RISK FACTORS Female sex
Medical Care:
" Anticoagulation
o Several studies, using both univariate and multivariate analyses, show that survival is increased when the patient is treated with anticoagulant therapy, regardless of histopathologic subtype. However, these studies were retrospectively performed. No randomized, controlled clinical trials of anticoagulation in PPH exist; thus, the data are mostly consensus-driven rather than based on prospective evidence-based medicine.
o Use warfarin to maintain an international normalized ratio of 1.5- to 2-times the control value, provided the patient has no contraindications to anticoagulation.
" Other oral agents
o Use digoxin therapy to improve right ventricular function in patients with right ventricular failure. However, no randomized controlled clinical study has been performed to validate this strategy for patients with PPH.
o Use diuretics to manage peripheral edema. The use of loop diuretics (eg, furosemide, bumetanide) requires potassium supplementation and close monitoring of serum potassium. Potassium-sparing diuretics may have a role in ameliorating the sometimes-intractable hypokalemia observed with daily diuretic use.
o Use oxygen supplementation in those patients with resting or exercise-induced hypoxemia. Use caution if patients have a left-to-right shunt via a patent foramen ovale because supplemental oxygen in these instances may provide little or no benefit.
" Conventional oral vasodilator therapy
o Until recently, CCBs had been the most widely used class of drugs for IPAH. These drugs are thought to act on the vascular smooth muscle to dilate the pulmonary resistance vessels and lower the pulmonary artery pressure. Several studies report clinical and hemodynamic benefits from the use of long-term calcium channel blockade. The use of these drugs produces a reduction in pulmonary vascular resistance by increasing the cardiac output and decreasing pulmonary artery pressure. It also improves the quality of life and survival rate, in patients who are proven "responders" to such therapy.
o Only use CCBs on patients without overt evidence of right-sided heart failure. A cardiac index of less than 2 L/min/m2 or elevated right atrial pressure above 15 mm Hg is evidence that CCBs may worsen right ventricular failure and, thus, are of no benefit. This is potentially harmful to patients with PPH.
o In general, high doses of CCBs are used in patients with PPH; however, only patients with an acute vasodilator response to an intravenous or inhaled pulmonary vasodilator challenge (eg, with adenosine, EPO, nitric oxide) derive any long-term benefit from CCBs (this corresponds to <20% of patients with PPH and probably <10% of patients with secondary, PPH-like pulmonary artery hypertension).
o Similarly, patients without an acute vasodilator response to a vasodilator challenge have a worse prognosis on long-term oral vasodilator therapy compared with those who have an initial response.
o Importantly, realize that the absence of an acute response to intravenous or inhaled vasodilators does not preclude the use of intravenous vasodilator therapy. In fact, continuous intravenous vasodilator therapy is strongly suggested for these patients because CCBs are contraindicated.
o This illustrates the importance of performing vasoreactivity testing in patients with PPH. Intravenous EPO or adenosine or inhaled nitric oxide are used most commonly for acute vasodilator testing. Oxygen, nitroprusside, and hydralazine should not be used as pulmonary vasodilator testing agents.
o Only up to 25% of patients with PPH demonstrate significant pulmonary vasoreactivity. If patients demonstrate vasoreactivity and are candidates for high-dose CCB therapy, administer a CCB challenge to stable patients to determine the vasodilator response. Perform this in the critical care unit with a balloon flotation catheter in the pulmonary artery. Administer oral nifedipine every hour (diltiazem can be used if resting tachycardia is present) until a 20% decrease in pulmonary artery pressure and pulmonary vascular resistance is observed or systemic hypotension or other adverse effects preclude further drug administration.
o Calculate the daily dosage requirement at half the total initial effective dose, and administer this every 6-8 hours. Typical doses of nifedipine and diltiazem can reach 240 mg/d and 900 mg/d, respectively. Use caution when withdrawing CCBs because rebound pulmonary hypertension has been reported with the cessation of vasodilator therapy.
o Four approved pulmonary vasodilator medications currently available in the United States for PPH are as follows:
" Epoprostenol IV (Flolan)
" Treprostinil IV or SQ (Remodulin)
" Bosentan PO (Tracleer)
" Iloprost Inhaled (Ventavis)
" Sildenafil PO (Revatio)
o Epoprostenol and treprostinil are administered parenterally, bosentan is administered orally, and iloprost is administered by nebulized inhalation.
