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The ductus arteriosus (DA) is a vital component of the fetal circulation, when the placenta is the source of oxygen to the fetus. The DA provides a conduit for blood to bypass the high resistance pulmonary vascular bed and shunt toward the descending aorta and low-resistance placental circulation. At birth, the lungs are inflated and resistance in the pulmonary vascular bed decreases as the lungs become the source of oxygenation, rendering the DA no longer necessary. Over the first few days of life, the DA undergoes active constriction and occlusion; failure of this process results in a patent ductus arteriosus (PDA). In the majority (> 95%) of term infants and those born > 28 weeks of gestation, closure of the ductus occurs within hours. In contrast, PDAs occur in 70% of infants born prior to 28 weeks of gestation, with an incidence that is inversely proportional to gestational age (GA) at birth.
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Closure of the DA involves a number of cellular and molecular processes that occur over 2 phases: (1) “functional” closure within hours after birth, characterized by ductal smooth muscle constriction; (2) “anatomic” occlusion over the next several days, characterized by ductal remodeling in response to hypoxia/ischemia of smooth muscle cells, resulting in permanent closure. Premature birth interrupts the normal maturation of ductal contractile mechanisms, increasing the likelihood of a PDA.
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Pathophysiology and Functional Closure of the Da
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In the fetus, most of the cardiac output from the right ventricle bypasses the lungs and flows from the main pulmonary artery (MPA) into the descending aorta via the DA. A number of factors regulate the magnitude of ductal shunting, including its size (diameter, length), pressure differences between the aorta and pulmonary artery, and systemic and pulmonary vascular resistances (SVR and PVR, respectively). If the diameter of the PDA is small, the diminutive cross-sectional opening offers a high resistance to flow; thus, shunting is minimal despite potentially large pressure differences. On the other hand, with a large ductal diameter, pressures tend to be similar, and the magnitude of the ductal shunting is determined primarily by a balance between SVR and PVR. The right-to-left ductal shunting in utero is due to the high PVR, which in combination with a low SVR, results in a low pulmonary blood flow during fetal life.
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At birth, ventilation of the lungs triggers a large decrease in PVR, which coincides with an increase in SVR following removal of the placental circulation by clamping of the umbilical cord. These events result in a marked increase in pulmonary blood flow, and as PVR falls below SVR, there may be left-to-right ductal shunting through the DA from the aorta and into the pulmonary circulation (see also Chapter 45).
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At birth, the dramatic, rapid rise in arterial oxygen content upon ventilation of the lungs triggers a cascade of events in which constriction of the DA would normally occur. With increasing gestational maturation, the amount of ductal constriction in response to increasing partial pressure of oxygen (pO2) is greater, and the level of pO2 required for initiation and maintenance of this process decreases.
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The potential cellular mechanisms responsible for ductal constriction are summarized in Figure 58-1, and include the inhibition of voltage-dependent potassium channels by production of reactive oxygen species, the endothelin-1 constrictor pathway, and a fall in circulating prostaglandin E2 (PGE2) levels following clamping of the umbilical cord. PGE2 is the most important prostanoid to regulate ductal patency in the fetus and neonate, and is produced by the placenta and ductus. In addition, the marked increase in pulmonary blood flow at birth promotes lung catabolism of circulating PGE2, promoting ductal closure.
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The mechanisms responsible for ductal constriction may be developmentally regulated. The formation of alveoli is believed to begin at approximately 28 weeks’ gestation. Studies in preterm animal models have demonstrated an immaturity of both potassium and calcium channels. These impairments and other physiological consequences of preterm birth lead to ineffective oxygen-mediated constriction of the DA. The reduced pulmonary blood flow and metabolism among preterm infants contributes to increased circulating concentrations of PGE2 and persistent ductal patency. Additionally, the sensitivity to PGE2 is greater in preterm neonates than in more mature infants. Excessive fluid intake (> 170 mL/kg/day) has also been associated with increased risk of continued patency of the DA.
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Anatomic Closure of the Da
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Successful “functional” closure of the ductus results locally in ischemic hypoxia of the ductal wall. This results in cell death and production of hypoxia-mediated growth factors, which play a role in vascular remodeling and permanent ductal closure. Intimal thickening of the DA is also required for permanent ductal closure. Insufficient ductal smooth muscle constriction prevents the histological changes (intimal thickening, fragmentation of the internal elastic lamina) necessary for permanent closure of the DA.
