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Refresher Courses - Sunday June 10 |
From the Department of Anesthesiology, Queen's University, Kingston General Hospital, Kingston, Ontario, Canada.
Address correspondence to: Dr. Joel Parlow, Department of Anesthesiology, Kingston General Hospital, 76 Stuart Street, Kingston, Ontario, Canada K7L 2V7. Phone: 613-548-7827; Fax: 613-548-1375; E-mail: parlowj{at}post.queensu.ca
CARDIOVASCULAR complications following surgery are common in patients at risk for coronary artery disease, and represent a major health and economic issue. Using U.S. figures, there are approximately three million people with at least two major risk factors for coronary artery disease who undergo noncardiac surgery per year. One million of these patients have previously diagnosed coronary artery disease (CAD). Since perioperative cardiac morbidity has been identified as the leading cause of death following anesthesia/surgery, tremendous research resources have been utilized to study its causes and prevention. This refresher lecture will review the scope of the problem, current ideas about the underlying causes of cardiovascular complications following surgery, and pharmacologic treatment strategies aimed at reducing these complications and improving long-term outcome.
Perioperative myocardial ischemia (PMI) occurs in 20–40% of patients at risk for cardiac complications.1 The importance of PMI from the point of view of its predictive value for serious cardiac events has been studied widely. Although it has been pointed out that PMI can represent an independent event or a marker for underlying disease rather than a precursor to myocardial infarction, there is abundant evidence confirming the predictive value of PMI for serious cardiac morbidity/mortality.2 Ischemic events occurring within one week of surgery are associated with a nine-fold incidence of serious cardiac complications such as unstable angina, MI, and cardiac death.3 In addition, a two-fold increase in long-term risk (up to two years after surgery) has been documented in patients experiencing PMI.4
While the association between PMI and serious outcomes is now generally accepted, researchers have only recently examined whether interventions aimed at reducing the incidence of PMI would lead to a reduction in serious cardiac morbidity and mortality. Many studies have used PMI as a surrogate marker for adverse cardiac outcomes; recent outcome studies have documented interventions which both reduce the incidence of PMI, and are associated with a reduction in long-term complications and mortality.3 Thus most research authorities and clinicians believe that reducing episodes of PMI is an important goal in the perioperative management of our patients at risk for CAD.
Causes of PMI
In surgical patients with known coronary disease, establishing hemodynamic goals has been a cornerstone of anesthetic management. It has long been recognized that the determinants of myocardial oxygen supply and demand play a major role in the genesis of myocardial ischemia in patients with limited coronary reserve. On the demand side, tachycardia, hypertension, and increases in preload, afterload and contractility are all modifiable factors which lead to increased oxygen consumption. On the supply side, modifiable factors that lead to reduced coronary filling include tachycardia, hypotension, decreased preload and increased afterload. Other potentially modifiable factors that reduce oxygen availability to the myocardium include increased blood viscosity, decreased hemoglobin, decreased oxygen saturation, left-shift of the oxyhemoglobin dissociation curve, and coronary spasm and steal.
As opposed to hemodynamic and other factors that are (potentially) under our influence, there are significant non-hemodynamic factors that come into play in this population. These factors have traditionally been ignored by physicians involved in perioperative care since they have often been considered to be "beyond our control". First, acute coronary intimal plaque rupture may lead to myocardial ischemia/infarction in patients whose coronary stenosis would not previously have been considered severe.5 Indeed coronary plaque rupture and subsequent thrombosis is associated with almost half of all postoperative myocardial infarctions.6 Factors associated with plaque rupture include increases in the shear forces present during coronary flow, which may in turn be amplified by increased flow velocity in response to sympathetic stimulation.5,7 In addition, sympathetically-mediated increases in coagulability have been suggested. Thus it seems that some "non-hemodynamic" factors involved in the genesis of cardiac complications, which were previously felt to be outside the control of anesthesiologists, could potentially be modifiable using drugs and techniques commonly employed by us as perioperative physicians.
