Targeted Therapies for Neonatal Pulmonary Hypertension: Beyond Nitric Oxide.

Pulmonary hypertension in the neonatal population can be acute or chronic and carries significant risk for morbidity and mortality. It can be idiopathic but more often is associated with comorbid pulmonary and heart disease. There are several pharmacotherapeutics aimed at pulmonary vasodilation. This review highlights the most common agents as well as those on the horizon for the treatment of pulmonary hypertension in the neonate.

Feasibility and Safety of Sildenafil to Repair Brain Injury Secondary to Birth Asphyxia (SANE-01): A Randomized, Double-blind, Placebo-controlled Phase Ib Clinical Trial.

OBJECTIVE: To test feasibility and safety of administering sildenafil in neonates with neonatal encephalopathy (NE), developing brain injury despite therapeutic hypothermia (TH). STUDY DESIGN: We performed a randomized, double-blind, placebo-controlled phase Ib clinical trial between 2016 and 2019 in neonates with moderate or severe NE, displaying brain injury on day-2 magnetic resonance imaging (MRI) despite TH. Neonates were randomized (2:1) to 7-day sildenafil or placebo (2 mg/kg/dose enterally every 12 hours, 14 doses). Outcomes included feasibility and safety (primary outcomes), pharmacokinetics (secondary), and day-30 neuroimaging and 18-month neurodevelopment assessments (exploratory). RESULTS: Of the 24 enrolled neonates, 8 were randomized to sildenafil and 3 to placebo. A mild decrease in blood pressure was reported in 2 of the 8 neonates after initial dose, but not with subsequent doses. Sildenafil plasma steady-state concentration was rapidly reached, but decreased after TH discontinuation. Twelve percent of neonates (1/8) neonates died in the sildenafil group and 0% (0/3) in the placebo group. Among surviving neonates, partial recovery of injury, fewer cystic lesions, and less brain volume loss on day-30 magnetic resonance imaging were noted in 71% (5/7) of the sildenafil group and in 0% (0/3) of the placebo group. The rate of death or survival to 18 months with severe neurodevelopmental impairment was 57% (4/7) in the sildenafil group and 100% (3/3) in the placebo group. CONCLUSIONS: Sildenafil was safe and well-absorbed in neonates with NE treated with TH. Optimal dosing needs to be established. Evaluation of a larger number of neonates through subsequent phases II and III trials is required to establish efficacy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.govNCT02812433.

Academic Health Centers and Humanitarian Crises: One Health System's Response to Unaccompanied Children at the Border.

University of California Health (UCH) provided a system-wide, rapid response to the humanitarian crisis of unaccompanied children crossing the southern U.S. border in the midst of the COVID-19 pandemic in 2021. In collaboration with multiple federal, state, and local agencies, UCH mobilized a multidisciplinary team to deliver acute general and specialty pediatric care to unaccompanied children at 2 Californian emergency intake sites (EISs). The response, which did not disrupt normal UCH operations, mobilized the capacities of the system and resulted in a safe and developmentally appropriate environment that supported the physical and mental health of migrant children during this traumatic period. The capacities of UCH's 6 academic health centers ensured access to trauma-informed medical care and culturally sensitive psychological and social support. Child life professionals provided access to exercise, play, and entertainment. Overall, 260 physicians, 42 residents and fellows, 4 nurse practitioners participated as treating clinicians and were supported by hundreds of staff across the 2 EISs. Over 5 months and across both EISs, a total of 4,911 children aged 3 to 17 years were cared for. A total of 782 children had COVID-19, most infected before arrival. Most children (3,931) were reunified with family or sponsors. Continuity of care after reunification or placement in a long-term shelter was enhanced by use of an electronic health record. The effort provided an educational experience for residents and fellows with instruction in immigrant health and trauma-informed care. The effort benefitted from UCH's recent experience of providing a system-wide response to the COVID-19 pandemic. Lessons learned are reported to encourage the alignment and integration of academic health centers' capacities with federal, state, and local plans to better prepare for and respond to the accelerating need to care for those in the wake of disasters and humanitarian crises.

