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Figure 1.
Evidence of Cerebral Ischemia Using Oxygen 15–Labeled Positron Emission Tomography After Head Injury
Evidence of Cerebral Ischemia Using Oxygen 15–Labeled Positron Emission Tomography After Head Injury

Fluid-attenuated inversion recovery (FLAIR), cerebral blood flow (CBF), cerebral oxygen metabolism (CMRO2), oxygen extraction fraction (OEF), ischemic brain volume (IBV), fluorine 18–labeled fluoromisonidazole ([18F]FMISO) trapping rate (k3), and hypoxic brain volume (HBV) are shown in patient 10, who sustained a head injury after a fall. During imaging, cerebral perfusion pressure was 82 mm Hg, and intracranial pressure was 12 mm Hg. The FLAIR image demonstrates bilateral contusions within the temporal and parietal lobes on the right and the temporal lobe on the left. Cerebral blood flow is low in these regions, particularly on the right side. Cerebral oxygen metabolism is mildly reduced within the right temporal region, but a large increase in the OEF is seen, particularly within the right but also within the left temporal and parietal cortices. Increased k3 values are found within the right temporal region but also across other injured and normal-appearing regions. The region with a critical increase in OEF above the individually calculated ischemic threshold (IBV) and the HBV are both shown in red overlying the FLAIR image. Within the total IBV of 131 mL in this patient, the mean CBF was 14 mL/100 mL/min; CBV, 3.4 mL/100 mL; CMRO2, 84 μmol/100 mL/min; and OEF, 90%. The total HBV in this patient was 70 mL, with a mean CBF of 13 mL/100 mL/min; CBV, 2.2 mL/100 mL; CMRO2, 47 μmol/100 mL/min; and OEF, 49%. The volume of overlap between these 2 tissues classes in this patient was 6 mL.

Figure 2.
Comparison of Physiologic Features Within the Ischemic Brain Volume (IBV) and Hypoxic Brain Volume (HBV)
Comparison of Physiologic Features Within the Ischemic Brain Volume (IBV) and Hypoxic Brain Volume (HBV)

Box and whisker plots of cerebral blood flow, cerebral blood volume, cerebral oxygen metabolism, and oxygen extraction fraction in brain tissue constituting the HBV, IBV, brain tissue that appeared to be structurally normal (normal appearance), and healthy volunteers (control). The central lines in each box denote median values; lower and upper boundaries, the 25th and 75th percentiles, respectively; error bars, the 10th and 90th percentiles, and solid circles, outliers. For all comparisons, Mann-Whitney tests with Bonferroni correction were used.

aP < .01, IBV vs normal appearance.

bP < .01, HBV vs control.

cP < .01, IBV vs control.

dP < .05, HBV vs normal appearance.

Figure 3.
Evidence of Tissue Hypoxia Using Fluorine 18–Labeled Fluoromisonidazole ([18F]FMISO) Positron Emission Tomography
Evidence of Tissue Hypoxia Using Fluorine 18–Labeled Fluoromisonidazole ([18F]FMISO) Positron Emission Tomography

Fluid-attenuated inversion recovery (FLAIR), cerebral blood flow (CBF), oxygen extraction fraction (OEF), ischemic brain volume (IBV), 18F-FMISO trapping rate (k3), and hypoxic brain volume (HBV) are shown in patient 9, who sustained a head injury after a fall. During imaging, cerebral perfusion pressure was 80 mm Hg and intracranial pressure was 21 mm Hg. The FLAIR image demonstrates hemorrhagic contusions with surrounding vasogenic edema within bilateral frontal and right temporal regions. Additional areas of high signal consistent with injury are evident within the left thalamus and bilateral occipital regions. Thin subdural hematomas are seen over the right cortex and left frontal region. Cerebral blood flow is low within the frontal regions and is associated with increased k3 values in the absence of an increase in OEF consistent with conventional macrovascular ischemia. The HBV (100 mL) in this patient had a mean CBF of 14 mL/100 mL/min; cerebral blood volume (CBV), 2.1 mL/100 mL; cerebral oxygen metabolism, 27 μmol/100 mL/min; and OEF, 35%. These values did not match the region of brain within the IBV (149 mL), with a mean CBF of 15 mL/100 mL/min; CBV, 3.4 mL/100 mL; CMRO2, 63 μmol/100 mL/min; and OEF, 88%. The volume of overlap between these 2 tissues classes in this patient was 10 mL.

