metabolic crisis can occur in part owing to impaired mitochondrial respiration.3 Fifth, therapeutic hyperventilation can increase the volume of ischemic tissue.4 Sixth, very low levels of brain tissue oxygen can occur in the setting of malignant cerebral edema and correlate with poor outcome.5 Despite these results, debate as to whether the brain is deprived of oxygen or whether the reduction in the metabolic rate of oxygen consumption is owing to nonischemic metabolic crisis continues. In this issue of JAMA Neurology, Veenith et al6 from Cambridge University use a novel positron emission tomography technique that features the tracer fluorine 18–labeled fluoromisonidazole ([18F]FMISO) that becomes trapped in tissue deprived of oxygen when the partial pressure of brain tissue oxygen (PbtO2) is less than 10 mm Hg.7 Fluorine 18–labeled fluoromisonidazole is a lipophilic compound that is delivered by CBF and easily enters cells, becomes reduced, and cannot be reoxidized under hypoxic states. The tracer has been used to detect cerebral ischemia in the setting of stroke8-10 and cerebral vasospasm after subarachnoid hemorrhage.11 Fluorine 18–labeled fluoromisonidazole is not trapped in the ischemic core of brain tissue owing to a lack of CBF. Veenith et al6 compare the volume and distribution of hypoxic tissue with that of ischemic tissue. The principal findings are that ischemic brain volume and hypoxic brain volume are higher after TBI than in control participants. This finding was manifest by many small regions of hypoxic brain that were widely dispersed as small nonconfluent voxels scattered in the brain. These areas do not appear to be typical of macrovascular ischemic stroke and appear to be distributed in areas adjacent to but also remote from visible contusions in many cases. In 1 example, positron emission tomography ischemia and hypoxemia measures correspond anatomically in the bilateral temporal lobe region in a patient without PtbO2 or ICP monitoring. The distribution of hypoxemia also differs from that in published studies in ischemic stroke, in which the [18F]FMISO accumulates in the peristroke penumbral region. Normal-appearing and edematous areas had scattered regions of hypoxia, as opposed to the pattern seen in ischemic stroke. How should we interpret these findings of Veenith et al6 and what caveats are worth considering? First, hypoxia and ischemia both appear in the post-TBI brain, but regions of the brain can be hypoxic but not ischemic, and vice versa. This suggests that hypoxia may be unrelated to CBF and may be related to other mechanisms, such as a diffusion barrier to oxygen into edematous tissue,4,12 enhanced reduction of [18F]FMISO owing to inflammation, a lack of oxygen diffusion into the tissue despite adequate CBF, or some enhanced trapping of [18F]FMISO owing to abnormal redox state in slowly dying cells. Slow progression of cell death in pericontusional tissue as a result of impaired metabolism has been shown in previous positron emission tomography studies.13 Second, these findings suggest that PbtO2 values greater than 15 mm Hg are not correlated with tissue hypoxia, because no patient had [18F]FMISO accumulation despite having PbtO2 ranging from 15 to 55 mm Hg. This finding may help define the PbtO2 threshold for treatment. Third, brain hypoxia can occur in patients with TBI who do not have suspected elevated ICP and hence no ICP monitor (patient 10). This finding is unexpected and suggests caution when considering whether to exclude ICP monitoring from the care paradigm. In conclusion, ischemia and hypoxia occur after TBI in nonoverlapping regions. The brain volume is limited in most patients, but can be large and does not easily explain the widespread reduction