Cardiology and Angiology: An International Journal

9(4): 5-14, 2020; Article no.CA.59903 ISSN: 2347-520X, NLM ID: 101658392

Patent : Update Review

Lucilla do Espírito Santo Brandão1*, Rose Mary Ferreira Lisboa da Silva2, Roberto Max Lopes1 and Cristiane Nunes Martins1

1Biocor Instituto, Brazil. 2Department of Internal Medicine, Faculty of Medicine, Federal University of Minas Gerais, Brazil.

Authors’ contributions

This work was carried out in collaboration among all authors. All authors read and approved the final manuscript.

Article Information

DOI: 10.9734/CA/2020/v9i430140 Editor(s): (1) Gen-Min Lin, National Defense Medical Center, Taiwan. Reviewers: (1) S. Ramakrishnan, India. (2) José Luis García Serrano, University of Granada, Spain. Complete Peer review History: http://www.sdiarticle4.com/review-history/59903

Received 02 June 2020 Accepted 08 August 2020 Review Article Published 17 August 2020

ABSTRACT

The Ductus Arteriosus (DA) is a vascular structure of the fetal that communicates the isthmus of the (at the junction of the aortic root with the descending aorta) to the roof of the bifurcation of the pulmonary trunk. It is an essential structure of the fetal heart that connects the pulmonary circulation to de systemic circulation bypassing the lungs. The DA is usually patent at birth. It undergoes through muscle contraction between 10 and 15 hours of life and closes due to fibrous proliferation of the intimal layer by the third week of life. The change in the natural history of DA, with consequent permeability beyond the predicted period, promotes the Patent Ductus Arteriosus (PDA) a congenital acyanotic heart disease. The most important risk factor for PDA is prematurity. Other risk factors are the congenital , chromosomal abnormalities, genetic factors, low , perinatal asphyxia and birth in high altitude places. The clinical manifestations of a PDA are determined by the degree of left-to-right shunting, which is dependent upon age, the size and length of the PDA and the difference between pulmonary and systemic vascular resistances. The diagnosis of PDA is usually based on its characteristic clinical findings and confirmation by . The proper management of PDA depend on age, hemodynamic impact and resource available and may include conservative management, pharmacologic treatment, surgical approach and percutaneous closure. The rates for percutaneous and surgical closure are rare.

Keywords: Patent ductus arteriosus; congenital heart defects; therapy; treatment outcome. ______

*Corresponding author: E-mail: [email protected];

Brandão et al.; CA, 9(4): 5-14, 2020; Article no.CA.59903

1. INTRODUCTION 2. CAUSES AND RISK FACTORS

1.1 Definition and Epidemiology The most important risk factor for PDA is prematurity. Premature infants have a lower The Ductus Arteriosus (DA) is a vascular oxygen concentration and therefore are structure of the fetal heart that communicates the more susceptible to PDA, since one of the prime isthmus of the aorta (at the junction of the aortic mechanisms of ductal contraction is not effective root with the descending aorta) to the roof of the [1,3]. bifurcation of the pulmonary trunk (PT). It is an essential structure of the fetal heart that connects Another risk factor is the Congenital Rubella the pulmonary circulation to de systemic Syndrome that can present with congenital heart circulation bypassing the lungs. Once the blood disease in 60% of the patients and PDA is the exits the right ventricle through the PT, it finds a most frequent. The incidence of PDA is also high pulmonary resistance due to immature increased in high altitude locations compared lungs, which are still a liquid-filled organ. On the with those born at sea level, for the same lower other hand, the systemic circulation is connected oxygen concentration typical of such places [5]. to the placenta, a low blood resistance organ.

