Diseases of the pulmonary circulation


  • Updated definitions and classification of pulmonary hypertension have helped to advance the understanding of pulmonary hypertensive diseases and facilitate drug trials.

  • Four classes of drugs have been extensively studied for the treatment of pulmonary hypertension: prostanoids, endothelin receptor antagonists, phosphodiesterase 5 inhibitors, and calcium channel blockers. The use of approved vasodilator drugs, either alone or in combination, has led to an improvement in the quality of life and clinical outcomes in pediatric patients with pulmonary hypertension. Unfortunately, there has been no significant effect on mortality.

  • Pulmonary vascular remodeling, as a characteristic of chronic pulmonary hypertension, is both the result of, and a contributor to, increased pulmonary vascular pressures.

  • Emerging evidence suggests an important role of novel mechanisms contributing to pulmonary vascular and right ventricle remodeling, which are not adequately addressed by current therapies, perhaps explaining continuing disease morbidity and mortality.

  • The observation of differences in genes associated with pulmonary hypertension in children compared with adults support the idea that it is at least in part a developmental lung disease when it presents early in life; technologic advances in genetic sequencing will provide important information to the patient, families, and caregivers.

  • Therapy for pulmonary hypertension remains challenging, and gaps in the current clinical and lab-based research need to be addressed to more specifically define the pathology of the disease and accurately measure the symptoms correlated with disease progression with the future goal of identifying curative therapies.

Definition and classification

Pulmonary hypertension (PH), defined as an increase in pressure in lung blood vessels, is a heterogeneous, complex, and often misunderstood condition. PH is associated with diverse cardiac, pulmonary, and systemic diseases in both adults and children and is associated with significant morbidity and mortality. Since the first World Symposium on PH in 1973, PH has been defined as mean pulmonary artery pressure (mPAP) of 25 mm Hg or greater measured by right heart catheterization in the supine position at rest. However, at the 6th World Symposium on PH in 2018, discussions took place to determine whether the definition should be changed to an mPAP at rest of 20 mm Hg or greater. This was due to studies showing that, in normal subjects, comprising nearly 1200 patients from 47 studies, mPAP at rest was 14.0 ± 3.3 mm Hg. Thus, two standard deviations suggest mPAP of 20 mm Hg or greater as above the upper limit of normal. The committee determined that it was essential to emphasize that this value, used in isolation, cannot characterize a clinical condition and does not define the pathologic process, per se. Indeed, increases in mPAP have several different causes with different outcomes as well as various management approaches. Since an increase in pulmonary pressure can be due to purely precapillary causes (as is described in groups 1, 3, 4, and 5 in Box 53.1 ), it was determined that it is essential to include pulmonary vascular resistance (PVR) in the definition of precapillary PH. This allows a separation of the elevation in pulmonary artery pressure due to pulmonary vascular disease from those due to elevation of pulmonary artery wedge pressure or due to high cardiac output. Measuring PVR and using a cutoff of PVR of 3 units or more is important to separate precapillary PH (group 1) from combined or isolated pre- and postcapillary PH due to left heart disease (group 2; see Box 53.1 ).

• BOX 53.1

Updated Clinical Classification of PH

  • 1.


    • 1.1

      Idiopathic PAH

    • 1.2

      Heritable PAH

    • 1.3

      Drug- and toxin-induced PAH

    • 1.4

      PAH associated with

      • 1.4.1

        Connective tissue disease

      • 1.4.2

        HIV infection

      • 1.4.3

        Portal hypertension

      • 1.4.4

        Congenital heart disease

      • 1.4.5


    • 1.5

      PAH long-term responders to calcium channel blockers

    • 1.6

      PAH with overt features of venous/capillaries (PVOD/PCH) involvement

    • 1.7

      Persistent PH of the newborn syndrome

  • 2.

    PH due to left heart disease

    • 2.1

      PH due to heart failure with preserved LVEF

    • 2.2

      PH due to heart failure with reduced LVEF

    • 2.3

      Valvular heart disease

    • 2.4

      Congenital/acquired cardiovascular lesions leading to postcapillary PH

  • 3.

    PH due to lung diseases and/or hypoxia

    • 3.1

      Obstructive lung disease

    • 3.2

      Restrictive lung disease

    • 3.3

      Other lung disease with mixed restrictive/obstructive pattern

    • 3.4

      Hypoxia without lung disease

    • 3.5

      Developmental lung disorders

  • 4.

    PH due to pulmonary artery obstruction

    • 4.1

      Chronic thromboembolic PH

    • 4.2

      Other pulmonary artery obstruction

  • 5.

    PH with unclear and/or multifactorial mechanisms

    • 5.1

      Hematologic disorders

    • 5.2

      Systemic and metabolic disorders

    • 5.3


    • 5.4

      Complex congenital heart disease

HIV, Human immunodeficiency virus; LVEF, left ventricular ejection fraction; PAH, pulmonary arterial hypertension; PCH, pulmonary capillary hemangiomatosis, PH, pulmonary hypertension; PVOD, pulmonary veno-occlusive disease.

Data from Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension . Eur Respir J. 2019;53(i).

