Morphologic analysis of the pulmonary vascular bed in infants exposed in utero to prostaglandin synthetase inhibitors.

Since the effects of prostaglandin synthetase inhibitors on the developing human fetal pulmonary vasculature are unknown, we studied the lungs of two infants, one whose mother took salicylates and the other whose mother took indomethacin during pregnancy. Lungs were fixed by perfusion and fifth generation (resistance) vessels identified. The infant with chronic exposure to aspirin had premature constriction of the ductus arteriosus, tricuspid insufficiency, increased pulmonary arterial medial width/external diameter ratio due to increased smooth muscle, and a decreased number of pulmonary vessels/cm2 lung tissue. The infant with short-term exposure to indomethacin had hypoxemia, increased pulmonary arterial m/d ratio due to increased smooth muscle, and a normal number of pulmonary vessels/cm2 lung tissue. These abnormalities may be due to the effects of prostaglandin synthetase inhibitor drugs on the ductus arteriosus and/or the pulmonary vessels of the human fetus.     

Constriction of the fetal ductus arteriosus after administration of indomethacin to the pregnant ewe.

The prostaglandin synthetase inhibitor indomethacin was given orally or intravenously to pregnant ewes. This resulted in the fetal pulmonary to systemic arterial mean blood pressure difference across the ductus arteriosus rising significantly, presumably secondary to constriction of the ductus arteriosus. The pressure difference was due to pulmonary arterial hypertension, and not due to a fall in systemic arterial mean blood pressure. Fetal arterial blood gas tensions and pH values were normal throughout. In five experiments the pressure difference could be promptly but temporarily reversed by the administration of PGE1 into the fetal inferior vena cava. Indomethacin was present in fetal blood, and maternal plasma prostaglandin levels were suppressed. Indomethacin administration during pregnancy causes constriction of the fetal ductus arteriosus and fetal pulmonary arterial hypertension which, if severe, may cause rapid fetal death. It is possible that this mechanism may be one cause of persistent pulmonary hypertension or tricuspid insufficiency or both in the newborn infant.     

Ligating the ductus arteriosus before birth causes persistent pulmonary hypertension in the newborn lamb

We determined whether closing the ductus arteriosus of the fetal lamb several d before birth would cause persistent pulmonary hypertension after birth. Six experimental fetuses who had their ductus arteriosus ligated 3-17 d before delivery, three control fetuses who had sham ligation of the ductus arteriosus 14 d before delivery, and six control fetuses who had no prenatal surgery were delivered by cesarean section between 138 and 144 d of gestation. Each was instrumented to measure pulmonary and systemic arterial pressures and pulmonary blood flow. Each newborn lamb was ventilated with room air during the first 45 min after birth and then with decreasing amounts of inspired oxygen from 100 to 9%. Pulmonary arterial pressure decreased significantly when ventilation was begun in the control lambs but not in the lambs who had their ductus arteriosus ligated before delivery. Throughout the experiment, pulmonary arterial pressure and total pulmonary resistance were significantly higher, and pulmonary blood flow was significantly lower in the lambs who had their ductus arteriosus ligated before delivery. In two of them, pulmonary arterial pressure was greater than or equal to systemic arterial pressure, even during ventilation with 100% oxygen. This animal preparation provides a method of investigating persistent pulmonary hypertension in the newborn lamb and may provide insight into an etiology of the syndrome of persistent pulmonary hypertension of the newborn.     

Aortopulmonary transposition in the fetus: speculation on pathophysiology and therapy

Fetuses with transposition and abnormalities of the foramen ovale and/or ductus arteriosus detected by ultrasound may develop severe hypoxemia postnatally. Higher than normal oxygen content in the pulmonary artery has been considered to be responsible. Patterns of blood flow in the normal fetus and the fetus with aortopulmonary transposition were reviewed. Well-oxygenated ductus venosus is preferentially directed through the foramen ovale into the left atrium. Normally this produces a higher oxygen content in the ascending aorta. In the fetus with transposition, pulmonary arterial oxygen content is higher. Pulmonary vascular resistance is decreased and the ductus arteriosus constricted. Increased pulmonary venous return to the left atrium tends to close the foramen ovale. Changes are more likely in the last trimester because sensitivity of the pulmonary circulation and ductus arteriosus increases. Severe ductus arteriosus constriction could result in pulmonary arterial hypertension and increased pulmonary arteriolar smooth muscle development. Variability of responses could be related to the proportion of umbilical venous blood passing through the ductus venosus. It is proposed that, in fetuses with evidence of abnormalities of the ductus arteriosus and/or the foramen ovale, methods to occlude the ductus venosus be developed to avoid progressive changes.     

