Norepinephrine is a potent alpha-adrenergic agonist and less potent beta-adrenergic agonist. The primary vasoactive effect of norepinephrine is arterial and venous vasoconstriction. The inotropic properties of norepinephrine are usually offset by increases in afterload. Norepinephrine is more potent than dopamine and is commonly considered the first-choice vasopressor to reverse hypotension in vasodilatory shock (Cooper 2008; Poor and Stanke 2005; Kee 2003). Norepinephrine seems to improve parameters of visceral microperfusion when hypotension is reversed in septic shock, compared with epinephrine or dopamine. This may explain why norepinephrine therapy was associated with some survival benefit in septic shock, compared with high-dosage dopamine and epinephrine (Cooper 2008; Poor and Stanke 2005; Kee 2003).

Norepinephrine may be preferential to other catecholamine pressors as first-line therapy for septic shock because it does not substantially worsen end-organ ischemia in most studies of crystalloid-resuscitated septic shock patients. In comparison with epinephrine, norepinephrine demonstrates fewer metabolic adverse effects; however, the use of norepinephrine is not advisable in forms of shock exclusively with low cardiac output (Overgaard and Davík 2008).

At low rates of infusion (0.5–5 mcg/kg/min), dopamine causes vasodilation that is presumed to be due to a specific agonist action on dopamine receptors in the renal, mesenteric, coronary, and intracerebral vascular beds (Cooper 2008; Poor and Stanke 2005; Kee 2003). The vasodilation in these vascular beds is accompanied by increased renal blood flow, sodium excretion, and urine flow. The clinical significance of “renal-dose” dopamine is somewhat controversial, however, because it does not increase glomerular filtration rate and a renal protective effect has not been demonstrated (Overgaard and Davík 2008).

At intermediate rates of infusion (5–10 mcg/kg/min), dopamine acts to stimulate the beta1-adrenoceptors, resulting in improved myocardial contractility, increased SA rate, and enhanced impulse conduction in the heart. There is little, if any, stimulation of the beta2-adrenoceptors (peripheral vasodilation). Blood flow to the peripheral vascular beds may decrease while mesenteric flow increases due to increased cardiac output. At low (0.5–5 mcg/kg/min) and intermediate doses (5–10 mcg/kg/min), total peripheral resistance (which would be raised by alpha activity) is usually unchanged (Cooper 2008; Poor and Stanke 2005; Kee 2003).

At higher rates of infusion (>10–20 mcg/kg/min), the predominant effect is on alpha-adrenoceptors, with consequent vasoconstrictor effects and a rise in blood pressure. The vasoconstrictor effects are first seen in the skeletal muscle vascular beds, but with increasing doses, they are also evident in the renal and mesenteric vessels. At very high rates of infusion (above 20 mcg/kg/min), stimulation of alpha-adrenoceptors predominates and vasoconstriction may compromise the circulation of the limbs (Cooper 2008; Poor and Stanke 2005; Kee 2003).

Dosage-dependent effects vary by individual and have not been reproduced in critically ill patients. The alpha- and beta-adrenergic effects of dopamine are generally weaker compared with epinephrine or norepinephrine. Dopamine is used as a vasoconstrictor in vasodilatory shock and as an inotrope in low cardiac output. Low-dose (“renal-dose”) dopamine should not be used for renal protection because evidence does not support this practice.

Phenylephrine is a powerful vasoconstrictor that strongly stimulates alpha-adrenergic receptors but has minimal affects on beta-adrenergic receptors of the heart therefore not arrhythmogenic. Vasoconstrictor properties are similar to norepinephrine and useful for non-cardiogenic hypotension (Cooper 2008; Poor and Stanke 2005; Kee 2003).

