Persistent pulmonary hypertension of the newborn with transposition of the great arteries: successful treatment with bosentan

Persistent pulmonary hypertension of the newborn (PPHN) occurs in 1–4% of neonates with transposition of the great arteries with intact ventricular septum (TGA/IVS). This association is often lethal. To our knowledge, only eight survivors have been described in the literature, two of whom benefited from extracorporeal membrane oxygenation (ECMO). We report two cases of PPHN complicating a TGA/IVS that were refractory to multiple therapies and resolved 48 hours after initiation of bosentan therapy. Bosentan, an oral dual endothelin-1 receptor antagonist, is a new treatment for pulmonary arterial hypertension that was both effective and safe in these two cases of TGA/IVS with PPHN. To our knowledge, it is the first use of bosentan in newborns.     

Severe persistent pulmonary hypertension of the newborn in a setting where limited resources exclude the use of inhaled nitric oxide: successful treatment with sildenafil

We present the case of a full term neonate with severe persistent pulmonary hypertension of the newborn (PPHN) after birth asphyxia cared for at the St. Elizabeth Hospital in Curacao, Netherlands Antilles. Although the child was ventilated with high pressures and was given high doses of cardiovascular pressors, the arterial oxygen levels remained low with an alveolar-arterial O₂ gradient of 651 mmHg. As a last resort, sildenafil (1.5 mg/kg) was given via a nasogastric tube. This resulted in an immediate and sustained elevation of arterial oxygenation and subsequent complete recovery. After administration of sildenafil there was a transient hypotension which was corrected by a single bolus of saline. Conclusion:We discuss the current treatment modalities of persistent pulmonary hypertension of the newborn and the potential use of phosphodiesterase 5 inhibitors such as sildenafil in a situation where the standard of practice with inhaled nitric oxide and extracorporeal membrane oxygenation is not available.     

Endogenous nitric oxide and endothelin-1 in persistent pulmonary hypertension of the newborn

We studied changes in endogenous nitric oxide (NO) synthesis and endothelin-1 (ET-1) production in infants with persistent pulmonary hypertension of the newborn (PPHN). We determined concentrations of serum NO metabolites, i.e., nitrites and nitrates (NOx), and of plasma ET-1 in five infants with PPHN (PPHN group) and in 25 healthy full-term neonates (control group). In both groups, serum NOx concentrations increased over time and plasma ET-1 concentrations decreased with age. The differences in serum NOx concentrations between groups were not significant at <12 h and 24 h of age; however, they were significantly higher in the PPHN group than in the control group at 5 days of age. The differences in plasma ET-1 concentrations between groups were not significant at 5 days of age, but were significantly higher in the PPHN group than in the control group at <12 h and 24 h of age. Conclusion Limited endogenous nitric oxide synthesis and elevated endogenous endothelin-1 production during the first few days of life may contribute to pulmonary hypertension in infants with persistent pulmonary hypertension of the newborn. Received: 2 September 2000 / Accepted: 15 June 2000     

Follow-up of 5- to 11-year-old children treated for persistent pulmonary hypertension of the newborn

Aim: Determine the prevalence of sensorineural hearing loss (SNHL) and relate this to cumulative exposure to hypoxia, hypocapnia and hypotension. Describe chronic health problems among 5- to 11-year-old children treated for persistent pulmonary hypertension of the newborn (PPHN).
Methods: The index group consisted of 85 children and a reference group was matched for age, sex and municipality of current residence. Questionnaires were sent to the families. The families in the index group were asked to participate in an examination of their child's hearing.
Results: Seven children (11%) had SNHL. SNHL was not associated with hypoxia, hypocapnia or hypotension during treatment for PPHN. In the index group chronic health problems were reported in 42% compared with 17% in the reference group (chi-square test, p = 0.001). Twenty-one percent in the index group were treated with bronchodilator therapy compared with 8% in the reference group (chi-square test, p = 0.028). In the index group five children had cerebral palsy and two had developmental delay. Nineteen percent in the index group and 5% in the reference group had remedial education (chi-square test, p = 0.008).
Conclusion: Children treated for PPHN are at high risk for SNHL. Exposure to hypoxia, hypocapnia or hypotension did not predict SNHL. The incidence of chronic health problems and use of remedial education was high.     

