Advances in Neuromonitoring at the University of Pennsylvania

W. Andrew Kofke, MD, MBA, FCCM, FNCS
Past President, Society for Neuroscience in Anesthesiology and Critical Care
Chair, International Council for Perioperative Neuroscience Training

W. Andrew Kofke, MD, MBA, FCCM, FNCS

Present state-of-the-art clinical care has created the altogether unsettling situation wherein many critically ill patients are admitted to the hospital with no infarcted brain tissue and yet, after a period of extremely intense and expensive surgery and critical care, the patients are discharged with new hospital-acquired dead brain tissue, with associated life-long disability or brain death. This situation arises in part from the critical barrier of there being no straightforward bedside methods to monitor cerebral blood flow (CBF) and its adequacy during progression of post-insult secondary brain damage. This is important because of the expectation that decrements in CBF in dangerous excess of decrements in cerebral metabolic rate for oxygen (CMRO₂), if detected early, can be treated to avert brain infarction. Clinical examples of this issue, among many others, include post ischemic stroke edema, post thrombolysis hyperemia or occlusion, post subarachnoid hemorrhage (SAH) vasospasm, hyperemic and oligemic intracranial hypertension after traumatic brain injury or stroke, ICH associated global ischemia, and intra and post carotid endarterectomy oligemia and hyperperfusion.

Critical care and anesthesiology physicians need a bedside monitor of CBF coupled to CMRO2. The CMRO2 data will allow delineation of adequacy of CBF, as occasionally CBF decrements are simply matching changes in CMRO2 as occurs under anesthesia. The lack of such monitoring capability has resulted in clinicians making often not helpful therapeutic decisions directed to non-neurologic endpoints, e.g., blood pressure,⁴ PaCO₂⁵ and so on, hoping that such interventions will have a desired effect on brain perfusion and metabolism.

Diffuse Correlation Spectroscopy (DCS) and Diffuse Optical Spectroscopy (DOS) are promising noninvasive near infra-red optical techniques under development at UPenn (Yodh et.al; four US patents) which can provide continuous bedside quantitative CBF, CMRO₂ and oxygen extraction fraction (OEF) information. Determination of capability to detect anaerobic conditions with technology such as this will make feasible the notion of individualized CBF, CMRO₂, and OEF measurement and brain-directed therapeutic optimization by bedside caregivers.

Retrospective studies indicate that when CBF decreases to <10ml/100gm/min infarction ensues.^6-9 Given the dependence of ischemic injury on time of ischemia⁶ it seems clear, although not formally proven, that rapid awareness of such a condition, related to any of a number of original insults, should lead to therapies to reverse it and prevent neural loss. There are several critical neurologic situations, where such ischemia can arise (as can damaging hyperemia.^10,11 Unfortunately, there are no currently available bedside monitors of the adequacy of CBF in a particular patient. Such monitors would permit rapid bedside detection and treatment of such dangerous ischemic/hyperemic insults. The lack of such tools is a significant barrier to progress in designing individualized, dynamic, treatment plans in neurocritical care and increasing pathophysiologic knowledge about acute neurologic diseases.

NeuroMonitoring State of the Technology Several bedside CBF methods have been used to infer or directly evaluate CBF in critically ill patients; but none are suitable for widespread and continuous bedside use. These include ¹³³XeCBF,^12,13 jugular bulb oximetry,^14,15 transcranial Doppler(TCD),^16,17 EEG-based methods^18,19 one and serial examination.²⁰ Many are indirect CBF monitors (e.g., TCD and EEG) providing relatively unreliable CBF assessment and all have problems related to complexity or inability to perform continuously that disqualify them as acceptable bedside CBF monitors. We and others are evaluating near infrared spectroscopy (NIRS) based monitors which provide quantitative data on changes in CBF and CMRO₂. This has been a great advance but generally is not yet well validated and suffers from the need to compare with a baseline condition, which in ICU patients, is not likely to be normal. Presently, there is no clinically available bedside monitor that can provide continuous information on both relative and absolute measures of CBF and CMRO₂ and reliably identify emergency conditions of low CBF jeopardizing neural tissue. The research we describe below proposes a solution to this pressing clinical need.