Figure 4.
Association Between Positron Emission Tomography Variables
Association Between Positron Emission Tomography Variables

The association between the oxygen extraction fraction (OEF) and fluorine 18–labeled fluoromisonidazole ([18F]FMISO) trapping rate (k3) within voxels across the whole brain of individual patients (n = 10) is plotted using locally weighted scatterplot smoothing (LOWESS) with 66% tension45 in Statview software (version 5; SAS Institute Inc). LOWESS is an outlier-resistant method based on local polynomial fits.46 For this comparison, voxels with cerebral oxygen metabolism of less than 37.6 μmol/100 mL/min were excluded based on the lower 95% CI for nonlesion voxels after head injury.5

Table.  
Patient Characteristics
Patient Characteristics
1.
Coles  JP, Fryer  TD, Smielewski  P,  et al.  Incidence and mechanisms of cerebral ischemia in early clinical head injury.  J Cereb Blood Flow Metab. 2004;24(2):202-211.PubMedGoogle ScholarCrossref
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Coles  JP, Fryer  TD, Coleman  MR,  et al.  Hyperventilation following head injury: effect on ischemic burden and cerebral oxidative metabolism.  Crit Care Med. 2007;35(2):568-578.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.
Xu  Y, McArthur  DL, Alger  JR,  et al.  Early nonischemic oxidative metabolic dysfunction leads to chronic brain atrophy in traumatic brain injury.  J Cereb Blood Flow Metab. 2010;30(4):883-894.PubMedGoogle ScholarCrossref
5.
Cunningham  AS, Salvador  R, Coles  JP,  et al.  Physiological thresholds for irreversible tissue damage in contusional regions following traumatic brain injury.  Brain. 2005;128(pt 8):1931-1942.PubMedGoogle ScholarCrossref
6.
Coles  JP, Cunningham  AS, Salvador  R,  et al.  Early metabolic characteristics of lesion and nonlesion tissue after head injury.  J Cereb Blood Flow Metab. 2009;29(5):965-975.PubMedGoogle ScholarCrossref
7.
Hutchinson  PJ, Jalloh  I, Helmy  A,  et al.  Consensus statement from the 2014 International Microdialysis Forum.  Intensive Care Med. 2015;41(9):1517-1528.PubMedGoogle ScholarCrossref
8.
Dienel  GA.  Lactate shuttling and lactate use as fuel after traumatic brain injury: metabolic considerations.  J Cereb Blood Flow Metab. 2014;34(11):1736-1748.PubMedGoogle ScholarCrossref
9.
Verweij  BH, Muizelaar  JP, Vinas  FC, Peterson  PL, Xiong  Y, Lee  CP.  Impaired cerebral mitochondrial function after traumatic brain injury in humans.  J Neurosurg. 2000;93(5):815-820.PubMedGoogle ScholarCrossref
10.
Beynon  C, Kiening  KL, Orakcioglu  B, Unterberg  AW, Sakowitz  OW.  Brain tissue oxygen monitoring and hyperoxic treatment in patients with traumatic brain injury.  J Neurotrauma. 2012;29(12):2109-2123.PubMedGoogle ScholarCrossref
11.
Ponce  LL, Pillai  S, Cruz  J,  et al.  Position of probe determines prognostic information of brain tissue Po2 in severe traumatic brain injury.  Neurosurgery. 2012;70(6):1492-1502.PubMedGoogle ScholarCrossref
12.
Spiotta  AM, Stiefel  MF, Gracias  VH,  et al.  Brain tissue oxygen-directed management and outcome in patients with severe traumatic brain injury.  J Neurosurg. 2010;113(3):571-580.PubMedGoogle ScholarCrossref
13.
Rockswold  SB, Rockswold  GL, Zaun  DA, Liu  J.  A prospective, randomized phase II clinical trial to evaluate the effect of combined hyperbaric and normobaric hyperoxia on cerebral metabolism, intracranial pressure, oxygen toxicity, and clinical outcome in severe traumatic brain injury.  J Neurosurg. 2013;118(6):1317-1328.PubMedGoogle ScholarCrossref
14.
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(1):273-281.PubMedGoogle ScholarCrossref
15.
Menon  DK, Coles  JP, Gupta  AK,  et al.  Diffusion limited oxygen delivery following head injury.  Crit Care Med. 2004;32(6):1384-1390.PubMedGoogle ScholarCrossref
16.
Bullock  R, Maxwell  WL, Graham  DI, Teasdale  GM, Adams  JH.  Glial swelling following human cerebral contusion: an ultrastructural study.  J Neurol Neurosurg Psychiatry. 1991;54(5):427-434.PubMedGoogle ScholarCrossref
17.
Stein  SC, Graham  DI, Chen  XH, Smith  DH.  Association between intravascular microthrombosis and cerebral ischemia in traumatic brain injury.  Neurosurgery. 2004;54(3):687-691.PubMedGoogle ScholarCrossref
18.
Takasawa  M, Moustafa  RR, Baron  JC.  Applications of nitroimidazole in vivo hypoxia imaging in ischemic stroke.  Stroke. 2008;39(5):1629-1637.PubMedGoogle ScholarCrossref
19.
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
20.
Markus  R, Donnan  GA, Kazui  S,  et al.  Statistical parametric mapping of hypoxic tissue identified by [(18)F]fluoromisonidazole and positron emission tomography following acute ischemic stroke.  Neuroimage. 2002;16(2):425-433.PubMedGoogle ScholarCrossref
21.
Markus  R, Reutens  DC, Kazui  S,  et al.  Hypoxic tissue in ischaemic stroke: persistence and clinical consequences of spontaneous survival.  Brain. 2004;127(pt 6):1427-1436.PubMedGoogle ScholarCrossref
22.
Sarrafzadeh  AS, Nagel  A, Czabanka  M, Denecke  T, Vajkoczy  P, Plotkin  M.  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(1):36-45.PubMedGoogle ScholarCrossref
23.
Marshall  LF, Marshall  SB, Klauber  MR,  et al.  The diagnosis of head injury requires a classification based on computed axial tomography.  J Neurotrauma. 1992;9(suppl 1):S287-S292.PubMedGoogle Scholar
24.
