Tiffany S. Ko

Objectives: Preservation of cerebral blood flow (CBF) during and around the time of cardiac arrest (CA) is critical, but validated measurement methods are lacking. We investigated whether a novel, hands-free continuous carotid Doppler ultrasound (RescueDoppler; RD) time averaged velocity (TAV) will be correlated with an invasive measurement of CBF (laser Doppler flowmetry) in a swine model of asphyxia-associated pediatric CA.Design: Prospective observational study with repeated-measures, within-subjects analysis.Setting: Translational large-animal operating room with invasive hemodynamic monitoring, controlled mechanical ventilation and under general anesthesia.Subjects: Eighteen one month old piglets (twelve for analysis) that underwent asphyxia-associated CA treated with hemodynamic-directed CPR (HD-CPR; systolic blood pressure target 90 mmHg, coronary perfusion pressure target 20 mmHg).Interventions: NoneMeasurements and Main Results: Repeated measures correlation and linear mixed-effects modeling were performed to quantify the relationship between devices. During asphyxia (n=12), RD TAV is strongly correlated with invasive CBF (rmcorr = 0.86, 95% CI [0.83, 0.88]) with a 1.01 ± 0.04% change in RD TAV per 1% change in invasive CBF (p<0.001). This correlation is weaker, but significant during CPR (n=8, rmcorr=0.28, 95% CI [0.2, 0.35]) with a .97 ± 0.19% change in RD TAV per 1% change in invasive CBF (p<0.001).Conclusions: RescueDoppler is correlated with invasive CBF during asphyxia and, to a lesser degree, during CPR in pediatric swine. The narrow physiologic range during HD-CPR, motion artifact, and presence of intra-arrest diastolic reversal of flow may contribute to reduced correlation during CPR. RescueDoppler is a non-invasive CBF surrogate in this pediatric porcine model and may be a promising physiologic tool for targeted CPR to improve neurologic outcomes.

Was not provided for this article.

Background/Objectives: Mitochondrial dysfunction is a major cause of brain injury in patients with primary mitochondrial disease. New mitochondrial therapeutics and non-invasive tools for efficacy monitoring are urgently needed. To these ends, succinate prodrug NV354 (methyl 3-[(2-acetylaminoethylthio)carbonyl]propionate) and diffuse optical techniques are promising. In this proof-of-concept study, we characterize NV354’s effects on microdialysis metrics of cerebral metabolism in a swine model of mitochondrial dysfunction and assess the associations of diffuse optical metrics with mitochondrial dysfunction and metabolic improvement. Methods: One-month-old swine received a four-hour co-infusion of rotenone with either the succinate prodrug NV354 (n = 5) or placebo (n = 5). Rotenone is a mitochondrial complex I inhibitor. Before and during co-infusion, cerebral metabolism was probed with microdialysis and diffuse optics. Microdialysis acquired interstitial lactate and pyruvate levels invasively, while diffuse optics measured changes in oxygen extraction fraction (OEF) and oxidized cytochrome-c-oxidase concentration (oxCCO). Results: Interstitial lactate continually increased in the placebo group (p < 0.01), but lactate levels plateaued in the NV354 group (p = 0.90). oxCCO also increased in the placebo group (p = 0.05), but OEF remained constant (p = 0.80). In the NV354 group, oxCCO increased (p < 0.01) while OEF decreased (p < 0.01). Conclusions: Microdialysis results suggest that NV354 treatment can increase oxygen metabolism in large animals with mitochondrial dysfunction. The optical oxCCO metric was also sensitive to metabolic changes induced by rotenone and NV354 administration.

We used a hybrid diffuse optical instrument to monitor cerebral physiology after severe closed-head injury in swine (n=21). At 6 hours post-injury, we observed a significant increase in total hemoglobin concentration (p<0.001) and tissue water content (p=0.01). In a subset of subjects treated with hyperosmolar therapy (n=11), we observed a decrease in intracranial pressure, hemoglobin concentration and tissue water content, and an increase in cerebral blood flow. Changes in optical tissue water content was correlated to ex-vivo brain moisture content (r=0.75) and invasive intracranial pressure (r=0.58). Our results support the utility of diffuse optics for monitoring brain health after TBI.

