Spatial and Temporal Pattern of Ischemia and Abnormal Vascular Function Following Traumatic Brain Injury | Traumatic Brain Injury | JAMA Neurology | JAMA Network
[Skip to Content]
Sign In
Individual Sign In
Create an Account
Institutional Sign In
OpenAthens Shibboleth
[Skip to Content Landing]
Figure 1.  Spatial Variation in Regional Physiology After Traumatic Brain Injury
Spatial Variation in Regional Physiology After Traumatic Brain Injury

Example findings from a patient with a traumatic brain injury on day 3 after injury. The patient’s initial Glasgow Coma Scale score was 12 but deteriorated on admission, requiring sedation and ventilation for management of intracranial pressure. Within the vicinity of the right frontal and temporal hemorrhagic contusions, cerebral blood flow and cerebral oxygen metabolism are decreased, but within the contralateral hemisphere, which appears structurally normal, cerebral blood flow is variably reduced and the oxygen extraction fraction is markedly increased, suggesting ischemia.

Figure 2.  Spatial and Temporal Pattern of Regional Physiological Derangements in Patients With Traumatic Brain Injury
Spatial and Temporal Pattern of Regional Physiological Derangements in Patients With Traumatic Brain Injury

Individual regional values for cerebral blood flow, blood volume, oxygen metabolism, and oxygen extraction fraction in patients with traumatic brain injury, plotted against time postinjury (orange, within 24 hours [early]; brown, days 2-5 [intermediate]; blue, days 6-10 [late]). The fitted blue lines represent modeling of the association between each parameter and hours postinjury using locally weighted scatterplot smoothing, with the 95% CIs shown in light blue. The solid and dashed black lines represent the median and the full range of values for healthy volunteers, respectively.

Figure 3.  Burden of Cerebral Ischemia
Burden of Cerebral Ischemia

A, The ischemic brain volume in patients with traumatic brain injury is plotted against time postinjury (orange, within 24 hours [early]; brown, days 2-5 [intermediate]; blue, days 6-10 [late]). The dashed lines represent minimal and maximal values for ischemic brain volume in control participants. Open circles represent patients with intracranial pressure of 20 mm Hg or less, and filled circles represent patients with intracranial pressure greater than 20 mmHg. B, Association between the ischemic brain volume and jugular venous saturation in 63 patients who had jugular bulb catheters in place during 15oxygen positron emission tomography studies. Data are shown for studies within 24 hours (orange circles), days 2 through 5 (gray), and days 6 through 10 (blue) postinjury, with the blue line denoting the fit using a locally weighted scatterplot smoothing regression model, with the 95% CI shown in lighter blue. The dashed lines represent minimal and maximal values for ischemic brain volume in control participants. C, Association between ischemic brain volume and brain tissue oximetry. The ischemic brain volume in patients with traumatic brain injury is plotted against brain tissue oximetry in 38 patients with monitoring in place during 15oxygen positron emission tomography studies. Data are shown for studies within 24 hours (orange circles), days 2 through 5 (gray), and days 6 through 10 (blue) postinjury. The dashed lines represent minimal and maximal values for ischemic brain volume in control participants.

Table 1.  Baseline Demographics and Physiology During Imaging
Baseline Demographics and Physiology During Imaging
Table 2.  Temporal Pattern of Global Physiological Derangements
Temporal Pattern of Global Physiological Derangements
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
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    1 Comment for this article
    EXPAND ALL
    Oxygen May Not Be the Only Problem
    Harutunyan Gurgen, MD (1); Harutyunyan Garnik; Soghomonyan Suren. MD, PhD (2); Avitsian Rafi MD, FASA (3) | (1) Hospital 9 De Octubre VITHAS, Valencia, Spain. E-mail: varsenik@hotmali.es; (2) Universitat De València, Faculty of Pharmacy, Valencia, Spain . The Ohio State University Wexner Medical Center
    We read with interest the study by Launay, et al. investigating the spatial and temporal pattern of ischemia and abnormal vascular function following traumatic brain injury. Similar to many other publications, the investigators characterize posttraumatic ischemia as an equivalent of hypoxia. The assumption that maintenance of cerebral blood flow (CBF) is a factor sufficient for oxygen and substrate delivery remains a fundamental management strategy as mentioned in other studies (1).                                       

