What happens when the patent ductus arteriosus is treated less aggressively in very low birth weight infants?

Abstract

Objective:

It remains unclear whether indomethacin (INDO) and/or surgical ligation (LIGATE) are necessary to improve outcomes in premature infants with a patent ductus arteriosus (PDA). We have adopted a conservative approach to PDA management that emphasizes waiting for spontaneous closure unless certain cardiorespiratory distress criteria are met.

Study Design:

This was a before-after observational study in infants born 501 to 1500 g in two distinct epochs. Era 1 (January 2005 to December 2007) featured traditional management with INDO and LIGATE used early to close all moderate and large PDAs in infants receiving any respiratory support. Era 2 (January 2008 to June 2009) emphasized modest fluid restriction, watchful waiting and limited INDO and LIGATE to only those infants with large PDAs who met certain cardiorespiratory distress criteria.

Result:

Era 1 included 139 infants with a PDA, mean (s.d.) gestational age 27.5 (2) weeks; Era 2 72 infants, mean (s.d.) gestational age 27.5 (2) weeks. In Era 2, INDO use significantly decreased (79% of infants to 26%, P<0.001), and 28 day total fluids decreased (140 vs. 130 ml kg−1 day−1, P<0.001). LIGATE rate was 45% in Era 1, 33% in Era 2 (P=0.11). There were no significant differences in supplemental oxygen, nasal continuous positive airway pressure, or mechanical ventilation days. There were no significant differences in mortality or individual morbidities. The combined outcome of chronic lung disease (CLD) or mortality after Day 7 significantly increased (Era 1, 40%, Era 2, 54%, P=0.04). More infants were discharged home with a PDA in Era 2, but most resolved spontaneously and the need for closure therapy after discharge from the neonatal intensive care unit (NICU) did not increase. Multiple regression analysis demonstrated Era 2 management did not predict an increased risk of one or more interlinked morbidities.

Conclusion:

Tolerance of the PDA with watchful waiting for spontaneous closure, modest fluid reduction, and less INDO use is a reasonable treatment strategy that is not associated with significant changes in NICU mortality or individual morbidities. We did note an increase in the combined outcome of CLD or mortality after Day 7, thus our investigation supports the urgency of a randomized controlled trial comparing traditional PDA management with a true control group similar to our Era 2 management to answer important questions of short and long-term outcomes.

Introduction

The patent ductus arteriosus (PDA) is diagnosed in 38% of infants born 501 to 1500 g and appears to be considered a serious condition by most neonatologists as 87% of these infants receive cyclo-oxygenase inhibitors and 21% undergo surgical ligation (LIGATE).1 In three recent comprehensive reviews, Bose and Laughon,2 Benitz,3 and Hamrick and Hansmann,4 have highlighted significant complexities that make rational, evidence based management of the PDA challenging. First, although the presence of a PDA has been associated with several morbidities such as chronic lung disease (CLD), necrotizing enterocolitis and intraventricular hemorrhage, the relationships have not been proven to be causal. Second, there has never been a large randomized controlled trial (RCT) in which there was a true control group, that is, an arm with no specific initial PDA therapy other than watchful waiting for spontaneous closure with supportive care. Third, current therapies for the PDA (cyclo-oxygenase inhibitors and LIGATE) are associated with untoward side effects, such as renal, intestinal and cardiac dysfunction, as well as neurodevelopmental delay.

Because of the paucity of published trials documenting outcomes in neonatal intensive care units (NICUs) where PDAs were not treated reflexively with cyclo-oxygenase inhibitors or LIGATE,5, 6, 7 we adopted PDA management guidelines in 2008 that emphasized watchful waiting for spontaneous closure, modest fluid restriction and limited use of indomethacin (INDO) and LIGATE to only those infants who met certain cardiorespiratory distress criteria. The purpose of this manuscript is to describe our before-after observational study to determine whether our new PDA management guidelines were associated with improved, worsened or unusual NICU outcomes.

