Pathophysiology-based management of the hemodynamically significant patent ductus arteriosus in the very preterm neonate

Chapter 19: Pathophysiology-based management of the hemodynamically significant patent ductus arteriosus in the very preterm neonate

Stephanie M. Boyd, Elizabeth Rachel Fisher, Martin Kluckow

Key points


Historically, the default position of most neonatologists has been to treat the patent ductus arteriosus (PDA), particularly in the very-low-birth-weight (VLBW) infant (<1500 g). More recently, as our intensive care practices have evolved and outcomes continue to improve for the smallest, most vulnerable infants, the need for medical treatment, particularly with non-steroidal anti-inflammatory drugs (NSAIDs), has been increasingly questioned. This uncertainty has been driven by a number of factors, including our inability to identify infants who would most benefit from treatment, high spontaneous closure rates in infants >1000 g, variable efficacy of the medications available, balancing the risks of side effects, and the failure of trials of treatment to show clear short- or long-term benefits. However, it is not likely that an “all or none” solution is applicable – there are likely to be a subset of newborns with a PDA who should be treated at an appropriate time in order to avoid possible deleterious effects from a hemodynamically significant left-to-right shunt. Identification of these infants with a hemodynamically significant PDA (hsPDA) in whom treatment is more likely to be beneficial has become a priority. This is essential in seeking to avoid unnecessary therapies and undesirable side effects, balanced with minimizing the potential risks of exposure to adverse PDA physiology. A necessary prerequisite for appropriate patient selection for PDA treatment is an in-depth understanding of individual pathophysiology; specifically, the effects will be dependent on a number of underlying elements – the gestational age of the infant, the magnitude of any left-to-right transductal shunt (which is governed by the Poiseuille law of fluid dynamics), and associated degrees of systemic hypoperfusion and pulmonary over-circulation, as well as myocardial performance. Systemic hypoperfusion, due to the effects of circulatory “steal” on the systemic circulation, is manifested through alterations in systemic arterial pressure and perfusion to the brain, kidney, and gut. Pulmonary over-circulation, or excessive pulmonary blood flow, can result in higher respiratory support needs and pulmonary hemorrhage, as well as contribute to risks of subsequent bronchopulmonary dysplasia (BPD) and chronic pulmonary hypertension. Clinician-performed ultrasound (CPU) of the heart in the neonatal intensive care unit (NICU) by the clinician caring for the baby in a longitudinal setting is an important adjunct to clinical assessment when defining the hemodynamic profile of an infant with a PDA. Understanding how to assess the underlying elements of the pathophysiological scenario allows a more individualized decision to be made regarding the need for treatment, in order to both maximize potential benefit and minimize risks of treatment-related harm.

Pathophysiology of patent ductus arteriosus

The tendency of the ductus arteriosus (DA) to remain patent in preterm infants is thought to be related to developmental immaturity of ductal anatomy,1 as well as altered prostaglandin responsiveness2 and metabolism (see also Chapter 16).3 Not all PDAs are pathological, however, even in the preterm population. It is important to consider the PDA in the context of the clinical picture and associated hemodynamic state of the patient. For example, a PDA may be considered supportive in the setting of critically low pulmonary blood flow (either due to right ventricular outflow tract obstruction or severe pulmonary hypertension), left ventricular (LV) dysfunction, or left heart obstruction (e.g., coarctation of the aorta). A PDA is considered hemodynamically significant, and potentially pathological, when there are clinical and/or echocardiographic markers of a moderate or large volume left-to-right (systemic-to-pulmonary) shunt.