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Even minor alterations in the hypoxia-dependent mechanism may prevent anatomic DA closure. This potentially explains the proclivity of the ductus to “reopen” after echocardiographic evidence of its closure. The localized region of hypoxia within the ductal wall is promoted by the initial constriction of the ductus, which leads to cell death and ductal remodeling. It has been reported that, in DAs with no clinical signs of ductal patency after pharmacological therapy, those with residual luminal blood flow had a higher rate of reopening than did those with no luminal flow. The residual blood flow may provide sufficient oxygen to the luminal cells and tissues, preventing hypoxia-promoted closure. Mechanisms promoting ductal relaxation may then eventually lead to “reopening” of the ductus.
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Diagnosis and Evaluation
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The clinical features associated with shunting through the PDA depend on the magnitude of the ductal shunt and the compensatory ability of the immature myocardium to handle the additional volume load. The cardiac function of preterm infants (< 37 weeks) is more vulnerable to preload and afterload changes than those in their more mature counterparts.
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The murmur associated with a PDA is commonly heard best at the left sternal border in the second and third intercostal spaces. While older children may display the classic continuous, machinery murmur, very premature infants more commonly have a high frequency systolic murmur with a “rocky” quality. With increasing left-sided volume loading, a prominent second heart sound, mid-diastolic flow rumble at the apex, and a third heart sound may be present. As the left-to-right ductal shunt increases, the precordium becomes hyperactive, pulse pressure widens, and the peripheral pulses become more prominent. If the shunt becomes sufficiently large, evidence of left ventricular failure, including tachycardia, tachypnea, and rales on auscultation of the lung, may develop.
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Usefulness of Clinical Assessment
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Recent investigators have challenged the isolated use of clinical signs, with evidence of poor consistency and limited accuracy. During the first few days of life, preterm infants with large PDAs may have no clinical signs on physical examination due to a higher PVR, lower ductal shunt velocity, and compensatory increases in pulmonary lymph flow clearing the respiratory interstitum of excess fluid and protein. Thus, in most cases, even in the presence of a large PDA, pulmonary mechanics may not be adversely affected during the first 72 hours after birth. Following the expected drop in PVR over the first week of life, the murmur becomes apparent. After this time, the sensitivity and specificity of a murmur to diagnose a PDA are 79% and 94%, respectively. The left-to-right ductal shunt leads to tachycardia and increased stroke volume, which manifest clinically as hyperactive precordium, increased pulse volume, and wide pulse pressure. While these physical exam findings, alongside evidence of pulmonary overcirculation and left heart dilation on a chest radiograph, increase clinical suspicion for a PDA, the accurate diagnosis of ductal patency requires Doppler echocardiography.
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Echocardiography is the gold standard for PDA diagnosis. Two-dimensional echocardiography with Doppler flow studies provide accurate assessment of (1) ductal size (diameter), (2) pattern of ductal shunting, and (3) volume of ductal shunting. These echocardiographic indices can be used to define a hemodynamically significant PDA (HSPDA), discussed below (Figs. 58-2, 58-3, 58-4, 58-5, 58-6).
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Ductal size is measured at the site of maximal constriction in end systole (Fig. 58-3). Traditionally, a ductal diameter > 1.5 mm is used define a HSPDA. However, this dimension cannot alone determine the need for PDA treatment or predict the likelihood of spontaneous closure. Alternatively, others have proposed indexing ductal diameter-to-body weight (in mm per kg) or left pulmonary artery (LPA) diameter (PDA:LPA ratio). The likelihood of spontaneous ductal closure during the first 3 days of life when there is a low PDA:LPA ratio (< 0.5) is 3-fold higher than if the ratio is large (≥ 1) or moderate (≥ 0.5–1). The relative benefits and limitations of different indices of PDA size remain incompletely characterized.
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The primary direction and velocity of ductal shunting can be approximated using color Doppler; however, accurate determination of shunt velocity and directionality requires pulsed Doppler interrogation (Figs. 58-4, 58-5, 58-6). The pattern of Doppler shunting reflects the relative pressures (aortic and main pulmonary artery) at each end of the ductus in systole and diastole. For instance, when aortic pressure exceeds the pressure in the MPA, the shunt is left to right (positive tracing), but when MPA pressure exceeds aortic pressure, the shunt is right to left (negative tracing).
