Cardiovascular Pharmacology in Noncardiac Surgery

Phenylephrine

Phenylephrine is a widely used vasopressor in the operating room for the treatment of hypotension. The primary binding target of phenylephrine is the α-adrenergic receptor with the highest affinity for the α ₁ -receptor. Phenylephrine is an α ₁ selective agonist but may affect β-receptors in high doses. It is equipotent to norepinephrine but has a slightly longer duration of action. Binding of phenylephrine to the α ₁ receptor leads to a number of pharmacologic effects. On the arterial vasculature, α ₁ -receptor activation by phenylephrine leads to increases in arterial pressure, systemic vascular resistance (SVR), and ventricular afterload. On the venous side, α ₁ -adrenergic receptor stimulation leads to a reduction in venous capacitance, which may lead to increased venous return depending on the preload dependency or position of the heart on the Frank-Starling curve. In patients with preload-recruitable stroke work, phenylephrine titration can lead to increased stroke volume and cardiac output. By contrast, patients who are operating on the plateau of the Frank-Starling relationship and are not preload dependent may exhibit a phenylephrine-induced decrease in stroke volume caused by a rise in SVR and reflex decreases in heart rate. Clinically, the biphasic response of phenylephrine mandates a careful determination of the patient's fluid or preload responsiveness to achieve the desired hemodynamic result.

Box 11.1

Vasoconstrictor Agents That Increase Mean Arterial Blood Pressure

• Phenylephrine is a widely used vasopressor in the operating room for the treatment of hypotension. On the arterial vasculature, α ₁ -receptor activation by phenylephrine leads to increases in arterial pressure, systemic vascular resistance, and ventricular afterload. On the venous side, α ₁ -adrenergic receptor stimulation leads to a reduction in venous capacitance, which may lead to increased venous return depending on the preload dependency or position of the heart on the Frank-Starling curve.

• Ephedrine is a short-acting indirect α- and β-adrenergic agonist that also enhances the endogenous release of norepinephrine from adrenergic nerve terminals. The overall hemodynamic effect is characterized by an elevation in mean arterial pressure through an increase in systemic vascular resistance and a rise in heart rate and cardiac output to varying degrees.

• Arginine vasopressin causes potent vasoconstriction throughout the circulation, leading to increases in systemic vascular resistance and arterial blood pressure. Vasopressin binding in the kidney mediates its antidiuretic effect and markedly increases renal concentrating ability to increase intravascular volume.

• Methylene blue is a heterocyclic aromatic molecule that blocks the nitric oxide synthase and soluble guanylate cyclase pathways, leading to the restoration of vascular tone and arterial pressure.

Box 11.2

Vasoactive Agents That Increase Cardiac Output

• Epinephrine is an endogenous catecholamine that stimulates both α- and β-adrenergic receptors in a dose-dependent fashion. The β-selective pharmacology of epinephrine is characterized by a higher binding affinity for the β-receptor at lower doses (0.01–0.04 µg/kg/min) and a stronger preference for the α−receptor at higher doses (0.05–0.2 µg/kg/min). This provides the clinical basis for the biphasic response observed for epinephrine, in which at lower doses, the hemodynamic effects are predominated by increased inotropy and chronotropy of the heart (β effect), and at higher doses, a vasopressor effect (α effect) is primarily observed.

• Dobutamine is a synthetic catecholamine that displays a strong affinity for the β-receptor (β ₁ and β ₂ ), resulting in dose-dependent increases in cardiac output and heart rate and reductions in systemic vascular resistance and diastolic filling pressures. Dobutamine is a rational choice for patients with right or left ventricular dysfunction and afterload mismatch.

• Isoproterenol is a potent, nonselective β-adrenergic agonist devoid of α-adrenergic agonist activity. The potent chronotropic, inotropic, and vasodilatory effects of isoproterenol make it an excellent candidate for the treatment of acute bradyarrhythmias or atrioventricular heart block, pulmonary hypertension, and heart failure.