Flow through the DA is determined by the Poiseuille law (Q = ΔPπr4/8Lμ), where Q denotes flow, ΔP is the pressure gradient across the ductus, L is the ductal length, and μ is the viscosity (see Chapter 16). This has important implications for understanding factors that modulate ductal flow. The pressure difference in the systemic and pulmonary circulations is an important determinant of transductal shunt, particularly during the postnatal transition. The high systemic vascular resistance (SVR) and declining pulmonary vascular resistance (PVR) state of the transitioning preterm neonate creates a unique physiological vulnerability to high-volume left-to-right ductal shunting. The inherent diastolic “dysfunction” of the preterm myocardium and poor adaptive ability in the face of adverse loading conditions further compounds this risk. Physiologically, the negative consequences of an hsPDA can be considered complications relating to one or more among pulmonary over-circulation, systemic hypoperfusion, and/or hypoperfusion-reperfusion, which arise as a result of a significant left-to-right transductal shunt. Retrograde diastolic blood flow (ductal “steal”) diverts blood flow from post-ductal organs, such as the kidneys and gut, resulting in hypoperfusion. Conversely, the increased left ventricular output (LVO) secondary to left-to-right ductal shunting increases blood flow to pre-ductal organs, such as the brain. The latter is a potential mechanism for both peri-/intraventricular hemorrhage (P/IVH) associated with reperfusion, and white matter injury.4 As is evident from the Poiseuille equation, blood viscosity, and specifically red cell mass, blood platelet levels, and intravascular volume status, also have the potential to modulate flow across the PDA and should not be disregarded when considering factors contributing to the ductal flow pattern. Although PDA size is frequently ascertained as part of a comprehensive hemodynamic assessment, ductal morphology is less commonly evaluated. Several different anatomical subtypes of PDA exist,5 which may contribute to the limitations of using PDA size as a single marker from which to estimate shunt volume. The several factors regulating PDA flow highlight the importance of a comprehensive hemodynamic assessment when appraising the ductus and embarking on treatment-related decisions. The concept of hsPDA involves complex interactions between intrinsic, patient-related conditions, the anatomy of the PDA itself, and the medical therapies used as part of newborn intensive care practice. In summary, relevant considerations include:

Factors to consider in PDA clinical decision-making

Although the relative contribution of the preterm patent ductus to important neonatal morbidities has been studied extensively and evidence of association is strong, the role and merits of treatment remain controversial. The argument that the PDA is an innocent bystander with high likelihood of spontaneous closure, rather than a pathologic condition, is becoming increasingly prevalent in neonatology.6 As a result, there is a secular trend toward a conservative or non-intervention approach to PDA. Opting for non-treatment and awaiting spontaneous closure implies acceptance of any short- and long-term consequences of a PDA, which are in part related to the timing of intervention. The adverse effects of hsPDA relate to the duration and magnitude of exposure to a left-to-right shunt, inherent circulatory adaptive mechanisms,4 and interplay of important clinical factors (e.g., gestational age, comorbidities, chronological age, end-organ function). Prolonged patency is associated with numerous adverse outcomes, including prolongation of assisted ventilation and higher rates of BPD, pulmonary hemorrhage, P/IVH, periventricular leukomalacia (PVL), renal impairment, necrotizing enterocolitis (NEC), systemic hypotension, and death.7,32 The key issue is whether intervention at a particular time point prevents some or all of these complications with minimal side-effects related to treatment. Importantly, for each individual infant, there will be a different risk/benefit equation.

Consequences of a patent ductus arteriosus

In most newborn infants, even in the first postnatal hours, the ductal shunt is completely left-to-right or bidirectional with a dominant left-to-right component, illustrating that pulmonary pressures are usually sub-systemic shortly after birth. Using superior vena cava (SVC) flow as a surrogate measure of systemic blood flow, a negative association has been observed between duct diameter and SVC flow at 5 hours of age, but this association was not significant in subsequent studies at 12, 24, and 48 hours.8 The association between the early low systemic blood flow and development of P/IVH and later necrotizing enterocolitis (NEC) suggests a possible mechanism by which PDA shunting contributes to the pathophysiology of these conditions.8 There is also mounting evidence to suggest a PDA may cause pulmonary hemorrhage in preterm neonates because of overload of the pulmonary circulation in the presence of a low resistance pulmonary vasculature and that early ductal treatment may prevent this.911

A pathological PDA causes high left-to-right shunt volumes, which may flood the lungs and cause pulmonary edema. Pulmonary edema reduces lung compliance, resulting in increased ventilator and oxygen requirements. All these factors together might contribute to the development of BPD, known to be associated with the persistence of an hsPDA. Each week of exposure to a hemodynamically significant DA represented an added risk for BPD (odds ratio 1.7).12 A higher incidence of BPD has also been observed in extremely preterm infants receiving conservative management of PDA, compared with infants without PDA.13 There is emerging but not unequivocal14 evidence that a tolerant approach to PDA may be associated with a higher incidence of BPD, particularly if treatment is delayed until after the first postnatal week.13,15,16 Use of multiparameter scoring systems may also be predictive of future BPD and death – a high PDA severity score on day 2 is associated with these outcomes.17

