In this chapter the pharmacology of cardiovascular drugs that are used in the intensive care unit (ICU) is reviewed. Specific indications for particular drugs are discussed in other relevant chapters. Guidelines for the reintroduction of medications following routine cardiac surgery are provided in Chapter 17.
Inotropes and vasopressors are some of the most widely used drugs in the ICU, and they can be broadly classified on the basis of their effects on circulation. Inotropic drugs with vasodilatory effects (e.g., isoproterenol, milrinone, levosimendan) are termed inodilators; inotropic drugs with vasoconstrictive effects (e.g., norepinephrine) are termed inoconstrictors. Some drugs are inodilators at lower doses and inoconstrictors at higher doses (e.g., dopamine, epinephrine). Other drugs are pure vasoconstrictors or vasodilators. Vasoactive drugs can also be classified on the basis of their mechanism of action, for example, as sympathomimetics, phosphodiesterase inhibitors, or calcium sensitizers.
The effect of a drug on a vascular bed depends on the activity of the drug at various receptors and the relevant receptor population in that vascular bed. However, the overall effects of a drug on blood pressure, cardiac output, and regional blood flow depend on a complex interplay of factors, of which the direct pharmacologic properties of the drug is but one. Other relevant factors include:
For these reasons it is often difficult to predict the precise effect of a particular agent on an individual patient. These concepts are discussed in greater detail in the following material.
Infusions of vasoactive drugs are prescribed in different ways in different institutions. Three common methods are micrograms per kilogram per minute (μg/kg/min), micrograms per minute (μg/min), and milligrams per hour (mg/hr). In this book μg/kg/min is used. A conversion among the methods is provided in Appendix 1.
All sympathomimetics are derived from β-phenylethylamine. The presence of hydroxyl groups on the 3- and 4-carbons in the benzene ring designates a compound as a catecholamine, which may be endogenous or synthetic (Fig. 3-1). The noncatecholamine sympathomimetics include a diverse range of drugs, such as the asthma medication albuterol and the central nervous system stimulant amphetamine. Two commonly used vasoactive noncatecholamine sympathomimetics are ephedrine and phenylephrine.
Sympathomimetics bind to and stimulate adrenergic receptors that are located on cell membranes. In 1948, Alquist described two adrenergic receptor subtypes, alpha (α) and beta (β), based on their relative responsiveness to norepinephrine, epinephrine, and isoproterenol.1 In the 1970s this classification was refined to include α 1, α 2, β 1, and β 2 receptor subtypes. Subsequently, further divisions of each receptor subtype have been discovered, but clinically useful drugs to exploit these expanded classifications have not been developed.
Adrenergic receptors are part of a family of receptors known as G protein coupled receptors. Receptor stimulation by an agonist (see Chapter 4) facilitates the binding of the nucleotide guanosine triphosphate to a G protein, which activates it. The activated G protein then stimulates or inhibits one of a number of second messenger systems. Two second messenger systems mediate the actions of adrenergic receptors:
The direct cardiovascular effects of the adrenergic receptor subtypes are summarized in Table 3-1.
Epinephrine is a potent catecholamine with actions at both α and β receptors. At lower doses (0.01 to 0.03 μg/kg/min) β effects predominate, resulting in an increase in contractility and heart rate. Despite β 2 receptor-mediated vasodilation, a fall in blood pressure is uncommon. As the dose increases, α receptor-mediated vasoconstriction predominates, such that at higher doses (>0.05 to 0.1 μg/kg/min) vasoconstriction occurs in most vascular beds. In the acutely failing heart, epinephrine has the advantage of providing increased cardiac output while maintaining coronary perfusion pressure. Epinephrine can cause sinus tachycardia, atrial and ventricular arrhythmias, and marked metabolic disturbance, particularly hypokalemia, hyperglycemia, and lactic acidosis.