It is clear that the etiologic origins of PH are complex and can be associated with diverse pathologic conditions. The classification system for PH in adults was first established in 1998 and has since gone through several revisions, the last one at the 6th World Symposium on PH in 2018. The general purpose of the clinical classification of PH was and continues to be to categorize clinical conditions associated with PH based on similar pathophysiologic mechanisms, clinical presentation, hemodynamic characteristics, and therapeutic management. The most recent updated classification system is shown in Box 53.1 . , This classification system has helped to advance not only our understanding of pulmonary hypertensive diseases but has also facilitated drug trials, particularly in group 1 pulmonary arterial hypertension (PAH).

It is important to note that, in children, the distribution of etiologies for PH is quite different from that observed in adults. In pediatric patients, PH is often a heterogeneous disease with several contributing factors ( Fig. 53.1 ), for example, a patient born prematurely with trisomy 21 and an endocardial cushion defect who develops PH. The Pediatric Taskforce of the Pulmonary Vascular Research Institute (PVRI) has proposed a complementary classification system in their 2011 Panama Consensus review ( Table 53.1 ) to take into account the diverse, multifactorial nature of pediatric PH. The classification system suggested by the PVRI Pediatric Taskforce is based on the clinical diagnosis of pediatric diseases associated with PH encountered in clinical practice. The aim of the PVRI Panama classification system is not to stratify PH groups to give therapeutic guidelines but rather to create a framework to facilitate diagnostic workup, advance understanding of pathophysiology and epidemiology, and to direct the development of in vivo and in vitro laboratory-based models that are relevant to human disease. The Panama consensus classification of PH divides pediatric pulmonary hypertensive vascular disease into 10 broad categories listed in order of frequency (see Table 53.1 ). The strength of this classification, which is meant as a complementary system and not as a replacement for the World Health Organization (WHO) classification system, is that it takes into consideration patients with multifactorial causes of PH primarily when associated with a syndrome or chromosomal abnormality (see Fig. 53.1 ).

• Fig. 53.1

Heterogeneity and multifactorial elements in pediatric pulmonary hypertensive vascular disease.

TABLE 53.1

Basic Categories of Pediatric Pulmonary Hypertensive Vascular Disease Developed by the PVRI Pediatric Taskforce

Category Description
1 Prenatal or developmental pulmonary hypertensive disease
2 Perinatal vascular maladaptation
3 Pediatric cardiovascular disease
4 Bronchopulmonary dysplasia
5 Isolated pediatric pulmonary hypertensive vascular disease
6 Multifactorial pulmonary hypertensive vascular disease in congenital malformation syndromes
7 Pediatric lung disease
8 Pediatric thromboembolic disease
9 Pediatric hypobaric hypoxic disease
10 Pediatric pulmonary vascular disease associated with other systemic disorders

PVRI , Pulmonary Vascular Research Institute.

Of note, there is a subgroup of patients with pulmonary vascular disease (PVD) that have diverse abnormalities of the pulmonary vascular bed but do not fulfill the formal criteria for a diagnosis of PH. PVD characterizes a pathophysiologically mixed group of abnormalities of vascular tone, reactivity, growth, and structure. Although PVD often results in the development of PH, PVD can exist without the development of increased PAP. For example, congenital cardiac defects with single-ventricle physiology are often associated with abnormalities of the pulmonary vasculature that can lead to decreased pulmonary blood flow and subsequent decreased cardiac function, yet the mPAP may never be elevated enough to be formally classified as PH.

Pathology of pulmonary hypertension

Pulmonary vascular remodeling is a characteristic of chronic PH defined by hemodynamic alterations of the pulmonary circulation in which the mPAP is in excess of 25 mm Hg ( Fig. 53.2 ). Pulmonary vascular remodeling is both the result of, and a contributor to, increased pulmonary vascular pressures by increasing PVR. , In this process, pulmonary arteries undergo several structural alterations, which can involve intimal fibrosis, medial hypertrophy, and adventitial/perivascular inflammation and fibrosis. , Complex intimal lesions comprise different elements, such as onion skin lesions, plexiform core lesions, and dilation lesions, which are commonly observed in close topographic association. In some cases of group 1 PAH, capillary thickening and hypertrophy of the veins is observed. Recent reports suggest that systemic vessels, such as the vasa vasorum and bronchial arteries running within the adventitia of pulmonary arteries or within the peribronchial connective tissue, respectively, could be involved in these atypical vascular changes in PAH. ,

• Fig. 53.2

Key pathologic alterations in pulmonary arterial hypertension lungs.

Other pathologic alterations are presenting in PH. In experimental and human PH/PAH, angiogenesis is disturbed with loss and progressive obliteration of precapillary arteries, leading to a pattern of pulmonary vascular rarefaction (“dead tree” picture). There is also accumulating evidence supporting the involvement of the postcapillary pulmonary venous vasculature (vascular wall thickening) in all PH groups with varying degrees of intensity. , In PAH, it is also established that the dynamic and unadapted remodeling of the extracellular matrix forms a permissive milieu that not only favors cell motility, proliferation, apoptosis, and differentiation of resident vascular cells and recruitment of inflammatory cells but can also have a considerable effect on vessel stiffness. ,