• Norepinephrine is an endogenous catecholamine exhibiting potent α-adrenergic activity with a mild to modest effect on the β-adrenergic receptor. The higher affinity for norepinephrine for the α-adrenergic receptor provides the basis for its powerful overall vasoconstrictor effect and less potent inotropic and chronotropic properties. The overall hemodynamic effects of norepinephrine are characterized by increases in systolic, diastolic, and pulse pressures, with minimal net impact on cardiac output and heart rate.

• Milrinone has a unique mechanism of action independent of the adrenergic receptor. Its inotropic effects are mediated primarily through an inhibition of the phosphodiesterase enzyme and not through β-receptor stimulation. As a result, the effectiveness of milrinone is not altered by previous β-blockade, nor is it reduced in patients who may experience β-receptor downregulation. Milrinone is also effective in improving diastolic relaxation and compliance.

Box 11.3

Vasoactive Agents That Lower Arterial Blood Pressure

• Nitroglycerin belongs to the nitrovasodilator group of drugs that exert their effect through the donation of nitric oxide (NO) and activation of the soluble guanylate cyclase pathway in smooth muscle. Nitroglycerin preferably dilates the venous capacitance vessels, resulting in decreases in right atrial, pulmonary artery, pulmonary capillary wedge, and ventricular end-diastolic pressures with minimal effects on systemic vascular resistance. Nitroglycerin also has a vasodilator effect on coronary arteries, reducing the resistance to blood flow.

• Nitroprusside is a potent nitrovasodilator that acts by releasing NO to induce both arterial and venous dilation. Nitroprusside possesses a quick onset of action and great potency, making it a rational choice for management of intraoperative hypertension and for afterload reduction during surgery.

• Clevidipine is an ultra-fast-acting, dihydropyridine L-type calcium channel blocker with a direct action on arteriolar resistance vessels and limited effects on venous capacitance vessels. Clevidipine inhibits the L-type calcium channel in arterial smooth muscle, causing potent vasodilation. Because of its rapid metabolism by circulating esterases, its effect is quickly terminated independent of hepatic or renal function. Hemodynamically, clevidipine reduces arterial pressure through direct action on the arterioles without affecting the filling pressures or causing reflex changes in heart rate.

• Nicardipine is a dihydropyridine L-type calcium channel blocker with a selective arterial vasodilator mode of action. Nicardipine has unique pharmacologic effects in that the drug selectively reduces systemic and coronary artery resistance, thereby decreasing left ventricular afterload and increasing coronary blood flow.

• The β-adrenergic antagonists reduce myocardial work and oxygen demand by decreasing heart rate, blood pressure, and myocardial contractility. β-Blocker–mediated heart rate reduction may also have a salient effect on increasing coronary blood flow.

Hemodynamically, the clinical effect of phenylephrine is complex and is essentially dose dependent. The initial starting dose for an infusion of phenylephrine typically ranges from 0.2 to 2.0 µg/kg per minute or 5 to 200 µg/min. Bolus administration of phenylephrine typically starts at 50 to 100 µg/dose. At the lower dose range, patients under the vasodilatory effects of general anesthesia typically respond to phenylephrine with an increase in preload return and concomitant augmentation of stroke volume. An increase in MAP may result as a consequence of increased recruitable stroke work as well as a modest rise in SVR. The effect of low-dose phenylephrine on pulmonary vascular resistance (PVR) is generally negligible. As the dose of phenylephrine is increased, a critical threshold is eventually reached, and reductions in stroke volume and heart rate, combined with rises in SVR and PVR, are generally observed. The dose that induces decreases in stroke volume and reflex bradycardia is complex and dependent on a myriad of factors, highlighting the careful individual titration of phenylephrine in each patient.