Brain Trauma Foundation; American Association of Neurological Surgeons.  Congress of Neurological Surgeons. Guidelines for the management of severe traumatic brain injury.  J Neurotrauma. 2007;24(suppl 1):S1-S106.Google ScholarCrossref
25.
World Medical Association.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.  JAMA. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053.PubMedGoogle ScholarCrossref
26.
Hong  YT, Fryer  TD.  Kinetic modelling using basis functions derived from two-tissue compartmental models with a plasma input function: general principle and application to [18F]fluorodeoxyglucose positron emission tomography.  Neuroimage. 2010;51(1):164-172.PubMedGoogle ScholarCrossref
27.
Hong  YT, Beech  JS, Smith  R, Baron  JC, Fryer  TD.  Parametric mapping of [18F]fluoromisonidazole positron emission tomography using basis functions.  J Cereb Blood Flow Metab. 2011;31(2):648-657.PubMedGoogle ScholarCrossref
28.
Smielewski  P, Coles  JP, Fryer  TD, Minhas  PS, Menon  DK, Pickard  JD.  Integrated image analysis solutions for PET datasets in damaged brain.  J Clin Monit Comput. 2002;17(7-8):427-440.PubMedGoogle ScholarCrossref
29.
Smith  SM.  Fast robust automated brain extraction.  Hum Brain Mapp. 2002;17(3):143-155.PubMedGoogle ScholarCrossref
30.
Newcombe  VF, Williams  GB, Outtrim  JG,  et al.  Microstructural basis of contusion expansion in traumatic brain injury: insights from diffusion tensor imaging.  J Cereb Blood Flow Metab. 2013;33(6):855-862.PubMedGoogle ScholarCrossref
31.
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
32.
Peeters  SG, Zegers  CM, Lieuwes  NG,  et al.  A comparative study of the hypoxia PET tracers [18F]HX4, [18F]FAZA, and [18F]FMISO in a preclinical tumor model.  Int J Radiat Oncol Biol Phys. 2015;91(2):351-359.PubMedGoogle ScholarCrossref
33.
Moustafa  RR, Baron  JC.  Clinical review: imaging in ischaemic stroke—implications for acute management.  Crit Care. 2007;11(5):227.PubMedGoogle ScholarCrossref
34.
Patlak  CS, Blasberg  RG, Fenstermacher  JD.  Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data.  J Cereb Blood Flow Metab. 1983;3(1):1-7.PubMedGoogle ScholarCrossref
35.
Coles  JP, Steiner  LA, Johnston  AJ,  et al.  Does induced hypertension reduce cerebral ischaemia within the traumatized human brain?  Brain. 2004;127(pt 11):2479-2490.PubMedGoogle ScholarCrossref
36.
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
37.
Bartlett  RM, Beattie  BJ, Naryanan  M,  et al.  Image-guided Po2 probe measurements correlated with parametric images derived from 18F-fluoromisonidazole small-animal PET data in rats.  J Nucl Med. 2012;53(10):1608-1615.PubMedGoogle ScholarCrossref
38.
Read  SJ, Hirano  T, Abbott  DF,  et al.  Identifying hypoxic tissue after acute ischemic stroke using PET and 18F-fluoromisonidazole.  Neurology. 1998;51(6):1617-1621.PubMedGoogle ScholarCrossref
39.
Veenith  TV, Carter  EL, Grossac  J,  et al.  Use of diffusion tensor imaging to assess the impact of normobaric hyperoxia within at-risk pericontusional tissue after traumatic brain injury.  J Cereb Blood Flow Metab. 2014;34(10):1622-1627.PubMedGoogle ScholarCrossref
40.
Markus  R, Reutens  DC, Kazui  S,  et al.  Topography and temporal evolution of hypoxic viable tissue identified by 18F-fluoromisonidazole positron emission tomography in humans after ischemic stroke.  Stroke. 2003;34(11):2646-2652.PubMedGoogle ScholarCrossref
41.
Moen  KG, Skandsen  T, Folvik  M,  et al.  A longitudinal MRI study of traumatic axonal injury in patients with moderate and severe traumatic brain injury.  J Neurol Neurosurg Psychiatry. 2012;83(12):1193-1200.PubMedGoogle ScholarCrossref
42.
Gross  MW, Karbach  U, Groebe  K, Franko  AJ, Mueller-Klieser  W.  Calibration of misonidazole labeling by simultaneous measurement of oxygen tension and labeling density in multicellular spheroids.  Int J Cancer. 1995;61(4):567-573.PubMedGoogle ScholarCrossref
43.
Pennings  FA, Schuurman  PR, van den Munckhof  P, Bouma  GJ.  Brain tissue oxygen pressure monitoring in awake patients during functional neurosurgery: the assessment of normal values.  J Neurotrauma. 2008;25(10):1173-1177.PubMedGoogle ScholarCrossref
44.
Meixensberger  J, Dings  J, Kuhnigk  H, Roosen  K.  Studies of tissue Po2 in normal and pathological human brain cortex.  Acta Neurochir Suppl (Wien). 1993;59:58-63.PubMedGoogle Scholar
45.
Cleveland  WS, Devlin  SJ.  Locally weighted regression: an approach to regression analysis by local fitting.  J Am Stat Assoc. 1988;83:596-610.Google ScholarCrossref
46.
Alian  AA, Rafferty  T.  The best fit function for the tee short axis left ventricular ejection fraction and radionuclear “gold standard” relationship is curvilinear.  J Clin Monit Comput. 2008;22(3):169-173.PubMedGoogle ScholarCrossref
47.
Valadka  AB, Gopinath  SP, Contant  CF, Uzura  M, Robertson  CS.  Relationship of brain tissue Po2 to outcome after severe head injury.  Crit Care Med. 1998;26(9):1576-1581.PubMedGoogle ScholarCrossref
48.
Bouma  GJ, Muizelaar  JP, Choi  SC, Newlon  PG, Young  HF.  Cerebral circulation and metabolism after severe traumatic brain injury: the elusive role of ischemia.  J Neurosurg. 1991;75(5):685-693.PubMedGoogle ScholarCrossref
49.
Schwarzmaier  SM, Kim  SW, Trabold  R, Plesnila  N.  Temporal profile of thrombogenesis in the cerebral microcirculation after traumatic brain injury in mice.  J Neurotrauma. 2010;27(1):121-130.PubMedGoogle ScholarCrossref
Original Investigation
May 2016

