When measured directly in the cardiac catheterization laboratory, the normal pulmonary artery (PA) systolic pressure of children and adults is 30 mm Hg or below, and the mean PA pressure is 25 mm Hg or below. A diagnosis of pulmonary hypertension can be made when the mean PA pressure is 25 mm Hg or above in a resting individual at sea level. The PA pressure is higher at high elevations.
The noninvasive Doppler method, however, often overestimates the PA pressure in people with normal PA pressure. Using tricuspid regurgitation jet velocity and the modified Bernoulli equation and adding assumed a right atrial (RA) pressure of 10 mm Hg will usually overestimate the right ventricular (RV) systolic pressure. The assumed RA pressure of 10 mm Hg is too high unless RV dysfunction or severe tricuspid regurgitation (TR) is present. The directly measured RA pressure is normally 3 to 5 mm Hg in infants and children. Using this assumption, the mean PA systolic pressure (± standard deviation [SD]) was found to be 28.3 ± 4.9 mm Hg (range, 15–57 mm Hg) in infants and adults, higher values than previously reported using invasive methods ( McQuillan et al, 2001 ). The estimated upper 95% limit for PA systolic pressure by the Doppler method was 37.2 mm Hg. (This results from a TR jet velocity of 2.7 m/sec in the absence of pulmonary stenosis [PS].) Thus, Doppler-estimated PA systolic pressure of 36 to 40 mm Hg has been assumed as the cut-off value for mild PA hypertension. Thus, the Doppler estimates are relatively imprecise and are not a substitute for cardiac catheterization.
There is a wide range of severity in pulmonary hypertension; in some, it reaches or surpasses the systemic pressure. The status of pulmonary hypertension also varies; in some, it is static, and in others, it is dynamic.
Pulmonary hypertension is a group of conditions with multiple causes rather than a single one. Pathogenesis and management differ among entities. Box 29-1 lists, according to pathogenesis, conditions that cause pulmonary hypertension of a temporary or permanent, acute or chronic nature.
Large left-to-right shunt lesions (hyperkinetic pulmonary hypertension): ventricular septal defect, patent ductus arteriosus, endocardial cushion defect
Pulmonary parenchymal disease
Hypoplasia of lungs (primary or secondary, such as that seen in diaphragmatic hernia)
Interstitial lung disease (Hamman-Rich syndrome)
Upper airway obstruction (large tonsils, macroglossia, micrognathia, laryngotracheomalacia, sleep-disordered breathing)
Lower airway obstruction (bronchial asthma, cystic fibrosis)
Inadequate ventilatory drive (central nervous system diseases, obesity hypoventilation syndrome)
Disorders of chest wall or respiratory muscles
Weakening or paralysis of skeletal muscle
High altitude (in certain hyperreactors)
Pulmonary venous hypertension: mitral stenosis, cor triatriatum, total anomalous pulmonary venous return with obstruction, chronic left heart failure, left-sided obstructive lesions (aortic stenosis, coarctation of the aorta); rarely, congenital pulmonary vein stenosis cause incurable pulmonary hypertension
Primary pulmonary vascular disease
Persistent pulmonary hypertension of the newborn
Primary pulmonary hypertension (rare, fatal form of pulmonary hypertension with obscure cause)
Other diseases that involve pulmonary parenchyma or pulmonary vasculature, directly or indirectly.
Thromboembolism: ventriculoatrial shunt for hydrocephalus, sickle cell anemia, thrombophlebitis
Connective tissue disease: scleroderma, systemic lupus erythematosus, mixed connective tissue disease, dermatomyositis, rheumatoid arthritis
Disorders directly affecting the pulmonary vasculature: schistosomiasis, sarcoidosis, histiocytosis X
Portal hypertension (hepatopulmonary syndrome)
The causes of pulmonary hypertension can be grouped into the following five. Some oversimplification is inevitable in dividing this diverse group into five categories.
Increased PBF seen in congenital heart defects (CHDs) with large left-to-right shunts (hyperkinetic pulmonary hypertension)
Increased pulmonary venous pressure
Primary pulmonary vascular disease
Other diseases that involve pulmonary parenchyma or pulmonary vasculature, directly or indirectly
Although a new classification of pulmonary hypertension was proposed in Dana Point in 2008, it is not better than the one used here because it is difficult to apply in some cases of pediatric pulmonary hypertension.
Physiology of Pulmonary Circulation
The basics of physiology of pulmonary circulation and pulmonary vascular responses are summarized below for a quick review.
