Hemodynamically Significant Patent Ductus Arteriosus in Preterm Infants: Clinical Guidelines

List of Abbreviations

Ao — aorta

CW — continuous-wave Doppler

FiO₂ — fraction of inspired oxygen

IQ — (intelligence quotient) — mental development coefficient

La/Ao — left atrium to aortic root ratio

La — left atrium

PW — pulsed-wave Doppler

RI — resistance index

S` IVS — peak systolic myocardial velocity of the interventricular septum

TDI PW — spectral tissue Doppler

Vmax — peak systolic velocity

Vmin — end-diastolic velocity

Vpulv — diastolic wave velocity in pulmonary veins

VeddLPA — end-diastolic velocity in the left pulmonary artery

VmeanLPA — mean velocity in the left pulmonary artery

Z-score — Standard score — a statistical value showing how many standard deviations its spread is relative to the mean value

SVR — systemic vascular resistance

BPD — bronchopulmonary dysplasia

IVH — intraventricular hemorrhage

IVRT — isovolumic relaxation time of the left ventricle

SVC — superior vena cava

CHD — congenital heart defect

GA — gestational age

hsPDA — hemodynamically significant persistent ductus arteriosus

CP — cerebral palsy

E/A — ratio of early (E) to late (A) transmitral flow velocities

GI — gastrointestinal tract

EDD — end-diastolic dimension

LVEDD — left ventricular end-diastolic dimension

ESD — end-systolic dimension

PA — pulmonary artery

LV — left ventricle

LPA — left pulmonary artery

LA — left atrium

MAP — mean airway pressure

PMR — pulmonary circulation

NSAIDs — nonsteroidal anti-inflammatory and antirheumatic drugs (ATC code M01A)

NSG — neurosonography

NEC — necrotizing enterocolitis

PDA — patent ductus arteriosus

VLBW — very low birth weight (less than 1500 g)

ARF – acute renal failure

NICU — neonatal intensive care unit

PVL — periventricular leukomalacia

RDS — respiratory distress syndrome

CO — cardiac output

LVCO — left ventricular cardiac output

LVCO/SVC — ratio of LVCO to superior vena cava blood flow

CDI — color Doppler imaging

COX — cyclooxygenase

ASA scale — American Society of Anesthesiologists scale

ELBW — extremely low birth weight (less than 1000 g)

Terms and Definitions

The arterial duct is an anatomical channel connecting the left pulmonary artery and the descending aorta, allowing oxygenated blood from the placenta to bypass the fetus's airless lungs and enter the systemic circulation. The arterial duct is maintained patent throughout fetal life [1].

hsPDA (hemodynamically significant persistent ductus arteriosus) is a large-diameter functioning arterial duct with a left-to-right shunt direction from the aorta to the pulmonary artery, the functioning of which in extremely premature newborns is accompanied by significant disorders of central and regional hemodynamics detected by echocardiography [2].

Persistent arterial duct (patent ductus arteriosus) is an arterial duct whose patency persists after birth and is not accompanied by additional congenital anomalies of the cardiovascular system.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

hsPDA is a functioning arterial duct 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 intestine, kidneys, and brain. Persistence of hsPDA is associated with numerous adverse outcomes and complications, such as high mortality, prolonged mechanical ventilation dependence, bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), renal impairment, intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), and cerebral palsy (CP).

According to modern studies, a direct link has been established between the presence of hsPDA and the development of IVH in extremely immature, deeply premature newborns [3].

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

The functioning of the arterial duct is a major component of fetal circulation, establishing a connection between the pulmonary artery and the aorta under conditions when the baby's lungs are non-functional and the placenta serves as the gas exchange organ. 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 pulmonary artery into the aorta.

After birth and the first breath, a drop in pulmonary vascular pressure and an increase in systemic vascular resistance occur, resulting in a reversal of blood flow direction through the duct – from left to right (from the aorta to the pulmonary artery). At the same time, the arterial duct constricts under the action of oxygen, but its immediate closure does not occur. The time of spontaneous closure of the arterial duct 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 [4].

A number of mechanisms lead to the functional closure of the arterial duct, which continues over the next 24–72 hours, including int intima thickening and vessel constriction [5]. In full-term infants, the arterial duct typically narrows immediately after birth and becomes functionally closed by 72 hours of life, followed by anatomical remodeling [6]. Subsequently, due to the cessation of blood flow through the duct, the vessels supplying the muscular wall close, and ischemia leads to apoptosis of the vascular smooth muscle cells. The process of anatomical closure of the duct occurs during the first week of life, after which the transformation of the duct into the arterial ligament takes very few months. At the same time, in very low birth weight and especially in extremely low birth weight newborns, a disruption in the mechanisms of duct closure is frequently observed. Anatomical closure of the duct occurs within the first week of life.

Maternal risk factors for hemodynamically significant patent ductus arteriosus (hsPDA) include: absence of antenatal systemic corticosteroid prophylaxis (ATC code H02A), chorioamnionitis, and maternal preeclampsia. Postnatal factors include prematurity, birth asphyxia, low birth weight, late-onset neonatal sepsis, fluid overload during the first days of life, thrombocytopenia in the first 24 hours of life, need for mechanical ventilation, and pulmonary surfactant therapy (ATC code R07AA) [7–14].

A complex interplay of factors influencing the prolonged patency of the ductus arteriosus has been identified: increased sensitivity to the vasodilating effects of prostaglandin E2 (PGE2), a less developed muscular wall of the arterial duct, transient adrenal insufficiency, and platelet dysfunction [4].

1.3 Epidemiology of the Disease or Condition

Extremely immature premature neonates are at the highest risk for hsPDA: occurring in 93% of neonates with a gestational age (GA) of 23–24 weeks; 64% in neonates with a GA of 25–26 weeks; and 21% in neonates with a GA of 27–28 weeks [15]. The incidence is inversely proportional to gestational age and birth weight. Spontaneous closure of the PDA on the eighth day of life occurs in 94% of neonates with a birth weight > 1000 g, and in 34% of extremely low birth weight (ELBW) neonates [16,17].

Very preterm neonates with a gestational age of 23–26 weeks are at high risk for massive pulmonary hemorrhage and intraventricular hemorrhage (IVH) within the first 72 hours of life associated with hsPDA. In extremely immature premature neonates, the development of hsPDA increases mortality risk by 8-fold [18].

The ductus arteriosus remains patent at seven days of life in 87% of neonates with a GA of 24 weeks, 65% of neonates with a GA of 25–28 weeks, and 2% of neonates with a GA greater than 29 weeks [19]. In 30% of cases, reopening of the PDA is observed, which can become hemodynamically significant and require medical or surgical closure [20].

The lack of antenatal systemic corticosteroid prophylaxis (ATC code H02A), the development of respiratory distress syndrome, and the use of mechanical ventilation promote PDA patency and hinder its spontaneous closure [21].

Changes in respiratory therapy strategies, the use of non-invasive mechanical ventilation, the widespread use of antenatal systemic corticosteroids (ATC code H02A), as well as an expectant management approach allowing for spontaneous PDA closure in more mature preterm neonates, have led to a reduced need for medical and surgical treatment of hsPDA [20].

1.4 Features of Coding the Disease or Condition

P29.3 Persistent fetal circulation of newborn

Currently, under ICD-10, code P29.3 is used to designate conditions with varying pathophysiology, management, and outcomes—specifically, "delayed closure of ductus arteriosus in newborn" and "persistent pulmonary hypertension of the newborn".

1.5 Classification of the disease or condition

Depending on the degree of hemodynamic significance of the PDA, hsPDA is classified as mild, moderate, or severe in significance [22] (see "Diagnostic Criteria" - Table 1).

1.6 Clinical presentation of the disease or condition

Clinical signs of hsPDA depend on the volume of blood shunted through the arterial duct, which is primarily determined by systemic and pulmonary vascular resistance, the myocardium's ability to adapt to the increased shunt volume, and the size of the arterial duct [23,24].

