Defining the Typical Course of Persistent Pulmonary Hypertension of the Newborn: When to Think Beyond Reversible Causes.

OBJECTIVES: To describe the typical clinical course of reversible persistent pulmonary hypertension of the newborn (PPHN) from perinatal etiologies and compare that with the clinical course of PPHN due to underlying fetal developmental etiologies. STUDY DESIGN: This was a single-center, retrospective cohort study of liveborn newborns either born or transferred to our facility for higher level of care between 2015 and 2020 with gestational age ≥35 weeks and a clinical diagnosis of PPHN in the electronic health record. Newborns with complex congenital heart disease and congenital diaphragmatic hernia were excluded. Using all data available at time of collection, newborns were stratified into 2 groups by PPHN etiology - perinatal and fetal developmental causes. Primary outcomes were age at initiation, discontinuation, and total duration of extracorporeal life support, mechanical ventilation, supplemental oxygen, inhaled nitric oxide, inotropic support, and prostaglandin E1. Our secondary outcome was age at echocardiographic resolution of pulmonary hypertension. Groups were compared by t-test. Time-to-event Kaplan Meier curves described and compared (log-rank test) discontinuation of each therapy. RESULTS: Sixty-four (72%) newborns had perinatal etiologies whereas 24 (28%) had fetal developmental etiologies. The resolution of perinatal PPHN was more rapid compared with fetal developmental PPHN. By 10 days of age, more neonates were off inotropes (98% vs 29%, P < .01), decannulated from extracorporeal life support (100% vs 0%, P < .01), extubated (75% vs 37%, P < .01), and had echocardiographic resolution of PH (35% vs 7%, P = .02). CONCLUSIONS: An atypical PPHN course, characterized by persistent targeted therapies in the second week of life, warrants further work-up for fetal developmental causes.

Efficacy and safety of a novel nitric oxide generator for the treatment of neonatal pulmonary hypertension: Experimental and clinical studies.

Persistent pulmonary hypertension of the newborn (PPHN) is a complex pathology resulting from a failure of the post-natal reduction in pulmonary vascular resistance leading to hypoxemia. The standard therapy is inhaled Nitric Oxide (NO) improving oxygenation but its availability is limited, especially in hospitals with restricted financial resources. We evaluated the efficacy and safety of a new device generating NO (TAS + PLUS), in three experimental piglet models of pulmonary hypertension (PH), and we later tested its application in a pilot study of newborn patients suffering from PPHN. Piglets with experimentally induced PH showed a decrease in pulmonary arterial pressure (PAP) after breathing NO. Both acute and chronic exposure of piglets and rats did not cause any adverse effect in blood gas levels and biological parameters. A pilot study including 32 patients suffering from PPHN showed an increase in oxygen saturation (SatO2) and partial pressure of oxygen in arterial blood (PaO2) leading to a decrease of Oxygenation Index (OI) after compassionate treatment with NO from TAS + PLUS device. The device showed effectiveness and safety both in experimental PH and in the clinical setting. Therefore, it represents an excellent alternative for PPHN management in conditions where commercial NO is unavailable.

Randomized controlled trial of early compared with delayed use of inhaled nitric oxide in newborns with a moderate respiratory failure and pulmonary hypertension.

OBJECTIVE: To evaluate whether early treatment with inhaled nitric oxide (iNO) will prevent newborns with moderate respiratory failure from developing severe hypoxemic respiratory failure (oxygenation index (OI)>or=40). STUDY DESIGN: A total of 56 newborns with moderate respiratory failure (OI between 10 and 30) were randomized before 48 h after birth to early treatment with 20 p.p.m. of iNO (Early iNO group, n=28) or conventional mechanical ventilation with FiO(2) 1.0 (Control group, n=28). Infants received iNO and/or high-frequency oscillatory ventilation (HFOV) if they developed an OI>40. RESULT: 7 of 28 early iNO patients (25%) compared to 17 of 28 control patients (61%) developed an OI>40 (P<0.05). In the Early iNO group mean OI significantly decreased from 22 (baseline) to 19 at 4 h (P<0.05) and remained lower over time: 19 (12 h), 18 (24 h) and 16 at 48 h. In contrast, OI increased in the Control group and remained significantly higher than the Early iNO group during the first 48 h of study: 22 (baseline), 29, 35, 32 and 23 at 4, 12, 24 and 48 h, respectively (P<0.01). Of 17, 6 control patients who developed an OI>40 were successfully treated with iNO. Nine of the remaining eleven control patients and six of seven Early iNO patients who had an OI>40 despite use of iNO responded with the addition of HFOV. One patient of the Early iNO group and two of the Control group died. Median (range) duration of oxygen therapy was significantly shorter in the Early iNO group: 11.5 (5 to 90) days compared to 18 (6 to 142) days of the Control group (P<0.03). CONCLUSION: Early use of iNO in newborns with moderate respiratory failure improves oxygenation and decreases the probability of developing severe hypoxemic respiratory failure.

