Diffuse Optical Monitoring of Cerebral Hemodynamics and Oxygen Metabolism during and after Cardiopulmonary Bypass: Hematocrit Correction and Neurological Vulnerability.

Cardiopulmonary bypass (CPB) provides cerebral oxygenation and blood flow (CBF) during neonatal congenital heart surgery, but the impacts of CPB on brain oxygen supply and metabolic demands are generally unknown. To elucidate this physiology, we used diffuse correlation spectroscopy and frequency-domain diffuse optical spectroscopy to continuously measure CBF, oxygen extraction fraction (OEF), and oxygen metabolism (CMRO2) in 27 neonatal swine before, during, and up to 24 h after CPB. Concurrently, we sampled cerebral microdialysis biomarkers of metabolic distress (lactate-pyruvate ratio) and injury (glycerol). We applied a novel theoretical approach to correct for hematocrit variation during optical quantification of CBF in vivo. Without correction, a mean (95% CI) +53% (42, 63) increase in hematocrit resulted in a physiologically improbable +58% (27, 90) increase in CMRO2 relative to baseline at CPB initiation; following correction, CMRO2 did not differ from baseline at this timepoint. After CPB initiation, OEF increased but CBF and CMRO2 decreased with CPB time; these temporal trends persisted for 0-8 h following CPB and coincided with a 48% (7, 90) elevation of glycerol. The temporal trends and glycerol elevation resolved by 8-24 h. The hematocrit correction improved quantification of cerebral physiologic trends that precede and coincide with neurological injury following CPB.

Comparison of optical measurements of critical closing pressure acquired before and during induced ventricular arrhythmia in adults.

Significance: The critical closing pressure (CrCP) of cerebral circulation, as measured by diffuse correlation spectroscopy (DCS), is a promising biomarker of intracranial hypertension. However, CrCP techniques using DCS have not been assessed in gold standard experiments. Aim: CrCP is typically calculated by examining the variation of cerebral blood flow (CBF) during the cardiac cycle (with normal sinus rhythm). We compare this typical CrCP measurement with a gold standard obtained during the drops in arterial blood pressure (ABP) caused by rapid ventricular pacing (RVP) in patients undergoing invasive electrophysiologic procedures. Approach: Adults receiving electrophysiology procedures with planned ablation were enrolled for DCS CBF monitoring. CrCP was calculated from CBF and ABP data by three methods: (1) linear extrapolation of data during RVP ( CrCP RVP ; the gold standard); (2) linear extrapolation of data during regular heartbeats ( CrCP Linear ); and (3) fundamental harmonic Fourier filtering of data during regular heartbeats ( CrCP Fourier ). Results: CBF monitoring was performed prior to and during 55 episodes of RVP in five adults. CrCP RVP and CrCP Fourier demonstrated agreement ( R = 0.66 , slope = 1.05 (95%CI, 0.72 to 1.38). Agreement between CrCP RVP and CrCP Linear was worse; CrCP Linear was 8.2 ± 5.9 mmHg higher than CrCP RVP (mean ± SD; p < 0.001 ). Conclusions: Our results suggest that DCS-measured CrCP can be accurately acquired during normal sinus rhythm.

Low frequency power in cerebral blood flow is a biomarker of neurologic injury in the acute period after cardiac arrest.

AIM: Cardiac arrest often results in severe neurologic injury. Improving care for these patients is difficult as few noninvasive biomarkers exist that allow physicians to monitor neurologic health. The amount of low-frequency power (LFP, 0.01-0.1 Hz) in cerebral haemodynamics has been used in functional magnetic resonance imaging as a marker of neuronal activity. Our hypothesis was that increased LFP in cerebral blood flow (CBF) would be correlated with improvements in invasive measures of neurologic health. METHODS: We adapted the use of LFP for to monitoring of CBF with diffuse correlation spectroscopy. We asked whether LFP (or other optical biomarkers) correlated with invasive microdialysis biomarkers (lactate-pyruvate ratio - LPR - and glycerol concentration) of neuronal injury in the 4 h after return of spontaneous circulation in a swine model of paediatric cardiac arrest (Sus scrofa domestica, 8-11 kg, 51% female). Associations were tested using a mixed linear effects model. RESULTS: We found that higher LFP was associated with higher LPR and higher glycerol concentration. No other biomarkers were associated with LPR; cerebral haemoglobin concentration, oxygen extraction fraction, and one EEG metric were associated with glycerol concentration. CONCLUSION: Contrary to expectations, higher LFP in CBF was correlated with worse invasive biomarkers. Higher LFP may represent higher neurologic activity, or disruptions in neurovascular coupling. Either effect may be harmful in the acute period after cardiac arrest. Thus, these results suggest our methodology holds promise for development of new, clinically relevant biomarkers than can guide resuscitation and post-resuscitation care. Institutional protocol number: 19-001327.

