Review
Preterm patent ductus arteriosus: A continuing conundrum for the neonatologist?

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Summary

How to manage the preterm patent ductus arteriosus (PDA) remains a conundrum. On the one hand, physiology and statistical association with adverse outcomes suggest that it is pathological. On the other hand, clinical trials of treatment strategies have failed to show any long-term benefit. Ultrasound studies of PDA have suggested that the haemodynamic impact may be much earlier after birth than previously thought (in the first hours); however, we still do not know when to treat PDA. Studies that have tested symptomatic or pre-symptomatic treatment are mainly historical and have not tested the effect of no treatment. Prophylactic treatment is the best-studied regimen but improvements in some short-term outcomes do not translate to any difference in longer-term outcomes. Neonatologists have been reluctant to engage in trials that test treatment against almost never treating. Observations of very early postnatal haemodynamic significance suggest that targeting treatment on the basis of the early postnatal constrictive response of the duct may optimize benefits. A pilot trial of this strategy showed reduction in the incidence of pulmonary haemorrhage but more trials of this strategy are needed.

Introduction

A conundrum is defined as an intricate and difficult puzzle; how we should manage the preterm patent ductus arteriosus (PDA) is indeed a conundrum. On the one hand, there is evidence that the preterm PDA can be pathological. First, haemodynamic studies show that the PDA facilitates shunting of large volumes of blood from the systemic to the pulmonary circulation, draining blood from the former and overloading blood into the latter. Second, observational studies that have consistently associated persistent PDA shunting with a range of adverse outcomes including necrotizing enterocolitis (NEC), peri/intraventricular haemorrhage (P/IVH), chronic lung disease (CLD) and death [1], [2], [3]. Interpretation of these studies is limited by the co-linearity between each of these outcomes, persistent PDA and immaturity, and also by the wide range of ways in which PDA has been defined using a menagerie of clinical and, latterly, echocardiographic criteria [4].

On the other hand, since PDA is causing these adverse outcomes then treating it should reduce the incidence of those outcomes. Yet amalgamations of the results of randomized trials show little evidence of consistent effect of treating PDA on outcomes [5], [6], [7], [8]. However, again there are limitations in that, with the exception of prophylactic treatment, these trials are historically and methodologically diverse.

A purist interpretation of this conundrum would be that if treating makes no difference to outcomes then preterm PDA may not be pathological. However, lack of evidence of effect is not the same as evidence of lack of effect, and the other interpretation could be that we have not understood the natural history of the pathology of the PDA or what happens when we try to treat PDA medically. In other words, in many babies the treatment may not be doing what we want it to do.

Systematic review is important for defining the limitations of our understanding, but it is less useful for defining whether the right treatment questions have been asked in the right way. For that, you have to study the babies and their ducts with the goal of understanding what is pathological and what is not pathological about their behaviour. Good treatment strategies still depend on accurate diagnosis and an understanding of the natural history of the pathophysiology.

Section snippets

Cardiac ultrasound and the ductus

Cardiac ultrasound has been pivotal to the development of our understanding about the ductus. Ultrasound allows direct imaging of the ductus, assessment of constriction, the shunt direction and velocity, and the disturbance to blood flow patterns in the great vessels either side of the ductus (Fig. 1).

Treatment of the preterm ductus arteriosus

So should we be treating PDA in preterm babies? It has been apparent for many years from systematic review of the literature that there is no clear evidence of effect on long-term outcomes of treating PDA. The issue has been brought into sharper focus by several review articles, which have essentially re-worked the same studies and, perhaps not surprisingly, have failed to produce a clear answer. Laughon and Bose [5], [6] proposed that the reason for the lack of effect might be that the patency

If you are going to treat, when to treat?

This is the really difficult part. There are essentially three strategies that have been studied. The first is to wait to see if the PDA becomes clinically apparent (e.g murmur, bounding pulses or active praecordium) and/or symptomatic (e.g. respiratory deterioration or ventilator dependence) and then treat. Despite being probably the commonest strategy in clinical practice, the studies of this symptomatic approach are surprisingly limited. Second is pre-symptomatic treatment; these studies

What is the role of surgical ligation?

Although few centres would use surgical ligation as a first-line treatment, it is still used in babies who fail to respond to medical treatment and who continue to have medical conditions potentially attributable to the presence of a large PDA. There appears to be an international trend to a less aggressive approach to ductal ligation, reflecting concerns that ligation of PDA may do more harm than good [40]. Several studies have shown acute, potentially detrimental, hemodynamic effects after

How should PDA be managed in 2015?

All this hand-wringing over the evidence is not particularly helpful to the practising clinician who wants to know what to do. Despite all the copy decrying our lack of understanding of treatment of PDA, the proposed trials remain elusive because they are so difficult to perform.

It could be argued that, if you were an evidence-based purist, then you should either never treat any PDA in any baby or you should use prophylactic indomethacin. It would be my opinion that the former should be applied

What next: very early ultrasound targeted treatment?

Few would argue about the need for more trials of PDA therapy, but in the real world, rightly or wrongly, many clinicians have difficulty accepting no treatment in individual babies with significant PDA. There have been proposals to compare conventional treatment of PDA after a few days, either symptomatically or pre-symptomatically, with a control group where the aim would be that almost no babies receive treatment. It is my understanding that these trials have floundered on clinician

Conflict of interest statement

None declared.

Funding sources

None.

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