Inotropic and vasoactive agents in the cardiac intensive care unit

CHAPTER 38 Inotropic and Vasoactive Agents in the Cardiac Intensive Care Unit Sympathomimetic Agents Phosphodiesterase Inhibitors Calcium Sensitizing Agents Other Parenteral Inotropes Vasodilators Ino.

Inotropic and Vasoactive Agents in the Cardiac Intensive Care Unit CHAPTER 38 Andreia Biolo, Wilson S Colucci, Michael M Givertz Sympathomimetic Agents Other Parenteral Inotropes Phosphodiesterase Inhibitors Vasodilators Calcium-Sensitizing Agents Inotropic and vasoactive agents often play an important role in the management of hemodynamic instability in the intensive care setting In this chapter, we discuss the relevant pharmacology and clinical indications for the parenteral inotropic, vasodilator, and vasoconstrictor agents most frequently used in the cardiac intensive care unit These agents are used to correct or stabilize hemodynamic function and, therefore, in many cases their proper selection and dosing requires hemodynamic information based on a pulmonary artery catheter, an intra-arterial pressure monitor, and electrocardiographic monitoring (Table 38-1) However, the use of a pulmonary artery catheter did not show benefit in either acute decompensated heart failure patients in the ESCAPE trial1 or a recent meta-analysis of 13 randomized trials including more than 5000 critically ill patients.2 This lack of benefit may result from the absence of effective strategies to use in combination with pulmonary artery catheter information These studies also demonstrated no increase in mortality or hospitalization associated with pulmonary artery catheter use Based on the available data, there is no indication for routine use of a pulmonary artery catheter in patients hospitalized with acute decompensated heart failure Nevertheless, a pulmonary artery catheter may provide valuable information and help guide therapy in specific situations (e.g., patients in whom congestion does not resolve after initial therapy, or in whom the presence of congestion is unclear or associated with worsening renal function) myocardial stimulation, but in addition may exert a mild vasoconstrictor effect due to stimulation of vascular α-adrenergic receptors At high doses of dopamine (i.e., to 20 μg/kg/min), the effect of peripheral α-adrenergic stimulation predominates, resulting in vasoconstriction in all vascular beds and leading to increases in mean arterial pressure and systemic vascular resistance At high doses, the vasoconstrictor effect overshadows the dopaminergic vasodilator effects, so that renal blood flow decreases and urine output may decline However, in patients with acute decompensated heart failure the dose required for improving systemic and renal hemodynamics may be higher (on the order of to μg/kg/min) than the usual “low dose” range, leading to the suggestion that severe heart failure may impair the renal effects of dopamine.5 Table 38-1.  Intravenous Drug Selection in Patients with Elevated Left Heart Filling Pressures and a Reduced Cardiac Output Low CO High PCWP SVR HIGH NORMAL LOW Initial Agents Nitroprusside Nitroglycerin Nesiritide Nitroprusside Milrinone Dobutamine/ Nitroprusside Dobutamine Dopamine Sympathomimetic Agents Dopamine Dopamine is the immediate precursor of epinephrine and norepinephrine It has both cardiac and vascular sites of action, depending in part on the dose used3,4 (Table 38-2) At low doses (i.e., to μg/kg/min), dopamine directly activates dopaminergic receptors in the kidney and splanchnic arteries, thereby causing vasodilation of these beds The resultant increase in renal blood flow leads to increased urine output and sodium excretion At moderate doses (i.e., to μg/kg/min), dopamine is a weak partial agonist at myocardial β1-receptors and causes the release of norepinephrine from sympathetic nerve terminals in the myocardium and vasculature The direct stimulation of myocardial β-adrenergic receptors exerts positive chronotropic and inotropic effects The increased release of norepinephrine from nerve terminals (a tyramine-like effect) also contributes to Table 38-2.  Receptor Activities of Several Sympathomimetic Agents Myocardial β1/β2 Vascular α1 β2 Dopaminergic Dobutamine +++ ++ ++ Dopamine (low dose) 0 +++ Dopamine (high dose) +++ +++ +++ Isoproterenol +++ +++ Norepinephrine +++ +++ + Dobutamine Dobutamine is a direct-acting synthetic sympathomimetic amine that stimulates β1-, β2-, and α-adrenergic receptors (see Table 38-2) Clinically, it is available as a racemic mixture in which the (+) enantiomer is both a β1- and β2-adrenergic receptor agonist and an α-adrenergic receptor competitive antagonist, and the (−) enantiomer is a potent β1-adrenergic receptor agonist and an α-adrenergic receptor partial agonist.13,14 The net effect of this pharmacologic profile is that dobutamine causes a relatively selective stimulation of β1-adrenergic receptors, and accordingly, dobutamine's