Treating volume overload or elevated filling pressures generally begins with diuretics. Diuretics have been shown to provide symptomatic relief, though they have not yet been proven safe.4 Initial treatment can include a loop diuretic at a dose higher than the patient’s chronic dose, with intravenous dosing offering greater bio-absorption and rapidity in onset of action.5 If perfusion is inadequate, escalate therapy beyond diuretics to include vasoactive agents.
Review of the Data
The use of vasoactive medications is largely based on anecdotal experiences and physiologic assumptions rather than on adequately powered prospective randomized controlled trials.6 Vasoactive therapy includes vasodilator and inotropic support and is generally limited for use in patients with advanced disease not responding to standard medical treatment and diuresis. The physiologic premise rests in the expected improvement in ventricular filling pressures and cardiac output with reduction in afterload and/or preload. Vasodilators counteract vascular constriction, reducing both preload and afterload. Positive inotropic agents amplify cardiac output by increasing the strength of myocardial contraction.
Vasodilators
The Heart Failure Society of America (HFSA) 2006 Comprehensive Heart Failure Practice Guidelines state, “In the absence of symptomatic hypotension, intravenous vasodilators (nitroglycerin, nitroprusside, or nesiritide) may be considered as an addition to diuretic therapy for rapid improvement of congestive symptoms.”7 The clinical utility of nesiritide remains in question with clinical and hemodynamic improvement demonstrated in three randomized trials 8-10; but tempered against meta-analyses 11-12 of selected trials, demonstrating a non-significant trend toward increased kidney dysfunction and death within 30 days (35/485 [7.2%] vs. 15/377 [4.0%] patients; risk ratio from meta-analyses, 1.74; 95% confidence interval, 0.97-3.12; p=0.059). In a randomized trial of 489 in-patients with dyspnea at rest from AHFS, treatment with three hours of intravenous nesiritide resulted in a significant improvement in dyspnea compared with placebo (p=0.03). Similar improvement was observed with intravenous nitroglycerin and did not differ statistically from that observed with nesiritide.8 Nitroprusside, an attractive option among those with hypertension and cardiogenic pulmonary edema, is limited by the need for invasive hemodynamic monitoring and potential for either cyanide toxicity or worsening myocardial ischemia.
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Inotropes
Again, there is little evidence from adequately powered randomized controlled trials guiding the use of inotropes. Their use is generally limited to the following indications (see figure 2): (1) Short-term treatment for AHFS that is unresponsive to adequate doses of diuretics and especially when associated with systemic hypotension, (2) Bridge to recovery (as following myocarditis) or to definitive treatment (as with transplant), or (3) For palliation when symptomatic relief is the agreed upon goal.13 The HFSA 2006 guideline states: “Intravenous inotropes may be considered to relieve symptoms and improve end-organ function in patients with advanced HF characterized by left ventricle dilation, reduced left ventricular ejection fraction, and diminished peripheral perfusion or end-organ dysfunction, particularly if these patients have marginal systolic blood pressure, have symptomatic hypotension despite adequate filling pressures, or are unresponsive to, or intolerant of, intravenous vasodilators.”7
Dobutamine and milrinone are the most commonly used IV inotropes for the treatment of AHFS and increase contractility by increasing intracellular levels of cyclic adenylate monophosphate (cAMP). Dobutamine is a catechlamine agonist that increases cAMP production through stimulation of adenylate cyclase. Milrinone selectively inhibits phosphodiesterase III, which catalyzes the breakdown of cAMP.
Despite their frequent use when traditional treatments have failed, the data supporting the use of dobutamine and milrinone is limited. The largest registry of patients with AHFS to date associated excess mortality with intravenous inotrope use compared to nitroglycerin or nesiritide.14 In a study population of 255 patients randomized to receive either intravenous nesiritide or intravenous dobutamine, Burger et al.15 demonstrated that dobutamine significantly increased the mean number of ventricular tachycardia events per 24 hours (p=0.001), suggesting increased arrhythmogenicity associated with inotrope use. Nonetheless, in a randomized trial of 15 patients admitted with AHFS, functional class improved in six of eight dobutamine-treated patients, but in only two of seven patients treated with placebo, suggesting clinical improvement as a consequence of inotropic stimulation.16 Unverferth et al. demonstrated a similar sustained functional improvement up to 10 weeks following a 72-hour infusion of intravenous dobutamine. 17