Dynamic PEEP Study: A Non-invasive Diagnostic Exam to Assess for Effective PEEP in Children with Severe BPD.

OBJECTIVE: Tracheobronchomalacia (TBM) is common in neonates with bronchopulmonary dysplasia (BPD) and is associated with higher morbidity. This study evaluates the value of a CT protocol to assess the degree of TBM and gauge the adequacy of prescribed PEEP. STUDY DESIGN: Four infants with severe BPD on invasive mechanical ventilation underwent a chest CT protocol, including limited reduced-dose expiratory scans with varying PEEP levels. RESULTS: Baseline PEEP was adjusted in all subjects after performing the Dynamic PEEP CT. In two infants, the PEEP was increased due to significant TBM and in the other two without signs of TBM PEEP was decreased. The clinical course improved in all patients after adjusting PEEP. CONCLUSION: A "Dynamic PEEP" study may be reliable and non-invasive imaging modality for the evaluation of adequate ventilator settings in infants with severe BPD who are not optimal candidates for bronchoscopy.

Optimizing respiratory management in preterm infants: a review of adjuvant pharmacotherapies.

Adjuvant respiratory therapies in preterm neonates aim to reduce long-term morbidities and mortality. Commonly utilized therapies include caffeine, systemic glucocorticosteroids, inhaled steroids, inhaled bronchodilators, and diuretics. This review discusses the available literature that supports some of these practices and points out where clinical practices are not corroborated by evidence. Therapies with no proven clinical benefit must be weighed against potential adverse effects.

Efficacy and Safety of IV Sildenafil in the Treatment of Newborn Infants with, or at Risk of, Persistent Pulmonary Hypertension of the Newborn (PPHN): A Multicenter, Randomized, Placebo-Controlled Trial.

OBJECTIVE: To investigate the efficacy and safety of sildenafil added to inhaled nitric oxide (iNO) for newborn infants with persistent pulmonary hypertension of newborn (PPHN) or hypoxic respiratory failure (HRF) at risk of PPHN. STUDY DESIGN: Part A of a multinational, randomized, double-blind, placebo-controlled trial. Infants ≤96 hours' old, >34 weeks of gestation, receiving iNO (10-20 ppm on ≥50% FiO2) for PPHN or HRF at risk of PPHN, and oxygen index >15 to <60, were randomized (1:1) to intravenous (IV) sildenafil (loading: 0.1 mg/kg, over 30 minutes; maintenance: 0.03 mg/kg/h) or placebo, for up to 14 days. Coprimary end points were treatment failure rate (day 14/discharge) and time on iNO without treatment failure. Secondary end points included time on ventilation and oxygenation measures. RESULTS: Of 87 infants screened, 29 were randomized to IV sildenafil and 30 to placebo; 13 discontinued treatment (sildenafil, n = 6; placebo: n = 7), including 3 deaths (sildenafil: n = 2; placebo: n = 1). Treatment failure rates did not differ with sildenafil (27.6%) vs placebo (20.0%; P = .4935). Mean time on iNO was not different with sildenafil (4.1 days) vs placebo (4.1 days; P = .9850). No differences were noted in secondary end points. Most common adverse events (AEs) with sildenafil (≥10% infants) were hypotension (n = 8/29), hypokalemia (n = 7/29), anemia, drug withdrawal syndrome (n = 4/29, each), and bradycardia (n = 3/29). One serious AE (hypotension) was considered treatment-related. CONCLUSIONS: IV sildenafil added to iNO was not superior to placebo in infants with PPHN or HRF at risk of PPHN. A review of AEs did not identify any pattern of events indicative of a safety concern with IV sildenafil. Infants will have developmental follow-up (Part B). TRIAL REGISTRATION CLINICALTRIALS.GOV: NCT01720524.

Development of a severity scale to assess chronic lung disease after extremely preterm birth.

