Tiffany Ko

Fast blood flow monitoring in deep tissues with real-time software correlators

We introduce, validate and demonstrate a new software correlator for high-speed measurement of blood flow in deep tissues based on diffuse correlation spectroscopy (DCS). The software correlator scheme employs standard PC-based data acquisition boards to measure temporal intensity autocorrelation functions continuously at 50 - 100 Hz, the fastest blood flow measurements reported with DCS to date. The data streams, obtained in vivo for typical source-detector separations of 2.5 cm, easily resolve pulsatile heart-beat fluctuations in blood flow which were previously considered to be noise. We employ the device to separate tissue blood flow from tissue absorption/scattering dynamics and thereby show that the origin of the pulsatile DCS signal is primarily flow, and we monitor cerebral autoregulation dynamics in healthy volunteers more accurately than with traditional instrumentation as a result of increased data acquisition rates. Finally, we characterize measurement signal-to-noise ratio and identify count rate and averaging parameters needed for optimal performance.

Pressure modulation algorithm to separate cerebral hemodynamic signals from extracerebral artifacts.

Abstract. We introduce and validate a pressure measurement paradigm that reduces extracerebral contamination from superficial tissues in optical monitoring of cerebral blood flow with diffuse correlation spectroscopy (DCS). The scheme determines subject-specific contributions of extracerebral and cerebral tissues to the DCS signal by utilizing probe pressure modulation to induce variations in extracerebral blood flow. For analysis, the head is modeled as a two-layer medium and is probed with long and short source-detector separations. Then a combination of pressure modulation and a modified Beer-Lambert law for flow enables experimenters to linearly relate differential DCS signals to cerebral and extracerebral blood flow variation without a priori anatomical information. We demonstrate the algorithm’s ability to isolate cerebral blood flow during a finger-tapping task and during graded scalp ischemia in healthy adults. Finally, we adapt the pressure modulation algorithm to ameliorate extracerebral contamination in monitoring of cerebral blood oxygenation and blood volume by near-infrared spectroscopy.

Cerebral Blood Flow Response to Hypercapnia in Children with Obstructive Sleep Apnea Syndrome.

STUDY OBJECTIVES Children with obstructive sleep apnea syndrome (OSAS) often experience periods of hypercapnia during sleep, a potent stimulator of cerebral blood flow (CBF). Considering this hypercapnia exposure during sleep, it is possible that children with OSAS have abnormal CBF responses to hypercapnia even during wakefulness. Therefore, we hypothesized that children with OSAS have blunted CBF response to hypercapnia during wakefulness, compared to snorers and controls. METHODS CBF changes during hypercapnic ventilatory response (HCVR) were tested in children with OSAS, snorers, and healthy controls using diffuse correlation spectroscopy (DCS). Peak CBF changes with respect to pre-hypercapnic baseline were measured for each group. The study was conducted at an academic pediatric sleep center. RESULTS Twelve children with OSAS (aged 10.1 ± 2.5 [mean ± standard deviation] y, obstructive apnea hypopnea index [AHI] = 9.4 [5.1-15.4] [median, interquartile range] events/hour), eight snorers (11 ± 3 y, 0.5 [0-1.3] events/hour), and 10 controls (11.4 ± 2.6 y, 0.3 [0.2-0.4] events/hour) were studied. The fractional CBF change during hypercapnia, normalized to the change in end-tidal carbon dioxide, was significantly higher in controls (9 ± 1.8 %/mmHg) compared to OSAS (7.1 ± 1.5, P = 0.023) and snorers (6.7 ± 1.9, P = 0.025). CONCLUSIONS Children with OSAS and snorers have blunted CBF response to hypercapnia during wakefulness compared to controls. Noninvasive DCS blood flow measurements of hypercapnic reactivity offer insights into physiopathology of OSAS in children, which could lead to further understanding about the central nervous system complications of OSAS.

