Patency Of The Ductus Arteriosus Research Articles

Patency of the ductus arteriosus after balloon dilatation: an experimental study.

Balloon dilatation of the ductus arteriosus was carried out in vivo in newborn pigs and on postmortem specimens from humans and piglets. The ductus was functionally closed in all newborn animals but patency resulted in all animals after balloon dilatation. Left-to-right shunts of 50% to 70% were found with anatomic lumen sizes of 3 to 5 mm. Patency was demonstrated up to 6 weeks after dilatation. Histologic examination showed splitting of the internal elastic layer and media, areas of hemorrhage confined to the media, and preservation of the adventitia. Mediastinal hemorrhage did not occur. This new technique is useful as an animal model of patent ductus arteriosus and could theoretically be used for palliative treatment of ductus-dependent congenital heart disease.

Effect of gestational age on ductus arteriosus response to circulating prostaglandin E 2

Premature newborn lambs with a patent ductus arteriosus have higher plasma prostaglandin E2 concentrations than near-term newborn lambs with a contricted ductus arteriosus. To see whether these concentrations of PGE2 could produce patency of the ductus arteriosus, we studied eight near-term lambs (with constricted ductuses) delivered by cesarean section, paralyzed, and mechanically ventilated. After ductus arteriosus resistance and plasma PGE2 concentrations had stabilized, a continuous PGE2 infusion into the superior vena cava was started to determine threshold concentrations needed to dilate the ductus in vivo. By two hours after birth, circulating PGE2 concentrations in near-term lambs were considerably less then the threshold concentration, and the ductuses were constricted. In five premature newborn lambs, significantly lower concentrations of PGE2 were required to dilate the ductus: threshold and ED50 concentrations were one sixth and one third, respectively. In these premature lambs during the first two hours after birth, circulating PGE2 concentrations were twice as high as the calculated in vivo threshold level. Therefore, circulating PGE2 concentrations probably played a significant role in the patency of the ductus arteriosus in these premature lambs.

Postoperative Ketotic Hyperglycemia During Prostaglandin E1 Infusion in Infancy

Prostaglandin E1 (PGE-1) has recently been approved for intravenous infusion in infants as a palliative treatment in selected cardiovascular anomalies (E. Micalizzi, personal communication, 1981). These include lesions in which patency of the ductus arteriosus is necessary to assure either pulmonary or systemic blood flow.1 In addition to its vasoactive properties, PGE-1 has many metabolic properties, some of which are now coming under close scrutiny. This case report describes the postoperative course of an infant who, while under treatment with PGE-1, became severely hyperglycemic with apparent ketoacidosis. CASE REPORT J.R. was the product of a 35-week gestation as determined by dates. The mother was an insulin-dependent diabetic with renal-vascular involvement.

Cryosurgery of the fetal ductus arteriosus

The effects of cryosurgical treatment of the fetal ductus arteriosus (DA) on the structure and function of the neonatal DA are assessed for the first time. A cryosurgical probe, cooled with nitrous oxide, was used to freeze the wall of the DA in 5 fetal lambs. Six fetal lambs were used as control animals. After birth, all the cryosurgically treated lambs had a patent DA whereas all the control lambs had a closed DA. Only the cryosurgically treated group had these histologic findings: calcific deposits, necrosis and focal ganglion cell necrosis in the outer one third to two thirds of the media with a decrease or loss of muscle cells and elastic fibers. This study suggests the feasibility of developing a cryosurgical approach for maintaining patency of the DA.

Pulmonary artery growth during treatment with oral prostaglandin E2 in ductus dependent cyanotic congenital heart disease.

Growth of the pulmonary arteries was assessed in 11 patients with cyanotic congenital heart disease treated with oral prostaglandin E2. Each patient was dependent on patency of the ductus arteriosus for maintenance of the pulmonary circulation. Measurements were made initially from angiographic data obtained in the neonatal period. Subsequent assessments were made at the time of surgery after an interval of 2-8 months, during which time all the infants had gained weight normally. Comparisons were made with data obtained from 13 normal necropsy specimens. In only 4 of the 11 patients had the pulmonary arteries grown appreciably during the treatment period. In 2 patients no growth occurred, while in 5 patients the pulmonary arteries had actually become smaller. It had been hoped that the pulmonary arteries would grow in all 11 patients during this period, facilitating later surgical intervention. In patients with ductus-dependent cyanotic congenital heart disease, the prolonged use of oral prostaglandin E2 should be restricted to patients in whom the pulmonary arteries are too small to allow a palliative operation to be performed initially.

Administration of E-type prostaglandins in ductus-dependent congenital heart disease.

