Prostaglandins and the ductus arteriosus.
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Ductus Arteriosus↗
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The pharmacologic closure of the patent ductus arteriosus.
The ductus arteriosus is a fetal vessel that allows most of the blood leaving the right ventricle of the heart to bypass the lungs. Fetal patency of the ductus, and its spontaneous closure after birth, is the result of a balanced interaction of locally produced and circulating mediators (of which prostaglandins seem to be the most important), and the unique structure of the vessel wall. Persistent patency of the ductus occurs in almost 60% of very low birthweight infants. A significant left-to-right shunt through the ductus increases morbidity and mortality in premature infants. As prostaglandins play a major role in patency of the ductus, cyclooxygenase inhibitors are conventionally used to induce its closure. This chapter focuses on some of the basic mechanisms underlying ductal patency and the clinical attempts to diminish side effects associated with indomethacin, including the alternative use of ibuprofen.
Cyclooxygenase Inhibitors↗
Comparative tolerability of pharmacological treatments for patent ductus arteriosus.
The ductus arteriosus is a vascular channel which, although vital to the fetal circulation, rapidly becomes unnecessary and even deleterious after birth. As such, it is 'preprogrammed' to constrict within the first few hours of life. In infants born prematurely this natural closure is often delayed and/or ineffective. In this review, we summarise the current knowledge of the delicately orchestrated control of normal ductal closure, with emphasis on the role of various biochemical mediators. The major focus of this review, however, is on pharmacological approaches designed to prevent and/or treat the persistently patent ductus arteriosus (PDA) which often fails to constrict spontaneously in the premature infant. The standard treatment regimen is based on the administration of 3 doses of the nonselective cyclo-oxygenase inhibitor, indomethacin. We begin by examining, from the vantage point of the ductus, the use of this indomethacin as a tocolytic. It seems that antenatal administration of indomethacin can cause transient, reversible ductus constriction which renders the post-treatment ductus resistant to subsequent closure, both natural and therapeutic. We then review some of the pros and cons associated with the prophylactic administration of indomethacin. Although prophylactic indomethacin is aimed primarily at preventing intraventricular haemorrhages in premature neonates, it does tend to reduce the risk of PDA as well. We then describe some novel therapeutic approaches to effect ductal closure with indomethacin, including the use of continuous infusions to minimise toxic vasoconstrictive phenomena and the use of prolonged maintenance dose to prevent PDA recurrences. Finally we discuss some of the newer agents described more recently which play a role in closing the persistently patent ductus over the next decade. Most prominent of these is ibuprofen which some studies have shown to have less undesirable vasoconstrictive adverse effects. Studies which compare the use of ibuprofen to indomethacin are summarised.
Cyclooxygenase Inhibitors↗
3-D CT angiographic demonstration of a neonatal ductus arteriosus aneurysm with development of ductal calcification: are the "ductus bump", ductus arteriosus aneurysm, and ductal calcification related?
A "ductus bump" was noted as an incidental finding on a chest radiograph in a newborn infant with congenital cystic adenomatoid malformation. A chest CT performed on the first day of life demonstrated this to be a ductus arteriosus aneurysm (DAA), which subsequently thrombosed. Ductal calcification was noted on follow-up imaging. We propose that the "ductus bump" may actually be a DAA, which resolves presumably by thrombus formation. Ductal calcification may also be related to the regression of the thrombus.
Aneurysm↗
Persistent responsiveness of the neonatal ductus arteriosus in immature lambs: a possible cause for reopening of patent ductus arteriosus after indomethacin-induced closure.
Reopening of the ductus arteriosus after successful indomethacin-induced closure has become a major problem with indomethacin treatment. In full-term human newborns and lambs, the ductus behaves like ischemic tissue after its initial constriction. Its ability to continue to relax or contract depends on the amount of left-to-right shunt through the ductus lumen. To see if ductus constriction in preterm lambs would produce the same loss of ductus responsiveness, we delivered 42 lambs by cesarean section and ventilated them for 6.6 +/- 0.5 (+/- SE) hr. We measured ductus arteriosus resistance and left-to-right shunt with the use of radionuclide-labeled microspheres. After the hemodynamic measurements were obtained, the ductus was studied in vitro. Immature lambs were more likely to have reactive ductus (after their initial ductus constriction) than were more mature lambs. This was due to a diminished degree of ductus constriction as well as persistence of ductus responsiveness in immature lambs when compared with more mature lambs. This persistence of ductus responsiveness in immature lambs after ductus constriction may account for the high reopening rate in preterm infants after successful indomethacin-induced closure.
Animals↗
[Thrombosis of the ductus arteriosus. Contribution on the pathology of the ductus arteriosus in the newborn].
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Autopsy↗
Retrievable patent ductus arteriosus plug for interventional, transvenous occlusion of the patent ductus arteriosus. Evaluation in lambs and preliminary clinical results.
