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Cardiac Surgical
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Pharmacology
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Jerrold H. Levy • Jacob N. Schroder • James G. Ramsay
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Clinical pharmacology associated with cardiac surgery is an for a series of intracellular reactions resulting in higher lev-
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important part of patient management. Patients in the peri- els of intracellular calcium during systole. Less well known
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operative period receive multiple therapeutic agents that is that drugs with only alpha-adrenergic agonist activity also
affect cardiovascular and pulmonary functions. This chapter may increase intracellular Ca2+ levels, although by a different
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summarizes the pharmacology of the agents commonly used mechanism.5,6 Although under investigation, the probable
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for treating the primary physiologic disturbances associated
with cardiac surgery, hemodynamic instability, respiratory
insufficiency, and alterations of hemostasis. For cardiovascu-
lar drugs, the common theme is that pharmacologic effects
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basis for the inotropic effect of alpha-adrenergic drugs is the
stimulation of phospholipase C, which catalyzes hydrolysis
of phosphatidyl inositol to diacylglycerol and inositol tri-
phosphate (see Fig. 4-2). Both of these compounds increase

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are produced by intracellular ion fluxes. the sensitivity of the myofilament to calcium, whereas ino-
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Several basic subcellular/molecular pathways are impor- sitol triphosphate stimulates the release of calcium from its
tant in cardiovascular pharmacology, as shown in Fig. 4-1. intracellular storage site, the sarcoplasmic reticulum. There
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The action potential in myocardial cells is a reflection of ion is still some debate about the mechanism for the inotropic
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fluxes across the cell membrane, especially Na+, K+, and Ca2+.1,2 effect of alpha-adrenergic agonists and its significance for the
Numerous drugs used to control heart rate and rhythm act by acute pharmacologic manipulation of contractility, but there
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altering Na+ (eg, lidocaine and procainamide), K+ (eg, amiod- is little debate about the importance of this mechanism in
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arone, ibutilide, and sotalol), or Ca2+ (eg, diltiazem) currents. vascular smooth muscle, where the increase in intracellular
Calcium also has a dominant effect on the inotropic state but calcium stimulated by alpha-adrenergic agonists can increase
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by highly specialized intracellular mechanisms.3,4 smooth muscle tone significantly. However, intracellular cal-
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Myocardial contractility is a manifestation of the interac-
tion of actin and myosin, with conversion of chemical energy
from adenosine triphosphate (ATP) hydrolysis into mechani-
cal energy. The interaction of actin and myosin in myocytes is
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cium in vascular smooth muscle is also controlled by cyclic
nucleotides.7,8 In contrast to the myocyte, in vascular smooth
muscle, cyclic AMP has a primary effect of stimulating the
uptake of calcium into intracellular storage sites, decreasing

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inhibited by the associated protein tropomyosin. This inhibi- its availability (Fig. 4-3). Thus drugs that stimulate cyclic
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tion is “disinhibited” by intracellular calcium. A similar situa- AMP production (beta agonists) or inhibit its breakdown
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tion occurs in vascular smooth muscle, where the interaction (phosphodiesterase inhibitors) will cause vasodilation. In
of actin and myosin (leading to vasoconstriction) is modu- addition, cyclic guanosine monophosphate (cyclic GMP) also
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lated by the protein calmodulin, which requires calcium as fre

increases intracellular calcium storage (see Fig. 4-3), decreas-
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a cofactor. Thus intracellular calcium has a “tonic” effect in ing its availability for modulating the interaction of actin and
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both the myocardium and vascular smooth muscle. myosin. Several commonly used pharmacologic agents act via
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Numerous drugs used perioperatively alter intracellular cyclic GMP. For example, nitric oxide stimulates the enzyme
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calcium.3,4 guanylate cyclase, increasing cyclic GMP levels. Drugs such

Catecholamines (eg, norepinephrine, epinephrine, and as nitroglycerin and sodium nitroprusside achieve their effect
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dobutamine) with beta1 agonist activity regulate intramyocyte by producing nitric oxide as a metabolic product. Vasodila-
calcium levels via the nucleotide cyclic adenosine monophos- tion is also produced by “cross-talk” between K+ and Ca2+
phate (cyclic AMP) (Fig. 4-2). Beta agonists bind to recep- fluxes. Decreased levels of ATP, acidosis, and elevated tissue
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tors on the cell surface that are coupled to the intracellular lactate levels increase the permeability of the ATP-sensitive
enzyme adenylate cyclase via the stimulatory transmembrane K+ channel. This increased permeability results in hyperpo-
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GTP-binding protein. This leads to increased cyclic AMP larization of the cell membrane that inhibits the entry of Ca2+
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synthesis, and cyclic AMP, in turn, acts as a second messenger into the cell. This results in decreased vascular tone.
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Part I  Fundamentals

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120
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0 Time
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1 2

Action potential (mV)

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220

Depolarization
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240
0 3

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280
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290

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4
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Membrane Plateau phase repolarization
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resting potential
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Intracellular fluid space
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1
K
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Sarcolemma
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1 21
Na Ca

Extracellular fluid space

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FIGURE 4-1  Cardiac ion fluxes and the action potential. The resting membrane potential is largely a reflection of the intercellular/intracellular potas-
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sium gradient. Depolarization of the membrane during phase 4 triggers an initial fast sodium channel with overshoot (phase 0) followed by recovery
(phase 1) to a plateau (phase 2) maintained by an inward calcium flux and then repolarization owing to an outward potassium flux (phase 3).
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The simplistic overview of pathways of cardiac pharma- combinations of both.9,10 Abnormal impulse initiation occurs
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cology as summarized in Figs. 4-1 through 4-3 also suggests as a result of increased automaticity (spontaneous depolar-
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the primary cause of difficulty in the clinical use of the drugs ization of tissue that does not normally have pacemaking
discussed in this chapter. The mechanisms of action for con- activity) or as a result of triggered activity from abnormal
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trol of heart rate and rhythm, contractility, and vascular tone conduction after depolarizations during phase 3 or 4 of the
are interrelated. For example, beta-adrenergic agonists not action potential. Abnormal conduction often involves reentry
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only increase intracellular calcium to increase contractility,
but they also alter K+ currents, leading to tachycardia. Cat-
echolamines not only have beta-adrenergic agonist activity,
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phenomena, with recurrent depolarization around a circuit
owing to unilateral conduction block in ischemic or dam-
aged myocardium and retrograde activation by an alternate

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with inotropic and chronotropic effects, but they also pos- pathway through normal tissue. In this simplistic view, it is
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sess alpha-agonist activity, leading to increased intracellular logical that dysrhythmias could be suppressed by slowing the
calcium in vascular smooth muscle and vasoconstriction. conduction velocity of ectopic foci, allowing normal pace-
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Phosphodiesterase (PDE) inhibitors like milrinone not only maker cells to control heart rate, or by prolonging the action
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increase contractility by increasing cyclic AMP in the myo- potential duration (and hence refractory period) to block
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cyte, but they also cause vasodilation by increasing cyclic conduction into a limb of a reentry circuit.
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AMP in the vasculature. The interplay of the various mecha- A scheme proposed originally by Vaughan Williams
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nisms means the clinical art of cardiac surgical pharmacology and modified subsequently11,12 is used often to classify
lies as much in selecting drugs for their side effects as for their antidysrhythmic agents, and although alternative schemes
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primary therapeutic effects. describing specific channel-blocking characteristics have

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been proposed and may be more logical,13 this discussion is

organized using the Vaughan Williams system of four major
ANTIARRHYTHMICS drug categories. In this scheme, class I agents are those with
Arrhythmias are common in the cardiac surgical period. A local anesthetic properties that block Na+ channels, class
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stable cardiac rhythm requires depolarization and repolariza- II drugs are beta-blocking agents, class III drugs prolong
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tion in a spatially and temporally coordinated manner, and action potential duration, and class IV drugs are calcium
dysrhythmias may occur when this coordination is disturbed. entry blockers. Amiodarone is discussed in detail owing
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The mechanisms for arrhythmias can be divided into abnor- to its expanding role in treating both supraventricular and
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mal impulse initiation, abnormal impulse conduction, and ventricular arrhythmias and because its use has replaced
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Chapter 4  Cardiac Surgical Pharmacology

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Na - Ca 21
Na - H Na1- K1 AC - linked
21
PLC - linked
1 1 1
Ca

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exchanger exchanger ATPase receptors channel receptors
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21
Ca a1
b1
21
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1
Ca H 2 Na1 1 1
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Sarcolemma
G2
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Gp
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AC PLC Pl
P

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1 1 1
3 Na Na 3K 2 1
ATP 21
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cAMP 1 Ca lP3, DAG
Digoxin
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PDE
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AMP
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2
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1 Amrinone
milrinone
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1
P Protein
kinases
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21
1 Ca
Actin
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P 1 1
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TnC 21
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Myosin Ca
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FIGURE 4-2 Mediators of cardiac contractility. Myocardial contractility is a manifestation of the interaction of actin and myosin, which is
facilitated by the binding of calcium to troponin C (TnC). Intercellular calcium levels are controlled by direct flux across the membrane, by cyclic
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m
AMP, and by inositol triphosphate (IP3) and diacylglycerol (DAG) produced by the action of phospholipase C (PLC). The synthesis of cyclic AMP
is catalyzed by adenylate cyclase (AC), which is activated by binding of agonist to the beta-adrenergic receptor, and its breakdown is catalyzed
by phosphodiesterase (PDE), which is inhibited by amrinone and milrinone. The action of PLC is activated by binding of agonist to the alpha-
adrenergic receptor.
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many of the previously used agents. Because of the efficacy (corresponding to phase 4), the drug will accumulate in the
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of intravenous amiodarone and its recommendations in channel to reach a steady state, slowing conduction in normal
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Advanced Cardiac Life Support (ACLS) guidelines, many tissue. This occurs with class Ia (eg, procainamide, quinidine,
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of the older drugs used in cardiac surgery have a historical and disopyramide) and class Ic (eg, encainide, flecainide, and
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perspective and are considered briefly. propafenone) drugs. In contrast, for the class Ib drugs (eg,
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lidocaine and mexiletine), the time constant for dissociation

from the Na+ channel is short, the drug does not accumu-
Class I Agents
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late in the channel, and conduction velocity is affected mini-

Although each of the class I agents blocks Na+ channels, they mally. However, in ischemic tissue, the depolarized state is
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may be subclassified based on electrophysiologic differences. more persistent, leading to greater accumulation of agent in
These differences can be explained, to some extent, by con- the Na+ channel and slowing of conduction in the damaged
sideration of the kinetics of the interaction of the drug and myocardium.
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the Na+ channel.14,15 Class I drugs bind most avidly to open Procainamide is a class Ia drug that has various electro-
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(phase 0 of the action potential; see Fig. 4-1) or inactivated physiologic effects.16 Administration may be limited by the
(phase 2) Na+ channels. Dissociation from the channel occurs side effects of hypotension and decreased cardiac output.17,18
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during the resting (phase 4) state. If the time constant for The loading dose is 20 to 30 mg/min, up to 17 mg/kg, and
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dissociation is long in comparison with the diastolic interval should be followed by an intravenous infusion of 20 to
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Part I  Fundamentals

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Bradykinin

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AA Substance P

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ADP Histamine

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Endothelial Cell
PGI2 PGI2, PGE1,
LT
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Tx A2 PGE2, PGD2
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TNG
++
Ca SNP EDRF Ca
++
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Membrane

Receptor
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NO. cAMP Adenylate
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cyclase
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++
Ca +
NO. ATP
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smooth muscle

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+ Sarcoplasmic
cytoplasm
k Vascular

reticulum
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Guanylate Guanylate
++
cyclase cyclase Ca
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inactive active
5’-AMP
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GTP
cGMP cAMP
5’-GMP
++ ++
Ca PDE Ca PDE
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Contraction Relaxation
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FIGURE 4-3  Mediators of vascular tone. Cyclic AMP and cyclic GMP increase the uptake of calcium into cellular storage sites in vascular smooth
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muscle, leading to vasodilation. The synthesis of cyclic GMP is catalyzed by guanylate cyclase, which is activated by nitric oxide (NO), which,
in turn, is produced by nitroglycerin (NTG) and sodium nitroprusside (SNP). Excessive vasodilation often is a reflection of other endogenous
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mediators such as prostaglandins (PGI2, PGE1, PGE2, and PGD2) and thromboxane A2 (Tx A2). Several mediators, such as arachidonic acid (AA),
bradykinin, histamine, and substance P, stimulate the release of endothelium-derived relaxing factor (EDRF), which is identified with NO. (Repro-
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duced with permission from Levy JH: Anaphylactic Reactions in Anesthesia and Intensive Care, 2nd ed. Boston, Butterworth-Heinemann, 1992.)
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80 mg/kg per minute. Because procainamide prolongs action

potential duration, widening of the QRS complex often her- m
lidocaine, plasma levels decrease rapidly owing to redistribu-
tion to muscle, fat, etc. Effective plasma concentrations are
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alds a potential overdose. The elimination of procainamide maintained only by following the bolus dose with an infu-
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involves hepatic metabolism, acetylation to a metabolite with sion of 20 to 50 mg/kg per minute.20 Elimination occurs
antiarrhythmic and toxic side effects, and renal elimination via hepatic metabolism to active metabolites that are cleared
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of this metabolite. Thus the infusion rate for patients with by the kidneys. Consequently, the dose should be reduced
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significant hepatic or renal disease should be at the lower end by approximately 50% in patients with liver or kidney dis-
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of this range. ease. The primary toxic effects are associated with the central
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Class Ib drugs include what is probably the best-known nervous system (CNS), and a lidocaine overdose may cause
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antiarrhythmic agent, lidocaine. As noted, lidocaine is a drowsiness, depressed level of consciousness, or seizures in
Na+ channel blocker that has little effect on conduction very high doses. Negative inotropic or hypotensive effects are
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velocity in normal tissue but slows conduction in ischemic less pronounced than with most other antiarrhythmics. The
myocardium.14,15 Other electrophysiologic effects include other class Ib drugs likely to be encountered in the periop-
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a decrease in action potential duration but a small increase erative period are the oral agents tocainide and mexiletine,
in the ratio of effective refractory period to action potential which have effects similar to lidocaine.15
duration. The exact role of these electrophysiologic effects on The class Ic agents, including flecainide, encainide, and
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arrhythmia suppression is unclear. Lidocaine has no signifi- propafenone, markedly decrease conduction velocity.20,21 The
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cant effects on atrial tissue, and it is not recommended for Cardiac Arrhythmia Suppression Trial (CAST) study20,21 of
therapy in shock-resistant ventricular tachycardia/fibrillation moricizine found that although ventricular arrhythmias were
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(VT/VF) in the recent Guidelines for Emergency Cardiovas- suppressed, the incidence of sudden death was greater than
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cular Care.19 After an initial bolus dose of 1 to 1.5 mg/kg of with placebo with encainide and flecainide, and these drugs
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Chapter 4  Cardiac Surgical Pharmacology

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are not in wide use. Propafenone is available for oral use in been replaced by intravenous amiodarone in clinical therapy
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the United States, but IV form is available in Europe. The of SVT and prophylaxis (see Amiodarone).

