title: Pathophysiologic Mechanisms of Cerebral Ischemia and Diffusion Hypoxia in Traumatic Brain Injury.
abstract: Combined oxygen 15-labeled positron emission tomography (15O PET) and brain tissue oximetry have demonstrated increased oxygen diffusion gradients in hypoxic regions after traumatic brain injury (TBI). These data are consistent with microvascular ischemia and are supported by pathologic studies showing widespread microvascular collapse, perivascular edema, and microthrombosis associated with selective neuronal loss. Fluorine 18-labeled fluoromisonidazole ([18F]FMISO), a PET tracer that undergoes irreversible selective bioreduction within hypoxic cells, could confirm these findings.
  
  
  
  To combine [18F]FMISO and 15O PET to demonstrate the relative burden, distribution, and physiologic signatures of conventional macrovascular and microvascular ischemia in early TBI.
  
  
  
  This case-control study included 10 patients who underwent [18F]FMISO and 15O PET within 1 to 8 days of severe or moderate TBI. Two cohorts of 10 healthy volunteers underwent [18F]FMISO or 15O PET. The study was performed at the Wolfson Brain Imaging Centre of Addenbrooke's Hospital. Cerebral blood flow, cerebral blood volume, cerebral oxygen metabolism (CMRO2), oxygen extraction fraction, and brain tissue oximetry were measured in patients during [18F]FMISO and 15O PET imaging. Similar data were obtained from control cohorts. Data were collected from November 23, 2007, to May 22, 2012, and analyzed from December 3, 2012, to January 6, 2016.
  
  
  
  Estimated ischemic brain volume (IBV) and hypoxic brain volume (HBV) and a comparison of their spatial distribution and physiologic signatures.
  
  
  
  The 10 patients with TBI (9 men and 1 woman) had a median age of 59 (range, 30-68) years; the 2 control cohorts (8 men and 2 women each) had median ages of 53 (range, 41-76) and 45 (range, 29-59) years. Compared with controls, patients with TBI had a higher median IBV (56 [range, 9-281] vs 1 [range, 0-11] mL; P < .001) and a higher median HBV (29 [range, 0-106] vs 9 [range, 1-24] mL; P = .02). Although both pathophysiologic tissue classes were present within injured and normal appearing brains, their spatial distributions were poorly matched. When compared with tissue within the IBV compartment, the HBV compartment showed similar median cerebral blood flow (17 [range, 11-40] vs 14 [range, 6-22] mL/100 mL/min), cerebral blood volume (2.4 [range, 1.6- 4.2] vs 3.9 [range, 3.4-4.8] mL/100 mL), and CMRO2 (44 [range, 27-67] vs 71 [range, 34-88] μmol/100 mL/min) but a lower oxygen extraction fraction (38% [range, 29%-50%] vs 89% [range, 75%-100%]; P < .001), and more frequently showed CMRO2 values consistent with irreversible injury. Comparison with brain tissue oximetry monitoring suggested that the threshold for increased [18F]FMISO trapping is probably 15 mm Hg or lower.
  
  
  
  Tissue hypoxia after TBI is not confined to regions with structural abnormality and can occur in the absence of conventional macrovascular ischemia. This physiologic signature is consistent with microvascular ischemia and is a target for novel neuroprotective strategies.
authors.affiliation: Division of Anaesthesia, University of Cambridge, Addenbrooke's Hospital, Cambridge, England2Department of Critical Care Medicine, University Hospital of Birmingham National Health Service Trust, Queen Elizabeth Medical Centre, Birmingham, England.
authors.forename: Tonny V
authors.initials: TV
authors.lastname: Veenith
authors.affiliation: Division of Anaesthesia, University of Cambridge, Addenbrooke's Hospital, Cambridge, England.
authors.forename: Eleanor L
authors.initials: EL
authors.lastname: Carter
authors.affiliation: Division of Anaesthesia, University of Cambridge, Addenbrooke's Hospital, Cambridge, England3Department of Anesthesiology and Critical Care, University Hospital of Toulouse, Toulouse, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Geeraerts
authors.affiliation: Division of Anaesthesia, University of Cambridge, Addenbrooke's Hospital, Cambridge, England3Department of Anesthesiology and Critical Care, University Hospital of Toulouse, Toulouse, France.
authors.forename: Julia
authors.initials: J
authors.lastname: Grossac
authors.affiliation: Division of Anaesthesia, University of Cambridge, Addenbrooke's Hospital, Cambridge, England.
authors.forename: Virginia F J
authors.initials: VF
authors.lastname: Newcombe
authors.affiliation: Division of Anaesthesia, University of Cambridge, Addenbrooke's Hospital, Cambridge, England.
authors.forename: Joanne
authors.initials: J
authors.lastname: Outtrim
authors.affiliation: Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, England.
authors.forename: Gloria S
authors.initials: GS
authors.lastname: Gee
authors.affiliation: Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, England.
authors.forename: Victoria
authors.initials: V
authors.lastname: Lupson
authors.affiliation: Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, England.
authors.forename: Rob
authors.initials: R
authors.lastname: Smith
authors.affiliation: Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, England.
authors.forename: Franklin I
authors.initials: FI
authors.lastname: Aigbirhio
authors.affiliation: Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, England.
authors.forename: Tim D
authors.initials: TD
authors.lastname: Fryer
authors.affiliation: Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, England.
authors.forename: Young T
authors.initials: YT
authors.lastname: Hong
authors.affiliation: Division of Anaesthesia, University of Cambridge, Addenbrooke's Hospital, Cambridge, England.
authors.forename: David K
authors.initials: DK
authors.lastname: Menon
authors.affiliation: Division of Anaesthesia, University of Cambridge, Addenbrooke's Hospital, Cambridge, England.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Coles
mesh_terms: D000328:Adult; D000368:Aged; D000070642:Brain Injuries, Traumatic / Q000150:complications*; D002545:Brain Ischemia / Q000000981:diagnostic imaging / Q000209:etiology*; D016022:Case-Control Studies; D002560:Cerebrovascular Circulation / Q000502:physiology*; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000000981:diagnostic imaging / Q000209:etiology*; D008297:Male; D008875:Middle Aged; D008920:Misonidazole / Q000031:analogs & derivatives / Q000378:metabolism; D010092:Oximetry; D010100:Oxygen / Q000378:metabolism; D049268:Positron-Emission Tomography
chemical_list: C031843:fluoromisonidazole; D008920:Misonidazole; D010100:Oxygen