Patent Ductus Arteriosus (PDA): Clinical Guidelines

List of Abbreviations

Ao — aorta

IVH – intraventricular hemorrhage

CHD - congenital heart disease

HFOV — high-frequency oscillatory ventilation

hsPDA — hemodynamically significant patent ductus arteriosus

PAP – pulmonary artery pressure

IMV – invasive mechanical ventilation

CPB — cardiopulmonary bypass

CT – computed tomography

PA - pulmonary artery

PH – pulmonary hypertension

MRI — magnetic resonance imaging

NSAIDs – nonsteroidal anti-inflammatory drugs

PDA - patent ductus arteriosus

PVR — pulmonary vascular resistance

PG — prostaglandins (E1, E2, etc.)

HF – heart failure

ECG - electrocardiography

EchoCG – echocardiography

NT-proBNP — N-terminal pro-brain natriuretic peptide

Terms and Definitions

Angiocardiography is an invasive diagnostic imaging method that involves the visualization of the heart chambers and blood vessels by administering a radiopaque agent into the bloodstream, directly measuring pressure in the heart chambers and blood vessels, obtaining blood samples from them to assess blood gas composition, and performing morphometric calculations based on the obtained radiopaque images of the cardiovascular system.

"Hemodynamic coarctation of the aorta" — development of a clinical picture identical to aortic coarctation, but in the absence of an organic obstruction to blood flow in the aorta. This phenomenon occurs due to the presence of a large PDA and the difference between pulmonary and systemic vascular resistances, causing blood to flow from the aorta into the pulmonary artery, mimicking aortic coarctation (typically seen in low-birth-weight premature infants).

hsPDA — (hemodynamically significant patent ductus arteriosus) is a patent ductus arteriosus of large diameter with a left-to-right shunt (from the aorta to the pulmonary artery), the persistence of which in extremely premature infants is accompanied by significant disorders of central and regional hemodynamics detected via echocardiography [1,113].

Cardiac catheterization – an invasive procedure performed for therapeutic or diagnostic purposes in cardiovascular pathology by inserting catheters into the heart chamber or the lumen of great vessels.

Computed tomography (CT) – a non-invasive diagnostic imaging method that yields a series of submillimeter cross-sectional axial images of human body organs and structures, based on measuring and complex computer processing of X-ray attenuation differences by tissues of varying densities; to improve the differentiation of organs from one another, as well as normal and pathological structures, various contrast enhancement techniques are used with iodine-based radiocontrast agents. To visualize the structures of the cardiovascular system, CT angiography is used—a technique of intravenous bolus injection of a radiocontrast agent into the bloodstream using an intravascular contrast injection system at a preset injection rate and time, based on which computer post-processing with 3D reconstruction builds a three-dimensional model of the heart and vessels.

Magnetic resonance imaging (MRI) is a non-invasive, non-ionizing computerized technique for obtaining tomographic medical images to study internal organs and tissues, based on the phenomenon of nuclear magnetic resonance and the measurement of the electromagnetic response of atomic nuclei located in a strong constant magnetic field, in response to their excitation by a specific combination of electromagnetic waves; such nuclei are hydrogen atomic nuclei present in the human body as part of water and other substances. MR angiography is a method for imaging the vascular lumen using an MRI scanner. The method makes it possible to evaluate both the anatomical and functional features of blood flow. MR angiography is based on the difference in signal between moving protons (blood) and surrounding stationary tissues, which allows vascular imaging without the use of any contrast agents — unenhanced angiography (phase-contrast MR angiography). In some cases, intravenous bolus contrast administration is used with paramagnet-based contrast agents (gadolinium).

Pulse pressure — the difference between systolic and diastolic blood pressure.

Patent ductus arteriosus (persistent ductus arteriosus) — an arterial duct whose patency persists after birth without associated congenital anomalies of the cardiovascular system.

Endocarditis — inflammation of the inner lining of the heart, often a manifestation of other diseases.

Echocardiography — an ultrasound imaging method aimed at studying morphological and functional changes of the heart, valve apparatus, and great vessels.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Patent ductus arteriosus (PDA) — pathological persistence of the lumen of the arterial duct after birth. The PDA must necessarily be present in the fetus, but closes after birth [2,114].

In a left-sided aortic arch, the ductus arteriosus arises from the aortic arch opposite the left subclavian artery and runs obliquely anteriorly and downward, emptying into the bifurcation of the pulmonary trunk at the level of the left pulmonary artery (PA) orifice. In a right-sided aortic arch, the duct typically connects to the proximal part of the right pulmonary artery. The duct may occasionally connect to the adjacent subclavian or brachiocephalic artery rather than the upper descending thoracic aorta [2,114].

Cases of two ducts connecting the aorta to the right and left pulmonary arteries have been described in the literature.

In rare cases, the PDA presents as a tortuous, fistula-like tract of small diameter (up to 1.0 mm). In such cases, blood shunting through the PDA does not lead to hemodynamic disorders, but increases the risk of infective endocarditis [112].

hsPDA is a patent ductus arteriosus in a premature infant with a shunt direction from the aorta to the pulmonary artery, the functioning of which is accompanied by clinical or echocardiographic signs of pulmonary hypervolemia and systemic hypoperfusion, leading to impaired perfusion in the intestines, kidneys, and brain [1,113].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Patency of the ductus arteriosus is a major component of fetal circulation, establishing a connection between the PA and the aorta when the baby's lungs are non-functional and gas exchange occurs at the placental level. The direction of blood flow through the duct is determined by high pulmonary vascular resistance and low placental vascular resistance. Blood is directed right-to-left — from the PA to the aorta.

After birth and the first breath, a drop in pulmonary vascular pressure occurs, resulting in a reversal of blood flow through the duct from left to right (from the aorta to the pulmonary artery). Concurrently, the ductus arteriosus constricts under the action of oxygen, but immediate closure does not occur. The time to spontaneous closure of the ductus arteriosus is proportional to gestational age, averaging 71 days of life for newborns <26 weeks of gestation and 6 days of life for newborns >30 weeks of gestation [3].

Postnatal closure occurs in two stages. The first stage is completed within 10–15 hours after birth in term infants. The smooth muscle cells of the medial layer contract, causing shortening and thickening of the duct wall. This functional closure is facilitated by the approximation of intimal cushions. Intimal cushions are protrusions consisting of longitudinally oriented smooth muscle cells that bulge into the lumen and lie between the endothelium and the internal elastic lamina within the intima [4-5]. They thicken as the duct matures and are most prominent at the pulmonary end of the duct. Muscle contraction occurs both circumferentially via circularly arranged smooth muscle cells and longitudinally via several muscle bundles located inside the duct. The second stage of closure is usually completed in 2–3 weeks. It results from diffuse fibrous intimal proliferation, sometimes combined with necrosis of the inner medial layer and intramural hemorrhage. The latter may be associated with intimal tears causing limited dissection of the duct wall. Small thrombi may also be present in the lumen, but large luminal thrombi are rare. These changes lead to permanent closure of the lumen and the formation of the ligamentum arteriosum [2,4-7,114].

Closure typically begins at the pulmonary end and may remain incomplete on the aortic side, leaving an aortic ampulla from which the ligamentum arteriosum originates. Less commonly, there may be a ductal diverticulum originating from the proximal left pulmonary artery [2,114].

The ductus arteriosus closes completely by 8 weeks of age in 88% of newborns with a normal cardiovascular system.

When the process of ductal closure is delayed, it is appropriate to use the term prolonged ductal patency. If closure does not occur within the first 3 months after birth, it is referred to as persistent patent ductus arteriosus. Closure or patency of the duct is mediated by the release of vasoactive substances (acetylcholine, bradykinin, endogenous catecholamines), pH fluctuations, but primarily by oxygen tension and prostaglandins (PGE1, PGE2, and prostacyclin PGI2). Oxygen tension and prostaglandins act in opposite directions: rising PO2 constricts the duct, while prostaglandins relax it [8-9]. The activity of each substance varies depending on gestational age. Thus, the duct is significantly more sensitive to PO2 in the mature fetus and to prostaglandins (particularly PGE1) in the immature fetus. The complex interaction of these factors is the reason why prolonged ductal patency is more common in premature than in term infants, especially in the presence of respiratory distress syndrome [2,114].

Thus, postnatal risk factors for PDA persistence include: prematurity, birth asphyxia, low birth weight, late-onset neonatal sepsis, fluid overload during the first days of life, thrombocytopenia on the first day of life, need for mechanical ventilation, and surfactant therapy [2,10-13,114,132].

1.3 Epidemiology of the Disease or Condition

The exact incidence of the defect is unknown, as it is unclear when exactly a patent ductus arteriosus should be considered pathological. It is conventionally assumed that it normally closes within the first two to three weeks of life, though persistence up to 3 months of life is permissible. PDA typically occurs in premature infants and extremely rarely in term infants. Under these criteria, the prevalence of isolated pathology is about 0.14–0.3 per 1,000 live births, accounting for 7% of all congenital heart defects (CHD) and 3% of critical CHD [14-15].

