Advances in Prostacyclin Therapy for Pulmonary Arterial Hypertension (2004)

Pulmonary arterial hypertension presents a diagnostic challenge and is difficult to manage. Critical care nurses play a pivotal role in the treatment and education of these patients. This article reviews current advances in prostacyclin therapy.Pulmonary arterial hypertension (PAH) is a progressive, life-threatening, incurable disease. It is characterized by mean pulmonary artery pressure greater than 25 mm Hg at rest or 30 mm Hg with activity.1,2 Pulmonary hypertension was once differentiated into primary and secondary forms but was reclassified in 1998 after the World Health Organization symposium on pulmonary hypertension. This reclassification was designed to reflect clinical patterns of disease. The current classification is based on differences between primary pulmonary hypertension (PPH) and pulmonary hypertension of certain known causes.1,3 These types of hypertension differ with respect to patients’ clinical manifestations and pulmonary histopathologic findings.1,2,4 The reclassification allows categorization by common clinical features (Table 1).A diagnosis of PPH indicates PAH with no identifiable cause and includes the familial or the genetic form of the disease.5 Although most cases of PPH are sporadic, the prevalence of familial disease is at least 6%.1,2,6 Other forms of pulmonary hypertension as described in the World Health Organization proposals include pulmonary venous hypertension, pulmonary hypertension associated with disorders of the respiratory system and/or hypoxemia, pulmonary hypertension caused by chronic thrombotic and/or embolic disease, and pulmonary hypertension resulting from disorders that affect the pulmonary vasculature.1,2 Before the World Health Organization reclassification, the aforementioned categories were referred to as secondary pulmonary hypertension.Patients with PAH are further classified according to their level of functional ability. This classification is determined by patients’ exercise performance. The functional assessment grading scale shown in Table 2 has been modified according to the functional classification system of the New York Heart Association.1,2 Patients with class I disease have PAH but are symptom-free. Patients with class IV disease may have signs or symptoms of PAH while at rest and cannot undertake physical activity without having signs and symptoms of PAH.1,2The incidence of PPH is 1 to 2 cases per 1 million per year. PPH is rapidly progressive and fatal when left untreated.1,2 Other causes of PAH may account for an additional 1 to 2 cases per million each year.1,2 Histological changes take place sequentially and include smooth muscle hypertrophy of the arterial wall, intimal proliferation, in situ thrombosis, occlusion of small vessels, and the formation of plexiform lesions that are unevenly distributed throughout the pulmonary vasculature.3,7,8 The cross-sectional area of the pulmonary vascular bed is severely diminished by the obliteration of small vessels (Figure 1).9Altered function of the pulmonary vascular endothelium may also be an important consideration in patients with PAH.8,10,11 An imbalance in the ratio of prostacyclin, which causes vasodilatation, and thromboxane, which causes vasoconstriction, may occur. This finding suggests that either enhanced activity of thromboxane or diminished production of prostacyclin may contribute to the pathogenesis of PAH.10,11 Additionally, impaired synthesis of the endothelium-derived vasodilator nitric oxide and increased production of the endothelium-derived vasoconstrictor endothelin have been associated with PAH.5,10–12Progressive and sustained elevations in pulmonary artery pressure and pulmonary vascular resistance ultimately lead to right ventricular failure.3 According to data from a US national registry of patients started in 1981, without treatment, the median survival of patients with PPH is 2.8 years after diagnosis, with survival rates of 68%, 48%, and 34% after 1, 3, and 5 years, respectively.13,14 Variables associated with poor prognosis include New York Heart Association functional class III or IV, the presence of Raynaud phenomenon, increased right atrial pressure, increased mean pulmonary artery pressure, reduced cardiac index, and decreased carbon monoxide diffusion capacity.14The diagnosis of PAH remains difficult and is often elusive, particularly early in the course of the disease. Initial signs and symptoms are typically subtle and nonspecific, and the onset of the disease is gradual.1 In addition, the incidence of the disease is relatively low, and caregivers most likely are not familiar with the potential signs and symptoms. As a result, the diagnosis of PAH is commonly delayed, sometimes for more than 2 years after the onset of signs and symptoms.2,5In general, the signs and symptoms of PAH reflect the inability of the pulmonary vascular bed to accommodate increases in cardiac output. Initial signs and symptoms may include pallor, shortness of breath, dyspnea on exertion, syncope, and chest pain related to right ventricular ischemia.2,5 Physical findings depend on the severity of the disease and may include a loud S2 in the pulmonary region, a right ventricular heave, and a pulmonary flow murmur. Progression of right-sided heart failure is