The clinical use of phenylephrine in the operating room is quite broad; therefore only a few clinical scenarios are highlighted in this section. The administration of phenylephrine is commonly used in the setting of hypotension to counter the vasodilatory effects of anesthetic agents. Indeed, phenylephrine may be used to treat hypotension after induction or during maintenance of anesthesia. In this setting, initial low doses of phenylephrine may increase preload and MAP through constriction of the venous and arterial beds, respectively. If the anesthesiologist increases the dose or administers a large initial bolus, reflex bradycardia may result with a detrimental effect on cardiac output. In patients who are more afterload sensitive because of poor contractile reserve, abrupt rises in preload and afterload may result in a more exaggerated decrease in cardiac output after phenylephrine administration. Phenylephrine is also appropriate for the treatment of hypotension in the setting of aortic stenosis. As the left ventricular (LV) afterload is relatively fixed by the stenotic valve, increases in diastolic blood pressure with phenylephrine therapy may increase coronary perfusion. Any phenylephrine-induced reductions in heart rate may also prove beneficial because lower heart rates may improve diastolic filling time and minimize myocardial oxygen consumption. Another important clinical use of phenylephrine is for the hemodynamic management of patients with hypertrophic subaortic stenosis or dynamic LV outflow obstruction from systolic anterior motion of the mitral valve. The dynamic nature of outflow obstructions is such that they worsen as ventricular volume decreases because of increased contractility. Increases in LV afterload may act to decrease contractility, thereby reducing the severity of the outflow obstruction.

Ephedrine

Ephedrine is a short-acting indirect α- and β-adrenergic agonist that also enhances the endogenous release of norepinephrine from adrenergic nerve terminals. Ephedrine, a plant alkaloid, has a duration of effect of approximately 10 to 15 minutes, is minimally metabolized, with an elimination half-life of 6 hours in urine. Repeated dosing may lead to tachyphylaxis because of intrinsic catecholamine depletion. The overall hemodynamic effect is characterized by an elevation in MAP through an increase in SVR and rises in heart rate and cardiac output to varying degrees. Initial intravenous (IV) bolus doses of ephedrine typically start at 5 to 10 mg (0.07–0.1 mg/kg) and is carefully titrated to prevent deleterious and unwanted effects such as tachycardia. At higher doses (0.15–0.2 mg/kg), unpredictable rises in heart rate and MAP may be observed as well as the potential for tachyphylaxis, especially with repetitive dosing. The mechanism governing the acute tolerance after repeat boluses of ephedrine may be caused by a depletion of endogenous norepinephrine levels and a decrease in adrenergic receptor density. In addition to the hemodynamic effects, ephedrine possesses bronchodilator properties through its stimulation of the β ₂ -receptor, leading to its use in patients with reactive airway disease and possibly in the treatment of anaphylaxis.

Clinically, ephedrine can be titrated cautiously to treat intraoperative hypotension during general anesthesia. It is particularly useful when a temporizing measure is needed to improve hemodynamics in the setting of relative bradycardia and hypotension. It has been recommended for the treatment of propofol-induced hypotension and bradycardia after induction of anesthesia. It may also be a rational choice for the treatment of hypotension and bradycardia following sympathectomy after epidural or spinal anesthesia.

Vasopressin

Arginine vasopressin (antidiuretic hormone) is a peptide hormone produced in the posterior pituitary that plays a crucial role in the regulation of vascular tone and circulating blood volume. The half-life of vasopressin is approximately 10 minutes with a range between 5 and 20 minutes. Exogenous vasopressin must be administered intravenously, and in bolus form, its effects are brief; hence, it is typically administered by continuous infusion. Activation of the vasopressin receptor (V ₁ ) in the vasculature leads to potent vasoconstriction throughout the circulation, leading to increases in SVR and arterial blood pressure. Vasopressin (V ₂ ) receptor activation in the kidney mediates its antidiuretic effect and markedly increases renal concentrating ability to promote volume avidity. Moreover, binding of vasopressin in the pulmonary vasculature may confer a vasodilatory effect through a nitric oxide (NO)-mediated pathway, resulting in a decrease in PVR in certain patients.

