Myocardial Function

The influence of volatile anesthetics on contractile function has been investigated extensively, and it is now widely agreed that volatile agents cause dose-dependent depression of contractile function (Box 7-1). Moreover, different volatile agents are not identical in this regard and the preponderance of information indicates that halothane and enflurane exert equal but more potent myocardial depression than do isoflurane, desflurane, or sevoflurane.¹ This reflects in part reflex sympathetic activation with the latter agents. It is also widely accepted that in the setting of preexisting myocardial depression, volatile agents have a greater effect than in normal myocardium. At the cellular level, volatile anesthetics exert their negative inotropic effects mainly by modulating sarcolemmal (SL) L-type Ca²⁺ channels, the sarcoplasmic reticulum (SR), and the contractile proteins. However, the mechanisms whereby anesthetic agents modify ion channels are not completely understood.

Cardiac Electrophysiology

Volatile anesthetic agents lower the arrhythmogenic threshold for epinephrine. Moreover, not all volatile agents are similar, with the order of sensitization being halothane > enflurane > sevoflurane > isoflurane = desflurane. The molecular mechanisms underlying this effect of volatile anesthetics are poorly understood.

Coronary Vasoregulation

Volatile anesthetic agents modulate several determinants of both myocardial oxygen supply and demand. Moreover, it is now established that volatile agents also directly modulate the response of myocytes to ischemia.

The effect of isoflurane on coronary vessels was controversial and dominated much of the literature in this area in the 1980s and early 1990s. The current assessments of the effects of isoflurane have been succinctly detailed by Tanaka and associates.² Several reports had indicated that it caused direct coronary arteriolar vasodilatation in vessels of 100 μm or less and that isoflurane could cause “coronary steal” in patients with “steal-prone” coronary anatomy. Several studies in which potential confounding variables were controlled indicated clearly that isoflurane did not cause coronary steal. Studies of sevoflurane and desflurane showed similar results and are consistent with a mild direct coronary vasodilator effect of these agents.

Systemic Vascular Effects

All volatile anesthetic agents decrease systemic blood pressure (BP) in a dose-dependent manner. With halothane and enflurane, the decrease in systemic BP is primarily due to decreases in stroke volume (SV) and cardiac output (CO) whereas isoflurane, sevoflurane, and desflurane decrease overall systemic vascular resistance (SVR) while maintaining CO.

Baroreceptor Reflex

All volatile agents attenuate the baroreceptor reflex. Baroreceptor reflex inhibition by halothane and enflurane is more potent than that observed with isoflurane, desflurane, or sevoflurane, each of which has a similar effect. Each component of the baroreceptor reflex arc (afferent nerve activity, central processing, efferent nerve activity) is inhibited by volatile agents.

Reversible Myocardial Ischemia

Prolonged ischemia results in irreversible myocardial damage and necrosis (Box 7-2). Shorter durations of myocardial ischemia can, depending on the duration and sequence of ischemic insults, lead to either preconditioning or myocardial stunning (Fig. 7-1). Stunning, first described in 1975, occurs after brief ischemia and is characterized by myocardial dysfunction in the setting of normal restored blood flow and by an absence of myocardial necrosis. Ischemic preconditioning (IPC) was first described by Murray and colleagues in 1986 and is characterized by an attenuation in infarct size after sustained ischemia, if this period of sustained ischemia is preceded by a period of brief ischemia. Moreover, this effect is independent of collateral flow. Thus, short periods of ischemia followed by reperfusion can lead to either stunning or preconditioning with a reduction in infarct size (Fig. 7-2).³

Figure 7-1 Effects of ischemia and reperfusion on the heart based on studies in anesthetized canine model of proximal coronary artery occlusion. Brief periods of ischemia of less than 20 minutes followed by reperfusion are not associated with development of necrosis (reversible injury). Brief ischemia/reperfusion results in the phenomenon of stunning and preconditioning. If duration of coronary occlusion is extended beyond 20 minutes, a wavefront of necrosis marches from subendocardium to subepicardium over time. Reperfusion before 3 hours of ischemia salvages ischemic but viable tissue. (This salvaged tissue may demonstrate stunning.) Reperfusion beyond 3 to 6 hours in this model does not reduce myocardial infarct size. Late reperfusion may still have a beneficial effect on reducing or preventing myocardial infarct expansion and left ventricular (LV) remodeling.