In 1938 yon Eu/er first demonslrated the remarkable sensitivity of placental vessels to a crude extract from the prostate gland [25]. Nearly 30 years were to elapse before prostaglandins were identified in the human umbilical cord [14]. Subsequently the F-type prostaglandins were shown to cause profound vasoconstriction of isolated umbilical vessels, while the E-series caused vasodilatation [13]. These findings were to have important implications because, in common with the umbilical vessels, the ductus arteriosus is a fetal vessel. Both in vin-o [3] and in vivo [22] experiments confirmed that the E-type prostaglandins (PGE) caused relaxation of ductus arteriosus muscle. In the clinical studies that followed it soon became apparent that infusions of PGE~ or PGE2 were consistently effective in relieving hypoxemia and acidemia in neonates Whose pulmonary blood flow was dependent on patency of the ductus arteriosus [2, 5, 11, 16-19]. A major clinical trial of PGE~ infusion is in progress in the United States and in Europe, several hundreds of neonates having been treated. The indications for treatment have expanded to include not only those with a severe decrease in pulmonary blood flow, but also those who depend on the dUctus arteriosus for a major part of the systemic blood flow, e.g. interrupted aortic arch, juxtaductal COarctation of the aorta and hypoplastic left heart Syndrome [6, 12, 16, 21]. Neonates with complete transposition of the great arteries have also been shown to benefit from PGEI infusions [18, 20]. The increased flow through Address reprint requests ta: Eric D. Silove, MD, FRCP, FRCPE, The Children's Hospital, Ladywood Middleway, Birrningham, BI6 SET, England the ductus fl'om aorta to pulmonary artery with consequent increase in pulmonary blood flow results in an increased puhnonary venous return to the left atrium. Thus, left atrial pressure may rise, encouraging the flow of oxygenated blood across the interatrial communication and thence into the systemic circulation. The earlier clinical reports suggested that PGE should be used as an emergency measure in neonates with pulmonary atresia in order to relieve hypoxemia and acidemia and so improve the prospects of early palliative surgery. It was suggested that the preferred route of administration was via an umbilical artery catheter placed just proximal to the aortic end of the ductus arteriosus [11, 20] and that PGEI might be more effective than PGE2. These choices were influenced by two important considerations: (l) infusion near the origin of the ductus might not only achieve higher concentrations of PGE in that region, but cerebral side effects might be fewer if the infusion was distal to the origins of the cerebral vessels; (2) PGEI is a more powerful pulmonary vasodilator than PGE2 and might therefore promote a greater increase in pulmonary blood flow. However, no clinical evidence has been presented to show that PGE~ is any less effective than PGEI in improving oxygenation in right ventricular outflow obstruction. Similarly, infusion by either the intravenous or the intra-aortic route appears to be equally effective. Both routes of administration have practical difficulties and a significant incidence of side effects [15, 16, 19, 20]. It is likely that these limitations have discouraged prolonged infusions, reports of which have been few [16]. For some years an oral preparation of PGE: has

Alprostadil (Prostin VR Pediatric Sterile Solution, The Upjohn Company).

Alprostadil is a naturally occurring prostaglandin used in the treatment of infants with congenital heart defects to maintain the patency of the ductus arteriosus until palliative or corrective surgery can be performed. In infants with defects restricting pulmonary blood flow (cyanotic), alprostadil improves arterial blood oxygenation. In infants with defects restricting systemic blood flow, alprostadil improves arterial blood pH, urine output, and femoral arterial pulses. Alprostadil is administered by continuous intraarterial or intravenous infusion, usually at a starting dose of 0.1 microgram/kg/min, with maintenance doses as low as 0.002 microgram/kg/min. The most common side effects include fever, apnea, flushing, bradycardia, hypotension, and seizures; although in some cases, some of these effects may be related to the infant's underlying condition. Literature reports of clinical experience with alprostadil are reviewed.

Uptake and metabolism of prostaglandin E 1 in isolated pzbfuseb petal, newborn and adult rabbit lungs

PGE 1 has been used to maintain the patency of the ductus arteriosus in newborns with pulmonary hypertension. However, it is known that adult lungs avidly take up and metabolize circulating PGE 1. We compared the ability of isolated perfused lungs from previable, 26-day gestation, fetal rabbits; newborn rabbits (within 12 hours of birth) and 3 month old adult rabbits to metabolize a 20-second bolus of PGE 1. The concentration of PGE 1 infused was approximately 2 orders of magnitude below the Km for the PGE 1 uptake process so that first order uptake kinetics are assured. The retention time of a vascular marker dye was monitored as an index of pulmonary vascular surface area. In all three sizes of lungs perfusate flow was adjusted to produce an approximately 7 second dye retention time. At these flows the adult lungs inactivate about 45 percent of the infused PGE 1. In contrast, fetal and newborn rabbit lungs both inactivate about 22 percent of the infused PGE 1. We conclude that the ability of the lung to take up and metabolize circulating PGE 1 is markedly reduced in premature and term newborns.