This difference of pressures between the Mutations in the TFAP2B gene cause Char pulmonary and systemic circulations leads to a syndrome, a rare condition that presents with shunt from the to the distinctive face appearance, PDA and hand descending aorta. This deviation of abnormalities. The TFAP2B gene appears to pulmonary blood to the systemic circulation does play a role in the normal formation of structures not harm the , since the oxygenated in the face, heart and limbs. Other genetic blood is delivered by the placenta and not the syndromes associated with PDA are CHARGE lungs [1]. syndrome, Holt-Oram syndrome, Noonan The DA is usually patent at birth. It undergoes syndrome and DiGeorge syndrome [6]. There is through muscle contraction between 10 and 15 a higher frequency in siblings, even without any hours of life and closes due to fibrous , with a recurrence rate of 5%. In proliferation of the intimal layer by the third week addition to prematurity, chromosomal of life. Higher oxygen concentration at the blood abnormalities, genetic factors and infections, on the DA associated with a drop in the other etiological factors are , E2 production of the placenta and perinatal asphyxia and birth in high altitude a decrease in within the DA places [3]. lumen are the main factors that lead to DA closure through muscular contraction. 3. MORPH OLOGY Thus, the functional closure of the DA occurs within the first 24 to 48 hours and the In 1989, Krichenko developed an angiography- anatomical closure occurs in 2 to 3 weeks [1,2]. based classification in 5 categories: conical (type The change in the natural history of DA, with A), window (type B), tubular (type C), complex consequent permeability beyond the predicted (type D) and elongated (type E) [7]. period, promotes the Patent Ductus Arteriosus (PDA) a congenital acyanotic heart The right definition of the morphology is disease. important to define the proper treatment, considering that some categories are more In term infants, the reported incidence of isolated challenging to be treated with percutaneous PDA ranges from 2 to 6 per 1000 live births. closure and should be consider closure with the Isolated PDA accounts for 5 to 10% of congenital surgical approach. heart defects. For unknown reasons, there is a female predominance for PDA with a 2:1 female Type A is the most frequent and it is to male ratio [1]. In premature infants, its characterized by a conical shape with the incidence is approximately 0.008%. Up to 30% of narrowing point at the pulmonary end. On Type B newborns weighing less than 2500 g develop PDAs there is no constrictive point and is PDA [3]. Its prevalence is estimated at 14.2% in resembles aortopulmonary window. This the total population (12.4% in children and 16.3% morphology makes percutaneous closure in adults). It is among the five most difficult , due to the lack of narrow point to hold common diagnoses of congenital heart the closure device. Type C is tubular shaped and [4]. is also related with higher complications when

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percutaneously closed. Type D is rare and has Large, tubular PDAs offer low resistance and multiple constrictive points. At last, type E makes aortic end pressure similar to the resembles type A but is more elongated and also pulmonary end pressure. It is known by the Ohm has a narrow point at the pulmonary end (Fig. 1). Law that pressure = flow x resistance, therefore Frequently PDA is associated with other pulmonary extremity pressure of the PDA = flow congenital heart diseases (CHD), sometimes through the ductus x pulmonary resistance. By being the responsible for the maintenance of the similarity, aortic extremity pressure = flow infant’s life. In the group of the CHD that course through the ductus x systemic resistance. If no with low pulmonary flow, the PDA compensates narrowing points are present, pressure in both the deficiency of pulmonary circulation. The most extremities are similar and the proportion of common CHD in this group are Tetralogy of pulmonary and aortic flow (Qp/Qs) will be defined Fallot, , pulmonary stenosis, by the relation between systemic resistance (Rs) with intact ventricular septum and pulmonary resistance (Rp). At birth, the Rp and single ventricle with pulmonary stenosis and is 25% the Rs and therefore, pulmonary flow can transposition of great arteries. In the cases of be 4 times the systemic (Table 1) [9]. hypoplasic left heart disease, the PDA represents the only path for systemic 5. SYMPTOMS AND PHYSICAL EXAM circulation. In the presence of other CHC with left to right shunt, PDA can worsen left The PDA has great clinical variability and may chambers overflow and therefore result in remain asymptomatic or be associated with more precocious hemodynamic consequences symptoms of and pulmonary [8]. vascular remodeling, leading to inversion of the shunt and characterization of Eisenmenger 4. PHATOPHYSIOLOGY Syndrome. The clinical manifestations of a PDA are determined by the degree of left-to-right The clinical features of the PDA depend on the shunting, which is dependent upon age, the size amount of blood that deviates from the and length of the PDA and the difference systemic to pulmonary circulation. The intrinsic between pulmonary and systemic vascular resistance of the PDA and the pulmonary resistances. In term infants, the most typical resistance regulate the flow that reach the presentation of PDA in the absence of other lungs. congenital heart defects is murmur [10].