Vascular endothelium: Normally, balanced release of vasodilators and vasoconstrictors by endothelial cells is a key factor in the regulation of the pulmonary vascular tone. Three endothelium signaling cascades are known: (a) nitric oxide (NO)–cyclic guanosine monophosphate (cGMP) cascade, (b) prostanoids, and (c) endothelin-1 (ET-1). The most widely used drug therapy of pulmonary hypertension works by altering one of these signaling cascades (see Management):
NO, a vasodilator, is produced in the vascular endothelium by the enzyme endothelial nitric oxide synthase (eNOS) from the precursor l -arginine. After formation, NO diffuses into the adjacent smooth muscle cell and produces cGMP (by activation of guanylate cyclase), which results in smooth muscle relaxation. cGMP is broken down by a family of phosphodiesterases, which is prominent in the pulmonary circulation. Blocking breakdown of cGMP helps maintain vasodilation.
Arachidonic acid metabolism within vascular endothelial cells results in the production of prostaglandin I 2 (PGI 2 or prostacyclin) and thromboxane (TXA 2 ). PGI 2 is a vasodilator, and TXA 2 is a vasoconstrictor.
ET-1, the dominant isoform of ET, is produced by vascular endothelial cells. ET-1 is a potent vasoconstrictor.
The lung is unique in its response to hypoxia. Alveolar oxygen tension in the alveolar capillary region is the major physiologic determinant of pulmonary arteriolar tone. Alveolar hypoxia causes vasoconstriction in the lungs. In all other tissues, hypoxia causes vasodilation. In hypoxia-induced vasoconstriction, NO production is reduced, and ET production is increased. High altitude (with low alveolar oxygen tension) is associated with pulmonary vasoconstriction (and pulmonary hypertension) of varying degrees. There is a large species and individual variation in the reactivity of the pulmonary arteries to low alveolar oxygen tension.
Pulmonary vascular resistance (PVR) is primarily determined by the cross-sectional area of small muscular arteries and arterioles. With stenosis or thrombosis of the pulmonary arteries, PVR will increase. Other determinants of PVR include blood viscosity, total mass of the lungs (pneumonectomy or hypoplasia), and extramural compression on the vessels. Normal PVR is 1 Wood unit (or 67 ± 23 [SD] dyne-sec/cm -5 ), which is one tenth of systemic vascular resistance.
With exercise, a large increase in pulmonary blood flow (PBF) is accomplished by only a small increase in PA pressure because of recruitment of near collapsed capillaries. The increase in the left atrial (LA) pressure appears to account for most of the increase in PA pressure.
Pathogenesis of Pulmonary Hypertension
Pressure (P) is related to both flow (F) and vascular resistance (R), as shown in the following formula:
P = F × R
An increase in flow, vascular resistance, or both can result in pulmonary hypertension. Regardless of its cause, pulmonary hypertension eventually involves constriction of the pulmonary arterioles, resulting in an increase in PVR and hypertrophy of the RV.
Pathogenesis of pulmonary hypertension is discussed according to the (first four) general categories of causes because each is distinctly different from the other.
Hyperkinetic Pulmonary Hypertension
Pulmonary hypertension associated with large left-to-right shunt lesions, such as ventricular septal defect (VSD), patent ductus arteriosus (PDA), is called hyperkinetic pulmonary hypertension. It is the result of an increase in PBF, a direct transmission of the systemic pressure to the PA, and an increase in PVR by compensatory pulmonary vasoconstriction. If no vasoconstriction occurs, the increase in PBF will be much larger, and intractable congestive heart failure (CHF) will result. Defects in the vasodilation machinery of the endothelial cell, such as overproduction of vasoconstrictor elements, have been implicated in this form of pulmonary hypertension. Hyperkinetic pulmonary hypertension is usually reversible if the cause is eliminated before permanent changes occur in the pulmonary arterioles (see later section).
If large left-to-right shunt lesions (e.g., VSD, PDA, complete atrioventricular canal) are left untreated, irreversible changes take place in the pulmonary vascular bed, with severe pulmonary hypertension and cyanosis caused by a reversal of the left-to-right shunt. This stage is called Eisenmenger’s syndrome or pulmonary vascular obstructive disease (PVOD). Surgical correction is not possible at this stage. The time of onset of PVOD varies, ranging from infancy to adulthood, but the majority of patients develops PVOD during late childhood or early adolescence. It develops even later in patients with atrial septal defect (ASD). Many patients with uncorrected transposition of the great arteries (TGA) begin to develop PVOD within the first year of life for reasons not entirely clear. Children with Down syndrome with large left-to-right shunt lesions tend to develop PVOD much earlier than other children with similar lesions.
