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The Patent or Persistent Ductus Arteriosus in the Preterm Neonate: Review of the Literature and A Pragmatic Approach to Management

3 months ago
INTRODUCTION
During foetal life, blood flows through the ductus arteriosus (DA) from the pulmonary artery into the aorta, thereby bypassing the lungs. After birth, the DA undergoes active vasoconstriction and eventual closure. A patent ductus arteriosus (PDA) occurs when the DA does not close completely after delivery.

Preterm infants with moderate to large PDA have a greater mortality, increased risk of pulmonary oedema, pulmonary haemorrhage and bronchopulmonary dysplasia, as well as decrease in perfusion and oxygen delivery to end-organs. This review focuses on the recent advances in management of PDA in preterm infants and recommends a pragmatic approach.

SIGNIFICANCE OF PDA WITH RESPECT TO CLINICAL OUTCOMES
The left-to-right shunting of blood through a PDA in premature infants from the aorta into the pulmonary arteries results in excessive flow through the pulmonary circulation and hypoperfusion of the systemic circulation. Systemic hypoperfusion may be due to a “ductal steal” phenomenon shunting blood from systemic to pulmonary circulation. The effect of systemic hypoperfusion in turn depends upon the size of the shunt and the response of the brain, lungs, and other end-organs to the shunt.

In preterm infants, a clinically significant PDA, also called a haemodynamically significant PDA (HSPDA), is associated with effects on both pulmonary overcirculation and systemic hypoperfusion.

Pulmonary overcirculation effects include pulmonary oedema, pulmonary haemorrhage, bronchopulmonary dysplasia, and worsening of pulmonary function. PDA closure improves pulmonary compliance and ventilation.1 Systemic hypoperfusion effects include reduced cerebral perfusion and oxygenation, which may contribute to intraventricular haemorrhage, periventricular leukomalacia and cerebral palsy while higher left ventricular output and lower abdominal aortic blood flow may contribute to necrotising enterocolitis, impaired renal function, cardiac failure and hypotension.

However, what is unclear, despite decades of research, is whether closure of the PDA would help to improve these clinical outcomes.

The Patent or Persistent Ductus Arteriosus_Table1

EVALUATION OF THE HAEMODYNAMICALLY SIGNIFICANT PDA
Clinical signs such as heart rate, blood pressure and capillary refill provide only limited insight into the adequacy of systemic blood flow and end-organ perfusion, and echocardiography, particularly functional echocardiography (fECHO), is able to address some of these limitations by providing novel physiological insights for evaluation, monitoring and assisting in management decisions.2

fECHO refers to a bedside, limited assessment of the ductus arteriosus, myocardial performance and pulmonary or systemic haemodynamics, which is brief in nature and addresses a specific clinical question or management dilemma. This point-of-care ultrasound is increasingly used internationally and locally among neonatal units to assist with management of neonatal haemodynamic conditions. fECHO is different from echocardiography performed by a paediatric cardiologist, where the main focus is to provide a consultative, cross-sectional opinion regarding structural heart disease assessment. The provision of real-time information on haemodynamics, non-invasive nature of the technique, rapidity of data acquisition and report generation, and ability to perform longitudinal functional assessments have all contributed to the increased use of fECHO by neonatologists in the NICU.

The complexity and dynamic nature of transitional circulation, variable responsiveness of the immature myocardium in the early neonatal period, the presence of intracardiac and PDA shunting, makes therapeutic decision making and clinical evaluation challenging.

APPROACHES TO MANAGEMENT OF PDA
Controversy remains about the exact definition of HSPDA. The PDA is a dynamic vessel with variable architecture, with an unpredictable response to treatment. It is not possible to directly measure the magnitude of transductal flow, but its impact on pulmonary and systemic circulations is quantifiable. It is clear that an approach which combines both clinical parameters and echocardiographic measures represents the best contemporary compromise to assess the significance of the PDA. The role of closure of PDA in improving adverse outcomes, the best method to do so and appropriate timing of treatment remain controversial, resulting in great heterogeneity in practice. However, broadly speaking, these can be classified as (a) various forms of medical treatment including prophylactic treatment (within 12 hours after birth), early targeted treatment (6–72 hours after birth), or treatment when clinical signs associated with a PDA appear (b) conservative management and (c) PDA ligation.