The importance of autonomic control of the cardiovascular system
The maintenance of perioperative hemodynamic stability is the classic goal when dealing with patients at risk for cardiac complications. The autonomic nervous system is a key player in maintaining hemodynamic stability, with both the parasympathetic and sympathetic axes involved in the short and medium term control of blood pressure and heart rate. Beat-by-beat heart rate and blood pressure control is effected to a large extent through the cardiac baroreflex arc. Here, increases in blood pressure are buffered by immediate decreases in heart rate (as well as contractility and vascular tone). Opposite responses occur with decreases in pressure. The afferent signals from arterial baroreceptors are received and processed in brainstem centres, which then alter efferent parasympathetic and sympathetic flow appropriately. Although the details about this central processing is beyond the scope of this review, this brainstem "black box" is also under the influence of higher brain centres, thus being modified by such events as pain and anxiety. The beat by beat baroreflex-mediated heart rate responses to both increases and decreases in pressure are primarily under parasympathetic control; these responses are commonly used as indices of vagal "health" or responsiveness.
Recent data in the cardiology literature have emphasized the protective effects of parasympathetic heart rate control against serious consequences of myocardial ischemia. In both animal and human models, indices of impaired parasympathetic control have been shown to be independent predictors of adverse outcomes following ischemic stresses, including arrhythmias and death.8
In the perioperative setting, parasympathetic control is affected by numerous factors, including premorbid conditions, anesthetic drugs, and the stress response to surgery. Pre-existing hypertension, diabetes mellitus and CAD are all associated with reduced vagal heart rate control, evidenced by decreased baroreflex sensitivity and a reduced operating range of the baroreflex system.9 This results in a markedly reduced heart rate response to changes in blood pressure, leading to a disturbed state of cardiovascular equilibrium. Similarly, general anesthesia further reduces cardiac responses to blood pressure fluctuations. This is clinically observed in this population in the form of wide swings in blood pressure under anesthesia, with virtually no heart rate responses. Furthermore, the postoperative period is characterized by a prolonged impairment of parasympathetic control in these patients, which may be associated with ischemic events and their consequences.10,11 In fact, prolonged vagal dysfunction has been demonstrated in a group of patients who exhibited postoperative myocardial ischemia and ventricular dysrhythmias, but not in those who were free of ischemic events.12
In addition to reduced parasympathetic control, the perioperative period is also characterized by exaggerated activity of the sympathetic nervous system. Increased catecholamine, vasopressin and cortisol levels are a consistent finding in these patients, particularly in the early postoperative period.10 The stress response to surgery is magnified by pain and anxiety, and reduced by techniques which inhibit sympathetic nervous system responses, such as sympatholytic drugs, and neuraxial local anesthetics. Interestingly, there is a complicated interplay between the parasympathetic and sympathetic systems, whereby elevated sympathetic activity further inhibits parasympathetic control, potentially rendering patients more susceptible to serious consequences of myocardial ischemia. Conversely, drugs that inhibit sympathetic effects tend to improve vagal control of the heart.10
In summary, the perioperative period is characterized by sympathetic overactivity and reduced vagal control of the heart. The result of this impairment of autonomic regulatory mechanisms is a poorly controlled hemodynamic state which, in vulnerable populations, could contribute to the development of PMI. Drugs or techniques which limit the degree of sympathetic overactivity may thus: 1) reduce episodes of myocardial ischemia; and 2) improve those mechanisms which are protective against the consequences of PMI. Two classes of drugs have been widely employed with these goals in mind. Beta adrenergic blockers act at the level of the end organs to prevent the physiologic effects caused by sympathetic activation and high sympathetic tone. Alpha2 agonists decrease central sympathetic outflow and transmission of sympathetic impulses, thereby lowering the level of stimulation at the end organs. The following sections will present the findings of research into the perioperative use of alpha2 agonists and beta blockers to reduce sympathetic overactivity, as well as PMI and its consequences.
The case for perioperative alpha2 agonists
Alpha2 receptor agonists, the most widely used of which is clonidine, have been investigated widely as adjuncts to both general and regional anesthesia. These drugs reduce central sympathetic outflow, and inhibit norepinephrine release from presynaptic nerve terminals. Clinically, the decrease in stimulation of alpha and beta adrenergic receptors manifests itself in lower resting heart rate and blood pressure. Alpha2 agonists also exert a strong central effect, characterized by marked sedation at moderate doses.