Type B Type A Type C

Type D Type E

Fig. 1. Krichenko PDA classification. Type A: Conical shape with the narrowing point at the pulmonary end. Type B: No constrictive point and resembles aortopulmonary window. Type C: Tubular shaped. Type D: Multiple constrictive points. Type E: Resembles type A but is more elongated and also has a narrow point at the pulmonary end. Red vessel: Proximal aorta; blue vessel: Pulmonary artery

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Table 1. Relationship between volume, pressure and resistance

Pp = Qp x Rp and Ps = Qs x Rs If Pp = Ps (present at tubular and window shaped PDA), then Qp x Rp = Qs x Rs Qp/Qs (proportion of pulmonary flow and systemic flow) = Rs/Rp Rp/Rs = ¼ at birth or Rs/Rp = 4

So Qp/Qs = 4 (4 times the amount of blood reaches pulmonary circulation compared to systemic flow) Pp: pulmonary pressure / Qp: pulmonary flow / Rp: pulmonary resistance / Ps: systemic pressure / Qs: systemic flow / Rs: systemic resistance

In preterm infants, typical signs are absent in the Adults with large PDA that still with left-to-right first hours of life, due to the transition of the shunting have clinical manifestations similar than pulmonary vascular resistance that take several older children. The diastolic component of the hours or days to be complete. The increased murmur disappears when there is moderate shunt velocity coinciding with declining . Once Eisenmenger pulmonary vascular resistance produces a typical syndrome is established, there is an inversion on murmur described by Gibson in 1898 (a louder shunting and the adult may present with continuous or machinery murmur in the first or and clubbing [10]. Both cyanosis and clubbing second left intercostal space). As the can be more pronounced in the lower extremities myocardium performance improves, there can be (differential cyanosis) because the ductus seen hyperactive precordium, increased pulse typically delivers unoxygenated blood distal to volume and wide [3,9]. the left subclavian artery.

Large PDA with considerable pulmonary flow can 6. DIAGNOSIS - COMPLEMETARY have hemodynamic consequences such as EXAMS enlargement of left chambers and congestive heart failure resistant to clinical treatment. If not The diagnosis of PDA is usually based on its treated, the child can have , characteristic clinical findings and confirmation feeding disorders, swelling, by echocardiography. Before echocardiogram, and fatigue. angiography was the only diagnostic method for PDA. Currently, catheterization is only necessary Term infants, children and adults show clinical in the context of treatment, not diagnosis [10]. manifestation according to pulmonary-to- ECG has a low sensitivity and specificity for systemic-flow ratio (Qp:Qs). A small PDA (Qp:Qs PDA, and when alterations are present, it is due < 1,5 to 1) that restricts excessive blood flow into left chambers enlargements such as wide P the lungs may go undetected with no symptoms. wave (for left atrium) and signs of ventricular The diagnosis is usually incidental after murmur hypertrophy (R wave seen at derivations I, II, identification at routine primary care visit or by a aVL, V5 and V6, S wave at V1 and V2) [11]. diagnostic study performed for other medical conditions. Patients will have normal precordial Chest radiography is usually normal. When activity, heart sounds and pulses. The PDA altered it can present , left atrium murmur is characteristically continuous best (LA), left ventricle (LV) and aorta dilatation if heard in the left infraclavicular region. Murmur significant shunt happens. If so, prominent main does not change according to patient’s position. pulmonary artery blending with a prominent Patients with moderate PDA (Qp:Qs between 1,5 aortic knob along the upper left heart border can and 2 to 1) can show exercise intolerance. The be seen. Pulmonary vascular marking can be physical exam shows the typical murmur, a wide found if significant pulmonary overflow [3,10]. systemic pulse pressure and signs of left ventricular , such as displaced Echocardiogram is the current main diagnostic left ventricular apex. Infants with large PDA tool for PDA. PDA can be well identified between (Qp:Qs > 2,2 to 1) may present with heart failure, the origin of the left pulmonary artery and failure to thrive, poor feeding and respiratory descending aorta, distal the left subclavian artery distress. The older child may present with at the parasternal and suprasternal views. shortness of breath or easy fatigability, dynamic Chamber enlargements measures and shunt left ventricular impulse and wide pulse pressure. velocity are important to define the hemodynamic

