Hypoplastic left heart syndrome: clinical guidelines

List of Abbreviations

Ao – aorta

BP – blood pressure

AV – aortic valve

ACG - angiocardiography

LVOT – left ventricular outflow tract

BCPA – bidirectional cavopulmonary anastomosis

VSD – ventricular septal defect

ASD – atrial septal defect

IMV – invasive mechanical ventilation

EDVI – end-diastolic volume index

CoA – coarctation of the aorta

CT – computed tomography

LV – left ventricle

LA – left atrium

MV – mitral valve

IAC – interatrial communication

MRI – magnetic resonance imaging

CIR – circulatory insufficiency

PDA – patent ductus arteriosus

PFO – patent foramen ovale

NICU – neonatal intensive care unit

PTFE – polytetrafluoroethylene

HLHS – hypoplastic left heart syndrome

MODS – multiple organ dysfunction syndrome

RR – respiratory rate

ECG – electrocardiography

EchoCG – echocardiography

Terms and Definitions

Hypoplasia is a term denoting underdevelopment of a tissue, organ, or entire organism caused by disruptions during embryogenesis.

Stenosis is an abnormal narrowing of any lumen or orifice, such as a blood vessel or heart valve.

Atresia is a congenital absence or acquired closure of natural body orifices and canals.

Cardiac catheterization and angiocardiography are an invasive diagnostic method for assessing central hemodynamics, involving direct measurement of pressure in the heart chambers, obtaining blood samples from them to assess blood gas composition, and contrast imaging.

"Left heart" is a conventional morphological unit that includes the left atrium, mitral valve, left ventricle, aortic valve, and aorta. Each of the listed structures plays an important role in ensuring the adequate functioning of the left heart chambers.

Hybrid stage I of HLHS surgical correction is a variant of the first stage of surgical hemodynamic correction of HLHS, consisting of separate pulmonary artery banding and stenting of the patent ductus arteriosus.

Hypoplastic left heart syndrome complex represents various combinations of the following six criteria: mitral valve hypoplasia without severe stenosis, left ventricle hypoplasia, left ventricular outflow tract narrowing, aortic valve hypoplasia without severe stenosis, aortic arch hypoplasia, and the presence of antegrade blood flow through the left heart chambers and ascending aorta. The combination of such anomalies usually does not lead to severe left ventricular dysfunction, which creates prerequisites for subsequent surgical conversion of hemodynamics via a biventricular pathway.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Hypoplastic left heart syndrome (HLHS) is a term used to describe variants of congenital heart disease represented by a wide spectrum of underdevelopment of the "left heart" structures. The main anatomical feature uniting the entire spectrum of left heart pathologies into a single hypoplastic left heart syndrome is pathology of the aortic and/or mitral valve (most often atresia) and, consequently, underdevelopment (hypoplasia) of the left heart structures, ascending aorta, and aortic arch [1-5,151].

The definition of hypoplastic left heart syndrome is functional rather than morphological, despite the fact that morphological anomalies are the main cause of functional failure of the left heart.

Hypoplastic left heart syndrome from a physiological perspective is the inability of the "left heart" to maintain adequate cardiac output immediately after birth due to the underdevelopment of one or more structures of the left half of the heart (prior to surgical or medical intervention). An important aspect in this situation is that the "left heart" is unable to maintain systemic cardiac output, which necessitates subsequent surgical conversion of hemodynamics via a single-ventricle pathway or requires heart transplantation to preserve biventricular hemodynamics [5].

Morphological criteria of the defect [5]:

HLHS includes various combinations of the following six lesions and underdevelopment of cardiovascular system structures in combination with left ventricular hypoplasia:

1. mitral valve defect (marked hypoplasia; stenosis; atresia);

2. fibroelastosis of the left-sided structures;

3. aortic valve defect (marked hypoplasia; stenosis; atresia);

4. ascending aorta hypoplasia;

5. hypoplasia/interruption of the aortic arch;

6. coarctation of the aorta;

A certain degree of left heart hypoplasia is present within a wide spectrum of "left heart" lesions. This spectrum varies from simple isolated lesions (e.g., discrete coarctation) to complex multi-level lesions (e.g., combination of aortic atresia, mitral atresia, and a rudimentary left ventricle). Thus, HLHS can develop either as a result of a severe anomaly of a single left ventricular structure (e.g., mitral atresia) or due to a combination of several milder anomalies (e.g., mitral stenosis, left ventricular hypoplasia, and aortic stenosis).

Associated defects:

The frequency of associated congenital heart defects in the setting of HLHS is about 25% [1,6]. Associated heart anomalies are variable and play an important role in determining treatment tactics. Associated intracardiac pathology can both complicate and "ease" the course of HLHS. Defects that improve prognosis may include ventricular septal defect (VSD, ASD, partial or total anomalous pulmonary venous return). Factors that significantly worsen the prognosis of the course and treatment of HLHS include structural abnormalities of the right heart chambers, namely tricuspid valve and pulmonary valve involvement; restrictive IAC or intact atrial septum.

Other associated anomalies are much less common and are represented by the following pathologies:

• common atrioventricular canal (unbalanced form);

• total anomalous pulmonary venous return;

• discordant ventriculoarterial connection;

• coronary sinus atresia;

• pulmonary venous atresia;

• quadricusp pulmonary valve;

• duplication of the pulmonary valve orifice

• ventriculocoronary fistulae, etc. [1,5-7,66,139,140].

Hypoplastic left heart syndrome with restrictive or intact atrial septum:

A restrictive or intact atrial septum is present in 6–20% of fetuses with HLHS [141-142]. Typically, these infants have one of three types of left atrium:

Type A: a relatively large left atrium with a thick septum secundum and a thin septum primum fused together, with massively dilated pulmonary veins. The decompression pathway from the left atrium (LA) may lead to the innominate vein, the right superior vena cava, and the right atrium (total anomalous pulmonary venous drainage).

Type B: a small, hypertrophied LA with circumferential atrial wall thickening and a thick muscular interatrial septum without a clear distinction between the septum primum and septum secundum. The pulmonary veins are usually small.

Type C: a giant left atrium with a thin interatrial septum bowing to the right in the setting of severe mitral regurgitation. The pulmonary veins are usually enlarged [60, 143-144].

After birth, in infants with HLHS and an intact atrial septum, pulmonary blood flow increases 5-fold compared to intrauterine hemodynamics, leading to profound hypoxemia and a high risk of mortality. Most commonly, left atrial hypertension leads to pulmonary edema, which in turn increases resistance to antegrade pulmonary blood flow, exacerbating hypoxemia [145].

Intrauterine elevation of pulmonary vascular pressure leads to "nutmeg lung", representing terminal damage. Microscopically, the main feature of "nutmeg lung" is lymphangiectasia (enlarged lymphatic vessels); macroscopically, the lungs acquire a "cobblestone" appearance. Due to impaired blood outflow from the left atrium, rapid clinical deterioration occurs, and without surgical treatment, such infants die within the first 3 days of life [147-150].

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

To date, the etiopathogenesis of HLHS is not fully understood. It remains unclear whether the etiology is the same for all cases of this pathology. Abnormal formation and leftward displacement of the septum primum are frequently noted and may be one of the causes of HLHS development. However, the most likely cause of HLHS is aortic and mitral valve pathology [7,53]. According to autopsy studies, practically all cases of HLHS involve aortic and/or mitral valve lesions. The severity of these lesions can vary significantly from case to case [5,7]. The influence of genetic factors on the development of HLHS in some patients has also been proven, but these factors are numerous, complex, and currently poorly understood [51,54].

Some researchers propose another embryological mechanism for the onset of HLHS: primary impaired formation of the patent foramen ovale with its restriction or atresia in early stages of fetal development, leading to a decrease or absence of blood flow through the left heart chambers, which in turn results in their hypoplasia [7,52].

The formation of the aortic arch and brachiocephalic arteries in the vast majority of HLHS cases proceeds uneventfully, while hypoplasia of the ascending aorta and arch is caused by the absence or sharp reduction of antegrade blood flow therein due to aortic valve stenosis as another primary mechanism of HLHS development. Arch anomalies may occur in cases associated with interrupted aortic arch or coarctation of the aorta [5,7,52].

Genetic syndromes

Genetic syndromes are present in ~10–25% of patients with HLHS. The most frequent syndromes include Turner, Noonan, Holt-Oram, trisomies, CHARGE association, and Jacobsen syndrome [152-154].