in oxidative metabolism seen in most cases after TBI. This study is hypothesis generating and should stimulate additional studies to explain brain hypoxia. Back to top Article Information Corresponding Author: Paul M. Vespa, MD, Departments of Neurosurgery and Neurology, University of California, Los Angeles, School of Medicine, 757 Westwood Blvd, Ste 6236A, Los Angeles, CA 90095 (pvespa@mednet.ucla.edu). Published Online: March 28, 2016. doi:10.1001/jamaneurol.2016.0251. Conflict of Interest Disclosures: None reported. References 1. Wu HM, Huang SC, Hattori N, et al. Subcortical white matter metabolic changes remote from focal hemorrhagic lesions suggest diffuse injury after human traumatic brain injury. Neurosurgery. 2004;55(6):1306-1317.PubMedGoogle ScholarCrossref 2. Coles JP, Fryer TD, Smielewski P, et al. Defining ischemic burden after traumatic brain injury using 15O PET imaging of cerebral physiology. J Cereb Blood Flow Metab. 2004;24(2):191-201.PubMedGoogle ScholarCrossref 3. Vespa P, Bergsneider M, Hattori N, et al. Metabolic crisis without brain ischemia is common after traumatic brain injury: a combined microdialysis and positron emission tomography study. J Cereb Blood Flow Metab. 2005;25(6):763-774.PubMedGoogle ScholarCrossref 4. Hutchinson PJ, Gupta AK, Fryer TF, et al. Correlation between cerebral blood flow, substrate delivery, and metabolism in head injury: a combined microdialysis and triple oxygen positron emission tomography study. J Cereb Blood Flow Metab. 2002;22(6):735-745.PubMedGoogle ScholarCrossref 5. Maloney-Wilensky E, Gracias V, Itkin A, et al. Brain tissue oxygen and outcome after severe traumatic brain injury: a systematic review. Crit Care Med. 2009;37(6):2057-2063.PubMedGoogle ScholarCrossref 6. Veenith TV, Carter EL, Geeraerts T, et al. Pathophysiologic mechanisms of cerebral ischemia and diffusion hypoxia in traumatic brain injury [published online March 28, 2016]. JAMA Neurol. doi:10.1001/jamaneurol.2016.0091.Google Scholar 7. Lawrentschuk N, Poon AM, Foo SS, et al. Assessing regional hypoxia in human renal tumours using 18F-fluoromisonidazole positron emission tomography. BJU Int. 2005;96(4):540-546.PubMedGoogle ScholarCrossref 8. Takasawa M, Moustafa RR, Baron JC. Applications of nitroimidazole in vivo hypoxia imaging in ischemic stroke. Stroke. 2008;39(5):1629-1637.PubMedGoogle ScholarCrossref 9. Markus R, Donnan GA, Kazui S, et al. Statistical parametric mapping of hypoxic tissue identified by [18F]fluoromisonidazole and positron emission tomography following acute ischemic stroke. Neuroimage. 2002;16(2):425-433.PubMedGoogle ScholarCrossref 10. Alawneh JA, Moustafa RR, Marrapu ST, et al. Diffusion and perfusion correlates of the 18F-MISO PET lesion in acute stroke: pilot study. Eur J Nucl Med Mol Imaging. 2014;41(4):736-744.PubMedGoogle ScholarCrossref 11. Sarrafzadeh AS, Nagel A, Czabanka M, Denecke T, Vajkoczy P, Plotkin M. Imaging of hypoxic-ischemic penumbra with 18F-fluoromisonidazole PET/CT and measurement of related cerebral metabolism in aneurysmal subarachnoid hemorrhage. J Cereb Blood Flow Metab. 2010;30(1):36-45.PubMedGoogle ScholarCrossref 12. Rosenthal G, Hemphill JC III, Sorani M, et al. Brain tissue oxygen tension is more indicative of oxygen diffusion than oxygen delivery and metabolism in patients with traumatic brain injury. Crit Care Med. 2008;36(6):1917-1924.PubMedGoogle ScholarCrossref 13. Wu HM, Huang SC, Vespa P, Hovda DA, Bergsneider M. Redefining the pericontusional penumbra following traumatic brain injury: evidence of deteriorating metabolic derangements based on positron emission tomography. J Neurotrauma. 2013;30(5):352-360.PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Neurology American Medical Association