primary cardiovascular effect is to increase cardiac output by increasing myocardial contractility This positive inotropic effect is associated with relatively little increase in heart rate The drug causes modest decreases in left ventricular filling pressure and systemic vascular resistance due to a combination of direct vascular effects and the withdrawal of sympathetic tone15 (see Table 38-3) Dobutamine also directly improves left ventricular relaxation (positive lusitropic effect) via stimulation of myocardial β-adrenergic receptors.16 Dobutamine has no effect on dopaminergic receptors and therefore no direct renal vasodilator effect However, renal blood flow often increases with dobutamine in proportion to the increase in cardiac output Pulmonary capillary wedge pressure (mm Hg) 90 8.0 80 70 2.0 4.0 2.5 6.0 5.0 10.0 7.5 30 8.0 28 26 6.0 4.0 24 22 20 18 2.0 2.5 16 5.0 7.5 10.0 14 Total systemic resistance (dynes/cm/sec–5) Given its varying actions, there are several potential uses for dopamine in the cardiac intensive care unit In patients with decompensated heart failure, dopamine is frequently used at low infusion rates to improve renal function by increasing renal blood flow.6,7 Increased water and sodium excretion results in a decrease in right and left ventricular filling pressures Low dose dopamine is frequently combined with one or more other inotropic (e.g., dobutamine) or vasodilator (e.g., nitroprusside) agents.8 In patients with severe compromise of the arterial pressure or frank cardiogenic shock, higher doses of dopamine are used to increase systemic vascular resistance At these higher doses, the increased left ventricular afterload is partially offset by the positive inotropic action In addition, when it is necessary to use vasoconstrictor doses of dopamine to manage systemic hypotension in the setting of myocardial failure, it is often useful to add dobutamine to augment the level of positive inotropic support beyond that provided by dopamine alone When used alone at vasoconstrictor doses in patients with left ventricular failure, dopamine may increase both left and right heart filling pressures9 (Fig 38-1 and Table 38-3) This effect reflects increased left and right ventricular afterload and increased peripheral venoconstriction, the latter causing increased return of venous blood to the heart To counteract these actions, high dose dopamine is sometimes combined with vasodilators (e.g., ­nitroglycerin).10 The inotropic responses to dopamine may be attenuated because of desensitization of the β-adrenergic pathway and depletion of myocardial catecholamine stores, both of which are common in patients with advanced heart failure.11,12 Although generally well tolerated at low doses, higher infusion rates of dopamine may result in unwanted sinus tachycardia and/or arrhythmias (supraventricular and ventricular) Other adverse effects of dopamine include digital gangrene in patients with underlying peripheral arterial disease, tissue necrosis at sites of infiltration, and nausea at high doses Local infiltration may be counteracted by the local injection of the α-adrenergic antagonist phentolamine Heart rate (beats/min) Inotropic and Vasoactive Agents in the Cardiac Intensive Care Unit 1600 8.0 1400 2.0 4.0 2.5 6.0 5.0 1200 7.5 10.0 1000 2.50 3.00 3.50 Cardiac index (L/min/m2) Figure 38-1.  Comparative effects of dopamine (•) and dobutamine (△) on heart rate, pulmonary capillary wedge pressure, and total systemic resistance in patients with moderate to severe heart failure Each agent was titrated over the doses shown These data illustrate that dopamine, when given alone at vasoconstrictor doses to patients with severe heart failure, increases left heart filling pressures (Adapted from Leier CV: Regional blood flow responses to vasodilators and inotropes in congestive heart failure Am J Cardiol 1988;62:86E.) Dobutamine is a valuable agent for the initial management of patients with acute or chronic systolic heart failure characterized by a low cardiac output.17 It is often initiated at an infusion rate of μg/kg/min (without a loading dose) and titrated upward by to μg/kg/min every 15 to 30 minutes until the hemodynamic 471 38 Pharmacologic Agents in the CICU Table 38-3.  