    However, we should not forget that only approximately 30 -
    40% of the oxygen and 10% of the glucose delivered to the brain are consumed (2), and the oxygen is not the rate-limiting factor. According to the Haldane coefficient, the maximum amount of protons (H+) that are carried by human haemoglobin for each mole of delivered oxygen is 0.6 (3). In contrast, the brain tissue has a respiratory quotient of one: the metabolism of one mole of oxygen will produce one mole of CO2. Also, one mole of CO2 in the erythrocytes will generate one mole of H+. That is, ischemia in TBI is characterized not only by the amount of oxygen delivery and uptake but also by the blood buffering capacity (BBC) and the ability to remove dissolved CO2. We have previously discussed the important role of BBC (4,5).

    Clinical studies suggest that brain regions can survive in the setting of prolonged ischemia with local cerebral venous oxygen content (CvO2) levels as low as 3.5 mL/100 mL (6,7). According to this value of CvO2, critical oxygen extraction fraction (OEF) can be calculated (8,9). Thus, in ischemic tissue there is a significant amount of oxygen that is delivered but not used, since the BBC is depleted in the decreased regional cerebral blood flow.

    CO2 removal (and concomitantly BBC) will depend on the rate of ventilation. Optimizing the ventilation and improving the elimination of by-products will increase OEF more than 75% without inducing ischemia with the net result of improved regional oxygen consumption and oxidative metabolism.

    References:

    1. Stocchetti N et al. Severe traumatic brain injury: targeted management in the intensive care unit. Lancet Neurol. 2017

    2. Powers WJ: Hemodynamics and metabolism in ischemic cerebrovascular disease. Neurol Clin 10

    3. Voet D. Biochemistry, 4th ed. New York, NY: John Wiley & Sons; 2010

    4. Harutyunyan G et al. New viewpoint in exaggerated increase of PtiO2 with normobaric hyperoxygenation and reasons to limit oxygen use in neurotrauma patients. Front Med. 2018

    5. Harutyunyan G et al. Revisiting Ischemia After Brain Injury: Oxygen May Not Be the Only Problem. J Neurosurg Anesthesiol. 2019

    6. Powers WJ et al. Cerebral blood flow and cerebral metabolic rate of oxygen requirements for cerebral function and viability in humans. J Cereb Blood Flow Metab 1985

    7. Yundt KD et all. The use of hyperventilation and its impact on cerebral ischemia in the treatment of traumatic brain injury. Crit Care Clin 1997

    8. Coles JP et al. Defining ischemic burden after traumatic brain injury using 15O PET imaging of cerebral physiology. J Cereb Blood Flow Metab 2004

    9. Coles JP et al. Incidence and mechanisms of cerebral ischemia in early clinical head injury. J Cereb Blood Flow Metab 2004
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Original Investigation
    November 11, 2019

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

    Author Affiliations
    • 1Division of Anaesthesia, Department of Medicine, Addenbrooke’s Hospital, University of Cambridge, Cambridge, United Kingdom
    • 2Department of Anaesthesia and Critical Care Medicine, Centre Hospitalier Universitaire de Rennes, Rennes, France
    • 3Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, Addenbrooke’s Hospital, University of Cambridge, Cambridge, United Kingdom
    • 4Department of Anaesthesiology, University Hospital Basel, Basel, Switzerland
    • 5Department of Clinical Research, University of Basel, Basel, Switzerland
    • 6Department of Anaesthesia, Norfolk and Norwich University Hospitals National Health Service Foundation Trust, Norwich, United Kingdom
    • 7Birmingham Acute Care Research Group, Department of Critical Care Medicine, Queen Elizabeth Hospital, University of Birmingham, Birmingham, United Kingdom
    • 8Division of Neurosurgery, Department of Clinical Neurosciences, Addenbrooke’s Hospital, University of Cambridge, Cambridge, United Kingdom
    JAMA Neurol. 2020;77(3):339-349. doi:10.1001/jamaneurol.2019.3854
    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.

