Impaired Maternal-Fetal Environment and Risk for Preoperative Focal White Matter Injury in Neonates With Complex Congenital Heart Disease.

Background Infants with congenital heart disease (CHD) are at risk for white matter injury (WMI) before neonatal heart surgery. Better knowledge of the causes of preoperative WMI may provide insights into interventions that improve neurodevelopmental outcomes in these patients. Methods and Results A prospective single-center study of preoperative WMI in neonates with CHD recorded data on primary cardiac diagnosis, maternal-fetal environment (MFE), delivery type, subject anthropometrics, and preoperative care. Total maturation score and WMI were assessed, and stepwise logistic regression modeling selected risk factors for WMI. Among subjects with severe CHD (n=183) who received a preoperative brain magnetic resonance imaging, WMI occurred in 40 (21.9%) patients. WMI prevalence (21.4%-22.1%) and mean volumes (119.7-160.4 mm3) were similar across CHD diagnoses. Stepwise logistic regression selected impaired MFE (odds ratio [OR], 2.85 [95% CI, 1.29-6.30]), male sex (OR, 2.27 [95% CI, 1.03-5.36]), and older age at surgery/magnetic resonance imaging (OR, 1.20 per day [95% CI, 1.03-1.41]) as risk factors for preoperative WMI and higher total maturation score values (OR, 0.65 per unit increase [95% CI, 0.43-0.95]) as protective. A quarter (24.6%; n=45) of subjects had ≥1 components of impaired MFE (gestational diabetes [n=12; 6.6%], gestational hypertension [n=11; 6.0%], preeclampsia [n=2; 1.1%], tobacco use [n=9; 4.9%], hypothyroidism [n=6; 3.3%], and other [n=16; 8.7%]). In a subset of 138 subjects, an exploratory analysis of additional MFE-related factors disclosed other potential risk factors for WMI. Conclusions This study is the first to identify impaired MFE as an important risk factor for preoperative WMI. Vulnerability to preoperative WMI was shared across CHD diagnoses.

Long-term function, quality of life and healthcare utilization among survivors of pediatric out-of-hospital cardiac arrest.

BACKGROUND: Survival following pediatric out-of-hospital cardiac arrest (OHCA) has improved over the past 2 decades but data on survivors' long-term outcomes are limited. We aimed to evaluate long-term outcomes in pediatric OHCA survivors more than one year after cardiac arrest. METHODS: OHCA survivors <18 years old who received post-cardiac arrest care in the PICU at a single center between 2008-2018 were included. Parents of patients <18 years and patients ≥18 years at least one year after cardiac arrest completed a telephone interview. We assessed neurologic outcome (Pediatric Cerebral Performance Category [PCPC]), activities of daily living (Pediatric Glasgow Outcomes Scale-Extended, Functional Status Scale (FSS)), HRQL (Pediatric Quality of Life Core and Family Impact Modules), and healthcare utilization. Unfavorable neurologic outcome was defined as PCPC > 1 or worsening from pre-arrest baseline to discharge. FINDINGS: Forty four patients were evaluable. Follow-up occurred at a median of 5.6 years [IQR 4.4, 8.9] post-arrest. Median age at arrest was 5.3 [1.3,12.6] years; median CPR duration was 5 [1.5, 7] minutes. Survivors with unfavorable outcome at discharge had worse FSS Sensory and Motor Function scores and higher rates of rehabilitation service utilization. Parents of survivors with unfavorable outcome reported greater disruption to family functioning. Healthcare utilization and educational support requirements were common among all survivors. CONCLUSIONS: Survivors of pediatric OHCA with unfavorable outcome at discharge have more impaired function multiple years post-arrest. Survivors with favorable outcome may experience impairments and significant healthcare needs not fully captured by the PCPC at hospital discharge.

Association Between Quantitative Diffusion Weighted Magnetic Resonance Neuroimaging and Outcome After Pediatric Cardiac Arrest.