Pathophysiologic Mechanisms of Cerebral Ischemia and Diffusion Hypoxia in Traumatic Brain Injury

Author Affiliations
  • 1Division of Anaesthesia, University of Cambridge, Addenbrooke’s Hospital, Cambridge, England
  • 2Department of Critical Care Medicine, University Hospital of Birmingham National Health Service Trust, Queen Elizabeth Medical Centre, Birmingham, England
  • 3Department of Anesthesiology and Critical Care, University Hospital of Toulouse, Toulouse, France
  • 4Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Addenbrooke’s Hospital, Cambridge, England
 

Copyright 2016 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.

JAMA Neurol. 2016;73(5):542-550. doi:10.1001/jamaneurol.2016.0091
Abstract

Importance  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.

Objective  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.

Design, Setting, and Participants  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.

Main Outcomes and Measures  Estimated ischemic brain volume (IBV) and hypoxic brain volume (HBV) and a comparison of their spatial distribution and physiologic signatures.

Results  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.

Conclusions and Relevance  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.

Introduction

Previous studies1,2 have used oxygen 15–labeled positron emission tomography (15O PET) to define evidence of cerebral ischemia after early traumatic brain injury (TBI). Although other 15O PET studies3,4 have found less convincing evidence of ischemia, they typically demonstrate evidence of metabolic dysfunction that correlates with focal microdialysis. The relevance of such early physiologic derangements are evidenced by their association with local tissue fate,5,6 chronic brain atrophy,4 and clinical outcome.1

Although nonischemic derangements after TBI7 have been attributed to mitochondrial dysfunction,3,8,9 studies have shown reductions in brain tissue Po2 (Pbto2).10-12 These Pbto2 reductions are associated with worse outcome,10-12 and interventions aimed at optimizing oxygen delivery show promise.10,13,14 These discordant findings are best explained by an increased gradient for oxygen diffusion from the cerebral microvasculature to the interstitium. A previous study15 used Pbto2 monitoring and 15O PET to demonstrate increased gradients for oxygen diffusion within hypoxic regions in the absence of macrovascular ischemia. Further, several investigators15-17 have shown that diffusion barrier ischemia can be explained by microvascular failure due to endothelial swelling, perivascular edema, and microthrombosis, particularly surrounding focal lesions.

Fluorine 18–labeled fluoromisonidazole ([18F]FMISO) is a hypoxia PET tracer that undergoes irreversible selective bioreduction within hypoxic but viable cells18 and has been used after stroke19-21 and subarachnoid hemorrhage.22 This study is the first clinical investigation, to our knowledge, to combine [18F]FMISO with 15O PET measurement of cerebral blood flow (CBF), cerebral blood volume (CBV), cerebral oxygen metabolism (CMRO2), and oxygen extraction fraction (OEF) to interrogate pathophysiologic derangements. Imaging tissue hypoxia in the absence of macrovascular ischemia would confirm evidence of microvascular ischemia. We aimed to use [18F]FMISO and 15O PET to demonstrate the burden, distribution, and physiologic signatures of conventional macrovascular and microvascular ischemia after TBI.

Box Section Ref ID

Key Points

  • Question Do cerebral ischemia and diffusion hypoxia have distinct pathophysiologic mechanisms in traumatic brain injury (TBI)?

