The Journal of Pediatrics
Volume 157, Issue 3 , Pages 355-357, September 2010

Patent Ductus Arteriosus Management: What Are the Next Steps?

  • Matthew Laughon, MD, MPH

      Affiliations

    • Corresponding Author InformationReprint requests: Matthew Laughon, MD, MPH, Division of Neonatal-Perinatal Medicine, UNC Hospital, CB#7596, Chapel Hill, NC 27599-7596.
    • ,
  • Carl Bose, MD

School of Medicine, Division of Neonatal-Perinatal Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, California

published online 28 June 2010.

Article Outline

BPD, Bronchopulmonary dysplasia, NEC, Necrotizing enterocolitis, PDA, Patent ductus arteriosus

 

See related article, p 381

Over the past several decades, development of exogenous surfactant, increasing use of antenatal steroids, advances in parenteral nutrition and infant ventilation, and other innovations have dramatically reduced mortality rates and improved outcomes of surviving premature infants. Some of these practices (antenatal steroids,1 surfactant2) were supported by evidence from randomized controlled trials. However, justification for the incorporation of others into routine practice was merely the association between either their adoption and improved outcomes or that the diagnosis itself was associated with important morbidities of prematurity, such as a patent ductus arteriosus (PDA) and bronchopulmonary dysplasia (BPD). During this time, the use of indomethacin or surgical ligation for closure of the persistent PDA was advocated and widely adopted, on the basis of growing knowledge of the disordered circulatory and pulmonary physiology associated with this condition and not on solid evidence for the efficacy of these therapies in reducing mortality or important morbidities of prematurity. Enthusiasm for these treatments has continued until today.

In this issue of The Journal, Jhaveri et al3 examine the impact of adoption of a “conservative” approach to the ductus that remains patent after 1 or 2 courses of indomethacin therapy. Using a historical cohort study design, the authors demonstrate that an aggressive approach (ligation of all PDAs after failure of indomethacin therapy) compared with a conservative approach (watchful waiting and only ligating when signs of “cardiopulmonary compromise” occur) has no apparent benefits and is associated with an increase in the risk of necrotizing enterocolitis (NEC). The authors are to be commended for the thoughtful change in their practice and for publishing these observations. The take-home message seems clear. It appears safe and beneficial to avoid immediate ligation of all infants with persistent PDA after failure of medical therapy. However, we believe that this report has broader implications.

Might a less-aggressive approach to ligation of the PDA result in improvement in outcomes in addition to NEC? Despite the relatively modest sample size of infants who did not respond to indomethacin, a significant reduction in the rate of NEC was demonstrable with multivariate regression analysis. In addition, morbidity rates of prematurity such as sepsis, intraventricular hemorrhage, death, and BPD were lower in the era of the less-aggressive approach. After adjustment in multivariate analysis, only NEC remained statistically significant. However, all of the odds ratios were in favor of the less-aggressive era. These results were achieved despite much longer periods of exposure to larger ductal shunts, implying that this circumstance might not be as harmful as previously believed. One possibility is that reduction in other outcomes might have been demonstrable with a larger sample. We conclude that the less-aggressive strategy described by Jhaveri et al3 might have benefits in addition to a reduction in NEC.

It is not clear whether benefits during the less-aggressive era derived from a delay in PDA ligation or avoidance of the procedure. If avoidance imparted benefit, even greater benefit might have resulted from an even more conservative approach. It is possible that a portion of the nearly 3 of 4 infants who underwent ligation in this era might also have benefitted by avoidance of ligation. Surgical ligation of the ductus can cause vocal cord paralysis, feeding difficulties, and growth failure4 and is associated with significant long-term morbidity such as increased risk of BPD and retinopathy of prematurity5; scoliosis6; and neurodevelopmental impairment.3, 5 Whether ligation contributes to some of these adverse outcomes or is merely a marker of disease severity is not clear.3 However, there appears to be a reasonable likelihood that an even less-aggressive approach,7 compared with that described by Jhaveri et al, might be more beneficial.