A PDA may cause hemodynamic disturbances, resulting in “steal” of blood from the systemic circulation, including the mesenteric arteries, with consequences of decreased oxygen delivery to the gut and the potential for tissue injury and NEC. Even a low-volume PDA shunt can reduce mesenteric artery flow and decrease the expected postprandial increase in blood flow.18 Because reduced intestinal blood flow is a contributor to the development of NEC, hsPDA may be a causative factor for NEC.19 In a study involving a relatively large number of neonates, presence of a PDA was an independent risk factor for the development of NEC in VLBW infants.20

There is ample evidence on the basis of Doppler and near-infrared spectroscopy (NIRS) studies to suggest that cerebral blood flow is reduced in the presence of a PDA.18 In a recent study using NIRS, cerebral tissue oxygen saturation was lowest in a group of newborns just prior to the surgical closure of PDA. Magnetic resonance imaging (MRI)–measured global and regional cerebral (and cerebellar) volumes were lower in the subgroup of infants that met criteria for surgical ligation compared with patients treated medically and those without a PDA. The surgical group also had a lower cerebellar volume compared with other groups. The authors speculated that prolonged exposure to left-to-right shunting, based on the amount of time elapsed between the diagnosis of PDA and actual surgical closure, was contributary.21 Although hsPDA has an effect on cerebral hemodynamics, whether it is causative for P/IVH is a question that remains unanswered. Cerebral autoregulation is likely to play some role, particularly in immature infants, in protecting against P/IVH (see Chapter 7 for pathophysiology of P/IVH). Intact autoregulation is variable in immature infants,22 and one of the risk factors for impaired autoregulation may be a PDA-attributable reduction in cerebral blood flow. Early (in particular prophylactic) treatment with indomethacin results in both closure of the PDA and decreased risk of severe P/IVH. However, many clinicians are not convinced that prophylactic or early targeted treatment of the PDA is helpful because of the lack of demonstration of improved neuro developmental outcomes.42 PDA is also a risk factor for development of PVL.23 Finally, PDA is associated with a higher mortality rate.7,32 In a retrospective study, after adjustment for perinatal factors, level of maturity, disease severity, and morbid pathologies, the hazard risk for death in neonates with a PDA was eightfold higher than in those with a closed ductus.24 Exclusion of patients who died during the first 2 weeks or inclusion of those who underwent ductal ligation did not alter the findings. In neonates born prior to 28 weeks of gestation a PDA diameter ≥1.5 mm on postnatal day 3 was associated with greater odds of mortality.25

What about spontaneous closure of a PDA – is it possible to do nothing and just wait?

Spontaneous closure

Due to reduced spontaneous ductal closure rates coupled with significant pulmonary-systemic pressure differences and immature cardiovascular adaptive responses, extremely preterm infants (<28 weeks’ gestation) are at higher risk of complications from hsPDA. These risks exist both in the early postnatal period, with susceptibility to pulmonary flooding and systemic hypoperfusion and their consequences, as well as on a more chronic basis due to effects of prolonged left-to-right shunting on the developing heart, brain, kidneys, intestines, and lungs. A PDA in a relatively mature preterm neonate is of less concern, as the left-to-right shunt appears to be better tolerated and the cardiovascular system and cerebral autoregulation protective mechanisms are more developed. Despite this, previous systematic meta-analyses regarding PDA treatment include many trials more than 20 years old and those that focused on larger, more mature infants of up to 33–34 weeks’ gestation, where spontaneous closure in the first few days is almost inevitable.26 Inclusion of both extremely preterm and relatively mature neonates in the same studies makes it difficult to understand the efficacy of treatment versus the effects of spontaneous closure. The protagonists of no treatment argue on the basis of these studies, despite inclusion of a wide mix of gestational age groups, poor diagnostic criteria for PDA, including limited and inconsistent assessment of hemodynamic significance, high rates of open-label treatment in control groups, small sample sizes, selection bias, and/or lack of objective enrolment criteria at randomization. Importantly, spontaneous closure in the placebo control arm of the randomized controlled trials, as well as high levels of open-label treatment in both trial arms (from 30 to 70%),27 make the interpretation of outcomes in many of the PDA trials difficult at best. In fact, much of the efficacy of our current treatment drugs may be ascribed more to high spontaneous closure rates, particularly in more mature infants, rather than the treatments themselves. The real natural course of PDA in treatment-naïve extremely preterm neonates and the true efficacy of the medications used for treatment are not well understood, although literature on outcomes of non-intervention has evolved in more recent years.