Our neuroICU has utilized several FDA-approved invasive monitors of cerebral oxygenation and metabolism, primarily brain O₂ tension (PbrO₂) and, to a lesser extent, microdialysis (MD). PbrO₂ provides continuous clinical information and thus provides direct feedback on the efficacy of clinical interventions. MD measurements are performed every 30 minutes providing information primarily on whether anaerobic conditions are present evidenced by increased lactate. The data suggest PbrO₂ values < 15-20mmHg predispose to poor outcomes^21-24 such that this is a likely threshold for anaerobic metabolism²⁵, although that is not the precise parameter that it actually measures. Like ICP and PbrO₂ monitoring, MD monitoring has not undergone randomized prospective evaluation for impact on outcome. However, numerous MD correlation studies have been done with increased lactate/pyruvate ratio (LPR) and /or glutamate having been shown to predict and coincide with increased ICP in TBI,^{25, 26} intracerebral hemorrhage(ICH)^27,28 and SAH^29,30 subsequent frontal brain atrophy after TBI,³¹ subsequent poor outcome or death after TBI²⁵ and SAH,³² detection of ischemia after SAH^33-41 (with PET correlation)⁴² and TBI,²⁵ ICH-associated depolarizations,⁴³ lower FiO2 in TBI,^44,45 lower paCO2 in TBI,⁴⁶ anemia with SAH,^{47, 48} and subsequent infarct in SAH.^{29, 33} Overall, MD appears to be a suitable beside standard for detection of the occurrence of anaerobiasis as evidenced by increased LPR or glutamate. Some authors question the specificity of increased LPR indicating an anaerobic stress.^49,50 However, it seems likely that when combined with low P_brO₂ and CBF that the specificity should be excellent.

We developed a Non-invasive Neuro-metabolic Optical Monitoring (NNOM) device combining functional Near Infrared Spectroscopy (fNIRS) with Diffuse Correlation Spectroscopy (DCS) to measure cerebral oxygen metabolism (CMRO₂) and absolute cerebral blood flow (CBF) concurrently and continuously at the bedside. We validated NNOM with absolute CBF by MRI, and we showed it identifies episodes of brain hypoxia, altered cerebral vascular tone, and perfusion/metabolism mismatch. A summary of some of these researches follows.

Optical monitoring of cortical CBF indicates subcortical tissue CBF

Development of ICG calibrated DCS: The UPenn group has developed Diffuse Correlation Spectroscopy (DCS) to non-invasively measure changes in cerebral blood flow. (Figure 1) DCS estimates blood flow by quantifying rapid speckle intensity fluctuations of light scattered through brain tissue induced by red blood cell motion. The DCS blood flow index (BFI, derived from a semi-infinite tissue model^51,52 is directly proportional to tissue blood flow and has been validated against multiple gold standard techniques in vivo , including direct comparisons with Doppler ultrasound,^53,54 laser Doppler,⁵ arterial spin labeled MR,^1,56-58 XeCT in SAH patients⁵⁹ (figure 2) and against physiological expectations from literature reports.^55,60-65 DCS enables continuous monitoring of relative changes in cerebral blood flow; however, absolute CBF measurements are not possible with DCS alone. To overcome this limitation, we calibrated the relative DCS measurements by concurrent NIRS measurement of the absorption kinetics of a bolus of intravenous indocyanine green (ICG). ICG is an FDA approved IR absorbing dye.^{66, 67} used in multiple neurosurgical applications.^68-73 ICG bolus tracking employs a method analogous to dynamic contrast enhanced (DCE) CT and MRI techniques, and provides a single measure of absolute CBF by relating the ICG concentration in the brain to the arterial ICG concentration (Fig 3):

C_a(t) (arterial ICG concentration) is measured using pulse oximetry,⁷⁴ Cb(t) (brain ICG concentration) is measured with time-resolved NIRS,⁷⁵ and R(t) is the ICG brain concentration for an idealized unit-concentration impulse injection.⁷⁶ A CBF-scaled R(t) is recovered from Eq.¹ using an in-house developed deconvolution algorithm that generates CBF estimates with a precision of 10%.^{77, 78} The development and construction of an instrument that can perform time resolved functional NIRS and DCS simultaneously was a major focus of our initial efforts, and has enabled the first non-invasive continuous absolute CBF measurements in humans.