Alpha2 agonist drugs are felt to act by reducing the overall tonic sympathetic action, while relatively preserving phasic sympathetic responses.13 This suggests that in situations where acute sympathetic responses are necessary, such as during sudden hypovolemia, appropriate compensatory mechanisms will be preserved.14 Similarly, sensitivity to boluses of vasodilator drugs is unchanged.15 On the other hand, clonidine treated patients show exaggerated responses to vasopressors such as phenylephrine and ephedrine.15
In addition to their sympatholytic effects, alpha2 agonists have been shown both experimentally and clinically to improve vagally-mediated circulatory control. Clonidine exhibits a direct enhancing effect of vagally-mediated responses, in part through a central effect at vagal motoneurons.16 Alpha2 agonists also decrease the inhibitory effect that elevated sympathetic tone exerts on vagal responsiveness. Thus alpha2 agonists have been shown to improve baroreflex control in both healthy and hypertensive populations.17–19
Perioperatively, beneficial effects of alpha2 agonists include: decreased anesthetic and opioid requirements, reduced hemodynamic responses to intubation and other stimuli,20,21 improved postoperative analgesia, reduced shivering and oxygen uptake,22 and improved postoperative renal function. In the nonoperative setting, alpha2 agonists have also been shown to have significant anti-ischemic properties.23 Many studies have confirmed the usefulness of alpha2 agonists in reducing perioperative hemodynamic lability, particularly in patients with underlying cardiovascular disease. The theory that clonidine improves hemodynamic stability due to its enhancement of baroreflex-mediated control has been tested recently in hypertensive patients undergoing major surgery.10 Here, patients receiving placebo showed increased blood pressure lability, accompanied by a marked deterioration of baroreflex heart rate control during the recovery period. Patients pretreated with clonidine showed a preservation of vagally mediated heart rate control, accompanied by a more stable hemodynamic profile.
Although perioperative hemodynamic derangements have frequently been used as predictors of myocardial ischemia, relatively few studies of perioperative alpha2 agonist use have focussed directly on PMI as the primary outcome measure. In patients undergoing coronary artery surgery, clonidine led to a reduction in ischemic events from 38% to 4%.24 In 297 noncardiac vascular surgery patients, clonidine reduced ischemic episodes from 39% to 24%.25 In this latter study there was also a trend toward reduction in nonfatal myocardial infarctions with clonidine, although the sample was too small to reach significance. Finally, a European trial of the highly specific alpha2 agonist drug mivazerol showed a reduction in PMI in 300 patients undergoing peripheral vascular surgery, particularly during emergence from general anesthesia (11% vs 30% in placebo group).26 Again, no difference in myocardial infarction rate or mortality was demonstrable.
Only one large multicentre outcome study examining perioperative alpha2 agonists has been undertaken.27 In this European trial, almost 3,000 patients undergoing noncardiac surgery were randomized to receive mivazerol or placebo and followed for 30 days postoperatively. In addition to beneficial hemodynamic effects, mivazerol reduced mortality in a subgroup of 904 patients with previously diagnosed CAD undergoing vascular procedures. Although these results have been promising, no long-term follow-up data are available. In light of the potential for long-term benefits of short-term interventions, such an outcome study is necessary to clarify which populations are most likely to benefit from perioperative alpha2 agonist administration.
Clonidine has been the most frequently used alpha2 agonist in the perioperative setting. One limitation of clonidine is that it has only been available as an oral preparation in Canada, making postoperative administration awkward. Parenteral formulations are available for epidural use in the U.S.; parenteral clonidine has also been used widely in Europe in the form of slow iv infusions.10 Another successful strategy for maintaining adequate clonidine blood levels in use in the United States is transdermal clonidine, which provides prolonged and effective sympatholysis.28,29 Newer alpha2 agents which are much more highly selective for the alpha2 receptor have been investigated widely, including dexmedetomidine, rilmenidine and mivazerol. Dexmedetomidine is now available commercially in the U.S., although its formulary indication is for intensive care unit sedation. In light of the evidence in the literature emphasizing the importance of the postoperative period, the full potential for alpha2 agonist use in anesthesia in Canada will not be realized until a convenient and effective method of postoperative administration is available.
