Changes in pulmonary circulation in severe bronchopulmonary dysplasia.

Eight patients with severe bronchopulmonary dysplasia underwent cardiac catheterisation. Seven had a pulmonary vascular resistance greater than 3 mm Hg.l-1 min.m2 (mean 8.9, range 2.2-13.8). All had raised intrapulmonary shunts (mean 25.6%, range 5.4-50%, normal less than 5%). Two had a high alveolar dead space, and two had unsuspected congenital heart disease. Epoprostenol (prostacyclin), but not 100% oxygen, caused a significant fall in pulmonary vascular resistance. Death was associated with a high pulmonary vascular resistance and a high shunt. Morphometric studies in three cases showed normal numbers of airways, but increased thickness of bronchial muscle. The numbers of alveoli were reduced and the walls thickened. There was increased medial thickness in small pulmonary arteries with distal extension of muscle. In the oldest child some vessels were obliterated by fibrosis. We speculate that measurements of pulmonary vascular resistance and shunt may have prognostic value; that a trial of pulmonary vasodilators other than oxygen might be worthwhile in patients with poor prognosis; and that abnormalities of the pulmonary circulation contribute to the difficulties of managing patients with bronchopulmonary dysplasia.     

Combination therapy for life-threatening pulmonary hypertension in a premature infant: first report on bosentan use

Premature infants with preterm premature rupture of membranes (PPROM) are at high risk of severe respiratory failure because of lung hypodysplasia associated with persistent pulmonary hypertension of the newborn (PPHN). We describe the clinical course of a 28-week gestation infant with PPROM from the 20th week and prolonged oligohydramnios before delivery, who developed refractory hypoxia treated with oral bosentan as adjunct therapy to inhaled nitric oxide (iNO) and oral sildenafil. Conclusion Our experience suggests that bosentan can be used in the premature infant with PPHN after PPROM. To the best of our knowledge, this is the first report of bosentan treatment in a premature infant.     

Diagnosis and management of pulmonary hypertension in infants with bronchopulmonary dysplasia

Chronic pulmonary hypertension of infancy (cPHi) is a heterogeneous disease process that contributes to morbidity and mortality in preterm infants. cPHi is most commonly associated with chronic lung disease of prematurity and represents a unique phenotype of bronchopulmonary dysplasia. It is characterized by persistently elevated or newly rising pulmonary vascular resistance and pulmonary artery pressure beyond the first weeks of age. The high-pressure afterload on the right ventricle may or may not be tolerated, depending upon additional cardiovascular shunting and co-morbidities. A comprehensive clinical evaluation combined with advanced hemodynamic assessment by echocardiography and other cardiac imaging modalities help decipher the etiopathologies of disease, identify cardiopulmonary compromise earlier and guide individualized therapeutic intervention tailored by the phenotype. This review summarizes the underlying etiologies, risk factors for development, hemodynamic assessment, management, and follow-up of cPHi in preterm infants. We offer an algorithm for early detection of cPHi and outline research priorities.     

早产儿支气管肺发育不良防治环节中早期呼吸支持的策略

虽然呼吸窘迫综合征( RDS)仍然是导致极早和超早早产儿呼吸衰竭最常见疾病,但由于NICU呼吸技术的进步,其已经不再是死亡的主要病因。伴随着 RDS的发生,支气管肺发育不良( BPD)这一成熟依赖性肺疾病的发生和发展成为现代NICU防治的核心疾病之一。在早期呼吸支持策略环节中有以下共识与建议：(1)最大可能的使具有高风险RDS或RDS的极早和超早早产儿期避免气管插管,接受无创通气(nCPAP);(2)早期选择合适的方式接受肺表面活性物质(PS)治疗;(3)个体化的制定nCPAP或其他无创通气失败的标准,尽早接受PS救治和适宜的有创通气模式;(4)缩短通气时间,应用无创通气方式辅以咖啡因治疗降低拔管失败率。这些临床研究成果仍需要不断在实践中改进与完善,BPD的发生是多因素作用的结果,需要多维度的管理的进步才能真正实现有效的防治。     

Lipid intolerance in neonates receiving dexamethasone for bronchopulmonary dysplasia.