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usual adult dose is 150 to 300 mg orally every 8 hours. It

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has beta-blocking (with resulting negative inotropic effects)
Other Drugs
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as well as Na+ channel-blocking activity; lengthens the PR,
QRS, and QT duration; and may be used to treat both atrial One of the difficulties of classifying antiarrhythmics by the
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and ventricular dysrhythmias.15 Vaughan Williams classification is that not all drugs can be
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incorporated into this scheme. Three examples are digoxin,
adenosine, and magnesium, each of which has important uses
Class II Agents in the perioperative period.
Digoxin inhibits the Na+, K+-ATPase pump, leading to
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Beta-receptor-blocking agents are another important group
of antiarrhythmic (denoted class II in the Vaughan Williams decreased intracellular K+, a less negative resting membrane
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potential, increased slope of phase 4 depolarization, and

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scheme). However, because of their use as antihypertensive
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as well as antiarrhythmic agents, they are discussed elsewhere decreased conduction velocity. These direct effects, however,
usually are dominated by indirect effects, including inhibi-
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in this chapter, and we will move on to consider bretylium,
amiodarone, and sotalol, the class III agents in the Vaughan tion of reflex responses to congestive heart failure (HF) and
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Williams scheme. These drugs have a number of complex ion a vagotonic effect.10,32 The net effect is greatest at the AV
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channel-blocking effects, but possibly the most important node, where conduction is slowed and the refractory period
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activity is K+ channel blockade.22 Because the flux of K+ out is increased, explaining the effectiveness of digoxin in slowing
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of the myocyte is responsible for repolarization, an important the ventricular response to AF. The major disadvantages of
electrophysiologic effect of class III drugs is prolongation of digoxin are the relatively slow onset of action and many side
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the action potential.23 effects, including proarrhythmia effects, and it is now used
rarely for rate control in acute AF because of the advent of IV
amiodarone and diltiazem.
Class III Agents
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Adenosine is an endogenous nucleoside that has an electro-
physiologic effect similar to that of acetylcholine. Adenosine
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Ibutilide, dofetilide, sotalol, and bretylium are class III agents.
Intravenous ibutilide and oral dofetilide are approved for the decreases AV node conductivity, and its primary antiarrhyth-
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treatment of atrial fibrillation (AF) but carry the risk of tors- mic effect is to break AV nodal reentrant tachycardia.33 An
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ades de pointes.24,25 Sotalol is a nonselective beta-blocker that intravenous dose of 100 to 200 μg/kg is the treatment of
also has K+ channel-blocking activity.26 In the United States, choice for paroxysmal SVT. Adverse effects, such as broncho-
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it is now available for IV and previously for oral administra- spasm, are short-lived because its plasma half-life is so short
(1 to 2 seconds). This short half-life makes it ideal for treat-
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tion. The approved indication is for treating life-threatening
ventricular arrhythmias, although it is effective against atrial ing reentry dysrhythmia, in which transient interruption can
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arrhythmias as well. Bretylium is no longer available or rec- fully suppress the dysrhythmia.
ommended in the most recent American Heart Association Appropriate acid-base status and electrolyte balance are
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(AHA) Guidelines for Emergency Cardiovascular Care.19 important because electrolyte imbalance can perturb the
membrane potential, leading to arrhythmia generation,
as can altered acid-base status, by effects on K+ concentra-
Class IV Agents
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tions and sympathetic tone. Therapy for dysrhythmia should
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Calcium entry blockers (class IV in the Vaughan Williams include correction of acid-base and electrolyte imbalances.
scheme), including verapamil and diltiazem, are antiar- Magnesium supplementation should be considered.34 Mag-
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rhythmics. In sinoatrial (SA) and atrioventricular (AV) nodal nesium deficiency is common in the perioperative period,
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tissues, Ca2+ channels contribute significantly to phase 0 and magnesium administration has been shown to decrease
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depolarization, and the AV nodal refractory period is pro- the incidence of postoperative dysrhythmia.35
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longed by Ca2+ entry blockade.27,28

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This explains the effectiveness of verapamil and diltiazem

in treating supraventricular arrhythmias. It is also clear why
Amiodarone
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these drugs are negative inotropes. Both verapamil and dil- Intravenous amiodarone has become one of the most admin-
istered intravenous antiarrhythmics used in cardiac surgery
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tiazem are effective in slowing the ventricular response to AF,

flutter, and paroxysmal supraventricular tachycardia (SVT) because of its broad spectrum of efficacy. Amiodarone was
and in converting to sinus rhythm.29-31 Verapamil has greater developed originally as an antianginal agent because of its
negative inotrope effects than diltiazem; therefore, it is used vasodilating effects, including coronary vasodilation.36 It has
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rarely for supraventricular arrhythmias. The intravenous dose various ion channel-blocking activities.10,29,36 The resulting
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of diltiazem is 0.25 mg/kg, with a second dose of 0.35 mg/kg electrophysiologic effects are complex, and there are differ-
if the response is inadequate after 15 minutes. The loading ences in acute intravenous and chronic oral administration.
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dose should be followed by an infusion of 5 to 15 mg/h. Acute intravenous administration can produce decreases in
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Intravenous diltiazem, although useful for rate control, has heart rate and blood pressure, but there are minimal changes
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Part I  Fundamentals

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in QRS duration or QT interval. After chronic use, there may ventricular tachycardia (VT) and ventricular refractoriness
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be significant bradycardia and increases in action potential emerge more gradually during oral therapy, becoming maxi-

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duration in AV nodal and ventricular tissue, with increased mal after 10 weeks or more.

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QRS duration and QT interval.37-39
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Indications
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Pharmacokinetics The primary indication for amiodarone is VT or fibrillation.40-48
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Amiodarone is a complex highly lipophilic drug that under-
goes variable absorption (35 to 65%) after oral administra-
tion and is taken up extensively by multiple tissues with
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It is also effective for the treatment of atrial dysrhythmias and
in treating AF (see Atrial Fibrillation).

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interindividual variation and complex pharmacokinetics.38-40
The short initial context-sensitive half-life after intravenous Side Effects
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administration represents drug redistribution. The true Although there are numerous adverse reactions to amio-
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elimination half-life for amiodarone is extremely long, up to darone, they occur with long-term oral administration and
re

fre

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re
40 to 60 days. Because of the huge volume of distribution are rarely associated with acute intravenous administra-
(~60 L/kg) and a long duration of action, an active metabo- tion. The most serious is pulmonary toxicity, which has not
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f
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lite loading period of several months may be required before been reported with acute administration in a perioperative
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reaching steady-state tissue concentrations. Further, in life- setting. Some case series have reported an increased risk of
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threatening arrhythmias, intravenous loading often is start- marked bradycardia and hypotension immediately after car-
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ing to establish initial plasma levels. Measuring amiodarone diac surgery in patients already on amiodarone at the time
plasma concentrations is not useful owing to the complex of surgery.49,50 Other case-control studies, however, have not
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pharmacokinetics and the metabolites of the parent drug.
Plasma concentrations greater than 2.5 mg/L have been asso-
ciated with an increased risk of toxicity. The optimal dose
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m
reproduced this finding.51 None of the placebo-controlled tri-
als of prophylactic amiodarone for perioperative atrial fibrilla-
tion prevention report adverse cardiovascular effects, although

m
of amiodarone has not been well characterized and may vary bradycardia and hypotension are known side effects.52-56 Case
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depending on the specific arrhythmias treated. Further, there reports and case series of postoperative acute pulmonary tox-
may be differences in dose requirements for therapy of supra- icity are similarly lacking in the rigor of randomized, con-
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ventricular and ventricular arrhythmias.37-40 trolled methodology.
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Because of these distinctive pharmacokinetic properties,
steady-state plasma levels are achieved slowly. Oral admin-
PHARMACOLOGIC THERAPY OF
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istration for a typical adult consists of a loading regimen of
SPECIFIC ARRHYTHMIAS
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80 to 1600 mg/d (in two or three doses) for 10 days, 600 to
800 mg/d for 4 to 6 weeks, and then maintenance doses of
Ventricular Tachyarrhythmias
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200 to 600 mg/d. For intravenous loading, specific studies
will be reviewed, but the recommended dosing is 150 mg Intravenous amiodarone is approved for rapid control of
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given over 10 minutes for acute therapy in an adult, followed
first by a secondary loading infusion of 60 mg/h for 6 hours
and then by a maintenance infusion of 30 mg/h to achieve a
m
m
recurrent VT or VF. Three randomized controlled trials
of patients with recurrent in-hospital, hemodynamically
unstable VT or VF with two or more episodes within the

m
1000 mg/d dosing.37-40 past 24 hours who failed to respond to or were intolerant of
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lidocaine, procainamide, and (in two of the trials) bretylium
have been reported.42,44,46 Patients were critically ill with isch-
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Electrophysiology emic cardiovascular disease, 25% were on a mechanical ven-
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The electrophysiologic actions of amiodarone are complex tilator or intraaortic balloon pump before enrollment, and
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and incompletely understood. Amiodarone produces all four 10% were undergoing cardiopulmonary resuscitation at the
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effects according to the Vaughan Williams classification. It time of enrollment. One study compared three doses of IV
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also has been shown to have use-dependent class I activ- amiodarone: 525, 1050, and 2100 mg/d.44 Because of the use
ity, inhibition of the inward sodium currents, and class II of investigator-initiated intermittent open-label amiodarone
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activity.10 The antiadrenergic effect of amiodarone, however, boluses for recurrent VT, the actual mean amiodarone doses
m

is different from that of beta-blocker drugs because it is
noncompetitive and additive to the effect of beta-blockers.
Amiodarone depresses SA node automaticity, which slows
the heart rate and conduction and increases refractoriness of
m
received by the three groups were 742, 1175, and 1921 mg/d.
There was no statistically significant difference in the num-
ber of patients without VT/VF recurrence during the 1-day
study period: 32 of 86 (41%), 36 of 92 (45%), and 42 of 92

the AV node, properties useful in managing supraventricular (53%) for the low-, medium-, and high-dose groups, respec-
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arrhythmia. Its class III activity results in increases in atrial tively. The number of supplemental 150-mg bolus infusions
and ventricular refractoriness and prolongation of the QTc of amiodarone given by blinded investigators was statisti-
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interval. The effects of oral amiodarone on SA and AV nodal cally significantly less in those randomized to higher doses of
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function are maximal within 2 weeks, whereas the effects on amiodarone.

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Chapter 4  Cardiac Surgical Pharmacology

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A wider range of amiodarone doses (125, 500, and The Amiodarone in the Out-of-Hospital Resuscitation
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1000 mg/d) was evaluated by Sheinman and colleagues, of Refractory Sustained Ventricular Tachycardia (ARREST)

sf
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including a low dose that was expected to be subtherapeutic.46 study was randomized, double blind, and placebo controlled.

k
This stronger study design, however, also was confounded by The ARREST study in 504 patients showed that amioda-
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open-label bolus amiodarone injections given by study inves- rone 300 mg administered in a single intravenous bolus sig-
tigators. There was, however, a trend toward a relationship nificantly improves survival to hospital admission in cardiac
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between intended amiodarone dose and VT/VF recurrence arrest still in VT or VF after three direct-current shocks (44%
m

rate (p = .067). After adjustment for baseline imbalances, the
median 24-hour recurrence rates of VT/VF, from lowest to
highest doses, were 1.68, 0.96, and 0.48 events per 24 hours.
The third study compared two intravenous amiodarone
m
m
vs 34%; p < .03).43 Although the highest survival rate to hos-
pital admission (79%) was achieved when the amiodarone
was given within 4 to 16 minutes of dispatch, there was no
significant difference in the proportional improvement in the

om
doses (125 and 1000 mg/d) with bretylium (2500 mg/d).42 amiodarone group compared with the placebo group when
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Once again, the target amiodarone dose ratio of 8:1 was drug administration was delayed (up to 55 minutes). Amio-

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compressed to 1.8:1 because of open-label boluses. There darone also had the highest efficacy in patients (21% of all
was no significant difference in the primary outcome, which study patients) who had a return of spontaneous circulation
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was median VT/VF recurrence rate over 24 hours. For low- before drug administration (survival to hospital admission
sf

f
ks

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dose amiodarone, high-dose amiodarone, and bretylium, increased to 64% from 41% in the placebo group). Among
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these rates were 1.68, 0.48, and 0.96 events per 24 hours, patients with no return of spontaneous circulation, amioda-
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respectively (p = .237). There was no difference between high- rone only slightly improved outcome (38% vs 33%).
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dose amiodarone and bretylium; however, more than 50% of Dorian performed a randomized trial comparing intrave-
patients had crossed over from bretylium to amiodarone by nous lidocaine with intravenous amiodarone as an adjunct
m

m
16 hours. to defibrillation in victims of out-of-hospital cardiac arrest.48
The failure of these studies to provide clear evidence of Patients were enrolled if they had out-of-hospital ventricular
amiodarone efficacy may be related to the “active-control fibrillation resistant to three shocks, intravenous epineph-
m

m
study design” used, a lack of adequate statistical power, high rine, and a further shock or if they had recurrent ventricu-
rates of supplemental amiodarone boluses, and high cross- lar fibrillation after initially successful defibrillation. They
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over rates. Nonetheless, these studies provide some evidence were randomly assigned in a double-blind manner to receive
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that IV amiodarone (1 g/d) is moderately effective during a intravenous amiodarone plus lidocaine placebo or intrave-
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24-hour period against VT and VF. nous lidocaine plus amiodarone placebo. The primary end
point was the proportion of patients who survived to be
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admitted to the hospital. In total, 347 patients (mean age
Sustained Monomorphic Ventricular 67 ± 14 years) were enrolled. The mean interval between the
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Tachycardia and Wide QRS Tachycardia time at which paramedics were dispatched to the scene of the
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Although the most effective and rapid treatment of any hemo- cardiac arrest and the time of their arrival was 7 ± 3 minutes,
dynamically unstable sustained ventricular tachyarrhythmia and the mean interval from dispatch to drug administra-
m

is electrical cardioversion or defibrillation, intravenous antiar-
rhythmic drugs can be used for arrhythmia termination if the
VT is hemodynamically stable. The Guidelines for Emergency
m
m
tion was 25 ± 8 minutes. After treatment with amioda-
rone, 22.8% of 180 patients survived to hospital admission
compared with 12.0% of 167 patients treated with lidocaine

m
Cardiovascular Care19 has removed the former recommen- (p = .009). Among patients for whom the time from dispatch
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dation of lidocaine and adenosine use in stable wide QRS to the administration of the drug was equal to or less than
tachycardia, now labeled as “acceptable” but not primarily the median time (24 minutes), 27.7% of those given amioda-
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recommended (lidocaine) or not recommended (adenosine). rone and 15.3% of those given lidocaine survived to hospital
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Intravenous procainamide and sotalol are effective, based on admission (p = .05). The authors concluded that compared
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randomized but small studies;10 amiodarone is also consid- with lidocaine, amiodarone leads to substantially higher rates
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of survival to hospital admission in patients with shock-
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ered acceptable.19
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resistant out-of-hospital ventricular fibrillation.

