PULMONARY HYPERTENSION
Pulmonary hypertension is an elevation in pulmonary vascular pressure that can be caused by an isolated increase in pulmonary artery pressure or by combined increases in both pulmonary artery and pulmonary venous pressures (see Plate 4-123). Normal pressures in the pulmonary vascular bed are quite low. Pulmonary arterial hypertension (PAH) refers to isolated elevation of pulmonary arterial pressure, hemodynamically defined as a resting mean pulmonary artery pressure above 25 mm Hg with a normal left atrial pressure (15 mm Hg). PAH that occurs in the absence of a demonstrable cause, formerly known as primary pulmonary hypertension (PPH), may occur sporadically (idiopathic PAH [IPAH]) or as an inherited condition (familial PAH or FPAH). Mutations in the bone morphogenetic protein receptor II (BMPR2) gene occur in 50% of families with a history of FPAH and in nearly 25% of patients thought to have sporadic IPAH. Genetic testing and counseling may be recommended for relatives of patients with FPAH. PAH occurs in association with connective tissue diseases (particularly scleroderma), HIV infection, sickle cell disease, and chronic liver disease (portopulmonary hypertension). The “Venice” classification scheme of pulmonary hypertension is shown in Plate 4-123.
WHO CLASSIFICATION SYSTEM OF PULMONARY HYPERTENSION
PATHOPHYSIOLOGY OF PULMONARY ARTERIAL HYPERTENSION
Patients with significant PAH rarely undergo lung
biopsy because of the surgical and anesthetic risk involved (see Plate 4-124).
For this reason, much of the available pathologic information regarding the
disease comes from patients with late-stage disease who die or undergo lung
transplantation. In these later stages of the disease, IPAH reveals the
presence of plexiform arteriopathy. The plexiform lesion is a complex tuft of
proliferating intimal cells thought to be of endothelial cell or smooth muscle
cell origin. Multiple small channels may remain where there was once an open
arterial lumen. This obstructive, proliferative arteriopathy leads to increased
resistance to pulmonary blood flow. Some patients with IPAH may demonstrate
microscopic in situ thrombosis in the small pulmonary arterioles. Although IPAH
is often associated with plexiform arteriopathy, some patients with underlying
associated conditions such as scleroderma may demonstrate a more concentric,
“onion skin” form of hypertrophy of the pulmonary vascular wall.
Obliteration of the pulmonary vascular lumen leads to
an increase in pulmonary vascular resistance, ultimately placing a strain on
the right ventricle. If the pulmonary vascular resistance increases slowly, as
it often does in patients with PAH occurring in association with congenital
heart disease, the right ventricle may adapt over time through hypertrophy,
with maintenance of contractility and preservation of cardiac output. A more
rapid increase in pulmonary vascular resistance, perhaps in the presence of a
genetically determined less adaptive response, may lead to right ventricular
dilatation, with a progressive decline in function and ultimately right
ventricular failure. Right- sided heart failure is typically manifest
clinically by progressive dyspnea on exertion, fatigue, fluid retention, edema,
ascites, and signs of venous congestion. The most common cause of death in
patients with PAH is right-sided heart failure.
DIAGNOSIS
Screening
Although PAH may be asymptomatic, exertional dyspnea
is the most frequently encountered symptom (see Plate 4-125). Accordingly, PAH
should be suspected in patients with unexplained dyspnea. Anginal chest pain or
syncope is less common and portends a poor prognosis. Peripheral edema or
ascites indicates right ventricular failure. The symptoms of PAH are nonspecific
and are similar to those occurring in more commonly encountered diseases, such
as obstructive lung disease and left-sided heart disease. A family history of
pulmonary hypertension may lead to early recognition of clinical disease in
other individuals. Pulmonary hypertension occurs more frequently in patients
with autoimmune or connective tissue disease, especially scleroderma. Use of
amphetamines or cocaine should be explored because these have been implicated
in the development of PAH in some users. A history of acute pulmonary embolism
requires a careful search for chronic thromboembolic pulmonary hypertension,
although this condition may occur in the absence of symptomatic venous
thromboembolic disease. Patients with a history of such underlying disorders or
exposures who develop unexplained dyspnea should be screened for possible
pulmonary hypertension.
The diagnostic strategy uses testing to determine
whether PAH is the cause of symptoms and which of its causes is present (see
Plate 4-125). A process of screening with less invasive and lower risk tests is
followed by specific and confirmatory tests.
The electrocardiogram may provide evidence of pulmonary
hypertension, such as right ventricular hypertrophy, right-axis deviation, or
right atrial enlargement.