BACKGROUND: We hypothesized that dexamethasone induces hypertriglyceridemia (triglyceride levels >2.82 mmol/L [250 mg/dL]) and increases free fatty acid (FFA) levels and that steroid-induced hypertriglyceridemia is associated with hyperinsulinemia and elevated FFA levels. OBJECTIVE: To study the effect of dexamethasone sodium phosphate on lipid metabolism in neonates receiving intravenous lipids. DESIGN: A prospective cohort study with patients serving as their own controls. SETTING: Neonatal Intensive Care Unit, Children's Hospital at Strong, Rochester, NY. METHODS: All neonates younger than 29 weeks' gestational age at birth receiving 3 g/kg per day of intravenous lipids who were to start dexamethasone therapy for bronchopulmonary dysplasia were eligible. Exclusion criteria included neonates with active infection, prior hypertriglyceridemia, bleeding manifestations, recent surgery, thyroid medication, and human recombinant insulin intravenous infusion therapy. Ten neonates were studied. Blood was drawn for triglyceride, FFA, and insulin assays before initiating and at 1, 2, 3, and 5 days after starting dexamethasone therapy. On day 3, dexamethasone dosage was decreased as per protocol. Intravenous lipid intake was kept constant. Statistical analysis was done using a paired t test. RESULTS: Six of 10 neonates reached a state of hypertriglyceridemia (95% confidence interval, 26.2%-87.8%). The mean average increase in triglycerides, insulin, and FFA levels in neonates receiving 3 g/kg per day of intravenous lipids after initiation of dexamethasone therapy was 0.75 mmol/L (66.6 mg/dL) (P=.007), 127 pmol/L (P = .006), and 47.5 micromol/L (P = .65), respectively. Six neonates who developed hypertriglyceridemia had significantly elevated mean peak FFA levels (918.3 micromol/L) prior to developing hypertriglyceridemia compared with 4 neonates (mean peak FFA levels, 380.2 micromol/L) who had triglyceride levels lower than 2.82 mmol/L (250 mg/dL) (P = .002). CONCLUSION: We conclude that dexamethasone induces hypertriglyceridemia in the presence of hyperinsulinemia and increased FFA levels.     

Pharmacokinetics and pharmacodynamics of nifedipine in children with bronchopulmonary dysplasia and pulmonary hypertension

The pharmacokinetics and associated pharmacodynamics of nifedipine were studied in nine children aged 5 to 68 mo with bronchopulmonary dysplasia and pulmonary artery hypertension after a single oral dose of 1.44 mumol/kg (0.5 mg/kg). In the cardiac catheterization laboratory, hemodynamic measurements were made in duplicate just before the nifedipine dose and at 5 min and 0.5 and 1.0 h after the dose. The plasma nifedipine concentration was measured by HPLC at each of the above times and at 2.5, 4.0, 6.0, and 8.0 h after the dose. The mean (+/- SD) maximum plasma concentration and the time to maximum plasma concentration were 243.4 +/- 194.5 nmol/L and 1.0 +/- 0.8 h, respectively. The mean area under the plasma concentration-time curve was 761 +/- 509 nmol.h/L. The mean elimination rate constant and t1/2 were 0.456 +/- 0.194 h-1 and 1.8 +/- 0.8 h, respectively. Nifedipine caused a significant (p less than or equal to 0.05) reduction in the mean pulmonary artery pressure by 5 min and in the mean pulmonary vascular resistance index and mean aortic pressure by 30 min, and these reductions remained significant through the 1-h measurement interval. The magnitude of acute hemodynamic response correlated closely with the plasma nifedipine concentrations. No significant change occurred in the mean arterial oxygen saturation or cardiac index during the study period. The percentage changes from baseline in the mean pulmonary artery pressure and mean pulmonary vascular resistance index were approximately double the percentage change in the mean aortic pressure, suggesting that nifedipine had some degree of selective impact on the pulmonary vascular bed.(ABSTRACT TRUNCATED AT 250 WORDS)     