Methods

Approval for this investigation was obtained from our institutional review board. Providence St Vincent Medical Center is a tertiary care NICU with 900 admissions per year, 150 are 501 to 1500 g (92% inborn), and we have the full array of Level 3 subspecialty and surgical support services. We included for analysis all infants born 501 to 1500 g who were admitted to our NICU, were diagnosed with a PDA and survived at least 7 days. PDA management did not affect those infants who died before 7 days (most were within 24 h) and no early deaths were related to PDA complications. The clinical definition of gestational age (postmenstrual age (PMA)) and all standard morbidities were taken from the Vermont Oxford Network Manual of Operations.8 Specifically, a PDA was diagnosed if an infant had evidence of a left to right shunt as documented by a systolic murmur, hyperdynamic precordium, bounding pulses, wide pulse pressure, increased pulmonary vasculature or cardiomegally, and/or increased oxygen administration or echocardiographic demonstration of a PDA with a left to right shunt.8 CLD was defined as any supplemental oxygen use at 36 weeks PMA, or if the infant was discharged home before 36 weeks PMA on supplemental oxygen.8 The control period Era 1 was January 2005 to December 2007, a time period when respiratory and PDA management was relatively uniform. During Era 1, infants with PDAs were treated early with INDO if they received supplemental oxygen and/or any level of nasal continuous positive airway pressure (NCPAP) or mechanical ventilation (MV). INDO dose was usually 0.2 mg kg−1 given every 12 to 24 h for three to six doses. LIGATE was used for persistent PDAs unresponsive to INDO. We emphasized non-invasive respiratory support using bubble NCPAP to minimize exposure to MV in both eras.9, 10

After a comprehensive review of the literature combined with analysis of our own outcomes data we elected to adopt a more conservative PDA approach for Era 2 (January 2008 to June 2009). This time interval was felt adequate to detect clinical differences in outcomes but not so long as to potentially put an undue number of infants at risk for significant deleterious events related to untreated PDAs. Our revised management re-emphasized NCPAP as the primary means of respiratory support, adopted modest fluid restriction and encouraged watchful waiting for spontaneous PDA closure. Identical criteria were used in both eras to diagnose a PDA. Infants with a PDA were considered for INDO only if they could not maintain adequate oxygenation and ventilation on NCPAP, or could not be weaned from MV, both often associated with feeding intolerance. At that point an echocardiogram was obtained and only those infants with significantly large PDAs were treated with INDO (size >2 to 3 mm, left to right shunt and left heart chamber enlargement). LIGATE was used if the symptomatic PDA was unresponsive to INDO. Ibuprofen was not used in either era. Although not a rigid practice parameter, physicians were urged to follow these guidelines knowing we were conducting a before-after observational study. Oxygen saturation targeting with pulse oximetry was similar during both eras, 86 to 94% for any infant receiving supplemental oxygen, NCPAP or MV. In both eras, the hemoglobin level was generally maintained 12 g dl−1 (grams/deciliter) if an infant was receiving MV, 9 to 10 g dl−1 if receiving NCPAP and 8 g dl−1 in all others.

To measure compliance with the new practice guidelines we calculated the total daily fluids in the first 28 days (intravenous plus oral), tracked respiratory support measurements, INDO and LIGATE utilization, growth velocity, and all the principle Vermont Oxford Network morbidity categories. For comparison of categorical variables χ2 or Fisher's exact tests were used, and for continuous variables t-tests or Mann–Whitney U-tests were used where applicable. Stepwise Poisson regression was used to determine the predictors for multiple NICU morbidities with length of stay as the offset variable. Stepwise logistic regression was used to determine the predictors of CLD. Era of birth was forced into the models to evaluate its effect when adjusted by the predictors. Statistical analysis was performed using PASW 17 (SPSS Chicago, IL, USA), and R 2.11 (http://www.R-project.org).

Results

In Era 1, 139/385 (36%) of the infants born 501 to 1500 g were diagnosed with a PDA and survived the first week of life, 72/196 (37%) in Era 2. 131/139 (94%) of Era 1 infants had their PDAs confirmed with an echocardiogram, 64/72 (89%) in Era 2. The racial profile in both eras was 65% Caucasian, 20% Hispanic, 10% Asian and 4% African-American. Table 1 lists the demographic features of those infants diagnosed with a PDA, as well as clinical management descriptors. In Era 2, total daily fluids were lower, the number of NICU days an infant had a PDA listed as an active diagnosis significantly increased, and INDO use declined (P<0.001). When INDO was used, it was initiated significantly later in the NICU stay during Era 2, and this was also true for LIGATE (P<0.001). There were no significant differences in the use of supplemental oxygen, NCPAP, or MV between eras (Table 2).

