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.     

Early functional echocardiogram and inhaled nitric oxide: usefulness in managing neonates born following extreme preterm premature rupture of membranes (PPROM)

Aim: Poor neonatal outcome of preterm premature rupture of membranes (PPROM) <24 weeks' gestational age (GA) is probably a result of abnormalities in both airway and vascular developments, ventilation perfusion mismatch, and possibly persistent pulmonary hypertension of the newborn (PPHN). Perinatal mortality of 50–90% has been reported in the past, with recent literature reporting significant improvement in neonatal survival. We report our 8‐year experience in this group of infants using early diagnostic functional echocardiography (fECHO), high‐frequency ventilation (HFV) and inhaled nitric oxide (iNO). Methods: The obstetric and neonatal databases were searched to identify babies with PPROM (<20 weeks' gestation) or rupture earlier than 25 weeks for more than 14 days. Results: Twenty‐six infants were identified, of whom 20 were admitted to the neonatal intensive care unit (NICU; mean GA 27.8 weeks, mean birth weight (BW) 1207 g). Early echocardiographic data were available in 12/15 infants requiring mechanical ventilation of whom 10 had evidence of PPHN. All infants who received iNO therapy survived to discharge and only two infants died. Survival to discharge was 69% for the whole cohort of infants and 90% for infants admitted to the NICU. In contrast, for the cohort from pre‐iNO and ‐HFV era, the overall survival to discharge was 62% and 66% for the infants admitted to the NICU. Conclusion: Premature infants with PPROM and presumed severe hypoxemic respiratory failure because of hypoplastic lungs often have significant PPHN and may show improvement in oxygenation after treatment with HFV and iNO. Early fECHO results in earlier identification and treatment of infants with PPHN in this high‐risk group.     

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.     

Früh- und Neugeborenennachsorge in der Praxis

Advances in neonatal intensive care medicine have resulted in an improved survival of preterm infants. However, these infants are at increased risk for medical problems which may result in post-discharge morbidities or special health care needs. Formerly preterm infants also have increased rates of readmissions within the first years of life. Therefore standardized and multidisciplinary follow-up care in addition to routinely performed health check-ups (“Mutter-Kind-Pass” examinations) is important. Infants with perinatal asphyxia, meconium aspiration syndrome (MAS), persistent pulmonary hypertension of the newborn (PPHN), infection, and congenital malformations also require intensive care and are at risk for health and neurodevelopmental sequelae. This article focuses primarily on preterm infants.     

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.     

Factors relating caesarean section to persistent pulmonary hypertension of the newborn

Background

Several studies have clearly demonstrated a significantly higher incidence of persistent pulmonary hypertension of the newborn (PPHN) in neonates delivered by caesarean section (CS) compared to those delivered vaginally. The pathophysiological factors underlying the link between CS and PPHN are still poorly understood. In this review, we describe the mechanisms that could explain the association between CS delivery and subsequent PPHN, as well as potential preventive measures.

Data sources

A literature search was conducted by electronic scanning of databases such as PubMed and Web of Science using the key words “persistent pulmonary hypertension of the newborn”, “caesarean section”, “iatrogenic prematurity”, “oxidative stress”, “late preterm”, “labor” and “vasoactive agents”.

Results

Iatrogenic prematurity, higher rates of late preterm delivery and lack of physiological changes of labor play an important role in the association between CS and PPHN. CS delivery also results in limited endogenous pulmonary vasodilator synthesis and lower levels of protective anti-oxidants in the neonates. In addition, CS delivery exposes infants to a higher risk of respiratory distress syndrome and its concomitant increase in endothelin-1 levels, which might indirectly lead to a higher risk of developing PPHN. We believe that neonates delivered by CS are exposed to a combination of these pathophysiological events, culminating in an endpoint of respiratory distress, hypoxia, acidosis, and delayed transition and thereby increased risks of PPHN. The use of antenatal corticosteroids prior to elective CS in late preterm deliveries, promoting accurate informedconsent process, delaying elective CS to 39 weeks of gestation or beyond and antenatal maternal anti-oxidant supplementation could potentially mitigate the effects of CS delivery and minimize CS-related PPHN.

Conclusions

The link between CS delivery and PPHN is complex. In view of the rising rates of CS worldwide, there is an urgent need to further explore the mechanisms linking CS to PPHN and experimentally test therapeutic options in order to allow effective targeted interventions.