High frequency oscillatory ventilation and extracorporeal membrane oxygenation in severe persistent pulmonary hypertension of the newborn

We report on 50 term and near-term neonates (birth weight > 1800 g, gestational age > 33 weeks) with severe persistent pulmonary hypertension of the newborn (PPHN), referred to us from January 1987 to July 1991 after failure of maximum conventional treatment. All infants had paO₂<45 mm Hg when ventilated with peak inspiratory pressure >38 cm H₂O and FiO₂=1.0, hence meeting entry criteria for extracorporeal membrane oxygenation (ECMO). High frequency oscillatory ventilation (HFOV) was tried in all patients. If sufficient oxygenation could not be achieved (paO₂<40 mm Hg for at least 2 h), ECMO therapy was begun, which was the case in 25 children. Neonates responding to HFOV (n=25) were of a slightly younger gestational age (37.0 weeks vs 38.8 weeks,P<0.05), had higher Apgar scores and were less hypoxaemic before HFOV (paO₂ 36.6 mm Hg vs 28.8 mm Hg,P<0.01); during HFOV there was a significant rise in paO₂ (> 150 mm Hg;P<0.001) and a fall in pCO₂ to 21.6 mm Hg (P<0.001). Due to air leaks, which was the main complication of HFOV (52%), ECMO therapy had to be begun in two additional infants after an initial positive effect. HFOV tended to be successful in cases of primary PPHN, meconium aspiration and sepsis, but not in infants with lung hypoplasia as a result of diaphragmatic hernia or other reasons. Success or failure of HFOV could not be reliably predicted by any parameter. Mean duration of HFOV was 37.8 h vs 84.9 h of ECMO. PPHN could be overcome in 88% of the HFOV-treated and in 76% of the ECMO-treated infants; overall survival rate was 74% (predicted probability of survival using maximum conventional treatment <10%). There were no significant differences between HFOV/ECMO groups with regard to duration of ventilation following HFOV/ECMO, total time in hospital, rate of bronchopulmonary dysplasia and neurological complications (intracranial haemorrhage, brain infarction). Among the survivors, the rate of mentally handicapped children was equal in both groups (overall 18.9%). Our analysis shows that about 50% of neonates with PPHN who fail to respond to conventional ventilatory support and maximum treatment can be treated successfully with HFOV, thus avoiding ECMO. By applying both forms of therapy, the survival rate of infants with severe PPHN can be increased from an estimated rate of <10% up to 80%.     

先天性膈疝继发新生儿持续肺动脉高压的研究进展

先天性膈疝(CDH)继发新生儿持续性肺动脉高压(PPHN)是新生儿高病死率的重要原因之一,是导致CDH 患儿生后出现呼吸、循环衰竭的重要因素。CDH 继发PPHN 的病情危重,治疗困难,治疗预后差,故针对阻止CDH 病理进程的产前干预已成为研究热点,尤其是关于阻断PPHN 形成过程的病因治疗。鉴于PPHN 的病因尚不明确,治疗效果差,该文以国内外相关研究为基础,综述CDH-PPHN 的发病机制与治疗研究进展,以期为相关研究与临床治疗提供参考     

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.     

常频通气联合一氧化氮吸入治疗新生儿持续肺动脉高压

目的 探讨常频通气联合一氧化氮吸入(iNO)治疗新生儿持续肺动脉高压(PPHN)的疗效.方法 对22例确诊为PPHN且入院时采取常频通气疗效不满意的患儿给予iNO.NO初始吸入浓度上,20例为(10～20)×10-6,2例为(20～40)×10-6.当SpO2≥93%并已经稳定20min以上,开始下调呼吸机参数,并逐渐下调NO吸入浓度.当NO吸入浓度降至(5～10)×10-6时,再持续2～3h后,若PaO2>55mm Hg(1 mm Hg=0.133 kPa)、SpO2>93%时停止吸入.在NO吸入前和吸入后1～6 h分别进行血气分析,连续记录生命体征、SpO2和监测NO2值等.结果 20例在吸人NO后5～20 min左右SpO2逐渐升高,临床缺氧状态逐步改善.有效率达91%.吸入NO 1～6 h,SpO2、PaO2分别由吸入前的(76.3±13.3)%、(46.4±10.1)mm Hg升到(94.4±2.9)%和(92.8±24.7)mm Hg,FiO2由(0.9±0.1)降至(0.6±0.1),差异均有非常显著性(P<0.001).患儿生命体征平稳,未发现急性合并症.全组治愈18例,治愈率达82%,自动放弃4例.结论 iNO能有效地缓解PPHN患儿的乏氧状态.提高氧分压和治愈率.NO吸入不良反应小、易操作.iNO初始吸人浓度以(10～20)×10-6开始为宜,极个别病例可以(20～40)×10-6开始.     