  • Findings In this case-control study using oxygen 15–labeled and fluorine 18–labeled fluoromisonidazole positron emission tomography in 10 patients with TBI and 20 controls, tissue hypoxia after TBI was not confined to regions with structural abnormality and could occur in the absence of conventional ischemia.

  • Meaning This physiologic signature is consistent with microvascular ischemia and is a target for novel neuroprotective strategies.

Methods
Participants

Ten patients with TBI (9 men and 1 woman) with a median age of 59 (range, 30-68) years were recruited from Addenbrooke’s Hospital. The patients presented with a median postresuscitation Glasgow Coma Scale score of 7 (range, 3-12), but required sedation and ventilation for control of intracranial pressure (Table). Patient management included protocol-driven care aiming for an intracranial pressure of less than 20 mm Hg, cerebral perfusion pressure of greater than 65 mm Hg, and, where available, Pbto2 values of greater than 15 mm Hg.14,24 Patients who received surgical intervention or second-tier medical therapies (barbiturate coma or moderate hypothermia [33°C-35°C]) are specified in the Table. The outcome was evaluated using the Glasgow Coma Scale at 6 months. Ten healthy volunteers (8 men and 2 women) with a median age of 45 (range, 29-59) years underwent 15O PET and another 10 healthy volunteers (8 men and 2 women) with a median age of 53 (range, 41-76) years underwent [18F]FMISO PET (control groups). The Cambridge Central Research Ethics Committee and Administration of Radioactive Substances Advisory Committee approved this study. Written informed consent or consultee agreement from the next-of-kin was obtained in accordance with the Declaration of Helsinki.25

Imaging

Data were collected from November 23, 2007, to May 22, 2012. Participants underwent magnetic resonance imaging using a 3-T scanner (Magnetom Verio; Siemens AG) within the Wolfson Brain Imaging Centre at the University of Cambridge. Sequences included a 3-dimensional T1-weighted magnetization prepared rapid gradient echo (MPRAGE), fluid-attenuated inversion recovery (FLAIR), gradient echo, and susceptibility-weighted imaging. Patients underwent 15O PET, followed by [18F]FMISO PET in the same session and scanner (Advance; GE Medical Systems), with FMISO injection at least 15 minutes after 15O delivery.

15O Positron Emission Tomography

Emission data were acquired in 3-dimensional mode for the last 10 minutes of a 20-minute steady-state infusion of 800 MBq of 15O water, in 3-dimensional mode for 5 minutes after a 1-minute inhalation of 750 MBq of 15O carbon monoxide, and in 2-dimensional mode for the last 10 minutes of a 20-minute steady-state inhalation of 7200 MBq of 15O oxygen (to convert to megacuries, multiply by 2.7 × 10−11). Parametric maps of CBF, CBV, CMRO2, and OEF were calculated by inputting simultaneous PET and arterial tracer radioactivity concentration measurements into standard models.1

[18F]FMISO Positron Emission Tomography

After [18F]FMISO injection (300 MBq), PET data were acquired in 3-dimensional mode for 2.5 hours. Arterial plasma samples provided the input function for kinetic analysis. Voxel-wise compartmental modeling used the irreversible version of BAFPIC, a basis function approach to 2-tissue compartmental modeling with a plasma input function.26 Hypoxia was mapped using the parameter k3 determined from BAFPIC, which denotes the tissue-trapping rate of [18F]FMISO.27

Image Processing

We processed the PET data using an integrated image analysis gateway (PETAn)28 that incorporates Statistical Parametric Mapping (SPM; Wellcome Department of Imaging Neuroscience, University College London), Matlab (MathWorks, Inc), and Analyze (AnalyzeDirect, Inc). Using the brain extraction tool in the FMRIB Software Library,29 the skull and extracranial soft tissue were stripped from the MPRAGE and the extracted brain registered to the summed H215O and [18F]FMISO images. The cerebrospinal fluid segment and CBF voxels of less than 2.36 mL/100 mL/min consistent with the core lesion in PET studies were removed based on a positive predictive value of 0.95 for nonviable tissue.5 To avoid artifacts within regions of obvious injury, analyses were conducted in native PET space, rather than using spatial transformation to a standard template.20,30

Imaging Analysis
Region of Interest Analysis

Focal contusions were defined on FLAIR and segregated into core, contusion, and pericontusion using MPRAGE, gradient echo, and susceptibility-weighted imaging.30 The lesion core was identified as a region of mixed-signal intensity consistent with hemorrhage and necrotic tissue and excluded from subsequent analyses. Contusion was identified as an area of high FLAIR signal consistent with edema; pericontusion, as a 1-cm border zone of normal-appearing tissue surrounding a contusion. The FLAIR images were coregistered to PET space using SPM8, and coregistration parameters were applied to lesion regions of interest. For comparison, a region of normal-appearing mixed gray and white matter was defined in the patients with TBI.