Therefore, in addition to the lesions mainly occurring in distal muscular-type arteries, ranging in diameter from 500 μm down to 70 μm in humans (medial hypertrophy/hyperplasia, intimal and adventitial fibrosis, perivascular inflammation, plexiform lesions), PH can be attributed to stiffening of large elastic main, lobar, and segmental pulmonary arteries (large vessel abnormalities). Clinical treatment of PH in children has focused on the distal vasculature. However, it is now clear that right ventricular (RV) afterload is not solely determined by the distal pulmonary vascular bed (as reflected in the PVR) but is also impacted by proximal pulmonary vascular stiffness (PVS). Recent clinical work has highlighted the importance of PVS in the progression of PH, and it has been demonstrated that inclusion of impedance and PVS outcomes analysis has value over PVR alone. , Mechanical studies have begun to elucidate the gross vascular changes responsible for stiffening; existing and novel studies of cellular mechanical transduction suggest that PVS may play a role in pulmonary disease pathogenesis and progression. , In adults, the stiffness of lung elastic pulmonary arteries increases in several forms of PH and contributes to the disease course. ,

Diagnostic evaluation of pulmonary hypertension/pulmonary vascular disease

Because PH/PVD is a complex and multifactorial disease, it is important that children with the suspected diagnosis of PH/PVD undergo a multidisciplinary evaluation in PH centers, as they have experience both in specialized diagnostic procedures and initiation and monitoring of therapies. A comprehensive history and physical examination, combined with diagnostic testing for the assessment of PH pathogenesis/classification and formal assessment of cardiac function, should be performed. Specifically, a chest radiograph, electrocardiogram (ECG), echocardiogram, chest computed tomography (CT) with and without contrast, 6-minute walk test in older children, laboratory studies including brain natriuretic peptide (BNP), and cardiac catheterization should be considered critical components of a thorough evaluation. Other tests—such as a sleep study, cardiac positron emission tomography (CPET), additional laboratory work, magnetic resonance imaging (MRI), and lung perfusion scans—may have greater value in select populations. Genetic testing is also important, discussed later.

The 2015 American Heart Association/American Thoracic Society (AHA/ATS) consensus guidelines summarize the following recommendations for the diagnosis and evaluation of pediatric PH/PVD ( Fig. 53.3 ):

  • 1.

    Initial PH diagnosis: Comprehensive history and physical examination combined with diagnostic testing to diagnose PH pathogenesis/classification and formal assessment of cardiac function should be performed before the initiation of therapy at an experienced center (Class I, Level of Evidence B).

  • 2.

    Imaging to diagnose pulmonary thromboembolic disease, peripheral pulmonary artery stenosis, pulmonary vein stenosis, pulmonary vascular occlusive disease, and parenchymal lung disease should be performed at the time of diagnosis (Class I, Level of Evidence B).

  • 3.

    Serial echocardiograms should be performed to follow clinical course, especially in the setting of changes in therapy or clinical condition (Class I, Level of Evidence B).

  • 4.

    Cardiac catheterization is recommended before initiation of PAH-targeted therapy (Class I, Level of Evidence B). Exceptions may include critically ill patients requiring immediate initiation of empiric therapy (Class I, Level of Evidence B).

  • 5.

    Cardiac catheterization should include acute vasoreactivity testing (AVT) unless there is a specific contraindication (Class I, Level of Evidence A).

  • 6.

    The minimal hemodynamic change that defines a positive response to AVT for children should be considered as a 20% or greater decrease in PAP and PVR/SVR (systemic vascular resistance) without a decrease in cardiac output (Class I, Level of Evidence B).

  • 7.

    Intervals for repeat catheterizations should be based on clinical judgment but include worsening clinical course or failure to improve during treatment (Class I, Level of Evidence B).

  • 8.

    MRI can be useful as part of the diagnostic evaluation and during follow-up to assess changes in ventricular function and chamber dimensions (Class IIa, Level of Evidence B).

  • 9.

    BNP or N-terminal (NT)-pro hormone BNP (NT-proBNP; BNP’s more stable by-product) is released from the atrium and ventricle in response to stretch or volume overload. BNP or NT-proBNP is directly correlated with the severity of PH. BNP or NT-proBNP should be measured at diagnosis and during follow-up to supplement clinical assessment (Class I, Level of Evidence B). However, it is important to note that in children with Eisenmenger syndrome (e.g., in patients with unrepaired ventricular septal defects [VSDs] in whom the ventricle is adapted to chronic volume overload, BNP may not be elevated).

  • 10.

    The 6-minute walk distance should be measured to follow exercise tolerance in pediatric patients of appropriate age with PH (Class I, Level of Evidence A).

  • 11.

    A sleep study is recommended in the following situations:

    • a.

      Patients at risk for sleep-disordered breathing (Class I, Level of Evidence B).

    • b.

      Patients with poor responsiveness to PAH-targeted therapies (Class I, Level of Evidence B).

• Fig. 53.3

Pediatric pulmonary hypertension (PH): diagnostic evaluation algorithm. ECG , electrocardiogram; HIV , human immunodeficiency virus.


At present, four classes of drugs have been extensively studied for the treatment of PAH: prostanoids (epoprostenol, treprostinil, iloprost, beraprost), endothelin receptor antagonists (ERAs; bosentan, ambrisentan), phosphodiesterase 5 (PDE5), inhibitors (sildenafil, tadalafil), and calcium channel blockers ( Fig. 53.4 ). Cardiac catheterization and AVT should be performed prior to initiating chronic pharmacotherapy. Improved survival has been noted in children with positive acute vasodilator response. , Furthermore, anatomic obstruction resulting from PVD or left-sided heart disease should be ruled out. A current treatment algorithm is presented in Fig. 53.5 .

