Persistent pulmonary hypertension of the newborn: Historical perspectives

For many decades, persistent pulmonary hypertension of the newborn (PPHN) remained a baffling disorder, often confused with cyanotic congenital heart disease, with a very high mortality. Originally described as a condition characterized by clear lung fields and profound hypoxemia, modern diagnostic techniques and novel therapeutics have improved the outcomes of affected newborns. This paper will review the historical aspects of PPHN and enable the reader to see how far we have come but also how far we have to go in conquering this unique disorder.     

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.     

Nitric oxide

Although persistent pulmonary hypertension of the newborn (PPHN) has been considered to be a relatively rare condition, there is increasing evidence that pulmonary vasoconstriction is a common finding in moderate and severe respiratory distress syndrome. High pressure, high rate ventilation may overcome this problem but it is associated with an unacceptably high incidence of pneumothorax and chronic lung disease. Vasodilators including tolazoline, prostacyclin and nitroprusside have a nonspecific effect, often producing systemic as well as pulmonary hypotension. Nitric oxide (NO) offers an exciting alternative therapy. NO is produced by the conversion of arginine to citrulline by NO synthase in the vascular endothelial cells. The NO then diffuses through to the underlying smooth muscle leading to relaxation. It then combines with haemoglobin to form small quantities of methaemoglobin, preventing spread of its effect elsewhere. The main potential toxic effect is due to the rapid conversion of NO to nitrogen dioxide in the presence of oxygen. Animal studies have shown that concentrations of NO up to 100 ppm are safe and also effective in relieving vasoconstriction induced by hypoxia, thromboxane analogues and infusions of group B haemolytic streptococcus. Preliminary studies on adults with respiratory distress syndrome have been encouraging showing reductions in pulmonary artery pressure and improvements in oxygenation without any changes in systemic blood pressure. Two small studies indicate that NO therapy is both effective and safe when given to full term babies with PPHN. Further data are urgently needed to find optimal concentrations so that multicentre studies can be carried out.     

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.     

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.     

Neonatal hypoxemia due to misaligned pulmonary vessels with alveolar capillary dysplasia]

BACKGROUND: Refractory hypoxemia in the newborn requires a precise diagnostic investigation for optimal and fast management. CASE REPORT: A full term newborn presented with refractory hypoxemia associated with radiologically clear lung fields and extrapulmonary shunt. Echocardiography ruled out a cardiac malformation. The persistence of hypoxemia despite treatment of the extrapulmonary shunt and the absence of parenchymatous pulmonary disease led to suspect misaligned lung vessels with alveolar capillary dysplasia. This diagnosis was confirmed by post mortem microscopic examination of the lung. CONCLUSION: The diagnosis of misaligned lung vessels with alveolar capillary dysplasia can be suspected on clinical features. The disposition of pulmonary veins must be checked to recognize this disease in case of neonatal death with pulmonary hypertension.     

Neonatal persistent pulmonary hypertension treated with milrinone: four case reports

Current standard therapy for persistent pulmonary hypertension of the newborn (PPHN) consists of optimal lung inflation, hemodynamic support and selective vasodilation with inhaled nitric oxide (iNO). However, not all infants will respond. Milrinone, a phosphodiesterase (PDE) III inhibitor, is routinely used in pediatric cardiac intensive care units to improve inotropy and reduce afterload. Although its use in post-operative cardiac failure has been proven in a randomized trial, it has not been reported to be beneficial in PPHN. We report four cases with severe PPHN treated with a combination of iNO and Milrinone. All four cases were unresponsive to therapy including iNO, with a mean oxygenation index (OI) of 40 (standard deviation (SD) 12)) before Milrinone. Substantial improvement in OI (mean of 28; SD 16) was followed by extubation and survival. However, of 4 patients, 2 developed serious intraventricular hemorrhages (IVHs), and 1 had a small IVH. To clarify the risk benefit ratio, of death versus survival with impairment, a randomized controlled trial is needed.     

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.     

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.     

The management of neonatal pulmonary hypertension

Most neonates with clinically significant pulmonary hypertension (PH) will have either persistent PH of the newborn (PPHN) or bronchopulmonary dysplasia. Cyanotic congenital heart disease must be actively ruled out as part of the differential diagnosis of PPHN. The maintenance of ductal patency with prostaglandins E1 or E2 in cases of doubt is safe and potentially beneficial given their pulmonary vasorelaxant properties. Specific tools in the treatment of PPHN include modern ventilatory strategies, inhaled nitric oxide, sildenafil, prostacyclin and extracorporeal membrane oxygenation. Rarely will a cardiac lesion be primarily responsible for neonatal PH although pulmonary vein stenosis and the persistence of an arterial duct must be considered, particularly in the older preterm baby with bronchopulmonary dysplasia.     