Comparative Hemodynamic Effects of Commonly Used Positive Inotropic Agents + dP/dt PCWP SVR CO Dobutamine ↑↑ ↓ ↓ ↑ Dopamine (low dose) ↔ ↔ ↓ ↔↑ Dopamine (high dose) ↑↑ ↑ ↑↑ ↑↔↓ Milrinone ↑ ↓↓ ↓↓ ↑↑ Levosimendan ↑ ↓↓ ↓↓ ↑ goal is reached or a dose-limiting event, such as unacceptable tachycardia or arrhythmias, occurs Maximum effects are usually achieved at a dose of 10 to 15 μg/kg/min, although higher infusion rates may occasionally be used In patients with more severe decompensation, and presumably greater β-adrenergic receptor downregulation, dobutamine can be started at μg/ kg/min If the maximum tolerated infusion rate of dobutamine does not result in a sufficient increase in cardiac index, a second drug (e.g., milrinone) may be added.8,18 In patients with elevated systemic vascular resistance and/or left heart filling pressures, the co-administration of a vasodilator such as nitroprusside or nitroglycerin may be required In patients who remain hypotensive on dobutamine, consideration should be given to the addition of a pressor dose of dopamine and/or the use of mechanical circulatory support Other clinical situations in which dobutamine is effective include cardiogenic shock complicating acute myocardial infarction, low cardiac output following cardiopulmonary bypass, and as a “bridge” to cardiac transplantation.19 There is some evidence that short-term or intermittent infusions of dobutamine can result in sustained improvement in hemodynamics and functional status for days or weeks after the infusion is stopped.20-22 However, there are limited clinical data to suggest that the intermittent use of dobutamine either has no effect on outcomes23 or may increase mortality.24 As a result, the administration of dobutamine should be limited to the inpatient setting Dobutamine may increase heart rate, thereby limiting the dose that can be infused However, in some patients with very depressed cardiac output the improvement in hemodynamic function may cause a withdrawal of sympathetic tone such that heart rate falls Hypotension is uncommon, but can occur in patients who are hypovolemic Arrhythmias, including supraventricular and ventricular tachycardia, may limit the dose Likewise, myocardial ischemia secondary to increased myocardial oxygen consumption may occur Some patients with chronic severe heart failure may be tolerant to dobutamine, or tolerance to dobutamine may develop after several days of a continuous infusion.25 In this situation, the addition or substitution of a phosphodiesterase inhibitor may be helpful Hypersensitivity myocarditis has also been reported with chronic infusions of dobutamine and should be suspected if a patient develops worsening hemodynamics or peripheral eosinophilia Isoproterenol A synthetic sympathomimetic structurally related to epinephrine, isoproterenol is a nonselective β-adrenergic receptor agonist with little or no effect on α-receptors (see Table 38-2) 472 Its cardiovascular effects include increased myocardial contractility, heart rate, and atrioventricular conduction due to stimulation of myocardial β1- and β2-adrenergic receptors, and vasodilation of skeletal muscle and pulmonary vasculature due to stimulation of vascular β2-adrenergic receptors Isoproterenol increases cardiac output and lowers both systemic and pulmonary vascular resistance Because of its propensity to increase heart rate, isoproterenol has relatively limited applications in the cardiac intensive care unit However, isoproterenol may be useful in the management of torsades de pointes that is refractory to magnesium,26 inotropic and chronotropic support immediately following cardiac transplant,27 and treatment of pulmonary hypertension secondary to acute pulmonary embolism.28 Isoproterenol is usually administered as a continuous infusion at 0.5 to μg/min The dose of isoproterenol may be limited by tachycardia, increased myocardial oxygen consumption leading to ischemia, and atrial or ventricular arrhythmias Epinephrine Like isoproterenol, epinephrine stimulates β1- and β2-adrenergic receptors in the myocardium, thereby causing marked positive chronotropic and inotropic responses Unlike isoproterenol, it also has potent agonist effects at vascular α-adrenergic receptors causing increased arterial and venous constriction Because of this latter effect, epinephrine (like high-dose dopamine and norepinephrine) plays little role in the acute management of heart failure, except when complicated by severe hypotension Epinephrine may be useful for the treatment of low cardiac output, with or without bradycardia, immediately following cardiopulmonary bypass or cardiac transplantation.29 Continuous infusions may be started at a low dose (0.5 to μg/min), and titrated upwards to 10 μg/min, as needed The use of epinephrine may be limited by tachycardia, arrhythmias, increased myocardial oxygen consumption leading to ischemia, and oliguria from renal vasoconstriction In the setting of cardiac arrest, epinephrine may be used as per the Advanced Cardiac Life Support (ACLS) protocol (1 mg intravenous push or via endotracheal tube every to minutes) to manage ventricular fibrillation, pulseless ventricular tachycardia, asystole, or pulseless electrical activity.30 Epinephrine may also be infused at to 10 μg/min to manage symptomatic bradycardia that is unresponsive to atropine, while awaiting placement of an external or temporary transvenous pacemaker Norepinephrine The myocardial and peripheral vascular effects of this endogenous catecholamine are similar to those of epinephrine except that norepinephrine causes little stimulation of