     

Inhalation therapy with nitric oxide in pulmonary hypertension: Comparison of preterm infants versus newborn infants

BACKGROUND: Inhaled nitric oxide (iNO) is used as a vasodilator in pulmonary hypertension (PH) of the newborn infant. PATIENTS AND METHODS: Retrospective analysis of patients, who were treated at our department with iNO in the period from 1994-2001. Response was defined as an increase of the paO (2)/FiO (2) Ratio > or = 20 % and/or a decrease of the oxygenation index (OI) >/= 20 % after 2 h (early response), and consecutively after 24 h (late response). The patients were divided into a) primary persistent pulmonary hypertension of the newbom (PPHN), or b) pulmonary hypertension secondary to meconium aspiration syndrome (MAS), sepsis or congenital diaphragmatic hernia (CDH). RESULTS: Between 1994 and 2001 we treated 47 patients with iNO at our neonatal intensive care unit. We included 16 (35 %) preterm infants (GA 34,5 [25 - 37] weeks, GG 2061 [680 - 3410] g) (Median/Range) and 31 (65 %) newbom (GA 40 [38 - 42] weeks, GG 3510 [2550 - 4560] g). 18 (38 %) patients suffered from primary PPHN, 29 (62 %) from secondary PPHN (14 MAS [30 %], 8 sepsis [17 %], 4 CDH [8 %]). 8 (50 %) preterm and 20 (64 %) term infants showed a positive iNO response after 2 h, again 8 (50 %) preterm and 20 (64%) term infants showed a positive iNO response after 24 h. There was neither a significant difference between term and preterm infants at 2 h, nor at 24 h. Between 2 h and 24 h 10 patients changed in their response to iNO. 5 (18 %) patients with early response showed a significant degradation after 24 h, whereas 5 (26 %) of the patients without early response showed a significant improvement of the oxygenation alter 24 h. Alltogether 13 (72 %) patients with PPHN, 8 (57 %) with MAS, 2 (50 %) with CDH, 4 (50 %) with sepsis showed a positive iNO response after 24 h. In regard to the oxygenation parameters at start of iNO-therapy, the patients with early response did not differ from the patient without response (median OI: 20,0 versus 21,8, median paO (2)/FiO (2) Ratio: 59,3 versus 55,0 mmHg at the start of the iNO therapy). CONCLUSION: In regard to iNO response, there was no significant difference between term and preterm infants. Due to the changing response, a positive iNO-response after 2 h had no predictive value for the further prognosis of the oxygenation situation under iNO therapy.     

系统性红斑狼疮合并妊娠子代早产儿42例临床分析

目的 探讨系统性红斑狼疮（SLE）合并妊娠子代早产儿的临床特点,提高新生儿科医师对这部分早产儿的认识。方法 收集2000年1月至2012年6月间SLE合并妊娠子代早产儿的临床资料进行回顾性分析,并与同期出生的除SLE合并妊娠子代早产儿以外的2 308例早产儿住院期间并发症发生情况进行对比。结果 SLE合并妊娠子代早产儿共42例,女婴比例明显高于男婴,其中确诊新生儿狼疮综合征4例。新生儿感染为SLE合并妊娠子代早产儿最常见并发症（47.62%）,其次为小于胎龄儿（28.57%）,新生儿呼吸窘迫综合征（26.19%）,新生儿窒息和先天性心脏病（均为14.29%）,肺出血（4.76%）;与同期收治的2 308例早产儿合并新生儿感染（16.81%）、小于胎龄儿（13.21%）和先天性心脏病（5.16%）的发生率进行比较,差异均有统计学意义（均P<0.05）;其他合并症的发生率在两组早产儿间比较差异均无统计学意义。结论 SLE合并妊娠子代早产儿易合并感染性疾病、小于胎龄儿及先天性心脏病,而呼吸方面并发症与同期其他早产儿相比无显著差异。     

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.     

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.     

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.     

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.     

Thrombomodulin serum levels in ventilated preterm babies with respiratory distress syndrome

A soluble form of thrombomodulin (TM), an anticoagulant proteoglycan of the endothelial cell membrane, considered a marker of vascular endothelial damage, was measured in plasma of preterm infants with respiratory distress syndrome (RDS). In these patients, lung immaturity leads to endothelial leak of plasma proteins and to surfactant inhibition. In 18 babies with RDS, plasma TM concentration was significantly elevated compared with values of a matched group of babies without pulmonary disease (276.1 ng/ml vs 141.3 ng/ml) (P<0.05). Furthermore, TM levels of mechanical ventilated babies (IPPV) with severe RDS were higher than those of babies with moderate RDS and treated with nasal CPAP (340.9 ng/ml vs 174.2 ng/ml) (P<0.05). Conclusion These data show that TM can be used as marker of pulmonary endothelial damage in preterm babies treated with mechanical ventilation for RDS and suggest early intervention with exogenous surfactant to limit alveolar protein leakage and surfactant inactivation. Received: 20 February 1997 and in revised form: 7 July 1997 / Accepted: 8 July 1997     

Neonatal pulmonary haemorrhage, birthweight, gestational age and intrauterine growth

The relation between neonatal pulmonary haemorrhage and its underlying cause was studied by reviewing the clinical data and necropsy records of 315 newborn babies who had died between day 0 and 31 of life. Necropsy revealed massive and focal pulmonary haemorrhage in 6.9% and 19.3% of the infants, respectively. It has been concluded that pulmonary haemorrhage is a complication of various neonatal diseases related to hypoxia and/or infection, which occur in preterm infants with a much higher frequency than in term babies. Among patients with pulmonary haemorrhage, males and low birthweight babies predominated.     

