The Case for -Adrenergic Blockade as Prophylaxis Against Perioperative
Cardiovascular Morbidity and Mortality
Craig H. Selzman, MD; Stephanie A. Miller, MD; Michael A. Zimmerman, MD;
Alden H. Harken, MD
Perioperative morbidity and mortality are
frequently cardiac in origin. Many studies have prospectively attempted to
define risk factors for cardiac ischemic events. Although we can now identify
high-risk patients, optimal cardioprotective management strategies remain
unclear. Treatment with -adrenergic
antagonists decreases myocardial oxygen consumption and is generally well
tolerated. This article reviews the physiologic and clinical basis for using
these agents as prophylaxis against cardiovascular events in high-risk surgical
patients.
Arch Surg. 2001;136:286-290
In patients with known cardiovascular disease,
myocardial ischemia remains the principal cause of morbidity and mortality
after cardiac and noncardiac surgery. As our population ages, this problem will
affect nearly 35 million people, with a yearly estimated cost of more than $20
billion.1 Numerous
investigators2, 3 have
prospectively attempted to identify factors that place patients at high risk. A
potpourri of historical factors have been implicated, including age, recent
myocardial infarction, congestive heart failure, active angina, ventricular
dysrhythmias, diabetes, and the type and urgency of the operation. Although we
generally can identify patients at high risk for perioperative cardiovascular
events, it remains unclear what we should do with this information. No
randomized, prospective trial, to our knowledge, has demonstrated the benefit
or efficacy of preoperative myocardial revascularization. Indeed, excessive
preoperative cardiac screening and subsequent intervention might prove
detrimental.4 The Coronary
Artery Revascularization Prophylaxis trial is currently enrolling patients to
answer this question.5 In the
meantime, we are left with the dilemma of how best to reduce cardiovascular
complications in patients undergoing noncardiac surgery. The purpose of the
present article is to review the physiologic and clinical basis for -adrenergic
antagonism in surgical patients.
Neurohormonal Stress of Surgery
The neurohormonal stress of elective surgery begins well before the skin
incision. Activation of the hypothalamus-pituitary-adrenal axis is initiated by
just scheduling the operation and persists throughout surgery until at least a
week after surgery. This period, often referred to as the adrenergic-corticoid
phase, is defined by hypercatabolism and hypersecretion of neuroendocrine
substances. One of the earliest events after afferent stimulation of the
hypothalamus is the release of corticotropin and subsequent elaboration of
cortisol. Concomitant with adrenal cortical stimulation is medullary activation
by the sympathetic nervous system and release of catecholamines.6 Although the
evolutionary intent of these stress reactions is clear in the jungle, these
same survival responses, especially if dysregulated, might threaten a
debilitated patient with poor reserve. Adrenergic receptors are located in
virtually every organ, orchestrating the stress response. In the human heart, 1-, 1-, and 2-adrenergic
receptors promote several biologic responses, including inotropy, chronotropy,
myocyte apoptosis, and direct myocyte toxicity. Left unabated, chronic
adrenergic stimulus results in pathologic ventricular remodeling, acute
coronary syndromes, arrythmogenesis, and end-stage cardiomyopathy.
Myocardial Oxygen Consumption
Surgery itself obligates myocardial work; patients with coronary artery disease
are unable to meet this increased demand. Myocardial ischemia within 48 hours
of surgery, either clinically occult or overt, confers a 9-fold increase in
risk of unstable angina, nonfatal myocardial infarction, and cardiac death.7 Therapeutic
strategies to attenuate this ischemic insult must therefore favorably
manipulate the physiologic balance of myocardial oxygen supply and demand.
Myocardial oxygen consumption ultimately
reflects the utilization of mitochondrial adenosine triphosphate. As such,
conditions that deplete myocardial adenosine triphosphate levels inversely
increase oxygen uptake. In 1969, Braunwald8 presented a
unified concept of the determinants of myocardial oxygen consumption. Examining
nearly a century of experimental studies and a decade of his own work, he
elucidated 8 key componentsand their relative
contributionsof myocardial oxygen
consumption. He concluded that the major contributors to cardiac work are heart
rate, developed force, and contractile state. In fact, he demonstrated that the
catecholamine-induced increase in myocardial oxygen consumption was not so much
a function of their direct metabolic effect but rather of their effect on
myocardial contractile activity.