The case for perioperative beta blockers
Beta-adrenergic blockers have clearly been shown to improve outcome after myocardial ischemia/infarction outside the perioperative setting. Although the mechanisms for the protective effects of these drugs are multifactorial, a relation between beta blocker treatment and autonomic heart rate control is evident. For example, in patients experiencing myocardial infarction, beta blockers were shown to improve indices of vagal control, and to reduce the commonly observed phenomenon of early morning sympathetic activation, an event often implicated in myocardial infarction.30 In an animal study, dogs were pretreated with beta blockers before surgically- induced myocardial infarction. The subset of dogs that showed improvement of autonomic control after beta blockade were most resistant to fatal arrhythmias after myocardial infarction.31
Practices regarding beta blocker use in the perioperative setting is a classic study of how attitudes can change dramatically as new knowledge evolves. In the early 1970's most clinicians believed that interactions of beta blockers with anesthetic drugs necessitated their discontinuation prior to surgery.32 In fact, one authority warned that "propranolol should be used cautiously during anesthesia, and only after atropine premedication" (Drugs in Anesthetic Practice, 1978). However toward the end of the 1970's, the beta blocker withdrawal phenomenon was recognized, with episodes of arrhythmias, ischemia, infarction and death documented following abrupt discontinuation of propranolol.33 Over the next two decades numerous studies have documented the beneficial effects of beta blocker use in the perioperative setting, both as treatment and prophylaxis, in reducing the hemodynamic results of sympathetic overactivity.
The ability of prophylactic beta blockers to reduce episodes of tachycardia and hypertension is beyond question. In the past decade, the incidence of myocardial ischemia has predominated as an end-point in beta blocker research. Numerous studies have since confirmed the beneficial effects of perioperative beta blockade, either prophylactically or therapeutically, in reducing the incidence and duration of PMI in patients at risk for cardiac complications.34–36
In the past few years the focus has turned from studying these surrogate markers of outcome to studying direct outcome variables such as mortality and serious cardiac events. One of the first major outcome studies was undertaken by the MACB Study Group, who examined the effects of postoperative metoprolol on major cardiac events over two years following coronary bypass surgery.37 This group of almost 1000 patients showed an incidence of 8% of major cardiac events, with no difference between metoprolol and placebo. In a European study published in 1999, a large group of patients scheduled to undergo major vascular surgery were screened prior to inclusion.38 Of these, 112 patients with positive (but not critical) dobutamine stress echocardiograms were assigned to receive bisoprolol or placebo preoperatively and for 30 days postoperatively. Beta blocker treatment reduced the 30 day incidence of mortality or myocardial infarction rate tenfold, from 34% to 3.4%.
Arguably the most promising outcome study in this field was published by the McSPI group, in which a short course of atenolol was administered to patients at risk for CAD undergoing noncardiac surgery. With a total sample size of only 200 patients, the atenolol group showed a reduction in mortality from 21% to 10% at two years following surgery. Furthermore, in a follow-up publication, this group confirmed from their data that those patients experiencing episodes of PMI within seven days of surgery (39% placebo, 24% atenolol) were significantly less likely to survive over the next two years. Despite criticisms about the study design and small sample size, this research demonstrated for the first time that short-term cardiac autonomic modification at the time of surgery may have a long-term impact on survival in patients at risk for CAD. Much discussion ensued about the mechanisms by which several days of beta blockade could lead to an improvement in outcome many months later. As alluded to above, it has been speculated that sympathetically-mediated shear forces may enhance the disruption, fissuring and rupture of coronary artery intimal plaque, making the vessels susceptible to thrombosis. Following this theory, beta blockers may act by reducing intimal damage (and/or hypercoagulability) that may result in thrombosis and myocardial infarction in subsequent months.7 The definitive large scale outcome study using multivariate techniques to identify subpopulations most likely to benefit is yet to come. However with the large accumulated body of data confirming the efficacy and safety of perioperative beta blockade, authorities such as the American College of Physicians have strongly advised that this strategy become a standard of care in the treatment of patients at risk for cardiac complications.
Summary
Cardiovascular complications are common in patients at risk for coronary disease undergoing surgery. The role of hyperactivity of the sympathetic nervous system and impaired parasympathetic control mechanisms in the genesis and consequences of perioperative myocardial ischemia has been discussed. Sympathetic blocking drugs of the beta blocker and alpha2 agonist classes have been used extensively in the perioperative setting to control hemodynamic responses and reduce episodes of myocardial ischemia. To date, perioperative beta blockade is the only strategy shown to improve long-term outcome after surgery in this population.
APPENDIX 1 Proposed guidelines for perioperative beta blockade
Inclusions:
all patients with known, or at least two risk factors for, coronary artery disease.
