treating patent ductus arteriosus in neonates: evaluating...

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Treating Patent Ductus Arteriosus inNeonates: Evaluating Current Therapies CME/CE

Kris C. Sekar, MD

Supported by an independent educational grant from Recordati Rare Diseases

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Treating Patent Ductus Arteriosus in Neonates: Evaluating Current Therapies

This article is a CME-certified activity.To earn credit for this activity visit:

www.medscape.org/expertcolumn/pda

CCME/CE Released: 05/30/2014; Valid for credit through 05/30/2015

Target AudienceThis activity is intended for cardiologists, cardiac surgeons, pediatricians, hospitalists, neonatologists, primary care physicians, pharmacists, and other healthcare practitioners involved in the diagnosis and treatment of patent ductus arteriosus (PDA).

GoalPersistent PDA in preterm infants can result in serious hemodynamic changes causing respiratory, gastrointestinal, and renal morbidities if not treated within the first week of life. The goal of this activity is to review treatment options available and assist clinicians in choosing the most appropriate therapy based on the safety and efficacy of each option.

Learning ObjectivesUpon completion of this activity, participants will be able to:

1. Review the anatomy and pathophysiology of neonatal PDA

2. Evaluate current treatment options for neonates with PDA

Credits AvailablePhysicians - maximum of 0.75 AMA PRA Category 1 Credit(s)™

Pharmacists - 0.75 Knowledge-based ACPE (0.075 CEUs)

Accreditation StatementsFor Physicians (ACCME) to provide continuing medical education for physicians. Medscape, LLC designates this enduring material for a maximum of 0.75 AMA PRA Category 1 Credit(s)™ . Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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Medscape, LLC designates this continuing education activity for 0.75 contact hour(s) (0.075 CEUs) (Universal Activity Number 0461-0000-14-033-H01-P).


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AuthorAs an organization accredited by the ACCME, Medscape, LLC, requires everyone who is in a position to control the content of an education activity to disclose all relevant financial relationships with any commercial interest. The ACCME defines “relevant financial relationships” as financial relationships in any amount, occurring within the past 12 months, including financial relationships of a spouse or life partner, that could create a conflict of interest.

Medscape, LLC, encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content.

Kris C. Sekar, MD Professor of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma Disclosure: Kris C. Sekar, MD, has disclosed the following relevant financial relationship: Received grants for clinical research from: Ikaria, Inc. Dr Sekar does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States. Dr Sekar does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

EditorCaroline M. Padbury, B.PharmLead Scientific Director, Medscape, LLC

Disclosure: Caroline M. Padbury, B.Pharm, has disclosed no relevant financial relationships.

CME ReviewerNafeez Zawahir, MDCME Clinical Director, Medscape, LLC

Disclosure: Nafeez Zawahir, MD, has disclosed no relevant financial relationships.

Peer ReviewerThis activity has been peer reviewed and the reviewer has disclosed no relevant financial relationships.


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INTRODUCTION AnatomyDuctus arteriosus is a blood vessel between the pulmonary artery and the proximal aorta that diverts the oxygenated blood from the placenta away from the fluid-filled lungs in fetal circulation (Figure 1). Thus, the ductus is vital for fetal survival. The shunting of the blood in the fetus is therefore right to left, which is due to the high resistance of the pulmonary vasculature.[1-3]

Figure 1. Representation of patent ductus arteriosus.

The ductus develops from the distal dorsal sixth aortic arch and is well developed by the sixth week of gestation (Figure 2).[4,5] After birth, in term babies the ductus generally closes within the first few days of life, first with functional closure and then followed by anatomical closure by vascular remodeling. In premature infants, the ductal closure is delayed or does not occur at all.[6] Persistent patent ductus arteriosus (PDA) is defined as the failure of the ductus to close within the first 72 hours of life.[7]

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Figure 2: Schematic diagram indicating the various components of the aortic arch complex in the human embryo.