Vasopressin is often administered as an IV infusion, with dosing regimens starting at 0.01 to 0.04 U/min for the treatment of low SVR and hypotension. The pharmacology of vasopressin lends itself to be used in unique clinical scenarios. Because its vasoconstrictive effects are mediated through the V ₁ receptor as opposed to the adrenergic receptor, vasopressin infusions may represent a rational strategy to decrease high doses of catecholamines such as norepinephrine or epinephrine to treat refractory vasodilation. In particular, vasopressin therapy has found great utility in the treatment of septic shock caused by vasopressin depletion, profound vasoplegia during cardiac surgery, and catecholamine-resistant hypotension from adrenergic receptor downregulation. The use of vasopressin may also be a rational choice for the treatment of low SVR and concomitant pulmonary hypertension. Because of the differential vasoconstricting and vasodilating effects on the systemic and pulmonary vasculature, respectively, vasopressin provides a means to manage hypotension in the setting of coexisting elevated PVR. Similarly, vasopressin therapy may find utility in patients with right ventricular (RV) dysfunction and systemic hypotension as the vasoconstricting effects of vasopressin may spare the pulmonary vasculature. Vasopressin is also an excellent adjunct in patients on vasodilatory inotropes such as milrinone, dobutamine, or isoproterenol. The addition of vasopressin may be used to augment arterial pressure in patients who have adequate cardiac output in the setting of low SVR.

Methylene Blue

Methylene blue is a heterocyclic aromatic molecule that blocks the nitric oxide synthase (NOS) and soluble guanylate cyclase (sGC) pathway that regulates smooth muscle function and vascular tone. IV methylene blue administration exhibits complex pharmacokinetics because of multiphasic distribution into various tissue compartments along with a slow terminal rate of disappearance. Methylene blue is excreted in the urine anywhere between 4 and 24 hours after administration with a half-life of 5 to 6.5 hours. Methylene blue–mediated downregulation of the endothelial NOS and sGC pathway restores vascular tone in patients with vasopressor-refractory hypotension. The hemodynamic effects of methylene blue are often observed with an initial single IV dose of 1.0 to 2 mg/kg. However, it is common for the effects to be transient, and some clinical scenarios may necessitate repeat dosing or maintenance with a continuous infusion at 0.25 to 2 mg/kg per hour to ameliorate the hypotension. Administration of methylene blue for the treatment of vasoplegic syndrome may be useful in a variety of clinical scenarios, including after cardiopulmonary bypass, congestive heart failure, anaphylaxis (including protamine reaction), sepsis, renal failure, and hepatic failure.

Epinephrine

Epinephrine is an endogenous catecholamine that stimulates both α- and β-adrenergic receptors in a dose-dependent fashion (see Tables 11.1 and 11.2 ). The pharmacology of epinephrine is characterized by a higher binding affinity for the β-receptor at lower doses (0.01–0.04 µg/kg per minute) and a stronger preference for the α receptor at higher doses (0.05–0.2 µg/kg per minute). This provides the clinical basis for the biphasic response observed for epinephrine; at lower doses, the hemodynamic effects are predominated by increased inotropy and chronotropy of the heart (β effect), and at higher doses, a vasopressor effect (α effect) is primarily observed. Epinephrine infusion in the lower dose range of 0.01 to 0.04 µg/kg per minute may be used to increase stroke volume, with mild elevations in heart rate in patients requiring augmentation of myocardial contractility. As the dose of epinephrine is increased to the range of 0.05 to 0.2 µg/kg per minute, the physiologic effects of both the α-receptor and β-receptor activation are combined as rises in SVR and heart rate are observed, respectively (see Tables 11.1 and 11.2 ). The biphasic hemodynamic response makes epinephrine an excellent choice for clinical situations that simultaneously mandate an increase in myocardial contractility and augmentation of arterial blood pressure. Under the vasodilatory effects of anesthetic agents, the titration of epinephrine may prove useful in the patient with hypotension secondary to a combination of systemic vasodilation and poor ventricular performance. In this instance, careful titration of epinephrine to achieve the desired effect is crucial to prevent untoward tachycardia or arrhythmias. Compared with dobutamine, epinephrine may exhibit less tachycardia and vasodilation, which may improve hemodynamics in patients with poor ejection fraction under general anesthesia.

