Naturally Occurring Catecholamines
Naturally occurring catecholamines are epinephrine, norepinephrine, and dopamine (see Table 18-1 and Fig. 18-1).
Epinephrine
Epinephrine is the prototype sympathomimetic. It is a circulating hormone synthesized, stored, and released from the adrenal medulla. Its natural functions upon release into the circulation include regulation of myocardial contractility, heart rate, vascular and bronchial smooth muscle tone, glandular secretions, and metabolic processes such as glycogenolysis and lipolysis. It is a potent activator of α-adrenergic receptors and also activates β1 and β2receptors. Oral administration is not effective as epinephrine is rapidly metabolized in the gastrointestinal mucosa and liver. Therefore, epinephrine is administered subcutaneously, intravenously, or intramuscularly. Absorption after subcutaneous injection is slow because of local epinephrine–induced vasoconstriction. Epinephrine is poorly lipid soluble, preventing its ready entrance into the central nervous system (CNS) and accounting for the lack of cerebral effects.
Clinical Uses
Clinical uses of epinephrine include treatment of life-threatening allergic reactions/anaphylaxis, treatment of severe asthma and bronchospasm, administration during cardiopulmonary resuscitation as a vital therapeutic drug,1administration during periods of hemodynamic instability to promote myocardial contractility and increase vascular resistance, and continuous infusion for continuous support of myocardial contractility and vascular resistance. Epinephrine is used to promote inotropy during weaning from cardiopulmonary bypass. It is also used as a vasoconstrictor to increase oxygen delivery and increase cardiac output in sepsis.2,3 Lastly, epinephrine is added to local anesthetic solutions to decrease systemic absorption prolonging the duration of action of the anesthetic for regional and local anesthesia. Epinephrine is used in local and field blocks to promote a bloodless surgical field.
Cardiovascular Effects
The cardiovascular effects of epinephrine result from stimulation of α- and β-adrenergic receptors (see Table 18-1).4 Stimulation of α1 receptors leads to arteriolar vasoconstriction and pulmonary artery vasoconstriction. α1 Receptors are predominantly located in cutaneous, splanchnic, and renal vascular beds. Stimulation of α2 receptors also leads to vasoconstriction. β2 Receptor stimulation leads to vasodilation, predominantly in the skeletal muscles. The relative balance of α1 and β2 receptors in the vasculature of an organ determines epinephrine’s overall effect on blood flow to the organ. The net effect of these changes in peripheral vascular tone is preferential distribution of cardiac output to skeletal muscles and increased systemic vascular resistance. Renal blood flow is substantially decreased by epinephrine, even in the absence of changes in systemic blood pressure. Epinephrine is estimated to be 2 to 10 times more potent than norepinephrine as a renal vasoconstrictor. In general, β2 receptors are more sensitive to lower epinephrine doses while effects on α1 receptors predominate at higher doses. At high doses, the predominant α activity and resultant vasoconstriction leads to increased afterload, which may impede increases in cardiac output. Initial tachycardia may be followed by heart rate decreases due to baroreceptor reflexes. Venous return is also enhanced by venoconstriction from the high density of α receptors in the venous vasculature system. Blood pressure is increased by an increase in cardiac index as well as an increase in systemic vascular resistance.
Epinephrine stimulates β1 receptors causing an increase in heart rate, myocardial contractility, and cardiac output. There may be a mild decrease in diastolic blood pressure, reflecting vasodilation in skeletal muscle vasculature due to stimulation of β2 receptors. The net effect of these systemic blood pressure changes is an increase in pulse pressure and a mild change in mean arterial pressure.
Epinephrine increases heart rate by accelerating the rate of spontaneous phase 4 depolarization, which also increases the likelihood of cardiac dysrhythmias. Epinephrine increases conduction velocity and decreases the refractory period in the atrioventricular node, bundle of His, Purkinje fibers, and ventricular muscle. It also may increase automaticity of latent pacemakers. Tachycardia, premature ventricular contraction, ventricular tachycardia, and ventricular fibrillation all may occur.
Increased cardiac output reflects epinephrine-induced increases in heart rate, myocardial contractility, and venous return. Repeated doses of epinephrine produce similar cardiovascular effects in contrast to the tachyphylaxis that accompanies administration of synthetic noncatecholamines that cause the release of norepinephrine, such as ephedrine. Myocardial oxygen consumption is increased with enhanced left ventricular preload, increased contractility, increased afterload, and tachycardia. Diastolic function is improved by increasing the rate of myocardial relaxation, and early left ventricular filling is enhanced.
Epinephrine stimulates renal β receptors, resulting in increased secretion of renin. In usual therapeutic doses, epinephrine has no significant vasoconstrictive effect on cerebral arterioles. Coronary blood flow is enhanced by epinephrine,5 even at doses that do not alter systemic blood pressure.
Chronic increases in the plasma concentrations of epinephrine, as in patients with pheochromocytoma, result in a decrease of plasma volume because of a loss of protein-free fluid into the extracellular space. Arterial wall damage and local areas of myocardial necrosis may also accompany chronic circulating excesses of epinephrine. Conventional doses of epinephrine, however, do not produce these effects.
The hemodynamic effects of epinephrine are attenuated and can be blocked by prior administration of α- or β-adrenergic receptor antagonists.4 Supratherapeutic doses of epinephrine may lead to acute heart failure, pulmonary edema, arrhythmias, hypertension, and myocardial ischemia.
Airway Smooth Muscle
Smooth muscles of the bronchi are relaxed by epinephrine-induced activation of β2 receptors. By increasing intracellular concentrations of cyclic adenosine monophosphate (cAMP), β2 stimulation decreases release of vasoactive mediators associated with symptoms of bronchial asthma. The bronchodilating effects of epinephrine are not seen in the presence of β-adrenergic blockade. In the presence of β-adrenergic blockade, epinephrine instead induces bronchoconstriction from stimulation of bronchial α receptors.
Metabolic Effects
Epinephrine has the most significant effect on metabolism of all the catecholamines.6 β1 Receptor stimulation due to epinephrine increases liver glycogenolysis and adipose tissue lipolysis, whereas α1 receptor stimulation inhibits release of insulin. Liver glycogenolysis results from epinephrine-induced activation of hepatic phosphorylase enzyme. Lipolysis is due to epinephrine-induced activation of triglyceride lipase, which accelerates the breakdown of triglycerides to form free fatty acids and glycerol. Infusions of epinephrine usually increase plasma concentrations of glucose, cholesterol, phospholipids, and low-density lipoproteins. Release of endogenous epinephrine and the resulting glycogenolysis and inhibition of insulin secretion is the most likely explanation for perioperative hyperglycemia. In addition, epinephrine can inhibit peripheral glucose uptake, which is also due in part to inhibition of insulin secretion. Increased plasma concentrations of lactate presumably reflect epinephrine-induced glycogenolysis in skeletal muscles. Some studies demonstrate that epinephrine-induced hyperlactemia is primarily a transient phenomenon associated with inhibition of pyruvate dehydrogenase and has no relationship with cellular hypoxia and tissue perfusion or associated metabolic acidosis.7
Electrolytes
Selective β2-adrenergic agonist effects of epinephrine are speculated to reflect activation of the sodium–potassium pump in skeletal muscles, leading to a transfer of potassium ions into cells (Fig. 18-2).8 The observation that serum potassium measurements in blood samples obtained immediately before induction of anesthesia are lower than measurements 1 to 3 days preoperatively is presumed to reflect stress-induced release of epinephrine (Fig. 18-3).9 The ability of a nonselective β1 and β2 antagonist (propranolol) but not a cardioselective β1 antagonist (atenolol) to prevent “preoperative hypokalemia” is consistent for a β2-adrenergic agonist effect as the explanation for potassium transfer (Fig. 18-4).9 In making therapeutic decisions based on a preinduction serum potassium measurement, especially in patients without a reason to experience hypokalemia, one should consider the possible role of preoperative anxiety and the release of epinephrine.
Epinephrine-induced hypokalemia may contribute to cardiac dysrhythmias, which occasionally accompany stimulation of the sympathetic nervous system. Conversely, epinephrine may stimulate the release of potassium from the liver, tending to offset the decrease in extracellular concentration of this ion produced by entrance into skeletal muscles.
Ocular Effects
Epinephrine causes contraction of the radial muscles of the iris, producing mydriasis. Contraction of the orbital muscles produces an appearance of exophthalmos. Adrenergic receptors responsible for these ocular effects are likely α receptors as norepinephrine is less potent than epinephrine and isoproterenol has practically no ocular effects.
Gastrointestinal and Genitourinary Effects
Epinephrine, norepinephrine, and isoproterenol produce relaxation of gastrointestinal smooth muscle. Activation of β-adrenergic receptors relaxes the detrusor muscle of the bladder, whereas activation of α-adrenergic receptors contracts the trigone and sphincter muscles.
Hepatosplanchnic vasoconstriction occurs as well as impaired renal blood flow as cardiac output is diverted to the dilated skeletal muscle vasculature.10 This results in decreased hepatosplanchnic oxygen exchange and lactate clearance. The impairment of splanchnic circulation that occurs is greater than that associated with norepinephrine or dopamine.11,12 It may be dependent on the severity of the shock state and the dose of epinephrine used.
Coagulation
Coagulation is accelerated by epinephrine. A hypercoagulable state present during the intraoperative and postoperative period may reflect stress-associated release of epinephrine. Epinephrine increases the total leukocyte count but causes eosinopenia. It is a potent inducer of platelet aggregation and increases factor V activity.