Clinical manifestations of hsPDA in ELBW infants can be divided into two main aspects: reduced systemic blood flow due to systemic "steal" and increased blood engorgement of the pulmonary arterial system caused by left-to-right shunting of a large volume of blood from the aorta.

Clinical and laboratory signs of hsPDA [215]:

- Mild significance: requirement for supplemental oxygen (FiO₂) < 30%, requirement for non-invasive mechanical ventilation with a mean airway pressure < 8 cm H₂0;

- Moderate significance: requirement for supplemental oxygen (FiO₂) = 30–50%, requirement for non-invasive mechanical ventilation with a mean airway pressure > 8 cm H₂0; oliguria, requirement for 1 vasopressor/inotrope;

- Severe significance: requirement for supplemental oxygen (FiO₂) > 50%, requirement for invasive mechanical ventilation; significant or recurrent pulmonary hemorrhage, acute kidney injury (oliguria with rising creatinine), requirement for 2 vasopressors/inotropes.

Clinical signs of hsPDA have extremely low sensitivity and specificity, lagging behind echocardiographic signs by an average of two days [25].

There are risk assessment scales for the development of a hemodynamically significant ductus in preterm neonates, based on risk factors and clinical data [26]. (see Appendix G1).

The persistence of hsPDA in preterm neonates can lead to various hemodynamic disturbances manifested by clinical signs of pulmonary overcirculation or systemic hypoperfusion. A clinical manifestation of the hemodynamic significance of a PDA is the presence of diastolic and/or systolic hypotension. The risk of refractory hypotension is significantly increased in preterm neonates with hsPDA [27].

In the early stage of systemic hypotension associated with hsPDA, the left ventricular myocardium adapts to the increase in left atrial preload (due to increased pulmonary venous return) by increasing its stroke volume (SV). In hsPDA, systemic vascular resistance (SVR) decreases, reducing left ventricular preload. Clinically, this results in a wide pulse pressure (normal systolic BP due to increased left ventricular cardiac output and decreased diastolic BP). At later stages, the left ventricle fails to maintain stroke volume, leading to decreased contractility, further pulmonary congestion, systemic hypoperfusion, and severe target organ damage. Clinically, a decrease in both systolic and diastolic blood pressure is observed. The systemic "steal phenomenon" impairs the perfusion of target organs such as the kidneys and gastrointestinal tract [28]. Immature cerebral autoregulation in preterm neonates with hsPDA during cerebral hypoperfusion increases the risk of periventricular leukomalacia (PVL) [128]. Additionally, the risk of early intraventricular hemorrhage (IVH) (within the first 72 hours of life) increases proportionally with the persistence of hsPDA in extremely preterm neonates [29]. Late manifestations of hsPDA include the onset of congestive heart failure.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing a diagnosis based on echocardiography data

A patent ductus arteriosus is hemodynamically significant if the ductal diameter is greater than 1.5 mm, the shunt across the duct is left-to-right, and at least one sign of pulmonary overcirculation and one criterion of systemic hypoperfusion are present [23,192,193,196–198]

To assess the degree of hemodynamic significance of a PDA, it is necessary to determine:

-(A) ductal characteristics: diameter, direction of the shunt, flow velocity across the PDA, and the systolic-diastolic ratio (SDR);

-(B) assess signs of pulmonary hyperperfusion (at least one sign):

markers of pulmonary hyperperfusion — right pulmonary artery acceleration time (V_ETRPA), left pulmonary vein diastolic flow velocity (V_DFLPV), markers of left heart volume overload — LA/Ao, and pressure overload criteria — E/A;

-(C) assess signs of systemic hypoperfusion (at least one sign): evaluation of Doppler parameters in peripheral arteries (descending (or abdominal) aorta, celiac trunk, or superior mesenteric artery).

Determining these criteria (see Table 1) will help assess the degree of hsPDA as a pathological condition and guide treatment management.

Table 1. Echocardiographic criteria for diagnosing hsPDA [215].

2.1 Complaints and Anamnesis

See 1.6. "Clinical Presentation".

2.2 Physical Examination

See Section 1.6 "Clinical Presentation".

• To detect hemodynamically significant patent ductus arteriosus (hsPDA) and determine further management strategy, a physical examination of the preterm patient is recommended [26,30,31].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

• A preterm newborn with hsPDA is recommended to have urine output measured to identify contraindications to therapy and ensure safety during pharmacological and surgical treatment [32,33].

Level of Recommendations CLevel of Evidence 3Level of Recommendation C (Level of Evidence – 3)

Comments: renal blood flow is impaired by the functioning hsPDA and pharmacological therapy with #ibuprofen**. If urine output is less than 0.6 mL/kg/h over the past 8 hours, pharmacological closure should be delayed until urine output is restored.

2.3 Laboratory Diagnostics

• A preterm newborn with a gestational age of less than 32 weeks and hsPDA is recommended to undergo a complete blood count (CBC) with platelet count to determine contraindications to therapy, ensure safety during conservative treatment, and prior to surgical intervention [34,35].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: nonsteroidal anti-inflammatory and antirheumatic drugs (ATC code M01A) affect platelet aggregation and can cause thrombocytopenia.

• For a preterm newborn with GA less than 32 weeks with HSDA, in order to assess the risks of hemorrhagic complications when preparing for surgical intervention, it is recommended to perform a coagulogram (screening study of the hemostatic system): study of blood fibrinogen level, activated partial thromboplastin time, determination of prothrombin time in blood or plasma [36,214].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

Comments: if the coagulogram reveals clotting factor deficiencies accompanied by active hemorrhagic syndrome, surgical intervention may be initiated after antihemorrhagic therapy once bleeding has stopped.

• A preterm newborn with a gestational age of less than 32 weeks and hsPDA is recommended to undergo a general biochemical blood test (including blood sodium, blood creatinine, free and conjugated bilirubin, alanine aminotransferase [ALT], aspartate aminotransferase [AST], and gamma-glutamyl transferase [GGT] activity) to identify contraindications to therapy, ensure safety during pharmacological treatment, and follow-up after surgery [37,214].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

Comments: the presence of hsPDA contributes to hyponatremia and elevated creatinine levels, considering its effect on reducing renal blood flow and activating the renin-angiotensin-aldosterone system.

Monitoring of the general biochemical blood test is recommended prior to initiating pharmacological therapy for hsPDA and after the first course of medical treatment [32,38,39].

• A preterm newborn with hsPDA is recommended to have serial monitoring of acid-base balance and blood gases (blood pH, carbon dioxide partial pressure, buffer substances) to determine contraindications to conservative or surgical treatment, as well as following ductal closure (medical or surgical) [43].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: metabolic and lactic acidosis occurs in hsPDA due to tissue hypoperfusion resulting from systemic blood flow "steal".

2.4 Instrumental Diagnostics

• To diagnose the hemodynamic significance of a patent ductus arteriosus (PDA) and assess response to treatment, a preterm infant is recommended to undergo echocardiography—including transcranial color duplex scanning of cerebral arteries and veins, and duplex scanning of the abdominal aorta and its visceral branches [42,44–53].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

Comments: echocardiography is appropriate for assessing the dynamics of PDA hemodynamic significance; its use improves the efficacy of pharmacological therapy for hsPDA, reduces hemodynamic complications of surgical correction, and leads to lower mortality rates and a decreased incidence of pulmonary hemorrhage in preterm infants with hsPDA [54–57].

All preterm newborns should undergo serial echocardiography within the first 72 hours of life [216,232].

• To identify contraindications to surgical intervention for hsPDA and to monitor the postoperative period, a preterm infant with hsPDA is recommended to undergo chest X-ray [60].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: detection of tension pneumothorax on a chest X-ray is a contraindication to surgical intervention for hsPDA.

Following surgical treatment, considering the thoracic approach, it is advisable to perform a chest X-ray [61].

• To rule out intraventricular hemorrhage (IVH), a preterm newborn with hsPDA is recommended to undergo cranial ultrasound (neurosonography) [62–64].