vascular β2adrenergic receptors and therefore causes more intense vasoconstriction (see Table 38-2) Norepinephrine may be used to provide temporary circulatory support in the setting of hemodynamically significant hypotension (e.g., following cardiac surgery or with cardiogenic shock complicating acute myocardial infarction or pulmonary embolism) Norepinephrine is titrated to improve blood pressure at doses of to 10 μg/min As with epinephrine, the use of norepinephrine in the cardiac intensive care unit may be limited by arrhythmias, myocardial ischemia, renal impairment, or tissue necrosis at the site of local infiltration If extravasation occurs, phentolamine to 10 mg may be infiltrated into the affected area Inotropic and Vasoactive Agents in the Cardiac Intensive Care Unit Phosphodiesterase Inhibitors The breakdown of cAMP is mediated by a membrane-bound enzyme, phosphodiesterase (PDE) In myocardium and vascular smooth muscle, the predominant isoform of this enzyme, termed type III, is inhibited by the type-III selective PDE inhibitors milrinone and inamrinone, leading to an increase in intracellular cAMP concentrations In the myocardium, intracellular cAMP increases both contractility and the rate of relaxation (positive lusitropic effect) PDE III inhibitors are also potent vasodilators in the systemic and pulmonary vasculature.31-33 In patients with acute decompensated heart failure, type III PDE inhibitors increase cardiac output by increasing stroke ­volume Balanced arterial and venous dilation cause decreases in right atrial, pulmonary artery, pulmonary capillary wedge, and mean arterial pressures Because PDE inhibitors exert both positive inotropic and vasodilator actions, their net hemodynamic effects differ from those of dobutamine and nitroprusside Thus, for a comparable increase in cardiac output, the PDE inhibitor milrinone decreases systemic vascular resistance and left ventricular filling pressure to a greater extent than dobutamine34 (Fig 38-2; see Table 38-3) Conversely, for a comparable decrease in arterial blood pressure, milrinone increases cardiac output to a greater extent than nitroprusside35 (Table 38-4) +40 % Change + dP/dt Dob MiI +20 PDE inhibitors are used for the treatment of heart failure characterized by low cardiac output, high filling pressures, and elevated or normal systemic vascular resistance They may also be useful in the management of low cardiac output following cardiopulmonary bypass and as a bridge to mechanical support or cardiac transplant,36 especially in patients tolerant of β-adrenergic agonists Chronic infusions of milrinone at home have also been used for palliative care in selected patients with end-stage heart failure The positive inotropic effects of these drugs are additive to those of digoxin and may be synergistic with those of sympathomimetics such as dobutamine37,38 (Fig 38-3) Milrinone In patients with heart failure, milrinone is administered as a 25 to 50 μg/kg intravenous bolus over 10 minutes followed by a constant infusion at 0.25 to 0.75 μg/kg/min Lower infusion rates without a bolus may be used in patients with low baseline blood pressure If a lower bolus dose (i.e., 25 μg/kg) is used to initiate therapy and the response is not adequate, a second bolus of 25 μg/kg may be given before increasing the infusion rate The dose of milrinone tolerated may be limited by tachycardia or tachyarrhythmias In addition, relatively volume-depleted patients may not tolerate its vasodilator effects and will experience symptomatic hypotension that may necessitate stopping the drug Thrombocytopenia is rarely seen with milrinone (less than 0.5%) Milrinone has a half-life of 30 to 60 minutes in patients with heart failure It can be used alone or in combination with other agents (e.g., dobutamine or nitroprusside) The routine use of milrinone was assessed in a study of 900 patients admitted to the hospital with an exacerbation of heart failure In this setting, a 48-hour infusion did not reduce the subsequent need for hospitalization and was associated with an increased risk of arrhythmias and sustained hypotension.39 Ntp –20 –40 % Change SVR Figure 38-2.  The relative effects of dobutamine (Dob), milrinone (Mil), and nitroprusside (Ntp) on left ventricular contractility, as reflected by peak +dP/dt, and systemic vascular resistance (SVR) in patients with severe heart failure (From Colucci WS, Wright RF, Jaski BE, et al: Milrinone and dobutamine in severe heart failure: ­differing hemodynamic effects and individual patient responsiveness Circulation 1986;73:III-175.) Table 38-4.  Comparative Hemodynamic Effects of Intravenous Vasodilators PCWP SVR 35 –60 CO Nitroprusside ↓↓ ↓↓ ↑ Nitroglycerin ↓↓ ↔↓ ↑↔↓ Milrinone ↓↓ ↓↓ ↑↑ Hydralazine ↓ ↓↓ ↔↑ ACE Inhibitor ↓↓ ↓↓ ↑ Nesiritide ↓↓ ↓↓ ↑ Stroke volume index (mL/m2) A+D D 30 A 25 C 20 15 Dobutamine Amrinone 10 10 15 20 25 30 35 Left ventricular end diastolic pressure (mm Hg) Figure 38-3.  