Interest in the role of non-treatment or conservative management of the PDA has prompted a number of studies attempting to address these questions. In a study of the natural evolution of PDA in extremely-low-birth-weight (ELBW) neonates,5 the authors observed a 73% spontaneous DA closure rate in newborns born at less than 28 weeks. However, deaths (both early and late), undiagnosed probable PDAs, and infants discharged home with persistent PDAs were excluded from the study. In the end, 41% of potentially eligible neonates were excluded, many with morbidity and mortality potentially attributable to or contributed to by the PDA, including pulmonary hemorrhage, severe P/IVH, and hypoxic respiratory failure. This significantly impacts upon our ability to draw conclusions about the potential risks of non-treatment based on this study, noting also that a high incidence of pulmonary hemorrhage (25%) was observed.28 Similarly, Koch et al. reported a 34% permanent closure rate of PDA in ELBW neonates.29 Of note, around one-quarter of potentially eligible infants were omitted as a result of either death or provision of comfort care, and there was no use of cardiac ultrasound (US) to adjudicate hemodynamic significance. Despite these shortcomings, the observation that for each week of increase in gestational age above 23 weeks, the odds of spontaneous PDA closure increased by a ratio of 1.5 is noteworthy. This is consistent with the known direct relationship between gestational age, birth weight, and persistence of the PDA.24 Spontaneous closure rates of 21–31% among infants with 23–27 weeks of gestation have been reported historically, with lowest rates in the most immature infants.30,31 It is important to note that these earlier studies were undertaken prior to the widespread adoption of non-invasive ventilation for extremely preterm newborns and preceding the higher survival rates currently achieved at <25 weeks of gestation.

Two larger observational studies of minimal/no treatment of the PDA have been published from the same group. The first study14 compares three different PDA management approaches in 138 VLBW infants. Infants received either symptomatic, early targeted (during the first 48 hours), or conservative treatment. The authors found no short-term differences between the groups and a decreased rate of BPD in the conservative treatment group. The second, more contemporaneous study32 is a retrospective cohort study in two European units that enrolled 297 VLBW infants, of whom 280 received conservative PDA management. The authors documented a median time to PDA closure of 71 days for infants born at <26 weeks, compared with 8 days at 28–29 weeks and just 6 days for infants born at or above 30 weeks.32 Despite closure rates at hospital discharge of 85% for the overall cohort, spontaneous closure rates <750 g were particularly low, with a substantial proportion of these infants experiencing a prolonged period of exposure to ductal shunting.32 Detailed assessment of PDA hemodynamic significance was not provided; however, it can be assumed that a subset of patients, perhaps 30–50%,33 would have had a moderate or large volume left-to-right shunt. In addition, of 26 infants who died, 16 had a cause of death potentially related to PDA. In 2022, among a large cohort of infants discharged home with a PDA after preterm birth, lower rates of spontaneous closure than previously observed (47–58%) were reported in the first 12–18 months after birth.34 There were also three infant deaths in this group, of whom two had documented evidence of pulmonary hypertension, which was progressive.34 A greater likelihood of BPD and death has also been reported elsewhere with non-treatment,35,36 with an increase in BPD rates of 31% in one study in an era of non-intervention.37 Pulmonary vascular remodeling as a result of chronic pulmonary over-circulation has been postulated as a mechanism for some of these observations, as well as a potential driver of preterm ductal closure.38 Elevations in pulmonary arterial pressure are initially due to increased pulmonary blood flow (PBF) in the setting of hsPDA, which chronically may relate to pulmonary vascular remodeling and altered vasoreactivity.39,40 Increases in PVR may eventually be substantial enough to lead to PDA shunt reversal in some patients.39,40 These studies highlight that non-intervention of PDA is not necessarily benign, even if early morbidities such as P/IVH and pulmonary hemorrhage are avoided. They also serve to emphasize the importance of considering individual patient factors, such as gestational age and PDA hemodynamic significance, in clinical decision-making. Notwithstanding the limitations of the literature, it is clear that spontaneous closure rates are lowest among the smallest, most preterm infants, who are also the most vulnerable to PDA-related morbidities.