ABCA3 deficiency presenting as persistent pulmonary hypertension of the newborn.

A newborn with persistent pulmonary hypertension (PH) unresponsive to conventional therapies was found to be homozygous for a mutation in the gene encoding adenosine triphosphate binding cassette protein, member A3 (ABCA3). Most causes of PH respond to lung recruitment, inhaled nitric oxide, and hemodynamic support. When PH is prolonged and does not respond to standard therapies, genetic causes of surfactant abnormalities should be considered in the differential diagnosis.

Planejamento do cuidado de enfermagem para recém-nascidos em terapia de óxido nítrico / Planning of nursing care for newborn infants in therapy of nitric oxide

Nós enfermeiras especialistas em Neonatologia começamos a refletir sobre uma prática do nosso cotidiano, que é a terapia de óxido nítrico inalatório em recém-nascido. Devido à ampliação do uso do óxido nítrico inalatório no tratamento da hipertensão pulmonar persistente neonatal, juntamente com a escassez de trabalhos científicos nacionais sobre os cuidados de enfermagem prestados a recém-nascidos submetidos a esta terapia, sentimos a necessidade de realizar este estudo que tem como objetivo, apresentar os principais cuidados de enfermagem relacionados ao preparo, instalação e utilização do óxido nítrico inalatório e justificá-los baseadas na literatura pesquisada. Concluímos que a enfermeira neonatologista tem papel fundamental no tratamento do recém-nascido com óxido nítrico inalatório, devendo conhecer a utilização correta do equipamento e os principais cuidados de enfermagem a serem prestados, visando o atendimento adequado ao recém-nascido.

Neurodevelopmental and medical outcomes of persistent pulmonary hypertension in term newborns treated with nitric oxide.

OBJECTIVE: To determine the medical and neurodevelopmental outcome of children with moderately severe persistent pulmonary hypertension of the newborn (PPHN) treated with or without inhaled nitric oxide (I-NO). STUDY DESIGN: Term infants with PPHN and a baseline oxygenation index of 24 +/- 9 at study entry were randomly assigned to early treatment with placebo or initial doses of I-NO (5, 20, and 80 ppm). Outcome was measured at approximately 1 year by frequency of hospitalization, growth, and neurodevelopmental and audiologic evaluation. RESULTS: Of 155 children enrolled, 144 survived, and there was follow-up for 133. No significant differences between the placebo and the I-NO groups were seen in any long-term outcome. Rehospitalization occurred in 22%, and growth did not differ. The composite neurodevelopment and audiologic outcome showed impairment in 46% of the infants. There were major neurologic abnormalities in 13%, cognitive delays in 30%, and hearing loss in 19% of the infants. CONCLUSIONS: Moderately severe PPHN at 24 hours after birth is associated with high rates of rehospitalization and disability at 1 year. Adverse outcomes were the same in I-NO and control groups.

The effect of inhaled nitric oxide therapy on bleeding time and platelet aggregation in neonates.

The effect of inhaled nitric oxide (iNO) on bleeding time and platelet aggregation was studied in nine newborn infants with resolving pulmonary hypertension. Infants treated with iNO at 40 ppm for 30 minutes had bleeding times that were nearly twofold longer than those obtained 24 hours after iNO was discontinued. iNO had no effect on in vitro platelet aggregation studies.

Randomized, multicenter trial of inhaled nitric oxide and high-frequency oscillatory ventilation in severe, persistent pulmonary hypertension of the newborn.