Modern interpretation of the thesis by Braunwald8 has focused
on 4 prime determinants of oxygen demand: heart rate, preload, afterload, and
contractility. Elevated heart rate is associated with shortening of diastolic
perfusion (nutrient and oxygen) time. Wall stress (as defined by Laplace's law)
accounts for the contributions of preload and afterload to myocardial oxygen
demand. Enhanced contractility affects the equation by changing the
relationship between developed pressure and ventricular volume. Cumulatively, a
clinical index of myocardial oxygen demand is represented by the
"rate-pressure product" (heart rate mean
arterial pressure). This is one basis for the anesthestic goal of maintaining a
patient's rate-pressure product within 10% of the preoperative value.
Catecholamines and Myocardial
Work
Catecholamines conspire to increase each of the 4 major determinants of
myocardial oxygen consumption. The chronotropic effects of 1-receptor stimulation are well recognized.
Macrovascular and microvascular tone are, in part, controlled by adrenergic
tone. 1-Receptor
stimulationship promotes venoconstriction, thus affecting afterload and
preload. Figure 1
graphically depicts the relationship among heart rate, blood pressure, and
myocardial oxygen consumption (area integrated under each curve). Compared with
the basal state, stimulation with epinephrine increases heart rate (cycles per
second), vascular resistance (peak pressure), and contractility (steeper slope,
ie, an increase in the developed pressure per time). Cumulatively, these
catecholamine effects result in an increase in myocardial oxygen consumption.
Early Studies of Perioperative -Adrenergic
Blockade
Just as adrenergic stimulation can magnify each determinant of myocardial
oxygen demand, adrenergic antagonism can attenuate each variable. Individual
studies have associated -adrenergic
blockade–mediated decreases in myocardial oxygen consumption with a reduction
in heart rate, wall tension, and contractility. As a clinical correlate,
several studies demonstrate that -adrenergic
blockade can also decrease perioperative myocardial ischemia.9 Yet, few dataand until recently, no
randomized trialshave positively
correlated this physiologic effect with clinical outcomes.
The initial study10
demonstrating the beneficial effect of adrenergic antagonism on perioperative
morbidity and mortality involved patients with hypertension taking propranolol
hydrochloride who seemed to be at risk for propranolol withdrawl syndrome at
the time of surgery (Table 1).
Thirteen patients were treated with continuous propranolol infusions after
abdominal operations. They strictly monitored serum drug levels, noticed no
withdrawal, and reported no perioperative cardiovascular complications.
Perioperative propranolol administration subsequently proved to be
cardioprotective during cardiac surgery. In another study,11 50 patients
undergoing coronary artery bypass surgery were randomized to receive
propranolol or placebo 24 to 48 hours before surgery and continuing for 30 days
after surgery. Propranolol treatment significantly decreased the rate-pressure
product on induction of anesthesia and sternotomy. Cumulatively, patients
taking -adrenergic
blocking agents had less need for antihypertensive therapy after surgery and
experienced reduced incidence and frequency of supraventricular and ventricular
arrhythmias and no mortality. Although these studies are small, they suggest
the clinical relevance of -adrenergic
blocking agent–dependent decreases in myocardial oxygen consumption as it
pertains to myocardial ischemia and possibly arrhythmogenesis.
During the 1990s, several more retrospective and
case-controlled studies promoted perioperative -adrenergic
blockade. Stone and colleagues9 gave
untreated hypertensive patients undergoing abdominal and vascular surgery a
single oral dose of labetalol hydrochloride or atenolol. Whereas 11 of 39
control patients exhibited intraoperative myocardial ischemia, tachycardia and
electrocardiographic evidence of ischemia was observed in only 2 of 89 treated
patients.9 This study
was corroborated in another group of vascular surgery patients given
metoprolol, 50 mg, before surgery.12 Compared
with controls, treated patients had less frequent and shorter periods of
intraoperative silent ischemia.12 These
studies did not correlate intraoperative ischemia with cardiovascular outcome.
In a retrospective study13 from the
University of Oregon, factors associated with perioperative myocardial
infarction were analyzed in more than 2000 vascular surgery patients. Use of -adrenergic
blocking agents conferred a 50% reduction in the relative risk of perioperative
myocardial infarction. Although this risk reduction is impressive, a
surprisingly high number of patients who experienced myocardial infarction were
taking -adrenergic
blocking agents (30%). As with the previous studies, outcomes relating the
perioperative event to ultimate cardiovascular morbidity and mortality were not
reported.