IncidencePDA is one of the most common congenital cardiac defects and occurs with a frequency of 1 in 2000 in infants born at term. This accounts for 5% to 10% of all congenital heart disease.[8] The incidence of PDA in premature infants weighing <1000 g and 29 weeks’ gestational age is 70% and inversely related to birth weight and gestational age.[9]The female-to-male ratio is 3:1 based on various reports.[7,8]

Although spontaneous closure of the ductus will occur in 34% of infants with extremely low birth weight (ELBW), failure of the ductus to close in the remaining infants can result in potentially life-threatening sequelae. This is particularly seen when the shunting of the blood reverses from right to left to left to right after birth, when the pulmonary vascular resistance begins to fall, and when the compliance of the lungs begins to improve. This will result in overcirculation of the blood to pulmonary vasculature, leading to undesirable pulmonary, renal, and gastrointestinal effects, including pulmonary edema and hemorrhage, congestive cardiac failure, intraventricular hemorrhage, cerebral vascular accidents, necrotizing enterocolitis (NEC), feeding intolerance, poor weight gain, bronchopulmonary dysplasia, and death.[9,10] Therefore, appropriate diagnosis and treatment of PDA is important to prevent these morbidities.

Regulation of Ductal Patency and ClosureThe fetal ducts appear very similar to the adjacent descending aorta, but it is now known that there are histological differences between the two, with the intimal layer of the ductus showing irregular neointimal cushions composed of smooth muscle and endothelial cells compared with aorta.[8,11] The fetal patency is controlled by low fetal oxygen tension and circulating prostanoids, predominantly prostaglandin E2 (PGE2) and prostacyclin (PGI2). PGE2 and PGI2levels are high in the fetus due to placental production and diminished clearance by the lungs. PGE2 activates the G-coupled prostaglandin receptors, which leads to vasodilation and smooth muscle relaxation of the ductus due to accumulation of cyclic adenosine monophosphate, increased protein kinase A, and a decrease in myosin light chain kinase.[8,12-15]

After birth, ductal closure occurs due to the following cascade of events. The postnatal increase in partial pressure of oxygen in arterial blood results in the amount of circulating prostanoids to decrease. This is associated with a decrease in sensitivity to PGE2 by the ductus.[16] Increase in circulating oxygen also contributes to an influx of calcium into the ductal smooth muscle cells.[17,18] Potassium channels also regulate calcium influx into the cells.[19,20] Oxygen also induces the release of potent vasoconstrictors such as endothelin 1 by the ductus.[21]

V.Ao = ventral aorta; A.Ao - arch of aorta; D.Ar = ductus arteriosus; In. = innominate artery; R.I.C.-L.I.C. = right and left internal carotid arteries; D.B. = Duct of Botalli; R.S.-L.S. = right and left subclavian arteries; R.V.-L.V. – right and left vertebral arteries; P.A. = posterior auricular artery; Oph. = ophthalmic artery; D.Ao.= dorsal aorta; P.T. = pulmonary trunk; R.P.A.-L.P.A. = right and left pulmonary arteries; R.C.C.-L.C.C. = right and left common carotid arteries; E.C. = external carotid artery; Oc. = occipital artery; I.M. = internal maxillary artery; From Encyclopædia Britannica, 1911 [Public domain], via Wikimedia Commons.


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In term neonates, the ductal closing is also facilitated by profound ischemia of the vasa vasorum, which decreases luminal blood flow.[22] Profound ischemia also inhibits prostaglandin and nitric oxide production in the remodeling process.[23] In contrast to term infants, preterm infants fail to produce the same degree of ischemia essential for cell death and anatomic remodeling. In addition, the vasodilatory effects of PGE2 and hyaluronic acid may also play a role.[24,25] In addition, a number of inflammatory mediators are upregulated, affecting the cascade of events required for permanent anatomic closure.[26] Therefore, there is weaker constriction after birth, no anatomic remodeling, and high risk of reopening even after echocardiographic confirmation of closure. Recently, platelets have been shown to play a role in ductal closure by promoting thrombotic sealing of the constricted ductus and luminal remodeling.[27]Infection-associated inflammatory mediators have been shown to play a role in late patency of the ductus.[28]

