Survival and Neurodevelopmental Outcomes in Congenital Diaphragmatic Hernia Patients with Single versus Repeat Extracorporeal Membrane Oxygenation Runs.

OBJECTIVE: We describe the survival and neurodevelopmental outcomes of congenital diaphragmatic hernia (CDH) patients who received single and repeat extracorporeal membrane oxygenation (ECMO). STUDY DESIGN: This is a retrospective single-center study comparing neurodevelopmental outcomes in CDH patients who were managed without ECMO, who received one ECMO run, and those who received two ECMO runs. Neurodevelopmental testing was performed utilizing the Bayley Scales of Infant Development-III. RESULTS: There were 68 neonates identified with CDH from January 2011 to June 2019: 30 did not receive ECMO, 29 received single ECMO run, and 9 received two ECMO runs. Survival of ECMO patients was 50%, with 48% of single run and 57% of repeat run patients surviving to discharge. Second-run ECMO patients had increased median ventilator days (60 vs. 33, p = 0.04) and increased median length of hospital stay (159 vs. 89, p = 0.01). Neurodevelopmental testing via Bayley Scales of Infant Development-III was performed on 74% of survivors at the mean age of 24 months. CDH neonates who underwent ECMO (single or repeat runs) were more likely to have lower cognitive, language, and motor composite scores as compared with CDH neonates who had not required ECMO. Motor composite scores were significantly lower in repeat ECMO run neonates as compared with single ECMO run (72 + 6 vs. 85 + 4, p = 0.0003), but there were no further deficits noted in language or cognitive domains. CONCLUSION: Survival after a second ECMO run in CDH is possible, although with increased ventilator days and increased length of hospitalization. We also find further deficits in motor outcomes in the second-run ECMO group compared with single-run ECMO. Our findings do not preclude a second ECMO run, but rather inform our counseling to families and reinforce the need for close neurodevelopmental follow-up for these patients. KEY POINTS: · A repeat ECMO run is associated with further neurodevelopmental deficits in the motor domain.. · Survival is possible after repeat ECMO and is associated with increased length of hospital stay.. · Neurodevelopmental follow-up is critical for all CDH ECMO patients..

Bi-allelic POLR3A Loss-of-Function Variants Cause Autosomal-Recessive Wiedemann-Rautenstrauch Syndrome.

Wiedemann-Rautenstrauch syndrome (WRS), also known as neonatal progeroid syndrome, is a rare disorder of unknown etiology. It has been proposed to be autosomal-recessive and is characterized by variable clinical features, such as intrauterine growth restriction and poor postnatal weight gain, characteristic facial features (triangular appearance to the face, convex nasal profile or pinched nose, and small mouth), widened fontanelles, pseudohydrocephalus, prominent scalp veins, lipodystrophy, and teeth abnormalities. A previous report described a single WRS patient with bi-allelic truncating and splicing variants in POLR3A. Here we present seven additional infants, children, and adults with WRS and bi-allelic truncating and/or splicing variants in POLR3A. POLR3A, the largest subunit of RNA polymerase III, is a DNA-directed RNA polymerase that transcribes many small noncoding RNAs that regulate transcription, RNA processing, and translation. Bi-allelic missense variants in POLR3A have been associated with phenotypes distinct from WRS: hypogonadotropic hypogonadism and hypomyelinating leukodystrophy with or without oligodontia. Our findings confirm the association of bi-allelic POLR3A variants with WRS, expand the clinical phenotype of WRS, and suggest specific POLR3A genotypes associated with WRS and hypomyelinating leukodystrophy.

Extracorporeal Membrane Oxygenation for Pediatric Patients With Coronavirus Disease 2019-Related Illness.