Shock-Resistant Ventricular Fibrillation
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Supraventricular Arrhythmias
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The Guidelines for Emergency Cardiovascular Care recom-

mends at least three shocks and epinephrine or vasopressin A supraventricular arrhythmia is any tachyarrhythmia that
before any antiarrhythmic drug are administered.10,19 No requires atrial or AV junctional tissue for initiation and
large-scale controlled, randomized studies have demonstrated maintenance. It may arise from reentry caused by unidirec-
m

efficacy for lidocaine, bretylium, or procainamide in shock- tional conduction block in one region of the heart and slow
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resistant VF,10,19 and lidocaine and bretylium are no longer conduction in another, from enhanced automaticity akin to
recommended in this setting.19 Two pivotal studies have been that seen in normal pacemaker cells of the sinus node and in
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reported recently studying the efficacy of agents in acute latent pacemaker cells elsewhere in the heart, or from trig-
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shock-resistant cardiac arrest. gered activity, a novel type of abnormally enhanced impulse
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Part I  Fundamentals

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initiation caused by membrane currents that can be activated a double-blind fashion to IV amiodarone (1 g/d for 2 days)
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and inactivated by premature stimulation or rapid pacing.56-58 versus placebo immediately after open-heart surgery.54 The

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Pharmacologic approaches to treating supraventricular primary end points of the trial were incidence of AF and

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arrhythmias, including AF, atrial flutter, atrial tachycardia, length of hospital stay. AF occurred in 67 of 142 (47%)
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AV reentrant tachycardia, and AV nodal reentrant tachycar- patients on placebo versus 56 of 158 (35%) on amiodarone
dia, continue to evolve.56-60 Because AF is perhaps the most (p = .01). Length of hospital stay for the placebo group
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common arrhythmia after cardiac surgery, this condition is was 8.2 ± 6.2 days, and 7.6 ± 5.9 days for the amiodarone
m

m
emphasized in detail. group. Low-dose IV amiodarone was safe and effective in
reducing the incidence of AF after heart surgery but did not
significantly alter length of hospital stay.
Atrial Fibrillation In summary, AF is a frequent complication of cardiac
m

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Atrial fibrillation is a common complication of cardiac sur- surgery. Many cases can be prevented with appropriate
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prophylactic therapy. Beta-adrenergic blockers should be

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gery that increases the length of stay in the hospital with
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resulting increases in health-care resource utilization.56-61 administered to most patients without contraindication.
Prophylactic amiodarone should be considered in patients
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Advanced age, previous AF, and valvular heart operations are
the most consistently identified risk factors for this arrhyth- at high risk for postoperative AF. The lack of data on cost-
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mia. Because efforts to terminate AF after its initiation are benefits and cost-efficiency in some studies may reflect the
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problematic, current interests are directed at therapies to pre- lack of higher-risk patients in the study. Patients who are
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vent postoperative AF. Most studies suggest that prophylaxis poor candidates for beta-blockade may not tolerate sotalol,
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with antiarrhythmic compounds can decrease the incidence whereas amiodarone does not have this limitation. Additional
of AF, length of hospital stay, and cost significantly. Class III studies also need to be performed to better assess the role of
m

m
antiarrhythmic drugs (eg, sotalol and ibutilide) also may be prophylactic therapy in off-pump cardiac surgery.
effective but potentially pose the risk of drug-induced poly-
morphic VT (torsades de pointes). Newer intravenous agents
INOTROPIC AGENTS
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including vernakalant were investigated but in the current
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Food and Drug Administration (FDA) era of drug safety Some depression of myocardial function is common after car-
concerns, antiarrhythmic agents are difficult to get approved. diac surgery.63-65 The etiology is multifactorial—preexisting
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Defining which subpopulations benefit most from such disease, incomplete repair or revascularization, myocardial
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therapy is important as older and more critically ill patients edema, postischemic dysfunction, reperfusion injury, etc—
undergo surgery. Intravenous sotalol is currently available in and usually is reversible. Adequate cardiac output usually can
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the United States. be maintained by exploiting the Starling curve with higher
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Amiodarone is also an effective approach for prophylac- preload, but often the cardiac function curve is flattened, and
tic therapy of AF. Intravenous amiodarone is an important it is necessary to use inotropic agents to maintain adequate
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consideration because loading with oral therapy is often not organ perfusion.
feasible in part owing to the time required. There also may be The molecular basis for the contractile property of the
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added benefits of prophylactic therapies in high-risk patients,
especially those prone to ventricular arrhythmias (ie, patients
with preexisting HF).
m
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heart is the interaction of the proteins actin and myosin, in
which chemical energy (in the form of ATP) is converted into
mechanical energy. In the relaxed state (diastole), the inter-

m
Two studies deserve mention regarding prophylaxis with action of actin and myosin is inhibited by tropomyosin, a
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amiodarone. To determine if IV amiodarone would pre- protein associated with the actin-myosin complex. With the
vent AF and decrease hospital stay after cardiac surgery, onset of systole, Ca2+ enters the myocyte (during phase 1 of
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Daoud and colleagues assessed preoperative prophylaxis the action potential). This influx of Ca2+ triggers the release
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in 124 patients who were given either oral amiodarone of much larger amounts of Ca2+ from the sarcoplasmic reticu-
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(64 patients) or placebo (60 patients) for a minimum of 7 lum. The binding of Ca2+ to the C subunit of the protein
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days before elective cardiac surgery.62 Therapy consisted of troponin interrupts inhibition of the actin-myosin inter-
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600 mg amiodarone per day for 7 days and then 200 mg/d action by tropomyosin, facilitating the hydrolysis of ATP
until the day of discharge from the hospital. The preopera- with the generation of a mechanical force. With repolar-
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tive total dose of amiodarone was 4.8 ± 0.96 g over 13 ± 7 ization of the myocyte and completion of systole, Ca2+
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days. Postoperative AF occurred in 16 of the 64 patients in
the amiodarone group (25%) and 32 of the 60 patients in
the placebo group (53%). Patients in the amiodarone group
were hospitalized for significantly fewer days than were
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is taken back up into the sarcoplasmic reticulum, allowing
tropomyosin to again inhibit the interaction of actin and
myosin with consequent relaxation of contractile force. Thus
inotropic action is mediated by intracellular Ca2+.66 A novel

patients in the placebo group (6.5 ± 2.6 vs 7.9 ± 4.3 days; drug, levosimendan, currently under clinical development
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p = .04). Total hospitalization costs were significantly less in the United States but approved in several countries,
for the amiodarone group than those for the placebo group increases the sensitivity of the contractile apparatus to Ca2+,67
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($18,375 ± $13,863 vs $26,491 ± $23,837; p = .03). Guar- whereas the positive inotropic agents available for clinical use
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nieri and colleagues evaluated 300 patients randomized in achieve their end by increasing intracellular Ca2+ levels.
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Chapter 4  Cardiac Surgical Pharmacology

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The first drug to be considered is simply Ca2+ itself. In period. Although there are differences in their binding at the
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general, administration of calcium will increase the inotropic beta1 receptor, the most important differences between the

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state of the myocardium when measured by load-independent various catecholamines are their relative effects on alpha- and

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methods, but it also will increase vascular tone (afterload) and beta2 adrenergic receptors. In general, alpha receptor stimu-
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impair diastolic function. In addition, the effects of calcium lation on the peripheral vasculature causes vasoconstriction,
on myocardial performance depend on the plasma Ca2+ con- whereas beta2 receptor stimulation leads to vasodilation (see
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centration. Ca2+ plays important roles in cellular function, the discussion elsewhere in this chapter). For some time it was
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and the intracellular Ca2+ concentration is highly regulated
by membrane ion channels and intracellular organelles.68,69 If
the extracellular Ca2+ concentration is normal, administration
of Ca2+ will have little effect on the intracellular level and less
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believed that beta2 and alpha receptors were found only in the
peripheral vasculature, as well as in a few other organs, but not
in the myocardium. However, alpha receptors are also found
in the myocardium and mediate a positive inotropic effect.5,6

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pronounced hemodynamic effects. On the other hand, if the The mechanism for this positive inotropic effect is probably
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ionized plasma calcium concentration is low, exogenous cal- the stimulation of phospholipase C, leading to hydrolysis of

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cium administration may increase cardiac output and blood phosphatidyl inositol to diacylglycerol and inositol triphos-
pressure.70 It also should be realized that even with normal phate, compounds that increase Ca2+ release from the sarco-
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plasma Ca2+ concentrations, administration of Ca2+ may plasmic reticulum and increase myofilament sensitivity to
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increase vascular tone, leading to increased blood pressure Ca2+. It is also possible that alpha-adrenergic agents increase
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but no change in cardiac output. This increased afterload, intracellular Ca2+ by prolonging action potential duration by
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as well as the deleterious effects on diastolic function, may inhibition of outward K+ currents during repolarization or by
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be the basis of the observation that Ca2+ administration can activating the Na+/H+ exchange mechanism, increasing intra-
blunt the response to epinephrine.71 Routine use of Ca2+ at cellular pH and increasing myofilament sensitivity to Ca2+.
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the end of bypass should be tempered by the realization that
Ca2+ may have little effect on cardiac output while increasing
systemic vascular resistance, although this in itself may be of
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Just as the exact mechanism is uncertain, the exact role of
alpha-adrenergic stimulation in control of the inotropic state
is unclear, although it is apparent that onset of the effect is

m
importance. If there is evidence of myocardial ischemia, Ca2+ slower than that of beta1 stimulation.
administration may be deleterious because it may exacerbate Besides the discovery of alpha receptors in the myocar-
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both coronary spasm and the pathways, leading to cellular dium, beta2 receptors are present in the myocardium.74 The
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injury.72,73 fraction of beta2 receptors (compared with beta1 receptors) is
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Digoxin, although not effective as acute therapy for low- increased in chronic HF, possibly explaining the efficacy of
cardiac-output syndrome in the perioperative period, never- drugs with beta2 activity in this setting. This phenomenon
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theless well illustrates the role of intracellular Ca2+. Digoxin is part of the general observation of beta1 receptor down-
functions by inhibiting Na+, K+-ATPase, which is responsible regulation (decrease in receptor density) and desensitization
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for the exchange of intracellular Na+ with extracellular K+.3,4 (uncoupling of effect from receptor binding) that is observed
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It is thus responsible for maintaining the intracellular/extra- in chronic HF.75 Interestingly, it has been demonstrated in a
cellular K+ and Na+ gradients. When it is inhibited, intra- dog model that this same phenomenon occurs with cardio-
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cellular Na+ levels increase. The increased intracellular Na+
is an increased chemical potential for driving the Ca2+/Na+
exchanger, an ion exchange mechanism in which intracellular
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pulmonary bypass (CPB).76 In this situation, a newer class of
drugs, the phosphodiesterase inhibitors, may be of benefit.
These drugs, typified by the agents available in the United

m
Na+ is removed from the cell in exchange for Ca2+. The net States, amrinone and milrinone, increase cyclic AMP levels
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effect is an increase in intracellular Ca2+ with an enhancement independently of the beta receptor by selectively inhibiting
of the inotropic state. the myocardial enzyme responsible for the breakdown of
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The most commonly used positive inotropic agents are the cyclic AMP.3,4
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beta-adrenergic agonists. The beta1 receptor is part of a com-

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In clinical use, selection of a particular inotropic agent
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plex consisting of the receptor on the outer surface of the cell usually is based more on its side effects than its direct ino-
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membrane and membrane-spanning G proteins (so named tropic properties. Of the commonly used catecholamines,
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because they bind GTP), which in turn stimulate adenylate norepinephrine has alpha and beta1 but little beta2 activity
cyclase on the inner surface of the membrane, catalyzing the and is both an inotrope and a vasopressor. Epinephrine and
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formation cyclic adenosine monophosphate (cyclic AMP). dopamine are mixed agonists with alpha, beta1, and beta2
The inotropic state is modulated by cyclic AMP via its cataly- activities. At lower doses, they are primarily inotropes and
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sis of phosphorylation reactions by protein kinase A. These not vasopressors, although vasopressor effects become more
phosphorylation reactions “open” Ca2+ channels on the cell pronounced at higher doses. This is especially true for dopa-
membrane and lead to greater release and uptake of Ca2+ from mine, which achieves effects at higher doses by stimulat-
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the sarcoplasmic reticulum.3,4 ing the release of norepinephrine.77 Dobutamine is a more

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There are many drugs that stimulate beta1 receptors and selective beta1 agonist, in contrast to isoproterenol, which
have a positive inotropic effect, including epinephrine, nor- is a mixed beta agonist. Selection of a drug depends on the
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epinephrine, dopamine, isoproterenol, and dobutamine, the particular hemodynamic problem at hand. For example, a
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most commonly used catecholamines in the perioperative patient with depressed myocardial function in the presence of
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Part I  Fundamentals

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profound vasodilation may require a drug with both positive is well tolerated without arrhythmogenicity. In addition to
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inotropic and vasopressor effects, whereas a patient who is sensitizing troponin to intracellular calcium, levosimen-

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vasoconstricted may benefit from some other choice. Recent dan inhibits phosphodiesterase III and open ATP-sensitive

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studies report that in patients with myocardial infarction potassium channels (KATP), which may produce vasodilation.
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(MI) who develop cardiogenic shock, dopamine increases Unlike currently available intravenous inotropes, levosimen-
mortality compared to norepinephrine.78,79 On the basis of dan does not increase myocardial oxygen use and has been
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multiple considerations, we recommend an empiric approach used effectively in beta-blocked patients. Levosimendan does
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to selecting inotropic agents with careful monitoring of the
response to the drug and selection of the agent that achieves
the desired effect.
Clinical experience suggests that phosphodiesterase
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not impair ventricular relaxation. Clinical studies have dem-
onstrated short-term hemodynamic benefits of levosimendan
over both placebo and dobutamine. Although large-scale,
long-term morbidity and mortality data are scarce, the Levo-

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inhibitors are effective when catecholamines do not produce simendan Infusion versus Dobutamine in Severe Low-Out-
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an acceptable cardiac output. Milrinone is the phosphodi- put Heart Failure (LIDO) study suggested a mortality benefit

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esterease most used, and amrinone is no longer available. of levosimendan over dobutamine. Clinical studies compar-
Enoximone, a similar agent with different pharmacokinetic ing levosimendan with other positive inotropes, namely, mil-
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properties, was used in Europe but not available in the United rinone, are lacking. Currently, this agent is being evaluated in
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States. All agents increase contractility with minimal effect a clinical trial in North America for patients with left ventric-
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on heart rate, and both are vasodilators. There is significant ular dysfunction undergoing CPB (https://clinicaltrials.gov/
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venodilation, as well as pulmonary and systemic vasodilation, ct2/show/NCT02025621?term=levosimendan&rank=14).
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and maintaining adequate preload is important in avoiding
hypotension.80-82 Administering the loading dose over 15 to
Clinical Trials
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30 minutes may also attenuate possible hypotension, or alter-
nately starting an infusion alone without loading is an alter-
native method. Plasma levels drop rapidly after a loading dose
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Despite their common use after cardiac surgery, there have
been relatively few comparative studies of inotropic agents in

m
because of redistribution, and the loading dose should be the perioperative period. In 1978, Steen reported the hemo-
followed immediately by a continuous infusion.82-84 Because dynamic effects of epinephrine, dobutamine, and epineph-
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of their longer half-lives, it is rather more difficult to readily rine immediately after separation from CPB.91 The largest
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titrate plasma levels than with catecholamines (which have mean increase in cardiac index was achieved with dopamine at
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plasma half-lives of a few minutes). 15 mcg/kg per minute. However, it should be noted that the
Phosphodiesterase inhibitors, specifically milrinone, only epinephrine dose studied was 0.04 mcg/kg per minute. In
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facilitate separation from CPB with biventricular dysfunc- a later comparison of dopamine and dobutamine, Salomon con-
tion and are used for treating low-cardiac-output syndrome cluded that dobutamine produced more consistent increases
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after cardiac surgery.82-86 Doolan and colleagues also demon- in cardiac index, although the hemodynamic differences were
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strated that milrinone, in comparison with placebo, signifi- small, and all patients had good cardiac indices at the onset
cantly facilitated separation of high-risk patients from CPB.87 of the study.92 Fowler also found insignificant differences
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Despite the extensive use of pharmacologic therapy, there are
no convincing data to support a distinct inotropic or vasodi-
lator drug-based therapy as a superior solution to treat biven-
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in the hemodynamic effects of dobutamine and dopamine,
although they reported that coronary flow increased more in
proportion to myocardial oxygen consumption with dobuta-

