Persistent Doppler Flow Predicts Lack of Response to Multiple Courses of Indomethacin in Premature Infants With Recurrent Patent Ductus Arteriosus
* Department of Pediatrics
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California
 |
ABSTRACT |
|---|
 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Objective. Although indomethacin produces ductus arteriosus constriction in extremely premature newborns, a recurrent symptomatic patent ductus arteriosus (PDA) frequently develops after the initial course of indomethacin. Currently, there is little information available to determine the effectiveness of a second course of indomethacin in producing permanent ductus closure. The objective of this study was to determine the rate of permanent ductus closure after a second course of indomethacin for a recurrent, symptomatic PDA and to identify the factors associated with permanent ductus closure.
Methods. We identified 32 infants (<28 weeks’ gestational age) 1) whose ductus was considered to be clinically closed after an initial course of indomethacin and 2) who subsequently developed a symptomatic PDA and received a second course of indomethacin. Clinical variables were evaluated for their association with failure of the second course (defined as surgical ligation after the second course for recurrence of a hemodynamically significant PDA). Data were analyzed by 
2 analysis, Fisher’s exact test, and the Mann-Whitney rank sum test.
Results. After the second course of indomethacin, 56% (18 of 32) of the infants had persistent or recurrent PDA-related symptoms that were considered to be hemodynamically significant. The only significant predictor of failure of the second indomethacin course was the demonstration (by Doppler echocardiogram) of persistent ductus flow within 24 hours of completing the initial indomethacin course. All of the 9 newborns with persistent Doppler ductus flow after the initial indomethacin course failed the second course of indomethacin. In contrast, only 39% (9 of 23) of newborns with absent Doppler flow after the initial indomethacin course failed the second course of indomethacin.
Conclusions. Newborns who are <28 weeks’ gestational age and develop a recurrent, symptomatic PDA after completion of an initial indomethacin course rarely respond to multiple courses of indomethacin if there was persistent Doppler evidence of ductus flow after completion of the initial course. Additional indomethacin treatment is unlikely to produce permanent ductus closure.
Key Words: nonsteroidal anti-inflammatory drug
Abbreviations: PDA, patent ductus arteriosus • UCSF, University of California, San Francisco • GA, gestational age
Extremely premature neonates have a high incidence of patent ductus arteriosus (PDA).1–3 A clinically symptomatic PDA is associated with significant morbidity in this population.2–4 Indomethacin produces ductus constriction in premature neonates and is relatively well tolerated despite its effects on mesenteric, renal, and cerebral perfusion.1 However, between 13% and 53% of ductus in extremely premature newborns will reopen, and infants will develop ductus-related symptoms after their initial course of indomethacin.5–8
Permanent anatomic closure of the ductus arteriosus9 is caused by hypoxia in the ductus wall.10,11 In the preterm ductus, hypoxia is caused by ductus constriction and obliteration of the ductus lumen.10,12 More than 80% of extremely premature infants (<28 weeks’ gestation) will develop permanent closure if they have no evidence of Doppler-detectable ductus luminal flow after indomethacin therapy. However, 90% of preterm infants who have a clinically closed ductus (defined by the absence of clinical signs or symptoms) and still have evidence of persistent luminal flow on the posttreatment Doppler examination will subsequently develop PDA-related symptoms that are considered to be hemodynamically significant (see below).5 There is little information regarding the efficacy of a second course of indomethacin treatment in infants who develop a recurrent, symptomatic PDA.
Our purpose was to determine the rate of permanent ductus closure after a second course of indomethacin in premature infants (<28 weeks’ gestation) with a recurrent, symptomatic PDA. We examined prenatal and postnatal factors that might be associated with failure to achieve permanent ductus closure after a second course of indomethacin. We hypothesized that infants who were unable to constrict their ductus tightly during the initial course of indomethacin would also be unlikely to develop the degree of ductus constriction that is necessary to produce permanent ductus closure during the second course of indomethacin. We hypothesized that the ductus these infants would reopen, even after a second course of indomethacin, and would ultimately need surgical ligation.
|
METHODS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
This study was approved by the University of California, San Francisco (UCSF) institutional review board, the Committee on Human Research.