Role of conservative management

The role of conservative management of PDA is an important area of research, although there are no data focusing on the impact in the most extremely preterm infants with prolonged exposure to moderate-high volume shunts. A systematic review and meta-analysis on outcomes of conservative management of PDA, which encompassed 12 cohort studies and 4 randomized controlled trials (RCTs), was recently published.41 Findings of cohort studies included a higher risk for mortality (risk ratio 1.34) and a lower risk of BPD, P/IVH, NEC, and retinopathy of prematurity with conservative management.41 Reductions in prematurity complications may be contributed to by survival bias, however. In a subgroup analysis of two cohort studies where echocardiographic criteria for PDA were used, a lower risk of BPD in the group receiving conservative treatment, with no difference in mortality or other morbidities between the two groups, was noted. Meta-analyses of the RCTs showed no difference in outcome with conservative management when compared with intervention (pharmacological or surgical).41 This is consistent with findings from a network meta-analysis of all major treatment options for PDA, including placebo or non-treatment,42 although relatively high rates of open-label treatment in the “no treatment” arms were observed in included studies. Two recent trials documented lower rates of open-label treatment and may offer a more accurate assessment of the effects of true conservative PDA management. One was a small pilot trial of 72 infants receiving either intravenous NSAID treatment or placebo in the first 72 hours after birth, with no difference in secondary outcomes.43 The second randomized 142 infants to oral ibuprofen or placebo between postnatal days 6 and 1444 and, although no differences were identified in clinical outcomes, the authors noted low efficacy of NSAIDs, particularly in the most preterm infants. Although these are small studies, they provide a starting point for design of larger trials investigating conservative management without a requirement for high rates of open-label NSAID treatments as “rescue”.

Lastly, it is worth drawing a distinction between non-treatment and “conservative treatment” that involves shunt modulation strategies to attempt to reduce ductal flow or treatments to improve heart failure symptoms, without the use of medications or surgery for PDA closure. These include fluid restriction, use of diuretics, positive end-expiratory pressure (PEEP), postnatal corticosteroids, targeted hematocrit, hemoglobin level or platelet thresholds, and increased caloric intake. There are limited data available on the efficacy of these supportive care measures, and documentation of how strategies such as these are utilized in clinical trials of pharmacological PDA treatment is variable. In general, judicious fluid management is suggested, in part based on evidence that excessive fluid intake in the first week after birth is associated with an increased incidence of both hsPDA and NEC.45 There is not strong evidence for fluid restriction, however, and an overly restricted fluid intake has been associated with a greater risk of acute kidney injury44 as well as concerns about inadequate nutritional intake. In addition, theoretically, reducing overall circulating fluid volume without any effect on the proportion of cardiac output that is directed toward the lungs may risk exacerbating post-ductal hypoperfusion from hsPDA. Cerebral hypoperfusion is an additional risk, with a small prospective multicenter study demonstrating a significant reduction in SVC flow with fluid restriction for PDA.46

Furosemide, a loop diuretic, is commonly used for treatment of congestive cardiac failure, including in neonates. The role of frusemide in modulating ductal shunt has not been well studied due to historical concerns, including prostaglandin-mediated dilatation of ductus arteriosus vessels in an animal model47 and an increased incidence of PDA in an RCT where the drug was used.48 There is also considerable overlap in symptomatology between longstanding hsPDA with pulmonary congestion, and BPD, which makes the role of diuretics in this setting difficult to study. More evidence is needed, particularly in infants with pulmonary venous congestion due to diastolic dysfunction, to ascertain the role of diuretics in supportive care of infants with PDA. Appraisal of diastolic function has therefore been suggested as a means of more carefully selecting patients for a trial of diuretic therapy from a research perspective.43

Increasing PVR through use of PEEP, generally through use of continuous positive airway pressure (CPAP) for respiratory support, has been implemented but has not been shown to produce changes in lung function (from reduced pulmonary congestion),49 although there is a suggestion ductal flow may be reduced.50 Physiologically, higher hematocrit, and hence greater blood viscosity, has the potential to limit shunt volume. However, clinical trials of targeted hematocrit to date – either by delayed cord clamping or liberal blood transfusion thresholds – have not shown a reduction in NSAID exposure or surgical ligation for PDA treatment.51,52 A more liberal approach to platelet transfusion has similarly not translated into meaningful clinical benefit in the trial setting53 and is not presently routinely recommended.