BACKGROUND: Although inhaled nitric oxide (iNO) causes selective pulmonary vasodilation and improves oxygenation in newborn infants with persistent pulmonary hypertension, its effects are variable. We hypothesized (1) that the response to iNO therapy is dependent on the primary disease associated with persistent pulmonary hypertension of the newborn (PPHN) and (2) that the combination of high-frequency oscillatory ventilation (HFOV) with iNO would be efficacious in patients for whom either therapy alone had failed. METHODS: To determine the relative roles of iNO and HFOV in the treatment of severe PPHN, we enrolled 205 neonates in a randomized, multicenter clinical trial. Patients were stratified by predominant disease category: respiratory distress syndrome (n = 70), meconium aspiration syndrome (n = 58), idiopathic PPHN or pulmonary hypoplasia (excluding congenital diaphragmatic hernia) ("other": n = 43), and congenital diaphragmatic hernia (n = 34); they were then randomly assigned to treatment with iNO and conventional ventilation or to HFOV without iNO. Treatment failure (partial pressure of arterial oxygen [PaO2] < 60 mm Hg) resulted in crossover to the alternative treatment; treatment failure after crossover led to combination treatment with HFOV plus iNO. Treatment response with the assigned therapy was defined as sustained PaO2 of 60 mm Hg or greater. RESULTS: Baseline oxygenation index and PaO2 were 48 +/- 2 and 41 +/- 1 mm Hg, respectively, during treatment with conventional ventilation. Ninety-eight patients were randomly assigned to initial treatment with HFOV, and 107 patients to iNO. Fifty-three patients (26%) recovered with the initially assigned therapy without crossover (30 with iNO [28%] and 23 with HFOV [23%]; p = 0.33). Within this group, survival was 100% and there were no differences in days of mechanical ventilation, air leak, or supplemental oxygen requirement at 28 days. Of patients whose initial treatment failed, crossover treatment with the alternate therapy was successful in 21% and 14% for iNO and HFOV, respectively (p = not significant). Of 125 patients in whom both treatment strategies failed, 32% responded to combination treatment with HFOV plus iNO. Overall, 123 patients (60%) responded to either treatment alone or combination therapy. By disease category, response rates for HFOV plus iNO in the group with respiratory syndrome and the group with meconium aspiration syndrome were better than for HFOV alone or iNO with conventional ventilation (p < 0.05). Marked differences in outcomes were noted among centers (percent death or treatment with extracorporeal membrane oxygenation = 29% to 75%). CONCLUSIONS: We conclude that treatment with HFOV plus iNO is often more successful than treatment with HFOV or iNO alone in severe PPHN. Differences in responses are partly related to the specific disease associated with PPHN.

Inhaled nitric oxide enhances oxygenation but not survival in infants with alveolar capillary dysplasia.

A complex vascular abnormality in the lungs, termed alveolar capillary dysplasia (ACD) and misalignment of the lung vessels, has been recently recognized in some infants with persistent pulmonary hypertension. These infants die despite maximal medical support including extracorporeal membrane oxygenation (ECMO). Inhaled nitric oxide has been reported to improve oxygenation in neonates with persistent pulmonary hypertension of the newborn, and may allow some infants to avoid the need for ECMO. We identified five infants who had received inhaled nitric oxide to treat refractory hypoxemia caused by persistent pulmonary hypertension of the newborn, and who subsequently died and had autopsy confirmation of ACD. Each infant received care at a different medical center. In each patient, inhaled NO increased the arterial partial pressure of oxygen dramatically. Despite initial clinical improvement, the response to NO was not sustained in any patient. As responsiveness was lost, each infant with ACD required inhaled NO concentrations of 80 ppm or higher to sustain oxygenation. Each infant died, four after extensive periods of ECMO support. This experience demonstrates that a short-term improvement after inhalation of nitric oxide does not lead to long-term survival in ACD. Further, in three infants the diagnosis of ACD was established by lung biopsy before death. Increasing awareness of this clinical entity may allow for the avoidance of costly, invasive procedures such as ECMO until more specific therapies become available.

Neutrophil and cytokine activation with neonatal extracorporeal membrane oxygenation.

