Steven H. Abman

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

Abstract 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 [Pa on 2 ] <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 Pa on 2 of 60 mm Hg or greater. Results: Baseline oxygenation index and Pa on 2 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 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. (J Pediatr 1997;131:55-62)

Variable expression of endothelial NO synthase in three forms of rat pulmonary hypertension

Endothelial nitric oxide (NO) synthase (eNOS) mRNA and protein and NO production are increased in hypoxia-induced hypertensive rat lungs, but it is uncertain whether eNOS gene expression and activity are increased in other forms of rat pulmonary hypertension. To investigate these questions, we measured eNOS mRNA and protein, eNOS immunohistochemical localization, perfusate NO product levels, and NO-mediated suppression of resting vascular tone in chronically hypoxic (3-4 wk at barometric pressure of 410 mmHg), monocrotaline-treated (4 wk after 60 mg/kg), and fawn-hooded (6-9 mo old) rats. eNOS mRNA levels (Northern blot) were greater in hypoxic and monocrotaline-treated lungs (130 and 125% of control lungs, respectively; P < 0.05) but not in fawn-hooded lungs. Western blotting indicated that eNOS protein levels increased to 300 +/- 46% of control levels in hypoxic lungs (P < 0.05) but were decreased by 50 +/- 5 and 60 +/- 11%, respectively, in monocrotaline-treated and fawn-hooded lungs (P < 0.05). Immunostaining showed prominent eNOS expression in small neomuscularized arterioles in all groups, whereas perfusate NO product levels increased in chronically hypoxic lungs (3.4 +/- 1.4 microM; P < 0.05) but not in either monocrotaline-treated (0.7 +/- 0.3 microM) or fawn-hooded (0.45 +/- 0.1 microM) lungs vs. normotensive lungs (0.12 +/- 0.07 microM). All hypertensive lungs had increased baseline perfusion pressure in response to nitro-L-arginine but not to the inducible NOS inhibitor aminoguanidine. These results indicate that even though NO activity suppresses resting vascular tone in pulmonary hypertension, there are differences among the groups regarding eNOS gene expression and NO production. A better understanding of eNOS gene expression and activity in these models may provide insights into the regulation of this vasodilator system in various forms of human pulmonary hypertension.Endothelial nitric oxide (NO) synthase (eNOS) mRNA and protein and NO production are increased in hypoxia-induced hypertensive rat lungs, but it is uncertain whether eNOS gene expression and activity are increased in other forms of rat pulmonary hypertension. To investigate these questions, we measured eNOS mRNA and protein, eNOS immunohistochemical localization, perfusate NO product levels, and NO-mediated suppression of resting vascular tone in chronically hypoxic (3-4 wk at barometric pressure of 410 mmHg), monocrotaline-treated (4 wk after 60 mg/kg), and fawn-hooded (6-9 mo old) rats. eNOS mRNA levels (Northern blot) were greater in hypoxic and monocrotaline-treated lungs (130 and 125% of control lungs, respectively; P < 0.05) but not in fawn-hooded lungs. Western blotting indicated that eNOS protein levels increased to 300 ± 46% of control levels in hypoxic lungs ( P < 0.05) but were decreased by 50 ± 5 and 60 ± 11%, respectively, in monocrotaline-treated and fawn-hooded lungs ( P < 0.05). Immunostaining showed prominent eNOS expression in small neomuscularized arterioles in all groups, whereas perfusate NO product levels increased in chronically hypoxic lungs (3.4 ± 1.4 μM; P < 0.05) but not in either monocrotaline-treated (0.7 ± 0.3 μM) or fawn-hooded (0.45 ± 0.1 μM) lungs vs. normotensive lungs (0.12 ± 0.07 μM). All hypertensive lungs had increased baseline perfusion pressure in response to nitro-l-arginine but not to the inducible NOS inhibitor aminoguanidine. These results indicate that even though NO activity suppresses resting vascular tone in pulmonary hypertension, there are differences among the groups regarding eNOS gene expression and NO production. A better understanding of eNOS gene expression and activity in these models may provide insights into the regulation of this vasodilator system in various forms of human pulmonary hypertension.