Scoring system for periventricular leukomalacia in infants with congenital heart disease.

Background:Currently two magnetic resonance imaging (MRI) methods have been used to assess periventricular leukomalacia (PVL) severity in infants with congenital heart disease: manual volumetric lesion segmentation and an observational categorical scale. Volumetric classification is labor intensive and the categorical scale is quick but unreliable. We propose the quartered point system (QPS) as a novel, intuitive, time-efficient metric with high interrater agreement.Methods:QPS is an observational scale that asks the rater to score MRIs on the basis of lesion size, number, and distribution. Pre- and postoperative brain MRIs were obtained on term congenital heart disease infants. Three independent observers scored PVL severity using all three methods: volumetric segmentation, categorical scale, and QPS.Results:One-hundred and thirty-five MRIs were obtained from 72 infants; PVL was seen in 48 MRIs. Volumetric measurements among the three raters were highly concordant (ρc = 0.94–0.96). Categorical scale severity scores were in poor agreement between observers (κ = 0.17) and fair agreement with volumetrically determined severity (κ = 0.26). QPS scores were in very good agreement between observers (κ = 0.82) and with volumetric severity (κ = 0.81).Conclusion:QPS minimizes training and sophisticated radiologic analysis and increases interrater reliability. QPS offers greater sensitivity to stratify PVL severity and has the potential to more accurately correlate with neurodevelopmental outcomes.

Calibration of diffuse correlation spectroscopy blood flow index with venous-occlusion diffuse optical spectroscopy in skeletal muscle.

Abstract. We investigate and assess the utility of a simple scheme for continuous absolute blood flow monitoring based on diffuse correlation spectroscopy (DCS). The scheme calibrates DCS using venous-occlusion diffuse optical spectroscopy (VO-DOS) measurements of arm muscle tissue at a single time-point. A calibration coefficient (γ) for the arm is determined, permitting conversion of DCS blood flow indices to absolute blood flow units, and a study of healthy adults (N=10) is carried out to ascertain the variability of γ. The average DCS calibration coefficient for the right (i.e., dominant) arm was γ=(1.24±0.15)×108 (mL·100  mL−1·min−1)/(cm2/s). However, variability can be significant and is apparent in our site-to-site and day-to-day repeated measurements. The peak hyperemic blood flow overshoot relative to baseline resting flow was also studied following arm-cuff ischemia; excellent agreement between VO-DOS and DCS was found (R2=0.95, slope=0.94±0.07, mean difference=−0.10±0.45). Finally, we show that incorporation of subject-specific absolute optical properties significantly improves blood flow calibration accuracy.

Preoperative cerebral hemodynamics from birth to surgery in neonates with critical congenital heart disease

Background Hypoxic–ischemic white matter brain injury commonly occurs in neonates with critical congenital heart disease. Recent work has shown that longer time to surgery is associated with increased risk for this injury. In this study we investigated changes in perinatal cerebral hemodynamics during the transition from fetal to neonatal circulation to ascertain mechanisms that might underlie this risk. Methods Neonates with either transposition of the great arteries (TGA) or hypoplastic left heart syndrome (HLHS) were recruited for preoperative noninvasive optical monitoring of cerebral oxygen saturation, cerebral oxygen extraction fraction, and cerebral blood flow using diffuse optical spectroscopy and diffuse correlation spectroscopy, 2 noninvasive optical techniques. Measurements were acquired daily from day of consent until the morning of surgery. Temporal trends in these measured parameters during the preoperative period were assessed with a mixed effects model. Results Forty‐eight neonates with TGA or HLHS were studied. Cerebral oxygen saturation was significantly and negatively correlated with time, and oxygen extraction fraction was significantly and positively correlated with time. Cerebral blood flow did not significantly change with time during the preoperative period. Conclusions In neonates with TGA or HLHS, increasing cerebral oxygen extraction combined with an abnormal cerebral blood flow response during the time between birth and heart surgery leads to a progressive decrease in cerebral tissue oxygenation The results support and help explain the physiological basis for recent studies that show longer time to surgery increases the risk of acquiring white matter injury.