Background: Infants with congenital heart disease require early lifesaving heart surgery, which increases risk for brain injury and neurodevelopmental delay. Cerebral microhemorrhages (CMH) are frequently seen after surgery, but whether they are benign or constitute injury is unknown. Methods and Results: One hundred ninety‐two infants with congenital heart disease undergoing cardiac surgery with cardiopulmonary bypass were evaluated with pre‐ (n=183) and/or postoperative (n=162) magnetic resonance imaging. Perioperative risk factors for CMH and neurodevelopmental outcomes were analyzed using linear regression. Eighteen‐month neurodevelopmental outcomes were assessed in a subset of patients (n=82). The most common congenital heart disease subtypes were hypoplastic left heart syndrome (37%) and transposition of the great arteries (33%). Forty‐two infants (23%) had CMH present on magnetic resonance imaging presurgery and 137 infants (85%) postsurgery. We found no significant risk factors for preoperative CMH. In multivariable analysis, neurodevelopmental duration ( P P P =0.02), and lower birth weight ( P =0.03) were associated with new or worsened CMH postoperatively. A higher CMH number was associated with lower motor scores ( P =0.01) at 18 months. Conclusions: CMH are common imaging findings in infants with congenital heart disease, particularly after cardiopulmonary bypass conferring adverse impact on neurodevelopmental outcomes at 18 months. Longer duration of cardiopulmonary bypass and extracorporeal membrane oxygenation use demonstrated greatest risk for developing CMH. However, the presence of CMH on preoperative scans indicates yet unidentified nonperioperative risk factors. Neuroprotective strategies to mitigate CMH risk may improve neurodevelopmental outcomes in this vulnerable population.

We summarize physiologic changes in cerebral and peripheral hemodynamics detected by diffuse optical tissue monitoring in three pediatric patients during weaning from venoarterial extracorporeal membrane oxygenation (VA-ECMO) support.

Pediatric neurological injury and disease is a critical public health issue due to increasing rates of survival from primary injuries (e.g., cardiac arrest, traumatic brain injury) and a lack of monitoring technologies and therapeutics for treatment of secondary neurological injury. Translational, preclinical research facilitates the development of solutions to address this growing issue but is hindered by a lack of available data frameworks and standards for the management, processing, and analysis of multimodal datasets. Here, we present a generalizable data framework that was implemented for large animal research at the Children’s Hospital of Philadelphia to address this technological gap. The presented framework culminates in a custom, interactive dashboard for exploratory analysis and filtered dataset download. Compared with existing clinical and preclinical data management solutions, the presented framework better enables management of various data types (single measure, repeated measures, time series, and imaging), integration of datasets for comparison across experimental models, cohorts, and groups, and facilitation of predictive modeling from integrated datasets. Further, a predictive model development use case demonstrated utilization and value of the data framework. The general outline of a preclinical data framework presented here can serve as a template for other translational research labs that generate heterogeneous datasets and require a dynamic platform that can easily evolve alongside their research.

