Dopamine is an endogenous catecholamine that functions as a central neurotransmitter and a synthetic precursor of norepinephrine and epinephrine. When administered intravenously, the effects of dopamine are mediated by dose-dependent stimulation of dopaminergic and adrenergic receptors, and by stimulation of norepinephrine release from nerve terminals.

At low doses (less than 5 μg per kg per minute), dopamine predominantly stimulates dopaminergic receptors in renal, mesenteric, and coronary vessels with minimal adrenergic effects. In normal subjects, so-called renal-dose dopamine augments renal blood flow, glomerular filtration rate, and natriuresis, with little effect on blood pressure. Low-dose dopamine has frequently been used by itself or in combination with other drugs as a renoprotective agent. However, the efficacy and safety of this strategy remain controversial [2]. Although a recent study demonstrated renal vasodilatory effects of dopamine in patients with heart failure [3], a randomized placebo-controlled trial in 328 critically ill patients with evidence of early renal dysfunction demonstrated no protective effect of low-dose dopamine on renal function and no difference in ICU or hospital length of stay [4]. Moderate doses of dopamine (5 to 10 μg per kg per minute) stimulate β₁-adrenergic receptors in the myocardium, augmenting cardiac output by increasing contractility and, to a lesser extent, heart rate (Fig. 32.1). In addition, venoconstriction mediated by serotonin and dopaminergic receptors may occur [5]. At higher doses (greater than 10 μg per kg per minute), α₁-adrenergic
receptor stimulation predominates, resulting in systemic arteriolar vasoconstriction. The overall effects of dopamine at the highest doses resemble those of norepinephrine (see later). However, it should be remembered that there is a great deal of overlap in the dose-dependent effects of dopamine in critically ill patients [1,2].

Moderate- to high-dose dopamine is a mainstay in the treatment of hypotension. In studies of fluid-resuscitated patients with septic shock, dopamine produced a mean increase in mean arterial pressure of approximately 25%, primarily owing to an increase in cardiac index and, to a lesser extent, systemic vascular resistance [2]. In the setting of hyperdynamic septic shock when excessive vasodilation is the primary source of hypotension, addition or substitution of a more potent α-adrenergic agonist such as norepinephrine may be more effective. Moreover, evidence of worsening splanchnic oxygen utilization with the use of high-dose dopamine has made it a less attractive agent.

By itself or in combination with other agents, dopamine may be used at moderate doses in the management of patients with acute decompensated heart failure and hypotension. Venodilating agents (e.g., nitroprusside and nitroglycerin) may be added to moderate the tendency of dopamine to increase cardiac-filling pressures [6]. Dopamine may also be combined with dobutamine for added inotropic effects or used at low doses to augment diuresis [7], although the benefits of “renal-dose” dopamine remain controversial and other agents may be more effective for preserving renal function in critically ill patients [8].

The use of dopamine is associated with several adverse effects, including tachycardia, tachyarrhythmias, and excessive vasoconstriction. Although these effects are generally dose dependent, in individual patients there may be substantial overlap of receptor affinity such that even at low doses dopamine may result in toxicity. In patients with ischemic heart disease, increased myocardial oxygen consumption coupled with some degree of coronary vasoconstriction with high-dose dopamine can result in myocardial ischemia. As with other positive inotropes, dopamine can increase flow to poorly oxygenated regions of the lung and cause shunting and hypoxemia. In addition, dopamine has been shown to depress minute ventilation in normoxic heart failure patients [9]. When dopamine is used in patients with acute decompensated heart failure, increased venous tone and pulmonary arterial pressure may exacerbate pulmonary edema in the setting of already high cardiac filling pressures. Despite these caveats, oxygen saturation generally remains constant due to improved hemodynamics.