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tricular dysfunction and/or potentially reduce mortality in mine.93 Although neither of these groups reported significant
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hemodynamically unstable patients with cardiogenic shock increases in heart rate for either dopamine or dobutamine,
or low cardiac output, especially complicating an acute MI.88 clinical experience has been otherwise. This is supported by
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a study by Sethna, who found that the increase in cardiac
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Levosimendan index with dobutamine occurs simply because of increased

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heart rate, although they found that myocardial oxygen was

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Levosimendan is a class of drugs known as calcium sensitiz- maintained.94 Butterworth subsequently demonstrated that
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ers. The molecule is a pyridazinone-dinitrile derivative with the older and much cheaper agent, epinephrine, effectively
additional action on ATP-sensitive potassium channels.67,89,90 increased stroke volume without as great an increase in heart
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Levosimendan is used intravenously for treating decompen- rate as dobutamine.95 More recently, Feneck compared dobuta-
sated HF because it increases contractility and produces anti- mine and milrinone and found them to be equally effective in
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stunning effects without increasing myocardial intracellular treating low-cardiac-output syndrome after cardiac surgery.96
calcium concentrations or prolonging myocardial relaxation. This study was a comparison of two drugs, and the investiga-
Levosimendan also causes coronary and systemic vasodila- tors emphasized that the most efficacious therapy is probably a
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tion. In patients with HF, IV levosimendan reduced worsen- combination of drugs. In particular, phosphodiesterase inhibi-
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ing HF or death significantly. IV levosimendan significantly tors require the synthesis of cyclic AMP to be effective, and
also increased cardiac output and decreased filling pressure in thus use of a combination of a beta1-adrenergic agonist and
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decompensated HF in large, double-blind, randomized tri- a phosphodiesterase inhibitor would be predicted to be more
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als and after cardiac surgery in smaller trials. Levosimendan effective than either agent alone.
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Chapter 4  Cardiac Surgical Pharmacology

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Finally, while global hemodynamic goals (ie, heart rate, is deficiency of vasopressin. As noted earlier, CPB often
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blood pressure, filling pressures, and cardiac output) may induces the release of vasopressin, and this may contribute

sf
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be achieved with inotropic agents, this does not guarantee to the excessive vasoconstriction sometimes seen after CPB.

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adequate regional perfusion, in particular renal and mesen- However, it has been observed in several experimental models
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teric perfusion. So far there have been few investigations of of shock that the initially high levels of vasopressin decrease
regional perfusion after cardiac surgery. There has been more as shock persists, leading some investigators to suggest that
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interest in regional (especially mesenteric) perfusion in the vasopressin stores are limited and are depleted by the initial
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critical care medicine literature, and some of the studies
may be relevant to postoperative care of the cardiac surgi-
cal patient. Two studies have indicated that epinephrine may
impair splanchnic perfusion, especially in comparison with
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response to hypotension.
Excessive vasodilation during shock usually is treated with
catecholamines, most typically phenylephrine, dopamine,
epinephrine, or norepinephrine.103 Although catecholamines

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combining norepinephrine and dobutamine.97,98 Norepi- produce both alpha- and beta-adrenergic effects, alpha1-
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nephrine alone has variable effects on splanchnic blood flow adrenergic receptor stimulation produces vasoconstriction.

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in septic shock,99 although adding dobutamine can improve As noted, stimulation of these receptors activates membrane
splanchnic perfusion significantly when blood pressure is sup- phospholipase C, which in turn hydrolyzes phosphatidylino-
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ported with norepinephrine.98 Low-dose dopamine improves sitol 4,5-diphosphate.7 This leads to the subsequent genera-
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splanchnic blood flow,100 but there is evidence that dopamine tion of two second messengers, including diacyl glycerol and
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in higher doses impairs gastric perfusion.101 The relevance of inositol triphosphate. Both these second messengers increase
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these studies of septic patients for the cardiac surgical patient cytosolic Ca2+ by different mechanisms, which include facili-
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is unclear, although there are similarities between the inflam- tating release of calcium from the sarcoplasmic reticulum and
matory responses to CPB and to sepsis. potentially increasing the calcium sensitivity of the contrac-
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tile proteins in vascular smooth muscle.
Mediator-induced vasodilation often is poorly responsive
VASOPRESSORS to catecholamines,103 and the most potent pressor among cat-
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CPB often is characterized by derangements of vascular tone. echolamines, norepinephrine, is required frequently. Some
Sometimes CPB induces elevations in endogenous catechol- clinicians are concerned about renal, hepatic, and mesenteric
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amines, as well as other mediators, such as serotonin and argi- function during norepinephrine administration. However,
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nine vasopressin (AVP), leading to vasoconstriction. However, in septic patients, norepinephrine can improve renal func-
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more often CPB is characterized by a systemic inflammatory tion,102-107 and there is evidence that it may improve mesen-
response, with a cascade of cytokine and inflammatory medi- teric perfusion as well.108 Given the hemodynamic similarities
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ator release and profound vasodilation. The pathophysiology between septic patients and some patients at the end of CPB,
has a striking resemblance to that of sepsis or an anaphylactic these results often are extrapolated to the cardiac surgical
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reaction. Further, vasodilation after cardiac surgery may be patient but have not been confirmed by a systematic study.
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exacerbated by the preoperative use of angiotensin-convert- In some cases of profound vasodilatory shock, even norepi-
ing enzyme (ACE) inhibitors and post-CPB use of milrinone. nephrine is inadequate to restore systemic blood pressure.
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The mechanisms of vasodilatory shock have been reviewed
previously.102 Vascular tone is modulated by intracellular
Ca2+, which binds calmodulin. The Ca2+-calmodulin com-
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In this situation, low doses of vasopressin may be useful.
Argenziano109 studied 40 patients with vasodilatory shock
(defined as a mean arterial blood pressure of less than 70 mm

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plex activates myosin light-chain kinase, which catalyzes the Hg with a cardiac index greater than 2.5 L/m2 per minute)
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phosphorylation of myosin to facilitate the interaction with after cardiac surgery. AVP levels were inappropriately low
actin. Conversely, intracellular cyclic GMP activates myosin in this group of patients, and low-dose vasopressin infusion
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phosphatase (also via a kinase-mediated phosphorylation (≤0.1 U/min) effectively restored blood pressure and reduced
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of myosin phosphatase), which dephosphorylates myosin norepinephrine requirements without significantly changing
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and inhibits the interaction of actin and myosin. A primary cardiac index. These observations were similar to an earlier
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mediator of vasodilatory shock is nitric oxide (NO), which report of the use of vasopressin in vasodilatory septic shock.110
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is induced by cytokine cascades. NO activates guanylate Vasopressin also has been reported to be useful in treating
cyclase, with resulting loss of vascular tone. Another mecha- milrinone-induced hypotension.111 In this latter report, vaso-
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nism of vasodilation that may be particularly relevant to pro- pressin was reported to increase urine output, presumably via
longed CPB is activation of ATP-sensitive potassium (KATP) glomerular efferent arteriole constriction. However, the over-
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channels. These channels are activated by decreases in cellular all effects on renal function are unclear. In addition, there
ATP or increases in hydrogen ion or lactate. All these could are still important unanswered questions about vasopressin
result from the abnormal perfusion associated with CPB and/ and mesenteric perfusion. Although vasopressin effectively
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or hypothermia. Increases in potassium channel conductance may restore blood pressure in vasodilatory shock, it must be
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result in hyperpolarization of the vascular smooth muscle remembered that in physiologic concentrations it is a mes-
membrane, which decreases Ca2+ flux into the cell, leading to enteric vasoconstrictor, and mesenteric hypoperfusion may
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decreased vascular tone. A third mechanism of vasodilatory be a factor in developing sepsis and multiorgan dysfunction
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shock that also may be particularly relevant to cardiac surgery syndrome.

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Part I  Fundamentals

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VASODILATORS Nitrates, Nitrovasodilators, and
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Stimulation of Guanylyl Cyclase

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Different pharmacologic approaches are available to produce
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(Cyclic GMP)

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vasodilation (Table 4-1). Potential therapeutic approaches
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include (1) blockade of alpha1-adrenergic receptors, ganglionic The vascular endothelium modulates vascular relaxation by
transmission, and calcium channel receptors; (2) stimulation
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releasing both nitric oxide and prostacyclin.114-116 Inflamma-
of central alpha2-adrenergic receptors or vascular guanylate tory mediators also can stimulate the vascular endothelium
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cyclase and adenylate cyclase; and (3) inhibition of phospho-
diesterase enzymes and ACEs.112 Adenosine in low concentra-
tions is also a potent vasodilator with a short half-life, but it is
used, as noted earlier, for its ability to inhibit AV conduction.
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to release excessive amounts of endothelium-derived relax-
ing factor (EDRF, or nitric oxide), which activates guany-
lyl cyclase to generate cyclic GMP.89,90 Nitrates and sodium

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nitroprusside, however, generate nitric oxide directly, inde-
Losartan, a novel angiotensin II (AII) antagonist, has just been pendent of vascular endothelium.115,116 The active form of any
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released for treating hypertension but is not available for intra-

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nitrovasodilator is nitric oxide (NO), in which the nitrogen is
venous use.
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in a +2 oxidation state. For any nitrovasodilator to be active,
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it first must be converted to NO. For nitroprusside, this is
Stimulation of Adenylate Cyclase easily accomplished because nitrogen is in a +3 oxidation
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(Cyclic AMP) state, with the nitric oxide molecule bound to the charged
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iron molecule in an unstable manner, allowing nitroprusside

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Prostacyclin, prostaglandin E1, and isoproterenol increase cyclic
to readily donate its nitric oxide moiety. For nitroglycerin,
nucleotide formation (eg, adenosine-3′,5′-monophosphate
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nitrogen molecules exist in a +5 oxidation state, and thus they
and cyclic AMP) in vascular smooth muscle to produce cal-
must undergo significant metabolic transformations before
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cium mobilization out of vascular smooth muscle. Inhibit-
they are converted to an active molecule. Nitroglycerin is a
ing the breakdown of cyclic AMP by phosphodiesterase also
selective coronary vasodilator and does not produce coronary
will increase cyclic AMP.112 Increasing cyclic AMP in vascular
steal compared with nitroprusside because the small intra-
smooth muscle facilitates calcium uptake by intracellular
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coronary resistance vessels, those less than 100 μm thick, lack
storage sites, thus decreasing calcium available for contrac-
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whatever metabolic transformation pathway is required to
tion. The net effect of increasing calcium uptake is to produce
convert nitroglycerin into its active form of nitric oxide.115,116
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vascular smooth muscle relaxation and hence vasodilation.
Chronic nitrate therapy can produce tolerance through dif-
However, most catecholamines with beta2-adrenergic activity
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ferent mechanisms.114-118 Sodium nitroprusside and nitroglyc-
(eg, isoproterenol) and phosphodiesterase inhibitors have posi-
erin are effective vasodilators that produce venodilation that
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tive inotropic and other side effects that include tachycardia,
contributes significantly to the labile hemodynamic state.114
glycogenolysis, and kaluresis.113 Prostaglandins (ie, prostacyclin
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Intravenous volume administration often is required with
and prostaglandin E1) are potent inhibitors of platelet aggre-
nitroprusside owing to the relative intravascular hypovolemia.
gation and activation. Catecholamines with beta2-adrenergic
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activity, phosphodiesterase inhibitors, and prostaglandin E1
Dihydropyridine Calcium Channel
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and prostacyclin have been used to vasodilate the pulmonary
circulation in patients with pulmonary hypertension and right Blockers
ventricular failure (see Table 4-1).113
Dihydropyridine calcium channel blockers are direct arterial
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vasodilators.119 Nifedipine was the first dihydropyridine cal-
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cium channel blocker, and intravenous forms studied in cardiac
TABLE 4-1:  Vasodilators Used in the surgery include clevidipine, isradipine, and nicardipine. These
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Treatment of Hypertension, Pulmonary agents are selective arterial vasodilators that have no effects on
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Hypertension, and Heart Failure the vascular capacitance bed, AV nodal conduction, or negative
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inotropic effects.120-125 Clevidipine and nicardipine are available

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Angiotensin-converting enzyme inhibitors
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in the United States and offer novel and important therapeutic

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Angiotensin II antagonists
options to treat perioperative hypertension following cardiac
Alpha1-adrenergic antagonists (prazosin)
surgery. Also, intravenous dihydropyridines can be used to
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Alpha2-adrenergic agonists (clonidine)

treat acute hypertension that occurs during the perioperative
Endothelin antagonists
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period (ie, intubation, extubation, CPB-induced hypertension,

Nitrates
and aortic cross-clamping) and postoperative hypertension.
Nitric oxide
Hydralazine
Phosphodiesterase Inhibitors
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Phosphodiesterase inhibitors (milrinone, sildenafil)

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Prostacyclin, PGE1 Two major classes of phosphodiesterase inhibitors are currently

Calcium channel blockers available for use. Milrinone is a prototypic type III inhibi-
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Dihydropyridine agents (clevidipine, nicardipine, amlodipine) tor that is cyclic AMP specific, as previously described, and
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Chapter 4  Cardiac Surgical Pharmacology

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produces both positive inotropic effects and vasodilation.126 offer advantages over ACE inhibitors for heart failure therapy
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When administered to patients with ventricular dysfunction, in terms of tolerability and more complete A-II blockade.

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milrinone increases cardiac output, venodilates, vasodilates, Although ARBs were better tolerated, all-cause mortality

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and is a pulmonary vasodilator. Sildenafil is a type V-specific and the number of sudden deaths or resuscitated cardiac
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inhibitor that is cyclic GMP specific and is a pulmonary and arrests were not different when losartan (Cozaar) and capto-
systemic vasodilator without a primary inotropic response, pril (Capoten) were compared in patients (>60 years of age,
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although isotypes for phosphodiesterases exist. Because of their New York Heart Association (NYHA) classes II to IV, left-
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unique mechanisms of vasodilation, these agents are especially
useful for patients with acute pulmonary vasoconstriction
and right ventricular dysfunction. Multiple forms of the drug
are available including bipyridines (eg, amrinone and milri-
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ventricular ejection fraction (LVEF) <40%).128 Perioperative
hypotension may be encountered in ARB-treated patients as
well as ACE inhibitor-treated patients, and increased inotro-
pic support may be required.

