[Skip to Content]
[Skip to Content Landing]

Spatial and Temporal Pattern of Ischemia and Abnormal Vascular Function Following Traumatic Brain Injury

Educational Objective
To investigate whether 15oxygen positron emission tomography characterization of cerebral physiology after traumatic brain injury can inform clinical practice.
1 Credit CME
Key Points

Question  How does 15oxygen positron emission tomography characterization of cerebral physiology after traumatic brain injury inform clinical practice?

Findings  In this single-center observational cohort study of 68 patients and 27 control participants, early ischemia was common in patients, but hyperemia coexisted in different brain regions. Cerebral blood volume was consistently increased, despite low cerebral blood flow.

Meaning  Per this analysis, pathophysiologic heterogeneity indicates that bedside physiological monitoring with devices that measure global (jugular venous saturation) or focal (tissue oximetry) brain oxygenation should be interpreted with caution.

Abstract

Importance  Ischemia is an important pathophysiological mechanism after traumatic brain injury (TBI), but its incidence and spatiotemporal patterns are poorly characterized.

Objective  To comprehensively characterize the spatiotemporal changes in cerebral physiology after TBI.

Design, Setting, and Participants  This single-center cohort study uses 15oxygen positron emission tomography data obtained in a neurosciences critical care unit from February 1998 through July 2014 and analyzed from April 2018 through August 2019. Patients with TBI requiring intracranial pressure monitoring and control participants were recruited.

Exposures  Cerebral blood flow (CBF), cerebral blood volume (CBV), cerebral oxygen metabolism (CMRO2), and oxygen extraction fraction.

Main Outcomes and Measures  Ratios (CBF/CMRO2 and CBF/CBV) were calculated. Ischemic brain volume was compared with jugular venous saturation and brain tissue oximetry.

Results  A total of 68 patients with TBI and 27 control participants were recruited. Results from 1 patient with TBI and 7 health volunteers were excluded. Sixty-eight patients with TBI (13 female [19%]; median [interquartile range (IQR)] age, 29 [22-47] years) underwent 90 studies at early (day 1 [n = 17]), intermediate (days 2-5 [n = 54]), and late points (days 6-10 [n = 19]) and were compared with 20 control participants (5 female [25%]; median [IQR] age, 43 [31-47] years). The global CBF and CMRO2 findings for patients with TBI were less than the ranges for control participants at all stages (median [IQR]: CBF, 26 [22-30] mL/100 mL/min vs 38 [29-49] mL/100 mL/min; P < .001; CMRO2, 62 [55-71] μmol/100 mL/min vs 131 [101-167] μmol/100 mL/min; P < .001). Early CBF reductions showed a trend of high oxygen extraction fraction (suggesting classical ischemia), but this was inconsistent at later phases. Ischemic brain volume was elevated even in the absence of intracranial hypertension and highest at less than 24 hours after TBI (median [IQR], 36 [10-82] mL), but many patients showed later increases (median [IQR] 6-10 days after TBI, 24 [4-42] mL; across all points: patients, 10 [5-39] mL vs control participants, 1 [0-3] mL; P < 001). Ischemic brain volume was a poor indicator of jugular venous saturation and brain tissue oximetry. Patients’ CBF/CMRO2 ratio was higher than controls (median [IQR], 0.42 [0.35-0.49] vs 0.3 [0.28-0.33]; P < .001) and their CBF/CBV ratio lower (median [IQR], 7.1 [6.4-7.9] vs 12.3 [11.0-14.0]; P < .001), suggesting abnormal flow-metabolism coupling and vascular reactivity. Patients’ CBV was higher than controls (median [IQR], 3.7 [3.4-4.1] mL/100 mL vs 3.0 [2.7-3.6] mL/100 mL; P < .001); although values were lower in patients with intracranial hypertension, these were still greater than controls (median [IQR], 3.7 [3.2-4.0] vs 3.0 [2.7-3.6] mL/100 mL; P = .002), despite more profound reductions in partial pressure of carbon dioxide (median [IQR], 4.3 [4.1-4.6] kPa vs 4.7 [4.3-4.9] kPa; P = .001).