Signs and Symptoms of PDAThe signs and symptoms of PDA depends on the degree of left-to-right shunting of the blood and usually presents with one or more of the following symptoms: bounding pulses with wide pulse pressure, diastolic hypotension, hyperdynamic precordium, systolic murmur, cardiomegaly, hepatomegaly, congestive cardiac failure, worsening respiratory status, and increase in ventilator support, edema, oliguria, and metabolic acidosis.[1,7]

Persistent ductus has been associated with comorbidities such as chronic lung disease bronchopulmonary dysplasia, NEC, and death. The prophylactic indomethacin trial did show a reduction in intraventricular hemorrhage (IVH), but neurological follow-up at 18 months of age in another large trial did not show significant difference in the developmental outcomes.[29,30]

Diagnosis of PDAAlthough echocardiogram remains the mainstay for diagnosing PDA, there is still no accepted consensus as to what is considered a “hemodynamically significant” PDA that requires closure.

Image courtesy of Bart Van Overmeire, MD.Figure 2: Echocardiogram of patent ductus arteriosus.

The natural history of PDA in a premature baby if left without treatment is not known. The criteria for the diagnosis of significant PDA is a ductal diameter of >1.5 mm, left atrium-to-aorta ratio of >1.4 in the parasternal long axis view, left ventricular enlargement, and holodiastolic flow reversal in the descending aorta.[31] The reversal of holodiastolic flow could steal the blood flow to cerebral circulation. This adverse effect on cerebral blood flow could be assessed by performing Doppler examination of the anterior cerebral artery and measuring the resistive index. The resistive index is >0.9 In the presence of significant ductal shunting.[16] This is also proven by near infrared spectroscopy and superior vena cava blood flow studies in the presence of significant PDA.[32,33] These observations may be related to the risk of IVH in the presence of PDA.[34, 35] The timing of the echocardiogram is also important, as in the first 24 hours of life approximately one-third of the ductus will start to close spontaneously. Therefore, the ideal time to perform an echocardiogram is at approximately 72 hours of age, as persistent PDA is the ductus that is present beyond 72 hours of age (Figure 3).

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Recently, studies measuring levels of biomarkers such as plasma B-type natriuretic peptide (BNP) or NT-pro- BNP levels, which are frequently elevated in patients with heart failure, have been suggested to guide treatment of symptomatic PDA.[36,37] Measuring the levels of these biomarkers along with clinical and echocardiographic signs may narrow the number of infants requiring treatment.[38]

TREATMENT OF PDAPharmacological or surgical treatment if pharmacological treatment is not successful has been the traditional treatment of PDA. Recently, controversy regarding treatment of PDA has emerged. In particular, some have questioned whether PDA in premature infants is even pathological and requiring treatment[39,40-42] because all the randomized controlled trials were performed several decades ago and allowed for rescue treatment in the protocols if the PDA remained open. Moreover, the treatments were started at different times and at different gestational ages.[43] Therefore, the impact of PDA on common complications such as NEC and chronic lung disease is not well known.[44] Another important argument is the lack of impact of PDA treatment on long-term outcomes.[30]

Further complicating this is a very high rate of spontaneous closure of the ductus, and identifying the infant whose ductus will close spontaneously and exposing the infant to unnecessary therapy has been difficult.[46] An argument in favor of ductal closure is the finding in a retrospective study that the failure of ductal closure is associated with increased mortality [47]; however, identifying the patients who would benefit from treatment is very difficult. Because of these difficulties, significant practice variations exist among institutions in the United States, and there is no consensus as to when the PDA needs to be treated.[48] Pharmacological agents used to treat PDA have significant undesirable adverse effects.[45] To standardize treatment, an algorithm-based approach established on clinical and echocardiogram criteria has been suggested but not systematically studied in controlled trials.[38,49,50] The current treatment approach based on best evidence is described below.