早产儿支气管肺发育不良相关肺动脉高压诊治研究进展

支气管肺发育不良(BPD)相关肺动脉高压(PH)是早产儿BPD最严重的并发症,是BPD患儿后期死亡的重要原因,近年日益受到关注。肺血管发育异常和重构是PH发生的病理基础。对中重度BPD患儿进行监测和筛查肺动脉压力,可早期诊断BPD相关PH,对BPD相关PH早期防治、改善预后具有重要意义。由于BPD相关PH为慢性过程,持续时间长,治疗仍然比较困难,主要药物是肺血管扩张剂,尚缺乏足够的证据支持,有待更多的研究进一步验证其有效性和安全性。     

Acute hemodynamic effects of nifedipine in infants with bronchopulmonary dysplasia and pulmonary hypertension

The acute hemodynamic effects of nifedipine were evaluated and compared to the effects of 95% oxygen in six children with bronchopulmonary dysplasia and pulmonary artery hypertension. The children ranged in age from 7-26 months and all were oxygen dependent. In the cardiac catheterization laboratory, hemodynamic data were collected in 95% oxygen, room air, and 15 and 30 min after nifedipine administration (0.5-0.6 mg/kg per nasogastric tube). Compared to values in room air, nifedipine resulted in a 34% decrease in pulmonary artery mean pressure (from 69.3 +/- 2.4 to 45.8 +/- 1.2 mm Hg, p = 0.03) and a 49% decrease in pulmonary vascular resistance (from 14.8 +/- 1.4 to 7.5 +/- 0.9 U/m2, p = 0.03). A linear relationship was found between the arterial pO2 and the change in the ratio of pulmonary to systemic resistance after nifedipine (% decrease in Rp/Rs ratio = 86.3 - 1.3 x pO2, r = -0.95, p = 0.004) suggesting that nifedipine may act to oppose the vascular effects of arterial hypoxemia. There was no significant change in heart rate, arterial pO2, or pCO2 with nifedipine, but cardiac output increased significantly. Compared to 95% oxygen, nifedipine achieved a lower pulmonary vascular resistance (7.5 +/- 0.9 versus 10.9 +/- 1.2 U/m2, p = 0.03) and a greater cardiac output (5.25 +/- 0.71 versus 3.54 +/- 0.35 liter/min/m2, p = 0.03) with comparable systemic oxygen delivery (699 +/- 85 ml versus 698 +/- 91 ml O2/min/m2, p = 1.0). Thus, nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Oral sildenafil for treatment of severe pulmonary hypertension in an infant

We report the use of oral sildenafil in a 5-month-old preterm infant with severe bronchopulmonary dysplasia and pulmonary arterial hypertension refractory to inhaled nitric oxide treatment, maximal ventilatory support and conventional vasodilator therapy. Sildenafil was prepared as a liquid suspension by the method of trituration and administered via an orogastric tube to the patient. Forty-eight hours after sildenafil treatment, echocardiography revealed that the tricuspid incompetence was substantially diminished and the contractility of both ventricles improved, indicating a marked reduction in pulmonary arterial pressure. Oral sildenafil treatment was continued for 6 months until complete resolution of pulmonary arterial hypertension, and oxygen supplement was weaned off. There was no adverse effect during the treatment period. Oral sildenafil may be useful in reducing pulmonary vascular resistance and can be considered for treatment of severe pulmonary arterial hypertension secondary to bronchopulmonary dysplasia.     

早产儿支气管肺发育不良伴肺动脉高压的临床特征及预后

目的 调查早产儿支气管肺发育不良（BPD）并发肺动脉高压（PH）的临床特征及预后。方法 对191例BPD患儿的临床资料进行回顾性分析。结果 191例BPD患儿中,37例（19.4%）在纠正胎龄36周后并发PH,均发生于中度和重度BPD患儿,中度、重度BPD患儿的PH发生率分别为5.7%（5/87）和47.8%（32/67）。并发PH组患儿的出生胎龄、出生体重明显小于无PH组患儿（P < 0.01）;并发PH组患儿小于胎龄儿（SGA）比例、重度BPD比例、动脉导管未闭（PDA）手术率及新生儿呼吸窘迫综合征、有血流动力学意义的PDA、肺部感染的发生率明显高于无PH组（P < 0.01）;并发PH组患儿的吸氧、气管插管、正压通气时间均明显大于无PH组（P < 0.01）;并发PH组患儿的早产儿视网膜病、宫外生长发育迟缓发生率及病死率均明显高于无PH组,住院时间明显延长（P < 0.01）。37例PH患儿中（6例为轻度PH,14例中度,17例重度）,轻、中度PH患儿均存活,重度PH患儿中15例（88%）死亡。结论 中重度BPD患儿的PH发生率较高,建议定期筛查BPD患儿的肺动脉压力。低出生胎龄和体重、SGA和重度BPD患儿更易并发PH。BPD并发PH患儿的并发症发生率和病死率较高,预后相对不良。     