The potential benefits of a less-aggressive approach, one that might result in very low rates of ligation, are supported by other observational studies. Rates of PDA ligation vary dramatically among centers, and low rates do not appear to adversely impact outcomes. To the contrary, low rates of ligation are associated with potential benefit. For example, in the Trial of Indomethacin Prophylaxis in Preterms, rates of ligation among centers ranged from 0% to greater than 20%.3 Centers that had higher rates of ligation had a higher risk of death or neurodevelopmental impairment. After adjustment for antenatal steroid use, gestational age at birth, sex, multiple births, and mother's education, the association between rates of ligation and outcomes was reduced, suggesting that differences in the population at the center contributed to a portion of the observed variability in outcomes. However, the trends in association persisted after adjustment. Therefore, although one cannot conclude with certainty that avoidance of PDA ligation improves outcome, it appears safe to assume that it does not worsen outcome. How did centers in the Trial of Indomethacin Prophylaxis in Preterms with low ligation rates achieve these rates? These centers might have developed practices (such as selective use of indomethacin or ibuprofen, fluid restriction, or the use of diuretics) that lead to consistent early ductal closure. However, it is likely that some PDAs in these centers remained open and were managed with medical strategies that effectively obviated the hemodynamic consequence of ductal patency by clinicians who chose these strategies as an alternative to ligation. In choosing these strategies, they may have avoided potential morbidities directly attributable to the surgical procedure without increasing other serious morbidities.

What should be the next steps in our approach to ligation of the PDA? We should implement what we know and study what we don't know. We can begin by educating ourselves and our colleagues about the harmful effects of surgical ligation. Quality improvement techniques might be useful in investigating the effectiveness of less intervention in the management of the PDA, beginning with those infants whose conditions have failed to respond to indomethacin3 and progressing to all infants with birth weights > 1000 g, for whom spontaneous closure should be expected.8 Identification and emulation of practices from centers reporting good outcomes with low ligation rates, supplemented by monitoring rates of significant morbidities of prematurity (necrotizing enterocolitis, BPD, periventricular leukomalacia, etc), might allow extension of this approach to all very low–birth weight infants.

There is a pressing need to better understand the benefits and risks of all treatments for the PDA. The lack of benefit from PDA ligation observed by Jhaveri et al,3 among infants who are presumably at the highest risk for later sequelae, raises the possibility that other therapies to effect closure might also be without benefit. A recent systematic review examined all clinical trials of treatments for closure of the PDA and found no evidence to support any treatment.9 Observational data suggests that ductal closure is likely even among infants discharged with a PDA.10 Perhaps there are no adverse consequences to patency until spontaneous closure, even if the period of patency is weeks to months. We need to determine whether a permissive approach to management, patiently awaiting spontaneous closure, is as appropriate for very low–birth weight infants in general because it appears to be in the subgroup studied by Jhaveri et al.3 We need a better understanding of the optimal strategies for management of the hemodynamic disturbances associated with persistent patency.

Clinical trials designed to determine whether any interventions intended to close the PDA reduce mortality and morbidity rates are clearly necessary. The most informative design would be a randomized controlled trial of aggressive versus conservative treatment, with aggressive treatment consisting of an approach similar to the “conservative” arm in this study: early indomethacin or ibuprofen therapy followed by ligation for infants who manifest cardiopulmonary compromise with a persistent PDA. The alternative arm would be watchful waiting, with no medical or surgical intervention to close the ductus unless congestive heart failure or persistent hypotension attributable to the PDA develops.7 In an ideal trial, increasing need for respiratory support would not be a criterion for intervention in the latter group, because many infants will have pulmonary deterioration in the second postnatal week, with or without a PDA.11 Ideally, specific ancillary measures would be used to mitigate effects of the ductal shunt. Selection of such measures might require foundational investigations of their effects of on ductal, cerebral, renal, or pulmonary blood flow.