• Fig. 53.4

Current pharmacologic pathways in pulmonary hypertension therapy. cGMP, Cyclic guanosine monophosphate; ERA, endothelin receptor antagonist; FDA, US Food and Drug Administration; IV, intravenous; PDE5, phosphodiesterase 5; SQ, subcutaneous.

• Fig. 53.5

Pediatric pulmonary arterial hypertension treatment algorithm. CCB, Calcium channel blocker; ERA, endothelin receptor antagonist; IV, intravenous; PDE5, phosphodiesterase 5; SQ, subcutaneous.

Prostacyclin (PGI 2 ) analogs

An imbalance in thromboxane A2 and PGI 2 with preferential synthesis of the potent vasoconstrictor thromboxane A2 has been described in children with congenital heart disease (CHD) and adults with idiopathic PAH (IPAH) or heritable PAH (HPAH). PGI 2 and PGI 2 analogs augment pulmonary vasodilation via the second messenger cyclic adenosine monophosphate. Since it became available in 1979, intravenous PGI 2 (epoprostenol) remains the gold standard for treating severe PAH with RV failure. Long-term use of epoprostenol, the first approved PGI 2 analog, has been shown to increase survival rates and improve quality of life in children and adults with PAH. Epoprostenol is started at 2 ng/kg per minute, and then up titrated until side effects such as nausea, diarrhea, jaw pain, bone pain, and headaches develop. The dosing range of 40 to more than 150 ng/kg per minute is quite broad, with children frequently requiring higher doses than adult patients. The logistics of PGI 2 and epoprostenol are challenging. Due to its very short half-life (2–5 minutes), epoprostenol treatment requires 24-hour infusion via a permanent central line and constant cooling of the medication. Abrupt interruption of the medication puts the patient at risk for rebound PH crisis. Central line–related complications, such as sepsis or local infections, are also common. Inhaled epoprostenol has been used in the critical care setting. , Newer analogs of PGI 2 , such as treprostinil, are chemically stable at room temperature and have longer half-lives. Treprostinil is available as subcutaneous injection, inhaled, and the US Food and Drug Administration (FDA) has approved oral formulations for adults but not for pediatric patients. One of the newer PGI 2 analogs, treprostinil, is chemically stable at room temperature and has a longer half-life. The FDA has approved treprostinil for subcutaneous, inhaled administration and as an oral medication for adults. Studies suggest that it is safe for pediatric patients, but it has not received FDA approval for use in children. Iloprost is an inhalational PGI 2 analog approved for the treatment of adult PAH in the United States. Inhaled PGI 2 analogs have the advantage of having minimal effects on blood pressure compared with systemic PGI 2 analogs.

Endothelin receptor antagonists

Endothelin-1, a protein secreted from endothelial cells and perhaps the most potent endogenous vasoconstrictor, acts through two endothelin receptor subtypes, ET A and ET B . Vascular smooth muscle cells express both ET A and ET B receptors and mediate vasoconstriction. ET B receptors are expressed by endothelial cells and stimulate the release of nitric oxide (NO) and PGI 2 in response to endothelin-1. Additionally, the ET B receptor clears free, circulating endothelin-1. Patients with PH have increased levels of endothelin-1. Bosentan, a nonspecific ERA, decreases PAP and PVR, improves exercise capacity, and is well tolerated in children with IPAH or PAH associated with CHD. A selective ET A antagonist, ambrisentan, may have the advantage of blocking the vasoconstrictive effects mediated by ET A receptors while preserving the vasodilator and clearance functions of ET B receptors. The FDA approved ambrisentan in June 2007 for adults with WHO group 1 PAH. In a retrospective study, 38 pediatric patients with PAH were treated with ambrisentan as add-on therapy or as replacement therapy for bosentan. Functional class and mPAP improved in both groups, but one patient required an atrial septostomy because of disease progression. Thus, blockade of ERAs emerged as a logical therapeutic target. ERAs can cause elevated liver aminotransferase levels (hence, monthly monitoring of liver enzymes is required), teratogenicity, anemia, peripheral edema (possibly due to the negative inotropic effect on the RV), decreased effectiveness of oral contraceptive agents, and effects on male fertility. Ambrisentan is less likely than bosentan to cause elevation of aminotransferases.

Phosphodiesterase 5 inhibitors

Specific PDE5 inhibitors, such as sildenafil or tadalafil, act via increasing the second messenger cyclic guanosine monophosphate and thus stimulate pulmonary vascular dilation. PDE5 expression and activity are upregulated in PH. Exercise capacity and hemodynamics were improved with sildenafil in children with persistent pulmonary hypertension of the newborn (PPHN), IPAH, and PH. In several small studies of children with PPHN, IPAH, and PH associated with CHD, sildenafil has been shown to improve exercise capacity and hemodynamics. , Sildenafil is also used in the critical care setting to facility weaning off inhaled nitric oxide (iNO) or postoperative PH after CHD repair. Additionally, sildenafil is used in PH secondary to chronic lung disease, such as bronchopulmonary dysplasia (BPD). High-dose sildenafil is associated with a higher mortality rate: in the sildenafil dose-extension studies (STARTS), patients randomized to high-dose sildenafil had increased mortality. Tadalafil, a long-acting PDE5 inhibitor, is approved by the FDA for adults with group 1 PAH. A pediatric study evaluated the safety and efficacy of tadalafil. Of the 33 patients enrolled, 29 were switched from sildenafil to tadalafil; 14 showed significant improvement in mPAP and PVR by cardiac catheterization.