    Introduction

    Outcome after traumatic brain injury (TBI) is associated with not only initial injury severity but also secondary insults, including ischemia, brain swelling, and intracranial hypertension.1 Changes in cerebrovascular physiology after TBI contribute to all of these insults. Quiz Ref IDEnsuring that cerebral blood flow (CBF) is adequate for oxygen and substrate delivery represents a fundamental management aim, which is pursued by optimizing cerebral perfusion pressure (CPP) and ventilation and controlling intracranial pressure (ICP).2

    The physiology that underpins these aims and therapies used to achieve them are incompletely understood. Many studies have measured CBF without reference to regional cerebral oxygen metabolism (CMRO2), making it difficult to distinguish ischemia from CBF appropriately coupled to reduced metabolism and neuronal loss.3-5 Where studies have measured CMRO2,6-10 sample sizes have been small and do not cover the dynamic temporal and spatial evolution of cerebrovascular pathophysiology.11-16 Further, many studies have concentrated on physiology within lesions and have not examined regions that initially appear structurally normal.17-20

    While brain swelling and ICP elevation drive up to half of TBI-associated mortality21 and remain therapeutic targets, the underlying physiology is unclear. Studies suggest that intracranial hypertension is predominantly attributable to brain edema, with cerebral blood volume (CBV) playing a limited role.22 However, in these studies, CBV was indirectly calculated rather than directly measured. These issues are important, since ICP-lowering therapies have competing benefits and harms. For example, lowering the partial pressure of carbon dioxide (Paco2) reduces vascular caliber and hence CBV and ICP, but it also reduces CBF,23 increasing the risk of ischemia.

    Quiz Ref IDWhile cerebrovascular physiology can be assessed with several imaging techniques,515oxygen positron emission tomography (15O PET) is the current reference standard for CBF, CBV, CMRO2, and oxygen extraction fraction (OEF).24 While results from multiple centers6,11,12,18 have been integrated,25 this is hampered by differences in PET methodology (eg, bolus vs steady-state techniques)24 and approaches to data analysis (eg, voxel-based vs region-of-interest analysis).6,11,12,18 There remains a need for comprehensive characterization of cerebrovascular physiology after TBI using standardized 15O PET in a large patient sample across the full temporal disease narrative.

    We aimed to comprehensively characterize cerebrovascular physiology within brain regions that initially appear structurally normal, using standardized 15O PET in a large patient cohort up to 10 days after TBI. We describe temporal changes in physiology, document changes in flow-metabolism coupling (CBF/CMRO2) and local microvascular flow-volume associations (CBF/CBV), disentangle ischemia from coupled hypoperfusion, and assess the contribution of vascular engorgement to ICP elevation.

    Methods

    Additional details are provided within the eMethods in the Supplement. Control participants and patients with TBI requiring ICP monitoring within intensive care underwent 15O PET between February 1998 and July 2014. We excluded technically inadequate imaging studies and those with large variations of arterial pressure or Paco2. Some data have been reported previously,4,6,14,19,23 but none for the aims of the current article.

    Studies were approved by the Cambridgeshire Research Ethics Committee and UK Administration of Radioactive Substances Advisory Committee and conducted in accordance with 1964 Declaration of Helsinki and later amendments. Volunteers provided informed consent, and assent was obtained from patient representatives, with patient consent obtained at follow-up if capacity was regained.

    Clinical Protocols
    Patients

    Quiz Ref IDProtocol-driven therapy targeted an ICP of less than 20 mm Hg and a CPP of 60 to 70 mm Hg, as described by Menon.26 Mechanical ventilation and tight control of respiratory and cardiovascular physiology during PET studies with (where available) Paco2 reductions titrated against jugular venous saturation (SJVO2) and brain-tissue oximetry (BTPO2). Outcomes were recorded using the Glasgow Outcome Score (GOS)27 at 6 months after TBI.

    Imaging

    Maps of CBF, CBV, CMRO2, and OEF were calculated as previously described6,28,29 after PET, using a General Electric Advance scanner (GE Medical Systems) at the Wolfson Brain Imaging Centre of the University of Cambridge (Cambridge, United Kingdom). We categorized studies into 3 groups: within 24 hours of TBI (early), 2 to 5 days after TBI (intermediate), and 6 to 10 days after TBI (late).