Norepinephrine causes potent stimulation at α and β 1 receptors, but unlike epinephrine, it has minimal effect at β 2 receptors. Blood pressure is reliably increased but the effect on cardiac output is variable. Although β 1 receptor stimulation has a direct inotropic effect, in the setting of hypovolemia or impaired ventricular function, increased left ventricular afterload due to α 1 receptor stimulation can cause cardiac output to fall. Similarly, the effect on heart rate is variable: direct β 1 stimulation has a chronotropic effect but increased blood pressure can cause baroreceptor-mediated bradycardia.
Norepinephrine is useful following cardiac surgery to counter the vasodilatory effects of cardiopulmonary bypass and sedation. However, doses above 0.05 to 0.1 μg/kg/min should be avoided in patients with impaired ventricular function unless cardiac output is being measured. Norepinephrine is commonly combined with an inodilator such as dobutamine or milrinone. Norepinephrine is typically commenced at a dose of 0.01 to 0.05 μg/kg/min and titrated to blood pressure. There is no maximum dose, but infusions greater than 0.1 to 0.2 μg/kg/min are rarely needed in cardiac surgery patients except in the presence of vasoplegic syndrome (Chapter 2) or septic shock, in which case doses as high as 0.5 to 1 μg/kg/min may be required. Troublesome metabolic effects, particularly lactic acidosis, are much less common with norepinephrine than with epinephrine.2
Dopamine is a precursor to norepinephrine and is itself an important neurotransmitter in the peripheral and central nervous systems. Dopamine stimulates α and β receptors and type 1 and 2 dopamine (DA) receptors. DA-1 receptors are found in the renal, mesenteric, and cerebral circulations,3 and their stimulation results in vasodilation. DA-1 receptors are also found in the renal tubule, where they mediate natriuresis. DA-2 receptors are analogous to α 2 receptors in that they are found presynaptically and inhibit the release of norepinephrine. Dopamine also has an indirect mechanism of action.
At low doses (<3 μg/kg/min), dopaminergic effects predominate. At higher doses, initially β receptor effects predominate; then α receptor effects predominate. The widely accepted dose range is 3 to 10 μg/kg/min for β effects and more than 10 μg/kg/min for α effects. However, these dose ranges must be viewed with skepticism. There is huge individual variability in the pharmacokinetics of dopamine such that dramatically different plasma concentrations may occur in different patients who are receiving the same dose.4 Furthermore, the clinical effects of a given plasma concentration are dependent on the functional activity of the adrenergic receptors. β Receptors are desensitized in a variety of clinical settings, including after cardiac surgery and with heart failure.5–7 Because of its indirect action, dopamine has reduced effectiveness in patients with heart failure or shock. Despite these caveats, it is generally true that as the dose of dopamine increases, there is a progressive increase in blood pressure and heart rate.
Dopamine at a dose of 1 to 3 μg/kg/min has been termed “renal-dose dopamine” and has traditionally been used to provide selective renal vasodilation in patients at risk for renal dysfunction. However, it is now clear that although low-dose dopamine may increase blood flow to the renal cortex, blood flow to the renal medulla may actually decrease.8 Given the relatively hypoxic environment of the renal medulla under normal circumstances (Chapter 1), this effect is potentially harmful. Furthermore, the increase in urine output that occurs with low-dose dopamine is due primarily to a direct tubular natriuretic effect rather than to renal vasodilation. In a well-conducted, large, randomized trial, low-dose dopamine did not reduce the incidence of acute renal failure in patients with early renal dysfunction.9 Dopamine has a number of other potentially detrimental effects, including inhibition of hypoxic ventilatory drive, impairment of ventilation-perfusion matching in the lung, and suppression of the secretion of some anterior pituitary hormones, such as prolactin, growth hormone, and thyrotropin.8
The phosphodiesterases (PDEs) are a family of enzymes that catalyze the breakdown of cyclic nucleotides, including cAMP and cGMP. There are multiple subtypes of PDE that have varying tissue distributions and actions.12 Caffeine and theophylline are nonspecific PDE inhibitors that are used as bronchodilators. Papaverine is a vasodilator and nonspecific PDE inhibitor that is used by cardiac surgeons during coronary artery bypass graft (CABG) surgery to prevent spasm of the internal mammary artery.
Drugs that selectiv
