Neurological Injury and Cerebral Blood Flow in Single Ventricles Throughout Staged Surgical Reconstruction.

BACKGROUND: Patients with a single ventricle experience a high rate of brain injury and adverse neurodevelopmental outcome; however, the incidence of brain abnormalities throughout surgical reconstruction and their relationship with cerebral blood flow, oxygen delivery, and carbon dioxide reactivity remain unknown. METHODS: Patients with a single ventricle were studied with magnetic resonance imaging scans immediately prior to bidirectional Glenn (pre-BDG), before Fontan (BDG), and then 3 to 9 months after Fontan reconstruction. RESULTS: One hundred sixty-eight consecutive subjects recruited into the project underwent 235 scans: 63 pre-BDG (mean age, 4.8±1.7 months), 118 BDG (2.9±1.4 years), and 54 after Fontan (2.4±1.0 years). Nonacute ischemic white matter changes on T2-weighted imaging, focal tissue loss, and ventriculomegaly were all more commonly detected in BDG and Fontan compared with pre-BDG patients (P<0.05). BDG patients had significantly higher cerebral blood flow than did Fontan patients. The odds of discovering brain injury with adjustment for surgical stage as well as ≥2 coexisting lesions within a patient decreased (63%-75% and 44%, respectively) with increasing amount of cerebral blood flow (P<0.05). In general, there was no association of oxygen delivery (except for ventriculomegaly in the BDG group) or carbon dioxide reactivity with neurological injury. CONCLUSIONS: Significant brain abnormalities are commonly present in patients with a single ventricle, and detection of these lesions increases as children progress through staged surgical reconstruction, with multiple coexisting lesions more common earlier than later. In addition, this study demonstrated that BDG patients had greater cerebral blood flow than did Fontan patients and that an inverse association exists of various indexes of cerebral blood flow with these brain lesions. However, CO2 reactivity and oxygen delivery (with 1 exception) were not associated with brain lesion development. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02135081.

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.

Development and validation of a semiquantitative brain maturation score on fetal MR images: initial results.

PURPOSE: To develop a valid, reliable, and simple-to-use semiquantitative visual scale of fetal brain maturation for use in clinical fetal MR imaging assessment and interpretation. MATERIALS AND METHODS: This is a retrospective assessment of data from a previous study that was prospective, institutional review board approved, and HIPAA compliant. Forty-eight normal pregnancies with a gestational age (GA) of 25 to 35 weeks were studied. A fetal total maturation score (fTMS) was developed by utilizing six subscores that evaluated cortical sulcation, myelination, and the germinal matrix and provided a single combined numerical value to be evaluated as a marker of brain maturity. The fTMS was correlated with GA and segmented brain volume. A regression model that associated GA based on the visual fTMS scoring was determined. The model was validated with a leave-one-out cross validation procedure. RESULTS: Mean GA was 29.3 weeks ± 2.9 (standard deviation) (range, 25.2-35.3 weeks) and mean fTMS was 8.6 ± 3.7 (range, 4-16). The intraclass correlation coefficient between the three readers (independent and blinded) was 0.948 (P < .001). The correlations were as follows: GA and brain volume, r = 0.964 (P < .001); fTMS and brain volume, r = 0.970 (P < .001); and GA and fTMS, r = 0.975 (P < .001). A regression model to calculate GA based on fTMS yielded the following equation: calculated GA (weeks) = 22.86 + 0.748 fTMS (P < .001; adjusted R(2) = 0.946). The standard error of the model for calculation of fetal GA from the visual fTMS scale was ± 4.8 days. CONCLUSION: If validated further, the fTMS scale might be used to assess morphologic brain maturity of fetuses between 25 and 35 weeks GA on a single-case basis in a clinical setting.

Sodium bicarbonate causes dose-dependent increases in cerebral blood flow in infants and children with single-ventricle physiology.

