0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Investigation |

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

Tonny V. Veenith, FRCA1,2; Eleanor L. Carter, FRCA1; Thomas Geeraerts, PhD1,3; Julia Grossac, MD1,3; Virginia F. J. Newcombe, PhD1; Joanne Outtrim, MSc1; Gloria S. Gee, AS4; Victoria Lupson, BSc4; Rob Smith, PhD4; Franklin I. Aigbirhio, PhD4; Tim D. Fryer, PhD4; Young T. Hong, PhD4; David K. Menon, PhD1; Jonathan P. Coles, PhD1
[+] Author Affiliations
1Division of Anaesthesia, University of Cambridge, Addenbrooke’s Hospital, Cambridge, England
2Department of Critical Care Medicine, University Hospital of Birmingham National Health Service Trust, Queen Elizabeth Medical Centre, Birmingham, England
3Department of Anesthesiology and Critical Care, University Hospital of Toulouse, Toulouse, France
4Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Addenbrooke’s Hospital, Cambridge, England
JAMA Neurol. 2016;73(5):542-550. doi:10.1001/jamaneurol.2016.0091.
Text Size: A A A
Published online

Importance  Combined oxygen 15–labeled positron emission tomography (15O PET) and brain tissue oximetry have demonstrated increased oxygen diffusion gradients in hypoxic regions after traumatic brain injury (TBI). These data are consistent with microvascular ischemia and are supported by pathologic studies showing widespread microvascular collapse, perivascular edema, and microthrombosis associated with selective neuronal loss. Fluorine 18–labeled fluoromisonidazole ([18F]FMISO), a PET tracer that undergoes irreversible selective bioreduction within hypoxic cells, could confirm these findings.

Objective  To combine [18F]FMISO and 15O PET to demonstrate the relative burden, distribution, and physiologic signatures of conventional macrovascular and microvascular ischemia in early TBI.

Design, Setting, and Participants  This case-control study included 10 patients who underwent [18F]FMISO and 15O PET within 1 to 8 days of severe or moderate TBI. Two cohorts of 10 healthy volunteers underwent [18F]FMISO or 15O PET. The study was performed at the Wolfson Brain Imaging Centre of Addenbrooke’s Hospital. Cerebral blood flow, cerebral blood volume, cerebral oxygen metabolism (CMRO2), oxygen extraction fraction, and brain tissue oximetry were measured in patients during [18F]FMISO and 15O PET imaging. Similar data were obtained from control cohorts. Data were collected from November 23, 2007, to May 22, 2012, and analyzed from December 3, 2012, to January 6, 2016.

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

Results  The 10 patients with TBI (9 men and 1 woman) had a median age of 59 (range, 30-68) years; the 2 control cohorts (8 men and 2 women each) had median ages of 53 (range, 41-76) and 45 (range, 29-59) years. Compared with controls, patients with TBI had a higher median IBV (56 [range, 9-281] vs 1 [range, 0-11] mL; P < .001) and a higher median HBV (29 [range, 0-106] vs 9 [range, 1-24] mL; P = .02). Although both pathophysiologic tissue classes were present within injured and normal appearing brains, their spatial distributions were poorly matched. When compared with tissue within the IBV compartment, the HBV compartment showed similar median cerebral blood flow (17 [range, 11-40] vs 14 [range, 6-22] mL/100 mL/min), cerebral blood volume (2.4 [range, 1.6- 4.2] vs 3.9 [range, 3.4-4.8] mL/100 mL), and CMRO2 (44 [range, 27-67] vs 71 [range, 34-88] μmol/100 mL/min) but a lower oxygen extraction fraction (38% [range, 29%-50%] vs 89% [range, 75%-100%]; P < .001), and more frequently showed CMRO2 values consistent with irreversible injury. Comparison with brain tissue oximetry monitoring suggested that the threshold for increased [18F]FMISO trapping is probably 15 mm Hg or lower.

Conclusions and Relevance  Tissue hypoxia after TBI is not confined to regions with structural abnormality and can occur in the absence of conventional macrovascular ischemia. This physiologic signature is consistent with microvascular ischemia and is a target for novel neuroprotective strategies.

Figures in this Article

Sign in

Purchase Options

• Buy this article
• Subscribe to the journal
• Rent this article ?

Figures

Place holder to copy figure label and caption
Figure 1.
Evidence of Cerebral Ischemia Using Oxygen 15–Labeled Positron Emission Tomography After Head Injury

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

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Comparison of Physiologic Features Within the Ischemic Brain Volume (IBV) and Hypoxic Brain Volume (HBV)

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

aP < .01, IBV vs normal appearance.

bP < .01, HBV vs control.

cP < .01, IBV vs control.

dP < .05, HBV vs normal appearance.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.
Evidence of Tissue Hypoxia Using Fluorine 18–Labeled Fluoromisonidazole ([18F]FMISO) Positron Emission Tomography

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

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.
Association Between Positron Emission Tomography Variables

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

Graphic Jump Location

Tables

References

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.

Multimedia

Some tools below are only available to our subscribers or users with an online account.

1,909 Views
1 Citations
×

Sign in

Purchase Options

• Buy this article
• Subscribe to the journal
• Rent this article ?

Related Content

Customize your page view by dragging & repositioning the boxes below.

See Also...
Articles Related By Topic
Related Collections
PubMed Articles
Jobs
JAMAevidence.com

Users' Guides to the Medical Literature: A Manual for Evidence-Based Clinical Practice, 3rd ed
Clarifying Your Question

Users' Guides to the Medical Literature: A Manual for Evidence-Based Clinical Practice, 3rd ed
Three Examples of Question Clarification

brightcove.createExperiences();