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.

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.

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.

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.

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.

Oxygen and pulmonary vasodilation: The role of oxidative and nitrosative stress.

Respiratory failure complicates up to 2% of live births and contributes significantly to neonatal morbidity and mortality. Under these conditions, supplemental oxygen is required to support oxygen delivery to the brain and other organs, and to prevent hypoxic pulmonary vasoconstriction. However, therapeutic oxygen is also a source of reactive oxygen species that produce oxidative stress, along with multiple intracellular systems that contribute to the production of free radicals in pulmonary endothelium and vascular smooth muscle. These free radicals cause vasoconstriction, act on multiple sites of the nitric oxide pathway to reduce cGMP-mediated vasodilation, and nitrate and inactivate essential proteins such as surfactant. In addition to oxygen, antenatal stressors such as placental insufficiency, maternal diabetes, and fetal growth restriction increase pulmonary and vascular oxidant stress and may amplify the adverse effects of oxygen. Moreover, the effects of free radical damage may extend well beyond infancy as suggested by the increased risk of childhood malignancy after neonatal exposure to hyperoxia. Antioxidant therapy is theoretically promising, but there are not yet clinical trials to support this approach. Targeting the abnormal sources of increased oxidant stress that trigger abnormal pulmonary vascular responses may be more effective in treating disease and preventing long term consequences.

The developing gut-lung axis: postnatal growth restriction, intestinal dysbiosis, and pulmonary hypertension in a rodent model.

BACKGROUND: Postnatal growth restriction (PNGR) in premature infants increases risk of pulmonary hypertension (PH). In a rodent model, PNGR causes PH, while combining PNGR and hyperoxia increases PH severity. We hypothesized that PNGR causes intestinal dysbiosis and that treatment with a probiotic attenuates PNGR-associated PH. METHOD: Pups were randomized at birth to room air or 75% oxygen (hyperoxia), to normal milk intake (10 pups/dam) or PNGR (17 pups/dam), and to probiotic Lactobacillus reuteri DSM 17938 or phosphate-buffered saline. After 14 days, PH was assessed by echocardiography and right ventricular hypertrophy (RVH) was assessed by Fulton's index (right ventricular weight/left ventricle + septal weight). The small bowel and cecum were analyzed by high-throughput 16S ribosomal RNA gene sequencing. RESULTS: PNGR with or without hyperoxia (but not hyperoxia alone) altered the microbiota of the distal small bowel and cecum. Treatment with DSM 17938 attenuated PH and RVH in pups with PNGR, but not hyperoxia alone. DSM 17938 treatment decreased α-diversity. The intestinal microbiota differed based on oxygen exposure, litter size, and probiotic treatment. CONCLUSION: PNGR causes intestinal dysbiosis and PH. Treatment with DSM 17938 prevents PNGR-associated RVH and PH. Changes in the developing intestine and intestinal microbiota impact the developing lung vasculature and RV.

Late Rescue Collaborative: Reducing Non-ICU Arrests.

OBJECTIVE: To reduce the frequency of non-ICU arrests through the implementation of an intramural collaborative focused on patient deterioration. DESIGN: Prospective quality improvement project. SETTING: Single-center, free-standing, tertiary children's hospital. PATIENTS: All patients admitted to acute care units. INTERVENTIONS: The Late Rescue Collaborative was formed in 2014 to monitor compliance with hospital escalation protocols and evaluate episodes of patient deterioration. The collaborative is a multidisciplinary team of physicians, nurses, and respiratory care providers. Three monthly meetings occur: 1) individual acute care unit-based meetings to evaluate trends and performance; 2) hospital-wide multidisciplinary whole group meetings to review hospital trends in deterioration and share lessons learned; and 3) steering committee to determine areas of focus. Based on these three meetings, unit- and hospital-based interventions have been put in place to improve recognition of deterioration and promote early rescue. MEASUREMENTS AND MAIN RESULTS: Rates of rapid response team activations, unplanned transfers, and non-ICU arrest are reported. Non-ICU arrest rates fell from a baseline of 0.31 per 1,000 non-ICU patient days to a new centerline of 0.11 and sustained for 36 months. Days between non-ICU arrests increased from a baseline of 15.5 days in year 2014 to a new centerline of 61.5 days and sustained for 37 months. Mortality following non-ICU arrests fell from four in 2014 and 2015 to zero in years 2016-2018. CONCLUSION: The Late Rescue Collaborative is an effective tool to improve patient safety by reducing non-ICU arrests.