Increased shunt through the patent ductus arteriosus after surfactant replacement therapy

Instillation of surfactant into the trachea of preterm infants with respiratory distress syndrome is associated with a 90% incidence of patent ductus arteriosus. We studied the effects of surfactant therapy on the ductus arteriosus in 12 preterm lambs. Flow across the ductus arteriosus and systemic blood flow were calculated from radioactive microsphere injections. All developed respiratory failure (pH less than 7.1, Paco2 greater than 60) by 30 minutes after birth. Between 30 and 60 minutes after birth, six lambs were treated with tracheal instillation of 50 mg/kg surfactant lipid. By two hours after birth, treated lambs differed significantly from controls in pH (7.27 +0.02 vs 6.97 +0.08) and Paco2 (43.3 +4.1 vs 85 + 15). There were no differences in Pao2 or PGE2 concentrations or ductus arteriosus resistance, but there was a significantly larger shunt through the ductus arteriosus in treated lambs. This increased shunt resulted from the significant drop in pulmonary vascular resistance and not from a change in patency of the ductus arteriosus. Surfactant replacement may require interventions directed specifically at the patent ductus arteriosus in sick preterm infants.

Prostaglandins during pregnancy and the perinatal period.

Administration of prostaglandins (PGs) E-2 and F-2{alpha} will provoke contractions of the human uterus at any stage of pregnancy. The use of these compounds for the induction both of labour at term and of abortion is now widespread and well documented (Bygdeman, 1980). Recently, it has been found that PGs can effect cervical ripening and this property is being put to good clinical advantage (Bygdeman, 1980). There is evidence also that prostaglandin synthetase inhibitors (PGSI) can inhibit uterine contractions in pregnant and non-pregnant women (Wiqvist, 1979). Unfortunately, the therapeutic potential of PGSI, as a treatment for pre-term labour, is drastically reduced by the adverse side effect (now well documented) of closure of the ductus arteriosus in utero, after transplacental passage of the drug, leading to primary pulmonary hypertension of the newborn. The occurrence of this phenomenon is consistent with results from studies using experimental animals, strongly suggesting that PGE maintains the patency of the ductus arteriosus in utero (Coceani, Olley & Bodach, 1976).

1271 PDA WITH SURFACTANT REPLACEMENT THERAPY

Surfactant instillation into the trachea of preterm infants with RDS is associated with a 90% incidence of PDA. We studied the effects of surfactant therapy on the ductus arteriosus (DA) in 12 preterm lambs (.89 gestation). Flow (Q) across the DA and systemic blood flow were calculated from microsphere injections. All 12 lambs were paralyzed and ventilated with 100% O2. All developed respiratory failure (pH<7.1, PCO>60) by 30 min after birth. Between 30-60 mins after birth, 6 lambs were treated with tracheal instillation of 50 mg/kg surfactant lipid (purified from alveolar washes from adult sheep). There were no significant differences between control and treated animals prior to surfactant instillation for PCO2, pH, prostaglandin (PG) E2 concentrations, the ratio of L→R shunt through the DA vs systemic flow (Q shunt/Q syst), DA resistance, or the ratio of pulmonary to systemic vascular resistance (RP/RS). By 2 hr after birth treated lambs differed significantly from controls in pH (7.27±02 vs 6.97±08) and PCO2 (43.3±4.1 vs 85±15). There were no differences in PO2 (146±50 vs 84±44), PGE2 concentrations or DA resistance. However, there was a significantly larger shunt through the DA in treated lambs (Q shunt/syst=.70±.14 vs .25±10). This increased DA shunt was due to the significant drop in pulmonary vascular resistance (RP/RS=.47±.08 vs .76±.08) and not to a change in patency of the DA. Surfactant replacement may require interventions directed at the PDA to adequately treated sick preterm infants.

