Intravenous inotropes are useful in patients with severe systolic dysfunction with relative hypotension and evidence of inadequate end-organ perfusion, who are not responsive to, or are intolerant of, vasodilators and diuretics. Inotropic agents relieve acute heart failure symptoms and may preserve end-organ function but have not been demonstrated to improve survival. On the contrary, several studies have demonstrated increased adverse outcomes, including increased mortality with chronic intravenous inotropic therapy.
Dobutamine, a synthetic catecholamine, is primarily a β-adrenergic stimulant with minimal α1
-cardiac sympathetic activity. Its β1
-sympathetic activity accounts for its inotropic activity through β-receptor mediated-activation of intracellular cyclic AMP. The resulting sarcoplasmic reticulum calcium release mediates myocardial contractility. Similar β1
activity at the sinoatrial (SA) node accounts for its modest chronotropic activity. Patients taking β-blockers on admission may have an attenuated initial response to dobutamine, until the β-blocker has been metabolized or renally eliminated.1
However, cardiac output response to increasing doses of dobutamine has been observed in patients on chronic carvedilol.2
The dose-dependent β2
effect produces mild peripheral arteriolar dilation. As with most intravenous sympathetic stimulants, dobutamine has a rapid onset of action (1 to 2 minutes) and has a peak effect within 10 minutes. The drug is rapidly methylated providing for a short duration of action (t 1: 2 minutes), ideal for a drug requiring titration based on hemodynamic effects.
The hemodynamic effects of dobutamine in heart failure patients include increased cardiac output, arteriolar dilation, reduction of pulmonary artery occlusive pressure (PAOP or wedge pressure), and small but variable change in blood pressure (Table 14.1
). In responsive patients, the hemodynamic benefits of the drug increase end-organ perfusion, manifest by improved renal function and urine output, decreased pulmonary vascular congestion, and improved skin perfusion and mentation.
Adverse effects that should be monitored in heart failure patients include dose-related tachycardia, most concerning in ischemic cardiomyopathy, and atrial (atrial fibrillation) or ventricular (ventricular tachycardia) arrhythmias.
Dobutamine dosing begins at 2.5 to 5 μg/kg/minute and is progressively increased based on clinical and hemodynamic response. Because it is not a vasoconstrictor (pressor), dobutamine does not need to be administered through a central line. Dosing may be increased to 15 μg/kg/minute, although maximum hemodynamic benefit may be achieved at lower doses, and ventricular ectopy risk increases as the dose is increased. Once hemodynamic stability has been accomplished, dobutamine infusions should be gradually tapered off. Although intermittent ambulatory dobutamine infusions have been used for quality of life enhancement in patients who are not candidates for transplantation or pump implantation, or as a pharmacologic bridge to cardiac transplantation, the practice has generally been replaced by implantation of ventricular assist devices.3
In addition randomized trials have demonstrated increased mortality with the use of ambulatory dobutamine infusions.4
Milrinone is a selective inhibitor of phospodiesterase III, an enzyme responsible for the intracellular breakdown of c-AMP. Cyclic-AMP accumulation increases intracellular calcium and thereby facilitates myocardial contractility. Although milrinone’s hemodynamic effects are similar to those of dobutamine, milrinone produces more arterial and venous dilation, earning it the label “inodilator” (Table 14.1
). Theoretical advantages of milrinone as compared with dobutamine include greater afterload reduction, augmenting the cardiac output produced by its inotropic effect, and its postreceptor mechanism of action, a potential benefit in patients receiving β-blockers for chronic heart failure. Hemodynamic improvement is usually observed within 15 minutes of initiation of therapy. The drug is renally eliminated with an elimination half-life of approximately
3 hours in heart failure patients, and the maintenance infusion should be adjusted based on creatinine clearance (Table 14.2
TABLE 14.1 Hemodynamic Effects of Intravenous Agents Used in the Treatment of Acute Decompensated Heart Failure
Bolus: 2 μg/kg
Infusion: 0.01 μg/kg/min
CO, cardiac output; HR, heart rate; MAP, mean arterial pressure; PAOP, pulmonary artery occlusive pressure; SVR, systemic vascular resistance. Adopted from DiPiro JT, Talbert RL, Yee GC, et al. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York, NY: McGraw Hill; 1999.
Although the package insert recommends a 50 μg per kg loading dose, many heart failure practitioners refrain from administering the loading dose to reduce the risk of hypotension. Typical maintenance doses of milrinone range from 0.375 to 0.75 μg/kg/minute (Table 14.1
). At maintenance doses above 0.5 μg/kg/minute, once hemodynamic and clinical stability has been achieved, the infusion should be gradually tapered. However, because the drug has a longer elimination half-life than dobutamine, lower milrinone maintenance doses may be reduced more rapidly than dobutamine, provided hemodynamic stability has been achieved. In addition to hypotension, the most common side effects are tachyarrhythmias. Milrinone may produce less tachycardia than dobutamine, but it also has the potential to produce both atrial and ventricular arrhythmias.