Dobutamine

Dobutamine is a synthetic catecholamine that displays a strong affinity for the β receptor (β ₁ and β ₂ ), resulting in dose-dependent increases in cardiac output and heart rate and reductions in SVR and diastolic filling pressures (see Tables 11.1 and 11.2 ). Dobutamine has a half-life of 2 minutes, a rapid onset of effect, and steady-state concentrations reached within 10 minutes. Tachyphylaxis may occur with dobutamine infusions longer than 72 hours. In patients with a low cardiac output syndrome, dobutamine often increases the heart rate, and depending on the patient, it may induce an increase or decrease in the SVR and MAP. However, under the effects of general anesthesia, a rise in SVR with dobutamine is generally not observed, and the overall effect is a negligible or mild decrease in SVR. The starting low dose range for dobutamine is 3 to 5 µg/kg per minute. At this dose, dobutamine may be associated with higher incidences of tachycardia and atrial or ventricular arrhythmias compared with low-dose epinephrine infusions at 0.01 to 0.03 µg/kg per minute. Moreover, because of its primary selectivity for the β receptor, dobutamine is a rational choice for patients with right or LV dysfunction and afterload mismatch. Because of a minimal effect on PVR, dobutamine can be used to augment RV stroke volume, especially in the setting of pulmonary hypertension. Similarly, patients who are sensitive to LV afterload mismatch may find dobutamine to be an appropriate drug to increase contractility while unloading the left ventricle. Additionally, dobutamine may be a useful inotrope for the patient with a previously transplanted heart. Because a newly denervated heart relies primarily on β-receptor stimulation to control myocardial contractility and heart rate, dobutamine therapy may provide the necessary chronotropic and inotropic support required for the hemodynamic management of heart transplant recipients.

Isoproterenol

Isoproterenol is a potent, nonselective β-adrenergic agonist, devoid of α-adrenergic agonist activity. Compared with other catecholamines, isoproterenol is a poorer substrate for MAO and has less uptake by sympathetic neurons; hence, its duration of action may be slightly longer than that of epinephrine, but it still is brief. Isoproterenol dilates skeletal, renal, and mesenteric vascular beds and decreases diastolic blood pressure (see Tables 11.1 and 11.2 ). The potent chronotropic, inotropic, and vasodilatory effects of isoproterenol make it an excellent candidate for the treatment of bradycardia (especially after orthotopic heart transplantation), pulmonary hypertension, and heart failure. Isoproterenol remains the inotrope of choice for stimulation of cardiac pacemaker cells in the management of acute bradyarrhythmias or atrioventricular (AV) heart block. It reduces refractoriness to conduction and increases automaticity in myocardial tissues. The tachycardia seen with isoproterenol is a result of direct effects of the drug on the sinoatrial (SA) and AV nodes and reflex effects caused by peripheral vasodilation. It is routinely used in the setting of cardiac transplantation for increasing automaticity and inotropy, as well as for its vasodilatory effect on the pulmonary arteries. To normalize arterial blood pressure, it may be necessary to combine isoproterenol with vasopressin to counter the potent vasodilatory effects of β ₂ -receptor agonism. The recommended dose range of isoproterenol is 0.5 to 10 µg/min or 0.01 to 0.10 µg/kg per minute.

Dopamine

Dopamine is an endogenous catecholamine and an immediate precursor of norepinephrine and epinephrine (see Tables 11.1 and 11.2 ). Its actions are mediated by stimulation of both adrenergic (α and β) and dopaminergic receptors (D ₁ receptors). The dose response of dopamine is characterized by the D ₁ and β effects predominating at lower doses and α effects at higher doses. Dopamine is unique in comparison with other endogenous catecholamines because of its effects on the kidneys. It has been shown to increase renal artery blood flow by vasodilating the afferent arteries and indirect vasoconstriction of the efferent arteries through D ₁ -receptor activation. At the lower dose range (0.5–3.0 µg/kg per minute), dopamine predominantly stimulates the dopaminergic receptors; at doses ranging from 3 to 7 µg/kg per minute, it activates most adrenergic receptors in a nonselective fashion; and at higher doses (>10 µg/kg per minute), dopamine behaves as a vasoconstrictor. But it is important to highlight that the dose-dependent effects of dopamine can be very unpredictable because of a large degree of inter- and intraindividual variability. There is also significant overlap between the dose ranges, in that titration at the lower dose range of 2.5 and 5.0 µg/kg per minute may still exert a positive effect on the β, α, and D ₁ receptors, resulting in increases in cardiac index, heart rate, and SVR, as well as mild increases in renal blood flow, respectively. Nevertheless, the dopaminergic effect may be useful in patients with preexisting renal disease or in the setting of oliguria. As the dose increases above 5 µg/kg per minute, significant increases in MAP and PVR without increasing cardiac output may result. Compared with dobutamine and epinephrine, dopamine may be inferior with respect to improving stroke volume and cardiac output. In addition, dopamine may cause more frequent and less predictable degrees of tachycardia than dobutamine or epinephrine at doses that produce comparable improvement in contractile function. The propensity of dopamine to increase heart rate and induce tachyarrhythmias may therefore limit its utility in clinical practice.