PHARMACOLOGICAL MANAGEMENT OF PDA
Systematic review of prophylactic treatment showed a reduction in symptomatic DAs (relative risk [RR], 0.44, 95% confidence interval [CI], 0.38-0.50), but with no difference in long-term neurodevelopmental outcome.3 This occurred despite the lower incidence of intraventricular haemorrhage. It would therefore seem that the infants whose DAs tend to close spontaneously and were hence unnecessarily exposed to indomethacin do not benefit or may even suffer adverse effects. With the prophylactic approach, approximately 40% of patients were unnecessarily treated.4

Early targeted treatment allows us to select patients based on fECHO parameters, which predicts to some extent the likelihood of DA persisting and requiring treatment. However, multiple trials had so far not shown any benefits, particularly long-term benefits.5

Treatment after clinical signs avoids overtreatment, but clinical signs such as murmur and wide pulse pressure appear late in the clinical course and significant ductal steal from organ perfusion might occur before clinical signs. Although widely practised, this approach had not been subjected to rigorous trials. However, a meta-analysis demonstrated that early (2 or 3 days after delivery) versus late (7–10 days after delivery) administration of indomethacin in preterm infants with HSPDAs was associated with shorter duration of mechanical ventilation and decreased risk of bronchopulmonary dysplasia (BPD) (odds ratio [OR], 0.39, 95% CI, 0.21-0.76), necrotizing enterocolitis (NEC) (OR, 0.24, 95% CI, 0.06-0.96), and need for surgical ligation (OR, 0.37, 95% CI, 0.20-0.68).6

CONSERVATIVE SUPPORTIVE MANAGEMENT
Conservative management avoids the use of direct medical or surgical therapy for ductal closure. Supportive features include use of a neutral thermal environment and adequate oxygenation to minimize demands on left ventricular (LV) function, use of positive end-expiratory pressure (PEEP) to improve gas exchange and increase pulmonary vascular resistance and reduce left to right shunting. Maintenance of haematocrit at 35–40% using blood transfusions may also improve gas exchange and hence improve pulmonary vascular resistance.

This has led to a suggested strategy for less aggressive and more permissive management for PDA management with the view that it may not result in worse outcomes. In some retrospective cohort studies, management strategies, which avoid the use of indomethacin or ibuprofen obtain outcomes similar to medical treatment. However, more and better evidence is needed before this can emerge as the approach of choice.7-8

However, the most recent studies had associated a conservative approach with greater mortality and morbidity. A retrospective study of very low birthweight infants comparing two epochs, changing from early indomethacin and/or ligation to a permissive approach resulted in higher incidence of bronchopulmonary dysplasia (BPD), and the composite outcome of death or BPD.10 Another publication studying preterm infants at ≤28 weeks’ GA with a persistent PDA after failure of indomethacin treatment, compared periods for which surgical ligation was available or unavailable. Infants with a persistent PDA had similar rates of chronic lung disease (CLD), intraventricular haemorrhage (IVH) and NEC, but higher mortality.9 Noori, et al described similar report that showed an increase in mortality among infants with a persistent PDA, even after adjusting for various confounders.15

A PRAGMATIC APPROACH TO THE ASSESSMENT AND MANAGEMENT OF HSPDA
A pragmatic approach would entail more information on HSPDA with fECHO and quantify the DA into small, moderate, and large, as well as taking into account the various critical clinical parameters. McNamara, et al designed an integrated clinical and fECHO staging system that could be used to define thresholds for pharmacological treatment.11-12 The clinical markers used to assess the disease severity in this staging system included oxygenation index (OI), number of desaturations, level of respiratory support, oliguria, hypotension, and degree of metabolic acidosis.12