GCR CLoE 3Grade of Recommendation C (Level of Evidence – 3)

Comments: if grade II–III IVH is detected, treatment may be initiated provided there is no progression of IVH over 24–48 hours.

• To rule out necrotizing enterocolitis (NEC), a preterm infant with hsPDA is recommended to undergo a comprehensive abdominal ultrasound [65–66].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: diagnosed or suspected NEC or other surgical abdominal pathology are contraindications to pharmacological therapy for hsPDA [67].

• A preterm infant with hsPDA is recommended to have an electrocardiogram (ECG) recorded prior to surgery to assess anesthetic risk, and postoperatively [68,69].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

2.5 Other Procedures

• A preterm newborn with hsPDA undergoing pharmacological or surgical intervention is recommended to undergo continuous bedside monitoring of vital signs and parameters (heart rate and blood pressure) during and after the procedure to evaluate cardiovascular status [68-71].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

• A preterm newborn with hsPDA is recommended to have a preoperative consultation with an anesthesiologist-resuscitologist on the eve of surgery, including an assessment of anesthesia risk according to the ASA classification [1].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: see Appendix G2.

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

3.1 Conservative Treatment

Therapeutic treatment strategies for hsPDA [106–113]:

1. Early targeted treatment (days 3 to 6 of life): indicated at > 72 hours of life in the presence of a persistently functioning hsPDA in extremely immature preterm infants < 26 weeks of gestational age with moderate to severe hsPDA [58,114].

2. Symptomatic treatment (expectant management with pharmacological therapy initiated after 7 days of life).

3. Considering the high rate of spontaneous PDA closure in preterm infants with a gestational age ≥ 28 weeks, a conservative "wait-and-watch" approach is acceptable, supported by serial echocardiographic monitoring of PDA significance criteria [128,225].

• For the pharmacological closure of hsPDA in a preterm newborn, it is recommended to prescribe nonsteroidal anti-inflammatory and antirheumatic drugs (ATC code M01A) — #ibuprofen** (ATC code M01AE01) at an initial dose of 10 mg/kg/day on day 1 of therapy, followed by 5 mg/kg/day for the subsequent 2 days (oral suspension or concentrate for solution for intravenous infusion), or other analgesics and antipyretics (ATC code N02B) — #paracetamol** (ATC code N02BE05) at a dose of 15 mg/kg/dose (infusion solution or oral suspension) every 6 hours for 3–7 days [42,80,85,86-89,229-231].

GCR ALoE 1Grade of Recommendation A (Level of Evidence – 1) – for #ibuprofen**

GCR BLoE 2Grade of Recommendation B (Level of Evidence – 2) – for #paracetamol**

Comments: absolute contraindications for pharmacological closure of the PDA include conditions with blood shunting from the pulmonary artery to the aorta where PDA patency is life-saving: congenital heart disease (pulmonary atresia, Tetralogy of Fallot, aortic coarctation, etc.), as well as persistent pulmonary hypertension;

Additional contraindications for #ibuprofen** therapy (ATX code M01AE01):

- Life-threatening infectious disease (sepsis) with untreated status;

- Active bleeding, coagulation disorders (treatment may be initiated after antihemorrhagic therapy provided the bleeding has stopped);

- Grade II–III IVH (treatment may be initiated after antihemorrhagic therapy provided there is no IVH progression);

- Diuresis less than 0.6 mL/kg/h over the past 8 hours;

- Creatinine ≥ 1.5 mg/dL (132 µmol/L);

- Platelet count less than 60*10⁹/L (treatment may be initiated following platelet concentrate transfusion);

- Suspected NEC and other surgical abdominal pathology;

- Severe hyperbilirubinemia requiring exchange transfusion.

• For a preterm infant with GA ≤ 26 weeks and confirmed hemodynamically significant PDA (hsPDA) of severe severity starting from day 3 of life according to echocardiography, regardless of clinical symptoms, or hsPDA of moderate severity combined with clinical manifestations, it is recommended to initiate pharmacotherapy for PDA closure based on a medical board decision [215]. #Ibuprofen** (ATX code M01AE01) is preferred as the first-line drug at an initial dose of 10 mg/kg/day on day 1 of therapy, followed by 5 mg/kg/day for the subsequent 2 days (oral suspension or concentrate for solution for intravenous infusion) [83,84,222].

GCR BLEL 2Grade of Recommendations B (Level of Evidence – 2)

Comments: in a cohort of extremely preterm newborns with a GA of less than 26 weeks, hsPDA was found to influence the development of massive pulmonary hemorrhage, IVH, mortality, and BPD [115,118]; they are less responsive to medical treatment [218].

Early treatment up to 7 days of life in extremely immature newborns with GA less than 26 weeks helps reduce the incidence of severe IVH (grade II and above) and early pulmonary hemorrhage, but does not reduce mortality, BPD development, or neurodevelopmental impairment [76,113,116–119].

• For a preterm infant with GA greater than 26 weeks and hsPDA, it is not recommended to prescribe pharmacotherapy in the first 7 days of life for hsPDA closure [215,220,221,222].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comments: due to the high rate of spontaneous PDA closure, an expectant management approach is appropriate [232].

Duration of treatment

• For a preterm newborn with hsPDA when the PDA diameter decreases to ≤ 1.5 mm (mild severity hsPDA) or upon echocardiographic closure of the PDA during pharmacotherapy, it is recommended to complete the course of drug therapy [108,131,132].

Level of Evidence AGrade of Evidence 2Level of Recommendations A (Grade of Evidence – 2)

Comments: shortening the course of pharmacotherapy based on echocardiography data does not increase the rate of treatment failure, PDA reopening, surgical intervention, or clinical outcomes such as pulmonary hemorrhage, bronchopulmonary dysplasia, necrotizing enterocolitis, or acute kidney injury [108,131,132].

• For a preterm newborn with GA less than 32 weeks, if signs of hsPDA persist on echocardiography 24 hours after the first course of pharmacotherapy, it is recommended to administer a second course of pharmacotherapy [133].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: when performing a re-course, switching the drug to an alternative group is possible (#ibuprofen** (ATX code M01AE01) to #paracetamol** (ATX code N02BE05) and vice versa) [45,88,94,134,135,222,228].

If a severe hsPDA persists 24 hours after completing the second course of pharmacotherapy, surgical intervention should be considered.

• For a preterm infant with GA less than 32 weeks undergoing pharmacological closure of hsPDA with non-steroidal anti-inflammatory and antirheumatic drugs (ATX code M01A) - #ibuprofen^** (ATX code M01AE01), it is not recommended to concurrently administer antibacterial drugs from other aminoglycosides (ATX code J01GB) to reduce the risk of acute kidney injury, or systemic corticosteroids (ATX code H02A) for BPD therapy and arterial hypotension, to reduce the risk of intestinal perforation [136].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

3.2 Surgical Treatment

• For a preterm newborn with hsPDA on invasive mechanical ventilation when two courses of medical treatment are ineffective, it is recommended to perform surgical treatment for PDA closure (patent ductus arteriosus ligation) by decision of a medical board [137,138,139-142,153].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comments: the surgical technique for hsPDA is performed in accordance with the clinical guidelines for "Patent Ductus Arteriosus" (Q25.0).

Contraindications to surgical closure of PDA in preterm infants [153]:

- Unstable central hemodynamics: uncorrected arterial hypotension, shock;

- Hemostatic disorders, DIC syndrome in the hypocoagulation stage;

- Decompensated metabolic acidosis;

- Severe infectious process accompanied by multiorgan failure;

- Tension pneumothorax.

3.3 Other Treatment

• For a preterm newborn with GA less than 32 weeks and hsPDA without signs of pulmonary edema, it is not recommended to administer sulfonamide loop diuretics (ATX code C03CA) (#furosemide^**) to avoid maintaining ductal patency [177].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comments: #Furosemide** (ATX code C03CA) increases prostaglandin production and may potentially reduce PDA sensitivity to COX inhibitors; it is advisable to limit its use in the first three weeks, when spontaneous PDA closure occurs more frequently.

