Mechanisms of Tissue Hypoxia and Cerebral Ischemia in Traumatic Brain Injury
By Halinder S. Mangat, MD
Assistant Professor of Neurology, Weill Cornell Medical College
Dr. Mangat reports no financial relationships relevant to this field of study.
SYNOPSIS: Tissue hypoxia after traumatic brain injury occurs in a widespread manner in the brain, including areas that appear structurally normal. Moreover, cerebral tissue hypoxia appears to occur independent of ischemia with areas of no overlap, implying a microvascular etiology.
SOURCE: Veenith TV, Carter EL, Geeraerts T, et al. Pathophysiologic mechanisms of cerebral ischemia and diffusion hypoxia in traumatic brain injury. JAMA Neurol 2016; May 1. Doi:10.1001/jamaneurol.2016.0091. Published online March 28, 2016.
This study explores the mechanism of cerebral tissue hypoxia based on earlier studies demonstrating oxygen diffusion gradient. Ten patients with moderate and severe traumatic brain injury (TBI) underwent MRI with a 3-T scanner for structural imaging. Subsequently, they underwent sequential 15O-PET and [18F]-fluoromisonidazole (FMISO) to examine cerebral ischemia and hypoxia, respectively. Data were compared with 10 controls who each underwent 15O-PET and [18F]-FMISO PET. Patients were treated using standard unit-specific ICP-CPP-PbtO2 protocol with thresholds being ICP < 25 mmHg, CPP > 65 mmHg, and PbtO2 > 15 mmHg.
TBI patients had significantly higher ischemic and hypoxic brain volumes than controls. There was no volumetric and spatial correlation between the ischemic and hypoxic brain regions and volumes. Although both ischemic and hypoxic areas were seen in contusion and pericontusional areas, there were also significant areas of hypoxic tissue in brain tissue that appeared normal on structural MRI. Although cerebral blood flow (CBF), cerebral blood volume (CBV), and cerebral metabolic rate (CMRO2) were similar in the two areas, oxygen extraction fraction (OEF) was significantly higher in ischemic regions compared to hypoxic regions, which were similar to controls.
This study confirms that regions of hypoxia and ischemia occur in normal-appearing brain tissue following TBI, and that tissue hypoxia does not appear to be a result of macrovascular ischemia but rather a microvascular abnormality and an oxygen diffusion gradient.
In studies of brain injury following interruption of cerebral blood flow, cerebral ischemia and hypoxia have been demonstrated to co-exist in areas of macrovascular ischemia in stroke and subarachnoid hemorrhage.1-3 However, previous PET studies have demonstrated areas of diffuse and distant metabolic derangements after TBI as well as reduction in CBF in contusional and pericontusional regions.4,5 Metabolic crises in the absence of brain ischemia also have been described both by PET and in vivo cerebral microdialysis.6 Diffusion-limited oxygen delivery also has been described following severe TBI.7 And variable improvement in PbtO2 and CMRO2 occurs in at-risk tissue with normobaric hyperoxia and augmentation of CPP.8,9
In this elegant study, the authors combined measurement and spatial localization of hypoxia and ischemia using respective metabolic PET markers. While cerebral ischemia and hypoxia are seen both in contusional and pericontusional regions, they also occur scattered throughout other normal-appearing brains. In addition, their spatial co-localization is poor, demonstrating areas that are either hypoxic or ischemic in isolation. Ischemic regions increase oxygen extraction to a very high degree prior to becoming hypoxic and may be the reason that hypoxic tissue was not seen within ischemic region, as FMISO is trapped in dying hypoxic cells. In ischemic tissues, in addition to low CBF, very high OEF was seen, which is consistent with tissue in the throes of compensation. However, no ischemia was seen in isolated hypoxic tissue. This may imply that while there is no macrovascular ischemia, the microcirculation is altered due to capillary edema, or collapse from cerebral edema creating an oxygen diffusion barrier/gradient. Due to the absence of oxygen, hypoxic tissue may not be able to increase OEF unlike ischemic regions.
In addition, in patients who had PbtO2 probes in place, no area of hypoxia was seen in the vicinity of the probes. And the lowest PbtO2 was 15 mmHg, which may at least be a threshold at which tissue hypoxia is not seen.
In conclusion, this study demonstrates the presence of cerebral ischemia and hypoxia in normal-appearing tissue and in spatially distinct regions. This generates the discussion that there are two distinct mechanisms for the two processes, which may be macro- and micro-vascular, respectively, or perhaps mediated by more complex mechanisms.
- 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;41:736-744.
- Markus R, Reutens DC, Kazui S, et al. Hypoxic tissue in ischaemic stroke: Persistence and clinical consequences of spontaneous survival. Brain 2004;127:1427-1436.
- Sarrafzadeh AS, Nagel A, Czabanka M, et al. Imaging of hypoxic-ischemic penumbra with (18)F-fluoromisonidazole PET/CT and measurement of related cerebral metabolism in aneurysmal subarachnoid hemorrhage. J Cereb Blood Flow Metab 2010;30: 36-45.
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- 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;55:1306-1317.
- 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;25:763-774.
- Menon DK, Coles JP, Gupta AK, et al. Diffusion limited oxygen delivery following head injury. Crit Care Med 2004;32: 1384-1390.
- Nortje J, Coles JP, Timofeev I, et al. Effect of hyperoxia on regional oxygenation and metabolism after severe traumatic brain injury: Preliminary findings. Crit Care Med 2008;36:273-281.
- Steiner LA, Coles JP, Johntson AJ, et al. Responses of posttraumatic pericontusional cerebral blood flow and blood volume to an increase in cerebral perfusion pressure. J Cereb Blood Flow Metab 2003;23:1371-1377.
Tissue hypoxia after traumatic brain injury occurs in a widespread manner in the brain, including areas that appear structurally normal. Moreover, cerebral tissue hypoxia appears to occur independent of ischemia with areas of no overlap, implying a microvascular etiology.
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