The thoughtful and well-written report by Jhaveri et al3 has added one more piece of evidence that ligation is, at best, not helpful and, at worst, harmful. We hope that neonatologists have enough equipoise to thoroughly test management strategies of the PDA with thoughtful, well-designed clinical trials using a measure of restraint in the conservative group. As a profession, we are currently using approaches to the PDA without sufficient evidence of the risks and benefits of treatment. As the late Bill Silverman said,12 “We cannot always make our patients better, but we can always make them worse.” He also said, “Enroll me in the trial.” We owe it to our patients, present and future, to do the trials necessary to inform our practice.

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References 

  1. Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev. 2006;3:CD004454
  2. Soll RF. Prophylactic synthetic surfactant for preventing morbidity and mortality in preterm infants. Cochrane Database Syst Rev. 2000;(2):CD001079
  3. Jhaveri N, Moon-Grady A, Clyman RI. Early surgical ligation versus a conservative approach for management of patent ductus arteriosus that fail to close after indomethacin treatment. J Pediatr. 2010;157:381–387
  4. Benjamin JR, Smith PB, Cotten CM, Jaggers J, Goldstein RF, Malcolm WF. Long-term morbidities associated with vocal cord paralysis after surgical closure of a patent ductus arteriosus in extremely low birth weight infants. J Perinatol. 2009 Sep 17;[Epub ahead of print]
  5. Kabra NS, Schmidt B, Roberts RS, Doyle LW, Papile L, Fanaroff A. Neurosensory impairment after surgical closure of patent ductus arteriosus in extremely low birth weight infants: results from the Trial of Indomethacin Prophylaxis in Preterms. J Pediatr. 2007;150:229–23434 e1
  6. Roclawski M, Sabiniewicz R, Potaz P, et al. Scoliosis in patients with aortic coarctation and patent ductus arteriosus: does standard posterolateral thoracotomy play a role in the development of the lateral curve of the spine?. Pediatr Cardiol. 2009;30:941–945
  7. Vanhaesebrouck S, Zonnenberg I, Vandervoort P, Bruneel E, Van Hoestenberghe MR, Theyskens C. Conservative treatment for patent ductus arteriosus in the preterm. Arch Dis Child. 2007;92:F244–F247
  8. Nemerofsky SL, Parravicini E, Bateman D, Kleinman C, Polin RA, Lorenz JM. The ductus arteriosus rarely requires treatment in infants > 1000 grams. Am J Perinatol. 2008;25:661–666
  9. Benitz W. Treatment of persistent patent ductus arteriosus in preterm infants: time to accept the null hypothesis?. J Perinatol. 2010;30:241–252
  10. Herrman K, Bose C, Lewis K, Laughon M. Spontaneous closure of the patent ductus arteriosus in very low birth weight infants following discharge from the neonatal unit. Arch Dis Child Fetal Neonatal Ed. 2009;94:F48–F50
  11. Laughon M, Allred EN, Bose C, et al. Patterns of respiratory disease during the first 2 postnatal weeks in extremely premature infants. Pediatrics. 2009;123:1124–1131
  12. Silverman WA. Where's the evidence? Debates in modern medicine. Oxford, United Kingdom: Oxford University Press; 1999;

 The authors declare no conflicts of interest.

PII: S0022-3476(10)00425-7

doi:10.1016/j.jpeds.2010.05.022

Refers to article:

  • Early Surgical Ligation Versus a Conservative Approach for Management of Patent Ductus Arteriosus That Fails to Close after Indomethacin Treatment , 03 May 2010

    Nami Jhaveri, Anita Moon-Grady, Ronald I. Clyman
    The Journal of Pediatrics September 2010 (Vol. 157, Issue 3, Pages 381-387.e1)

The Journal of Pediatrics
Volume 157, Issue 3 , Pages 355-357, September 2010

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