Calcium channel blockers

Calcium channel blockers (CCBs) are one of the drug classes used during cardiac catheterization to test vasoreactivity. The potential risk of using CCBs is that they can lead to a significant drop in cardiac output, resulting in hypotension. Therefore, elevated right atrial (RA) pressure and low cardiac output are contraindications. Furthermore, a trial of CCB therapy should be performed only in those patients who have previously been shown to be acutely reactive to either iNO or intravenous epoprostenol. CCBs are contraindicated in children who have not undergone AVT, are nonresponders to AVT, or have RV failure regardless of acute response. The negative inotropic effects of CCBs are more pronounced in children younger than 1 year; CCBs are usually not recommended in this age group. The advantages of CCBs are that they do not require continuous administration and are available as oral preparations. Unfortunately, the majority of children with severe PAH are nonresponsive to AVT, and therapy other than a CCB is usually required.

Combination therapy targets multiple pathways involved in the pathogenesis of PAH striving to provide synergistic benefits compared with monotherapy. Consensus is building that treating adults with combination therapy from the outset is beneficial. However, few studies have evaluated the safety and efficacy of combination therapy, none of them in pediatric patients.

Pulmonary hypertension in the context of specific diseases

Group 1 pulmonary arterial hypertension

Isolated pulmonary arterial hypertension

IPAH and HPAH are part of the group 1 WHO classification of PAH (see Box 53.1 ). With an estimated incidence and prevalence of 0.7 and 4.4 per million children, respectively, isolated PAH is rare but carries high mortality. The hallmark of the disease is the progressive obliteration of the pulmonary vascular bed, ultimately resulting in right heart failure and death. IPAH is a diagnosis of exclusion and can be made only when evaluation for all PH-associated conditions has been done and is unrevealing.

The WHO group 1 also contains pulmonary venoocclusive disease (PVOD) and pulmonary capillary hemangiomatosis, which can occur across the entire age spectrum. PVOD is a rare disorder that is often initially misdiagnosed as IPAH owing to its similar clinical presentation. PVOD is diagnosed by lung biopsy, which has a high risk in patients with PAH. However, a lung biopsy should be considered in a patient with a high suspicion of PVOD, as might be suggested by rapid onset or “flash” pulmonary edema during vasodilator treatment, absence of elevated PA occlusion pressure and left atrial (LA) pressure. Histology of PVOD is characterized by extensive fibrous intimal proliferation that involves predominantly pulmonary venules and small veins, whereas IPAH displays frequent plexiform and possible thrombotic lesions. A lung transplant is the only long-term therapeutic option for PVOD.

Isolated abnormal pulmonary angiogenesis is the key feature of pulmonary capillary hemangiomatosis (or pulmonary microvasculopathy). Histopathologic findings of pulmonary capillary hemangiomatosis are proliferation of capillary-sized vessels within the alveolar walls, interstitium, and postcapillary venules of the lung. Additionally, similar to other types of PAH, intimal thickening and medial hypertrophy of the small muscular pulmonary arteries are also present. The pathogenesis of this rare disease is unknown, and there are no effective medical therapies. If pulmonary capillary hemangiomatosis is suspected due to failure to respond to conventional PAH therapy, a lung biopsy should be considered to evaluate for histologic evidence of this disease. Lung transplantation is the only long-term therapeutic option. Case studies are suggesting that interferon-α 2a might be a therapeutic option in a bridge to transplantation.

PH due to amphetamine-methamphetamine exposure is also part of group 1 PAH. Therefore, evaluating for exposure to these medications should be part of all PH evaluations. Therapeutic options include those medications currently approved for group 1 PAH.

Autoimmune disorders

Adult patients with autoimmune disorders and concomitant PH fall in the category of connective tissue disorders (e.g., scleroderma in which PH is fairly common in adult patients). Connective tissue disorders are rare in the pediatric population. Juvenile-onset scleroderma represents a subform of scleroderma in which the incidence of PAH before 21 years of age is low (<10%). In contrast with adult patients with systemic lupus erythematosus, who have a prevalence of PH of up to 10%, PH occurs only sporadically in pediatric patients. Though PH is a rare complication of connective tissue disorders in childhood, it carries high morbidity and mortality; thus, screening echocardiography is recommended. Currently, there is insufficient data to provide evidence-based recommendations of PH-specific drug therapies versus modifying the antiinflammatory therapy of the underlying autoimmune disorder.