Hemodynamic effects of dobutamine (D), amrinone (A), and the combination (A + D) in patients with moderate to severe heart failure As shown here, the additive effect of the two agents may exceed the effect of either agent alone C, hemodynamics during the control periods (Adapted from Gage J, Rutman H, Lucido D, LeJemtel TH: Additive effects of dobutamine and amrinone on myocardial contractility and ventricular performance in patients with severe heart failure Circulation 1986;74:367.) 473 38 Pharmacologic Agents in the CICU It is important to note that patients requiring inotropic support (with shock or severe hypotension) were excluded from this study Thus, milrinone, like dobutamine, should be reserved for the short-term management of patients with symptomatic hemodynamic compromise that is not responsive to diuretics and vasodilators Patients with pulmonary hypertension secondary to chronically elevated left heart filling pressures may be particularly responsive to milrinone The data from these trials suggest short-term symptomatic ­benefit with levosimendan in patients with acute decompensated heart failure, but no impact on survival compared with placebo Levosimendan may be useful in other situations, such as the perioperative and postoperative setting, acute coronary syndromes, and cardiogenic and septic shock.42 In addition to positive inotropic effects, levosimendan exerts dose-dependent lusitropic effects in failing hearts.49 Inamrinone Inamrinone is administered as an intravenous bolus of 0.5 to 0.75 mg/kg over to minutes, followed by a continuous infusion at to 10 μg/kg/min titrated to hemodynamic goals The major dose-limiting effects of inamrinone are similar to milrinone, and include tachycardia, atrial or ventricular arrhythmias, and hypotension The latter effect is most likely to occur in patients who are hypovolemic Thrombocytopenia, which is seldom severe, occurs in 2% to 3% of patients This effect is dose-dependent, occurring with higher doses and/or more prolonged infusions, and appears to be due to decreased platelet survival.40 Other adverse effects include liver function abnormalities, headache, and nausea Other Parenteral Inotropes Calcium-Sensitizing Agents Positive inotropic agents, such as dobutamine and milrinone, act by increasing myocyte calcium influx, and therefore may be associated with increased arrhythmias An alternative approach that may avoid such complications is to enhance myocardial response to a given concentration of calcium with a class of agents referred to as “calcium sensitizers.”41 Several calcium sensitizers have been studied in heart failure and acute coronary syndromes and most have additional effects such as phosphodiesterase inhibition that may contribute significantly to their clinical profile Levosimendan Levosimendan, the most widely studied calcium sensitizer,42 increases myocardial contractility by increasing myofilament sensitivity to calcium Levosimendan is also a potent vasodilator due to activation of adenosine triphosphate-dependent potassium channels in vascular smooth muscle cells, leading to decreases in both preload and afterload In patients with severe heart failure, levosimendan increases cardiac output and reduces pulmonary capillary wedge pressure and systemic vascular resistance (see Table 38-3).43,44 The effects of levosimendan are dose-dependent at infusion rates ranging from 0.05 to 0.6 μg/kg/min, with higher incidence of side effects (headache, nausea, and hypotension) at rates above 0.2 μg/kg/min.45 Levosimendan is completely metabolized before excretion Approximately 5% is converted to a highly active metabolite, OR-1896, that exhibits hemodynamic effects similar to those of levosimendan and has an elimination half-life of 75 to 80 hours (compared with hour for levosimendan itself ) Because of the long half-life of this active metabolite, hemodynamic effects last for up to to days after discontinuation of a 24-hour infusion of levosimendan.43 Several clinical trials have evaluated the efficacy of levosimendan in patients with acute decompensated heart failure, in comparison with placebo46 or dobutamine,47,48 and its use is approved in several European and South American countries 474 Digoxin Although digoxin can be given intravenously, it is seldom used as a positive inotropic agent in the acute management of heart failure Digoxin may be useful for the control of a rapid ventricular rate in patients with or without heart failure complicated by atrial fibrillation or atrial flutter Vasodilators For many patients with acute decompensated heart failure characterized hemodynamically by low cardiac output, high filling pressures and elevated systemic vascular resistance and/or clinically by symptomatic congestion with normal or elevated blood pressure, a parenteral vasodilator is the initial agent of choice As discussed later, intravenous vasodilators can be used alone or