OBJECTIVE: To describe current hospital guidelines and the opinions of extracorporeal membrane oxygenation leaders at U.S. children's hospitals concerning the use of extracorporeal membrane oxygenation for coronavirus disease 2019-positive pediatric patients. DESIGN: Confidential, self-administered questionnaire. SETTING: One hundred twenty-seven U.S. pediatric extracorporeal membrane oxygenation centers. SUBJECTS: Extracorporeal membrane oxygenation center program directors and coordinators. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In March 2020, a survey was sent to 127 pediatric extracorporeal membrane oxygenation centers asking them to report their current hospital extracorporeal membrane oxygenation guidelines for coronavirus disease 2019-positive patients. Respondents were also asked their opinion on three ethical dilemmas including: prioritization of children over adults for extracorporeal membrane oxygenation use, institution of do-not-resuscitate orders, and the use of extracorporeal cardiopulmonary resuscitation for coronavirus disease 2019-positive patients. Forty-seven extracorporeal membrane oxygenation centers had enacted guidelines including 46 (100%) that offer venovenous-extracorporeal membrane oxygenation and 42 (89%) that offer venoarterial-extracorporeal membrane oxygenation for coronavirus disease 2019-positive pediatric patients. Forty-four centers (94%) stated that the indications for extracorporeal membrane oxygenation candidacy in coronavirus disease 2019 disease were similar to those used in other viral illnesses, such as respiratory syncytial virus or influenza. Most program directors (98%) did not endorse that children hospitalized with coronavirus disease 2019 should be made do-not-resuscitate and had variable opinions on whether children should be given higher priority over adults when rationing extracorporeal membrane oxygenation. Over half of program directors (60%) did not support the use of extracorporeal cardiopulmonary resuscitation for coronavirus disease 2019. CONCLUSIONS: The majority of pediatric extracorporeal membrane oxygenation centers have proactively established guidelines for the use of extracorporeal membrane oxygenation for coronavirus disease 2019-related illnesses. Further work is needed to help guide the fair allocation of extracorporeal membrane oxygenation resources and to determine the appropriateness of extracorporeal cardiopulmonary resuscitation.

Nicardipine for the Treatment of Neonatal Hypertension During Extracorporeal Membrane Oxygenation.

Extracorporeal membrane oxygenation (ECMO) is one of the primary reasons systemic hypertension is experienced in hospitalized neonates. Commonly used antihypertensive agents have resulted in significant adverse effects in neonatal and pediatric populations. Nicardipine is a desirable option because of its rapid and titratable antihypertensive properties and low incidence of adverse effects. However, data for use in neonatal ECMO are limited. We conducted a retrospective review of patients less than 44 weeks post-menstrual age who received a nicardipine infusion for first-line treatment of systemic hypertension while on ECMO at our institution between 2010 and 2016. Systolic (SBP), diastolic (DBP), and mean arterial (MAP) blood pressures were evaluated for 48-h after nicardipine initiation. Eight neonates received a nicardipine infusion while on ECMO during the study period. Nicardipine was initiated at a mean dose of 0.52 ( ± 0.22) mcg/kg/min and titrated to a maximum dose of 1.1 ( ± 0.85) mcg/kg/min. The median duration of nicardipine use was 51 (range 4-227) hours. Significant decreases in SBP, DBP, and MAP occurred within one hour of initiation of nicardipine and were sustained through the majority of the 48-h evaluation period. No patients experienced hypotension. Prospective studies are warranted to evaluate the optimal dose, safety, and efficacy of nicardipine in neonates who require ECMO.

A definition of gentle ventilation in congenital diaphragmatic hernia: a survey of neonatologists and pediatric surgeons.

Ventilation practices have changed significantly since the initial reports in the mid 1980 of successful use of permissive hypercapnia and spontaneous ventilation [often called gentle ventilation (GV)] in infants with congenital diaphragmatic hernia (CDH). However, there has been little standardization of these practices or of the physiologic limits that define GV. We sought to ascertain among Diaphragmatic Hernia Research and Exploration; Advancing Molecular Science (DHREAMS) centers' GV practices in the neonatal management of CDH. Pediatric surgeons and neonatologists from DHREAMS centers completed an online survey on GV practices in infants with CDH. The survey gathered data on how individuals defined GV including ventilator settings, blood gas parameters and other factors of respiratory management. A total of 87 respondents, from 12 DHREAMS centers completed the survey for an individual response rate of 53% and a 92% center response rate. Approximately 99% of the respondents defined GV as accepting higher carbon dioxide (PCO2) and 60% of the respondents also defined GV as accepting a lower pH. There was less consensus about the use of sedation and neuromuscular blocking agents in GV, both within and across the centers. Acceptable pH and PCO2 levels are broader than the goal ranges. Despite a lack of formal standardization, the results suggest that GV practice is consistently defined as the use of permissive hypercapnia with mild respiratory acidosis and less consistently with the use of sedation and neuromuscular blocking agents. GV is the reported practice of surveyed neonatologists and pediatric surgeons in the respiratory management of infants with CDH.