Norepinephrine
Norepinephrine is the endogenous neurotransmitter synthesized and stored in postganglionic sympathetic nerve endings and released with sympathetic nerve stimulation. It is the immediate precursor of epinephrine. Norepinephrine stimulates β1- and α1-adrenergic receptors. It is approximately equal in potency to epinephrine for stimulation of β1 receptors but, unlike epinephrine, has minimal effect at β2receptors (see Table 18-1). Through its action on β1receptors, norepinephrine increases heart rate, conduction, and contractility. Norepinephrine is a potent α1 agonist producing intense arterial and venous vasoconstriction in all vascular beds except for the coronary arteries.13Norepinephrine causes greater increase in systemic vascular resistance and diastolic blood pressure, mean arterial pressure, and systolic blood pressure than epinephrine. Venous vasoconstriction decreases venous capacitance, thereby increasing venous return to augment stroke volume and cardiac output. Heart rate changes may be minimal as baroreceptor reflexes triggered by arterial vasoconstriction are counteracted by β1-mediated increases in heart rate. This is in contrast to epinephrine, which has a more significant chronotropic effect. Norepinephrine increases mean arterial pressure primarily by vasoconstriction and to lesser degree by increasing stroke volume and cardiac output. At higher doses, vasoconstriction predominates to an even greater extent. Norepinephrine and epinephrine increase total peripheral vascular resistance more than dobutamine (described in the following texts). Unlike epinephrine, norepinephrine has minimal metabolic effects. Hyperglycemia is unlikely to occur as a result of norepinephrine administration.
Intravenous administration of norepinephrine results in intense vasoconstriction in skeletal muscle, liver, kidneys, and skin vascular beds. Peripheral vasoconstriction may decrease tissue blood flow to the extent that metabolic acidosis occurs. Chronic infusion of norepinephrine or increased circulating concentrations of this catecholamine, as may be associated with pheochromocytoma, may cause precapillary vasoconstriction and loss of protein-free fluid into the extracellular space. Like epinephrine, norepinephrine dilates coronary arteries.13
A continuous infusion of norepinephrine, 2 to 16 µg per minute, may be used to treat refractory hypotension. Placement of norepinephrine in a 5% glucose solution provides sufficient acidity to prevent oxidation of the catecholamine. Extravasation during infusion can produce severe local vasoconstriction and possible necrosis; hence, administration should be via central venous access. Norepinephrine administration should be accompanied by invasive hemodynamic monitoring. The primary method of elimination is by reuptake into the adrenergic nerve endings where it is stored for subsequent release with only small amounts being metabolized.
Clinical Uses
The primary use of norepinephrine is as a potent vasoconstrictor to increase total peripheral vascular resistance and mean arterial pressure. It is a first-line agent in the treatment of refractory hypotension during severe sepsis.2,3,14Norepinephrine-induced vasoconstriction and redistribution of flow may increase splanchnic blood flow and urine output in severely hypotensive septic patients. Norepinephrine is also used for patients with low systemic vascular resistance after cardiopulmonary bypass. In patients with coronary artery disease, norepinephrine can be used to maintain perfusion pressure, although it should be balanced with the resultant increased afterload associated with high doses.
Side Effects
Norepinephrine should be used cautiously in patients with right ventricular failure. Norepinephrine increases venous return to the heart and also raises pulmonary artery pressures via stimulation of pulmonary vascular α1-adrenergic receptors. Both of these may be poorly tolerated by patients with right heart failure.
The use of norepinephrine as an inotropic agent is limited by its action as a potent vasoconstrictor. The increased peripheral resistance and afterload may decrease cardiac output and increase the work of the left ventricle. Its use is also limited by the potential for tachycardia, although its arrhythmogenic potential is less than that of epinephrine.
One of the major concerns with norepinephrine use is organ ischemia. Excessive vasoconstriction and decreased perfusion of renal, splanchnic, and peripheral vascular beds may lead to end-organ hypoperfusion and ischemia. Renal arteriolar vasoconstriction may lead to oliguria and renal failure. However, when large doses of norepinephrine accompanied by adequate fluid volume resuscitation are used with caution to treat profound hypotension, perfusion pressure and renal blood flow may actually increase.
Dopamine
Dopamine is an endogenous catecholamine that is the immediate precursor of norepinephrine. Dopamine regulates cardiac, vascular, and endocrine function and is an important neurotransmitter in the central and peripheral nervous systems. The pharmacology of dopamine is complex as this catecholamine differentially stimulates a variety of dopaminergic as well as adrenergic receptors. It is a relatively nonspecific agonist at both dopamine1 (D1) and dopamine2 (D2) receptors and the α- and β-adrenergic receptors. D1 receptors are located postsynaptically. When activated D1 receptors elicit vasodilation in renal, mesenteric, coronary, and cerebral vascular beds and inhibition of sodium–potassium adenosine triphosphatase (Na+–K+ ATPase).15 Activation of these receptors is mediated by adenylate cyclase stimulation. D2 receptors are principally presynaptic and inhibit adenylate cyclase activity and release of norepinephrine in autonomic nervous system ganglia and adrenergic nerves (in renal and mesenteric vessels) leading to vasodilation.16,17 D2 receptors are also present in the pituitary gland, emetic center of the medulla, and kidney. Nausea and vomiting produced by dopamine probably reflect stimulation of D2 receptors. Dopamine receptors may also be associated with the neural mechanism for “reward” that is associated with cocaine and alcohol dependence.
Traditionally, the pharmacokinetics of dopamine has been attributed to dose-dependent effects on varying receptors.16 At low intravenous (IV) infusion rates (0.5 to 3 µg/kg/minute), dopamine primarily stimulates D1 and D2receptors leading to vasodilation, decreased arterial blood pressure, and increased renal and splanchnic vascular blood flow. Diuresis and natriuresis also occur. The decrease in diastolic blood pressure might lead to a reflex increase in heart rate. At higher infusion rates (3 to 10 µg/kg/minute), dopamine primarily stimulates β1-adrenergic receptors in the heart as well as α receptors in the peripheral vasculature. It also induces norepinephrine release from vascular sympathetic neurons. The activation of β receptors leads to increased cardiac output by increasing chronotropy and contractility along with vasodilation and afterload reduction. As the infusion rate is increased even further (>10 µg/kg/minute), dopamine predominantly stimulates α1 receptors, acting similarly to a pure α agonist. The predominant stimulation of vascular smooth muscle α1 receptors at these higher doses lead to arterial and venous vasoconstriction, increased systemic vascular resistance, and increased blood pressure attenuating further increases in cardiac output. Reflex bradycardia may also occur at this point.
This aforementioned dose-dependent model of dopamine’s effects is too simplistic, even in healthy individuals. There are a wide range of clinical responses depending on individual variability in pharmacokinetics as well as other variables. For example, despite identical IV infusion rates, there may be a 10- to 75-fold variability in plasma dopamine concentrations produced even in healthy individuals with normal drug metabolism.18 The etiology of the wide pharmacokinetic variability and variation in individual responses is likely multifactorial, reflecting differences in drug distribution, elimination, and endogenous levels, among other factors. Such differences may be even more profound in critically ill patients. Hence, the effects of dopamine cannot be predicted based on the dose,19 and the drug must be titrated to effect.
Dopamine increases cardiac output by stimulation of β1 receptors, increasing stroke volume. This increase in cardiac output is usually accompanied by only modest increases in heart rate, systemic blood pressure, and systemic vascular resistance. A portion of the effect of dopamine is also due to stimulation of endogenous norepinephrine release, which may predispose to the development of cardiac dysrhythmias. Nevertheless, dopamine is less dysrhythmogenic than epinephrine. The release of norepinephrine caused by dopamine may be an unreliable mechanism for increasing cardiac output when catecholamine stores are depleted, as occurs with patients in chronic cardiac failure. Dopamine increases myocardial oxygen consumption.
Dopamine causes both relaxation and contraction of vascular smooth muscle with the predominant effect varying by vascular bed, predominant receptor type, and dose administered. Dopamine’s effect on pulmonary vascular resistance has not been well studied in humans, though there are some reports it may decrease pulmonary vascular resistance in patients with chronic obstructive pulmonary disease.
Rapid metabolism of dopamine with an elimination half-life of 1 to 2 minutes mandates its use as a continuous infusion (1 to 20 µg/kg/minute) to maintain therapeutic plasma concentrations. Dopamine should be dissolved in 5% glucose in water for IV administration to avoid the inactivation that may occur in alkaline solutions. Extravasation of dopamine, like norepinephrine, produces intense local vasoconstriction, which may be treated with local infiltration of phentolamine.20 Dopamine is not effective orally and does not cross the blood–brain barrier in sufficient amounts to cause CNS effects. The immediate precursor of dopamine, L-dopa, is absorbed from the gastrointestinal tract and readily crosses the blood–brain barrier. Dopamine is partially protein bound. Approximately 25% is converted to norepinephrine. Dopamine undergoes metabolism in the liver with conjugation to sulfates and glucuronides, pulmonary endothelium by catechol-O-methyltransferase (COMT) and excretion by the kidneys.
Clinical Uses
Dopamine is used clinically to increase cardiac output in patients with decreased contractility, low systemic blood pressure, and low urine output as may be present after cardiopulmonary bypass or with chronic heart failure.21 It is unique among the catecholamines in being able to simultaneously increase myocardial contractility, renal blood flow, glomerular filtration rate, excretion of sodium, and urine output.22 Dopamine exerts its positive chronotropic, dromotropic, inotropic, and lusitropic (myocardial relaxant) effects via β1-adrenergic receptors. Activation of arterial and venous α1 receptors increases systemic vascular resistance, preload, and left ventricular afterload.23 However, as dopamine increases pulmonary vascular resistance as well, it may not be the preferred inotropic agents in patients with pulmonary hypertension or right ventricular dysfunction.
The divergent pharmacologic effects of dopamine and dobutamine make their use in combination potentially useful. For example, infusions of dopamine and dobutamine in combination have been noted to produce a greater improvement in cardiac output, at lower doses, than can be achieved by either drug alone. Both are inotropic but each drug dilates different vascular beds such that the summation of afterload reduction by both drugs may produce a greater improvement in cardiac output than could be achieved by either drug alone. Dopamine may distribute the cardiac output to the renal and mesenteric vascular beds, whereas dobutamine may provide additional afterload reduction by dilating skin and skeletal muscle vascular beds. The objective of combination therapy is to increase coronary perfusion and cardiac output while decreasing afterload, similar to an intraaortic balloon pump.