Radiographic signs of pulmonary hypertension include
enlarged main and hilar pulmonary arteries (17 mm) with attenuation of
peripheral pulmonary vascular markings (“pruning”). Right ventricular
enlargement is evidenced by anterior displacement of the right ventricle into
the retrosternal space on the lateral view (see Plate 3-9). The chest radiograph is
also useful in demonstrating comorbid or causal conditions, such as pulmonary
venous congestion, chronic obstructive pulmonary disease, or interstitial lung
disease.
Doppler echocardiography is often the test that
suggests a diagnosis of pulmonary hypertension. Echocardiography also provides information
about the cause and consequences of pulmonary hypertension. Studies in patients
with PAH have reported good correlations between Doppler-derived estimates of
pulmonary artery systolic pressure and direct measurements obtained by
right-sided heart catheterization. Echocardiography also provides evidence
regarding left ventricular systolic and diastolic function and valvular
function and morphology that can provide clues to causes of pulmonary
hypertension stemming from elevated pulmonary venous pressures. Left atrial
enlargement, even in the absence of definite left ventricular dysfunction,
should raise the possibility of elevated left-sided filling pressures
contributing to pulmonary hypertension.
Cardiac catheterization is ultimately required to confirm
the presence of pulmonary hypertension, assess its severity, and guide therapy.
The evaluation of PAH includes assessment for an
underlying cause (see Plate 4-125). Pulmonary function testing is a necessary
part of the initial evaluation of patients with suspected pulmonary
hypertension to exclude or characterize the contribution of underlying airways
or parenchymal lung disease. In general, the degree of pulmonary hypertension
seen in chronic obstructive lung disease is less severe than in PAH, and the
presence and severity of pulmonary hypertension correlate with the degree of
airflow obstruction and hypoxemia. Approximately 20% of IPAH patients have a
mild restrictive defect. In chronic thromboembolic pulmonary hypertension
(CTEPH), a mild to moderate restrictive defect is thought to be caused by
parenchymal scarring from prior infarcts. In both conditions, the diffusing
capacity for carbon monoxide is often mildly to moderately reduced. Mild to
moderate arterial hypoxemia is caused by V/Q mismatch and reduced mixed venous
oxygen saturation resulting from low cardiac output. Severe hypoxemia is caused
by right- to-left intracardiac or intrapulmonary shunting. In patients with
scleroderma, a decreasing diffusing capacity may indicate the development of pulmonary
hypertension.
Overnight oximetry may demonstrate oxygen desaturation
and might be the first clue to sleep apnea sufficient to contribute to pulmonary
hypertension. Nocturnal hypoxemia can occur in patients with IPAH without sleep
apnea. Because hypoxemia is a potent pulmonary vasoconstrictor, all patients
with unexplained pulmonary hypertension require assessment of both sleep and
exercise oxygen saturation.
It is important to screen for autoimmune and
connective tissue disease, including physical examination and serologic testing
for antinuclear antibodies. However, up to 40% of patients with IPAH have
serologic abnormalities, usually an antinuclear antibody in a low titer and
nonspecific pattern. Additional serologic studies may be indicated if initial
testing suggests an underlying autoimmune disorder.
CTEPH is a potentially curable form of pulmonary
hypertension and should be sought in all patients undergoing evaluation for
possible pulmonary hypertension. Ventilation/perfusion (V/Q) lung scanning is the preferred test to rule out
CTEPH. CTEPH is manifest by at least one segmental-sized or larger perfusion
defect, which are typically mismatched and larger than ventilation
abnormalities. Patchy, nonsegmental defects are less specific but may be associated
with CTEPH. Although a normal perfusion scan essentially excludes surgically
accessible chronic thromboembolic disease, scans suggestive of thromboembolic
disease may also be seen in other conditions. Pulmonary angiography is the
definitive test for diagnosing CTEPH and for determining operability and should
be performed in experienced centers when this entity is a consideration.
Computed tomography (CT) scanning may suggest a cause
for pulmonary hypertension, such as severe airway or parenchymal lung diseases.
A spectrum of abnormalities on CT scan have been described in patients with
CTEPH, including right ventricular enlargement, dilated central pulmonary
arteries, chronic thromboembolic material within the central pulmonary
arteries, increased bronchial artery collateral flow, variability in the size and
distribution of pulmonary arteries, parenchymal abnormalities consistent with
prior infarcts, and mosaic attenuation of the pulmonary parenchyma.
Open or thoracoscopic lung biopsy entails substantial
risk in patients with significant pulmonary hypertension. Because of the low
likelihood of altering the clinical diagnosis, routine biopsy is discouraged.
Under certain circumstances, histopathologic diagnosis may be needed when
vasculitis, granulomatous or interstitial lung disease, pulmonary venocclusive
disease, or bronchiolitis are suggested on clinical grounds or by radiographic
studies.