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.     

Ligating the ductus arteriosus before birth remodels the pulmonary vasculature of the lamb

The clinical syndrome of persistent pulmonary hypertension of the newborn includes a developmentally abnormal pulmonary microvasculature which contains excessive amounts of muscle and which cannot adapt to air breathing in the perinatal period. Surgical ligation of the ductus arteriosus of the fetal lamb has produced a physiologic model of pulmonary hypertension of the newborn. The aim of the present investigation is to determine whether surgical ligation of the ductus arteriosus in fetal sheep produces anatomic changes in the pulmonary blood vessels. The pulmonary vasculature of seven neonatal lambs that underwent surgical ligation of the ductus arteriosus from 6 to 17 d before birth was compared to that of five control lambs with a patent ductus arteriosus without fetal surgery and three control lambs with a patent ductus arteriosus that underwent sham surgery. Quantitative microscopic analysis of the barium gelatin-filled peripheral pulmonary vascular bed revealed an increase in the proportion of partially and fully muscularized pulmonary arteries at the level of the terminal bronchiole and within the acinus (p less than 0.0001). This finding demonstrates that medial muscle develops in areas of the distal pulmonary vascular bed where it is normally absent. Periadventitial fibrosis surrounding intraacinar pulmonary arteries was also present. No change in the number of small intraacinar arteries was detected. This structural remodeling of the peripheral pulmonary vascular bed was initiated in utero by ductus arteriosus occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of increased pulmonary vascular pressures on the closure of the ductus arteriosus in newborn lambs

Neonatal conditions associated with increased pulmonary artery pressure have an increased incidence of patent ductus arteriosus. We operated on 15 near term fetal lambs and placed mechanical occluders into or around both branch pulmonary arteries so that main pulmonary artery blood pressure could be controlled. The lambs were delivered and ventilated for 4 h. In seven lambs, the branch vessels were obstructed so that pulmonary artery pressure increased to equal aortic pressure; in eight lambs (control), the branch vessels were not obstructed. There were no significant differences between the two groups in circulating prostaglandin E2 or 6 keto F1 alpha concentrations, PaO2, pH, or PaCO2. Despite these similarities, ductus resistance in the lambs with elevated pulmonary pressure was significantly less than that in the control lambs. After the 4 h measurements, we studied the ductus in vitro. We have previously found that ductus arteriosus constriction produces ischemia of its muscle wall that limits its ability to dilate or constrict any further. Ductus from lambs with elevated pulmonary pressure had a significantly increased ability to respond to oxygen, prostaglandin E2, and indomethacin compared with ductus from control lambs; these findings are consistent with less ductus constriction in vivo. Thus, the high incidence of patent ductus arteriosus in neonates with elevated pulmonary vascular resistance may be due in part to the increased pulmonary vascular pressure, which opposes ductus constriction and preserves ductus responsiveness. Conversely, the normal drop in pulmonary pressure that occurs in full term infants may facilitate the closure of the ductus after delivery.     

Familial persistent pulmonary hypertension.

We report three siblings who presented with a clinical picture of persistent pulmonary hypertension of newborn and died between 4 and 15 days of age. Pulmonary artery pressure in all was above systemic values, with a right to left shunt via either the foramen ovale or ductus arteriosus, or both. Histology of the pulmonary vascular bed showed extension of muscle into small arteries which are normally non-muscular.     