BACKGROUND AND OBJECTIVES: Diffusion magnetic resonance imaging (MRI) can quantify extent of hypoxic-ischemic brain injury after cardiac arrest. Our objective was to determine the association between adult-derived threshold of apparent diffusion coefficient (ADC) <650x10-6mm2/s in >10% of brain tissue and unfavorable outcome after pediatric cardiac arrest. Since ADC decreases exponentially as a function of increasing age, we determined association 1) having >10% of brain tissue below a novel age-dependent ADC threshold, and 2) age-normalized whole brain mean ADC and unfavorable outcome. METHODS: Retrospective study of patients ≤18 years old who had cardiac arrest and a clinically obtained brain MRI within 7 days. Primary outcome was unfavorable neurologic status at hospital discharge based on Pediatric Cerebral Performance Category (PCPC) score. ADC images were extracted from three-direction diffusion imaging. We determined whether each patient had >10% of voxels with ADC below prespecified thresholds. We computed whole brain mean ADC for each patient. RESULTS: One-hundred-thirty-four patients were analyzed. Patients with ADC <650x10-6mm2/s in >10% of voxels had 15 times higher odds (95%CI 5, 65) of unfavorable outcome compared to patients with ADC <650x10-6mm2/s (AUROC 0.72 [95%CI 0.63, 0.80]). This ADC criteria had a sensitivity and specificity of 0.49 and 0.94, and positive and negative predictive values of 0.93 and 0.52 for unfavorable outcome. The age-dependent ADC threshold that yielded optimal sensitivity and specificity for unfavorable outcome was <300x10-6mm2/s below each patient's predicted whole brain mean ADC. The sensitivity, specificity, positive and negative predictive values for this ADC threshold were 0.53, 0.96, 0.96, and 0.54, respectively (OR: 26.4 [95%CI 7.5, 168.3]; AUROC 0.74 [95%CI 0.66, 0.83]). Lower age-normalized whole brain mean ADC was also associated with unfavorable outcome (OR 0.42 [0.24, 0.64], AUROC 0.76 [95%CI 0.66, 0.82]). DISCUSSION: Quantitative diffusion thresholds on MRI within 7 days after cardiac arrest were associated with unfavorable outcome in children. Age-independent ADC threshold was highly specific for predicting unfavorable outcome. However, specificity and sensitivity increased when using age-dependent ADC thresholds. Age-dependent ADC thresholds may improve prognostic accuracy and require further investigation in larger cohorts. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that quantitative diffusion-weighted imaging (DWI) within 7 days post-arrest can predict an unfavorable clinical outcome in children.

Serial Neurologic Assessment in Pediatrics (SNAP): A New Tool for Bedside Neurologic Assessment of Critically Ill Children.

OBJECTIVES: We developed a tool, Serial Neurologic Assessment in Pediatrics, to screen for neurologic changes in patients, including those who are intubated, are sedated, and/or have developmental disabilities. Our aims were to: 1) determine protocol adherence when performing Serial Neurologic Assessment in Pediatrics, 2) determine the interrater reliability between nurses, and 3) assess the feasibility and acceptability of using Serial Neurologic Assessment in Pediatrics compared with the Glasgow Coma Scale. DESIGN: Mixed-methods, observational cohort. SETTING: Pediatric and neonatal ICUs. SUBJECTS: Critical care nurses and patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Serial Neurologic Assessment in Pediatrics assesses Mental Status, Cranial Nerves, Communication, and Motor Function, with scales for children less than 6 months, greater than or equal to 6 months to less than 2 years, and greater than or equal to 2 years old. We assessed protocol adherence with standardized observations. We assessed the interrater reliability of independent Serial Neurologic Assessment in Pediatrics assessments between pairs of trained nurses by percent- and bias- adjusted kappa and percent agreement. Semistructured interviews with nurses evaluated acceptability and feasibility after nurses used Serial Neurologic Assessment in Pediatrics concurrently with Glasgow Coma Scale during routine care. Ninety-eight percent of nurses (43/44) had 100% protocol adherence on the standardized checklist. Forty-three nurses performed 387 paired Serial Neurologic Assessment in Pediatrics assessments (149 < 6 mo; 91 ≥ 6 mo to < 2 yr, and 147 ≥ 2 yr) on 299 patients. Interrater reliability was substantial to near-perfect across all components for each age-based Serial Neurologic Assessment in Pediatrics scale. Percent agreement was independent of developmental disabilities for all Serial Neurologic Assessment in Pediatrics components except Mental Status and lower extremity Motor Function for patients deemed "Able to Participate" with the assessment. Nurses reported that they felt Serial Neurologic Assessment in Pediatrics, compared with Glasgow Coma Scale, was easier to use and clearer in describing the neurologic status of patients who were intubated, were sedated, and/or had developmental disabilities. About 92% of nurses preferred to use Serial Neurologic Assessment in Pediatrics over Glasgow Coma Scale. CONCLUSIONS: When used by critical care nurses, Serial Neurologic Assessment in Pediatrics has excellent protocol adherence, substantial to near-perfect interrater reliability, and is feasible to implement. Further work will determine the sensitivity and specificity for detecting clinically meaningful neurologic decline.

Association of MRI Brain Injury With Outcome After Pediatric Out-of-Hospital Cardiac Arrest.

