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Bailey JM, Tanaka KA, Levy JH. Cardiac Surgical Pharmacology.
In: Cohn LH, Edmunds LH Jr, eds. Cardiac Surgery in the Adult. New York: McGraw-Hill, 2003:85118.

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Chapter 4

Cardiac Surgical Pharmacology

James M. Bailey/ Kenichi A. Tanaka/ Jerrold H. Levy

ANTIARRHYTHMICS
????Class I Agents
????Class II Agents
????Class III Agents
????Class IV Agents
????Other Drugs
AMIODARONE
????Pharmacokinetics
????Electrophysiology
????Indications
????Side Effects
PHARMACOLOGIC THERAPY OF SPECIFIC ARRHYTHMIAS
????Ventricular Tachyarrhythmias
????????SUSTAINED MONOMORPHIC VENTRICULAR TACHYCARDIA AND WIDE QRS TACHYCARDIA
????????SHOCK-RESISTANT VENTRICULAR FIBRILLATION
????Supraventricular Arrhythmias
????Atrial Fibrillation
INOTROPIC AGENTS
????Levosimendan
????Clinical Trials
VASOPRESSORS
VASODILATORS
????Stimulation of Adenylate Cyclase (Cyclic AMP)
????Nitrates, Nitrovasodilators, and Stimulation of Guanylyl Cyclase (Cyclic GMP)
????Dihydropyridine Calcium Channel Blockers
????Phosphodiesterase Inhibitors
????Angiotensin-Converting Enzyme Inhibitors
????Angiotensin II Receptor Blockers
PHARMACOLOGIC MANIPULATION OF THE HEMOSTATIC SYSTEM DURING CARDIAC SURGERY
????Pharmacology of Anticoagulation
????Heparin
????Low Molecular Weight Heparin
????Antithrombin
????New Anticoagulants
????Aprotinin
????Antifibrinolytic Agents and Desmopressin
????Acquired Platelet Dysfunction
????Protamine
????Antifibrinolytics
????Blood Products
????Recombinant Coagulation Products
????Fibrinolytics
BETA-ADRENERGIC RECEPTOR BLOCKERS
????Acute Myocardial Infarction
????Supraventricular Tachycardias and Ventricular Dysrhythmias
????Hypertension
????Acute Dissecting Aortic Aneurysm
????Pheochromocytoma
????Chronic Heart Failure
????Other Indications
????Side Effects and Toxicity
????Drug Interactions
DIURETICS
????Osmotic Diuretics
????High Ceiling (Loop) Diuretics
????Benzothiazides
????Carbonic Anhydrase Inhibitors
????Potassium-Sparing Diuretics
????Other Measures to Enhance Urine Output and Mobilization of Edema Fluid
HERBAL MEDICINE
DRUGS FOR AIRWAY MANAGEMENT
????Airway Obstruction
????Aspiration
????Endotracheal Intubation
????Normalizing Pulmonary Function During Positive Pressure Ventilation
????Restoration of Spontaneous Ventilation and Airway Protective Mechanisms
REFERENCES

?? INTRODUCTION
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Clinical pharmacology associated with cardiac surgery is fascinating and challenging. The perioperative period is often characterized by the administration of multiple, potent, rapid-acting drugs with diverse, and sometimes opposing, effects and side effects. In this chapter we summarize the pharmacology of the agents most commonly used for the treatment of the primary physiological disturbances associated with cardiac surgery, hemodynamic instability, respiratory insufficiency, and alterations of hemostasis. Even with this restriction, we must consider a wide variety of chemical classes and mechanisms of action. However, the common theme is that pharmacologic effect is achieved via control of intracellular ion fluxes.

It is worthwhile to briefly review several basic subcellular/ molecular pathways. As shown in Figure 4-1, the action potential in myocardial cells is a reflection of ion fluxes across the cell membrane, especially Na+, K+, and Ca++.1,2 Numerous drugs used to control heart rate and rhythm act by altering Na+ (lidocaine, procainamide), K+ (amiodarone, bretylium), or Ca++ (verapamil) currents. Calcium also has a dominant effect on the inotropic state.3,4 Myocardial contractility is a manifestation of the interaction of actin and myosin, with the conversion of chemical energy from ATP hydrolysis into mechanical energy. The interaction of actin and myosin in myocytes is inhibited by the associated protein tropomyosin. This inhibition is "disinhibited" by intracellular calcium. A very similar situation occurs in vascular smooth muscle, where the interaction of actin and myosin (leading to vasoconstriction) is modulated by the protein calmodulin, which requires calcium as a cofactor. Thus, intracellular calcium has a "tonic" effect in both the myocardium and in vascular smooth muscle.



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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 potassium 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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Numerous drugs used during or around cardiac surgery act by altering intracellular calcium.3,4 Catecholamines (epinephrine, dobutamine, etc.) with beta-agonist activity regulate intramyocyte calcium levels via the nucleotide cyclic adenosine monophosphate (cAMP) (Fig. 4-2). Beta agonists bind to receptors on the cell surface that are coupled to the intracellular enzyme adenylate cyclase via the stimulatory transmembrane GTP binding protein. This leads to increased cAMP synthesis, and cAMP in turn acts as a "second messenger" for a series of intracellular reactions culminating in higher levels of intracellular calcium during systole. Less well known is that drugs with only alpha-adrenergic agonist activity may also increase intracellular Ca++ levels, although by a different mechanism.5,6 While under investigation, the probable 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 triphosphate (Fig. 4-2). Both of these compounds increase the sensitivity of the myofilament to calcium, while inositol triphosphate stimulates the release of calcium from its intracellular storage site, the sarcoplasmic reticulum. There is still some debate about the mechanism for the inotropic effect of alpha-adrenergic agonists and its significance for the acute pharmacologic manipulation of contractility, but there is little debate about the importance of this mechanism in vascular smooth muscle, where the increase in intracellular calcium stimulated by alpha-adrenergic agonists can significantly increase smooth muscle tone. However, intracellular calcium in vascular smooth muscle is also controlled by cyclic nucleotides.7,8 In contrast to the myocyte, in vascular smooth muscle cAMP has a primary effect of stimulating the uptake of calcium into intracellular storage sites, decreasing its availability (Fig. 4-3). Thus, drugs that stimulate cAMP production (beta agonists) or inhibit its breakdown (phosphodiesterase inhibitors) will cause vasodilation. In addition, cyclic guanosine monophosphate (cGMP) (Fig. 4-3) also increases intracellular calcium storage, decreasing its availability for modulating the interaction of actin and myosin. Several commonly used pharmacologic agents act via cGMP. For example, nitric oxide stimulates the enzyme guanylate cyclase, increasing cGMP levels. Drugs such as nitroglycerin and sodium nitroprusside achieve their effect by producing nitric oxide as a metabolic product. Vasodilation is also produced by "cross-talk" between K+ and Ca++ fluxes. Decreased levels of ATP, acidosis, and elevated tissue lactate increase the permeability of the ATP-sensitive K+ channel. This increased permeability results in hyperpolarization of the cell membrane that inhibits the entry of Ca++ into the cell. This results in decreased vascular tone.



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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 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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FIGURE 4-3 Mediators of vascular tone. Cyclic AMP and cyclic GMP increase the uptake of calcium into cellular storage sites in vascular smooth 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 mediators such as prostaglandins (PGI2, PGE1, PGE2, PGD2) and thromboxane A2 (TxA2). 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.

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The simplistic overview of pathways of cardiac pharmacology summarized in Figures 4-1 through 4-3 also suggests the primary cause of difficulty in the clinical use of the drugs discussed in this chapter. The mechanisms of action for control of heart rate and rhythm, contractility, and vascular tone are interrelated. For example, beta-adrenergic agonists not only increase intracellular calcium to increase contractility, but they also alter K+ currents, leading to tachycardia. Catecholamines not only may have beta-adrenergic agonist activity, with inotropic and chronotropic effects, but they may possess alpha-agonist activity, leading to increased intracellular calcium in vascular smooth muscle and vasoconstriction. Phosphodiesterase inhibitors may increase contractility by increasing cAMP in the myocyte, but may also cause excessive vasodilation by increasing cAMP in the vasculature. The interplay of the various mechanisms means that the clinical art of cardiac surgical pharmacology lies as much in the selection of drugs for their side effects as for their primary therapeutic effects.


?? ANTIARRHYTHMICS
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Arrhythmias are common in the cardiac surgical period. A stable cardiac rhythm requires depolarization and repolarization in a spatially and temporally coordinated manner, and dysrhythmias may occur when this coordination is disturbed. The mechanisms for arrhythmias can be divided into abnormal impulse initiation, abnormal impulse conduction, or combinations of both.9,10 Abnormal impulse initiation occurs as a result of increased automaticity (spontaneous depolarization of tissue which does not normally have pacemaking activity) or as a result of triggered activity from abnormal conduction after depolarizations during phase 3 or 4 of the action potential. Abnormal conduction often involves reentry phenomena, with recurrent depolarization around a circuit due to unilateral conduction block in ischemic or damaged myocardium and retrograde activation via an alternate pathway through normal tissue. In this simplistic view, it is logical that dysrhythmias could be suppressed by slowing the conduction velocity of ectopic foci, allowing normal pacemaker cells to control heart rate, or by prolonging the action potential duration (and hence refractory period) to block conduction into a limb of a reentry circuit.

Antidysrhythmic agents are often classified by a scheme originally proposed by Vaughan Williams and subsequently modified,11,12 and although alternative schemes describing specific channel-blocking characteristics have been proposed and may be more logical,13 we will organize our discussion using the Vaughan Williams system of 4 major drug categories. In this scheme, class I agents are those with local anesthetic properties that block Na+ channels, class II drugs are beta-blocking agents, class III drugs prolong action potential duration, and class IV are calcium entry blockers. Amiodarone will be discussed in detail due to its expanding role in treating both supraventricular and ventricular arrhythmias, and because its use has replaced many of the previous agents. Because of the efficacy of intravenous amiodarone and its recommendations in ACLS guidelines, many of the older drugs used in cardiac surgery have a historical perspective, and will be briefly considered.

Class I Agents

While each of the class I agents blocks Na+ channels, they may be subclassified on the basis of electrophysiological differences. These differences can be explained, to some extent, by consideration of the kinetics of the interaction of the drug and the Na+ channel.14,15 Class I drugs bind most avidly to open (phase 0 of the action potentialsee Figure 4-1) or inactivated (phase 2) Na+ channels. Dissociation from the channel occurs during the resting (phase 4) state. If the time constant for dissociation is long in comparison to the diastolic interval (corresponding to phase 4), the drug will accumulate in the channel to reach a steady state, slowing conduction in normal tissue. This occurs with class Ia (procainamide, quinidine, disopyramide) and class Ic (encainide, flecainide, lorcainide, propafenone) drugs. In contrast, for the class Ib drugs (lidocaine, tocainide, mexiletine), the time constant for dissociation from the Na+ channel is short, drug does not accumulate in the channel, and conduction velocity is minimally affected. However, in ischemic tissue the depolarized state is more persistent, leading to greater accumulation of agent in the Na+ channel, and slowing of conduction in the damaged myocardium.

Procainamide is a class Ia drug that has a variety of electrophysiological effects.16 Administration may be limited by the side effects of hypotension and decreased cardiac output.17,18 The loading dose is 20 to 30 mg/min, up to 17 mg/kg, and should be followed by an intravenous infusion of 20 to 80 mg/kg/min. Since procainamide prolongs action potential duration, widening of the QRS complex often heralds a potential overdose. The elimination of procainamide involves hepatic metabolism, acetylation to a metabolite with antiarrhythmic and toxic side effects, and renal elimination of this metabolite. Thus the infusion rate for patients with significant hepatic or renal disease should be at the lower level of this range.

