Mothers of infants in the cardiac intensive care unit (CICU) experience stress, anxiety, and impaired bonding. Infants with congenital heart disease (CHD) experience dysregulation of autonomic function. Skin-to-skin contact (SSC) alleviates stress in both mothers and infants, but its use remains understudied in the CHD population. In this single-center, prospective pilot study, we evaluated the impact of low-dose postoperative SSC (three sessions within a 10-day period) on maternal mood, measured by the State Trait Anxiety Inventory (STAI-6) and the Depression Anxiety Stress Scale (DASS-21), mother-infant bonding, and autonomic function, measured by heart rate variability (HRV), in infants with CHD and their mothers. Twenty-one mother-infant dyads participated in 51 SSC sessions. STAI-6 and bonding scores significantly improved after just one session of SSC (p < 0.001, p = 0.004, respectively). All metrics of HRV—low frequency (LF) (p < 0.001), high frequency (HF) (p < 0.001), the standard deviation of normal-to-normal intervals (SDNN) (p < 0.001), the root mean square of successive differences RMSSD (p = 0.032), and the SDNN/ RMSSD ratio (p < 0.001)—significantly decreased during SSC in mothers. LF (p = 0.036), HF (p = 0.034), and the SDNN/ RMSSD ratio (p = 0.008) significantly decreased during SSC in infants. Our data suggest that low-dose SSC significantly impacts autonomic function of both mothers and CHD infants and improves maternal anxiety and perceptions of bonding, although more studies are needed to understand the relationship between HRV and stress in this population.

BACKGROUND:Neurological injury is common in neonates undergoing cardiac surgery with cardiopulmonary bypass, yet perioperative neuroimaging and neuromonitoring practices vary across centres. We aimed to characterise current practices and provider perceptions across Pediatric Cardiac Intensive Care Society-affiliated centres. METHODS:We conducted an online, cross-sectional survey of Pediatric Cardiac Intensive Care Society members between August and October 2024. Part 1, completed by medical directors, assessed institutional characteristics and perioperative practices. Part 2, completed by multidisciplinary providers, evaluated perceptions of utility and sufficiency. RESULTS:A total of 143 responses from 60 institutions were analysed, including 38 medical directors. Most centres had a dedicated cardiac ICU (87%) and were academically affiliated (76%). Routine neuroimaging was more common preoperatively than postoperatively (87% vs. 32%), with head ultrasound most frequently used. Near-infrared spectroscopy was the most common neuromonitoring modality, while routine electroencephalography was reported at 18% of centres preoperatively and 50% postoperatively. Physicians were more likely than advanced practice providers and nurses to report practices as sufficient. Neurocritical care teams were present at 42% of centres but were not associated with greater use of neuroimaging or monitoring. CONCLUSIONS:Significant variability exists in perioperative practices and provider perceptions, highlighting the need for multidisciplinary alignment and standardised guidelines.

The treatment of status epilepticus (SE) in children with cardiac disease is challenging given their often-tenuous hemodynamic state. We aim to determine whether ketamine is safe and effective in children with cardiac disease as the first-line continuous infusion for the treatment of refractory SE (RSE) and to compare ketamine to midazolam for the treatment of RSE in this population. This is a single-center retrospective cohort study of pediatric patients with cardiac disease and RSE admitted to the cardiac intensive care unit at a tertiary children’s hospital between January 1, 2017 and June 30, 2023. Consecutive patients < 18 years of age who had electroencephalogram-confirmed RSE treated with a continuous infusion of ketamine and/or midazolam were included. Clinical variables were extracted from the electronic medical record, and descriptive statistics were used. Thirty-four patients with cardiac disease and RSE were treated with a continuous infusion: 15 were treated with ketamine first, and 19 were treated with midazolam first. An equivalent number of patients in both groups required a single infusion for seizure cessation (11 [73

Neonates with critical congenital heart disease are at high risk for brain injury and neurodevelopmental disabilities. Neurocardiac care is a developing field, and there are few guidelines for front-line providers regarding neuromonitoring and neuroprotection. Understanding influences on early brain development, risk for seizures and brain injury, and long-term developmental outcomes can help providers formulate appropriate action plans for individual patients. Current evidence suggests that prenatal diagnosis, minimizing medical risk factors, monitoring for brain injury and seizures, providing individualized developmental care, supporting parental mental health, and referral to long-term developmental follow-up are components of care that may improve outcomes.