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The accurate measurement of the volume of ductal shunting requires cardiac catheterization, but the invasive nature of the procedure limits the feasibility of this in fragile neonates. A number of echocardiographic indices have been proposed to assess the volume of ductal shunting indirectly, including left atrial–to–aortic root ratios, left ventricular size, left ventricular output, and diastolic flow in the descending aorta. Retrograde diastolic blood flow in the descending aorta may represent the echocardiographic marker that best reflects the circulatory consequences of an HSPDA. The normal diastolic flow in the postductal descending aorta is low-velocity forward flow but as ductal shunting increases, the diastolic flow becomes progressively less and may become retrograde (Fig. 58-6).
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DEFINING A HEMODYNAMICALLY SIGNIFICANT PDA
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Rather than an all-or-none approach in the determination and treatment of PDAs, efforts to define HSPDA according to the severity of echocardiographic criteria may provide a more selective approach to care and help to identify the subset of infants that are most likely to benefit from treatment (Table 58-1). Targeted use of PDA treatment in those with an HSPDA may enable healthcare providers to minimize risk and yield the greatest benefits.
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An HSPDA has been defined based on ductal size or left heart dimensions (ratio of left atrium to aorta), and those echocardiographic indices are correlated to the likelihood of subsequent ductal closure or to a range of short or longer-term clinical outcomes. For instance, neonates with ductal diameters > 1.5 mm had the highest odds of an adverse outcome, whereas infants with PDA diameters ≤ 1.5 mm had outcomes similar to those with no PDA. Moreover, HSPDAs are less likely to close spontaneously than are small PDAs. However, marked heterogeneity in the criteria to define an HSPDA and the threshold for diagnosis or treatment of an HSPDA, limit equitable comparisons among studies. Despite widespread use of the term, consensus on the definition of HSPDA is lacking. More importantly, no studies have shown that treating, or not treating, an HSPDA improves longer-term outcomes. Recently, PDA scoring systems that take into account both clinical and echocardiographic data have been proposed and may provide more robust models for outcome prediction and allow further refinements in PDA management.
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RISK FACTORS AND COMORBIDITIES ASSOCIATED WITH PDA
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A ductal left-to-right shunt increases the pulmonary blood flow, which may eventually lead to pulmonary edema and decreased lung compliance. These changes in lung mechanics often require positive pressure and higher oxygen concentrations to maintain respiratory stability, but over time these contribute to the development of bronchopulmonary dysplasia (BPD).
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Among preterm infants, persistent left-to-right shunting not only decreases lung function but also may lead to cardiac dysfunction, due to left-sided volume overload. These factors, coupled with a ductal steal phenomenon, may worsen systemic perfusion and contribute to a number of PDA-related morbidities. Although no causal link has been established, a PDA is considered by some to be a precursor to a number of morbidities, including BPD, neurological abnormalities, and necrotizing enterocolitis (NEC). Infants with a PDA have an 8-fold higher mortality than age-matched controls with a closed ductus.
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Neurological Morbidities
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Immediately after birth, preterm infants may lack cerebral autoregulation, placing them at risk for decreased cerebral perfusion in the setting of hypotension. This renders premature neonates vulnerable to neurological morbidities, including intraventricular hemorrhage (IVH). Because IVH typically occurs shortly after birth, prophylactic PDA treatment as a strategy to prevent IVH has gained considerable interest. Prophylactic indomethacin reduces IVH, but longer-term neurodevelopmental benefits at a corrected age of 18 months have not been observed.
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Irrespective of the treatment approach, all neonates with PDA should receive supportive care to minimize symptoms related to ductal shunting.
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Positive Pressure Ventilation
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Positive pressure ventilation (positive end-expiratory pressure, or PEEP) is intended to improve gas exchange and minimize the adverse effects of ductal shunting with pulmonary edema. However, the impact of prolonged positive pressure respiratory ventilation on feeding behavior and neurodevelopment remains poorly understood.