Pathophysiology

In aortic and mitral atresia or aortic atresia with mitral stenosis, systemic circulation is maintained by the right ventricle via retrograde blood flow in the aortic arch through the patent ductus arteriosus. In patients with a milder form of HLHS with aortic and mitral stenosis, systemic circulation may depend only partially on right ventricular function and the patent ductus arteriosus, since antegrade flow in the ascending aorta and aortic arch is provided by the left ventricle. In rare cases, with borderline left ventricle dimensions and moderate stenosis of the mitral and aortic valves, systemic blood supply may be provided entirely by the left ventricle, although such patients usually present with severe congestive heart failure requiring surgical intervention [145].

1.3 Epidemiology of the Disease or Condition

HLHS is the fourth most common congenital heart defect diagnosed in the neonatal period and the most frequent defect with single-ventricle hemodynamics. Its frequency among all congenital heart defects ranges from 1.4 to 9%. The prevalence of this syndrome per 1000 live births is 0.16–0.2, and this CHD occurs twice as often in males as in females [8-11,55,58].

The clinical course of the defect largely depends on the degree of hypoplasia of the left heart structures. Without surgical intervention, virtually all infants with HLHS die by 6 months of age, with 25% of deaths occurring in the first week of life [10,56-57,146].

1.4 Features of Coding the Disease or Condition

Q23.4 – Hypoplastic left heart syndrome.

1.5 Classification of the disease or condition

There is no universally accepted classification of hypoplastic left heart syndrome. Clinical practice utilizes a classification based on the morphology of the left heart valves. Five anatomical subtypes of HLHS are distinguished:

• aortic and mitral stenosis;

• aortic and mitral atresia;

• aortic atresia and mitral stenosis;

• aortic stenosis and mitral atresia

• hypoplastic left heart complex [5,33].

The most severe form of HLHS is the variant with mitral and aortic valve atresia, which results in the absence of antegrade blood flow in the ascending aorta. Systemic hemodynamics in such a situation is possible only if fetal communications are present, namely: a patent ductus arteriosus and an interatrial communication.

1.6 Clinical presentation of the disease or condition

The clinical presentation after birth can vary significantly depending on the morphological subtype of HLHS; nevertheless, patients with HLHS frequently exhibit signs such as:

1. tachycardia;

2. dyspnea;

3. acrocyanosis/cyanosis, worsening with agitation;

4. hepatomegaly

5. low blood pressure

In the neonatal period, infants with HLHS typically present with mild cyanosis, respiratory distress syndrome, and tachycardia. Without supportive measures (maintaining the patency of fetal communications: the foramen ovale and ductus arteriosus), rapid deterioration can occur with swift progression of heart failure and patient death (due to pulmonary hyperperfusion leading to pulmonary edema and critical systemic hypoperfusion). Simultaneously, peripheral pulses are markedly diminished (or absent), with signs of decreased peripheral perfusion, centralization of circulation, and low blood pressure. Palpation reveals hepatomegaly.

Spontaneous closure of the ductus arteriosus without prostaglandin infusion is inevitable, but the timing of natural ductal closure varies from hours to weeks, or sometimes months. And as previously noted, closure of the ductus arteriosus is accompanied by rapid circulatory collapse.

Approximately 5% to 6% of infants with HLHS have significant blood flow obstruction at the level of the atrial septum (restrictive interatrial communication). When present, this obstruction causes severe impairment of blood outflow from the left atrium (especially in mitral atresia or critical mitral stenosis). This subsequently leads to impaired pulmonary venous drainage, which in turn results in postcapillary pulmonary hypertension and lung injury. Newborns with marked obstruction to blood flow at the atrial septum level typically exhibit critically low systemic blood oxygenation and almost always show signs of developing and progressing pulmonary edema. This situation is critical and requires urgent surgical intervention (atrioseptostomy) [59-61].

Auscultation in HLHS typically reveals a moderate systolic murmur along the left sternal border due to a functioning patent ductus arteriosus. In the presence of heart failure or a restrictive foramen ovale, crepitant rales may be auscultated over the lung fields.

Capillary blood gas analysis is extremely critical for assessing the severity of the patient's condition and allows evaluation of the balance of blood flow between the systemic and pulmonary circulations (for details, see the laboratory diagnostics section).

Plain chest radiography typically reveals cardiomegaly due to enlargement of the right heart chambers. The lung fields show signs of pulmonary hypervolemia.

ECG changes are usually non-specific and present with signs of right heart strain.

Echocardiography is the primary diagnostic method for HLHS, allowing visualization of the signs of the defect with a high degree of certainty both postnatally and prenatally, starting from the 16th week of pregnancy. Echocardiography makes it possible to identify all necessary signs of the defect, namely: hypoplasia and abnormal structure of the mitral and aortic valves; hypoplasia of the ascending aorta; detection or exclusion of antegrade flow through the mitral and aortic valves and the ascending aorta; determination of the linear dimensions of the left ventricle; determination of the degree of left ventricular fibroelastosis; dimensions of the interatrial communication, etc. [5,7,10,12].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Prenatal echocardiographic examination is of great importance, as it allows suspecting HLHS at 16–18 weeks of gestation [12]. Immediately after birth, the vast majority of newborns are in a critical condition, requiring the fastest possible transfer of the patient to a specialized facility.

Diagnostic criteria for establishing a diagnosis

Symptoms:

• dyspnea;

• palpitations.

Anamnesis: prenatal diagnosis of congenital heart disease.

Physical examination:

• tachycardia;

• dyspnea;

• respiratory disorders;

• lung rales;

• hepatomegaly;

• cyanosis of varying severity;

• intestinal pneumatosis, free fluid in the abdominal cavity (signs of enterocolitis development);

• moderate systolic murmur along the left sternal border (the second sound over the aorta is single-component, often attenuated or absent).

Laboratory tests: do not provide characteristic information for HLHS.

Instrumental Studies:

Targeted chest X-ray:

• hyperemia with interstitial or alveolar pulmonary edema (or without edema).

• targeted chest X-ray also allows identifying concomitant lung diseases (pneumonia, meconium aspiration, atelectasis, etc.).

ECG (electrocardiogram recording, interpretation, description, and analysis of electrocardiographic data)

• ECG changes are non-specific and manifest as signs of right heart strain, namely:

1. peaked, widened P waves in leads II, III, and aVF;

2. rightward axis deviation;

3. signs of right ventricular enlargement with the appearance of R waves in V1, or qR in the right precordial leads, rS waves in V5-V6.

Echocardiography with color Doppler mapping:

• allows detecting hypoplasia, abnormal structure, stenosis, or atresia of the mitral valve; hypoplasia, stenosis, or atresia of the aortic valve; hypoplasia of the ascending aorta, aortic arch, and/or aortic isthmus; detecting or excluding the presence of antegrade flow through the mitral and aortic valves; determining the linear dimensions of the left ventricle and the severity of fibroelastosis; the dimensions of the interatrial communication and patent ductus arteriosus; assessing blood flow in the abdominal aorta, and evaluating right ventricular and tricuspid valve function.

2.1 Complaints and Anamnesis

• At the stage of diagnosis refinement, it is recommended to perform an examination, a thorough collection of anamnesis and complaints in all patients (parents of patients) with suspected HLHS in order to determine the severity of the condition and treatment tactics [5,7,10].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

2.2 Physical Examination

• All patients with HLHS are recommended to be evaluated by a cardiologist or cardiovascular surgeon (initial examination/consultation by a cardiologist, initial examination/consultation by a pediatric cardiologist, initial examination/consultation by a cardiovascular surgeon) to assess the severity of the patient's condition [5,7,10].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

• All patients with HLHS during physical examination are recommended to pay attention to the presence of dyspnea and cyanosis, and to keep in mind the high frequency of respiratory disorders in this group of patients during the first days of life [5,7,10].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

Comments: It is important to understand that the clinical presentation after birth can vary significantly depending on the class and anatomical subtype of HLHS. Patients with this diagnosis almost always present with signs of circulatory failure and/or respiratory failure (tachycardia; dyspnea; rales in the lungs; cyanosis; enlargement of the liver borders). In most cases, there is a decrease in tissue and organ perfusion, accompanied by peripheral spasm and low blood pressure. With pronounced cardiac dysfunction, multiple organ dysfunction syndrome (MODS) rapidly develops. There is no direct correlation between the severity of the condition and the degree of cyanosis. Severe cyanosis is often caused by restricted blood flow through the patent foramen ovale (PFO), or concomitant cardiac/extracardiac pathology (total anomalous pulmonary venous return with collector stenosis, diaphragmatic hernias, etc.).

• In all patients with suspected HLHS, cardiac auscultation (auscultation for heart and pericardial pathology) is recommended to detect heart murmurs [5,7,10].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

Comments: HLHS is characterized by a moderate systolic murmur along the left sternal border (the second sound over the aorta is single-component, often attenuated or absent) [5,7,10].