There is a correlation between PDA and the birth weight of the premature newborn: the lower the body weight, the more frequently PDA persists. Thus, with a body weight of 1500–2000 g, PDA occurs in 15–20% of cases; in premature infants weighing less than 1000 g, it occurs in 80% of cases [111].

Females develop PDA three times more frequently than males. PDA can be an isolated defect, but in 5–10% of cases, it is combined with other CHDs (ASD, VSD, etc.) [111].

The average life expectancy of patients with PDA is approximately 40 years. By the age of 30, 20% of patients die; by 45 years, 42%; and by 60 years, 60%. The main causes of mortality are heart failure (HF), infective endocarditis (endarteritis), and the development and rupture of a ductal aneurysm [15].

Risk factors for PDA persistence:

1. Premature birth. Patent ductus arteriosus occurs more frequently in babies born too early compared to those born at term.

2. Family history and other genetic conditions. A family history of heart defects and other genetic disorders, such as Down syndrome, increases the risk of patent ductus arteriosus.

3. Rubella during pregnancy. If you contracted rubella during pregnancy, the risk of heart defects in the child increases. The rubella virus crosses the placenta and spreads through the child's circulatory system, damaging blood vessels and organs, including the heart.

High altitude. Infants born at altitudes above 10,000 feet (3,048 meters) have a higher risk of developing a patent ductus arteriosus.

1.4 Features of Coding the Disease or Condition

Q25.0 – Patent ductus arteriosus.

1.5 Classification of the disease or condition

Taking into account the pressure level in the PA, 4 grades of the defect are distinguished [14-17]:

1. systolic pulmonary artery pressure (PAP) does not exceed 40% of the arterial (systemic) pressure;

2. PAP is 40-75% of the arterial pressure (moderate pulmonary hypertension (PH));

3. PAP is more than 75% of the arterial pressure (severe PH with preserved left-to-right blood shunting);

4. PAP equals or exceeds the systemic pressure (severe PH, leading to a right-to-left blood shunt).

The natural history of patent ductus arteriosus exhibits 3 stages [14]:

Stage I: Stage of primary adaptation (the first 2-3 years of the child's life). It is characterized by the clinical manifestation of patent ductus arteriosus; it is often accompanied by the development of critical conditions, which in 20% of cases result in mortality without timely cardiac surgery.

Stage II: Stage of relative compensation (from 2-3 years to 20 years). It is characterized by the development and prolonged persistence of pulmonary hypervolemia, relative stenosis of the left atrioventricular orifice, and systolic overload of the right ventricle.

Stage III: Stage of pulmonary vascular sclerotic changes. Further natural course of patent ductus arteriosus is accompanied by remodeling of pulmonary capillaries and arterioles with the development of irreversible sclerotic changes in them. At this stage, the clinical manifestations of patent ductus arteriosus are gradually superseded by symptoms of PH.

PDA is also classified according to the degree of hemodynamic significance into mild, moderate, and severe.

1.6 Clinical presentation of the disease or condition

The clinical presentation depends on the size of the ductus and the stage of hemodynamic disorders. The course of the defect ranges from asymptomatic to extremely severe.

Large patent ductus arteriosus (PAP greater than 75% of arterial pressure [severe PH with preserved left-to-right blood shunting])

Aortic and PA pressures are practically identical in large PDA, and the magnitude and direction of shunting depend on changes in pulmonary vascular resistance, because systemic vascular resistance remains virtually constant after birth. Right-to-left blood shunting increases over time, and severe heart failure develops within a month or so after birth. Tachypnea, tachycardia, diaphoresis, irritability, poor feeding, and slow weight gain are observed.

Thus, the clinical manifestations in children with a large/hemodynamically significant PDA in the early neonatal period (especially in premature infants) are caused by:

1. systemic blood flow steal due to a volume shunt through the PDA from the aorta into the pulmonary artery;

2. hypervolemia (hypertension) of the lesser circulation with overload of the left heart chambers and frequent development of acute left ventricular HF.

Clinical and laboratory signs:

• tachycardia;

• tachypnea or apnea escalating over time, as the main manifestation of respiratory distress syndrome / dependence on mechanical ventilation;

• pulmonary edema and pneumonia, as well as recurrent respiratory infection;

• need for inotropic and/or vasopressor therapy;

• signs of pulmonary circulation overload according to chest X-ray data (decreased lung aeration, atelectasis of the apical lobes) or pulmonary hemorrhage;

• oliguria (≤ 1.0 mL/kg/h) and/or an increase in creatinine level above 100 µmol/L;

• signs of enteral feeding intolerance (abdominal distension, regurgitation, signs of necrotizing enterocolitis);

• persistent metabolic/lactate acidosis (pH 7.1-7.25 and/or BE from -7 to -12) [2,18-19,114].

Medium-sized patent ductus arteriosus (PAP is 40-75% of arterial pressure [moderate PH])

The volume of the left-to-right shunted blood in medium-sized PDA is also determined by the size of the ductus. Initially, PAP is only moderately elevated. As neonatal pulmonary vascular resistance decreases, the shunt increases, and HF may occur. However, most commonly by the second or third month of life, the situation is usually accompanied by clinical improvement and symptom stabilization. Physical development may lag slightly, dyspnea and fatigue, frequent pulmonary infections may occur, but many patients with medium-sized PDA remain virtually asymptomatic until the second decade of life or later [2,114].

Small-sized patent ductus arteriosus (systolic PAP does not exceed 40% of arterial pressure)

The left-to-right shunt at an early age is small, and pulmonary vascular resistance rapidly decreases to normal after birth. Left ventricular failure does not occur, and symptoms are usually absent in infancy and childhood. They may appear at an older age, but attention to the persistent ductus is typically drawn by a murmur detected during a medical examination [2,114].

Permanent cyanosis occurs only in adults, with irreversible changes in blood flow shunting and the sclerotic form of pulmonary hypertension;

2. Diagnostics, medical indications and contraindications for diagnostic methods

Characteristic signs that can be used to suspect the diagnosis include a continuous systolic-diastolic murmur in the II–III intercostal space to the left of the sternum and a decrease in diastolic blood pressure.

In premature infants and children with respiratory distress syndrome (RDS), a heart murmur appears by the 4th–6th day of life. The murmur can be systolic or systolic-diastolic, depending on the pressure gradient between the aorta and PA. The murmur is typically localized at the base of the heart in the second–third left intercostal space and may radiate to the back.

The diagnosis is established based on:

1. Echocardiography, or

2. Retrograde left heart catheterization,

3. Contrast-enhanced cardiac computed tomography,

4. Magnetic resonance imaging of the heart and vessels.

2.1 Complaints and Anamnesis

ESC IA, Level of Evidence (LoE) 5, Grade of Recommendation (GoR) C

Comments: when collecting anamnesis in case of suspected PDA in all patients or their parents, it is necessary to obtain information about family history, premature birth and prematurity, infectious and somatic diseases of the pregnant woman to verify the diagnosis [2,14-16,114].

• When taking complaints from all patients with patent ductus arteriosus or their parents, it is recommended to clarify information about dyspnea, fatigue occurring during physical exertion, palpitations, sensations of irregular heartbeats, and frequent pulmonary infections to determine the severity of the condition [2,14-16,114].

ESC IA, Level of Evidence (LoE) 5, Grade of Recommendation (GoR) C

Comments: patient complaints in patent ductus arteriosus (PDA) are nonspecific. Clinical manifestations depend on the ductal size and the stage of hemodynamic disorders. The course of the defect ranges from asymptomatic to extremely severe. With a large ductus, PDA manifests itself from the first weeks of life with signs of heart failure and delayed physical growth. In infants, crying may provoke cyanosis, which is more pronounced on the lower half of the body, particularly the lower extremities. Notably, cyanosis disappears once the exertion stops. Persistent cyanosis occurs only in adults and is a sign of reverse blood shunting due to the sclerotic form of pulmonary hypertension [2,14-16,114].

2.2 Physical Examination

• To determine the hemodynamic and clinical significance of PDA, it is recommended to perform an evaluation (examination, consultation) by a cardiologist/pediatric cardiologist or a cardiovascular surgeon [2,14-15,19-22,114].

          ESC IA, LoE 5, GoR C

ESC IA, Level of Evidence (LoE) 5, Grade of Recommendation (GoR) C

Comments: inspection and palpation (in large and medium-sized ducts) may reveal a systolic thrill and signs of left ventricular enlargement. Pronounced blood shunting through the PDA leads to cardiomegaly and, over time, potentially to the formation of a precordial bulge.

The pulse is often intermittent or weak, and pulse pressure is high. This is particularly noticeable in medically compensated heart failure.

In the absence of medical compensation for the condition, signs of heart failure generally dominate (tachypnea, tachycardia, sweating, irritability, hepatomegaly, poor feeding and slow weight gain, short stature). In some newborns with a large PDA, heart failure may be less pronounced, presumably because pulmonary vascular resistance fails to drop to normal levels. In such situations, histological changes in the pulmonary vessels may develop over the first few months of life, requiring earlier closure of the PDA. For small, hemodynamically insignificant PDAs, the child's physical development is usually normal (age-appropriate), and the pulse is unchanged.