" Future therapies
o Clinical trials are under way to determine the safety and efficacy of several new therapies that include inhaled agents (ie, other prostacyclin agents), phosphodiesterase inhibitors, and other oral agents.
o Efforts are currently focused on prostacyclin analogues, newer endothelin antagonists, and phosphodiesterase-5 inhibitors (see below).
Surgical Care:
" A single- or double-lung transplant is indicated for patients who do not respond to medical therapy. Simultaneous cardiac transplantation may not be necessary even with severe right ventricular dysfunction; however, this is dependent on the transplant institution.
" Atrial septostomy is a palliative procedure that may afford some benefit to patients with deteriorating conditions. This procedure works by allowing interatrial right-to-left shunting to occur, thus delivering more overall oxygen content to the respiring tissues, albeit with a lower overall saturation.
Diet:
" No specific diet is recommended; however, a low-sodium and low-fluid diet is recommended for those with significant volume overload due to right ventricular failure.
" Patients taking warfarin must limit their intake of vitamin K-containing foods, such as green leafy and coliform vegetables.
" L-arginine supplementation (a precursor to nitric oxide) may be helpful; however, more studies are needed to confirm its role in the management of IPAH.
Activity:
" Few data are available on cardiopulmonary rehabilitation. The generally accepted recommendation is that patients with pulmonary hypertension and heart failure perform mild symptom-limited aerobic activity and avoid complete bed rest. Isometric exercises (weight-lifting) are contraindicated.
PATIENT MONITORING : Frequent
POSSIBLE COMPLICATIONS :
- Thromboembolism
- heart failure
- sudden death
EXPECTED COURSE/PROGNOSIS :
. Mean survival 2-3 years from time of diagnosis, 75% mortality at 5 years, although survival is quite variable
as learned from the NIH registry.
. Mean age at diagnosis 34 years
. Mode of death:
. Right heart failure 63%
. Indeterminate 15%
. Pneumonia 7%
. Sudden death 7%
. Cardiac death 5%
. Poor prognostic factors: . PaO2 < 63%, RA pressure > 20 mm Hg, Cardiac index < 2 L/min/m2 , . Mean pulmonary arterial pressure > 85 mm Hg , New York Heart Assn. (NYHA) class 3 or 4, . Raynaud phenomenon
DRUG(S) OF CHOICE
. Medical therapy may be guided by suspected subtype:
. Plexogenic (clear lung fi elds, normal perfusion scan) - vasodilators potentially useful. Vasodilators
- calcium channel blockers, fi rst line, may be more effective in high doses. Other agents: ACE-inhibitors,
alpha-antagonists, hydralazine - none shown to improve survival.
. Thrombotic (clear lung fi elds, patchy perfusion scan)
- anticoagulants potentially useful. Anticoagulants
- warfarin, heparin, antiplatelet agents.
. Veno-occlusive (pulmonary venous congestion, patchy perfusion scan) - vasodilators probably useless
. All types: Heart failure may be treated with diuretics.
Digoxin use controversial - not shown to be beneficial or detrimental. Digoxin may adversely affect exercise
capacity due to increase in pulmonary vascular resistance.
. Chronic vasodilator therapy
. Nifedipine, diltiazem
. Prostacyclin
. Hydralazine
. Isoproterenol
. Terbutaline
. Prazosin
. Phentolamine
. Phenoxybenzamine
. Screening for responsiveness
. Prostacyclin
. Iloprost; stable analog of prostacyclin
. Acetylcholine
. Adenosine
. Nitric oxide
. Nitroprusside
. Isoproterenol
. Hydralazine
. Phentolamine
. Anticoagulation: 2 small studies suggest prolonged survival. Warfarin with INR .2.0.