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Fluid restriction is widely recommended as a measure to limit the physiologic consequences of excessive volume load on the pulmonary circulation. Randomized studies and meta-analyses have demonstrated an association between higher fluid intake and PDA, and in turn between PDA and both congestive heart failure and NEC. Fluid restriction has been shown to reduce the risks of PDA, without increasing the risk of adverse consequences.
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Diuretic therapy is intended to optimize lung compliance and oxygenation. However, furosemide (a loop diuretic) stimulates renal synthesis of PGE2, and has been shown to increase the rate of ductal patency twofold when compared to chlorothiazide. In view of the evidence that furosemide may increase the prevalence of PDA, its routine use is not recommended.
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Treatment of the Patent Ductus Arteriosus
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There exists consensus that a PDA should be closed by 2 years of age, to avoid the risks of pulmonary hypertension or bacterial endocarditis, but disagreement remains about the thresholds and strategies for PDA closure among extremely premature infants earlier in life. Some advocate closing PDAs aggressively, based on observational data showing improved short-term outcomes following ductal closure. However, evidence for improved outcomes following treatment is not strong. Although associated with higher mortality and morbidity, PDA may not be causative. The treatment of PDA in preterm infants can be conservative, pharmacological (indomethacin, ibuprofen, acetaminophen), or nonpharmacological (catheter-based closure or surgical ligation), but the optimal approach has not been determined through prospective studies with long-term follow-up (Fig. 58-7).
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Conservative Management
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The conservative approach to the management of PDA through supportive therapy is aimed at reducing symptoms from the ductal shunt and providing the opportunity for spontaneous closure, thereby avoiding the risks of potentially unnecessary interventions. To date, the only randomized controlled trial (RCT) comparing treatment of an HSPDA versus conservative management was conducted over 30 years ago. In that study, the early surgical ligation group had lower rates of adverse outcomes than did the nonintervention group; however, the applicability of these findings in the setting of contemporary neonatal treatment (eg, antenatal corticosteroids, surfactant therapy) is controversial.
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The rate of spontaneous ductal closure within the first 4 days of life is greater than 95% in neonates with birth weights > 1500 grams. In a single-center, prospective study of 122 infants with average birth weight of less than 800 grams, spontaneous permanent ductal closure occurred in 42 (34%), whereas the vast majority (80/122) had a persistent ductal shunt. Factors that predicted spontaneous closure included greater GA and absence of respiratory distress syndrome.
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The natural history of the PDA in premature infants remains poorly characterized, though persistence beyond the first few days of life can still be associated with later closure. Spontaneous closure rates of around one-third have been observed by day 8 of life in infants with birth weights < 1000 grams, while closure by 165 days has been reported in approximately three-quarters of those born at 24 to 27 weeks of gestation. In a single-center, retrospective, observational study of infants with birth weights < 1500 grams, 21 infants were discharged home with an open ductus. Of those infants, 18 (86%) PDAs spontaneously closed at a mean post menstrual age of 48 weeks (51 days of life); none of the infants had evidence of heart failure secondary to prolonged PDA exposure.
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Despite insufficient data on the risks associated with prolonged exposure to PDAs, recent evidence suggests a marked change among US providers away from traditional drug therapy and surgical ligation toward a conservative treatment approach. While conservative treatment may be a useful adjunct to ductal closure and may reduce unnecessary medical therapy or surgical ligation in an appreciable number of infants, the question remains as to what to do when PDAs fail to close following a period of conservative treatment, particularly if there are clinical and echocardiographic signs of an HSPDA or a need for continued respiratory support at a corrected age of 36 weeks.
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Pharmacological Therapy
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Among infants with a PDA warranting closure, 3 primary pharmacological options are available: indomethacin, ibuprofen, and acetaminophen (paracetamol) (Table 58-2). Studies have consistently shown that cyclooxygenase (COX) inhibitors, including indomethacin and ibuprofen, are more effective than placebo in closing the PDA in preterm infants. While indomethacin and ibuprofen are the only 2 US Federal Drug Administration–approved drugs for closure of a ductus in preterm babies, recent published experiences suggest that acetaminophen also may have a role. Data are not clear on which infants will respond to drug therapy. Some studies report no differences between responders and nonresponders, while other studies have suggested that failure is related to maturational factors (eg, birth weight, GA). The choice of 1 drug over the other also depends on local availability of the intravenous or enteral preparation.