Percussion findings: rightward expansion of cardiac borders or unchanged; a dullness band 1-2 cm lateral to the left sternal border in the 2nd intercostal space. [2,14-15,19-22, 114].

• All patients with PDA are recommended to undergo cardiac auscultation to detect pathological murmurs [2,14-15,23,114].

ESC IA, LoE 5 GoR C

Comments: large PDAs are characterized on auscultation by a systolic murmur with maximal transmission to the lung fields, late appearance of a systolic accent, and minimal diastolic propagation (occasionally a continuous murmur), radiating to the interscapular region and carotid arteries, along with an accentuated second heart sound over the pulmonary artery. In severe heart failure, the murmur is usually inaudible. Heart sounds are accentuated, often with a third heart sound at the apex or a prominent mid-diastolic mitral flow murmur. Rales at the lung bases are frequently auscultated. Medium-sized ducts are characterized by a classic continuous murmur, which is usually best heard between 2 and 3 months of age, with variable intensity. The murmur is typically loud and often masks the heart sounds (the maximum murmur is also usually detected over the pulmonary artery and radiates upward to the middle third of the clavicle). A small PDA by 2–3 months of age is characterized by a short systolic murmur, which later usually changes into a murmur transitioning into a diastolic or continuous one (best auscultation point - second left intercostal space), but less intense and with less radiation than in moderate-sized ducts. The intensity of the continuous murmur varies greatly among patients and can sometimes only be detected when the patient is sitting or standing upright.

A pronounced volume of blood shunting also leads to functional mitralization of the defect, manifesting as a systolic murmur of mitral regurgitation and a protodiastolic murmur of relative mitral stenosis. With a high volume of shunting, a tricuspid regurgitation murmur is recorded.

It should be remembered that a PDA begins to produce a murmur when its diameter exceeds 4 mm. Silent forms of the defect occur in 0.5–1% of observations when the duct diameter is less than 4 mm or when the duct is very wide [2,14-15,23,114].     

• All patients with PDA are recommended to have blood pressure measured in peripheral arteries to evaluate diastolic and pulse pressure (the difference between systolic and diastolic pressure) to verify the diagnosis [13-16].

          ESC IA, LoE 5, GoR C

Comments: due to blood shunting from the aorta into the pulmonary artery, diastolic pressure decreases (sometimes significantly), and pulse pressure increases. Systolic pressure is mostly within normal ranges, while diastolic pressure may drop to zero. Therefore, measuring blood pressure on the legs is mandatory to rule out the combination of patent ductus arteriosus and aortic coarctation. Preductal aortic coarctation can be suspected due to the presence of "differential cyanosis"—its presence in the lower extremities and absence in the upper ones.

• In newborns (especially premature infants) with a large, hemodynamically significant PDA, it is recommended to assess peristalsis via abdominal auscultation, and perform abdominal percussion and palpation to detect intestinal pneumatosis and free fluid in the peritoneal cavity [2,18-19,114].

ESC IA, Level of Evidence (LoE) 5, Grade of Recommendation (GoR) C

Comments: when blood flow in the descending aorta is impaired due to significant shunting from the aorta to the pulmonary artery, bowel function may be compromised, manifesting as a sharp decrease or absence of peristalsis (so-called "hemodynamic aortic coarctation," which requires prompt elimination of the PDA shunt).

• In newborns (especially premature infants) with a large, hemodynamically significant PDA, it is recommended to evaluate daily and hourly urine output to assess the severity of the condition [2,18-19,114].

ESC IA, LoE 5 GoR C

Comments: when blood flow in the descending aorta is impaired due to significant shunting from the aorta to the pulmonary artery, blood flow in the lower half of the body may be disrupted, leading to impaired renal function, which manifests as a sharp decrease/absence of urine output (a potential manifestation of "hemodynamic aortic coarctation," which similarly requires prompt elimination of the PDA shunt, analogous to intestinal dysfunction).

2.3 Laboratory Diagnostics

There are no specific laboratory diagnostics for PDA.

ESC IA, Level of Evidence (LoE) 5, Grade of Recommendation (GoR) C

Comments: for differential diagnosis with aortic coarctation, capillary sampling must be performed simultaneously from both an upper and a lower extremity. If the difference in blood oxygen saturation between the upper and lower extremities is greater than 3%, aortic coarctation should be suspected, and additional instrumental diagnostics for congenital heart disease should be performed.

• All patients with PDA are recommended to undergo a complete blood count (CBC) with hemoglobin level assessment, hematocrit evaluation, red blood cell, white blood cell, and platelet counts, as well as an erythrocyte sedimentation rate (ESR) test as part of the initial examination, and in the case of surgical treatment, when necessary in the pre- and/or postoperative period to rule out concomitant pathology [2,24-25,114].

ESC IA, Level of Evidence (LoE) 5, Grade of Recommendation (GoR) C

• All patients with PDA admitted to a specialized inpatient facility for surgical correction of the defect, who are expected to receive donor blood and/or its components, are recommended to undergo AB0 blood group typing, D antigen (Rh factor) testing, C, c, E, e, Cw, K, k antigen phenotyping, and screening for anti-erythrocyte antibodies [2,24-26,114,120-121].

ESC IA, Level of Evidence (LoE) 5, Grade of Recommendation (GoR) C

• All patients with PDA admitted to an inpatient facility for surgical treatment are recommended blood testing for Hepatitis B virus surface antigen (HBsAg), antibodies to Hepatitis C virus, antibodies to Treponema pallidum, and IgM and IgG antibodies to Human immunodeficiency virus HIV-1 and HIV-2 to rule out association with HIV infection, hepatitis, and syphilis [2, 24-26, 114, 122-123].

ESC IA, Level of Evidence (LoE) 5, Grade of Recommendation (GoR) C

• All patients with PDA preparing for surgical correction, and especially premature newborns (with hemodynamically significant PDA), are recommended to undergo a coagulogram (screening hemostasis test: activated partial thromboplastin time, international normalized ratio (INR), and blood fibrinogen level) to rule out congenital and acquired hemostatic disorders and to predict postoperative thrombosis and bleeding [24-25, 124-125].

ESC IA, Level of Evidence (LoE) 5, Grade of Recommendation (GoR) C

Comments: if there are laboratory signs of hemostatic disorders, surgical intervention should reasonably be postponed until the causes of these disorders are identified and corrected [24-25, 124-125].

• All patients with PDA preparing for surgical correction, particularly premature newborns with hemodynamically significant PDA, and when necessary in the pre- and/or postoperative period, are recommended to undergo a general clinical blood biochemistry panel (levels of potassium, sodium, chlorides, glucose, creatinine, total protein, albumin, urea, total bilirubin, free and conjugated bilirubin, along with lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase activities in the blood) to assess renal and hepatic function, and blood electrolyte levels [26-27].

ESC IC, LoE 5, GoR C

Comments: a hemodynamically significant PDA can lead to hyponatremia and elevated creatinine (due to reduced renal blood flow and activation of the renin-angiotensin-aldosterone system) [26-27].

• All patients with PDA are recommended to undergo measurement of B-type natriuretic peptide or N-terminal pro-brain natriuretic peptide (NT-proBNP) levels to determine the hemodynamic significance of the defect (suspected chronic heart failure) [14, 31, 126-131, 134-136].

ESC IC, LoE 5, GoR C

Comments: determination of B-type natriuretic peptide or NT-proBNP levels in PDA facilitates an adequate assessment of cardiovascular functional disorders, as well as the efficacy of conservative and surgical treatment. An increase in these markers reflects the degree of pressure alteration in the heart chambers. Notably, through its influence on peripheral signals, NT-proBNP is involved in water and electrolyte metabolism and reflects the degree of pressure remodeling within the cardiac chambers [109, 110, 126-131].

2.4 Instrumental Diagnostics

The definitive diagnosis of PDA is established using imaging methods that demonstrate blood shunting through the arterial duct. In a patient with suspected PDA, diagnostics should aim to detect and measure the size of the arterial duct, clarify functional changes in the left atrium and left ventricle, obtain information on the state of pulmonary circulation, and determine the presence or absence of concomitant congenital heart defects.

• All patients with PDA are recommended to undergo transthoracic echocardiography (TTE) with color Doppler flow mapping to determine the presence and hemodynamic significance of the PDA, study the anatomy of the aortic arch (arch position, diameter and length of each segment, origin pattern of brachiocephalic branches, and other structural features), rule out obstruction at the junction of the arch and descending aorta, and assess the degree of "master" (systemic-type) blood flow in the abdominal aorta [2, 28-31, 110, 111, 114].

ESC IB, LoE 5, GoR C

Comments: Visualization of the PDA can be achieved from two acoustic windows—parasternal and suprasternal (see Appendices A3.2 and A3.3).

Aortopulmonary and coronaropulmonary fistulas are visualized only from the parasternal window, which can serve as an important ultrasound differential diagnostic sign [108].

Doppler ultrasonography with color flow mapping makes the examination more accurate, detects retrograde blood flow in the descending aorta, and helps rule out concomitant congenital heart defects, such as atrial and ventricular septal defects [110]. Color Doppler mapping is supplemented by spectral (pulsed/continuous wave) Doppler, which registers continuous systolic-diastolic shunting into the pulmonary artery through the PDA; the direction of this shunt is usually diametrically opposed to the main blood flow in the pulmonary artery trunk [111].