Validation of Optical DCS CBF in SAH with Pressor Induced Changes in Blood Pressure
Seven neurocritical care patients were included in a study comparing optical CBF with CBF measured with stable XeCTCBF during pressor induced changes in blood pressure for vasospasm.⁵⁹ Relative CBF measured by DCS (rCBF_DCS), and changes in oxy-hemoglobin (DHbO2), deoxy-hemoglobin (DHb), and total hemoglobin concentration (DTHC), measured by NIRS, were continuously monitored throughout XeCT during a baseline scan and a scan after intervention. CBF from XeCT regions-of-interest (ROIs) under the optical probes were used to calculate relative XeCT CBF (rCBF_XeCT) and were then compared to rCBF_DCS rCBF_DCS and rCBF_XeCT showed good correlation (rs = 0.73, P = 0.010) across the patient cohort. Moderate correlations between rCBF_DCS and DHbO2/DTHC were also observed. Both NIRS and DCS distinguished the effects of xenon inhalation on CBF, which varied among the patients. An individual patient’s data is depicted in Figure 3.

Validation of ICG-NIRS with ASL MRI
We confirmed excellent agreement between ICG-NIRS and ASL MRI (widely accepted as a gold standard method for CBF measurement) in healthy volunteers (Fig. 4). Hypercapnea induced changes in CBF were resolved using both ASL and ICG-NIRS.¹

Stability of ICG calibrated DCS
We next demonstrated stability of ICG calibration by calculating CBF across multiple ICG injections in neuroICU patients. The DCS calibration coefficient that permits the conversion of BFI into absolute CBF is defined as γ=CBF₀ /BFI₀, where BFI₀ is the DCS BFI at the time the ICG bolus was injected. In seven ICU patients where two ICG injections were given at least four hours apart, we observed a high correlation (R²=0.80, p < 0.01) and good agreement (slope= 1.02 ± 0.09) between two calibration coefficients for each patient (Fig. 5A). A high correlation between CBF measured by ICG bolus technique and BFI by DCS was also observed (Fig. 5B) with slope fitting: slope= (1.24±0.07) x109 (ml/min/100g)/(cm2/s).² This supports the use of the NNOM system as a continuous monitor of absolute CBF.

Optical neuromonitoring detects periods of brain hypoxia
We evaluated whether continuous neurometabolic optical monitoring can identify periods of brain hypoxia in seven patients with severe brain injury⁷⁹ (three TBI, one Subarachnoid Hemorrhage, two intracerebral hemorrhage, and one global anoxic injury). All seven patients had invasive brain tissue oxygen (PbO₂) probes placed in white matter for clinical care. Brain hypoxia events were associated with significant changes in both mean arterial pressure (MAP) and optical CBF (Fig. 6). Both MAP and CBF were able to discriminate between low and high PbO₂ values using ROC curve analysis (MAP AUC 0.761, CBF AUC 0.762, Fig. 7). Logistic regression was then utilized to produce a weighted linear combination of these parameters. This combined MAP and CBF signal improved the ability to discriminate between high and low PbO₂ episodes (AUC 0.876).

Continuous absolute CBF and brain tissue oxygen saturation monitoring in critically ill patients
Our NNOM instrument, which combines time domain NIRS with DCS, allows for simultaneous measurements of CBF and brain tissue oxygen saturation. When combined with ICG bolus calibration, continuous, simultaneous bedside measurements of absolute CBF, CMRO₂ , and oxygen extraction fraction (OEF) are feasible. We have performed such continuous measurements over multiple days in 22 ICU patients (example indicating CBF and CMRO2 mismatch shown in Fig. 8).⁷⁹

Critical Closing Pressure (CrCP)
CrCP is the blood pressure at which cerebral blood flow ceases, and is determined by both intracranial pressure (ICP) and cerebral vasomotor tone.^{80, 81} CrCP changes dynamically with brain injury, and may allow more accurate determination of cerebral perfusion pressure and cerebral vascular reserve. Heretofore there has been no way to assess CrCP non-invasively and continuously. We utilized fast DCS measurements to calculate CrCP in healthy volunteers and validated optical CrCP with transcranial Doppler in healthy volunteers (Fig 9).⁸² Studies are ongoing to further validate this technique in patients undergoing testing of implanted defibrillators.

Summary
Several other projects have been published using NNOM. Much of it is available on the web page of the inventor group: https://www.physics.upenn.edu/yodhlab/pubs.html. Other studies not described above include use of MMM in cardiac arrest patients, use of DCS to derive a direct non invasive autoregulation index, DCSx, akin to Prx and other new autoregulation indices, studies in stroke of autoregulation and impact of head of bed elevation, use of CBF information to derive ICP subsets based on hyperemia or oligemia detected by DCS, multiparametric analysis and prediction, and multiple studies in pediatric cardiac surgery. Other very notable research is also ongoing in spinal cord blood flow with preclinical studies indicating that one day there will be a monitor which resembles an epidural catheter by which therapy may be tailored to spinal cord blood flow.^{83, 84}

NNOM technology, I believe, has promise for fundamentally altering the approach to neurologically compromised or at-risk patients.