体外膜肺氧合技术在持续肺动脉高压新生儿救治中的临床应用北大核心CSCD

目的探讨体外膜肺氧合技术(extracorporeal membrane oxygenation,ECMO)在新生儿持续肺动脉高压(persistent pulmonary hypertension of the newborn,PPHN)救治中的临床应用价值。方法回顾性收集2015年1月至2021年12月在中山市人民医院新生儿重症监护室中应用ECMO支持的11例PPHN新生儿的临床资料,包括患儿的一般资料、临床诊断、实验室检查、ECMO支持时间及过程中各种并发症、住院时间、结局等,进行比较分析。结果11例患儿中有10例撤机成功,撤机成功率91%;存活8例,存活率73%。11例患儿ECMO治疗时间26~185 h,平均治疗时间(81±50)h;呼吸机治疗时间57~392 h,平均治疗时间(198±105)h;住院时间2~49 d,平均住院时间(22±15)d。11例患儿ECMO治疗24 h后氧合指数、血乳酸水平较ECMO治疗前均显著改善(P<0.05);其中10例患儿ECMO治疗24 h后肺动脉压力较ECMO治疗前均显著下降(P<0.05);1例患儿在EMCO治疗期间肺动脉压力呈进行性升高,最终死亡,结合尸检肺组织病理及全外显子测序结果,确诊为肺泡毛细血管发育不良。11例患儿ECMO治疗期间发生颅内出血5例,弥散性血管内凝血1例,胃出血1例,肺出血2例,肾功能不全1例,穿刺处出血3例。结论ECMO技术是一种有效应用于常规治疗无效的PPHN新生儿救治的心肺支持措施。应用ECMO技术的并发症发生率高,需严格掌握适应证、把握时机、提高ECMO管理水平,才能提高患儿的撤机率及存活率。     

A prospective clinical study on inhaled nitric oxide therapy for neonates in Japan

BACKGROUND: This is the first report about a prospective clinical investigation to study the efficacy and safety of nitric oxide (NO) inhalation in infants with persistent pulmonary hypertension of the newborn (PPHN) in Japan. METHODS: Patients in the present study had to meet the following entry criteria: (i) they had to be younger than 7 days of age; (ii) they had to have evidence of PPHN as defined by echocardiograph; (iii) they had to have severe systemic hypoxemia under mechanical ventilation at 100% oxygen supplementation; and (iv) they had to have a failure to respond to conventional therapies. Patients were excluded from this trial if they had any of the following: hypoplastic lung, structural cardiac lesions or severe multiple anomalies. RESULTS: Nitric oxide inhalation therapy was performed in 68 infants who had severe PPHN at 18 hospitals between May 1995 and May 1997. At birth, 21 of 68 infants (31%) weighed less than 1,500 g and 39 infants weighed more than 2,500 g. The diagnoses associated with PPHN were as follows: 27 infants had meconium aspiration syndrome, 15 infants had dry lung syndrome, nine infants had congenital diaphragmatic hernia, six infants had respiratory distress syndrome, three infants had pneumonia and eight infants had other diagnoses. The mean oxygenation index (OI) before NO inhalation therapy in 68 infants was 43.2; 55 infants (81%) had good responses. CONCLUSIONS: These results may be valuable for further randomized controlled and double-blind trials in Japan to evaluate whether NO inhalation therapy is more effective than conventional therapy in infants with severe PPHN.     

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.     

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.     

Neonatal Pulmonary Hypertension: Pathophysiologic-Based Therapy

Rational management of pulmonary artery hypertension (PAH) in the newborn infant must be based on an understanding of underlying causes. When a specific diagnosis can be made, empirical treatment gives way to specific therapy. For every pathophysiologic abnormality potentially resulting in PAH, clinical entities can be identified and key therapeutic interactions can be considered. 1. Pulmonary Venous Hypertension: PAH is secondary to obstruction of blood flow through the left heart. If based on anatomic abnormality (mitral or left atrial), surgical relief of obstruction is required. If PAH is the result or functional abnormality of the left ventricle (transient left ventricular ischemia), medical treatment of left ventricular failure is most important. 2. Functional Obstruction of Pulmonary Vascular Bed: Hyperviscosity of blood (polycythemia - HCT > 65) results in increased pulmonary vascular resistance. Treatment consists of reduction of red blood cell volume. 3. Pulmonary Vascular Constriction: Hypoxemia with or without pulmonary parenchymal disease (primary or secondary persistent fetal circulation [PFC] syndrome). Therapy is directed at improvement of oxygenation and dilatation of pulmonary arteriolar bed (e.g. O₂ hyperventilation and/or pulmonary vasodilator therapy). 4. Decreased Pulmonary Vascular Bed: If primary pulmonary hypoplasia is present, no treatment is available. If secondary form (diaphragmatic hernia), surgical repair and pulmonary vasodilatation of contralateral lung is indicated. Extracorporeal membrane oxygenation (ECMO) can be used in severe cases. 5. Increased pulmonary blood flow: Causes in the neonate include complex heart disease without pulmonary stenosis; and peripheral A—V fistula. Treatment: Surgical limitation of pulmonary blood flow may be required. Even when PAH is the result of combined etiologies, a prompt well-organized clinical management plan can follow from understanding of pathologic principles.     

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.     