Conclusions and Relevance  Ischemia is common early, detectable up to 10 days after TBI, possible without intracranial hypertension, and inconsistently detected by jugular or brain tissue oximetry. There is substantial between-patient and within-patient pathophysiological heterogeneity; ischemia and hyperemia commonly coexist, possibly reflecting abnormalities in flow-metabolism coupling. Increased CBV may contribute to intracranial hypertension but can coexist with abnormal CBF/CBV ratios. These results emphasize the need to consider cerebrovascular pathophysiological complexity when managing patients with TBI.

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 Credit(s)™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Accepted for Publication: September 20, 2019.

Published Online: November 11, 2019. doi:10.1001/jamaneurol.2019.3854

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2019 Launey Y et al. JAMA Neurology.

Corresponding Author: Jonathan P. Coles, PhD, Division of Anaesthesia, Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Hills Road, PO Box 93, Cambridge, Cambridgeshire CB2 0QQ, United Kingdom (jpc44@cam.ac.uk).

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

Concept and design: Hutchinson, Pickard, Coles, Menon.

Acquisition, analysis, or interpretation of data: Launey, Fryer, Hong, Steiner, Nortje, Veenith, Hutchinson, Ercole, Gupta, Aigbirhio, Coles, Menon.

Drafting of the manuscript: Launey, Hutchinson, Pickard, Coles, Menon.

Critical revision of the manuscript for important intellectual content: Launey, Fryer, Hong, Steiner, Nortje, Veenith, Hutchinson, Ercole, Gupta, Aigbirhio, Coles, Menon.

Statistical analysis: Launey, Coles, Menon.

Obtained funding: Launey, Steiner, Hutchinson, Pickard, Coles, Menon.

Administrative, technical, or material support: Fryer, Steiner, Veenith, Hutchinson, Ercole, Gupta, Aigbirhio, Pickard, Coles, Menon.

Supervision: Hutchinson, Pickard, Coles, Menon.

Conflict of Interest Disclosures: Dr Launey reports a grant from the French association Les Gueules Cassées during the conduct of the study. Dr Steiner reports grants from the Margarete und Walter Lichtenstein-Stiftung (Basel, Switzerland), a Myron B. Laver Grant (Department of Anaesthesia, University of Basel, Switzerland), the Swiss National Science Foundation, and an Overseas Research Student Award (Committee of Vice-Chancellors and Principals of the Universities of the United Kingdom) during the conduct of the study. Dr Nortje reports a grant from the Royal College of Anaesthetists/British Journal of Anaesthesia. Dr Veenith reports a grant from the National Institute of Academic Anaesthesia. Dr Hutchinson reports grants from the Royal College of Surgeons of England, British Brain and Spine Foundation, Academy of Medical Sciences/Health Foundation, and National Institute of Health Research (Research Professorship, Cambridge BRC, and Global Health Research Group on Neurotrauma). Dr Gupta reports a paid consultancy from Pressura Neuro Ltd. Drs Fryer, Aigbirhio, Pickard, Coles, and Menon report grants from the UK Medical Research Council. Dr Pickard reports a Technology Foresight Award from the UK government. Dr Coles reports grants from the Royal College of Anaesthetists/British Journal of Anaesthesia, National Institute of Academic Anaesthesia, Addenbrooke’s Charities, the Wellcome Trust, Beverley and Raymond Sackler, the Academy of Medical Sciences/Health Foundation, and National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre during the conduct of the study. Dr Menon reports paid consultancy, research grants, or membership of data monitoring committees for GlaxoSmithKline Ltd, Ornim Medical, Neurovive Ltd, Calico Ltd, NeuroTrauma Sciences LLC, and Pfizer Ltd; personal fees from Lantmannen AB; and grants and personal fees from PressuraNeuro outside the submitted work. No other disclosures were reported.