187 Q-Kd IN NEONATES: RELATIONS TO PDA

The time interval in milliseconds (ms) from the onset of the QRS complex of the EKG to the onset of Korotkoff sounds in the arm at diastolic cuff pressure (Q-Kd) was determined with a microprocessor based instrument (NB-200 Blood Pressure Interval Analyzer; Nicolet Biomedical). The Q-Kd is dependent primarily upon the pre-ejection period & pulse transmission time. A previous study in older patients suggested a shortening of the time with PDA (Am. J. Cardiol. 19: 147, 1967). Forty-one neonates ((wt. 2148 (±835), 700-4000 g; G.A. 34.7 (±3.8), 27-42 wk)) were studied e over 300 Q-Kd determinations obtained. The standard deviation of repeat Q-Kd's in a neonate was within 7% or less of the mean of five repeat determinations. Q-Kd correlated significantly with weight (80 ms 3000 gm) corr. coef. .492, p< .01; y=.0078X + 8.14. The Q-Kd correlated significantly but less well with gestational age. Ten infants treated (Indomethacin or surgery) for a PDA were evaluated serially. There was no correlation of Q-Kd with the PDA open or closed. This negative correlation was probably due to other cardiovascular parameters such as heart failure which also effects Q-Kd. An unexpected finding was that the instrument was extremely accurate in determining systolic & diastolic blood pressure indirectly. In summary, the Q-Kd was not helpful in diagnosing patency or closure of the ductus arteriosus in neonates.

270 EXOGENOUS ARACHIDONIC ACID IS NOT CONVERTED TO PROSTAGLANDIN E2 BY THE LAMB DUCTUS ARTERIOSUS

Prostaglandin (PG) E2 regulates the patency of the ductus arteriosus (DA) in the fetus and preterm neonate. Numerous investigators have used exogenous arachidonic acid (aa), a precursor of PG synthesis, to study the biological effects of endogenous PG production. We have shown that 0.2 μg/m1 aa relaxes isometrically-constricted rings of lamb DA in vitro. Since inhibitors of PGE2 production block this relaxation, we postulated that the conversion of exogenous aa to PGE2 causes the relaxation of the DA. To test this hypothesis, we incubated rings of DA from 8 fetal lambs in buffer containing 0.2 μg/ml aa: 47±25 pg immunoreactive PGE2/mg wet weight/90 min incubation (±SEM, n=8) was measured. This is consistent with the above hypothesis. To see if the measured PGE2 is formed from the exogenous aa added to the incubation media or from the endogenous aa pools within the tissue, we incubated another group of rings in buffer containing 14C-labeled aa. We measured the conversion of 14C-aa to PGE2 and tissue phospholipids by radiochromatographic analysis. Only 0.048±0.019 pg radiolabeled PGE2/mg wet weight/90 min incubation (±SEM, n=9) was measured. Thus, only 0.1% of the PGE2 produced when aa is added to rings of DA is formed from the added aa. Although PGE2 mediates the relaxation caused by exogenous aa, the exogenous aa is not converted to PGE2. Rather, exogenous aa appears to be a potent stimulator of phospholipid breakdown in the DA; the subsequent endogenous aa released is the actual source of the PGE2 produced.

1270 DEVELOPMENT OF PULMONARY METABOLISM OF PROSTAGLANDIN E2

The preterm newborn lamb has high concentrations of circulating prostaglandin E2 (PGE2) that may play a role in maintaining the patency of the ductus arteriosus. PGE2 is removed rapidly from the venous circulation by the lung and is metabolized to its 15-keto metabolites by the intracellular enzyme, 15-OH prostaglandin dehydrogenase (15-OHPD). We studied the ability of the isolated, perfused lung from 100 days gestation (n=8) and near term (term is 150 days) lamb fetuses (n=10) to metabolize PGE2. After an intraaterial infusion of 3H-PGE2 and 14C-inulin (to act as a marker of extracellular space), the majority of 3H activity was cleared through the lung after the 14C activity had fallen to negligible values. The 3H activity that was retained longer in the lung was primarily associated with the 15-keto metabolites of PGE2. Lungs from immature fetal lambs metabolized 25% less PGE2 than did lungs from animals near term. 15-OHPD activity in homogenates of lamb lung is not higher near term than at 100 days. This suggests that transport processes that regulate the uptake of PGE2 into the intracellular compartment, and not 15-OHPD, may represent the limiting step in the pulmonary clearance of PGE2 in the developing lamb lung. This is consistent with our prior observation that premature lambs have decreased plasma clearance rates (in vivo) and elevated circulating concentrations of PGE2 when compared with term newborn lambs.

Oral prostaglandin E2 in ductus-dependent pulmonary circulation.