Despite high mortality rates, pediatric extracorporeal membrane oxygenation (ECMO) redeployments are frequently discussed in everyday clinical care. We aim to investigate predictors of mortality in those patients. Clinical data from a single pediatric center were retrospectively analyzed. Patients with multiple ECMO runs between 2010 and 2023 were included. A total of 70 (13%) patients required multiple ECMO runs. Of those, 56 (80%) died before discharge; late mortality was 89% at a median of 1.6 (1.0-3.9) years. A total of 47 (67%) patients had neurologic findings. Only one (1%) survivor had a normal neurodevelopmental follow-up. Duration of the first ECMO run (odds ratio [OR]: 2.63, 1.08-7.96), total duration on ECMO (OR: 4.72, 1.29-23.54), neurologic findings at any time (OR: 7.94, 1.46-43.24), need for renal replacement therapy (OR: 4.79, 1.06-25.58), and lactate values correlated with late mortality. All 19 (27%) patients with neurologic findings before the second run died. The frequency of multiple-run ECMOs increased within the study period. Outcomes in pediatric patients with multiple ECMO runs are disheartening. Given all patients in our cohort with neurological findings before the second ECMO run died, neurological findings should be taken into consideration when determining the utility of further ECMO support.

Introduction/Background: Neurodevelopmental impairment is a challenge for many children with complex congenital heart disease who undergo surgical intervention with cardiopulmonary bypass during the early postnatal period. Research Questions/Hypothesis: We hypothesized that bone marrow-derived mesenchymal stromal cell (BM-MSC) delivery through cardiopulmonary bypass (CPB) will improve neurodevelopmental outcome and post-operative course. Goals/Aims: The primary goal of this single-center, dose-escalation phase 1 trial was to assess the safety/feasibility and determine the maximum tolerated dose (MTD) of BM-MSC treatment. Methods/Approach: Inclusion criteria of the phase 1 trial were neonates/infants (ages ≤ 6 months) who underwent scheduled two-ventricle repair without arch reconstruction. Dose escalation was guided by a modified continual reassessment method at four dose levels (1-40x10^6 cells/kg). Dose limiting toxicity was assessed for 45 days after BM-MSC delivery. Secondary endpoints before discharge were compared with a historical cohort (n=222) by inverse probability of treatment weighting (IPTW) using the propensity score to balance the groups. Results/Data: Seventeen patients were enrolled from July 2020 to June 2023 (ventricular septal defect, n=9; tetralogy of Fallot, n=7; transposition of the great arteries, n=1; male, n=10). There were 3 serious adverse events all of which were related to cardiac surgery and not the BM-MSC product (junctional ectopic tachycardia, n=2; diaphragm paresis, n=1). Among 50 total events, there were no adverse events related to BM-MSCs. The BM-MSC dose was successfully escalated to the planned MTD (40x10^6 cells/kg), demonstrating safety and feasibility of this therapeutic delivery strategy. Consistent with results indicating little interference on CPB functions, electron microscopy studies showed no BM-MSC adherence on the CPB filter mesh at the MTD. Multivariable analyses with IPTW identified a reduction of CO2 and lactate levels in MeDCaP cases. We observed differences in white blood cell, monocyte, and platelet numbers between the two groups, suggesting possible interaction between endogenous blood cells and applied BM-MSCs. Conclusions: We confirmed the safety and feasibility of BM-MSC treatment during CPB at the proposed MTD level. Successful design and completion of a future phase 2 trial is needed to determine efficacy.

Comparison of midazolam and ketamine efficacies as first-line continuous infusions (CIs) for the treatment of status epilepticus (SE) in children with (CHD).

Fetal ventriculomegaly is a source of apprehension for expectant parents and may present prognostic uncertainty for physicians. Accurate prenatal counseling requires knowledge of its cause and associated findings as the differential diagnosis is broad. We have observed an association between ventriculomegaly and incomplete hippocampal inversion. To determine whether ventricular size is related to incomplete hippocampal inversion. We retrospectively evaluated pre- and postnatal brain MRIs in normal subjects (mean GA, 31 weeks; mean postnatal age, 27 days) and patients with isolated ventriculomegaly (mean GA, 31 weeks; mean postnatal age, 68 days) at a single academic medical center. Lateral ventricular diameter, multiple qualitative and quantitative markers of hippocampal inversion, and evidence of intraventricular hemorrhage were documented. Incomplete hippocampal inversion and ventricular size were associated in both normal subjects (n=51) and patients with ventriculomegaly (n=32) (P<0.05). Severe ventriculomegaly was significantly associated with adverse clinical outcome in postnatal (P=0.02) but not prenatal (P=0.43) groups. In all additional cases of isolated ventriculomegaly, clinical outcome was normal over the time of assessment (mean 1±1.9 years; range 0.01 to 10 years). Lateral ventricular atrial diameter and incomplete hippocampal inversion are associated. Less hippocampal inversion correlates with larger atria. For every 1-mm increase in fetal ventricular size, the odds of incomplete hippocampal inversion occurring increases by a factor of 1.6 in normal controls and 1.4 in patients with ventriculomegaly.

