In Reply Lazaridis highlights that while we found evidence of low cerebral blood flow and increased oxygen extraction consistent with ischemia following clinical head injury,1 tissue hypoxia can also result from pathophysiological mechanisms that cannot be explained by macrovascular ischemia with such classic characteristics. Despite comparable perfusion deficits, oxygen extraction is not increased in such regions. We postulate that this may result from an inability to increase the fraction of oxygen extracted from that available due to microvascular occlusion and perivascular edema within the injured brain (diffusion hypoxia). Such pathophysiological mechanisms are distributed heterogeneously across the injured brain, but particularly within the vicinity of brain lesions. Few participants in this cohort underwent monitoring of brain tissue oxygen and microdialysis, and those who did were not placed in the vicinity of regions with relevant pathophysiology. Despite this, flourine 18–labeled fluoromisonidazole trapping is a marker of hypoxia2 and was used in this imaging study to define tissue hypoxia across the whole brain in relation to cerebral blood flow, blood volume, oxygen metabolism, and oxygen extraction fraction. Mitochondrial dysfunction has been found following head injury3 and could contribute to the metabolic derangements that we have shown, particularly in the presence of tissue hypoxia,4 but would not explain the presence of tissue hypoxia per se (and by inference, increased flourine 18–labeled fluoromisonidazole uptake). The predominant finding in this article was that tissue hypoxia can occur in the absence of macrovascular ischemia. This finding may characterize a region of microvascular failure and is a target for future neuroprotective strategies.
Coles JP, Menon DK. Diffusion Hypoxia and/or Primary Mitochondrial Failure?—Reply. JAMA Neurol. 2016;73(11):1373. doi:10.1001/jamaneurol.2016.3263
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