Pulmonary arterial changes in patients with ventricular septal defects and severe pulmonary hypertension

Summary In 25 patients, aged eight months to 31 years, with ventricular septal defect (VSD; isolated in 15, the others with atrial septal defect, PDA, coarctation or patent ductus arteriosus + coarctation), each with severe pulmonary artery hypertension (pulmonary artery systolic pressure [Ppa] at least 75% of systemic and an elevated pulmonary vascular resistance), we related morphologic and morphometric data from open-lung biopsy to hemodynamic measurements obtained at cardiac catheterization during the same hospital admission. Of the hemodynamic features measured, only the ratios of pulmonary-to-systemic flow and pulmonary-to-systemic resistance correlated significantly with structure. Neither pulmonary artery pressure (Ppa) nor pulmonary vascular resistance correlated significantly with any structural feature studied. The increased external diameter of respiratory bronchiolar arteries in those with the more advanced Heath-Edwards grades reflects dilatation and suggests that it is in the small arteries of the distal arterial bed that the changes of pulmonary hypertension are most significant. Neither age nor body weight correlated significantly with the degree of structural or hemodynamic abnormality. In the ten patients who underwent VSD closure, Ppa was measured postoperatively. The Heath-Edwards grade (no more than one grade-III lesion) and arterial density (at least one-half that normal for age) were the best correlates of the difference between preoperative Ppa and Ppa immediately after corrective surgery. The presurgical catheterization data, including pulmonary resistance and the resistance ratio, did not correlate significantly with change in Ppa following VSD closure. Lung biopsy is an important diagnostic aid because it helps in predicting the early response in postoperative Ppa in patients with VSD and elevated pulmonary vascular resistance.     

Pulmonary vasculature changes associated with idiopathic closure of the ductus arteriosus and hydrops fetalis

Summary Antenatal closure of the ductus arteriosus has been considered as a potential risk factor for the development of hydrops fetalis and persistent fetal circulation of the newborn. We present an infant with antenatal ductal closure who had not received prenatal prostaglandin synthetase inhibitors. The pulmonary vascular morphological findings are described and compared to three additional infants in whom the ductus arteriosus was known to be patent; one with neonatal sepsis and two others with hydrops fetalis.The infants with fetal hydrops, regardless of etiology, had increased muscularization of the acinar pulmonary arteries. In addition, the infant with antenatal closure of the ductus arteriosus also had both a significant decrease in preacinar arterial external diameter and an increase in medial wall thickness. Antenatal closure of the ductus arteriosus appears to enhancein utero pulmonary blood flow and this may be the cause of pulmonary vascular remodeling.     

Tetralogy of Fallot, cardiac hypertrophy, pulmonary hypertension, and anomalies of great vessels in fetuses and neonates of WKY/NCrj rats

We examined anatomically the hearts, lungs, and great vessels of 269 WKY/NCrj rats at three fetal and three neonatal stages. Severe pulmonary valve thickening was present in 16 and ventricular septal defects with overriding of the aorta in 15 of the 90 near-term fetuses and in 10 and nine, respectively, of the 79 neonates at 2-4 d of age. These abnormalities occurred together (tetralogy of Fallot) in seven of the near-term fetuses and in five of the neonates. A narrow pulmonary outflow tract was present in 55% of the fetuses and in 56% of the neonates. The wall of the pulmonary arterial branch was abnormally thick in 19% of the fetuses and in 26% of the neonates, most of which did not have septal defects. In about 80% of the fetuses, the middle latitudinal muscle bundle of the ventricular septum was not continuous with the left ventricular free wall, but rather with the right; after birth, it was discontinuous with both free walls. The heart was abnormally heavy in 49% of the 79 neonates. In about half of the heavy hearts, there were no septal defects or pulmonary valvular and arterial lesions. There were double aortic arches in four and right aortic arches in six of the total WKY fetuses and neonates; the ductus arteriosus was abnormally small in 47% and the aorta was large in 51% of the near-term fetuses. This constellation of congenital heart disease is genetic in origin, but altered by hemodynamics late in fetal life.     

