609CHAPTER 53 Diseases of the Pulmonary Circulation helped to advance not only our understanding of pulmonary hy pertensive diseases but has also facilitated drug trials, particularly in group 1 pulmo[.]
CHAPTER 53 Diseases of the Pulmonary Circulation • BOX 53.1 Updated Clinical Classification of PH 2 3 5 PAH 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 Schistosomiasis 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 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 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 PH due to pulmonary artery obstruction 4.1 Chronic thromboembolic PH 4.2 Other pulmonary artery obstruction PH with unclear and/or multifactorial mechanisms 5.1 Hematologic disorders 5.2 Systemic and metabolic disorders 5.3 Others 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) helped to advance not only our understanding of pulmonary hypertensive diseases but has also facilitated drug trials, particularly in group 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.3 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 609 Genetic syndromes Pathologic insults during lung growth Embryologic abnormalities: lung hypoplasia Multifactorial conditions • Fig 53.1 Heterogeneity and multifactorial elements in pediatric pulmonary hypertensive vascular disease Basic Categories of Pediatric Pulmonary TABLE Hypertensive Vascular Disease Developed by 53.1 the PVRI Pediatric Taskforce Category Description Prenatal or developmental pulmonary hypertensive disease Perinatal vascular maladaptation Pediatric cardiovascular disease Bronchopulmonary dysplasia Isolated pediatric pulmonary hypertensive vascular disease Multifactorial pulmonary hypertensive vascular disease in congenital malformation syndromes Pediatric lung disease Pediatric thromboembolic disease Pediatric hypobaric hypoxic disease 10 Pediatric pulmonary vascular disease associated with other systemic disorders PVRI, Pulmonary Vascular Research Institute disease The Panama consensus classification of PH divides pediatric pulmonary hypertensive vascular disease into 10 broad categories listed in order of frequency3 (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) 610 S E C T I O N V Pediatric Critical Care: Pulmonary Of note, there is a subgroup of patients with pulmonary vascular disease (PVD) that have diverse abnormalities of the pulmonary vascular bed but 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.4 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.5,6 In this process, pulmonary arteries undergo several structural alterations, which can involve intimal fibrosis, medial hypertrophy, and adventitial/perivascular inflammation and fibrosis.5,6 Complex intimal lesions comprise different elements, such as A B onion skin lesions, plexiform core lesions, and dilation lesions, which are commonly observed in close topographic association In some cases of group 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.7,8 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.8,9 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.10,11 Therefore, in addition to the lesions mainly occurring in distal muscular-type arteries, ranging in diameter from 500 mm down to 70 mm in humans (medial hypertrophy/hyperplasia, intimal and adventitial fibrosis, perivascular inflammation, plexiform C D • Fig 53.2 Key pathologic alterations in pulmonary arterial hypertension lungs CHAPTER 53 Diseases of the Pulmonary Circulation lesions), PH can be attributed to stiffening of large elastic main, lobar, and segmental pulmonary arteries (large vessel abnormalities).8 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,12–14 and it has been demonstrated that inclusion of impedance and PVS outcomes analysis has value over PVR alone.15,16 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.17,18 In adults, the stiffness of lung elastic pulmonary arteries increases in several forms of PH and contributes to the disease course.14,19–21 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.22–24 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 guidelines4 summarize the following recommendations for the diagnosis and evaluation of pediatric PH/PVD (Fig 53.3): 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) 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) 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) 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) Cardiac catheterization should include acute vasoreactivity testing (AVT) unless there is a specific contraindication (Class I, Level of Evidence A) Suspected PH PH unlikely Yes ECG Chest radiograph Echocardiogram normal? No Echocardiogram indicates left heart disease with PH Yes Evaluate for left heart and valvular disease No Pulmonary function test normal Plus polysomnography No Evaluation for lung diseases, connective tissue disease, neuromuscular disease, or chest wall restrictive disease Yes Ventilation/perfusion scan normal or low probability Workup for connective tissue disease, hypercoagulability, HIV, liver disease, hemoglobinopathies, others Yes Cardiac catheterization with acute vasodilator testing prior to initiation of PH-specific drug therapy 6-minute walk test, cardiopulmonary exercise test • Fig 53.3 Pediatric pulmonary hypertension (PH): diagnostic evaluation algorithm