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none), imidazolones (eg, enoximone), and methylxanthines
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(eg, aminophylline), and sildenafil. Papaverine, a benzyl iso-

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quinolinium derivative isolated from opium, is a nonspecific
phosphodiesterase inhibitor and vasodilator used by cardiac BETA-ADRENERGIC RECEPTOR
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surgeons for its ability to dilate the internal mammary artery.126 BLOCKERS
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Not surprisingly, most of the effects observed after administra-
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Angiotensin-Converting Enzyme
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tion of a beta-adrenergic receptor blocker reflect the reduced
Inhibitors responsiveness of tissues containing beta-adrenergic receptors
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to catecholamines present in the vicinity of those receptors.
ACE inhibitors have growing use in managing HF, and more Hence the intensity of the effects of beta-blockers depends on
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patients are receiving these drugs. The ACE inhibitors prevent
the conversion of angiotensin I to angiotensin II by inhibit-
ing an enzyme called kininase in the pulmonary and systemic
m
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both the dose of the blocker and the receptor concentrations
of catecholamines, primarily epinephrine and norepineph-
rine. In fact, a purely competitive interaction of beta-blockers

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vascular endothelium. This enzyme is also important for the and catecholamines can be demonstrated in normal human
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metabolism of bradykinin, a potent endogenous vasodilator, volunteers as well as in isolated tissues studied in the labora-
and for release of EDRF. Although there are little data in the tory. The presence of disease and other types of drugs modi-
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literature regarding the preoperative management of patients fies the responses to beta-blockers observed in patients, but the
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receiving these drugs, withholding them on the day of sur- underlying competitive interaction is still operative. The key to
gery has been our clinical practice based on their potential to successful use of beta-adrenergic receptor blockers is to titrate
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produce excessive vasodilation during CPB. Although Tuman the dose to the desired degree of effect and to remember that
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was unable to find any difference in blood pressure during excessive effects from larger than necessary doses of beta-adren-
CPB in patients receiving ACE inhibitors, contact activation ergic receptor blockers can be overcome by (1) administering
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during CPB has the ability to generate bradykinin and thus a catecholamine to compete at the blocked receptors; and/or
amplify the potential for vasodilation. The vasoconstrictor (2) administering other types of drugs to reduce the activity
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requirements were increased after bypass in his study. of counterbalancing autonomic mechanisms that are unop-
posed in the presence of beta-receptor blockade. An example
Angiotensin II-Receptor Blockers of the latter is propranolol-induced bradycardia, which reflects
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the increased dominance of the vagal cholinergic mechanism
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ACE inhibitors may not be tolerated in some patients owing on cardiac nodal tissue. Excessive bradycardia may be relieved
to cough (common) and angioedema (rare). Inhibition of by administering atropine to block the cholinergic receptors,
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kininase II by ACE inhibitors leads to bradykinin accumula- which are also located in the SA and AV nodes (see Table 4-2).
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tion in the lungs and vasculature, causing cough and vaso- Knowledge of the type, location, and action of beta recep-
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dilation. Alternative treatment with angiotensin II-receptor tor is fundamental to understanding and predicting effects
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blockers (ARBs) may be associated less frequently with these
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of beta-adrenergic receptor-blocking drugs129 (see Table 4-2).

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side effects because ARBs do not affect kinin metabolism. Six Beta-adrenergic receptor blockers are competitive inhibitors;
ARBs are currently available for antihypertensive therapy in hence, the intensity of blockade depends on both the dose of
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the United States: losartan (Cozaar), valsartan (Diovan), irbe- the drug and the receptor concentrations of catecholamines,
sartan (Avapro), candesartan (Atacand), eprosartan (Teveten),
m

primarily epinephrine and norepinephrine.

and telmisartan (Micardis). Mortality in chronic HF is related Beta-adrenergic receptor antagonists (blockers) include
to activation of the autonomic nervous and renin-angiotensin many drugs (Table 4-3) that typically are classified by their
systems, and ACE inhibitor therapy seems to attenuate pro- relative selectivity for beta1 and beta2 receptors (ie, cardioselec-
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gression of myocardial dysfunction and remodeling. ACE tive or nonselective), the presence or absence of agonistic activ-
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inhibitors do not completely block angiotensin II (A-II) ity, membrane-stabilizing properties, alpha-receptor-blocking
production,127 and may even increase circulating A-II levels efficacy, and various pharmacokinetic features (eg, lipid solu-
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in patients with HF. It was thought initially that ARBs might bility, oral bioavailability, and elimination half-time).129 The
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Part I  Fundamentals

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TABLE 4-2:  Location and Actions of Beta-Adrenergic Receptors

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Tissue Receptor Action Opposing Actions

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Heart      
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Sinus and AV nodes 1 ↑ Automaticity Cholinergic receptors
Conduction pathways 1 ↑ Conduction velocity Cholinergic receptors
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    ↑ Automaticity Cholinergic receptors
Myofibrils 1 ↑ Contractility —
    ↑ Automaticity —
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Vascular smooth muscle (arterial, venous) 2 Vasodilation Alpha-adrenergic receptors
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Bronchial smooth muscle 2 Bronchodilation Cholinergic receptors

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Kidneys 1 ↑ Renin release (juxtaglomerular cells) Alpha1-adrenergic receptors
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Liver 2 ↑ Glucose metabolism Alpha1-adrenergic receptors
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    ↑ Lipolysis  
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Fat/adipose tissue 3 ↑ Lipolysis —
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Skeletal muscle 2 ↑ Potassium uptake glycogenolysis —

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Eye, ciliary muscle 2 Relaxation Cholinergic receptors
↑ Motility
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GI tract 2 Cholinergic receptors
Gallbladder 2 Relaxation Cholinergic receptors
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Urinary bladder detrussor muscle 2 Relaxation Cholinergic receptors
Uterus 2 Relaxation Oxytocin
Platelets 2 ↓ Aggregation Alpha2-adrenergic receptors
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(aggregation)
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practitioner must realize that the selectivity of individual drugs beta-blocking action. Beta-adrenergic blocking agents also
for beta1 and beta2 receptors is relative, not absolute. For exam- decrease intramyocardial conduction in ischemic tissue and
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ple, the risk of inducing bronchospasm with a beta1-adrenergic reduce the risks of dysrhythmias to the extent that they
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(cardioselective) blocker (eg, esmolol or metoprolol) may be decrease myocardial ischemia.
relatively less than that with a nonselective blockers (eg, pro-
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pranolol); however, the risk is still present.
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TABLE 4-3:  Beta-Adrenergic Receptors
Acute Myocardial Infarction Blockers
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Earlier clinical trials of intravenous beta-adrenergic blockers Generic Trade Dosage Beta1-
in the early phases of acute myocardial infarction suggest they Name Name Forms Selective
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decrease mortality. Following myocardial infarction, chronic
oral beta-blocking agents reduce the incidence of recurrent
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Acebutolol Sectral PO Yes
myocardial infarction (see Table 4-3).130 Atenolol Tenormin IV, PO Yes
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Betaxolol Kerlone PO Yes
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fre

Supraventricular Tachycardias and Bisoprolol

Esmolol
Zebeta
Brevibloc
PO
IV
Yes
Yes fre
sf

Ventricular Dysrhythmias
ks

ks

ks
Metoprolol Lopressor, IV, PO Yes
k

Beta-adrenergic blocking agents are Vaughan Williams class II

oo

oo

oo

oo

Toprol-XL
antidysrhythmics that primarily block cardiac responses to Carvedilol* Coreg PO No
eb

eb

eb

eb

catecholamines. Metoprolol and esmolol are used commonly Carteolol Cartrol PO No

for this indication. Beta-blocking agents decrease spontane- Labetalol* Normodyne, IV, PO No
m

ous depolarization in the SA and AV nodes, decrease auto- Trandate

maticity in Purkinje fibers, increase AV nodal refractoriness, Nadolol Corgard PO No
increase threshold for fibrillation (but not for depolarization), Penbutolol Levatol PO No
m

and decrease ventricular slow responses that depend on cat- Pindolol Visken PO No
co

co

co

co

co

echolamines. Amiodarone, a class III agent, also exerts non- Propranolol Inderal IV, PO No
competitive alpha- and beta-adrenergic blockade, which may Sotalol Betapace PO No
e.

e.

e.

e.

contribute its antidysrhythmic and antihypertensive actions. Timolol Blocadren PO No

fre

fre

fre

fre

Sotalol is another class III antidysrhythmic with nonselective

*Alpha1: beta-adrenergic blocking ratio; carvedilol 1:10, labetalol 1:3 (oral)/1:7 (IV).
s

ks

ks

ks
ok

oo

oo

oo
o
eb

eb

eb

eb
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85
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co

co
Chapter 4  Cardiac Surgical Pharmacology

c
e.

e.

e.

e.
Hypertension inotropy and ventricular ejection fraction. They also may
fre

fre

fre

re
limit reflex sympathetic responses to vasodilators used to con-

sf
Hypertension, if not treated, is a major risk factor for myo-
ks

ks

ks
trol systemic arterial pressure.

k
cardial infarction, stroke, renal failure and death, and patients
oo

oo

oo

oo
often present for cardiac surgery with poorly controlled blood
pressure (BP) management. The recently published recom- Pheochromocytoma
eb

eb

eb

eb
mendations of Eighth Joint National Committee (JNC 8)
The presence of catecholamine-secreting tissue is tantamount
m

provide an evidence-based approach to recommend treat-
ment thresholds, goals and specific therapy for management
of hypertension, and have been liberalized since the last
report.131 They recommend treating patients aged >60 years
m
m
to the continuous or intermittent infusion of a varying mixture
of norepinephrine and epinephrine. It is absolutely essential
that virtually complete alpha-adrenergic receptor blockade be

om
with <150/90 mm Hg whereas younger patients 30 to established prior to administering the beta-blocker to prevent
co

co

co

co
59 years to a diastolic goal of <90 mm Hg, and in younger exacerbation of hypertensive episodes by unopposed alpha-

c
patients a BP of <140/90 mm Hg, whether or not they have adrenergic receptor activity in vascular smooth muscle.
e.

e.

e.

e.
diabetes or chronic kidney disease (CKD). They suggest ini-
re

fre

re

re
tiating therapy with an ACE inhibitor, angiotensin receptor
Chronic Heart Failure
sf

f
blocker, calcium channel blocker, or thiazide-type diuretic in
ks

ks

ks
k

the nonblack hypertensive population, including those with It is now understood that activation of the autonomic nervous
oo

oo

oo

oo
diabetes. In the black hypertensive population, a calcium system (ANS) and renin-angiotensin system (RAS) as compen-
channel blocker or thiazide-type diuretic is recommended as satory mechanisms for the failing heart actually may contribute
eb

eb

eb

eb
initial therapy. There is moderate evidence to support initial to deterioration of myocardial function. Mortality in chronic
m

or add-on antihypertensive therapy with an ACE inhibitor or
angiotensin receptor blocker in persons with CKD to improve
kidney outcomes. Of note, they emphasize the importance of
clinical judgment as a critical component.131,132
m
m
HF seems related to activation of ANS and RAS. Progression of
myocardial dysfunction and remodeling may be attenuated by
the use of beta-blocking agents and ACE inhibitors. Carvedilol
(Coreg) is a beta-blocker approved by the FDA to treat patients

m
with HF. It has an alpha1- and nonselective beta-blocking activ-
co

co

co

co

co
ity (alpha:beta = 1:10). It is contraindicated in severe decom-
Hypertenisve Emergencies and
e.

e.

e.

e.
pensated HF and asthma. In patients with AF and left-sided
Urgencies HF treated with carvedilol, improved ejection fraction, and a
fre

fre

fre

fre
Hypertensive emergencies/crises include multiple clinical pre- trend toward a decreased incidence of death and chronic HF
ks

ks

ks

ks
sentations where uncontrolled hypertension leads to progres- hospitalization were observed in a retrospective analysis of a US
carvedilol study. There are several ongoing clinical trials with
oo

oo

oo

oo
sive or impending end-organ dysfunction requiring BP to be
lowered aggressively over minutes to hours. Neurologic end- carvedilol, metoprolol (Toprol), and bisoprolol (Zebeta). The
eb

eb

eb

eb
organ dysfunction due to uncontrolled hypertension includes results of these studies may provide answers as to which beta-
encephalopathy, cerebral vascular infarction, subarachnoid blocking agent would be most successful in the treatment of
m

m
hemorrhage, and/or intracranial hemorrhage. Cardiovascular specific patient populations.
end-organ injury includes myocardial ischemia and/or infarc-
tion, acute HF, pulmonary edema, and/or aortic dissection.
Other Indications
m

m
Other organ systems may also be affected by uncontrolled
co

co

co

co

co
hypertension, which may lead to acute renal failure/insuf- The other clinical applications of beta-adrenergic receptor
ficiency, eclampsia, or coagulopathy. In hypertensive emer- blockers listed in Table 4-4 are based on largely symptomatic
e.

e.

e.

e.
gencies, intravenous therapy with specific BP titration is the treatment or empirical trials of beta-adrenergic antagonists.
re

fre

fre

cornerstone of therapy.
fre
sf

Hypertensive urgencies are seen in a clinical setting where

ks

ks

ks
patients present asymptomatically with high blood pressures Side Effects and Toxicity
k
oo

oo

oo

oo

that should be treated but with oral therapies, restarting on The most obvious and immediate signs of a toxic overdose of
their medications or therapy initiated with care to avoid over- a beta-adrenergic receptor blocker are hypotension, bradycar-
eb

eb

eb

eb

shoot and hypotenstion. Hypertensive urgencies are common dia, congestive HF, decreased AV conduction, and a widened
in cardiac surgery where BP is maintained at specific arbitrary
m

QRS complex on the electrocardiogram. Treatment is aimed

levels based on concerns about bleeding and/or suture line at blocking the cholinergic receptor responses to vagal nerve
disruption. activity (eg, atropine) and administering a sympathomimetic
to compete with the beta-blockers at adrenergic receptors. In
m

patients with asthma and chronic obstructive pulmonary dis-

Acute Dissecting Aortic Aneurysm
co

co

co

co

co

ease (COPD), beta-blockers may cause bronchospasm. Beta-

The primary goal in managing dissecting aneurysms is to blockers may increase levels of plasma triglycerides and reduce
e.

e.

e.

e.

reduce stress on the dissected aortic wall by reducing the sys- levels of high-density lipoprotein (HDL) cholesterol. Rarely,
fre

fre

fre

fre

tolic acceleration of blood flow. Beta-blockers reduce cardiac beta-blockers may mask the symptoms of hypoglycemia in
s

ks

ks

ks
ok

oo

oo

oo
o
eb

eb

eb

eb
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86
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Part I  Fundamentals

c
e.

e.

e.

e.
hydrostatic pressure that produces glomerular filtration.
fre

fre

fre

re
TABLE 4-4:  Clinical Applications of There are no drugs that act directly on the renal glomerulus

sf
Beta-Adrenergic Receptor Blockers
ks

ks

ks
to affect glomerular filtration rate (GFR). In the normal adult

k
human of average size, GFR averages 125 mL/min and urine
oo

oo

oo

oo
Angina pectoris
Acute myocardial infarction (prophylaxis) production approximates 1 mL/min. In other words, 99% of
eb

eb

eb

eb
Supraventricular tachycardia the glomerular filtrate is reabsorbed. Diuretics act primarily
Ventricular dysrhythmias on specific segments of the renal tubule to alter reabsorption
m