Endothelial Colony-forming Cells from Preterm Infants Are Increased and More Susceptible to Hyperoxia

RATIONALEnPreterm birth and hyperoxic exposure increase the risk for bronchopulmonary dysplasia (BPD), a chronic lung disease characterized by impaired vascular and alveolar growth. Endothelial progenitor cells, such as self-renewing highly proliferative endothelial colony-forming cells (ECFCs), may participate in vascular repair. The effect of hyperoxia on ECFC growth is unknown.nnnOBJECTIVESnWe hypothesize that umbilical cord blood (CB) from premature infants contains more ECFCs with greater growth potential than term CB. However, preterm ECFCs may be more susceptible to hyperoxia.nnnMETHODSnECFC colonies were quantified by established methods and characterized by immunohistochemistry and flow cytometry. Growth kinetics were assessed in room air and hyperoxia (FI(O(2)) = 0.4).nnnMEASUREMENTS AND MAIN RESULTSnPreterm CB (28-35 wk gestation) yielded significantly more ECFC colonies than term CB. Importantly, we found that CD45(-)/CD34(+)/CD133(+)/VEGFR-2(+) cell number did not correlate with ECFC colony count. Preterm ECFCs demonstrated increased growth compared with term ECFCs. Hyperoxia impaired growth of preterm but not term ECFCs. Treatment with superoxide dismutase and catalase enhanced preterm ECFC growth during hyperoxia.nnnCONCLUSIONSnPreterm ECFCs appear in increased numbers and proliferate more rapidly but have an increased susceptibility to hyperoxia compared with term ECFCs. Antioxidants protect preterm ECFCs from hyperoxia.

Impaired Vascular Endothelial Growth Factor Signaling in the Pathogenesis of Neonatal Pulmonary Vascular Disease

Abstract Of diverse growth factors that contribute to normal lung development, vascular endothelial growth factor (VEGF) plays an especially prominent role in the normal growth and development of the pulmonary circulation in the fetus and newborn. Strong experimental and clinical data support the role of impaired VEGF signaling in the pathogenesis of two major clinical disorders of the developing lung circulation: persistent pulmonary hypertension of the newborn (PPHN) and bronchopulmonary dysplasia (BPD). These disorders are each characterized by impaired vascular growth, structure and reactivity, which are at least partly due to endothelial cell dysfunction. This chapter will briefly discuss VEGF signaling during normal lung development and how disruption of VEGF signaling contribute to the pathogenesis of neonatal pulmonary vascular disease in these settings.

Role of Endothelin Receptor Antagonists in the Treatment of Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a severe disease with marked morbidity and mortality for which therapeutic strategies have been limited. Basic research in vascular biology has implicated endothelin-1 (ET-1) and its receptors (ET(A) and ET(B)) in diverse preclinical models of PAH, and ET-1 has been shown to contribute significantly to PAH in human patients. Despite the complexity of roles of the ET receptors in the development or reversal of PAH in the laboratory, the introduction of endothelin receptor antagonists (ETRAs) to clinical medicine has substantially expanded our therapeutic approach toward severe PAH. This article briefly reviews preclinical data and the current status of ETRAs in the clinical management of PAH.

Experience with Home Oxygen in the Management of Infants with Bronchopulmonary Dysplasia

We followed the clinical course of 23 infants with bronchopulmonary dysplasia (BPD) on home oxygen therapy during the first year of life in order to monitor patterns of growth, need for hospital readmission, and improvement in oxygenation. Oxygenation was assessed by serial, resting, awake, and room air transcutaneous PO2 (tcPO2) measurements at clinic visits. Weight gain was poor, with boys growing below the fifth percentile and girls growing at the tenth percentile. Ten of the 23 infants (43%) required rehospitalizations. There were no deaths. Fourteen of the 23 infants (61%) were taken off supplemental oxygen by 12 months corrected age, at a mean age of 7.9 months. Mean rate of improvement in tcPO2 was 3 torr/month, but wide individual variation was found. Infants off of oxygen treatment at 12 months corrected age grew at a significantly greater rate than those still requiring oxygen supplementation (p < 0.02). Infants with right ventricular hypertrophy (RVH) by electrocardiogram tended to resolve their RVH while on home oxygen therapy. We conclude that infants with BPD on home oxygen therapy generally show steady improvement in oxygenation, but grow poorly and require frequent hospitalizations.