Class Ib drugs include what is probably the best known antiarrhythmic agent, lidocaine. As noted above, lidocaine is a Na+ channel blocker that has little effect on conduction velocity in normal tissue but slows conduction in ischemic myocardium.14,15 Other electrophysiological effects include a decrease in action potential duration but a small increase in the ratio of effective refractory period to action potential duration. The exact role of these electrophysiological effects on arrhythmia suppression is unclear. Lidocaine has no significant effects on atrial tissue and it is not recommended for therapy in shock-resistant ventricular tachycardia/ fibrillation (VT/VF) in the Guidelines 2000 for Emergency Cardiovascular Care.19 After an initial bolus dose of 1 to 1.5 mg/kg of lidocaine, plasma levels decrease rapidly due to redistribution to muscle, fat, etc. Effective plasma concentrations are maintained only by following the bolus dose with an infusion of 20 to 50 mg/kg/min.20 Elimination occurs via hepatic metabolism to active metabolites that are cleared by the kidney. Consequently, the dose should be reduced by approximately 50% in patients with liver or kidney disease. The primary toxic effects are associated with the central nervous system, and a lidocaine overdose may cause drowsiness, depressed level of consciousness, or seizures in very high doses. Negative inotropic or hypotensive effects are less pronounced than with most other antiarrhythmics. The other class Ib drugs likely to be encountered in the perioperative period are the oral agents tocainide and mexiletine, which have effects very similar to lidocaine.15

The class Ic agents, including flecainide, encainide, and propafenone, markedly decrease conduction velocity.20,21 The Cardiac Arrhythmia Suppression Trial (CAST) study20,21 of moricizine found that, while ventricular arrhythmias were suppressed, the incidence of sudden death was greater than placebo with encainide and flecainide, and these drugs are not in wide use. Propafenone is available for oral use. The usual adult dose is 150 to 300 mg every 8 hours. It has beta-blocking (with resultant negative inotropic effects) as well as NA+ channel-blocking activity, lengthens the PR, QRS, and QT duration, and may be used to treat both atrial and ventricular dysrhythmia.15

Class II Agents

Beta-receptor blocking agents are another important group of antiarrhythmic (denoted class II in the Vaughan Williams scheme). However, because of their use as antihypertensive as well as antiarrhythmic agents they are discussed elsewhere in this chapter, and we will move on to consider bretylium, amiodarone, and sotalol, the class III agents in the Vaughan Williams scheme. These drugs have a number of complex ion channel-blocking effects, but possibly the most important activity is K+ channel blockade.22 Since the flux of K+ out of the myocyte is responsible for repolarization, an important electrophysiological effect of Class III drugs is prolongation of the action potential.23

Class III Agents

Ibutilide, dofetilide, sotalol, and bretylium are class III agents. Intravenous ibutilide and oral dofetilide are approved for the treatment of atrial fibrillation, but carry the risk of torsades de pointes.24,25 Sotalol is a nonselective beta blocker that also has K+ channel-blocking activity.26 In the United States, it is available only for oral administration and has an approved indication for the treatment of life-threatening ventricular arrhythmias, although it is effective against atrial arrhythmias also. It is not a first-line therapy and should be reserved for arrhythmias refractory to other therapy. Bretylium is not recommended in the Guidelines 2000 for Emergency Cardiovascular Care.19

Class IV Agents

Calcium entry blockers (class IV in the Vaughan Williams scheme), such as verapamil and diltiazem, are antiarrhythmics. In sinoatrial and atrioventricular nodal tissue, Ca++ channels contribute significantly to phase 0 depolarization and the atriovetricular (AV) nodal refractory period is prolonged by Ca++ entry blockade.27,28 This explains the effectiveness of verapamil and diltiazem in the treatment of supraventricular arrhythmias. It is also clear why these drugs are negative inotropes. Both verapamil and diltiazem are effective in slowing the ventricular response to atrial fibrillation, flutter, or paroxysmal supraventricular tachycardia and in converting to sinus rhythm.2931 Verapamil has greater negative inotrope effects than diltiazem and, for this reason it is rarely used for supraventricular arrhythmias. The intravenous dose of diltiazem is 0.25 mg/kg with a second dose of 0.35 mg/kg if the response is inadequate after 15 minutes. The loading dose should be followed by an infusion of 5 to 15 mg/hr. Intravenous diltiazem, although useful for rate control, has been replaced by intravenous amiodarone for the most part in clinical therapy of supraventricular tachycardia (SVT) and prophylaxis (see amiodarone, to follow).

Other Drugs

One of the difficulties of classifying antiarrhythmics by the Vaughan Williams classification is that not all drugs can be incorporated into this scheme. Three examples are digoxin, adenosine, and magnesium, each of which has important uses in the perioperative period.

Digoxin inhibits the Na+/K+ ATPase, leading to decreased intracellular K+, a less negative resting membrane potential, increased slope of phase 4 depolarization, and decreased conduction velocity. These direct effects, however, are usually dominated by indirect effects, including inhibition of reflex responses to congestive heart failure and a vagotonic effect.10,32 The net effect is greatest at the AV node, where conduction is slowed and refractory period is increased, explaining the effectiveness of digoxin in slowing the ventricular response to atrial fibrillation. The major disadvantages of digoxin are the relatively slow onset of action and numerous side effects including proarrhythmia effects, and it is now rarely used for rate control in acute atrial fibrillation because of the advent of IV amiodarone and diltiazem.

Adenosine is an endogenous nucleoside that has an electrophysiological effect very similar to acetylcholine. Adenosine decreases AV node conductivity and its primary antiarrhythmic effect is to break AV nodal reentrant tachycardia.33 An intravenous dose of 100 to 200 ?/kg is the treatment of choice for paroxysmal supraventricular tachycardia. Adverse effects, such as bronchospasm, are short-lived because its plasma half-life is so short (12 seconds). This short half-life makes it ideal for the treatment of reentry dysrhythmia, in which transient interruption can fully suppress the dysrhythmia.

Appropriate acid-base and electrolyte balance is important because electrolyte imbalance can perturb the membrane potential, leading to arrhythmia generation, as can altered acid-base status, via effects on K+ concentrations and sympathetic tone. Therapy for dysrhythmia should include correction of acid-base and electrolyte imbalance. Magnesium supplementation should be considered.34 Magnesium deficiency is common in the perioperative period and magnesium administration has been shown to decrease the incidence of postoperative dysrhythmia.35


?? AMIODARONE
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Intravenous amiodarone has become one of the most administered intravenous antiarrhythmics used in cardiac surgery because of its broad spectrum of efficacy. Amiodarone was originally developed as an antianginal agent because of its vasodilating effects, including coronary vasodilation.36 It has a variety of ion channel-blocking activities.10,29,36 The resultant electrophysiological effects are complex, and there are also differences in the acute intravenous and chronic oral administration. Acute intravenous administration can produce decreases in heart rate and blood pressure, but there are minimal changes in QRS duration or QT interval. After chronic use, there may be significant bradycardia and increases in action potential duration in AV nodal and ventricular tissue, with increased QRS duration and QT interval.3739

Pharmacokinetics

Amiodarone is a complex drug, markedly lipophilic, undergoes variable absorption (35% to 65%) after oral administration, and is extensively taken up by multiple tissues with interindividual variation and complex pharmacokinetics.3840 The short initial context-sensitive half-life after intravenous administration represents drug redistribution. The true elimination half-life for amiodarone is extremely long, up to 40 to 60 days. Because of the huge volume of distribution (approximately 60 L/kg) and a very long duration of action, an active metabolite loading period of several months may be required before reaching steady-state tissue concentrations. Further, in life-threatening arrhythmias, intravenous loading is often starting to establish initial plasma levels. Measuring amiodarone plasma concentrations is not useful, due to the complex pharmacokinetics and the metabolites of the parent drug. Plasma concentrations greater than 2.5 mg/L have been associated with increased risk of toxicity. The optimal dose of amiodarone has not been well characterized, and may vary depending on the specific arrhythmias treated. Further, there may be differences in dose requirements for therapy of supraventricular and ventricular arrhythmias.3740

Because of these distinctive pharmacokinetic properties, steady-state plasma levels are slowly achieved. Oral administration for a typical adult consists of a loading regimen of 80 to 1600 mg/day (in 2 or 3 doses) for 10 days, 600 to 800 mg/day for 4 to 6 weeks, and then maintenance doses of 200 to 600 mg/day. For intravenous loading specific studies will be reviewed, but recommended dosing is 150 mg given over 10 minutes for acute therapy in an adult, followed first by a secondary loading infusion of 60 mg/hr for 6 hours and then by a maintenance infusion of 30 mg/hr to achieve a 1000 mg/day dosing.3740

Electrophysiology

The electrophysiological actions of amiodarone are complex and incompletely understood. Amiodarone produces all four effects according to the Vaughan Williams classification. It also has been shown to have use-dependent class I activity, inhibition of the inward sodium currents, and class II activity.10 The antiadrenergic effect of amiodarone, however, is different from that of beta-blocker drugs because it is noncompetitive and additive to the effect of beta blockers. Amiodarone depresses sinoatrial node automaticity that slows the heart rate and conduction, and increases refractoriness of the AV node, properties useful in the management of supraventricular arrhythmia. Its class III activity results in increases in atrial and ventricular refractoriness and in prolongation of the QTc interval. The effects of oral amiodarone on sinoatrial and AV nodal function are maximal within 2 weeks, whereas the effects on VT and ventricular refractoriness tend to emerge more gradually during oral therapy, becoming maximal after 10 weeks or more.

Indications

The primary indication for amiodarone is ventricular tachycardia or fibrillation refractory to other therapy.4048 It is the most efficacious agent for reducing ventricular arrhythmias and suppresses the incidence of postmyocardial infarction sudden death.37 It is also effective, in doses lower than those used for ventricular dysrhythmia, for the treatment of atrial dysrhythmia and is effective in converting atrial fibrillation to sinus rhythm (see atrial fibrillation).

Side Effects

Although there are numerous adverse reactions to amiodarone, they occur with long-term oral administration and have not been associated with acute intravenous administration. The most serious is pulmonary toxicity, which has not been reported with acute administration in a perioperative setting. Some case series have reported an increased risk of marked bradycardia and hypotension immediately after cardiac surgery in patients already on amiodarone at the time of surgery.49,50 Other case-control studies, however, have not reproduced this finding.51 None of the placebo-controlled trials of prophylactic amiodarone for perioperative AF prevention found any adverse cardiovascular effects of the drug.5256 Thus, it is relatively unlikely that amiodarone poses a serious cardiovascular risk to the postoperative patient. Case reports and case series of postoperative acute pulmonary toxicity are similarly lacking in the rigor of randomized controlled methodology.


?? PHARMACOLOGIC THERAPY OF SPECIFIC ARRHYTHMIAS
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Ventricular Tachyarrhythmias

Intravenous amiodarone is approved for rapid control of recurrent VT or VF. Three randomized controlled trials of patients with recurrent in-hospital, hemodynamically unstable VT or VF with 2 or more episodes within the past 24 hours who failed to respond to or be intolerant of lidocaine, procainamide, and (in 2 of the trials) bretylium have been reported.42,44,46 Patients were critically ill with ischemic cardiovascular disease, 25% were on a mechanical ventilator or intra-aortic balloon pump before enrollment, and 10% were undergoing cardiopulmonary resuscitation at the time of enrollment.

One study compared 3 doses of intravenous amiodarone: 525, 1050, and 2100 mg per day.44 Because of the use of investigator-initiated, intermittent, open-label amiodarone boluses for recurrent VT, the actual mean amiodarone doses received by the 3 groups were 742, 1175, and 1921 mg/d. There was no statistically significant difference in the number of patients without VT/VF recurrence during the 1-day study period: 32 of 86 (41%), 36 of 92 (45%), and 42 of 92 (53%) for the low-, medium-, and high-dose groups, respectively. The number of supplemental amiodarone 150-mg bolus infusions given by blinded investigators was statistically significantly less in those randomized to higher doses of amiodarone.

A wider range of amiodarone doses (125, 500, and 1000 mg/d) was evaluated by Sheinman et al, including a low dose that was expected to be subtherapeutic.46 This stronger study design, however, was also confounded by open-label bolus amiodarone injections given by study investigators. There was, however, a trend toward a relationship between intended amiodarone dose and VT/VF recurrence 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 doses (125 and 1000 mg/d) to bretylium (2500 mg/d).42 Once again, the target amiodarone dose ratio of 8 to 1 was compressed to 1.8 to 1 as a result of open-label boluses. There was no significant difference in the primary outcome, which was median VT/VF recurrence rate over 24 hours. For low-dose amiodarone, high-dose amiodarone, and bretylium, these rates were 1.68, 0.48, and 0.96 events per 24 hours, respectively (p = .237). There was no difference between high-dose amiodarone and bretylium; however, more than 50% of patients had crossed over from bretylium to amiodarone by 16 hours.

The failure of these studies to provide clear evidence of amiodarone efficacy may be related to the "active-control" study design used, a lack of adequate statistical power, high rates of supplemental amiodarone boluses, and high crossover rates. Nonetheless, these studies provide some evidence that IV amiodarone (1 g/d) is moderately effective during a 24-hour period against VT and VF.

SUSTAINED MONOMORPHIC VENTRICULAR TACHYCARDIA AND WIDE QRS TACHYCARDIA

Although the most effective and rapid treatment of any hemodynamically unstable sustained ventricular tachyarrhythmia is electrical cardioversion or defibrillation, intravenous antiarrhythmic drugs can be used for arrhythmia termination if the ventricular tachycardia (VT) is hemodynamically stable. The Guidelines 2000 for Emergency Cardiovascular Care19 removed the former recommendation of lidocaine and adenosine use in stable wide QRS tachycardia, now labeled as "acceptable" but not primarily recommended (lidocaine) or not recommended (adenosine). Intravenous procainamide and sotalol are effective, based on randomized but small studies10; amiodarone is also considered acceptable.19

SHOCK-RESISTANT VENTRICULAR FIBRILLATION

The Guidelines 2000 for Emergency Cardiovascular Care recommend at least three shocks and epinephrine or vasopressin before any antiarrhythmic drug is administered.10,19 No large-scale controlled randomized studies have demonstrated efficacy for lidocaine, bretylium, or procainamide in shock-resistant VF,10,19 and lidocaine and bretylium are no longer recommended in this setting.19 Two pivotal studies have been reported recently studying the efficacy of agents in acute shock-resistant cardiac arrest.

The Amiodarone in the Out-of-Hospital Resuscitation of Refractory Sustained Ventricular Tachycardia (ARREST) study was randomized, double-blind, and placebo-controlled. The ARREST study in 504 patients showed that amiodarone 300 mg administered in a single intravenous bolus significantly improves survival to hospital admission in cardiac arrest still in VT or VF after three direct-current shocks (44% vs. 34%, p 43 Although the highest survival rate to hospital admission (79%) was achieved when the amiodarone was given within 4 to 16 minutes from dispatch, there was no significant difference in the proportional improvement in the amiodarone group compared with the placebo group when the drug administration was delayed (up to 55 minutes). Amiodarone also had the highest efficacy in those patients (21% of all study patients) who had a return of spontaneous circulation before drug administration (survival to hospital admission to 64% from 41% in the placebo group). Among patients with no return of spontaneous circulation, amiodarone only slightly improved outcome (38% vs. 33%).

