How does 15oxygen positron emission tomography characterization of cerebral physiology after traumatic brain injury inform clinical practice?
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.
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.
Ischemia is an important pathophysiological mechanism after traumatic brain injury (TBI), but its incidence and spatiotemporal patterns are poorly characterized.
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.
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.
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.
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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.
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 (firstname.lastname@example.org).
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.
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