I. Definition
Thirty 30 mm Hg has been used as the normal upper limit for systolic PA pressure and 25 mm Hg as the normal upper limit for mean PA pressure when measured directly by cardiac catheterization in adults and children older than 3 months of age at sea level. Thus a diagnosis of pulmonary hypertension (PH) was made when mean PA pressure was ≥25 mm Hg.
However, at the 2018 Sixth World Symposium on PH, consensus was reached to define PH in adults when mean PA pressure is ≥20 mm Hg and to include pulmonary vascular resistance of ≥3 Woods units to identify precapillary PH. The pediatric task force chose to follow the same recommendations. Of note is that the PA pressure is higher at high elevations. There is a wide range of severity in PH; in some, it reaches or surpasses the systemic pressure.
II. Causes
PH is a group of conditions with multiple causes rather than a single one. Pathogenesis and management differ among entities. Box 24.1 shows five groups of conditions that cause PH according to the pathogenesis and examples of the diseases belonging to each group.
- 1.
Large L-R shunt lesions (hyperkinetic pulmonary hypertension): VSD, PDA, ECD
- 2.
Alveolar hypoxia
- a.
Pulmonary parenchymal disease
- i.
Extensive pneumonia
- ii.
Hypoplasia of lungs (primary or secondary, such as that seen in diaphragmatic hernia)
- iii.
Bronchopulmonary dysplasia
- iv.
Interstitial lung disease (Hamman-Rich syndrome)
- v.
Wilson-Mikity syndrome
- b.
Airway obstruction
- i.
Upper airway obstruction (large tonsils, macroglossia, micrognathia, laryngotracheomalacia, sleep-disordered breathing)
- ii.
Lower airway obstruction (bronchial asthma, cystic fibrosis)
- c.
Inadequate ventilatory drive (central nervous system diseases, obesity hypoventilation syndrome)
- d.
Disorders of chest wall or respiratory muscles
- i.
Kyphoscoliosis
- ii.
Weakening or paralysis of skeletal muscle
- e.
High altitude (in certain hyperreactors)
- a.
- 3.
Pulmonary venous hypertension: MS, cor triatriatum, TAPVR with obstruction, chronic left heart failure. Rarely, congenital pulmonary vein stenosis causes incurable pulmonary hypertension.
- 4.
Primary pulmonary vascular disease
- a.
Persistent pulmonary hypertension of the newborn
- b.
Primary pulmonary hypertension—rare, fatal form of pulmonary hypertension with obscure cause
- a.
- 5.
Other diseases that involve pulmonary parenchyma or pulmonary vasculature, directly or indirectly
- a.
Thromboembolism: ventriculoatrial shunt for hydrocephalus, sickle cell anemia, thrombophlebitis
- b.
Connective tissue disease: scleroderma, systemic lupus erythematosus, mixed connective tissue disease, dermatomyositis, rheumatoid arthritis
- c.
Disorders directly affecting the pulmonary vasculature: schistosomiasis, sarcoidosis, histiocytosis X
- d.
Portal hypertension (hepatopulmonary syndrome)
- e.
HIV infection
- a.
III. Pathophysiology
- 1.
The endothelial cells and lung tissues normally synthesize and/or activate some vasoactive hormones and inactivate others. Three endothelium signaling cascades are known: (a) nitric oxide–cyclic guanosine monophosphate (cGMP) cascade, (b) prostanoids, and (c) endothelin-1 (ET-1). Balance among the vasoactive substances maintains vascular tone in normal and pathologic situations.
- a.
Normally, balanced release of nitric oxide (NO, a vasodilator) and ET-1, a potent vasoconstrictor, by endothelial cells is a key factor in the regulation of the pulmonary vascular tone.
- b.
Prostanoids: 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.
- a.
- 2.
Reduced alveolar oxygen tension ( alveolar hypoxia ) induces vasoconstriction (by reducing NO production and increasing endothelin production).
- a.
Acidosis significantly increases PVR, acting synergistically with hypoxia.
- b.
High altitude (with low alveolar oxygen tension) is associated with pulmonary vasoconstriction (and pulmonary hypertension), for which large species and individual variations exist.