in combination with a positive inotropic agent (see Table 38-1) Nitroprusside Nitroprusside is a sodium salt consisting of ferricyanide and nitric acid Its reduction by intracellular glutathione leads to the local production of nitric oxide, which mediates the drug's potent vasodilator effect.50 The onset of action is rapid, in to minutes, making it an ideal agent for use in urgent situations which require rapid dose titration and a predictable hemodynamic effect Nitroprusside is both an arterial and venous dilator and, therefore, it reduces both filling pressures and vascular resistance (systemic and pulmonary) Stroke volume and cardiac output increase, and pulmonary artery, pulmonary capillary wedge, and right atrial pressures decrease (Fig 38-4) In patients with heart failure, heart rate is generally unchanged or may fall because of reflex sympathetic withdrawal.51 There are several indications for the use of nitroprusside in the cardiac intensive care unit.52 One indication is acute decompensated heart failure manifested by low cardiac output, elevated filling pressures, high systemic vascular resistance, and a systolic blood pressure adequate to maintain vital organ perfusion, usually greater than or equal to 90 mm Hg This hemodynamic picture is often seen with heart failure in the setting of acute myocardial infarction, acute mitral or aortic regurgitation, and fulminant myocarditis In acute myocardial infarction, nitroprusside may be particularly useful if the infarction is complicated by significant hypertension, mitral regurgitation secondary to papillary muscle rupture, or rupture of the ventricular septum.53 Acute valvular regurgitation secondary to endocarditis, aortic dissection, or ruptured chordae is another situation in which nitroprusside may be used effectively, often as a “bridge” to more definitive therapy (e.g., valve replacement or repair).54 A recent study showed increased cardiac output with nitroprusside administration in patients with severe aortic stenosis and left ventricular dysfunction occurring with severe heart failure, Inotropic and Vasoactive Agents in the Cardiac Intensive Care Unit N.S N.S 0.001 N.S 0.001 0.001 0.001 100 Mean arterial pressure (mm Hg) Cardiac index (L/min/m2) 3.5 0.05 3.0 2.5 2.0 1.5 1.0 0.5 0.001 0.001 N.S 0.03 90 80 70 60 50 40 30 20 10 B1 N B2 D B3 M B1 N B2 D B3 M N.S 0.005 N.S 30 0.01 0.001 35 0.01 0.001 0.001 25 20 15 10 Pulmonary capillary wedge pressure (mm Hg) Right arterial pressure (mm Hg) 35 0.001 0.001 N.S 0.001 30 25 20 15 10 B1 N B2 D B3 M B1 N B2 D B3 M Figure 38-4.  The comparative effects of nitroprusside (N), dobutamine (D), and milrinone (M) on cardiac index, mean arterial pressure, right atrial pressure, and pulmonary capillary wedge pressure in patients with severe heart failure.79 The agents were administered in doses that caused comparable increases in cardiac index Under these conditions, nitroprusside and milrinone significantly reduced mean arterial pressure, but dobutamine had no effect All three agents reduced right atrial pressure, although the effect of dobutamine was less pronounced Nitroprusside and milrinone significantly reduced pulmonary capillary wedge pressure, and this effect was significantly more pronounced than the effect of dobutamine B, baseline hemodynamics (Adapted from Monrad ES, Baim DS, Smith HS, Lanoue AS: Milrinone, dobutamine, and nitroprusside: comparative effects on hemodynamics and myocardial energetics in patients with severe congestive heart failure Circulation 1986;73:III-168.) suggesting it may also be useful in this context as a bridge to aortic valve replacement.55 Nitroprusside is also used in patients with chronic heart failure due to dilated cardiomyopathy, both to manage acute decompensation and to determine whether pulmonary hypertension is acutely reversible during the evaluation for cardiac transplantation.56,57 Following optimization of hemodynamics with intravenous nitroprusside and diuretic therapy, patients should be titrated on to oral vasodilator/diuretic therapy before discharge Finally, nitroprusside is often the parenteral agent of choice for treating hypertensive emergencies as it can be rapidly titrated to blood pressure goals.58 The infusion of nitroprusside should be guided by close hemodynamic monitoring, ideally with a pulmonary artery catheter and radial or femoral arterial line Nitroprusside may be started at a rate of 10 to 20 μg/min (or 0.1 to 0.2 μg/kg/min) and increased by 20 μg/min every to 15 minutes until the ­ emodynamic goal is achieved (e.g., a systemic vascular resish tance of 1000 to 1200 dynes-sec-cm–5 and a pulmonary capillary wedge pressure of less than or equal to 16 to 18 mm Hg) while maintaining an adequate systolic blood pressure (generally, >80 mm Hg) Doses of 300 μg/min (5 μg/kg/min) or higher are seldom required and increase the risk of toxicity Nitroprusside is a potent vasodilator and its use may be