Henry H. Cheng

Perioperative cerebral hemodynamics and oxygen metabolism in neonates with single-ventricle physiology

Congenital heart disease (CHD) patients are at risk for neurodevelopmental delay. The etiology of these delays is unclear, but abnormal prenatal cerebral maturation and postoperative hemodynamic instability likely play a role. A better understanding of these factors is needed to improve neurodevelopmental outcome. In this study, we used bedside frequency-domain near infrared spectroscopy (FDNIRS) and diffuse correlation spectroscopy (DCS) to assess cerebral hemodynamics and oxygen metabolism in neonates with single-ventricle (SV) CHD undergoing surgery and compared them to controls. Our goals were 1) to compare cerebral hemodynamics between unanesthetized SV and healthy neonates, and 2) to determine if FDNIRS-DCS could detect alterations in cerebral hemodynamics beyond cerebral hemoglobin oxygen saturation (SO 2). Eleven SV neonates were recruited and compared to 13 controls. Preoperatively, SV patients showed decreased cerebral blood flow (CBFi ), cerebral oxygen metabolism (CMRO 2i ) and SO 2; and increased oxygen extraction fraction (OEF) compared to controls. Compared to preoperative values, unstable postoperative SV patients had decreased CMRO 2i and CBFi , which returned to baseline when stable. However, SO 2 showed no difference between unstable and stable states. Preoperative SV neonates are flow-limited and show signs of impaired cerebral development compared to controls. FDNIRS-DCS shows potential to improve assessment of cerebral development and postoperative hemodynamics compared to SO 2 alone.

Cerebral blood flow velocity and neurodevelopmental outcome in infants undergoing surgery for congenital heart disease.

BACKGROUND Cerebral blood flow velocity (CBFV) measured by transcranial Doppler sonography has provided information on cerebral perfusion in patients undergoing infant heart surgery, but no studies have reported a relationship to early postoperative and long-term neurodevelopmental outcomes. METHODS CBFV was measured in infants undergoing biventricular repair without aortic arch reconstruction as part of a trial of hemodilution during cardiopulmonary bypass (CPB); CBFV (Vm, mean; Vs, systolic; Vd, end-diastolic) in the middle cerebral artery and change in Vm (rVm) were measured intraoperatively and up to 18 hours post-CPB. Neurodevelopmental outcomes, measured at 1 year of age, included the psychomotor development index (PDI) and mental development index (MDI) of the Bayley Scales of Infant Development-II. RESULTS CBFV was measured in 100 infants; 43 with D-transposition of the great arteries, 36 with tetralogy of Fallot, and 21 with ventricular septal defects. Lower Vm, Vs, Vd, and rVm at 18 hours post-CPB were independently related to longer intensive care unit duration of stay (p<0.05). In the 85 patients who returned for neurodevelopmental testing, lower Vm, Vs, Vd, and rVm at 18 hours post-CPB were independently associated with lower PDI (p<0.05) and MDI (p<0.05, except Vs: p=0.06) scores. Higher Vs and rVm at 18 hours post-CPB were independently associated with increased incidence of brain injury on magnetic resonance imaging in 39 patients. CONCLUSIONS Postoperative CBFV after biventricular repair is related to early postoperative and neurodevelopmental outcomes at 1 year of age, possibly indicating that low CBFV is a marker of suboptimal postoperative hemodynamics and cerebral perfusion.

Non-invasive Assessment of Cerebral Blood Flow and Oxygen Metabolism in Neonates during Hypothermic Cardiopulmonary Bypass: Feasibility and Clinical Implications

The neonatal brain is extremely vulnerable to injury during periods of hypoxia and/or ischemia. Risk of brain injury is increased during neonatal cardiac surgery, where pre-existing hemodynamic instability and metabolic abnormalities are combined with long periods of low cerebral blood flow and/or circulatory arrest. Our understanding of events associated with cerebral hypoxia-ischemia during cardiopulmonary bypass (CPB) remains limited, largely due to inadequate tools to quantify cerebral oxygen delivery and consumption non-invasively and in real-time. This pilot study aims to evaluate cerebral blood flow (CBF) and oxygen metabolism (CMRO2) intraoperatively in neonates by combining two novel non-invasive optical techniques: frequency-domain near-infrared spectroscopy (FD-NIRS) and diffuse correlation spectroscopy (DCS). CBF and CMRO2 were quantified before, during and after deep hypothermic cardiopulmonary bypass (CPB) in nine neonates. Our results show significantly decreased CBF and CMRO2 during hypothermic CPB. More interestingly, a change of coupling between both variables is observed during deep hypothermic CPB in all subjects. Our results are consistent with previous studies using invasive techniques, supporting the concept of FD-NIRS/DCS as a promising technology to monitor cerebral physiology in neonates providing the potential for individual optimization of surgical management.

Stroke in Acquired and Congenital Heart Disease Patients and Its Relationship to Hospital Mortality and Lasting Neurologic Deficits.

