Diagnosis and treatment of pulmonary hypertension in infancy

Normal pulmonary vascular development in infancy requires maintenance of low pulmonary vascular resistance after birth, and is necessary for normal lung function and growth. The developing lung is subject to multiple genetic, pathological and/or environmental influences that can adversely affect lung adaptation, development, and growth, leading to pulmonary hypertension. New classifications of pulmonary hypertension are beginning to account for these diverse phenotypes, and or pulmonary hypertension in infants due to PPHN, congenital diaphragmatic hernia, and bronchopulmonary dysplasia (BPD). The most effective pharmacotherapeutic strategies for infants with PPHN are directed at selective reduction of PVR, and take advantage of a rapidly advancing understanding of the altered signaling pathways in the remodeled vasculature.     

Pulmonary vasodilator strategies in neonates with acute hypoxemic respiratory failure and pulmonary hypertension

The management of acute hypoxemic respiratory failure (AHRF) in newborns continues to be a clinical challenge with elevated risk for significant morbidities and mortality, especially when accompanied with persistent pulmonary hypertension of the newborn (PPHN). PPHN is a syndrome characterized by marked hypoxemia secondary to extrapulmonary right-to-left shunting across the ductus arteriosus and/or foramen ovale with high pulmonary artery pressure and increased pulmonary vascular resistance (PVR). After optimizing respiratory support, cardiac performance and systemic hemodynamics, targeting persistent elevations in PVR with inhaled nitric oxide (iNO) therapy has improved outcomes of neonates with PPHN physiology. Despite aggressive cardiopulmonary management, a significant proportion of patients have an inadequate response to iNO therapy, prompting consideration for additional pulmonary vasodilator therapy. This article reviews the pathophysiology and management of PPHN in term newborns with AHRF while highlighting both animal and human data to inform a physiologic approach to the use of PH-targeted therapies.     

Pulmonary hypertension in newborn infants: pathophysiology,clinical assessment and management

Clinically significant pulmonary hypertension (PH) affects up to 1 in 2000 infants after birth and is a major contributor to morbidity and mortality globally in newborn populations. Pulmonary hypertension is a component of many different neonatal diseases and can present a significant treatment challenge in both acute and chronic stages. PH is most commonly due to elevated pulmonary vascular resistance (PVR). This may be caused by structural and functional changes in the pulmonary vasculature, which may be combined with left, right or bi-ventricular dysfunction. Elevated PVR is frequently present from birth due to failure of the normal transition from fetal to extra-uterine environments, giving rise to the classic presentation of persistent pulmonary hypertension of the newborn (PPHN). Regardless of aetiology, the hallmarks of clinically significant PH are hypoxaemic right-to-left shunting, and cardiac dysfunction resulting in systemic cyanosis, hypotension and acidosis. Assessment of these informs targeted treatment aimed at optimising PVR and a supporting cardiac function. In this review we aim to provide an overview of the underlying pathophysiological concepts in PH, and use this to guide practical clinical management in all infants with PH. Based on the latest available evidence we discuss assessment of the severity of PH, and a structured, targeted approach to clinical management, acknowledging areas of uncertainty and controversy.     

Using real-world data in pediatric clinical trials: Lessons learned and future applications in studies of persistent pulmonary hypertension of the newborn

Persistent pulmonary hypertension of the newborn (PPHN) is a complication of term birth, characterized by persistent hypoxemia secondary to failure of normal postnatal reduction in pulmonary vascular resistance, with potential for short- and long-term morbidity and mortality. The primary pharmacologic goal for this condition is reduction of the neonate's elevated pulmonary vascular resistance with inhaled nitric oxide, the only approved treatment option. Various adjunctive, unapproved therapeutics have been trialed with mixed results, likely related to challenges with recruiting the full, intended patient population into clinical studies. Recently, real-world data and subsequent derived evidence have been utilized to improve the efficiency of various pediatric clinical trials. We aim to provide recent perspectives regarding the use of real-world data in the planning and execution of pediatric clinical trials and how this may facilitate more streamlined assessment of future therapeutics for the treatment of PPHN and other neonatal conditions.     