Rights were not granted to include this figure in electronic media. Please refer to the printed book.

(From Kloner RA, Jennings RB: Consequences of brief ischemia: Stunning, preconditioning, and their clinical implications: I. Circulation 104:2981, 2001.)

Figure 7-2 Schematic of stunning and preconditioning. Short coronary artery occlusions result in stunning, in which there is prolonged regional wall motion abnormality, despite presence of reperfusion and viable myocardial cells. Brief episodes of ischemia/reperfusion also precondition the heart. When the heart is then exposed to a longer duration of ischemia and reperfusion, myocardial infarct size is reduced.

Rights were not granted to include this figure in electronic media. Please refer to the printed book.

(From Kloner RA, Jennings RB: Consequences of brief ischemia: Stunning, preconditioning, and their clinical implications: I. Circulation 104:2981, 2001.)

Anesthetic Preconditioning

Volatile agents can elicit delayed (late), as well as classic (early), preconditioning. Moreover, APC is dose dependent, exhibits synergy with ischemia in affording protection, and, perhaps not surprisingly in view of differential uptake and distribution of volatile agents, has been demonstrated to require different time intervals between exposure and the maintenance of a subsequent benefit that is agent dependent. Volatile agents that exhibit APC activate mitochondrial K⁺_ATP channels, and this effect is blocked by specific mitochondrial K⁺_ATP channel antagonists. However, the precise relative contributions of SL versus mitochondrial K⁺_ATP channel activation to APC remain to be elucidated (Fig. 7-3).

Figure 7-3 Multiple endogenous signaling pathways mediate volatile anesthetic-induced myocardial activation of an end-effector that promotes resistance against ischemic injury. Mitochondrial K⁺_ATP channels have been implicated as the end-effector in this protective scheme, but sarcolemmal K⁺_ATP channels may also be involved in this mechanism of protection. A trigger initiates a cascade of signal transduction events, resulting in the protection. Volatile anesthetics signal through adenosine and opioid receptors, modulate G proteins, stimulate protein kinase C (PKC) and other intracellular kinases, or have direct effects on mitochondria to generate reactive oxygen species (ROS) that ultimately enhance K⁺_ATP channel activity. Volatile anesthetics may also directly facilitate K⁺_ATP channel opening. Dotted arrows delineate the intracellular targets that may be regulated by volatile anesthetics; solid arrows represent potential signaling cascades.

(From Tanaka K, Ludwig LM, Kersten JR, et al: Mechanisms of cardioprotection by volatile anesthetics. Anesthesiology 100:707, 2004.)

Myocardial Contractility

With regard to propofol, the studies remain controversial as to whether there is a direct effect on myocardial contractile function at clinically relevant concentrations. However, the weight of evidence suggests that the drug has a modest negative inotropic effect, which may be mediated by inhibition of L-type Ca²⁺ channels or modulation of Ca²⁺ release from the sarcoplasmic reticulum.

In one of the few human studies using isolated atrial muscle tissue, no inhibition of myocardial contractility was found in the clinical concentration ranges of propofol, midazolam, and etomidate. In contrast, thiopental showed strong negative inotropic properties whereas ketamine showed slight negative inotropic properties. Thus, negative inotropic effects may explain in part the cardiovascular depression on induction of anesthesia with thiopental but not with propofol, midazolam, and etomidate. Improvement of hemodynamics after induction of anesthesia with ketamine is a function of sympathoexcitation.

The effect of drugs such as propofol may also be markedly affected by the underlying myocardial pathology. For instance, Sprung and coworkers determined the direct effects of propofol on the contractility of human nonfailing atrial and failing atrial and ventricular muscles obtained from the failing human hearts of transplant patients or from nonfailing hearts of patients undergoing coronary artery bypass graft (CABG) surgery.⁴ They concluded that propofol exerts a direct negative inotropic effect in nonfailing and failing human myocardium but only at concentrations larger than typical clinical concentrations. Negative inotropic effects are reversible with β-adrenergic stimulation, suggesting that propofol does not alter the contractile reserve but may shift the dose responsiveness to adrenergic stimulation.