Table 1 Clinical characteristics, fluid totals, PDA burden, indomethacin use and surgical ligation in Era 1 vs. Era 2
Table 2 Respiratory support Era 1 vs. Era 2

Table 3 lists the principle NICU Vermont Oxford Network morbidities in both eras. There were no significant differences except in Era 2 we noted a higher rate of the combined outcome of CLD or mortality after Day 7 (P=0.04). Length of stay was not different between eras (Era 1 65 days, Era 2 68 days), nor was the percentage of infants who were hospitalized beyond 40 weeks PMA (Era 1 to 10%, Era 2 to 11%).

Table 3 Clinical outcomes Era 1 vs. Era 2

Figure 1 shows the percentage of infants in each era who had none, or one or more of the major Vermont Oxford Network morbidities (CLD, Grade 3 to 4 intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, spontaneous intestinal perforation, late onset sepsis, and Stage 3 to 4 retinopathy of prematurity, all weighted equally). There was no indication our less aggressive PDA management in Era 2 improved or worsened the adverse outcome burden. The morbidity rates for Era 2 were 0.011 per day of NICU stay (55/4867) vs. 0.011 (101/9093) in Era 1, a rate ratio of 1.0 (P=0.88 by Likelihood ratio test for Poisson counts). Poisson regression was performed to evaluate the effect of era of birth adjusted by the clinical profiles of the infants. Younger gestational age, lower birth weight, male gender and slower growth velocity were found to be the significant predictors of NICU morbidities, not the era of birth (Table 4). Logistic regression suggested lower birth weight was associated with CLD not the era of birth.

Figure 1
figure1

Morbidity burden Era1 vs. Era 2. Chronic lung disease, severe intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, spontaneous intestinal perforation severe retinopathy of prematurity, and late onset sepsis all weighted equally.

Table 4 Predictors identified by Poisson regression analysis for multiple NICU morbidities, and predictors identified by logistic regression analysis for chronic lung disease

In Era 1, 9/139 (6%) of the infants were discharged home with a still open PDA (6/9 had received INDO). In six of these nine infants, the PDA closed spontaneously within 1 year of age without specific therapy. In two of the nine patients the PDA was closed using a coiling technique. One of the nine infants had a small, asymptomatic PDA at 8 months of age when lost to follow-up. In Era 2, significantly more infants were discharged home with a still open PDA, 14/72 (19%, P<0.01), (2/14 had received INDO). In 10 of these infants, the PDA closed spontaneously within 1 year of age without specific therapy, 1 infant was coiled, 1 infant was surgically ligated, and 2 infants had asymptomatic open PDAs at 18 months of age.

Discussion

Our before-after observational investigation in two distinct time periods suggests less aggressive management of the PDA with reduced use of INDO and LIGATE does not change a broad spectrum of individual NICU morbidities or mortality. Because there currently are no definitive RCTs comparing closure therapies like INDO and LIGATE with a true control group (watchful waiting for PDA closure), our experience supports the safety and need for such a trial.

Three recent comprehensive reviews have been instrumental in clarifying the PDA controversy and suggesting how we might make rational progress. Bose and Laughon argue that despite three decades of therapy and research, the question of whether active closure therapy for PDAs is beneficial compared with a restrained, conservative approach allowing spontaneous closure is largely unanswered.2 The authors recommend against routine use of cyclo-oxygenase inhibitors or LIGATE because of the adverse effects and lack of demonstrative long-term benefits. They believe the neonatology community has an ethical obligation to conduct proper RCTs with objective criteria for PDA closure therapy and a true placebo control arm that allows for spontaneous closure.

Benitz3 has published an exhaustive review of PDA closure therapies (49 controlled trials with 4728 infants) and concluded there is no evidence these practices benefit premature infants. He believes the available evidence indicates later PDA treatment of fewer infants produces better outcomes. Further, his meta-analysis conclusions are not a call to simply ignore large symptomatic PDAs, but rather a plea to devise alternative supportive strategies (for example, fluid restriction, NCPAP and transfusion therapy), and most importantly to support properly designed RCTs with an arm that allows for spontaneous closure.