Effects of antenatal glucocorticoids on circulatory adaptation at birth in the ovine fetus

OBJECTIVE: Adaptation to extra-uterine life requires dramatic increase in pulmonary blood flow. Mechanisms that induce pulmonary vasodilatation at birth are incompletely understood but include alveolar ventilation, increase in PaO2, and production of vasoactive mediators. We hypothesized that antenatal glucocorticoids (GC) increase pulmonary vasodilatation to birth-related stimuli. STUDY DESIGN: To test this hypothesis, we studied the pulmonary hemodynamic response at birth to mechanical ventilation with low (<10%) and then with high (100%) FiO2 in chronically prepared late-gestation fetal lambs treated or not by antenatal maternal steroids. RESULTS: Basal mean aortic and pulmonary artery pressure (PAP), left pulmonary blood flow, pulmonary vascular resistance (PVR), and blood gas were similar between control and dexamethasone-treated animals (GC group). During mechanical ventilation with low FiO2, mean PVR decreased by 40% in the control group (from 0.44 +/- 0.01 to 0.25 +/- 0.01 mm Hg/ml/min) and by 60% in the GC group (from 0.44 +/- 0.02 to 0.19 +/- 0.02 mm Hg/ml/min) (p < 0.01). When subsequently ventilated with 100% O2, there was no difference in PVR decrease between groups (0.15 +/- 0.02 mm Hg/ml/min in the GC group vs. 0.14 +/- 0.01 mm Hg/ml/min in the control group). CONCLUSION: Antenatal GC enhance pulmonary vasodilatation induced by alveolar ventilation at birth but do not alter the pulmonary vascular response to O2. We speculate that antenatal steroids exposure improve adaptation at birth through acceleration of both parenchymal and vascular lung maturation.     

低氧性新生儿持续肺动脉高压与肺血管重建发生机制

新生儿持续肺动脉高压(PPHN)为新生儿期的严重疾病,出生后肺动脉压力等于或超过体循环压力,出现动脉导管和(或)卵圆孔水平的右向左分流,导致明显的低氧血症.肺血管重建与PPHN的形成和发展过程有较强相关性,低氧引起的肺血管重建以血管壁的内膜、中膜和外膜细胞组成成分和调节机制紊乱,血管壁增厚为基本特征.该文从内皮细胞、平滑肌细胞和细胞外基质三方面来阐述低氧性PPHN与肺血管重建的关系及其可能机制.     

Persistent pulmonary hypertension in preterm-infants

Persistent pulmonary hypertension of the newborn (PPHN) is a cyanotic syndrome that occurs primarily in full-term and postmature infants and causes right-to-left shunts at the atrial or ductal levels or both. Term babies with PPHN show structural changes in pulmonary vascular smooth muscle as a result of chronic prenatal distress. It is our opinion that in preterm babies the PPHN syndrome also exists. In this group of patients the potential pathways to the persistence of high pulmonary vascular resistence are only functional vascular changes precipitated by acute perinatal stress. The cyanosis of PPHN is rapidly regredient in preterm infants and clinical resolution occurs promptly if the diagnosis is correct and the treatment is started as early as possible in centers capable of extensive monitoring and neonatal supportive care to minimize the risks of Tolazoline therapy.     

Neonatal thyrotoxicosis and persistent pulmonary hypertension necessitating extracorporeal life support

We report a case of neonatal Graves' disease involving an infant with severe persistent pulmonary hypertension (PPHN) associated with neonatal thyrotoxicosis that necessitated extracorporeal membrane oxygenation. Hyperthyroidism, although uncommon in the newborn period, has been associated with pulmonary hypertension among adults. The exact mechanisms responsible for this effect on pulmonary vascular pressure are not well understood. Recent studies have provided evidence that thyrotoxicosis has direct and indirect effects on pulmonary vascular maturation, metabolism of endogenous pulmonary vasodilators, oxygen economy, vascular smooth muscle reactivity, and surfactant production, all of which may contribute to the pathophysiologic development of PPHN. Therefore, because PPHN is a significant clinical entity among term newborns and the symptoms of hyperthyroidism may be confused initially with those of other underlying disorders associated with PPHN (eg, sepsis), it would be prudent to perform screening for hyperthyroidism among affected newborns.     

