title: Factors associated with permanent closure of the ductus arteriosus: a role for prolonged indomethacin therapy.
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 (< or =26; 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 24 hour-intervals, starting 24 hours after the third dose.
  
  
  RESULTS
  Sixty-eight of the 69 infants survived long enough to complete all of the study evaluations. Seventy-five percent (51/68) reopened their ductus and became symptomatic; 71% (48/68) were eventually ligated. Only gestational age and duration of indomethacin treatment were significantly and independently associated with permanent closure. A prolonged 6-dose course of indomethacin was more likely than the standard 3-dose course to be associated with an increased incidence of echocardiographic closure, a decreased incidence of symptomatic reopening (odds ratio: 0.19; 95% confidence interval: 0.04-0.96), and a decreased incidence of ductus ligation (odds ratio: 0.14; 95% confidence interval: 0.03-0.68).
  
  
  CONCLUSIONS
  Several older studies have suggested that a longer initial course of indomethacin therapy may be more effective in producing permanent ductus closure than the standard 3-dose course. In contrast, more recent studies have found that a longer course of indomethacin is no more effective than the standard 3-dose course in producing permanent closure. We hypothesize that the different outcomes among these studies may be attributable to differences in the degree of ductus constriction during the standard 3-dose course of indomethacin. Both the increased use of antenatal steroids and the earlier use of indomethacin has increased the effectiveness of the standard 3-dose course of indomethacin in recent years. We hypothesize that, in contrast with earlier studies, a significant proportion of the infants in the recent studies may have developed complete Doppler closure with just 3 doses of indomethacin (as occurred in 214 of the 313 infants treated with the standard 3-dose course in our study). Because the degree of ductus constriction seems to determine the rate of anatomic remodeling and permanent closure, daily echocardiographic evaluations of ductal patency may be the best way to decide when indomethacin therapy is no longer needed. Our study suggests that infants who still have evidence of luminal patency, after a standard 3-dose course of indomethacin, may be likely to benefit from a longer course of indomethacin. Future randomized trials that examine the benefits of different lengths of indomethacin treatment may wish to take this into consideration.
  
  
  CONCLUSIONS
  Despite the increased effectiveness of a prolonged course of indomethacin, the rates of ductus reopening and surgical ligation were still very high in infants with a partially closed ductus. Other therapeutic approaches will need to be developed before permanent closure is likely to occur in this group of immature infants.
authors.affiliation: Cardiovascular Research Institute, Department of Pediatrics, University of California, San Francisco, California 94143-0544, USA.
authors.forename: Dolores
authors.initials: D
authors.lastname: Quinn
authors.forename: Bruce
authors.initials: B
authors.lastname: Cooper
authors.forename: Ronald I
authors.initials: RI
authors.lastname: Clyman
mesh_terms: D002317:Cardiovascular Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004373:Ductus Arteriosus / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology; D004374:Ductus Arteriosus, Patent / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology; D004452:Echocardiography; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology / Q000627:therapeutic use*; D007231:Infant, Newborn; D007235:Infant, Premature, Diseases / Q000188:drug therapy; D012044:Regression Analysis; D012189:Retrospective Studies; D013997:Time Factors
chemical_list: D002317:Cardiovascular Agents; D007213:Indomethacin