Identification of Subjects
We performed a retrospective study using a prospectively assembled database of 455 newborns who were delivered at <28 weeks gestational age (GA) and admitted to the UCSF Intensive Care Nursery within 12 hours of birth (from December 1, 1991, through June 15, 2001). A total of 374 infants were treated with indomethacin. We identified 32 subjects who had received a second course of indomethacin for a recurrent, symptomatic PDA.
Initial Indomethacin Treatment Course
During the period covered by this study, 2 approaches were used for the initial course of indomethacin treatment: 1) "prophylactic treatment" (infants were treated within 15 hours of birth before ductus-related signs [a murmur, with or without either increased precordial activity or bounding pulses] became apparent and 2) "symptomatic treatment" (infants were treated only after ductus-related signs appeared [usually by 3 days of age]). The prophylactic treatment approach was introduced in December 1994 as a change in nursery protocol. Both treatment regimens consisted of 3 doses of indomethacin (0.2, 0.1, and 0.1 mg/kg during a 48-hour period). Between 12 and 24 hours after the third dose of indomethacin, a color Doppler evaluation was performed to detect the presence of persistent flow through the ductus. In both treatment regimens, if persistent flow was detected on Doppler examination, then the initial course of indomethacin was extended by 3 additional doses (0.1 mg/kg at 24-hour intervals) unless there were contraindications to the additional use of indomethacin (serum creatinine 
1.8 mg/dL or necrotizing enterocolitis).
Evaluation of Initial Treatment Response
Between 12 and 24 hours after completion of the initial course of indomethacin, infants were examined for the presence or absence of ductus-related signs (see above) and an echocardiographic and color Doppler evaluation was performed as previously described.5 If any color Doppler flow was seen in the region of the ductus, even if it was intermittent, then the ductus was considered to have persistent flow through its lumen. Infants with clinical symptoms and persistent ductus flow (as demonstrated by Doppler) after the initial course of indomethacin were referred for surgical ligation (n = 36; 10% of those treated with indomethacin).
Evaluation of Recurrent, Symptomatic PDA: Study Population
After the initial indomethacin course, infants with a clinically closed ductus (those without any PDA-related symptoms; see above) were monitored for the appearance of a hemodynamically significant PDA. Infants were considered to have a "hemodynamically significant PDA" when they developed the following 3 clinical symptoms: 1) a prolonged systolic murmur, 2) the presence of bounding pulses, and 3) a hyperactive precordium, in addition to echocardiographic evidence of left-to-right flow through the PDA. The need for mechanical ventilation was not a criterion for retreatment of a hemodynamically significant PDA.
After the initial indomethacin course, 89 infants with a clinically closed ductus developed a recurrent, hemodynamically significant, symptomatic PDA. All 89 infants were treated with either a second course of indomethacin (3 doses; n = 32) or surgical ligation (n = 57). The decision to use a second course of indomethacin or to proceed directly to surgical ligation was made by the attending neonatologist and was based on the severity of the clinical symptoms and the presence of contraindications to the use of indomethacin.
Primary Outcome
The 32 infants who received a second course of indomethacin for a recurrent, hemodynamically significant PDA formed our study population. Echocardiograms were performed on all infants between 12 and 24 hours after completing the second course of indomethacin to determine the contractile response to the second indomethacin course. Infants who continued to have symptoms (see above) of a hemodynamically significant PDA after completing the second indomethacin course or who developed recurrence of a hemodynamically significant PDA at a later date underwent surgical ligation according to our nursery policy. This policy was based on the results of controlled clinical trials that found an association between the presence of untreated ductus-related symptoms and the need for prolonged respiratory support and the delayed establishment of enteral nutrition.4
Our purpose was to determine the rate of permanent ductus closure after the second course of indomethacin. We used the development of a hemodynamically significant PDA that met our criteria for ligation as our primary study outcome.