支气管肺发育不良的肺血管发育与肺动脉高压的诊断和治疗相关问题

肺动脉高压( PH)是支气管肺发育不良( BPD)的严重并发症,伴随着高病死率,肺血管发育的异常、肺血管的高反应性及结构的重建是导致PH的病理生理基础,本病临床症状隐匿,与本身肺部疾病难以鉴别,出现症状后诊断往往不可逆,建议具有高危因素的BPD患儿应常规进行筛查。心脏超声是无创、动态监测最常用的检查手段,对治疗效果不佳者行心导管或CT检查排除心血管异常,治疗包括急性阶段的综合治疗和降低肺动脉压力的药物选择,早期诊断、治疗将改善其预后。     

Bronchial compression in an infant with isolated secundum atrial septal defect associated with severe pulmonary arterial hypertension

Symptomatic pulmonary arterial hypertension (PAH) in patients with isolated atrial septal defect (ASD) is rare during infancy. We report a case of isolated ASD with severe PAH in an infant who developed airway obstruction as cardiomegaly progressed. The patient presented with recurrent severe respiratory insufficiency and failure to thrive before the repair of the ASD. Echocardiography confirmed volume overload on the right side of heart and severe PAH (tricuspid regurgitation [TR] with a peak pressure gradient of 55 to 60 mmHg). The chest radiographs demonstrated severe collapse of both lung fields, and a computed tomography scan showed narrowing of the main bronchus because of an intrinsic cause, as well as a dilated pulmonary artery compressing the main bronchus on the left and the intermediate bronchus on the right. ASD patch closure was performed when the infant was 8 months old. After the repair of the ASD, echocardiography showed improvement of PAH (TR with a peak pressure gradient of 22 to 26 mmHg), and the patient has not developed recurrent respiratory infections while showing successful catch-up growth. In infants with symptomatic isolated ASD, especially in those with respiratory insufficiency associated with severe PAH, extrinsic airway compression should be considered. Correcting any congenital heart diseases in these patients may improve their symptoms.     

Pulmonary vascular response to oxygen in infants with severe bronchopulmonary dysplasia

The cardiac catheterization data of six infants with bronchopulmonary dysplasia (BPD) were reviewed to examine the responsiveness of their pulmonary vascular beds to changes in oxygen tension. The infants were studied because of slow recovery from their oxygen requirements and clinical evidence of persistent pulmonary hypertension. All were receiving home oxygen therapy and had abnormal chest radiographs and right ventricular hypertrophy by ECG at the time of catheterization (mean age, 25 months). All infants had mean pulmonary artery pressure greater than 25 mm Hg in room air, with a mean of 48 mm Hg. All decreased mean pulmonary artery pressure by at least 10 mm Hg when placed in high levels of inspired oxygen (FiO2 greater than 80), with a mean pulmonary artery pressure of 25 mm Hg. This represented a significant decrease in mean pulmonary artery pressure from room air pressures (P less than .005). Mean pulmonary artery pressure was also measured in three infants who were breathing supplemental oxygen by nasal cannula at flow rates similar to levels used for outpatient therapy. Most of the reduction in mean pulmonary artery pressure that occurred at high FiO2 occurred at these lower flow rates of supplemental oxygen. It is concluded that infants with bronchopulmonary dysplasia who have pulmonary hypertension generally have reactive pulmonary vascular beds, responsive to supplemental oxygen. Continuous oxygen therapy by nasal cannula may be useful in the treatment of pulmonary hypertension associated with bronchopulmonary dysplasia.     

