Pharmacological Treatment of Patent Ductus Arteriosus in Preterm Infants

Abstract

The patent ductus arteriosus contribute to many neonatal morbidities. There are different approaches for treatment including conservative, pharmacological and definitive closure. Most commonly, pharmacological therapy is attempted before consideration of surgical intervention.

1. Introduction

Patent ductus arteriosus (PDA) was described a long time ago as a pathological entity in preterm babies [1]. From the physiological point of view, and outside the context of ductal-dependent lesions, PDA cannot be physiologically helpful when it comes to neonatal morbidity [2, 3].

In animal studies, there is significant engorgement and increased lymphatic conspicuity, secondary to dilated lymphatic architecture, in lambs with PDAs [4]. In primates, there is data suggesting that closing the PDA early makes a great difference in terms of the ventilation scores [4].

In humans, it takes only 3–7-day exposure to a moderate-large PDA shunt which significantly increases the incidence of bronchopulmonary dysplasia (BPD) [5] and BPD baseline incidence increases in preterm infants exposed to PDA [6].

PDA plays a critical role in the pathophysiology of many neonatal morbidities. This includes pulmonary hemorrhage [7, 8], myocardial changes in shape and size due to volume overload [9, 10], impaired bowel tissue oxygenation and other GI morbidities including necrotizing enterocolitis (NEC) [11, 12, 13, 14], increased incidence of renal injury [15], mortality and intraventricular hemorrhage (IVH) [14].

Different approaches exist and vary between centers. In this chapter, we will concentrate on the pharmacological approach.

Role of targeted neonatal echocardiography in detecting hemodynamically significant PDA:

There has not been a standardized consensus to define hemodynamically significant PDA [16, 17].

Clinical assessment on its own was found not sensitive or specific in predicting PDA shunt volume especially in the first few days of life [18]. In addition, ductal size (diameter) only does not define the significance of the ductal shunt. There are large size PDAs that have no hemodynamic significance, and the opposite is true as well.

It appears that a detailed echocardiographic assessment is the key using targeted neonatal echocardiography (TnEcho). This comprehensive assessment includes multiple domains (Figure 1). PDA characteristics are crucial to look at, which includes the diameter, PDA flow Doppler pattern as well as PDA shape. It is interesting to think about the morphology of the duct and how is it different in preterm as opposed to less preterm babies. Initially, 5 types of ducts were described from A to E, however, with the increasing number of preterm babies being referred for catheter closure, a 6th type was recognized. The F type (fetal type) ductus is exclusively found in children born prematurely and is long, wide, tortuous and unlikely to close with pharmacological treatments [19].

Figure 1.

Targeted neonatal parameters needed to establish the hemodynamic significance of PDA.

Assessment of pulmonary circulation is important to establish using multiple parameters (Figure 1). Due to poor compliance, assessment of myocardial adaptation to the high shunt load is crucial. In addition, the atrial shunt needs to be assessed and established. Finally, any evidence of systemic compromise should be elaborated as well.

Recently, few biochemical markers were suggested as a part of ductal assessment especially in resource-limited areas. This includes cardiac troponin T (TnT), atrial natriuretic peptide (ANP), brain-type natriuretic peptide (BNP), N-terminal pro-BNP (NTpBNP) and urinary neutrophil gelatinase-associated lipocalin and urinary heart-type fatty acid-binding protein [20, 21, 22, 23]. It appears that TnEcho is the proper tool to establish and define hemodynamically significant duct; only then treatment of PDA is shown to have an impact on neonatal outcomes [14, 17, 24, 25].

2. Pharmacological treatment of PDA in preterm infants

Pharmacological treatments induce ductal constriction with good effectiveness overall, whether using non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen in different routes of administration [25, 26, 27, 28, 29]. However, complete ductal closure or shunt elimination cannot be guaranteed even when combining these agents together; this is in addition to potential adverse side effects [30, 31, 32].

3. Non-steroidal anti-inflammatory drugs (NSAIDs)

It was known early on that NSAIDs induce ductal constriction and closure [25, 33, 34, 35]; this is even in infants who are born prematurely [36, 37]. Early treatment with indomethacin induces ductal closure, however, with concerns about compromising renal function [38]. This is probably due to the vasoconstrictive effects of those agents contributing to the development of renal hypoperfusion, NEC and spontaneous intestinal perforation (SIP), as well as platelet dysfunction and hyperbilirubinemia [39, 40].

