Beta-adrenoceptor antagonists are composed of a large number of drugs that possess a host of pharmacologic properties, some of which are attributable to activity at the beta receptor, whereas others are not. These features include cardioselectivity for beta1-adrenergic receptors, intrinsic sympathomimetic activity (partial agonist-type properties), membrane-stabilizing effects, pharmacokinetic advantages (e.g, inability to cross the blood-brain barrier or ability to be rapidly metabolized), or inclusion of additional properties (e.g, alpha-adrenergic receptor antagonism or vasodilator actions) that make each agent of particular advantage for a patient. These drugs were initially developed for the management of cardiac arrhythmias, hypertension, and angina pectoris. Other significant potential benefits of beta blockers are now recognized and include protection against reinfarction and reduction of long-term mortality after myocardial infarction.
In this issue of Anesthesiology, Wallace et al. have demonstrated in a randomized, placebo-controlled, double-blind study that relatively brief treatment with the beta-adrenergic antagonist, atenolol, of patients at risk for coronary artery disease undergoing noncardiac surgery decreases the incidence of perioperative myocardial ischemia. This reduction in perioperative ischemic events may ultimately translate into a decrease in cardiac morbidity and mortality rates as shown by the same group of investigators in a long-term follow-up evaluation of these patients. The evidence is overwhelming that patients at risk for coronary artery disease will dramatically benefit from administration of these drugs. Unfortunately, the beta blockers are underused [3–7]for reasons that are not clear.
The mechanism of action of beta blockers in myocardial ischemia is most certainly multifactorial. These agents improve myocardial oxygen supply-demand balance. Beta-adrenergic-blocking agents decrease myocardial oxygen consumption by reducing major determinants of oxygen demand. A decrease in heart rate and inotropic state result in less “stress” placed on potentially ischemic myocardium. The drugs prevent the deleterious actions of an increase in sympathetic nervous system tone by attenuating the actions of endogenous catecholamines on beta-adrenergic receptors. Some of these agents may also act within the central nervous system to reduce overall sympathetic outflow. In general, beta blockers have no direct vasodilator activity, but these agents increase oxygen supply to ischemic zones through a redistribution of myocardial blood flow from normal regions. This is evident whether the origin of perfusion is via coronary collaterals in the presence of a total coronary artery occlusion or via decreased ante-grade flow in the presence of a critical coronary stenosis. Increased perfusion of ischemic myocardium, especially in subendocardial areas most susceptible to infarction, occurs as a result of a decrease in heart rate and is also accompanied by a decrease in myocardial oxygen consumption. As a result, the intensity of ischemia is decreased, and even the extent of myocardial infarction can be demonstrated to be decreased. This is a basic principal well established in a variety of experimental models of coronary artery disease. Further, the antiischemic properties of beta-blockers in ambulatory patients have been documented in small and large multicenter clinical investigations. If so, why are beta-adrenergic antagonists relatively underused?
The answer to this question lies in the misperception of the risk-to-benefit ratio for a patient. Blockade of beta-adrenergic receptors can result in conduction disturbances, left ventricular dysfunction as a result of a reduction in inotropic state in patients dependent on sympathetic nervous system activity, and other actions that are not related to the cardiovascular system, such as exacerbation of reactive airway disease. Such risks probably represent the motivating factor for many physicians to avoid use of beta-adrenergic antagonists. This may be especially true in the intraoperative period wherein patients are also exposed to other negative inotropic agents such as volatile anesthetics. Unfortunately, for the patient, avoidance of such risks at the expense of not receiving beta-adrenergic antagonists is detrimental [3,6]and for the most part unnecessary. For example, in the presence of left ventricular dysfunction, beta-adrenergic blockers may actually improve filling dynamics and provide beneficial systemic hemodynamic effects. 
Wallace et al. and Mangano et al. have demonstrated that beta blockers administered perioperatively not only decreased the number of ischemic events in treated patients acutely but also resulted in a reduction in mortality and cardiovascular complications for as long as 2 yr after the surgical procedure. Moreover, this was accomplished without any detectable increase in the frequency of side effects, despite many of their patients having coexisting cardiac and pulmonary disease. Their work supports and extends several major multicenter studies, including ISIS-1, MIAMI, MAPHY, and ASYST studies of beta-adrenergic blockade in ambulatory patients with coronary artery disease. The present investigation strongly suggests that the majority of patients with risk factors for coronary artery disease should be treated with at least some type of beta blocker perioperatively. Long-term medical management of untreated patients identified at the time of surgery might also best be accomplished with the chronic oral administration of beta-blocking agents, although whether such would result in a greater clinical benefit needs to be further tested. The mechanism for a reduction in mortality 2 yr after perioperative administration of atenolol is unclear, but the evidence from this and other studies indicates the short-term and long-term benefits of beta blockers are remarkable.
Beta-adrenergic antagonists are especially underused in elderly and female patients and in those patients with a history of heart failure or bronchospastic disease. Unfortunately, the assumption that adverse drug effects will occur has caused these agents to be avoided in a variety of clinical situations despite evidence in multiple investigations that beta blockers are well tolerated. The intraoperative period represents a special example in which the tolerance to this class of drugs can be examined acutely and rapidly reversed if required. Intravenous administration of a short-acting, quickly metabolized beta blocker allows rapid assessment of efficacy, and if adverse effects are not observed, prolonged oral administration may be indicated. Patients with relative contraindications to beta blockers undergoing thrombolytic therapy for acute myocardial infarction have been treated with esmolol relatively successfully, and it has been suggested that esmolol may be a good predictor of subsequent outcome with oral beta-adrenergic-blocking therapy in these patients. 
Previous investigations [9–12]have demonstrated the utility of beta-adrenergic blockade perioperatively. These studies have certain limitations, including few patients or a lack of follow-up evaluation of long-term mortality. Wallace et al. are convincing in their argument that patients with risk factors for coronary artery disease undergoing general anesthesia should be treated with a beta-adrenergic-blocking agent. Further, the investigators demonstrate excellent tolerance to these drugs. Whether ancillary properties such as cardioselectivity, lipophilicity, intrinsic sympathomimetic activity, and so on would be of special benefit to specific patients remains controversial and requires further study. Whether patients that continue to have perioperative ischemia despite adequate treatment with beta-adrenergic antagonists have an especially poor prognosis also deserves investigation. Nevertheless, if adequate blockade of beta-adrenergic receptors can be achieved, it is highly likely that the benefit to the patient would be reflected in a decrease of perioperative ischemia, cardiac morbidity, and long-term mortality.
David C. Warltier, M.D., Ph.D., F.A.C.C.
Professor of Anesthesiology, Pharmacology and Toxicology, and Medicine (Division of Cardiovascular Diseases); Vice Chairman for Research, Department of Anesthesiology; Medical College of Wisconsin; MEB-Room 462C; 8701 Watertown Plank Road; Milwaukee, Wisconsin 53226