Renal-Dose Dopamine
The term renal-dose dopamine or low-dose dopamine refers to the continuous infusion of small doses (1 to 3 µg/kg/minute) of dopamine to patients to promote renal blood flow. In healthy individuals, low-dose dopamine increases renal blood flow and induces natriuresis and diuresis. Theoretically, dopamine’s renal vasodilating effects may be useful in patients with impaired renal function or in patients at risk of decreased renal perfusion as may occur with decreased cardiac output. Small doses of dopamine increase renal blood flow predominantly by D1 receptors in the renal vasculature and possibly by D2receptors via inhibition of norepinephrine release. Larger doses predominantly increase renal blood flow by β-adrenergic–mediated increases in cardiac output. Higher doses of dopamine presumably stimulate α receptors to increase perfusion pressure. In addition, dopamine triggers natriuresis and diuresis through direct effect on tubular cell function. Dopamine binds to D1 and D2 receptors in the proximal tubule, thick ascending loop of Henle, and cortical collecting ducts inhibiting Na+–K+ ATPase activity, increasing Na+ excretion, inducing natriuresis and diuresis.24 The activation of D2 in inner medullary collecting ducts stimulates prostaglandin E2 (PGE2) production. This antagonizes the effects of antidiuretic hormone and results in increased free water clearance. PGE2 enhances blood flow in the inner medulla. Inhibition of aldosterone also increases sodium excretion and diuresis. Hence, dopamine has direct and indirect effects on the renal vasculature in addition to functioning as a diuretic.
The term renal-dose or low-dose dopamine is misleading as dopamine has many effects at sites other than the kidneys, even at low doses. Dopamine’s effects based on dose alone are unpredictable. Low-dose dopamine also implies an unproven beneficial effect on renal function.25–27 In patients receiving dopamine before a “renal insult,” there is a clear diuretic effect but none for improved creatinine clearance or decreased need for hemodialysis.26Despite drug-induced diuresis, there is no evidence that urine output in the presence of low cardiac output and/or hypovolemia protects renal function. The use of dopamine after the renal insult has occurred has not been shown to improve glomerular filtration rate. There is evidence that the beneficial effect of low-dose dopamine on renal blood flow and glomerular filtration rate observed in healthy individuals is due to drug-induced increases in cardiac output, and this benefit is lost in early renal failure.27–29 No randomized controlled studies have demonstrated a decrease in the incidence of acute renal failure when dopamine is administered to patients considered to be at risk for developing acute renal failure in multiple patient populations (major vascular surgery,30 cardiopulmonary bypass, intensive care,31 heart failure, sepsis,32 transplantation, patients exposed to nephrotoxic drugs33) confirming the results of two large retrospective studies25,26 and two meta-analyses,32,33 finding that dopamine does not prevent or reverse acute renal failure or improve outcome. Aside from one study demonstrating dopamine selectively increases renal blood flow in heart failure patients via dilation of both large conductance and small resistance renal blood vessels,34 there exists no proven improvement in renal perfusion, creatinine clearance, or glomerular filtration rate and no alteration in the course of renal failure or the need for renal replacement therapy.
Dopamine leads to an increase in cortical and inner medullary blood flow, shunting flow from the outer medulla. It increases solute delivery to the distal tubular cells increasing medullary oxygen consumption. The outer medulla is highly metabolically active and highly susceptible to ischemic injury and acute renal failure. Dopamine can induce renal failure in both normo- and hypovolemic patients.
Low-dose dopamine is associated with multiple complications affecting the cardiovascular, pulmonary, gastrointestinal, endocrine, and immune systems. A multicenter observational study demonstrated that dopamine is an independent risk factor for death for patients with shock due to any cause.35 In the absence of data confirming the efficacy of dopamine in preventing acute renal failure, renal-dose dopamine cannot be recommended.25,36 In fact, not only does low-dose dopamine not confer any renal protective mechanism, it may in fact be detrimental.27,37
Cardiovascular Effects
Dopamine is associated more than dobutamine or epinephrine with dose-related sinus tachycardia and the potential to cause ventricular arrhythmias23,38 and may predispose to myocardial ischemia by precipitating tachycardia, increasing contractility, increasing afterload, and precipitating coronary artery vasospasm. Dopamine increases peripheral vascular resistance and pulmonary artery pressures. Unlike dobutamine, dopamine does not inhibit hypoxic pulmonary vasoconstriction. Nevertheless, dopamine is not recommended for use in right heart failure.
Gastrointestinal Effects
Gastrointestinal mucosal ischemia and subsequent translocation of bacteria and bacterial toxins play an important role in the development of multiple organ dysfunction syndrome. Dopamine’s effect on splanchnic blood flow and gastric intramucosal pH is controversial and inconsistent. There is no evidence that low-dose dopamine has beneficial effects on splanchnic function or reduces the progression to multiorgan failure in sepsis. Dopamine may increase flow to the muscular layer of the gut with decreased flow to the mucosal layer with detrimental effects and possibly gut ischemia. In septic patients, dopamine but not norepinephrine, as administered to maintain an acceptable mean arterial pressure, resulted in an uncompensated increase in splanchnic oxygen requirements. Although dopamine infusion in septic patients led to increased hepatosplanchnic perfusion, hepatosplanchnic oxygen uptake was reduced suggesting an impairment of hepatosplanchnic metabolism.40 Most of these studies have looked at the effects of low-dose dopamine rather than doses used to treat hypotension.
D2 receptors are also located in the enteric nervous system. Dopamine agonists interfere with gastrointestinal motility. Low-dose dopamine has been demonstrated to slow gastric motility in mechanically ventilated intensive care patients.41
Endocrine and Immunologic Effects
Dopamine disrupts metabolic and immunologic functions through its effects on hormones and lymphocyte function. The anterior pituitary plays a crucial role in metabolic and immunologic homeostasis. The initial stress response stimulates pituitary hormone release, whereas the chronic phase is associated with suppression of the hypothalamic-pituitary axis. In the acute phase of an illness, dopamine induces the pattern of hypopituitarism seen in prolonged critical illness and chronic stress. When dopamine is used in the chronic phase of illness, it further suppresses the circulating concentrations of pituitary hormones.42
Dopamine depresses the immune status by reducing serum prolactin levels. Prolactin is an immunoregulatory hormone affecting T and B lymphocytes. Dopamine inhibits lymphocyte proliferation, immunoglobulin synthesis, and cytokine production and promotes lymphocyte apoptosis. Dopamine also decreases the secretion of growth hormone, which has anabolic, lipolytic, and immune-stimulating properties. Growth hormone deficiency can contribute to impaired anabolism and a negative nitrogen balance. Dopamine’s inhibition of thyrotropin-releasing hormone leads to “euthyroid sick syndrome.” It also decreases dehydroepiandrosterone sulfate and may affect luteinizing hormone release. Dopamine’s overall effect is to suppress the secretion and function of anterior pituitary hormones, aggravating catabolism and cellular immune function and inducing central hypothyroidism.42
Respiratory Effects
The infusion of low-dose dopamine in healthy subjects as well as heart failure patients interferes with the ventilatory response to arterial hypoxemia and hypercapnia, reflecting the role of dopamine as an inhibitory neurotransmitter at the carotid bodies.43 The result is depression of ventilation in patients who are being treated with dopamine to increase myocardial contractility.44 Dopamine also decreases arterial oxygen saturation by impairing regional ventilation/perfusion matching in the lungs.45 Dose-dependent reductions in arterial PO2 with increasing rates of dopamine in critically ill patients after major surgery have been demonstrated.46 Arterial blood gases have been observed to deteriorate during infusion of dopamine.
One study demonstrated low-dose dopamine did not influence ventilation specifically in patients with chronic obstructive pulmonary disease either breathing spontaneously or being weaned from mechanical ventilation.47Dopamine may even decrease pulmonary vascular resistance in patients with chronic obstructive pulmonary disease. Other potential beneficial effects are improved respiratory muscle contraction, increased lung edema clearance, and inhibition of bronchoconstriction.47,48 However, such reports are anecdotal or not tested in clinical studies.
Intraocular Pressure
Continuous infusions of dopamine to critically ill patients are associated with increases in intraocular pressure.49 This may create a risk in patients with preexisting glaucoma especially if they are sedated and mechanically ventilated.
Synthetic Catecholamines
The two clinically useful synthetic catecholamines are isoproterenol and dobutamine (see Table 18-1 and Fig. 18-1).
Isoproterenol
Isoproterenol is the most potent activator of all the sympathomimetics with β1 and β2 receptor activity. It is two to three times more potent than epinephrine and at least 100 times more active than norepinephrine. In clinical doses, isoproterenol is devoid of α agonist effects and does not cause the vasoconstriction associated with the naturally occurring catecholamines.
The cardiovascular effects of isoproterenol reflect activation of β1 receptors in the heart and β2 receptors in skeletal muscle and to a lesser extent renal and splanchnic vascular beds. In an adult, continuous infusion of isoproterenol, 1 to 5 µg per minute, greatly increases heart rate, myocardial contractility, and cardiac automaticity, whereas vasodilation in skeletal muscles decreases systemic vascular resistance. Although cardiac output may increase thereby increasing systolic blood pressure, the mean arterial pressure may decrease due to decreases in systemic vascular resistance and associated decreases in diastolic blood pressure. Increases in cardiac output may be attenuated by impaired left ventricular filling due to tachycardia as well as decreased preload from venous vasodilation. There is preferential vasodilation in nonessential areas such as skeletal muscle. Decreased diastolic blood pressure, increased heart rate, and cardiac dysrhythmias may lead to a decrease in coronary blood flow at the same time that myocardial oxygen requirements are increased by tachycardia and increased myocardial contractility.50Compensatory baroreceptor-mediated reflex slowing of the heart rate does not occur during infusion of isoproterenol because mean arterial pressure is not increased. This combination of events may be deleterious in patients with coronary artery disease.
Compared to dobutamine, for a comparable increase in cardiac output, isoproterenol is associated with larger decreases in total peripheral vascular resistance and blood pressure. It is also associated with more tachycardia both from direct β effects as well as a reflex increase in heart rate with decreased vascular tone.
Metabolism of isoproterenol in the liver by COMT is rapid, necessitating a continuous infusion to maintain therapeutic plasma concentrations. Uptake of isoproterenol into postganglionic sympathetic nerve endings is minimal.