• For a preterm newborn with hsPDA, it is recommended to optimize mechanical ventilation settings and maintain optimal blood oxygen saturation levels (91–95%) to achieve PDA closure [179,180,226].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: as part parameter optimization, it is advisable to increase PEEP during non-invasive or invasive mechanical ventilation and reduce inspiratory time [226].

Medical Nutrition Therapy

• For a preterm newborn with hsPDA receiving #ibuprofen** therapy (ATX code M01AE01), it is recommended to administer trophic enteral nutrition to prevent the development of NEC or spontaneous intestinal perforation during therapy with non-steroidal anti-inflammatory and antirheumatic drugs (ATX code M01A) [182].

Level of Recommendations CLevel of Evidence 3Level of Recommendation C (Level of Evidence – 3)

Comments: it has been proven that maintaining enteral nutrition within trophic volumes (up to 24 mL/kg/day) during medical treatment of hsPDA facilitates the rapid achievement of full enteral nutrition (150 mL/kg/day) without increasing the incidence of infectious complications, NEC, and spontaneous intestinal perforation.

Pain Management

• For a preterm newborn following surgical treatment of hsPDA, it is recommended to prescribe opioid analgesics (ATX code N01AH) - #fentanyl** (ATX code N01AH01) 0.005% solution for intravenous and intramuscular administration at a dose of 5 mcg/kg/hour intravenously as a continuous infusion, or natural opium alkaloids (ATX code N02AA) - #morphine** (ATX code N02AA01) 1% solution for injection at a dose of 10-15 mcg/kg/hour intravenously as a continuous infusion for pain management, followed by a 50% dose reduction starting on the second day. On the third and fourth postoperative days, analgesia is administered as needed based on the assessment of pain intensity in the child [153].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Not applicable.

5. Prevention and Dispensary Observation

Prevention

• For a preterm infant, it is not recommended to prescribe pharmacotherapy for the prevention of hsPDA development [183–186].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: according to modern studies, prophylactic PDA closure without the appearance of clinical and echocardiographic signs has not shown efficacy due to an increased incidence of side effects and a reduced chance of spontaneous PDA closure. Prophylactic administration in newborns with a GA of less than 27 weeks reduces the incidence of hsPDA, BPD, or BPD-related mortality, but does not reduce the incidence of severe IVH or improve neurodevelopmental outcomes.

• For a preterm newborn with GA less than 32 weeks, it is recommended to prevent fluid overload in the early neonatal period to reduce the risk of hsPDA development [176].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comments: fluid volume in the first week of life should not exceed 170 mL/kg/day; in the first three days, no higher than 130 mL/kg.

Dispensary follow-up (Active surveillance)

• A premature infant with PDA is recommended to undergo a dispensary follow-up examination (consultation) by a pediatric cardiologist, including echocardiography and electrocardiography [187,188]. The frequency of examinations and interventions is presented in Table 2 [190].

Table 2. Frequency of outpatient visits and interventions

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: the most frequent complication of a long-standing PDA is pulmonary arterial hypertension with the development of Eisenmenger syndrome in severe cases. When pulmonary vascular resistance exceeds systemic pressure, the shunt reverses to right-to-left, resulting in Eisenmenger syndrome with the development of right ventricular systolic heart failure [189].

Spontaneous closure of PDA after discharge (up to 18 months) is possible in approximately 47–58% of cases [190].

Following surgical intervention, echocardiography is performed immediately after surgery and at 1, 3, 6, and 12 months post-operatively [191].

6. Organization of Medical Care

Indications for hospital admission to a medical organization:

1) Pharmacological closure of hemodynamically significant patent ductus arteriosus (HSPDA) must be performed in an ICU setting (preferably at a Level III obstetric care facility);

2) Surgical treatment of HSPDA is performed in a specialized cardiac surgery hospital. If transportation is not feasible, surgical closure is performed "on-site" in the neonatal intensive care unit by a cardiovascular surgeon or pediatric surgeon.

Indications for discharging a patient from a medical organization:

1) Absence of a hemodynamically significant ductus arteriosus according to echocardiography;

2) Absence of other contraindications to discharge.

7. Additional Information

Prolonged patency of HSPDA is associated with the development of severe intraventricular hemorrhage, pulmonary hemorrhage, and bronchopulmonary dysplasia in extremely premature infants born at a gestational age of less than 28 weeks, and leads to a 3-fold increase in mortality.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Ekaterina N. Balashova – Candidate of Medical Sciences, Leading Researcher at the Prof. A.G. Antonov ICU, Institute of Neonatology and Pediatrics, Russian Ministry of Health; Associate Professor, Department of Neonatology, Institute of Professional Education, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov; Associate Professor, Department of Neonatology, N.F. Filatov Clinical Institute of Children's Health, I.M. Sechenov First Moscow State Medical University (Sechenov University); Member of the Council of the Russian Society of Neonatologists.

2. Irina Yu. Baryshnikova – Candidate of Medical Sciences, Ultrasound Diagnostics Physician, Department of Ultrasound Diagnostics in Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov, Russian Ministry of Health, and National Medical Research Center for Cardiovascular Surgery named after A.N. Bakulev, Russian Ministry of Health.

3. Artem A. Burov – Candidate of Medical Sciences, Head of the Neonatal ICU, Department of Neonatal and Pediatric Surgery, Institute of Neonatology and Pediatrics; Associate Professor, Department of Anesthesiology and Intensive Care, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov, Russian Ministry of Health; Member of the Council of the Russian Society of Neonatologists.

4. Degtyarev Dmitry Nikolaevich – Doctor of Medical Sciences, Professor, Deputy Director for Research, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Head of the Department of Neonatology, Pediatric Faculty, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University), member of the Council of the Russian Society of Neonatologists.

5. Oleg V. Ionov – Doctor of Medical Sciences, Professor, Head of the Prof. A.G. Antonov ICU, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov, Russian Ministry of Health; Professor, Department of Neonatology, N.F. Filatov Clinical Institute of Children's Health, I.M. Sechenov First Moscow State Medical University (Sechenov University); Chairman of the Russian Society of Neonatologists.

6. Anna R. Kirtbaya – Doctor of Medical Sciences, Head of Clinical Work, Prof. A.G. Antonov ICU, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov, Russian Ministry of Health; Professor, Department of Neonatology; Member of the Russian Society of Neonatologists.

7. Daria S. Kryuchko – Doctor of Medical Sciences, Head of the Department of Translational Medicine and Innovative Technologies, Federal Medical-Biological Agency (FMBA) of Russia; Professor, Department of Neonatology, N.F. Filatov Clinical Institute of Children's Health, I.M. Sechenov First Moscow State Medical University (Sechenov University); Member of the Council of the Russian Society of Neonatologists.

8. Anna A. Lenyushkina – Candidate of Medical Sciences, Head of ICU 2, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov, Russian Ministry of Health; Member of the Council of the Russian Society of Neonatologists.

9. Olga G. Malozemova – Ultrasound Diagnostics Physician, Department of Ultrasound Diagnostics in Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov, Russian Ministry of Health.

10. Zorikto B. Mitupov – Doctor of Medical Sciences, Highest Category Surgeon, Thoracic Surgery Department, N.F. Filatov Children's City Clinical Hospital of Moscow.

11. Ruben R. Movsesyan – Doctor of Medical Sciences, Head of the Cardiac Surgery Department, Children's City Multidisciplinary Clinical Center for High Medical Technologies; Chief Cardiac Surgeon of Saint Petersburg; Member of the Russian, European, and American Societies of Surgeons.

