In full term neonates, the ductus arteriosus closure is mainly due to

(Low pressure O2): Ref 45-Dutta 6th (394-Ghai 7th) Changes of the fetal circulation at birth 1. Closure of the umbilical arteries: Functional closure is almost instaneous preventing even slight amount of the fetal blood to drain out. Actual obliteration takes about 2-3 months. The distal parts from the lateral umbilical ligaments and the proximal parts remain open as superior vesical arteries. 2. Closure of umbilical vein: - The obliteration occurs a little latter than the arteries, After obliteration, the umbilical vein forms the ligamentum teres and the ductus venosus becomes ligamentum venosum 3. Closure of the ductus arteriosus - Within few hours of respiration, the muscle wall of the ductus arteriosus contracts probably in response to rising oxygen tension of the blood flowing through the duct. The effects of the variation of the O2 tension on the ductus arteriosus are thought to be mediated through the action of prostaglandins. Prostaglandin antagonists given to the mother may lead to the premature closure of the ductus arteriosus. Whereas functional closure of the ductus may occur soon after the establishment of pulmonary circulation, the anatomical obliteration takes about 1-3 months and becomes ligamentum arteriosum 4. Closure of the foramen ovale: - This is caused by an increased pressure of the left atrium combined with a decreased pressure on the right atrium. Functional closure occurs soon after birth but anatomical closure occurs in about 1 year time. Within one or two hours following birth ,the cardiac output is estimated to be a bout 500 ml per minute, and the heart rate varies from 120 -140 per minute * During foetal life, patency of the ductus arteriosus appears to be maintained by the combined relaxant effects of low oxygen tension and endogenously produced prostaglandins (PGE2), In full term neonates the oxygen is the most important factor controlling ductual closure (1480- Nelson 17th) Ref 2 - PATHOPHYSIOLOGY The DA is derived from the distal dorsal sixth aortic arch and is completely formed by the eighth week of gestation.6 Its role is to shunt the blood from the nonfunctional fetal lung through its connection between the main pulmonary artery and the proximal descending aorta. This right-to-left shunt allows the blood with a relatively low oxygen concentration to be carried from the right ventricle through the descending aorta and eventually to the placenta, where gas exchange will occur. Before birth, approximately 90% of right ventricular output flows through the DA. Figure 1 illustrates the role of the DA in redirecting fetal circulation in comparison to neonatal circulation.15 Premature closure in the fetus is associated with significant morbidities, including right-sided heart failure, which may result in fetal hydrops.6 Normally, the DA closes within 24-72 hours after a full-term birth; if after 72 hours the ductus fails to close, a diagnosis of persistent PDA may be made.1,16 Figure 1. Left-The ductus arteriosus is an essential component of fetal circulation. It functions by shunting blood away from the nonfunctional fetal lung and into the systemic circulation through the aorta. Right-After birth, decreases in PGE2 and oxygen tension contribute to the closure of the ductus Arteriosus, allowing gas exchange to occur in the newly functioning lungs rather than the now absent placenta. Blue = oxygen-poor blood; Red = oxygen-rich blood; LA = left atrium; LV = left ventricle; RA = right atrium; RV = right ventricle. The paradoxical patent ductus arteriosus. J Clin Invest 166:2863-2866 by Ivey KN, and Srivastava D. Copyright 2006 by J Clin Invest. Reproduced with permission of J Clin Invest via Copyright Clearance Center. The patency of the DA is primarily controlled by low fetal oxygen tension and the circulation of prostanoids produced from the metabolism of arachidonic acid by COX, with PGE2 producing the most profound ductal relaxation among the prostanoids.16,17 Smooth muscle relaxation of the DA results from the activation of the G-coupled prostaglandin receptor EP4 by PGE2. Following the activation of prostaglandin receptor EP4, a cascade of events ensues, which includes the accumulation of cyclic adenosine monophosphate, increased protein kinase A, and finally, decreased myosin light chain kinase, leading to vasodilation and ultimately DA patency.15 The preterm ductus is especially sensitive to the vasodilatory effects of prostaglandins, contributing to the failure of ductal closure.18 In term infants, as birth approaches, decreased sensitivity of the DA to prostaglandins and decreased circulating levels of PGE2 contribute to DA closure.19 Within 24-72 hours after a full-term birth, the DA closes as a result of increased oxygen tension and decreased circulating PGE2 and prostacyclins (PGI2). As oxygen tension increases, smooth muscle voltage-dependent potassium channels are inhibited. Through this inhibition, an influx of calcium contributes to ductal constriction. This oxygen-induced constriction fails in preterm infants potentially due to immaturity of oxygen-sensing receptors.20 Levels of circulating PGE2 and PGI2 are decreased as a result of increased metabolism in the newly functioning lung, as well as the removal of the placental source. The decreased circulating levels of these potent vasodilators allow the DA to constrict. These factors collectively contribute to smooth muscle constriction, leading to ischemic hypoxia of the inner muscle wall of the DA. As the ductus constricts, the luminal area is diminished, resulting in a thickened vessel wall and obstructed flow through the vasa vasorum, the essential capillary network nourishing the outer cells of the vessel. This causes an increased distance of diffusion for oxygen and nutrients, including glucose, glycogen, and adenosine triphosphate (ATP), which results in nutritional deficit and oxygen starvation, leading to cell death.21 Ductal constriction in preterm infants is not sufficiently profound. Consequently, preterm infants are resistant to smooth muscle hypoxia, which is paramount in triggering the cell death and remodeling required for permanent closure of the DA.22 Inhibition of prostaglandin and nitric oxide resulting from tissue hypoxia is not as extensive in the preterm neonate in comparison to the term infant, further contributing to resistance to DA closure in the preterm infant.23 The main provider of nutrients to the DA is the lumen; however, the vasa vasorum is also a substantial provider to the outer wall of the ductus. The vasa vasorum grows toward the lumen and extends 400-500 mm from the outer wall of the ductus. The distance between the lumen and the vasa vasorum (40-500 mm) is referred to as the avascular zone and represents the maximum distance allowable for effective nutrient diffusion. In full-term infants, this avascular zone is expanded beyond the effective diffusion distance, therefore contributing to cell death. In preterm infants, the avascular zone does not sufficiently expand, resulting in cell survival and maintenance of ductal patency.24 If the levels of circulating PGE2 and other prostaglandins are decreased through COX inhibition, closure is facilitated. The abovementioned differences between ductal vessel wall thickness of the fetus, term neonate, and preterm neonate are illustrated in Figure 2.16 In response to the nutritional deficit and ischemic hypoxia, vascular endothelial growth factor and transforming growth factor beta (both of which contribute to endothelial proliferation), in combination with other inflammatory mediators, contribute to the remodeling of the DA into the non-contractile ligament commonly referred to as the ligamentum arteriosum.16,24 Figure 2. Comparison of fetal and both the premature and full-term newborn ductus arteriosus. The avascular zone in the preterm ductus (bottom row) does not sufficiently expand beyond the effective diffusion distance after birth (bottom right). Hermes-deSantis et al.16 Reprinted by permission from Macmillan Publishers Ltd: J Perinatol 26: s14-s18, copyright 2006.