- a.
- 3.
Other agents or conditions that affect pulmonary vascular tones include the following.
- a.
Angiotensin II, a vasoconstrictor, is activated from angiotensin I in the lungs by angiotensin-converting enzyme (ACE).
- b.
Serotonin is a vasoconstrictor that promotes smooth muscle cell hypertrophy.
- c.
Stimulation of α- and β-adrenoceptors produces vasoconstriction and vasodilation, respectively.
- a.
- 4.
Pressure (P) is related to both flow (F) and vascular resistance (R), as shown in the following formula:
<SPAN role=presentation tabIndex=0 id=MathJax-Element-1-Frame class=MathJax style="POSITION: relative" data-mathml='P=F×R’>𝑃=𝐹×𝑅P=F×R
P = F × R
An increase in pulmonary blood flow, pulmonary vascular resistance, or both can result in PH. Regardless of its cause, PH eventually involves constriction of the pulmonary arterioles, resulting in an increase in PVR and hypertrophy of the RV.
- 5.
The normally thin RV cannot sustain sudden increase in the PA pressure over 40 to 50 mm Hg and results in right-sided heart failure. Examples of this include infants who develop acute upper airway obstruction and adult patients who develop massive pulmonary thromboembolism.
- 6.
However, if PH develops slowly, the RV hypertrophies and can tolerate mild PH (with a systolic pressure of about 50 mm Hg) without producing clinical problems. The RV pressure rises gradually with accompanying RV hypertrophy, and the PA pressure may eventually exceed the systemic pressure.
IV. Pathogenesis of Pulmonary Hypertension
Pathogenesis of PH is presented in the following text according to the (first four) general categories of causes, because they are distinctly different from each other.
A. Hyperkinetic Pulmonary Hypertension
- 1.
PH associated with large L-R shunt lesions (e.g., VSD, PDA) is called hyperkinetic PH . It is the result of an increase in pulmonary blood flow, a direct transmission of the systemic pressure to the PA, and compensatory pulmonary vasoconstriction. Endothelial cell dysfunction with overproduction of ET-1 and reduced NO production result.
- 2.
Hyperkinetic PH is usually reversible if the cause is eliminated before permanent changes occur in the pulmonary arterioles (see later section). If large L-R shunt lesions are left untreated, irreversible changes take place in the pulmonary vascular bed, with severe PH and cyanosis due to a reversal of the L-R shunt. This stage is called Eisenmenger syndrome or PVOD. Surgical correction is not possible at this stage.
B. Alveolar Hypoxia
- 1.
An acute or chronic reduction in the oxygen tension (P o 2 ) in the alveolar capillary region (alveolar hypoxia) elicits a strong pulmonary vasoconstrictor response, which may be augmented by acidosis. Although the exact mechanisms of the pulmonary vasoconstrictor response to alveolar hypoxia are not completely understood, ET-1 and NO are the strongest candidates responsible for the response.
- 2.
Alveolar hypoxia may be an important basic mechanism of many forms of PH, 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.
C. Pulmonary Venous Hypertension
- 1.
Increased pressures in the pulmonary veins produce reflex vasoconstriction of the pulmonary arterioles and raise the PA pressure to maintain a high enough pressure gradient between the PA and the pulmonary vein. The mechanism for the vasoconstriction is not entirely clear, but a neuronal component may be present. Moreover, an elevated pulmonary venous pressure may also close small airways, resulting in alveolar hypoxia, which may contribute to the vasoconstriction. Mitral stenosis, TAPVR with obstruction (of pulmonary venous return to the LA), and chronic left-sided heart failure are examples of this entity.
- 2.
PH with increased pulmonary venous pressure is usually reversible when the cause is eliminated.
D. Primary Pulmonary Hypertension
- 1.
Primary pulmonary hypertension is characterized by progressive, irreversible vascular changes similar to those seen in Eisenmenger syndrome but without intracardiac lesions. The pathogenesis of primary PH is not fully understood, but endothelial dysfunction of the pulmonary vascular bed (with overproduction of ET-1) and enhanced platelet activities may be important factors. Overproduction of ET-1 is associated with not only vasoconstriction but also cell proliferation, inflammation, medial hypertrophy, and fibrosis.