OBJECTIVE: Chronic lung disease of prematurity (CLDP) is a frequent complication of prematurity. We aimed to identify what clinicians believe are the most important factors determining the severity of CLDP in extremely preterm infants (<28 weeks gestational age) after discharge from the neonatal intensive care unit (NICU) through 12 months corrected age (CA), and to evaluate how these factors should be weighted for scoring, to develop a CLDP severity scale. STUDY DESIGN: Clinicians completed a three-round online survey utilizing Delphi methodology. Clinicians rated the importance of various factors used to evaluate the severity of CLDP, from 0 (not at all important) to 10 (very important) for the period between discharge home from the NICU and 12 months CA. Fourteen factors were considered in Round 1; 13 in Rounds 2 and 3. The relative importance of factors was explored via a set of 16 single-profile tasks (i.e., hypothetical patient profiles with varying CLDP severity levels). RESULTS: Overall, 91 clinicians from 11 countries who were experienced in treating prematurity-related lung diseases completed Round 1; 88 completed Rounds 2 and 3. Based on Round 3, the most important factors in determining CLDP severity were mechanical ventilation (mean absolute importance rating, 8.89), supplemental oxygen ≥2 L/min (8.49), rehospitalizations (7.65), and supplemental oxygen <2 L/min (7.56). Single-profile tasks showed that supplemental oxygen had the greatest impact on profile classification. CONCLUSION: The most important factors for clinicians assigning CLDP severity during infancy were mechanical ventilation, supplemental oxygen ≥2 L/min, and respiratory-related rehospitalizations.

Malnutrition, poor post-natal growth, intestinal dysbiosis and the developing lung.

In extremely preterm infants, poor post-natal growth, intestinal dysbiosis and bronchopulmonary dysplasia are common, and each is associated with long-term complications. The central hypothesis that this review will address is that these three common conditions are interrelated. Challenges to studying this hypothesis include the understanding that malnutrition and poor post-natal growth are not synonymous and that there is not agreement on what constitutes a normal intestinal microbiota in this evolutionarily new population. If this hypothesis is supported, further study of whether "correcting" intestinal dysbiosis in extremely preterm infants reduces postnatal growth restriction and/or bronchopulmonary dysplasia is indicated.

Optimal Oxygen Targets in Term Lambs with Meconium Aspiration Syndrome and Pulmonary Hypertension.

Optimal oxygen saturation as measured by pulse oximetry (SpO2) in neonatal lung injury, such as meconium aspiration syndrome (MAS) and persistent pulmonary hypertension of newborn (PPHN), is not known. Our goal was to determine the SpO2 range in lambs with MAS and PPHN that results in the highest brain oxygen delivery (bDO2) and pulmonary blood flow (Qp) and the lowest pulmonary vascular resistance and oxidative stress. Meconium was instilled into endotracheal tubes in 25 near-term gestation lambs, and the umbilical cord was occluded to induce asphyxia and gasping, causing MAS and PPHN. Lambs were randomized into four groups and ventilated for 6 hours with fixed fraction of inspired oxygen (FiO2) = 1.0 irrespective of SpO2, and three groups had FiO2 titrated to keep preductal SpO2 between 85% and 89%, 90% and 94%, and 95% and 99%, respectively. Tissues were collected to measure nitric oxide synthase activity, 3-nitrotyrosine, and 8-isoprostanes. Throughout the 6-hour exposure period, lambs in the 95-99% SpO2 target group had the highest Qp, lowest pulmonary vascular resistance, and highest bDO2 but were exposed to higher FiO2 (0.5 ± 0.21 vs. 0.29 ± 0.17) with higher lung 3-nitrotyrosine (0.67 [interquartile range (IQR), 0.43-0.73] ng/mcg protein vs. 0.1 [IQR, 0.09-0.2] ng/mcg protein) and lower lung nitric oxide synthase activity (196 [IQR, 192-201] mMol nitrite/mg protein vs. 270 [IQR, 227-280] mMol nitrite/mg protein) compared with the 90-94% target group. Brain 3-nitrotyrosine was lower in the 85-89% target group, and brain/lung 8-isoprostane levels were not significantly different. In term lambs with MAS and PPHN, Qp and bDO2 through the first 6 hours are higher with target SpO2 in the 95-99% range. However, the 90-94% target range is associated with significantly lower FiO2 and lung oxidative stress. Clinical trials comparing the 90-94% versus the 95-99% SpO2 target range in term infants with PPHN are warranted.