Effects of indomethacin in utero on the pulmonary vasculature of the newborn guinea pig

The clinical syndrome of persistent pulmonary hypertension of the newborn results from failure of the normal perinatal vascular adaptation, and functionally is characterized by persistent right to left shunting of blood through the foramen ovale and ductus arteriosus. Exposure of the fetus to drugs that inhibit prostaglandin synthesis and cause closure of the ductus arteriosus has been suggested as one cause of persistent pulmonary hypertension of the newborn. We attempted to produce a functional and structural model of persistent pulmonary hypertension of the newborn by administration of indomethacin, a cyclooxygenase inhibitor, to pregnant guinea pigs. Five pregnant guinea pigs received 3.5 mg/kg indomethacin intravenously twice each day for the 12 to 19 days before delivery and seven controls received saline. Hemodynamic studies were performed in eight "treated" newborns and in 12 controls. After sacrifice, the ductus was ligated and, for morphometric studies, the pulmonary arteries were distended with barium/gelatin. The treated animals did not show the intraacinar structural or hemodynamic changes of persistent pulmonary hypertension of the newborn. It seems that the indomethacin did cross the placenta because lung structure was modified. The radical alveolar count and alveolar/artery ratio were increased and the preacinar arteries dilated, with more increase in muscle mass. This could be explained by increased pulmonary blood flow because of ductal constriction but direct effect of indomethacin cannot be excluded.     

Effects of prostaglandin H2 on perinatal pulmonary circulation

A pivotal intermediate in prostaglandin (PG) biosynthesis is the endoperoxide PGH2. This endoperoxide is capable of eliciting direct responses in biological systems without undergoing conversion to other PGs. Effects of PGH2 include stimulation of platelet aggregation and vascular smooth muscle contraction in vitro; injections of PGH2 in vivo cause increases in pulmonary arterial pressure. The response of the pulmonary vasculature of perinatal lambs to PGH2 was measured using an in situ pump-perfused left lower lung preparation. Intrapulmonary injections of PGH2 (0.24-0.61 microgram/kg) into six unventilated fetal lambs (0.93-0.97 gestation) produced decreases in pulmonary vascular resistance (PVR) of 10-21%. The fall in PVR was rapid in onset, reached a peak at 10 s after injection, and returned to baseline within 35 s. Following ventilation (FIO2 = 0.21) of fetal lambs, injections of PGH2 (0.24-0.61 microgram/kg) caused increases in PVR (ave increase = 50% over control PVR). The pulmonary pressor response to PGH2 in ventilated fetal lambs was depressed almost 50% by inhibition of thromboxane synthetase. Injections of a "heat-inactivated" PGH2 did not affect PVR in ventilated fetuses. We did not observe any effects on systemic blood pressure or heart rate of intrapulmonary arterial injections of PGH2. These findings suggest a metabolism of PGH2 to dilator PGs before ventilation and constrictor PGs and thromboxanes after ventilation, and/or direct effects of PGH2 on vascular smooth muscle that are dependent on existing vascular tone.     

Management of cardiac dysfunction in neonates with pulmonary hypertension and the role of the ductus arteriosus

Pulmonary hypertension in the neonate is associated with cardiopulmonary disturbances and neurodevelopment morbidity. The patent ductus arteriosus is a persistent fetal shunt that can be pathologic vs supportive in the setting of neonatal pulmonary hypertension. Understanding the underlying pathophysiology of pulmonary hypertension and the cardiopulmonary effects of various phenotypes can guide management in this vulnerable population. In this narrative, we will summarize the physiologic principles of pulmonary hypertension, the impact of the patent ductus arteriosus on various phenotypes, and the utility of serial targeted neonatal echocardiography to individualize clinical assessment and management.     