Conservative Medical ManagementConservative medical management involves fluid restriction to minimal physiological levels, ventilator support, and watchful waiting after confirmation of PDA by echocardiography. As for most infants the ductus will close spontaneously, this approach may be ideal for larger babies. In preterm infants, this approach may not be ideal, as postponing pharmacological therapy will decrease the response to cyclooxygenase (COX) inhibitors, resulting in a high failure rate.[1,51]

Pharmacotherapy of PDAThe role played by PGE2 and PGI2 in ductal patency in the fetus is well known. Therefore, the inhibition of COX, which converts arachidonic acid to various prostaglandins, becomes an ideal therapeutic-targeted agent to close persistent PDA.[52,53] There are 2 isoforms of COX inhibitors -- COX1 and COX 2 -- described.[54] Nonselective inhibition of COX isoenzyme is more effective than selective inhibition, as both COX enzymes are responsible for the production of PGE2. Pharmacotherapy of PDA involves the use of COX inhibitors, which have been shown to be safe and effective in the majority (70% to 80%) of treated infants with LBW.[55]

The 2 COX inhibitors approved for use in the United States are intravenous (IV) indomethacin and IV ibuprofen lysine (NeoProfen®, Recordati Rare Diseases). These drugs are chemically different and inhibit COX-1 and COX-2 isoforms to different degrees.[54] The pharmacokinetic studies of COX inhibitors show wide inter-individual variability in serum concentrations that result in prolonged half-lives.[55] The serum half-life and volume of distribution significantly decrease from the first dose to the third dose. Indomethacin has stronger COX-1 inhibition, which has been attributed to undesirable gastrointestinal, cerebral, and renal adverse effects. Ibuprofen lysine has less COX-1 inhibition, with less vasoconstrictor effect in these organs.[56]

Because of these differences in COX inhibition, indomethacin is a more powerful vasoconstrictor and decreases cerebral blood flow and oxygen consumption to a greater degree than ibuprofen.[57,58] This action is associated with a preventive effect on the occurrence of IVH when given prophylactically in infants with LBW.[29] Ibuprofen lysine has no such protective effects. Likewise, indomethacin decreases renal blood flow more profoundly than ibuprofen, resulting in oliguria and an increase in serum creatinine levels.[59,60] Both drugs are equally effective in closing PDA, are highly protein bound, and are eliminated by the liver.[54]

Enteral ibuprofen and enteral acetaminophen (which works at a different site) have similar effects in closing PDA, but there are less published studies with enteral medications, and the use of these enteral medications at present should be considered “off label” in the treatment of PDA.


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Studies that have evaluated indomethacin compared with placebo in presymptomatic and symptomatic PDA have shown significant closure rates.[61,62] Indomethacin given as prophylaxis reduces the incidence of IVH as evaluated by cranial ultrasound.[29] The trial of indomethacin prophylaxis in preterm infants (TIPP) did not show any significant differences in neurological outcome at 18 months when indomethacin was compared with placebo.[30] Ibuprofen lysine when given as prophylaxis compared with placebo showed significant PDA-closure rates but did not have any effect on the incidence of IVH.[61,62]

Studies comparing indomethacin and ibuprofen lysine have shown equal efficacy rates in ductal closure.[63] In these studies, patients who received indomethacin had a higher incidence of oliguria and elevated creatinine levels. There were no differences in the incidence of NEC, bronchopulmonary dysplasia, or short-term neurological outcomes in patients receiving either one of these COX inhibitors.[61,62]

Meta-analysis of these studies has confirmed these observations.[63] Because these drugs are highly protein-bound, they can potentially compete with bilirubin for albumen-binding sites and increase the risk of bilirubin encephalopathy. This does not appear to be a risk factor, as the levels achieved at the current recommended doses are below this threshold value.[64,65] Long-term follow-up of children at 4½ and 8 years of age who were treated with indomethacin prophylaxis vs placebo has shown favorable outcome in the patients treated with indomethacin.[66,67] A gender difference in outcomes, with a negative effect of indomethacin treatment in females, was been observed in TIPP.[68]

It is important to note that pharmacological agents used to treat PDA may have significant undesirable adverse effects.[45] The potential benefits of these agents should be balanced with the possibility of adverse side effects.