IMPACT OF fECHO ON CLINICAL OUTCOMES FOR PDA
Increasing evidence supports the effectiveness of fECHO in NICU for detecting haemodynamic compromise, changing management, and in improving outcomes.13 For instance, the introduction of a neonatologist-performed screening programme for haemodynamically significant ductus arteriosus (HSDA) on day 3 of life with targeted intervention was associated with a reduction in severe intraventricular haemorrhage and duration of ventilation, which were temporal in nature.14 A retrospective review of fECHO in a tertiary neonatal unit performed by neonatologists under cardiologist supervision showed that this resulted in direct change in management in 66% of infants examined.15

Lee, et al showed that fECHO can provide quick and accurate identification of PDA with a sensitivity of 87% and specificity of 71%.15 Moss, et al reported 82% concordance between scans by trained neonatologists and paediatric cardiologists.16

PDA LIGATION
Surgical ligation may be performed if there is failure of ductal closure after two courses of medical treatment or if medical treatment is contraindicated. Pharmacologic therapy is preferred as initial treatment because PDA ligation is associated with risks of blood pressure fluctuations, respiratory compromise, infection, IVH, chylothorax, recurrent laryngeal nerve paralysis, BPD, death, and long-term neurodevelopmental impairment.17–18

However, as the evidence are observational, it remains uncertain whether PDA ligation or anaesthesia are the major contributors, or if these patients were already more severely compromised to begin with. However, evidence is gathering that surgical ligation itself may compromise cerebral oxygen saturation intra-operatively and together with post-operative haemodynamic instability, contribute to increase morbidities and mortality. Current evidence supports the presence of a clinical phenomenon called the Post Ligation Cardiac Syndrome (PLCS). These post ligation patients post–operatively have a significant decrease in left ventricular (LV) output and hypoperfusion, because of decreased LV preload and increased systemic vascular resistance.19 Where PDA ligation is unavoidable, these patients should be carefully monitored post-operatively, both clinically and with fECHO.

Current consensus is that early routine surgical ligation subjects many infants to the risks of surgery whose PDAs may close spontaneously, and is unwarranted. A period of conservative management for a PDA in preterm infants may be a useful adjunct to ductal closure, either as primary therapy or after failure of medical treatment, though the optimal duration of “watchful waiting” requires further study. Nonetheless, increased mortality and CLD associated with persistent symptomatic PDA suggests that the ductal shunt is potentially hazardous, should continue to be considered in the routine prescription of intensive care support, and that surgical ligation remains an important treatment modality.20

RESEARCH
Recent literature is emerging on the use of both oral and intravenous paracetamol for ductal closure. Most of these studies used a daily dose of 60 mg/kg over a period of 2–7 days, which is much higher than the recommended doses for pain and fever control, and there remain concerns regarding hepatotoxicity and long-term neurodevelopmental effects. The quality of these studies was generally judged to be poor to moderate. Further data are hence needed.21

More research on the selective use of medical methods of ductal closure, either for high-risk infants such as preterm infants of 28 weeks’ gestation or less, or for older infants with persistent PDA is needed. Additional research need to address firstly, the relationship between haemodynamic significance and increased risks for prolonged patency and adverse clinical outcomes, such as chronic lung disease or neurodevelopmental impairment. Secondly, well-designed and executed intervention trials, for which the end points are clinically important long-term outcomes and not simply rates of ductal closure or measures of short-term physiologic changes, are needed.7

CONCLUSION
Although the approach to HSPDA remain controversial, a pragmatic approach on therapeutic decisions based on an integrated approach using clinical parameters, particularly the severity of respiratory disease and the continued need for mechanical ventilation together with fECHO parameters while balancing the risk and benefits of pharmacological therapy appears prudent.

About the author
Dr Poon Woei Bing is Senior Consultant Paediatrician and Neonatologist in the department of Neonatal and Developmental Medicine, Singapore General Hospital.
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