Endothelin B receptor blockade attenuates pulmonary vasodilation in oxygen-ventilated fetal lambs

BACKGROUND: Endothelin-1 (ET-1) contributes to the regulation of pulmonary vascular tone in the normal ovine fetus and in models of perinatal pulmonary hypertension. In the fetal lamb lung, the effects of ET-1 depend on the balance of at least two endothelin receptor subtypes: ETA and ETB. ETA receptors are located on smooth muscle cells and mediate vasoconstriction and smooth muscle proliferation. Stimulation of endothelial ETB receptors causes vasodilation through release of nitric oxide and also functions to remove ET-1 from the circulation. However, whether activation of ETB receptors contributes to the fall in pulmonary vascular tone at birth is unknown. OBJECTIVE AND METHODS: To determine the role of acute ETB receptor blockade in pulmonary vasodilation in response to birth-related stimuli, we studied the hemodynamic effects of selective ETB receptor blockade with BQ-788 during mechanical ventilation with low (<10%) and high FiO2 (100%) in near-term fetal sheep. RESULTS: Intrapulmonary infusion of BQ-788 did not change left pulmonary artery (LPA) blood flow and pulmonary vascular resistance (PVR) at baseline. In comparison with controls, BQ-788 treatment attenuated the rise in LPA flow with low and high FiO2 ventilation (p <0.001 vs. control for each FiO2 concentration). PVR progressively decreased during mechanical ventilation with low and high FiO2 in both groups, but PVR remained higher after BQ-788 treatment throughout the study period (p <0.001). CONCLUSIONS: We conclude that selective ETB receptor blockade attenuates pulmonary vasodilation at birth. We speculate that ETB receptor stimulation contributes to pulmonary vasodilation at birth in the ovine fetus.     

Pulmonary hemodynamics in neonatal lambs resuscitated with 21%, 50%, and 100% oxygen

The effect of resuscitation with varying levels of O2 on pulmonary hemodynamics at birth is not well known. We hypothesized that the decrease in pulmonary vascular resistance (PVR) and subsequent response to pulmonary vasoconstrictors and vasodilators will differ following resuscitation with 21%, 50%, or 100% O2 for 30 min at birth in normal term lambs. Lambs at 141 d gestation were delivered by cesarean section and ventilated with 21% (21% Res; n=6), 50% (50% Res; n=6), or 100% 02 (100% Res; n=7) for 30 min followed by ventilation with 21% O2 in all three groups. A greater decrease in PVR was seen with 50% and 100% O2 ventilation than with 21% O2 (0.21 +/- 0.02, 0.21 +/- 0.02, and 0.34 +/- 0.05 mm Hg/mL/min/kg, respectively). Subsequent pulmonary vasoconstriction to hypoxia (10% O2) and the thromboxane,analog U46619 (0.5 and 1 mcirog/kg/min) was similar in all three groups. After inducing a stable elevation in PVR with U46619, impaired pulmonary vasodilation to inhaled NO (59 +/- 4, 65 +/- 4, and 74 +/- 5% of baseline PVR with 21, 50, and 100%Res, respectively) and acetylcholine infusion (67 +/- 8, 75 +/- 6, and 87 +/- 4% of baseline PVR with 21, 50, and 100%Res, respectively) and rebound pulmonary hypertension following their withdrawal were observed in the 100%Res group. We conclude that, while ventilation with 100% O2 at birth results in a greater initial decrease in PVR, subsequent pulmonary vasodilation to NO/acetylcholine is impaired.     

Influence of fetal breathing movements on pulmonary hemodynamics in fetal sheep

During fetal development, pulmonary vascular resistance (PVR) is high, and, as a result, blood flow through the fetal lungs is low. Although PVR markedly decreases at the time of birth, the factors that regulate pulmonary blood flow (PBF) and PVR before and immediately after birth are not clear. Our aim was to examine the relationship between episodes of fetal breathing movements (FBM) and pulmonary hemodynamics during late gestation to further understand the relationship among lung luminal volume, phasic changes in intrapulmonary pressure, and PVR before birth. In chronically catheterized fetal sheep (120-128 d gestation; n = 5; term approximately 147 d), PBF and PVR were measured during periods of FBM and apnea. Episodes of FBM were divided into periods of accentuated (amplitude of >3.5 mm Hg change in tracheal pressure) and nonaccentuated periods of FBM. During accentuated episodes of FBM, mean PBF was increased to 159.5 +/- 23.4% (p < 0.0025) of the preceding apneic period and was associated with a 19.1 +/- 5.2% reduction in PVR. In addition, during accentuated episodes of FBM, the retrograde flow of blood through the left pulmonary artery was reduced to 90.1 +/- 1.0% of the preceding apneic period, which most likely contributed to the increase in mean PBF at this time. Although a change in PBF and PVR could not be detected during nonaccentuated FBM, compared with the preceding apneic period, PBF was linearly and positively correlated with the amplitude (change in pressure) of FBM. We conclude that PVR is decreased and PBF is increased during accentuated episodes of FBM, possibly as a result of phasic reductions in intrapulmonary pressures.     