Exclusions:
current congestive heart failure, conditions in which reduced heart rate and sympathetic tone would be detrimental, bradydysrhythmias, severe reactive airways disease (many studies utilizing cardioselective beta blockers have safely included patients with chronic obstructive lung disease, mild chronic congestive failure and other conditions sometimes felt to contraindicate use of beta blockers).
Protocol:
APPENDIX 2 Proposed guidelines for perioperative alpha2 agonists
Inclusions:
all patients with hypertension or two risk factors for coronary artery disease.
Exclusions:
conditions in which reduced heart rate and sympathetic tone would be detrimental, bradydysrhythmias.
Protocol:
References
1 Mangano DT, Siliciano D, Hollenberg M, et al. Postoperative myocardial ischemia. Anesthesiology 1992; 76: 342–53.[Medline]
2 Wallace A, Layug B, Tateo I, et al. Prophylactic atenolol reduces postoperative myocardial ischemia. Anesthesiology 1998; 88: 7–17.[Medline]
3
Mangano DT, Layug E, Wallace A. Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. N Engl J Med 1996; 335: 1713–20.
4 Mangano DT, Browner WS, Hollenberg M, Li J, Tateo IM. Long-term cardiac prognosis following noncardiac surgery. JAMA 1992; 268: 233–9.[Abstract]
5
Eagle KA, Froelich JB. Reducing cardiovascular risk in patients undergoing noncardiac surgery. N Engl J Med 1996; 335: 1761–2.
6 Cohen MC, Aretz TH. Histological analysis of coronary artery lesions in fatal postoperative myocardial infarction. Cardiovasc Pathol 1999; 8: 133–9.[Medline]
7 Frishman WH, Lazar EJ. Reduction of mortality, sudden death and non-fatal reinfarction with beta- adrenergic blockers in survivors of acute myocardial infarction: a new hypothesis regarding the cardioprotective action of beta-adrenergic blockade. Am J Cardiol 1990; 66: 66G–70G.[Medline]
8 La Rovere MT, Bigger JT, Marcus FI, Mortara A, Schwartz P. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. Lancet 1998; 351: 478–84.[Medline]
9 Alicandri C, Boni E, Fariello R, Zaninelli A, Grassi V. Baroreceptor sensitivity in hypertension and vagal activity. J Hypertension 1991; 9: S90–1.
10 Parlow JL, Begou G, Sagnard P, et al. Cardiac baroreflex during the postoperative period in hypertensive patients: effect of clonidine. Anesthesiology 1999; 90: 681–92.[Medline]
11 Amar D, Fleisher M, Pantuck CB, et al. Persistent alterations of the autonomic nervous system after noncardiac surgery. Anesthesiology 1998; 89: 30–42.[Medline]
12 Dworschad M, Gasteiger P, Rapp HJ, van Ackern K. Perioperative myocardial ischemia is associated with a prolonged cardiac vagal dysfunction after non-cardiac surgery. Acta Anaesthesiol Scand 1997; 41: 1247–56.[Medline]
13 Saunier CF, Akaoka H, de La Chapelle B, et al. Activation of brain noradrenergic neurons during recovery from halothane anesthesia. Anesthesiology 1993; 79: 1072–82.[Medline]
14 Dodd-o JM, Breslow MJ, Dorman T, Rosenfeld BA. Preserved sympathetic response to hypotension despite perioperative a-2 agonist administration. Anesth Analg 1997; 84: 1208–10.[Medline]
15
Parlow JL, Sagnard P, Begou G, Viale JP, Quintin L. The effects of clonidine on sensitivity to phenylephrine and nitroprusside in patients with essential hypertension recovering from surgery. Anesth Analg 1997; 88: 1239–43.
16 Isaac L. Clonidine in the central nervous system: site and mechanism of hypotensive action. J Cardiovasc Pharmacol 1980; 2(suppl.1): S5–19.
17
Mancia G, Ferrari A, Gregorini L, Zanchetti A. Clonidine and carotid baroreflex in essential hypertension. Hypertension 1979; 1: 362–70.
18 Muzi M, Goff DR, Kampine JP, Roerig DL, Ebert TJ. Clonidine reduces sympathetic activity but maintains baroreflex responses in normotensive humans. Anesthesiology 1992; 77: 864–71.[Medline]
19
Parlow JL, Viale JP, Annat G, Hughson RL, Quintin L. Spontaneous cardiac baroreflex activity in humans: comparison with pharmacological responses. Hypertension 1995; 25: 1058–68.