limited by hypotension In patients with underlying coronary artery disease, drug-induced hypotension accompanied by reflex tachycardia may worsen myocardial ischemia In patients with acute decompensated heart failure, hemodynamic deterioration may occur following the withdrawal of nitroprusside, apparently due to a transient “rebound” increase in systemic vascular tone.59 Other adverse effects of nitroprusside are due to the accumulation of its metabolites: cyanide and thiocyanate.60 The build-up of cyanide results in lactic acidosis and methemoglobinemia, and may manifest itself as nausea, restlessness, and dysphoria 475 38 Pharmacologic Agents in the CICU Cyanide toxicity is most likely to occur in patients with liver dysfunction or following prolonged infusions, but may occur even in patients with normal hepatic function who have received the drug for only a few hours If cyanide toxicity is suspected, serum levels should be drawn and the infusion stopped In severe cases, treatment with sodium nitrate, sodium thiosulfate, or vitamin B12 may be necessary Cyanide is converted in the liver to thiocyanate, which is cleared by the kidney The half-life of elimination of thiocyanate is to days Thiocyanate toxicity generally occurs gradually and is manifested by nausea, confusion, weakness, tremor, hyperreflexia and, rarely, coma Thiocyanate toxicity is more likely to occur in patients with renal dysfunction and with prolonged infusions or high rates of infusion If mild, it can be managed by cessation of the drug; in severe cases, hemodialysis may be necessary Nitroglycerin When administered parenterally, nitroglycerin has an immediate onset of action and a plasma half-life of to minutes It is cleared by vascular endothelium, hydrolyzed in the blood, and metabolized in the liver At lower infusion rates, its main cardiovascular effect is venodilation, with a resultant fall in ventricular volumes and filling pressures At higher infusion rates, nitroglycerin also causes arterial dilation, resulting in decreases in both pulmonary and systemic vascular resistance51 (see Table 38-4) Nitroglycerin plays several important roles in the cardiac intensive care unit.52 In the setting of cardiogenic pulmonary edema, especially when due to myocardial ischemia or infarction, nitroglycerin provides immediate symptomatic relief and improves both hemodynamics and oxygen saturation.61 By causing direct coronary vasodilation, nitroglycerin also has the theoretical advantage of improving myocardial perfusion and limiting infarct size.62 Intravenous nitroglycerin is often useful in the management of patients with new onset heart failure or acute decompensation of chronic heart failure, particularly in patients who are refractory to diuretic therapy and continue to manifest elevated right- and left-sided filling pressures, in patients with disproportionate right-sided failure, and in patients in whom nitroprusside is not tolerated Intravenous nitroglycerin is usually started at a low infusion rate of 20 to 30 μg/min, and increased by 10 to 20 μg/min every to 10 minutes until the desired response is observed or a dose of 400 μg/min is reached In patients with acute decompensated heart failure, upward titration should be guided by filling pressures and systemic vascular resistance or, if invasive monitoring is not available, by signs and symptoms of pulmonary and/or systemic venous congestion While awaiting intravenous access, nitroglycerin can be administered by the sublingual, buccal, or transdermal route Use of nitroglycerin may be limited by hypotension, which may require discontinuation of the drug and/or supportive care with intravenous fluids and leg elevation Other common side effects related to vasodilation include headache, flushing and diaphoresis Some patients with heart failure will not respond to the acute administration of nitroglycerin.63 This resistance is usually seen in patients with significant right-sided failure and peripheral edema, and often resolves following diuresis.64 In addition, patients may develop pharmacologic tolerance to nitroglycerin Strategies to prevent the development of such tolerance include avoidance of excessive dosing, limiting fluid retention, and the use of intermittent dosing.65,66 476 Nesiritide Nesiritide (recombinant human B-type natriuretic peptide) is identical to and mimics the actions of the endogenous BNP molecule Clinical studies with intravenous infusion of nesiri­ tide in patients with acute decompensated heart failure have shown that it exerts potent, dose-related vasodilator effects that are rapid in onset and sustained for the duration of drug infusion.67 Balanced arterial and venous vasodilation is reflected by decreases in systemic vascular resistance, systemic arterial pressure, pulmonary capillary wedge pressure, and right atrial pressure Vasodilation in the absence of symptomatic hypotension occurs without a change in heart