Norepinephrine

Norepinephrine is an endogenous catecholamine exhibiting potent α-adrenergic activity with a mild to modest effect on the β-adrenergic receptor (see Tables 11.1 and 11.2 ). The higher affinity for norepinephrine of the α-adrenergic receptor provides the basis for its powerful overall vasoconstrictor effect and less potent inotropic and chronotropic properties. The overall hemodynamic effects of norepinephrine are characterized by increases in systolic and diastolic blood pressure and MAP, with minimal net impact on cardiac output and heart rate. In this regard, norepinephrine is used primarily as a vasopressor to manage low SVR caused by vasodilation. For instance, norepinephrine has been used effectively in combination with milrinone or dobutamine to counteract the vasodilatory effects of inodilators and maintain arterial pressure. Norepinephrine also plays a prominent role in the management of septic shock. As a potent vasoconstrictor, it is important to highlight that in certain patients, norepinephrine may produce reflex reductions in heart rate by increasing SVR and arterial pressure. Infusion of norepinephrine in patients with poor ventricular function should therefore be used with caution. Recommended starting doses of norepinephrine are in the range of 2 to 16 µg/min or 0.01 to 0.3 µg/kg per minute.

Milrinone

The PDE III milrinone has a unique mechanism of action independent of the adrenergic receptor. Its inotropic effects are mediated primarily through an inhibition of the phosphodiesterase enzyme (PDE III) and not through β-receptor stimulation (see Tables 11.1 and 11.2 ). As a result, the effectiveness of milrinone is not altered by previous β-blockade, nor is it reduced in patients who may experience β-receptor downregulation. With IV administration, milrinone has an elimination half-life of 1 hour, is 80% protein bound, has a volume of distribution (Vd) of 0.3 L/kg, and has a clearance rate of 6.1 mL/kg per minute. In patients with chronic heart failure, clearance and elimination are at least doubled compared with healthy patients. Moreover, significant renal insufficiency prolongs milrinone's plasma half-life in proportion to the decrement in creatinine clearance. Milrinone dosing should be reduced in patients with reduced creatinine clearance.

In addition to the positive inotropic effects, milrinone has been shown to improve myocardial diastolic relaxation and compliance (i.e., positive “lusitropic” effect) while augmenting coronary perfusion. The proposed mechanism for this effect on diastolic performance is that by decreasing LV wall tension, ventricular filling is enhanced, and myocardial blood flow and oxygen delivery are optimized. Milrinone dosing is unique in that the drug can be loaded at 50 µg/kg over 10 minutes followed by a maintenance infusion of 0.375 to 0.75 µg/kg per minute. Significant increases in stroke volume and cardiac index are observed with significant decreases in pulmonary capillary wedge (PCW) pressure, central venous pressure, pulmonary artery pressure (PAP), and SVR. A major advantage of milrinone is the marked afterload reduction of both the PVR and SVRs as the dose of milrinone is increased. The pulmonary and systemic vasodilatory effects of milrinone render it an excellent choice for patients with RV dysfunction and pulmonary hypertension and LV dysfunction and elevated SVR, respectively. The lusitropic effects of milrinone on ventricular relaxation and compliance make it an attractive choice to improve the diastolic filling parameters of a stiff, noncompliant heart. Caution is necessary when milrinone doses above 0.75 µg/kg per minute are used because this is associated with more severe degrees of hypotension. The combination of milrinone with vasopressin may be useful in patients who do not respond to catecholamines secondary to adrenergic receptor downregulation. The combination of vasopressin, which spares the pulmonary vasculature and an inodilator, may be an attractive choice for the hemodynamic management of RV dysfunction in the presence of elevated PVR.