Alterations in cerebral and cardiac mitochondrial function in a porcine model of acute carbon monoxide poisoning.

OBJECTIVES: The purpose of this study is the development of a porcine model of carbon monoxide (CO) poisoning to investigate alterations in brain and heart mitochondrial function. DESIGN: Two group large animal model of CO poisoning. SETTING: Laboratory. SUBJECTS: Ten swine were divided into two groups: Control (n = 4) and CO (n = 6). INTERVENTIONS: Administration of a low dose of CO at 200 ppm to the CO group over 90 min followed by 30 min of re-oxygenation at room air. The Control group received room air for 120 min. MEASUREMENTS: Non-invasive optical monitoring was used to measure cerebral blood flow and oxygenation. Cerebral microdialysis was performed to obtain semi real time measurements of cerebral metabolic status. At the end of the exposure, both fresh brain (cortical and hippocampal tissue) and heart (apical tissue) were immediately harvested to measure mitochondrial respiration and reactive oxygen species (ROS) generation and blood was collected to assess plasma cytokine concentrations. MAIN RESULTS: Animals in the CO group showed significantly decreased Complex IV-linked mitochondrial respiration in hippocampal and apical heart tissue but not cortical tissue. There also was a significant increase in mitochondrial ROS generation across all measured tissue types. The CO group showed a significantly higher cerebral lactate-to-pyruvate ratio. Both IL-8 and TNFα were significantly increased in the CO group compared with the Control group obtained from plasma. While not significant there was a trend to an increase in optically measured cerebral blood flow and hemoglobin concentration in the CO group. CONCLUSIONS: Low-dose CO poisoning is associated with early mitochondrial disruption prior to an observable phenotype highlighting the important role of mitochondrial function in the pathology of CO poisoning. This may represent an important intervenable pathway for therapy and intervention.

Development of Low Frequency (20-100 kHz) Clinically Viable Ultrasound Applicator for Chronic Wound Treatment.

This paper details the systematic approach used to develop a viable clinical prototype of a therapeutic ultrasound applicator and discusses the rationale and deliberations that led to the design strategy. The applicator was specifically devised to treat chronic wounds and-to the best of the author's knowledge-is the first truly wearable device with a proven record of reducing healing time, directly translating to a reduction of healthcare costs. The prototype operates in the kHz (20-100) range of frequencies and uses noncavitational and nonthermal levels of ultrasound energy. Hence, in the absence of inertial cavitation and temperature elevation, the tissue-ultrasound interaction is considered to be dependent on stable cavitation (if any) and radiation force. The peak acoustic output pressure amplitude is limited to 55 kPa, corresponding to a spatial peak-temporal peak intensity of 100 mW/cm2. This level of intensity is considered to be safe to apply for extended (up to 4 h) periods of time. The patch-like applicator design is suitable to be embedded in wound dressing. With its lightweight (<20 g) and circular (40 mm dia) disk-shape architecture, the applicator is well suited for chronic wound treatment. A small ( n = 8 ) pilot study on the effects of the applicator on diabetic ulcers (DUs) healing time is presented. The average time to wound closure was 4.7 weeks for subjects treated with the active ultrasound applicator, compared to 12 weeks for subjects treated with a sham applicator, suggesting that patients with DUs may benefit from the proposed treatment.

Pressure injury prediction using diffusely scattered light.