TREATMENT OF PULMONARY ARTERIAL HYPERTENSION
General Measures
There are few data on which to base recommendations
regarding physical activity or cardiopulmonary rehabilitation in PAH (see Plate
4-126). Cautious, graduated physical activity is generally encouraged. Heavy
physical activity can precipitate syncope. Hot baths or showers are discouraged
because resultant peripheral vasodilatation can produce systemic hypotension
and syncope. Excessive sodium intake can contribute to fluid retention. Exposure
to high altitude (6000 ft above sea level) should generally be discouraged
because it may produce hypoxic pulmonary vasoconstriction. Supplemental oxygen
should be used to maintain oxygen saturations above 91%. Air travel can be
problematic for patients with PAH because commercial air- craft are typically
pressurized to the equivalent of approximately 8000 feet above sea level.
Patients with borderline oxygen saturations at sea level may require 3 to 4
L/min of supplemental oxygen on commercial aircraft, and those already using
supplemental oxygen at sea level should increase their oxygen flow rate. Because
of the potential adverse effects of respiratory infections, immunization
against influenza and pneumococcal pneumonia is recommended.
Pregnancy and Birth Control
The hemodynamic changes occurring in pregnancy impose
significant stress in women with PAH, leading to a potential 30% to 50%
mortality rate. Although there have been reports of successful treatment of
pregnant IPAH patients using chronic intravenous epoprostenol, most experts
recommend early termination of the pregnancy. Estrogen-containing
contraceptives may increase the risk of venous thromboembolism and are not
recommended for women with childbearing potential with PAH. Additionally, the
endothelin receptor antagonists bosentan and ambrisentan may decrease the
efficacy of hormonal contraception, and dual mechanical barrier contraceptive
techniques are recommended in female patients of childbearing age taking these
medications.
Concomitant Medications and Surgery
Use of vasoconstricting sinus or cold medications
(e.g., pseudoephedrine) or serotonergic medications for migraine headaches may
be problematic. Concomitant use of glyburide or cyclosporine with bosentan is
contraindicated, and the use of azole-type antifungal agents is discouraged
because of potential drug-drug interactions that may increase the risk of
hepatotoxicity. Patients taking warfarin should be cautioned regarding
potential drug interactions with this medication. Bosentan may decrease
International Normalized Ratio (INR) levels slightly in patients taking
warfarin.
Invasive procedures and surgery can be associated with
an increased risk. Patients with severe PAH are particularly prone to vasovagal
events leading to syncope, cardiopulmonary arrest, and death. Cardiac output often depends on the heart rate
in this situation, and the bradycardia and systemic vasodilatation accompanying
a vasovagal event may result in hypotension. Heart rate should be monitored
during invasive procedures, with availability of an anticholinergic agent.
Oversedation may lead to ventilatory insufficiency and cause clinical
deterioration. Caution should be exercised with laparoscopic procedures in
which carbon dioxide is used for abdominal insufflation because absorption can
produce hypercarbia, which is a pulmonary vasoconstrictor. The induction of
anesthesia and intubation may
be problematic because it may induce vasovagal events, hypoxemia, hypercarbia, and shifts
in intrathoracic pressure.
Anticoagulation
Anticoagulation of IPAH patients with warfarin is
recommended in the absence of contraindications. Although there is little
evidence to guide such therapy, current consensus suggests targeting an INR of
approximately 1.5 to 2.5. Anticoagulation is controversial for patients with
PAH caused by other etiologies, such as scleroderma or congenital heart
disease, because of a lack of evidence supporting efficacy, and the increased
risk of gastrointestinal bleeding in patients with scleroderma, and hemoptysis
congenital heart disease. The relative risks and benefits of anticoagulant
therapy should be considered on a case-by-case basis. Patients with documented
right-to-left intracardiac shunting caused by an atrial septal defect or patent
foramen ovale and a history of transient ischemic attack or embolic stroke
should be anticoagulated. Patients receiving treatment with chronic intravenous
epoprostenol are generally anticoagulated in the absence of contraindications
partly because of the additional risk of catheter- associated thrombosis.
Diuretics
Diuretics are indicated for volume overload or right
ventricular failure. Rapid and excessive diuresis may precipitate systemic
hypotension and renal insufficiency. Spironolactone, an aldosterone antagonist
of benefit in patients with left-sided heart failure, is used by some experts to
treat right-sided heart failure.
Digitalis
Although not extensively studied in PAH, digitalis is
sometimes used for refractory right ventricular failure. Atrial flutter or other
atrial dysrhythmias often complicate late-stage right-sided heart dysfunction,
and digoxin may be useful for rate control.