ECG, electrocardiogram; HIV, human immunodeficiency virus 611 612 S E C T I O N V Pediatric Critical Care: Pulmonary Endothelin pathway Pre-proendothelin Proendothelin Endothelin-1 ERA Nitric oxide pathway L-arginine Prostacyclin pathway L-citrulline Prostacyclin NO Prostaglandin I2 Arachidonic acid PGI2 ERA Endothelin receptor A Endothelin receptor B IP2 receptor sGC cGMP PDE-5 cAMP FDA-approved PAH drugs PDE-5 inhibitor ERA Bosentan Ambrisentan PDE-5i Sildenafil Tadalafil Prostacyclins Epoprostenol (IV) Iloprost (inhalation) Treprostinil Beraprost (IV, SQ, inhalation, oral) • 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 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) 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) 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) 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.25–27 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) Pharmacotherapy 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 (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.28,29 Furthermore, anatomic obstruction resulting from PVD or leftsided heart disease should be ruled out A current treatment algorithm is presented in Fig 53.5 Prostacyclin (PGI2) Analogs An imbalance in thromboxane A2 and PGI2 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).30 PGI2 and PGI2 analogs augment pulmonary vasodilation via the second messenger cyclic adenosine monophosphate Since it became available in 1979, intravenous PGI2 (epoprostenol) remains the gold standard for treating severe PAH with RV failure.31 Long-term use of epoprostenol, the first approved PGI2 analog, has been shown to increase survival rates and improve quality of life in children and adults with PAH.32 Epoprostenol is started at 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 PGI2 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.4,33 Newer analogs of PGI2, such as treprostinil, are CHAPTER 53 Diseases of the Pulmonary Circulation Consider: diuretics, oxygen, anticoagulation, digoxin 613 Acute vasoreactivity testing Positive Negative Oral CCB Improved Lower risk No Higher risk ERA or PDE-5i (oral) Iloprost (inhaled) Treprostinil (inhaled) Epoprostenol IV or treprostinil (IV/SQ) Consider early combination ERA or PDE-5i (oral) Reassess: consider combo-therapy Atrial septostomy Lung transplant Yes Continue CCB Ambrisentan (Class Ila; Level B), bosentan (Class 1; Level B), CCB (Class 1; Level B), epoprostenol (Class 1; Level B), iloprost (Class Ila; Level B), sildenafil (Class 1; Level B), tadalafil (Class Ila; Level B), treprostinil IV/SQ (Class 1; Level B), treprostinil Inhaled (Class Ila; Level B) • Fig 53.5 Pediatric pulmonary arterial hypertension treatment algorithm CCB, Calcium channel blocker; ERA, endothelin receptor antagonist; IV, intravenous; PDE5, phosphodiesterase 5; SQ, subcutaneous 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 PGI2 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.34 Studies suggest that it is safe for pediatric patients, but it has not received FDA approval for use in children.35 Iloprost is an inhalational PGI2 analog approved for the treatment of adult PAH in the United States Inhaled PGI2 analogs have the advantage of having minimal effects on blood pressure compared with systemic PGI2 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, ETA and ETB Vascular smooth muscle cells express both ETA and ETB receptors and mediate vasoconstriction ETB receptors are expressed by endothelial cells and stimulate the release of nitric oxide (NO) and PGI2 in response to endothelin-1 Additionally, the ETB receptor clears free, circulating endothelin-1 Patients with PH have increased levels of endothelin-1.36–38 Bosentan, a nonspecific ERA, decreases PAP and PVR, improves exercise capacity, and is well tolerated in children with IPAH or PAH associated with CHD.39–41 A selective ETA antagonist, ambrisentan, may have the advantage of blocking the vasoconstrictive effects mediated by ETA receptors while preserving the vasodilator and clearance functions of ETB receptors The FDA approved ambrisentan in June 2007 for adults with WHO group 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.42 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 Inhibitors Specific PDE5 inhibitors, such as sildenafil or tadalafil, act via increasing the second messenger cyclic guanosine monophosphate and thus stimulate pulmonary vascular dilation.43 PDE5 expression and activity are upregulated in PH.44 Exercise capacity and hemodynamics were improved with sildenafil in children with persistent pulmonary hypertension of the newborn (PPHN), IPAH, and PH.4 In several small studies of children with PPHN, IPAH, and PH associated with CHD, sildenafil has been shown to improve exercise capacity and hemodynamics.43,45–49 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.50 Tadalafil, a long-acting PDE5 inhibitor, is approved by the FDA for adults with group 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.51 ... group 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... result of, and a contributor to, increased pulmonary vascular pressures by increasing PVR.5,6 In this process, pulmonary arteries undergo several structural alterations, which can involve intimal... 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