    Image Analysis

    This analysis used whole-brain and standardized regions of interest (ROIs),23 excluding regions with lesions identified on registered computed tomography or magnetic resonance imaging. To account for pathophysiological heterogeneity within ROIs and assess ischemic burden, we estimated an individualized critical OEF threshold using a previously validated technique.3,4,6 Calculation of the volume of voxels with OEF greater than this threshold allowed estimation of the ischemic brain volume (IBV). We plotted IBV against SJVO2 and BTPO2 to identify thresholds for critical ischemia.

    We calculated CBF/CMRO2 to assess the efficiency of flow-metabolism coupling and CBF/CBV as an index of local CPP.30,31 To determine whether differences in CBF/CBV represented intrinsic differences in vascular physiology or CPP variance, we calculated CBF/CBV divided by CPP.

    Statistical Analysis

    Because data were not normally distributed, results are expressed as median (interquartile range [IQR]), and we used nonparametric statistical tests within R version 3.5.2 (R Foundation for Statistical Computing). In addition, we undertook linear mixed-effects regression of log-transformed PET parameters, adjusting for ROI, to analyze the difference in regional physiology between patients with TBI and healthy control participants, and we added time as a covariate (linear and quadratic to allow for nonlinear effects) to examine the association of time with changes in cerebrovascular physiology. We compared models with and without these terms using χ2 tests. Correlation coefficients were calculated using Spearman rank tests, and Mann-Whitney tests were used when comparing patients and control participants. For comparisons between groups, we used the Kruskal-Wallis test with the Dunn test for post hoc comparisons. Linear plots were used to help visualize the associations between parameters.

    For between-group comparisons of basic demographic and clinical data, a P value of .05 or less was regarded as significant. Additional results were interpreted taking into consideration that, to infer statistical significance, a Bonferroni correction for 7 variables (CBF, CBV, CMRO2, OEF, CBF/CMRO2, CBF/CBV, and IBV) would require P < .007, and for regional comparisons (14 ROIs), P < 5.0 × 10−4 would be required. We also sought associations between IBV and GOS stratified for time after injury to replicate a previous finding4 in the early phase after TBI.

    Results

    A total of 27 control participants and 68 patients with TBI were recruited; imaging studies from 7 control participants and 1 study from 1 patient with TBI were excluded because of poor quality. We analyzed data from 20 control participants with no clinically significant neurological or psychiatric illness and 90 PET sessions in 68 patients with TBI with stable physiology during imaging (eFigure 1 in the Supplement).

    Included patients had severe TBI (Glasgow Coma Scale score ≤8 on admission) or presented with moderate TBI (Glasgow Coma Scale score, 9-12) and subsequently deteriorated. Of the 90 PET studies, 17 were within 24 hours of the TBI (early), 54 between 2 and 5 days after the TBI (intermediate), and 19 after 6 or more days after the TBI (late). Seventeen patients had PET studies on more than 1 occasion, but only 3 had studies at all 3 times. Table 1 summarizes the baseline demographics and physiology during imaging (median [IQR] age: control participants, 43 [31-47] years; patients with TBI, 29 [22-47] years; female participants: control participants, 5 of 20 [25%]; patients with TBI, 13 of 55 [19%]).

    Patients had lower CPP (median [IQR], 73 [70-80] vs 81 [75-88]; P = .008) and Paco2 (median [IQR], 4.6 [4.2-4.8] kPa vs 5.6 [5.2-5.7] kPa; P < .001) than control participants. With the exception of CPP, which was significantly higher in the TBI group with late imaging compared with those with intermediate imaging (median [IQR] values, 80 [77-91] vs 73 [69-78] mm Hg; P = .008; Table 1), there were no differences in physiological variables (hemoglobin, Pao2, Paco2, and ICP) between the different TBI groups. Despite attempted management to a target ICP of 20 mm Hg or less, this was not achieved in all patients; 9 patients had ICP levels of 25 mm Hg or more during imaging.

