Standard Therapies For Pulmon... Health Article

Diuretics

The long-term role of diuretics in RHF and PAH has not been systematically studied. The use of diuretics in patients who have PAH with peripheral edema secondary to RHF is widespread and universally accepted. Almost all PAH patients with peripheral edema secondary to RHF are treated with diuretics, and the effect of the diuretics on edema is usually obvious. Most patients with edema report some improvement after “effective diuresis” as assessed by change in weight or pedal edema over relatively short periods of time. For many patients, maximal effects are only obtained when salt and fluid intake restrictions are used with diuresis. Whether diuretics alter mortality or morbidity in patients who have PAH with RHF is not known, however. Diuretics also can decrease the sensation of dyspnea in patients with enlarged right heart chambers compromising left heart function (see later discussion).

The effect of most diuretics (eg, furosemide) on mortality or morbidity either in left or right heart failure has not been evaluated by long-term trials. Spironolactone, an aldosterone antagonist used as a potassium-sparing diuretic, decreased mortality in a long-term prospective, randomized, placebo-controlled trial of patients with recent hospitalization for severe left heart failure with NYHA III or IV symptoms [67]. In this study, a relatively low dose of spironolactone (12.5 mg/d taken orally) was used as an add-on therapy to angiotensin-converting enzyme inhibitor therapy. Two-year mortality rate in the treatment group was 35% compared with 46% in controls, indicating 24% relative risk reduction (number needed to treat to save one life in approximately nine). The study also showed a 35% decrease in hospitalizations secondary to worsening of heart failure and improvement in functional class in treated patients. No studies have evaluated the long-term role of aldosterone antagonists in patients who have PAH and RHF. Secondary to convincing data regarding left heart failure, however, spironolactone is widely used in patients who have PAH and RHF as an adjunct to loop diuretics. Long-term value of spironolactone in such patients remains unknown. It should be noted that many interventions known to have a beneficial effect in LV failure (eg, angiotensin-converting enzyme inhibitors and beta adrenergic antagonists) have not been proven to be beneficial in patients who have PAH and RHF. Spironolactone should not be used in patients with serum creatinine >2.5 mg/dL or potassium >5.0 mEq/L or in patients with history of severe refractory hyperkalemia. Extreme caution should be observed in patients who have impaired renal function or diabetes, in elderly persons, and in patients with concurrent use of angiotensin-converting enzyme inhibitors or nonsteroidal anti-inflammatory agents [68].

Amiloride (a potassium-sparing diuretic) analogs have been shown to inhibit development of hypoxia-induced pulmonary hypertension in animal models [69]. The proposed mechanism is inhibition of sodium-proton (Na+/H+) exchange to prevent intracellular alkalinization, which seems to play a permissive role in pulmonary artery smooth muscle cell proliferation in the process of vascular remodeling [24]. There are no clinical studies in patients who have PAH to speculate the clinical significance of these observations.

In most recent trials of pharmacologic therapy for PAH [4–21] , diuretics were used as adjunct therapy in a large proportion of patients, but the effect of diuretics was not tested as an end point in any of these trials. In severe RHF, large doses of diuretics may be required for effective diuresis. Some patients may require doses as high as furosemide, 600 mg/d, or bumetanide, 10 mg/d, or the addition of metolazone (up to 20 mg/d). Edema in many patients with severe RHF and impaired renal function may be disabling and can be refractory to even such high doses of diuretics ( Box 1).

Right ventricular (RV) performance is preload dependant. Because of ventricular interdependence (ie, shared pericardium and septum), however, extreme RV dilatation may compromise LV filling in part by displacing the interventricular septum into the LV, which results in LV diastolic dysfunction and a decrease in cardiac output [70–72]. Patients who have PAH are likely to develop interstitial edema at relatively lower pulmonary capillary wedge pressures because the effective hydrostatic pressure to favor interstitial edema formation is equal to pulmonary capillary wedge pressure plus 40% of the gradient between mPAP and pulmonary capillary wedge pressure (Gaar's equation). Relatively minor fluctuations in fluid status may result in significant change in cardiac output or gas exchange, resulting in arterial hypoxemia. Caution should be observed when adjusting diuretic dose. There is no evidence or scientific rationale to urgently diurese patients or remove large volumes of fluid over a short period of time, except when there is cardiogenic pulmonary edema or acute worsening of arterial hypoxemia. “Optimal fluid status” in patients who have PAH and RHF is often a relatively narrow window in which patient's cardiac output is maintained, arterial hypoxemia is minimized, and signs of tissue perfusion (as assessed by renal function, presence or absence of peripheral cyanosis, or altered mentation) are optimal.

Severe passive hepatic congestion and bowel wall edema and ischemia may be present when patients who have severe RHF and reduced cardiac output present with significantly deranged liver function tests or a sepsis-like picture secondary to translocation of colonic micro-organisms as a consequence of bowel wall edema and bowel ischemia. Patients may present with abdominal pain, mild diffuse abdominal tenderness (without rebound or rigidity), and occult blood in the stools with or without gram-negative bacteremia. This may be a terminal event in patients who have PAH and severe RHF. The appropriate therapy may include use of diuretics or IV fluids. Depending on the individual patient, low-dose dopamine or dobutamine (2–3 μg/kg/min) and inhaled NO (10–40 ppm) or inhaled prostacyclin (started at 50 ng/kg/min and titrated down to lowest effective dose) IV antibiotics covering colonic flora (ie, covering gram-negative and anaerobic bacteria) should be considered. There are no published data to define the optimal way to manage acutely decompensated patients who have severe PAH and acute RHF.

Diuretic dosing should be revised if patients develop orthostatic dizziness, which temporally correlates with decreased edema, decreased weight, and recently increased diuretic dose. Charting of daily weights, use of written sliding scale for diuretics, and potassium use, based on edema or weight, may be useful strategies. Many patients who have severe PAH and RHF have relatively low systemic blood pressure. Diuretics should be used with caution in these patients. Concern over low blood pressure and subsequent underdosing of diuretics actually may result in worsening of edema or overall clinical worsening, however [68].

Potassium supplementation should be managed carefully, especially if there is worsening or fluctuation of renal function, addition or withdrawal of potassium-sparing diuretics, or concurrent use of digoxin. Arrhythmias, prolonged palpitations, or syncopal episodes may be secondary to PAH and RHF; however, in patients on diuretics, electrolyte and digoxin level testing should be considered.

Edema is a relatively common side effect of many PAH therapies (eg, CCBs [2%–15%], bosentan [4%–8%], sitaxsentan [7%], and less commonly, prostacyclin). Adjusting the dose of diuretics often can ameliorate such edema. In some instances, however, this medication-related edema is refractory to diuretics. Patients may benefit from scheduled elevation of legs, compression stockings, or, if possible, switching from the suspected causative agent to other alternatives. In other instances in which the PAH therapy is otherwise believed to be effective, patients are asked to tolerate increased pedal edema.