There is mounting evidence that dopamine adversely effects splanchnic perfusion at doses usually required to treat septic shock. A small, randomized study of patients with sepsis using selective splanchnic and hepatic cannulation showed that infusion of dopamine was associated with a disproportionate increase in splanchnic oxygen delivery compared with oxygen extraction (65% vs. 16%). In contrast, norepinephrine produced better-matched increases in oxygen delivery and extraction (33% vs. 28%) [10]. Another study showed that in patients with septic shock randomly assigned to treatment with norepinephrine or dopamine, gastric intramucosal pH worsened significantly in patients treated with dopamine despite similar improvements in mean arterial pressure [11]. Thus, the use of dopamine in septic shock may be associated with splanchnic shunting, impairment of gastric mucosal oxygenation, and increased risk of gastrointestinal bleeding [2].

Epinephrine is an endogenous catecholamine that is a potent nonselective agonist of α- and β-adrenergic receptors.
Stimulation of myocardial β₁ and β₂ receptors increases contractility and heart rate, resulting in a rise in cardiac output (Fig. 32.2). Cardiac output is further augmented by an increase in venous return as a result of α₁-mediated venoconstriction. Blood flow to skeletal muscles is increased owing to β₂-mediated vasodilation. With very low-dose infusions of epinephrine (0.01 to 0.05 μg per kg per minute), β-adrenergic–mediated positive chronotropic and inotropic effects predominate. Diastolic blood pressure and overall peripheral vascular resistance may actually decrease owing to vasodilation in skeletal muscle. With higher doses of epinephrine, stimulation of α-adrenergic receptors in precapillary resistance vessels of the skin, mucosa, and kidneys outweighs β₂-mediated vasodilation in skeletal muscle, causing increased mean and systolic blood pressure [1].

Epinephrine plays a central role in cardiovascular resuscitation (see Chapter 23) and the management of anaphylaxis (see Chapter 194). Epinephrine is also used to reverse hypotension with or without bradycardia after cardiopulmonary bypass or cardiac transplantation [12]. Because of its adverse effects on splanchnic and renal blood flow and potential for inducing myocardial ischemia and tachyarrhythmias, epinephrine has generally been regarded as a second-line agent in the management of septic shock [2,13]. However, a recent randomized trial showed no difference in efficacy or safety between epinephrine alone versus norepinephrine plus dobutamine in patients with septic shock [14]. For patients with symptomatic bradycardia and hypotension who have failed atropine or external pacing, epinephrine may be used to stabilize the patient while awaiting more definitive therapy (e.g., transvenous placement of a temporary or permanent pacemaker) [15]. When used to treat hypotension, epinephrine is given as a continuous infusion starting at a low dose (0.5 to 1.0 μg per minute) and titrating up to 10 μg per minute as needed. Continuous infusions of epinephrine may cause restlessness, tremor, headache, and palpitations. Epinephrine should be avoided in patients taking β-adrenergic antagonists, as unopposed α-adrenergic vasoconstriction may cause severe hypertension and cerebral hemorrhage.

Norepinephrine is an endogenous catecholamine that is a potent β₁– and α₁-adrenergic agonist, with little β₂ activity. The main cardiovascular effect of norepinephrine is dose-dependent arterial and venous vasoconstriction owing to α-adrenergic stimulation (Fig. 32.2). The positive inotropic and chronotropic effects of β₁ stimulation are generally counterbalanced by the increased afterload and reflex vagal activity induced by the elevated systemic vascular resistance. Thus, heart rate and cardiac output usually do not change significantly, although cardiac output may increase or decrease depending on vascular resistance, left ventricular function, and reflex responses [5].