Infectious diseases

PH as a complication of an infectious disease occurs most commonly in the human immunodeficiency virus (HIV) and schistosomiasis, which has now been recognized in the most recent iteration of the WHO classification of PH (see Box 53.1 ). The incidence of PAH in patients with HIV infection is estimated to be 0.5% and has not been reduced by the increasing availability of highly active retroviral therapy. PH due to HIV infection has been linked to alveolar macrophages that produce specific angioproliferative proteins. , Schistosomiasis is endemic in Africa, Southeast Asia, China, and some parts of Brazil. Some 5% to 10% of infected patients develop hepatosplenic disease; of these patients, 7% to 10% develop PAH. Published literature describing PAH in pediatric patients with HIV and schistosomiasis is sparse, and there is little information evaluating PAH pharmacotherapy in these children.

Group 2 pulmonary arterial hypertension (cardiac disease)

Group 2 PH is caused by left heart disease that may be secondary to left heart failure (with or without reduction of the left ventricular [LV] ejection fraction), valvular heart disease, or cardiovascular conditions leading to postcapillary PH. A detailed description of those conditions and treatment is beyond the scope of this chapter.

Group 3 pulmonary arterial hypertension (intrinsic pulmonary diseases)

Pulmonary arterial hypertension due to parenchymal lung disease

Parenchymal lung disease associated with PAH may occur owing to genetic disorders or originate from disturbances in fetal or early postnatal lung development ( Box 53.2 ). These disorders are either present at birth or become symptomatic in the first months to years of life, with BPD and lung hypoplasia due to congenital diaphragmatic hernia (CDH) being the most common. Alveolar capillary dysplasia (ACD) is a rare disorder characterized by misalignment of pulmonary veins and severe hypoplasia of the alveolar capillaries. Many cases of ACD are caused by mutations of the FOXF1 gene. ACD is usually fatal; lung transplantation is the only therapeutic option.

• BOX 53.2

Developmental Lung Diseases Associated With Pulmonary Hypertension

  • Bronchopulmonary dysplasia

  • Congenital diaphragmatic hernia

  • Alveolar capillary dysplasia with misalignment of veins

  • Lung hypoplasia

  • Surfactant protein abnormalities

    • Surfactant protein B deficiency

    • Surfactant protein C deficiency

  • ABCA3

    • ABCA3 deficiency

    • TTF-1/Nkx2 deficiency or mutation

  • Pulmonary interstitial glycogenosis

  • Pulmonary alveolar proteinosis

  • Pulmonary lymphangiectasia

Pulmonary hypertension secondary to bronchopulmonary dysplasia

BPD is a chronic lung disease of infancy that occurs predominantly in infants born prematurely. It is the sequelae of inadequate pulmonary development in conjunction with injury associated with oxygen and ventilator therapy required to support the immature lungs. Despite significant progress in the management of acute infant respiratory disease over the last decades, BPD continues to have a high prevalence in premature infants, with PH contributing significantly to the morbidity and mortality in these patients. , Even in the postsurfactant era, PH persisting beyond the first few months of life continues to be strongly linked with poor survival. Reduced size of small pulmonary arteries and an abnormal distribution pattern are characteristic signs of pulmonary vascular disease in BPD. , The consequence of the dysmorphic pulmonary vascular system is a decrease in alveolar-capillary surface area, leading to impaired gas exchange and a prolonged need for oxygen supplementation and ventilator support. Animal models of BPD suggest that the ventilator-induced lung injury inflicted on the developing lung can impair angiogenesis, which leads to decreased alveolarization, creating a vicious cycle of lung injury. PAH in BPD is not exclusively due to abnormal growth and remodeling of the small pulmonary vessels, as vascular tone and reactivity are abnormal as well. Patients with BPD are reported to display an exaggerated vasoconstrictive response to hypoxia, , even in infants with only modest PH at baseline. PVD in BPD can be present in the absence of baseline PH, which likely contributes to the increase in pulmonary artery pressure in response to hypoxia and respiratory infections. In addition, there is growing evidence that prematurity has long-term effects on the pulmonary and cardiovascular system, which is particularly important as more infants are surviving extreme prematurity and growing to adulthood.

Diagnostic PH evaluation in BPD

Early echocardiograms for the diagnosis of PH are recommended in preterm infants with severe respiratory distress syndrome who require high levels of ventilator support and supplemental oxygen. Of note, preterm infants born at less than 26 weeks’ gestation are at especially high risk for late-onset PH. Additionally, infants with a persistent or progressive need for high levels of respiratory support should be assessed for PH, especially if the oxygen required is disproportionate to their degree of lung disease. Serial ECGs may not be an adequate screening tool for PH, as some patients can have significant RVH and PH despite normal ECGs. The 2015 AHA/ATS guidelines recommend echocardiograms to screen for PH in patients with BPD, with follow-up studies performed at 4- to 6-month intervals depending on changes in clinical course, such as recurrent respiratory exacerbations, persistent oxygen requirement, severity of PH, and changes in drug therapy. However, it should not be used as the sole measure to assess the presence or severity of PH. There is a poor correlation between echocardiogram and subsequent cardiac catheterization in infants with BPD, which is considered to be the gold standard. In the absence of a measurable tricuspid regurgitation (TR) jet, qualitative echocardiogram findings of PH—including RA enlargement, RV hypertrophy, RV dilation, pulmonary artery dilation, and septal flattening—have relatively weak predictive value. However, due to its noninvasive nature, echocardiography remains the best available screening tool for PH in patients with BPD despite its limitations. In summary, in their 2015 consensus review, the AHA/ATS guidelines recommend cardiac catheterizations for patients with BPD and an echocardiographic diagnosis of PH in the following settings: (1) persistent signs of severe cardiorespiratory disease or clinical deterioration not directly related to airway disease; (2) clinical suspicion of significant PH despite optimal management of lung disease and associated morbidities; (3) candidates for long-term PH drug therapy; and (4) patients with unexplained, recurrent pulmonary edema.