12. Aleksey V. Mostovoy – Doctor of Medical Sciences, Head of the Neonatal Anesthesiology and Intensive Care Service, City Clinical Hospital No. 67 named after L.A. Vorokhobov, Moscow Healthcare Department; Chief Freelance Neonatologist of the Russian Ministry of Health in the North Caucasian Federal District; Assistant Professor, Department of Outpatient Therapy, Clinical Laboratory Diagnostics and Medical Biochemistry, Yaroslavl State Medical University, Russian Ministry of Health, Yaroslavl; Member of the Council of the Russian Society of Neonatologists.

13. Mark E. Prutkin – Head of the Neonatal Anesthesiology and Intensive Care Unit No. 1, Yekaterinburg; Member of the Council of the Russian Society of Neonatologists.

14. Alexander Yu. Razumovsky – Doctor of Medical Sciences, Professor, Corresponding Member of the Russian Academy of Sciences; Chief Freelance Pediatric Surgeon; Head of the Department of Pediatric Thoracic Surgery, Children's City Clinical Hospital No. 13 named after N.F. Filatov, Moscow Healthcare Department; Head of the Department of Pediatric Surgery, Pirogov Russian National Research Medical University, Russian Ministry of Health.

15. Alesya A. Rudakova – Senior Researcher, Anesthesiologist-Intensivist, Prof. A.G. Antonov ICU, Ultrasound Diagnostics Physician, Department of Ultrasound Diagnostics in Neonatology and Pediatrics, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov, Russian Ministry of Health; Member of the Russian Society of Neonatologists.

16. Olga I. Sapun – Head of the Neonatal ICU No. 2, Children's Regional Clinical Hospital, Krasnodar; Chief Freelance Neonatologist of the Ministry of Health of Krasnodar Krai; Member of the Council of the Russian Society of Neonatologists.

17. Elena A. Filippova – Candidate of Medical Sciences, Head of the Department of Ultrasound Diagnostics in Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov, Russian Ministry of Health.

Conflict of interest: none.

Appendix A2. Methodology for Developing Clinical Guidelines

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

Description of methods used for evidence collection/selection: the evidence base for the recommendations included publications from the Cochrane Library, PubMed, EMBASE and MEDLINE, Scopus, Web of Science, eLIBRARY, clinicaltrials.gov, electronic libraries, and clinical guidelines published by The National Institute for Health and Care Excellence, The European Association of Perinatal Medicine, The European Society for Pediatric Research, The European Foundation for the Care of Newborn Infants, and The European Society for Neonatology. The search depth was 40 years.

Methods used for assessing the quality and strength of evidence:

• expert consensus;

• assessment of significance in accordance with the rating scheme.

Scales for assessing levels of evidence (LE) (Tables 1, 2) for diagnostic, preventive, therapeutic, and rehabilitation methods (diagnostic, preventive, therapeutic, rehabilitation interventions) with definitions, and the scale for assessing grades of recommendation (GR) (Table 3) for preventive, diagnostic, therapeutic, and rehabilitation methods (preventive, diagnostic, therapeutic, rehabilitation interventions).

Methods used for analyzing evidence:

• reviews of published meta-analyses;

• systematic reviews with evidence tables.

Description of methods used for analysis of evidence.

When selecting publications as potential sources of evidence, the methodology used in each study was reviewed to ensure its validity. Methodological evaluation was based on questions focused on study design features that significantly affect the validity of the results and conclusions.

To minimize potential subjective errors, each study was evaluated independently by at least two members of the working group. Any discrepancies in assessments were discussed by the full working group. If consensus could not be reached, an independent expert was involved.

Economic analysis:

Cost analysis was not performed, and pharmacoeconomic publications were not reviewed.

Method of guidelines validation:

• external expert review;

• internal expert review.

Description of the guidelines validation method:

The preliminary version of these guidelines was reviewed by independent experts who were asked to comment primarily on whether the interpretation of the evidence underlying the recommendations was accessible and understandable.

Comments were received from primary care physicians and district pediatricians regarding the clarity of the presentation of the guidelines and their assessment of the importance of the guidelines as a working tool in daily practice.

The draft version was also sent to a non-medically trained reviewer to obtain comments from a patient perspective.

Comments received from experts were carefully systematized and discussed by the chair and members of the working group. Each point was discussed, and resulting modifications to the guidelines were recorded. If no changes were made, the reasons for declining the changes were recorded.

Consultation and peer review:

Recent changes to these guidelines are presented as a draft for discussion. The updated version for broad discussion was posted on the website of the Russian Society of Neonatologists (RSN) www.neonatology.pro and the website of the Russian Association of Perinatal Medicine Specialists (RAPMS) www.raspm.ru to provide all interested parties with the opportunity to participate in the discussion and improvement of the guidelines.

The draft guidelines were reviewed by independent experts who were asked to comment primarily on the clarity and accuracy of the interpretation of the evidence base underlying the recommendations.

For the final revision and quality control, the recommendations were re-evaluated by the members of the working group, who concluded that all comments and feedback from the experts had been taken into account and the risk of bias in the development of the recommendations was minimized.

Target audience for these clinical guidelines:

1. neonatologists;

2. anesthesiologists-intensivists;

3. pediatricians;

4. obstetricians-gynecologists;

5. ultrasound diagnostics physicians;

Table 1. Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 2. Levels of Evidence (LoE) grading scale for prevention, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitation interventions)

Table 3. Scale for assessing the grades of recommendation (GR) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitation interventions)

Procedure for updating clinical guidelines

The mechanism for updating clinical guidelines provides for their systematic revision—at least once every three years or upon the emergence of new information on patient management tactics for a given disease, but no more frequently than once every 6 months. The decision to update is made by the Russian Ministry of Health based on proposals submitted by professional medical non-profit organizations. The proposals formed must take into account the results of a comprehensive evaluation of drugs and medical devices, as well as the results of clinical approbation.

Appendix A3. Reference Materials

These clinical guidelines have been developed taking into account the following regulatory and legal documents:

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

2. Ministry of Health of the Russian Federation, Order No. 203n dated April 14, 2025 "On Approval of Criteria for Assessing the Quality of Medical Care".

3. International Classification of Diseases, Injuries and Causes of Death, 10th Revision (ICD-10) (World Health Organization), 2019 version.

4. Order of the Russian Ministry of Health No. 804n dated October 13, 2017 (as amended on September 24, 2020, with amendments dated October 26, 2022) "On Approval of the Nomenclature of Medical Services" (Registered with the Ministry of Justice of Russia on November 7, 2017, No. 48808).

5. Order of the Russian Ministry of Health dated April 17, 2025 No. 222n "On approval of the Procedure for the provision of medical care in the profile "neonatology". (Registered with the Ministry of Justice of Russia on June 2, 2025, No. 82516)

6. Decree of the Government of the Russian Federation No. 3867-r dated December 18, 2025 <On Approval of the List of Vital and Essential Medicines, as well as Lists of Medicinal Products for Medical Use and the Minimum Assortment of Medicinal Products Required for the Provision of Medical Care>.

7. State Register of Medicinal Products: https://grls.rosminzdrav.ru

8. Clinical guidelines "Patent Ductus Arteriosus" (adults, children), 2024.

Appendix A3.1 ULTRASOUND DIAGNOSTICS OF hsPDA

Screening echocardiography is performed prior to the study primarily to rule out congenital heart disease (CHD), as well as to assess myocardial contractility, the patent foramen ovale (PFO), and aspects of transitional hemodynamics, such as high pulmonary hypertension. It is necessary to purposefully visualize the left and right ventricular outflow tracts (LV and RV), the aortic valve, the pulmonary artery (PA) valve, and ensure there are no prerequisites for obstruction; anatomy and function of the mitral valve (MV) are assessed from various acoustic windows to rule out stenosis and significant valve insufficiency (regurgitation). It should be borne in mind that screening aimed at ruling out CHD is performed exclusively by a sonographer experienced in diagnosing cardiovascular pathologies [44,192–195].