- 2.
This condition is rare in pediatric patients; it is a condition of adulthood and is more prevalent in women. It has a poor prognosis.
E. Other Disease States
PH associated with other disease states has similar pathogenesis to that described in the earlier four categories, singly or in combination.
V. Pathology
- 1.
Heath and Edwards classified the changes into six grades.
- a.
Grade 1: hypertrophy of the medial wall of the small muscular arteries
- b.
Grade 2: hyperplasia of the intima
- c.
Grade 3: hyperplasia and fibrosis of the intima with narrowing of the vascular lumen
- d.
Grades 4 to 6: dilatation and plexiform lesions, angiomatous and cavernous lesions, hyalinization of intimal fibrosis, and necrotizing arteritis
- a.
- 2.
Changes up to grade 3 are considered reversible if the cause is eliminated. Changes seen in grades 4 through 6 are considered irreversible and preclude surgical repair of CHDs.
- 3.
The progressive vascular changes that occur in primary PH are identical to those that occur with CHDs.
- 4.
With pulmonary venous hypertension, pulmonary arteries may show severe medial hypertrophy and intimal fibrosis. However, the changes are limited to grades 1 through 3 of Heath and Edwards’ classification and they are often reversible when the cause is eliminated.
VI. Clinical Manifestations
- 1.
With significant PH, exertional dyspnea and fatigue may manifest. Some patients complain of headache. Syncope, presyncope, or chest pain also occurs on exertion.
- 2.
On physical examination, cyanosis with or without clubbing may be present. The neck veins are distended, and a right ventricular lift or tap occurs on palpation. The S2 is loud and single. An ejection click and an early diastolic decrescendo murmur of PR are usually present along the MLSB. A holosystolic murmur of TR may be audible at the LLSB. Signs of right-sided heart failure (e.g., hepatomegaly, ankle edema) may be present.
- 3.
The electrocardiogram (ECG) shows RAD and RVH with or without “strain.” RAH is frequently seen. Arrhythmias occur in the late stage.
- 4.
Chest radiographs show either normal or slightly enlarged heart. A prominent PA segment and dilated hilar vessels with clear lung fields are characteristic.
- 5.
Echo studies usually demonstrate the following:
- a.
Enlargement of the RA and RV, with normal or small LV dimensions.
- b.
With an elevated RV pressure, the interventricular septum shifts toward the LV and appears flattened at the end of systole.
- c.
PA pressure can be estimated by a Doppler study (see Chapter 4 for detailed discussion).
- (1)
Using the peak TR velocity, the RV systolic pressure (P) can be estimated by the simplified Bernoulli equation (ΔP = 4V 2 ) and adding estimated RA pressure. Using estimated RA pressure is often unreliable and error prone. Therefore, recently the European Society of Echocardiography guidelines (2015) suggested just using the TR max without adding estimated RA pressure, and suggested the following probabilities of PH (Galie N et al., 2016):
TR max ≤2.8 m/sec: Low probability of PH
TR max 2.9 to 3.4 m/sec: Intermediate probability of PH
TR max >3.4 m/sec: High probability of PH
- (2)
With a shunt lesion, such as VSD or PDA, the peak systolic velocity across the shunt is used to estimate the RV pressure.
- (3)
The end-diastolic velocity of PR can be used to estimate the diastolic pressure in the PA.
- a.
- 6.
Exercise testing: A symptom-limited exercise test, such as the 6-minute walk test, may be useful in children for following disease progression or measuring the response to medical interventions.
- 7.
Natural history and prognosis
- a.
PH secondary to the upper airway obstruction is usually reversible when the cause is eliminated.
- b.
PH associated with large L-R shunt lesions or that associated with pulmonary venous hypertension improves or disappears after surgical removal of the cause, if performed early.
- c.
Chronic pulmonary conditions that produce alveolar hypoxia have a relatively poor prognosis.
- d.
Primary PH is progressive and has a fatal outcome, usually 2 to 3 years after the onset of symptoms.