Dorian performed a randomized trial comparing intravenous lidocaine with intravenous amiodarone as an adjunct to defibrillation in victims of out-of-hospital cardiac arrest.48 Patients were enrolled if they had out-of-hospital ventricular fibrillation resistant to three shocks, intravenous epinephrine, and a further shock, or if they had recurrent ventricular fibrillation after initially successful defibrillation. They were randomly assigned in a double-blind manner to receive intravenous amiodarone plus lidocaine placebo or intravenous lidocaine plus amiodarone placebo. The primary end point was the proportion of patients who survived to be admitted to the hospital. In total, 347 patients (mean age, 67 ? 14 years) were enrolled. The mean interval between the time at which paramedics were dispatched to the scene of the cardiac arrest and the time of their arrival was 7 ? 3 minutes, and the mean interval from dispatch to drug administration was 25 ? 8 minutes. After treatment with amiodarone, 22.8% of 180 patients survived to hospital admission, as compared with 12.0% percent of 167 patients treated with lidocaine (p = .009). Among patients for whom the time from dispatch to the administration of the drug was equal to or less than the median time (24 minutes), 27.7% of those given amiodarone and 15.3% of those given lidocaine survived to hospital admission (p = .05). The authors concluded that compared with lidocaine, amiodarone leads to substantially higher rates of survival to hospital admission in patients with shock-resistant out-of-hospital ventricular fibrillation.

Supraventricular Arrhythmias

A supraventricular arrhythmia is any tachyarrhythmia that requires atrial or atrioventricular junctional tissue for initiation and maintenance. It may arise from reentry caused by unidirectional conduction block in one region of the heart and slow conduction in another, from enhanced automaticity akin to that seen in normal pacemaker cells of the sinus node and in latent pacemaker cells elsewhere in the heart, or from triggered activity, a novel type of abnormally enhanced impulse initiation caused by membrane currents that can be activated and inactivated by premature stimulation or rapid pacing.5658 Pharmacologic approaches to the treatment of supraventricular arrhythmias, including atrial fibrillation, atrial flutter, atrial tachycardia, AV reentrant tachycardia, and AV nodal reentrant tachycardia, continue to evolve.5660 Because atrial fibrillation is perhaps the most common arrhythmia after cardiac surgery, this condition will be emphasized in detail.

Atrial Fibrillation

Atrial fibrillation (AF) is a common complication of cardiac surgery that increases the length of stay in the hospital with resultant increases in health care resource utilization.5661 Advanced age, previous AF, and valvular heart operations are the most consistently identified risk factors for this arrhythmia. Because efforts to terminate AF after its initiation are problematic, current interests are directed at therapies to prevent postoperative AF. Most studies suggest that prophylaxis with antiarrhythmic compounds can significantly decrease the incidence of AF, length of hospital stay, and cost. Newer class III antiarrhythmic drugs (i.e., sotalol, ibutilide) may also be effective, but potentially pose the risk of drug-induced polymorphic ventricular tachycardia (torsades de pointes). Defining which subpopulations benefit most from such therapy is particularly important as older and more critically ill patients undergo surgery.

In addition to beta-adrenergic blockers, amiodarone has evolved as an effective approach for prophylactic therapy of AF. However, most clinicians are confused by the different studies that have evaluated oral versus intravenous (IV) amiodarone. IV amiodarone has continue to evolve in clinical practice because acute loading with oral therapy is often not feasible, in part due to time required and due to the complex pharmacokinetics and variable absorption of oral therapy. There may also be additional benefits of prophylactic therapies in high-risk patients, especially those prone to ventricular arrhythmias (i.e., patients with preexisting heart failure).

Two pivotal studies deserve mention regarding prophylaxis with amiodarone. To determine if IV amiodarone would prevent atrial fibrillation and decrease hospital stay after cardiac surgery, Daoud assessed preoperative prophylaxis in 124 patients who were given either oral amiodarone (64 patients) or placebo (60 patients) for a minimum of seven days before elective cardiac surgery.62 Therapy consisted of 600 mg of amiodarone per day for seven days, then 200 mg per day until the day of discharge from the hospital. The preoperative total dose of amiodarone was 4.8 ? 0.96 g over a period of 13 ? 7 days. Postoperative atrial fibrillation 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 patients in the placebo group (6.5 ? 2.6 vs. 7.9 ? 4.3 days, p = .04). Total hospitalization costs were significantly less for the amiodarone group than for the placebo group ($18,375 ? $13,863 vs. $26,491 ? $23,837, p = .03). Guarnieri evaluated 300 patients randomized in a double-blind fashion to IV amiodarone (1 g/d for 2 days) versus placebo immediately after open-heart surgery.54 The primary end points of the trial were incidence of atrial fibrillation and length of hospital stay. Atrial fibrillation occurred in 67/142 (47%) patients on placebo versus 56/158 (35%) on amiodarone (p = .01). Length of hospital stay for the placebo group was 8.2 ? 6.2 days, and 7.6 ? 5.9 days for the amiodarone group. Low-dose IV amiodarone was safe and effective in reducing the incidence of atrial fibrillation after heart surgery, but did not significantly alter length of hospital stay.

In summary, AF is a frequent complication of cardiac surgery. Many cases can be prevented with appropriate prophylactic therapy. Beta-adrenergic blockers should be administered to most patients without contraindication. Prophylactic amiodarone should be considered in patients at high risk for postoperative AF. The lack of data on cost benefits and cost-efficiency in some studies may reflect the lack of higher risk patients in the study. Patients who are poor candidates for beta blockade may not tolerate sotalol, while amiodarone does not have this limitation. Additional studies need also to be performed to better assess the role of prophylactic therapy in off-pump cardiac surgery.


?? INOTROPIC AGENTS
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Some depression of myocardial function is common after cardiac surgery.6365 The etiology is multifactorialpreexisting disease, incomplete repair or revascularization, myocardial edema, postischemic dysfunction, reperfusion injury, etc.and is usually reversible. Adequate cardiac output can usually be maintained by exploiting the Starling curve with higher preload. But often the cardiac function curve is flattened and it is necessary to utilize inotropic agents to maintain adequate organ perfusion.

The molecular basis for the contractile property of the 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 interaction of actin and myosin is inhibited by tropomyosin, a protein associated with the actin-myosin complex. With the onset of systole, Ca++ enters the myocyte (during phase 1 of the action potential). This influx of Ca++ triggers the release of much larger amounts of Ca++ from the sarcoplasmic reticulum. The binding of Ca++ to the C subunit of the protein troponin interrupts the inhibition of the actin-myosin interaction by tropomyosin, facilitating the hydrolysis of ATP with the generation of a mechanical force. With repolarization of the myocyte and the completion of systole, Ca++ 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 Ca++.66 A novel drug, levosimendan, currently under clinical development in the United States but approved in several countries, increases the sensitivity of the contractile apparatus to Ca++,67 whereas the positive inotropic agents available for clinical use achieve their end by increasing intracellular Ca++ levels.

The first drug to be considered is simply Ca++ itself. In general, administration of calcium will increase the inotropic state of the myocardium, when measured by load-independent methods, but it will also increase vascular tone (afterload) and impair diastolic function. Also, the effects of calcium on myocardial performance are dependent on the plasma Ca++ concentration. Ca++ plays important roles in cellular function and the intracellular Ca++ concentration is highly regulated by membrane ion channels and intracellular organelles.68,69 If the extracellular Ca++ concentration is normal, administration of Ca++ will have little effect on the intracellular level and will have less pronounced hemodynamic effects. On the other hand, if the ionized plasma calcium is low, exogenous calcium administration may increase cardiac output and blood pressure.70 It should also be realized that even with normal plasma Ca++ concentrations, administration of Ca++ may increase vascular tone, leading to increased blood pressure but no change in cardiac output. This increased afterload, as well as the deleterious effects on diastolic function, may be the basis of the observation that Ca++ administration can blunt the response to epinephrine.71 Routine use of Ca++ at the end of bypass should be tempered by the realization that Ca++ may have little effect on cardiac output while increasing systemic vascular resistance, although this in itself may be of importance. If there is evidence of myocardial ischemia, Ca++ administration may be deleterious since it may exacerbate both coronary spasm and the pathways leading to cellular injury.72,73

Digoxin, while not effective as acute therapy for low cardiac output syndrome in the perioperative period, nevertheless well illustrates the role of intracellular Ca++. Digoxin functions by inhibiting the Na+/K+ ATPase, which is responsible for the exchange of intracellular Na+ with extracellular K+.3,4 It is thus responsible for maintaining the intracellular/ extracellular K+ and Na+ gradients. When it is inhibited, intracellular Na+ levels increase. The increased intracellular Na+ is an increased chemical potential for driving the Ca++/Na+ exchanger, an ion exchange mechanism in which intracellular Na+ is removed from the cell in exchange for Ca++. The net effect is an increase in intracellular Ca++, with an enhancement of the inotropic state.

By far the most commonly used positive inotropic agents are the beta-adrenergic agonists. The beta1 receptor is part of a complex comprised of the receptor on the outer surface of the cell membrane, coupled with membrane-spanning G-proteins (so named because they bind GTP), which, in turn, stimulate adenylate cyclase on the inner surface of the membrane, catalyzing the formation cyclic adenosine monophosphate (cAMP). The inotropic state is modulated by cAMP via its catalysis of phosphorylation reactions by protein kinase A. These phosphorylation reactions "open" Ca++ channels on the cell membrane and lead to greater release and uptake of Ca++ from the sarcoplasmic reticulum.3,4

There are a large number of drugs that will stimulate beta1 receptors and have a positive inotropic effect, including epinephrine, norepinephrine, dopamine, isoproterenol, and dobutamine, the most commonly used catecholamines in the perioperative period. While there are differences in their binding at the beta1 receptor, the most important differences between the various catecholamines are their relative effects on alpha- and beta2-adrenergic receptors. In general, alpha stimulation of receptors on the peripheral vasculature causes vasoconstriction while beta2 stimulation leads to vasodilation (see the discussion elsewhere in this chapter). For some time it was believed that beta2 and alpha receptors were found only in the peripheral vasculature, as well as a few other organs, but not in the myocardium. However, recent investigation has shown that alpha receptors are found in the myocardium and mediate a positive inotropic effect.5,6 The mechanism for this positive inotropic effect is probably the stimulation of phospholipase C leading to hydrolysis of phosphatidyl inositol to diacylglycerol and inositol triphosphate, compounds that increase Ca++ release from the sarcoplasmic reticulum and increase myofilament sensitivity to Ca++. It is also possible that alpha-adrenergic agents increase intracellular Ca++ by prolonging action potential duration via inhibition of outward K+ currents during repolarization or by activating the Na+/H+ exchange mechanism, increasing intracellular pH, and increasing myofilament sensitivity to Ca++. 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 slower than that of beta1 stimulation.

In addition to the discovery of alpha receptors in the myocardium, it has also been discovered that beta2 receptors are present in the myocardium.74 The fraction of beta2 receptors (compared to beta1 receptors) is increased in chronic heart failure, possibly explaining the efficacy of drugs with beta2 activity in this setting. This phenomenon is part of the general observation of beta1-receptor downregulation (decrease in receptor density) and desensitization (uncoupling of effect from receptor binding) that is observed in chronic heart failure.75 Interestingly, it has been demonstrated in a dog model that this same phenomenon occurs with cardiopulmonary 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 States, amrinone and milrinone, increase cAMP levels independently of the beta receptor by selectively inhibiting the myocardial enzyme responsible for the breakdown of cAMP.3,4

In clinical use, selection of a particular inotropic agent is usually based more on its side effects than its direct inotropic properties. Of the commonly used catecholamines, norepinephrine has alpha and beta1 but little beta2 activity and is both an inotrope and a vasopressor. Epinephrine and dopamine are mixed agonists with alpha, beta1, and beta2 activity. At lower doses they are primarily inotropes and not vasopressors, although vasopressor effects become more pronounced at higher doses. This is especially true for dopamine, which achieves effects at higher doses by stimulating the release of norepinephrine.77 Dobutamine is a more selective beta1 agonist, in contrast to isoproterenol, which is a mixed beta agonist. Selection of a drug depends on the particular hemodynamic problem at hand. For example, depressed myocardial function in the presence of profound vasodilation may require a drug with both positive inotropic and vasopressor effects, while a patient who is vasoconstricted may benefit from some other choice. We highly recommend an empirical approach to the selection of inotropic agents with careful monitoring of the response to the drug and selection of the agent that achieves the desired effect.

Clinical experience indicates that phosphodiesterase inhibitors can be very effective when catecholamines do not produce an adequate cardiac output.7880 There are few differences in the hemodynamic effects of the two drugs available for use in the United States, amrinone and milrinone. Both agents increase contractility with little effect on heart rate and both are vasodilators. There is significant venodilation, as well as arteriodilating, and maintaining adequate preload is important in avoiding significant hypotension.81 We prefer milrinone to amrinone because of a less pronounced thrombocytopenia, a problem with both drugs.82 If amrinone is used, it should be noted that the bolus dose recommended in the product insert, 0.75 mg/mL, is inadequate to maintain therapeutic plasma levels, and a loading dose of 1.5 to 2.0 mg/mL should be used.83 With either drug, administering the loading dose over 15 to 30 minutes may ameliorate possible hypotension. It should also be realized that despite the fact that both drugs have long half-lives, plasma levels drop quickly after a loading dose due to redistribution and the loading dose should be followed immediately by a continuous infusion.83,84 Because of their long half-lives, it is relatively difficult to readily titrate plasma levels, in comparison to catecholamines (which have plasma half-lives of a few minutes).

