Inotropic and Vasoactive Agents

Inotropic and vasoactive agents are used to correct or stabilize hemodynamic function in the CICU setting ( Table 17.1 ).

Dopamine is the immediate precursor of epinephrine and norepinephrine.

It has both cardiac and vascular sites of action, depending, in part, on the dose used.

At low doses (1 to 3 µg/kg/min), dopamine directly activates dopaminergic receptors in the kidney and splanchnic arteries, thereby causing vasodilation of these beds.

The resultant increase in renal blood flow leads to increased urine output and sodium excretion.

At moderate doses (3 to 8 µg/kg/min), dopamine is a weak partial agonist of myocardial β ₁ -receptors and causes the release of norepinephrine from sympathetic nerve terminals in the myocardium and vasculature.

The direct stimulation of myocardial β-adrenergic receptors exerts positive chronotropic and inotropic effects.

The increased release of norepinephrine from nerve terminals (a tyramine-like effect) also contributes to myocardial stimulation but in addition may exert a mild vasoconstrictor effect due to stimulation of vascular α-adrenergic receptors.

At high doses of dopamine (5 to 20 µg/kg/min), the effect of peripheral α-adrenergic stimulation predominates, resulting in vasoconstriction in all vascular beds and leading to increases in mean arterial pressure and systemic vascular resistance.

At high doses, the vasoconstrictor effect overshadows the dopaminergic vasodilator effects so that renal blood flow decreases, and urine output may decline.

However, in patients with acute decompensated heart failure, the dose required for improving systemic and renal hemodynamics may be higher (on the order of 4 to 6 µg/kg/min) than the usual low-dose range, leading to the suggestion that severe heart failure may impair the renal effects of dopamine.

Low-dose dopamine is frequently combined with one or more other inotropic (e.g., dobutamine) or vasodilator (e.g., nitroprusside) agents.

In patients with severe hypotension or frank cardiogenic shock, higher doses of dopamine are used to increase systemic vascular resistance.

At these higher doses, the increased left ventricular afterload is partially offset by the positive inotropic action.

In addition, when it is necessary to use vasoconstrictor doses of dopamine to manage systemic hypotension in the setting of myocardial failure, it is often useful to add dobutamine to augment the level of positive inotropic support beyond that provided by dopamine alone.

When used alone at vasoconstrictor doses in patients with left ventricular failure, dopamine may increase both left and right heart filling pressures ( Fig. 17.1 ).

This effect reflects increased left and right ventricular afterload and increased peripheral venoconstriction, the latter causing increased return of venous blood to the heart.

To counteract these actions, high-dose dopamine is sometimes combined with vasodilators (e.g., nitroglycerin).

The inotropic responses to dopamine may be attenuated owing to desensitization of the β-adrenergic pathway and depletion of myocardial catecholamine stores, both of which are common in patients with chronic severe myocardial failure.

Although generally well tolerated at low doses, higher infusion rates of dopa­mine may result in unwanted sinus tachycardia and/or arrhythmias (supraventricular and ventricular).

Other adverse effects of dopamine include digital gangrene in patients with underlying peripheral vascular disease, tissue necrosis at sites of infiltration, and nausea at high doses.

Local infiltration may be counteracted by the local injection of the α-adrenergic antagonist phentolamine.

Dobutamine is a direct-acting synthetic sympathomimetic amine that stimulates β ₁ -, β ₂ -, and α-adrenergic receptors ( Table 17.2 ).

Clinically, dobutamine is available as a racemic mixture in which the (+) enantiomer is both a β ₁ - and β ₂ -adrenergic receptor agonist and an α-adrenergic receptor competitive antagonist, and the (–) enantiomer is a potent β ₁ -adrenergic receptor agonist and an α-adrenergic receptor partial agonist.

The net effect of this pharmacologic profile is that dobutamine causes a relatively selective stimulation of β ₁ -adrenergic receptors.

Dobutamine's primary cardiovascular effect is to increase cardiac output by increasing myocardial contractility with relatively little increase in heart rate.

The drug causes modest decreases in left ventricular filling pressure and systemic vascular resistance owing to a combination of direct vascular effects and the withdrawal of sympathetic tone ( Table 17.3 ).

Dobutamine also directly improves left ventricular relaxation (positive lusitropic effect) via stimulation of myocardial β-adrenergic receptors.

Although dobutamine has no effect on dopaminergic receptors and therefore no direct renal vasodilator effect, renal blood flow often increases with dobutamine in proportion to the increase in cardiac output.

Dobutamine is a valuable agent for the initial treatment of patients with acute or chronic systolic heart failure characterized by a low cardiac output.

It is often initiated at an infusion rate of 2.5 µg/kg/min (without a loading dose) and titrated upward by 2.5 µg/kg/min every 15 to 30 minutes until the hemodynamic goal is reached or a dose-limiting event occurs, such as unacceptable tachycardia or arrhythmias.

Maximum effects are usually achieved at a dose of 15 µg/kg/min, although higher infusion rates may be used occasionally.

If the maximally tolerated infusion rate of dobutamine does not result in a sufficient increase in cardiac index, a second drug (e.g., milrinone) may be added.

In patients with elevated systemic vascular resistance and/or left heart filling pressures, the coadministration of a vasodilator, such as nitroprusside or nitroglycerin, may be required.

In patients who remain hypotensive on dobutamine, consideration should be given to the addition of a pressor dose of dopamine and/or the use of mechanical support.

Although dobutamine may increase heart rate, in some patients with very depressed cardiac output, the improvement in hemodynamic function may cause a withdrawal of sympathetic tone such that heart rate falls.

Hypotension is uncommon, but it can occur in patients who are hypovolemic or who have unrecognized vasodilatory states, such as sepsis.

Arrhythmias, including supraventricular and ventricular tachycardia, may limit the dose.

Likewise, myocardial ischemia secondary to increased myocardial oxygen consumption may occur.

Some patients with chronic severe heart failure may be tolerant to dobutamine, or tolerance to dobutamine may develop after several days of a continuous infusion.

In this situation, the addition or substitution of a phosphodiesterase inhibitor may be helpful.

Hypersensitivity myocarditis has also been reported with chronic infusions of dobutamine and should be suspected if a patient develops worsening hemodynamics in association with fever or peripheral eosinophilia.