All patients with HLHS are recommended to have their blood pressure measured to assess systolic and diastolic pressure [1,4-5,7,10].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

Comments: due to the absence of direct ejection (critical reduction of ejection) of blood through the ascending aorta, systemic blood pressure depends on the presence and size of the PDA, as well as the pulmonary-to-systemic vascular resistance ratio

• In newborn infants with HLHS, it is recommended to assess peristalsis by abdominal auscultation. It is also necessary to perform abdominal percussion and palpation to detect intestinal pneumatosis and free fluid in the abdominal cavity (signs of enterocolitis development) [5,7,10,58-59,75].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

Comments: immediately after birth, when pulmonary vascular resistance remains relatively high and the arterial duct is wide, the physical examination results are most often close to normal (with adequate oxygenation and systemic perfusion). This is due to the balance between the volume of blood directed to the pulmonary circulation for oxygenation and the volume delivered to the systemic circulation. However, as pulmonary vascular resistance naturally drops, more blood is shunted through the pulmonary vasculature at the expense of systemic circulation, leading to tachypnea, relative hypotension, and the development of acidosis. When the arterial duct begins to close, systemic perfusion deteriorates further. Symptoms in such newborns usually appear within the first few hours of life or at 2 to 3 days of age, starting with signs of enterocolitis and respiratory distress syndrome, and without intervention, they rapidly progress to heart failure and shock.

2.3 Laboratory Diagnostics

There are no specific laboratory diagnostics for HLHS.

• All patients with HLHS are recommended to undergo acid-base balance and blood gas testing (pH, BE, pCO2, PO2, Lac — capillary/arterial/venous blood samples) to assess the severity of hypoxemia and the degree of metabolic disorders (simultaneous blood samples from the upper and lower extremities are preferred) [5,7,10,12].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

Comments: capillary blood gas analysis allows assessing the balance of blood flow between the pulmonary and systemic circulations:

1. if before the initiation of treatment, arterial blood oxygen saturation is within 75–90%, pH fluctuates within acceptable values, and pCO₂ is at 40–50 mmHg, this indicates that blood flows are balanced

2. if the arterial blood oxygen saturation level is greater than 90–93% combined with metabolic acidosis (pH < 7.3) and pCO₂ is at 30–40 mmHg, the situation should be regarded as a shift in balance towards pulmonary blood flow, and appropriate correction of therapy should be performed, as discussed below.

• All patients with HLHS are recommended to undergo a general (clinical) urinalysis and a general (clinical) blood test including total hemoglobin and hematocrit assessment, red blood cell, white blood cell, and platelet counts, and erythrocyte sedimentation rate (ESR) as part of the initial evaluation upon admission to the hospital, including prior to surgical treatment, during follow-up at least once a year, and in the postoperative period if necessary [5,10,62-63].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

• For all patients with HLHS admitted to a specialized inpatient facility for surgical correction of the defect who are expected to receive donor blood and/or its components, it is recommended to determine the main blood groups using the ABO system, the D antigen of the Rhesus system (Rh factor), the C, c, E, e, C^w, K, k antigen phenotype, and to screen for anti-erythrocyte antibodies [5,10,62,176-177].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

• For all patients with HLHS admitted to an inpatient facility for surgical treatment, it is recommended to determine Hepatitis B virus surface antigen (HBsAg) in the blood; to determine antibodies to Hepatitis C virus in the blood; to determine antibodies to Treponema pallidum in the blood; to determine IgM and IgG antibodies to human immunodeficiency virus HIV-1 in the blood; to determine IgM and IgG antibodies to human immunodeficiency virus HIV-2 in the blood to rule out associated HIV infection, hepatitis, and syphilis [5,10,62,174-175].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

• Before performing a surgical intervention, all patients with HLHS are recommended to undergo a coagulogram (exploratory hemostasis study) (determination of activated partial thromboplastin time (APTT), international normalized ratio (INR), and blood fibrinogen level) to rule out congenital and acquired blood coagulation disorders, and to predict postoperative thrombosis and bleeding [5,7,10,62,178-179].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

Comments: if the patient presents with hemorrhagic syndrome and/or laboratory signs of blood coagulation disorders in the preoperative period, surgical intervention should ideally be postponed until the cause of these disorders is identified and corrected.

• All patients with HLHS are recommended to undergo a routine general biochemical blood test (levels of potassium, sodium, chlorides, glucose, creatinine, total protein, albumin, urea, total and conjugated bilirubin in the blood, serum iron, and the activity of aspartate aminotransferase and alanine aminotransferase in the blood) to assess renal and hepatic function as part of the initial evaluation upon admission to the inpatient facility, including for surgical treatment, during follow-up at least once a year, and in the postoperative period when necessary [5,10,43,44].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

• For all patients with HLHS who undergo thromboprophylaxis with heparin preparations (B01AB Heparin group) after surgical treatment, laboratory monitoring of the efficacy of these medicinal products is recommended [178,179,197,198].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

Comments: When using unfractionated heparin (B01AB Heparin group), it is recommended to determine the APTT (activated partial thromboplastin time) (the optimal target range for children is 60–85 seconds) and measure the blood heparin level (anti-Xa assay): the optimal range is 0.35–0.7. When using low-molecular-weight heparin preparations (B01AB Heparin group), it is recommended to measure the blood heparin level (anti-Xa assay): the optimal range is 0.5–1.0 [178,179,197,198].

2.4 Instrumental Diagnostics

The definitive diagnosis of HLHS is established using imaging methods that confirm morphological features of the defect and functional insufficiency of the left ventricle. Another goal of instrumental diagnostics is to detect associated congenital anomalies (if present).

• All patients with suspected HLHS are recommended to undergo a transthoracic echocardiogram (TTE) using color Doppler flow mapping to determine the anatomical features of the defect and select the optimal surgical strategy [7,10,13-15,62-64].

Level of Evidence (LE) 4, Grade of Recommendation (GR) C

Comments: this study allows for the identification of all essential features of the defect: hypoplasia, abnormal structure, stenosis, or atresia of the mitral valve; hypoplasia, stenosis, or atresia of the aortic valve; hypoplasia of the ascending aorta, aortic arch, and/or aortic isthmus; detection or exclusion of antegrade flow through the mitral and aortic valves; measurement of left ventricular linear dimensions and the severity of fibroelastosis; dimensions of the interatrial communication and patent ductus arteriosus; assessment of blood flow in the abdominal aorta; and evaluation of right ventricular and tricuspid valve function.

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

• Neonatal patients with HLHS are not recommended to undergo transvenous cardiac catheterization and panaortography [5,10,55,182].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

Comments: It should be noted that the administration of even a small volume of contrast medium to patients with HLHS leads to the worsening of pre-existing renal failure. Angiocardiography (ACG) may be indicated in neonates with HLHS when echocardiography and/or computed tomography raises suspicion of coronary artery anomalies or abnormal branching of the brachiocephalic vessels [10].

• In cases where echocardiographic data are insufficient or contradictory for verifying the diagnosis, patients with suspected HLHS are recommended to undergo contrast-enhanced computed tomography (CT) of the heart or magnetic resonance imaging (MRI) of the heart and great vessels [16-17].

LE 4, GR C – for CT

LE 5, GR C – for MRI

Comments: MRI and CT help to clarify the morphology of the defect, determine the spatial relationship of the cardiac structures and great vessels, and are also important for diagnosing concomitant intracardiac/extracardiac malformations. In addition, tomographic techniques are used in borderline sizes of the left heart chambers, which allows clarifying the feasibility of biventricular repair and surgical management in this group of patients.

• All patients with suspected HLHS are recommended to undergo targeted chest X-ray to rule out other heart and great vessel diseases, as well as extra-cardiac pathology (pathology of other mediastinal organs, lungs, pleura), to clarify the anatomical features of this congenital heart disease, the state of the lesser circulation and detect pulmonary congestion, and pre- and/or postoperatively when surgical treatment is performed [5,7,10,13,55,155].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

Comments: plain chest radiography almost always reveals hypervascularity with interstitial or alveolar pulmonary edema (or without edema). Chest X-ray also allows for the detection of concomitant pulmonary diseases (pneumonia, meconium aspiration, atelectasis, etc.).

• All patients with HLHS are recommended to undergo electrocardiography (ECG) (recording of the electrocardiogram, interpretation, description, and analysis of electrocardiographic data) to assess cardiac rhythm and conduction [5,7,10,55].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

Comments: ECG changes are usually non-specific and manifest as signs of right heart overload, specifically:

1. peaked, widened P waves in leads II, III, and aVF;

2. rightward axis deviation;

3. signs of right ventricular enlargement with the appearance of R waves in V1, or qR in the right precordial leads, rS waves in V5-V6.