Hypertension (usually in combination with other drugs)
Pheochromocytoma (after alpha-receptor blockade is established)
Acute dissecting aortic aneurysm
m
m
of electrolytes, principally sodium, and water.
There are two basic mechanisms behind the renal tubu-
lar reabsorption of sodium. First, sodium is extruded from

om
Hyperthyroidism the tubular cell into peritubular fluid primarily by active
transport of the sodium ion, which reflects the action of the
co

co

co

co
Hypertrophic obstructive cardiomyopathy (IHSS)

c
Dilated cardiomyopathy (selected patients) Na+, K+ ATPase pump, as well as the bicarbonate reabsorp-
e.

e.

e.

e.
Migraine prophylaxis tion mechanism (see the following). This extrusion of sodium
re

fre

re

re
Acute panic attack creates an electrochemical gradient that causes diffusion of
sodium from the tubular lumen into the tubular cell. Second,
sf

f
Alcohol withdrawal syndrome
ks

ks

ks
Glaucoma (topically) sodium moves from the glomerular filtrate in the tubular fluid
k

into the peritubular fluid by several different mechanisms.

oo

oo

oo

oo
The most important quantitatively is the sodium electro-
eb

eb

eb

eb
chemical gradient created by the active extrusion of sodium
from the tubular cell into the peritubular fluid. In addition,
m

diabetic patients. Other side effects include mental depres-
sion, physical fatigue, altered sleep patterns, sexual dysfunc-
tion, and gastrointestinal symptoms, including indigestion,
constipation, and diarrhea (see Table 4-4).
m
m
sodium is coupled with organic solutes and phosphate ions,
exchanged for hydrogen ions diffusing from the tubular cell
into the tubular lumen, and coupled to the transfer of a chlo-

m
ride ion or a combination of potassium and two chloride ions
(Na+-K+-2Cl– cotransport) from the tubular fluid into the
co

co

co

co

co
tubular cell. Diuretics are classified by their principal site of
Drug Interactions
e.

e.

e.

e.
action in the nephron and by the primary mechanism of their
fre

fre

fre

fre
Pharmacokinetic drug interactions include reduced gas- natriuretic effect (Table 4-5).
trointestinal absorption of the beta-blocker (eg, alumi-
ks

ks

ks

ks
num-containing antacids and cholestyramine), increased
biotransformation of the beta-blocker (eg, phenytoin, phe- Osmotic Diuretics
oo

oo

oo

oo
nobarbital, rifampin, and smoking), and increased bioavail-
Mannitol is the principal example of this type of diuretic,
eb

eb

eb

eb
ability owing to decreased biotransformation (eg, cimetidine
which is used for two primary indications: (1) prophylaxis
and hydralazine). Pharmacodynamic interactions include an
m

m
and early treatment of acute renal failure that is characterized
additive effect with calcium channel blockers to decrease con-
by a decrease in GFR leading to a decreased urine volume
duction in the heart and a reduced antihypertensive effect of
and an increase in the concentration of toxic substances in
beta-blockers when administered with some of the nonsteroi-
the renal tubular fluid; and (2) enhancing the actions of other
m

m
dal anti-inflammatory drugs (NSAIDs).
diuretics by retaining water and solutes in the tubular lumen,
co

co

co

co

co
thereby providing the substrate for the action of other types
e.

e.

e.

e.
of diuretics. Normally, 80% of the glomerular filtrate is reab-
DIURETICS sorbed isosmotically in the proximal tubules. By its osmotic
re

fre

fre

Diuretics are drugs that act directly on the kidneys to increase effect, mannitol limits the reabsorption of water and dilutes fre
sf

ks

ks

ks
urine volume and produce a net loss of solute (principally the proximal tubular fluid. This reduces the electrochemical
k

sodium and other electrolytes) and water. Diuretics and beta- gradient for sodium and limits its reabsorption so that more is
oo

oo

oo

oo

blockers are initial drugs of choice for uncomplicated hyper- delivered to the distal portions of the nephron. Mannitol pro-
duces a prostaglandin-mediated increase in renal blood flow
eb

eb

eb

eb

tension in patients younger than 65 years.132 The currently

available diuretic drugs have a number of other uses in medi- that partially washes out the medullary hypertonicity, which
m

cine (eg, glaucoma and increased intracranial pressure). The is essential for the countercurrent mechanism promoting the
principal indications for the use of diuretics by intravenous reabsorption of water in the late distal tubules and collecting
administration in the perioperative period are to: (1) increase system under the influence of antidiuretic hormone (ADH).
m

urine flow in oliguria; (2) reduce intravascular volume in Mannitol is used often (25 to 50 g) as part of the priming
patients at risk for acute HF from excessive fluid administra- solution of CPB for the above-mentioned indications. The
co

co

co

co

co

tion or acute HF; and (3) mobilize edema. principal toxicity of mannitol is acute expansion of the extra-
e.

e.

e.

e.

Renal function depends on adequate renal perfusion cellular fluid volume leading to HF in the patient with com-
promised cardiac function (see Table 4-5).
fre

fre

fre

fre

to maintain the integrity of renal cells and provide the

s

ks

ks

ks
ok

oo

oo

oo
o
eb

eb

eb

eb
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Chapter 4  Cardiac Surgical Pharmacology

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e.

e.

e.

e.
fre

fre

fre

re
TABLE 4-5:  Classification of Diuretics

sf
ks

ks

ks
Site of Action Mechanism  

k
oo

oo

oo

oo
Osmotic Proximal convoluted and late proximal for Na+ diffusion ↓ Electrochemical gradient
eb

eb

eb

eb
from tubular fluid into tubular cell
  Late proximal tubule ↓ Gradient for Cl- (accompanying
m

m
Na+ diffusion)
  Thick ascending loop of Henle ↓ Na+-K+-2Cl- cotransport
Carbonic Proximal convoluted tubule anhydrase inhibitors ↓ Na+-H+ exchange
m

om
Thiazides Distal convoluted tubule ↓ Na+-Cl- cotransport
co

co

co

co
High-ceiling loop diuretics Thick ascending loop of Henle ↓ Na+-K+-2Cl- cotransport

c
Potassium-sparing diuretics Late distal tubule and collecting duct ↓ Electrogenic Na+ entry into cells (driving
e.

e.

e.

e.
force for K+ secretion)
re

fre

re

re
sf

f
ks

ks

ks
k

High-Ceiling (Loop) Diuretics loop diuretics are favored for intravenous administration in
oo

oo

oo

oo
the perioperative period to treat the three principal problems
Furosemide (Lasix), bumetanide (Bumex), and ethacrynic
eb

eb

eb

eb
cited earlier. Dosage requirements vary considerably among
acid (Edecrin) are three chemically dissimilar compounds patients. Some may only require furosemide 3 to 5 mg (IV)
m

m
that have the same primary diuretic mechanism of action. to produce a good diuresis. And for some patients, the less
They act on the tubular epithelial cell in the thick ascend- potent benzothiazides may be sufficient.
ing loop of Henle to inhibit the Na+-K+-2Cl– cotransport
mechanism. Their peak diuretic effect is far greater than that
m

m
of the other diuretics currently available. Administered intra- Benzothiazides
co

co

co

co

co
venously, they have a rapid onset and relatively short duration Hydrochlorothiazide (HCTZ) is the prototype of more than
e.

e.

e.

e.
of action, the latter reflecting both the pharmacokinetics of a dozen currently available diuretics in this class. Although
the drugs and the body’s compensatory mechanisms to the the drugs differ in potency, they all act by the same mecha-
fre

fre

fre

fre
consequences of diuresis. nism of action and have the same maximum efficacy. All are
ks

ks

ks

ks
These three diuretics increase renal blood flow without actively secreted into the tubular lumen by tubular cells and
increasing GFR and redistribute blood flow from the medulla act in the early distal tubules to decrease the electroneutral
oo

oo

oo

oo
to the cortex and within the renal cortex. These changes in Na+-Cl– cotransport reabsorption of sodium. Their moder-
renal blood flow are also short-lived, reflecting the reduced
eb

eb

eb

eb
ate efficacy probably reflects the fact that more than 90% of
extracellular fluid volume resulting from diuresis. Minor the filtrated sodium is reabsorbed before reaching the distal
m

actions, including carbonic anhydrase inhibition by furose-
mide and bumetanide and actions on the proximal tubule
and on sites distal to the ascending limb, remain controver-
m
m
tubules. Their action is enhanced by their combined admin-
istration with an osmotic diuretic such as mannitol. The
benziothiazides increase urine volume and the excretion of

m
sial. All three of the loop diuretics increase the release of renin sodium, chloride, and potassium. The decreased reabsorption
and prostaglandin, and indomethacin blunts the release as of potassium reflects the higher rate of urine flow through the
co

co

co

co

co
well as the augmentation in renal blood flow and natriure- distal tubule (diminished reabsorption time).
e.

e.

e.

e.
sis. All three of the loop diuretics produce an acute increase This class of diuretics produces the least disturbance of
re

fre

fre

fre
in venous capacitance for a brief period of time after the extracellular fluid composition, reflecting their moderate effi-
first intravenous dose is administered, and this effect is also cacy as diuretics and perhaps suggesting their usefulness when
sf

ks

ks

ks
blocked by indomethacin. a moderate degree of diuretic effect is indicated. Their prin-
k

Potassium, magnesium, and calcium excretion is increased cipal side effects include hyperuricemia, decreased calcium
oo

oo

oo

oo

in proportion to the increase in sodium excretion. In addi- excretion, and enhanced magnesium loss. Hyperglycemia can
eb

eb

eb

eb

tion, there is augmentation of titratable acid and ammonia occur and reflects multiple variables. With prolonged use and
excretion by the distal tubules leading to metabolic alkalosis, development of a contracted extracellular fluid volume, urine
m

which is also produced by contraction of the extracellular vol- formation decreases (ie, tolerance develops to their diuretic
ume. Hyperuricemia can occur but usually is of little physi- actions). These agents also have a direct action on the renal
ologic significance. The nephrotoxicity of cephaloridine, and vasculature to decrease GFR.
m

possibly other cephalosporins, is increased. A rare but serious

side effect of the loop diuretics is deafness, which may reflect
co

co

co

co

co

Carbonic Anhydrase Inhibitors

electrolyte changes in the endolymph.
e.

e.

e.

e.

Because of their high degree of efficacy, prompt onset, Acetazolamide (Diamox) is the only diuretic of this class
fre

fre

fre

fre

and relatively short duration of action, the high-ceiling or available for intravenous administration. Its use is directed
s

ks

ks

ks
ok

oo

oo

oo
o
eb

eb

eb

eb
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Part I  Fundamentals

c
e.

e.

e.

e.
primarily toward alkalinization of urine in the presence of relates to the fact that the osmotic effect of albumin and
fre

fre

fre

re
metabolic alkalosis, which is a common consequence of pro- plasma expanders is transient because they can diffuse (at a

sf
ks

ks

ks
longed diuretic therapy. It acts in the proximal convoluted rate slower than water) from blood through capillary mem-

k
tubule to inhibit carbonic anhydrase in the brush border of branes into tissue. The albumin or plasma expander then
oo

oo

oo

oo
the tubular epithelium, thereby reducing the destruction of tends to hold water and its accompanying electrolytes in tis-
bicarbonate ions (ie, conversion to CO2 that diffuses into the sue (ie, rebound edema). The same limiting feature applies to
eb

eb

eb

eb
tubular cell). The carbonic anhydrase enzyme in the cytoplasm osmotic diuretics such as mannitol, which may transiently
m

of the tubular cell is also inhibited, and as a consequence,
conversion of CO2 to carbonic acid is reduced markedly, as
is the availability of hydrogen ions for the Na-H exchange
mechanism. Hence the reabsorption of both sodium and
m
m
draw water and its accompanying electrolytes from tissues
into the circulating blood for delivery to the kidneys, where
the mannitol passes through the glomerulus and delays the
reabsorption of water and its accompanying electrolytes from

om
bicarbonate in the proximal tubules is diminished. However, the proximal tubular fluid. Although this mechanism may
co

co

co

co
more than half the bicarbonate is reabsorbed in more distal enhance the actions of other diuretics, it is a transient effect

c
e.

e.

e.

e.
segments of the nephron, thereby limiting the overall efficacy that is limited by the diffusion of mannitol from blood into
of this class of diuretics. tissues with the production of rebound edema.
re

fre

re

re
Dopamine, at doses from 1 to 3 μg/kg per minute, has
sf

f
ks

ks

ks
been used conventionally to support mesenteric and renal
Potassium-Sparing Diuretics
k

perfusion as “renal dose dopamine.” Vasodilation at low doses

oo

oo

oo

oo
Spironolactone (Aldactone) is a competitive antagonist of is mediated via vascular dopamine 1 (D1) receptors in coro-
eb

eb

eb

eb
aldosterone. Spironolactone binds to the cytoplasmic aldoste- nary, mesenteric, and renal vascular beds. By activating adenyl
rone receptor and prevents its conformational change to the cyclase and raising intracellular concentrations of cyclic AMP,
m

active form, thereby aborting the synthesis of active transport
proteins in the late distal tubules and collecting system in
which the reabsorption of sodium and secretion of potassium
m
m
D1-receptor agonists cause vasodilatation. There are also
dopamine 2 (D2) receptors that antagonize D1-receptor stim-
ulation. Fenoldopam (Corlopam), a parenteral D1-receptor-

m
are reduced. specific agonist, is also available as a therapy. However, there
Triamterene (Dyrenium) and amiloride (Midamor) are are no data supporting its use to improve renal function other
co

co

co

co

co
potassium-sparing diuretics with a mechanism of action than by increasing cardiac output, and it also increases the
e.

e.

e.

e.
independent of the mineralocorticoids. They have a mod- risk of postoperative AF.133 Infusion of fenoldopam (0.1 to
fre

fre

fre

fre
erate natriuretic effect leading to an increased excretion of 0.3 μg/kg per minute) causes an increase in GFR, renal blood
sodium and chloride with little change or a slight increase in flow, and Na+ excretion.
ks

ks

ks

ks
potassium excretion when the latter is low. When potassium Clinical trials of dopamine failed to show improvement
secretion is high, they produce a sharp reduction in the elec- in renal function, which probably is a result of the nonspeci-
oo

oo

oo

oo
trogenic entry of sodium ions into the distal tubular cells and ficity of dopamine. As a catecholamine and a precursor in
eb

eb

eb

eb
thereby reduce the electrical potential that is the driving force the metabolic synthesis of norepinephrine and epinephrine,
for potassium secretion. dopamine has inotropic and chronotropic effects on the
m

Both types of potassium-sparing diuretics are used primar-
ily in combination with other diuretics to reduce potassium
loss. Their principal side effect is hyperkalemia. It is appro-
m
m
heart. The inotropic effect is mediated by beta1-adrenergic
receptors and usually requires infusion rates higher than those
able to produce enhanced renal perfusion and diuresis. How-

m
priate to limit the intake of potassium when using this type ever, there are varied pharmacokinetic responses to dopamine
co

co

co

co

co
of diuretic. It is also appropriate to use this type of diuretic infusion even in healthy subjects; therefore, the use of a “renal
cautiously in patients taking ACE inhibitors, which decrease dose” dopamine regimen may not always result in the desir-
e.

e.

e.

e.
aldosterone formation and consequently increase serum able effects. Stimulation of catecholamine receptors and D2
re

fre

fre

potassium concentrations. receptors antagonizes the effects of D1-receptor stimulation.

fre
sf

Current data do not consistently demonstrate improved

ks

ks

ks
renal outcomes with use of the D1-receptor-specific agonist
k

Other Measures to Enhance Urine

oo

oo

oo

oo

fenoldopam.
Output and Mobilization of Edema Fluid
eb

eb

eb

eb

The infusion of albumin (5–25% solutions) or other plasma

HERBAL MEDICINE
m

volume expanders (eg, hetastarch) is often employed in an

attempt to draw water and its accompanying electrolytes A large number of Americans take herbal remedies for their
(ie, edema fluid) osmotically from the tissues into the circu- health. Most of these herbal therapies are not supported by
lating blood and thereby enhance their delivery to the kid- clear scientific evidence and are not under rigorous control
m

neys for excretion. In the presence of a reduced circulating by the FDA.134-136 Patients who take alternative remedies may
co

co

co

co

co

blood volume, this approach seems to be a logical method not necessarily disclose this information to their physicians.135
to increase the circulating blood volume and renal perfusion. There are increasing concerns regarding serious drug inter-
e.

e.

e.

e.

