Detection of Brain Hypoxia Based on Noninvasive Optical Monitoring of Cerebral Blood Flow with Diffuse Correlation Spectroscopy
Diffuse correlation spectroscopy (DCS) noninvasively permits continuous, quantitative, bedside measurements of cerebral blood flow (CBF). To test whether optical monitoring (OM) can detect decrements in CBF producing cerebral hypoxia, we applied the OM technique continuously to probe brain-injured patients who also had invasive brain tissue oxygen (PbO2) monitors.
Comatose patients with a Glasgow Coma Score (GCS) < 8) were enrolled in an IRB-approved protocol after obtaining informed consent from the legally authorized representative. Patients underwent 6–8 h of daily monitoring. Brain PbO2 was measured with a Clark electrode. Absolute CBF was monitored with DCS, calibrated by perfusion measurements based on intravenous indocyanine green bolus administration. Variation of optical CBF and mean arterial pressure (MAP) from baseline was measured during periods of brain hypoxia (defined as a drop in PbO2 below 19 mmHg for more than 6 min from baseline (PbO2 > 21 mmHg). In a secondary analysis, we compared optical CBF and MAP during randomly selected 12-min periods of “normal” (> 21 mmHg) and “low” (< 19 mmHg) PbO2. Receiver operator characteristic (ROC) and logistic regression analysis were employed to assess the utility of optical CBF, MAP, and the two-variable combination, for discrimination of brain hypoxia from normal brain oxygen tension.
Seven patients were enrolled and monitored for a total of 17 days. Baseline-normalized MAP and CBF significantly decreased during brain hypoxia events (p < 0.05). Through use of randomly selected, temporally sparse windows of low and high PbO2, we observed that both MAP and optical CBF discriminated between periods of brain hypoxia and normal brain oxygen tension (ROC AUC 0.761, 0.762, respectively). Further, combining these variables using logistic regression analysis markedly improved the ability to distinguish low- and high-PbO2 epochs (AUC 0.876).
The data suggest optical techniques may be able to provide continuous individualized CBF measurement to indicate occurrence of brain hypoxia and guide brain-directed therapy.
KeywordsBrain ischemia Hypoxia neuromonitoring Cerebral ischemia Hypoxia Neuromonitoring Clark electrode Near-infrared spectroscopy Diffuse correlation spectroscopy Cerebral blood flow Indocyanine green Oxygen extraction fraction Cerebral metabolic rate Coma
DRB and WG are involved in data analysis, conceptualization of protocol, and manuscript composition contribution; RB, data analysis, patient recruitment, conceptualization of protocol, and manuscript composition contribution); WBB, data analysis, collection and organization of patient data, ICG CBF analysis, conceptualization of protocol, and manuscript composition contribution; LH, building and maintaining of instrumentation, collection and maintenance of patient data, ICG CBF analysis, and manuscript composition contribution; MD, DM, and KSL, ICG CBF analysis, manuscript composition contribution; VK, instrument construction and bioengineering; OA, data collection and management, patient enrollment, manuscript composition contribution; AGY, biomedical optics, physics and analysis oversight, conceptualization of protocol, manuscript composition contributions; WAK, conceptualization of protocol, clinical oversight, patient recruitment, and manuscript composition contribution.
Source of support
We acknowledge support from the National Institute of Health (R01-NS082309-01A1, R01-NS060653, P41-EB015893).
Compliance with Ethical Standards
Conflict of interest
Several of the investigators received salary support from the National Institutes of Health, Canadian Institutes of Health Research, and the National Science Foundation; Wesley B. Baker has submitted two Patents to the US Patent office on behalf of the Trustees of the University of Pennsylvania: provisional patent number 17-8261/103241.000816, and provisional patent number 14-6924/103241.005919; Ramani Balu has participated in a patent submitted to the US Patent office on behalf of the Trustees of the University of Pennsylvania, US20160361017A1; Mamadou Diop, Olivia Amendolia, Wensheng Guo, Keith St. Lawrence, have no additional conflicts of interest to disclose; Venkaiah Kavuri works for Masimo, a biooptics corporation and has a patent US20170049417A1 pending on behalf of the University of Texas System; W. Andrew Kofke is on the editorial board of the Journal of Neurosurgical Anesthesiology and is on the editorial board of Neurocritical Care, and he has participated in a patent submitted to the US Patent office on behalf of the Trustees of the University of Pennsylvania: provisional patent number 17-8261/103241.000816; Arjun G. Yodh has his name is on eight patents submitted on behalf of the Trustees of the University of Pennsylvania, US6304771B1, US5917190A, US6076010A, US20080292164A1, US20060063995A1, US6487428B1, US6831741B1, and provisional patent number 17-8261/103241.000816. David R. Busch has a International Patent Applications PCT/US2015/017277 and PCT/US2015/017286.
The Institutional Review Board of the University of Pennsylvania approved all aspects of the study. All procedures performed were in accordance with the ethical standards of the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants’ legally authorized representatives.
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