Cerebral mitochondrial dysfunction associated with deep hypothermic circulatory arrest in neonatal swine

Abstract OBJECTIVES Controversy remains regarding the use of deep hypothermic circulatory arrest (DHCA) in neonatal cardiac surgery. Alterations in cerebral mitochondrial bioenergetics are thought to contribute to ischaemia–reperfusion injury in DHCA. The purpose of this study was to compare cerebral mitochondrial bioenergetics for DHCA with deep hypothermic continuous perfusion using a neonatal swine model. METHODS Twenty-four piglets (mean weight 3.8 kg) were placed on cardiopulmonary bypass (CPB): 10 underwent 40-min DHCA, following cooling to 18°C, 10 underwent 40 min DHCA and 10 remained at deep hypothermia for 40 min; animals were subsequently rewarmed to normothermia. 4 remained on normothermic CPB throughout. Fresh brain tissue was harvested while on CPB and assessed for mitochondrial respiration and reactive oxygen species generation. Cerebral microdialysis samples were collected throughout the analysis. RESULTS DHCA animals had significantly decreased mitochondrial complex I respiration, maximal oxidative phosphorylation, respiratory control ratio and significantly increased mitochondrial reactive oxygen species (P < 0.05 for all). DHCA animals also had significantly increased cerebral microdialysis indicators of cerebral ischaemia (lactate/pyruvate ratio) and neuronal death (glycerol) during and after rewarming. CONCLUSIONS DHCA is associated with disruption of mitochondrial bioenergetics compared with deep hypothermic continuous perfusion. Preserving mitochondrial health may mitigate brain injury in cardiac surgical patients. Further studies are needed to better understand the mechanisms of neurological injury in neonatal cardiac surgery and correlate mitochondrial dysfunction with neurological outcomes.

Electroencephalographic Response to Deep Hypothermic Circulatory Arrest in Neonatal Swine and Humans

BACKGROUND Piglets are used to study neurologic effects of deep hypothermic circulatory arrest (DHCA), but no studies have compared human and swine electroencephalogram (EEG) responses to DHCA. The importance of isoelectricity before circulatory arrest is not fully known in neonates. We compared the EEG response to DHCA in human neonates and piglets. METHODS We recorded 2 channel, left and right centroparietal, subdermal EEG in 10 neonatal patients undergoing operations involving DHCA and 10 neonatal piglets that were placed on cardiopulmonary bypass and underwent a simulated procedure using DHCA. EEG waveforms were analyzed for the presence and extent of burst suppression and isoelectricity by automated moving window analysis. The patients were monitored with 16-channel array EEG for 48 hours postoperatively and underwent postoperative brain magnetic resonance imaging. RESULTS After induction of anesthesia, humans and piglets both displayed slowing or brief suppression, then mild burst suppression, and then severe burst suppression during cooling. All piglets subsequently achieved isoelectricity at 22.4° ± 6.9°C, whereas only 1 human did at 20.2°C. Piglets and humans emerged from severe, mild, and then brief suppression patterns during rewarming. Among the patients, there were no seizures during postoperative monitoring and 1 instance of increased white matter injury on postoperative magnetic resonance imaging. CONCLUSIONS Our data suggest that current cooling strategies may not be sufficient to eliminate all EEG activity before circulatory arrest in humans but are sufficient in swine. This important difference between the swine and human response to DHCA should be considered when using this model.

Effect of anesthesia on cerebral oxygenation and blood flow in neonates with critical congenital heart disease

We quantified the effect of anesthesia on cerebral oxygen saturation and blood flow in infants with congenital heart disease. We find that both ScO2 and CBF decrease after induction of anesthesia independent of cardiac diagnosis.