Severe Coronavirus Disease-2019 in Children and Young Adults in the Washington, DC, Metropolitan Region.

Despite worldwide spread of severe acute respiratory syndrome coronavirus-2, few publications have reported the potential for severe disease in the pediatric population. We report 177 infected children and young adults, including 44 hospitalized and 9 critically ill patients, with a comparison of patient characteristics between infected hospitalized and nonhospitalized cohorts, as well as critically ill and noncritically ill cohorts. Children <1 year and adolescents and young adults >15 years of age were over-represented among hospitalized patients (P = .07). Adolescents and young adults were over-represented among the critically ill cohort (P = .02).

Intestinal Dysbiosis and the Developing Lung: The Role of Toll-Like Receptor 4 in the Gut-Lung Axis.

Background: In extremely premature infants, postnatal growth restriction (PNGR) is common and increases the risk of developing bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH). Mechanisms by which poor nutrition impacts lung development are unknown, but alterations in the gut microbiota appear to play a role. In a rodent model, PNGR plus hyperoxia causes BPD and PH and increases intestinal Enterobacteriaceae, Gram-negative organisms that stimulate Toll-like receptor 4 (TLR4). We hypothesized that intestinal dysbiosis activates intestinal TLR4 triggering systemic inflammation which impacts lung development. Methods: Rat pups were assigned to litters of 17 (PNGR) or 10 (normal growth) at birth and exposed to room air or 75% oxygen for 14 days. Half of the pups were treated with the TLR4 inhibitor TAK-242 from birth or beginning at day 3. After 14 days, pulmonary arterial pressure was evaluated by echocardiography and hearts were examined for right ventricular hypertrophy (RVH). Lungs and serum samples were analyzed by western blotting and immunohistochemistry. Results: Postnatal growth restriction + hyperoxia increased pulmonary arterial pressure and RVH with trends toward increased plasma IL1ß and decreased IκBα, the inhibitor of NFκB, in lung tissue. Treatment with the TLR4 inhibitor attenuated PH and inflammation. Conclusion: Postnatal growth restriction induces an increase in intestinal Enterobacteriaceae leading to PH. Activation of the TLR4 pathway is a promising mechanism by which intestinal dysbiosis impacts the developing lung.

The Impact of Telemedicine on Transfer Rates of Newborns at Rural Community Hospitals.

BACKGROUND AND OBJECTIVE: Telemedicine may have the ability to reduce avoidable transfers by allowing remote specialists the opportunity to more effectively assess patients during consultations. In this study, we examined whether telemedicine consultations were associated with reduced transfer rates compared to telephone consultations among a cohort of term and late preterm newborns. We hypothesized that neonatologist consultations conducted over telemedicine would result in fewer interfacility transfers than consultations conducted over telephone. METHODS: We collected data on all newborns who received a neonatal telemedicine or telephone consultation at 6 rural hospitals in northern and central California between August 2014 and June 2018. We used adjusted analyses to compare transfer rates between telemedicine and telephone cohorts. RESULTS: A total of 317 patients were included in the analysis; 89 (28.1%) of these patients received a telemedicine consultation and 228 (71.9%) received a telephone consultation only. The overall transfer rate was 77.0%. Patient consultations conducted using telemedicine were significantly less likely to result in a transfer than patient consultations conducted using the telephone (64.0% vs 82.0%, P = .001). After controlling for 5-minute Apgar score, birthweight, gestational age, site of consultation, and Transport Risk Index of Physiologic Stability score, the odds of transfer for telemedicine consultations was 0.48 (95% confidence interval: 0.26, 0.90, P = .02). CONCLUSIONS: Our findings suggest that telemedicine may have the potential to reduce potentially avoidable transfers of term and late preterm newborns. Future research on potentially avoidable transfers and patient outcomes is needed to better understand the ways in which telemedicine affects clinical decision-making.