The limiting feature of this approach to enhancing diuresis actions between herbal therapy and prescribed medication.
fre

fre

fre

fre
s

ks

ks

ks
ok

oo

oo

oo
o
eb

eb

eb

eb
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Chapter 4  Cardiac Surgical Pharmacology

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e.

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e.

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fre

fre

fre

re
TABLE 4-6:  Commonly Used Herbal Remedies

sf
ks

ks

ks
Name Common Uses Side Effects/Drug Interactions

k
oo

oo

oo

oo
Cayenne (paprika) Muscle spasm, GI disorders Skin ulcers/blistering
eb

eb

eb

eb
    Hypothermia
Echinacea Common cold, antitussive, urinary tract May cause hepatotoxicity
m

m
infections
    May decrease effects of steroids and cyclosporine
Ephedra (Mahuang) Antitussive, bacteriostatic Enhanced sympathomimetic effects with guanethidine or
m

om
monoamine oxidase inhibitor (MAOI)
co

co

co

co
    Arrhythmias with halothane or digoxin

c
    Hypertension with oxytocin
e.

e.

e.

e.
Feverfew Migraine, antipyretic Platelet inhibition, rebound headache, aphthous ulcers,
re

fre

re

re
GI irritation
Garlic Lipid-lowering, antihypertensive May potentiate warfarin
sf

f
ks

ks

ks
antithrombotic
k
oo

oo

oo

oo
Ginger Antinauseant, antispasmodic May potentiate aspirin and warfarin
Ginkgo Improve circulation May potentiate aspirin and warfarin
eb

eb

eb

eb
Ginseng Adaptogenic, enhance energy level, antioxidant Ginseng abuse syndrome: sleepiness, hypertonia, edema
    May cause mania in patients on phenelzine
m

m
    May decrease effects of warfarin
    Postmenopausal bleeding
    Mastalgia
m

m
Goldenseal Diuretic, anti-inflammatory, laxative, Overdose may cause paralysis; aquaretic (no sodium excretion);
co

co

co

co

co
hemostatic may worsen edema/hypertension
Kava-kava Anxiolytic Potentiates barbiturates and benzodiazepines
e.

e.

e.

e.
    Potentiates ethanol
fre

fre

fre

fre
    May increase suicide risk in depression
Licorice Antitussive, gastric ulcers High blood pressure, hypokalemia, and edema
ks

ks

ks

ks
Saw palmetto Benign prostatic hypertrophy, Additive effects with other hormone replacement therapy
oo

oo

oo

oo
antiandrogenic (eg, HRT)
St. John’s wort Antidepressant, anxiolytic Possible interaction with MAOIs
eb

eb

eb

eb
    Decreases metabolism of fentanyl and ondansetron
Valerian Mild sedative, anxiolytic Potentiates barbiturates and benzodiazepines
m

m
m

m
Some of the most common herbal remedies and drug interac- pathophysiologic problems contributing to airway obstruc-
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tions are summarized in Table 4-6. tion and to facilitate manipulation and instrumentation of
the airway. Pharmacologic agents are considered at the end
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of this section.
AIRWAY MANAGEMENT
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Five major challenges may be encountered in airway

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sf

Airway management in cardiovascular surgical patients is management. Each of these is described succinctly below
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to facilitate understanding of the roles that drugs play in
k

important because patients often present with coexisting

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conditions that may complicate endotracheal intubation. For meeting the challenges. The five challenges are (1) over-
example, a patient with morbid obesity and sleep apnea may coming airway obstruction, (2) preventing pulmonary
eb

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eb

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require awake intubation with a fiberoptic bronchoscope, or aspiration, (3) performing endotracheal intubation, (4)
maintaining intermittent positive-pressure ventilation
m

a history of smoking and COPD may make the patient sus-

ceptible to rapid desaturation and/or bronchospasm. Airway (IPPV), and (5) reestablishing spontaneous ventilation
management in the perioperative period is a primary respon- and airway protective reflexes.
sibility of the anesthesiologist, but the surgeon becomes
m

involved in the absence of the anesthesiologist or in assisting Airway Obstruction

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the anesthesiologist in difficult situations. Airway manage-

ment involves instrumentation and mechanics (not discussed Obstruction to gas flow can occur from the entry of a for-
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here) and employs pharmacologic approaches to overcome eign object (including food) into the airway and as a result
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ok

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Part I  Fundamentals

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of pathophysiologic processes involving airway structures Antiemetic drugs are used more commonly in the post-
fre

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re
(eg, trauma and edema). In the anesthetized or comatose operative period and include several different drug classes:

sf
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patient, the loss of muscle tone can allow otherwise nor- anticholinergics (eg, scopolamine [Transderm Scop]),

k
mal tissues (eg, tongue and epiglottis) to collapse into the antihistamines (eg, hydroxyzine [Vistaril] and prometha-
oo

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airway and cause obstruction. The first measure in reliev- zine [Phenergan]), and antidopaminergics (eg, droperidol
ing such obstructions involves manipulation of the head [Inapsine] and prochlorperazine [Compazine]). Antidopami-
eb

eb

eb

eb
and jaw, insertion of an artificial nasal or oral airway device, nergic agents may cause extrapyramidal side effects in elderly
m

and evacuation of obstructing objects and substances (eg,
blood, secretions, or food particles). Except for drugs used
to facilitate endotracheal intubation (see the following), the
only drug useful to improve gas flow through a narrowed
m
m
patients. More costly but effective alternatives include the use
of antiserotinergics (eg, ondansetron [Zofran] and dolasetron
[Anzemet]).

om
airway is a mixture of helium and oxygen (Heliox), which
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has a much reduced viscosity resulting in reduced resistance Endotracheal Intubation

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to gas flow. Drugs are employed for three purposes in facilitating endo-
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tracheal intubation: (1) to improve visualization of the larynx
during laryngoscopy; (2) to prevent closure of the larynx; and
sf

f
Aspiration
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(3) to facilitate manipulation of the head and jaw.
k

The upper airway (above the larynx/epiglottis) is a shared For bronchoscopy, laryngoscopy, or fiberoptic endotra-
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porthole to the lungs (gas exchange) and gastrointestinal cheal intubation, the reflex responses to airway manipulation
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tract (fluids and nutrition). Passive regurgitation or active can be suppressed by several different methods alone or in
vomiting resulting in accumulation of gastric contents in combination. Topical anesthesia (2 or 4% lidocaine spray)
m

the pharynx places the patient at risk of pulmonary aspira-
tion, especially under circumstances in which airway reflexes
(eg, glottic closure and coughing) and voluntary avoidance
m
m
can be used to anesthetize the mucosal surfaces of the nose,
oral cavity, pharynx, and epiglottis. Atomized local anes-
thetic can be inhaled to anesthetize the mucosa below the

m
maneuvers are suppressed (eg, anesthesia or coma). Par- vocal cords. The subglottic mucosa also can be anesthetized
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ticulate matter can obstruct the tracheobronchial tree, and topically by injecting local anesthetic into the tracheal lumen
acidic fluid (pH < 2.5) can injure the lung parenchyma. The through the cricothyroid membrane. A bilateral superior
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resulting pneumonitis can cause significant morbidity (eg, laryngeal nerve block eliminates sensory input from mechani-
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acute respiratory distress syndrome) and has a high mortal- cal contact or irritation of the larynx above the vocal cords.
ity rate. Preoperative restriction of fluids and food (NPO It must be remembered that anesthesia of the mucosal sur-
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status) does not guarantee the absence of aspiration risks. faces to obtund airway reflexes compromises the reflex-pro-
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Similarly, the advance placement of a nasogastric or orogas- tective mechanisms of the airway and increases the patient’s
tric tube may serve to reduce intragastric pressure but does vulnerability to aspiration of substances from the pharynx.
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not guarantee complete removal of gastric contents. Never- Improvement of visualization of the larynx includes decreas-
theless, both NPO orders and the insertion of a nasogastric ing salivation and tracheal bronchial secretions by administra-
m

or orogastric tube under some circumstances are worthwhile
measures to reduce the risks of pulmonary aspiration. In
some circumstances, the deliberate induction of vomiting in
m
m
tion of an anticholinergic drug (eg, glycopyrrolate), reducing
mucosal swelling by topical administration of a vasoconstric-
tor (eg, phenylephrine), and minimizing bleeding owing to

m
a conscious patient may be indicated, but this is done rarely mucosal erosion by instrumentation, which also is minimized
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and almost never involves the use of an emetic drug. In fact, by topical vasoconstrictors. The use of steroids in minimizing
more often antiemetic drugs are employed to reduce the acute inflammatory responses in the airway may have some
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risks of vomiting during airway manipulation and induc- delayed benefit, but steroids usually are not indicated just
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tion of anesthesia. before intubation.

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Drug therapy to reduce the risks of pulmonary aspiration Systemic drugs, usually administered intravenously, can
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is focused on decreasing the quantity and acidity of gastric be used to obtund the cough reflex. Intravenous lidocaine
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contents and on facilitating endotracheal intubation (see (1 to 2 mg/kg) transiently obtunds the cough reflex without
the following). Nonparticulate antacids (eg, sodium citrate affecting spontaneous ventilation to any significant degree.
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eb

[Bicitra]) are used to neutralize the acidity of gastric fluids. The risks of CNS stimulation and seizure-like activity have to
m

Drugs to reduce gastric acid production include H2-recep-
tor blockers (eg, cimetidine [Tagamet], ranitidine [Zantac],
famotidine [Pepcid]), and inhibitors of gastric parietal cell
hydrogen-potassium ATPase (proton pump inhibitors, eg,
m
be kept in mind and can be reduced by the prior administra-
tion of an intravenous barbiturate or benzodiazepine in small
doses. Intravenous opioids are effective in suppressing cough
reflexes, but the doses required impair spontaneous ventila-

omeprazole [Prilosec], lansoprazole [Prevacid], and esome- tion to the point of apnea. A combination of an intravenous
co

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prazole [Nexium]). Metoclopramide [Reglan] enhances gas- opioid and a major tranquilizer (eg, neuroleptic analgesia)
tric emptying and increases gastroesophageal sphincter tone. allows the patient to tolerate an endotracheal tube with much
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Cisapride [Propulsid] also increases gastrointestinal motility smaller doses of the opioid and less embarrassment of spon-
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via the release of acetylcholine at the myenteric plexus. taneous ventilation. Small doses of opioids are also useful in
s

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ok

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o
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Chapter 4  Cardiac Surgical Pharmacology

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obtunding airway reflexes during general anesthesia provided intrathoracic substances (eg, pneumothorax, hemothorax,
fre

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re
by either intravenous (eg, thiopental) or inhaled anesthetics or tumor mass). Treatment of these involves drug therapy of

sf
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(eg, isoflurane). Not only do the opioids obtund the cough HF and infection and procedures such as bronchoscopy and

k
reflex that results in closure of the larynx, but they also are thoracentesis.
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useful in limiting the autonomic sympathetic response to Bronchoconstriction may exist chronically (eg, asthma
endotracheal intubation that typically leads to hypertension or reactive airways disease), and these conditions can be
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eb

eb

eb
and tachycardia. exacerbated by the collection of tracheobronchial secretions
m

Skeletal muscle relaxants are used most commonly in
conjunction with a general anesthetic to allow manipulation
of the head and jaw and prevent reflex closure of the lar-
ynx. Of course, they also render the patient apneic, and two
m
m
in the presence of an endotracheal tube, which reduces the
effectiveness of coughing in clearing the airway. Occasionally
bronchoconstriction can be induced by mechanical stimula-
tion of the airway by an endotracheal tube or other object

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procedures are used commonly to maintain oxygenation of in an otherwise normal patient. Drug treatment is focused
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the patient’s blood. First, the patient breathes 100% oxygen on reducing bronchial smooth muscle tone (eg, beta2 sympa-

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by mask while still awake to eliminate nitrogen from the thomimetic or anticholinergic agents), minimizing tracheal
lungs, and then a rapid-sequence administration of an intra- bronchial secretions, and decreasing sensory input from the
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venous anesthetic (eg, thiopental) is followed immediately tracheal bronchial tree (eg, topical anesthetic, deeper general
sf

f
ks

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ks
by a rapid-acting neuromuscular blocker (eg, succinylcho- anesthesia, intravenous lidocaine, or an opioid). Acute treat-
k

line or rocuronium), and cricoid pressure is applied (Sellick ment of bronchoconstriction may involve any combination of
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maneuver). As soon as the muscle relaxation is apparent the following: (1) an aerosolized beta2 sympathomimetic and/
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(30 to 90 seconds), laryngoscopy is performed, an endo- or anticholinergic agent; and (2) systemic intravenous admin-
tracheal tube is inserted, the tracheal tube cuff is inflated, istration of a beta2 sympathomimetic agent, a phosphodies-
m

and the position of the tube in the trachea is verified. Sec-
ond, when there is minimal risk of pulmonary aspiration
(eg, presumed empty stomach), the patient is anesthetized
m
m
terase inhibitor (eg, theophylline salts [aminophylline]), and/
or an anticholinergic agent.
Intravenous steroids are indicated in severe broncho-

m
and paralyzed while ventilation is supported by intermittent constriction, especially in asthmatic patients, for whom
positive pressure delivered via a face mask. At the appropri- they have been effective in the past. With the administra-
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ate time, laryngoscopy is performed and the endotracheal tion of 100% oxygen, blood oxygenation usually is not the
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tube is inserted. main problem in patients with bronchoconstriction; the
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progressive development of hypercarbia and the trapping
of air in lung parenchyma reduce ventilatory compliance
Normalizing Pulmonary Function during
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and increase intrathoracic pressure. These, in turn, reduce
Positive-Pressure Ventilation venous return and may cause a tamponade-like impairment
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Once an endotracheal tube is in place, it is common practice of cardiac function.
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in the operating room to maintain general anesthesia and par- Impaired alveolar-capillary membrane gas exchange can
tial muscular paralysis in order to facilitate positive-pressure result from alveolar pulmonary edema (treated by diuretics,
m

ventilation and continued toleration of the endotracheal tube
by the patient. Postoperatively, in the post-anesthesia care
unit (PACU) and intensive care unit (ICU), general anes-
m
m
inotropes, and vasodilators), decreased pulmonary perfusion
(treated by inotropes and vasodilators), and lung consolida-
tion (antibiotic therapy for infection).