Ischemic Brain Volume

We used OEF to assess the burden of ischemia with a technique that was previously validated in TBI.1,2,31 We estimated an individualized critical OEF threshold (OEFcrit) (which equated to a cerebral venous oxygen content [CvO2] of 3.5 mL/100 mL) for each participant using OEFcrit = (CaO2 − 3.5)/CaO2, where CaO2 = 1.34 HbSao2 + 0.0225Pao2. CaO2 is arterial oxygen content, Hb is the hemoglobin concentration in grams per 100 mL, Sao2 is the fractional arterial oxygen saturation, and Pao2 is the arterial Po2. Application of these patient-specific OEF thresholds allowed calculation of the volume of voxels with CvO2 values below this threshold, and hence estimation of the ischemic brain volume (IBV).

Hypoxic Brain Volume

We used k3 values to assess the burden of tissue hypoxia because k3 represents the rate constant for FMISO trapping under hypoxic conditions. Using the mean and SD of voxel k3 values within the whole brain of each control participant, we calculated the upper 99% CI threshold using the mean plus 3 SDs. We used the brain volume with k3 values above this threshold to calculate the hypoxic brain volume (HBV). We examined the volume, spatial location, and mismatch between the HBV and IBV.

Comparison With Pbto2

For participants who underwent Pbto2 monitoring, monitoring was continuous with values recorded every 5 to 10 minutes throughout PET. A 20-mm-diameter region of interest15 was drawn around the sensor tip (LICOX; Integra Neurosciences Corp), and the [18F]FMISO k3 values were compared with Pbto2 values.

Statistical Analysis

Data were analyzed from December 3, 2012, to January 6, 2016. Statistical analyses were conducted using Statview (version 5; SAS Institute Inc). Data are expressed as median (range), unless otherwise stated. Data were compared using Mann-Whitney and Spearman rank correlation tests and P values quoted after Bonferroni correction (where appropriate), with corrected P < .05 considered significant. The Dice similarity coefficient32 was used to measure the degree of spatial overlap between IBV and HBV.

Results
Regional Physiologic Findings

Physiologic findings were highly variable even within regions that appeared structurally normal (eFigure in the Supplement). When compared with data from controls, contusions showed lower CBF and CMRO2 (P < .01, Mann-Whitney test with Bonferroni correction), whereas CBV and OEF were variable but similar to those of the controls. Pericontusional tissue and regions that appeared structurally normal had lower CMRO2 than tissue in controls (P < .01, Mann-Whitney test with Bonferroni correction), whereas CBF, CBV, and OEF were similar to those of controls.

Ischemic Brain Volume

When compared with controls, the IBV in the patient group was significantly higher (56 [9-281] mL vs 1 [0-11] mL; P < .001, Mann-Whitney test). Although much of the IBV was close to visible lesions, with 23% (4%-65%) found within contusional and pericontusional regions, the IBV was also distributed across normal-appearing brain tissue (Figure 1). Physiologic features within the IBV are shown in Figure 2. We found no association between the IBV and days since injury or age (P = .49 and P = .34, respectively, Spearman correlation rank test).

Hypoxic Brain Volume

The HBV was variable but significantly higher in patients compared with controls, with a median of 29 (0-106) mL vs 9 (1-24) mL (P = .02, Mann-Whitney test). A group change toward correlation between the IBV and HBV failed to achieve significance (ρ = 0.61 and P = .07, Spearman rank correlation test). The overlap volume between these 2 pathophysiologic tissue classes was 1 (0-19) mL, and we found substantial spatial mismatch (Dice similarity coefficient, 0 [0-0.1]) (Figure 1 and Figure 3). Although the HBV was often related to visible lesions, with 37% (21%-57%) found within contusional and pericontusional regions, HBV was also seen within normal-appearing brain tissue (Figures 1 and 3). Figure 2 compares summary physiologic data from the IBV and HBV tissue classes, tissue that appeared structurally normal and was in neither of these classes, and tissue from controls. When tissue constituting the HBV was compared with tissue within the IBV (Figure 2), they showed similar median CBF (17 [range, 11-40] vs 14 [range, 6-22] mL; P = .22), CBV (2.4 [range, 1.6-4.2) vs 3.9 [range, 3.4-4.8] mL/100 mL; P = .09), and CMRO2 (44 [range, 27-67] vs 71 [range, 34-88] μmol/100 mL/min; P = .14), but lower OEF (38% [range, 29%-50%] vs 89% [range, 75%-100%]; P < .001, Mann-Whitney tests with Bonferroni correction). Cerebral metabolism below published 15O PET thresholds for irreversible injury (37.6 μmoL/100 mL/min) in TBI5 was observed in 3 of 10 patients in the HBV tissue class compared with 1 within the IBV tissue class. We found no relationship between the HBV and the days since injury or age (P = .70 and P = .90, respectively, Spearman rank correlation test).

Comparison With Pbto2 Measurements

Brain tissue Po2 was available in 5 participants, and measurements during PET were 34 (16-55) mm Hg. The region of interest around the probe tip showed no [18F]FMISO k3 or OEF values that exceeded our HBV and IBV thresholds.