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Indomethacin mediates its effects, at least in part, by inhibiting local prostaglandin synthesis, and evidence exists to support its use. The potential timing of indomethacin varies according to whether a prophylactic, early, or late treatment is being considered.
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The relative benefits of early versus late therapy have not yet been clearly established. Indomethacin therapy in the first 2 days of life is associated with higher rates of PDA closure than later treatment. Among 8 trials including 264 infants, early symptomatic treatment was associated with lower risks for BPD (odds ratio [OR], 0.39; 95% confidence interval [CI], 0.21–0.76) or NEC (OR, 0.24; 95% CI, 0.06–0.96), and need for surgical ligation (OR, 0.37; 95% CI, 0.20–0.68). On the other hand, in a large population-based cohort of infants born prior to 27 weeks of gestation, no differences in the rates of PDA surgery or death were observed following early (0–2 days), intermediate (3–6 days), or late (≥ 7 days) pharmacological treatment.
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The optimal dosing strategy of indomethacin remains unknown. Although plasma drug concentrations correlate poorly with drug efficacy and side effects, some advocate for the potential value of obtaining plasma drug levels to titrate treatment regimens; however, data on optimal levels are not widely available and this approach is poorly characterized. A multicenter RCT that investigated the correlation between indomethacin levels and continued ductal patency showed that higher serum indomethacin concentrations were not associated with lower rates of patency, but were linked with higher rates of nephrotoxicity and retinopathy of prematurity.
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Because indomethacin provides only transient suppression of prostaglandin synthesis, multiple courses of indomethacin are typically provided to achieve ductal constriction; however, data to support the provision of multiple courses of indomethacin are lacking, and prolonged treatment courses have been associated with an increased risk of NEC and renal impairment. These observations are consistent with a recent RCT that reported no difference in ductal closure rates but did report trends toward lower rates of NEC (1.4% vs 7%), following therapy with 3 versus 6 doses of indomethacin. These studies suggest that prolonged courses of indomethacin treatment should not be part of the routine management of the PDA during neonatal period.
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Among the COX inhibitors, it has been advocated that ibuprofen should be the preferred agent for PDA closure. Some studies have shown that while the rate of successful ductal closure with ibuprofen and indomethacin are similar, the rates of NEC and renal insufficiency, and the duration of mechanical ventilation are lower with ibuprofen. However, data on the safety of ibuprofen versus indomethacin are mixed. A recent study of over 6300 infants born at < 28 weeks of gestation reported similar short-term safety outcomes following exposure to indomethacin versus ibuprofen. Moreover, data shows that ibuprofen, but not indomethacin, interferes with binding of serum albumin at standard doses of the drugs, which would increase the risk of kernicterus among infants treated with ibuprofen.
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Regarding the optimal route for administration, it has been shown that orogastric administration is as effective as intravenous administration. However, questions regarding the optimal dosing strategy, early versus expectant administration, and continuous versus intermittent dosing, remain unanswered. Data showing that prophylactic ibuprofen does not appear to be effective in preventing IVH, and may be associated with an increased risk of pulmonary hypertension, have led experts to recommend against the use of prophylactic ibuprofen.
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Complications and Contraindications of COX Inhibitors
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A number of studies have examined the short-term adverse effects of COX inhibitors in preterm infants. Indomethacin decreases gastrointestinal, renal, and cerebral blood flow. Consequently, treatment with indomethacin has been associated with spontaneous intestinal perforation, necrotizing enterocolitis, renal insufficiency, and altered cerebral perfusion. Importantly, healthcare providers should be aware of the high risk for isolated gastrointestinal perforation among preterm infants treated concurrently with indomethacin and dexamethasone. Despite the lack of consensus, a number of contraindications to COX inhibitors are shown in Table 58-3.