Objective: To advance understanding of perinatal and early postnatal outcomes of fetal intracranial hemorrhage (ICH) prenatally diagnosed by fetal MRI (magnetic resonance imaging).Methods: A retrospective study of cases with fetal ICH diagnosed by fetal MRI at Children’s National Hospital, Washington, DC, from 2012 to 2020 was conducted. Maternal characteristics, prenatal imaging, pregnancy outcome, and child developmental outcomes were recorded. Abnormal outcomes were categorized as: mild for required physical/occupational therapy without other delays; moderate for intermediate multi-domain developmental delays; severe if non-ambulatory, non-verbal, or significant intellectual disability.Results: Fifty-seven cases with fetal ICH were included. The mean (SD) maternal age was 31.1(6.9) years, gestational age at fetal evaluation was 28.1(5.3) weeks, and gestational age at birth was 38.2(1.3) weeks. Pregnancy outcomes were 75% (n=43) live births, 14% (n=8) termination of pregnancy, and 11% (n=6) intrauterine demise (IUD). Live births decreased from 90% to 33% and IUD increased 10% to 22% comparing unilateral intraventricular hemorrhage (IVH) to more extensive hemorrhages. Among the 37 live born infants with clinical follow-up to 1.8(1.6) years of age, neurodevelopmental outcome was normal in 57%, mildly abnormal in 24%, moderately abnormal in 14%, and severely abnormal in 5%. In five cases, an etiology was identified; two had placental pathologies, two had genetic findings (fetal neonatal alloimmune thrombocytopenia [FNAIT] and COL4A1 mutation) and one had congenital cytomegalovirus infection.Conclusion: Perinatal and early child outcomes following fetal ICH have a wide spectrum of outcomes. Fetal MRI description of ICH location may aid in pregnancy and postnatal outcome prediction.

Children with congenital heart disease (CHD) are at increased risk for neurodevelopmental challenges across the lifespan. These are associated with neurological changes and potential acquired brain injury, which occur across a developmental trajectory and which are influenced by an array of medical, sociodemographic, environmental, and personal factors. These alterations to brain development lead to an array of adverse neurodevelopmental outcomes, which impact a characteristic set of skills over the course of development. The current paper reviews existing knowledge of aberrant brain development and brain injury alongside associated neurodevelopmental challenges across the lifespan. These provide a framework for discussion of emerging and potential interventions to improve neurodevelopmental outcomes at each developmental stage.

This review presents a practical approach to imaging the fetal brain by MRI. Herein, we demonstrate how to measure brain structures and fluid spaces, and discuss the importance of comparing measurements to normative biometric references at a corresponding gestational age. We present some common imaging dilemmas of the technical aspects of fetal MRI with regard to typical regions of abnormality including the cerebrum, the ventricular system, and the posterior fossa, and discuss how to resolve them.

Background: Fetal magnetic resonance imaging (MRI) is increasingly utilized for prenatal diagnosis of agenesis of the corpus callosum (ACC). This study aimed to (1) describe cases of ACC diagnosed by fetal MRI, (2) determine the frequency of postnatal confirmation by MRI, and (3) understand postnatal out-comes of infants with ACC. Methods: Maternal records from Children's National Hospital between January 2012 and June 2019 with a prenatal neurological consultation, fetal MRI, and ACC on imaging were included. Maternal, prenatal, and postnatal infant data were collected. Each case was categorized as complete or partial ACC and isolated or complex ACC by fetal MRI and group comparisons of outcomes were analyzed. Results: A total of 127 maternal-fetal dyads with ACC were categorized into 45 isolated-complete, 17 isolated-partial, 46 complex-complete, and 19 complex-partial ACC. Of 75 live births, 72 had postnatal evaluations. In 43 of 59 (73%) cases with postnatal neuroimaging, prenatal ACC subcategory was confirmed. Children with isolated or complex and with partial or complete ACC had similar rates of developmental delays and epilepsy. Complex ACC cases had worse outcomes than isolated ACC, with complex ACC having more postnatal dysmorphisms and abnormal feeding and vision compared with isolated ACC. Similar neurodevelopmental outcomes were seen for partial and complete ACC.Conclusions: Children with isolated or complex ACC and with partial or complete ACC have a range of neurodevelopmental outcomes. Fetal and postnatal brain MRI is a valuable tool to understand differences of the corpus callosum that can guide genetic testing, prenatal counseling, and postnatal care.(c) 2022 Elsevier Inc. All rights reserved.