m
thesia and partial muscular paralysis may be continued if
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prolonged positive-pressure ventilation is anticipated, or sed- Restoration of Spontaneous Ventilation
atives may be administered by intravenous infusion to allow
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toleration of the endotracheal tube in anticipation of recovery
and Airway Protective Mechanisms
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of spontaneous ventilation and tracheal extubation. The anesthesiologist attempts to tailor the anesthetic plan
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Three other problems are encountered in the patient according to postoperative expectations for the patient. In the
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whose ventilation is supported mechanically by an endotra- relatively healthy patient for whom tracheal extubation can be
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cheal tube: (1) poor ventilatory compliance; (2) bronchocon- anticipated in the operating room, the goal is to have the patient
striction; and (3) impaired gas exchange. Poor ventilatory breathing spontaneously with airway reflexes intact and the
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compliance can reflect limited compliance of the chest wall patient arousable to command immediately on completion of
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and diaphragm, limited compliance of the lungs per se, or
both. Deepening general anesthesia and administration of
a skeletal muscle relaxant can be used to reduce intercostal
and diaphragmatic muscle tone, but they obviously cannot
m
the operation. The challenge for the anesthesiologist is to main-
tain satisfactory general anesthesia through the entire course
of the operation and yet have the patient sufficiently recov-
ered from anesthetic drugs, including hypnotics and opioids,

improve the chest cavity compliance that is fixed by disease shortly after conclusion of the operation. If this is not possible,
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(eg, scoliosis or emphysema). then the patient is transferred to the PACU to allow additional
Poor lung compliance may reflect pulmonary intersti- time for elimination of drugs that depress spontaneous venti-
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tial edema, consolidation, bronchial obstruction (eg, mucus lation and cough reflexes. Another possibility is to adminis-
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plugs), bronchoconstriction, or compression of the lung by ter antagonists to opioids (eg, naloxone) and benzodiazepines
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ok

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Part I  Fundamentals

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(eg, flumazenil), but this approach risks sudden awakening, and therefore facilitates rapid awakening. This drug is not
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pain, and uncontrolled autonomic sympathetic activity lead- water soluble so is supplied in a lipid emulsion; for short-term

sf
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ing to undesirable hemodynamic changes. And there is the infusions (less than a day or two) lipid accumulation is not an

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risk of recurrent ventilatory depression because it is difficult to issue, but triglyceride levels should be measured if the drug is
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match the doses of the antagonists to the residual amounts of given in high doses, especially at the same time as intravenous
anesthetic drugs. On the other hand, it is fairly routine for the feeding. The hemodynamic effects of propofol are mostly a
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effects of neuromuscular blockers to be antagonized by admin- result of vasodilation, both arterial and venous, as well as the
m

istration of an anticholinesterase (eg, neostigmine) in combina-
tion with an anticholinergic agent (eg, atropine) to limit the
autonomic cholinergic side effects of the anticholinesterase.
When the expectation is for maintenance of mechanical
m
m
usual “withdrawal of sympathetic tone,” which occurs when
anxious, stressed patients are sedated. In addition there is a
mild bradycardia and blunted heart rate response to hypoten-
sion, and a mild negative inotropic effect usually not relevant

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ventilation for some time in the postoperative period, then at clinical doses. The clinical dose range for sedation is 25 to
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the patient’s tolerance of the endotracheal tube is facilitated 75 μg/kg per minute but must be titrated.

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by the persistent effect of residual anesthetic drugs subse-
quently supplemented by administration of intravenous hyp-
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notics (eg, propofol) and opioids (eg, fentanyl or morphine).
Benzodiazepines
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f
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These agents can be associated with side effects, including Benzodiazepines are also used to facilitate mechanical ventila-
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respiratory depression, especially when they are used concur- tion, commonly midazolam (Versed) or lorazepam (Ativan).
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rently. Dexmedetomidine (Precedex), an alpha2-adrenergic These drugs do not have the vasodilating effects of propofol,
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agonist, may offer advantages for sedation during weaning are good amnestic agents, but have a major disadvantage in
from mechanical ventilation because it provides sedation, that awakening is less predictable and more often prolonged,
m

pain relief, anxiety reduction, stable respiratory rates, and
predictable cardiovascular responses. Dexmedetomidine
facilitates patient comfort, compliance, and comprehension
m
m
especially with lorazepam. In addition, these drugs appear to
be more associated with postoperative delirium than other
sedative drugs. Despite these problems, benzodiazepines are

m
by offering sedation with the ability to rouse patients. This useful in the sedation of severely hypotensive patients requir-
“arousability” allows patients to remain sedated yet commu- ing vasoconstrictor support. They have minimal, if any, direct
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nicate with health-care workers. cardiovascular effects, but withdrawal of sympathetic tone
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When the appropriate time comes to have the patient take can lead to hypotension. Midazolam is usually administered
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over his or her own ventilation completely, these sedative as a continuous infusion of 1 to 4 mg/h, while lorazepam is
and analgesic drugs are weaned to a level allowing satisfac- most often given by intermittent dosing of 1 to 2 mg every
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tory maintenance of blood oxygenation and carbon dioxide 4 to 6 hours.
removal, easy arousal of the patient, and at least partial resto-
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ration of airway reflex mechanisms.
Dexmedetomidine
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eb
A relatively new addition to the sedative drug family is dex-
m

m
Pharmacology Related to Airway and medetomidine (Precedex), a centrally acting alpha2 agonist.
Lung Management This drug is the same class as clonidine, but has a much
Cardiac surgical patients are usually kept intubated and venti- greater affinity for the alpha receptor. Not surprisingly, the
m

m
lated at the end of surgery, and ventilator support is withdrawn most common hemodynamic effect, which sometimes limits
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in the ICU. Sedative drugs are required to facilitate this transfer its use, is bradycardia and hypotension. This drug can be used
as a single agent to facilitate transfer from the operating room
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from operating room to intensive care, and while the patient is
ventilated. Some patients require continued ventilation because (OR) to the ICU and the period of ventilator weaning and
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of primary pulmonary disease, underlying cardiac disease and/or extubation. The major advantage of dexmedetomidine is that
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it does not affect ventilatory drive and patients can usually

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perioperative complications. Others may require medications to
be aroused while receiving the drug. It also has a significant
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treat bronchospasm or airway obstruction, or to facilitate reintu-

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bation if they develop respiratory failure once extubated. analgesic component, different from propofol or the benzodi-
azepines. The usual infusion rate of dexmedetomidine is 0.2
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to 0.7 μg/kg per hour, preceded by a loading dose of 1 μg/kg

Sedative Medications to Facilitate over 20 to 30 minutes. The loading dose can be reduced or
m

Mechanical Ventilation not given if hemodynamics warrant.

PROPOFOL
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The medications used in cardiac surgery patients are the same Opioids
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as those used in other mechanically ventilated patients. A The main reason patients need sedation during mechanical
common approach is to use propofol, an intravenous anes- ventilation is to tolerate the presence of a transoral tracheal
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thetic/sedative agent that is rapidly eliminated by the liver tube. In addition to general discomfort, there is continuous
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Chapter 4  Cardiac Surgical Pharmacology

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airway stimulation by the foreign object. To blunt airway providing cricoid pressure (to occlude the esophagus), and
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reflexes as well as to treat postoperative pain, it is useful to manual ventilation is minimized until the tube is in place.

sf
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add an opioid drug to whichever sedative agent the patient is

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receiving. For early postoperative awakening (ie, in the first
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hours), this is less of an issue as there is usually residual opioid Drugs to Treat Airway Pathology:
effect from drugs given intraoperatively; however, patients
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Stridor/Edema, Bronchospasm,
will need additional opioid as they awaken and experience
Secretions
m

m
pain. For patients ventilated overnight or longer, use of opi-
oid drugs will have these same benefits and likely result in a Fluid overload, prolonged positioning with the head depen-
reduced need for the sedative drug. Fentanyl is a commonly dent, or superior vena cava obstruction may all lead to edema
used drug in this setting, partly because it has a rapid onset
m

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of the upper airway. Alternatively, trauma from intubation or
of action and relatively rapid recovery if dosing is not pro- other devices in the oropharynx (eg, transesophageal echo-
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longed. Infusions of 1 to 4 μg/kg per hour are used. Alterna- cardiography [TEE] probe) may cause glottis edema. There

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tively intermittent dosing with 1 to 4 mg morphine or 0.5 to may be edema below the cords resulting from presence of the
1 mg hydromorphone (Dilaudid) every 1 to 4 hours may be
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endotracheal tube/cuff. The common treatments for airway
employed. narrowing resulting from edema are: (1) use of a mixture of
sf

f
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helium/oxygen; (2) inhaled racemic epinephrine; (3) diuret-
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Medications Used to Facilitate Urgent ics and head-up position; and (4) a brief course of dexameth-
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asone (IV).
Tracheal Intubation
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Patients in extremis (eg, during cardiac or respiratory arrest) Helium/Oxygen.  Helium with oxygen (Heliox) is supplied
m

rarely require medications to facilitate intubation. In decom-
pensating patients who are fully or partially conscious, chal-
lenges may include agitation, resistance to opening the mouth,
m
m
as an 80:20 mix. Helium is less dense than nitrogen, facilitat-
ing laminar rather than turbulent flow through a narrowed
airway. If a patient cannot tolerate the relatively low concen-

m
and/or closed vocal cords when intubation is attempted. In tration of oxygen (20%), then additional oxygen will need
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some patients small doses of sedative/opioid medications to be administered. Although the greatest benefit is provided
with a rapid onset such as midazolam and fentanyl, respec- by 80% helium, concentrations of 40 to 50% provide some
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tively, are adequate; in others an anesthetic induction agent benefit.
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such as propofol or etomidate can be used, with or without a
paralytic drug. The disadvantage to propofol is hypotension Racemic Epinephrine.  Racemic epinephrine is supplied as
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caused by vasodilation, as referred to in the preceding. This 1% solution and administered through an aerosol mask in a
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drug should be used in incremental doses, 10 to 20 mg at dose of 2.5 mL to cause vasoconstriction and reduced airway
time, until a dose of 1 to 2 mg/kg has been given. Etomidate edema. Absorption of epinephrine can cause tachycardia and
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has no direct cardiovascular effects and is usually given in a hypertension.
dose of 0.15 to 0.3 mg/kg. This drug has an unusual side
m

effect of impairing steroid synthesis and has been associated
with adrenal insufficiency in critically ill patients when given
by infusion. In addition, many patients experience unusual
m
m
Diuretics and Dexamethasone. Specific diuretic drugs
are discussed in the preceding; when a rapid effect is desired,
then usually a loop diuretic such as furosemide is employed.

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movements as this drug is administered. In general, the use of Although this may not specifically treat airway edema, the
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paralytic drugs is discouraged unless there is an anesthesiol- combination of elevated head and diuresis will reduce edema
ogy provider or someone skilled in the use of these drugs and in the upper body. Dexamethasone is used as part of the
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airway management present. “steroids for anything that swells” philosophy. There is little
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Succinylcholine is the most rapidly acting paralytic agent

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evidence of efficacy of corticosteroids in this setting; dexa-
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with an onset of 30 to 60 seconds and is given in a dose of methasone is used to avoid the mineralocorticoid effect of
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1 mg/kg. This depolarizing agent causes potassium release
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other potent intravenous steroid preparations. The usual dose

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and must be avoided in hyperkalemic patients. It causes is 8 mg followed by 4 mg every 6 hours for four to eight doses.
stimulation of muscarinic and nicotinic receptors, an increase
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in serum catecholamines, and many different, usually mild, Bronchodilators and Mucolytics.  A summary of bron-
dysrhythmias have been reported. Alternatively, rocuronium
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chodilator and mucolytic drugs is given in Table 4-7. In the

in a dose of 0.5 mg/kg can be given, but 60 to 90 seconds cardiac surgical patient, wheezing is more likely because of
are required for adequate paralysis. Rocuronium in this dose fluid overload or left ventricular failure than primary bron-
has no cardiovascular effect. If an anesthetic induction agent chospastic disease, but inhaled bronchodilators may give
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and/or a neuromuscular blocking agent are being considered, some relief while treatment of the primary disorder is being
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an important issue is the possibility of aspiration of stomach instituted (eg, diuresis or administration of an inotropic
contents. In an urgent situation the risk of this is reduced if drug). In order of preference, inhaled beta agonists, anticho-
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the drugs are administered in rapid sequence with an assistant linergic agents, and intravenous steroids are used.137 All three
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Part I  Fundamentals

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TABLE 4-7:  Inhaled Bronchodilators and Mucolytics

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  Drug Mechanism Dosage Frequency

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Bronchodilators Albuterol Beta2 agonist 2.5 mg/3 mL Q 4-6 h*
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  Levalbuterol Beta2 agonist 0.63-1.25 mg/3 mL Q6h
  Ipratropium Anticholinergic 0.5 mg/3 mL Q 4-6 h
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Mucolytic Dornase alpha Cleaves DNA 2.5 mg/3 cc Q 12 h
*May be given more frequently.
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may be indicated. Beta agonists relax smooth muscle in the Society of Cardiology Committee for Practice Guidelines (writing com-
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mittee to develop Guidelines for Management of Patients With Ven-
airways and usually have the most rapid therapeutic effect.
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tricular Arrhythmias and the Prevention of Sudden Cardiac Death):
In the acute setting aerosolized drug via a facemask is more developed in collaboration with the European Heart Rhythm Associa-
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effective than metered-dose inhalers. It should be noted tion and the Heart Rhythm Society. Circulation 2006; 114:e385.
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that management of chronic asthma focuses on inhaled 16. Hoffman BF, Rosen MR, Wit AL: Electrophysiology and pharmacology
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of cardiac arrhythmias: VII. Cardiac effects of quinidine and procain-

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anti-inflammatory agents, but these drugs are not helpful amide. Am Heart J 1975; 90:117.
in the acute setting, such as postoperatively. The presence 17. Giardenia EG, Heissenbuttel RH, Bigger JT Jr: Intermittent intravenous
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of tenacious secretions should prompt consideration of an procaine amide to treat ventricular arrhythmias: correlation of plasma
inhaled mucolytic such as dornase/DNAse (Pulmozyme). concentration with effect on arrhythmia, electrocardiogram, and blood
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N-acetylcysteine (Mucomyst) is another mucolytic but may
cause airway irritation so should not be given in the setting
of acute bronchospasm. See the table for dosages of these
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pressure. Ann Intern Med 1973; 78:183.
18. Stiell IG, Wells GA, Field B, et al: Advanced cardiac life support in out
of-hospital cardiac arrest. N Engl J Med 2004; 351:647.
19. The 2010 American Heart Association Guidelines for Cardiopulmonary

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Resuscitation and Emergency Cardiovascular Care. Circulation 2010;
drugs (see Table 4-7). 122:S639.
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20. Cardiac Arrhythmia Suppression Trial (CAST) Investigators: Prelimi-
nary report, effect of encainide and flecainide on mortality in a random-
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Chapter 4  Cardiac Surgical Pharmacology

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