Objective: To describe strokes in patients with acquired or congenital heart disease and investigate risk factors for in-hospital mortality and ongoing neurologic deficits. Design: Single-center, retrospective review of cardiac, neurologic, and radiologic patient databases. Setting: Tertiary care children’s hospital. Patients: All patients with acquired or congenital heart disease admitted from January 2010 to October 2014 identified with stroke. Interventions: None. Measurements and Main Results: Eighty-four stroke events were identified in 83 patients (median age, 5.9 mo; interquartile range, 0.8–33.4). Thirty-two patients (38%) had single ventricle congenital heart disease. Eight patients (9%) presented with symptoms at home, and the remainder was diagnosed while already admitted to the hospital. Forty patients (48%) presented with clinically evident neurologic deficits (e.g., weakness, seizures). Fifty-eight patients (69%) had arterial ischemic strokes, and 13 (15%) had parenchymal hemorrhages. At diagnosis, 54 patients (64%) were on inotropes. Twenty-nine patients (35%) had greater than or equal to 3 cardiac procedures during their hospitalization before stroke diagnosis. In-hospital mortality occurred in 28 patients (33%). Under multivariate analysis, inotropes, number of cardiac procedures, lack of seizure, and parenchymal hemorrhage were independently associated with in-hospital mortality (p < 0.05). Fifty-four percent of survivors with neurologic follow-up had ongoing neurologic deficits attributable to strokes (median follow-up, 15.3 mo; interquartile range, 7.0–29.9). With multivariate analysis, longer hospital stay (p = 0.02) was independently associated with ongoing deficits. Conclusions: A majority of patients with acquired or congenital heart disease who suffer stroke present while hospitalized and without focal neurologic findings. In-hospital mortality is associated with inotropes, cardiac procedures, lack of seizure, and parenchymal hemorrhage. The majority of survivors have lasting neurologic deficits associated with longer hospital stay.

Fractures Related to Metabolic Bone Disease in Children with Congenital Heart Disease.

OBJECTIVE Critically ill children with congenital heart disease (CHD) are at risk for metabolic bone disease (MBD) and bone fractures. Our objective was to characterize a cohort of CHD patients with fractures and describe a Fragile Bone Protocol (FBP) developed to reduce fractures. DESIGN/SETTING Patients who developed fractures in the Cardiac Intensive Care Unit (CICU) of Boston Childrens Hospital from 3/2008 to 6/2014 were identified via quality improvement and radiology databases. The FBP (initiated July 2011) systematically identifies patients at risk for MBD and prescribes special handling precautions. RESULTS Twenty-three fractures were identified in 15 children. Median age at fracture identification was 6.2 months, with a median duration of hospitalization before fracture diagnosis of 2.7 months. Six patients (40%) had single ventricle CHD. Hyperparathyroidism and low 25-OH vitamin D levels were present in 77% and 40% of those tested, respectively. Compared with patients not diagnosed with fractures, fracture patients had increased exposure to possible risk factors for MBD and had elevated parathyroid and decreased calcitriol levels.Six patients (40%) did not survive to hospital discharge, compared with an overall CICU mortality rate of 2.6% (P < .01). The fracture case rate before implementation of the FBP was 2.6 cases/1000 admissions and was 0.7/1000 after implementation of the FBP (P = .04). CONCLUSIONS Critically ill CHD patients are at risk for fractures. They represent a complex group who frequently has hyperparathyroidism and decreased calcitriol levels, and each may predispose to fractures. FBPs consisting of identification and careful patient handling should be considered in at-risk patients.

Advanced diffusion imaging for assessing normal white matter development in neonates and characterizing aberrant development in congenital heart disease

