Persistent pulmonary hypertension of the newborn

Failure of the normal circulatory adaptation to extrauterine life results in persistent pulmonary hypertension of the newborn (PPHN). Although this condition is most often secondary to parenchymal lung disease or lung hypoplasia, it may also be idiopathic. PPHN is characterized by elevated pulmonary vascular resistance with resultant right-to-left shunting of blood and hypoxemia. Although the preliminary diagnosis of PPHN is often based on differential cyanosis and labile hypoxemia, the diagnosis is confirmed by echocardiography. Management strategies include optimal lung recruitment and use of surfactant in patients with parenchymal lung disease, maintaining optimal oxygenation and stable blood pressures, avoidance of respiratory and metabolic acidosis and alkalosis, and pulmonary vasodilator therapy. Extracorporeal membrane oxygenation is considered when medical management fails. Although mortality associated with PPHN has decreased significantly with improvements in medical care, there remains the potential risk for neurodevelopmental disability which warrants close follow-up of affected infants after discharge.     

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.     

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.     

Persistent pulmonary hypertension of the newborn

In utero, fetal pulmonary vascular resistance (PVR) is high, but rapidly falls after birth. Expansion of the lungs, increase in oxygenation, release of vasoactive mediators, growth factors and remodeling of the vascular wall, all contribute to the reduction in PVR. Persistent pulmonary hypertension of the newborn (PPHN) is defined as a failure of the pulmonary vasculature to relax at birth, resulting in hypoxemia. PPHN is in fact a variety of disorders that have a common presentation. Some of the pathophysiological mechanisms and the therapeutic approaches are discussed below.     

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.     

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.     

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.     

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.     

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.     

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.     

Alveolar capillary dysplasia as a cause of failure in treatment of a neonate with pulmonary persistent hypertension of the newborn - case report

A patient with severe persistent pulmonary hypertension of the newborn (PPHN) due to alveolar capillary dysplasia, congenital (ACD), is presented. In the treatment, apart from standard methods, high frequency oscillatory ventilation (HFOV), inhaled nitric oxide and activated C protein have been applied. In spite of treatment the patient died and post-mortem diagnosis was based on lung histopathology examination. ACD occurs very rarely and is a congenital disease. Diagnosis is by pulmonary tissue histopathology examination. Pathological structure of the lungs leads to severe dysfunction of gas exchange as well as increasing pulmonary hypertension. No effective treatment is known and all so far described cases have ended up with death. The described case and literature data lead the authors to the following conclusions: 1. in case of PPHN resistant to treatment, ACD diagnosis should be taken into consideration, 2. histopathological examination determines the diagnosis, 3. limited capabilities of diagnosis are the reason for applying non-standard and expensive treatment methods which so far are doomed to failure, 4. in case of a patient with severe, persistent pulmonary hypertension and unclear aetiology, not reacting to nitrous oxide treatment, a diagnostic lung biopsy should be considered.     

Kongenitale alveolar-kapilläre Dysplasie

Background

Congenital alveolar capillary dysplasia (CACD) is a rare cause of persistent pulmonary hypertension in neonates (PPHN). This idiopathic PPHN is mostly diagnosed by exclusion.

Case report

We report an unusual clinical course in a male newborn with PPHN caused by patchy CACD. Following an uneventful postnatal period the infant decompensated at the age of 10 weeks. His condition improved temporarily after 2 weeks of intensive medical care including medication to combat the pulmonary hypertension and support the heart. A few days later the patient died of heart failure. The final diagnosis was established by autopsy and histopathological examination of the lung tissue, which exhibited typical signs of CACD.

Conclusions

CACD should be considered in the differential diagnosis in all neonates with refractory PPHN when there is no recognizable secondary disturbance. Only an open lung biopsy can yield a definitive diagnosis of CACD.     

钙敏感受体在新生小鼠持续性肺动脉高压中的作用

目的探讨钙敏感受体(CaSR)激动剂及抑制剂在新生小鼠持续性肺动脉高压(PPH)模型中对CaSR的表达影响,明确其在新生小鼠PPH模型中的作用。方法将49只新生小鼠随机分为对照组(n=10)、PPH组(n=11)、激动剂组(n=13)和抑制剂组(n=15);将PPH组、激动剂组和抑制剂组小鼠暴露在12%的氧浓度中,对照组小鼠暴露在空气中。激动剂组和抑制剂组每日分别给予GdCl3(16 mg/kg)、NPS2390(1 mg/kg)腹腔注射1次,低氧组和对照组每日以生理盐水替代,共持续14 d。采用苏木精-伊红染色和免疫组化检测肺血管的变化;采用激光共聚焦技术观察CaSR在新生小鼠肺组织中的表达位置及含量;qRT-PCR技术检测新生小鼠肺组织中CaSR mRNA表达;Western blot法检测新生小鼠肺组织中CaSR蛋白的表达。结果与对照组相比,PPH组肺小动脉血管壁厚度(WT%)及右心室与左心室壁厚度比(RV/LV)均较对照组明显增大(P0.05),模型验证成功。与对照组相比,PPH组CaSR mRNA和蛋白表达水平明显增加(P0.05),激动剂组表达水平增加更加明显(P0.05),而抑制剂组表达减少(均P0.05)。结论 CaSR参与了低氧诱导的新生小鼠PPH,可能发挥重要作用。     

Abnormal vascular tone in infants and children with lung hypoplasia: Findings from cardiac catheterization and the response to chronic therapy.