signaled by jugular venous distention, edema, and an S3 gallop.5,6 Of note, however, no signs and symptoms are specific to PAH, and additional clinical tests are required to confirm the diagnosis.The algorithm presented in Figure 2 shows appropriate diagnostic testing for patients being evaluated for PAH.5,15 Radiographs may show enlarged central pulmonary arteries and right ventricular enlargement.6 An echocardiogram is obtained to determine the presence or absence of left ventricular dysfunction and valvular disease. Estimated pressure readings from the right ventricle may be helpful in predicting disease severity. The right atrium or right ventricle may be enlarged.2 Evaluation of the right side of the heart can assist in building of a more complete picture of the degree of heart failure. An echocardiogram is used to detect any congenital heart disease and to assess any shunts present.6 Serial echocardiograms are helpful in long-term follow-up to monitor disease progression and the patient’s response to treatment.1 Electrocardiograms may be used to detect evidence of right atrial and right ventricular hypertrophy.2,6A ventilation-perfusion lung scan is required to exclude chronic thromboembolic disease.5 Pulmonary angiography can be performed if the ventilation-perfusion scan indicates intermediate probability of thromboembolic disease. Other diagnostic studies may include computed tomography to detect interstitial lung disease or high-resolution computed tomography in place of ventilation-perfusion studies. Pulmonary function tests may also be used to detect any common respiratory ailments that might be causing shortness of breath.6 A sleep study should be done to screen for sleep apnea, which may contribute to pulmonary hypertension.5 A standardized exercise test known as the 6-minute walk is also used to give an estimate of a patient’s exercise tolerance.6 This test should be repeated over time in patients with PAH. Results from the 6-minute walk are useful in assessing a patient’s response to therapy and/or disease progression. In addition, serological tests are done to detect collagen vascular disease, hepatitis, or infection with human immunodeficiency virus.5Right heart catheterization is the most important and useful diagnostic tool in the evaluation of patients with PAH. This procedure is the only way in which pulmonary artery pressure, cardiac output, and pulmonary vascular resistance can be specifically determined.5 Catheterization is also important in excluding left-sided cardiac dysfunction. During catheterization, vasoreactivity must be evaluated to determine the appropriate treatment pathway (Figure 3).16 Patients who are in heart failure or whose hemodynamic status is unstable are not suitable candidates for vasoreactivity testing, because this may cause further deterioration in their hemodynamics.Vasoreactivity testing involves assessing a patient’s response to the short-term administration of a selected vasodilator. Accepted vasodilators for this type of testing include inhaled nitric oxide, intravenous adenosine, and intravenous epoprostenol.1,5 A patient’s acute response may correlate with his or her response to oral vasodilator therapy. Although not uniformly defined, a positive or favorable response may be indicated by a reduction in baseline mean pulmonary artery pressure of at least 20%, with either no change or an increase in cardiac output, and minimal effect on systemic blood pressure.17,18 Patients who have a positive response are generally appropriate candidates for therapy with oral calcium channel blockers. However, such responses typically occur in only 20% to 30% of patients.1,2,5,11 A negative response is indicated by no significant improvement or by a deterioration in pulmonary hemodynamics.2 Patients who have a negative response are unlikely to benefit from therapy with oral calcium channel blockers.1Historically, conventional therapy of patients with PAH involved treatment with oral calcium channel blockers, diuretics, and anticoagulants and the restriction of physical activity. Recent advances in therapeutics and in the understanding of the pathophysiology of pulmonary hypertension have led to new medical treatment options with prostacyclin therapies. Surgical treatment options, which are not discussed here, include lung or heart-lung transplantation for patients who are unresponsive to conventional therapy and atrial septostomy, which also typically is reserved for patients in whom medical management is unsuccessful.Most patients with PAH are started on anticoagulant therapy at the time of diagnosis, unless they have any known contraindications.6 Patients with PAH experience a decrease in cardiac output due to the left ventricular compression that occurs with right ventricular hypertrophy. As a result, they are at risk for pulmonary embolism. The decrease in cardiac output is also associated with injury to the pulmonary vascular bed.5 In studies19,20 in adults with PPH, use of anticoagulants was associated with improved survival. Treatment guidelines1,2 recommend a target international normalized ratio of 1.5 to 2.0, although individual clinical circumstances may require adjustment of this range.In patients with PAH, the decision to use oral vasodilators is based on the occurrence of pulmonary vasoconstriction.13,19,21 