Acknowledgement
It takes a team. I acknowledge the invaluable contributions of my collaborators at UPenn and University of Western Ontario: Physicists/bioengineers: Arjun Yodh, Keith St Lawrence, Rickson Mesquita, Venkaiah Kavuri, Wesley Baker, Lian He, Karla Bergonzi, David Busch, Daniel Milej; Neurointensivists Ramani Balu, Elizabeth Mahanna-Gabrielli, Jovany Cruz-Navarro; Neurosurgical Clinical Research Group, Eileen Maloney, Olivia Amendolia, Suzanne Frangos, Francis Quattrone, et al; Biostatistician Wensheng Guo.

The work described was supported by multiple NIH grants by several principal investigators including R01-NS060653, P41-EB015893, 1R01NS082309-01A1.

Figures and Figure Legends

Figure 1. Diffuse Correlation Spectroscopy. An infrared light source is used to probe turbid media with moving particles (such as blood). The light scattered back from the tissue is measured at a detector placed adjacent to the source. In our studies, the source/detector combination was incorporated into a single non-invasive optode patch. Light scattering by moving particles induces rapid temporal fluctuations in the detected speckle intensity, and the autocorrelation of the intensity fluctuations provides a measure of the coherence of particle flow. Changes in the decay of the autocorrelation function over time are due to changes in CBF, which allows for a relative CBF index to be calculated over time. The rCBF index can be converted to absolute CBF by concurrent near infrared spectroscopic measurement of the transit of ICG through brain tissue using the same optode.³

Figure 2. Patient with SAH underwent trial with decreased phenylephrine given for vasospasm. Data from XeCTCBF and DCS optical CBF compared. A. XeCTCBF images at two anatomic levels (level 4 and 5) on pressors (Scan 1) and off pressors (Scan 2). Decreased CBF as noted with lower pressors. B. Bilateral DCS optical CBF data obtained concurrently showing %changes in CBF from baseline on high and low pressor doses. Lower pressor dose associated with lower rCBF as noted. C. CT scan showing position of the DCS optodes. D. Comparison of the relative changes in rCBF detected by the two methods suggesting concordant observations in this patient.

Figure 2b

Figure 3. Overview of ICG-NIRS bolus measured in systemic (pulse ox) and cerebral (optode) circulation to derive CBF using equation 1.

Figure 4. Comparison of ICG-NIRS and ASL CBF estimates. Overall excellent correlation (R² = 0.79, mean difference in fits not significantly different from zero). Hypercapnea induces similar CBF changes using both methods.¹ Subsequent analysis indicates that there may be dependence on baseline tissue optical properties such that further work establishing this agreement and correlation between the two methods is ongoing.

Figure 5. A. DCS calibration coefficients obtained by 1st (γ1) and 2nd (γ1) ICG across 13 monitoring days in seven patients. B. Absolute NIRS-CBF (CBFICG) compared with DCS blood flow index.²

Figure 6. A. Identification of hypoxia episodes in brain injured patients by invasive brain tissue oxygen (PbO₂, Licox) monitoring. During hypoxia episodes, there are significant decreases in MAP (B) and optical CBF (C, normalized to baseline).⁷⁹

Figure 7. ROC analysis demonstrating ability of MAP and optical CBF measurements to discriminate low and high PbO₂ episodes. MAP and absolute CBF were associated with low PbO₂ (ROC AUC 0.761, 0.762 respectively). Combining these variables using logistic regression analysis markedly improved the ability to distinguish low and high PbO₂ epochs (AUC 0.876). TPR-True positive rate, FPR-False positive rate.⁷⁹

Figure 8. Optical CBF and brain oxygen saturation (StO₂) recordings in a brain injured patient during an episode of paroxysmal sympathetic hyperactivity. During the abrupt increase in HR and MAP, there is an increase in CBF with a concomitant decrease in StO₂ (consistent with a CMRO2 increase). Later, CBF drops without changing StO₂, suggesting a matched reduction in CMRO₂.

Figure 9. Using Fast DCS technology, Correlation and agreement between TCD and DCS based CrCP measures.⁸²

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