Prostaglandin E2 (PGE2) was administered orally, in doses of 12-65 microgram/kg at intervals of 1-4 hours, to 12 neonates in whom the pulmonary circulation depended on patency of the ductus arteriosus. After an oral dose, both oxygen saturation (SaO2) and plasma PGE2 concentration increased consistently within 15-30 minutes, reaching values comparable to those during i.v. infusions. Treatment continued for 5 days to 4 months. In eight infants, PGE2 withdrawal resulted in a decrease of SaO2, from a mean of 75 +/- 7% to 57 +/- 10% (+/- SD). The ductus remained responsive for long periods--in four infants, for over 3 months. Consequently, surgery could be delayed until the infants and their pulmonary arteries had grown. Side effects during oral therapy were similar to those during i.v. infusion but were less severe in this series. The effectiveness and simplicity of oral PGE2 administration have advantages over i.v. administration, especially for long-term treatment.

Effect of gestational age on pulmonary metabolism of prostaglandin E 1 & E 2

The fetus and prematurely delivered newborn lamb have high concentrations of circulating PGE 2 that may play a hormonal role, particularly in maintaining the patency of the ductus arteriosus. We studied the ability of the isolated, perfused lung from immature (100 ± 150 days) lamb fetuses to metabolize PGE 2 as a function of PGE 2 concentration in the perfusate. After an intra-arterial infusion of 3H-PGE 2 and 14C-inulin (to act as a marker of extracellular space), the bulk of the 14C-inulin was rapidly cleared through the isolated lung and the majority of the 3H activity appeared after the 14C activity had fallen to negligible values. The 3H activity that was retained longer in the lung was primarily associated with the 15-keto prostaglandin E 2 and 15-keto-13,14 dihydro prostaglandin E 2 metabolites. Lungs from immature fetal lambs metabolized 25% less PGE 2 than did lungs from animals near term. This is consistent with our prior observation that premature lambs have decreased plasma clearance rates (in vivo) and elevated circulating concentrations of PGE 2 when compared with term newborn lambs.

Prostaglandins and the ductus arteriosus.

Fetal patency of the ductus arteriosus is an active state maintained by the relaxant action of a prostaglandin, most probably prostaglandin E2. This PG mechanism is most active in the immature ductus and decreases toward term. The ductus closes when this prostaglandin effect if withdrawn. Indomethacin may induce closure of the patent ductus arteriosus of prematurity. It is most likely to be successful if given intravenously and early in postnatal life. Prostaglandin E1, to maintain patency of the ductus, is now established in the emergency management of several congenital heart defects causing problems in the newborn.

Pharmacology of the Ductus Arteriosus

Dramatic advances in the understanding of the factors that control normal patency of the ductus arteriosus during fetal life and that allow its closure after birth have resulted in major new therapeutic approaches to the management of infants with congenital heart disease. Infusion of PGE 1 and PGE 2 have been used in several congenital malformations to maintain a dilated ductus arteriosus, and indomethacin has been used to constrict a persistently patent ductus arteriosus.

Circulating Prostaglandin E2 Concentrations and Incidence of Patent Ductus Arteriosus in Preterm Infants with Respiratory Distress Syndrome

In several species prostaglandin E2 (PGE2) appears to be the most important prostanoid to regulate patency of the ductus arteriosus. We measured the arterial plasma concentration of PGE2 in 29 premature infants (17 with respiratory distress syndrome alone and 12 with respiratory distress syndrome and patent ductus arteriosus) to determine if there was an association between circulating PGE2 and patent ductus arteriosus. The PGE2 concentrations during the first two days after birth were higher than PGE2 concentrations after the third postnatal day (17.1 +/- 3.1 pg/ml, mean +/- SEM, n = 23, vs 6.12 +/- 0.63 pg/ml, n = 19, P < .005). By the third postnatal day, arterial concentrations were similar to adult venous values. There was no significant difference between the plasma PGE2 concentrations in the 12 infants with patent ductus arteriosus and the concentrations in the 17 infants who had no signs of patent ductus arteriosus. These findings do not support the hypothesis that an increased concentration of circulating PGE2 is the primary cause for the persistent patency of the ductus arteriosus in preterm infants with respiratory distress syndrome.

Medical Treatment of Ductus Arteriosus

In the April 1978 issue of Pediatrics (61:534, 1978) Lewis and Lurie report the use of prostaglandin E1 (PGE,1) (Upjohn) infusion for 29 days in a small-for-gestational age, premature infant with severe tetralogy of Fallot. We have had a similar experience using an intermittent infusion of PGE1, for 18 days in a term infant with transposition of the great vessels and high pulmonary pressure after a balloon septostomy. In an effort to maintain patency of the ductus arteriosus and increased pulmonary blood flow, we began a peripheral infusion of PGE1 at a dose of 0.1 µg/kg/min (the same dose as used by Lewis and Lurie).