Objective: Critical congenital heart disease (CHD) is associated with neuropsychiatric impairment that may stem from altered cerebral hemodynamics. While cerebral hemodynamics are shown to differ in neonates with CHD, the effect of CHD on cerebral physiology earlier in life during the fetal to neonatal transition period is yet to be elucidated. This period of neonatal resuscitation could represent an opportunity for intervention in critical CHD, so we aimed to characterize cerebral physiology immediately after birth in neonates with critical CHD using noninvasive optical monitoring. Methods: This case series analysis included term neonates with hypoplastic left heart syndrome (HLHS; n=2) and with transposition of the great arteries (TGA; n=2) who were born at Children’s Hospital of Philadelphia. Continuous measurements of cerebral hemodynamics were acquired during the first hour after birth with novel non-invasive frequency-domain diffuse optical spectroscopy (FD-DOS) and diffuse correlation spectroscopy (DCS), as well as commercial near-infrared spectroscopy (NIRS). NIRS measures cerebral oxygenation, and the combined FD-DOS/DCS device measures cerebral oxygenation, blood flow, and metabolism. Results: In all four patients, cerebral oxygen saturation was lower than reference values in the literature. Additionally, we observed decreases in cerebral blood flow and oxygen metabolism during postnatal transition that were not reflected by peripheral oxygen saturation. The decreases were spontaneous in infants with HLHS and temporally associated with invasive respiratory support in infants with TGA. Conclusion: This study demonstrates periods of neurological vulnerability during postnatal transition in CHD and motivates further research on the use of noninvasive optical monitoring during neonatal resuscitation. Clinical Perspective: What is New?: An advanced noninvasive hybrid FD-DOS/DCS system detects periods of neurological vulnerability during neonatal resuscitation in patients with critical CHD that are not reflected by peripheral oxygen saturation trends. Invasive respiratory support is associated with cerebral desaturations. What Are the Clinical Implications?: These findings suggest the utility of noninvasive cerebral monitoring during neonatal resuscitation in neonates with critical CHD and motivate further studies to assess this.

Advanced optical neuromonitoring of cerebral hemodynamics with hybrid diffuse optical spectroscopy (DOS) and diffuse correlation spectroscopy (DCS) methods holds promise for non-invasive characterization of brain health in critically ill patients. However, the methods’ fiber-coupled patient interfaces (probes) are challenging to apply in emergent clinical scenarios that require rapid and reproducible attachment to the head. To address this challenge, we developed a novel chassis-based optical probe design for DOS/DCS measurements and validated its measurement accuracy and reproducibility against conventional, manually held measurements of cerebral hemodynamics in pediatric swine (n = 20). The chassis-based probe design comprises a detachable fiber housing which snaps into a 3D-printed, circumferential chassis piece that is secured to the skin. To validate its reproducibility, eight measurement repetitions of cerebral tissue blood flow index (BFI), oxygen saturation (StO₂), and oxy-, deoxy- and total hemoglobin concentration were acquired at the same demarcated measurement location for each pig. The probe was detached after each measurement. Of the eight measurements, four were acquired by placing the probe into a secured chassis, and four were visually aligned and manually held. We compared the absolute value and intra-subject coefficient of variation (CV) of chassis versus manual measurements. No significant differences were observed in either absolute value or CV between chassis and manual measurements (p > 0.05). However, the CV for BFI (mean ± SD: manual, 19.5% ± 9.6; chassis, 19.0% ± 10.8) was significantly higher than StO₂ (manual, 5.8% ± 6.7; chassis, 6.6% ± 7.1) regardless of measurement methodology (p<0.001). The chassis-based DOS/DCS probe design facilitated rapid probe attachment/re-attachment and demonstrated comparable accuracy and reproducibility to conventional, manual alignment. In the future, this design may be adapted for clinical applications to allow for non-invasive monitoring of cerebral health during pediatric critical care.

Despite improvements in survival after illnesses requiring extracorporeal life support, cerebral injury continues to hinder successful outcomes. Cerebral autoregulation (CA) is an innate protective mechanism that maintains constant cerebral blood flow in the face of varying systemic blood pressure. However, it is impaired in certain disease states and, potentially, following initiation of extracorporeal circulatory support. In this review, we first discuss patient-related factors pertaining to venovenous and venoarterial extracorporeal membrane oxygenation (ECMO) and their potential role in CA impairment. Next, we examine factors intrinsic to ECMO that may affect CA, such as cannulation, changes in pulsatility, the inflammatory and adaptive immune response, intracranial hemorrhage, and ischemic stroke, in addition to ECMO management factors, such as oxygenation, ventilation, flow rates, and blood pressure management. We highlight potential mechanisms that lead to disruption of CA in both pediatric and adult populations, the challenges of measuring CA in these patients, and potential associations with neurological outcome. Altogether, we discuss individualized CA monitoring as a potential target for improving neurological outcomes in extracorporeal life support.