Clinical Variables
We collected clinical data that might affect the infants’ response to indomethacin: maternal betamethasone treatment, chorioamnionitis and preeclampsia, neonatal GA, sex, initial respiratory course and fluid management, the presence of late-onset sepsis at the time of retreatment, and the infants’ Doppler echocardiographic responses to indomethacin treatment (Tables 1 and 2).
|
|
Infants were considered to have been exposed to antenatal betamethasone if it was administered
6 hour before delivery. Virtually the entire cohort received at least a single dose of exogenous surfactant because it has been our policy to intubate the trachea and administer prophylactic surfactant shortly after delivery and before radiologic evaluation in infants delivered at <28 weeks’ GA. Infants who were born at outside hospitals and then transported to UCSF received surfactant according to the discretion of the referring pediatrician. The diagnosis of respiratory distress syndrome was based on radiographic findings and clinical course, regardless of previous surfactant therapy. A ventilator support score, designed to evaluate the degree of respiratory support required, was calculated for each subject (equal to mean airway pressure x fraction of inspired oxygen at 24 hours of life). Temporally related late-onset sepsis was defined as 1) the presence of 2 positive cultures from a sterile site (blood, urine, or cerebral spinal fluid) or a pneumonia (diagnosed by radiographic findings consistent with the infant’s respiratory status), 2) requiring at least 7 days of appropriate antibiotic therapy, and 3) diagnosed and treated within 5 days of the start of the second course of indomethacin.6
All newborns were screened with serial cranial ultrasound studies to detect intracranial hemorrhage and periventricular leukomalacia.13,14 The diagnosis of necrotizing enterocolitis was determined by the attending neonatologist.15 Bronchopulmonary dysplasia was defined as the need for oxygen supplementation at 36 weeks’ corrected GA.
Data Analysis
The primary outcome was the development of a hemodynamically significant PDA that met our criteria for surgical ligation after the second course of indomethacin. We examined each of our predictors of interest in univariate analyses (2 analysis and Fisher exact test for categorical variables and the Mann-Whitney rank sum test for nonparametric continuous variables). Statistical analyses (Stata 6.0; Stata Corp, College Station, TX) were 2-tailed, and results were considered statistically significant at P < .05. Results are expressed as mean ± standard deviation.
|
RESULTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
None of the study infants had any PDA-related symptoms after the first indomethacin course, and all were considered to be clinically closed at that time. All of the infants subsequently developed a recurrent, hemodynamically significant PDA that was diagnosed and treated with a second course of indomethacin (Fig 1). The second course of indomethacin was started 13 ± 8 days after completion of the initial course. Ninety-one percent of the infants were receiving mechanical ventilation at the time of the second indomethacin course. Despite the second course of indomethacin, 18 (56%) of 32 ultimately met our criteria for surgical PDA ligation. All 32 infants survived to hospital discharge. One infant had a grade 4 intracranial hemorrhage, 1 infant had periventricular leukomalacia, 2 infants had necrotizing enterocolitis, and 20% of the study group had a diagnosis of bronchopulmonary dysplasia.
|
We evaluated predictors that might be associated with failure of the second indomethacin course: gestational age, birth weight, sex, exposure to antenatal betamethasone, maternal diagnoses of chorioamnionitis and preeclampsia, presence of respiratory distress syndrome, ventilator support score, maximum serum creatinine after the initial course of indomethacin, fluid administration (normalized to body weight) during the first 96 hours of life (data not shown), indomethacin treatment approach (symptomatic versus prophylactic), year of birth (December 1, 1991, to December 21, 1996, vs January 1, 1997, to June 15, 2001), number of indomethacin doses and the cumulative dose administered in the initial course, the postnatal age when infants were treated initially and when they were retreated for symptomatic reopening, the number of days between indomethacin treatment courses, the results of the Doppler examination after the initial course of indomethacin, and temporally related sepsis at indomethacin retreatment. These univariate analyses revealed that the only significant predictor of PDA ligation after the second course of indomethacin was the demonstration (by Doppler) of persistent ductus flow after the first course of indomethacin (Tables 1 and 2). Among the 32 newborns who received a second course of indomethacin, 9 had persistent ductus flow on Doppler examination after the initial indomethacin course. All of these newborns ultimately met our criteria for surgical ligation of a hemodynamically significant PDA after the second course of indomethacin. In contrast, only 9 of (39%) 23 newborns with absent Doppler flow after the initial indomethacin course developed a hemodynamically significant PDA and underwent surgical ligation after the second course (P = .002,
2 analysis).