BACKGROUND: Sodium bicarbonate (NaHCO3) is a common treatment for metabolic acidemia; however, little definitive information exists regarding its treatment efficacy and cerebral hemodynamic effects. This pilot observational study quantifies relative changes in cerebral blood flow (ΔrCBF) and oxy- and deoxyhemoglobin concentrations (ΔHbO2 and ΔHb) due to bolus administration of NaHCO3 in patients with mild base deficits. METHODS: Infants and children with hypoplastic left heart syndrome (HLHS) were enrolled before cardiac surgery. NaHCO3 was given as needed for treatment of base deficit. Diffuse optical spectroscopies were used for 15 min postinjection to noninvasively monitor ΔHb, ΔHbO2, and ΔrCBF relative to baseline before NaHCO3 administration. RESULTS: Twenty-two anesthetized and mechanically ventilated patients with HLHS (aged 1 d to 4 y) received a median (interquartile range) dose of 1.1 (0.8, 1.8) mEq/kg NaHCO3 administered intravenously over 10-20 s to treat a median (interquartile range) base deficit of -4 (-6, -3) mEq/l. NaHCO3 caused significant dose-dependent increases in ΔrCBF; however, population-averaged ΔHb and ΔHbO2 as compared with those of controls were not significant. CONCLUSIONS: Dose-dependent increases in cerebral blood flow (CBF) caused by bolus administration of NaHCO3 are an important consideration in vulnerable populations wherein risk of rapid CBF fluctuations does not outweigh the benefit of treating a base deficit.

Virtual Reality Tools for Assessing Unilateral Spatial Neglect: A Novel Opportunity for Data Collection.

Unilateral spatial neglect (USN) is a syndrome characterized by inattention to or inaction in one side of space and affects between 23-46% of acute stroke survivors. The diagnosis and characterization of these symptoms in individual patients can be challenging and often requires skilled clinical staff. Virtual reality (VR) presents an opportunity to develop novel assessment tools for patients with USN. We aimed to design and build a VR tool to detect and characterize subtle USN symptoms, and to test the tool on subjects treated with inhibitory repetitive transcranial magnetic stimulation (TMS) of cortical regions associated with USN. We created three experimental conditions by applying TMS to two distinct regions of cortex associated with visuospatial processing- the superior temporal gyrus (STG) and the supramarginal gyrus (SMG) - and applied sham TMS as a control. We then placed subjects in a virtual reality environment in which they were asked to identify the flowers with lateral asymmetries of flowers distributed across bushes in both hemispaces, with dynamic difficulty adjustment based on each subject's performance. We found significant differences in average head yaw between subjects stimulated at the STG and those stimulated at the SMG and marginally significant effects in the average visual axis. VR technology is becoming more accessible, affordable, and robust, presenting an exciting opportunity to create useful and novel game-like tools. In conjunction with TMS, these tools could be used to study specific, isolated, artificial neurological deficits in healthy subjects, informing the creation of VR-based diagnostic tools for patients with deficits due to acquired brain injury. This study is the first to our knowledge in which artificially generated USN symptoms have been evaluated with a VR task.

Prediction of periventricular leukomalacia occurrence in neonates after heart surgery.

This paper is concerned with predicting the occurrence of periventricular leukomalacia (PVL) using vital and blood gas data which are collected over a period of 12 h after the neonatal cardiac surgery. A data mining approach has been employed to generate a set of rules for classification of subjects as healthy or PVL affected. In view of the fact that blood gas and vital data have different sampling rates, in this study we have divided the data into two categories: 1) high resolution (vital), and 2) low resolution (blood gas), and designed a separate classifier based on each data category. The developed algorithm is composed of several stages; first, a feature pool has been extracted from each data category and the extracted features have been ranked based on the data reliability and their mutual information content with the output. An optimal feature subset with the highest discriminative capability has been formed using simultaneous maximization of the class separability measure and mutual information of a set. Two separate decision trees (DTs) have been developed for the classification purpose and more importantly to discover hidden relationships that exist among the data to help us better understand PVL pathophysiology. The DT result shows that high amplitude 20 min variations and low sample entropy in the vital data and the defined out of range index as well as maximum rate of change in blood gas data are important factors for PVL prediction. Low sample entropy represents lack of variability in hemodynamic measurement, and constant blood pressure with small fluctuations is an important indicator of PVL occurrence. Finally, using the different time frames of data collection, we show that the first 6 h of data contain sufficient information for PVL occurrence prediction.

Noninvasive optical quantification of cerebral venous oxygen saturation in humans.