Short-term outcomes and medical and surgical interventions in infants with congenital diaphragmatic hernia.

OBJECTIVE: The aim of this study is to characterize medical and surgical therapies and short-term outcomes in infants with congenital diaphragmatic hernia (CDH). STUDY DESIGN: Retrospective analysis of CDH infants admitted to 27 children's hospitals submitting data to Children's Hospital Neonatal Database (CHND) from 2010 to 2013, stratified by gestational age, birth weight, and survival. RESULTS: A total of 572 infants were identified, 508 (89%) born ≥ 34 weeks' gestation and ≥ 2 kg. More mature infants had higher APGAR scores, shorter duration of mechanical ventilation, and were more likely to receive extracorporeal membrane oxygenation (ECMO). Overall, mortality for the cohort was 29%, with mortality lower in infants born ≥ 34 weeks' gestation and ≥ 2 kg (26 vs. 50%, p < 0.01). Nonsurvivors were more likely to receive treatment with high-frequency oscillatory ventilation (HFOV), vasopressors, pulmonary vasodilators, and ECMO, and to have associated major congenital anomalies than survivors. In hospital morbidity and complications were relatively uncommon among survivors. CONCLUSION: Infants with CDH have a high risk of morbidity and mortality, and for preterm infants with CDH those risks are amplified. Patterns of respiratory and circulatory support appeared to be different for survivors. In addition to established data registries, this consortium of regional neonatal intensive care units provides a new collaborative effort to describe short-term outcomes for infants referred with CDH.

A clinical consensus guideline for nutrition in infants with congenital diaphragmatic hernia from birth through discharge.

OBJECTIVE: To develop a consensus guideline to meet nutritional challenges faced by infants with congenital diaphragmatic hernia (CDH). STUDY DESIGN: The CDH Focus Group utilized a modified Delphi method to develop these clinical consensus guidelines (CCG). Topic leaders drafted recommendations after literature review and group discussion. Each recommendation was sent to focus group members via a REDCap survey tool, and members scored on a Likert scale of 0-100. A score of > 85 with no more than 25% outliers was designated a priori as demonstrating consensus among the group. RESULTS: In the first survey 24/25 recommendations received a median score > 90 and after discussion and second round of surveys all 25 recommendations received a median score of 100. CONCLUSIONS: We present a consensus evidence-based framework for managing parenteral and enteral nutrition, somatic growth, gastroesophageal reflux disease, chylothorax, and long-term follow-up of infants with CDH.

Impact of hospital volume on in-hospital mortality of infants undergoing repair of congenital diaphragmatic hernia.

OBJECTIVES: Congenital diaphragmatic hernia (CDH) remains a significant cause of neonatal morbidity and mortality. SUMMARY OF BACKGROUND DATA: Previous studies have suggested that hospital volume is an independent predictor of in-hospital mortality. We sought to validate this effect using a large national database incorporating 37 free-standing children's hospitals in the United States. METHODS: Infants who underwent repair of CDH from 2000 to 2008 at Pediatric Health Information Systems-member hospitals were evaluated. Hospitals were categorized by tertiles into low-volume (≤6 cases/yr), medium-volume (6-10 cases/yr), and high-volume (>10 cases/yr). Using generalized linear mixed models with random effects, we computed the risk-adjusted odds ratio of mortality by yearly hospital volume of CDH repair, after adjustment for salient patient and hospital characteristics. RESULTS: There were 2203 infants who underwent repair with an overall survival of 82%. Average yearly hospital volume of CDH repair varied from 1.4 to 17.5 cases per year. Smaller birthweight (adjusted odds ratio [aOR]: 0.56 per kg, P < 0.001), year of birth (P < 0.001), chromosomal abnormalities (aOR: 3.83, P < 0.01), longer time to repair (aOR: 1.12 per week, P < 0.05), the thoracic approach for repair (P < 0.02), and requirement for extracorporeal membrane oxygenation (aOR: 10.31, P < 0.0001), or inhaled nitric oxide (aOR: 5.25, P < 0.0001) were each independently associated with mortality. Compared with low-volume hospitals, medium-volume (aOR: 0.56, P < 0.05) and high-volume (aOR: 0.44, P < 0.01) hospitals had a significantly lower mortality. The rate of extracorporeal membrane oxygenation use at each facility was not independently associated with mortality. CONCLUSIONS: This large study suggests that hospitals which perform high volumes of CDH repair achieve lower in-hospital mortality. These data support the paradigm of regionalized centers of excellence for the management of infants with this morbid condition.