Clinical Uses
A continuous infusion of isoproterenol, 1 to 5 µg per minute, is effective in increasing the heart rate in adults in the presence of heart block. Isoproterenol is used to provide sustained increases in heart rate before insertion of a temporary or permanent cardiac pacemaker in the treatment of bradydysrhythmias. Isoproterenol’s ability to decrease pulmonary vascular resistance may be useful in the management of pulmonary hypertension and right ventricular dysfunction.51 The use of isoproterenol as an inotropic drug has decreased with the availability of inotropic agents such as dobutamine and phosphodiesterase inhibitors. Likewise, the use of isoproterenol as a bronchodilator has been supplanted by the availability of specific β2 agonists.
Adverse Effects
Vasodilation and decreased blood pressure may limit the use of isoproterenol. In addition, it can lead to tachyarrhythmias. The combination of decreased diastolic blood pressure and increased heart rate and dysrhythmias may lead to myocardial ischemia.
Dobutamine
Dobutamine is a synthetic catecholamine derived from isoproterenol consisting of a 50:50 racemic mixture of two stereoisomers.52 The (−) enantiomer is a potent α1-adrenergic agonist as well as a weak β1- and β2-adrenergic agonist. The (+) enantiomer is a competitive antagonist at the α1 receptor site as well as a potent β1- and β2-adrenergic agonist.53 Dobutamine has potent β1-adrenergic effects with weaker β2-adrenergic activity. Its effect on α receptors increases at higher doses. Dobutamine’s cardiovascular effects are a result of the combination of activity of its two stereoisomers.53–56
Dobutamine acts primarily as a positive inotropic agent. Dobutamine leads to an increase in intracellular cAMP, increasing calcium release from the sarcoplasmic reticulum to increase contractility. Cardiac output is increased primarily by an increase in stroke volume. Contractility is increased from its action on myocardial β1 and α1 receptors and, to a lesser extent, by decreased afterload from its effect on vascular smooth muscle β2 receptors. Dobutamine has weak effects on vascular tone causing peripheral vasodilation. At higher doses, the (−) isomer stimulates α1 receptors, limiting further vasodilation. Blood pressure usually is not significantly affected as α1-mediated vasoconstriction by the (−) enantiomer is countered by α1 antagonism by the (+) enantiomer and by its β2 activity, although the latter may be unmasked by β blockade therapy.53–56 In addition, there may be minimal effects on the mean arterial pressure as the increased cardiac output offsets the decrease in peripheral vascular resistance. Because dobutamine does not possess clinically important vasoconstrictor activity, it may be ineffective in patients who require increased systemic vascular resistance rather than augmentation of cardiac output to increase systemic blood pressure.
Dobutamine affects heart rate through its action on β1-adrenergic receptors. Dobutamine stimulates sinoatrial node automaticity as well as atrioventricular nodal and ventricular conduction.38 The chronotropic effects of dobutamine per unit gain in cardiac output are less than that of dopamine and isoproterenol but may be greater than that of epinephrine.52,57,58 The increase in calcium that facilitates increased contractility also facilitates increased arrhythmias. At low doses, increases in heart rate may be minimal. However, high doses of dobutamine (>10 µg/kg/minute IV) may predispose the patient to tachycardia and cardiac dysrhythmias.
Dobutamine increases myocardial oxygen consumption by increasing tachycardia and myocardial contractility. Conversely, dobutamine-induced increases in cardiac output may indirectly lead to a decrease in heart rate in heart failure patients as sympathetic nervous system tone is reduced. Similarly, systemic vascular resistance may decrease by reflex withdrawal of sympathetic tone in addition to dobutamine’s β2agonist effect. Myocardial oxygen consumption may also be reduced with improved contractility, decreased left ventricular end diastolic pressure (LVEDP), and decreased wall tension.
Dobutamine causes modest reductions in pulmonary arterial pressure and vascular resistance through its effects on β2 receptors. In patients with increased pulmonary artery pressure after mitral valve replacement, an infusion of dobutamine (up to 10 µg/kg/minute) increases cardiac output and decreases systemic and pulmonary vascular resistance.59 Dobutamine inhibits hypoxic pulmonary vasoconstriction. Pulmonary vasodilation may worsen ventilation/perfusion mismatching and may be associated with increased intrapulmonary shunt flow.59
Unlike dopamine, dobutamine does not act indirectly by stimulating the release of endogenous norepinephrine.52 Dobutamine does not activate dopaminergic receptors to increase renal blood flow. Renal blood flow, however, may improve as a result of drug-induced increases in cardiac output.60 Dobutamine but not dopamine is a coronary artery vasodilator. Redistribution of cardiac output in the presence of dobutamine may contribute to increased cutaneous heat loss manifesting as an additional decrease in body temperature.61
Rapid metabolism of dobutamine (half-life of 2 minutes) necessitates its administration as a continuous infusion of 2 to 10 µg/kg/minute to maintain therapeutic plasma concentrations. Tachyphylaxis may occur as it acts on β-adrenergic receptors. Like dopamine, dobutamine should be dissolved in 5% glucose in water for infusion to avoid inactivation of the catecholamine that may occur in an alkaline solution. Dobutamine undergoes biotransformation in the liver to inactive glucuronide conjugates and 3-0-methyldobutamine, most of which is excreted in the urine.62
Clinical Uses
Dobutamine produces potent β-adrenergic agonist effects at doses less than 5 µg/kg/minute IV increasing myocardial contractility (β1 and α1 receptors) and causing a modest degree of peripheral vasodilation (β2 receptors). The levorotatory isomer of dobutamine stimulates α1 receptors at higher doses (>5 µg/kg/minute) limiting further vasodilation. Individual variations exist with dose-dependent effects. Dobutamine is used to improve cardiac output in patients with congestive heart failure.60,63 Dobutamine is also useful for weaning from cardiopulmonary bypass.58 It may be of use in patients with pulmonary hypertension, although its effect on the pulmonary vasculature is less than that of the phosphodiesterase inhibitors. Combinations of drugs may be useful to increase the spectrum of activity and improve the distribution of cardiac output. For example, vasodilators may be combined with dobutamine or dopamine to decrease afterload, optimizing cardiac output in the presence of increased systemic vascular resistance. Most studies demonstrate minimal hemodynamic difference between dopamine and dobutamine use.21 Dobutamine does not have significant venoconstrictor activity compared to dopamine, so increase in ventricular filling pressures may be seen at low doses.
When used in the context of ischemia as opposed to heart failure, the reduction in filling pressures and oxygen requirements from the increased contractility is not offset by the increased tachycardia. Myocardial oxygen consumption is increased by the increasing tachycardia and contractility, whereas coronary blood flow is decreased by vasodilation.62 These properties make dobutamine useful for pharmacologic stress testing to detect potential areas of myocardial ischemia.
Adverse Effects
The use of dobutamine may be limited by the occurrence of tachyarrhythmias, although it is less likely than dopamine or isoproterenol. Sinus tachycardia occurs most commonly, although ventricular arrhythmias may also occur.38Tachyarrhythmias occur more frequently at higher dosages or in patients with underlying arrhythmias or heart failure. Also, prolonged continuous infusion of dobutamine associated with eosinophilic myocarditis and peripheral eosinophilia have been reported.
Synthetic Noncatecholamines
The commonly used noncatecholamine sympathomimetic drugs are ephedrine and phenylephrine (Fig. 18-5). These will be familiar to every reader.
Ephedrine
Ephedrine is an indirect-acting synthetic sympathomimetic that stimulates α- and β-adrenergic receptors. The pharmacologic effects of ephedrine are partly due to direct stimulation of adrenergic receptors (direct-acting)64 and partly due to stimulation of release of endogenous norepinephrine (indirect-acting). Ephedrine is resistant to metabolism by monoamine oxidase (MAO) in the gastrointestinal tract, thus permitting unchanged drug to be absorbed into the circulation after oral administration. Intramuscular injection of ephedrine is clinically acceptable because drug-induced local vasoconstriction is insufficient to delay systemic absorption or lead to tissue injury.
Up to 40% of a single dose of ephedrine is excreted unchanged in urine. Some ephedrine is deaminated by MAO in the liver, and hepatic conjugation also occurs. The slow inactivation and excretion of ephedrine are responsible for the prolonged duration of action of this sympathomimetic.
Ephedrine, unlike epinephrine, does not produce marked hyperglycemia. Mydriasis accompanies the administration of ephedrine, and CNS stimulation does occur, although less than that produced by amphetamine.
Clinical Uses
Ephedrine, 5 to 10 mg IV administered to adults, is a commonly selected sympathomimetic to increase systemic blood pressure in the presence of sympathetic nervous system blockade produced by regional anesthesia or hypotension due to inhaled or injected anesthetics. In an animal model, ephedrine more specifically corrected the noncardiac circulatory changes produced by spinal anesthesia than did a selective α or β agonist drug.65 Until recently, ephedrine was considered the preferred sympathomimetic for administration to parturients experiencing decreased systemic blood pressure owing to spinal or epidural anesthesia. Support for this practice was the observation in pregnant ewes that uterine blood flow was not greatly altered when ephedrine was administered to restore maternal blood pressure to normal after production of sympathetic nervous system blockade.66,67 Recent reviews of trials of ephedrine versus phenylephrine have concluded that systemic blood pressure control is similar with both drugs but phenylephrine is associated with a higher umbilical artery pH at delivery than ephedrine.68 Administration of phenylephrine by infusion during cesarean section to maintain maternal systolic blood pressure at baseline is associated with a lower incidence of fetal acidosis than is ephedrine.69 Based on these data, it seems that α agonists such as phenylephrine may be preferable to ephedrine for treatment of maternal hypotension.