A meta-analysis by Ohlsson et al. show that ibuprofen is equal to indomethacin in terms of efficacy in closing PDA with fewer side effects on the kidneys as well as reduced risk for NEC [41]. Rectal ibuprofen has been used as well with similar efficacy to oral ibuprofen [42]. It appears that indomethacin, the most widely used agent, is more prevalent in North America, and ibuprofen is more commonly used in Europe and Asia [43].

Repeated courses of NSAIDs are a common practice when initial treatment wasn’t completely successful in closing the PDA, keeping in mind, decreased efficacy with repeated courses [44, 45].

A higher dose of ibuprofen has been attempted as well, and this includes a loading dose of 20 mg/kg, followed by two subsequent doses of 10 mg/kg, 24 hours apart; this is in comparison to the standard dosing regimen which is a loading dose of 10 mg/kg, followed by two subsequent doses of 5 mg/kg, 24 hours apart. It appears that a higher dose of ibuprofen is more effective in closing the PDA, without an obvious increase in the side effects [41, 46].

3.1 Acetaminophen

Hammerman et al. reported the first case series of the use of acetaminophen as a therapeutic agent to facilitate ductal closure [27]. Acetaminophen inhibits the POX receptors on the prostaglandin synthesis pathway [29]. In a recent systematic review, Ohlsson et al. included 916 infants in eight studies comparing oral or intravenous acetaminophen to ibuprofen and found similar efficacy for acetaminophen with lower gastrointestinal bleeds, lower serum levels of creatinine, lower serum levels of bilirubin, and higher platelet count but no difference in the neurological outcomes between 18 and 24 months [28].

It is possible that acetaminophen may increase pulmonary vascular resistance [47].

3.2 Combination therapy

Another strategy that has been attempted, is combining acetaminophen with NSAIDs specifically ibuprofen which may provide a synergetic effect on the reduction of prostaglandin production, resulting in PDA closure. In a small randomized controlled trial (RCT), Hochwald et al. compared the combination of intravenous ibuprofen and intravenous acetaminophen versus intravenous ibuprofen alone. There was a trend towards increased efficacy with combination therapy but without a statistical difference (83% vs. 42%, p = 0.08); also, there was no increase in the side effects [30]. In an observational study by Yurttutan et al., combination therapy with oral ibuprofen and oral acetaminophen was successful in closing the ductus in 9 out of 12 infants who had failed two previous courses with no increase in the side effects [31]. A retrospective cohort by Kimani et al. did not demonstrate any increased adverse effects in the combination group [32].

3.3 Other strategies

Diuretics have been used as an adjunct agent to facilitate ductal closure. While diuretics help with symptomatic management of pulmonary over circulation, it appears that it compromises the systemic blood flow and may not provide a significant increase in the closure rates [48]. This is similar to a fluid restriction which may help managing the symptoms of chronic lung disease, but it would worsen the systemic blood flow [49, 50].

4. Conclusion

The PDA is common morbidity in preterm infants. There has been a trend towards more conservative management over surgical treatment [51]. The pharmacological treatment causes ductal constriction with good effectiveness overall whether using NSAIDs or acetaminophen in different routes of administration. However, complete ductal closure or shunt elimination cannot be guaranteed even when combining these agents together; this is in addition to potential adverse side effects.

Recently, FDA approved the use of Piccolo device for the purpose of PDA closure in preterm infants which was based of the efficacy and safety of such a device in this fragile population [2]. It appears that this catheter closure approach is becoming more popular as it is feasible, effective, and relatively safe [19, 52]. Whether this approach would result in more favorable neonatal morbidities and outcomes, needs further research.

Abbreviations

BPD	Bronchopulmonary dysplasia
NEC	Necrotizing enterocolitis
NSAIDs	Non-steroidal anti-inflammatory drugs
PDA	Patent ductus arteriosus
RCT	Randomized controlled trial
SIP	Spontaneous intestinal perforation
TnEcho