Levosimendan

Levosimendan is a calcium-sensitizing drug that exerts positive inotropic properties by sensitizing myofilaments to calcium and vasodilatation by opening adenosine triphosphate–dependent potassium channels on vascular smooth muscles. This inodilator usually increases cardiac output and decreases preload.

Pharmacokinetics and pharmacodynamics of levosimendan are unique in that an active metabolite is formed with potency and efficacy similar to those of the parent compound. After a loading dose, steady-state levels are reached at approximately 4 hours after drug infusion. However, an active metabolite known as OR-1986 peaks at 48 hours and remains active for more than 300 hours (12–14 days after the end of infusion). This leads to clinical effects for up to 7 days after the discontinuation of a levosimendan infusion.

The active metabolite, OR-1986, is primarily responsible for the sustained increase in stroke volume index, decrease in cardiac workload, and improved coronary and renal blood flow in patients with low cardiac output after cardiac surgical procedures. The formation of an intermediate- or long-acting metabolite may allow for earlier pharmacologic weaning without fear of losing the beneficial inotropic and hemodynamic effects as a result of drug discontinuation.

Nitroglycerin

Nitroglycerin belongs to the nitrovasodilator group of drugs that exert their effect through the donation of NO and activation of the sGC pathway in smooth muscle (see Table 11.3 ). Nitroglycerin is a NO donor, a class of drugs that activates guanylate cyclase, resulting in cyclic guanosine monophosphate (cGMP) production, causing reuptake of calcium by the sarcoplasmic reticulum with resultant vasodilation.

The Vd of nitroglycerin is 3 L/kg, and it is cleared from this volume at extremely rapid rates, with a resulting serum half-life of about 3 minutes. The observed clearance rates (0.5–1 L/kg per minute) exceed hepatic blood flow. Nitroglycerin is enzymatically denitrated in the liver, erythrocytes, and vascular endothelium. Renal insufficiency has no impact on its pharmacokinetics. The first products in the metabolism of nitroglycerin are inorganic nitrate and the 1,2- and 1,3-dinitroglycerols. The dinitrates are less effective vasodilators than the parent compound, but they are longer lived in the serum, and their overall contribution to the effect of chronic nitroglycerin regimens is not known. The dinitrates are further metabolized to nonvasoactive mononitrates and, finally, to glycerol and carbon dioxide.

The hemodynamic effects of nitroglycerin mainly stem from the NO-mediated smooth muscle relaxation. Low-dose nitroglycerin preferably dilates the venous capacitance vessels compared with arteriole dilation. The resultant venodilation reduces right atrial, pulmonary artery, PCW, and ventricular end-diastolic pressures with minimal effects on SVR. Nitroglycerin also exerts important effects on the coronary circulation, with a vasodilator effect on coronary arteries reducing the resistance to blood flow. As the vasodilator of choice for the treatment of ischemia, nitroglycerin-mediated dilation of coronary arteries in combination with decreases in ventricular end-diastolic pressure may overall improve the blood flow to the subendocardium, especially with the addition of phenylephrine to maintain CPP. Similarly, in the management of ventricular volume overload, use of nitroglycerin is advantageous because of its predominant influence on the venous bed; preload can be reduced without significantly compromising systemic arterial pressure. Initial IV doses of nitroglycerin start at 5 to 10 µg/min and can range up to 75 to 150 µg/min for the treatment of myocardial ischemia. At doses above 150 µg/min, arterial dilation may become clinically evident.