Measurement of the left atrium and left ventricle dimensions allows for an indirect estimation of the shunt size (the larger their size, the larger the shunt).

Echocardiography is also useful for assessing the hemodynamic significance of a PDA. To this end, it is necessary to determine: the diameter, shunt direction, and blood flow velocity across the PDA; assess pulmonary hypervolemia/hypertension; evaluate signs of systemic hypoperfusion (assessing Doppler parameters in peripheral arteries, such as the descending or abdominal aorta); and compare the transverse dimension of the left atrium with the aortic diameter (normally, this ratio does not exceed 1.2).

Frequency of echocardiographic examinations in extremely premature newborns: First examination on the 1st day of life for premature infants <32 weeks of gestation, facility permitting. Second examination, if possible, on the 2nd or 3rd day of life for newborns ≤28 weeks of gestation, depending on the type of respiratory and cardiotonic therapy administered and gestational age. Subsequent TTE evaluations are determined by the clinical status and type of respiratory support to assess the dynamics of signs of PDA significance, taking into account the clinical picture (see clinical practice guidelines: "Hemodynamically significant patent ductus arteriosus in a premature newborn»).

Echocardiography is also performed prior to discharge of the patient from the hospital.

ESC IC, LoE 5, GoR C

Comments: cardiac catheterization makes it possible to assess the magnitude of the shunt, its direction, total pulmonary vascular resistance (PVR), and vascular bed reactivity. Angiography also provides precise determination of the size and shape of the duct.

• Cardiac and great vessel magnetic resonance imaging (MRI) is recommended for patients with PDA in the presence of complex congenital heart disease to obtain additional information (supplementary to echocardiography) on the anatomy and morphology of the heart and great vessels, as well as to screen for extracardiac pathology [14-16, 32].

ESC IIA, LoE 5, GoR C

Comments: this examination provides quantitative data on heart chamber dimensions and volumes, and ventricular function. ECG-gated cardiac MRI allows for precise evaluation of ventricular myocardial hypertrophy. This method enables a detailed assessment of the dimensions and anatomical features of all major arteries and veins. Phase-contrast MRI technology permits quantification of blood flow volume through the PDA (if clinically indicated).

• During the preoperative preparation period in the presence of complex combined congenital heart disease (e.g., aortic arch hypoplasia, suspected anomalous origin of brachiocephalic vessels), computed tomography (CT) of the chest with intravenous bolus contrast enhancement (preferably ECG-gated), multiplanar and three-dimensional reconstruction, is recommended to obtain additional information on the anatomy and morphology of heart chambers, major arteries and veins, assess the condition of the lungs and pulmonary vessels, and evaluate mediastinal structures, abdominal organs, and the retroperitoneal space [32-35].

ESC IIA, LoE 4, GoR C

Comments: this imaging study provides reliable information on the localization, length, and diameter of the ductus, as well as the anatomy of the brachiocephalic vessels, all segments of the thoracic aorta, and the condition of its walls (detection of calcifications). CT effectively detects extracardiac pathology of the chest, alterations in pulmonary blood flow, and abdominal organ anomalies. The creation of multiplanar and volumetric reconstructions based on CT data, along with their quantitative analysis, helps predict the volume and technical feasibility of various surgical correction methods when PDA is combined with other congenital heart defects (primarily coarctation of the aorta), thereby enabling the selection of optimal individualized surgical tactics. CT and MRI can also be used to evaluate the results of surgical treatment and detect complications.

• In all patients with suspected PDA, it is recommended to perform targeted chest X-ray to determine heart configuration and assess the pulmonary vascular pattern [14-16,32].

ESC IB, LoE 5, GoR C

Comments: a targeted chest X-ray in cases of a large, hemodynamically significant ductus typically reveals marked cardiomegaly due to the enlargement of first the left, and subsequently both ventricles and the left atrium, bulging of the pulmonary artery, widening of the ascending aorta, as well as plethora with or without interstitial or pulmonary edema. With a moderate arterial ductus, there is a moderate increase in heart size and widening of the ascending aorta. In the absence of hypertension (small ductus), X-ray findings may be normal. In the presence of high pulmonary vascular resistance due to sclerotic changes in the pulmonary vessels and a decreased shunt volume, heart sizes decrease. Adult patients with PDA may exhibit ductal calcification.

• In all patients with PDA, it is recommended to perform resting electrocardiography (ECG), including the analysis, description, and interpretation of electrocardiographic data (12-lead ECG) to determine left and right heart chamber overload, assess cardiac rhythm and conduction, and, if necessary, in the event of surgical treatment during the pre- and postoperative periods [14-16,32].

ESC IA, LoE 5, GoR C

Comments: in large, hemodynamically significant PDA, the electrocardiogram typically shows left ventricular enlargement with a deep Q wave and tall R wave in leads V4-V6. Signs of right ventricular hypertrophy with positive T waves in the right leads and signs of left atrial enlargement with broadened P waves are also frequently observed. With a moderate ductus, the ECG usually shows no significant deviations from normal in infancy, but in older children, signs of left ventricular hypertrophy almost always develop. With small ductus sizes, the ECG is normal or nearly normal.

In the sclerotic stage of PH, signs of right ventricular hypertrophy come to the fore.

2.5 Other Procedures

• Before initiating medical and/or surgical treatment in a preterm infant with a hsPDA, it is recommended to perform neurosonography [36,137-140].

ESC IIA, LoE 5, GoR C

Comments: If grade II-III IVH is detected, treatment may be initiated provided there is no progression of IVH within 24-48 hours (see clinical guideline: 'Hemodynamically significant patent ductus arteriosus in a preterm newborn')

• In a newborn with a hemodynamically significant patent ductus arteriosus, before and after medical or surgical intervention, it is recommended to perform continuous bedside monitoring of vital signs (heart rate and blood pressure) to assess cardiovascular disorders [37].

ESC IIA, LoE 4, GoR C

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Conservative Treatment

• In infants with a large patent ductus arteriosus and symptoms of heart failure, it is recommended: to limit energy expenditure, including reducing the work of breathing, to use inotropic therapy, and to maintain a balanced fluid intake (administering fluids below physiological requirements, with diuresis stimulation if necessary) in order to relieve clinical symptoms [32,38-40,94].

ESC IA, LoE 5, GoR C

Comments: in non-progressive heart failure, it is optimal to manage with medications from the pharmacotherapeutic group of cardiotonic agents excluding cardiac glycosides (C01C). However, if heart failure progresses, it is necessary to prescribe medications from the pharmacotherapeutic group of adrenergic and dopaminergic agents: dobutamine** or dopamine** is recommended (at initial doses from 2.5 mcg/kg/min with subsequent dose titration until the desired effect is achieved); if the aforementioned drugs are insufficiently effective, additional administration of #epinephrine** is required (at a dose of 0.01-0.1 mcg/kg/min with the possibility of subsequent dose titration under the control of blood pressure and blood gas composition until the desired effect is achieved) [38-40].

• In a preterm infant with a hemodynamically significant PDA, it is recommended to prescribe pharmacotherapy for ductal closure based on the decision of a medical board. The first-line drug is a non-steroidal anti-inflammatory and antirheumatic propionic acid derivative (ibuprofen**) [42].

ESC IB, LoE 2, GoR A

Comments: Medical treatment of hemodynamically significant patent ductus arteriosus (hsPDA) is based on the suppression of prostaglandin synthesis, which is one of the main factors keeping the ductus open. Nonsteroidal anti-inflammatory drugs—specifically cyclooxygenase inhibitors—are used for this purpose. Medical therapy reduces the risk of adverse clinical conditions, decreases the need for surgical treatment, and avoids the side effects and complications of surgery in this group of patients [43-44]. Indications for medical therapy include: the need for continuous invasive mechanical ventilation / high-frequency oscillatory ventilation, congestive heart failure, deterioration of renal function, and pulmonary hemorrhage (the decision on medical closure must be based on a combination of echocardiographic findings and the clinical picture) [20].

Currently, only one drug for PDA closure is registered in the Russian Federation: ibuprofen** (ATC code C01EB16) for intravenous administration. A course of ibuprofen** therapy consists of three intravenous administrations with 24-hour intervals between doses. The dose of ibuprofen** is calculated based on body weight: 1st administration: 10 mg/kg; 2nd and 3rd administrations: 5 mg/kg. The timing for medical closure of hsPDA is from the 2nd to the 6th day of life [43-45].

In recent years, it has been shown that oral administration of #ibuprofen** is more effective than intravenous administration, especially in newborns older than 48 hours of life who are able to tolerate enteral nutrition (more detailed information, including contraindications for medical therapy, is specified in the clinical guideline: 'Hemodynamically Significant Ductus Arteriosus in Preterm Newborns').

ESC IIaB, LOR 5, GOR C

Comments: Clinical data demonstrate a clear improvement in symptoms when using "loop" diuretics in patients with heart failure.