Measurement of the LV end-diastolic dimension (LVEDD) and quantitative assessment of LV contractility (LV ejection fraction, LVEF) are advisable to determine from the left parasternal short-axis view at the level of the MV leaflets in M-mode, which will serve as a reference point for placing the cursor perpendicular to the mitral valve leaflet coaptation line. Measurements are taken from the posterior surface of the interventricular septum to the anterior surface of the LV posterior wall [196]. Z-score charts [111] (https://zscore.chboston.org/) will help quantitatively assess LVEDD; qualitative (visual) assessment of the LV can be performed from the standard apical four-chamber view in comparison with the right heart chambers. Immediately after birth, the right heart chambers predominate; in healthy newborns, approximately on the third to fifth day of life, the ratio of the right and left chambers changes to 1:1—the heart chambers become equal, and closer to the fifth day of life, the dimensions of the left heart begin to predominate over the right chambers (RV ~ 2/3 LV). In the presence of an hemodynamically significant patent ductus arteriosus (hsPDA), the described changes will occur much faster due to a combination of falling pressure in the pulmonary circulation and increased preload on the left chambers, which is a consequence of the functioning arterial duct and decreased pulmonary vascular resistance (PVR), leading to a persistent left-to-right shunt. Therefore, it is important to assess changes in LVEDD dynamically. Reference values for LVEF range from 55–80%. In case of unsatisfactory visualization (absence of an acoustic window) from the apical and parasternal views, LV contractility is also assessed qualitatively ("eyeballing") in several projections from the subcostal view [44].

The study results can be significantly affected by concomitant intracardiac shunts both at the atrial level (PFO, ASD—will unload the left chambers, allowing parameters such as LA/Ao, E/A, and LVEDD _{to remain} within normal limits in the presence of an hsPDA) and at the ventricular level—VSD, which conversely will enhance the hemodynamic effects of the PDA; therefore, it is important to remember the limitations of each criterion in each specific clinical situation [23,192,193,196–198].

(A) Ductal characteristics:

Visualization of the ductus arteriosus is best achieved from the suprasternal or high left parasternal short-axis views [198]. The series of ultrasound slices obtained from these views allows visualization of the duct simultaneously with the descending aorta (DAo), the main pulmonary artery, and PA branches; obtaining an ultrasound slice along the left branch of the pulmonary artery (LBPA) is considered optimal. In these projections, the duct diameter is measured, the direction of the shunt through the duct is determined, and blood flow in the LBPA and DAo is assessed [23,192,196].

The PDA diameter is measured in B-mode along the inner contour of the duct at the site of maximum narrowing (at the narrowest point), since the smallest diameter—which is usually located on the PA side at the ostium of the LBPA (Fig. 1)—will have clinical significance. For a more precise targeted diameter measurement, use the Zoom function. If a satisfactory acoustic window allowing clear visualization of the duct contours in B-mode is absent, the PDA diameter should be measured using color Doppler flow imaging (CDFI), though this may potentially lead to an overestimation of the true dimensions of the duct if image settings are incorrect [131,192,198–200]. The obtained measurement is indexed to the LBPA diameter (PDA/LBPA), measured in a similar manner, or to the newborn's weight in kg (PDA/weight) with a threshold value of ≥ 1.4 mm/kg. Indexed parameters will have the same limitations as absolute measurements of duct diameter [192,193,196]. Indexing the duct relative to weight will not maintain its ratio as the child's body weight increases, since the growth of heart structures, including the duct, is not proportional to weight gain [196]. Given this fact, using the PDA/LBPA index may seem more rational. Recently, Fernando de Freitas Martins et al. demonstrated in their study a weak correlation between indexed duct parameters and other individual ultrasound criteria for assessing hsPDA, which once again emphasizes the need for a comprehensive echocardiographic evaluation in addition to duct diameter measurements [193].

The direction of the shunt and blood flow velocity across the PDA depend on the pressure gradient between the systemic (SAP) and pulmonary (mPAP) circulation, as well as the vascular resistance of the duct itself (its diameter) [198, 23] (Diagram 1). With a short and wide duct, almost equal to the DAo diameter, resistance to its blood flow is small; therefore, the magnitude and direction of the shunt will depend on the ratio of vascular resistances of both circulatory circuits.

In hsPDA, a left-to-right blood shunt is noted, i.e., from the aorta (with high systemic pressure) into the pulmonary artery (with low pressure); bidirectional or right-to-left shunting (from the PA to the DAo) across the duct will indicate another pathological condition—severe pulmonary hypertension. In CDFI mode, under standard machine settings, a left-to-right shunt will be color-coded in red (flow directed toward the transducer), and right-to-left in blue (flow directed away from the transducer). Quantitative assessment of these parameters, given the high heart rate in newborns, is performed using continuous-wave Doppler (CW) or pulsed-wave Doppler (PW) with the sample volume placed just beyond the narrowest point of the duct [192,198]. To precisely position the cursor as parallel to the shunt flow as possible (along the flow), CDFI mode must be used. Left-to-right shunting (from Ao to PA) across the duct is recorded above the baseline—flow is directed toward the transducer; right-to-left shunting (from PA to DAo) is recorded below the baseline—the shunt flow direction is away from the transducer [198].

The systolo-diastolic ratio (SDR) is defined as the ratio of the peak (maximum) systolic blood flow velocity across the duct—Vmax, to the end-diastolic velocity—Vmin. An SDR greater than 2 (Vmax/Vmin > 2) is a criterion for a pulsatile (unrestricted) flow type, which has a low peak systolic velocity with a high gradient between systolic and end-diastolic velocities, and in the first 7 days of life is associated with hsPDA (sensitivity 93%, specificity 100%) [23,192,198,199,201]. Duct flow with an SDR < 2 is regarded as a restrictive (restricted) shunt, which on the 1st day of life will indicate closure of the ductus arteriosus; at an older age (> 2 days of life), persistent large-diameter shunts may have a high peak systolic velocity and can be mistakenly regarded as restricted [3].

(B) Assessment of pulmonary hyperperfusion:

A significant left-to-right shunt across the duct will lead to increased pulmonary blood flow and, consequently, increased preload on the left heart chambers—an increase in blood inflow to the LA and LV during diastole.

Increased pulmonary blood flow is assessed as an increase in the end-diastolic and mean blood flow velocities in the LBPA (V_EDLBPA and V_meanLBPA) and the diastolic wave velocity in the pulmonary veins (V_DWPV) [4] (Fig. 2).

In the absence of a PDA, the flow through the LBPA is monophasic, systolic only or with a minimal diastolic component, practically along the baseline. A significant left-to-right shunt through the duct will enhance blood flow in the PA, as evidenced by an increase in the mean (V_meanLBPA ≥ 0.42 m/s) and end-diastolic velocity (V_EDLBPA > 0.2 m/s). Despite the fact that numerical threshold values for these parameters have been defined, in practice it is sufficient to record the absence or presence of a diastolic flow component, given the fact that normally the blood flow in the LBPA is systolic only [3,5,6]. Ostial stenoses of the PA branches will be a limitation for using these criteria in assessing hsPDA.

Increased pulmonary blood flow is also reflected in an increased outflow in the pulmonary veins due to an increased diastolic wave velocity (V_DVPV > 0.3 m/s) (Fig. 3). The blood flow spectrum in the PVs should be evaluated in the lower pulmonary veins (to minimize the insonation angle) from a high parasternal long-axis view with a slight clockwise rotation into the "crab view" position using pulsed-wave (PW) Doppler, which consists of two positive waves: the systolic wave (S)—in preterm neonates, the systolic wave frequently has two peaks, S₁ and S₂, the diastolic wave (D), and one negative wave—the atrial wave (A), reflecting atrial contraction with blood regurgitation back into the PV [23,192]. This ultrasound criterion can also be reproduced from the apical four-chamber view by placing the sample volume at the PV ostium or slightly deeper; it is easiest to visualize the right upper pulmonary vein [196].

The ratio of the left atrium anteroposterior diameter to the aortic root diameter (LA/Ao) will reflect the degree of volume overload of the left heart chambers (Fig. 4).