OBJECTIVE: We describe four cases of chronic pulmonary hypertension in infants and children with chronic lung disease and pulmonary hypoplasia due to severe congenital diaphragmatic hernia (CDH) or congenital cystic adenomatoid malformation (CCAM). We report data from cardiac catheterization under various conditions: baseline respiratory support and room air, hyperoxic and inhaled nitric oxide challenge. We further report cardiac catheterization measures after chronic pulmonary vasodilator therapy with sildenafil alone or a combination of sildenafil and inhaled nitric oxide (three patients). DESIGN: Case series. SETTING: Tertiary academic center. PATIENTS: Infants and children ages 0-11 yrs with CDH (n = 3) or CCAM (n = 1) with evidence of chronic pulmonary hypertension by echocardiogram and cor pulmonale (n = 3). INTERVENTIONS: Catheterization and pulmonary vasodilator therapy. MEASUREMENTS AND MAIN RESULTS: Pulmonary vascular resistance, pulmonary arterial pressure, and changes in these measures were assessed. A 20% change in pulmonary vascular resistance was considered a clinically significant response. Ten catheterizations were performed in four patients. All patients had elevated pulmonary vascular resistance and pulmonary arterial pressures at initial catheterizations and significant vasodilation during inhaled nitric oxide. CONCLUSIONS: Chronic lung disease following pulmonary hypoplasia from CDH and CCAM is associated with abnormal pulmonary vascular tone in infants and children with evidence of chronic pulmonary hypertension. Chronic pulmonary vasodilator therapy may improve pulmonary vascular function and enhance lung growth in infants and children who are treated during their period of potential for rapid lung growth.     

Persistent pulmonary hypertension in a very low birthweight preterm infant

Persistent pulmonary hypertension of the neonate (PPHN) characteristically is seen in full-term or postterm infants. Occasionally, PPHN complicates the course of hyaline membrane disease in preterm infants. This report documents the unusual occurrence of PPHN in a preterm very low birthweight infant without apparent pulmonary parenchymal disease.     

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.     

Pulmonary microthrombi syndrome in newborn infants with unresponsive persistent pulmonary hypertension

Some newborn infants with either primary or secondary persistent pulmonary hypertension (PPHN) remain hypoxemic, hypercarbic, and acidotic despite therapeutic efforts. In autopsies of 23 infants who had PPHN, diffuse platelet-fibrin thrombi were present in the pulmonary microcirculation of eight (15.2 +/- 18.1 thrombi/cm2 lung tissue) and absent in 15 (0.2 +/- 0.3 thrombi/cm2 lung tissue), (P less than 0.004). Diagnoses in group A (thrombi) were pneumonia and sepsis (four patients), meconium inhalation (3), and primary PPHN (1); and in group B (no thrombi) pneumonia and sepsis (4), meconium inhalation (4), primary PPHN (4), hyaline membrane disease (2), and diaphragmatic hernia (1). The only significant differences between the two groups were the response to tolazoline infusion as assessed by changes in partial pressure of arterial oxygen (PaO2) and the platelet counts. Group A responded less favorably to tolazoline (14.8 mm Hg vs 83.6 mm Hg; P less than 0.05) and had lower platelet counts (51,000/microliter vs 128,000/microliter) (P less than 0.01) than group B. No significant differences could be detected in Apgar scores, duration or mode of mechanical ventilation, oxygen requirements, arterial blood gas tensions or pH, systemic arterial blood pressure, coagulation profile, amount of blood product transfusions, or intravascular catheter use. Pulmonary microthrombi should be added to the list of mechanisms for PPHN and may explain why some infants do not respond well to therapeutic efforts aimed at vasodilation. Thrombocytopenia and failure to respond to pulmonary vasodilators might suggest the diagnosis.     

Incidence of alveolar capillary dysplasia in severe idiopathic persistent pulmonary hypertension of the newborn

OBJECTIVE: To determine the incidence and outcome and to review the management of alveolar capillary dysplasia (ACD) among newborns with severe idiopathic persistent pulmonary hypertension (PPHN). METHODS: A retrospective review of medical records of infants admitted to a paediatric intensive care unit from 1982 to 2000 with a diagnosis of severe PPHN, and re-examination of lung histological sections was carried out. Results: Thirteen new-born infants with pulmonary hypertension not associated with any known cause were identified. All were treated with conventional mechanical ventilation or high-frequency oscillatory ventilation with high inspired-oxygen and non-specific pulmonary vasodilators. Nine infants were also treated with inhaled nitric oxide therapy and eight with extracorporeal membrane oxygenation (ECMO). Seven infants died and six survived. At autopsies, the histological features of ACD were seen in the six who had died in the newborn period. All these had been treated with ECMO. In two of these six infants, lung biopsies had been performed showing similar features, suggesting the possibility of diagnosis during life. In the remaining infant, who died at 3 months of age, there was only marked hypertrophy of the muscle coat in the small pulmonary arteries. CONCLUSIONS: Alveolar capillary dysplasia is probably not as rare a condition as previously suggested in sporadic case reports from literature on the subject. It should be entertained as a cause of otherwise severe idiopathic PPHN of the newborn, particularly if ECMO is required. Diagnosis during life is possible by lung biopsy. It is uncertain if survival occurs with milder forms of the condition.     

Developmental biology of the pulmonary circulation

From the earliest stage of lung development, there is an accompanying blood circulation. In the adult lung, the pulmonary arteries are closely associated with the airways. During early fetal development, the airways act as a template for pulmonary blood vessel development in that the vessels form by vasculogenesis around the branching airways. In later lung development, as the alveoli multiply, new capillaries form by angiogenesis. As blood vessels increase in size, they develop a muscle wall that is relatively thick during fetal life and shows a rapid reduction after birth. The control of development by growth factors and the physiological changes immediately after birth are described in this review. Abnormal pulmonary vascular development leading to pulmonary arterial hypertension and strategies for treatment are also discussed.