RATIONALE AND OBJECTIVES: The clinically most widely used devices (Porstmann-plug, Rashkind-umbrella, Botallooccluder) have inherent specific limitations (eg, transarterial approach, residual shunts, limited retrieval). The authors assess practicability, efficacy, and tissue reaction of the new retrievable transvenous plug device for the occlusion of the persistent patent ductus arteriosus (PDA). METHODS: A foam plug (polyvinyl alcohol) is mounted on a titanium core pin where, at both ends, small legs (titanium nickel alloy) with titanium heads are anchored, to ensure safe fixation in the ductus. The device is introduced transvenously through a long sheath (Mullins sheath) and held by a modified biopsy forceps allowing complete retrieval until final release. A common lamb model of large PDAs (n = 11) was used to test for practicability and the histomorphologic outcome. Clinical results were obtained from a consecutive series of 16 patients (aged 13 to 71 years). RESULTS: In all lambs, placement of the plug within the PDA was possible. Histopathology (follow-up 10 to 215 days; mean 112 days) revealed an adequate ingrowing of the device and no pathologic foreign body reaction. The diameter of the human PDAs ranged from 3 to 7 mm (mean 5 mm). The size of the sheath used for introducing the plug (diameter 8 to 16 mm) ranged from 8 to 16 French. Fourteen of 16 PDAs were closed immediately after or on day 1 after implantation, 1 was closed after the 12-month follow-up, and 1 needed an additional plug after 30 months for definitive closure. CONCLUSIONS: The device demonstrated practicability and biocompatibility in our experimental lamb model and effectively closed the PDA in a consecutive series of 16 patients. A greater number of patients and a longer follow-up period are necessary for the definitive clinical assessment of the new device.
Adolescent↗
Morphology of the ductus arteriosus in fetal and neonatal dogs genetically predisposed to patent ductus arteriosus.
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Animals↗
Lipid mediators in the control of the ductus arteriosus.
The ductus arteriosus (DA) is kept open during fetal development by the continuous relaxant effects of prostaglandins (PG), primarily E2. Although this PGE2 is probably intramurally produced. a subsidiary role for blood-borne PGE2 and PGI2 is not excluded. PGE2 synthetic activity develops early in the developing ductus and is greater in immature than in mature tissues. Ductus sensitivity to PGE2 is greatly diminished after exposure to oxygen. Arachidonic acid (the precursor of PGE2) may inactivates cytochrome P-450, completely reverses the contractile tension of the DA at both low (4 to 12 torr) and high (511 to 712 torr) oxygen tension and is equally effective in the presence and absence of indomethacin. Carbon monoxide-induced relaxation occurs with a PCO/PO2 ratio of 0.27 and is reversed by white light and by monochromatic light with maximal reversal seen at 450 nm wavelength. Both these findings favor involvement of a cytochrome P-450. Metyrapone and phenylimidazole, chemical inhibitors of cytochrome P-450, also relax the ductus. These findings suggest that ductus tone is controlled through the opposing activities of cyclooxygenase and monooxygenase products of AA. The former predominate in the fetus, and the latter at birth when they induce closure/
Animals↗
Primary hypertrophic osteoarthropathy: another heritable disorder associated with patent ductus arteriosus.
Patent ductus arteriosus (PDA) is a congenital malformation that has been linked to diverse heritable and chromosomal disorders. Primary hypertrophic osteoarthropathy (HOA) is a rare heritable syndrome in which digital clubbing and periostosis become evident without any underlying illness. The objective of this article is to describe four patients with coexisting PDA and primary HOA. Surgical closure of the ductus showed no effect on the skeletal changes. Primary HOA should be included among the heritable disorders that may be associated with PDA.
Child↗
Closure of calcified patent ductus arteriosus.
Patent ductus arteriosus (PDA) in adults is occasionally associated with calcification and pulmonary hypertension, for which an anterior approach through a median sternotomy with cardiopulmonary bypass is often used. Sutures are placed without circulatory arrest by using a transpulmonary balloon catheter as an occluder. To secure the suture tie, we used Nélaton's catheters as tourniquets.
Calcinosis↗
Effect of dexamethasone therapy on the neonatal ductus arteriosus.