Infants who had no evidence on Doppler of ductus luminal flow after the initial course of indomethacin were more likely to constrict their ductus tightly and have no evidence of luminal flow after the second course of indomethacin. Seventy-four percent of infants (17 of 23) who had no Doppler-detectable flow after the initial indomethacin course also had no evidence of Doppler flow after completing the second course. In contrast, none of the 9 infants who still had Doppler-detectable flow after the initial indomethacin course was able to constrict the ductus tightly enough to eliminate Doppler flow after the second course (P < .001, 2 analysis; Fig 1).
The only other factor that approached statistical significance as a predictor of PDA ligation was the time interval between the first and second indomethacin courses (P = .07, Mann-Whitney U rank sum test; Table 2). However, the interval between the first and second indomethacin courses was also significantly related to the presence of persistent ductus flow after the first indomethacin course. Infants who still had Doppler-detectable flow after the initial indomethacin course developed their recurrent, hemodynamically significant PDA after a shorter interval than those who had no evidence of ductus flow after their initial indomethacin course (8 ± 2 vs 15 ± 2 days; P = .03, Mann-Whitney U rank sum test).
|
DISCUSSION |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
Previously, we have shown that, despite the absence of initial clinical symptoms, infants who are <28 weeks’ GA and have persistent Doppler flow after completing the first course of indomethacin have a 90% chance of subsequently developing a recurrent, symptomatic PDA.5 In the current study, we found that infants (<28 weeks’ GA) who still had Doppler evidence of ductus luminal flow after completing an initial course of indomethacin were also very unlikely to close permanently their PDA with subsequent courses of indomethacin.
Previous studies have shown that factors such as GA, antenatal betamethasone exposure, rate of fluid administration, and prophylactic use of indomethacin affect the rate and degree of ductus constriction during both spontaneous and indomethacin-induced closure.5,16–21 Our findings suggest that although these factors may play a role in determining the success of the initial course of indomethacin, they may not play as important a role in determining the outcome of subsequent treatment courses. However, because of the small size of our study population, it is possible that some of these factors might be predictive of indomethacin failure if a greater number of infants had been studied.
The only other factor approaching significance for an association with failure to achieve permanent closure with a second indomethacin course was the time interval between the initial and second indomethacin courses. This was not surprising because infants with persistent Doppler-detectable ductus flow after the initial course developed a recurrent symptomatic PDA significantly earlier than those who had no evidence of Doppler flow after the initial course. Because no infants with persistent Doppler flow after the initial indomethacin course avoided surgical PDA ligation, we were unable to test the independent effects of this variable by logistic regression.22
The limitations of our study are those of any uncontrolled clinical experience: there may be unmeasured confounders that we are unable to account for, and there may be factors influencing treatment decisions (including the decision to surgically ligate a PDA) that we are unable to ascertain or evaluate definitively. We think that it is unlikely that unmeasured changes in practice during the interval of this study were an important factor, because the year of birth was not significantly related to the primary outcome of surgical ligation.
Unlike the ductus arteriosus in the term infant, the premature ductus requires luminal obliteration to initiate the cascade of biochemical events that results in anatomic remodeling and permanent ductus closure.5,10,12,23 We found that infants whose ductus lumen closed after the initial course of indomethacin were more likely to obliterate the lumen during the second course of treatment and develop permanent anatomic closure. In contrast, infants who were unable to eliminate luminal flow during the initial course of indomethacin also were unable to close the lumen completely during the second course. As a result, they were unable to initiate the process of anatomic remodeling. We hypothesize that the inability of indomethacin to produce tight ductus constriction in the latter group of infants may indicate that these vessels are less dependent on prostaglandin synthesis and that other factors may be responsible for persistent ductus patency.11
In this study of infants who were <28 weeks’ GA and received a second course of indomethacin, after developing a recurrent symptomatic PDA, we found that failure to develop tight ductus constriction during the initial indomethacin course was strongly associated with a lack of response to the second indomethacin course. Our findings suggest that exposing these infants to additional treatment courses is unlikely to produce permanent ductus closure.
|
ACKNOWLEDGMENTS |
|---|
This work was supported in part by grants from the US Public Health Service; National Heart, Lung and Blood Institute (HL 46691 and HL 56061); and a gift from the Perinatal Associates Research Foundation.
