Indian J Pediatr DOI 10.1007/s12098-014-1646-6

REVIEW ARTICLE

Management of Patent Ductus Arteriosus in Premature Infants Rama Bhat & Utpala G. Das

Received: 9 October 2014 / Accepted: 28 November 2014 # Dr. K C Chaudhuri Foundation 2014

Abstract Patency of the ductus arteriosus is required for fetal survival in utero. In infants born prematurely, ductus fails to close and shunt reverses from left to right. Incidence of patent ductus arteriosus (PDA) is inversely proportional to the gestational age. A large PDA (>1.5 mm diameter) with left to right shunt in very low birth weight infants can cause pulmonary edema, congestive heart failure, pulmonary hemorrhage and increase the risk for bronchopulmonary dysplasia. Attempts to prevent or close the duct by pharmacological or surgical methods have not changed the morbidity or the long term outcome. Pharmacological treatment with indomethacin or ibuprofen is successful in 75 to 80 % of infants but its use also exposes these infants to undesirable side effects like gastrointestinal bleeding, perforation and necrotizing enterocolitis. Prophylactic therapy with indomethacin or ibuprofen to prevent PDA has not altered the morbidity or long term outcome. Currently, there is a dilemma as to how to treat, when to treat and whom to treat. Recent literature suggests a trial of conservative management during the first week followed by selective use of anti-inflammatory drugs. Surgical ligation is reserved for infants who fail medical therapy and still remain symptomatic. Spontaneous closure of the PDA has been reported in up to 40–67 % of very low birth weight (VLBW) infants by 7 d. In this review authors discuss these controversies and propose a more rational approach.

Keywords hsPDA: Hemodynamically significant PDA . BNP: Brain natriuretic peptide . NSAID: Non-steroidal anti inflammatory drugs . NT pro BNP: N-terminal-pro-B R. Bhat (*) : U. G. Das Division of Neonatology, Department of Pediatrics, Children’s Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, WI 53201, USA e-mail: [email protected]

natriuretic peptide . TnT: Troponin T . VEGF: Vascular endothelial growth factor . VLBW: Very low birth weight

Introduction The ductus arteriosus, a remnant of the left 6th aortic arch is one of the major conduits essential for fetal survival. In utero, 90 % of the right ventricular output is shunted across the ductus arteriosus to the descending aorta. Closure of the ductus in utero has been associated with fetal death [1]. In term infants (>37 wk) constriction of ductus is complete by 3 d in all except 0.05 %. In preterm infants especially under 32 wk gestation, the ductal closure is delayed and differs significantly due to developmental differences in smooth muscle and factors related to prematurity [2]. Delayed closure of ductus arteriosus (PDA) in preterm infants under 28 wk is associated with higher incidence of pulmonary hemorrhage, intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), chronic lung disease (CLD) and higher mortality [3, 4]. Recent systematic reviews and meta-analysis have cast a doubt as to whether ductus is the cause of above morbidities or is it simply a bystander, as early closure of PDA has not altered the morbidities or mortality [5]. Recent reports have also shown that 40 to 67 % of PDA’s in very low birth weight infants (VLBW) close spontaneously during the first week [6, 7]. Thus, there is continued controversy regarding-whom to treat, when to treat, how best to treat (medications vs. ligation) PDA’s in preterm infants. Recently a new terminology “Permissive Tolerance of PDA” was introduced to describe a less aggressive, expectant management of PDA. This study reported significantly higher rate of chronic lung disease (48 % vs. 34 %, p1.05 %, the diagnosis of hsPDA should be considered. This test may be of special value in resource poor countries where echocardiography is not readily available [24]. Further studies are needed to confirm this finding. Two-Dimensional Echocardiography with Color Doppler Flow Mapping Among all markers used for the diagnosis of PDA, 2D echocardiography with color flow Doppler is considered as the gold standard or criterion standard [25]. Advantages of echocardiography are that the test is done at the bedside and the results are available quickly. Either a cardiologist or a neonatologist with some training can diagnose a) patency of the ductus, b) direction of the shunt, c) left ventricular size and contractility, d) pulmonary to systemic blood flow ratio, e) internal ductal diameter and f) presence and quantitation of retrograde diastolic flow in the descending aorta. A recent retrospective report of 29 infants 1.5 mm assessed by early color Doppler (between 6 and 48 h) predicted the development of symptomatic PDA (20 of 29 infants). The sensitivity and specificity were 91 and 100 %, respectively [26]. Figure 1 shows color Doppler image of hsPDA in an extremely preterm infant. At present most cardiologists and neonatologists define a large or hsPDA, when the ductal size is ≥1.5 mm or more with unrestrictive pulsatile left to right flow. Others include not only the size of the ductus but also the left atrial to aortic ratio by M-mode echo and retrograde diastolic flow in the descending aorta as criteria for the diagnosis of hsPDA. PDA Biomarkers Various serum and urinary biomarkers have been used in the diagnosis of hsPDA. Of the 4 biomarkers, namely brain natriuretic peptide (BNP), N-terminal-pro-B type natriuretic peptide (NTproBNP), Mid-regional pro atrial natriuretic