Is adrenomedullin involved in the pathophysiology of persistent pulmonary hypertension of the newborn?

Although adrenomedullin (ADM) is a potent vasodilating peptide reported to play a possible role in the mechanisms of fetal lung differentiation and maturation, the ADM blood level in fetuses and in neonates with persistent pulmonary hypertension (PPHN) and pulmonary hypoplasia is not known. Therefore, we examined 15 patients with PPHN: 10 with congenital diaphragmatic hernia, four with congenital cystic adenomatoid malformation of the lung, and one with misalignment of pulmonary vessels with alveolar capillary dysplasia. Eight surgical patients with neonatal conditions such as intestinal atresia served as controls. Blood samples were drawn from the umbilical artery and vein at birth, and arterial blood was drawn from patients with PPHN on the 3rd and 6th days after birth. Plasma levels of ADM were measured by radiometric assay. Plasma levels of ADM in the umbilical artery and vein were elevated in patients with PPHN compared with controls, and in all groups the levels in the umbilical vein were higher than those in the umbilical artery. The arterial levels in patients with poor prognoses were elevated on the 3rd and 6th days after birth compared with those in survivors. These results indicate that ADM may be involved in the pathophysiology of PPHN and in the mechanisms of lung differentiation and/or maturation.     

Inhaled nitric oxide therapy for persistent pulmonary hypertension of the newborn

Increasing evidence suggests that the pulmonary vascular endothelium is an important mediator of resting pulmonary vascular tone through the synthesis and release of a variety of vasoactive substances including nitric oxide (NO). In addition, pulmonary endothelial dysfunction (such as impairment of NO synthesis) is present in lung injury and may contribute to the pathophysiology of pulmonary hypertensive disorders. Recently, exogenously administered NO gas has been utilized to treat infants with persistent pulmonary hypertension of the newborn (PPHN). These preliminary studies suggest that inhaled NO is a promising new therapy for the treatment of infants with PPHN. Controlled clinical trials must now be performed to determine if the use of inhaled NO improves the long-term outcome of patients with PPHN. Long-term exposure must be monitored closely for potential toxicity which includes methemoglobinemia and lung injury secondary to peroxynitrite and nitrogen dioxide production.     

Developmental regulation of GTP-CH1 in the porcine lung and its relationship to pulmonary vascular relaxation

Nitric oxide (NO) plays an important role in lowering pulmonary vascular resistance after birth. However, in persistent pulmonary hypertension of the newborn (PPHN) NO-mediated dilation is dysfunctional. GTP-cyclohydrolase 1 (GTP-CH1) is the rate-limiting enzyme for the biosynthesis of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) an essential cofactor for nitric oxide synthase (NOS) activity. Suboptimal levels of BH4 may result in NOS uncoupling and the subsequent generation of harmful superoxide anions. We therefore investigated the functional effects of supplementing BH4 and/or a superoxide dismutase mimetic (MnTMPyP) in porcine intrapulmonary arteries from normal animals and from a porcine model of PPHN. We investigated whether any functional effects of BH4 could be explained by changes in GTP-CH1 expression. Supplementation of BH4 significantly improved endothelium-dependent relaxations in arteries from 3- and 14-d-old healthy animals, whereas no effect was seen in vessels from younger animals and adults. GTP-CH1 protein expression was lowest at 3 and 14 d, suggesting a rate limitation of BH4 at this time. BH4 supplementation alone did not improve the relaxant response to acetylcholine in arteries obtained in a porcine model of PPHN. Furthermore, GTP-CH1 protein expression was normal for age. However, co-treatment with both BH4 and MnTMPyP restored endothelial function. GTP-CH1 is developmentally regulated in the pulmonary vasculature of neonates and this results in a functionally significant limitation of BH4. Although GTP-CH-1/BH4 levels alone do not explain the profound endothelial dysfunction seen in PPHN, increasing NO bioavailability by supplementing BH4 and quenching superoxide may prove to be therapeutically beneficial.     

Diagnosis and management of pulmonary hypertension of the newborn

Persistent pulmonary hypertension of the newborn (PPHN) is a clinical condition associated with significant mortality and morbidity unless managed quickly and expertly. PPHN occurs following failure of normal postnatal adaptation of the fetal circulation. If pulmonary pressures fail to reduce following birth the resulting pulmonary hypertension leads to right to left shunting of blood which will lead to hypoxaemia, cyanosis and poor perfusion. The thrust of treatment is early diagnosis, appropriate ventilator strategies to help lower pulmonary pressures, aggressive cardiovascular support to maintain systemic pressures and minimal handling.     