Funding/Support: This work was supported by grants from the Royal College of Anaesthetists/British Journal of Anaesthesia, National Institute of Academic Anaesthesia, Royal College of Surgeons of England, British Brain and Spine Foundation, Academy of Medical Sciences/Health Foundation, Medical Research Council (grants G9439390, G0600986, and G0001237), Wellcome Trust (grant 093267), a Technology Foresight Award from the UK government, and researchers at the National Institute for Health Research Cambridge Biomedical Research Centre. Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge acted as the sponsor for this study.

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

Additional Contributions: We thank all the patients and their families and the control participants for participating in this study.

References
1.
Pearn  ML, Niesman  IR, Egawa  J,  et al.  Pathophysiology associated with traumatic brain injury: current treatments and potential novel therapeutics.  Cell Mol Neurobiol. 2017;37(4):571-585. doi:10.1007/s10571-016-0400-1PubMedGoogle ScholarCrossref
2.
Stocchetti  N, Carbonara  M, Citerio  G,  et al.  Severe traumatic brain injury: targeted management in the intensive care unit.  Lancet Neurol. 2017;16(6):452-464. doi:10.1016/S1474-4422(17)30118-7PubMedGoogle ScholarCrossref
3.
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. doi:10.1097/01.WCB.0000100045.07481.DEPubMedGoogle ScholarCrossref
4.
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. doi:10.1097/01.WCB.0000103022.98348.24PubMedGoogle ScholarCrossref
5.
Rostami  E, Engquist  H, Enblad  P.  Imaging of cerebral blood flow in patients with severe traumatic brain injury in the neurointensive care.  Front Neurol. 2014;5:114. doi:10.3389/fneur.2014.00114PubMedGoogle Scholar
6.
Veenith  TV, Carter  EL, Geeraerts  T,  et al.  Pathophysiologic mechanisms of cerebral ischemia and diffusion hypoxia in traumatic brain injury.  JAMA Neurol. 2016;73(5):542-550. doi:10.1001/jamaneurol.2016.0091PubMedGoogle ScholarCrossref
7.
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. doi:10.1038/sj.jcbfm.9600073PubMedGoogle ScholarCrossref
8.
Diringer  MN, Videen  TO, Yundt  K,  et al.  Regional cerebrovascular and metabolic effects of hyperventilation after severe traumatic brain injury.  J Neurosurg. 2002;96(1):103-108. doi:10.3171/jns.2002.96.1.0103PubMedGoogle ScholarCrossref
9.
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. doi:10.1038/jcbfm.2009.22PubMedGoogle ScholarCrossref
10.
Yamaki  T, Imahori  Y, Ohmori  Y,  et al.  Cerebral hemodynamics and metabolism of severe diffuse brain injury measured by PET.  J Nucl Med. 1996;37(7):1166-1170.PubMedGoogle Scholar
11.
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. doi:10.1038/jcbfm.2009.263PubMedGoogle ScholarCrossref
12.
Diringer  MN, Aiyagari  V, Zazulia  AR, Videen  TO, Powers  WJ.  Effect of hyperoxia on cerebral metabolic rate for oxygen measured using positron emission tomography in patients with acute severe head injury.  J Neurosurg. 2007;106(4):526-529. doi:10.3171/jns.2007.106.4.526PubMedGoogle ScholarCrossref
13.
Johnston  AJ, Steiner  LA, Coles  JP,  et al.  Effect of cerebral perfusion pressure augmentation on regional oxygenation and metabolism after head injury.  Crit Care Med. 2005;33(1):189-195. doi:10.1097/01.CCM.0000149837.09225.BDPubMedGoogle ScholarCrossref
14.
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. doi:10.1093/brain/awh268PubMedGoogle ScholarCrossref
