with the distribution and intensity of mural hypoxia.86 The biologic consequences of these changes include a decline in tissue distensibility and increased contractile potential.87 The ductal wall of fetuses during late gestation has a high level of intrinsic tone, which is further increased after delivery by unopposed oxygen-induced contractile forces.88 After delivery, the increase in arterial content of oxygen, along with the decrease in circulating prostaglandins following placental separation,89 and reduced intraluminal blood pressure, contribute toward ductal closure.90,91 As transductal flow decreases, the wall becomes progressively more ischemic and eventually fibrotic.88 Ductal Closure in Infants Born With Extremely Low Weight The duct remains patent in up to four-fifths of infants born prior to term and weighing less than 1200 g Such infants have no mural vessels in the medial layer and are nourished entirely via transluminal diffusion or from adventitial vessels The immature duct, when studied experimentally, has also been shown to have less intrinsic tone81 and lacks both intimal folds and circumferential medial musculature.92 It is less responsive to oxygen86,92 and more sensitive to prostaglandin E2 and nitric oxide.84 It is possible for the immature infant to develop comparable hypoxia in the medial muscle but only if transluminal flow is completely obliterated Even when the duct constricts, profound hypoxia in the medial wall and anatomic remodeling fails to develop.81 A progressive increase in levels of nitric oxide synthetase in the ductal mural vessels after the first 15 days of life makes the preterm duct even less sensitive to prostaglandins.88,93 Nonsteroidal antiinflammatory agents therefore are less likely to be effective In baboons, coadministration of an inhibitor of nitric oxide synthase, along with indomethacin, leads to increased contractility and luminal obliteration of the preterm duct.94 Gestational age may impact on the response to nonsteroidal antiinflammatory agents, although the evidence for this is limited Gestational age less than 33 weeks at treatment was associated with greater likelihood of response to indomethacin in one small study, although echocardiography was not used universally.95 Advanced gestational age has also been associated with a reduced likelihood of response to second course indomethacin in those infants who have had a persistent hemodynamically significant ductus arteriosus after one course of nonsteroidal antiinflammatory therapy.96 However, other studies have identified a greater likelihood of response in infants of older gestational age.97,98 It is likely that other ambient conditions have a significant impact on response to indomethacin regardless of gestation The presence of infection,99 prenatal exposure to maternal medications such as indomethacin tocolysis100–102 or magnesium sulfate for prevention of intraventricular hemorrhage,103 and platelet count98,104 are some factors that have been implicated Pathophysiologic Continuum of Ductal Shunt It is important to emphasize the difference between pulmonary artery pressure and pulmonary artery resistance When there is an anatomically large communication between the aorta and pulmonary artery, the pressure will be equal in each However, the net flow through this communication is dependent on the differences between the systemic and pulmonary vascular resistance Commonly, in clinical vernacular, “pulmonary hypertension” is used synonymously with elevated pulmonary vascular resistance; however, they are not the same Pulmonary hypertension is defined as elevated pressure in the pulmonary artery: this can be seen when (1) there is an anatomically large ductus or ventricular septal defect, where the systemic pressure is transmitted into the pulmonary vascular bed, and (2) when there is elevated pulmonary vascular resistance, which results in elevated pulmonary artery pressure relatively independent of the amount of flow into the pulmonary vascular bed It is clinically important to distinguish between the two clinical scenarios The presence of a persistent ductus arteriosus may have widely varied clinical implications depending on the circulatory circumstances and the balance of pulmonary and systemic arterial resistance A patent arterial duct may be pathologic in the setting of a marked difference between the systemic and pulmonary vascular resistance, where the net flow across the ductus is left to right and the volume of shunt is high, leading to the classical symptoms described subsequently For neonates in whom the pulmonary and systemic resistances are approximately equal, the ductus arteriosus, regardless of its size, may have relatively small volume of shunt and be of minimal clinical significance In situations where either pulmonary artery resistance is high (e.g., pulmonary hypertension) or systemic delivery of pulmonary venous return is poor (e.g., significant left ventricular dysfunction, or anatomic obstruction to systemic flow, such as in coarctation of the aorta, or hypoplastic left heart syndrome), the presence of an open arterial duct may be beneficial or even lifesaving Echocardiography assessment of the ductus arteriosus should include both assessment of shunt volume and surveillance for anatomic or physiologic contraindications to ductal treatment before treatment decisions are made Pathophysiologic Effects of a Hemodynamically Significant Arterial Duct Failure of ductal closure, coinciding with the normal postpartum fall in pulmonary vascular resistance, results in a left-to-right transductal shunt The consequences may include pulmonary overcirculation and/or systemic hypoperfusion, both of which may be associated with significant morbidity (Fig 15.6) The clinical impact is dependent on the magnitude of the shunt and the ability of the infant to initiate compensatory mechanisms These infants are less capable of compensating and are prone to developing left ventricular failure, which may lead to alveolar edema and/or low cardiac output syndrome.105 The increased pulmonary flow and accumulation of interstitial fluid secondary to the large ductal shunt contribute to decreased lung compliance.106 The cumulative effects of increasing or prolonged ventilator requirements and myocardial dysfunction may increase the risk of chronic lung disease.107,108 Systemic flow may also be compromised with left-to-right ductal shunts due to retrograde diastolic flow in the aorta and the arteries supplying organs such as the kidneys and gut; this may be worsened by the effects of supplemental oxygen, hypocarbia, or both (see later) The redistribution of systemic flow is significantly altered even with shunts of small volume Oftentimes there may be significant hypoperfusion to the kidneys and gastrointestinal tract before a hemodynamically significant duct is clinically suspected This may lead to significant morbidity, including renal insufficiency, necrotizing enterocolitis, intraventricular hemorrhage, and myocardial ischemia.109,110 Early detection and targeted intervention may potentially improve long-term neonatal outcomes