Childhood sequelae of infant lung disease: exercise and pulmonary function abnormalities after bronchopulmonary dysplasia

To determine the long-term pulmonary sequelae and effect on exercise tolerance of bronchopulmonary dysplasia (BPD), we studied 10 children at a mean age of 10.4 years, who had been born prematurely, survived respiratory distress syndrome, and subsequently developed BPD, and compared them with eight age-matched normal children born at term. Pulmonary function tests and graded exercise stress tests were performed. Residual volume, the ratio between residual volume and total lung capacity, vital capacity, forced expiratory volume in 1 second, forced expiratory flow between 25% and 75% of vital capacity, and maximal expiratory flows at 80%, 70%, and 60% of total lung capacity were all abnormal (P less than 0.02) in the children with BPD, compared with control values. Pre-exercise transcutaneous CO2 tension was higher (P less than 0.05) in the BPD group than in the control group. At maximal workload, tcPCO2 remained high in patients with BPD compared with control values (P less than 0.05). Arterial oxygen saturation at maximal workload fell below pre-exercise levels in the BPD group (P less than 0.05) but not in control children. There were no differences in maximal oxygen consumption between the BPD group and control children. Exercise-induced bronchospasm occurred in 50% of the BPD group, but not in the control group. We conclude that long-term survivors of BPD have evidence of airway obstruction, hyperinflation, and airway hyperreactivity, compared with a control group. Aerobic fitness was not significantly different in the BPD and control groups, but was achieved in the BPD group at the expense of a fall in SaO2 and a rise in tcPCO2.     

Prognosis factors in severe bronchopulmonary dysplasia. A retrospective study of 65 premature infants with bronchopulmonary dysplasia

The annual incidence of bronchopulmonary dysplasia (BPD) is presently 1.3 case p. 1,000 alive births. The most severe forms of BPD are characterized by a prolonged oxygen-dependence and a spontaneous evolution marked by numerous complications which could be life-threatening. We studied retrospectively 65 premature infants with BPD who underwent ventilation for one month or more during the first weeks of life. Comparison between survivors and children deceased during the first year of life allowed for discerning 5 prognostic criteria: the nature and severity of initial respiratory disease, the respiratory improvement during the first trimester, the results of hematosis by age 3 months, the ability of maintaining and increasing the respiratory improvement while reducing the therapeutic management, the weight and head circumference gains. The respective parts and conditions of oxygen therapy and prolonged mechanical ventilation in severe cases of BPD are discussed.     

Fatal pulmonary arterial hypertension in an infant girl with incontinentia pigmenti

We report the case of an infant girl with incontinentia pigmenti (IP) complicated by fatal pulmonary arterial hypertension (PAH). She was diagnosed with IP, based on the presence of specific skin lesions, neonatal seizures, hypereosinophilia and a maternal family history of IP. At the age of 2 months, she was diagnosed with PAH on systolic heart murmur due to tricuspid valve regurgitation. Despite several treatments for PAH but not including epoprostenol, severe PAH persisted and she died of pulmonary hypertensive crisis at the age of 5 months. On postmortem histopathology the pulmonary artery had severe intimal thickening, with occlusion or stenosis of the vascular lumen of the small pulmonary arteries as well as partial plexiform lesions, all of which were compatible with PAH. Modulation of nuclear factor‐κB signaling may be involved in the development of PAH in IP.     

Observations of a support group for parents of children with severe bronchopulmonary dysplasia

Parents of children with bronchopulmonary dysplasia (BPD) suffer severe stress and anxiety. In order to provide a group of peers and ready access to caregivers, a support group was developed for the families of children with severe BPD. Fifty percent of invited families attended 1 to 11 monthly meetings. Those attending were primarily upper middle social class, white, married parents with a good visiting record. Members initially focused on specific topics (medical and developmental problems), but later discussions were oriented to psychosocial problems. Many parental anxieties had never previously been discussed with staff members. Commonly, parents complained about not understanding the medical care system. The parents were usually aware of the death of a child with BPD prior to the meeting and dealt with their feelings in the group discussion. Continuing interactions outside the hospital were common. The development of similar groups in other hospitals should be encouraged.