    Global Physiology

    Patients, compared with control participants, had lower CBF (median [IQR], 26 [22-30] mL/100 mL/min vs 38 [29-49] mL/100 mL/min; P < .001) and CMRO2 (median [IQR], 62 [55-71] μmol/100 mL/min vs 131 [101-167] μmol/100 mL/min; P < .001) and higher CBV (median [IQR], 3.7 [3.4-4.1] mL/100 mL vs 3.0 [2.7-3.6] mL/100 mL; P < .001) despite lower Paco2 (median [IQR], 4.6 [4.2-4.8] kPa vs 5.6 [5.2-5.7] kPa; P < .001). The CBF/CMRO2 ratio was higher in patients (median [IQR], 0.42 [0.35-0.49] vs 0.3 [0.28-0.33]; P < .001), while CBF/CBV was lower (median [IQR], 7.1 [6.4-7.9] vs 12.3 [11.0-14.0]; P < .001). The difference in OEF between patients and control participants (median [IQR], 39% [35%-43%] vs 44% [40%-45%]; P = .02) did not survive correction for multiple comparisons but was significantly lower at the intermediate point (median [IQR], 38% [32%-42%]; P = .004; Table 2). Compared with the rest of the group, physiology in patients who underwent craniectomy was similar to those who did not, while barbiturate coma was associated with lower CMRO2 (median [IQR], 53 [43-64] μmol/100 mL/min vs 65 [57-74] μmol/100 mL/min; P = .004), but reductions in CBF (median [IQR], 21 [18-27] mL/100 mL vs 27 [23-32] mL/100 mL; P = .01) and CBV (median [IQR], 3.2 [3.1-4.3] mL/100 mL vs 3.8 [3.4-4.1] mL/100 mL; P = .03) did not remain significant after correction for multiple comparisons.

    Regional Physiology

    Spatial heterogeneity was obvious on imaging (Figure 1), with regional variability shown across the whole-brain ROI template (eFigure 2 in the Supplement) both within and between patients, compared with control participants (eTables 1 and 2 and eFigure 3 in the Supplement). Using a linear mixed-effects regression model comparing affected patients with control participants, regional CBF, CBV, and CMRO2 in patients were found to be significantly different (covariate effect estimates, −0.37, 0.16, and −0.71, respectively; all comparisons P < .001), while OEF (covariate effect estimate, −0.12; P = .01) did not remain significant after correction for multiple comparisons. There were also significant differences between control participants and patients at various points after injury (eTable 3 in the Supplement), and the time-dependent models for CBF, CBV, CMRO2, and OEF fit the data significantly better (−0.85, −0.39, 0.72, and 0.9 for standardized time, and 0.17, 0.09, −0.23, and 0.25 for standardized time2, respectively; all comparisons, P < .001). Temporal trends differed between patients and control participants (Figure 2): CBF was low, showed a transient recovery, and then decreased again, while CMRO2 was initially low and decreased further over time. Oxygen extraction fraction was initially high and fell in the intermediate period before trending toward normal values. Cerebral blood volume showed less variation and Cerebral blood volume showed less variation and showed a trend for higher values than normal at all points. The 17 patients who underwent PET on more than 1 occasion showed a pattern similar to the overall cohort (eTable 4 and eFigure 4 in the Supplement).

    Flow Metabolism Coupling

    Wide variations in OEF (which imply large variations in flow-metabolism coupling) and regions with particularly low OEF (implying hyperemia) were common and most prominent between days 2 through 5 (Figure 2 and eFigure 3 within the Supplement). These abnormalities in CBF/CMRO2 ratios were quantified across ROIs in individual patients using the Spearman rank test, with high ρ values providing evidence of preserved flow-metabolism coupling. While there was substantial interparticipant heterogeneity, patients with TBI (median ρ, 0.44 [IQR, 0.25-0.64]) showed lower correlation coefficients than control participants (ρ, 0.75 [0.67-0.86]; P < .001; eFigure 5 and eTable 5 in the Supplement).