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Enteral Feeding during Therapy with COX Inhibitors
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Indomethacin decreases intestinal blood flow and disrupts the gastrointestinal mucosal barrier function. While ibuprofen has less effect on gastrointestinal blood flow than does indomethacin, gastrointestinal permeability is altered following ibuprofen therapy. These findings have led to concerns that initiation or advancement of enteral feedings during PDA treatment with indomethacin or ibuprofen may increase the risk of adverse health outcomes in infants. However, a study of 177 infants born at < 31 weeks of gestation reported that infants randomized to trophic feeds (15 mL/kg/day) required less time to achieve the feeding goal (120 mL/kg/day) than did infants who remained nil per os (NPO) while receiving indomethacin or ibuprofen therapy. These observations are consistent with the growing body of literature on the safety and efficacy of enteral feeding during PDA treatment with COX inhibitors. Questions remain on optimal feeding regimens for high-risk subgroups of infants, including those with echocardiographic evidence of reversal or absence of perfusion in mesenteric arteries and those with intrauterine growth restriction. In these high-risk subgroups, a more judicious feeding regimen may be prudent.
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Failure to Respond to Initial Medical Management with COXI Inhibitors
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Initial medical therapy with COX inhibitors will close the PDA in 50% to 75% of infants. Among infants failing to respond to initial therapy and with persistent HSPDA, a second course of treatment can be provided. Despite limited data, available evidence suggests a second course of pharmacological therapy results in closure rates of 40% to 56%. If a patient fails to responds to 2 courses of therapy, the success of additional drug treatment in closing the PDA is unlikely. In this clinical scenario, healthcare providers must reassess the indications for PDA closure and the potential hemodynamic consequences of the persistent ductus. In settings of a persistently small PDA, a recent study suggests that approximately 75% will spontaneously close on their own without pharmacological treatment.
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Data on the risks of indomethacin and ibuprofen have led to interest in alternative medical therapies for PDA closure, including acetaminophen (paracetamol). While small, observational reports suggest that acetaminophen may be an effective treatment for PDA, data on the risk/benefit profile of acetaminophen among preterm infants remain unknown. A recent Cochrane review identified only 2 RCTs involving acetaminophen for PDA closure in preterm infants. No differences in the rates of ductal closure between infants treated with acetaminophen versus oral ibuprofen were observed, but a lack of high-quality studies to guide evidence-based decision-making was recognized. A recent systematic review and meta-analysis included 16 studies, 14 of which were uncontrolled studies, comparing acetaminophen versus indomethacin, ibuprofen, or placebo. The authors reported ductal closure rates with acetaminophen of 49% (95% CI, 29–69%) and 76% (95% CI, 61–88%), respectively, following 3 and 6 days of treatment. Moreover, a recent study showed that, among infants born at < 32 weeks of gestation with a confirmed PDA, the ductus closed faster in the acetaminophen group than the placebo group (177 hours versus 338 hours for acetaminophen versus placebo, respectively) without detectable side effects. However, studies in animal models raise concerns that acetaminophen may have adverse effects on brain maturation, thus its routine use cannot be recommended prior to a more robust understanding of potential longer-term risks, including neurocognitive status.
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Nonpharmacologic Intervention
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Surgical ligation provides definitive PDA closure. While early surgical mortality is low, known risks of PDA ligation include pneumothorax, bleeding, and left vocal cord paralysis. Preterm infants are at risk for post-ligation cardiac syndrome (PLCS), characterized by hypotension requiring inotropic support and respiratory failure within 12 hours after surgery. Potential physiological mechanisms of PLCS include a sudden increase in SVR and reduction in cardiac preload, leading to decreased myocardial performance and compromised systemic and cerebral blood flow. Moreover, growing evidence of anesthesia-related long-term morbidities is concerning.
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While no causal link has been established, infants undergoing surgical ligation have greater risk of short-term morbidities than do infants not treated surgically. While data on longer-term outcomes remain mixed, 2 large studies have shown that infants treated with surgical ligation had higher odds of neurodevelopmental impairment (NDI) at long-term follow-up. These observations have led to growing uncertainty on the safety and efficacy of surgical PDA ligation during infancy. In most contemporary settings, surgical ligation is reserved for infants with evidence of PDA-related morbidity (HSPDA) following failed drug therapy, or in clinical settings in which drug therapy is contraindicated.