BPD-specific therapies

Optimal management of the underlying lung disease is key in infants with BPD and PH. Patients should be evaluated and treated for associated comorbidities, such as reflux, reactive airway disease, and aspiration and evaluated for structural airway abnormalities (e.g., tonsillar and adenoidal hypertrophy, vocal cord paralysis, subglottic stenosis, and tracheomalacia). Periods of acute hypoxia, whether intermittent or prolonged, are common causes of persistent PH in BPD. Due to the variability of oxygen saturation, pulse oximetry should be monitored over an extended period to determine whether supplemental oxygen is needed. Targeting oxygen saturation of 92% to 94% is sufficient to balance the adverse effects of hypoxia with the increased risk of hyperoxia-induced lung injury. Pulmonary vasodilators are increasingly being used in the therapy of PH secondary to BPD. However, these agents should be used cautiously and only after a thorough diagnostic evaluation, as data demonstrating efficacy are extremely limited.

Current therapies used for PH in infants with BPD generally include iNO, sildenafil, endothelin receptor antagonists, and calcium channel blockers.

Congenital diaphragmatic hernia

CDH occurs in about 1 of every 2500 births and is characterized by marked lung hypoplasia with PH, which results in impaired cardiac performance. Of note, concomitant structural cardiac defects occur in 11% to 15% of children born with a CDH.

The severity of PH is a major determinant of survival in children with a CDH. Severe PH is present in about 63% of CDHs and carries a mortality of 45% , and contributes to the overall poor outcome of CDH beyond the immediate postnatal period throughout childhood. PVR often remains at suprasystemic levels in newborns with CDH, with the resulting R to L shunt causing profound hypoxemia. High PVR in CDH is the result of a combination of vasoconstriction, pulmonary vascular remodeling, and LV dysfunction. ,

General management of CDH

Surgical management of CDH has undergone marked changes over the last decades (mostly in regard to the timing of the repair from being an immediate after birth surgical emergency to delayed surgery for at least 24 hours to allow stabilization). However, most of the changes have not been studied in randomized controlled trials (RCTs). Equally, mechanical ventilation management strategies vary widely between centers and are not guided by evidence-based studies. Infants with CDH are at high risk for chronic lung disease due to severe lung hypoplasia. Additional pulmonary injury due to ventilator-induced lung injury further increases the risk of chronic lung disease. Therefore, avoiding lung overdistension by minimizing ventilation volumes and pressure is critically important for reducing lung overdistention and improving outcomes. Lung protective strategies often result in permissive hypercapnia, which has been thought to improve outcomes in regard to the development of chronic lung disease. However, this needs to be balanced with the fact that sustained hypercapnia increases baseline PVR and the subsequent hypoxic response. No RCTs of permissive hypercapnia have been conducted in CDH; furthermore, permissive hypercapnia has not been shown to reduce chronic lung disease in premature infants. Small clinical trials have shown that high-frequency oscillatory ventilation can be useful in the management of severe CDH when used as rescue.

PH-specific therapy in CDH

Despite the fact that severe PH is a common complication in children with CDH, the management of PH in CDH remains controversial, perhaps because (1) there are very few well designed and powered RCTs and (2) several therapies were not primarily studied in CDH but rather extrapolated from PPHN. iNO has been shown to decrease the need for extracorporeal membrane oxygenation (ECMO) in PPHN. However, in patients with CDH, two RCTs of iNO did not show improvement in mortality or progression to ECMO, despite the fact that iNO improved oxygenation in children with CDH in earlier studies. Failure of iNO treatment in newborns with CDH can likely be attributed to LV dysfunction combined with a relatively small LV size in CDH. Increasing the preload via iNO to an LV that is unable to respond properly by increasing the stroke volume can lead to pulmonary venous hypertension and thus worsening pulmonary edema. Therefore, therapies resulting in pulmonary vasodilation such as iNO must be used judiciously in infants with CDH, with close monitoring of LV function.

Some patients with severely impaired LV function might profit from the enhancement of right to left ductal shunt by prostaglandin infusion to maintain ductal patency, as in this setting the RV can be used to maintain cardiac output. Prostacyclin, prostaglandin E 1 , ethyl nitrite, sodium nitroprusside, and sodium nitrite have been used in pilot studies in infants with CDH but not in controlled clinical trials. The concerns are that, similarly to iNO, the impaired LV function in severe CDH might limit the utility of vasodilator drugs (although they might be useful as a temporizing measurement in severe preductal hypoxemia to facilitate ECMO cannulation.

Cystic fibrosis

PH can occur in advanced pulmonary cystic fibrosis (CF). PH in pediatric patients with CF is rare; PH is more commonly seen in adult CF patients with end-stage lung disease. However, even in pediatric patients, especially those with severe pulmonary manifestations of CF leading to hypoxemia, PH can be present and contribute to poor exercise tolerance and negatively affect the quality of life. There are no controlled clinical studies of PH pharmacotherapy in CF patients, but ERA therapy or PDE5 inhibitor therapy have been described in case reports.