Predictors of the need for extracorporeal membrane oxygenation and survival in congenital diaphragmatic hernia: a center's 10-year experience.

OBJECTIVE: To determine the prenatal factors associated with the need for extracorporeal membrane oxygenation (ECMO) and neonatal survival in congenital diaphragmatic hernia (CDH). STUDY DESIGN: A retrospective cohort study of all cases of CDH seen in our center between 1998 and 2008. Prenatal ultrasound and neonatal records were reviewed. Both univariable and logistic regression analyses were performed to determine the significant factors associated with the use of ECMO and survival. RESULTS: Among 107 cases of CDH seen during the study period, 62 were evaluated prenatally in our center and 49 had information on all variables evaluated. The overall rate of ECMO use was 27/107 (25%) and survival rate was 53/107 (49.5%). The lung area to head circumference ratio (LHR) and gestational age (GA) at delivery were the only significant factors associated with ECMO use, and the LHR and absence of liver herniation were significantly associated with survival. LHR values under 1.0 were associated with 57% need for ECMO and 100% neonatal death. Although, overall, the observed:expected LHR (O:E LHR) was not significantly associated with ECMO use or survival, levels below 65% were associated with 58% need for ECMO (p = 0.004) and 100% neonatal death (p = 0.002). CONCLUSION: The study confirms the LHR, GA at delivery and liver herniation as significant prenatal predictors of the need for ECMO or survival in cases with CDH. This information is helpful for counseling women with fetuses complicated by CDH.

Interval between clinical presentation of necrotizing enterocolitis and bowel perforation in neonates.

OBJECTIVE: To define the interval between clinical presentation of necrotizing enterocolitis (NEC) and bowel perforation in neonates. METHODS: Charts of neonates with discharge diagnosis of NEC (n = 124) from our NICU during 2004-2008 were retrospectively reviewed. Demographic data were collected. Acute episode of NEC was defined as the interval between clinical presentations to resumption of enteral feeds. Neonates are followed, as a standard of care, clinically and radiologically until resumption of enteral feeds at the discretion of the attending clinician. Abdominal radiograph results were reviewed serially to determine the interval between clinical presentation and bowel perforation using pneumoperitoneum as the surrogate radiological marker. Histological report of resected bowel specimens was reviewed for coagulative necrosis as evidence of NEC and to exclude spontaneous intestinal perforation (SIP). Neonates with stage 1 NEC and SIP were excluded from the results. RESULTS: 105 neonates with stage 2 NEC were included in the study. Forty-six needed surgical treatment (group 2) and 59 did not need surgery (group 1). Twenty-six (26/46, 56%) group 2 neonates had bowel perforation and hence required surgery. Pneumoperitoneum was noted at a median interval of 1 day after presentation of symptoms. Twenty neonates in group 2 needed surgery for clinical indications including worsening clinical examination, thrombocytopenia or persistent metabolic acidosis. Fifty-nine neonates (group 1) were treated with bowel rest, antibiotics and parenteral nutrition. Group 2 neonates were significantly more premature, weighed less and had less radiographs than group 1 neonates. Mortality was significantly higher in group 2 compared to group 1. CONCLUSION: Bowel perforation occurs at a median interval of 1 day after clinical presentation of NEC. Neonates not needing surgery for their disease are exposed to significantly more radiographs than those needing surgery. Radiological evaluation can be safely minimized or eliminated after 2 days of presentation.