Bronchopulmonary dysplasia.

In the absence of effective interventions to prevent preterm births, improved survival of infants who are born at the biological limits of viability has relied on advances in perinatal care over the past 50 years. Except for extremely preterm infants with suboptimal perinatal care or major antenatal events that cause severe respiratory failure at birth, most extremely preterm infants now survive, but they often develop chronic lung dysfunction termed bronchopulmonary dysplasia (BPD; also known as chronic lung disease). Despite major efforts to minimize injurious but often life-saving postnatal interventions (such as oxygen, mechanical ventilation and corticosteroids), BPD remains the most frequent complication of extreme preterm birth. BPD is now recognized as the result of an aberrant reparative response to both antenatal injury and repetitive postnatal injury to the developing lungs. Consequently, lung development is markedly impaired, which leads to persistent airway and pulmonary vascular disease that can affect adult lung function. Greater insights into the pathobiology of BPD will provide a better understanding of disease mechanisms and lung repair and regeneration, which will enable the discovery of novel therapeutic targets. In parallel, clinical and translational studies that improve the classification of disease phenotypes and enable early identification of at-risk preterm infants should improve trial design and individualized care to enhance outcomes in preterm infants.

Drugs for the Prevention and Treatment of Bronchopulmonary Dysplasia.

Rates of bronchopulmonary dysplasia (BPD) are increasing. After preterm birth, there are important developmental periods in which neonates are more vulnerable to stressful events. These periods are opportunities for pharmacologic interventions. Many drugs remain inadequately tested and no new drugs have been approved in more than 25 years for BPD prevention or therapy. More progress is needed in defining appropriate end points based on the pathophysiology of BPD and postdischarge chronic pulmonary insufficiency of prematurity and to develop effective new drugs. In addition, much work is needed to better define perinatal factors, early postnatal findings, and physiologic phenotypes or endotypes.

Optimal oxygenation and role of free radicals in PPHN.

Effective ventilation of the lungs is essential in mediating pulmonary vasodilation at birth to allow effective gas exchange and an increase in systemic oxygenation. Unsuccessful transition prevents the increase in pulmonary blood flow after birth resulting in hypoxemia and persistent pulmonary hypertension of the newborn (PPHN). Management of neonates with PPHN includes ventilation of the lungs with supplemental oxygen to correct hypoxemia. Optimal oxygenation should meet oxygen demand to the tissues and avoid hypoxic pulmonary vasoconstriction (HPV) while preventing oxidative stress. The optimal target for oxygenation in PPHN is not known. Animal models have demonstrated that PaO2<45 mmHg exacerbates HPV. However, there are no practical methods of assessing oxygen levels associated with oxidant stress. Oxidant stress can be due to free radical generation from underlying lung disease or from free radicals generated by supplemental oxygen. Free radicals act on the nitric oxide pathway reducing cGMP and promoting pulmonary vasoconstriction. Antioxidant therapy improves systemic oxygenation in an animal model of PPHN but there are no clinical trials to support such therapy. Targeting preductal SpO2 between 90 and 97% and PaO2 at 50-80 mmHg appears prudent in PPHN but clinical trials to support this practice are lacking. Preterm infants with PPHN present unique challenges due to lack of antioxidant defenses and functional and structural immaturity of the lungs. This review highlights the need for additional studies to mitigate the impact of oxidative stress in the lung and pulmonary vasculature in PPHN.