Ephedrine can be used as chronic oral medication to treat bronchial asthma because of its bronchodilating effects by activation of β2-adrenergic receptors. Compared with epinephrine, the onset of action of ephedrine is slow, becoming complete only 1 hour or more after administration. A decongestant effect accompanying oral administration of ephedrine produces symptomatic relief from acute coryza. Ephedrine, 0.5 mg/kg intramuscularly, has an antiemetic effect similar to that of droperidol but with less sedation when administered to patients undergoing outpatient laparoscopy using general anesthesia.70
Cardiovascular Effects
The cardiovascular effects of ephedrine resemble those of epinephrine, but its systemic blood pressure–elevating response is less intense and lasts approximately 10 times longer. Intravenous ephedrine results in increases in systolic and diastolic blood pressure, heart rate, and cardiac output. Renal and splanchnic blood flows are decreased, whereas coronary and skeletal muscle blood flows are increased. Systemic vascular resistance may be altered minimally because vasoconstriction in some vascular beds is offset by vasodilation (β2 stimulation) in other areas. These cardiovascular effects are due, in part, to α receptor–mediated peripheral arterial and venous vasoconstriction. The principal mechanism, however, for cardiovascular effects produced by ephedrine is increased myocardial contractility due to activation of β1receptors. In the presence of preexisting β-adrenergic blockade, the cardiovascular effects of ephedrine may resemble responses more typical of α-adrenergic receptor stimulation.
A second dose of ephedrine produces a less intense systemic blood pressure response than the first dose. This phenomenon, known as tachyphylaxis, occurs with many sympathomimetics. Tachyphylaxis to ephedrine appears to involve α receptor inhibition.64
Phenylephrine
Phenylephrine, 3-hydroxyphenylethylamine, is a synthetic noncatecholamine. Phenylephrine differs from epinephrine only in lacking a 4-hydroxyl group on the benzene ring. Clinically, phenylephrine mimics the effects of norepinephrine but is less potent and longer lasting. Phenylephrine principally stimulates α1-adrenergic receptors by a direct effect, with only a small part of the pharmacologic response being due to its ability to evoke the release of norepinephrine (indirect-acting).71 Phenylephrine exerts minimal effects on β-adrenergic receptors. The dose of phenylephrine necessary to stimulate α1 receptors is far less than the dose that stimulates α2 receptors. Phenylephrine primarily causes venoconstriction rather than arterial constriction. CNS stimulation is minimal.
Clinical Uses
Phenylephrine, 50 to 200 µg IV bolus, is often administered to adults to treat systemic blood pressure decreases that accompany sympathetic nervous system blockade produced by a regional anesthetic and peripheral vasodilation following administration of injected or inhaled anesthetics.72 Phenylephrine is believed to be particularly useful in patients with coronary artery disease and in patients with aortic stenosis because it increases coronary perfusion pressure without chronotropic side effects, unlike most other sympathomimetics.
Phenylephrine has been used as a continuous infusion (20 to 100 µg per minute) in adults to maintain normal blood pressure during surgery. The reflex vagal effects produced by phenylephrine can be used to slow heart rate in the presence of hemodynamically significant supraventricular tachydysrhythmias.
Phenylephrine sufficient to increase systemic blood pressure in combination with inhaled nitric oxide results in a greater improvement in arterial oxygenation than with either drug alone.73
Topically applied, phenylephrine is a widely available nasal decongestant, usually with the brand name Neo-Synephrine. The nasal spray is a 1% solution, the same concentration as the undilutedphenylephrine ampule in the operating room. Intense nasal vasoconstriction precludes rapid absorption in awake subjects but must be used very cautiously if applied to the surgical field.74
Cardiovascular Effects
Rapid IV injection of phenylephrine to patients with coronary artery disease produces dose-dependent peripheral vasoconstriction and increases in systemic blood pressure, which are accompanied by decreases in cardiac output (Fig. 18-6).75 Decreases in cardiac output may reflect increased afterload but more likely are due to baroreceptor-mediated reflex bradycardia in response to drug-induced increases in diastolic blood pressure. It is possible that decreases in cardiac output could limit the associated increases in systemic blood pressure. Rapid administration of phenylephrine, 1 µg/kg IV, to anesthetized patients with coronary artery disease causes a transient impairment of left ventricular global function.76 Oral clonidine premedication augments the pressor response to phenylephrine, presumably due to clonidine-induced potentiation of α1-mediated vasoconstriction.77 Renal, splanchnic, and cutaneous blood flows are decreased but coronary blood flow is increased. Pulmonary artery pressure is increased by phenylephrine.
Metabolic Effects
Stimulation of α receptors by a continuous infusion of phenylephrine during acute potassium loading interferes with the movement of potassium ions across cell membranes into cells (Fig. 18-7).78Administration of phenylephrine in the absence of an acute potassium load does not change the plasma potassium concentration. This effect of α-adrenergic stimulation on movement of potassium ions across cell membranes is opposite to that produced by β2 receptor stimulation (see Fig. 18-2).8
Treatment of Overdose
Systemic manifestations of sympathetic nervous system activation (systemic hypertension, tachycardia, baroreceptor-mediated bradycardia) may accompany vascular absorption of α agonists (phenylephrine, epinephrine) when used as topical or injected vasoconstrictors in the surgical field.74 Phentolamine, an α1-adrenergic receptor antagonist, is an appropriate pharmacologic choice for phenylephrine toxicity.79β2 receptor blockade increases peripheral vascular resistance. Additionally, phenylephrine overdose preferentially distributes blood to the pulmonary vascular beds. The natural protection of the pulmonary vascular overload is to maintain cardiac output. Since β1 receptor blockades reduces cardiac output, treatment of phenylephrine-induced hypertensive crisis with β-adrenergic blocking drugs is contraindicated. Case reports document that β-adrenergic blockade presages pulmonary edema and irreversible cardiovascular collapse in these cases.74
However, systemic hypertension induced by intravenously administered α agonists may not require treatment. The duration of action of IV phenylephrine and epinephrine is brief and hypertension may resolve spontaneously without pharmacologic interventions. Severe hypertension may require pharmacologic interventions but treatment must not decrease the ability of the stressed myocardium to increase contractility and heart rate. In this circumstance, vasodilating drugs such as nitroprusside or nitroglycerin may be helpful, along with phentolamine as noted earlier.
Selective β2-Adrenergic Agonists
Selective β2-adrenergic agonists relax bronchiole and uterine smooth muscle but in contrast to isoproterenol generally lack stimulating (β1) effects on the heart. Nevertheless, high concentrations of these drugs are likely to cause stimulation of β1 receptors. The chemical structure of selective β2-adrenergic agonists (placement of hydroxyl groups on the benzene ring at sites different than the catecholamines) renders them resistant to methylation by COMT, thus contributing to their sustained duration of action. The commonly used β2-adrenergic agonists are albuterol, metaproterenol, and terbutaline (Fig. 18-8) (Table 18-2).
Clinical Uses
β2-Adrenergic agonists are the preferred treatment for acute episodes of asthma and the prevention of exercise-induced asthma.80 Currently used β2-adrenergic agonists may be divided into those with an intermediate duration of action (3 to 6 hours) and those that are long-acting (>12 hours).80 Among the intermediate-acting drugs, there is little reason to choose one over the other. β2-Adrenergic agonists are also used regularly in patients with chronic obstructive pulmonary disease, resulting in improved air flow and exercise tolerance. The long-acting β2-adrenergic agonist salmeterol is highly lipophilic and has a high affinity for the β2 receptor, resulting in prolonged activation at this site. In addition to the treatment of bronchospasm, β2-adrenergic agonists may also be administered as continuous infusions to stop premature uterine contractions (tocolytics).
Route of Administration
β2-Adrenergic bronchodilators can be administered orally, by inhalation, subcutaneously, or via IV injection. The inhaled route is preferred because the side effects are fewer for any given degree of bronchodilation. Inhalation is as effective as parenteral administration for treating acute, severe attacks of asthma in most patients, although some who have severe bronchial obstruction may benefit initially from parenteral therapy.
Inhaled β2-adrenergic agonists can be administered as an aerosol from a jet or ultrasonic nebulizer, or they can be administered from a metered-dose inhaler either as a propellant-generated aerosol or as a breath-propelled dry powder. With optimal inhalation technique (discharge the inhaler while taking a slow deep breath over 5 to 6 seconds, and then hold the breath at full inspiration for 10 seconds), approximately 12% of the drug is delivered from the metered-dose inhaler to the lungs; the remainder is deposited in the mouth, pharynx, and larynx.80 The presence of an endotracheal tube decreases by approximately 50% to 70% the amount of drug delivered by a metered-dose inhaler that reaches the trachea.81 Actuation of the metered-dose inhaler during a mechanically delivered inspiration increases the amount of drug that passes beyond the distal end of the tracheal tube. In general, the dose required in a nebulizer is 6 to 10 times that used in a metered-dose inhaler to produce the same degree of bronchodilation.
Side Effects
The widespread distribution of β2-adrenergic receptors makes it likely that undesired responses may result when β2-adrenergic agonists undergo systemic absorption. The ability to minimize these systemic side effects by decreasing plasma drug concentrations is an advantage of administering β2-adrenergic bronchodilators by inhalation.