Phosphodiesterase inhibitors, specifically milrinone, are being increasingly used to facilitate separation from CPB and for the treatment of low cardiac output syndrome after cardiac surgery.82,8587 A study by Doolan et al also demonstrated that milrinone, in comparison to placebo, significantly facilitated separation of high-risk patients from CPB.88

Levosimendan

Levosimendan is one of the first agents of a new class of drugs known as calcium sensitizers. The molecule is a pyridazinone-dinitrile derivative with additional action on adenosine triphosphate (ATP)-sensitive potassium channels.67,89,90 Levosimendan is used intravenously for the treatment of decompensated cardiac failure, demonstrating enhanced contractility with no increase in oxygen demands, and produces antistunning effects without increasing myocardial intracellular calcium concentrations or prolonging myocardial relaxation. Levosimendan also causes coronary and systemic vasodilation. In patients with decompensated congestive heart failure, IV levosimendan significantly reduced the incidence of worsening CHF or death. IV levosimendan significantly increased cardiac output or cardiac index and decreased filling pressure in the acute treatment of stable or decompensated CHF in large, double-blind, randomized trials and after cardiac surgery in smaller trials. Levosimendan is well tolerated and has not been shown to be arrhythmogenic. In addition to sensitizing troponin to intracellular calcium, levosimendan has been shown to inhibit phosphodiesterase III and open ATP-sensitive potassium channels (K(ATP)), which may produce vasodilation. Unlike currently available intravenous inotropes, levosimendan does not increase myocardial oxygen utilization, has not been shown to be proarrhythmic, and has been used effectively in the presence of beta-blocking medications. Levosimendan also has not been shown to impair ventricular relaxation, which was an initial concern with this class of drugs. Clinical studies of levosimendan have demonstrated short-term hemodynamic benefits of levosimendan over both placebo and dobutamine. While large-scale, long-term morbidity and mortality data are scarce, the Levosimendan Infusion versus Dobutamine in severe low-output heart failure (LIDO) study suggested a mortality benefit of levosimendan over dobutamine up to 180 days after treatment. Clinical studies comparing levosimendan with other positive inotropes, namely milrinone, are lacking. Levosimendan treatment appears to be well tolerated, with the primary adverse events being headache and hypotension.

Clinical Trials

Despite their common use after cardiac surgery, there have been relatively few comparative studies of inotropic agents in the perioperative period. In 1978, Steen et al reported the hemodynamic effects of epinephrine, dobutamine, and epinephrine immediately after separation from CPB.91 The largest mean increase in cardiac index was achieved with dopamine at 15 ?g/kg/min. However, it should be noted that the only epinephrine dose studied was 0.04 ?g/kg/min. In a later comparison of dopamine and dobutamine, Salomon et al concluded that dobutamine produced more consistent increases in cardiac index, although the hemodynamic differences were small and all patients had good cardiac indices at the onset of the study.92 Fowler et al also found insignificant differences in the hemodynamic effects of dobutamine and dopamine, although they reported that coronary flow increased more in proportion to myocardial oxygen consumption with dobutamine.93 While neither of these groups reported significant increases in heart rate for either dopamine or dobutamine, clinical experience has been otherwise. This is supported by a study by Sethna et al, who found that the increase in cardiac index with dobutamine is simply due to increased heart rate, although they found that myocardial oxygen was maintained.94 Butterworth et al subsequently demonstrated that the older and much cheaper agent, epinephrine, effectively increased stroke volume without as great an increase in heart rate as dobutamine.95 More recently, Feneck et al compared dobutamine and milrinone and found them to be equally effective in the treatment of low cardiac output syndrome after cardiac surgery.96 This study was a comparison of two drugs, and the investigators emphasized that the most efficacious therapy is probably combinations of drugs. In particular, phosphodiesterase inhibitors require the synthesis of cAMP to be effective, and thus use of a combination of a beta1-adrenergic agonist and a phosphodiesterase inhibitor would be predicted to be more effective than either agent alone.

Finally, it must also be realized that while global hemodynamic goals (heart rate, blood pressure, filling pressures, cardiac output) may be achieved, this does not guarantee adequate regional perfusion, in particular renal and mesenteric perfusion. To date, there have been few investigations of regional perfusion after cardiac surgery. There has been more interest in regional (especially mesenteric) perfusion in the critical care medicine literature, and some of the critical care investigations may be relevant to postoperative care of the cardiac surgical patient. Two studies have indicated that epinephrine may impair splanchnic perfusion, especially in comparison to the combination of norepinephrine and dobutamine.97,98 Norepinephrine alone has variable effects on splanchnic blood flow in septic shock,99 although the addition of dobutamine can significantly improve splanchnic perfusion when blood pressure is supported with norepinephrine.98 Low-dose dopamine improves splanchnic blood flow,100 but there is evidence that dopamine in higher doses impairs gastric perfusion.101 The relevance of these studies of septic patients for the cardiac surgical patient is unclear, although there are similarities between the inflammatory response to CPB and sepsis.


?? VASOPRESSORS
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Cardiopulmonary bypass is often characterized by derangements of vascular tone. In some cases, CPB induces elevations in endogenous catecholamines as well as other mediators, such as serotonin and arginine vasopressin (AVP), leading to vasoconstriction. However, often CPB is characterized by endothelial injury and a systemic inflammatory response, with a cascade of cytokine and inflammatory mediator release and profound vasodilation. The pathophysiology has a striking resemblance to that of sepsis or an anaphylactic reaction. Furthermore, vasodilation after cardiac surgery may be exacerbated by the preoperative use of angiotensin-converting enzyme inhibitors and post-CPB use of milrinone.

The mechanisms of vasodilatory shock have recently been reviewed.102 Vascular tone is modulated by intracellular Ca++, which binds calmodulin. The Ca++-calmodulin complex activates myosin light chain kinase, which catalyzes the phosphorylation of myosin to facilitate the interaction with actin. Conversely, intracellular cGMP activates myosin phosphatase (also via a kinase-mediated phosphorylation of myosin phosphatase) that dephosphorylates myosin and inhibits the interaction of actin and myosin. A primary mediator of vasodilatory shock is nitric oxide (NO), which is induced by cytokine cascades. NO activates guanylate cyclase, with resultant loss of vascular tone. Another mechanism of vasodilation that may be particularly relevant to prolonged CPB is the activation of ATP-sensitive potassium (KATP) channels. These channels are activated by decreases in cellular ATP or increases in hydrogen ion or lactate. All of these could result from the abnormal perfusion associated with CPB and/or hypothermia. Increases in potassium channel conductance result in hyperpolarization of the vascular smooth muscle membrane, which decreases Ca++ flux into the cell, leading to decreased vascular tone. A third mechanism of vasodilatory shock that also may be particularly relevant to cardiac surgery is deficiency of vasopressin. As noted above, CPB often induces the release of vasopressin, and this may contribute to the excessive vasoconstriction sometimes seen after CPB. However, it has been observed in several experimental models of shock that the initially high levels of vasopressin decrease as shock persists, leading some investigators to suggest that vasopressin stores are limited and are depleted by the initial response to hypotension.

Excessive vasodilation during shock is usually treated with catecholamines, most typically phenylephrine, dopamine, epinephrine, or norepinephrine.103 Although catecholamines produce both alpha- and beta-adrenergic effects, alpha1-adrenergic receptor stimulation produces vasoconstriction. As noted earlier, stimulation of these receptors activates membrane phospholipase-C, which in turn hydrolyzes phosphatidylinositol 4,55 diphosphate.7 This leads to the subsequent generation of two second messengers, including diacyl glycerol and inositol triphosphate. Both of these second messengers increase cytosolic Ca++ by different mechanisms, which include facilitating release of calcium from the sarcoplasmic reticulum, and potentially increasing the calcium sensitivity of the contractile proteins in vascular smooth muscle.

Mediator-induced vasodilation is often poorly responsive to catecholamines,103 and the most potent pressor among catecholamines, norepinephrine, is often required. Some clinicians are concerned about renal, hepatic, and mesenteric function during norepinephrine administration. It should be noted, however, that in septic patients norepinephrine can improve renal function102107 and there is evidence it may improve mesenteric perfusion as well.108 Given the hemodynamic similarities between septic patients and some patients at the end of cardiopulmonary bypass, it would be hoped that these results could be extrapolated to the cardiac surgical patient. However, this has not been confirmed by a systematic study. And in some cases of profound vasodilatory shock, even norepinephrine is inadequate to restore systemic blood pressure. In this situation, low doses of vasopressin may be useful. Argenziano et al109 studied 40 patients with vasodilatory shock (defined as mean arterial blood pressure less than 70 mm Hg with a cardiac index greater than 2.5 L/min/m2) after cardiac surgery. Arginine vasopressin levels were inappropriately low in this group of patients, and low-dose vasopressin infusion (0.1 units/min or less) effectively restored blood pressure and reduced norepinephrine requirements without significant change in cardiac index. These observations were very similar to an earlier report of the use of vasopressin in vasodilatory septic shock.110 Vasopressin has also been reported to be useful in the treatment of milrinone-induced hypotension.111 In this latter report, vasopressin was reported to increase urine output, presumably via glomerular efferent arteriole constriction. However, the overall effects on renal function are unclear. And there are still important unanswered questions about vasopressin and mesenteric perfusion. While vasopressin may effectively restore blood pressure in vasodilatory shock, it must be remembered that in physiologic concentrations it is a mesenteric vasoconstrictor and mesenteric hypoperfusion may be a factor in the development of sepsis and multiorgan dysfunction syndrome.


?? VASODILATORS
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Different pharmacologic approaches are available to pro- duce vasodilation (Table 4-1). Potential therapeutic approaches include: (1) blockade of alpha1-adrenergic receptors, ganglionic transmission, and calcium channel receptors; (2) stimulation of central alpha2-adrenergic receptors or vascular guanylate cyclase and adenylate cyclase; (3) inhibition of phosphodiesterase enzymes and inhibition of angiotensin-converting enzymes.112 Adenosine in low concentrations is also a potent vasodilator with a short half-life but is used, as noted earlier, for its ability to inhibit atrioventricular conduction. Losartan, a novel angiotensin II antagonist (AII), has just been released for the treatment of hypertension but is not available for intravenous use.


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TABLE 4-1 Vasodilators used in the treatment of hypertension and heart failure

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Stimulation of Adenylate Cyclase (Cyclic AMP)

Prostacyclin, prostaglandin E1, and isoproterenol increase cyclic nucleotide formation (adenosine-3', 5'-monophosphate; cyclic AMP) in vascular smooth muscle to produce calcium mobilization out of vascular smooth muscle. Inhibiting the breakdown of cyclic AMP by phosphodiesterase will also increase cyclic AMP.112 Increasing cyclic AMP in vascular smooth muscle facilitates calcium uptake by intracellular storage sites, thus decreasing calcium available for contraction. The net effect of increasing calcium uptake is to produce vascular smooth muscle relaxation and, hence, vasodilation. However, most catecholamines with beta2-adrenergic activity (i.e., isoproterenol) and phosphodiesterase inhibitors have positive inotropic and other side effects that include tachycardia, glycogenolysis, and kaluresis.113 Prostaglandins (prostacyclin and prostaglandin E1) are potent inhibitors of platelet aggregation and activation. Catecholamines with beta2-adrenergic activity, phosphodiesterase inhibitors, and prostaglandin E1 and prostacyclin have been used to vasodilate the pulmonary circulation in patients with pulmonary hypertension and right ventricular failure.113

Nitrates, Nitrovasodilators, and Stimulation of Guanylyl Cyclase (Cyclic GMP)

The vascular endothelium modulates vascular relaxation by releasing both nitric oxide and prostacyclin.114116 Inflammatory mediators can also stimulate the vascular endothelium to release excessive amounts of endothelium-derived relaxing factor (EDRF or nitric oxide), which activates guanylyl cyclase to generate cyclic GMP.89,90 Nitrates and sodium nitroprusside, however, generate nitric oxide directly, independent of vascular endothelium.115,116 The active form of any nitrovasodilator is nitric oxide (NO), in which the nitrogen is in a +2 oxidation state. For any nitrovasodilator to be active, it must be first converted to nitric oxide. For nitroprusside, this is easily accomplished because nitrogen is in a +3 oxidation state, with the nitric oxide molecule bound to the charged iron molecule in an unstable manner, allowing nitroprusside to readily donate its nitric oxide moiety. In the case of nitroglycerin, nitrogen molecules exist in a +5 oxidation state, and thus they must undergo significant metabolic transformations before they are converted to an active molecule. Nitroglycerin is a relatively selective coronary vasodilator and does not produce coronary steal as compared to nitroprusside because the small intracoronary resistance vessels, those less than 100 microns, lack whatever metabolic transformation pathway required to convert nitroglycerin into its active form of nitric oxide.115,116 Chronic nitrate therapy can produce tolerance through different mechanisms, as shown in Table 4-2.114118 Sodium nitroprusside and nitroglycerin are effective vasodilators that produce venodilation that contributes significantly to the labile hemodynamic state.114 Intravenous volume administration is often required with nitroprusside due to the relative intravascular hypovolemia.


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TABLE 4-2 Mechanisms of nitrate tolerance

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Dihydropyridine Calcium Channel Blockers

Dihydropyridine calcium channel blockers are direct arterial vasodilators.119 Nifedipine was the first dihydropyridine calcium channel blocker, and the newer second-generation water-soluble agents that are available in intravenous form include isradipine and nicardipine. Isradipine and nicardipine produce arterial vasodilation without any effects on the vascular capacitance bed, no effects on atrioventricular nodal conduction, and no depression of ventricular function (i.e., contractility).120125 Nicardipine is the first intravenous drug of this class to be available in the United States, and it offers a novel and important therapeutic option to treat perioperative hypertension following cardiac surgery. Because currently available intravenous calcium channel blockers have longer half-lives than nitrovasodilators, rapid loading infusion rates or bolus loading doses need to be administered to obtain therapeutic levels. Bolus nicardipine administration can also be used to treat acute hypertension that occurs during the perioperative period (i.e., intubation, extubation, cardiopulmonary bypassinduced hypertension, and aortic cross-clamping).