Discussion

By combining 15O and [18F]FMISO PET, we demonstrate evidence of conventional macrovascular cerebral ischemia and tissue hypoxia as long as 1 week after TBI. Spatial matching of these 2 tissue classes was poor, with voxels contributing to the HBV more frequently found within the vicinity of lesions. The IBV and HBV voxels showed comparable reductions in CBF, but the HBV tissue class showed a tendency toward lower CBV and CMRO2 and significantly lower OEF. Further, the HBV more frequently exhibited CMRO2 values within the range of irreversible injury. Although the IBV identifies conventional macrovascular ischemia, the coexistence of normal OEF (identified by 15O PET) and low tissue Po2 (identified by high [18F]FMISO trapping) in the HBV is the typical signature of diffusion barrier hypoxia that, along with lower CBV, implies microvascular collapse and ischemia as an underlying mechanism. These findings confirm the existence of diffusion hypoxia, characterize its pathophysiologic signature as distinct from macrovascular ischemia, and show that they have incomplete spatial concordance. Diffusion hypoxia is a potential target for future novel neuroprotective strategies.

Although 15O and [18F]FMISO PET have been used separately to identify ischemia,19-21,33 we combined both tracers to interrogate pathophysiologic derangements after TBI. For [18F]FMISO PET, we used kinetic analysis to calculate k3 as a measure of hypoxia. Although the influx rate constant (Ki)34 is often used to quantify irreversible trapping or metabolism of a tracer in tissue, it is sensitive to changes in tracer delivery, which is CBF dependent. This confounding issue is obviated through estimation of k3, the rate constant for tissue [18F]FMISO trapping, and in the context of low CBF in the vicinity of contusions,35,36 k3 is more suited to represent trapping of [18F]FMISO within hypoxic brain tissue.27,37 The HBV was calculated from the total volume of voxels with k3 values larger than the upper 99% CI value from control data.

Because derangements are common across the whole brain after TBI,1,6,35 we cannot use a similar approach to that used after ischemic stroke that defined increased [18F]FMISO trapping greater than the upper 99% CI value from contralateral brain.38 Other studies20,21 used spatial normalization and voxel-wise statistical testing to compare with controls. These approaches are less applicable to TBI because structural distortions are usually larger, making spatial normalization less dependable. We sought to identify [18F]FMISO trapping within areas of obvious injury and normal-appearing regions, and therefore, used native PET space analyses to avoid artifacts from such processing techniques.30,39 The volumes of hypoxic brain with increased [18F]FMISO trapping in our participants were similar to those seen in ischemic stroke,19,40 with a mean HBV of 47 mL in our patients and 4 patients with an HBV of at least 5% of brain volume.

We removed lesion core using magnetic resonance imaging and excluding voxels where CBF was less than 2.36 mL/100 mL/min based on a positive predictive value of 0.95 for nonviable tissue in TBI.5 After TBI, increased FLAIR signal can disappear on sequential imaging41 and is not predictive of pan necrosis for all lesion voxels.5 Because derangements are often found in normal-appearing regions,6 we examined the whole brain, but highlighted when these regions were found within the vicinity of lesions using standard magnetic resonance imaging sequences. The mean HBV found outside contusion and pericontusion areas was 30 (0-75) mL, and 4 participants had greater than 50 mL of such tissue.

These results have implications for our understanding of oxygen delivery and use in clinical TBI. Although the HBV and IBV showed some overlap, most IBV voxels did not show significant [18F]FMISO trapping. This finding suggests that at least some of the voxels with OEF in excess of our threshold CvO2 values could maintain tissue Po2 levels above those that result in irreversible bioreduction of [18F]FMISO. The Po2 at which bioreduction occurs is unclear, but in vitro data show that, although FMISO bioreduction shows some enhancement with Po2 of less than 60 mm Hg, it rises steeply at a Po2 of less than 10 mm Hg.42 Given that the normal Pbto2 is approximately 25 mm Hg,43,44 many IBV voxels may have had Pbto2 values in the range of 10 to 20 mm Hg, and our HBV threshold may simply be a more stringent physiologic marker of tissue hypoxia. In comparison with the IBV, CMRO2 below thresholds previously identified for survival5 was more common in the HBV. Although [18F]FMISO trapping does not occur within necrotic tissue,18 a proportion of these voxels may be destined for infarction, and the HBV may provide a more specific marker of tissue on the cusp of survival.

To explore the relationship between OEF and [18F]FMISO k3 within viable brain, we excluded voxels at high risk for infarction based on the lower 95% CI for nonlesion brain after TBI, using a CMRO2 threshold of 37.6 μmol/100 mL/min.5 In Figure 4, the subsequent relationship between OEF and k3 values within individual patients is shown using locally weighted scatterplot smoothing.6,45,46 This association shows variability between patients, with a subset showing increased [18F]FMISO trapping above an OEF threshold of approximately 60% to 70%, broadly consistent with conventional ischemia. We must emphasize that levels of [18F]FMISO trapping were, in most cases, below our HBV thresholds and equivalent to tissue Po2 levels of about 10 to 25 mm Hg.42

Given that these data provide a transition zone between normal tissue and tissue that shows increased [18F]FMISO trapping, physiologic characterization of tissue that shows pathologic levels of [18F]FMISO trapping would be useful. Although participants showed increased [18F]FMISO trapping across the whole brain, none was found within the vicinity of focal Pbto2 monitoring probes. Clinically significant reductions in Pbto2 are typically reported below 10 to 15 mm Hg,47 and our local treatment protocol aims to maintain values of greater than 15 mm Hg, which were achieved in all participants. The lowest Pbto2 level recorded during PET was 16 mm Hg. In terms of the threshold value at which [18F]FMISO trapping occurs in TBI, we can conclude that Po2 values within the HBV may have been no greater than 10 to 15 mm Hg.

