Patent Ductus Arteriosus of the Preterm Infant

Abstract

Postnatal ductal closure is stimulated by rising oxygen tension and withdrawal of vasodilatory mediators (prostaglandins, nitric oxide, adenosine) and by vasoconstrictors (endothelin-1, catecholamines, contractile prostanoids), ion channels, calcium flux, platelets, morphologic maturity, and a favorable genetic predisposition. A persistently patent ductus arteriosus (PDA) in preterm infants can have clinical consequences. Decreasing pulmonary vascular resistance, especially in extremely low gestational age newborns, increases left-to-right shunting through the ductus and increases pulmonary blood flow further, leading to interstitial pulmonary edema and volume load to the left heart. Potential consequences of left-to-right shunting via a hemodynamically significant patent ductus arteriosus (hsPDA) include increased risk for prolonged ventilation, bronchopulmonary dysplasia, necrotizing enterocolitis or focal intestinal perforation, intraventricular hemorrhage, and death. In the last decade, there has been a trend toward less aggressive treatment of PDA in preterm infants. However, there is a subgroup of infants who will likely benefit from intervention, be it pharmacologic, interventional, or surgical: (1) prophylactic intravenous indomethacin in highly selected extremely low gestational age newborns with PDA (<26 + 0/7 weeks' gestation, <750 g birth weight), (2) early targeted therapy of PDA in selected preterm infants at particular high risk for PDA-associated complications, and (3) PDA ligation, catheter intervention, or oral paracetamol may be considered as rescue options for hsPDA closure. The impact of catheter-based closure of hsPDA on clinical outcomes should be determined in future prospective studies. Finally, we provide a novel treatment algorithm for PDA in preterm infants that integrates the several treatment modalities in a staged approach.

FIGURE 1

Factors affecting postnatal DA closure and preterm PDA. A and B, Postnatal DA closure (A) and preterm DA patency (B) are regulated by a combination of molecular, physiologic, and structural factors. Of note, several studies have identified distinct variants in CYP2C9*2 that are associated with failure of PDA closure in response to indomethacin.^, cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; O₂, oxygen.

FIGURE 2

Determinants of risk for preterm infants with an hsPDA. AAO, ascending aorta; ACA, anterior cerebral artery; CPAP, continuous positive airway pressure; CW, continuous wave; DAO, descending aorta; Fio₂, fraction of inspired oxygen; HFNC, high-flow nasal cannula; ID, inner diameter; LA/Ao, left atrium to aortic root diameter ratio; LPA, left pulmonary artery; LVEF, left ventricular ejection fraction; MPA, mean pulmonary artery; MV, mechanical ventilation; NIRS, near-infrared spectroscopy; NIV, noninvasive ventilation; PEEP, positive end-expiratory pressure; PIP, positive inspiratory pressure; PLAX, parasternal short axis; PSAX, parasternal short axis; RI, resistance index; Spo₂, pulse oxygen saturation; Vmax, maximum velocity.

FIGURE 3

Treatment algorithm of PDA in the preterm infant. The proposed treatment algorithm incorporates the following 4 main treatment categories into a stepwise approach: (1) early targeted prophylaxis, (2) targeted therapy of asymptomatic infants (<6 days after birth), (3) symptomatic treatment of hsPDA (≥6 days after birth), and (4) late symptomatic treatment after watchful waiting or rescue treatment (for details, see main text). The details on drug therapy are summarized in Table 2. Of note, these recommendations are mostly based on expert opinion and only provide a framework that needs to be adopted and modified to local practices. For example, given the wide variance in spontaneous constriction (8%–78% in screened PDA-TOLERATE infants <28 weeks’ GA in first week of life), it is first important to know your unit’s spontaneous closure rate. There may be unrecognized factors (eg, genetics, altitude, echo interpretation, fluid, or respiratory management) that determine unit variability. In addition, the optimal indication and timing of catheter-based interventions (especially in comparison to surgical ligation) have not yet been clearly defined, and thus there is a large variability of its use among different neonatal units. ^a Some units attempt for early catheter intervention (eg, after the first failed pharmacologic treatment cycle. ELBW, extremely low birth weight (<1000 g); FiO₂, fraction of inspired oxygen; GA, gestational age.