Phosphodiesterase Inhibitors

The phosphodiesterase inhibitors currently available for use produce both positive inotropic effects and vasodilation.126 When administered to patients with ventricular dysfunction, they increase cardiac output, while decreasing pulmonary artery occlusion pressure, systemic vascular resistance, and pulmonary vascular resistance. Because of their unique mechanisms of vasodilation, they are especially useful for patients with acute pulmonary vasoconstriction and right ventricular dysfunction. Multiple forms of the drug are currently under investigation. The bipyridines (amrinone and milrinone), the imidazolones (enoximone), and the methylxanthines (aminophylline) are the ones most widely available. Papaverine, a benzyl isoquinolinium derivative isolated from opium, is a nonspecific phosphodiesterase inhibitor and vasodilator used by cardiac surgeons for its ability to dilate the internal mammary artery.126

Angiotensin-Converting Enzyme Inhibitors

The angiotensin-converting enzyme (ACE) inhibitors have growing use in the management of heart failure, and more patients are receiving these drugs. The ACE inhibitors prevent the conversion of angiotensin I to angiotensin II by inhibiting an enzyme called kininase in the pulmonary and systemic vascular endothelium. This enzyme is also important for the metabolism of bradykinin, a potent endogenous vasodilator, and for release of EDRF. Although there is little data in the literature regarding the preoperative management of patients receiving these drugs, withholding them on the day of surgery has been our clinical practice based on their potential to produce excessive vasodilation during CPB. Although Tuman was unable to find any difference in blood pressure during CPB in patients receiving ACE inhibitors, contact activation during CPB has the ability to generate bradykinin and thus amplify the potential for vasodilation.127 The vasoconstrictor requirements were increased after bypass in his study.

Angiotensin II Receptor Blockers

Angiotensin-converting enzyme (ACE) inhibitors may not be tolerated in some patients due to cough (common) and angioedema (rare). Inhibition of kininase II by ACE inhibitors leads to bradykinin accumulation in the lungs and vasculature, which probably causes cough and vasodilation. Alternative treatment with angiotensin IIreceptor blockers (ARBs) may be less frequently associated with these side effects because ARBs do not affect kinin metabolism. Six ARBs are currently available for antihypertensive therapy in the United States: losartan (Cozaar), valsartan (Diovan), irbesartan (Avapro), candesartan (Atacand), eprosartan (Teveten), and telmisartan (Micardis). Mortality in chronic heart failure is related to activation of the autonomic nervous and renin-angiotensin systems, and ACE inhibitor therapy seems to attenuate progression of myocardial dysfunction and remodeling. ACE inhibitors do not completely block angiotensin II (A-II) production,128 and may even increase circulating A-II levels in patients with heart failure.129 It was initially thought that ARBs might offer advantages over ACE inhibitors for heart failure therapy in terms of tolerability and more complete A-II blockade. Although ARBs were more tolerated,130 all-cause mortality and the number of sudden deaths or resuscitated cardiac arrests were not different when losartan (Cozaar) and captopril (Capoten) were compared in patients (>60 years old, NYHA class II-IV, LVEF 131 Hence, the long-term benefits from ACE inhibitor therapy are, at least in part, attributable to increased bradykinin formation.132,133 For the treatment of heart failure, combination therapies with ACE inhibitors and ARBs are currently being investigated.134,135 Perioperative hypotension may be encountered in ARB-treated patients as well as ACE inhibitortreated patients, and increased inotropic support may be required.136138


?? PHARMACOLOGIC MANIPULATION OF THE HEMOSTATIC SYSTEM DURING CARDIAC SURGERY
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Numerous pharmacologic approaches to manipulate the hemostatic system in cardiac surgery include attenuating hemostatic system activation, preserving platelet function, and decreasing the need for transfusion of allogeneic blood products.139141 Different approaches currently available or under investigation are shown in Tables 4-3 and 4-4. Pharmacologic approaches to reduce bleeding and transfusion requirements in cardiac surgical patients are based on either preventing or reversing the defects associated with the CPB-induced coagulopathy.


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TABLE 4-3 Novel anticoagulant agents affecting the hemostatic system

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TABLE 4-4 Agents that improve hemostatic function in the bleeding patient

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Pharmacology of Anticoagulation

Anticoagulation therapy is based on inhibiting thrombus formation; however, thrombus is due to both thrombin activation and platelet activation (Table 4-5). Because of the complex humoral amplification system linking both hemostatic and inflammatory responses, there are multiple pathways to generate thrombin and platelet activation. During cardiac surgery, multiple aspects of the extracorporeal system can generate thrombin.


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TABLE 4-5 Preoperative anticoagulants used in cardiac surgical patients

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Heparin

Heparin is purified from either porcine intestine or from beef lung. Heparin that is used for cardiac surgery includes fragments that range from 3,000 to 30,000 daltons, and is also called unfractionated.141 Heparin acts as an anticoagulant by binding to antithrombin III (AT III), enhancing the rate of thrombin-AT III complex formation, and also inhibiting other clotting factors.142 One major advantage of unfractionated heparin is that it can be reversed immediately by protamine. Because heparin also binds to other proteins, it can also produce platelet dysfunction. Heparin dosing for CPB ranges from 300 to 500 units/kg. Despotis reported that the maintenance of patient-specific heparin concentrations during CPB was associated with more effective suppression of hemostatic activation.143,144 Further, Mochizuki has shown that excess protamine can further alter coagulation and coagulation tests, and the careful exact titrated reversal of heparin avoiding excess protamine may be an important contribution to work by Despotis.145 Heparin-induced thrombocytopenia (HIT) is an adverse effect of heparin produced by antibodies (IgG) to the composite of heparin-platelet factor 4 (PF4) that leads to the formation of immune complexes.145 These immune complexes bind to platelets via platelet Fc-receptors (CD 32) producing intravascular platelet activation, thrombocytopenia, and platelet activation with potential thromboembolic complications that can result in limb loss or death.

Low Molecular Weight Heparin

Low molecular weight heparin (LMWH) is manufactured by depolymerizing unfractionated heparin to produce a mean molecular weight of approximately 5000 daltons.146148 A pentasaccharide sequence is required for attachment of a heparin fragment to antithrombin, and additional 13-saccharide residues are necessary to allow the heparin fragment to simultaneously attach itself to the heparin-binding domain of thrombin.146148 LMWH fragments of less than 18 saccharides retain the critical pentasaccharide sequence required for formation of a Xa-antithrombin complex; LMWH inhibits both factor Xa and thrombin, but the ratio of factor Xa to thrombin is increased.146148 LMWH is widely used in cardiovascular medicine but poses a problem for cardiac surgical patients because of its long half-life. PTT and ACT are not affected by LMWH, and LMWH is not readily reversible with protamine.

Antithrombin

Antithrombin (AT) levels are normally present as approximately 100% activity, but decrease approximately 30% in patients receiving heparin. Following initiation of CPB, AT decreases by 40% to 50%, an important consideration that may be critical in determining the extent of thrombin inhibition, especially during CPB.149 Despotis suggested better anticoagulation during CPB may be associated with less bleeding postprocedure, presumably related to preservation of critical coagulation components. One promising therapy currently under investigation is the use of purified antithrombin III (AT).150 Supplemental AT, through improved heparin sensitivity and enhanced anticoagulation, may preserve hemostasis during CPB.151

New Anticoagulants

The new intravenous antithrombins recombinant hirudin (Refludan), bivalirudin (Hirulog), and argatroban inhibit fibrin-bound thrombin independent of AT.152158 The direct thrombin inhibitors do not require AT or access to the heparin binding site of thrombin, and inhibit fibrin-bound as well as fluid-phase thrombin.41 Recombinant hirudin (lepirudin), a 65-amino-acid polypeptide, is the most potent antithrombin. Although lepirudin has been used for cardiac surgical patients with HIT, it is nonreversible, its effect is difficult to monitor, and it is eliminated by renal mechanisms. Argatroban is a synthetic intravenous direct thrombin inhibitor with a relatively short elimination half-life that is approved for use in patients with HIT. Argatroban requires hepatic elimination, and can be used in patients with renal failure. Bivalirudin (Angiomax) is a short-acting hirudin analogue that requires infusions to be effective, and has been studied in patients with acute coronary syndromes.159

When patients with HIT require CPB, danaparoid (Orgaran), ancrod, recombinant hirudin (Refludan), and several other drug combinations have been used with various degrees of success.160163 One of the major problems with these drugs is their lack of reversibility and thus potential to produce bleeding. Danaparoid has a long half-life (t1/2 of antifactor Xa activity of 24 hours), and monitoring is complicated by the need to measure antifactor Xa. Recombinant hirudin, a direct thrombin inhibitor modified from a leech salivary protein, is the most potent and specific thrombin inhibitor currently known. It acts independently of cofactors such as antithrombin. Potzsch et al have reported using lepirudin during cardiopulmonary bypass for patients with HIT using a 0.25-mg/kg bolus and then 5-mg boluses when hirudin concentration was by ecarin clotting time.157 Koster has reported that the use of tirofiban, a platelet inhibitor, appears to be a better solution to this problem.164

Aprotinin

Aprotinin is a naturally occurring polypeptide with a molecular weight of 6512 daltons that reversibly complexes with the active serine site in various proteases in plasma to inhibit the serine proteases, trypsin, kallikrein, plasmin, and elastase, reversibly. Multiple mechanisms are responsible for aprotinin's ability to reduce bleeding after CPB.163170 Aprotinin is the most potent antifibrinolytic agent. The propagation of the "intrinsic" fibrinolysis through factor XIImediated kallikrein activation and the generation of plasmin through "extrinsic" or tPA-mediated activation of plasminogen is effectively inhibited by approximately 4 ? mol/L of aprotinin, which is maintained in plasma with the high-dose regimen. Aprotinin also has multiple anti-inflammatory effects, and inflammation and hemostasis are closely linked. Finally, aprotinin has been studied in multiple placebo-controlled studies, and is the only agent approved by the FDA to reduce bleeding in cardiac surgical patients.167170

Antifibrinolytic Agents and Desmopressin

The synthetic lysine analogues epsilon aminocaproic acid (EACA; Amicar) and tranexamic acid inhibit fibrinolysis by attaching to the lysine binding site of the plasmin(ogen) molecule, displacing plasminogen from fibrin. Levi et al reported a meta-analysis of all randomized, controlled trials of the three most frequently used pharmacological strategies to decrease perioperative blood loss (aprotinin, lysine analogues [aminocaproic acid and tranexamic acid], and desmopressin).170 Studies were included if they reported at least one clinically relevant outcome (mortality, rethoracotomy, proportion of patients receiving a transfusion, or perioperative myocardial infarction) in addition to perioperative blood loss. In addition, a separate meta-analysis was done for studies concerning complicated cardiac surgery. A total of 72 trials (8409 patients) met the inclusion criteria. Treatment with aprotinin decreased mortality almost 2-fold (OR = 0.55; 95% CI, 0.340.90) compared with placebo. Treatment with aprotinin and with lysine analogues decreased the frequency of surgical reexploration (OR = 0.37; 95% CI, 0.250.55 and OR = 0.44, 95% CI, 0.220.90, respectively). These two treatments also significantly decreased the proportion of patients receiving any allogeneic blood transfusion. The use of desmopressin resulted in a small decrease in perioperative blood loss, but was not associated with a beneficial effect on other clinical outcomes. Aprotinin and lysine analogues did not increase the risk of perioperative myocardial infarction; however, desmopressin was associated with a 2.4-fold increase in the risk of this complication. Studies in patients undergoing complicated cardiac surgery showed similar results.

Acquired Platelet Dysfunction

Acquired functional platelet disorders are caused by the multitude of potent antiplatelet agents that patents receive for atherosclerotic vascular disease or during percutaneous interventions.171173 Clopidogrel (Plavix), a drug that selectively interferes with ADP-induced platelet aggregation, is commonly used in patients with ischemic heart disease and those undergoing angioplasty.172 Clopidogrel requires 3 to 5 days for the onset to occur, and a similar length of time for the effect to disappear.172 Because of the pivotal role of the platelet glycoprotein (GP) IIb/IIIa complex in platelet-mediated thrombus formation, three different GP IIb/IIIa antagonists are currently available, but differ in antagonist affinity, reversibility, and receptor specificity.171 Glycoprotein (GP) IIb/IIIa (IIb?3) is a receptor on platelets that binds to key hemostatic proteins, including fibrinogen and von Willebrand factor (vWF), to allow cross-linking of platelets and platelet aggregation. By blocking this final common pathway using GP IIb/IIIa antagonists, these drugs function as inhibitors of platelet participation in acute thrombosis. Various antagonists of GP IIb/IIIa are available and include the monoclonal antibody abciximab (ReoPro); tirofiban (Aggrastat), a nonpeptide fiban molecule; and eptifibatide (Integrelin), a cyclic peptide. Tirofiban and eptifibatide are cleared predominantly through renal mechanisms and have a circulating plasma half-life of approximately 2 to 4 hours, and while abciximab has a relatively short plasma half-life, the monoclonal antibody avidly binds to platelets with a relatively longer duration of action.171

Antiplatelet agents are used primarily to treat and prevent arterial thrombosis. Ticlopidine and clopidogrel are believed to inhibit the binding of adenosine 5'-diphosphate (ADP) to its platelet receptor; this ADP-receptor blockade leads to direct inhibition of the binding of fibrinogen to the glycoprotein IIb/IIIa complex.172 Clopidogrel was approved by the FDA for the reduction of ischemic events in patients with recent myocardial infarction, stroke, or peripheral arterial disease with no added risk for neutropenia. The combination of clopidogrel and aspirin, as well as the use of clopidogrel in coronary stenting, is rapidly growing. Many heart centers now administer clopidogrel before anticipated stenting procedures. The variability in bleeding in patients receiving these agents for cardiac surgery may relate to the time and duration of therapy.