- e.
PH associated with Eisenmenger syndrome, collagen disease, and chronic thromboembolism is usually irreversible and has a poor prognosis but may be stable for two to three decades.
- f.
Right-sided heart failure and cardiac arrhythmias occur in the late stage. Chest pain, hemoptysis, and syncope are ominous signs.
- a.
VII. Diagnosis
- 1.
Noninvasive tools (ECG, chest radiographs, and echo) are used to detect and estimate the severity of PH. Collectively, they are reasonably accurate in assessing severity.
- 2.
Cardiac catheterization is performed to confirm the diagnosis and severity of PH and to determine whether the elevated PVR is due to active vasoconstriction (“responders”) or to permanent changes in the pulmonary arterioles (“nonresponders”). Protocol for vasodilator testing varies from center to center.
- a.
NO inhalation (20 ppm) with or without increased oxygen concentration for 10 minutes is commonly used. One may also use 100% oxygen, inhaled or intravenous (IV) prostacyclin, or IV adenosine.
- b.
“Acute responders” should show (1) a decrease of at least 10 mm Hg in the mean PA pressure to <40 mm Hg (with a normal or increase in cardiac output) or (2) a decrease of ≥20% in the mean PA pressure or PVR with an unchanged or increased cardiac output.
- a.
- 3.
Lung biopsies have been used in an attempt to evaluate the “operability” of patients with PH and CHD. Unfortunately, pulmonary vascular changes are not uniformly distributed and the biopsy findings correlated poorly with the natural history of the disease and operability. Hemodynamic data appear to predict survival better than biopsy findings.
VIII. Management
A. Treating Underlying Causes
Measures to remove or treat the underlying cause should be the primary emphasis whenever possible.
- 1.
Timely corrective surgery for CHDs (such as large-shunt VSD, ECD, or PDA).
- 2.
Tonsillectomy and adenoidectomy when the cause of PH is the upper airway obstruction.
- 3.
Treatment of underlying diseases, such as cystic fibrosis, asthma, pneumonia, or bronchopulmonary dysplasia.
B. General Measures
General measures are aimed at preventing further elevation of PA pressure or treating its complications.
- 1.
The patient should avoid or limit strenuous exertion, isometric activities (weight lifting), and trips to high altitude.
- 2.
Oxygen supplementation is provided as needed.
- 3.
The patient should avoid vasoconstrictor drugs, including decongestants with α-adrenergic properties.
- 4.
Patients should be strongly advised to avoid pregnancy. Pregnancy may increase the risk of pulmonary embolism from deep vein thrombosis or amniotic fluid, and may cause syncope and cardiac arrest.
- 5.
Oral contraceptives should not be used because they worsen PH (surgical contraception is preferred).
- 6.
CHF is treated with ACE inhibitors, digoxin, and diuretics and a low-salt diet.
- 7.
Cardiac arrhythmias are treated with antiarrhythmic agents.
- 8.
Partial erythropheresis is performed for polycythemia and headache.
- 9.
Annual flu shots are recommended.
C. Anticoagulation and Antiplatelet Agents
- 1.
Anticoagulation with warfarin (with the international normalized ratio of 2.0 to 2.5) is widely recommended in patients with thromboembolic disease. It may be beneficial in patients with PH from other causes.
- 2.
Some recommend antiplatelet drugs (aspirin) instead of warfarin to prevent microembolism in the pulmonary circulation.
D. Pharmacologic Treatment of Chronic Pulmonary Hypertension
The pulmonary vasodilators are used in responders. For nonresponders, vasodilators have limited success. Vasodilators should not be used without testing first in the catheterization laboratory.
Drugs that are used to relieve pulmonary vasoconstriction can be divided into endothelial-based and smooth muscle-based drugs (Oishi et al., 2011).
- •
Endothelial-based drugs act on endothelial mechanisms and cause vasodilatation:
- •
NO inhalation
- •
Phosphodiesterase type 5 inhibitors (PDE5i) (sildenafil, tadalafil)
- •
Prostacyclin analogues (epoprostenol, treprostinil, iloprost, beraprost)
- •
Endothelin receptor antagonists (bosentan, sitaxsentan, ambrisentan)
- •
- •
Smooth muscle–based drugs act directly on the smooth muscle.