Patent ductus arteriosus flow patterns in the treatment of congenital diaphragmatic hernia

Background: Congenital diaphragmatic hernia (CDH) mortality still remains high, due to lung hypoplasia and persistent pulmonary hypertension of the neonate (PPHN). Effective management of PPHN and time of operation are quite important to the improvement of CDH treatment. In order to determine the optimal time for operation, we monitored PPHN with cardiac ultrasound. Methods: PPHN was assessed with three parameters: patent ductus arteriosus flow patterns (PDAFP), %left ventricular diameter at diastole, and left ventricular fraction of shortening (LVFS). Four patients with an antenatal diagnosis were treated under this protocol. Diaphragm repair was performed when PDAFP became left to right shunt dominant and the pre‐ and postoperative course was analyzed with regular chart reviews. Results: The alveolar‐arterial oxygen difference levels of four patients were 590, 335, 613 and 530 mmHg, and operations were carried out when the patients were 2, 2, 3 and 2 days old, respectively. In three of the four patients (all except case 3) the PDAFP changed from right to left shunt dominant or bidirectional (BD), to left to right shunt dominant within 48 h. The %left ventricular diameter at diastole was relatively stable around the time of operation. The LVFS of all patients decreased after the operation. Only the LVFS of case 3 decreased temporarily to less than 30% (which indicates poor left ventricular function) but recovered. No patients needed extracorporeal membrane oxygenation support. All patients survived the procedure and were extubated. Case 3, who took 10 days to become left to right shunt dominant after the operation, needed home oxygenation therapy for 10 months. Conclusions: PDAFP was a reliable marker of PPHN on a high‐frequency oscillatory ventilator to determine the optimal time for the operation for CDH. The optimal time for operation is supposed to be the time when PDAFP become left to right shunt dominant.     

Inhaled nitric oxide therapy in the near-term or term neonate with hypoxic respiratory failure

Inhaled nitric oxide (iNO) has altered the management strategy for treating near-term and term infants with hypoxic respiratory failure (HRF). There is a strong relationship between HRF and persistent pulmonary hypertension of the newborn (PPHN). PPHN is characterized by elevated pulmonary resistance, pulmonary vasoconstriction, and altered vascular reactivity. The resulting high pulmonary pressure may lead to HRF, which is defined as a relative deficiency of oxygen in arterial blood and insufficient minute ventilation. iNO improves oxygenation and decreases the need for extracorporeal membrane oxygenation. Although iNO therapy is effective, its efficacy can depend on the fine points of its use and on other care the infant is receiving. Even in NICUs that do not have iNO available, those who care for term infants with HRF must be familiar with its use and know when and how to transfer these infants and how to help families through this difficult period. Because iNO therapy will probably be used more frequently in nurseries over the next few years, more information on the safety and efficacy of its use in the broader neonatal population needs to be available.     

Effectiveness and safety of intravenous iloprost for severe persistent pulmonary hypertension of the newborn

Objective

The aims of this study were to determine the effectiveness (oxygenation), safety (hemodynamic status) and short term outcomes of intravenous iloprost (IVI) administration as a rescue therapy in severe persistent pulmonary hypertension of the newborn (PPHN).

Design

Retrospective medical records review.

Setting

Tertiary neonatal intensive care unit at Songklanagarind Hospital, Songkhla Province, Hat Yai, Thailand.

Participants

Newborns who received IVI as an adjunctive therapy for treatment of severe PPHN, as defined by an oxygen index (OI) of >20 and without response to conventional therapies.

Main Outcome Measures

The change of OI and alveolar-arterial oxygen difference before and after commencement of IVI.

Results

33 neonates with severe PPHN at a median gestation of 39 weeks and a baseline OI of 40 (range, 21–101) received IVI. The median OI and alveolar-arterial oxygen difference had a statistically significant decrease after 2 hours of treatment and continued to decline thereafter (P<0.05). All infants received one or more inotropic medications and volume expanders to provide blood pressure support with no statistically significant difference of blood pressure and heart rate before and after IVI treatment. The mortality rate was 15.2%, all of them had initially severe hypoxemia with a median OI of 53.6.

Conclusions

IVI may be effective in improving oxygenation and should be considered as a rescue therapy for infants with severe PPHN, especially in a limited resource environment with no inhaled nitric oxide available. Systemic hypotension may be a cause for concern.     

Clinical spectrum of chronic interstitial lung disease in children.

To describe the clinical spectrum of interstitial lung disease in children, we reviewed our experience with 48 patients during a 12-year period. Most patients initially had typical findings of restrictive lung disease and hypoxemia. Growth failure or pulmonary hypertension or both were found in more than one third. Specific diagnosis, made in 35 patients (70%), most often required invasive studies, particularly open lung biopsy. Although the diagnostic yield from open lung biopsy was high, the diagnosis of many patients remained uncertain. Many different disorders were encountered. The response to corticosteroids, bronchodilators, and chloroquine was inconsistent. Six patients died, five within 1 year after the initial evaluation. The spectrum of pediatric interstitial lung disease includes a large, heterogeneous group of rare disorders associated with high morbidity and mortality rates.