Increased pulmonary venous return will lead to increased preload on the left heart chambers and, ultimately, to dilation of the LA and LV. The degree of left chamber dilation is indexed to the aortic root diameter, which is considered a relatively constant dimension for a given hemodynamics. LV dilation will occur secondary to the increase in LA dimensions [23,192,198].

Given the high intra- and inter-observer variability, this criterion is a rather imprecise marker of left heart volume overload [23,192,202]. It is advisable to follow the following algorithm [196]:

1. From the left parasternal short-axis view of the Ao in M-mode with the cursor positioned perpendicularly to the Ao;

2. The Ao root diameter is measured at end-diastole, when the valve cusps are closed, from the inner edge of the anterior wall to the outer edge of the posterior wall;

3. The LA anteroposterior dimension is measured at end-systole (maximum dimension) from the inner edge of the anterior wall to the posterior wall.

It is important to understand that the LA/Ao and LVEDD/Ao indices are potentially subject to the influence of a shunt at the atrial level. A significant left-to-right blood shunt through a patent foramen ovale (> 2 mm) will unload the left heart chambers, and these parameters will not manifest as markers of hemodynamically significant patent ductus arteriosus (hsPDA), i.e., in the presence of a significant shunt through the ductus, the values of the LA/Ao and LVEDD/Ao ratios will remain within the "normal" range [23,192,193,196–198].

An increase in pulmonary venous return will also entail an increase in left ventricular cardiac output (Fig. 5). Given that LVCO in neonates is determined with considerable inaccuracy, the CO value is adjusted (indexed) by body weight in kg—left ventricular output index (LVO) > 300 ml/kg/min [203].

This criterion, like the two previous ones (LA/Ao and LVEDD/Ao), will not manifest in the presence of a large atrial-level shunt or impaired LV contractility (LVEF < 55 %).

Evaluation of LVCO is performed according to the following formula:

The LVOT diameter is measured from the left parasternal long-axis view of the LV at the end of systole when the aortic valve leaflets are open. The diameter is measured at the hinge (attachment) points of the aortic valve leaflets; targeted magnification (Zoom function) is used for measurement accuracy [204]. Various methods for determining this measurement are described in the literature; the authors recommend adhering to the algorithm described above. The velocity-time integral (VTI) across the LV outflow tract is determined from the apical five-chamber view using pulsed-wave (PW) Doppler mode with the sample volume placed directly at the site of Ao diameter measurement. Minimizing the insonation angle—the angle between the ultrasound cursor and the Ao axis—should be pursued to avoid underestimating the VTI value [203,205,206]. Heart rate is calculated directly from the obtained LVOT blood flow Doppler spectrogram using the machine's "HR" option by measuring the distance from the beginning of the aortic flow spectrum to the beginning of the next one. Cardiac index (CI) can also be calculated using an online cardiac calculator; when selecting one, attention must be paid to the units of measurement and the rounding function of the final result—typically, calculations in ready-made calculators are performed in cm, and consequently, the final answer will be presented in cubic cm, i.e., in liters, whereas working with newborns requires the use of different units—mm and ml; thus, rounding to tenths in this context is very crude and may lead to significant errors. The variability of LVCO measurement results using echocardiography, according to various sources, is quite high for a single examiner—up to 22%, and among different examiners—even higher, respectively, while the variability between non-invasive and invasive methods can reach 36%. Such low reproducibility of the criterion is associated with several factors: the difficulty of accurately measuring the LVOT diameter to calculate the square of its radius—a 0.9 mm decrease in Ao diameter decreases CI by 100 mL/kg/min; the assumption of an ideal circular shape of the LVOT; inaccuracy in VTI measurement; the assumption of laminar blood flow; and errors related to the insonation angle [205]. Therefore, calculating CI requires not only good visualization but also manual skills of the physician, which will minimize errors associated with its reproducibility. When methodically performed, this criterion shows a high correlation with magnetic resonance imaging (MRI) results, which is the "gold standard," albeit only in isolated studies [206]. The shunt volume also helps assess the ratio of LVCO to superior vena cava (SVC) blood flow — LVCO/SVCf (LVO/SVCf). Blood flow through the SVC serves as a marker of cerebral blood flow and will decrease in the presence of a significant shunt across the ductus, whereas LVCO will, conversely, only increase; therefore, an LVO/SVCf ratio ≥ 4 will indirectly indicate the presence of an hsPDA. This statement is controversial and is not always confirmed in such newborns. SVC blood flow represents venous return from the upper body, which occurs primarily via preductal arteries, where blood flow can remain preserved for a sufficiently long time due to a compensatory increase in LV stroke volume [207].

Calculation of SVC flow is performed similarly to the LVCO index formula:

To measure the SVC diameter, a modified high left parasternal view is used with the ultrasound transducer tilted in the sagittal plane, using M-mode with the cursor positioned as perpendicular as possible to the course of the vessel (to avoid overestimating the diameter) at the junction with the right atrium (RA). Due to the significant change in SVC diameter throughout the cardiac cycle, 3 to 5 consecutive cardiac cycles are analyzed during the assessment by measuring two dimensions—the maximum and minimum diameters to obtain the mean SVC diameter. Since the cross-section of the SVC is not perfectly round, it also changes shape during respiration (changes in intrathoracic pressure) and due to pulsations of the nearby aorta during the cardiac cycle. Errors in measuring the SVC diameter will be squared when calculating the vessel cross-sectional area. Evaluation of the VTI of blood flow in the SVC is performed from a subcostal approach, similar to the visualization of a patent foramen ovale, using pulsed-wave Doppler with the sample volume placed at the SVC ostium, trying to minimize the insonation angle as much as possible. The blood flow spectrum in the SVC consists of three components—two positive waves: systolic, diastolic, and one negative wave—the atrial A-wave, reflecting atrial contraction with blood regurgitation back into the SVC. It is recommended to average the VTI curves over 8–10 cardiac cycles to minimize respiratory-related fluctuations. Negative blood flow velocities (the A-wave and sometimes the late systolic negative wave) should be subtracted from the obtained value for a more reliable assessment of blood flow across the SVC [206]. Heart rate is calculated in the same manner described previously. When interpreting the results, it is important to recognize the inherent limitations of this method.

The peak systolic velocity of the interventricular septum myocardium (S` IVS) can be reliably used by neonatologists for pre-symptomatic detection of hsPDA with a threshold value > 10 cm/s (100% sensitivity and 94% specificity). High heart rates in newborns are not a limitation for obtaining S` [4]. Markers of left heart pressure overload are the ratio of early (E) to late (A) trans-mitral flow velocities (E/A) and isovolumic relaxation time (IVRT) [23,131,192,199,208] (Fig. 6).

Trans-mitral blood flow velocities are evaluated from the apical four-chamber view using pulsed-wave (PW) Doppler, with the sample volume placed at the level of the mitral valve (MV) leaflets just beyond the fibrous ring plane in the LV. Due to the relatively low compliance of the immature myocardium in preterm neonates, passive LV filling is impaired, which is reflected in a moderately reduced diastolic function and a low early diastolic filling velocity (E/A < 1). Since term newborns usually have an E/A ratio > 1, such velocity measurements in the presence of a significant PDA shunt are termed E/A pseudonormalization. It should be kept in mind that in preterm infants without PDA, this ratio gradually becomes greater than 1 as myocardial compliance improves [131,192,196,198].

Isovolumic relaxation time (IVRT) is the time interval between aortic valve closure and mitral valve (MV) opening. An increase in LA pressure will lead to earlier opening of the MV leaflets; therefore, a decrease in IVRT (< 40 ms) will indirectly indicate the presence of a hemodynamically significant ductal shunt. IVRT is measured from the apical five-chamber view using pulsed-wave Doppler. The sample volume is placed in the mitro-aortic continuity area between the aortic and mitral valves, which allows recording both aortic valve closure and MV opening on the Doppler spectrogram.