2.5 Other Procedures

All neonatal patients with HLHS are recommended to undergo neurosonography to rule out brain malformations [45].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

Comments: HLHS is frequently associated with genetic disorders and central nervous system malformations. Neurosonography in these patients can reveal gross structural abnormalities, which helps determine the optimal surgical correction strategy.

• A newborn with HLHS, before and after medical or surgical intervention (up until discharge from the inpatient facility), is recommended to undergo continuous bedside vital sign monitoring (heart rate measurement, 24-hour blood pressure monitoring, pulse oximetry) to monitor the patient's condition [10,64,74].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

• All patients with HLHS are recommended to undergo transesophageal echocardiography before the final stage of the operation under cardiopulmonary bypass to check the quality of the surgical intervention [10,19,64].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

• All patients with HLHS are recommended to undergo electrocardiography recording (interpretation, description, and analysis of electrocardiographic data) before discharge from the inpatient facility following surgical intervention to assess the quality of the surgical procedure [10,19,64].

LE 5, GR C

• All patients with hypoplastic left heart syndrome (HLHS) and risk factors for infectious complications upon admission to the inpatient unit are recommended to undergo microbiological (culture) examination of tonsillar and posterior pharyngeal wall mucus for aerobic and facultatively anaerobic microorganisms, microbiological (culture) examination of feces for aerobic and facultatively anaerobic microorganisms, and microbiological (culture) examination of conjunctival discharge for aerobic and facultatively anaerobic opportunistic microorganisms to determine colonization by microorganisms [183-194].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

Comments:postoperative infectious complications in patients with congenital heart disease (CHD) are a serious problem[183-185], since this group of patients has a number of characteristic risk factors for their development (frequent combination of CHD with other congenital anomalies and malformations, invasiveness and duration of the surgical procedure, use of cardiopulmonary bypass, blood loss, hypothermia, etc.[186].In addition, such patients are often initially colonized by multiresistant microflora. This is due to the fact that prior to cardiac surgery, most children with CHD receive treatment in somatic hospitals, including the use of systemic antibacterial drugs, which is a significant risk factor for the colonization of open body biocenoses. When such microorganisms, resistant to systemic antibacterial drugs, are introduced into the hospital, preconditions are created for the emergence of nosocomial outbreaks as well as the deterioration of the hospital's microbiological landscape.[187-188].It is known that the most effective way to reduce the risk of infectious complications is the implementation of a set of infection control measures.[189-190].In this regard, it is recommended to perform molecular biological testing of oropharyngeal mucosa swabs for methicillin-susceptible and methicillin-resistant Staphylococcus aureus, methicillin-resistant coagulase-negative Staphylococcus spp, molecular biological testing of oropharyngeal mucosa swabs to detect acquired bacterial carbapenemase genes, molecular biological testing of oropharyngeal mucosa swabs for Pseudomonas aeruginosa, PCR-based molecular biological testing to detect acquired bacterial carbapenemases in rectal mucosa swabs, PCR-based determination of class metallo-β-lactamase (MBL) acquired bacterial carbapenemase genes of the VIM, IMP, and NDM groups in rectal mucosa swabs, and PCR-based detection of class metallo-β-lactamase (MBL) acquired carbapenemase genes of the VIM, IMP, and NDM groups in oropharyngeal mucosa swabs.[189,191-193]. Screening results should not serve as a guide for prescribing antimicrobial therapy in the absence of clinical signs of an infectious process, but may be taken into account when prescribing empirical therapy in the event of infection manifestation. Data obtained from screening are part of microbiological monitoring and determine the set of anti-epidemic measures that must be carried out upon hospitalization of a patient colonized by multiresistant flora.[194].

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

Delivery

Delivery should take place in a hospital of level 3 or higher to ensure a more accurate initial assessment of the newborn's condition and subsequent stabilization (catheterization of the cubital and other peripheral veins or catheterization of the subclavian and other central veins, initiation of prostaglandin infusion, and resuscitation measures). Due to the need for surgical intervention in the neonatal period, it is optimal to perform delivery in a hospital setting located near a specialized cardiac center [68]. Delivery can be performed either via spontaneous vaginal delivery or planned cesarean section. Planned uncomplicated delivery is optimally performed at 39 weeks of gestation (since delivery even at 37–38 weeks is associated with higher risks of adverse outcomes) [141, 156-157].

• Delivery of a fetus with hypoplastic left heart syndrome and a restrictive oval foramen or intact atrial septum

Delivery of a fetus with HLHS and a restrictive patent foramen ovale or intact atrial septum is optimally performed in a specialized cardiac surgery center or in close proximity to it, to enable emergency intervention for left atrial decompression (balloon atrioseptostomy or creation of an atrial septal defect with stenting, connection of an extracorporeal membrane oxygenation (ECMO) system). In this case, a planned cesarean section may be required for optimal coordination of multidisciplinary care [141, 159].

After the child's birth, a pediatric cardiologist must confirm the diagnosis of HLHS and conduct a joint consultation with the parents alongside a cardiovascular surgeon (pediatric cardiac surgeon). If extracardiac anomalies are detected, chromosomal aberration testing is indicated to obtain additional information and refine the prognosis [145].

In cases of a prenatally established diagnosis of HLHS, delivery is recommended to be performed in a specialized hospital with a neonatal intensive care unit, within close transport accessibility to a cardiac surgery center [5,10,64-70].

Level of Evidence (LE) 4, Grade of Recommendation (GR) C

• All patients with a prenatally established diagnosis of HLHS immediately after delivery are recommended to be transferred to the NICU for monitoring of vital functions (heart rate measurement, respiratory rate, pulse oximetry, and 24-hour blood pressure monitoring) and stabilization of the patient's condition [5,10,64-70].

Level of Evidence (LE) 4, Grade of Recommendation (GR) C

• All newborn patients with HLHS after stabilization of their condition in the NICU are recommended to be transferred to the nearest cardiac surgery hospital within the first 24–48 hours of life [5,10,64-70,116].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

Comments: for unstable newborns (including those with restrictive arterial duct and atrial communication, pulmonary venous stenosis): transport is optimally carried out within the first 24 hours of life, provided the patient is transportable [160].

3.1 Conservative Treatment

Brief algorithm for preoperative management of stable patients:

1. minimization of handling [49,78];

2. organization of adequate monitoring with control of respiratory rate (RR), PDA size by echocardiography, ECG, pulse oximetry on upper and lower extremities, and blood pressure measurement in peripheral arteries [161-163];

3. initiation of infusion of C01EA prostaglandins [48,49,64,65,72,101-103,160,167];

4. fluid loading in accordance with standard neonatal guidelines, while fluid balance should be closely monitored [145];

5. enteral nutrition remains controversial! However, it has been proven that enteral nutrition, especially with breast milk, can reduce the risk of necrotizing enterocolitis provided adequate blood flow in the lower half of the body is maintained [164-166].

Brief algorithm for preoperative management of unstable patients:

1. organization of adequate monitoring with control of respiratory rate (RR), PDA size by echocardiography, ECG, pulse oximetry on upper and lower extremities, and blood pressure measurement in the right upper extremity [161-163];

2. initiation of infusion of C01EA prostaglandins to maintain ductus arteriosus patency and adequate systemic circulation. However, it must be remembered that (C01EA) prostaglandins have two clinically significant dose-dependent side effects: hypotension (especially in patients in shock) and vasodilatory effects (risk of bleeding and necrotizing enterocolitis). At the same time, high doses of C01EA prostaglandins do not lead to further PDA enlargement, especially under conditions of decompensated acidosis, so the general trend is to minimize the dose of prostaglandins [48,49,64,65,72,101-103,160,167];

3. stabilization of the condition by striving to normalize the ratio between pulmonary (Qp) and systemic blood flow (Qs) to unity (Qp=Qs). If necessary, transfer the patient to mechanical ventilation (normoventilation mode with FiO2 21% is indicated) [49,145];

4. correction of severe acidosis, but it should be remembered that moderate acidosis helps limit pulmonary blood flow by increasing pulmonary vascular resistance. Therefore, pH correction should be performed with caution, otherwise pulmonary vascular resistance may decrease significantly and the Qp/Qs ratio may shift toward the pulmonary circulation with a decrease in systemic blood flow and subsequent delayed worsening of systemic acidosis. However, patients in shock and profound metabolic acidosis require correction of base deficit. When administering alkaline agents (sodium bicarbonate**), one should aim to optimize Qp/Qs to unity (Qp=Qs) [145,162,168];

5. maintain adequate body temperature and avoid patient hypothermia (especially during transport) [160,196].