Nitroprusside

Nitroprusside is a potent nitrovasodilator that acts by releasing NO to induce both arterial and venous dilation (see Table 11.3 ). The hemodynamic response is a function of a combination of venous pooling and reduced arterial impedance. Sodium nitroprusside (SNP) is rapidly distributed to a volume that is approximately coextensive with the extracellular space. The drug is cleared from this volume by intraerythrocytic reaction with hemoglobin and SNP's resulting circulatory half-life is 2 minutes. SNP is unstable and decomposes when exposed to light. SNP metabolites are hemodynamically inactive but toxic. Hence, infusions exceeding 5 µg/kg per minute for longer than 24 hours may generate the production of the toxic metabolites cyanide and thiocyanate. SNP vasodilatory effects occur within 30 seconds of IV administration; cessation of effects occurs within 3 minutes of infusion termination. Renal elimination of SNP is 3 days; however, accumulation occurs with renal insufficiency. The cyanide byproduct is converted to thiocyanate by hepatic rhodanese; liver disease can lead to cyanide toxicity and resultant lactic acidosis.

Nitroprusside possesses a quick onset of action and great potency, making it a rational choice for management of intraoperative hypertension and for afterload reduction during surgery. In patients with impaired ventricular function, nitroprusside-mediated afterload reduction may yield improvements in cardiac output. Although SNP is an effective venous and arterial vasodilator during surgery, it has notable limitations. Nitroprusside use is associated with reflex tachycardia, tachyphylaxis, inhibition of hypoxic pulmonary vasoconstriction, increases in intracranial pressure, and reduced renal blood flow. The potential for cyanide toxicity is also an important consideration when administering SNP, especially in patients receiving high doses or prolonged infusions. Furthermore, SNP may be difficult to titrate and often causes hypotension because of overshoot. It is therefore prudent to start infusion rates at 0.1 to 0.3 µg/kg per minute with careful titration to maximum doses near 2.0 to 5 µg/kg per minute. Intraoperatively, SNP has been used during surgery to induce controlled hypotension to minimize bleeding complications. Nitroprusside in combination with a β-antagonist has also found use in controlling the rate of pressure rise in the aorta during acute dissection.

Clevidipine

Clevidipine is an ultra-fast-acting, dihydropyridine L-type calcium channel blocker (CCB) with a direct action on arteriolar resistance vessels and limited effects on venous capacitance vessels (see Table 11.3 ). Clevidipine is similar in structure to other dihydropyridine calcium channel antagonists, with the exception of an additional ester linkage, which enables its rapid metabolism (mean [standard deviation], 5.8 [1.1] minutes). In healthy subjects, clevidipine has a linear dose and steady-state blood concentration relationship.

Because clevidipine is metabolized by blood and tissue esterases, neither renal nor hepatic impairment has an impact on elimination, and there is no need for dose adjustment. Clevidipine's mechanism of action is not affected by inhibitors or activators of the cytochrome P450 metabolic pathway. Moreover, there is no indication that tolerance develops to prolonged infusions, although there is some evidence of rebound hypertension after discontinuation in patients not transitioned to alternative antihypertensive therapies. Because of its high lipid solubility, it is prepared in a lipid emulsion for IV infusion. The extremely fast onset and offset of about 1 to 3 minutes allow clevidipine to be especially suited for intraoperative management of acute hypertension. Clevidipine inhibits the L-type calcium channel in arterial smooth muscle, causing potent vasodilation. Because of its rapid metabolism by circulating esterases, its effect is quickly terminated independent of hepatic or renal function. Hemodynamically, clevidipine reduces arterial pressure through direct action on the arterioles without affecting the filling pressures or causing reflex changes in heart rate. Stroke volume and cardiac output typically increase. Because of its potency and rapid onset, it is an effective drug for the intraoperative management of hypertension. Clevidipine may be more effective at achieving blood pressure targets within a prespecified range than nitroglycerin or SNP in the intraoperative period. The initial recommended starting dosage is 1 to 2 mg/h with a maximum dose of 32 mg/h. In most cases, the target hemodynamic goals of clevidipine are reached within a dose range of 4 to 6 mg/h. Because of the relatively high lipid content, it is recommended that no more than 1000 mL of clevidipine be administered in the first 24-hour period.