RATIONALE AND OBJECTIVES: Cerebral oxygen extraction, defined as the difference between arterial and venous oxygen saturations (SaO2 and SvO2), is a critical parameter for managing intensive care patients at risk for neurological collapse. Although quantification of SaO2 is easily performed with pulse oximetry or moderately invasive arterial blood draws in peripheral vessels, cerebral SvO2 is frequently not monitored because of the invasiveness and risk associated with obtaining jugular bulb or super vena cava (SVC) blood samples. MATERIALS AND METHODS: In this study, near-infrared spectroscopy (NIRS) was used to noninvasively measure cerebral SvO2 in anesthetized and mechanically ventilated pediatric patients (n = 10). To quantify SvO2, the NIRS signal component that fluctuates at the respiration frequency is isolated. This respiratory component is dominated by the venous portion of the interrogated vasculature. The NIRS measurements of SvO2 were validated against the clinical gold standard: invasively measured oxygen saturations from SVC blood samples. This technique was also applied in healthy volunteers (n = 5) without mechanical ventilation to illustrate its potential for use in healthy populations with natural airways. RESULTS: Ten pediatric patients with pulmonary hypertension were studied. In these patients, SvO2 in the SVC exhibited good agreement with NIRS-measured SvO2 (R(2) = 0.80, P = .001, slope = 1.16 ± 0.48). Furthermore, in the healthy adult volunteers, mean (standard deviation) NIRS-measured SvO2 was 79.4 (6.8)%. This value is in good agreement with the expected average central venous saturation reported in literature. CONCLUSION: Respiration frequency-selected NIRS can noninvasively quantify cerebral SvO2. This bedside technique can be used to help assess brain health in neurologically unstable patients.

Cerebral oxygen metabolism in neonates with congenital heart disease quantified by MRI and optics.

Neonatal congenital heart disease (CHD) is associated with altered cerebral hemodynamics and increased risk of brain injury. Two novel noninvasive techniques, magnetic resonance imaging (MRI) and diffuse optical and correlation spectroscopies (diffuse optical spectroscopy (DOS), diffuse correlation spectroscopy (DCS)), were employed to quantify cerebral blood flow (CBF) and oxygen metabolism (CMRO(2)) of 32 anesthetized CHD neonates at rest and during hypercapnia. Cerebral venous oxygen saturation (S(v)O(2)) and CBF were measured simultaneously with MRI in the superior sagittal sinus, yielding global oxygen extraction fraction (OEF) and global CMRO(2) in physiologic units. In addition, microvascular tissue oxygenation (StO(2)) and indices of microvascular CBF (BFI) and CMRO(2) (CMRO(2)(i)) in the frontal cortex were determined by DOS/DCS. Median resting-state MRI-measured OEF, CBF, and CMRO(2) were 0.38, 9.7 mL/minute per 100 g and 0.52 mL O(2)/minute per 100 g, respectively. These CBF and CMRO(2) values are lower than literature reports for healthy term neonates (which are sparse and quantified using different methods) and resemble values reported for premature infants. Comparison of MRI measurements of global S(v)O(2), CBF, and CMRO(2) with corresponding local DOS/DCS measurements demonstrated strong linear correlations (R(2)=0.69, 0.67, 0.67; P<0.001), permitting calibration of DOS/DCS indices. The results suggest that MRI and optics offer new tools to evaluate cerebral hemodynamics and metabolism in CHD neonates.

Brain magnetic resonance immediately before surgery in single ventricles and surgical postponement.

BACKGROUND: Single-ventricle patients undergoing surgical reconstruction experience a high rate of brain injury. Incidental findings on preoperative brain scans may result in safety considerations involving hemorrhage extension during cardiopulmonary bypass that result in surgical postponement. METHODS: Single-ventricle patients were studied with brain scans immediately preoperatively, as part of a National Institutes of Health study, and were reviewed by neuroradiology immediately before cardiopulmonary bypass. RESULTS: Of 144 consecutive patients recruited into the project, 33 were studied before stage I (3.7±1.8 days), 34 before bidirectional Glenn (5.8±0.5 months), and 67 before Fontan (3.3±1.1 years) operations. Six operations (4.5%), 2 before stage I, 3 before bidirectional Glenn, and 1 before Fontan, were postponed because of concerning findings on brain magnetic resonance imaging. Five were due to unexpected incidental findings of acute intracranial hemorrhage, and 1 was due to diffuse cerebellar cytotoxic edema; none who proceeded to operation had these lesions. Prematurity and genetic syndromes were not present in any patients with a postponed operation. Four of 4 before bidirectional Glenn/Fontan with surgical delays had hypoplastic left heart syndrome compared with 44 of 97 who did not (p=0.048). After observation and follow-up, all eventually had successful operations with bypass. CONCLUSIONS: Preoperative brain magnetic resonance imaging performed in children with single ventricles disclosed injuries in 4.5% leading to surgical delay; hemorrhagic lesions were most common and raised concerns for extension during the operation. The true risk of progression and need for delay of the operation due to heparinization associated with these lesions remains uncertain.