rate and is associated with increases in stroke volume and cardiac output Administration of nesiritide in the short-term treatment of decompensated heart failure resulted in dose-dependent reductions in pulmonary capillary wedge pressure and improved clinical status compared with placebo.68 When compared with standard vasoactive therapy such as dobutamine, nesiritide produced a similar improvement in clinical status and dyspnea In another randomized, controlled trial, nesiritide reduced pulmonary capillary wedge pressure significantly more than nitroglycerin, and resulted in a similar improvement in dyspnea and clinical status.69 When compared with dobutamine, nesiritide is less likely to cause ventricular arrhythmias and may be associated with clinical benefit, including reduced 6-month mortality and a trend toward lower heart failure readmission rates.70,71 However, there has been concern about the possible adverse effects of nesiritide on survival and renal function Pooled meta-analyses found a trend to increased 30-day mortality and a greater degree of worsening renal function among patients treated with nesiritide.72,73 In general, nesiritide is given as an initial intravenous bolus of μg/kg, followed by a continuous infusion of 0.01 μg/kg/min For patients with systolic blood pressures between 90 and 100 mm Hg, it is more prudent to initiate nesiritide at a dose of 0.005 μg/ kg/min without a bolus In hypertensive patients or those with marked congestion, the dose may be increased (usually by 0.005 μg/kg/min, preceded by a bolus of μg/kg) if there is no therapeutic response, after to 24 hours, up to a maximum of 0.03 μg/kg/min The main adverse effect is dose-related hypotension If it occurs, the infusion should be discontinued and restarted when the blood pressure has stabilized, at a 30% to 50% lower dose without a repeat bolus Given the concerns about safety, nesiritide is reserved for patients with severe acute decompensated heart failure who remain dyspneic despite diuretics, and who are not hypotensive or in cardiogenic shock Hydralazine Hydralazine is a potent direct-acting arteriolar smooth muscle dilator that causes both pulmonary and systemic vasodilation Although nitroprusside and nitroglycerin are generally preferred as parenteral vasodilators in the acute management of heart failure, there are specific situations in which hydralazine given intravenously may be a useful or necessary alternative In particular, hydralazine may be useful in patients who have become toxic with nitroprusside or continue to have an elevated systemic vascular resistance despite the use of a maximally tolerated dose of nitroprusside or nitroglycerin In addition, hydralazine may be safely administered to pregnant women with heart failure74 or severe hypertension.75,76 Inotropic and Vasoactive Agents in the Cardiac Intensive Care Unit When used parenterally, hydralazine should be started at a low dose (5 mg given as an intravenous bolus every to hours), and increased gradually up to 25 to 30 mg, as tolerated The onset of action is rapid, and the magnitude of the hemodynamic effects may be unpredictable Patients should therefore be monitored with an intra-arterial line Nausea may be a limiting side effect in the acute setting Enalaprilat Enalapril, a commonly used oral angiotensin-converting enzyme inhibitor, is cleaved by plasma and tissue esterases to form enalaprilat, the active form of the drug When given parenterally, enalaprilat acts as a balanced vasodilator resulting in decreased right and left heart filling pressures.77 Enalaprilat is given as an intravenous bolus (0.625 to 1.25 mg every hours) Although the onset of action is rapid (minutes), the duration of effect is prolonged 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chronic heart failure J Am Coll Cardiol 1987;9:1131 78 Kiowski W, Beermann J, Rickenbacher P, et al: Angiotensinergic versus nonangiotensinergic hemodynamic effects of converting enzyme inhibition in patients with chronic heart failure Assessment by acute renin and converting enzyme inhibition Circulation 1994;90:2748 79 Monrad ES, Baim DS, Smith HS, et al: Milrinone, dobutamine, and nitroprusside: comparative effects on hemodynamics and myocardial energetics in patients with severe congestive heart failure Circulation 1986;73:III-168  ... Local infiltration may be counteracted by the local injection of the α-adrenergic antagonist phentolamine Heart rate (beats/min) Inotropic and Vasoactive Agents in the Cardiac Intensive Care Unit. .. extravasation occurs, phentolamine to 10 mg may be infiltrated into the affected area Inotropic and Vasoactive Agents in the Cardiac Intensive Care Unit Phosphodiesterase Inhibitors The breakdown of cAMP... occurring with severe heart failure, Inotropic and Vasoactive Agents in the Cardiac Intensive Care Unit N.S N.S 0.001 N.S 0.001 0.001 0.001 100 Mean arterial pressure (mm Hg) Cardiac index (L/min/m2)