Diuretics remain the mainstay for “congestive symptoms” but have not been shown to improve survival. Neurohormonal activation (as measured by circulating renin, angiotensin, endothelin, and BNP) has been shown to acutely decrease during short-term diuretic therapy administered to lower markedly elevated filling pressures [15]. Two pharmacologic classes of agents are relevant to acute heart failure management: loop diuretics and distal tubular agents (Table 33.2). The loop diuretics (e.g., furosemide, torsemide, bumetanide, and ethacrynic acid) are the most potent. Some data suggest that torsemide and bumetanide may be more effective than furosemide in advanced heart failure, perhaps due to superior absorption from the gastrointestinal tract in the setting of elevated right-sided filling pressures [15]. Although once daily dosing of loop diuretic is usually effective for outpatient therapy, patients with persistent symptoms or those with marked hemodynamic instability during hospitalization often require dosing two or three times a day to adequately manage volume overload.

Thiazide diuretics such as hydrochlorothiazide and metolazone act mainly by inhibiting reabsorption of sodium and chloride in the distal convoluted tubule of the kidney. Used alone, thiazides produce a fairly modest diuresis; these agents are ineffective when glomerular filtration rate (GFR) falls below 40 ml per minute [15].

Diuretic tolerance is often encountered in patients with advanced heart failure. Lack of response to diuretic therapy may be caused by excessive sodium intake, use of agents that antagonize their effects (particularly nonsteroidal anti-inflammatory drugs), worsening renal dysfunction, addition of potentially nephrotoxic agents during hospitalization or compromised renal blood flow due to worsening cardiac function. Combined intravenous loop diuretic plus thiazide creates a synergistic response and should be considered for patients who fail to diurese despite optimal doses of an intravenous loop diuretic alone. Metolazone is particularly effective when administered with a loop diuretic. High-dose furosemide when administered as a continuous infusion (1 to 10 mg per hour) may also be more effective than bolus administration for hospitalized patients [16].

Elevated vasopressin levels play an important role in mediating fluid retention and contributing to hyponatremia. Short-term treatment with the V2-receptor antagonist, tolvaptan, has been shown to lower filling pressures, enhance diuresis, correct hyponatremia, and improve renal function [17]. However, tolvaptan had no effect on long-term mortality or heart-failure–related morbidity in a study of over 500 hospitalized with acute decompensated failure [17]. Thus, the role of this class of agents remains uncertain.

Ultrafiltration using a venovenous access approach is now feasible and potentially useful for acutely lowering elevated ventricular filling pressures when conventional high-dose combination diuretic therapy fails to produce adequate diuresis. Small, short-term observational studies suggest improvements in weight loss during hospitalization but have not demonstrated decreased length of stay or better preservation of renal function [18]. The UNLOAD trial randomized 200 patients with acute decompensated heart failure to standard intravenous diuretics versus ultrafiltration and demonstrated greater weight loss at 48 hours in the ultrafiltration cohort [19]. Readmissions for heart failure were also lower at 90 days (32% vs. 18%) for the ultrafiltration group. However, no comment was made on overall rehospitalization rates. No difference in in-hospital or outpatient renal function was observed between treatment groups [19]. Importantly, hemodynamic instability has been an exclusion criterion in all published studies. The latest ACC/AHA practice guidelines recommend ultrafiltration as a class IIA therapeutic option for heart failure that remains refractory to conventional diuretic therapy [14]. Additional prospective controlled trials are needed to establish the exact role of this new treat modality.

Vasodilators remain a cornerstone of acute and chronic heart failure management [14]. Mechanisms of action vary and include a direct effect on venous capacitance vessels (e.g., nitrates), arterioles (e.g., hydralazine), or balanced effects (sodium nitroprusside, ACE inhibitors, and angiotensin II receptor blockers [ARBs]). Drugs that produce balanced venous and arteriolar dilatation should generally be chosen as first-line therapy since both preload and afterload are elevated in decompensated heart failure. However, in the ICU setting, it may sometimes be useful to use nitrates to reduce markedly elevated preload or hydralazine to treat elevated afterload for short periods of time. ACE inhibitors play a crucial role by altering the vicious cycle of hemodynamic abnormalities and neurohormonal activation that characterize advanced heart failure. Randomized, controlled clinical trials have demonstrated the beneficial effects of ACE inhibitors on functional capacity, neurohormonal activation, quality of life, and long-term survival in patients with chronic heart failure due to left ventricular systolic dysfunction (Table 33.3). There is compelling evidence that ACE inhibitor therapy should be prescribed whenever feasible in all symptomatic heart failure patients. Despite their unequivocal benefits, only 60% to 75% of all heart failure patients currently receive these agents [20]. The elderly and patients with advanced heart failure symptoms are least likely to receive this therapy [20]. It is especially important to recognize in patients with advanced heart failure that even low doses of vasodilator treatment confer benefit. Low-dose treatment should be considered for patients with marginal blood pressure (i.e., systolic pressure > 80 to 90 mm Hg) to permit the subsequent introduction of beta-blockers. An ACE inhibitor should be initiated for any patient who experiences a transmural myocardial infarction during hospitalization as postinfarction trials have shown 10% to 27% reduction in all-cause mortality and 20% to 50% reduction in the subsequent risk of developing overt heart failure when these agents are begun following acute infarction [21].

Alternative therapy with combination hydralazine and nitrates should be considered for patients with marginal renal function (creatinine > 2.5 mg per dL) and those with previously documented intolerance to ACE inhibitors or ARBs. Similar hemodynamic goals can be achieved with these agents among patients with advanced NYHA Class III or IV heart failure [22]. Women appear somewhat less responsive to ACE inhibitor therapy than do men [23]. Important racial differences may also exist in pharmacologic responsiveness to different vasodilator regimens. Two retrospective analyses from large trials confirmed ACE inhibitor therapy to be less effective in blacks than whites with heart failure of comparable severity [24]. The African-American Heart Failure trial (A-HeFT) confirmed the
benefit of hydralazine and isosorbide dinitrate in this population; this combination should be considered when initiating therapy for hospitalized black patients [25].

ARBs are now also considered suitable first-line therapy for heart failure patients [14]. These drugs should be selected for ACE-inhibitor intolerant, non–African-American patients who experience rash or cough with an ACE inhibitor. They cannot be used for patients who experience ACE-inhibitor–related deterioration in renal function, hypotension, or hypokalemia [25]. Symptomatic and mortality benefits appear comparable between ACE inhibitors and ARBs [14]. For patients with advanced heart failure, the addition of a low-dose ARB to standard therapy with ACE inhibitor and beta-blocker provides significant morbidity benefit with reduction in recurrent hospitalizations but no mortality benefit [26]. A modest reduction in maintenance ACE inhibitor dose may be necessary to introduce an ARB in this population.