20 Ghignone M, Calvillo O, Quintin L. Anesthesia and hypertension: the effect of clonidine on perioperative hemodynamics and isoflurane requirements. Anesthesiology 1987; 67: 3–10.[Medline]
21 Quintin L, Bouilloc X, Butin E, et al. Clonidine for major vascular surgery in hypertensive patients: a double-blind, controlled, randomized study. Anesth Analg 1996; 83: 687–95.[Abstract]
22 Quintin L, Viale JP, Annat G, et al. Oxygen uptake after major abdominal surgery: effect of clonidine. Anesthesiology 1991; 74: 236–41.[Medline]
23 Cocco G, Strozzi C, Haeusler G, et al. The therapeutic value of clonidine in patients with coronary heart disease. Eur J Cardiol 1979; 10: 221–8.[Medline]
24 Dorman BH, Zucker JR, Verrier ED, Gartman DM, Slachman FN. Clonidine improves perioperative myocardial ischemia, reduces anesthetic requirement, and alters hemodynamic parameters in patients undergoing coronary artery bypass surgery. J Cardiothorac Vasc Anesth 1993; 7: 386–95.[Medline]
25 Stuhmeier KD, Mainzer B, Cierpka J, Sandmann W, Tarnow J. Small, oral dose of clonidine reduces the incidence of intraoperative myocardial ischemia in patients having vascular surgery. Anesthesiology 1996; 85: 706–12.[Medline]
26 McSPI Europe Research Group. Perioperative sympatholysis: beneficial effects of the alpha-2 adrenoceptor agonist mivazerol on hemodynamic stability and myocardial ischemia. Anesthesiology 1997; 86: 346–63.[Medline]
27 Oliver MF, Goldman L, Julian DG, Holme I. Effect of mivazerol on perioperative cardiac complications during non-cardiac surgery in patients with coronary heart disease. Anesthesiology 1999; 91: 951–61.[Medline]
28
Ellis JE, Drijvers G, Pedlow S, et al. Premedication with oral and transdermal clonidine provides safe and efficacious postoperative sympatholysis. Anesth Analg 1994; 79: 1133–40.
29 Segal IS, Jarvis DJ, Duncan SR, White PF, Maze M. Clinical efficacy of oral-transdermal clonidine combination during the perioperative period. Anesthesiology 1991; 74: 220–5.[Medline]
30 Sandrone G, Mortara A, Torzillo D, et al. Effects of beta-blockers (atenolol or metoprolol) on heart rate variability after acute myocardial infarction. Am J Cardiol 1994; 74: 340–5.[Medline]
31
Adamson PB, Huang MH, Vanoli E, et al. Unexpected interaction between beta adrenergic blockade and heart rate variability before and after myocardial infarction. Circulation 1994; 90: 976–82.
32 Viljoen JF, Estafanous FG, Kellner GA. Propranolol and cardiac surgery. J Cardiovasc Surg 1972; 64: 826–30.
33 Miller RR, Olson HG, Amsterdam EA, Mason DT. Propranolol-withdrawal rebound phenomenon. Exacerbation of coronary events after abrupt cessation of antianginal therapy. N Engl J Med 1975; 293: 416–8.[Abstract]
34 Pasternack PF, Imparato AM, Baumann G, et al. The hemodynamics of beta-blockade in patients undergoing abdominal aortic aneurysm repair. Circulation 1987; 76(suppl III): III-1–7.
35
Raby KE, Brull SJ, Timimi F, et al. The effect of heart rate control on myocardial ischemia among high- risk patients after vascular surgery. Anesth Analg 1999; 88: 477–2.
36
Urban MK, Markowitz SM, Gordon MA, Urquhart BL, Kligfield P. Postoperative prophylactic administration of beta-adrenergic blockers in patients at risk for myocardial ischemia. Anesth Analg 2000; 90: 1257–61.
37
The MACB Study Group. Effect of metoprolol on death and cardiac events during a 2-year period after coronary artery bypass grafting. Eur Heart J 1995; 16: 1825–2.
38
Poldermans D, Boersma E, Bax JJ, et al. The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. N Engl J Med 1999; 341: 1789–94.
39 Talke P, Li J, Jain U, et al. Effects of perioperative dexmedetomidine infusion in patients undergoing vascular surgery. Anesthesiology 1995; 82: 620–33.[Medline]
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