An acute or chronic reduction in the oxygen tension (Po 2 ) in the alveolar capillary region (alveolar hypoxia) elicits a strong pulmonary vasoconstrictor response, which may be augmented by acidosis. Hypoxia in the alveolar space elicits a much stronger vasoconstrictor effect than low Po 2 in the PA.
The mechanisms of the pulmonary vasoconstrictor response to alveolar hypoxia are not completely understood, but studies in animals and humans suggest that ET and NO, the two important vascular endothelium-released vasoactive substances, are the strongest candidates responsible for the response. Normally, balanced release of NO and ET by endothelial cells regulates the pulmonary circulation. Whereas a reduction in NO production occurs in chronically hypoxic animals, prolonged inhalation of NO attenuates hypoxic pulmonary vasoconstriction and vascular remodeling (proliferation) in these animals. Conversely, plasma levels of ET-1 are increased in association with hypoxia in humans. ET receptor antagonists have been demonstrated to reduce hypoxic pulmonary vasoconstriction and vascular remodeling in animals. A number of other growth factors (including platelet-derived growth factors and vascular endothelial growth factor) also mediate pulmonary vascular remodeling in response to hypoxia.
Alveolar hypoxia may be an important basic mechanism of many forms of pulmonary hypertension, including that seen in pulmonary parenchymal disease, airway obstruction, inadequate ventilatory drive (central nervous system diseases), disorders of chest wall or respiratory muscles, and high altitude. Even a small area of affected lung may produce vasoconstriction throughout the lungs, possibly through a circulating humoral agent. Pulmonary hypertension caused by alveolar hypoxia is usually reversible when the cause is eliminated.
Pulmonary Venous Hypertension
Increased pressures in the pulmonary veins produce reflex vasoconstriction of the pulmonary arterioles, raising PA pressure to maintain a high enough pressure gradient between the PA and the pulmonary vein. This pressure gradient maintains a constant forward flow in the pulmonary circulation. There is a marked individual variation in the degree of reactive pulmonary arteriolar vasoconstriction. For example, when the pulmonary venous pressure is elevated in excess of 25 mm Hg from mitral stenosis, marked reactive pulmonary hypertension occurs only in less than one third of patients. The mechanism for the vasoconstriction is not entirely clear, but a neuronal component may be present. Moreover, an elevated pulmonary venous pressure may also narrow or close small airways, resulting in alveolar hypoxia, which may contribute to the vasoconstriction. Mitral stenosis, total anomalous pulmonary venous return (TAPVR) with obstruction (of pulmonary venous return to the LA), and chronic left-sided heart failure are examples of this entity. Pulmonary hypertension with increased pulmonary venous pressure is usually reversible when the cause is eliminated, with the exception of congenital pulmonary vein stenosis, for which no curative intervention is available.
Primary Pulmonary Vascular Disease
Primary pulmonary hypertension is characterized by progressive, irreversible vascular changes similar to those seen in Eisenmenger’s syndrome but without intracardiac lesions. There is a decrease in the cross-sectional area of the pulmonary vascular bed caused by pathologic changes in the vascular tissue itself, thromboembolism, platelet aggregation, or a combination of these. This condition is extremely rare in pediatric patients; it is a condition of adulthood and is more prevalent in women. The familial form of the disease has been reported worldwide in approximately 6% of the cases with primary pulmonary hypertension. It has a poor prognosis.
The pathogenesis of primary pulmonary hypertension is not fully understood, but endothelial dysfunction of the pulmonary vascular bed and enhanced platelet activities may be important factors. In a normal pulmonary vascular bed, the endothelial cells modulate the tone of vascular smooth muscles (by synthesizing prostacyclin, NO, and ET), control the potential proliferation of smooth muscle cells, and interact with platelets to release anticlotting factors in the blood to maintain a nonthrombotic state (by releasing prostacyclin, an inhibitor of platelet function). These delicate functions are themselves influenced by factors such as shear stress, hypoxia, and tissue metabolism.
The striking features of the pulmonary vasculature in patients with primary pulmonary hypertension are marked intimal proliferation (and in some vessels with complete vascular occlusion) and in situ thrombosis of the small pulmonary arteries. Interactions among ET, growth factors, platelets, and the vascular wall may play a fundamental role in the pathologic processes seen in this condition. ET is overproduced in pulmonary hypertension, and this excess ET is associated with not only vasoconstriction but also cell proliferation, inflammation, medial hypertrophy, and fibrosis. Endothelium receptor antagonists (e.g., bosentan) produce vasodilation.
Other Disease States
Pulmonary hypertension associated with other disease states has similar pathophysiologies described in the above four categories, singly or in combination.