Time to surgery and preoperative cerebral hemodynamics predict postoperative white matter injury in neonates with hypoplastic left heart syndrome.

OBJECTIVE: Hypoxic-ischemic white mater brain injury commonly occurs in neonates with hypoplastic left heart syndrome (HLHS). Approximately one half of HLHS survivors will exhibit neurobehavioral symptoms believed to be associated with this injury, although the exact timing of the injury is unknown. METHODS: Neonates with HLHS were recruited for pre- and postoperative monitoring of cerebral oxygen saturation, cerebral oxygen extraction fraction, and cerebral blood flow using 2 noninvasive optical-based techniques: diffuse optical spectroscopy and diffuse correlation spectroscopy. Anatomic magnetic resonance imaging was performed before and approximately 1 week after surgery to quantify the extent and timing of the acquired white matter injury. The risk factors for developing new or worsened white matter injury were assessed using uni- and multivariate logistic regression. RESULTS: A total of 37 neonates with HLHS were studied. On univariate analysis, neonates who developed a large volume of new, or worsened, postoperative white matter injury had a significantly longer time to surgery (P=.0003). In a multivariate model, a longer time between birth and surgery, delayed sternal closure, and greater preoperative cerebral blood flow were predictors of postoperative white matter injury. Additionally, a longer time to surgery and greater preoperative cerebral blood flow on the morning of surgery correlated with lower cerebral oxygen saturation (P=.03 and P=.05, respectively) and greater oxygen extraction fraction (P=.05 for both). CONCLUSIONS: A longer time to surgery was associated with new postoperative white matter injury in otherwise healthy neonates with HLHS. The results suggest that earlier Norwood palliation might decrease the likelihood of acquiring postoperative white matter injury.

Early postoperative changes in cerebral oxygen metabolism following neonatal cardiac surgery: effects of surgical duration.

OBJECTIVE: The early postoperative period following neonatal cardiac surgery is a time of increased risk for brain injury, yet the mechanisms underlying this risk are unknown. To understand these risks more completely, we quantified changes in postoperative cerebral metabolic rate of oxygen (CMRO(2)), oxygen extraction fraction (OEF), and cerebral blood flow (CBF) compared with preoperative levels by using noninvasive optical modalities. METHODS: Diffuse optical spectroscopy and diffuse correlation spectroscopy were used concurrently to derive cerebral blood flow and oxygen utilization postoperatively for 12 hours. Relative changes in CMRO(2), OEF, and CBF were quantified with reference to preoperative data. A mixed-effect model was used to investigate the influence of total support time and deep hypothermic circulatory arrest duration on relative changes in CMRO(2), OEF, and CBF. RESULTS: Relative changes in CMRO(2), OEF, and CBF were assessed in 36 patients, 21 with single-ventricle defects and 15 with 2-ventricle defects. Among patients with single-ventricle lesions, deep hypothermic circulatory arrest duration did not affect relative changes in CMRO(2), CBF, or OEF (P > .05). Among 2-ventricle patients, total support time was not a significant predictor of relative changes in CMRO(2) or CBF (P > .05), although longer total support time was associated significantly with greater increases in relative change of postoperative OEF (P = .008). CONCLUSIONS: Noninvasive diffuse optical techniques were used to quantify postoperative relative changes in CMRO(2), CBF, and OEF for the first time in this observational pilot study. Pilot data suggest that surgical duration does not account for observed variability in the relative change in CMRO(2), and that more comprehensive clinical studies using the new technology are feasible and warranted to elucidate these issues further.