Treatment approaches for hsPDA

Overall, there are clear limitations of PDA management, driven in large part by the considerable variation in PDA pathophysiology among individual patients. Therefore, one of the aims of contemporary PDA management could be to identify and target a population that would be most likely to benefit from PDA treatment while avoiding unnecessary treatment in others. To achieve this aim, we need to address three key questions:

When to treat a PDA?

There are a number of time points at which the PDA can be treated. These are:

The time frame of treatment is one determinant of the likely outcomes. P/IVH and pulmonary hemorrhage are early complications of a PDA, usually developing during the first 3–7 postnatal days. There is reasonably good evidence that prophylactic or early targeted treatment of the PDA, mainly with indomethacin, can prevent both P/IVH and pulmonary hemorrhage,9,54 with treatment given prior to entering the peak risk period (days 2–7) for these complications. Of note, indomethacin, unlike ibuprofen, transiently decreases cerebral blood flow and improves cerebral blood flow autoregulation, at least in part independently of its inhibitory effect on prostaglandin synthesis.55 Therefore the effect of prophylactic indomethacin on decreasing the rate of P/IVH42 or white matter injury56 is thought to be not only related to a direct effect on ductal shunting. Assessing whether PDA treatment can prevent later complications such as NEC or BPD, which have a multifactorial etiology and a longer development phase, is more difficult. There are some animal data to support prevention of BPD by early ductal closure with indomethacin.57,58 Demonstrating this in the human infant is more difficult, partly due to the multifactorial etiology, but also because in most clinical trials there is no true placebo group. High open-label rates of treatment mean that many infants enrolled in PDA treatment trials still receive NSAIDs – just at a later time point.

Clinical symptoms of an hsPDA, such as a murmur, active precordium, high volume pulses, poor growth, and increased work of breathing, are nonspecific and may become evident later in the clinical course.59,60 Signs of cardiac failure usually do not develop until the second or third postnatal week. Most randomized controlled trials have not been designed to address the question of whether a symptomatic PDA should be treated during the neonatal period; rather, they were designed to assess the relationship between timing of treatment and efficiency of PDA closure. Symptomatic treatment trials are scarce, and results have not shown any major advantage in terms of prevention of adverse effects from the PDA.61 By the time of PDA clinical symptomatology, it may already be too late and the PDA may already have contributed to the development of one or more of the complications of prematurity. Studies from the pre-surfactant and antenatal steroid era suggest early symptomatic treatment may reduce the duration of mechanical ventilation and BPD compared to late symptomatic treatment.62

The efficacy of NSAIDs commonly used for the treatment of PDA decreases with increasing postnatal age. Up to 85% of PDAs would close if the first dose of indomethacin was administered within 24 hours after birth, whereas the rate decreases to 48% if started at or beyond 72 hours.63 Earlier treatment, prior to a sustained period of systemic hypoperfusion, is associated with a reduced rate of gastrointestinal side-effects, such as spontaneous intestinal perforation (SIP) and NEC. The absence of an increased rate of gut-associated side effects in the prophylactic treatment studies9,64,65 supports this pathophysiology.

Prophylactic and early targeted treatment

Prophylactic and early targeted treatment, which are typically instituted within the first 24 hours after birth, are the most widely studied and probably most effective modes of PDA treatment. A Cochrane analysis including 19 trials comprising 2872 infants54 concluded that prophylactic treatment with indomethacin has a number of immediate benefits, in particular, a reduction in symptomatic PDA, the need for ductal ligation, and a decreased rate of P/IVH, particularly severe P/IVH. There was also a borderline decrease in PVL, ventriculomegaly, and other white matter abnormalities, with a trend toward a decrease in pulmonary hemorrhage. The large trial of Indomethacin Prophylaxis in Preterm infants (TIPP)64 did not show a statistically significant decrease in pulmonary hemorrhage, although re-analysis demonstrated a reduction in the rate of early serious pulmonary hemorrhage.66 This is consistent with the findings of a double-blinded RCT demonstrating a reduction in early pulmonary hemorrhage with cardiac US-targeted treatment.9 In addition, screening echocardiography before postnatal day 3, in a national population–based cohort of extremely preterm infants, was associated with lower in-hospital mortality and likelihood of pulmonary hemorrhage, though not with differences in NEC, severe BPD, or severe cerebral lesions.67