When prescribing diuretics, forced diuresis should be avoided and systemic blood pressure, electrolyte levels, blood creatinine, and urea should be carefully monitored, along with assessing hematocrit to avoid hemoconcentration in response to a decrease in intravascular blood volume, hypokalemia, and prerenal failure.

The initial dose of furosemide** (for parenteral administration) in children is from 1 mg/kg/day, but not more than 20 mg/kg. It is recommended to divide the daily dose into 2-3 administrations. Furosemide is not recommended for use in premature infants due to renal endogenous prostaglandin stimulation. Therefore, for premature patients, it is optimal to prescribe #spironolactone** (off-label) at a dosage of 2-3 mg/kg of body weight/day with monitoring of blood potassium levels and glomerular filtration rate [14-15,32,38-40].

• In patients with PDA who develop infective endocarditis, it is recommended to administer a course of systemic antibacterial drugs in age-appropriate dosages to sanitize the focus of infection [14-15,32,6].

ESC IB, LoE 5, GoR C

Comments: Bactericidal antibiotics (beta-lactam antibacterial drugs, penicillins; glycopeptide antibiotics) are preferred. To achieve high predictable concentrations, antibacterial drugs are administered intravenously. The average duration of antibiotic therapy is 4–6 weeks. The choice of antibacterial drugs and their doses should be based on the results of pathogen antibiotic susceptibility testing. PDA complicated by bacterial endocarditis and endarteritis or heart failure is currently successfully operated on after appropriate treatment (for the treatment of infective endocarditis, see the clinical guidelines "Infective Endocarditis").

• Medical therapy for PH is recommended only for patients with irreversible PH (with a persistent right-to-left shunt at the ductal level) (see clinical guidelines "Pulmonary Hypertension") to reduce pulmonary arterial pressure [16, 32].

ESC IIaB, LOR 5, GOR C

In children with PDA undergoing transcatheter closure, it is recommended to use heparin sodium** at a dose of 75–100 IU/kg IV bolus for thromboprophylaxis [133].

No ESC guideline (LoE 5, GoR C)

3.2 Surgical Treatment

The presence of a hemodynamically significant PDA, a history of bacterial endocarditis, or the presence of a ductal aneurysm are indications for surgical/endovascular treatment [2,46-47].

Surgical treatment is performed by specialists with experience in treating congenital heart disease. In cases where PDA is combined with other congenital heart defects requiring surgical correction, the ductus can be closed during the main procedure.

Surgical treatment of PDA is divided into surgical and endovascular treatment. Surgical correction methods are represented by the following techniques.

"Classic" posterolateral thoracotomy. Access is achieved via a curved skin incision centered approximately 1–2 cm below the scapular angle. In infants and young children, the incision is lateral because only the latissimus dorsi and the posterior part of the serratus anterior muscle are divided. In older children, the incision is posterolateral, extending posteriorly and superiorly with the division of a portion (1–2 cm) of the trapezius muscle. In patients in their second decade of life and older, the incision is made from the anterior axillary line around the scapula and then superiorly to the line located midway between the spine and the posterior border of the scapula, dividing 3–4 cm of the trapezius muscle. Entry into the thoracic cavity is through the 4th intercostal space. Next, the patent ductus arteriosus is routinely exposed and ligated, divided with closure of the pulmonary and aortic ends, or clipped (depending on the surgeon's preference or the patient's age). Suitable for patients of all age groups [2,48-51].

Transaxillary muscle-sparing lateral thoracotomy. Access is achieved via an incision (3–4 cm long) in the third intercostal space in the axilla. The serratus anterior muscle is retracted inferiorly and laterally, and the pectoralis major muscle is retracted anteriorly. Next, the patent ductus arteriosus is routinely exposed and ligated, divided with closure of the pulmonary and aortic ends, or clipped (depending on the surgeon's preference). This technique is applicable in all age categories [2,52-56].

Technique of PDA clipping (ligation) in premature newborns. Precise and adequate ventilation management, fluid administration control, and body temperature control are essential for success. The surgery is usually performed in the neonatal intensive care unit. This simplifies logistics and, with proper organization, can provide results as good as those in a standard operating room. There are various methods of surgical closure of PDA. The operation of choice in premature newborns weighing less than 1 kg with acute cerebrovascular accidents is PDA clipping using a muscle-sparing mini-approach (see transaxillary muscle-sparing lateral thoracotomy). Dissection of the ductus must be delicate yet allow visualization of its walls and the recurrent laryngeal nerve to prevent trauma to both the ductus and the nerve. Mobilization of the ductus is restricted to isolation of the upper and lower borders without circumferential dissection. Then, a Small or Medium clip is applied depending on the size of the ductus using a clip applier [2,57-62].

PDA closure in elderly patients. The aortic end is often calcified, and the ductus is very short. In this case, the technique using cardiopulmonary bypass (CPB) described by Goncalves-Estella and colleagues, and later by O’Donovan and Beck, is best [2,63-64]. Access is via median sternotomy. Then, cardiopulmonary bypass is established using the standard technique (via a single venous cannula), and cooling of the patient is initiated. The head of the operating table is lowered so that the patient is in a moderate Trendelenburg position. When the heart begins to slow down (due to cold perfusion), the ductus is obliterated by pressing the anterior wall of the left pulmonary artery against it with the index finger. This is important because otherwise, blood flow through the PDA into the pulmonary artery will lead to overdistension of the pulmonary vascular bed and the right ventricle (this occurs under CPB conditions during cooling and usually does not occur when the heart is contracting adequately). When the nasopharyngeal temperature reaches 20–22 °C, the aorta is cross-clamped, and cold cardioplegia is administered via the aortic root or retrogradely into the coronary sinus. The perfusion flow rate is reduced. The finger covering the ostium of the PDA from the pulmonary artery side is removed, and the distal pulmonary trunk is opened longitudinally, extending the incision onto the left pulmonary artery up to the level of the ductus. The ductal ostium is closed by placing and tying one or more 3-0 or 4-0 polypropylene horizontal mattress sutures. Hemostasis is usually easily achieved because the pulmonary artery end of the ductus is rarely calcified, and the pulmonary artery tissues are strong enough to hold the sutures securely. If the PDA ostium on the pulmonary artery side is too large, a xenopericardial, Dacron, or polytetrafluoroethylene patch can be used to close it. The operation is completed in the standard manner [2,63-64].

Thoracoscopic closure of patent ductus arteriosus. An alternative to percutaneous catheter closure of PDA is thoracoscopic closure. It is performed under general anesthesia using three to four 3 to 7 mm incisions in the left hemithorax with videoscopic assistance. The ductus is clipped. This method is used in term newborns, children of all ages, and adults. Recently, publications have described a series of successful thoracoscopic interventions in premature low-birth-weight infants [2,65-70,98,119].

• In a premature newborn with a hemodynamically significant PDA when conservative treatment is ineffective, surgical treatment is recommended to close the PDA (ligation/clipping of the patent ductus arteriosus) by decision of a medical council [48,85].

ESC IA, LoE 3, GoR B

Comments: Surgical correction of a hemodynamically significant patent ductus arteriosus in a severely premature infant is indicated in the simultaneous presence of three criteria [49-50,83-84].

• Hemodynamic significance of the hemodynamically significant patent ductus arteriosus, confirmed by echocardiography

• Mechanical ventilation dependency

• Ineffectiveness of two courses of pharmacotherapy for the hemodynamically significant patent ductus arteriosus or the presence of contraindications to pharmacotherapy.

Surgical treatment of the hemodynamically significant patent ductus arteriosus can be performed either by clipping/ligation or by percutaneous (transcatheter) closure.

An important organizational point is ensuring the possibility of performing the surgery within the neonatal intensive care unit or an operating room as close as possible to the intensive care unit, avoiding prolonged patient transport. For critically ill children, performing the surgery inside an open incubator is recommended to avoid patient transfer steps.

• Surgical closure of PDA (A16.10.041 ligation of patent ductus arteriosus) in term newborns, children of all ages, and adults is recommended to be performed in cases of left heart chamber volume overload and/or signs of pulmonary hypertension with a left-to-right shunt, or if there is a history of prior endocarditis [14-16,32,86-88,115-116].

ESC IIA, LoE 4, GoR C

Comments: The optimal patient age for surgery in childhood with an uncomplicated course is from 6 months to 5 years. However, in complicated cases, age is not a contraindication to surgery [14-16]. Currently, most surgeons use duct ligation with a suture or vessel clipping. Early mortality is practically absent. Recanalization of the duct is extremely rare. Complications may be associated with damage to the recurrent laryngeal or phrenic nerves and/or the thoracic duct [14-17].

Long-term results of PDA surgical treatment show that timely surgery achieves complete recovery. In patients with severe PH, the outcome depends on the reversibility of structural and functional changes in the pulmonary vasculature and myocardium.

• In full-term and preterm patients with persistent PDA, duct closure at an early age (under 3 months) is recommended only when a large left-to-right shunt leads to heart failure or other complications, in order to relieve symptoms [2,14-16,32,86-88,115].

ESC IIA, LoE 4, GoR C

Comments: in practice, this means that in full-term infants in the first three months of life, PDA closure is indicated only in the presence of clinical symptoms or heart failure.