Brain Hypoxia and Ischemia After Traumatic Brain Injury: Is Oxygen the Right Metabolic Target?

JAMA Neurology , Volume 73 (5) – May 1, 2016

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Publisher
American Medical Association
Copyright
Copyright © 2016 American Medical Association. All Rights Reserved.
ISSN
2168-6149
eISSN
2168-6157
DOI
10.1001/jamaneurol.2016.0251
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Abstract

Traumatic brain injury (TBI) is an important critical neurologic illness that requires neurocritical care. Traumatic brain injury is an active disease process in which primarily injured tissue manifests as brain hemorrhage and subsequent edema, which can lead to elevated intracranial pressure (ICP). For many years, secondary brain ischemia that resulted from elevated ICP, and a resultant reduction in cerebral perfusion, have been of concern. This concern has led to a number of investigations using brain positron emission tomography and parenchymal brain tissue oxygen monitoring. These investigations have resulted in several reproducible findings. First, cerebral blood flow (CBF) is reduced within and surrounding brain contusions.1 Second, cerebral oxidative metabolism is reduced heterogeneously across the brain and even within normal-appearing brain regions.1 Third, ischemic tissue volume ranges from 5% to 10% of the brain volume after TBI.2 Fourth, nonischemic metabolic crisis can occur in part owing to impaired mitochondrial respiration.3 Fifth, therapeutic hyperventilation can increase the volume of ischemic tissue.4 Sixth, very low levels of brain tissue oxygen can occur in the setting of malignant cerebral edema and correlate with poor outcome.5 Despite these results, debate as to whether the brain is deprived of oxygen or whether the reduction in the metabolic rate of oxygen consumption is owing to nonischemic metabolic crisis continues. In this issue of JAMA Neurology, Veenith et al6 from Cambridge University use a novel positron emission tomography technique that features the tracer fluorine 18–labeled fluoromisonidazole ([18F]FMISO) that becomes trapped in tissue deprived of oxygen when the partial pressure of brain tissue oxygen (PbtO2) is less than 10 mm Hg.7 Fluorine 18–labeled fluoromisonidazole is a lipophilic compound that is delivered by CBF and easily enters cells, becomes reduced, and cannot be reoxidized under hypoxic states. The tracer has been used to detect cerebral ischemia in the setting of stroke8-10 and cerebral vasospasm after subarachnoid hemorrhage.11 Fluorine 18–labeled fluoromisonidazole is not trapped in the ischemic core of brain tissue owing to a lack of CBF. Veenith et al6 compare the volume and distribution of hypoxic tissue with that of ischemic tissue. The principal findings are that ischemic brain volume and hypoxic brain volume are higher after TBI than in control participants. This finding was manifest by many small regions of hypoxic brain that were widely dispersed as small nonconfluent voxels scattered in the brain. These areas do not appear to be typical of macrovascular ischemic stroke and appear to be distributed in areas adjacent to but also remote from visible contusions in many cases. In 1 example, positron emission tomography ischemia and hypoxemia measures correspond anatomically in the bilateral temporal lobe region in a patient without PtbO2 or ICP monitoring. The distribution of hypoxemia also differs from that in published studies in ischemic stroke, in which the [18F]FMISO accumulates in the peristroke penumbral region. Normal-appearing and edematous areas had scattered regions of hypoxia, as opposed to the pattern seen in ischemic stroke. How should we interpret these findings of Veenith et al6 and what caveats are worth considering? First, hypoxia and ischemia both appear in the post-TBI brain, but regions of the brain can be hypoxic but not ischemic, and vice versa. This suggests that hypoxia may be unrelated to CBF and may be related to other mechanisms, such as a diffusion barrier to oxygen into edematous tissue,4,12 enhanced reduction of [18F]FMISO owing to inflammation, a lack of oxygen diffusion into the tissue despite adequate CBF, or some enhanced trapping of [18F]FMISO owing to abnormal redox state in slowly dying cells. Slow progression of cell death in pericontusional tissue as a result of impaired metabolism has been shown in previous positron emission tomography studies.13 Second, these findings suggest that PbtO2 values greater than 15 mm Hg are not correlated with tissue