Treatment of persistent pulmonary hypertension of the newborn

OBJECTIVE: To review the medical literature, emphasizing the new scientific advances in the treatment of persistent pulmonary hypertension of the newborn. SOURCES: Literature review using Medline and Cochrane library. SUMMARY OF THE FINDINGS: Persistent pulmonary hypertension of the newborn (PPHN) is characterized by an increase in pulmonary vascular resistance associated with right to left shunt through the foramen ovale or ductus arteriosus, leading to marked hypoxemia and respiratory failure. The balance between the vasoconstrictor (endothelin) and vasodilator (nitric oxide and prostaglandin I2) mediators plays an important role in the regulation of the transition from fetal circulation with high pulmonary vascular resistance to postnatal circulation with low pulmonary vascular resistance. In addition to general management, cardiovascular support, the treatment of the cause of the PPHN, and the use of selective pulmonary vasodilator such as inhaled nitric oxide (iNO) are indicated. Furthermore, the combined therapy with iNO and high-frequency oscillatory ventilation significantly improved the oxygenation of patients who were refractory to iNO therapy and conventional ventilation. The practice of hyperventilation and the administration of nonspecific pulmonary vasodilators (tolazoline) should be avoided. On the other hand, the administration of surfactant to patients with PPHN due to meconium aspiration should be considered. However, if all these therapies fail, extracorporeal membrane oxygenation (ECMO) should be considered as rescue therapy. CONCLUSIONS: The mortality due to PPHN has significantly decreased with the use of new therapies, and the major concern today is the quality of life of these patients, especially in terms of neuropsychomotor development.     

Idiopathic persistent pulmonary hypertension in an infant with Smith-Lemli-Opitz syndrome

Persistent pulmonary hypertension (PPHN) of the newborn remains a challenging condition to diagnose and treat. It has been reported in infants with Smith-Lemli-Opitz syndrome (SLOS), a rare defect in cholesterol synthesis. Typically, there is evidence of pulmonary hypoplasia. We report the first case of PPHN in the absence of pulmonary hypoplasia or other parenchymal diseases in an infant with SLOS. Perturbations in cholesterol metabolism interrupt key signaling pathways that participate in the normal maintenance of pulmonary vascular tone. We found that caveolae-dependent signaling may be involved in this process since our patient had altered expression of caveolin-1.     

Prolonged infusions of estradiol dilate the ovine fetal pulmonary circulation

Factors mediating both the rapid and sustained fall in pulmonary vascular resistance (PVR) at birth are incompletely understood. Acute or prolonged estrogen treatment causes vasodilation of several vascular beds in adults. Although fetal estrogen levels rise in late gestation, their effects in the fetal pulmonary circulation have not been studied. To determine whether estrogens can cause pulmonary vasodilation in the fetus, we infused 17beta-estradiol (E2) into the left pulmonary artery (LPA) of chronically catheterized fetal lambs, measured pulmonary artery pressure and LPA blood flow, and calculated PVR. Brief E2 administration (1-, 10-, and 100-microg doses) did not change baseline pulmonary hemodynamics and failed to enhance endothelium-dependent vasodilation as assessed by the dilator response to acetylcholine. However, prolonged E2 infusion (2- 8 d) caused a 2.6-fold increase in pulmonary blood flow (73+/-6 versus 188+/-44 mL/min, baseline versus E2 treatment, p<0.05), and the response was sustained for at least several hours. Treatment with the nitric oxide synthase inhibitor nitro-L-arginine (L-NA) reversed the E2-induced fall in PVR (0.15+/-0.05 versus 0.51+/-0.15 mm Hg/mL/min; before versus after L-NA, p<0.05). Endothelial nitric oxide synthase expression and endothelin-1 content were not different in E2-responders and controls, suggesting that altered expression of these mediators did not account for the increased flow. We conclude that prolonged E2 infusion causes an unusual pattern of vasodilation in the ovine fetal lung. On the basis of these observations of exogenous E2 treatment, we speculate that endogenous E2 enhances pulmonary vasodilation at birth.     

不对称二甲基精氨酸与新生儿持续性肺动脉高压病理进程的相关性研究

目的 探讨不对称二甲基精氨酸(asymmetric dimethylarginine,ADMA)在新生儿持续性肺动脉高压(persistent pulmonary hypertension of the newborn,PPHN)足月儿循环系统中的变化规律及其与治疗响应的关系,探索其成为治疗靶标和治疗响应标志物的可能性...