Norepinephrine, when infused at doses ranging from 0.5 to 30.0 μg per minute, is a potent vasopressor. Although generally reserved as a second-line agent or used in addition to other vasopressors in cases of severe distributive shock, norepinephrine is emerging as an agent of choice for the management of hypotension in hyperdynamic septic shock [14,16]. In a small, prospective double-blind trial, Martin et al. [17] randomized patients with hyperdynamic septic shock to dopamine or norepinephrine titrated to a mean arterial pressure greater than or equal to 80 mm Hg or systemic vascular resistance greater than 1,100 dynes per second per cm^{– 5}, or both. Although only 5 of 16 patients randomized to dopamine were able to achieve these endpoints, 15 of 16 patients randomized to norepinephrine were successfully treated with a mean dose of 1.5 μg per kg per minute. Moreover, 10 of the 11 patients who remained hypotensive on high-dose dopamine improved with the addition of norepinephrine. A subsequent prospective, nonrandomized, observational study suggested that in adults with septic shock treated initially with high-dose dopamine or norepinephrine, the use of norepinephrine was associated with improved survival [18]. In the setting of sepsis, norepinephrine improves renal blood flow and urine output [19], although large doses may be required to achieve these effects due to α-receptor downregulation [2].

Adverse effects of norepinephrine include increased myocardial oxygen consumption causing ischemia and renal and mesenteric vasoconstriction. Renal ischemia, may be of particular concern in patients with hemorrhagic shock. Norepinephrine can also cause necrosis and sloughing at the site of intravenous injection owing to drug extravasation. Norepinephrine is relatively contraindicated in patients with hypovolemia. As previously discussed, the overall effect of norepinephrine on gut mucosal oxygenation in septic patients compares favorably with that of high-dose dopamine.

Phenylephrine is a synthetic sympathomimetic amine that selectively stimulates α₁-adrenergic receptors. When administered intravenously, phenylephrine causes dose-dependent arterial vasoconstriction and increases peripheral vascular resistance. As blood pressure rises, activation of vagal reflexes causes slowing of the heart rate.

Phenylephrine, infused at 40 to 180 μg per minute, is commonly used in the management of anesthesia-induced hypotension [20,21] and hyperdynamic septic shock. Its rapid onset of action, short duration, and primary vascular effects make it an ideal agent for treating hemodynamically unstable patients in the intensive care setting. However, there are few data regarding its relative efficacy compared with older vasopressors such as norepinephrine and dopamine. In one small study of fluid-resuscitated patients with septic shock, the addition of phenylephrine to dobutamine or dopamine increased mean arterial pressure and systemic vascular resistance without a change in heart rate [22]. In addition, urine output improved while serum creatinine remained stable. The absence of β-adrenergic agonist activity at usual doses (phenylephrine activates β receptors only at much higher doses) makes phenylephrine an attractive agent for the management of hypotension in clinical situations where tachycardia or tachyarrhythmias, or both, limit the use of other agents [2]. As with other vasopressors, high-dose phenylephrine may cause excessive vasoconstriction. In addition, patients with poor ventricular function may not tolerate the increased afterload induced by α₁-stimulation [22]. Compared to epinephrine and norepinephrine, phenylephrine is less likely to decrease microcirculatory blood flow in the gastrointestinal tract [23].

Ephedrine is a naturally occurring sympathomimetic amine derived from plants. Its pharmacologic action results from direct nonselective activation of adrenergic receptors, as well as stimulation of norepinephrine release from storage sites. Although ephedrine is less potent and longer acting (half-life, 3 to 6 hours) than epinephrine, its hemodynamic profile is similar and includes cardiac stimulation and peripheral vasoconstriction.

Ephedrine is rarely used in the critical care setting except in the temporary treatment of hypotension induced by spinal anesthesia [20]. Ephedrine does not appear to compromise uterine blood flow and is considered by some to be the vasopressor of choice in the treatment of anesthesia-induced hypotension in the obstetric patient [24]. However, prophylactic use in pregnant woman undergoing Caesarian section is not recommended as it may cause hypertension and tachycardia [25]. Ephedrine can be administered in doses of 10 to 25 mg, given as an intravenous bolus every 5 to 10 minutes, with the total dose not to exceed 150 mg in 24 hours. In healthy women undergoing elective cesarean delivery that develop hypotension, pharmacogenomic data suggests that β₂-adrenoceptor genotype may affect dose requirements [26]. Adverse effects of ephedrine include myocardial ischemia and excessive vasoconstriction.