• All patients with HLHS are recommended to have a venous line placed (catheterization of the cubital and other peripheral veins or catheterization of the subclavian and other central veins) [10,65,67,71].

Level of Evidence (LoE) 3, Grade of Recommendation (GoR) C

Comments: in stable condition, placement of one or two peripheral venous lines is sufficient (catheterization of the cubital and other peripheral veins). In case of clinical deterioration or initial severity (low saturation levels, lactic acidosis, respiratory disorders), placement of a central venous line is required (catheterization of the subclavian and other central veins) [10,65-71].

• All patients with HLHS are recommended to receive an infusion of C01EA prostaglandin group drugs immediately after establishing venous access [48,49,64,65,72,101-103].

Level of Evidence (LE) 4, Grade of Recommendation (GR) C

Comments: infusion of #alprostadil** is carried out in stable patients until surgical intervention at a rate of 0.003-0.005 mcg/kg/min. In case of a restrictive patent ductus arteriosus (Echocardiography data, decreased saturation, lactic acidosis), an increase in the #alprostadil** dose from 0.01 to 0.05 mcg/kg/min is recommended [10,48,49,64,65,72,76-78,101-103,200].

• All patients with HLHS with maintained saturation levels within 75-85% are not recommended to receive additional oxygen therapy [5,10,72-73,77].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

• All patients with HLHS in a stable condition without pronounced metabolic disorders are not recommended to be switched to mechanical ventilation [49,72].

Level of Evidence (LE) 4, Grade of Recommendation (GR) C

• In patients with HLHS with saturation > 90% combined with lactic acidosis, arterial hypotension, and oliguria, recommended procedures include tracheal intubation and switching to mechanical ventilation with 21% fraction of inspired oxygen (air) [5,10,49,65,71-73].

LoE 2, GoR C

Comments: if hyperoxia and hypocapnia persist in blood gas analysis, the oxygen concentration in the breathing mixture should be reduced to 17-19% by increasing the nitrogen fraction. Mechanical ventilation should be continued until the patient's condition stabilizes.

• Conservative treatment for all patients with HLHS with decreased right ventricular function (heart failure) is recommended to be performed according to the following algorithm: first, exclude excessive pulmonary blood flow; second, exclude systemic hypovolemia; third, initiate an infusion of nitroferricyanide derivatives or peripheral antiadrenergic agents under blood pressure monitoring [5,7,10,72,76-78,104-108].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

Comments: in case of progressive deterioration in patients with HLHS, an infusion of nitroferricyanide derivatives with systemic vasodilating effects is prescribed (sodium nitroprusside dihydrate at an initial dose of 0.3 mcg/kg/min with subsequent dose titration under blood pressure and blood gas monitoring until the desired effect is achieved) or an infusion of #levosimendan** (belonging to other cardiotonic agents with additional vasodilating action) at 0.05-0.2 mcg/kg/min is prescribed [105,107-108]. If ineffective, initiation of cardiotonic agents excluding cardiac glycosides is recommended. With the progression of heart failure, prescribing drugs from the pharmacotherapeutic group of adrenergic and dopaminergic agents is necessary: dobutamine** or dopamine** is recommended (at intravenous doses of 4-6 mcg/kg/min with subsequent titration to the desired effect (maximum 10 mcg/kg/min)); if the aforementioned drugs are insufficiently effective, additional administration of #epinephrine** is required (at an initial dose of 0.01 mcg/kg/min with subsequent dose titration under blood pressure and blood gas monitoring until the desired effect is achieved) [72,104-106].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

Comments: high doses of adrenergic and dopaminergic agents also lead to an increase in peripheral systemic vascular resistance, which in turn redirects most of the output from the single functional right ventricle towards the pulmonary circulation, further aggravating the patient's condition. The doses of adrenergic and dopaminergic agents should be increased concurrently with systemic vasodilators.

• All patients with HLHS with risk factors for infection are recommended to receive systemic antibacterial drugs (initiating therapy in the maternity hospital if necessary and continuing administration for 48–72 hours, i.e., until cultures taken prior to therapy are negative) [79-80,109-111].

Level of Evidence (LE) 4, Grade of Recommendation (GR) C

Comments: risk factors for infection in a newborn include: acute infectious process in the mother in late pregnancy (immediately before delivery); fetoplacental insufficiency; detection of pericardial, pleural effusion, or ascites in the newborn, presence of cysts and calcifications in the brain; leukocytosis in the newborn's complete blood count (more than 20 x 10⁹/L); elevated serum C-reactive protein and/or procalcitonin levels. If an infectious pathogen is identified, etiopathogenetic administration of systemic antibacterial drugs at age-appropriate dosages is required. If risk factors are present without pathogen identification, other beta-lactam antibacterial drugs or beta-lactam penicillins are prescribed at age-appropriate dosages with subsequent adjustment of antibacterial therapy if necessary. In severe cases, reserve antibacterial drugs are appropriate: carbapenems, vancomycin**, fluoroquinolones, macrolides, polymyxins. In the absence of risk factors, antibiotics (systemic antibacterial drugs) are not prescribed [79-80,109-111,188-191,194].

• All patients with HLHS with restrictive interatrial communication confirmed by ultrasound diagnostics, severe metabolic disorders, and low saturation levels are recommended to undergo tracheal intubation, mechanical ventilation, dose escalation of C01EA prostaglandin group drugs, administration of muscle relaxants at calculated doses, and initiation of additional oxygen therapy [5,7,10,72,76-78,101-103].

Level of Evidence (LE) 4, Grade of Recommendation (GR) C

Comments: other intensive care measures are usually ineffective in this situation.

• Patients with HLHS at high risk of thrombosis after surgical treatment are recommended to undergo thromboprophylaxis with heparin and its derivatives (B01AB heparin group) [178,179,197,198].

Level of Evidence (LoE) 3, Grade of Recommendation (GoR) C

Comments: High-risk thrombosis groups include patients with a history of thrombosis, thrombophilia, infectious complications, and multiple organ failure [179].

Thromboprophylaxis with unfractionated sodium heparin** should be initiated with a bolus of 75 IU/kg in children, followed by intravenous infusion at a rate of: 28 IU/kg/h in children under 1 year of age, and 20 IU/kg/h in children older than 1 year. Dose adjustments are made based on laboratory test results.

Thromboprophylaxis with low-molecular-weight heparin (B01AB heparin group) is administered as follows: #enoxaparin sodium** (off-label in children under 18 years) in children under 2 months – 0.75 mg/kg, in children older than 2 months – 0.5 mg/kg subcutaneously every 12 hours; dalteparin sodium – in children from 1 month to 2 years 150 IU/kg, from 2 to 8 years – 125 IU/kg, older than 8 years – 100 IU/kg subcutaneously every 12 hours, with blood heparin level monitoring (anti-Xa assay) in accordance with the instructions. Fondaparinux sodium (off-label in children under 17 years); #fondaparinux sodium may be used in children older than 1 year at a dose of 0.1 mg/kg once daily subcutaneously. Dose adjustments are made based on laboratory test results [178,179,197,198].

• Patients with HLHS after Norwood-Blalock or Norwood-Sano procedures are recommended to receive thromboprophylaxis [178,179,197,198].

Level of Evidence (LoE) 3, Grade of Recommendation (GoR) C

Comments: in the early postoperative period, thromboprophylaxis should be carried out using heparin and its derivatives (B01AB heparin group), and subsequently

• Patients with HLHS after bidirectional cavopulmonary anastomosis (BCPA) or Fontan operation are recommended to receive thromboprophylaxis [178,179,197,198,199].

Level of Evidence (LoE) 3, Grade of Recommendation (GoR) C

Comments: in the early postoperative period, thromboprophylaxis should be carried out using heparin and its derivatives (B01AB heparin group), and thereafter – with vitamin K antagonists monitored by INR (target range 2.0-3.0) [178] or rivaroxaban granules for oral suspension with blood heparin level monitoring (anti-Xa assay), target range 0.5-1.0 [199].

3.2 Surgical Treatment

Surgical treatment for patients with HLHS is divided into two main categories:

1. Traditional staged surgical palliative treatment (where the Norwood procedure is performed as the first stage);

2. Modified methods, where the approach to the initial intervention is altered (a hybrid approach or performing bilateral pulmonary artery banding with prolonged infusion of C01EA prostaglandins until the second stage of hemodynamic correction, which may also vary—either the Norwood-Blalock or Norwood-Sano procedure, or a direct Norwood-bidirectional cavopulmonary anastomosis).