hypoxia, because no patient had [18F]FMISO accumulation despite having PbtO2 ranging from 15 to 55 mm Hg. This finding may help define the PbtO2 threshold for treatment. Third, brain hypoxia can occur in patients with TBI who do not have suspected elevated ICP and hence no ICP monitor (patient 10). This finding is unexpected and suggests caution when considering whether to exclude ICP monitoring from the care paradigm. In conclusion, ischemia and hypoxia occur after TBI in nonoverlapping regions. The brain volume is limited in most patients, but can be large and does not easily explain the widespread reduction in oxidative metabolism seen in most cases after TBI. This study is hypothesis generating and should stimulate additional studies to explain brain hypoxia. Back to top Article Information Corresponding Author: Paul M. Vespa, MD, Departments of Neurosurgery and Neurology, University of California, Los Angeles, School of Medicine, 757 Westwood Blvd, Ste 6236A, Los Angeles, CA 90095 (pvespa@mednet.ucla.edu). Published Online: March 28, 2016. doi:10.1001/jamaneurol.2016.0251. Conflict of Interest Disclosures: None reported. References 1. Wu HM, Huang SC, Hattori N, et al. Subcortical white matter metabolic changes remote from focal hemorrhagic lesions suggest diffuse injury after human traumatic brain injury. Neurosurgery. 2004;55(6):1306-1317.PubMedGoogle ScholarCrossref 2. Coles JP, Fryer TD, Smielewski P, et al. Defining ischemic burden after traumatic brain injury using 15O PET imaging of cerebral physiology. J Cereb Blood Flow Metab. 2004;24(2):191-201.PubMedGoogle ScholarCrossref 3. Vespa P, Bergsneider M, Hattori N, et al. Metabolic crisis without brain ischemia is common after traumatic brain injury: a combined microdialysis and positron emission tomography study. J Cereb Blood Flow Metab. 2005;25(6):763-774.PubMedGoogle ScholarCrossref 4. Hutchinson PJ, Gupta AK, Fryer TF, et al. Correlation between cerebral blood flow, substrate delivery, and metabolism in head injury: a combined microdialysis and triple oxygen positron emission tomography study. J Cereb Blood Flow Metab. 2002;22(6):735-745.PubMedGoogle ScholarCrossref 5. Maloney-Wilensky E, Gracias V, Itkin A, et al. Brain tissue oxygen and outcome after severe traumatic brain injury: a systematic review. Crit Care Med. 2009;37(6):2057-2063.PubMedGoogle ScholarCrossref 6. Veenith TV, Carter EL, Geeraerts T, et al. Pathophysiologic mechanisms of cerebral ischemia and diffusion hypoxia in traumatic brain injury [published online March 28, 2016]. JAMA Neurol. doi:10.1001/jamaneurol.2016.0091.Google Scholar 7. Lawrentschuk N, Poon AM, Foo SS, et al. Assessing regional hypoxia in human renal tumours using 18F-fluoromisonidazole positron emission tomography. BJU Int. 2005;96(4):540-546.PubMedGoogle ScholarCrossref 8. Takasawa M, Moustafa RR, Baron JC. Applications of nitroimidazole in vivo hypoxia imaging in ischemic stroke. Stroke. 2008;39(5):1629-1637.PubMedGoogle ScholarCrossref 9. Markus R, Donnan GA, Kazui S, et al. Statistical parametric mapping of hypoxic tissue identified by [18F]fluoromisonidazole and positron emission tomography following acute ischemic stroke. Neuroimage. 2002;16(2):425-433.PubMedGoogle ScholarCrossref 10. Alawneh JA, Moustafa RR, Marrapu ST, et al. Diffusion and perfusion correlates of the 18F-MISO PET lesion in acute stroke: pilot study. Eur J Nucl Med Mol Imaging. 2014;41(4):736-744.PubMedGoogle ScholarCrossref 11. Sarrafzadeh AS, Nagel A, Czabanka M, Denecke T, Vajkoczy P, Plotkin M. Imaging of hypoxic-ischemic penumbra with 18F-fluoromisonidazole PET/CT and measurement of related cerebral metabolism in aneurysmal subarachnoid hemorrhage. J Cereb Blood Flow Metab. 2010;30(1):36-45.PubMedGoogle ScholarCrossref 12. Rosenthal G, Hemphill JC III, Sorani M, et al. Brain tissue oxygen tension is more indicative of oxygen diffusion than oxygen delivery and metabolism in patients with traumatic brain injury. Crit Care Med. 2008;36(6):1917-1924.PubMedGoogle ScholarCrossref 13. Wu HM, Huang SC, Vespa P, Hovda DA, Bergsneider M. Redefining the pericontusional penumbra following traumatic brain injury: evidence of deteriorating metabolic derangements based on positron emission tomography. J Neurotrauma. 2013;30(5):352-360.PubMedGoogle ScholarCrossref

Journal

JAMA NeurologyAmerican Medical Association

Published: May 1, 2016

Keywords: oxygen,brain ischemia,cerebral ischemia,cerebral blood flow,traumatic brain injuries,hypoxia, brain,intracranial pressure,brain metabolism,brain volume

References