Factors Associated With Permanent Closure of the Ductus Arteriosus: A Role for Prolonged Indomethacin Therapy

Abstract

ABSTRACT. Background. The most important factor determining anatomic remodeling and permanent closure of the ductus arteriosus is the degree of ductus constriction after indomethacin treatment. Muscular constriction produces a region of ischemic hypoxia in the middle of the ductus muscle media that initiates the process of permanent closure. Previous studies have shown that infants delivered before 28 weeks' gestation, who still have evidence of ductus flow on Doppler examination (performed after the standard 3-dose course of indomethacin), have a high likelihood (>85% chance) of reopening their ductus in the future. In contrast, if there is no evidence of luminal patency on the posttreatment Doppler examination, the incidence of ductus reopening is <20%.In the following study, we examined infants who still had a patent ductus on Doppler examination after a 3-dose course of indomethacin, to identify which factors might be associated with permanent ductus closure. We hypothesized that infants who received additional doses of indomethacin after the standard 3-dose course might develop an even tighter degree of ductus constriction and increase their chance of developing permanent closure.Methods. We performed a retrospective cohort study of preterm infants (<26 6 ⁄7 weeks' gestation) who were treated with indomethacin. Between 12 and 24 hours after the third dose of indomethacin, infants were examined for the presence or absence of ductus-related signs, and an echocardiogram was performed. Infants responded to the initial 3 doses of indomethacin in 1 of 3 ways: 1) the ductus was closed clinically (absent clinical signs) with no evidence of luminal flow on Doppler examination ("clinically closed"; n ‫؍‬ 214); 2) the ductus was closed clinically, but a small amount of left-to-right luminal flow was evident on Doppler examination ("partially closed"; n ‫؍‬ 69); 3) or the ductus was open clinically and echocardiographically ("nonresponder"; n ‫؍‬ 30). Nonresponders underwent surgical ligation (n ‫؍‬ 30). Infants with a partially closed ductus formed our study population.We used a hierarchical regression model to identify which, if any, of the following factors might be associated with permanent anatomic closure in the 69 infants with a partially closed ductus: 1) gestational age, 2) exposure to antenatal steroids, 3) birth weight, 4) sex, 5) presence and severity of respiratory distress, 6) fluid administration during the first 96 hours after birth, 7) indomethacin treatment approach (prophylactic vs symptomatic), 8) year of birth, 9) use of surfactant, 10) preeclampsia, 11) chorioamnionitis, 12) bacterial septicemia, 13) necrotizing enterocolitis, or 14) duration of indomethacin treatment (standard 3-dose course vs prolonged 6-dose course). Infants who received the standard 3-dose course of indomethacin treatment were given 0.2, 0.1, and 0.1 mg/kg indomethacin during a 48-hour period. Infants who received the prolonged 6-dose course of indomethacin treatment were given a fourth, fifth, and sixth dose of 0.1 mg/kg at 2...

Echocardiographic predictors of symptomatic patent ductus arteriosus in extremely-low-birth-weight preterm neonates

“…This is consistent with earlier reports that an older EGA correlates with an increase in the spontaneous closure of the DA. [2][3][4][5]10 We did not examine the effect of BW as in our earlier analysis of this population of ELBW neonates it did not correlate with the closure or patency because of inclusion of older more mature growth restricted neonates. 10 In this report, a moderate to large PDA, defined by the PDA:LPA ratio on an ECHO obtained at p4 day postnatal in neonates <27 weeks EGA (neonates 15 times more likely to require ductal closure), had very good sensitivity, specificity and positive predictive value (91%) for the subsequent need for closure of a sPDA.…”

“…1 In contrast, it remains patent in a substantial population of very low BW (BW p1500 g) neonates. 2,3 In these neonates, the incidence of a persistent patent DA (PDA) increases with decreasing estimated gestational age (EGA) and BW, [2][3][4][5] although not all studies have arrived at this conclusion. 6 As a group, as many as 31% of very low BW neonates develop a clinically and hemodynamically significant PDA (sPDA) with signs of increased left to right shunting, pulmonary edema and an enlarged cardiothymic shadow on chest X-ray.…”

Patent ductus arteriosus: pathophysiology and management

“…This additional treatment will significantly increase the likelihood of permanent ductus closure. 11 An additional Doppler should be conducted after the sixth dose of indomethacin. 12 This Doppler reading will provide information about the likelihood of subsequent reopening.…”

Combined Treatment With a Nonselective Nitric Oxide Synthase Inhibitor (L-NMMA) and Indomethacin Increases Ductus Constriction in Extremely Premature Newborns

“…Studies in premature animals demonstrate that prolonged, tight constriction of the ductus arteriosus is necessary to produce ischemia of the ductus wall, anatomic remodeling, and permanent closure (1)(2)(3). A persistent patent ductus arteriosus (PDA) in premature infants is due in large part to the increased sensitivity of the ductus to endogenous vasodilators like prostaglandins.…”