• Currently, in patients with a large-diameter PDA or short duct, surgical closure (A16.10.041 Ligation of patent ductus arteriosus) is recommended [2,114-117].

ESC IIA, LoE 4, GoR C

Comment: this is due to the fact that transcatheter interventions for large-diameter ducts are associated with a higher number of non-fatal complications compared to "classical" surgical techniques.

• Surgical closure of PDA is not recommended for patients with PH and a right-to-left shunt [2,14-16,32,45,95-96,115-116].

ESC III, LoE 4, GoR C

• In adult and elderly patients with persistent PDA showing signs of calcification, closure using cardiopulmonary bypass (CPB) as described by Goncalves-Estella et al. and O’Donovan and Beck is recommended [63,64,95].

ESC IA, LoE 4, GoR C

Comments: advanced age is not a contraindication to isolated PDA closure in the absence of irreversible PH.

3.3 Interventional radiology treatment

Transcatheter treatment of patients with patent ductus arteriosus involves its closure either using an occluder (cardiac occluder***) or specialized occluding coils (non-CNS vascular embolization coil***), depending on the size of the duct.

Transcatheter (percutaneous) closure (A16.12.068.001 Endovascular coil embolization of patent ductus arteriosus and A16.12.068.002 Endovascular implant of occluder in patent ductus arteriosus). Transcatheter duct closure can be safely performed in children weighing more than 6 kg and adult patients with a left-to-right shunt. This procedure is performed by introducing an occlusion device via a peripheral access route: the femoral artery or vein. This strategy (via femoral vein access) is gaining increasing popularity for use in extremely low birth weight neonates as new devices are developed. Recently, evidence has emerged regarding the safety and effectiveness of the procedure in more mature neonates (in preterm infants weighing over 2000 grams in modern surgery, PDA closure is frequently performed using the transcatheter method), and studies are ongoing regarding the safe application of the procedure in extremely low birth weight neonates [2,71-81,117-118].

• Transcatheter PDA closure (A16.12.068.001 Endovascular coil embolization of patent ductus arteriosus using a non-CNS vascular embolization coil*** and A16.12.068.002 Endovascular implant of occluder in patent ductus arteriosus using a cardiac occluder***) is recommended for children weighing over 6 kg and adult patients with a left-to-right shunt, alongside thoracoscopic and other surgical techniques [2,71-81,117-118].

ESC IIA, LoE 4, GoR C

Comment: endovascular PDA closure is undesirable in early infancy in patients with low body weight (less than 6 kg) due to the high incidence of complications [15]. Complications arising from percutaneous PDA closure include: device embolization into a vessel (mainly pulmonary artery branches) or loss of pulse (significantly more frequent in younger children) [45,86-88,115].

• Transcatheter PDA closure in adult patients (A16.12.068.001 Endovascular coil embolization of patent ductus arteriosus using a non-CNS vascular embolization coil*** and A16.12.068.002 Endovascular implant of occluder in patent ductus arteriosus using a cardiac occluder***) is recommended in the presence of a left-to-right shunt across the duct and no signs of calcification or aneurysmal dilatation [2,63-64].

ESC IIA, LoE 4, GoR C

Comments: a persistent right-to-left shunt, confirmed by pharmacological testing, indicates irreversible pulmonary hypertension, which is an absolute contraindication to duct closure. The presence of calcification or aneurysmal dilatation carries a high risk of duct rupture, and therefore surgical techniques are preferred in such cases [2,63-64].

LeveL of Evidence (LoE) 4, Grade of Recommendation (GoR) C

Comments: in neonates and low-birth-weight patients, transvenous double-disc occluders can be used to mitigate the risk of access-related complications (femoral artery thrombosis) [81-82,86-88,117-118].

LeveL of Evidence (LoE) 4, Grade of Recommendation (GoR) C

Comments: transcatheter closure of the arterial duct in patients with reversible pulmonary hypertension should be performed in specialized centers and following pulmonary vasoreactivity testing. If the vasoreactivity test is positive and the diastolic aortic pressure exceeds the systolic pulmonary artery pressure, closure of the arterial duct with a double-disc occluder (cardiac occluder***) is feasible [81-82,86-88,117-118].

3.4 Other treatment

No.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

• Patients after surgical correction of PDA are recommended to avoid traction loads on the upper extremity on the side of the postoperative incision for 4-6 months following surgery [14,32,89].

ESC IA, LoE 5, GoR C

• Infants after surgical correction of PDA are recommended to avoid therapeutic gymnastics procedures for the subsequent 4 months [14,32,89].

ESC IC, LoE 5, GoR C

• Within 6 months after surgical correction of PDA, a patient with a complicated postoperative course (residual pulmonary hypertension, heart failure, infectious complications, repeated surgical interventions during a single hospitalization) is recommended to undergo rehabilitation in a specialized cardiological sanatorium-resort facility [100-102].

ESC IC, LoE 3, GoR C

5. Prevention and Dispensary Observation

• Patients who have undergone surgical correction of PDA are recommended to undergo an examination at least once during the first year after surgery (cardiologist/pediatric cardiologist consultation, echocardiography). Subsequently, if reoperation is not required, follow-up by a local cardiologist/pediatric cardiologist at least once every two years is acceptable [2,34,93].

ESC IC, LoE 5, GoR C

Comments: the most formidable yet rare long-term complication after surgery is the development of a false aneurysm, which typically occurs after duct ligation rather than transection and oversewing. The development of a false aneurysm is an indication for urgent reoperation. Delayed formation of aortic coarctation is also occasionally possible after prior duct closure. Routine examinations must include peripheral blood pressure measurement and echocardiography [2,32,34,90].

• Patients with a PDA of less than 3 mm without signs of left heart volume overload and without the development of other complications are recommended to be under dispensary observation by a cardiologist/pediatric cardiologist and undergo periodic follow-ups with an echocardiography (EchoCG) at least once every 1–2 years [32, 34, 91–92].

ESC IC, LoE 5, GoR C

6. Organization of Medical Care

Stages of medical care and indications for hospitalization:

1. clarification of the diagnosis;

2. if a hemodynamically significant PDA is confirmed, especially in premature newborns, conservative therapy aimed at ductal closure is prescribed (at the patient's location in the neonatal intensive care unit) or the patient is transferred to a cardiac surgery hospital for emergency surgical care immediately after medical stabilization of the clinical condition. If transportation is not feasible, surgical closure is performed at the hospital where the patient is located in the neonatal intensive care unit by a cardiovascular surgeon or thoracic surgeon;

3. asymptomatic forms of persistent PDA require dynamic follow-up by a cardiologist at the patient's place of residence. The optimal age for surgery in uncomplicated cases is from 6 months to 5 years. However, if complications occur, ductal closure is possible at an earlier age.

4. in the primary absence of clinical manifestations of persistent PDA and delayed development of the clinical picture (most frequently signs of heart failure), hospitalization of patients in a specialized cardiac surgery hospital is recommended to determine further management.

Indications for planned hospitalization:

1. presence of symptoms of circulatory insufficiency/heart failure (other complications);

2. pulmonary hypertension;

3. planned surgical treatment.

Indications for emergency hospitalization:

1. PDA aneurysm;

2. infective endocarditis (endarteritis).

Indications for patient discharge from the hospital:

1. absence of a shunt from the aorta to the pulmonary artery following surgical correction of the defect;

2. decrease in pressure in the pulmonary artery system;

3. absence of symptoms of circulatory insufficiency/heart failure (other complications).

7. Additional Information

Long-term functioning of a hemodynamically significant arterial duct frequently leads to the development of severe, life-threatening complications such as heart failure and circulatory insufficiency in the lower half of the body ("hemodynamic aortic coarctation"). In premature, low-birth-weight infants (born at a gestational age of less than 28 weeks), persistent PDA is frequently complicated by intraventricular hemorrhages, pulmonary hemorrhage, bronchopulmonary dysplasia, and retinopathies, which leads to a 3-fold or greater increase in mortality and disability rates [28–29, 31, 41, 62–63].

The severity of the condition in patients with persistent patent ductus arteriosus and the prognosis of the disease are additionally determined by the following factors:

• Cardiovascular anatomy features: isolated form of the duct or the duct as part (a component) of another congenital heart defect (an element of a vascular ring, etc.). In the presence of other congenital heart defects, it is necessary to exclude ductal dependence of both systemic and pulmonary circulation (pulmonary atresia, aortic arch interruption, aortic coarctation, critical pulmonary or aortic valve stenosis).

• Among extracardiac risk factors, low birth weight, prematurity and morphofunctional immaturity at birth, perinatal infection, concomitant extracardiac malformations, and dysmorphic stigmata should be highlighted [14–16, 32].