Although prophylactic indomethacin decreases severe forms of P/IVH, a significant benefit in terms of long-term effect on neurodevelopmental outcomes has not been demonstrated. There continues to be debate regarding the role of remote long-term outcomes in adjudicating the benefit of PDA treatment – this is particularly pertinent when considering the lack of assessment of hemodynamic significance in a large number of PDA treatment trials. Regarding NEC, there is little evidence to support or refute the role of PDA. The only study showing a decreased incidence of NEC with PDA treatment is an older study in infants <1000 g after early prophylactic PDA ligation.68 Research has consistently shown a reduction in intestinal blood flow in the presence of a PDA, providing biological plausibility for an association with gut injury and NEC. Superior mesenteric artery flow usually increases after feeding; however, this physiological phenomenon is blunted in the presence of an hsPDA.6972 Certainly the pathophysiology of hsPDA can result in disturbances of post-ductal arterial blood flow, providing a basis for concern regarding the risk of NEC with untreated hsPDA. It is likely that the magnitude and duration of left-to-right shunt, together with individual patient factors, modify the risk profile for preterm infants at risk of NEC and that treatment of carefully selected patients might be expected to reduce this risk.

Although prophylactic treatment has several important benefits, it also results in unnecessary treatment of infants in whom a PDA might have closed spontaneously without significant end-organ effects of left-to-right shunting. If prophylactic or early targeted treatment is desired, indomethacin is currently the drug of choice, as ibuprofen has not as yet been shown to have similar short-term benefits. On the other hand, high-dose oral ibuprofen has recently been shown to be the most effective agent overall for achieving closure of hsPDA.42 If gastrointestinal status permits, high-dose oral ibuprofen is increasingly preferred for treatment of an hsPDA outside the window for prophylactic or early targeted treatment, i.e. for treatment of PDA once symptomatic. There is little evidence, however, to suggest that treating a PDA when it becomes symptomatic is helpful in the long term73; rather, we may lose an opportunity to prevent significant early complications.9,64 Identification and targeting of a particular subset of the population who are least likely to undergo spontaneous PDA closure and are most vulnerable to complications are therefore priorities. Cardiac US is an obvious way to aid in identifying this subgroup of patients and it is in this area that significant research efforts in neonatal hemodynamics have been focused. The potential timings of interventions for PDA, along with their advantages and disadvantages based on pathophysiology, are shown in Table 19.1.

TABLE 19.1

Treatment Type Advantages Disadvantages
Prophylactic (within 6–24 hours after birth, preferably within the first 12 hours)

Most widely studied

Decreased P/IVH and pulmonary hemorrhage

Excellent closure rates

Due to frequency of spontaneous closure, exposes a large number of infants to the side effects of NSAID treatment; many unnecessarily

Early targeted (within 6–24 hours after birth, preferably within the first 12 hours)

Decreased P/IVH and pulmonary hemorrhage

Targets treatment to most significant shunts

Excellent closure rates

Exposes infants to treatment prior to onset of clinical symptoms; in some of these infants the PDA may spontaneously close without sequelae

Pre-symptomatic (usually by days 3–7 on the basis of ultrasound)

Exposes fewer babies to the risks of treatment

Targets treatment to most significant shunts

Very good closure rates

Few studies

Often outside window to prevent P/IVH and pulmonary hemorrhage

Early symptomatic (usually postnatal days 3–7)

Exposes fewer babies to the risks of treatment

Increases the chance of PDA-related morbidity and mortality (compared with earlier treatment)

Closure rate is lower

Few studies

Late symptomatic (after postnatal day 7)

Exposes fewest babies to the risks of treatment

Increases the chance of PDA related morbidity and mortality

Reduced closure rates

Unproven usefulness and safety profile Non-standardized approach

Conservative (no medication or surgery)

No initial exposure to medication but risk of need for later treatment

Increases the likelihood of PDA-related morbidity and mortality

Risks of long-standing hsPDA, including late morbidity post-discharge

How to treat a PDA?

First-line treatment for hsPDA is generally medical, with NSAIDs, namely indomethacin or ibuprofen. Success rates for hsPDA closure with indomethacin are around 60–80%,74 with similar results reported using ibuprofen.75 Indomethacin is generally preferred for prophylactic or early targeted treatment due to a demonstrated reduction in P/IVH and pulmonary hemorrhage rates. Paracetamol is increasingly being used for PDA closure,42,76,77 with advantages that include a more favorable side-effect profile42 and similar efficacy to indomethacin or ibuprofen.76 There are, however, a paucity of long-term follow-up data among infants receiving paracetamol,76 with a limited population studied to date78 and insufficient controlled trial data involving extremely preterm neonates <26 weeks.74 There is limited evidence to support use of paracetamol as a “rescue” treatment after NSAID therapy has failed,79 and clinicians sometimes opt to use paracetamol where NSAIDs are contraindicated. Detailed discussion of pharmacotherapy for PDA is available in Chapter 17.

Surgical closure of a PDA, either by ligation or transcatheter device closure (TCDC), is largely employed as a “rescue” therapy for infants who have failed medical management, or occasionally where NSAIDs are contraindicated. There has been a secular move away from early surgical closure following unsuccessful medical management due to concern regarding associations between PDA ligation and adverse outcomes in large studies of preterm infants,8084 including an increased risk of neurodevelopmental impairment.80,81,83 However, these studies have a number of limitations, including a lack of adjustment for the duration of ductal shunting, an important modifier of sequelae associated with hsPDA. One retrospective study of 754 extremely preterm infants, which accounted for neonatal comorbidities prior to PDA ligation, demonstrated improved survival without increased risk of neurodevelopmental impairment with ligation.85 TCDC is becoming an increasingly available option as interventional cardiologists become more skilled in the procedure for small, premature infants. Long-term follow-up data after TCDC are awaited. A detailed discussion of interventional management of PDA is available in Chapter 18.

Which PDA to treat: How to determine hemodynamic significance?

From the available evidence, early targeted treatment for a specific population is probably the best approach we can presently offer for management of the PDA. This is in view of the need to balance the risk of treatment side-effects in a vulnerable population with the adverse pathophysiology and potential consequences of persistent, large-volume left-to-right shunting. Parameters to take into consideration when making a decision regarding whether to treat the PDA include gestational age, postnatal age, level of respiratory support, existing comorbidities, clinical and US features of PDA, and possibly cardiac biochemical markers and additional measures of tissue oxygenation. The definition of hsPDA varies between clinicians and centers, as well as between trials of PDA management.26 Investigators have used cardiac US alone or in combination with physical examination findings, cardiac biochemical markers, and/or other hemodynamic assessment tools in an attempt to more objectively define an hsPDA. A number of scoring systems have been developed to try to provide some uniformity.86,87 Infants with a high composite score on a staging system by Sehgal et al. were noted to have a higher incidence of subsequent CLD.88 A more complex PDA scoring system has been published using five factors that were independently associated with CLD/death (gestation at birth, PDA diameter, maximum flow velocity, LV output, and LV a′ wave). This PDA score had a range from 0 (low risk) to 13 (high risk). Infants who developed CLD/death had a higher score than those who did not.17

Irrespective of whether formal scoring systems are used, bedside cardiac clinician-performed ultrasound (CPU), also referred to as targeted neonatal echocardiography (TnECHO), plays an important role in the management of PDA in preterm neonates in many units globally. A number of training programs for neonatal clinicians have been developed in recognition of the role of CPU in enhancing decision-making at the bedside.89 Given the lag of clinical features of PDA behind US markers by a mean of 2 days,59 CPU in the early postnatal period can facilitate identification of an hsPDA in the pre-symptomatic period. The details of techniques for echocardiography measurements used in PDA assessment are discussed in Chapter 16. In this chapter we shall discuss the clinical utility of these parameters in identifying hsPDA. Broadly, PDA evaluation should incorporate assessment of the following1:

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Mar 3, 2024 | Posted by in Uncategorized | Comments Off on Pathophysiology-based management of the hemodynamically significant patent ductus arteriosus in the very preterm neonate

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