OBJECTIVE: To determine whether extracorporeal membrane oxygenation (ECMO), like cardiopulmonary bypass, produces systemic inflammatory responses that could potentiate organ injury in infants with respiratory failure. STUDY DESIGN: We evaluated the effects of neonatal ECMO on neutrophil surface adherence proteins, elastase release, and cytokine levels in blood samples from 15 patients before and during ECMO, and from banked blood and ECMO circuit blood before cannulation. Neutrophil elastase, tumor necrosis factor alpha, and interleukin types 1 beta, 6, and 8 were measured. Chest radiographs were evaluated by a radiologist using a lung injury score in blinded fashion. RESULTS: Primed ECMO circuit blood, in comparison with patient pre-ECMO blood, demonstrated marked up-regulation of CD11b (mean fluorescence intensity 1660 +/- 109 vs 361 +/- 81; p < 0.001 (mean +/- SEM)), shedding of L-selectin (mean fluorescence intensity 10 +/- 2 vs 89 +/- 38; p < 0.01), and elevated elastase levels (349 +/- 76 vs 154 ng/ml +/- 38; p < 0.001), consistent with neutrophil activation. During ECMO, neutrophil CD11b levels increased but L-selectin was not significantly shed. Concentrations of circulating neutrophil elastase increase significantly during ECMO. Corrected circulating quantities of interleukin-8 also rose significantly, but the responses of tumor necrosis factor alpha and interleukin-1 beta were minimal. Radiographic lung injury scores worsened with the initiation of ECMO (median score: 6 before ECMO vs 11 in first hour of ECMO; p = 0.012), in conjunction with indicators of neutrophil activation. CONCLUSION: Neonates with respiratory failure have activation of the inflammatory cascade. ECMO incites additional neutrophil and cytokine activation in association with early pulmonary deterioration. Routine leukodepletion of blood for circuit priming to remove activated neutrophils may be beneficial.

Sulfato de magnesio como alternativa de manejo de hipertensión pulmonar persistente del recién nacido: informe de tres casos / Magnesium sulphate an alternative treatment of persistent pulmonary hypertension of thenewborn: a three case report

Introducción. La hipertención pulmonar persistente del recién nacido es producto de una falla en la adaptación de la circulación pulmonar a la vida postnatal. El tratamiento de este padecimiento comprende soporte ventilatorio, cardiovascular, alcalinización, sedación, relajación neuromuscular y uso de vasodilatadores pulmonares. El magnesio, antagonista natural del calcio, actúa como relajante muscular, sedante y vasodilatador. Casos cínicos. Se presentan los resultados de su uso en 3 neonatos con mortalidad predicha del 80 al 100 por ciento, La dosis empleada de sulfato de magnesio, fue de 200 mg/kg/durante 30 minutos seguida de infusión continua de 20 a 50 mg/kg/hora por 72 horas. Conclusion. La mejoría clínica, gasométrica y en índices ventilatorios de estos pacientes, así como sobrevida sin evidencia de complicaciones metabólicas plantean la necesidad de estudios prospectivos para apoyar su utilidad como elemento terapéutico en la hipertensión pulmonar persistente

Plasma cysteine concentrations in infants with respiratory distress.

Because factors that predispose infants to persistent pulmonary hypertension of the newborn (PPHN) may cause oxidant stress, which in turn may increase demands for cysteine and glutathione, we investigated the availability of cysteine and its precursors in PPHN and related disorders. Plasma concentrations of four sulfur-containing and two non-sulfur-containing amino acids were measured by gas chromatography-mass spectrometry in blood from infants with PPHN, both those managed conventionally (PPHN group) and those treated with extracorporeal membrane oxygenation, as well as from infants with hyaline membrane disease. Concentrations also were measured in umbilical venous cord blood samples from a healthy control population, in venous plasma from infants receiving only intravenously administered glucose-containing solutions because they had noncardiopulmonary illnesses ("fasted" group), and from otherwise healthy, orally fed infants ("fed" group). The plasma total cyst(e)ine concentration was markedly lower in the three groups (PPHN, PPHN and extracorpeal membrane oxygenation, and hyaline membrane disease) receiving an elevated inspired oxygen concentration (0.6 to 1.0) than in fasted or fed control infants. In contrast, levels of plasma methionine, the other major sulfur amino acid, were low in the three groups receiving an elevated inspired oxygen concentration, as well as in fasted infants. Glycine and serine, two non-sulfur-containing amino acids, had a pattern similar to that of plasma methionine. Thus infants with PPHN and hyaline membrane disease have low plasma total cyst(e)ine levels, an effect that does not appear to result primarily from nutritional deprivation. We speculate that the role of cysteine in bioactivation of nitric oxide and as a precursor of glutathione may be relevant to the pathogenesis and evolution of PPHN and respiratory distress syndrome. Further studies are needed to determine whether increased demands for cysteine exist in these disorders.