Previous recommendations for managing patients receiving antiplatelet agents and requiring cardiac surgery are summarized in Table 4-6. The fact that a patient is receiving antiplatelet agents should not preclude urgent revascularization. Platelets may be needed and should be available when operating on abciximab-treated patients. Platelets should not be administered prophylactically. Although recommendations have been made on reducing heparin dosing, we believe there are no data to support reductions in heparin dosing during CPB and for cardiac surgery. Therefore, standard loading doses should be considered and additional heparin doses, based on time and duration of bypass or on actual heparin levels, should be maintained. Further, the heparin is reduced at the end of CPB.


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TABLE 4-6 Recommendations for managing patients receiving platelet inhibitors for cardiac surgery

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Protamine

One of our most unusual clinical practices is to anticoagulate patients with heparin, an extract from bovine lung or porcine intestine, and reverse the heparin with protamine, which is a histone and a basic arginine-rich polypeptide extracted from salmon sperm. Protamine immediately reverses heparin by nonspecific polyionic-polycationic (acid-base) interactions. There are different methods to determine the amount of protamine to be administered: Use a ratio of 1.3 mg protamine per 100 units heparin administered; determine heparin levels based on heparin-protamine titrations; or use a dose based on the total amount of heparin administered over time.174

Protamine, a polypeptide isolated from fish sperm, does have the potential to produce anaphylactic reactions, and other potential adverse drug reactions.175,176 Although rapid protamine administration has the potential to produce hemodynamic instability, the life-threatening reactions to protamine seen clinically represent immediate hypersensitivity reactions.175,176 The incidence of anaphylaxis appears to be higher in certain patient groups, including diabetics receiving protamine-containing insulin like NPH. We have reported that the incidence of anaphylaxis to protamine in NPH insulindependent diabetics is 0.6% to 2% compared to 0.06% in most other patients.175,176 Other patient groups may be at an increased risk for adverse reactions to protamine including patients with a prior vasectomy or previous fish allergy; however, data do not support this contention.175176

New methods for reversing anticoagulation were once under investigation but may never come to market and include heparin binding filters, recombinant platelet factor 4, and heparinase.177

Antifibrinolytics

As discussed above, patients following fibrinolytic therapy have a complex coagulopathic state. Because of the potential half-lives of the fibrinolytic agents, using drugs that counteract their effects is potentially useful. Epsilon-aminocaproic acid (EACA; Amicar) and its analogue, tranexamic acid, are derivatives of the amino acid lysine. Both of these drugs inhibit the proteolytic activity of plasmin and the conversion of plasminogen to plasmin by plasminogen activators. Although aprotinin in clinically used concentrations is the most potent inhibitor of fibrinolysis and would represent a useful therapy, it is not approved for this use.169 Additional coagulation factors and platelets may be required in addition to inhibiting fibrinolysis to reverse the coagulopathy.

Blood Products

Blood products are widely administered in cardiac surgical patients and represent a major utilization for hospitals. Once widely administered as part of empirical therapy, specific indications for coagulation factors need to be determined prior to their administration (Table 4-7). In addition to costs, blood products carry significant risks. Although the risk of viral-induced transmission is low, immunosuppressive effects, transfusion-related acute lung injury, and costs need to be considered when administering blood products. The role of fresh frozen plasma administration needs to be considered because it represents an often inappropriately used product. Specific indications for blood products are listed in Table 4-7. Each institution needs to develop its own algorithm for blood product administration in cardiac surgical patients. Using specific therapies, excessive and inappropriate transfusions can be avoided.


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TABLE 4-7 Indications for blood product administration in the bleeding cardiac surgical patient

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Recombinant Coagulation Products

Coagulation products used to manage bleeding in patients with hemophilia, von Willebrand's disease (vWD), or acquired inhibitors to antihemophilic factor include AHF concentrates, factor IX concentrates, factor VIIa concentrate, factor IX complexes, anti-inhibitor coagulant complexes, and desmopressin acetate. These commercially available products are used to manage acute bleeding or to prevent excessive bleeding during cardiac and noncardiac surgery in patients with hematologic disorders. Recombinant activated factor VIIa (rFVIIa; NovoSeven, Novo Nordisk A/S) has been used as a novel and effective treatment for patients with hemophilia with inhibitors for the treatment of bleeding, and to secure hemostasis in complex clinical situations.178181

The role of rFVIIa in the treatment of bleeding was evaluated in an open pilot study in patients with complicated cardiac surgical procedures. Blood loss and hemostatic effects and safety following rFVIIa administration were evaluated.181 Five patients undergoing closure of atrial septal defect, De Vega's procedure (mitral valve replacement with tricuspid valve repair), and arterial switch (2.5 years old) were evaluated. Four patients received rFVIIa intraoperatively, while the fifth received it postoperatively. Satisfactory hemostasis was achieved with a single dose (30 ?g/kg) of rFVIIa. Four hours after treatment, mean blood loss was 262 mL for adults (220334 mL) and 85 mL for the child. No significant adverse events were reported. Laboratory parameters indicated a mean 18.5-fold (range 3.742) increase in FVII levels at 30 minutes postinjection and a mean reduction of 12 seconds (range 339 seconds) in prothrombin time.182

The modes of action of rFIIa are multiple, including tissue-factordependent mechanisms and generation of factors Xa and IXa on the surface of activated platelets. These studies relate thrombin generation on activated platelets to the high level of recombinant factor VIIa binding to platelet surfaces. Therapeutic doses of recombinant factor VIIa are not established; different doses have been used during surgery in patients with hemophilia and inhibitors, and with refractory bleeding following cardiac surgery. The use of recombinant factor VIIa has been reported to control bleeding in patients with thrombocytopathies, liver disease, and liver transplantation, and patients undergoing cardiac surgery. Recommended dose ranges for rFVIIa usually vary from 60 to 120 ?g/kg, although 90 ?g/kg is usually the initial starting dose.180

Fibrinolytics

Patients may also have received fibrinolytic drugs, including tissue plasminogen activator (TPA), streptokinase, or urokinase. These drugs inactivate fibrinogen and other adhesive proteins, and have the potential to affect platelets as well.181 Patients receiving these drugs within 24 hours of surgery should be considered to be at a high risk for coagulopathy, and fibrinogen levels should be measured.


?? BETA-ADRENERGIC RECEPTOR BLOCKERS
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Not surprisingly, most of the effects observed after administration of a beta-adrenergic receptor blocker reflect the reduced responsiveness of tissues containing beta-adrenergic receptors to cathecholamines present in the vicinity of those receptors. Hence, the intensity of the effects of beta blockers is dependent on both the dose of the blocker as well as the receptor concentrations of catecholamines, primarily epinephrine and norepinephrine. In fact, a purely competitive interaction of beta blockers and catecholamines can be demonstrated in normal human volunteers as well as in isolated tissues studied in the laboratory. The presence of disease and other types of drugs modifies the responses to beta blockers observed in patients, but the underlying competitive interaction is still operative. The key to successful utilization of beta-adrenergic receptor blockers is to titrate the dose to the desired degree of effect and to remember that excessive effects from larger than necessary doses of beta-adrenergic receptor blockers can be overcome by (1) administering a catecholamine to compete at the blocked receptors, and/or (2) administering other types of drugs to reduce the activity of counterbalancing autonomic mechanisms that are unopposed in the presence of beta-receptor blockade. An example of the latter is propranolol-induced bradycardia, which reflects the increased dominance of the vagal cholinergic mechanism on cardiac nodal tissue. Excessive bradycardia may be relieved by administering atropine to block the cholinergic receptors, which are also located in the sinus and atrioventricular (AV) nodes.

Knowledge of the type, location, and action of beta recep- tor is fundamental to understanding and predicting effects of beta-adrenergic receptorblocking drugs (Table 4-8).183 Beta-adrenergic receptor blockers are competitive inhibitors; hence the intensity of blockade is dependent on both the dose of the drug and receptor concentrations of catecholamines, primarily epinephrine and norepinephrine.


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TABLE 4-8 Location and actions of beta-adrenergic receptors

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Beta-adrenergic receptor antagonists (blockers) include many drugs (Table 4-9) that are typically classified by their relative selectivity for beta1 and beta2 receptors (i.e., cardioselective or nonselective); the presence or absence of agonistic activity; membrane-stabilizing properties; alpha-receptor blocking efficacy; and various pharmacokinetic features (e.g., lipid solubility, oral bioavailability, elimination half-time).184 The practitioner must realize that the selectivity of individual drugs for beta1 and beta2 receptors is relative, not absolute. For example, the risk of inducing bronchospasm with a beta1-adrenergic (cardioselective) blocker (e.g., esmolol, metoprolol) may be relatively less than with a nonselective blockers (e.g., propranolol); however, the risk is still present.


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TABLE 4-9 Beta-adrenergic receptor blockers

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Acute Myocardial Infarction

Clinical trials of intravenous beta-adrenergic blockers in the early phases of acute myocardial infarction suggest that mortality decreases by 10%. Following myocardial infarction, chronic oral beta-blocking agents reduce the incidence of recurrent myocardial infarction. A randomized, controlled trial of atenolol (Tenormin) in the perioperative period was performed by Mangano and his group. In their study, the incidence of myocardial ischemia was reduced by 50% in patients receiving atenolol. Overall mortality after discharge was lower in the atenolol group compared to the control group over a two-year period (10% vs. 21%).185 However, atenolol did not result in the reduction of death during hospitalization or of perioperative myocardial infarction. Poldermans and his group performed another randomized, controlled perioperative trial in using bisoprolol (Zebeta) in high-risk vascular surgical patients. Bisoprolol therapy, started one week before a major surgery and continued for 30 days postoperatively, has significantly reduced the rate of death and nonfatal myocardial infarction.186 The follow-up of their study showed that the reduction of cardiac events persisted over two years in the bisoprolol-treatment group (12 % vs. 32 %).187

Supraventricular Tachycardias and Ventricular Dysrhythmias

Beta-adrenergic blocking agents are Vaughan Williams class II antidysrhythmics that primarily block cardiac responses to catecholamines. Propranolol (Inderal), esmolol (Brevibloc), and acebutolol (Sectral) are commonly used for this indication. Beta-blocking agents decrease spontaneous depolarization in the sinus and atrioventricular (AV) nodes, decrease automaticity in Purkinje fibers, increase AV nodal refractoriness, increase threshold for fibrillation (but not for depolarization), and decrease ventricular slow responses that are dependent on catecholamines. Amiodarone, a class III agent, also exerts noncompetitive alpha- and beta-adrenergic blockade, which may contribute its antidysrhythmic and antihypertensive actions.188 Sotalol is another class III antidysrhythmic with nonselective beta-blocking action. There is evidence that beta-blocking agents also decrease intramyocardial conduction in ischemic tissue and reduce the risks of dysrhythmias, to the extent that they decrease myocardial ischemia. Beta-adrenergic blockers are not particularly effective in controlling dysrhythmias that are not induced or maintained by catecholamines.

Hypertension

Hypertension is a major risk factor for the development of heart failure and other end-organ damage. Beta blockers, along with diuretics, are considered to be the initial drug of choice for uncomplicated hypertension in patients aged less than 65 years.189

During the early phases of therapy there is a decrease in cardiac output, a rise in systemic vascular resistance (SVR), and relatively little change in mean arterial blood pressure. Within hours to days, SVR normalizes and blood pressure declines. In addition, the release of renin from the juxtaglomerular apparatus in the kidney is inhibited (beta1 blockade). Beta-blocking agents with intrinsic agonistic activity reduce systemic vascular resistance below pretreatment levels, presumably by activating beta2 receptors in vascular smooth muscle. Most beta-adrenergic blockers are used in conjunction with other agents in the treatment of chronic hypertension. When combined with a vasodilator, beta blockers limit reflex tachycardia. For example, when propranolol is combined with intravenous nitroprusside (a potent arterial dilator), it prevents reflex release of renin and reflex tachycardia induced by nitroprusside.

Acute Dissecting Aortic Aneurysm

The primary goal in the management of dissecting aneurysms is to reduce stress on the dissected aortic wall by reducing the systolic acceleration of blood flow. Beta blockers reduce cardiac inotropy and reduce ventricular ejection fraction. Beta blockers may also limit reflex sympathetic responses to vasodilators that are used to control systemic arterial pressure.

Pheochromocytoma

The presence of catecholamine-secreting tissue is tantamount 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 established prior to the administration of the beta blocker in order to prevent exacerbation of hypertensive episodes by unopposed alpha-adrenergic receptor activity in vascular smooth muscle.

Chronic Heart Failure

It is now understood that the activation of the autonomic nervous system (ANS) and rennin-angiotensin system (RAS) as a compensatory mechanism to the failing heart may actually contribute to the deterioration of myocardial function. Mortality in chronic heart failure (CHF) 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 with heart failure. It has an alpha1- and nonselective beta-blocking activity (alpha:beta = 1:10). It is contraindicated in severe decompensated heart failure and asthma. In patients with atrial fibrillation and left heart failure treated with carvedilol, improved ejection fraction and a trend of decreased incidence of death and CHF hospitalization were observed in a retrospective analysis of a U.S. carvedilol study.190 There are several on-going clinical trials with carvedilol, metoprolol (Toprol), or bisoprolol (Zebeta). The results of these studies may provide answers as to which beta-blocking agent would most successfully treat specific patient populations.