Randomized Trials of
Perioperative -Adrenergic
Blockade
In 1996, Mangano and colleagues14 published
the first randomized, prospective trial examining the effect of the
cardioselective agent, atenolol, on cardiovascular morbidity and mortality
after noncardiac surgery. Two hundred patients at a Veterans Affairs Medical
Center undergoing vascular, abdominal, orthopedic, and neurosurgical procedures
were randomized to receive placebo (n = 101) or treatment with atenolol (n =
99). Eligible patients were those with previous myocardial infarction, typical
angina, or atypical angina with a positive stress test result or those at risk
for coronary artery disease (2 traditional risk
factors). Treated patients received atenolol, 5 to 10 mg, intravenously before
surgery and atenolol, 5 to 10 mg, intravenously twice daily or 50 to 100 mg
orally until discharge or 7 days maximum. Goals of treatment included a heart
rate of 55 to 65 beats per minute (bpm) and systolic blood pressure of less than
100 to 110 mm Hg. The primary end point was all-cause mortality over a 2-year
period (99% follow-up); secondary end points included myocardial infarction,
congestive heart failure, unstable angina, and myocardial revascularization.
Overall mortality was less in the atenolol vs
the control group at 2 years (9% vs 21%). Risk reduction was evident within the
first 6 months (no cardiac events in the atenolol group vs 12% in the control
group), and the advantage was sustained throughout follow-up. Although the
results of this study suggest a role for perioperative atenolol use in
providing long-term cardioprotection, these results must be interpreted with
several caveats. First, the placebo group suggested a trend toward sicker
patients. Second, surgical patients in a Veterans Affairs facility might not be
representative of the population at large. Finally, more patients in the
treatment group were taking -adrenergic
blocking agents and angiotensin-converting enzyme inhibitors during follow-up.
Although atenolol treatment was associated with less perioperative ischemia, -adrenergic
blockade did not significantly reduce the incidence of in-hospital myocardial
infarction or cardiac mortality.17 Possibly,
the observed decrease in cardiac mortality had nothing to do with the 7 days of
atenolol treatment but rather the 6 to 24 months of treatment with other
risk-reducing agents.
In 1999, Poldermans and colleagues15 published
the second major randomized, controlled trial evaluating perioperative -adrenergic
blockade. This study attempted to define a subgroup of patients who might
benefit maximally from adrenergic antagonism. The study by Mangano and
colleagues14 reported an
extremely low incidence of perioperative cardiac events (3%). This observation
was due, in part, to the inclusion of patients with known coronary artery
disease and those with only coronary risk factors undergoing a diverse array of
operations. Conversely, the study by Poldermans and colleagues15 was limited
to high-risk patients undergoing only abdominal or infrainguinal arterial
procedures. Patients were included if they had 1 or more risk factors (previous
myocardial infarction, angina, history of or current congestive heart failure,
age >70 years, treated ventricular arrhythmia, hypertension, or diabetes) and a positive result on dobutamine
echocardiography. One hundred twelve patients were randomized to placebo (n =
53) or treatment with the cardioselective (1)
adrenergic receptor antagonist, bisoprolol (n = 59). Treatment with bisoprolol,
5 to 10 mg orally, was started a least 1 week before surgery and was continued
for 30 days after surgery. The primary end points were myocardial infarction
and cardiac mortality during the 30 days after surgery.
Cardiac events were observed in 34% of the
control group compared with only 3.4% of the bisoprolol group. In addition,
there were no myocardial infarctions in the treatment arm. These significant
differences prompted the safety committee to suspend the trial (original
recruitment goal was 266 patients). Although impressive, these results must
also be interpreted with several caveats. This was a nonblinded study with
fairly low patient numbers. Two groups of patients were excluded from
randomization: those already taking -adrenergic
blocking agents and those with extensive wall-motion abnormalities on stress
echocardiography. The authors offered no explanation for the 7.5% cardiac
mortality rate seen in 53 patients already receiving -adrenergic blockade. Intuitively, it seems that these patients
should also have been protected. Of 8 patients with extensive wall-motion
defects (defined by wall-motion index), 4 underwent coronary artery bypass (2
died) and 4 underwent vascular surgery with -adrenergic
blockade (1 perioperative myocardial infarction). Nonrandomization aside,
inclusion of these "fringe" patients would not significantly change
the overal impact of the study. These patients were clearly sicker and more
homogeneous than those in the study by Mangano and colleagues.14 As such, the
conclusion that perioperative -adrenergic
blockade is cardioprotective in high-risk patients undergoing major vascular
surgery seems valid.
Consistent in the surgical literature is that
use of -adrenergic
blocking agents by patients with cardiopulmonary disease is well tolerated.
Most patients could achieve the hemodynamic goals of heart rate and systolic
blood pressure without developing bronchospasm or congestive heart failure.