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consequences of the PDA. Typically, there is no 8.1 Preterm Infants need to magnetic resonance or tomography to diagnose PDA. Sometimes, however, it is an Infants born before proper gestational age are additional finding when examining different more likely to persist with a fetal structure after structure [10]. birth. This occur due to the comparative preterm children have comparing to 7. NATURAL HISTORY AND OUTCOME term infants.

In 1968 Mitchell first described the natural history Some important questions remain difficult to of PDA as it was at the time. He concluded that answer regarding the most advantageous way even if the DA does not close shortly after birth, it and the impact of PDA closure in preterm infants. still has the potential to close during the first year First, does the PDA need to be closed? It is well of life [12], with an estimated spontaneous known that a significant portion of symptomatic closure rate of 0.6% per year [3]. PDA can close spontaneously; therefore, which

As any left to right shunt congenital heart ones should be treated before? And if so, how to disease, long term pulmonary overflow can lead perform the closure? There is still a lack of to vascular remodeling of the lungs and studies supporting any answers to those pulmonary hypertension (PH). It is rare for PDA questions yet [14]. The 2020 Indian Guidelines to develop PH comparing with ventricular left to for Management of Congenital Heart disease right shunt situations such as ventricular septal recommend treating the preterm infants with defect and total atrioventricular septal defect. heart failure with 2 courses of drug therapy or The PDA usually offers pulmonary overflow surgical ligation when pharmacological approach resistance and the inversion of shunt is rare. If it is unsuccessful [15]. happens, eventually pulmonary pressure turns higher then systemic pressure and the shunt at The first line of treatment is the conservative the PDA instead of from left to right turns to right management in which general supportive to left. This is called Eisenmenger Syndrome [8]. measures are applied with no drugs or Once that endpoint is reached, there is no benefit procedures. If those measures do not work, and in PDA closure, since vascular remodeling will the child remains on mechanical ventilation when continue despite closure [12]. other factors have been excluded, such as infection or bronchopulmonary dysplasia, Other possible complications are endarteritis and pharmacologic closure can be performed. In a formation of aneurysms of the DA. Endarteritis is very low number of cases, and when the less the endocarditis inside the DA which can be invasive treatments were ineffective, surgical or difficult to diagnose for general physicians if the percutaneous closure may be the final option [5]. patient does not have the PDA diagnosis [13]. The risks of aneurysm are rupture and bleeding. 8.1.1 Conservative management

Premature neonates with low body weight may For infants with a hemodynamically significant present with respiratory distress and heart PDA, an initial conservative approach can failure, with indication of DA closure for a include fluid restriction, maintenance of a higher favorable impact on morbidity and mortality. The hematocrit, use of diuretic and minimal mortality rate of untreated patients is 20% at 20 respiratory support. Excessive fluid years of age, reaching 60% at 60 years of age administration is associated with an increased [3]. incidence of PDA and, therefore, a moderate daily intake of 120-130ml/kg is suggested. When 8. MANAGEMENT: PHARMACOLOGIC diuretic therapy is considered, it is wise not TREATMENT, SURGICAL INTERVEN- choosing furosemide, as it stimulates renal TION, CATHETER-BASED TREAT- synthesis of , a potent MENTS vasodilator that maintains ductus arteriosus patency. Hematocrit at 35 to 40 percent can The proper management of PDA depend on age, increase pulmonary vascular resistance and hemodynamic impact and resource available. reduce left to right shunting, and minimal They can be better summarized according mechanical ventilation minimize further patients age: pulmonary injury [14].