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Avramenko A.A. (Samara)

2. Arakelyan V.S., Prof. (Moscow)

3. Barbukhatti K.O., Prof. (Krasnodar), Russian Society of Cardiology

4. Bogdanov V.N. (Chelyabinsk)

5. Bokeria L.A., Academician of the RAS (Moscow), "Association of Cardiovascular Surgeons of Russia"

6. Boriskov M.V., MD (Krasnodar)

7. Gavrilov R.Yu. (Volgograd), "Association of Cardiovascular Surgeons of Russia"

8. Grigoryan A.M., PhD (Moscow), "Russian Scientific Society of Endovascular Diagnostics and Treatment Specialists"

9. Gorbatikov K.V., MD (Tyumen)

10. Gorbatykh Yu.N., MD (Novosibirsk)

11. Gushchin D.K., PhD (Moscow)

12. Irtyuga O.B., D.Sc. in Med. (Saint Petersburg), Russian Society of Cardiology

13. Kalashnikov S.V., Ph.D. in Med. (Moscow), Association of Cardiovascular Surgeons of Russia

14. Kim A.I., Prof. (Moscow), "Association of Cardiovascular Surgeons of Russia"

15. Kovalev I.A., MD, PhD (Moscow), "Association of Pediatric Cardiologists of Russia"

16. Kokshenev I.V., Prof. (Moscow), "Association of Cardiovascular Surgeons of Russia"

17. Kosmacheva E.D., Prof. (Krasnodar), Russian Society of Cardiology

18. Krivoshchekov E.V., MD, PhD (Tomsk), "Association of Cardiovascular Surgeons of Russia"

19. Kruchinova S.V., Ph.D. in Med. (Krasnodar), Russian Society of Cardiology

20. Kupryashov A.A., Prof. (Moscow)

21. Levchenko E.G., MD (Moscow)

22. Movsesyan R.R., Corresponding Member of the RAS (Saint Petersburg), "Association of Cardiovascular Surgeons of Russia"

23. Nalimov K.A., PhD (Khabarovsk)

24. Namitokov A.M., Ph.D. in Med. (Krasnodar), Russian Society of Cardiology

25. Petrushenko D.Yu., PhD (Kazan)

26. Plotnikov M.V., PhD (Astrakhan), "Association of Cardiovascular Surgeons of Russia"

27. Podzolkov V.P., Academician of the RAS (Moscow)

28. Rucheva N.A., PhD (Moscow), All-Russian Public Organization for the Promotion of the Development of Diagnostic Radiology and Therapy "Russian Society of Roentgenologists and Radiologists"

29. Sinitsyn V.E., MD, PhD, Professor (Moscow), All-Russian Public Organization for the Promotion of the Development of Diagnostic Radiology and Therapy "Russian Society of Roentgenologists and Radiologists"

30. Svobodov A.A., Prof. (Moscow)

31. Sinelnikov Yu.S., MD, PhD (Perm)

32. Tatarintseva Z.G., Ph.D. in Med. (Krasnodar), Russian Society of Cardiology

33. Teplov P.V. (Krasnoyarsk)

34. Trunina I.I., Prof. (Moscow), Association of Pediatric Cardiologists of Russia

35. Shatalov K.V., MD, PhD (Moscow)

36. Baryshnikova I.Yu., PhD in Medical Sciences (Moscow) All-Russian Public Organization for the Promotion of the Development of Radiation Diagnostics and Therapy "Russian Society of Roentgenologists and Radiologists"

No conflict of interest. All members of the Working Group confirmed the absence of financial support/conflict of interest that needs to be disclosed.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

• Functional Diagnostics Physician

• Pediatrician

• Cardiologist

• Pediatric Cardiologist

• Cardiovascular Surgeon

• Neonatologist

• Ultrasound Diagnostics Physician

• Radiologist.

Methods used for collecting/selecting evidence: electronic database search.

Description of methods used to assess the quality and strength of evidence: the evidence base for the guidelines includes publications indexed in the PubMed and Scopus databases. The literature search depth was 30 years.

Methods used to assess the quality and strength of evidence

• expert consensus;

• evaluation of the recommendation quality in accordance with the rating scheme (Table P1).

• evaluation of the evidence strength in accordance with the rating scheme (Table P2).

Table 1. Classes of recommendations according to the European Society of Cardiology (ESC) guidelines

Table 2. Levels of evidence certainty according to the European Society of Cardiology (ESC) guidelines

Table P1. Scale for assessing levels of evidence certainty (LEC) for methods of prevention, treatment, and medical rehabilitation, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitative interventions)

Table P2. Scale for assessing levels of evidence certainty (LEC) for diagnostic methods (diagnostic interventions)

Table A3. Scale for grading grades of recommendation (GoR) for preventive, diagnostic, therapeutic, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitation interventions)

Procedure for updating clinical guidelines.

The update mechanism for clinical guidelines provides for their systematic revision—at least once every three years, as well as upon the emergence of new evidence-based data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or the availability of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

A3.1 Regulatory documents

1. On the Fundamentals of Health Protection of Citizens in the Russian Federation (Federal Law No. 323-FZ of November 21, 2011);

2. Procedure for Providing Medical Care to Patients with Cardiovascular Diseases (Order of the Russian Ministry of Health No. 918n of November 15, 2012);

3. Order of the Russian Ministry of Health No. 103n dated February 28, 2019 "On approval of the procedure and timelines for the development of clinical guidelines, their revision, the standard template for clinical guidelines, and requirements for their structure, composition, and scientific validity of the information included in clinical guidelines" (Registered with the Ministry of Justice of the Russian Federation on May 8, 2019, No. 54588);

4. Order of the Ministry of Health of the Russian Federation No. 203n of May 10, 2017 "On Approval of Criteria for Assessing the Quality of Medical Care";

5. Order of the Ministry of Health of the Russian Federation No. 804n of October 13, 2017 "On Approval of the Nomenclature of Medical Services";

6. Order of the Ministry of Health of the Russian Federation No. 700n of October 7, 2015 "On the Nomenclature of Specialties of Specialists with Higher Medical and Pharmaceutical Education";

7. Order of the Russian Ministry of Health No. 4n of June 6, 2012 (as amended on July 7, 2020) "On Approval of the Nomenclature Classification of Medical Devices";

8. Order of the Ministry of Health of the Russian Federation No. 560n of June 9, 2020 "On Approval of the Rules for Performing X-ray Examinations";

9. Order of the Ministry of Health of the Russian Federation No. 557n of June 8, 2020 "On Approval of the Rules for Performing Ultrasound Examinations".

A3.2 Echocardiography methodology

Requirements: in neonates and infants: transducers with a frequency of 7.5–12 MHz; in adults: 2.5–7 MHz. Contraindications: integrity disruption of the skin in the area of examination. Limitations: cases of an inadequate acoustic window.

Performing Echocardiography

Echocardiography is a key diagnostic method for establishing the diagnosis of patent ductus arteriosus (PDA) and assessing the severity of hemodynamic changes in patients. The method allows obtaining information on the localization, size, severity of left ventricular volume overload, and the degree of pulmonary hypertension [103].

Overview echocardiography to exclude associated congenital heart disease, assess heart size and contractile function, and evaluate valve competence (mitral and aortic valves).

When assessing the hemodynamic significance of PDA in neonates, a comprehensive ultrasound approach is required (characterization of PDA, assessment of pulmonary and systemic perfusion). This is especially relevant for premature and low-birth-weight neonates.

Main objectives of echocardiography in suspected PDA:

• Determine the location and course of the PDA in B-mode and using color Doppler flow imaging.

• Measure the narrowest diameter of the PDA in B-mode and using color Doppler flow imaging.

• Determine the direction of blood shunting across the PDA using spectral and color Doppler modes.

• Measure the maximum systolic flow velocity across the PDA to assess pulmonary artery pressure (subtract the obtained pressure gradient from the systemic systolic blood pressure value).

• Assess the size of the left atrium, as well as the size and function of the left ventricle (to assess pulmonary hyperperfusion).

• Assess the blood flow profile in the abdominal aorta using spectral Doppler to record reverse diastolic flow (to assess systemic hypoperfusion).

• Exclude ductus-dependent lesions, such as coarctation of the aorta (measure the aortic arch, isthmus, and descending aorta).

The PDA is evaluated from the suprasternal or high left parasternal approaches in the long-axis and short-axis views of the aorta, respectively [104]. A left PDA with a left aortic arch is most common; therefore, to evaluate it, it is recommended to obtain an ultrasound slice along the left branch of the pulmonary artery. The PDA diameter is measured in B-mode along the inner contour of the ductus at its narrowest point. In case of a "poor acoustic window," measurements are performed using color Doppler flow imaging. The direction of the blood shunt through the PDA is also assessed in this mode. Care must be taken to distinguish the PDA from the aortic arch, especially during right-to-left shunting. The direction of blood shunting through the PDA can also be assessed in pulsed-wave or continuous-wave Doppler mode: left-to-right shunting is detected above the baseline (blood moving toward the transducer), and right-to-left shunting is below the baseline (blood moving away from the transducer).

Ideally, the entire PDA should be traced along its length, determining its connection with the aorta and pulmonary artery to diagnose rare forms: e.g., right-sided PDA, bilateral PDA (typically combined with other congenital heart diseases). Additionally, the combination of a left-sided PDA with a right aortic arch and an aberrant left subclavian artery may cause a vascular ring. Magnetic resonance imaging or computed tomography is the verification method for this pathology.

PDA aneurysm – saccular dilation of the ductus with a maximum internal diameter greater than the cross-section of the aortic arch or descending aorta.