Prophylactic Pharmacological Treatment (<24 Hours)The optimal approach to treating PDA is to treat when it will be most effective and to avoid unnecessary treatment in patients whose ductus will close spontaneously. This group is difficult to identify based on current available evaluation methods. Prophylactic treatment is indicated only if the risk of IVH is very high, such as in infants with ELBW (<1000 g). If prophylaxis is desired, indomethacin is the treatment of choice. Although indomethacin has been shown to assist in preventing IVH, the relative risk of developing IVH is similar with both COX inhibitors due to their effect on platelet aggregation. This should be taken into consideration, especially in infants with ELBW. Ibuprofen has no such effect on IVH.[1] Meta-analysis of prophylactic studies between these COX inhibitors has shown no differences in the incidence of pulmonary hemorrhage, bronchopulmonary dysplasia, NEC, gastrointestinal perforations, short-term neurological outcomes, and PDA requiring ligation.[62]

Early Presymptomatic Treatment (2 to 3 days)The current trend in clinical practice is to treat early presymptomatic PDA after echocardiogram confirmation of a “significant PDA” that would benefit from pharmacological treatment. These are infants who may develop worsening respiratory status due to ductal shunting, pulmonary overcirculation, and possibly cardiac failure. This approach will minimize the number of infants exposed to COX inhibitors in whom the ductus will close spontaneously and, at the same time, will benefit those who will respond to medical treatment.[46] Both indomethacin and ibuprofen are equally effective in treating PDA. The toxicity profile of ibuprofen is better with less renal adverse effects. Some physicians may obtain a head sonogram before starting therapy. If IVH (grade 2 or above) is identified, treatment is delayed for 24 hours. There is no reported advancement of IVH using this approach.

Therapeutic Treatment (3 to 7 days)In this scenario, patients are treated when signs and symptoms of PDA are evident both by clinical and echocardiographic criteria. The treatment approach is very similar to presymptomatic treatment. Here, both COX inhibitors are equally effective; however, there is less oliguria associated with ibuprofen.[69] An echocardiogram-directed treatment approach has been shown to minimize exposure to COX inhibitor therapy. This approach requires continuous evaluation of functional echocardiography, which requires skill and training. This is not available in many intensive care nurseries in the United States.[70]

Late Therapeutic Treatment (>7 days)Medical therapy should still be attempted in patients with PDA beyond 7 days of age. Although treatment in these patients may not be successful, as nonprostaglandin mechanisms are involved in keeping the ductus open as the patient gets older, medical treatment should always be attempted before resorting to any invasive surgical procedures.

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Surgical Ligation of PDAThere is no consensus as to when surgical ligation should be undertaken for PDA. In general, surgical ligation is considered if the ductus fails to close after 2 courses of COX-inhibitor therapy and there is convincing evidence that the clinical condition will improve after ligation. Surgical ligation involves thoracotomy and is associated with significant morbidities such as pneumothorax, chylothorax, infection, laryngeal nerve paralysis, respiratory compromise, blood pressure fluctuations, bronchopulmonary dysplasia, retinopathy of prematurity, and death.[1,14,71-73] It is not known whether the postoperative hypotension reported after PDA ligation is due to myocardial dysfunction or the indirect effect of anesthesia on vascular tone and respiratory status.[74-76]

