Sodium nitroprusside (SNP) is a potent vasodilator, with balanced action in the arteriolar and venous beds. It has a very short (seconds to minutes) half-life, and produces a dramatic increase in cardiac output, decrease in pulmonary capillary wedge pressure (PCWP), and decrease in mitral regurgitant fraction; this is typically associated with a decrease in mean arterial pressure. The initial dose is 10 mcg/min, with up titration to as high as 350 mcg/min. Since the coronary vasodilatory properties of SNP can promote coronary steal and ischemia in those with significant unrevascularized coronary artery disease, it is not recommend in patient with active ischemia. The metabolism of SNP leads to the release of nitric oxide and cyanide. The symptoms of cyanide toxicity include nausea, abdominal discomfort and dysphoria. As there can be accumulation of cyanide and thiocyanate, caution must be used in patients with renal and hepatic dysfunction.
Nitroglycerin is a potent venodilator, producing rapid decreases in pulmonary congestion, left ventricular end diastolic pressure, LV wall stress, and myocardial oxygen consumption. It has coronary vasodilatory effects as well, making it a good option for patient with ongoing ischemia. Initial intravenous dose is typically 20 mcg/min, with a doubling of the dose every 5 to 15 minutes. Other options for administration include sublingual tablets and sprays as well as topical pastes. Major side effects include hypotension and headache.
Nesiritide is recombinant B-type natriuretic peptide. It has balanced venous and arteriolar actions, and modestly enhances diuresis through direct renal effects. The dose starts at 0.01 mcg/kg/min. Major side effects include headache and hypotension. The ASCEND trial randomized 7141 patients with ADHF to either standard care or nesiritide plus standard of care. Nesiritide demonstrated a modest, statistically nonsignificant improvement in dyspnea; however, there was a higher rate of hypotension in the nesiritide arm of the trial. Importantly, there was no significant change in the rate of death, rehospitalization, or renal function in the nesiritide arm. Though there may be a role for nesiritide in some special populations (ie, diuretic resistant patients), the results of the ASCEND trial do not support the routine use of nesiritide in acute decompensate heart failure.
Milrinone is a positive inotropic agent as well as a vasodilator. It is a phosphodiesterase 3 inhibitor, and its mechanism of action is the inhibition of the breakdown of cyclic adenosine monophosphate (cAMP) in cardiac myocytes, leading to the increase of cAMP-mediated Ca++ in the myocyte and hence enhanced myocyte contractility. Similarly, in the vascular smooth muscle, its action is that of increasing cAMP-mediated contractile protein phosphorylation, leading to vascular relaxation. The hemodynamic changes seen with milrinone include an increased cardiac output, decreased SVR, reduced PCWP, and typically a mild decrease in mean arterial pressure. The half-life is approximately 2.4 hours, and it is renally cleared. The largest randomized clinical trial involving milrinone was the OPTIME-CHF trial, which randomized ADHF patients to either milrinone or placebo. Milrinone did not significantly decrease hospitalization length of stay, and did lead to significantly more hypotension and atrial arrhythmias. Use of milrinone is typically reserved patient with evidence of severely reduced cardiac output and end organ damage.
Dobutamine is a direct beta-1 agonist, which produces positive inotropic and chronotropic effects. The mechanism of action is the binding of the beta-1 receptor, leading to phosphorylation of protein kinase A, which ultimately leads to an increase in intracellular cAMP and Ca++, leading to enhanced myocardial contractility. There is also a modest alpha and beta-2 effect, which causes mild peripheral vasodilation; in the context of increasing cardiac output, this can cause a variable effect on mean arterial pressure. The major side effects of dobutamine are atrial and ventricular tachyarrhythmias. There is no equivalent large, randomized trial experience with dobutamine in AHF as there is with milrinone, however registry data of AHF patients suggest worse outcomes with dobutamine and hence its use is limited to patients with poor response to diuretics and vasodilators and patients in overt cardiogenic shock.
Dopamine is a naturally occurring compound that plays an important role in many aspects of human body homeostasis, including major roles in neural, cardiovascular, and renal physiology. Dopamine has variable effects on different receptors at different doses; conventionally at low doses (0-2 mcg/kg/min), there is preferential dopamine receptor activation leading to enhanced renal artery vasodilation and enhanced renal perfusion; at 2 to 10 mcg/kg/min, there is enhanced norepinephrine release, leading to enhanced myocardial contractility and mild peripheral vasoconstriction; at doses above 10 mcg/kg/min, there is preferential alpha adrenergic receptor activation causing peripheral vasoconstriction and an increase in mean arterial pressure. In the context of treatment of AHF, dopamine is often used at low or “renal” dose in diuretic resistant patients, or at higher doses in those with frank cardiogenic shock. The limited clinical trial data evaluating the use of “renally dosed” dopamine in heart failure has been mixed. The most recent trial examining this issue (ROSE trial) randomized 360 AHF patients with renal dysfunction to either usual care or renally dosed dopamine (there was an additional low-dose nesiritide arm of the trial); the trial did not demonstrate a significant benefit of dopamine infusion in terms of urine output or change in renal function. Based on prior trial data, renally dosed dopamine is currently given a IIb recommendation by the ACC/AHA Heart Failure guidelines to help enhance urine output and renal perfusion in AHF patients.
Ultrafiltration is a decongestive therapy in which water and small solutes are moved across a semipermeable membrane to reduce volume overload. Potential benefits of ultrafiltration over intravenous diuretics include more effective removal of sodium, minimal effects on serum electrolytes, decreased neurohormonal activation, and adjustable and potentially very rapid fluid removal rates. The outcomes in prospective heart failure trials in which patients were randomized to ultrafiltration versus diuretic therapy have varied. In the UNLOAD trial, 200 AHF patients were randomized to diuretics versus ultrafiltration; the ultrafiltration arm demonstrated greater fluid loss at 48 hours and a decrease in heart failure admissions in 90 days, with similar safety profile as diuretics. The CARESS-HF trial randomized AHF patients with cardiorenal syndrome to ultrafiltration or diuretics and failed to demonstrate a benefit with ultrafiltration. The cost, need for vascular access, need for nursing training and support are all potential barriers to ultrafiltration in clinical practice. Identifying the most appropriate patients for ultrafiltration therapy is an area of controversy and active clinical research.
Mechanical Circulatory Support
In cases of severe AHF, which is refractory to medical therapy, temporary circulatory support (TCS) can be utilized to improve end organ perfusion. TCS ranges from percutaneously inserted devices, such as intra-aortic balloon pump, tandem heart, and Impella which are able to augment cardiac output by up to 5 L/min. In cases of complete hemodynamic collapse or severe right ventricular failure, venoarterial extracorporeal membrane oxygenation can be placed to completely bypass the cardiopulmonary circulation. Additional surgically placed TCS includes semidurable continuous-flow ventricular assist devices, such as CentriMag. TCS can serve as a “bridge to recovery” or as a “bridge to decision” in patients who may need implantation of permanent LV assist devices or cardiac transplantation.