Roberta L. Keller is a recipient of the Glaser Pediatric Research Network Award.
We thank the fellows and attendings of the Division of Pediatric Cardiology who have been so helpful in performing and interpreting the echocardiographic studies and Dr John Neuhaus for guidance in the statistical analysis.
|
FOOTNOTES |
|---|
Received for publication Oct 1, 2002; Accepted Mar 20, 2003.
Address correspondence to Ronald I. Clyman, MD, University of California San Francisco, Box 0544, HSE 1492, San Francisco, CA 94143. E-mail: ric{at}itsa.ucsf.edu
|
REFERENCES |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
- Hammerman C. Patent ductus arteriosus. Clinical relevance of prostaglandins and prostaglandin inhibitors in PDA pathophysiology and treatment. Clin Perinatol.1995; 22 :457 –479[Web of Science][Medline]
- Rojas MA, Gonzalez A, Bancalari E, Claure N, Poole C, Silva-Neto G. Changing trends in the epidemiology and pathogenesis of neonatal chronic lung disease. J Pediatr.1995; 126 :605 –610[CrossRef][Web of Science][Medline]
- Marshall DD, Kotelchuck M, Young TE, Bose CL, Kruyer L, O’Shea TM. Risk factors for chronic lung disease in the surfactant era: a North Carolina population-based study of very low birth weight infants. North Carolina Neonatologists Association.
Pediatrics.1999; 104
:1345
–1350
[Abstract/Free Full Text] - Clyman RI. Commentary: recommendations for the postnatal use of indomethacin. An analysis of four separate treatment strategies. J Pediatr.1996; 128 :601 –607[CrossRef][Web of Science][Medline]
- Narayanan M, Cooper B, Weiss H, Clyman RI. Prophylactic indomethacin: factors determining permanent ductus arteriosus closure. J Pediatr.2000; 136 :330 –337[CrossRef][Web of Science][Medline]
- Gonzalez A, Sosenko IR, Chandar J, Hummler H, Claure N, Bancalari E. Influence of infection on patent ductus arteriosus and chronic lung disease in premature infants weighing 1000 grams or less. J Pediatr.1996; 128 :470 –478[CrossRef][Web of Science][Medline]
- Gersony WM, Peckham GJ, Ellison RC, Miettinen OS, Nadas AS. Effects of indomethacin in premature infants with patent ductus arteriosus: results of a national collaborative study. J Pediatr.1983; 102 :895 –906[CrossRef][Web of Science][Medline]
- Tammela O, Ojala R, Iivainen T, et al. Short versus prolonged indomethacin therapy for patent ductus arteriosus in preterm infants. J Pediatr.1999; 134 :552 –557[CrossRef][Web of Science][Medline]
- Gittenberger-de-Groot AC, Van Ertbruggen I, Moulaert AJMG, Harinck E. The ductus arteriosus in the preterm infant: histologic and clinical observations. J Pediatr.1980; 96 :88 –93[CrossRef][Web of Science][Medline]
- Kajino H, Chen YQ, Seidner SR, et al. Factors that increase the contractile tone of the ductus arteriosus also regulate its anatomic remodeling. Am J Physiol.2001; 281 :R291 –R301
- Seidner SR, Chen Y-Q, Oprysko PR, et al. Combined prostaglandin and nitric oxide inhibition produces anatomic remodeling and closure of the ductus arteriosus in the premature newborn baboon. Pediatr Res.2001; 50 :365 –373[Web of Science][Medline]
- Kajino H, Goldbarg S, Roman C, et al. Vasa vasorum hypoperfusion is responsible for medial hypoxia and anatomic remodeling in the newborn lamb ductus arteriosus. Pediatr Res.2002; 51 :228 –235[Web of Science][Medline]
- Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weight < 1500 grams. J Pediatr.1978; 92 :529 –534[CrossRef][Web of Science][Medline]