Although the bisoprolol study excluded patients with asthma, current
recommendations do not automatically exclude patients with reactive airway
disease from receiving -adrenergic
blocking agents. In fact, judicious titration of cardioselective adrenergic
antagonists seems to be indicated in patients with mild to moderately severe
asthma and coronary artery disease.18 Likewise,
the historic contraindication of -adrenergic
blockade in patients with reduced left ventricular function and congestive
heart failure has been revisited in the past decade. Cardioselective and
newer-generation -adrenergic
blocking agents have been successfully used in patients with New York Heart
Association class II and III symptoms.19
Although therapeutic delivery of adrenergic
antagonists is often premised on decreasing catecholamine-induced myocardial
oxygen consumption, several other mechanisms likely contribute to their
cardioprotective effect. Catecholamines instigate and perpetuate vascular
injury by promoting endothelial dysfunction, platelet aggregation, endovascular
adhesion molecule release, hypercoagulability, hypertension, and direct myocyte
toxicity. -Adrenergic
blockade, experimentally and epidemiologically, can reverse many of these
effects. In addition, use of -adrenergic
blocking agents might inhibit apoptosis and platelet deposition, thus
stabilizing the vulnerable coronary plaque. Finally, although use of -adrenergic
blocking agents has often been associated with dyslipidemias (particularly
reduction in high-density lipoprotein levels), changes in lipid profiles are
usually small and outweighed by the cumulative cardioprotective effect of these
agents.
There are several different approaches to
providing perioperative cardioprotection. Although many of these strategies
remain experimental or anecdotal, others have been studied in controlled
trials.20 The former
category includes synthetic oxygen carriers, antiplatelet agents, bradykinin
antagonists, adenosine, opioid receptor agonists, and inflammatory mediator
antagonists. Traditional perioperative pharmacotherapy has often included
calcium channel blockers, nitrates, and 2-adrenoceptor agonists. As with -adrenergic blocking agents, these agents affect the vasculature and
myocardial oxygen consumption at several levels. For example, use of
nitroglycerin decreases demand by its venodilatory properties. In addition,
nitroglycerin is also a coronary vasodilator and direct nitric oxide donor.
Although use of nitroglycerin intuitively makes sense and is supported in
several studies, results of a conflicting study21 suggest that
nitroglycerin use has no effect on intraoperative ischemia and might even be
deleterious. While we support the use of adrenergic antagonists, it would be
naive to suggest that use of these agents, alone, will independently confer
protection. -Adrenergic
blockade should be part of a comprehensive pharmacologic strategy that includes
other drugs, such as aspirin, angiotensin-converting enzyme inhibitors, and
hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins), that reduce
the risk of cardiovascular events.
In gratifyingly intuitive fashion, perioperative
administration of -adrenergic
blocking agents for the prevention of surgical cardiovascular morbidity and
mortality is based on physiologic principles and is supported by randomized,
prospective trials. In 1996, the American Heart Association published a
consensus statement addressing the preoperative workup and treatment of
patients undergoing noncardiac surgery.22
Subsequently, 2 major studies14, 15 have
reported the beneficial effect of perioperative -adrenergic blockade on the reduction of cardiovascular events. On
review, we therefore offer the following specific recommendations for patients
undergoing major elective noncardiac surgery:
1. Identify patients at high risk: Most of this
information can be obtained through the history and physical examination. A
12-lead electrocardiogram and basic laboratory tests to assess anemia, renal
function, and glucose tolerance cover most other risk factors. Although it is
tempting to obtain a functional study (such as a stress echocardiogram),
preoperative myocardial revascularization is currently indicated only in
patients who exhibit well-accepted criteria for coronary artery bypass (such as
unstable angina).
2. Continue or initiate -adrenergic blockade: If men older than 40 years and women older than
45 years are already taking a -adrenergic blocking
agent, continue therapy with a goal of lowering heart rate and systolic blood
pressure to 70 bpm and 110 mm Hg, respectively. If the patient is not taking a -adrenergic
blocking agent, begin an oral regimen as early as possible preceding the
scheduled surgery to achieve the previously stated hemodynamic goals. The
optimal -adrenergic
blocking agent remains unclear; however, a cardioselective agent (such as
atenolol or metoprolol) is likely the best choice.
3. Continue -adrenergic
blockade throughout hospitalization: In the absence of bradycardia (heart rate
<60 bpm) and hypotension (systolic blood pressure <100 mm Hg), judicious
use of intravenous and oral -adrenergic
blocking agents should be continued after surgery, with a target heart rate of
70 bpm and systolic blood pressure of 110 mm Hg.
4. Continue -adrenergic
blockade as an outpatient: Although in the study by Poldermans et al15 patients were
administered bisoprolol for only 30 days, many cardiologists recommend more
prolonged therapy. For reasons that remain unclear, protection against
cardiovascular events seems to extend beyond the period of direct adrenergic
inhibition.
Author/Article Information
From the Division of Cardiothoracic Surgery, Department of Surgery, University
of Colorado Health Sciences Center, