Risk factors, incidence, and outcomes of neonatal respiratory extracorporeal membrane oxygenation including association with therapeutic hypothermia in California during 2013-2020.

OBJECTIVE: To evaluate the incidence, indications and outcomes with neonatal extracorporeal membrane oxygenation (ECMO) and its association with therapeutic hypothermia (TH) among infants undergoing invasive mechanical ventilation (IMV) in California during 2013-2020. STUDY DESIGN: We analyzed data on neonates ≥34 weeks gestation with ≥4 h of IMV over an 8-year period (2013-2020) from the California Perinatal Quality Care Collaborative (CPQCC) database. RESULTS: Between 2013 and 2020, the ranges for utilization of iNO (13.9 to 17.2%), ECMO (2.1 to 2.5%), TH (10.2 to 15.7%) and TH + ECMO (0.4 to 0.8%) were observed. The most common association with neonatal ECMO was TH (148 cases, OR 3.2, 95% CI 2.6-4.3, p < 0.01). The combination of meconium aspiration syndrome (MAS) and hypoxic ischemic encephalopathy (HIE) increased risk of iNO and ECMO use (OR 11.3, 1.5-86.9), p = 0.02). CONCLUSION: Ventilated infants ≥34 weeks gestational age undergoing TH are at risk for iNO/ECMO use and need close monitoring.

Ventilator strategies in congenital diaphragmatic hernia.

This review focuses on contemporary mechanical ventilator practices used in the initial management of neonates born with congenital diaphragmatic hernia (CDH). Both conventional and non-conventional ventilation modes in CDH are reviewed. Special emphasis is placed on the rationale for gentle ventilation and the current evidence-based clinical practice guidelines that are recommended for supporting these fragile infants. The interplay between CDH lung hypoplasia and other key cardiopulmonary elements of the disease, namely a reduced pulmonary vascular bed, abnormal pulmonary vascular remodeling, and left ventricular hypoplasia, are discussed. Finally, we provide insights into future avenues for mechanical ventilator research in CDH.

Procedural closure of the patent ductus arteriosus in preterm infants: a clinical practice guideline.

IMPORTANCE: Transcatheter closure of the patent ductus arteriosus (PDA) is being increasingly adopted as an alternative to surgical PDA closure in preterm infants. OBJECTIVE: To develop rigorous clinical practice guideline recommendations on procedural PDA closure in preterm infants. METHODS: The principles of the GRADE (Grading of Recommendations Assessment, Development and Evaluation) Evidence-to-Decision (EtD) framework were used to develop the guideline recommendations. An e-Delphi survey of 45 experts was conducted and recommendations that reached ≥75% agreement were accepted as consensus. MAIN RECOMMENDATIONS: Procedural PDA closure may be considered in extremely preterm infants (<28 weeks gestational age) requiring invasive mechanical ventilation >10 postnatal days and confirmed to have a large hemodynamically significant PDA, at centers with high local rates of death and/or bronchopulmonary dysplasia (conditional recommendation). If sufficient institutional expertise is available and patient characteristics are suitable, transcatheter PDA closure may be considered as the preferred approach over PDA ligation (conditional recommendation).

Retrospective study of preterm infants exposed to inhaled nitric oxide in Kaiser Permanente Southern California: morbidity, mortality and follow-up.

OBJECTIVE: Describe characteristics of preterm infants exposed to inhaled nitric oxide (iNO) in Kaiser Permanente Southern California. STUDY DESIGN: Case review of preterm infants <34-weeks exposed to iNO during 2010-2020 including respiratory and echocardiographic status, NICU course, and 12-month follow-up. RESULTS: 270 infants, 2.63% of births<34 weeks, (median, range: 26.1, 225/7-336/7 weeks gestation) were exposed to iNO. Median FiO2 at iNO initiation was 1.0 (IQR 0.94-1.0). Pulmonary hypertension (PH) was not associated with risk-adjusted 2 h oxygenation response or improved survival. Mortality to NICU discharge was 37.4%. Median cost of iNO was $7,695/patient. Discharged survivors experienced frequent rehospitalization (34.9%), use of supplemental oxygen, sildenafil, diuretics, bronchodilators, and steroids. Four infants had persistent PH. Five infants died after NICU discharge. CONCLUSIONS: Preterm infants receiving iNO have high mortality and 1st year morbidity. As currently used, iNO may be an indicator of respiratory disease severity rather than mediator of improved outcomes.

Two-Year Outcomes of Umbilical Cord Milking in Nonvigorous Infants: A Secondary Analysis of the MINVI Randomized Clinical Trial.

Importance: Compared with early cord clamping (ECC), umbilical cord milking (UCM) reduces delivery room cardiorespiratory support, hypoxic-ischemic encephalopathy, and therapeutic hypothermia in nonvigorous near-term and full-term infants. However, UCM postdischarge outcomes are not known. Objective: To determine the 2-year outcomes of children randomized to UCM or ECC at birth in the Milking in Nonvigorous Infants (MINVI) trial. Design, Setting, and Participants: A secondary analysis to evaluate longer-term outcomes of a cluster-randomized crossover trial was conducted from January 9, 2021, to September 25, 2023. The primary trial took place in 10 medical centers in the US, Canada, and Poland from January 5, 2019, to June 1, 2021, and hypothesized that UCM would reduce admission to the neonatal intensive care unit compared with ECC; follow-up concluded September 26, 2023. The population included near-term and full-term infants aged 35 to 42 weeks' gestation at birth who were nonvigorous; families provided consent to complete developmental screening questionnaires through age 2 years. Intervention: UCM and ECC. Main Outcomes and Measures: Ages and Stages Questionnaire, 3rd Edition (ASQ-3) and Modified Checklist for Autism in Toddlers, Revised/Follow-Up (M-CHAT-R/F) questionnaires at ages 22 to 26 months. Intention-to-treat analysis and per-protocol analyses were used. Results: Among 1730 newborns from the primary trial, long-term outcomes were evaluated in 971 children (81%) who had ASQ-3 scores available at 2 years or died before age 2 years and 927 children (77%) who had M-CHAT-R/F scores or died before age 2 years. Maternal and neonatal characteristics by treatment group were similar, with median birth gestational age of 39 (IQR, 38-40) weeks in both groups; 224 infants (45%) in the UCM group and 201 (43%) in the ECC group were female. The median ASQ-3 total scores were similar (UCM: 255 [IQR, 225-280] vs ECC: 255 [IQR, 230-280]; P = .87), with no significant differences in the ASQ-3 subdomains. Medium- to high-risk M-CHAT-R/F scores were also similar (UCM, 9% [45 of 486] vs ECC, 8% [37 of 441]; P = .86). Conclusions and Relevance: In this secondary analysis of a randomized clinical trial among late near-term and full-term infants who were nonvigorous at birth, ASQ-3 scores at age 2 years were not significantly different between the UCM and ECC groups. Combined with previously reported important short-term benefits, this follow-up study suggests UCM is a feasible, no-cost intervention without longer-term neurodevelopmental risks of cord milking in nonvigorous near-term and term newborns. Trial Registration: ClinicalTrials.gov Identifier: NCT03631940.

Meconium Aspiration Syndrome, Hypoxic-Ischemic Encephalopathy and Therapeutic Hypothermia-A Recipe for Severe Pulmonary Hypertension?

Hypoxic-ischemic encephalopathy (HIE) is the leading cause of mortality among term newborns globally. Infants born through meconium-stained amniotic fluid are at risk of developing meconium aspiration syndrome (MAS) and HIE. Simultaneous occurrence of MAS and HIE is a perilous combination for newborns due to the risk of persistent pulmonary hypertension of the newborn (PPHN). Moreover, therapeutic hypothermia (TH), which is the current standard of care for the management of HIE, may increase pulmonary vascular resistance (PVR) and worsen PPHN. Infants with MAS and HIE require close cardiorespiratory and hemodynamic monitoring for PPHN. Therapeutic strategies, including oxygen supplementation, ventilation, use of surfactant, inhaled nitric oxide and other pulmonary vasodilators, and systemic vasopressors, play a critical role in the management of PPHN in MAS, HIE, and TH. While TH reduces death or disability in infants with HIE, infants with MAS and HIE undergoing TH need close hemodynamic monitoring for PPHN.

Machine Learning-Based Critical Congenital Heart Disease Screening Using Dual-Site Pulse Oximetry Measurements.

BACKGROUND: Oxygen saturation (Spo2) screening has not led to earlier detection of critical congenital heart disease (CCHD). Adding pulse oximetry features (ie, perfusion data and radiofemoral pulse delay) may improve CCHD detection, especially coarctation of the aorta (CoA). We developed and tested a machine learning (ML) pulse oximetry algorithm to enhance CCHD detection. METHODS AND RESULTS: Six sites prospectively enrolled newborns with and without CCHD and recorded simultaneous pre- and postductal pulse oximetry. We focused on models at 1 versus 2 time points and with/without pulse delay for our ML algorithms. The sensitivity, specificity, and area under the receiver operating characteristic curve were compared between the Spo2-alone and ML algorithms. A total of 523 newborns were enrolled (no CHD, 317; CHD, 74; CCHD, 132, of whom 21 had isolated CoA). When applying the Spo2-alone algorithm to all patients, 26.2% of CCHD would be missed. We narrowed the sample to patients with both 2 time point measurements and pulse-delay data (no CHD, 65; CCHD, 14) to compare ML performance. Among these patients, sensitivity for CCHD detection increased with both the addition of pulse delay and a second time point. All ML models had 100% specificity. With a 2-time-points+pulse-delay model, CCHD sensitivity increased to 92.86% (P=0.25) compared with Spo2 alone (71.43%), and CoA increased to 66.67% (P=0.5) from 0. The area under the receiver operating characteristic curve for CCHD and CoA detection significantly improved (0.96 versus 0.83 for CCHD, 0.83 versus 0.48 for CoA; both P=0.03) using the 2-time-points+pulse-delay model compared with Spo2 alone. CONCLUSIONS: ML pulse oximetry that combines oxygenation, perfusion data, and pulse delay at 2 time points may improve detection of CCHD and CoA within 48 hours after birth. REGISTRATION: URL: https://www.clinicaltrials.gov/study/NCT04056104?term=NCT04056104&rank=1; Unique identifier: NCT04056104.

Should neonatal-perinatal medicine move to two-year fellowships?

The duration of the majority of fellowships in pediatrics has been three-years. With increasing shortages of some outpatient-based pediatric subspecialists, shorter two-year fellowships are being considered for clinically oriented trainees not interested in a career based on research. Shortening the duration of fellowship may have some financial merits such as achieving a higher salary earlier after shorter training. However, we feel that continuing with a three-year duration for neonatology is more pragmatic at this time due to reductions in intensive care rotations during residency, time required to  achieve procedural excellence, the need for exposure to quality assurance methodology, proficiency in novel techniques such as bedside ultrasound, and to maintain the physician-scientist pipeline. The demand for neonatal fellowship continues to be high. Ongoing evaluation of the job market, training needs and fellowship curriculum is needed to determine if the duration of fellowship should be altered in the future.

Direct Umbilical Vein Injection of Epinephrine with Cut-Cord Milking in an Ovine Model of Neonatal Resuscitation.

BACKGROUND: An umbilical venous catheter (UVC) is the preferred route of epinephrine administration during neonatal resuscitation but requires specialized equipment, expertise, and time. HYPOTHESIS: Direct injection of epinephrine into the umbilical vein (UV) followed by milking a ~20 cm segment of cut umbilical cord to flush the epinephrine (DUV + UCM) will lead to a quicker administration and earlier return of spontaneous circulation (ROSC) compared with epinephrine given through a UVC. DESIGN: Eighteen near-term asphyxiated lambs were randomized to receive a low-UVC or DUV + UCM of epinephrine at 0.02 or 0.03 mg/kg doses. OUTCOME MEASURES: A total of 16/18 lambs achieved ROSC with a similar mean (±SEM) time to ROSC [DUV + UCM vs. low-UVC (4.67 ± 0.67 vs. 3.99 ± 0.58 min); p = 0.46]. Two out of ten lambs in the DUV + UCM group required UVC placement for additional epinephrine. The administration of the first dose of epinephrine was similar (DUV + UCM-2.97 ± 0.48 vs. UVC-4.23 ± 0.58 min; p = 0.12). Both methods yielded similar epinephrine concentrations (peak concentrations of 253 ± 63 and 328 ± 80 ng/mL for DUV + UCM and UVC EPI, respectively). CONCLUSIONS: DUV + UCM resulted in a ROSC success of 78% following the first epinephrine dose and showed similar epinephrine concentrations to UVC. Clinical studies evaluating DUV + UCM as an alternate route for epinephrine while intravenous access is being established are warranted.

Hemodynamic assessment by neonatologist using echocardiography: Primary provider versus consultation model.

Hemodynamic instability is very common in sick neonates and the currently used traditional hemodynamic monitoring tools lack sensitivity and specificity. Hemodynamic evaluation on echocardiography can provide direct information regarding the pathophysiology causing the hemodynamic instability and help the bedside clinician in making a personalized treatment approach based upon the deranged pathophysiology. Assessment of cardiac function and hemodynamics is essential in the management of neonates with cardiorespiratory failure, and hence neonatologist-performed echocardiography is becoming an essential tool in modern neonatal care. Depending on the level and size of the NICU, there is a daily need for echocardiography, and for a subset of sick infants, serial echocardiographic assessments are warranted. Comprehensive guidelines for neonatologists performing echocardiography and targeted neonatal echocardiography have been published providing a framework for training and quality assurance. There has been a significant interest among the providers to learn echocardiography skills. This manuscript explores the various needs of neonatal care providers around echocardiography, the current challenges neonatologists face in learning echocardiography, and how they, especially neonatal fellows, can learn these important skills during their training.