OBJECTIVE: To determine the association between the extent of diffusion restriction and T2/fluid-attenuated inversion recovery (FLAIR) injury on brain MRI and outcomes after pediatric out-of-hospital cardiac arrest (OHCA). METHODS: Diffusion restriction and T2/FLAIR injury were described according to the pediatric MRI modification of the Alberta Stroke Program Early Computed Tomography Score (modsASPECTS) for children from 2005 to 2013 who had an MRI within 14 days of OHCA. The primary outcome was unfavorable neurologic outcome defined as ≥1 change in Pediatric Cerebral Performance Category (PCPC) from baseline resulting in a hospital discharge PCPC score 3, 4, 5, or 6. Patients with unfavorable outcomes were further categorized into alive with PCPC 3-5, dead due to withdrawal of life-sustaining therapies for poor neurologic prognosis (WLST-neuro), or dead by neurologic criteria. RESULTS: We evaluated MRI scans from 77 patients (median age 2.21 [interquartile range 0.44, 13.07] years) performed 4 (2, 6) days postarrest. Patients with unfavorable outcomes had more extensive diffusion restriction (median 7 [4, 10.3] vs 0 [0, 0] regions, p < 0.001) and T2/FLAIR injury (5.5 [2.3, 8.2] vs 0 [0, 0.75] regions, p < 0.001) compared to patients with favorable outcomes. Area under the receiver operating characteristic curve for the extent of diffusion restriction and unfavorable outcome was 0.96 (95% confidence interval [CI] 0.91, 0.99) and 0.92 (95% CI 0.85, 0.97) for T2/FLAIR injury. There was no difference in extent of diffusion restriction between patients who were alive with an unfavorable outcome and patients who died from WLST-neuro (p = 0.11). CONCLUSIONS: More extensive diffusion restriction and T2/FLAIR injury on the modsASPECTS score within the first 14 days after pediatric cardiac arrest was associated with unfavorable outcomes at hospital discharge.

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.

Survey of Bedside Clinical Neurologic Assessments in U.S. PICUs.

OBJECTIVE: To understand how routine bedside clinical neurologic assessments are performed in U.S. PICUs. DESIGN: Electronic survey. SETTING: Academic PICUs throughout the United States. SUBJECTS: Faculty representatives from PICUs throughout the United States. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We surveyed how routine bedside neurologic assessments are reported to be performed in U.S. PICUs and the attitudes of respondents on the utility of these assessments. The survey contained questions regarding 1) components of neurologic assessments; 2) frequency of neurologic assessments; 3) documentation and communication of changes in neurologic assessment; and 4) optimization of neurologic assessments. Surveys were received from 64 of 67 institutions (96%). Glasgow Coma Scale and pupillary reflex were the most commonly reported assessments (80% and 92% of institutions, respectively). For patients with acute brain injury, 95% of institutions performed neurologic assessments hourly although assessment frequency was more variable for patients at low risk of developing brain injury and those at high risk for brain injury, but without overt injury. In 73% of institutions, any change detected on routine neuroassessment was communicated to providers, whereas in 27%, communication depended on the severity or degree of neurologic decline. Seventy percent of respondents thought that their current practice for assessing and monitoring neurologic status was suboptimal. Only 57% felt that the Glasgow Coma Scale was a valuable tool for the serial assessment of neurologic function in the ICU. Ninety-two percent felt that a standardized approach to assessing and documenting preillness neurologic function would be valuable. CONCLUSIONS: Routine neurologic assessments are reported to be conducted in nearly all academic PICUs in the United States with fellowship training programs although the content, frequency, and triggers for communication vary between institutions. Most physicians felt that the current paradigms for neurologic assessments are suboptimal. These data suggest that optimizing and standardizing routine bedside nursing neurologic assessments may be warranted.

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.

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.

The Venus effect in real life and in photographs.

The toilet of Venus is the subject of many paintings. Typically, Venus appears with a small mirror in which her face is visible. Observers tend to say that Venus is admiring herself in a mirror, even when the location of the mirror makes this impossible. We demonstrate that the Venus effect is not specific to paintings by showing that it occurs in real life (Experiment 1) and in photographs (Experiments 1-4). The original description of the effect implied that observers describe Venus as seeing in a mirror what they (the observers) see. We used different photographs to compare the responses when the person in front of the mirror could or could not see him or herself and when the image of his or her face was or was not visible to the observer. Observers tend to state that a person can see his or her own reflection when he or she appears near a mirror, whether or not his or her face is visible in the mirror. A task based on a top-down view of a room confirmed that people lack sensitivity to the role of the viewpoint (Experiment 5). We discuss these findings in relation to other evidence of difficulty in understanding what is visible in a mirror.