In all cases, the Fontan procedure must serve as the final stage.

The Norwood operation (the first stage for traditional staged surgical treatment and the second stage for modified methods). The main steps of this operation have remained unchanged since it was first performed, namely: 1) creation of an unobstructed outflow from the functionally single right ventricle into the reconstructed neoaorta (ensuring adequate antegrade systemic blood flow); 2) ensuring unobstructed venous return from the pulmonary veins to the right atrium via an atrial septal communication; 3) creation of controlled pulmonary blood flow (metered pulmonary blood flow) [67,112]. While the first two steps of the operation have remained practically unchanged, modifications have mainly concerned the methods of creating controlled pulmonary blood flow. In the classic Norwood procedure, a modified Blalock-Taussig shunt provides pulmonary blood flow by creating an anastomosis between the brachiocephalic or subclavian artery and the pulmonary artery (usually the right one) using a synthetic vascular graft made of polytetrafluoroethylene (PTFE). This shunt provides a continuous, direct blood flow from the systemic circulation to the pulmonary circulation during both systole and diastole. The Blalock-Taussig shunt may lead to the "coronary steal" phenomenon because diastolic pressure in the systemic circulation decreases (70–80% of coronary blood flow occurs during diastole; therefore, coronary steal may play an important role as a cause of mortality between stage I and stage II surgeries) [5,10,67].

An alternative to the Blalock-Taussig shunt is a shunt connecting the right ventricle to the pulmonary artery bifurcation. Although this type of shunt was initially described by Norwood and colleagues in 1981 [113], the technique was popularized and modified by Sano in the early 2000s (this shunt is now frequently referred to as the Sano shunt or Sano modification) [22,114]. This shunt is characterized by systolic-only flow and, consequently, there is no coronary steal. The disadvantage is the need for ventriculotomy, with a potential risk of single-ventricle dysfunction and a long-term risk of arrhythmias. Currently, the choice of shunt remains at the discretion of the surgeon [5,10,67,158].

Hybrid stage I was developed as a less invasive approach to palliative care for newborns with HLHS (allowing the postponement of major open-chest surgery at least until the end of the neonatal period). Gibbs et al. in 1993 reported the first successful single-stage stenting of the patent ductus arteriosus combined with bilateral pulmonary artery banding and balloon atrial septostomy as an alternative to the primary Norwood intervention [115]. This technique has proven viable in a number of subsequent publications and has even become the "standard" first-stage palliative surgical correction for HLHS [25-27,97,100,116]. Currently, percutaneous balloon atrial septostomy is typically deferred until the patient's discharge following the hybrid stage I palliation [100,116]. Regardless of the modification, this technique requires achieving the same three goals originally proposed for the Norwood operation: adequate systemic blood flow (via patent ductus arteriosus stenting), regulation of pulmonary blood flow (bilateral pulmonary artery banding), and unobstructed pulmonary venous outflow (balloon atrial septostomy). In modern practice, stage II should consist of the Norwood-BCPA procedure performed 3–5 months after the prior hybrid intervention [10,12,23-25, 64-67,96-100,116]. The "Achilles' heel" of this modified stage II is the high incidence of delayed left pulmonary artery stenosis.

A minimally invasive approach to palliative care for newborns with HLHS can also be performed without hybrid techniques, using only bilateral pulmonary artery banding as the first stage while maintaining ductal patency via prolonged prostaglandin infusion (from several weeks to two months), followed by a second-stage Norwood-Blalock, Norwood-Sano, or direct Norwood procedure with a cavopulmonary anastomosis. This technique is best suited for high-risk or critically ill patients [26,47-48,118-124,195-196].

• All patients with HLHS are recommended to undergo staged surgical treatment establishing single-ventricle hemodynamics, consisting of three stages: 1) Norwood procedure; 2) Glenn anastomosis; 3) Fontan procedure [18-22,48,64-67,71,85-86,114].

Level of Evidence (LE) 4, Grade of Recommendation (GR) C

• All patients with HLHS are recommended to undergo the Norwood-Sano or Norwood-Blalock procedure as the first stage of surgical treatment within the first 1 week of life [18-22,64-67,71,85-86,116-117].

Level of Evidence (LE) 4, Grade of Recommendation (GR) C

Comments: performing surgical intervention at a later date is associated with a significant increase in postoperative mortality and the rate of postoperative complications.

• Patients with HLHS are recommended to undergo diagnostic transvenous cardiac catheterization with pulmonary artery pressure measurement prior to the second stage of surgical treatment [18-22, 64-66,71,85-87,116-117].

Level of Evidence (LE) 4, Grade of Recommendation (GR) C

Comments: if the systolic pulmonary artery pressure drops below 25 mmHg or the mean pulmonary artery pressure drops below 15 mmHg, a decision is made to perform the second stage of surgical correction for HLHS.

• All patients with HLHS are recommended to undergo a bidirectional cavopulmonary anastomosis at the age of 2–10 months as the second stage of surgical treatment [18-22, 64-67,71,85-87,92,116-124].

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

Comments: the age for performing the second stage is individual for each child and depends on when pulmonary vascular resistance normalizes in the given patient.

• All patients with HLHS are recommended to undergo the Fontan procedure at the age of 18–36 months as the third stage of surgical treatment [18-22,48,64-67,71,88-91,122-124].

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

• In all patients with HLHS, the Fontan procedure is recommended to be performed using the extracardiac conduit modification [48,67,88-91,93-95,122].

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

• Performing hybrid stage I hemodynamic correction prior to the Norwood operation as the initial surgical treatment is recommended for patients with HLHS in the following cases: 1) admission to the hospital in extremely critical condition, 2) admission at an age older than 1 week of life, or 3) low birth weight patients [5,7,10,12,23-25,64-67,96-100].

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

Comments: performing the hybrid first stage is also preferred for patients with a complicated infectious and/or neurological history, or severe comorbid somatic pathology. Low body weight <2.5 kg is also an independent risk factor for high mortality. However, it is noted that survival in low-birth-weight patients after hybrid intervention currently remains higher compared to the Norwood procedure  [119,121,169-173].

• Following hybrid stage I hemodynamic correction, all patients with HLHS are recommended to undergo either the Norwood-bidirectional cavopulmonary anastomosis, Norwood-Sano, or Norwood-Blalock procedure at the age of 3–5 months as the second stage of surgical treatment [5,7,19-22,64-67,96-100,117-119].

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

Comments: the decision regarding the type of surgery is made based on the analysis of preoperative examination results and the clinical experience of the center.

• As an alternative to the hybrid first stage, it is recommended to consider performing bilateral pulmonary artery banding with a prolonged infusion of C01EA prostaglandins to maintain ductal patency [26,47-48,118-124].

Level of Evidence (LE) 4, Grade of Recommendation (GR) C

Comments: this technique is best suited for high-risk patients (with low birth weight, significant tricuspid regurgitation, concomitant cardiac or extracardiac pathology, etc.) or critically ill patients. That is, when the need to delay the Norwood procedure arises for only a relatively short period of time (usually just the neonatal period). Such patients remain in the hospital until the second stage of hemodynamic correction is performed. Continuing continuous prostaglandin infusion for more than 2 months is extremely undesirable, as it leads to a sharp increase in the risk of fatal complications (vasoplegia, etc.). Therefore, if it is necessary to delay the Norwood surgical intervention for a longer period of time, delayed patent ductus arteriosus stenting must be performed to discontinue the prostaglandin infusion (transitioning to a hybrid stage I)  [26,47-48,118-124].

3.3 Interventional radiology treatment

• Balloon atrioseptostomy is not recommended in preoperative patients with hypoplastic left heart syndrome (HLHS) who have a non-restrictive atrial septal defect [5,10,25-27,81-84].

Level of Evidence (LE) 4, Grade of Recommendation (GR) C

• All patients with HLHS who have a pressure gradient across the atrial communication greater than 10 mm Hg and pronounced metabolic disorders are recommended to undergo balloon atrioseptostomy to stabilize their condition [46,47,81-84].

Level of Evidence (LE) 4, Grade of Recommendation (GR) C

Comments: in cases of restrictive atrial septum, primary intervention may involve a Norwood hemodynamic correction or a hybrid stage I with atrioseptostomy. If an isolated atrioseptostomy is performed, it is optimal to postpone the first stage of single-ventricle HLHS correction for several days after this procedure. This tactic is driven by the need to reduce vascular resistance in the pulmonary circulation system. In patients with severe restriction at the atrial communication or an intact atrial septum, emergency intervention must be performed within the first 3 hours of life to decompress the left atrium [82,84].