Role of nitric oxide in neonatology

Nitric oxide has many roles in the body, but one major function is regulation of vascular tone. The discovery of this function in 1987 offered many therapeutic opportunities for mature and premature babies with significant lung disease. However clinical studies have produced different results in these two groups of babies. Term or near-term infants with hypoxic respiratory failure, despite standard intensive care support, should have a trial of inhaled nitric oxide. The situation is less clear with preterm infants. The evidence so far suggests that there is no role for short-term use of inhaled nitric oxide as an effective rescue therapy for very preterm infants with profound respiratory failure. In contrast, less ill preterm infants may benefit from nitric oxide, both in the short and over the long term.     

选择性剖宫产与足月儿呼吸窘迫综合征回顾性分析

目的 探讨选择性剖宫产对足月儿呼吸窘迫综合征(RDS)发生的影响,并比较两中心足月儿RDS发生情况及相关影响因素.方法 以2006年6月至2008年6月,在浙江大学附属儿童医院NICU及新生儿病房(A中心)和浙江大学附属妇产科医院NICU(B中心)收治的足月儿RDS为研究对象,分析选择性剖宫产RDS的胎龄分布、所有病例有并发症组与无并发症组的比较,以及两中心临床资料的分析比较.计数资料行χ~2检验,计量资料行t检验.结果 90例足月儿RDS中88例为选择性剖宫产,占97.8%,39、40周以后的RDS构成比明显低于37周及38周时.经losistic回归分析,开始上机时间12 h是足月儿RDS发生并发症的主要危险因素(OR=12.667,P=0.021).两中心的病例在入院年龄(t=11.833,P=0.001)、胸部X线分期(χ~2=4.85,P=0.028)、PS应用(t=11.911,P=0.002)、开始上机时间(t=10.051,P=0.018)、上机前PaO_2/FiO_2(χ~2=4.184,P=0.005)、OI>25(t=4.737,P=0.03)、用氧时间(χ~2=10.475,P=0.001)、并发低血压(t=11.020,P=0.01)以及住院时间(t=9.872,P=0.002)等均存在显著性差异.结论 选择性剖宫产是足月儿RDS发生的重要影响因素,早期诊断、早期干预可以减少足月儿RDS的并发症.     

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.     

Effect of blood pressure cuffs on neonatal circulation: Their potential application to newborns with persistent pulmonary hypertension

The contribution of vasoactive pharmacologic agents to the care of the infant with primary pulmonary hypertension of the newborn (PPHN) is hampered by their limited ability to act selectively on different vascular beds. In contrast, blood pressure (BP) cuffs decrease flow and increase resistance only in the extremities around which they are applied. They therefore offer a means of increasing systemic vascular resistance without affecting pulmonary vascular resistance, a hemodynamic effect that may be particularly desirable among PPHN patients receiving vasodilators. We studied the effect of BP cuffs on the circulation of nine healthy neonates and three infants with severe PPHN. Among the healthy neonates, inflation of the cuffs to 20 mmHg had no discernible hemodynamic effect. Inflation to systolic pressures, however, caused the left ventricular preejection period to increase from 36±9 ms to 45±10 ms, the end-diastolic dimension to increase from 1.80±0.16 cm to 1.92±0.16 cm, and the cardiac output to fall to 87±12% of baseline (allp<0.05)—changes indicative of an increase in systemic vascular resistance. Application of BP cuffs to the patients with PPHN was associated with 10–25 mmHg increases in transcutaneous arterial oxygen tensions. Administration of tolazoline to these patients while the cuffs were inflated resulted in additional 10–20 mmHg increases and did not precipitate hypotension. These observations suggest that BP cuffs can play a useful role in the management of patients with PPHN.     

Inhaled nitric oxide therapy in preterm infants

According to a number of recently published, randomized controlled trials, treatment of persistent pulmonary hypertension of the newborn (PPHN) by the use of inhaled nitric oxide (iNO) has emerged as an established procedure in neonatology. The situation in premature infants appears to be more complicated than in the term infant. Due to the fact that nitric oxide interferes with platelet aggregation, the risk of intraventricular hemorrhage or its aggravation during iNO therapy is being discussed in a controversial manner. Since most studies are aimed at endpoints like oxygenation parameters, the presently available studies report extremely variable incidences of intraventricular hemorrhages (IVH). Meanwhile two large studies could demonstrate that clinical application of iNO in preterm infants is not associated with an increased incidence of IVH. Further randomized controlled trials of iNO in preterm neonates are highly desirable in order to establish the future role of this therapy and its indications.