Vasodilator Testing and Calcium Channel Blockers
Patients with IPAH who acutely respond to vasodilators
often have improved survival with long-term use of calcium channel blockers (CCBs) (see Plate 4-126). A
variety of short-acting agents have been used to test vasodilator
responsiveness, including intravenous epoprostenol or adenosine and inhaled
nitric oxide. The most recent consensus definition of a positive acute
vasodilator response in PAH is decrease of at least 10 mm Hg in mean pulmonary
artery pressure to less than or equal to 40 mm Hg with an increased or
unchanged cardiac output. Most experts believe that true vasoreactivity is
uncommon, occurring in 10% of patients with IPAH and rarely in those with other
forms of PAH. Vasoreactivity testing should be performed in experienced
centers. Only patients demonstrating a significant response to the acute
administration of a short-acting vasodilator should be considered candidates
for treatment with CCBs; treatment should be monitored closely because maintenance
of response is not universal. Long-acting nifedipine or diltiazem or amlodipine
is suggested. Agents with negative inotropic effect, such as verapamil, should
be avoided.
Prostanoids
Prostacyclin is a metabolite of arachidonic acid that
is produced in vascular endothelium. It is a potent vasodilator, affecting both
the pulmonary and systemic circulations, and has antiplatelet aggregatory
effects. A relative deficiency of endogenous prostacyclin may contribute to the
pathogenesis of PAH. In IPAH, continuously intravenously infused epoprostenol
improved exercise capacity, assessed by the 6-minute walk distance (6MWD),
cardiopulmonary hemodynamics, and survival compared with conventional therapy
(oral vasodilators, anticoagulation). A similar study showed epoprostenol
improved exercise capacity and hemodynamics in patients with PAH caused by the
scleroderma spectrum of disease. Epoprostenol therapy is complicated by the
need for continuous intravenous infusion. Because of its short half-life, the
risk of rebound worsening with interruption of the infusion, and its irritant
effects on peripheral veins, epoprostenol should be administered through an
indwelling central venous catheter. Common side effects include headache,
flushing, jaw pain, diarrhea, nausea, a blotchy erythematous rash, and
musculoskeletal pain. Serious complications include catheter-related sepsis and
thrombosis. Although epoprostenol is approved by the Food and Drug
Administration for functional class III to IV patients with IPAH and PAH caused
by scleroderma, it is generally reserved for patients with advanced disease
refractory to oral therapies.
Other options for prostanoid therapy include
subcutaneous or inhaled treprostinil, which has a longer half-life than
epoprostenol, and inhaled iloprost, which must be inhaled six to nine times
daily. Both drugs have demonstrated improved exercise capacity, functional
class, and hemodynamics.
Endothelin Receptor Antagonists
Endothelin-1 (ET-1) is a vasoconstrictor and smooth
muscle mitogen that may contribute to increased vascular tone and proliferation
in PAH. Two endothelin receptor isoforms, ETA and ETB, and ET, have been identified. Controversy exists as to whether it
is preferable to block block both the ETA and ETB
receptors or to selectively target the ETA receptor. It has been
argued that selective ETA receptor antagonism may be beneficial for
the treatment of patients with PAH because of maintenance of the vasodilator
and clearance functions of ETB receptors. A dual ETA/ETB
receptor antagonist, bosentan, and a relatively selective ETA
receptor antagonist, ambrisentan, have been approved for use in patients with
PAH and moderate to severe heart failure.
Phosphodiesterase-5 Inhibitors
Sildenafil is a highly specific phosphodiesterase-5
inhibitor approved for male erectile dysfunction. Sildenafil reduces pulmonary
artery pressure and increases 6MWD and confers additional benefit to background
therapy with epoprostenol in patients with PAH. Sildenafil, and the longer acting
tadalafil, are approved in the United States for the treatment of PAH.
INTERVENTIONAL AND SURGICAL THERAPIES
Atrial septostomy involves the creation of a right-to
left interatrial shunt to decompress the failing pressure/volume-overloaded
right side of the heart. Where advanced medical therapies are available, atrial
septostomy is seen as a largely palliative procedure or as a stabilizing bridge
to lung transplantation. In areas lacking access to advanced medical therapies,
atrial septostomy may be an option. Patient selection, timing, and appropriate
sizing of the septostomy are critical to optimizing outcomes. Lung
transplantation is particularly challenging in patients with PAH and is often
reserved for those who are deteriorating despite the best available medical
therapy. Survival in patients undergoing lung transplantation is approximately
66% to 75% at 1 year. Most centers prefer bilateral lung transplantation for patients with
PAH.