15.
Diringer  MN, Yundt  K, Videen  TO,  et al.  No reduction in cerebral metabolism as a result of early moderate hyperventilation following severe traumatic brain injury.  J Neurosurg. 2000;92(1):7-13. doi:10.3171/jns.2000.92.1.0007PubMedGoogle ScholarCrossref
16.
Abate  MG, Trivedi  M, Fryer  TD,  et al.  Early derangements in oxygen and glucose metabolism following head injury: the ischemic penumbra and pathophysiological heterogeneity.  Neurocrit Care. 2008;9(3):319-325. doi:10.1007/s12028-008-9119-2PubMedGoogle ScholarCrossref
17.
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. doi:10.1089/neu.2012.2610PubMedGoogle ScholarCrossref
18.
Kawai  N, Nakamura  T, Tamiya  T, Nagao  S.  Metabolic disturbance without brain ischemia in traumatic brain injury: a positron emission tomography study.  Acta Neurochir Suppl. 2008;102:241-245. doi:10.1007/978-3-211-85578-2_46PubMedGoogle ScholarCrossref
19.
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. doi:10.1097/01.CCM.0000292014.60835.15PubMedGoogle ScholarCrossref
20.
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. doi:10.1093/brain/awh536PubMedGoogle ScholarCrossref
21.
Marmarou  A.  Pathophysiology of traumatic brain edema: current concepts.  Acta Neurochir Suppl. 2003;86:7-10.PubMedGoogle Scholar
22.
Marmarou  A, Fatouros  PP, Barzó  P,  et al.  Contribution of edema and cerebral blood volume to traumatic brain swelling in head-injured patients.  J Neurosurg. 2000;93(2):183-193. doi:10.3171/jns.2000.93.2.0183PubMedGoogle ScholarCrossref
23.
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. doi:10.1097/01.CCM.0000254066.37187.88PubMedGoogle ScholarCrossref
24.
Baron  JC, Frackowiak  RS, Herholz  K,  et al.  Use of PET methods for measurement of cerebral energy metabolism and hemodynamics in cerebrovascular disease.  J Cereb Blood Flow Metab. 1989;9(6):723-742. doi:10.1038/jcbfm.1989.105PubMedGoogle ScholarCrossref
25.
Menon  DK.  Brain ischaemia after traumatic brain injury: lessons from 15O2 positron emission tomography.  Curr Opin Crit Care. 2006;12(2):85-89. doi:10.1097/01.ccx.0000216572.19062.8fPubMedGoogle ScholarCrossref
26.
Menon  DK.  Cerebral protection in severe brain injury: physiological determinants of outcome and their optimisation.  Br Med Bull. 1999;55(1):226-258. doi:10.1258/0007142991902231PubMedGoogle ScholarCrossref
27.
Jennett  B, Bond  M.  Assessment of outcome after severe brain damage.  Lancet. 1975;1(7905):480-484. doi:10.1016/S0140-6736(75)92830-5PubMedGoogle ScholarCrossref
28.
Frackowiak  RS, Lenzi  GL, Jones  T, Heather  JD.  Quantitative measurement of regional cerebral blood flow and oxygen metabolism in man using 15O and positron emission tomography: theory, procedure, and normal values.  J Comput Assist Tomogr. 1980;4(6):727-736. doi:10.1097/00004728-198012000-00001PubMedGoogle ScholarCrossref
29.
Lammertsma  AA, Baron  JC, Jones  T.  Correction for intravascular activity in the oxygen-15 steady-state technique is independent of the regional hematocrit.  J Cereb Blood Flow Metab. 1987;7(3):372-374. doi:10.1038/jcbfm.1987.75PubMedGoogle ScholarCrossref
30.
Schumann  P, Touzani  O, Young  AR, Morello  R, Baron  JC, MacKenzie  ET.  Evaluation of the ratio of cerebral blood flow to cerebral blood volume as an index of local cerebral perfusion pressure.  Brain. 1998;121(pt 7):1369-1379. doi:10.1093/brain/121.7.1369PubMedGoogle ScholarCrossref