Background: Absent septum pellucidum (ASP) is a brain abnormality often associated with neuroanatomic abnormalities including septo-optic dysplasia (SOD). We aimed to determine how frequently prenatally diagnosed isolated ASP is confirmed by postnatal imaging and to examine clinical outcomes for ASP. Methods: This was a retrospective study of maternal-fetal dyads referred to Children's National Hospital from January 1, 2012, to June 30, 2019. We included cases with fetal diagnosis of isolated or complex ASP. Diagnosis was based on ASP and the presence or absence of additional neuroanatomic findings. Data included obstetric and birth history, genetic testing, imaging, and neurodevelopmental outcomes. Results: ASP was diagnosed in 35 fetuses. Of 17 fetuses with isolated ASP, 10 had postnatal evaluation. In five (50%) isolated ASP cases, postnatal imaging revealed additional brain abnormalities. The five children with postnatally confirmed isolated ASP had lower rates of hydrocephalus (0% vs 54%) and abnormal feeding (0% vs 20%), hearing (0% vs 14%), and vision (0% vs 14%) than those with complex ASP (n 1/4 17). Children with isolated ASP had lower rates of developmental delay (33% vs 50%) and seizures (11% vs 30%) than children with complex ASP. One child with prenatal isolated ASP was diagnosed with SOD (10%). Conclusions: Few children with prenatally diagnosed isolated ASP had SOD diagnosed postnatally. Overall, children with isolated ASP demonstrate better outcomes than children with complex ASP. Fetal magnetic resonance imaging is a useful tool to evaluate the septum pellucidum and may reveal addi-tional abnormalities that can impact prognosis and affect prenatal counseling. (C) 2022 Elsevier Inc. All rights reserved.

Background In premature infants, extubation failure is common and difficult to predict. Heart rate variability (HRV) is a marker of autonomic tone. Our aim is to test the hypothesis that autonomic impairment is associated with extubation readiness. Methods Retrospective study of 89 infants <28 weeks. HRV metrics 24 h prior to extubation were compared for those with and without extubation success within 72 h. Receiver-operating curve analysis was conducted to determine the predictive ability of each metric, and a predictive model was created. Results Seventy-three percent were successfully extubated. The success group had significantly lower oxygen requirement, higher sympathetic HRV metrics, and a lower parasympathetic HRV metric. α 1 (measure of autocorrelation, related to sympathetic tone) was the best predictor of success—area under the curve (AUC) of .73 ( p = 0.001), and incorporated into a predictive model had an AUC of 0.81 ( p < 0.0001)—sensitivity of 81% and specificity of 78%. Conclusions Extubation success is associated with HRV. We show an autonomic imbalance with low sympathetic and elevated parasympathetic tone in those who failed. α 1 , a marker of sympathetic tone, was noted to be the best predictor of extubation success especially when incorporated into a clinical model. Impact This article depicts autonomic markers predictive of extubation success. We depict an autonomic imbalance in those who fail extubation with heightened parasympathetic and blunted sympathetic signal. We describe a predictive model for extubation success with a sensitivity of 81% and specificity of 78%.

BACKGROUND:Posterior fossa anomalies can be diagnostic dilemmas during the fetal period. The prognosis for different diagnoses of the posterior fossa varies widely. We investigated whether fetal magnetic resonance imaging (MRI) and prenatal neurology consultation led to an alternate prognosis for fetuses referred due to concern for a fetal posterior fossa anomaly and concordance between pre- and postnatal diagnoses. METHODS:This is a retrospective study of cases referred to the Prenatal Pediatrics Institute at Children's National Hospital from January 2012 to June 2018 due to concern for posterior fossa anomaly. Each encounter was scored for change in prognosis based upon clinical and fetal MRI report. Postnatal imaging was compared with prenatal imaging when available. RESULTS:In total, 180 cases were referred for fetal posterior fossa anomalies based on outside obstetric ultrasound and had both fetal MRI and a neurology consultation. Fetal MRI and neurology consultation resulted in a change in fetal prognosis in 70% of cases. The most common referral diagnosis in our cohort was Dandy-Walker continuum, but it was not often confirmed by fetal MRI. In complex cases, posterior fossa diagnosis and prognosis determined by fetal MRI impacted choices regarding pregnancy management. Postnatal imaging was obtained in 57 (47%) live-born infants. Fetal and postnatal prognoses were similar in 60%. CONCLUSIONS:Fetal diagnosis affects pregnancy management decisions. The fetal-postnatal imaging agreement of 60% highlights the conundrum of balancing the timing of fetal MRI to provide the most accurate diagnosis of the posterior fossa abnormalities in time to make pregnancy management decisions.