• Following a hybrid stage I hemodynamic correction, all patients with HLHS are recommended to undergo balloon atrioseptostomy of the patent foramen ovale (regardless of its size) prior to hospital discharge [25-27,81-84].

Level of Evidence (LE) 4, Grade of Recommendation (GR) C

Comments: identical tactics should be followed if separate pulmonary artery banding with prolonged prostaglandin infusion was previously performed, but patent ductus arteriosus stenting was ultimately performed as the next stage instead of the Norwood procedure.

• In the interstage period, if complications occur (such as pulmonary artery stenoses, obstruction at the level of the descending aorta or the stented ductus, etc.), it is recommended to use percutaneous endovascular techniques [67,116-117].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

Comments: these techniques also include the creation of an atrial septal defect with stenting when balloon atrioseptostomy is ineffective, stenting of pulmonary artery stenoses, or repeat stenting of the patent ductus arteriosus. Regarding neo-aortic obstruction, open surgical techniques are preferred by the majority of surgeons.

3.4 Other treatment

• Patients with HLHS and severe right ventricular dysfunction and/or severe tricuspid regurgitation are recommended to undergo heart transplantation as the only alternative to staged correction [28-31,48,67,106,117,122].

Level of Evidence 4, Grade of Recommendation B

Comments: if waiting for a donor heart is necessary, a hybrid stage I or the use of mechanical hemodynamic support devices (such as extracorporeal membrane oxygenation (ECMO) or other artificial circulatory support systems) can serve as an interim treatment stage.

• In patients with forms of HLHS with special anatomy (a combination of aortic valve atresia, in the absence of severe mitral valve pathology with a large ventricular septal defect, and normal intrauterine development of the left ventricular cavity—indexed EDV greater than 20 mL/m²) or the presence of hypoplastic left heart syndrome variants, it is recommended to perform procedures aimed at preserving biventricular hemodynamics [32-37,125].

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

Comments: since biventricular correction is only possible in certain cases and is often risky, the choice of surgical treatment tactics is based on a thorough analysis of preoperative echocardiography data, supplemented by CT or MRI scans if necessary. The morphometric results obtained for each patient, combined with the morphological features of the mitral and aortic valves, the left ventricle, and hemodynamic characteristics, determine the final surgical strategy.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

• Patients with HLHS following any stage of surgical correction are recommended to avoid traction loads on the upper extremities for the subsequent 4–6 months of life [10,69,129].

Level of Evidence (LE) 4, Grade of Recommendation (GR) C

• All patients with HLHS are recommended to undergo rehabilitation measures lasting at least 6 weeks after each stage of surgical treatment [62,67,70-71,116-117,195-196].

Level of Evidence (LE) 4, Grade of Recommendation (GR) C

Comments: rehabilitation can in most cases be carried out at home, provided there is periodic monitoring of the patient's condition by the local pediatrician (once every 2-3 weeks). The optimal duration of the rehabilitation period is 10-12 weeks. If rehabilitation is ineffective, requires the selection of an individual program, or frequent monitoring by a subspecialist, the question of sending the patient to a specialized rehabilitation center should be considered.

• All patients with HLHS are recommended to have an individual optimal physical activity regimen selected during the outpatient follow-up stage after each stage of surgical treatment [10,62,67,71,116,129-130].

Level of Evidence (LE) 4, Grade of Recommendation (GR) C

5. Prevention and Dispensary Observation

• All patients with HLHS are recommended to undergo follow-up care by a pediatric cardiologist (dispensary appointment/examination/consultation by a pediatric cardiologist experienced in congenital heart disease) after each stage of hemodynamic correction to detect hemodynamic disturbances that may require surgical treatment [5,7,10,12,25-31,48,67,81-84,96-100,106,117,122-124].

Level of Evidence (LE) 4, Grade of Recommendation (GR) C

Comments: the most common pathologies requiring additional correction include: development of systemic atrioventricular (tricuspid) valve regurgitation, neo-aortic valve regurgitation, development of ascending aorta and/or aortic arch obstruction following previous reconstruction, development of pulmonary artery stenoses, and the need for conduit replacement, among others. When these complications develop, the feasibility of correcting the developed pathology must be assessed. If reconstructive interventions are possible, they are the method of choice; however, if reconstructive interventions are not feasible, heart transplantation remains the only possible solution.

Level of Evidence (LE) 4, Grade of Recommendation (GR) C

Comments: parents play an important role in adhering to medical recommendations (ensuring faster rehabilitation of children) and identifying early signs of clinical deterioration in children with HLHS. Therefore, cardiovascular medications must be safe, understandable, and easy to administer. Furthermore, parents must be taught to monitor the rate and character of breathing during the child's sleep, oral feeding volume, and body weight (reporting any detected deviations to the supervising physician).

• All patients with HLHS between stages of surgical treatment are recommended to have a dispensary appointment (examination, consultation) with the local general pediatrician at their place of residence (at least once every 2 weeks) and a dispensary appointment (examination, consultation) with a pediatric cardiologist (at least once every 7 days during the first 2 months, and at least once a month thereafter) [5,7,10,12,19-21,35,42,53,58,62,63,67,116,131-138,145].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

Comments: such a high frequency of outpatient check-ups by physicians is necessary for the timely detection of any hemodynamic imbalance at an early stage before a critical situation develops, as well as for the timely discovery of extracardiac complications or comorbidities that may affect the final treatment outcome. When hemodynamic or other issues are detected early, diagnostic and, if necessary, interventional procedures aimed at halting the progression of the identified disorders should be actively pursued.

• Patients with HLHS after each stage of surgical treatment are recommended to undergo evaluation at a specialized cardiosurgical hospital at least once every 3 months during the inter-stage period and throughout the first year after the Fontan procedure [5,7,10,67,87-96,101,106,116-117].

Level of Evidence (LE) 4, Grade of Recommendation (GR) C

• One year after the Fontan procedure, all patients with HLHS are recommended to be followed up at a specialized hospital at least once a year (optimally twice a year) [5,10,62,67,87-96,101,106,116-117,145].

Level of Evidence (LE) 4, Grade of Recommendation (GR) C

• All patients with HLHS at each evaluation in a specialized hospital are recommended to undergo echocardiography with monitoring of the contractile function of the single functional ventricle of the heart, monitoring of neoaortic and tricuspid valve regurgitation, as well as assessment of hemodynamics in the neoaorta (exclusion of systemic blood flow obstruction), dimensions of the atrial communication, and the character of blood flow in the pulmonary arteries (exclusion of pulmonary blood flow obstruction) [5,7,10,12,25-31,48,67,81-84,96-100,106,117,122-124].

Level of Evidence (LE) 4, Grade of Recommendation (GR) C

• All patients with HLHS are recommended to have dispensary follow-up by a neurologist at their place of residence [40-41,67,117,126-129,137-138,145].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

Comments: Rogers et al. published data showing that 73% of children with HLHS presented with microcephaly 38 months after surgical correction, and 45% maintained a weight deficit. Different degrees of mental retardation were observed in 64% of children, and significant functional disability was noted in 73% [38]. According to Kern et al., the mean IQ score (in children during the long-term period with HLHS) was 88, with 8.3% of patients exhibiting significant mental retardation [39]. Later studies have shown that children with HLHS lag behind in psychoemotional (IQ = 89) and physical development, but the differences are not significant compared to children with other congenital heart defects [40-41].

• All patients with HLHS after each stage of surgical correction are recommended to have individualized therapy tailored to correct circulatory failure and reduce vascular resistance in the lesser circulation [5,7,65,67,70,80,86-88,101,104-108,116-117,].

Level of Evidence (LoE) 3, Grade of Recommendation (GoR) C

Comments: therapy selection is carried out in the cardiosurgical hospital before discharge of the patient. If necessary, therapy correction is performed by the cardiologist at the patient's place of residence.

6. Organization of Medical Care

Stages of medical care and indications for hospitalization:

1. clarification of the diagnosis;

2. in case of confirmation of the diagnosis of HLHS (it should be understood that the defect is always critical), it is necessary to urgently transfer the child to the intensive care unit and initiate conservative therapy (administration of C01EA prostaglandins infusion, if necessary C01D vasodilators for heart diseases and C01C cardiotonic agents excluding cardiac glycosides, in the absence of effect – transfer to mechanical ventilation) and arrange emergency transfer to a cardiosurgical hospital for surgical care immediately after stabilization of the clinical condition;

3. if the patient's condition is stable against the background of C01EA prostaglandins infusion, it is still necessary to arrange the transfer of the patient to a cardiosurgical hospital as soon as possible, since decompensation of the condition may develop at any time (meanwhile, the patient must also be in the intensive care unit);

4. confirmed HLHS is always an absolute indication for cardiosurgical staged palliative treatment at 1-2 weeks of age, with preference for the Norwood procedure as the first stage if the patient's condition permits. In the presence of comorbid pathology or extreme severity of the condition, preference for the first stage may be given to the hybrid first stage of hemodynamic correction or bilateral pulmonary artery banding combined with prolonged infusion of C01EA prostaglandins. Subsequently, all patients undergo the following stages of surgical correction according to an individualized approach until the Fontan procedure is performed, which is the final stage of palliative correction of HLHS.