    Ischemia

    Oxygen extraction fraction showed a nonlinear association with CBF, with substantial within-participant and between-participant heterogeneity (eFigure 6 in the Supplement). Within 24 hours, OEF increased sharply when CBF was less than 25 mL/100 mL/min (the lower CBF limit in control participants), suggesting cerebral ischemia. Across all points, while some regions showed increases, OEF tended to plateau at approximately 45% when CBF was less than 25 mL/100 mL/min. While IBV elevations were most common within 24 hours of injury (median [IQR] IBV in early imaging, 36 [10-82] mL), high IBV was observed up to 10 days after TBI (median [IQR] in late imaging, 24 [4-42] mL) and were not associated with intracranial hypertension (Table 2; Figure 3). All patients had CPP greater than 60 mm Hg. Ischemic brain volume was not associated with CPP (ρ, –0.06; P = .60) and did not differ in those who underwent craniectomy (median [IQR], 11 [5-28] vs 10 [4-49] mL; P = .75) or barbiturate coma (median [IQR], 24 [5-67] vs 10 [4-37] mL; P = .36). Within 24 hours, IBV was associated with worse outcomes, as quantified via the GOS (ρ, –0.63; P = .006), but there was no association across the whole cohort (ρ, −0.06; P = .71). After TBI, there was no association between CBF and Paco2 (ρ, –0.39; P = .09) or CBF and IBV measured during PET (ρ, –0.17; P = .10) or within separate temporal cohorts.

    Bedside Monitors of Brain Oximetry

    We had 67 PET sessions with SJVO2 and 38 with BTPO2 monitoring. We found no association between IBV and SJVO2 (Figure 3). Within the first 24 hours, there was some evidence of an inflection point at an SJVO2 of approximately60%; when the level was less than this, IBV showed progressive increases. However, there were patients with high IBV who showed SJVO2 values greater than the 60% threshold.

    There was no association between IBV and BTPO2 (Figure 3). In fact, many individuals with BTPO2 values less than 15 mm Hg had IBV values within the control range.

    Cerebral Blood Flow and Volume

    When compared with control participants, patients with TBI showed lower whole-brain CBF/CBV for all points (Table 2); in nonlesion ROIs, this was particularly true within intermediate and late points (eTable 2 in the Supplement). Correcting for lower CPP in patients compared with control participants (73 mg vs 81 mm Hg; P = .008 ) did not remove this difference. Though patients showed more variability in the CBF/CBV correlation, we observed no group level differences in ρ values between control participants and any TBI temporal subgroups (eFigure 7 and eTable 5 in the Supplement).

    Cerebral Blood Volume and Intracranial Pressure

    Increases in ICP were found up to 10 days after TBI (Table 1) with CBV inversely associated with ICP (ρ, −0.23; P = .04; eFigure 8 in the Supplement), but no association between CBV and ICP after accounting for Paco2 during PET was found (ρ, −0.17; P = .13). There was a negative association between Paco2 and ICP (ρ, −0.39; P < .001), with lower Paco2 in patients with intracranial hypertension (median [IQR], 4.3 [4.1-4.6] kPa vs 4.7 [4.3-4.9] kPa; P = .001; eFigure 9 in the Supplement), presumably driven by hyperventilation therapy. Despite lower Paco2, CBV remained higher in patients with intracranial hypertension than control participants (median [IQR], 3.7 [3.2-4.0] vs 3.0 [2.7-3.6] mL/100 mL; P = .002; eFigure 9 in the Supplement). There was no association between CBV and Paco2 in all patients (ρ, 0.19; P = .07) or in those with ICP greater than 20 mm Hg (ρ, 0.03; P = .89).

    Discussion

    To our knowledge, this is the largest 15O PET study in patients with TBI, and it shows clear phasic changes in cerebral physiology. Our results have clinical relevance in 3 areas. First, they map the presence, temporal course, and association of ischemia with outcome. Second, they elucidate the association between CBV increases and intracranial hypertension and the relevance of this association for ICP management. Finally, these data document abnormal flow-metabolism coupling and cerebral vasoregulation after TBI, which is a potential target for the development of future therapeutic interventions.

    Ischemic Burden

    Quiz Ref IDAfter TBI, CBF shows a triphasic pattern, classically described as consisting of early hypoperfusion (<24 hours), hyperemia (1-3 days), and vasospasm (after 3 days).32 Most previous analyses have been based on indirect CBF measurement, typically using transcranial Doppler ultrasonography. Imaging has not commonly used CMRO2 measurement,5 making it impossible to differentiate ischemia from hypoperfusion appropriately coupled with hypometabolism. Our data show that classical ischemia (diagnosed by the incontrovertible metabolic signature of high OEF) is seen in many patients within 24 hours of injury, can be observed later, and can occur despite optimization of CPP, Paco2, and ICP.