The proportion of HBV voxels that had high OEF meeting the criteria for macrovascular ischemia (IBV) was small (8%). This finding may relate to the fact that our patients underwent imaging 1 to 8 days after injury, at a time when conventional ischemia is less prevalent,1,48 but lesions remain at risk for expansion.30,39 This timing may have meant that many tissue regions showed complex and varying mixtures of macrovascular ischemia and diffusion hypoxia, making detection of clear OEF thresholds for [18F]FMISO trapping challenging.

Our characterization of prominent [18F]FMISO trapping in perilesional regions is worth highlighting. Previous PET studies have shown severe derangements within and around cerebral contusions, but an increase in OEF consistent with cerebral ischemia is not always identified.5,36 We found that tissue within the vicinity of such lesions is hypoxic but does not fulfil the criteria for conventional macrovascular ischemia. An explanation for these findings comes from studies showing widespread microvascular occlusion and perivascular edema after TBI,16,49 associated with selective neuronal loss.17 Conventional physiology dictates that to maintain CMRO2 in the face of low CBF, OEF must be increased.1,33 However, hypoxic regions may be less able to increase OEF owing to an increased gradient for oxygen diffusion,15 which could explain our findings of low OEF and CBV despite evidence of low CBF and tissue hypoxia. Other studies have used diffusion-tensor imaging to demonstrate contusion expansion and that a rim of low apparent diffusion coefficient consistent with cytotoxic edema is often found surrounding contusions.30 This finding may characterize a region of microvascular failure and represent a traumatic penumbra that may be rescued by effective therapy such as hyperoxia14,39 or may be subsumed as the contusion enlarges.

Conclusions

These findings confirm the existence of diffusion hypoxia, characterize its pathophysiologic signature as distinct from conventional macrovascular ischemia, and show that diffusion hypoxia and macrovascular ischemia have incomplete spatial concordance. This physiologic signature is consistent with microvascular ischemia, and, importantly, this mechanism is also found within regions that appear structurally normal. Such findings require further scrutiny and are relevant to the development of future neuroprotective strategies.

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Article Information

Corresponding Author: Jonathan P. Coles, PhD, Division of Anaesthesia, University of Cambridge, Addenbrooke’s Hospital, Hills Road, PO Box 93, Cambridge CB2 0QQ, England (jpc44@wbic.cam.ac.uk).

Accepted for Publication: January 1, 2016.

Published Online: March 28, 2016. doi:10.1001/jamaneurol.2016.0091.

Author Contributions: Drs Menon and Coles are joint senior authors and contributed equally to the study. Dr Coles had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Veenith, Fryer, Menon, Coles.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Veenith, Newcombe, Gee, Aigbirhio, Fryer, Menon, Coles.

Critical revision of the manuscript for important intellectual content: Veenith, Carter, Geeraerts, Grossac, Newcombe, Outtrim, Lupson, Smith, Fryer, Hong, Menon, Coles.

Statistical analysis: Veenith, Geeraerts, Newcombe, Menon, Coles.

Obtained funding: Veenith, Newcombe, Fryer, Menon, Coles.

Administrative, technical, or material support: Veenith, Outtrim, Lupson, Smith, Aigbirhio, Fryer, Hong, Menon, Coles.

Study supervision: Fryer, Menon, Coles.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported by a clinical research training fellowship from National Institute of Academic Anaesthesia and Raymond Beverly Sackler studentship (Dr Veenith), a clinical research training fellowship from the Société Française d’Anesthésie et de Réanimation (Dr Geeraerts), a Clinician Scientist Fellowship from the Health Foundation/Academy of Medical Sciences (Dr Newcombe), a Senior Investigator Award from the National Institute for Health Research (Dr Menon), grant WT093267 from the Wellcome Trust Project, program grant G9439390 ID 65883 from the Medical Research Council (Acute Brain Injury: Heterogeneity of Mechanisms, Therapeutic Targets and Outcome Effects), the UK National Institute of Health Research Biomedical Research Centre at Cambridge, and the UK Department of Health (Drs Aigbirhio, Fryer, Menon, and Coles, for the Technology Platform).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: Josef Alawneh, PhD, Addenbrooke’s Hospital, Ramez Moustafa, PhD, Ain Shams University, Cairo, Egypt, and J. C. Baron, ScD, Institut National de la Santé et de la Recherche Medicale U894, Centre de Psychiatrie et Neurosciences, Hôpital Sainte-Anne, Université Paris, helped with recruitment and acquisition of fluorine 18–labeled fluoromisonidazole positron emission tomography among the controls. No compensation was received for these contributions.

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