- Schellinger D, Grant EG, Richardson JD. Cystic periventricular leukomalacia: sonographic and CT findings. AJNR Am J Neuroradiol.1984; 5 :439 –445[Abstract]
- Bell MJ, Ternberg JL, Feigin RD, et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg.1978; 187 :1 –7[Web of Science][Medline]
- Bell EF, Warburton D, Stonestreet B, Oh W. Effect of fluid administration on the development of symptomatic patent ductus arteriosus and congestive heart failure in premature infants. N Engl J Med.1980; 302 :598 –604[Abstract]
- Stevenson JG. Fluid administration in the association of patent ductus arteriosus complicating respiratory distress syndrome. J Pediatr.1977; 90 :257 –261[CrossRef][Web of Science][Medline]
- Weiss H, Cooper B, Brook M, Schlueter M, Clyman RI. Factors determining reopening of the ductus arteriosus after successful clinical closure with indomethacin. J Pediatr.1995; 127 :466 –471[CrossRef][Web of Science][Medline]
- Waffarn F, Siassi B, Cabal L, Schmidt PL. Effect of antenatal glucocorticoids on clinical closure of the ductus arteriosus.
Am J Dis Child.1983; 137
:336
–338
[Abstract/Free Full Text] - Firth J, Pickering D. Timing of indomethacin therapy in persistent ductus. Lancet.1980; 2 :144
- Clyman RI, Ballard PL, Sniderman S, et al. Prenatal administration of betamethasone for prevention of patent ductus arteriosus. J Pediatr.1981; 98 :123 –126[CrossRef][Web of Science][Medline]
- Katz MH. Multivariable Analysis: A Practical Guide for Clinicians. Cambridge, United Kingdom: Cambridge University Press; 1999
- Clyman RI, Chan CY, Mauray F, et al. Permanent anatomic closure of the ductus arteriosus in newborn baboons: the roles of postnatal constriction, hypoxia, and gestation. Pediatr Res.1999; 45 :19 –29[Web of Science][Medline]
PEDIATRICS (ISSN 1098-4275). ©2003 by the American Academy of Pediatrics
CiteULike 
Connotea 
Del.icio.us 
Digg 
Facebook 
Reddit 
Technorati 
Twitter What's this?
This article has been cited by other articles:
|
|
 |
|
  J. Richards, A. Johnson, G. Fox, and M. Campbell A Second Course of Ibuprofen Is Effective in the Closure of a Clinically Significant PDA in ELBW Infants Pediatrics, August 1, 2009; 124(2): e287 - e293. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Madan, D. Kendrick, J. I. Hagadorn, I. D. Frantz III, and the National Institute of Child Health and Human D Patent Ductus Arteriosus Therapy: Impact on Neonatal and 18-Month Outcome Pediatrics, February 1, 2009; 123(2): 674 - 681. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Chorne, C. Leonard, R. Piecuch, and R. I. Clyman Patent Ductus Arteriosus and Its Treatment as Risk Factors for Neonatal and Neurodevelopmental Morbidity Pediatrics, June 1, 2007; 119(6): 1165 - 1174. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Koch, G. Hensley, L. Roy, S. Brown, C. Ramaciotti, and C. R. Rosenfeld Prevalence of Spontaneous Closure of the Ductus Arteriosus in Neonates at a Birth Weight of 1000 Grams or Less Pediatrics, April 1, 2006; 117(4): 1113 - 1121. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Jaillard, B. Larrue, T. Rakza, E. Magnenant, H. Warembourg, and L. Storme Consequences of Delayed Surgical Closure of Patent Ductus Arteriosus in Very Premature Infants Ann. Thorac. Surg., January 1, 2006; 81(1): 231 - 234. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