    Other groups have found less consistent evidence of classical ischemia using 15O PET in patients with TBI.12,17,18,25 Several of these studies focused on patients with less severe TBI at later points, with less significant physiological derangements, and for a limited period. Some specifically addressed contused brain and provided little data on cerebrovascular pathophysiology in structurally normal brain, which often constitutes the largest tissue compartment after TBI. Additional contributors to this discrepancy include the use of bolus, as opposed to our use of steady-state PET techniques,24 and different approaches to quantifying ischemic burden (ROI vs voxel-based methods). Our data are in keeping with the frequent detection of cerebral ischemia and infarction after TBI, both with antemortem imaging33 and postmortem neuropathology.34-36

    Hyperventilation can result in acute CBF reductions,23 with increases in OEF and reductions in CMRO2 in some patients.23 However, IBV in this cohort was not associated with steady-state Paco2, perhaps because hyperventilation was being titrated to monitors of cerebral oximetry (SJVO2 or BTPO2) and used to control intracranial hypertension.37 Alternatively, hyperventilation-induced ischemia may resolve over time as extracellular pH in the brain normalizes.38 Although this compensation is incomplete for CBF reductions (as opposed to CBV39), it may make it difficult to detect ischemia at steady-state low Paco2 levels (which was the case in the participants in this study).

    CBF-OEF Associations

    Reductions in CBF to less than the normal range resulted in sharp OEF increases within the first 24 hours. However, such OEF increases were not systematically achieved by similar CBF reductions at later points, which could imply a failure of oxygen extraction or use. Microvascular dysfunction and diffusion hypoxia are known to occur in a normal-appearing brain of a patient with TBI6,40 and can limit the ability to increase OEF. Similarly, oxygen use may be prevented by mitochondrial dysfunction, either because of structural mitochondrial damage7,41 or competitive inhibition of the mitochondrial respiratory chain by nitric oxide.42 Finally, persistent CBF reductions may result in patchy necrosis or selective neuronal loss. The overall CBF in such heterogeneous regions may be low but appropriate for the remaining viable tissue.

    Abnormal Flow Metabolism Coupling and Bedside Monitoring of Ischemia

    These data show generalized abnormalities in flow-metabolism coupling, with weaker associations between CBF and CMRO2 in patients with TBI compared with control participants. A high CBF/CMRO2 ratio implies hyperemia and was most prominent 2 to 5 days postinjury. These findings are consistent with transcranial Doppler ultrasonography data,32 but our additional CMRO2 measurement allows confirmation that these represent true hyperemia. We documented between-participant heterogeneity, but also within-participant heterogeneity, since regions with high and low OEF often coexisted within the same patient. This heterogeneity may confound bedside monitoring, since global methods (SJVO2) may dilute and miss focal pathophysiology, while focal monitors (BTPO2) are critically dependent on sensor position. We saw some evidence of an SJVO2 threshold of approximately 60%, and at levels less than this, IBV increased (particularly within 24 hours of TBI). However, many patients with high IBV had SJVO2 values that were substantially greater than this threshold level, and use of the typical SJVO2 less than 50%43 would have missed all but 1 patient with critical brain ischemia. We found no reliable association between BTPO2 and IBV. In fact, many participants with low BTPO2 values (<15 mm Hg) did not show IBV increases. Our inference is that focal BTPO2 monitoring is not reliably associated with the global or regional burden of ischemia.

    Cerebral Ischemia and Outcome

    Quiz Ref IDAs demonstrated previously,4 IBV within the first 24 hours after TBI was associated with GOS, underlining the clinical significance of early ischemia. The lack of correlation between later IBV and GOS raises the possibility that later ischemia is better tolerated, but it is more likely that other energy failure mechanisms (such as diffusion hypoxia6 and mitochondrial dysfunction7) make greater contributions to outcome at these points.