Despite the potential adverse long-term impact on morbidity and mortality related to intravenous inotropic therapy, patients with acute decompensated heart failure benefit from the short-term hemodynamic improvement associated with the administration of these agents, pending the resolution of the underlying events that precipitate their hemodynamic deterioration.
TABLE 14.2 Renal Dosing of Milrinone
Creatinine Clearance (ml/min/1.73m2)
Milrinone Infusion Rate (µg/kg/min)
Dopamine possesses dose-dependent hemodynamic effects, stimulating D1
dopamine receptors, α1
-, and β2
-receptors. Other than the diuretic effect of low-dose (renal dose) dopamine to enhance volume loss in patients with diuretic-resistant heart failure, dopamine use is typically reserved for use in markedly hypotensive patients including those with cardiogenic shock. Inotropic doses in the 2 to 5 μg/kg/minute range promote increase cardiac output; however, intermediate- and high-dose dopamine increase systemic vascular resistance, increase afterload and PAOP, and impede cardiac output (Table 14.1
). In the setting of cardiogenic shock, dopamine may be required to maintain mean arterial pressure and coronary perfusion pressure until the underlying etiology can be treated or resolved.
Digoxin is a moderately potent inotrope with additional neurohormonal modulating effects producing increased parasympathetic nervous system activity and decreased central sympathetic nervous system drive. Its inotropic effect is related to inhibition of sarcolemmal sodium-potassium-ATPase, resulting in increased myocardial cell calcium, the final common pathway for all currently available inotropic agents. The benefit of digoxin in heart failure was debated for most of its first 200-year history. The drug has little use in the treatment of acute heart failure in patients with sinus rhythm. Perhaps the least controversial use of the drug in heart failure patients is to assist (in combination with β-blockers or amiodarone) in
the management of rate control in patients with atrial fibrillation. The Digoxin Investigation Group (DIG) clarified the role for digoxin in the management of heart failure patients with normal sinus rhythm.5
This study demonstrated that digoxin, in addition to background angiotensin converting enzyme inhibitor (ACEI) and diuretic therapy, improved exercise tolerance, and reduced heart failure related hospitalizations, but did not improve survival. Therefore, digoxin therapy for heart failure may be considered either in patients with atrial fibrillation, or in patients in sinus rhythm on target doses (if tolerated) of ACEI/ARB and β-blockers who exhibit continued exercise intolerance or recurrent heart failure related hospitalizations.
Digoxin is primarily renally eliminated with a serum elimination half-life of 1.6 days in patients with normal renal function. Recent trials have demonstrated that the efficacy of digoxin in heart failure can be achieved with doses that produce serum concentrations of 0.5 to 1.0 ng per ml, lower than those previously defined as “therapeutic.”6
Higher serum concentrations provide no added benefit and increase the risk of digoxin toxicity.
Digitalis intoxication is a clinical diagnosis based on the presence of signs and/or symptoms including anorexia, nausea, and vomiting, and atrial or ventricular arrhythmias. Given the establishment of lower effective serum concentration, the incidence of digoxin toxicity has likely diminished. It is important to understand that the diagnosis of digoxin toxicity is never based solely on the digoxin concentration. Elevated serum digoxin concentrations are only one etiology of drug toxicity, usually related to maintenance doses inappropriate for the level of renal function. Most patients with normal renal function require 0.125 mg digoxin daily. Patients with renal insufficiency typically require 0.125 mg every other day or less. Many other factors that do not produce elevated serum digoxin concentrations are capable of causing digoxin toxicity including diuretic-induced hypokalemia or hypomagnesemia, hypoxemia, acidosis, hyperthyroidism, and others. Concurrent amiodarone therapy may double the serum digoxin concentration, and typical digoxin dosing in these patients should be reduced by 50% of the usual dose, considering renal function.
TABLE 14.3 Diuretics Used in the Treatment of Heart Failure
Initial Daily Dose(s)
Maximum Total Daily Dose
Duration of Action
0.5-1.0 mg once or twice
20-40 mg once or twice
10-20 mg once
POTASSIUM SPARING DIURETICS
25 mg once
50 mg once
12.5-25 mg once
SEQUENTIAL NEPHRON BLOCKADE
2.5-10 mg once plus loop diuretic
500-1000 mg once plus loop diuretic