Interdisciplinary Care of Children with Severe Bronchopulmonary Dysplasia

Recommended Citation Abman, S. H., Collaco, J. M., Shepherd, E. G., Keszler, M., Cuevas-Guaman, M., Welty, S. E., Truog, W. E., McGrath-Morrow, S. A., Moore, P. E., Rhein, L. M., Kirpalani, H., Zhang, H., Gratny, L. L., Lynch, S. K., Curtiss, J., Stonestreet, B. S., McKinney, R. L., Dysart, K. C., Gien, J., Baker, C. D., Donohue, P. K., Austin, E., Fike, C., Nelin, L. D., . Interdisciplinary Care of Children with Severe Bronchopulmonary Dysplasia. The Journal of pediatrics 181, 12-28 (2017).

Reversal of Pulmonary Hypertension Associated with Plexiform Lesions in Congenital Heart Disease: A Case Report

We describe a 2-year-old child with severe pulmonary hypertension due to a patent ductus arteriosus (PDA) with plexiform lesions on lung biopsy. Despite high basal pulmonary vascular resistance with minimal responsiveness to inhaled nitric oxide and other vasodilators, and advanced plexogenic arteriopathy on lung biopsy, her pulmonary hypertension completely resolved after PDA ligation and during 8 years of follow-up.

Characterization of CMR-derived haemodynamic data in children with pulmonary arterial hypertension

AimsnPaediatric pulmonary arterial hypertension (PAH) is manifested as increased arterial pressure and vascular resistive changes followed by progressive arterial stiffening. The aim of this study was to characterize regional flow haemodynamic patterns and markers of vascular stiffness in the proximal pulmonary arteries of paediatric PAH patients, and to explore the association with right ventricular (RV) function.nnnMethods and resultsnForty paediatric PAH patients and 26 age- and size-matched controls underwent cardiac magnetic resonance studies in order to compute time-resolved wall shear stress metrics, oscillatory shear index (OSI), and vascular strain as measured by relative area change (RAC), and RV volumetric and functional parameters. Phase-contrast imaging planes were positioned perpendicular to the mid-main and right pulmonary arteries (MPA and RPA, respectively). Compared with controls, the PAH group had decreased systolic wall shear stress (dyne cm-2) and RAC (%) in both MPA (WSSsys: 6.5 vs. 4.3, P < 0.0001; RAC: 36 vs. 25, P < 0.0001) and RPA (WSSsys: 11.2 vs. 7.3, P < 0.0001; strain: 37 vs. 30, P < 0.05). The OSI was significantly higher in the MPA of PAH subjects (0.46 vs. 0.17, P < 0.05). WSS measured in the MPA correlated positively with RAC (r = 0.63, P < 0.0001) and RV ejection fraction (%) (r = 0.63, P < 0.0001).nnnConclusionnWall shear stress, the principal haemodynamic force driving endothelial functional changes, is severely decreased in paediatric PAH patients and correlates with increased stiffness in the proximal pulmonary vasculature and reduced RV function.

Nitric Oxide and Endothelin in the Developing Pulmonary Circulation: Physiologic and Clinical Implications

Within minutes after birth, pulmonary vascular resistance (PVR) rapidly falls from high fetal levels. This allows pulmonary blood flow to increase nearly tenfold and enables the lung to assume its postnatal role in gas exchange. Failure of the pulmonary circulation to successfully achieve and sustain this decrease in PVR causes severe hypoxemia in many neonatal cardiopulmonary disorders, which are referred to as the syndrome persistent pulmonary hypertension of the newborn (PPHN). Mechanisms leading to severe pulmonary hypertension after birth are poorly understood, but they include altered pulmonary vascular reactivity and structure. Persistent pulmonary hypertension of the newborn is a major clinical problem, contributing substantially to morbidity and mortality in both full-term and premature neonates. An understanding of basic mechanisms that underlie normal development of the pulmonary circulation in utero and that contribute to the marked pulmonary vasodilation during the normal transition at birth may provide insight into PPHN and related disorders.