The National Academies of Sciences, Engineering, and Medicine recommendations on Medicaid parity and future of pediatric subspecialty workforce.

Medicaid supports 41% of all births in the US and nearly 347,580 admissions to neonatal intensive care units in 2022. Medicaid reimbursement is critical to child health inclusive of departments of Pediatrics and children's hospitals. Low Medicaid reimbursement is one of the causes for low pediatric subspecialist salaries and has led to workforce challenges. The National Academies of Science, Engineering, and Medicine (NASEM) recently suggested increased Medicaid reimbursement as a strategy to sustain pediatric subspecialist workforce. This review article briefly outlines the importance of Medicaid reimbursement to Neonatal-Perinatal Medicine and its role in providing coverage for preterm births. We also highlight the recommendations of NASEM pertaining to reimbursement that are relevant to neonatal care and its impact on providers, patients, and families. It is imperative that neonatologists join the rest of pediatric subspecialists in lending their support to demonstrate unity in ensuring success in the implementation of the NASEM recommendations.

Caffeine pharmacokinetics following umbilical vein injection during delayed cord clamping in preterm lambs.

BACKGROUND: Spontaneous breathing during and after delayed cord clamping (DCC) stabilizes cardiopulmonary transition at birth. Caffeine stimulates breathing and decreases apnea in premature newborns. We evaluated the pharmacokinetics and physiological effects of early caffeine administration-direct injection into the umbilical vein (UV) during DCC or administered through a UV catheter (UVC) after delivery. METHODS: Eighteen extremely premature lambs (125-127d, term gestation 145d) were exteriorized and instrumented. Lambs received caffeine-citrate at high (40 mg/kg) or standard-dose (20 mg/kg) via direct UV (DUV) injection during DCC, or via the UVC. RESULTS: Mean peak plasma caffeine concentrations were lower with high-dose DUV compared to UVC (18 ± 4.3 vs. 46 ± 12 mg/L, p < 0.05). With standard-dose caffeine, mean peak plasma levels were 7.48 ± 2.6 with DUV and 28.73 ± 9.4 mg/L with UVC. The volume of distribution was higher in the DUV group compared to UVC (2.5 ± 1.0 vs. 0.69 ± 0.15 L/kg) with an estimated 39 ± 18% entering the maternal circulation. Maternal peak concentrations were 0.79 ± 0.71 and 1.43 ± 0.74 mg/L with standard and high-dose DUV, respectively. CONCLUSIONS: Caffeine injected directly into the UV during DCC is feasible but achieves lower concentrations due to high volume of distribution including maternal circulation. Further trials evaluating DUV caffeine injection should use higher caffeine doses. IMPACT: Respiratory stimulation with early caffeine may reduce the need for intubation in preterm infants. In the preterm lambs, caffeine injection directly into the umbilical vein during delayed cord clamping is feasible. Plasma caffeine concentrations are less than half when administered directly into the umbilical vein during delayed cord clamping compared to administration via an umbilical venous catheter following birth likely attributed to a larger volume of distribution or injection site leak. There were no significant hemodynamic alterations following caffeine injection.

Use of surfactant beyond respiratory distress syndrome, what is the evidence?

Surfactant replacement therapy is currently approved by the United States Food and Drug Administration (FDA) for premature infants with respiratory distress syndrome (RDS) caused by surfactant deficiency due to immaturity. There is strong evidence that surfactant decreases mortality and air leak syndromes in premature infants with RDS. However, surfactant is also used "off-label" for respiratory failure beyond classic RDS. This review discusses current evidence for the use of off-label surfactant therapy for (1) term infants with lung disease such as meconium aspiration syndrome (MAS), pneumonia/sepsis, and congenital diaphragmatic hernia (2) premature infants after 72 h for acute respiratory failure, and (3) the use of surfactant lavage. At last, we briefly describe the use of surfactants for drug delivery and the current evidence on evaluating infants for surfactant deficiency.

Comorbidities and Late Outcomes in Neonatal Pulmonary Hypertension.

Long-term outcomes of persistent pulmonary hypertension of newborn (PPHN) depend on disease severity, duration of ventilation, and associated anomalies. Congenital diaphragmatic hernia survivors may have respiratory morbidities and developmental delay. The presence of PPHN is associated with increased mortality in hypoxic-ischemic encephalopathy, though the effects on neurodevelopment are less clear. Preterm infants can develop pulmonary hypertension (PH) early in the postnatal course or later in the setting of bronchopulmonary dysplasia (BPD). BPD-PH is associated with higher mortality, particularly within the first year. Evidence suggests that both early and late PH in preterm infants are associated with neurodevelopmental impairment.