Persistent pulmonary hypertension in newborn infants with cogenital myotonic dystrophy.

We describe two infants with congenital myotonic dystrophy that was complicated by persistent pulmonary hypertension. Both infants died of respiratory insufficiency that was unresponsive to ventilatory and pharmacologic support. One of the two infants was supported with extracorporeal membrane oxygenation before the diagnosis of congenital myotonic dystrophy was made.

Early-onset respiratory failure caused by severe congenital neuromuscular disease.

Two unrelated infants with low Apgar scores, pneumothoraces, and severe pulmonary hypertension were treated with extracorporeal membrane oxygenation while receiving chemical sedation and neuromuscular paralysis. After decannulation from extracorporeal membrane oxygenation, hypotonia and hypoventilation persisted. Neurologic evaluation confirmed that both infants had a congenital myopathy.

Inhaled nitric oxide in infants referred for extracorporeal membrane oxygenation: dose response.

To determine the role of inhaled nitric oxide (NO) in a population of critically ill hypoxic near-term infants and to determine the dose response to inhaled NO, we examined a consecutive group of 23 infants referred for neonatal extracorporeal membrane oxygenation (ECMO) who had an oxygen index of 20 or greater after treatment with bovine surfactant. Inhaled NO was administered in concentrations from 5 to 80 ppm in random order to 23 infants. Overall, 13 infants had a significant response (an improvement in arterial oxygen pressure > 10 mm Hg or arterial oxygen saturation > 10%) to the first administration of inhaled NO, and one infant had a late response. There was no significant difference in the response to inhaled NO as measured by changes in arterial oxygen pressure or in the alveolar-arterial difference in partial pressure of oxygen, for any of the doses from 5 to 80 ppm. Thirteen infants had echocardiographic evidence of persisted pulmonary hypertension; 11 of these infants responded, compared with 3 responders among the 10 infants without persistent pulmonary hypertension of the newborn (p < 0.01). Overall, 11 infants required ECMO; there were two deaths in this group. Seven infants had congenital diaphragmatic hernia; five of those had a response to NO inhalation and four required ECMO. Our study demonstrates that there is no significant difference in response between low and high doses of inhaled NO and that this treatment may prevent the need for ECMO in some infants referred for this therapy, especially in infants with pulmonary hypertension. Prospective, controlled, randomized, and blinded trials of low doses of inhaled NO are needed to determine the clinical role of this potentially useful therapy.

Early changes in the neonatal circulatory transition.

To define the course of neonatal circulatory transition and to identify clinically relevant echocardiographic measurements in the diagnosis of persistent pulmonary hypertension, we prospectively studied 32 healthy term infants from 30 minutes to 24 hours after birth with color and quantitative Doppler echocardiography on the first day of life, and compared them with 33 term infants supported by mechanical ventilation for respiratory failure. Color Doppler imaging included measurements of cardiac output, left pulmonary artery flow, aortopulmonary pressure difference, ductal flow, left-to-right color-flow jet area of the ductus arteriosus, and ductal flow characteristics. In healthy infants the majority of measurable changes in cardiopulmonary hemodynamics had occurred by 8 hours after birth, although some degree of right-to-left ductal shunting was found up to 12 hours after birth. In the infants with respiratory failure, ductal flow and maximum aortopulmonary pressure difference measurements at 8, 12, and 24 hours showed a significant delay in ductal closure and a high incidence of persistent pulmonary hypertension, which correlated well with the severity of their respiratory failure. Factors such as aortopulmonary pressure difference, prolonged right-to-left shunting with decreased left pulmonary artery flow, and failure to develop a left-to-right ductal color-flow jet were found to be practical markers for assessing the course of neonatal circulatory transition in sick term infants.