A3.3 PDA classification based on auscultatory findings and minimum ductal diameter measured by echocardiography

Left atrial and left ventricular enlargement (increased pulmonary perfusion).

During left-to-right blood shunting through the PDA, left atrial (LA) enlargement occurs, followed by left ventricular (LV) dilation. The ratio of the left atrial diameter to the aortic root diameter is a marker of increased pulmonary venous return, given the relatively fixed structure of the aortic annulus, which does not dilate during left heart overload. In children, measurements are recommended to be performed from the parasternal long-axis view using M-mode with the cursor positioned perpendicular to the aorta at the level of the aortic valve. It is recommended to measure the ratio of the aortic root diameter at end-diastole to the LA diameter at end-systole. A ratio greater than 1.5 indicates LA enlargement [103–105].

Measurement of the LV end-diastolic dimension and quantitative assessment of LV contractile function are performed in M-mode from the parasternal long-axis or short-axis view at the level of the tips of the mitral valve leaflets, which serve as a reference point for placing the cursor perpendicular to the line of mitral valve leaflet closure. Measurements are made from the posterior surface of the interventricular septum to the anterior surface of the LV posterior wall [103–105]. Z-score charts (https://zscore.chboston.org/) will help quantify LV end-diastolic dimension [106]; qualitative (visual) assessment of the LV can be performed from the apical four-chamber view in comparison with the right heart chambers.

Ratio of pulmonary to systemic blood flow (Qp/Qs). To measure the ratio of pulmonary to systemic blood flow, it is necessary to measure the diameter of the aortic and pulmonary valve annuli and the velocity-time integral across the aortic and pulmonary valves using pulsed-wave Doppler mode. The semilunar valves must be free of stenosis and significant regurgitation. Furthermore, measuring the Qp/Qs ratio is not meaningful in the presence of high pulmonary vascular resistance (e.g., neonates) or severe pulmonary hypertension (PH); there are no clear recommendations for moderate PH (e.g., the clinical significance of Qp/Qs in patients with pneumonia, bronchopulmonary dysplasia, or chronic obstructive pulmonary disease is unclear), in the presence of an ASD greater than 5 mm, and in severe regurgitation of one or more heart valves [107].

In preterm infants, echocardiographic evaluation of a hemodynamically significant left-to-right shunt across a patent ductus arteriosus (PDA) may precede clinical signs. The table presents all echocardiographic parameters of a hemodynamically significant PDA (hsPDA) available in the literature, which are detailed in the corresponding clinical guideline «Hemodynamically Significant Arterial Ductus in a Preterm Neonate». A patent ductus arteriosus can be considered hemodynamically significant if all main criteria and at least one from each group of additional criteria are present. The main criteria refer to the characteristics of the ductus, while the additional criteria refer to indicators of systemic hypoperfusion and pulmonary hyperperfusion.

Important indicators in the analysis and interpretation of the obtained images:

• aortic arch type (right/left),

• presence/absence of obstructive lesions of the aortic arch,

• PDA localization,

• PDA type and grade,

• on color Doppler flow mapping: determination of the systolic pressure gradient.

Special attention should be paid to:

• signs of PH,

• presence of aortic coarctation,

• enlargement of the left heart chambers.

Challenges

During Doppler evaluation, due to decreased flow velocity and volume through the obstruction site, underestimated hemodynamic parameters may occur in the presence of a large PDA, coarctation, or aortic arch hypoplasia; depressed ventricular systolic function; or hemodynamically significant atrioventricular valve regurgitation. Overestimated gradient values may occur with increased systolic flow velocity and turbulence.

Echocardiography after surgical closure of PDA

Blood flow in the PA must be evaluated: residual shunt flows in the PA in the region of the PDA are ruled out. Left ventricular dimensions and function, left atrial dimensions, and heart valve function are determined, and pulmonary hypertension is ruled out.

Additionally, in patients after transcatheter PDA closure with a coil or occluder, patency of the left PA should be assessed with measurement of the systolic pressure gradient across it. When placing an occluder, it is also recommended to assess blood flow in the aortic isthmus.

Appendix B. Physician Action Algorithms

Pediatric population

Adults

Appendix C. Patient Information

Dear patient (patient's parents), the examination results revealed that you (your child) have a congenital heart disease: a persistent patent ductus arteriosus. By voluntarily consenting to the surgery, you must understand the purpose and potential complications of the procedure, which will be explained to you by your attending physician.

The ductus arteriosus (PDA) is a vessel connecting the descending aorta to the PA. The PDA is a physiological shunt that must necessarily exist in the fetus throughout pregnancy. The ductus is essential for intrauterine fetal life because the fetus does not breathe independently in utero but receives oxygen from the mother, and the ductus helps the fetus redirect oxygenated blood away from the lungs into the descending aorta. In term infants after birth, when the baby takes its first breath, blood begins to flow into the lungs, eliminating the need for the ductus arteriosus, and it should close on its own. Strictly speaking, a patent ductus arteriosus is not even a congenital heart defect. It is classified in this group due to the disorders it can lead to if closed untimely or left unclosed. If the ductus does not close, blood begins to flow through the PDA, but in the opposite direction: from the aorta into the pulmonary circulation (pulmonary vessels). In turn, this can lead to the development of severe, life-threatening complications: heart failure, lower body hypoperfusion (bottom half steal syndrome), intraventricular hemorrhages (intracranial hemorrhages), and irreversible changes in the pulmonary vasculature (pulmonary circulation). Failure of ductal closure and the occurrence of severe complications are particularly common in extremely preterm infants, which in turn can lead to patient disability or even death.

The main diagnostic method for patent ductus arteriosus is ultrasound examination of the heart (echocardiography).

Treatment of a patent ductus arteriosus depends on the gestational age at birth and the patient's condition. Based on this, the physician decides on the treatment method for this condition: medical or surgical closure of the ductus. There are several medications that help the ductus close. If, after two repeated courses, the ductus remains open and the infant requires mechanical ventilation, surgical closure must be resorted to. The operating surgeon will inform you about potential complications.

If the infant weighs less than one kilogram, is kept in a special closed incubator, and is unable to breathe independently (requiring mechanical ventilation), and a 3 to 4 millimeter ductus (or sometimes smaller) causes life-threatening hemodynamic disturbances, transporting such infants to a cardiosurgical hospital carries an extremely high risk of fatal complications. Therefore, cardiac surgeons frequently (when medical closure of the ductus fails) travel to maternity hospitals and units where such extremely low birth weight infants are being nursed and perform the ductus closure surgery on-site.

The surgery is performed under general anesthesia, and all associated surgical procedures are performed under general or local anesthesia. During the surgery, a mechanical ventilator will breathe for your child. Furthermore, during and after the surgery, transfusion of donor blood components may be necessary, which is vital and therefore requires your consent.

The surgeons make a small incision (or a series of smaller incisions for thoracoscopic techniques) on the side of the chest and close the ductus, after which the wound is closed in layers. The child is monitored by cardiac surgeons and intensive care specialists until discharge from the hospital. The risks of such surgery are quite high and are determined primarily by the degree of the infant's prematurity and the nature of the complications that developed prior to surgery. While staying in the room with your child as an attendant, you must strictly follow all orders and recommendations of your attending physician and medical staff. Caring for a preterm patient often requires a prolonged hospital stay, which also demands understanding and maximum responsibility from the parents.

Prior to discharge, the child must undergo a follow-up echocardiogram.

In most term patients, a moderate-sized persistent patent ductus arteriosus (not closed after 3 months of life) may be asymptomatic. Although the heart may enlarge, the child generally feels well. Pulmonary vascular pressure rises only slightly with a moderate ductus, and children grow and develop normally (except for a cardiac murmur), usually being indistinguishable from their peers. In such situations, the child can be monitored over the long term (periodic follow-up visits with a cardiologist) and undergo transcatheter ductal closure (without an incision) between the ages of 6 months and 5 years or even later.

If the ductus is large, however, manifestations of cardiac overload and clinical signs such as frequent colds, exertional dyspnea, and delayed growth and weight gain appear early (in the first 6 months of life). This situation (upon the appearance of clinical signs) requires surgical/transcatheter closure of the ductus to prevent irreversible pulmonary vascular damage. It should be understood that pharmacological ductal closure at an age older than one month of life is usually ineffective, leaving only surgical/transcatheter treatment as an option. In recent years, thanks to the advent of new instrumentation and accumulated experience, patent ductus arteriosus is increasingly closed using transcatheter methods. Currently, various devices (coils, occluders) can be used to close a ductus of virtually any diameter and shape.

Following the procedure (which carries minimal risk in a term infant), children generally feel well, and both they and their parents quickly put the situation behind them. Ligation of a patent ductus arteriosus is a radical operation (fully curative), and the individual usually feels healthy afterwards.

Despite successful surgical treatment, it is important to remember complications that may arise not only in the early period but also long-term after surgery, affecting not only the heart but also other organs of the child. In some cases, complications that develop may necessitate repeat interventions. Therefore, it is important not to miss postoperative follow-up examinations for a timely assessment of correction results and detection of potential complications, as well as to follow the physician's recommendations [97].

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

No.