(C) Assessment of systemic hypoperfusion (Fig. 7):

In the presence of hemodynamically significant patent ductus arteriosus (hsPDA), blood is shunted from the systemic circulation throughout the entire cardiac cycle—both in systole and diastole, with the most evident changes occurring during the diastolic phase, which can be visualized using pulsed-wave Doppler (PW). Retrograde diastolic blood flow or its absence in the anterior cerebral artery (ACA) or middle cerebral artery (MCA), descending or abdominal aorta, celiac trunk or superior mesenteric artery, as well as in the renal arteries, serve as markers of a significant shunt via the PDA, leading to systemic steal phenomenon—systemic hypoperfusion [23,131,196,198,199,201]. A limitation for these criteria can be severe aortic valve incompetence (regurgitation) [198]. Doppler visualization of blood flow in the descending aorta can be obtained from the suprasternal or high parasternal long-axis view of the aorta — the transducer is rotated clockwise by approximately 30° from the sagittal plane and tilted slightly to the left (transducer marker pointing towards the head); blood flow in the celiac trunk and superior mesenteric artery can be obtained with a slight leftward tilt of the transducer from the sagittal subcostal position (transducer marker pointing towards the newborn's head). Doppler assessment of blood flow in the ACA or MCA is performed via neurosonography through the anterior fontanelle in the sagittal scanning plane or through the anterolateral fontanelle in the 1st axial section, respectively. In case of increased gas production and unsatisfactory visualization from the subcostal approach, blood flow in the renal arteries is assessed from the right or left lateral positions — the transducer is placed along the lateral line a few centimeters above the umbilicus, with the transducer marker pointing upward (toward the head). Blood flow in preductal arteries (ACA and MCA) can be compensated for a long time by an increase in stroke volume and remain preserved, therefore manifesting as a marker of hsPDA much later than others, and, given the fact that the brain has its own mechanisms of circulatory regulation, as well as the presence of significant intraventricular hemorrhages in the newborn, makes the assessment of this parameter rather ambiguous [23,192,196,198,209].

To implement early targeted treatment and select a cohort of the most vulnerable newborns with evaluation of PDA significance signs, early, accurate, and easily reproducible ultrasound criteria are required. The simultaneous presence of these three qualities is a difficult task; easily reproducible parameters, for example, the ratio of the left atrium anteroposterior diameter to the aortic root (LA/Ao), according to a number of studies, are characterized by low sensitivity and specificity, as well as weak statistical correlation, whereas parameters that, when methodically performed, show a high correlation with magnetic resonance imaging data, which is the "gold standard" of diagnostics (LVO/SVCf)—are reproduced in practice with a greater margin of error due to the technically complex algorithm. Consequently, there is a need to develop new predictors of the hemodynamic significance of a patent ductus arteriosus. Based on this concept, over the past decade, several new ultrasound markers of hsPDA have been proposed: Vmax/Vmin [192], PDA/LPA [192], VPVFD, E/A > 1 [192], IVRT, S` IVS [194], ductal length < 5.2 mm (sensitivity 82%, specificity 83%) [210], half-systolic decay time — the time required for the peak systolic velocity across the duct to drop by half, 1/2 SDT < 90 ms (sensitivity 63% and specificity 100%) [192], and LA volume indexed to BSA, as a presumptive marker of hsPDA [211]. For now, current information on the diagnosis and evaluation of hsPDA is largely limited to the use of previous criteria and/or contains insufficient data on new variables. To date, there is no absolute and single marker of hsPDA — the ultrasound approach to the diagnosis and evaluation of this pathological condition remains comprehensive, and requires determining not only the characteristics of the ductus, but also assessing pulmonary and systemic perfusion, and consists in using a specific list of criteria that, through various hemodynamic mechanisms, will indirectly indicate the presence of a significant shunt at the ductus level.

According to published literature, there is no consensus among scientists regarding either the best parameter or the required number of criteria for diagnosing hsPDA. For obvious reasons, for point-of-care echocardiography aimed at monitoring and optimizing patient management, the presented list of ultrasound criteria needs to be rationalized, namely, by making a choice in favor of several criteria, taking into account, first of all, technical equipment and physicians' diagnostic skills, because it is the methodical reproducibility of the criteria that will affect the final result; the second point to consider when choosing criteria is the diagnostic significance of the protocol; for example, ductal parameters are different characteristics of a single structure—the ductus, so in this block one can at best choose one of the indexed ductal diameter parameters; whereas in the pulmonary perfusion assessment block, conversely, the criteria can conventionally be divided into three groups: pulmonary hyperperfusion markers — V_EDLPA, V_meanLPA, V_DFPV, left heart volume overload markers — LA/Ao, LVIDd/Ao, LVSV, LVSV/SVCi, and pressure overload criteria — E/A, IVRT, where it is sufficient to choose one criterion from each group, since parameters within a group will duplicate each other—indicating the same hemodynamic state, and thus preserve the diagnostic value of the protocol, as well as reduce the time required to perform the study in a premature newborn; nevertheless, the inclusion of more criteria in the study protocol will provide more information on the hemodynamic status and allow making the right decision in clinically complex/controversial cases.

An attempt to standardize the ultrasound diagnostic and evaluation protocol for hsPDA implies not only the inclusion of specific criteria, but also identical conditions for its execution. Taking into account factors such as different technical equipment in perinatal centers across the country and uneven levels of echocardiography skills among ultrasound specialists, which are decisive for the choice of criteria, one of the possible variants of the diagnostic protocol is proposed below, which may vary depending on the technical capabilities of the department and the operator's diagnostic experience.

Figure 1.Shunt direction and blood flow velocity across the PDA

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

The arterial duct is a blood vessel that helps obtain oxygen from the placenta in utero, bypassing the lungs. In full-term infants after birth, when the infant takes their first breath, blood begins to flow into the lungs, so the need for the arterial duct disappears and it ceases to function. However, in extremely premature infants, the arterial duct may remain patent, exerting an adverse effect on heart function and circulation in the pulmonary vessels. In significantly immature patients, the functioning of the duct can lead to pronounced adverse outcomes—the development of intraventricular hemorrhage and death.

The primary diagnostic method for a patent ductus arteriosus is cardiac ultrasound (echocardiography). Treatment of a patent ductus arteriosus depends on the gestational age and clinical condition of the preterm infant. Based on this, the physician determines the treatment approach: medical or surgical. There are special medications that allow the ductus to close pharmacologically. A course of three intravenous administrations is performed. If the ductus remains open after two repeated courses and the infant requires mechanical ventilation, surgical closure is necessary. A pediatric surgeon makes a small lateral incision on the chest, places a clamp on the ductus, and then closes the wound in layers. The infant is monitored by cardiovascular surgeons and pediatric anesthesiologists-intensivists.

A control echocardiography is mandatory before the infant is discharged.

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

Appendix G1. Scale of hemodynamic significance of PDA in ELBW without echocardiography data

Russian Title: PDA Hemodynamic Significance Score in ELBW Infants without Echocardiography Data.

Original Title: A novel clinical scoring system for predicting hemodynamically significant patent ductus arteriosus in extremely low birth weight infants[212]

Source: https://www.frontiersin.org/articles/10.3389/fped.2021.649515/full

Type:

- assessment scale

- score

- questionnaire

Purpose: a scoring system based on clinical and laboratory evaluation that determines the significance of hsPDA starting from 6 hours of life, the need for pharmacological closure of hsPDA, and can be used as a screening tool to determine indications for echocardiography in settings with limited echocardiography capabilities.

Contents: scoring system criteria

Key (Interpretation): A PDA is considered hemodynamically significant if the total score is above 8 points at 6–24 hours of life, or above 6 points at 24–48 hours of life.

Appendix G2. American Society of Anesthesiologists Physical Status Classification System

Russian Title: American Society of Anesthesiologists Physical Status Classification System [213].

Original Title: ASA physical status classification system.

Source: https://www.frontiersin.org/articles/10.3389/fped.2021.649515/full

Type:

- assessment scale

- score

- questionnaire

Purpose: assessment of the patient's condition prior to anesthesia administration.

Content and interpretation: