Metabolic derangements are associated with impaired glucose delivery following traumatic brain injury

Abstract

Metabolic derangements following traumatic brain injury are poorly characterised. In this single-centre observational cohort study we combined 18F-FDG and multi-tracer oxygen-15 PET to comprehensively characterise the extent and spatial pattern of metabolic derangements. Twenty-six patients requiring sedation and ventilation with intracranial pressure monitoring following head injury within a Neurosciences Critical Care Unit, and 47 healthy volunteers were recruited. Eighteen volunteers were excluded for age over 60 years (11), movement related artefact (three) or physiological instability during imaging (four). We measured cerebral blood flow, blood volume, oxygen extraction fraction, and 18F-FDG transport into the brain (K1) and its phosphorylation (k3). We calculated oxygen metabolism, 18F-FDG influx rate constant (Ki), glucose metabolism and the oxygen/glucose metabolic ratio. Lesion core, penumbra and peri-penumbra, and normal-appearing brain, ischaemic brain volume and k3 hot-spot regions were compared with plasma and microdialysis glucose in patients. Twenty-six head injury patients, median age 40 years (22 male, 4 female) underwent 34 combined 18F-FDG and oxygen-15 PET at early, intermediate, and late time-points (within 24 hours, days 2–5, and days 6–12 post injury; n = 12, 8, and 14, respectively), and were compared with 20 volunteers, median age 43 years (15 male, 5 female) who underwent oxygen-15, and 9 volunteers, median age 56 years (3 male, 6 female) who underwent 18F-FDG PET. Higher plasma glucose was associated with higher microdialysate glucose. Blood flow and K1 were decreased in the vicinity of lesions, and closely related when blood flow was less than 25 ml/100 ml/min. Within normal-appearing brain, K1 was maintained despite lower blood flow than volunteers. Glucose utilisation was globally reduced in comparison with volunteers (p < 0.001). k3 was variable; highest within lesions with some patients showing increases with blood flow less than 25 ml/100 ml/min, but falling steeply with blood flow lower than 12 ml/100 ml/min. k3 hot-spots were found distant from lesions, with k3 increases associated with lower plasma glucose (Rho -0.33, p < 0.001) and microdialysis glucose (Rho -0.73, p = 0.02). k3 hot-spots showed similar K1 and glucose metabolism to volunteers despite lower blood flow and oxygen metabolism (p < 0.001, both comparisons); oxygen extraction fraction increases consistent with ischaemia were uncommon. We show that glucose delivery was dependent on plasma glucose and cerebral blood flow. Overall glucose utilisation was low, but regional increases were associated with reductions in glucose availability, blood flow and oxygen metabolism in the absence of ischaemia. Clinical management should optimise blood flow and glucose delivery and could explore the use of alternative energy substrates.

Cerebral metabolic derangements following traumatic brain injury

“…1b) and recent combined multitracer oxygen-15 and 18 F-FDG PET studies confirm evidence of ischemic CBF reductions in acute TBI on the basis of a critical increase in both OEF and glycolysis (k 3 ) (Fig. 2) [5 ▪▪ ]. The authors demonstrated that the ischemic brain volume (IBV) within the first 24 h following injury was associated with worse outcome using the Glasgow Outcome Score.…”

“…In fact, bedside clinical monitoring of brain tissue oxygen and cerebral metabolism using microdialysis demonstrate evidence of persistent metabolic derangements which correlate with patient outcome [ 3 ▪▪ ]. Imaging studies using 15 oxygen PET demonstrate reductions in cerebral blood flow (CBF) and increases in oxygen extraction fraction (OEF) which are consistent with ischemia, but this finding is less common beyond the first 24 h after injury [ 4 ▪▪ , 5 ▪▪ ]. At these later time points following TBI, metabolic derangements are more consistent with disruption of the microcirculation resulting in tissue hypoxia or low brain glucose delivery, and/or mitochondrial dysfunction [ 5 ▪▪ ].…”

Brain Shock—Toward Pathophysiologic Phenotyping in Traumatic Brain Injury

“…The ability to address ischemic hypoxia due to inadequate CBF, and prevent hyperemia, may be enhanced by using bedside techniques that assess in real time the status of cerebrovascular pressure reactivity, and to determine patient-specific optimal CPP ( 19 , 20 ). Flow dependency is not only an issue for oxygen but also for glucose delivery; neuroglycopenia can be an independent cause for energy crisis ( 21 ). Recent studies employing multimodality imaging and invasive tissue monitoring suggest that flow-dependent cerebral energy crisis—that is, ischemia due to low CPP/CBF—is not the sole and may not be the dominant SBI mechanism beyond the resuscitative phase ( 21 – 23 ).…”

“…Flow dependency is not only an issue for oxygen but also for glucose delivery; neuroglycopenia can be an independent cause for energy crisis (21). Recent studies employing multimodality imaging and invasive tissue monitoring suggest that flow-dependent cerebral energy crisis-that is, ischemia due to low CPP/CBF-is not the sole and may not be the dominant SBI mechanism beyond the resuscitative phase (21)(22)(23).…”

Simultaneous estimation of a model-derived input function for quantifying cerebral glucose metabolism with [18F]FDG PET

“…However, characterizing glucose metabolism is often limited to measuring the cerebral metabolic rate of glucose (CMRGlu), due to the challenges associated with obtaining microparameters at a voxelwise level [4]. A growing interest in understanding how CMRGlu is potentially affected by disease-related alterations in glucose delivery and phosphorylation [5,6] fosters further investigations.…”