    Association of CBV With ICP

    Previous reports, using estimates based on a combination of xenon and perfusion CT,21,22 reported reduced CBV in patients with TBI. The direct CBV measurement in this report shows that it was consistently raised, but the contribution to ICP elevation was complex. Patients with intracranial hypertension showed lower CBV values than those with ICP values of 20 mm Hg or less, but this unexpected association was likely attributable to lower Paco2 in patients with intracranial hypertension, in whom hyperventilation therapy was used. Despite this, their CBV values remained significantly greater than those of control participants, suggesting that CBV elevations continued to contribute to intracranial hypertension. While cerebral edema is an important driver of intracranial hypertension, we show that CBV increases also contribute, providing a physiological basis for interventions aimed at reducing the vascular contribution to intracranial volume.

    CBF/CBV Associations

    We found regional differences in CBF/CBV (eFigure 3 in the Supplement) in patients with TBI, replicating past results from control participants.31 Since experimental studies suggest a linear association between CPP and CBF/CBV,30 we calculated CBF/CBV divided by CPP to account for lower CPP values in individuals with TBI. However, CBF/CBV divided by CPP remained lower in individuals with TBI (Table 2), suggesting that simple autoregulatory vasodilatation could not explain this finding. Reduced CBF/CBV in individuals with TBI may represent impaired dilatation of precapillary resistance units (resulting in low CBF) and/or a disproportionate increase in (probably venous) capacitance in the cerebrovascular circuit. These inferences are concordant with past TBI data, which show that the effect of hyperventilation on CBV (and hence ICP) is transient, while the CBF reductions it produces are dominant and sustained.39

    Limitations

    Although our data were collected prospectively in accordance with a common protocol, this was a retrospective collation with nonconsecutive recruitment driven by convenience and logistics, which makes generalizability difficult to assess. Imaging was not possible on days on which patients were too unstable or scanners were unavailable. Although data were acquired over 16 years, all patients were recruited after the introduction of the Cambridge ICP/CPP protocol, and any changes in physiological targets over the recruitment period were relatively small and have been detailed in a recent publication.44 Systemic physiology during each scan is available and explicitly summarized in Table 1. We used global, regional, and voxel-based analyses, but each has potential pitfalls; global and region-based measures may miss voxel-level pathophysiological heterogeneity, whereas voxel-based approaches are more susceptible to noise. While this was, to our knowledge, the largest single-center 15O PET study in individuals with TBI (90 scans), ideally an assessment of the temporal patterns of physiology would make use of sequential studies within participants. However, such studies are difficult to undertake and limited by considerations of patient safety and stability. Consequently, the sample available for analysis represents the data that were obtainable in this context. We did have 17 patients in whom PET were available on more than 1 occasion. The temporal patterns in this subset broadly replicate those of the overall cohort, suggesting the larger data set provides a useful representation of temporal trends in regional physiology. Further analysis, using a mixed-effects model that accounted for the inclusion of data from multiple ROIs within each participant, confirmed the association of time postinjury with regional cerebrovascular variables in comparison with data from control participants. Finally, this analysis explored pathophysiology in structurally normal tissue to examine the brain at risk of evolving injury, and hence it does not provide a complete picture of all pathophysiological tissue compartments after TBI.

    Conclusions

    In a large cohort of individuals with TBI, 15O PET imaging shows systematic changes in cerebrovascular physiology that have direct clinical relevance. Early ischemia (<24 hours) occurs in approximately two-thirds of patients, is detectable up to 10 days postinjury, and is not limited to patients with intracranial hypertension. We found significant outcome associations with ischemia that occurred early but not after 24 hours, implying that other pathophysiological mechanisms of energy failure may be dominant during later phases of the disease narrative. We demonstrate substantial pathophysiological heterogeneity within patients, with ischemia and hyperemia coexisting in different brain regions, reflecting abnormalities in flow-metabolism coupling. Global (SJVO2) or focal (BTPO2) measures of cerebral oximetry provide data that guide clinical management, but physiological heterogeneity dictates that these should be interpreted with caution. Cerebral blood volume is consistently increased in patients with TBI and remains higher than control values even in patients with intracranial hypertension, despite lower Paco2 being used to manage ICP. These data are in keeping with CBV increases as a contributor to intracranial hypertension. However, there may be disassociation of CBF/CBV homeostasis, with disproportionately high CBV seen across the entire postinjury period despite low CBF. Such physiological dissociation, along with the regional variations in physiology and the inconsistent associations with monitoring that we demonstrate in this study, may inform clinical management of patients with TBI.

    Back to top
    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
    ×