Other Indications

The other clinical applications of beta-adrenergic receptor blockers listed in Table 4-10 are based on largely symptomatic treatment or empiric trials of beta-adrenergic antagonists.


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TABLE 4-10 Clinical applications of beta-adrenergic receptor blockers

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Side Effects and Toxicity

The most obvious and immediate signs of a toxic overdose of a beta-adrenergic receptor blocker are hypotension, bradycardia, congestive heart failure, decreased AV conduction, and a widened QRS complex on the electrocardiogram. Treatment is aimed at blocking the cholinergic receptor responses to vagal nerve activity (e.g., atropine) and administering a sympathomimetic to compete with the beta blockers at adrenergic receptors. In patients with asthma and COPD, beta blockers may cause bronchospasm. Beta blockers may increase levels of plasma triglycerides and reduce levels of HDL cholesterol.191 Rarely, beta blockers may mask the symptoms of hypoglycemia in diabetic patients. Other side effects include mental depression, physical fatigue, altered sleep patterns, sexual dysfunction, and gastrointestinal symptoms including indigestion, constipation, and diarrhea.

Drug Interactions

Pharmacokinetic drug interactions include reduced gastrointestinal absorption of the beta blocker (aluminum-containing antacids, cholestyramine), increased biotransformation of the beta blocker (phenytoin, phenobarbital, rifampin, smoking), and increased bioavailability due to decreased biotransformation (e.g., cimetidine, hydralazine). Pharmacodynamic interactions include an additive effect with calcium channel blockers to decrease conduction in the heart and a reduced antihypertensive effect of beta blockers when administered with some of the NSAIDs.


?? DIURETICS
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Diuretics are drugs that act directly on the kidneys to increase urine volume and to produce a net loss of solute (principally sodium and other electrolytes) and water. Diuretics and beta blockers are initial drugs of choice for uncomplicated hypertension in patients younger than 65 years.189 The currently available diuretic drugs have a number of other uses in medicine (e.g., glaucoma, increased intracranial pressure). The principal indications for the use of diuretics by intravenous administration in the perioperative period are (1) to increase urine flow in oliguria, (2) to reduce intravascular volume in patients at risk of acute congestive heart failure from excessive fluid administration or acute heart failure, and (3) to mobilize edema.

Renal function depends on adequate renal perfusion to maintain the integrity of renal cells and to provide the hydrostatic pressure that produces glomerular filtration. There are no drugs that act directly on the renal glomerulus to affect glomerular filtration rate (GFR). In the normal adult human of average size, GFR averages 125 mL/min and urine production approximates 1 mL/min. In other words, 99% of the glomerular filtrate is reabsorbed. Diuretics act primarily on specific segments of the renal tubule to alter reabsorption of electrolytes, principally sodium, and water.

There are two basic mechanisms behind the renal tubular reabsorption of sodium. (1) Sodium is extruded from the tubular cell into peritubular fluid primarily by active transport of the sodium ion, which reflects the action of the Na+-K+ ATPase pump and also the bicarbonate reabsorption mechanism (see below). This extrusion of sodium creates an electrochemical gradient causing diffusion of sodium from the tubular lumen into the tubular cell. (2) Sodium moves from the glomerular filtrate in the tubular fluid into the peritubular fluid by several different mechanisms. The most important quantitatively is the sodium electrochemical gradient created by the active extrusion of sodium from the tubular cell into peritubular fluid. In addition, 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 chloride ion or a combination of a potassium and two chloride ions (Na+-K+-2Cl- cotransport) from tubular fluid into the tubular cell. Diuretics are classified by their principal site of action in the nephron and by the primary mechanism of their naturetic effect (Table 4-11).


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TABLE 4-11 Classification of diuretics

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Osmotic Diuretics

Mannitol is the principal example of this type of diuretic, which is used for two primary indications: (1) prophylaxis and early treatment of acute renal failure which is characterized by a decrease in GFR leading to a decreased urine volume and a increase in the concentration of toxic substances in the renal tubular fluid; (2) to enhance the actions of other diuretics by retaining water and solutes in the tubular lumen, thereby providing the substrate for the action of other types of diuretics. Normally, 80% of the glomerular filtrate is reabsorbed isosmotically in the proximal tubules. By its osmotic effect, mannitol limits the reabsorption of water and dilutes the proximal tubular fluid. This reduces the electrochemical gradient for sodium and limits its reabsorption so that more is delivered to the distal portions of the nephron. Mannitol produces a prostaglandin-mediated increase in renal blood flow that partially washes out the medullary hypertonicity, which is essential for the countercurrent mechanism promoting the reabsorption of water in the late distal tubules and collecting system under the influence of ADH. Mannitol is often used (2550 g) as a part of the priming solution of cardiopulmonary bypass for the above-mentioned indications. The principal toxicity of mannitol is acute expansion of the extracellular fluid volume leading to congestive heart failure in the patient with compromised cardiac function.

High Ceiling (Loop) Diuretics

Furosemide (Lasix), bumetanide (Bumex), and ethacrynic acid (Edecrin) are three chemically dissimilar compounds that have the same primary diuretic mechanism of action. They act on the tubular epithelial cell in the thick ascending loop of Henle to inhibit the Na+-K+-2Cl- cotransport mechanism. Their peak diuretic effect is far greater than that of the other diuretics currently available. Administered intravenously, they have a rapid onset and relatively short duration of action, the latter reflecting both the pharmacokinetics of the drugs and the body's compensatory mechanisms to the consequences of diuresis. These three diuretics increase renal blood flow without increasing GFR and redistribute blood flow from the medulla to the cortex and within the renal cortex. These changes in renal blood flow are also short-lived, reflecting the reduced extracellular fluid volume resulting from diuresis. Minor actions, including carbonic anhydrase inhibition by furosemide and bumetanide and actions on the proximal tubule and on sites distal to the ascending limb, remain controversial. All three of the loop diuretics increase the release of renin and prostaglandin, and indomethacin blunts the release as well as the augmentation in renal blood flow and naturesis. All three of the loop diuretics produce an acute increase in venous capacitance for a brief period of time after the first intravenous dose is administered, and this effect is also blocked by indomethacin.

Potassium, magnesium, and calcium excretion are increased in proportion to the increase in sodium excretion. In addition, there is augmentation of titratable acid and ammonia excretion by the distal tubules leading to metabolic alkalosis, which is also produced by contraction of the extracellular volume. Hyperuricemia can occur but usually is of little physiological significance. The nephrotoxicity of cephaloridine, and possibly other cephalorsporins, is increased. A rare but serious side effect of the loop diuretics is deafness, which may reflect electrolyte changes in the endolymph.

Because of their high degree of efficacy, prompt onset, and relatively short duration of action, the high ceiling or loop diuretics are favored for intravenous administration in the perioperative period to treat the three principal problems cited above. Dosage requirements vary considerably among patients. Some may only require furosemide 3 to 5 mg IV to produce a good diuresis. And for some patients the less potent benzothiazides may be sufficient.

Benzothiazides

Hydrochlorothiazide (HCTZ) is the prototype of more than a dozen currently available diuretics in this class. Although the drugs differ in potency, they all act by the same mechanism of action and have the same maximum efficacy. All are actively secreted into the tubular lumen by tubular cells and act in the early distal tubules to decrease the electroneutral Na+-Cl- cotransport reabsorption of sodium. Their moderate efficacy probably reflects the fact that more than 90% of the filtrated sodium is reabsorbed before reaching the distal tubules. Their action is enhanced by their combined administration with an osmotic diuretic such as mannitol. The benziothiazides increase urine volume and the excretion of sodium, chloride, and potassium. The decreased reabsorption of potassium reflects the higher rate of urine flow through the distal tubule (diminished reabsorption time).

This class of diuretics produces the least disturbance of extracellular fluid composition, reflecting their moderate efficacy as diuretics and perhaps suggesting their usefulness when a moderate degree of diuretic effect is indicated. Their principal side effects include hyperuricemia, decreased calcium excretion, and enhanced magnesium loss. Hyperglycemia can occur and reflects multiple variables. With prolonged use and the development of a contracted extracellular fluid volume, urine formation decreases (i.e., tolerance develops to their diuretic actions). These agents also have a direct action on the renal vasculature to decrease GFR.

Carbonic Anhydrase Inhibitors

Acetazolamide (Diamox) is the only diuretic of this class available for intravenous administration. Its use is primarily directed to alkalinization of urine in the presence of metabolic alkalosis, which is a common consequence of prolonged diuretic therapy. It acts in the proximal convoluted tubule to inhibit carbonic anhydrase in the brush border of the tubular epithelium, thereby reducing the destruction of bicarbonate ions (i.e., conversion to CO2 that diffuses into the tubular cell). The carbonic anhydrase enzyme in the cytoplasm of the tubular cell is also inhibited, with a consequence that the conversion of CO2 to carbonic acid is markedly reduced as is the availability of hydrogen ions for the Na-H exchange mechanism. Hence, the reabsorption of both sodium and bicarbonate in the proximal tubules is diminished. However, more than half of the bicarbonate is reabsorbed in more distal segments of the nephron, thereby limiting the overall efficacy of this class of diuretics.

Potassium-Sparing Diuretics

Spironolactone (Aldactone) is a competitive antagonist of aldosterone. Spironolactone binds to the cytoplasmic aldosterone receptor and prevents its conformational change to the active form, thereby aborting the synthesis of active transport proteins in the late distal tubules and collecting system where the reabsorption of sodium and secretion of potassium are reduced.

Triamterene (Dyrenium) and amiloride (Midamor) are potassium-sparing diuretics with a mechanism of action independent of the mineralocorticoids. They have a moderate naturetic effect leading to an increased excretion of sodium and chloride with little change or a slight increase in potassium excretion when the latter is low. When potassium secretion is high, they produce a sharp reduction in the electrogenic entry of sodium ions into the distal tubular cells and thereby reduce the electrical potential that is the driving force for potassium secretion.

Both types of potassium-sparing diuretics are used primarily in combination with other diuretics to reduce potassium loss. Their principal side effect is hyperkalemia. It is appropriate to limit the intake of potassium when using this type of diuretic. It is also appropriate to use this type of diuretic cautiously in patients taking ACE inhibitors, which decrease aldosterone formation and consequently increase serum potassium concentrations.

Other Measures to Enhance Urine Output and Mobilization of Edema Fluid

The infusion of albumin (5%25% solutions) or other plasma volume expanders (e.g., hetastarch) is often employed in an attempt to draw water and its accompanying electrolytes (i.e., edema fluid) osmotically from the tissues into the circulating blood and thereby enhance their delivery to the kidney for excretion. In the presence of a reduced circulating blood volume, this approach seems to be a logical method to increase the circulating blood volume and renal perfusion. The limiting feature of this approach to enhancing diuresis relates to the fact that the osmotic effect of albumin and plasma expanders is transient because they can diffuse (at a rate slower than water) from blood through capillary membranes into tissue. The albumin or plasma expander then tends to hold water and its accompanying electrolytes in tissue (i.e., rebound edema). The same limiting feature applies to osmotic diuretics such as mannitol, which may transiently draw water and its accompanying electrolytes from tissues into the circulating blood for delivery to the kidney, where the mannitol passes through the glomerulus and delays the reabsorption of water and its accompanying electrolytes from the proximal tubular fluid. While this mechanism may enhance the actions of other diuretics, it is a transient effect limited by the diffusion of mannitol from blood into tissues with the production of rebound edema.

Dopamine (Intropin), at doses 1 to 3 ?g/kg/min, has been used conventionally to support mesenteric and renal perfusion. Its vascular action is mediated via vascular dopamine-1 (D1) receptors in coronary, mesenteric, and renal vascular beds. By activating adenyl cyclase and raising intracellular concentrations of cyclic-AMP, D1-receptor agonist causes vasodilatation. There are also dopamine-2 (D2) receptors that antagonize D1-receptor stimulation. Fenoldopam (Corlopam), a parenteral D1-receptor-specific agonist, was recently approved by FDA. The JNC VI recommendation includes this drug for hypertensive emergencies.192,193 Infusion of fenoldopam (0.10.3 ?g/kg/min) causes an increase in glomerular filtration rate, renal blood flow, and Na+ excretion.

Clinical trials of dopamine failed to show improvement in renal function, which may probably be due to nonspecificity of dopamine. As a catecholamine and a precursor in the metabolic synthesis of norepinephrine and epinephrine, dopamine has inotropic and chronotropic effects on the 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. However, there are extremely varied pharmacokinetic responses to dopamine infusion even in healthy subjects194; therefore, the use of a "renal dose" dopamine regimen may not always result in the desirable effects. Stimulation of catecholamine receptors and D2 receptors antagonizes the effects of D1-receptor stimulation. There are a small number of studies where the improved renal outcome shown with the use of the D1-receptor-specific agonist fenoldopam.195197 A further large-scale study is needed to answer whether prophylactic use of fenoldopam reduces the incidence of perioperative renal insufficiency.