Abstract Hypoxia is an important condition in the tumor cell microenvironment and approximately 1% to 1.5% of the genome is transcriptionally responsive to hypoxia with hypoxia-inducible factor-1 (HIF-1) as a major mediator of transcriptional activation. Tumor hypoxia is associated with a more aggressive phenotype of many cancers in adults, but data on pediatric tumors are scarce. Because, by immunohistochemistry, HIF-1α expression was readily detectable in 18 of 28 primary Ewing's sarcoma family tumors (ESFT), a group of highly malignant bone-associated tumors in children and young adults, we studied the effect of hypoxia on ESFT cell lines in vitro. Intriguingly, we found that EWS-FLI1 protein expression, which characterizes ESFT, is upregulated by hypoxia in a HIF-1α–dependent manner. Hypoxia modulated the EWS-FLI1 transcriptional signature relative to normoxic conditions. Both synergistic as well as antagonistic transcriptional effects of EWS-FLI1 and of hypoxia were observed. Consistent with alterations in the expression of metastasis-related genes, hypoxia stimulated the invasiveness and soft agar colony formation of ESFT cells in vitro. Our data represent the first transcriptome analysis of hypoxic ESFT cells and identify hypoxia as an important microenvironmental factor modulating EWS-FLI1 expression and target gene activity with far-reaching consequences for the malignant properties of ESFT. Cancer Res; 70(10); 4015–23. ©2010 AACR.

BACKGROUND:Previous studies have described an association between preterm birth and maturation of the autonomic nervous system (ANS); however, this may be impacted by multiple factors, including prematurity-related complications. Our aim was to evaluate for the effect of prematurity-related morbidity on ANS development in preterm infants in the NICU.METHODS:We compared time and frequency domains of heart rate variability (HRV) as a measure of ANS tone in 56 preterm infants from 2 NICUs (28 from each). One cohort was from a high-morbidity regional referral NICU, the other from a community-based inborn NICU with low prematurity-related morbidity. Propensity score matching was used to balance the groups by a 1:1 nearest neighbor design. ANS tone was analyzed.RESULTS:The two cohorts showed parallel maturational trajectory of the alpha 1 time-domain metric, with the cohort from the high-morbidity NICU having lower autonomic tone. The maturational trajectories between the two cohorts differed in all other time-domain metrics (alpha 2, RMS1, RMS2). There was no difference between groups by frequency-domain metrics.CONCLUSIONS:Prematurity-associated morbidities correlate with autonomic development in premature infants and may have a greater impact on the extrauterine maturation of this system than birth gestational age.IMPACT:Autonomic nervous system development measured by time-domain metrics of heart rate variability correlate with morbidities associated with premature birth. This study builds upon our previously published work that showed that development of autonomic tone was not impacted by gestational age at birth. This study adds to our understanding of autonomic nervous system development in a preterm extrauterine environment. Our study suggests that gestational age at birth may have less impact on autonomic nervous system development than previously thought.

Brain injury is a serious and common complication of critical congenital heart disease (CHD). Impaired autonomic development (assessed by heart rate variability (HRV)) is associated with brain injury in other high-risk neonatal populations. To determine whether impaired early neonatal HRV is associated with pre-operative brain injury in CHD. In infants with critical CHD, we evaluated HRV during the first 24 h of cardiac ICU (CICU) admission using time-domain (RMS 1, RMS 2, and alpha 1) and frequency-domain metrics (LF, nLF, HF, nHF). Pre-operative brain magnetic resonance imaging (MRI) was scored for injury using an established system. Spearman's correlation coefficient was used to determine the association between HRV and pre-operative brain injury. We enrolled 34 infants with median birth gestational age of 38.8 weeks (IQR 38.1–39.1). Median postnatal age at pre-operative brain MRI was 2 days (IQR 1–3 days). Thirteen infants had MRI evidence of brain injury. RMS 1 and RMS 2 were inversely correlated with pre-operative brain injury. Time-domain metrics of autonomic function measured within the first 24 h of admission to the CICU are associated with pre-operative brain injury, and may perform better than frequency-domain metrics under non-stationary conditions such as critical illness.