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A recent meta-analysis of 40 studies including 32,345 preterm infants < 32 weeks of gestation investigated the association of surgical ligation with the risks of short- and long-term morbidity and mortality, including NDI at 2 years of age, and compared these to alternative treatment strategies, including medical management. Surgical ligation was associated with greater risks of chronic lung disease, severe retinopathy of prematurity, and NDI than were observed with medical management, but also was associated with a lower mortality. The authors acknowledge that “sicker” infants, who may be at higher risk of NDI, may have been more likely to be assigned to surgical ligation. Of note, recent studies have reported no increase in mortality after moving away from an aggressive, early surgical approach to more conservative management.
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Catheter-Based PDA Closure
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Catheter-based closure of the PDA is among the safest of interventional cardiac procedures and is considered by some to be the procedure of choice for PDA closure beyond the neonatal period. Although limited to observational and retrospective studies, more centers are reporting the safety and feasibility of catheter-based PDA closure in preterm infants. While data on short and longer-term outcomes of catheter-based PDA closure are limited, evidence of increased risk of vascular compromise (thrombus necessitating systemic anticoagulation) in lower weight infants is concerning. Although there are risks in any cardiac catheterization, certain technical challenges may be exaggerated in very low–weight infants; thus, the risks of catheter-based PDA closure in these patients have to be weighed against those associated with alternative surgical and medical management options. Presently, among infants who warrant PDA closure, the absence of studies comparing catheter-based versus surgical closure precludes determination of the optimal strategy for ductal closure.
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Screening and Prophylaxis
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While some investigators have suggested that selective echocardiography among infants with PDA-related symptoms is more cost-effective without evidence of increased harm, others advocate for universal screening to provide early detection of a PDA prior to potential ductal sequelae. A recent population-based study among over 1500 preterm infants born at < 29 weeks of gestation reported that, compared to no PDA screening, early screening (first 3 days of life) was associated with lower in-hospital mortality (14.2% vs 18.5%; OR, 0.73) and lower incidence of pulmonary hemorrhage (5.7% vs 8.4%; OR, 0.60). However, the study was observational, and caution is warranted in the interpretation of findings. The optimal screening approach for the detection of a PDA in preterm infants has yet to be defined.
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PDA Prophylaxis with COX Inhibitors
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In the Trial of Indomethacin Prophylaxis in Preterm Infants (TIPP), investigators randomized 1202 infants with birth weights of 500 to 1000 grams to receive prophylactic treatment (0.1 mg/kg of birth weight) or placebo intravenously, commencing within hours after birth, for 3 days. Infants receiving prophylactic indomethacin had a lower incidence of PDA (24% vs 50% in the placebo group; OR, 0.3) and of severe periventricular and IVH (9% vs 13% in the placebo group; OR, 0.6). There were no differences in the primary composite outcome of death or neurocognitive status at 18 months corrected age. These observations are consistent with a meta-analysis of 19 clinical trials including over 2800 infants that indicated that prophylactic indomethacin may have short-term benefits, including a reduction in the incidence of symptomatic PDA, the need for surgical ligation, and the incidence of severe IVH; however, these benefits did not translate into reductions in mortality or improvements in longer-term neurodevelopment. Thus, it could be argued that healthcare providers should not provide indomethacin prophylaxis with the expectation of increased survival or improved longer-term outcomes.
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In a follow-up analysis of the TIPP trial, infants without a PDA who were treated with prophylactic indomethacin had a higher incidence of chronic lung disease (43%, 170/391) than did those given placebo (30%, 78/257; P = 0.015). After adjusting for baseline prognostic factors, indomethacin prophylaxis among infants without a PDA was associated with a greater weight loss and need for supplemental oxygen. While prophylactic indomethacin decreases the incidence of a PDA, additional comorbidities of preterm birth (eg, BPD, NEC) remain unchanged or may, in fact, be increased following exposure.
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Medical and surgical interventions are effective in closing the PDA in most infants, but neither individual clinical trials nor meta-analyses have shown that closing the PDA results in improved long-term outcomes. Although many strategies for management of the persistent PDA have been proposed, none have been subject to systematic evaluation in RCTs that have been powered to detect differences in long-term outcomes. In the absence of clear data that adverse outcomes can be averted by closing the PDA, trials comparing closure to non-intervention are greatly needed. For a treatment to be the standard of care, the risks associated with a persistent PDA must outweigh the risks undertaken by the treatment; therefore, the primary endpoint for studies comparing PDA management strategies should not be successful closure, but rather mortality and longer-term outcomes.
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