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8.1.2 Pharmacologic treatment should be considered and liver blood test performed [5]. When the conservative approach fails and there is still hemodynamic impact of the PDA, There is still a lack of trials to determine the best pharmacologic intervention may be needed. The treatment choice. Recent Cochrane meta- drugs that show effectiveness on PDA closure analysis, however, states that prophylactic are those who target inhibiting prostaglandin treatment exposes a large proportion of infants synthetase, as prostaglandin promotes ductal unnecessarily to a drug that has important side patency. The best choices are non-selective effects without conferring any important cyclooxygenase (COX) inhibitors such as short‐term benefits. Current evidence does not and indomethacin and acetaminophen, support the use of ibuprofen for prevention of which interferes the peroxidase segment [16]. patent ductus arteriosus. Until long‐term follow‐up results of the trials included in this The choice of drug is center-bases. It is known review have been published, no further that between the two COX inhibitors, ibuprofen trials of prophylactic ibuprofen are recommended has lower risk of necrotizing enterocolitis and [17]. transient renal insufficiency then indomethacin, but shows no difference on mortality, 8.1.3 Percutaneous approach intraventricular hemorrhage, pulmonary hemorrhage, bowel hemorrhage, sepsis or Percutaneous transcatheter occlusion in preterm retinopathy rates. infants should be performed in specialized centers with expertise in this particular The standard dose for ibuprofen is an initial dose population. In 2019, the FDA approved the of 10 mg/kg followed by two additional doses of 5 Amplatzer Piccolo Occluder, used in infants > mg/kg given at 24 hours interval. This dosing is 700g and 3 days of life. This device in not largely the same for both oral and intravenous available yet [14]. administration. IV ibuprofen is typically used in developed countries because of availability and 8.1.4 Surgical approach because it is more expensive then the oral form. However, studies have shown the same Surgical ligation is the last option when effectiveness and developing countries continue conservative approach and two courses of to use the oral form with same results [16]. Some pharmacologic therapy fail and the patient studies suggest high dose ibuprofen as an remain with hemodynamic impact and need for alternative and point higher likelihood of success. maximum mechanical ventilation. It is associated In these cases, an initially dose of 15-20mg/kg with risk of infection, chylothorax, recurrent followed by two additional doses of 7,5-10mg/kg laryngeal nerve paralysis, bronchopulmonary administered every 12 to 24 hours can be used. dysplasia, pressure fluctuations, intraventricular hemorrhage and death. It still remains uncertain, Indomethacin is given intravenously with great however if the surgical ligation is the major dosing variety between neonatal centers. contributor to morbidity and mortality or if Typically, it is chosen 0,1-0,2mg/kg per dose patients who undergo surgical ligation are more administered every 12 to 24 hours in three severely compromised to begin with [18]. doses. Four or more doses show no additional increase in success rates. 8.2 Term Infants and Children

COX inhibitors are contraindicated in infants with In term infants and children with moderate to proven or suspected infections, active bleeding large PDA or in whom there is a prior episode of (especially intracranial hemorrhage or endocarditis, the closure decision is gastrointestinal bleeding), thrombocytopenia or straightforward, whereas in small or silent PDA coagulation defects, necrotizing enterocolitis without significant left-to-right shunt the decision suspected or confirmed and renal function for closure is less clear. In case of small audible impairment. In those cases, oral or IV PDA (i.e, those presenting with murmur), the acetaminophen (when available) are used. The closure is recommended because it prevent administered dose of acetaminophen is 60mg/kg occurrence of bacterial endocarditis, a rare but per day over a two to seven days program. This recognized complication of small PDA. Some dosage is significantly higher than the pain and physicians, however, believe that the chances of fever dose used, so attention to hepatotoxicity endocarditis in patients with small PDA is similar

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then general population, and therefore should be continue despite PDA closure. If Eisenmenger left untreated [18]. Syndrome is present (severe pulmonary hypertension that results in right to left shunt), Small silent PDA usually are incidentally closing the PDA may worsen clinical symptoms detected by imaging studies performed for other because they depend on the shunt to avoid heart indications. Silent PDA do not have failure and maintain [20]. hemodynamic consequences, and thus, the only impetus for closure is the theoretical risk of 8.4 Interventional Options bacterial endocarditis or family/personal preference. 8.4.1 Catheter-based treatment