?? HERBAL MEDICINE
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A large number of Americans take herbal remedies for their health. Most of these herbal therapies are not supported by clear scientific evidence, or under rigorous control of FDA.198 Patients who take alternative remedies may not necessarily disclose this information to their physicians.199 There are increasing concerns regarding serious drug interactions between herbal therapy and prescribed medication. Some of the most common herbal remedies and drug interactions are summarized in Table 4-12.200


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TABLE 4-12 Commonly used herbal remedies

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?? DRUGS FOR AIRWAY MANAGEMENT
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Airway management in cardiovascular surgical patients is very important because these patients often present with coexisting conditions that may complicate endotracheal intubation. For example, a patient with morbid obesity and sleep apnea may require awake intubation with a fiberoptic bronchoscope, or a history of smoking and chronic obstructive pulmonary disease (COPD) may make the patient susceptible to rapid desaturation and/or bronchospasm. Airway management in the perioperative period is a primary responsibility of the anesthesiologist, but the surgeon becomes involved in the absence of the anesthesiologist or in assisting the anesthesiologist in difficult situations. Airway management involves instrumentation and mechanics (not discussed here) and employs drugs to overcome pathophysiological problems that contribute to airway obstruction and to facilitate manipulation and instrumentation of the airway. Most of the drugs utilized for these purposes are taken from drug classes that have other important therapeutic applications (e.g., sympathomimetics).

Five major challenges may be encountered in airway management. Each of these is described succinctly below in order to facilitate understanding of the roles that drugs play in meeting the challenges. For the most part, details of pharmacology such as doses, side effects, and toxicity are left to standard textbooks of pharmacology and drug compendia. The five challenges are: (1) overcoming airway obstruction; (2) preventing pulmonary aspiration; (3) performing endotracheal intubation; (4) maintaining intermittent positive pressure ventilation (IPPV); and (5) reestablishing spontaneous ventilation and airway protective reflexes.

Airway Obstruction

Obstruction to gas flow can occur from the entry of a foreign object (including food) into the airway and as a result of pathophysiological processes involving airway structures (e.g., trauma, edema). In the anesthetized or comatose patient, the loss of muscle tone can allow otherwise normal tissues (e.g., tongue, epiglottis) to collapse into the airway and cause obstruction. The first measure in relieving such obstructions involves manipulation of the head and jaw, insertion of an artificial nasal or oral airway device, and evacuation of obstructing objects and substances (e.g., blood, secretions, food particles). Except for drugs used to facilitate endotracheal intubation (see below), the only drug useful to improve gas flow through a narrowed airway is a mixture of helium and oxygen (heliox), which has a much reduced viscosity resulting in reduced resistance to gas flow.

Aspiration

The upper airway (above the larynx/epiglottis) is a shared porthole to the lungs (gas exchange) and gastrointestinal tract (fluids and nutrition). Passive regurgitation or active vomiting resulting in accumulation of gastric contents in the pharynx places the patient at risk of pulmonary aspiration, especially under circumstances in which airway reflexes (glottic closure, coughing) and voluntary avoidance maneuvers are suppressed (e.g., anesthesia, coma). Particulate matter can obstruct the tracheal bronchial tree and acidic fluid (pH The resulting pneumonitis can cause significant morbidity (e.g., ARDS) and has a high mortality rate. Preoperative restriction of fluids and food (NPO status) does not guarantee the absence of aspiration risks. Similarly, the advance placement of a naso/orogastric tube may serve to reduce intragastric pressure but does not guarantee complete removal of gastric contents. Nevertheless, both NPO orders and insertion of a naso/orogastric tube under some circumstances are worthwhile measures to reduce the risks of pulmonary aspiration. In some circumstances, the deliberate induction of vomiting in a conscious patient may be indicated, but is rarely done and almost never involves the use of an emetic drug. In fact, more often antiemetic drugs are employed to reduce the risks of vomiting during airway manipulation and induction of anesthesia.

Drug therapy to reduce the risks of pulmonary aspiration is focused on decreasing the quantity and acidity of gastric contents and on facilitating endotracheal intubation (see below). Nonparticulate antacids (e.g., sodium citrate [Bicitra]) are utilized to neutralize the acidity of gastric fluids. Drugs to reduce gastric acid production include H2-receptor blockers (e.g., cimetidine [Tagamet], ranitidine [Zantac], famotidine [Pepcid]) and inhibitors of gastric parietal cell hydrogen-potassium ATPase (proton pump inhibitors, e.g., omeprazole [Prilosec], lansoprazole [Prevacid], esomeprazole [Nexium]). Metoclopramide (Reglan) enhances gastric emptying and increases the gastroesophageal sphincter tone. Cisapride (Propulsid) also increases gastrointestinal motility via the release of acetylcholine at the myenteric plexus.

Antiemetic drugs are more commonly used in the post- operative period and include several different drug classes: anticholinergics (scopolamine [Transderm Scop]), antihistamines (hydroxyzine [Vistaril], promethazine [Pherergan]), and antidopaminergics (droperidol [Inapsine], prochlorperazine [Compazine]). Antidopaminergic agents may cause extrapyramidal side effects in elderly patients. More costly, but effective, alternatives are the use of antiserotoninergics (e.g., ondansetron [Zofran], dolasetron [Anzmet]).

Of course, the most widely used measure to minimize the risks of pulmonary aspiration in the anesthetized or comatose patient is endotracheal intubation.

Endotracheal Intubation

Drugs are employed for three purposes in facilitating endotracheal intubation: (1) to improve visualization of the larynx during laryngoscopy; (2) to prevent closure of the larynx; (3) to facilitate manipulation of the head and jaw.

For bronchoscopy, laryngoscopy, or fiberoptic endotracheal intubation, the reflex responses to airway manipulation can be suppressed by several different methods, alone or in combination. Topical anesthesia (2% or 4% lidocaine spray) can be used to anesthetize the mucosal surfaces of the nose, oral cavity, pharynx, and epiglottis. Atomized local anesthetic can be inhaled to anesthetize the mucosa below the vocal cords. The subglottic mucosa can also be topically anesthetized by injecting local anesthetic into the tracheal lumen through the cricothyroid membrane. A bilateral superior laryngeal nerve block eliminates sensory input from mechanical contact or irritation of the larynx above the vocal cords. It must be remembered that anesthesia of the mucosal surfaces to obtund airway reflexes compromises the reflex protective mechanisms of the airway and increases the patient's vulnerability to aspiration of substances from the pharynx. Improvement of visualization of the larynx includes decreasing salivation and tracheal bronchial secretions by administration of an anticholinergic drug (e.g., glycopyrrolate), reducing mucosal swelling by topical administration of a vasoconstrictor (e.g., phenylephrine), and minimizing bleeding due to mucosal erosion by instrumentation, which also is minimized by topical vasconstrictors. The role of steroids in minimizing acute inflammatory responses in the airway may have some delayed benefit, but they are usually not indicated just prior to intubation.

Systemic drugs, usually administered intravenously, can be used to obtund the cough reflex. Intravenous lidocaine (12 mg/kg) transiently obtunds the cough reflex without affecting spontaneous ventilation to any significant degree. The risks of CNS stimulation and seizure-like activity have to be kept in mind and can be reduced by the prior administration of an intravenous barbiturate or benzodiazepine in small doses. Intravenous opioids are effective in suppressing cough reflexes, but the doses required impair spontaneous ventilation to the point of apnea. A combination of an intravenous opioid with a major tranquilizer (e.g., neuroleptanalgesia) allows the patient to tolerate an endotracheal tube with much smaller doses of the opioid and less embarrassment of spontaneous ventilation. Small doses of opioids are also useful in obtunding airway reflexes during general anesthesia provided either by intravenous (e.g., thiopental) or inhaled anesthetics (e.g., isoflurane). Not only do the opioids obtund the cough reflex that results in closure of the larynx, but also they are useful in limiting the autonomic sympathetic response to endotracheal intubation that typically leads to hypertension and tachycardia.

Skeletal muscle relaxants are most commonly used in conjunction with a general anesthetic to allow manipulation of the head and jaw and to prevent reflex closure of the larynx. Of course, they also render the patient apneic, and there are two common procedures utilized to maintain oxygenation of the patient's blood. (1)The patient breathes 100% oxygen by mask while still awake to eliminate nitrogen from the lungs, and then a rapid-sequence administration of an intravenous anesthetic (e.g., thiopental) is immediately followed by a rapid-acting neuromuscular blocker (e.g., succinylcholine, rocuronium [Zemuron]), and cricoid pressure is applied (Sellick maneuver). As soon as the muscle relaxation is apparent (3090 seconds), laryngoscopy is performed, an endotracheal tube is inserted, the tracheal tube cuff is inflated, and the position of the tube in the trachea is verified. (2) When there is minimal risk of pulmonary aspiration (presumed empty stomach), the patient is anesthetized and paralyzed while ventilation is supported by intermittent positive pressure delivered via a face mask. At the appropriate time, laryngoscopy is performed and the endotracheal tube is inserted.

Normalizing Pulmonary Function During Positive Pressure Ventilation

Once an endotracheal tube is in place, it is common practice in the operating room to maintain general anesthesia and partial muscular paralysis in order to facilitate positive pressure ventilation and continued toleration of the endotracheal tube by the patient. Postoperatively in the PACU and ICU, general anesthesia and partial muscular paralysis may be continued if prolonged positive ventilation is anticipated, or sedatives may be administered by intravenous infusion to allow toleration of the endotracheal tube in anticipation of recovery of spontaneous ventilation and tracheal extubation.

Three other problems are encountered in the patient whose ventilation is supported mechanically by way of an endotracheal tube: (1) poor ventilatory compliance, (2) bronchonstriction, and (3) impaired gas exchange.

Poor ventilatory compliance can reflect limited compliance of the chest wall 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 improve the chest cavity compliance that is fixed by disease (e.g., scoliosis, emphysema).

Poor lung compliance may reflect pulmonary interstitial edema, consolidation, bronchial obstruction (e.g., mucus plugs), bronchoconstriction, or compression of the lung by intrathoracic substances (e.g., pneumothorax, hemothorax, tumor mass). The treatment of these involves drug therapy of heart failure and infection and procedures such as bronchoscopy, thoracentesis, etc.

Bronchoconstriction may exist chronically (e.g., asthma, reactive airways disease), and these conditions can be exacerbated by the collection of tracheal bronchial secretions in the presence of an endotracheal tube, which reduces the effectiveness of coughing in clearing the airway. Occasionally bronchonstriction can be induced by mechanical stimulation of the airway by an endotracheal tube or other object in an otherwise normal patient. Drug treatment is focused on reducing bronchial smooth muscle tone (beta2 sympathomimetic, anticholinergic), minimizing tracheal bronchial secretions, and decreasing sensory input from the tracheal bronchial tree (e.g., topical anesthetic, deeper general anesthesia, intravenous lidocaine, or an opioid). Acute treatment of bronchonstriction may involve any combination of the following: (1) aerosolized beta2 sympathomimetic and/or anticholinergic, and (2) systemic intravenous administration of a beta2 sympathomimetic, a phosphodiestrerase inhibitor (e.g., theophylline salts [aminophylline]), and/or an anticholinergic.

Intravenous steroids are indicated in severe bronchonstriction, especially in the asthmatic patient for whom they have been effective in the past. With the administration of 100% oxygen, blood oxygenation is not usually the main problem in the patient with bronchonstriction; it is the progressive development of hypercarbia and the trapping of air in lung parenchyma, which reduces ventilatory compliance and increases intrathoracic pressure. This in turn reduces venous return and may cause a tamponade-like impairment of cardiac function.

Impaired alveolar capillary membrane gas exchange can result from alveolar pulmonary edema (treated by diuretics, inotropes, and vasodilators), decreased pulmonary perfusion (treated by inotropes and vasodilators), and lung consolidation (antibiotic therapy for infection).

Restoration of Spontaneous Ventilation and Airway Protective Mechanisms

The anesthesiologist attempts to tailor the anesthetic plan according to postoperative expectations for the patient. In the relatively healthy patient for whom tracheal extubation can be anticipated in the operating room, the goal is to have the patient breathing spontaneously with airway reflexes intact and the patient arousable to command immediately upon completion of the surgical operation. The challenge for the anesthesiologist is to maintain satisfactory general anesthesia through the entire course of the surgical operation and yet have the patient sufficiently recovered from anesthetic drugs, including hypnotics and opioids, shortly after conclusion of the operation. If that is not possible, then the patient is transferred to the PACU to allow additional time for elimination of drugs depressing spontaneous ventilation and cough reflexes. Another possibility is to administer antagonists to opioids (e.g., naloxone) and benzodiazepines (e.g., flumazenil), but this approach risks sudden awakening, pain, and uncontrolled autonomic sympathetic activity leading to undesirable hemodynamic changes. And there is the risk of recurrent ventilatory depression because it is difficult to match the doses of the antagonists to the residual amounts of anesthetic drugs. On the other hand, it is fairly routine for the effects of neuromuscular blockers to be antagonized by administration of an anticholinesterase (e.g., neostigmine) in combination with an anticholinergic (e.g., atropine) to limit the autonomic cholinergic side effects of the anticholinesterase.

When the expectation is for maintenance of mechanical ventilation for some time in the postoperative period, then the patient's toleration of the endotracheal tube is facilitated by the persistent effect of residual anesthetic drugs subsequently supplemented by administration of intravenous hypnotics (e.g., propofol) and opioids (e.g., fentanyl, morphine). These agents can be associated with a number of side effects, including respiratory depression, especially when agents are used concurrently. Dexmedetomidine (Precedex), an alpha2-adrenergic agonist, may offer advantages for sedation during and weaning from mechanical ventilation because it provides sedation, pain relief, anxiety reduction, stable respiratory rates, and predictable cardiovascular responses.201203 Dexmedetomidine facilitates patient comfort, compliance, and comprehension by offering sedation with the ability to rouse patients. This "rousability" allows patients to remain sedated yet communicate with health care workers.

When the appropriate time comes to have the patient take over his/her own ventilation completely, these sedative and analgesic drugs are weaned to a level allowing satisfactory maintenance of blood oxygenation and carbon dioxide removal, easy arousal of the patient, and at least partial restoration of airway reflex mechanisms.


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