Role of angiotensin-converting enzyme gene polymorphism in persistent pulmonary hypertension of the newborn

Aim: To evaluate the association of angiotensin‐converting enzyme (ACE) gene polymorphism with risk/severity of persistent pulmonary hypertension of the newborn (PPHN) among at risk infants. Methods: Infants ≥34 weeks with respiratory distress at birth were recruited. PPHN was diagnosed clinically and by cardiac echocardiogram. Control group consisted of infants with respiratory distress who did not develop PPHN. ACE genotyping (DD, II, DI genotypes) and serum ACE levels were determined. Results: A total of 120 infants were included (PPHN = 44; control = 76). Frequency of ACE DD genotype was not different between the two groups of infants (25% versus 33%). Among PPHN infants, severity of illness did not differ between genotypes. Mean (SD) serum ACE levels [15 (9) versus 24 (13) versus 29 (14) U/L] were positively associated with the number of D alleles and inversely associated with infants’ gestational age (GA) and level of cardiovascular support. Conclusion: Angiotensin‐converting enzyme gene polymorphism did not impact the risk or severity of PPHN among infants ≥34 weeks GA.     

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 and extracorporeal membrane oxygenation in persistent pulmonary hypertension of the newborn

Persistent pulmonary hypertension of the newborn (PPHN) may occasionally require an invasive treatment with extracorporeal membrane oxygenation (ECMO). Inhaled nitric oxide (NO) has recently been introduced as a selective pulmonary vasodilator for treatment of PPHN. We describe a case of PPHN in which neither inhaled NO nor ECMO was effective in reversing pulmonary hypertension. The clinical course of the patient suggested a potential role of NO inhalation in predicting the outcome of ECMO treatment for PPHN.     

Variable oxygenation response to inhaled nitric oxide in severe persistent pulmonary hypertension of the newborn

The causes of variable responsiveness to inhaled nitric oxide (NO) in Persistent Pulmonary Hypertension of the Newborn (PPHN) are unknown. The changes in the severity of respiratory failure after the onset of inhaled NO (maximal dose 20ppm) were studied in 13 consecutive neonates with severe PPHN. Response was defined as a sustained decrease of alveolar-arterial oxygen gradient (AaD0₂) by > 20%, or a decrease in oxygenation index (OI) by > 40%. Six neonates had a rapid response within 30min, three had an intermediate response within 8h, and three had a delayed response within 12 h after the onset of NO. Three infants with birth asphyxia responded rapidly to inhaled NO. One infant with sepsis did not respond, and two with suspected sepsis had a delayed response. The infants with Meconium Aspiration Syndrome and idiopathic PPHN had a variable response time. Twelve neonates required 4 to 14 days of mechanical ventilation and survived. Infants with PPHN may benefit from a trial of inhaled NO therapy that exceeds 30min. The variability of the response time to inhaled NO is likely to be multifactorial and dependent on the disease process associated with PPHN.     

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.     

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.     

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...     

Persistent pulmonary hypertension after lithium intoxication in the newborn

A case of lithium intoxication in the newborn is presented. Besides displaying extreme hypotonia and a goitre, the infant developed symptoms of congenital heart disease immediately after birth. Cardiac catheterization and angiocardiography revealed an elevated pulmonary vascular resistance and indicated that the cardiopulmonary symptoms were caused by persistent fetal circulation. Previously, four authors have independently reported cardiopulmonary symptoms in association with lithium intoxication without finding cardiac or pulmonary disease.The similarity between the present and the four earlier reported cases in regard to the symptoms and the course of illness, raises the question of the connection between lithium intoxication and persistent fetal circulation being more than coincidental. In view of recent investigations it is speculated that lithium intoxication in utero may result in the pulmonary vascular changes responsible for the persistence of fetal circulation.     

Steroids in full term infants with respiratory failure and pulmonary hypertension due to meconium aspiration syndrome

Persistent pulmonary hypertension of the newborn (PPHN) due to meconium aspiration syndrome (MAS), has a high morbidity and mortality especially in centres with limited access to extra-corporeal membrane oxygenation or nitric oxide therapy. In such a setting, we conducted a pilot study to evaluate the effect of dexamethasone on severe respiratory failure with PPHN due to MAS with a view to exploring possible justification for randomised controlled trials in similar patients. We prospectively managed a consecutive case series of 14 infants over a 3-year period with the above mentioned diagnosis, who were ventilated and with an oxygenation index >25. Dexamethasone was commenced in a dose of 0.5 mg/kg per day and given for up to a maximum of 9 days in a reducing schedule. Differences between time points were analysed using analysis of variance for repeated measures. The mean age of commencing dexamethasone was 79.9 h. There was a rapid, significant improvement (P < 0.05) in the respiratory status in 13 of these infants after commencing dexamethasone, allowing weaning from the ventilator and eventual extubation at a mean age of 8.7 days. One infant died. Two infants had infective episodes. Conclusion Dexamethasone, if started early in infants with respiratory failure and persistent pulmonary hypertension of the newborn due to meconium aspiration syndrome may be effective in improving gas exchange, and possibly avoiding extra-corporeal membrane oxygenation. A randomised controlled trial of using dexamethasone early in similar patients and setting is warranted. Received: 18 May 2000 / Accepted: 13 September 2000