Administration of vasopressin reverses vasodilation in vasopressor-resistant shock by activation of vasopressin1 receptors, inhibition of ATP-sensitive potassium channels and nitric oxide, and amplification of vasoconstrictive catecholamine effect (Cooper 2008; Poor and Stanke 2005). The recommended infusion rate for vasopressin in the treatment of shock in adults is 0.01–0.04 units/min (Overgaard and Davík 2008). This dosage range is reported to be effective in about 85 % of patients with norepinephrine-resistant hypotension. Doses greater than 0.04 units/min may lead to myocardial ischemia, peripheral necrosis, and cardiac arrest (Tsuneyoshi et al. 2001).

Because epinephrine is a potent alpha- and beta-adrenoreceptor agonist, it is also a powerful vasoconstrictor, a positive inotrope, and a positive chronotrope. Vasoconstrictor effects of epinephrine become more apparent as the dose is increased. Low-dosage epinephrine infusions primarily stimulate beta-receptors. For this reason, epinephrine at a dosage of <4.0 mcg/min is often considered to be a “pure” inotrope, and this low level of epinephrine infusion is commonly encountered in patients after cardiac surgery. Epinephrine is associated with the induction of pulmonary hypertension, tachyarrhythmia, myocardial ischemia, lactic acidosis, and hyperglycemia. Lactic acidosis and hyperglycemia are caused by epinephrine-induced hypermetabolism, suppression of insulin release, and glycolysis. In addition, epinephrine can compromise hepatosplanchnic perfusion, oxygen exchange, and lactate clearance, especially in septic shock. Epinephrine is the first-line catecholamine in cardiopulmonary resuscitation and anaphylactic shock. As a vasopressor and as an inotrope, epinephrine is usually considered a second-line agent (Cooper 2008; Overgaard 2008; Poor and Stanke 2005; Kee 2003).

There are no large randomized, well-controlled trials to guide the pharmacologic management of hypotension.

Use of vasopressors and positive inotropes are generally based on data from small, often poorly controlled clinical studies. Selection of the appropriate vasoactive agent should be made on a case-by-case basis with attention to the known or suspected underlying cause of hypotension. The ideal vasopressor remains controversial (Havel et al. 2011).

Dobutamine is a synthetic catecholamine with predominately beta-adrenergic and only limited alpha-adrenergic effects that directly stimulates the myocardium. As a result of beta1-receptor-mediated, positive inotropic, and beta2-receptor-mediated vasodilatory action, dobutamine increases cardiac output and decreases systemic and pulmonary vascular resistance. Dobutamine is the preferred vasoactive agent to treat cardiogenic shock with low output and increased afterload. In combination with norepinephrine, dobutamine is used in septic shock with myocardial dysfunction. As with all catecholamines with a beta-adrenergic effect, dobutamine may cause a mismatch of myocardial oxygen delivery and requirement (Cooper 2008; Poor and Stanke 2005; Kee 2003).

Dobutamine has a short half-life which provides a rapid onset and allows for quick dose escalation.

Milrinone, a phosphodiesterase (PDE) inhibitor, increases intracellular cAMP thereby increasing the rate and extent of calcium influx during systole and enhancing contractility. PDE inhibitors have vasodilatory and inotropic actions and improve diastolic ventricular relaxation. PDE inhibitors frequently require the addition of vasopressors because of their substantial vasodilatory action (Cooper 2008; Poor and Stanke 2005; Kee 2003).

Although its physiologic effects are not antagonized by beta-blockade, milrinone’s pharmacokinetic profile makes dosing more difficult compared to dobutamine. The long half-life prevents rapid onset, requires slower dose titration/escalation, and necessitates dose reduction for patients with renal impairment. Milrinone improves cardiac output in cardiogenic shock and is generally considered a second-line agent for this indication. Milrinone has shown a greater vasodilatory effect than dobutamine, as demonstrated by further reductions in mean pulmonary artery pressure (MAP), pulmonary capillary wedge pressure (PCWP), and systemic vascular resistance (SVR), improving right-sided heart performance in pulmonary hypertension. Because of these effects, milrinone may be considered as a first-line therapy over dobutamine in patients with more severe pulmonary hypertension (Cooper 2008) (Table 2.4).