The principal side effect in awake subjects of β2-adrenergic agonists treatment is tremor, which is caused by direct stimulation of β2 receptors in skeletal muscles. Increased heart rate is less common with the selective β2-adrenergic agonists, but even stimulation of β2 receptors may result in vasodilation and reflex tachycardia. As there are β2-adrenergic receptors in the heart, direct stimulation of the heart results from the use of selective β2-adrenergic agonists. In patients with acute, severe asthma, β2-adrenergic agonists may cause a transient decrease in arterial oxygenation presumed to reflect relaxation of compensatory vasoconstriction in areas of decreased ventilation. This is not a serious problem if supplemental oxygen is administered. Increased mortality in patients with severe asthma treated with β2-adrenergic agonists is most likely a reflection of the severity of the asthma rather than a toxic effect of the drug therapy.82,83
Acute metabolic responses to β2-adrenergic agonists include hyperglycemia, hypokalemia, and hypomagnesemia. Because these responses diminish with chronic administration, such changes are not important in patients receiving long-term therapy. Lactic acidosis may occur in association with β2 agonist therapy, perhaps reflecting excess glycogenolysis and lipolysis from β2 receptor activation.84
Albuterol
Albuterol, known as salbutamol outside the United States, is the preferred selective β2-adrenergic agonist for the treatment of acute bronchospasm due to asthma. Administration is most often by metered-dose inhaler, producing about 100 µg per puff; the usual dose is two puffs delivered during deep inhalations 1 to 5 minutes apart. This dose may be repeated every 4 to 6 hours, not to exceed 16 to 20 puffs daily. Alternatively, 2.5 to 5 mg of albuterol (0.5 to 1 mL of 0.5% solution in 5 mL of normal saline) may be administered by nebulization every 15 minutes for three to four doses, followed by treatments hourly during the initial hours of therapy. The duration of action of an inhaled dose is about 4 hours, but significant relief of symptoms may persist up to 8 hours. The effects of albuterol and volatile anesthetics on bronchomotor tone are additive.85
Continuous nebulization of albuterol using a large reservoir system to deliver up to 15 mg per hour for 2 hours may be appropriate and necessary in the presence of life-threatening asthma. Tachycardia and hypokalemia may accompany these large doses of albuterol. Nevertheless, larger doses and more frequent dosing intervals for inhaled β-adrenergic agonist therapy are needed in acute severe asthma due to decreased deposition at the site of action (low tidal volumes and narrowed airways), alteration in the dose-response curve, and altered duration of activity. Inhaled albuterol (four puffs) blunts airway responses to tracheal intubation in asthmatic patients.86
Metaproterenol
Metaproterenol is a selective β2-adrenergic agonist used to treat asthma. Administered by metered-dose inhaler, the daily dosage should not exceed 16 puffs, with each metered-aerosol actuation delivering approximately 650 µg. Oral administration is followed by excretion as conjugates of glucuronic acid.
Terbutaline
Terbutaline is a predominantly β2-adrenergic agonist that may be administered orally, subcutaneously, or by inhalation to treat asthma. The subcutaneous administration of terbutaline (0.25 mg) produces responses that resemble those of epinephrine, but the duration of action is longer. The subcutaneous dose of terbutaline for children is 0.01 mg/kg. Administered by metered-dose inhaler, the daily dose should not exceed 16 to 20 puffs, with each metered-dose actuation delivering about 200 µg.
Cardiac Glycosides
Digitalis is the term used for cardiac glycosides that occur naturally in many plants, including the foxglove plant. Digoxin, digitoxin, and ouabain are examples of clinically useful cardiac glycosides (Fig. 18-9). Of these, only digoxin remains commonly used.
Digoxin
Digoxin is used most often during the perioperative period for the management of supraventricular tachydysrhythmias (paroxysmal atrial tachycardia, atrial fibrillation, atrial flutter) associated with a rapid ventricular response rate based on the ability of these drugs to slow conduction of cardiac impulses through the atrioventricular node. The use of digoxin to treat acute decreases in left ventricular contractility is uncommon because of the availability of more potent and less toxic drugs. For example, patients treated with digoxin have a decreased risk of death from heart failure but an increased incidence of sudden death, presumably due to cardiac dysrhythmias (similar to increased risk of sudden death described for other positive inotropic drugs).87,88 Based on this observation, digoxin may be selected only for treatment of symptoms that persist after administration of drugs (angiotensin-converting enzyme inhibitors, β-adrenergic antagonists) that do decrease overall mortality.87 Nevertheless, digoxin continues to have an important therapeutic role in the treatment of chronic congestive heart failure. Digoxin may not be of benefit in high-output cardiac failure, such as that caused by hyperthyroidism or thiamine deficiency.
Intravenous administration of propranolol or esmolol combined with digoxin may provide more rapid control of supraventricular tachydysrhythmias and minimize the likelihood of toxicity by permitting decreases in the dose of both classes of drugs. Direct current cardioversion in the presence of digoxin may be hazardous because of increased risk of developing cardiac dysrhythmias, including ventricular fibrillation. In approximately 30% of patients with Wolff-Parkinson-White syndrome, digitalis decreases refractoriness in the accessory conduction pathway to the point that rapid atrial impulses can cause ventricular fibrillation. Digoxin may be harmful in patients with hypertrophic subaortic stenosis because increased myocardial contractility intensifies the resistance to ventricular ejection.
Pharmacokinetics
The bioavailability of oral digoxin is 60% to 80%.89,90 In some patients, the digoxin levels may be reduced by up to 40% due to digestion by colonic bacteria (see product monograph). Peak plasma concentrations are observed 1 to 3 hours following oral administration. Following IV administration, the bioavailability is 100%, and peak plasma concentrations are observed immediately following administration as expected for all drugs. Digoxin is eliminated almost entirely by renal excretion, with a half-life of 1 to 2 days. The half-life is inversely proportional to glomerular filtration rate and thus increases with age or renal disease.
Figure 18-10 shows the plasma and effect site time course of 0.5 mg of digoxin, given either orally (Fig. 18-10A) or intravenously (Fig. 18-10B), based on the pharmacokinetic model of Jelliffe et al.91 The time course of digoxin is reflected in the effect site concentration, shown in red, rather than the plasma concentration, shown in blue. The effect site is thought to include the myocardium, along with most other tissues.
The onset time for oral digoxin is 0.5 to 2 hours, with a peak effect about 6 hours after ingestion. With IV use, the onset time is 10 to 30 minutes, with a peak effect 2 to 4 hours after administration. After achievement of therapeutic plasma concentrations of digoxin by either the oral or IV route, the maintenance oral dose is adjusted according to the individual patient’s response, the electrocardiogram (ECG), and the plasma concentration of digoxin.
Mechanism of Action
The complex mechanisms of the positive inotropic effect evoked by cardiac glycosides includes direct effects on the heart that modify its electrical and mechanical activity and indirect effects evoked by reflex alterations in autonomic nervous system activity. Cardiac glycosides selectively and reversibly inhibit the Na+–K+ ATPase ion transport system (sodium pump) located in the sarcolemma (cell wall) of cardiac cells. Cardiac glycosides bind to the α subunit on the extracellular surface of the ATPase enzyme, inducing a conformational change that interferes with outward transport of sodium ions across cardiac cell membranes. The result is an increase in intercellular sodium. A second transporter is the sodium–calcium exchanger, which transports calcium out of the cell in exchange for sodium. Intracellular sodium accumulates when the sodium–potassium exchanger is blocked by cardiac glycosides. The resulting increase in cellular sodium ion concentration in turn blocks the sodium–calcium exchanger and increases intracellular calcium. Increased intracellular calcium is the primary mechanism of inotropic action for digitalis and related cardiac glycosides. The positive inotropic effects produced by cardiac glycosides occur without changes in heart rate and are associated with decreases in left ventricular preload, afterload, wall tension, and oxygen consumption in the failing heart.92
The principal cardiovascular effect of digitalis glycosides administered to patients with cardiac failure is a dose-dependent increase in myocardial contractility that becomes significant with less than full digitalizing doses. The positive inotropic effect manifests as increased stroke volume, decreased heart size, and decreased LVEDP. Indeed, cardiac glycosides can double stroke volume from a failing and dilated left ventricle. The ventricular function curve (Frank-Starling curve) is shifted to the left (Fig. 18-11). Improved renal perfusion due to an overall increase in cardiac output favors mobilization and excretion of edema fluid, accounting for the diuresis that often accompanies the administration of cardiac glycosides to patients in cardiac failure. Excessive sympathetic nervous system activity that occurs as a compensatory response to cardiac failure is decreased with the improved circulation that accompanies administration of cardiac glycosides. The resulting decrease in systemic vascular resistance further enhances forward left ventricular stroke volume.
Cardiac glycosides also increase myocardial contractility in the absence of cardiac failure. Nevertheless, the resulting tendency for cardiac output to increase may be offset by decreases in heart rate and direct vasoconstricting effects of cardiac glycosides on arterial, and to a lesser extent, venous smooth muscle. Indeed, cardiac output is often unchanged or even decreased when cardiac glycosides are administered to patients with normal hearts.
In addition to positive inotropic effects, cardiac glycosides enhance parasympathetic nervous system activity, leading to delayed conduction of cardiac impulses through the atrioventricular node and decreases in heart rate. The magnitude of this negative dromotropic and chronotropic effect depends on the preexisting activity of the autonomic nervous system. Increased parasympathetic nervous system activity decreases contractility in the atria, but direct positive inotropic effects of cardiac glycosides more than offset these nervous system–induced negative inotropic effects on the ventricles.
The electrophysiologic effects of therapeutic plasma concentrations of cardiac glycosides manifest on the ECG as (a) prolonged P-R intervals due to delayed conduction of cardiac impulses through the atrioventricular node, (b) shortened QTc intervals because of more rapid ventricular repolarization, (c) ST segment depression (scaphoid or scooped-out) due to a decreased slope of phase 3 depolarization of cardiac action potentials, and (d) diminished amplitude or inversion of T waves. The P-R interval is rarely prolonged to longer than 0.25 second, and the effect on the QTc interval is independent of parasympathetic nervous system activity. Changes in the ST segment and T wave do not correlate with therapeutic plasma concentrations of cardiac glycosides. Furthermore, ST-segment and T-wave changes on the ECG may suggest myocardial ischemia. When digitalis is discontinued, the changes on the ECG disappear in several weeks.
Toxicity
Cardiac glycosides have a narrow therapeutic range. Indeed, it is estimated that approximately 20% of patients who are being treated with cardiac glycosides experience some form of digitalis toxicity. The therapeutic effects of cardiac glycosides develop at approximately 35% of the fatal dose, and cardiac dysrhythmias typically manifest at approximately 60% of the fatal dose. The only difference between various cardiac glycosides when toxicity develops is the duration of adverse effects.
This increase in calcium responsible for the inotropic effects of digoxin are likely responsible for the arrhythmogenic effects as well.93 The increased calcium is stored in the sarcoplasmic reticulum. In the setting of myocardial sarcoplasmic reticulum calcium overload, calcium may be released in waves from the sarcoplasmic reticulum, resulting in delayed afterdepolarizations. If strong enough, delayed afterdepolarizations may result in myocardial action potentials and arrhythmias.