Basics of conservative therapy

• a key role in preoperative conservative therapy is assigned to intravenous infusion (C01EA) of prostaglandins maintaining ductus arteriosus patency;

• it is important to adhere to the following algorithm when stabilizing the patient's condition (in case of progressive deterioration of the patient's condition): first, rule out excessive pulmonary blood flow; second, rule out systemic hypovolemia; third, administration of nitroferricyanide derivatives or peripheral antiadrenergic agents infusion is recommended under blood pressure monitoring. Next, if necessary, cardiotonic agents excluding cardiac glycosides are prescribed (drugs with pronounced vasopressor effects should be avoided whenever possible);

• at saturation > 90% combined with lactacidemia, arterial hypotension, and oliguria, tracheal intubation and transfer to mechanical ventilation are recommended. Mechanical ventilation is performed with high positive end-expiratory pressure parameters and a fraction of inspired oxygen of 21%. In other cases, without extreme necessity, one should try to avoid transferring the patient to mechanical ventilation, as unjustified transfer may instead worsen the patient's condition;

• criteria for the effectiveness of preoperative conservative therapy are the normalization of acid-base balance, regression of serum lactate levels, a tendency towards normalization of diuresis and reduction of plasma residual nitrogen levels, and arterial blood oxygenation levels within the range of 75-90%.

Indications for patient discharge from a medical organization:

• balanced systemic and pulmonary blood flows;

• no need for continued respiratory support and intravenous infusion therapy;

• absence of signs of heart failure;

• sinus heart rhythm.

7. Additional Information

• All patients with HLHS are recommended to undergo neurosonography and/or brain CT scan and a repeat consultation (examination) by a neurologist before each stage of HLHS surgical correction in order to detect pathological changes that affect the outcome of surgical correction and may influence the choice of anesthetic and perfusion management [5,7,10, 40-41,67,117,126-129,145].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

• All patients with HLHS upon initial admission to a specialized hospital before the first stage of surgical correction are recommended to undergo assessment of liver and kidney functional state. In the presence of severe renal and hepatic failure, therapy aimed at normalizing their function is carried out. After normalization of the parameters, the question of the patient's readiness for surgery is addressed [5,10,48,67,70,80,86-88,101,104-108,116].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

• Inpatient treatment for all patients with HLHS is recommended to be carried out in medical institutions with extensive experience in performing these surgeries and corresponding experience in postoperative patient management. Clinics with a high volume of surgeries in patients with HLHS tend to have lower mortality rates [5,7,10,80,86,88,104].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Avramenko A.A. (Samara)

2. Apkhanova T.V., MD, "National Association of Experts in Spa Treatment"

3. Arkhipov A.N., PhD (Novosibirsk)

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

5. Bogdanov V.N. (Chelyabinsk)

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

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

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

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

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

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

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

13. Kalashnikov S.V., PhD (Moscow)

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. Konchugova T.V., MD, PhD, Professor, "National Association of Experts in Spa Treatment and Balneology" Krivoshchekov E.V., MD, PhD (Tomsk), "Association of Cardiovascular Surgeons of Russia

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

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

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

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

22. Nefedova I.E., MD, PhD (Moscow)

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

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

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

26. 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"

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

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

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. Teplov P.V. (Krasnoyarsk)

31. Fesyun Anatoly Dmitrievich, MD, PhD, Associate Professor, President of the National Association of Experts in Spa Treatment and Balneology

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

33. Yurlov I.A., PhD, is not a member of the ACSR (Moscow).

34. Yakovlev Maxim Yuryevich, MD, PhD, "National Association of Experts in Spa Treatment and Balneology"

All members of the Working Group have confirmed that they have no financial support or conflicts of interest to disclose.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

• Pediatrician

• Cardiologist

• Pediatric Cardiologist

• Cardiovascular Surgeon

• Neonatologist

• Ultrasound Diagnostics Physician

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).

During the development of the clinical guidelines, a new grading system for levels of evidence (LE) and grades of recommendation (GR) for therapeutic, rehabilitative, preventive, and diagnostic interventions was used (Tables P1, P2, and P3), introduced in 2018 by the Center for Healthcare Quality Assessment and Control of the Russian Ministry of Health. The National Guidelines were formulated based on the ESC guidelines, taking into account national specifics, diagnostic and treatment features, and the availability of medical care.

Table P1. Scale for grading levels of evidence (LE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table P2. Scale for grading levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table P3. Scale for grading grades of recommendation (GR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative 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

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

2. Order of the Russian Ministry of Health No. 918n dated November 15, 2012 "On approval of the procedure for providing medical care to patients with cardiovascular diseases"

3. Order of the Russian Ministry of Labor No. 585n dated August 27, 2019 "On classifications and criteria used in the implementation of medical and social assessment of citizens by federal state institutions"

4. 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);

5. Order of the Ministry of Health of the Russian Federation No. 804n dated October 13, 2017 "On approval of the nomenclature of medical services";

6. Order of the Ministry of Health of the Russian Federation No. 700n dated 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. 205n dated May 2, 2023 "On approval of the Nomenclature of positions of medical workers and pharmaceutical workers"

8. Order of the Russian Ministry of Health No. 4n dated June 6, 2012 "On approval of the nomenclature classification of medical devices".

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Dear patient (patient's parents), the examination results revealed a complex congenital heart defect in you (your child) — hypoplastic left heart syndrome. By voluntarily consenting to the surgery, you must understand the purpose and risks of the operation, which your attending physician will explain to you.

HLHS occurs in the early stages of fetal development. The causes of embryogenesis disorders are numerous: maternal infectious diseases in early pregnancy, chronic parental diseases, parental harmful habits, environmental and genetic factors, etc. Depending on the size of fetal communications (patent foramen ovale, patent ductus arteriosus), the clinical manifestations of the defect can vary significantly. However, in any case, with hypoplastic left heart syndrome, the condition after birth will be severe with progressive deterioration over time. Therefore, one should not impede the prompt transfer of the child from the maternity hospital to a cardiac surgery center. To stabilize the condition and ensure the child can withstand transportation immediately after birth, venous access will be established and intravenous administration of C01EA prostaglandins will be initiated to prevent the closure of the patent ductus arteriosus, otherwise its closure will lead to the immediate death of the infant. The administration of this drug in most cases leads to short-term stabilization, making it possible to transfer the child to a cardiac surgery center to clarify the anatomy of the defect and select the optimal surgical treatment.

After the child's transfer, the severity of the condition and the presence of comorbid pathology will be clarified. If the condition is stable, surgical intervention is usually performed within 24–48 hours from the moment of transfer. In cases of extreme severity, resuscitation measures aimed at stabilizing the condition will be performed first, and only after stabilization will the issue of surgical intervention be addressed.

Hypoplastic left heart syndrome involves a staged surgical approach and is characterized by the impossibility of complete anatomical correction of the defect. The staged approach consists of three or four surgical interventions and is aimed solely at creating acceptable conditions for the child's life and development. The main goal of reconstructive interventions is the separation of arterial and venous blood flows. Since this congenital heart defect is one of the most severe, one must also understand the high risks of an adverse outcome in the treatment of this pathology. After each stage of correction, various complications may occur in the early postoperative period: postoperative bleeding; heart failure; respiratory failure requiring prolonged mechanical ventilation; acute renal failure; infectious complications, etc. The progression of these complications can lead to irreversible consequences. The development of complications is also possible during the interstage periods.

In most cases, each subsequent staged operation leads to an improved condition. It should be understood that the number of stages is not final, and additional surgical interventions may be required (in the event of rapid deterioration of the child's condition).

An alternative to hemodynamic corrections can be heart transplantation or heart-lung transplantation. This procedure can be performed at any stage of treatment in the presence of vital indications.

Treatment of this congenital heart defect often requires a prolonged hospital stay and frequent monitoring in the interstage period, which also requires understanding and maximum responsibility from the parents.

It is important not to miss follow-up examinations after surgery for timely evaluation of correction results and detection of possible complications, to follow the doctor's recommendations, and to take all prescribed medications in a timely manner.

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

No.