Fig. 1 a 2-D image of a large PDA in a preterm infant with a birth weight of 700 g. Red arrow is pointed at PDA. b Color Doppler ultrasound image of the same large PDA with left to right shunt

peptide (MR-proANP) and Troponin T (TnT), BNP is the most studied biomarker in preterm infants. BNP is released from the ventricles in response to volume load or pressure load and has been used as a marker for heart failure in adults. In preterm infants with hsPDA, there is an excessive load on the left ventricle (LV), which results in LV dilatation and rise in BNP. Serial measurements of BNP can help in identifying hsPDA more than single measurement. However authors’ review of the five published studies on BNP showed large variations (Mean BNP level 392–2896 pg/ml) and poor predictive value [27, 28]. At this time they do not recommend measurement of these biomarkers to decide when to treat. In summary, 2D echocardiogram with color Doppler remains the current gold standard for the diagnosis of hsPDA. However, in its absence, clinicians should consider combination of clinical, radiological, and biochemical markers to diagnose hsPDA.

Management of PDA Currently there is no consensus regarding the best approach. Table 1 shows the chronology of PDA treatment from early 1970s, to the current period. During the last 40 y therapy for PDA has gone through a full circle from conservative therapy to aggressive medical and surgical therapy and back to conservative management. The rationale behind the current approach are 1) in infants >1000 g, up to 67 % of PDA close spontaneously by 7 d and >94 % close before discharge [6], even in infants 1.6 acidosis or hypotension No contraindications ++ Treat with NSAID. IV or oral 1st course, follow-up echo if already on feeds, continue feeding. Keep hematocrit > 35%

PDA still >1.5 mm and symptomatic, consider 2nd course of NSAID. If no response, continue fluid restriction and surgical ligation.

+

>1.0 kg/ > 29 wk

First Week

Week 2

Week 3

Fluid restriction (110-130 ml/kg/d) Respiratory support ( PEEP) Diuretic, if and when needed. Follow-up cardiac echo, blood gas, chest x-rays and BNP? + 64% close spontaneously

Large symptomatic PDA >1.5 mm Increasing respiratory support. acidosis and hypotension No contraindications ++ Consider NSAID, IV or oral fluid restriction, follow-up echo and continue feeding. Keep hematocrit > 35%

PDA still >1.5 mm and symptomatic, consider 2nd course of NSAID If no response and ventilator dependent, continue fluid restriction and surgical ligation.

BNP values vary considerably and not a reliable biomarker.

++

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Management of patent ductus arteriosus in premature infants.

Patency of the ductus arteriosus is required for fetal survival in utero. In infants born prematurely, ductus fails to close and shunt reverses from l...
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