Pressure injuries (PIs) originate beneath the surface of the skin at the interface between bone and soft tissue. We used diffuse correlation spectroscopy (DCS) and diffuse near-infrared spectroscopy (DNIRS) to predict the development of PIs by measuring dermal and subcutaneous red cell motion and optical absorption and scattering properties in 11 spinal cord injury subjects with only nonbleachable redness in the sacrococcygeal area in a rehabilitation hospital and 20 healthy volunteers. A custom optical probe was developed to obtain continuous DCS and DNIRS data from sacrococcygeal tissue while the subjects were placed in supine and lateral positions to apply pressure from body weight and to release pressure, respectively. Rehabilitation patients were measured up to four times over a two-week period. Three rehabilitation patients developed open PIs (POs) within four weeks and eight patients did not (PNOs). Temporal correlation functions in the area of redness were significantly different ( p < 0.01 ) during both baseline and applied pressure stages for POs and PNOs. The results show that our optical method may be used for the early prediction of ulcer progression.

A hand hygiene compliance check system: brief communication on a system to improve hand hygiene compliance in hospitals and reduce infection.

Hand hygiene compliance is the most significant, modifiable cause of hospital-acquired infections, yet national averages for compliance rates remain unsatisfactory. Noncompliance can contribute to patient mortality, extended hospital stays, higher re-admission rates, and lower reimbursement for hospitals under the Patient Protection and Affordable Care Act. Although several hand sanitizing tracking systems currently exist, they pose problems of personal tracking, workflow interference, system maintenance concerns, among others. Considering these barriers, we created a prototype system that includes compliance rate tracking, real-time sanitization reminders, and a data archive for future studies.

Optical metabolic imaging identifies glycolytic levels, subtypes, and early-treatment response in breast cancer.

Abnormal cellular metabolism is a hallmark of cancer, yet there is an absence of quantitative methods to dynamically image this powerful cellular function. Optical metabolic imaging (OMI) is a noninvasive, high-resolution, quantitative tool for monitoring cellular metabolism. OMI probes the fluorescence intensities and lifetimes of the autofluorescent metabolic coenzymes reduced NADH and flavin adenine dinucleotide. We confirm that OMI correlates with cellular glycolytic levels across a panel of human breast cell lines using standard assays of cellular rates of glucose uptake and lactate secretion (P < 0.05, r = 0.89). In addition, OMI resolves differences in the basal metabolic activity of untransformed from malignant breast cells (P < 0.05) and between breast cancer subtypes (P < 0.05), defined by estrogen receptor and/or HER2 expression or absence. In vivo OMI is sensitive to metabolic changes induced by inhibition of HER2 with the antibody trastuzumab (herceptin) in HER2-overexpressing human breast cancer xenografts in mice. This response was confirmed with tumor growth curves and stains for Ki67 and cleaved caspase-3. OMI resolved trastuzumab-induced changes in cellular metabolism in vivo as early as 48 hours posttreatment (P < 0.05), whereas fluorodeoxyglucose-positron emission tomography did not resolve any changes with trastuzumab up to 12 days posttreatment (P > 0.05). In addition, OMI resolved cellular subpopulations of differing response in vivo that are critical for investigating drug resistance mechanisms. Importantly, OMI endpoints remained unchanged with trastuzumab treatment in trastuzumab-resistant xenografts (P > 0.05). OMI has significant implications for rapid cellular-level assessment of metabolic response to molecular expression and drug action, which would greatly accelerate drug development studies.

A highly selective dual insulin receptor (IR)/insulin-like growth factor 1 receptor (IGF-1R) inhibitor derived from an extracellular signal-regulated kinase (ERK) inhibitor.

Dual inhibitors of the closely related receptor tyrosine kinases insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (IR) are promising therapeutic agents in cancer. Here, we report an unusually selective class of dual inhibitors of IGF-1R and IR identified in a parallel screen of known kinase inhibitors against a panel of 300 human protein kinases. Biochemical and structural studies indicate that this class achieves its high selectivity by binding to the ATP-binding pocket of inactive, unphosphorylated IGF-1R/IR and stabilizing the activation loop in a native-like inactive conformation. One member of this compound family was originally reported as an inhibitor of the serine/threonine kinase ERK, a kinase that is distinct in the structure of its unphosphorylated/inactive form from IR/IGF-1R. Remarkably, this compound binds to the ATP-binding pocket of ERK in an entirely different conformation to that of IGF-1R/IR, explaining the potency against these two structurally distinct kinase families. These findings suggest a novel approach to polypharmacology in which two or more unrelated kinases are inhibited by a single compound that targets different conformations of each target kinase.