31.
Watabe  T, Shimosegawa  E, Kato  H, Isohashi  K, Ishibashi  M, Hatazawa  J.  CBF/CBV maps in normal volunteers studied with (15)O PET: a possible index of cerebral perfusion pressure.  Neurosci Bull. 2014;30(5):857-862. doi:10.1007/s12264-013-1458-0PubMedGoogle ScholarCrossref
32.
Martin  NA, Patwardhan  RV, Alexander  MJ,  et al.  Characterization of cerebral hemodynamic phases following severe head trauma: hypoperfusion, hyperemia, and vasospasm.  J Neurosurg. 1997;87(1):9-19. doi:10.3171/jns.1997.87.1.0009PubMedGoogle ScholarCrossref
33.
Marino  R, Gasparotti  R, Pinelli  L,  et al.  Posttraumatic cerebral infarction in patients with moderate or severe head trauma.  Neurology. 2006;67(7):1165-1171. doi:10.1212/01.wnl.0000238081.35281.b5PubMedGoogle ScholarCrossref
34.
Graham  DI, Adams  JH.  Ischaemic brain damage in fatal head injuries.  Lancet. 1971;1(7693):265-266. doi:10.1016/S0140-6736(71)91003-8PubMedGoogle ScholarCrossref
35.
Graham  DI, Adams  JH, Doyle  D.  Ischaemic brain damage in fatal non-missile head injuries.  J Neurol Sci. 1978;39(2-3):213-234. doi:10.1016/0022-510X(78)90124-7PubMedGoogle ScholarCrossref
36.
Graham  DI, Ford  I, Adams  JH,  et al.  Ischaemic brain damage is still common in fatal non-missile head injury.  J Neurol Neurosurg Psychiatry. 1989;52(3):346-350. doi:10.1136/jnnp.52.3.346PubMedGoogle ScholarCrossref
37.
Carney  N, Totten  AM, O’Reilly  C,  et al.  Guidelines for the management of severe traumatic brain injury, fourth edition.  Neurosurgery. 2017;80(1):6-15.PubMedGoogle ScholarCrossref
38.
Lumb  AB.  Control of Breathing: Nunn’s Applied Respiratory Physiology. 8th ed. London, United Kingdom: Elsevier; 2017:51-72. doi:10.1016/B978-0-7020-6294-0.00004-6
39.
Steiner  LA, Balestreri  M, Johnston  AJ,  et al.  Sustained moderate reductions in arterial CO2 after brain trauma time-course of cerebral blood flow velocity and intracranial pressure.  Intensive Care Med. 2004;30(12):2180-2187. doi:10.1007/s00134-004-2463-6PubMedGoogle ScholarCrossref
40.
Menon  DK, Coles  JP, Gupta  AK,  et al.  Diffusion limited oxygen delivery following head injury.  Crit Care Med. 2004;32(6):1384-1390. doi:10.1097/01.CCM.0000127777.16609.08PubMedGoogle ScholarCrossref
41.
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. doi:10.3171/jns.2000.93.5.0815PubMedGoogle ScholarCrossref
42.
Brown  GC, Vilalta  A.  How microglia kill neurons.  Brain Res. 2015;1628(Pt B):288-297. doi:10.1016/j.brainres.2015.08.031PubMedGoogle ScholarCrossref
43.
Gopinath  SP, Valadka  AB, Uzura  M, Robertson  CS.  Comparison of jugular venous oxygen saturation and brain tissue Po2 as monitors of cerebral ischemia after head injury.  Crit Care Med. 1999;27(11):2337-2345. doi:10.1097/00003246-199911000-00003PubMedGoogle ScholarCrossref
44.
Donnelly  J, Czosnyka  M, Adams  H,  et al.  Twenty-five years of intracranial pressure monitoring after severe traumatic brain injury: a retrospective, single-center analysis.  Neurosurgery. 2019;85(1):E75-E82. doi:10.1093/neuros/nyy468PubMedGoogle ScholarCrossref
Close
Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
Close
Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close

Name Your Search

Save Search
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Close
Close

Lookup An Activity

or

My Saved Searches

You currently have no searches saved.

Close

My Saved Courses

You currently have no courses saved.

Close