Once the patients are not newborns anymore, Percutaneous closure of the ductus arteriosus they do not respond to pharmacologic closure. If began in 1966 when Portsmann was successful they are asymptomatic, it is recommended to in percutaneous prosthesis implantation in a 17- delay closure until proper weight for year-old patient [21]. In the last 5 decades, there percutaneous closure is achieved. If have been great advances in the development of symptomatic, medical management as digoxin prostheses and sheaths, making it possible to and diuretics can help waiting to suitable weight reduce the duration of the procedure and include for percutaneous closure. In symptomatic non- less weight children. responders to medical treatment, surgical closure is preferable. Although there have been many Its execution is particularly challenging if we devices used for smaller children with a huge consider the great morphological variability of success rate, the smaller the child less than 6kg this vascular structure, as seen in the is, the higher chance for procedure complication. morphology description above. In view of the In children over 6kg, percutaneous occlusion is increased number of possible configurations, no generally preferred over surgical ligation because device has been shown to be efficient for it is less invasive and less expensive or at least contemplating all anatomical variants of the as cost-effective [18]. ductus arteriosus.

Therefore, the timing of PDA closure depends on Ideally, the occlusion should be total so that the PDA’s size and hemodynamic there is no residual shunt, no part of the device consequences. Large to moderate PDA with should remain exposed, and there should be no significant left heart volume overload, congestive protrusion of the device into the pulmonary artery heart failure or pulmonary hypertension must and/or aorta (Fig. 2). Calibrated tubular channels, have early closure (by 3 months). When there is with small aortic ampulla and angled channels, some degree of left heart overload, mild or no especially in low weight patients, are at higher congestive heart failure and/or mild pulmonary risk of complications. arterial hypertension, it is considered moderate. In this case, it can be closed when the child is Currently, the proper devices for percutaneous between 6 and 12 months old. Small PDA should closure of the DA are prostheses specifically be closed by the age of 12-18 months and if designed for DA closure. Coils used to be silent PDA, the closure is not recommended [15]. particularly useful in closing small DA with reduced performance for large ductus. In those 8.3 Adults cases, sometimes it was necessary to use more than one coil to fill a single DA, increasing the In older patients, percutaneous occlusion is procedure time and the risk of embolization. always preferred than surgical [19]. Coils can be Specific designed prostheses, on the other hand, used for small PDA and, for moderate to large come in different sizes and brands; however, PDA, other devices such as ductal occluder or their use is limited due to cost, both at public and general vascular plugs are available. private levels [22].

It is important to point out that once there is In patients with an DA diameter of less than 8 irreversible pulmonary hypertension, there will be mm, there is ductal closure in more than 85% of no benefit in performing the procedure and cases during the 1-year follow-up and with less progressive pulmonary vascular disease will than 1% mortality [23].

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Fig. 2. Right anterior oblique (RAO) aortogram showing the device placed into the PDA ampulla by retrograde approach

8.4.2 Surgical treatment However, the mortality rate can reach 3.5%, especially in adults with PH [23]. Since the first successful surgical PDA ligation in 1939, the technique has been improved and now The complications reported after surgical ligation it can be performed safely inclusive in extremely include: recurrent laryngeal nerve paralysis, low birth weight infants (<1000 g) [20]. respiratory compromise, infection, pleural effusion or chylothorax, pneumothorax, bleeding, The surgical approach is the third left intercostal scoliosis or residual duct patency [20]. space in infants and fourth left intercostal space in infants and fourth left intercostal space in older 9. CONCLUSIONS patients. Many surgeons prefer multiple ligations or division to minimize the risk of Persistent ductus arteriosus is an acyanotic recurrent shunt. Video-assisted thorascopic congenital heart condition originated by main surgery is a safe and effective procedure for PDA patency of a fetal structure. It can have closure and is less invasive than standard hemodynamic pulmonary vascular thoracotomy surgical closure. It is consequences and treatment should be contraindicated if the PDA is greater than 9 mm, performed. The complication rates for in patients with prior thoracotomy, ductal percutaneous and surgical closure are rare. calcifications, active infections or ductal Complications include pulmonary device aneurysm [20]. In more than 95% of patients, the protrusion, aortic protrusion, embolization and murmur disappears on physical examination. residual shunt in the percutaneous approach,

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