Background Elucidating developmental trajectories of white matter (WM) microstructure is critically important for understanding normal development and regional vulnerabilities in several brain disorders. Diffusion Weighted Imaging (DWI) is currently the method of choice for in-vivo white matter assessment. A majority of neonatal studies use the standard Diffusion Tensor Imaging (DTI) model although more advanced models such as the Neurite Orientation Dispersion and Density Imaging (NODDI) model and the Gaussian Mixture Model (GMM) have been used in adult population. In this study, we compare the ability of these three diffusion models to detect regional white matter maturation in typically developing control (TDC) neonates and regional abnormalities in neonates with congenital heart disease (CHD). Methods Multiple b-value diffusion Magnetic Resonance Imaging (dMRI) data were acquired from TDC neonates (N = 16) at 38 to 47 gestational weeks (GW) and CHD neonates (N = 19) aged 37 weeks to 41 weeks. Measures calculated from the diffusion signal included not only Mean Diffusivity (MD) and Fractional Anisotropy (FA) derived from the standard DTI model, but also three advanced diffusion measures, namely, the fiber Orientation Dispersion Index (ODI), the isotropic volume fraction (Viso), and the intracellular volume fraction (Vic) derived from the NODDI model. Further, we used two novel measures from a non-parametric GMM, namely the Return-to-Origin Probability (RTOP) and Return-to-Axis Probability (RTAP), which are sensitive to axonal/cellular volume and density respectively. Using atlas-based registration, 22 white matter regions (6 projection, 4 association, and 1 callosal pathways bilaterally in each hemisphere) were selected and the mean value of all 7 measures were calculated in each region. These values were used as dependent variables, with GW as the independent variable in a linear regression model. Finally, we compared CHD and TDC groups on these measures in each ROI after removing age-related trends from both the groups. Results Linear analysis in the TDC population revealed significant correlations with GW (age) in 12 projection pathways for MD, Vic, RTAP, and 11 pathways for RTOP. Several association pathways were also significantly correlated with GW for MD, Vic, RTAP, and RTOP. The right callosal pathway was significantly correlated with GW for Vic. Consistent with the pathophysiology of altered development in CHD, diffusion measures demonstrated differences in the association pathways involved in language systems, namely the Uncinate Fasciculus (UF), the Inferior Fronto-occipital Fasciculus (IFOF), and the Superior Longitudinal Fasciculus (SLF). Overall, the group comparison between CHD and TDC revealed lower FA, Vic, RTAP, and RTOP for CHD bilaterally in the a) UF, b) Corpus Callosum (CC), and c) Superior Fronto-Occipital Fasciculus (SFOF). Moreover, FA was lower for CHD in the a) left SLF, b) bilateral Anterior Corona Radiata (ACR) and left Retrolenticular part of the Internal Capsule (RIC). Vic was also lower for CHD in the left Posterior Limb of the Internal Capsule (PLIC). ODI was higher for CHD in the left CC. RTAP was lower for CHD in the left IFOF, while RTOP was lower in CHD in the: a) left ACR, b) left IFOF and c) right Anterior Limb of the Internal Capsule (ALIC). Conclusion In this study, all three methods revealed the expected changes in the WM regions during the early postnatal weeks; however, GMM outperformed DTI and NODDI as it showed significantly larger effect sizes while detecting differences between the TDC and CHD neonates. Future studies based on a larger sample are needed to confirm these results and to explore clinical correlates.

Probabilistic tractography-based thalamic parcellation in healthy newborns and newborns with congenital heart disease: Thalamic Parcellation in Newborns

Given the central role of the thalamus in motor, sensory, and cognitive development, methods to study emerging thalamocortical connectivity in early infancy are of great interest.

Post-arrest therapeutic hypothermia in pediatric patients with congenital heart disease

BACKGROUND While therapeutic hypothermia (TH) is an effective neuroprotective therapy for neonatal hypoxic-ischemic encephalopathy, TH has not been demonstrated to improve outcome in other pediatric populations. Patients with acquired or congenital heart disease (CHD) are at high risk of both cardiac arrest and neurodevelopmental impairments, and therapies are needed to improve neurologic outcome. The primary goal of our study was to compare safety/efficacy outcomes in post-arrest CHD patients treated with TH versus controls not treated with TH. METHODS Patients with CHD treated during the first 18 months after initiation of a post-arrest TH protocol (temperature goal: 33.5 °C) were compared to historical and contemporary post-arrest controls not treated with TH. Post-arrest data, including temperature, safety measures (e.g. arrhythmia, bleeding), neurodiagnostic data (EEG, neuroimaging), and survival were compared. RESULTS Thirty arrest episodes treated with TH and 51 control arrest episodes were included. The groups did not differ in age, duration of arrest, post-arrest lactate, or use of ECMO-CPR. The TH groups post-arrest temperature was significantly lower than controls (33.6 ± 0.2 °C vs 34.7 ± 0.5 °C, p < 0.001). There was no difference between the groups in safety/efficacy measures, including arrhythmia, infections, chest-tube output, or neuroimaging abnormalities, nor in hospital survival (TH 61.5% vs control 59.1%, p = NS). Significantly more controls had seizures than TH patients (26.1% vs. 4.0%, p = 0.04). Almost all seizures were subclinical and occurred more than 24 h post-arrest. CONCLUSION Our data show that pediatric CHD patients who suffer cardiac arrest can be treated effectively and safely with TH, which may decrease the incidence of seizures.

Optimizing Unanesthetized Cerebral Oxygen Consumption Measures: Comparison of NIRS and MRI Approaches in Neonates with Congenital Heart Disease

Cerebral perfusion in neonates with congenital heart disease is a clinical concern. Combined measures of MRI and NIRS can provide complementary information to improve monitoring. We compare multimodal measures of cerebral hemodynamics in this group.

Lower Cerebral Oxygen Metabolism In Neonates With Congenital Heart Disease As Compared To Healthy Neonates

Frequency domain near infrared spectroscopy (FD-NIRS) and diffuse correlation spectroscopy (DCS) can provide noninvasive means to study cerebral hemodynamics in neonates with congenital heart disease (CHD). Using these advanced optical technologies, our preliminary data shows that neonates with CHD have lower cerebral oxygen metabolism than healthy neonates.