Patent ductus arteriosus (PDA) is believed to be a contributing factor in the etiopathogenesis of bronchopulmonary dysplasia (BPD). We studied the effects of early dexamethasone therapy on persistent ductal patency and the role of PDA in the etiopathogenesis of BPD during the course of a randomized double-blind trial of dexamethasone to prevent BPD. Infants, who weighed between 700 and 999 g, had severe RDS, and had been given surfactant, were randomized to receive a 12-day course of dexamethasone (n = 13) or placebo (n = 17) starting within the first 12 hours of postnatal life. The diagnosis of PDA was made clinically and was confirmed by cardiac ultrasound. The incidence of clinically significant ductus in infants who weighed less than 1000 g was 23% in the dexamethasone-treated group, as compared with 59% in infants who were given placebo. This difference was marginally significant, p = 0.05, odds ratio 0.21, 95% confidence interval 0.04-1.05. None of the infants in the dexamethasone group had recurrence of PDA after indomethacin therapy as compared with three infants in the placebo group. Dexamethasone significantly reduced the number of days infants required ventilator and supplemental oxygen as compared with infants who received placebo. Dexamethasone, as compared with placebo, also reduced the incidence of BPD, p = 0.025, odds ratio 0.08, 95% confidence interval 0.01-0.58. Dexamethasone may reduce the incidence of PDA in premature infants who weigh less than 1000 g at birth and thereby reduce the incidence of BPD.
Anti-Inflammatory Agents↗
Ibuprofen: alternative treatment for patent ductus arteriosus.
Patent ductus arteriosus (PDA) is a common problem for premature babies. Indomethacin, traditionally the treatment of choice for PDA closure, varies in effectiveness and can have serious side effects, such as intraventricular cerebral hemorrhage and decreased mesenteric and renal blood flow. Researchers abroad are examining the efficacy and safety of ibuprofen as an alternative PDA therapy. Their findings have been promising and indicate the need for clinical trials in the U.S.
Anti-Inflammatory Agents, Non-Steroidal↗
Transcatheter closure of the patent ductus arteriosus.
Patent ductus arteriosus (PDA) is one of the most common congenital heart defects. Although surgery is still required in symptomatic neonates, the majority of older infants and children can undergo safe and effective transcatheter device closure on an out-patient basis. First described in 1967, over the past four decades, numerous devices have been specifically developed for this purpose. This article will review the current status of transcatheter therapy. The experience with each device is detailed and issues and controversies are reviewed.
Cardiac Catheterization↗
Ibuprofen in the management of neonatal Patent Ductus Arteriosus.
Patent Ductus Arteriosus (PDA) has a prevalence of approximately 25% in neonates of less than 33 weeks gestation. Failure to treat increases the mortality risk in these preterm infants. Intravenous Ibuprofen has recently been licensed in the United Kingdom as a treatment for this condition. This article reviews the clinical efficacy, side effect profile and dosing/administration schedule of this drug and discusses the warnings and precautions currently attributed to this formulation. Ibuprofen provides a further option for neonatologists in the management of PDA.
Anti-Inflammatory Agents, Non-Steroidal↗
Bilateral branch pulmonary artery obstruction due to kinking at insertion sites of bilateral ductus arteriosus.
Bilateral ductus arteriosus (or ligamentum arteriosum) with right aortic arch and isolation of the left subclavian artery is a rare anomaly of the aortic arch system. We report on a patient with complete atrioventricular septal defect, right aortic arch, bilateral ligamentum arteriosum, and isolation of the left subclavian artery in whom kinking at the ductal insertions caused bilateral branch pulmonary artery obstruction. Complete surgical repair was performed when the patient was 4 months of age, and the pulmonary artery obstructions were entirely relieved by ligation and division of both ducts without pulmonary arterioplasty.
Aorta, Thoracic↗
The paradoxical patent ductus arteriosus.
The ductus arteriosus (DA) is a vessel whose patency is required for fetal survival but is incompatible with postnatal life. Because of developmental insufficiency, the DA in preterm infants often fails to close in a condition known as patent DA (PDA). Although COX inhibitors can be used to close the PDA by lowering circulating prostaglandin levels, their effectiveness is correlated with birth weight, and severely premature infants often require surgical repair. Paradoxically, targeted deletion of COX pathway components in mice results in PDA. In this issue of the JCI, Yokoyama et al. describe dual roles for prostaglandins in DA development and closure, offering new insights into the mechanism of negative effects of COX inhibitors that may influence the treatment of severely premature infants with PDA and lead to improvement of their outcomes (see the related article beginning on page 3026).
Animals↗
Treatment of patent ductus arteriosus.
Patent ductus arteriosus (PDA) continues to be one of the most common problems found in premature infants. The incidence is inversely related to gestation, but may be reduced by use of antenatal steroids, lower volume fluid regimen and judicious use of phototherapy. However, there continues to be controversy as to the appropriate indications for treatment, varying from prophylaxis on the basis of gestation to treatment only when a PDA is demonstrably significant. The situation is further complicated by differing diagnostic criteria for ductal patency or significance. Prophylactic treatment is likely to result in up to 64% of babies being treated unnecessarily. Early treatment of significant or symptomatic PDA depends upon accurate diagnosis. PDA closure can then be achieved using medical means, with surgery reserved for patients in whom this fails or in whom there are contra-indications. However, the optimum timing for intervention remains unknown.
Anti-Inflammatory Agents, Non-Steroidal↗