The most frequent cause of digitalis toxicity in the absence of renal dysfunction is the concurrent administration of diuretics that cause potassium depletion. During anesthesia, hyperventilation of the patient’s lungs can decrease the serum potassium concentration an average of 0.5 mEq/L for every 10 mm Hg decrease in PaCO2.94 Hypokalemia probably increases myocardial binding of cardiac glycosides, resulting in an excess drug effect. Indeed, binding of cardiac glycosides to the Na+–K+ ATPase enzyme complex is inhibited by increases in the plasma concentration of potassium. Other electrolyte abnormalities that contribute to digitalis toxicity include hypercalcemia and hypomagnesemia. An increase in sympathetic nervous system activity as produced by arterial hypoxemia increases the likelihood of digitalis toxicity.
Elderly patients with decreased renal function are vulnerable to the development of digitalis toxicity if usual doses of digoxin are administered. Impaired renal function and electrolyte changes (hypokalemia, hypomagnesemia) that may accompany cardiopulmonary bypass could predispose the patient to the development of digitalis toxicity.
Diagnosis
Digoxin is often administered in situations where digitalis toxicity is difficult to distinguish from the effects of the cardiac disease. For this reason, determination of the plasma digoxin concentration may be used to indicate the likely presence of digitalis toxicity. A plasma digoxin concentration of less than 0.5 ng/mL eliminates the possibility of digitalis toxicity. Plasma concentrations between 0.5 and 2.5 ng/mL are usually considered therapeutic, and levels greater than 3 ng/mL are in a toxic range. Infants and children have an increased tolerance to cardiac glycosides, and their range of therapeutic concentrations for digoxin is 2.5 to 3.5 ng/mL.
Anorexia, nausea, and vomiting are early manifestations of digitalis toxicity. These symptoms, when present preoperatively in patients receiving cardiac glycosides, should arouse suspicion of digitalis toxicity.
There are no unequivocal features on the ECG that confirm the presence of digitalis toxicity.95 Nevertheless, toxic plasma concentrations of digitalis typically cause atrial or ventricular cardiac dysrhythmias (increased automaticity) and delayed conduction of cardiac impulses through the atrioventricular node (prolonged P-R interval on the ECG), culminating in incomplete to complete heart block. Atrial tachycardia with block is the most common cardiac dysrhythmia attributed to digitalis toxicity. Activity of the sinoatrial node may also be directly inhibited by high doses of cardiac glycosides. Conduction of cardiac impulses through specialized conducting tissues of the ventricles is not altered, as evidenced by the failure of even toxic plasma concentrations of digoxin to alter the duration of the QRS complex on the ECG. Ventricular fibrillation is the most frequent cause of death from digitalis toxicity.
Treatment
Treatment of digitalis toxicity includes (a) correction of predisposing causes (hypokalemia, hypomagnesemia, arterial hypoxemia), (b) administration of drugs (phenytoin, lidocaine, atropine) to treat cardiac dysrhythmias, and (c) insertion of a temporary artificial transvenous cardiac pacemaker if complete heart block is present. Supplemental potassium decreases the binding of digitalis to cardiac muscle and directly antagonizes the cardiotoxic effects of cardiac glycosides. Serum potassium concentrations should be determined before treatment because supplemental potassium in the presence of a high preexisting plasma level of potassium will intensify atrioventricular block and depress the automaticity of ectopic pacemakers in the ventricles, leading to complete heart block. If renal function is normal and atrioventricular conduction block is not present, it is acceptable to administer potassium, 0.025 to 0.050 mEq/kg IV, to treat life-threatening cardiac dysrhythmias associated with digitalis toxicity, obviously with continuous ECG monitoring. Phenytoin (0.5 to 1.5 mg/kg IV over 5 minutes) or lidocaine (1 to 2 mg/kg IV) is effective in suppressing ventricular cardiac dysrhythmias caused by digitalis. Phenytoin is also effective in suppressing atrial dysrhythmias. Atropine, 35 to 70 µg/kg IV, can be administered to increase heart rate by offsetting excessive parasympathetic nervous system activity produced by toxic plasma concentrations of digitalis. Propranolol is effective in suppressing increased automaticity produced by digitalis toxicity, but its tendency to increase atrioventricular node refractoriness limits its usefulness when conduction blockade is present.
Life-threatening digitalis toxicity can be treated by administering digoxin antibodies,96 decreasing the plasma concentration of digoxin. The digoxin–antibody complex is eliminated by the kidneys.
Drug Interactions
Quinidine produces a dose-dependent increase in the plasma concentration of digoxin that becomes apparent within 24 hours after the first dose. This effect of quinidine may be due to displacement of digoxin from binding sites in tissues.
Succinylcholine, or any other drug that can abruptly increase parasympathetic nervous system activity, could theoretically have an additive effect with cardiac glycosides. Cardiac dysrhythmias also could reflect succinylcholine-induced catecholamine release and resulting cardiac irritability. Despite these theoretical concerns, clinical experience does not support the occurrence of an increased incidence of cardiac dysrhythmias in patients being treated with cardiac glycosides and receiving succinylcholine.97
Sympathomimetics with β-adrenergic agonist effects may increase the likelihood of cardiac dysrhythmias in the presence of cardiac glycosides.97 Intravenous administration of calcium may precipitate cardiac dysrhythmias in patients receiving cardiac glycosides. Any drug that facilitates renal loss of potassium increases the likelihood of hypokalemia and associated digitalis toxicity. The simultaneous administration of an oral antacid and digitalis decreases the gastrointestinal absorption of cardiac glycosides. Fentanyl, enflurane, and, to a lesser extent, isoflurane protect against digitalis-enhanced cardiac automaticity.98
Selective Phosphodiesterase Inhibitors
Phosphodiesterase inhibitors are a heterogeneous group of noncatecholamine nonglycoside compounds that exert a competitive inhibitory action on phosphodiesterase enzymes. Multiple types of phosphodiesterase enzymes exist in different tissues (cardiac muscle, vascular smooth muscle, platelets, liver, and lungs) possessing different cyclic nucleotide substrate specificity. Selective phosphodiesterase inhibitors exert different physiologic effects depending on their enzyme fraction specificity.99 Selective inhibitors of phosphodiesterase fraction III (PDE III) (Fig. 18-12) decrease the hydrolysis of cAMP, leading to increased intracellular concentrations of cAMP in the myocardium and vascular smooth muscle. They also have an indirect effect on cyclic guanosine monophosphate–dependent protein kinase in vascular smooth muscle. In myocardium, increased intracellular cAMP concentrations result in stimulation of protein kinases that phosphorylate the sarcoplasmic reticulum, increasing inward calcium current, increasing intracellular calcium and contractility. In vascular smooth muscle, increased cAMP decreases calcium available for contraction by facilitating the uptake of calcium by the sarcoplasmic reticulum, leading to smooth muscle relaxation and vasodilation. Although PDE III isoenzymes exist in airway smooth muscle, bronchodilation is not a predominant clinical effect of the current cardiac-selective PDE III inhibitors.
The overall effect of selective PDE III inhibitors is to combine positive inotropic effects with smooth muscle relaxation in both arteriolar and venous beds. Hence, they have been termed inodilators. Physiologic effects include increased contractility, increased cardiac output, and decreased LVEDP in addition to increased venous capacitance, decreased filling pressures (central venous pressure and pulmonary capillary wedge pressure), and decreased venous return to the heart. Mean pulmonary artery pressures and pulmonary and systemic vascular resistance are decreased. Selective PDE III inhibitors also improve the lusitropic state of the heart.100 Diastolic relaxation is facilitated by enhanced calcium removal from the sarcoplasm, thereby improving ventricular filling.
Selective PDE III inhibitors have mild effects on heart rate and mean arterial pressure having association with rare arrhythmias and some decrease in mean arterial pressure. These inodilators decrease preload and afterload. Hence theoretically, wall tension and myocardial oxygen consumption should decrease, in contrast to dobutamine, which increases myocardial oxygen consumption as it increases contractility. Wall tension decreases with decreasing ventricular volume and with decreasing afterload, and myocardial oxygen consumption depends primarily on heart rate, contractility, and ventricular wall tension.
Selective PDE III inhibitors act independently of β-adrenergic receptors and will increase myocardial contractility in patients with myocardial depression from β receptor blockade and in patients who have downregulation of β-adrenergic receptors and are refractory to catecholamine therapy. The effects of catecholamines, which also increase cAMP concentrations but through β-adrenergic stimulation, are potentially enhanced by PDE III inhibition. The hemodynamic response to selective PDE inhibitors exceeds that of cardiac glycosides and is synergistic to the actions of catecholamines. These drugs can be used in conjunction with digitalis without provoking digitalis toxicity. The PDE III inhibitors have their greatest clinical usefulness in patients who would benefit from combined inotropic and vasodilator therapy.
Amrinone (Inamrinone)
Amrinone is a bipyridine derivative that acts as a selective PDE III inhibitor and produces dose-dependent positive inotropic and vasodilator effects manifesting as increased cardiac output and decreased LVEDP.101 The name amrinone was changed to inamrinone in the United States in 2000 to avoid confusion with amiodarone, much to the confusion of those accustomed to the name amrinone.
Amrinone increases cardiac index, left ventricular stroke index, and left ventricular ejection fraction, decreasing LVEDP, pulmonary capillary wedge pressure, pulmonary artery pressure, right atrial pressure, and systemic vascular resistance, with minimal effect on heart rate.102 Depending on the cardiovascular status of the patient, amrinone may increase cardiac output either through its inotropic or vasodilating mechanisms.