- •
Calcium channel blockers (nifedipine)
- •
- 1.
For acute responders . The following vasodilators are used in acute responders. Most of the experiences are based on adult trials. Some vasodilators may lower the systemic vascular resistance more than the PVR and thus are not suitable.
- a.
Calcium channel blockers (CCBs) . For acute responders with primary PH treated with CCBs, survival was 97% and 81% at 1 and 10 years, respectively. Children who were not acute responders but were still treated with CCBs had survival rates of 45% and 29% at 1 and 4 years. Hypotension is a side effect of the medication. Nifedipine (at a dose of 0.2 mg/kg PO q8h) is one of the oldest drugs used with beneficial effects seen in 40% of children with primary PH. The dosages of other CCBs are diltiazem (3 to 5 mg/kg/day) and amlopidine (2.5 to 10 mg/day). Diltiazem lowers heart rate and therefore is used more frequently in younger children with higher heart rate. Verapamil is contraindicated because of its negative inotropic effects.
- b.
Prostacyclins . Continuous IV infusion of epoprostenol (PGI 2 ) has been shown to improve quality of life and survival in patients with primary PH, Eisenmenger syndrome, or chronic lung disease. The starting dose of epoprostenol was 2 ng/kg/min, with increments of 1 to 2 ng/kg/min every 15 min, until desired effects appeared; the average final dose was 9 to 11 ng/kg/min. Prostacyclins are administered by an ambulatory IV system because of a very short half-life (1 to 2 minutes).
- c.
Endothelin receptor antagonists, bosentan and sitaxsenton , have been used in both primary PH and Eisenmenger syndrome. Side effects of ET antagonists include elevation of hepatic aminotransferase levels, teratogenicity, anemia, and peripheral edema, decreased effectiveness of oral contraceptive agents, and effects on male fertility.
- (1)
In children with primary pulmonary hypertension or Eisenmenger syndrome, oral bosentan, a nonselective endothelin receptor blocker, in the dose of 31.25 mg BID for children <20 kg, 62.5 mg BID for children 20 to 40 kg, and 125 mg BID for children >40 kg (with or without concomitant IV prostacyclin therapy) for median duration of 14 months, resulted in a significant functional improvement in about 50% of the cases.
- (2)
Sitaxsentan, a selective endothelin-A (ET A ) receptor antagonist, given orally once daily at a dose of 100 mg (for mostly adult patients and children older than 12 years), resulted in improved exercise capacity after 18 weeks of treatment.
- d.
Sildenafil, a phosphodiesterase inhibitor, prevents the breakdown of cGMP resulting in pulmonary vasodilatation. Oral dose of 0.25 to 1 mg/kg, four times daily for 12 months’ duration, has resulted in improvement in hemodynamics and exercise capacity. Adverse effects include headache, flushing, exacerbation of nosebleed, and rare systemic hypotension or erection.
- e.
NO inhalation is effective in lowering PA pressure in adult respiratory distress syndrome, primary PH, and persistent PH of the newborn. NO can be administered only by inhalation because it is inactivated by hemoglobin. Rebound PH is problematic.
- a.
- 2.
For nonresponders . The following measures can be used in nonresponders.
- a.
NO inhalation and continuous IV or possibly nebulized prostacyclin (PGI 2 ) may provide selective pulmonary vasodilatation.
- b.
Atrial septectomy (either by catheter or surgery) improves survival rates and abolishes syncope by providing a R-L atrial shunt, thereby helping to maintain cardiac output but with increased hypoxemia.
- c.
Potts shunt placed between the LPA and descending aorta providing R-L shunting has shown improvement in functional status and midterm transplant free survival of patients with suprasystemic PH (Aggarwal, 2018).
- d.
Lung or heart-lung transplantation remains the only available treatment for patients unresponsive to vasodilator treatment. Bilateral lung transplantation is preferred at most centers, but some centers prefer single lung transplantation.
- a.
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