Diagnosis and management of primary pulmonary hypertension

Pulmonary arterial hypertension in children can occur secondary to shunt lesion like ventricular septal defect, patent ductus arteriosus or it may be idiopathic, the so-called primary pulmonary hypertension (PPH). The progression of PPH is usually rapid in children as compared to adults and the mean survival is 2–3 years after the diagnosis is made. Histological changes in the form of medical muscular hypertrophy, intinal hyperplasia and later angiornatous, plexiform lesions occur in pulmonary vasculature. The pulmonary vasculature normally is a high flow, low resistance circuit and allows large blood flow without marked increase in pulmonary arterial pressure. However, with prolonged increased flow or any other vasoconstrictor stimulus, histological changes start occuring in the pulmonary bed resulting in increasing pressure in pulmonary artery. Right ventricular hypertension follows resulting in right ventricular hypertrophy and later dysfunction. Life threatening arrhythmias may result in sudden death in some of these patients. Clinical presentation is in the form of exertional dyspnoea with syncope at times. Over 50% of children with PPH are helped by vasodilators. They may be treated with calcium channel blockers (e.g. nifedipine, dose titrated to blood pressure) orally. Those not responding to oral vasodilators can be put on chronic inhaled nitric oxide or continuous intravenous prostacyclin infusion. Chronic anticoagulation therapy may also increase survival. In symptomatic cases, blade/balloon atrial septostomy may increase survival in patients of PPH with intact atrial sptum. For children not responding to medical therapy, lung transplantation may be the answer in near future.     

Interventional stent implantation in a child with patent ductus venosus and pulmonary hypertension

 We report on the rare case of a 4-year-old boy with patent ductus venosus and pulmonary hypertension presenting with progressive fatigue, tachypnoea at rest and tachycardia. Cardiac catheterisation revealed suprasystemic pressure in the pulmonary arteries with severely elevated pulmonary vascular resistance. In order to reduce the diameter of the ductus venosus, a stent was implanted interventionally, which closed, as expected, spontaneously 2 years later. Pulmonary arterial pressure and pulmonary vascular resistance decreased significantly and the general condition of the boy improved dramatically. Conclusion To the best of our knowledge, this represents the first report of successful interventional stent occlusion of a patent ductus venosus associated with severe pulmonary hypertension. The future will tell whether this intervention is curative or represents a bridging procedure for subsequent liver transplantation. Received: 21 September 2000 / Accepted: 14 March 2001     

肺动脉高压病因学最新研究进展

肺动脉高压(pulmonary arterial hypertension,PAH)是一组少见的、预后不良的疾病,以进行性增高的肺动脉压力和阻力为特征.其病理变化包括肺血管收缩与重构、肺血管平滑肌和内皮细胞的异常增殖、血栓形成等.PAH的发病机制复杂,最新研究表明肺动脉高压病因包括骨形成蛋白Ⅱ型受体(BMPR2)和活化素受体样激酶(ALK1)等遗传基因变异以及过氧化物酶增殖物激活受体(PPAR)、Rho激酶信号通路等的异常.这为肺动脉高压的治疗和预防提供了更多的理论依据.     

Effects of prostaglandin D2 on pulmonary arterial pressure and oxygenation in newborn infants with persistent pulmonary hypertension

We studied the effects of prostaglandin D2 (PGD2) in six newborn infants, 1 to 2 days of age, who had persistent pulmonary hypertension syndrome and a PaO2 less than 75 torr during mechanical hyperventilation with an inspired oxygen concentration of 100%. Tolazoline and dopamine were used to treat some of the patients. No patients had congenital heart disease or sepsis. Catheters were placed to measure pulmonary and systemic arterial blood pressures. PGD2 was infused intravenously at doses of 1 to 25 micrograms/kg/min. Pulmonary and systemic arterial blood pressures, heart rate, and descending aortic blood gas values were measured before each dose change. Only two of six patients had a transient increase in PaO2. All had an increase in heart rate. Two of six patients had an increase in pulmonary arterial blood pressure. No deleterious effects occurred during the infusion. Four of six patients subsequently died. Although PGD2 is a specific pulmonary vasodilator in fetal and newborn animals, it did not lower pulmonary arterial blood pressure nor improve oxygenation in newborn infants with persistent pulmonary hypertension syndrome.     

Maternal diclofenac sodium ingestion and severe neonatal pulmonary hypertension

We describe a case of severe pulmonary hypertension and transient right-sided hypertrophic cardiomyopathy in a neonate, caused by premature closure of ductus arteriosus after short-term maternal use of diclofenac sodium (Voltaren). In view of this associated complication, diclofenac sodium should be avoided during pregnancy. In addition, maternal diclofenac sodium ingestion should be suspected if a newborn develops severe pulmonary hypertension and/or right-sided hypertrophic cardiomyoptathy with closed ductus arteriosus.