Amrinone is subject to minimal protein binding and has a rapid distribution half-life of 1 to 2 minutes. The principal route of excretion is 26% to 40% unchanged drug in the urine with a large fraction undergoing N-acetylation and glucuronidation by the liver. The elimination half-time of amrinone in healthy patients is approximately 2.6 to 4.1 hours but may increase further in patients with severe heart failure.102
Amrinone is effective when administered orally as well as intravenously. However, oral administration is confounded by uncertainties in bioavailability as well as increased side effects with long-term oral use. Intravenous administration of a loading dose, 0.5 to 1.5 mg/kg, increases cardiac output within 5 minutes, with detectable positive inotropic effects persisting for approximately 2 hours. After the initial dose, a maintenance infusion of 2 to 10 µg/kg/minute produces positive inotropic effects that are maintained during the infusion (tachyphylaxis does not occur) and for several hours after discontinuation of the infusion. The recommended maximum daily dose is 10 mg/kg including the initial loading dose, which may be repeated 30 minutes after the first injection. Bolus administration should be administered slowly and carefully given the potential for hypotension.102 The dose should be decreased in patients with severe renal dysfunction. Patients who have failed to respond to catecholamines may respond to amrinone.
Side Effects
Hypotension from vasodilation, especially with rapid bolus administration, may occur and may be attenuated by slower administration or concomitant administration with vasopressors.
Dose-related thrombocytopenia may occur particularly with chronic oral therapy.103 cAMP in platelets acts as intracellular messengers inhibiting the platelet activation sequence at several steps. Oral amrinone has been associated with accelerated peripheral platelet loss. Although the mechanism is unclear, it is thought to be a non–immune-mediated effect of amrinone or its metabolites.104,105
Phosphodiesterase inhibitors are thought to possess rare clinically significant dysrhythmogenic properties. Increased myocardial calcium is known to promote the development of cardiac arrhythmias. Amrinone increases atrioventricular nodal conduction and decreases atrial refractoriness.38 It is difficult to assess in human studies whether arrhythmias are drug-induced or due to underlying ventricular dysfunction. Any proarrhythmic potential of amrinone appears to be dose-related and associated primarily with rapid IV administration.38 Chronic oral amrinone has been associated with gastrointestinal intolerances in animals, as well as hepatic dysfunction.
Milrinone
Milrinone is a bipyridine derivative of amrinone with almost 30 times the inotropic potency of amrinone but less adverse side effects. Because of its reduced incidence of side effects, milrinone has replaced amrinone in clinical use. Cardiac output improves both as a result of increased inotropy as well as vascular smooth muscle relaxation of peripheral and pulmonary vessel.106 Dose-dependent increases in cardiac index occur with minimal increases in myocardial oxygen consumption. Decreases in LVEDP, mean arterial pressure, central venous pressure, pulmonary artery occlusion pressure, pulmonary vascular resistance, and systemic vascular resistance occur as well as improvements in diastolic function.107
Milrinone is administered as an IV bolus of 50 µg/kg over 10 minutes followed by a continuous infusion of 0.375 to 0.75 µg/kg/minute to maintain plasma milrinone concentrations at or above therapeutic levels.108 A bolus dose of 50 µg/kg was found to be as effective as a dose of 75 µg/kg with fewer side effects and more effective than a dose of 25 µg/kg.109 The maximum daily dose of milrinone should not exceed 1.3 mg/kg/day. Approximately 70% of the drug in circulation is protein-bound. The elimination half-time is 2.7 hours and about 80% of the drug is excreted unchanged by the kidneys with a minor part undergoing glucuronide conjugation before excretion. The dose should be decreased in patients with severe renal dysfunction.
Clinical Uses
Milrinone may be useful in the management of acute left ventricular dysfunction such as after cardiac surgery. Successful weaning of high-risk patients from cardiopulmonary bypass may be enhanced by administration of milrinone.107,109–111 Milrinone may potentiate the effects of adrenergic agents as well as help increase inotropy in chronic heart failure patients who have downregulation of β1-adrenergic receptors. In patients with congestive heart failure, symptomatic and hemodynamic improvements as well as improvement in exercise have been reported, although milrinone use does not slow the natural progression of disease.112 Routine short-term milrinone treatment for acute exacerbation of chronic heart failure without hypotension from a low cardiac output state is not supported,113 although milrinone may be used as a bridge to orthotopic heart transplantation. It is particularly useful in the setting of pulmonary hypertension. Milrinone decreases pulmonary artery pressures more effectively than other positive inotropic agents, even dobutamine.114,115 The inotropic effects of milrinone are reduced by acidosis, presumably reflecting decreased cAMP formation in acidotic muscle.116
Both milrinone and dobutamine improve cardiac index and decrease cardiac filling pressures although milrinone may be more effective for the latter with significant reductions in right and left heart filling pressures. Milrinone is associated with more vasodilation and greater decreases in systemic vascular resistance and blood pressure than dobutamine. Unlike dobutamine, milrinone rarely causes tachycardia. Both agents may increase myocardial oxygen consumption with milrinone doing so to a lesser extent. The choice between dobutamine and milrinone may be based on hemodynamic differences. Milrinone may be preferred in situations with high filling pressures, elevated pulmonary artery pressure, need for continued β blockade, decreased responsiveness to catecholamine therapy, and increased risk for tachyarrhythmias. Dobutamine may be preferred in situations with significant vasodilation or renal dysfunction.
Milrinone has the additional role of being able to reverse vasospasm in arterial grafts.117 Milrinone is also thought to have antiinflammatory effects, and thus perioperative administration may dilate splanchnic vasculature and attenuate systemic inflammation in the acute phase response after cardiopulmonary bypass.118,119
Side Effects
Rapid administration of milrinone may decrease systemic vascular resistance, decrease venous return, and result in hypotension. The hypotension may be attenuated by slower bolus administration and concomitant administration with vasopressors.
Despite its beneficial hemodynamic actions, chronic oral therapy with milrinone may increase morbidity and mortality in patients with severe chronic heart failure and is not approved by the U.S. Food and Drug Administration (FDA) for this indication.112,120 The mechanism for this remains unknown although a proarrhythmic effect has been suggested. Rapid administration of large IV loading doses may also be associated with arrhythmias.109 Enhanced atrioventricular nodal conduction is its major electrophysiologic effect. Milrinone may also increase ventricular automaticity in ischemic myocardium.38 Ventricular and supraventricular arrhythmias have been reported with milrinone.111–113
Because of its higher potency, milrinone has less of an effect on platelets than amrinone. Although both agents inhibit in vitro platelet aggregation, short-term milrinone use did not cause significant changes in platelet number or function after cardiopulmonary bypass beyond the usual effects of cardiopulmonary bypass and cardiac surgery.121
Calcium
Calcium is present in the body in greater amounts than any other mineral. Calcium is important for (a) neuromuscular transmission, (b) skeletal muscle contraction, (c) cardiac muscle contractility, (d) blood coagulation, and (e) exocytosis necessary for release of neurotransmitters. In addition, calcium is the principal component of bone. The cytoplasmic concentration of ionized calcium is maintained at low levels by extrusion from the cells and sequestration of calcium ions within cellular organelles, particularly mitochondria, and in the sarcoplasmic reticulum of skeletal muscles. The large gradient for calcium across cell membranes is essential for calcium’s role in transmembrane signaling in response to various electrical or chemical stimuli.
Calcium is a potent inotrope. Increasing the plasma concentrations of ionized calcium with exogenous administration of calcium chloride or calcium gluconate is commonly used to treat cardiac depression as may accompany delivery of volatile anesthetics, transfusion of citrated blood, and following termination of cardiopulmonary bypass. Calcium is necessary for excitation-contraction coupling in vascular smooth muscle and may result in a vasoconstricting effect on coronary arteries that impairs coupling of coronary blood flow to augment myocardial oxygen demand.122
Calcium Measurement
The plasma concentration of calcium is maintained between 4.3 and 5.3 mEq/L (8.5 to 10.5 mg/dL) by endocrine control of ion transport in the kidney, intestine, and bone, mediated by vitamin D, parathyroid hormone, and calcitonin.123 Total plasma calcium consists of (a) calcium bound to albumin, (b) calcium complexed with citrate and phosphorus ions, and (c) freely diffusible ionized calcium. As would be expected, total plasma calcium decreases with low serum albumin and with hypophosphatemia.
It is the ionized calcium, and not the total plasma calcium, that produces the physiologic effects of calcium. Therefore, hypoalbuminemia and hypophosphatemia typically are not associated with signs of hypocalcemia. Conversely, large transfusions may be associated with acute hypocalcemia because of the binding of ionized calcium to the citrate anticoagulant.
Ionized calcium typically represents approximately 45% of the total plasma concentration. The ionized fraction of calcium changes with pH because calcium and hydrogen ions compete for the binding site on albumin. Acidosis increases ionized calcium, whereas alkalosis reduces ionized calcium.
Most laboratories now directly measure ionized calcium, the moiety of clinical interest.124 A normal plasma ionized calcium concentration is 1 to 1.26 mmol/L124,125 (2 to 2.5 mEq/L or 4 to 5 mg/dL).
Calcium Sensitizers
Levosimendan
Levosimendan is the first drug in a novel class of inotropes that increases contractility by increasing the sensitivity of the myocardium to calcium (Fig. 18-13). The inotropic enhancement is a result of binding of levosimendan to troponin C, increasing the sensitivity of troponin to calcium.126,127 Levosimendan also activates adenosine triphosphate–regulated potassium channels (KATP),128 causing vasodilation129and myocardial protection.130 As a result, cardiac output is increased with decreased systemic vascular resistance and pulmonary vascular resistance. Oral bioavailability is 85%. Metabolism is largely hepatic with renal excretion.
Levosimendan was developed with an indication for the treatment of cardiogenic shock. A reduction in 180-day mortality has not been demonstrated compared to dobutamine in a meta-analysis performed by the Cochrane collaboration.131 However, a more recent meta-analysis suggested improved survival for patients with chronic heart failure.132 There are also data suggesting that perioperative levosimendan reduces the risk of kidney injury following cardiac surgery.133 Levosimendan is approved in many countries but is not currently approved by the FDA in the United States.
Pharmacokinetics
Levosimendan is available as a solution for IV administration. The IV loading dose is 6 to 12 µg/kg given over 10 minutes, followed by an infusion of 0.05 to 2 µg/kg/minute.134 It has a half-life of about 1.5 hours. The clinical effects persist beyond the duration expected from the rapid half-life, likely the result of an active metabolite.135 Oral bioavailability is about 84%.136 Although oral administration has been studied, the drug is not available commercially in oral form.
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