Hamrick and Hansmann4 address similar issues in addition to discussing the cellular and biochemical features of PDAs. They argue for clinical and echocardiographic PDA staging criteria that also include biomarkers like B-type natriuretic peptide as a means to create clinical treatment algorithms. They conclude it remains unclear whether and when pharmacologic, surgical or conservative PDA closure therapies may be advantageous for the premature infant.

In clinical scenarios that lack rigorous RCTs to guide decision making, it is reasonable to examine information from observational studies because such investigations can provide practical guidance in areas a RCT might face obstacles related to equipoise, context and external validity.11 We believe our observational experience has several important findings. First, a practice of watchful waiting for PDA closure creates a new experience for most NICU physicians and nurses, that is, taking care of 4, 8, and 12-week-old infants (or older) who have significant PDAs (Table 1). This can present challenges with respiratory management, fluid administration, feeding, as well as provider bias and comfort with a new type of chronic condition. Second, we have shown less aggressive PDA treatment does not impact the need for respiratory interventions (Table 2), and important morbidities and mortality did not significantly change (Table 3, Figure 1). Neonatologists are understandably concerned about the possible deleterious effects of day after day presence of PDAs especially in infants <28 weeks PMA. The upward trend in CLD we noted in Era 2, if valid, would require 299 infants in each treatment arm to achieve significance (α=0.05, power=0.8). The significant Era 2 increase in the combined outcome of CLD or mortality after Day 7 is biologically plausible given that a longer exposure to a left to right shunt might affect both pulmonary function and blood flow to other organs. This is an urgent issue to clarify in future RCTs.

Third, we addressed the possibility that our less aggressive PDA management in Era 2 might have exposed our infants to a greater risk of interlinked multiple morbidities, thereby increasing the risk of adverse short and long-term outcomes. Poisson regression analysis suggests our Era 2 management was not a distinct multiple morbidity predictor (Table 4), and furthermore, the pattern of one or more morbidities per infant was not different between eras (Figure 1). It is not unreasonable to theorize that our reduced use of INDO and LIGATE might actually improve short and long-term outcomes as suggested by Kabra et al.,12 Madan et al.13 and Jhaveri et al.14

Fourth, although our data show less aggressive PDA management to be associated with more infants being discharged home with a still open PDA, our follow-up experience with all of these infants is reassuring. Most PDAs closed spontaneously within 1 year of age in both eras without causing cardiorespiratory compromise, and there was not an increased need for post-NICU coiling or LIGATE, just two infants in each era, similar to the report from Herrman et al.7

The limitations of our trial include the single center, non-randomized design and the fact that we could not enforce strict adherence to our consensus PDA management guidelines, thus we observed some variation in provider comfort with persistent PDAs, not precisely quantified. Nevertheless, we have carefully documented highly significant changes in the process of care along with detailed NICU outcomes available for evaluation and comparison.

In conclusion, we agree with recent comprehensive reviews that aggressive PDA closure therapy is a largely unproven therapy with no clear benefits to the premature infant. Our before-after observational study suggests that INDO and LIGATE can be reduced, with no significant increase in mortality or individual morbidities. Our NICU's experience lends credence to the safety and efficacy of a true control group in the PDA RCT we need, that is, a control arm that patiently waits for spontaneous closure, utilizing cyclo-oxygenase inhibitors and/or LIGATE only when certain cardiorespiratory distress criteria are met.15

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Acknowledgements

We thank Catherine Wang and Nicole Tipping for their assistance with data collection. We also are grateful to the Vollum foundation and Northwest Newborn Specialists, PC for supporting this investigation. This investigation was supported by a grant from the Vollum Foundation and Northwest Newborn Specialists, PC.

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Correspondence to J W Kaempf.

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Kaempf, J., Wu, Y., Kaempf, A. et al. What happens when the patent ductus arteriosus is treated less aggressively in very low birth weight infants?. J Perinatol 32, 344–348 (2012). https://doi.org/10.1038/jp.2011.102

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Keywords

  • patent ductus arteriosus
  • indomethacin
  • surgical ligation
  • chronic lung disease
  • quality improvement

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