Follow-up evaluation of patients in the TIPP revealed an increased incidence of neurosensory impairment, bronchopulmonary dysplasia, and retinopathy of prematurity after PDA ligation.[77] Another report has confirmed an association with PDA ligation and bronchopulmonary dysplasia, with no effect on neurological impairment.[78] In a baboon model, PDA ligation has been shown to be associated with a decrease in brain growth and developmental index in both the ligated and unligated group; however, there was evidence of a brain-sparing effect in the ligated group.[79]

Both PDA ligation and ibuprofen treatment seem to affect alveolar growth in an animal model.[80] Therefore, PDA ligation should be undertaken only in a select group of patients after careful consideration of the significant morbidities reported. A less aggressive approach to PDA ligation has been evaluated in a carefully conducted study.[81] Surgical closure involves placement of either a surgical suture or a vascular clip. The surgical clip procedure is generally performed at the bedside in most of the neonatal intensive care units as these infants are very small and unstable. Due to technical difficulties, closure of the PDA with a coil or Amplatzer® vascular plug (AGA Medical Corporation) device is not performed routinely in very LBW infants. Using the Amplatzer vascular plug device to close the PDA is technically difficult and is done mostly in larger patients. It should be considered only if feasible. The procedure is invasive and is performed in the cardiac catheterization laboratory by well-trained cardiologists. However, it is less invasive than surgical ligation, which involves thoracotomy and its associated complications.

As an approach to ligation based on ductal size, clinical and ultrasound evidence of significance has been proposed for PDA unresponsive to COX inhibitors in infants less than 28 weeks’ gestational age and less than 1000 g at birth.[76] If the ductus is <1.5 mm in diameter, weekly echocardiogram is recommended until the ductus closes. If the ductus is 1.5 to 3 mm, clinical and ultrasound evidence of significance will determine the decision to ligate. If the ductus is >3 mm, ligation is recommended. This seems to be a logical approach but is not based on any controlled study. Large randomized controlled trials to clearly define the population who will benefit from PDA ligation are still needed. Finally, genetic and environmental factors have been suggested from a retrospective study for the variance in liability for PDA.[82] This novel finding warrants further investigation to guide treatment.

SUMMARY PDA is a common condition in infants with ELBW and has been associated with significant morbidity. In approximately one-third of cases, the ductus will close spontaneously. PDA should be evaluated and treated with one of the available COX inhibitors: indomethacin or ibuprofen. Both COX inhibitors are equally effective in closing the PDA. Ibuprofen has a better toxicity profile compared with indomethacin. Surgical closure of the PDA should be reserved only for rare cases after careful consideration and if the pharmacotherapy has failed to close the PDA. There is significant morbidity associated with surgical closure of the ductus.

Summary and Clinical Pearls

PDA is one of the most common congenital heart defects.

Presence of a PDA is inversely proportional to birth weight and gestational age. Almost two-thirds of the neonates <28 weeks’ gestational age will present with a PDA.

A persistent PDA is the one that is present beyond 72 hours of age.

PDA presents with significant hemodynamic and clinical effects, causing morbidity and occasionally mortality.

PDA diagnosis is made by an echocardiogram with defined findings. The definition of “hemodynamically significant PDA” is still not well determined.

The treatment approach involves conservative management, pharmacological closure, and surgical ligation.


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Pharmacological closure involves COX inhibitors (indomethacin and ibuprofen). COX inhibitors have undesirable adverse effects.

The exact time to treat PDA is still not exactly known.

When pharmacological treatment fails, surgery is the only option to ligate the PDA.

Surgery for PDA is associated with significant morbidities.

ABBREVIATIONSBNP = B-type natriuretic peptideCOX = cyclooxygenaseELBW = extremely low birth weightIV = intravenousIVH = intraventricular hemorrhageNEC = necrotizing enterocolitisPDA = patent ductus arteriosusPGE2 =prostaglandin E2 PGI2 = prostacyclinTIPP = trial of indomethacin prophylaxis in preterm infants

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