Diffuse lung disease

PVD can masquerade as diffuse lung disease (e.g., surfactant protein, pulmonary interstitial glycogenosis, pulmonary alveolar proteinosis, pulmonary lymphangiectasia; see Box 53.2 ). Therefore, screening for PAH is clinically indicated in all infants and children with these diseases, especially as PAH is associated with a worse outcome in patients with interstitial lung disease.

Pulmonary hypertension secondary to acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) is an acute lung injury due to direct lung injury, such as pneumonia or aspiration, or extrapulmonary causes, such as sepsis. PH can occur as a complication of ARDS, but the frequency is unknown. Himebauch et al. performed screening echocardiograms on 103 children within 24 hours of their diagnosis of ARDS. Of those, 21% met echocardiographic criteria for PH, which was associated with higher morbidity. In adult patients, a meta-analysis of 16 studies found that 23% of patients with ARDS showed evidence of PH.

PVD in ARDS is caused by areas of lung over- and underdistension, resulting in areas with significantly increased PVR. It is further exacerbated by changing flow-pressure dynamics due to the heterogeneity of pulmonary blood flow throughout the lungs. This acquired pulmonary vascular disease is clinically apparent in 22% to 50% of adults with ARDS and is independently associated with a higher risk of mortality. The incidence and risk factors for acquired PVD associated with pediatric ARDS is less well delineated. A small, retrospective cohort study estimates that 26% to 40% of children with ARDS show evidence of acquired PVD. Importantly, the development of PVD was not related to severity of lung disease but was associated with outcomes such as mortality and duration of mechanical ventilation. The reversibility of this pulmonary vascular injury and associated strain on the RV is unclear, but is likely related to the severity and duration of perturbed physiology as well as the reversibility and cessation of the inciting injury.

iNO has been studied extensively in pediatric ARDS mainly with the underlying hypothesis that it would improve the ventilation/perfusion mismatch and lead to better clinical outcomes. Furthermore, in patients with preexisting risk factors for PH (e.g., patients with BPD or Down syndrome), ARDS can acutely worsen preexisting PH. Three RCTs failed to demonstrate improved mortality, duration of mechanical ventilation, ventilator-free days, or length of ICU or hospital stay with iNO treatment. Therefore, iNO is not recommended for routine use in pediatric ARDS. However, it is important to note that those studies did not specifically investigate patients with ARDS and PH. iNO may have a role in patients with documented PH or severe RV dysfunction. Inhaled PGI 2 (epoprostenol or iloprost) has been used in ARDS in a manner similar to iNO, but data in pediatric patients are scant.

In summary, PH is associated with diverse intrinsic lung diseases in the pediatric population that can manifest from birth to late childhood. The exact incidence of PH in these disorders is unknown, and the role of PAH pharmacotherapy has not been rigorously studied. However, the link between PH and significantly increased morbidity and mortality is well established. Therefore, it is critical for clinicians to consider PH and evaluate using appropriate screening tests based on their clinical suspicion.

Group 5 pulmonary hypertension

Chronic hemolytic anemia

Although PH can occur in many chronic hemolytic anemias, it has been most rigorously studied in sickle cell disease (SCD) and is associated with increased mortality in adults with SCD. However, even though increased tricuspid regurgitant jet velocity (TRJV) is present in 10% to 20% of children with SCD, PH itself is rare and does not have the clear impact on mortality seen in adults. , It is also important to note that, in pediatric SCD, increased TRJV does not correlate well with PAP measured by cardiac catheterization. Furthermore, TRJV is unable to differentiate precapillary from postcapillary PH, which is critical to differentiate since PAH-specific drug therapy in children, with postcapillary PH vasodilation, can lead to pulmonary edema and worsening hypoxemia. Therefore, the 2012 AHA guidelines recommend against PAH-targeted therapy except for patients who have a high PVR and normal pulmonary capillary wedge pressure. In those cases, the recommendation is for a trial of ERA or PGI 2 analog.

Based on adult data that associate higher mortality risk with an elevated TRJV (>2.5 m/s), high NT-proBNP greater than 160 pg/mL, or mPAP greater than 25 mm Hg by cardiac catheterization, more aggressive treatment of the underlying SCD is recommended.

Acute pulmonary hypertension crisis/right ventricular failure

Pathophysiology and management of acute pulmonary hypertensive crises (PHCs) in critical care settings have focused mainly on the perioperative period after CHD surgery. In pulmonary hypertensive vascular disease, the adaptation of the RV to an increased afterload is critical in determining symptoms and outcome rather than the absolute increase in PVR or PAP. This explains why children with Eisenmenger syndrome, who have long-standing RV overload and adaptation, can remain stable with PH over many years. PHCs are sudden and potentially lethal increases in PAP and PVR that result in acute RV failure and ultimately lead to systemic hypotension, myocardial ischemia, and, at times, bronchoconstriction ( Fig. 53.6 ).

May 20, 2021 | Posted by in RHEUMATOLOGY | Comments Off on Diseases of the pulmonary circulation

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