Determination of the suitability of these agents for any given patient is based on the results of acute vasoreactivity testing performed during cardiac catheterization. Data22 obtained in children with PPH indicated 1-, 3-, and 5-year survival rates of 97% in those who responded positively to vasoreactive agents. Nonresponders had poor survival when treated with calcium channel blockers, with 1-, 3-, and 5-year survivals of 66%, 52%, and 35%, respectively. As stated previously, approximately only a quarter of patients respond to therapy with oral calcium channel blockers.1,2,5,11 Nifedipine and diltiazem are used most commonly. The major limitation of these agents is their nonselectivity for the pulmonary vasculature. Adverse effects include systemic hypotension, edema, and hypoxemia.6 Inappropriate use of vasodilators can result in rapid clinical deterioration, with worsening heart failure and hemodynamic measures. Oral vasodilators should not be used in patients with a cardiac index of 2.1 or less, and/or a pulmonary arterial saturation of 63% or less, and/or a right atrial pressure of 10 mm Hg or greater.2Inotropic agents are used to improve contractility and maintain cardiac output.1 Diuretics, such as furosemide, are used as needed to prevent volume overload, thereby reducing ventricular overload.5 Oxygen is used to maintain adequate arterial saturation, thereby preventing the vasoconstriction and increases in pulmonary pressure often associated with hypoxemia.2The prostaglandins are potent endogenous vasodilators with antiproliferative and cytoprotective properties. Their action is associated with remodeling of the pulmonary vascular bed and with reductions in endothelial cell injury and hyperco-agulability.2 Notably, imbalances in the ratio of thromboxane to prostacyclin metabolites have been detected in patients with pulmonary hypertension, with reduced pulmonary arterial levels of prostacyclin synthase.1 A comparison of current prostacyclin therapies highlights their unique differences and indications (Table 3).The naturally occurring prostaglandin epoprostenol (prostacyclin) is produced by the vascular endothelium. Epoprostenol is a potent, short-acting vasodilator of both the systemic and the pulmonary arterial vascular beds and is an inhibitor of platelet aggregation.23 In addition, epoprostenol may provide benefit through effects on vascular growth and remodeling of the vascular bed.11 As the agent is unstable at pH values less than 10.5, it cannot be given orally. Because of its short half-life in the circulation, epoprostenol must be given via continuous intravenous infusion.23Intravenous therapy with epoprostenol sodium (Flolan) was approved by the Food and Drug Administration in 1995 as a long-term treatment for patients with PPH and New York Heart Association class III or class IV disease. In an open, prospective, randomized 12-week clinical trial in 81 patients with class III or class IV PPH, continuous intravenous epoprostenol significantly improved hemodynamics, exercise capacity, quality of life, and survival.24 Since the approval of epoprostenol, patients with pulmonary hypertension associated with other conditions have also been treated with this agent. Intravenous epoprostenol has been administered as long-term therapy to patients with PAH associated with connective tissue disease, congenital heart disease, and infection with human immunodeficiency virus. Approval for long-term treatment of patients with pulmonary hypertension associated with the scleroderma spectrum of diseases was granted in 1999.Long-term therapy with intravenous epoprostenol was effective in the treatment of pulmonary hypertension in patients deemed to be nonresponders to conventional vasodilator therapy.21,22 In one study,22 a group of 24 children noted as nonresponders to vasoactive agents and subsequently treated with intravenous epoprostenol had 100% survival after 1 and 2 years, and 92% survival after 3 and 4 years. In contrast, 22 nonresponders treated with conventional therapy alone had survival rates of 43%, 34%, 29%, and 29% after 1, 2, 3, and 4 years, respectively.22 Intravenous therapy with epoprostenol was either declined or unavailable for the second group of children.Although successful in the treatment of pulmonary hypertension, intravenous epoprostenol therapy is both costly and complex. Therapy requires the insertion of a central venous catheter for continuous administration. This requirement predisposes patients to the complications of catheter infection, sepsis, thrombosis, paradoxical embolus, catheter fracture or displacement, and difficulties associated with pump malfunction.5,24,25 Because the elimination half-life of intravenous epoprostenol is only 2 to 3 minutes, any abrupt cessation in administration may cause a rebound episode of pulmonary hypertension and possibly sudden death.5,24 Conversely, inadvertent administration of a bolus of epoprostenol can cause abrupt, profound systemic hypotension and loss of consciousness. Adverse effects of the drug include headache, jaw pain, diarrhea, rash, flushing, stomachache, muscle pain, and arthralgia.2Another disadvantage of epoprostenol is the to a intravenous pump at Patients must also have a intravenous and with at for use in the of failure. 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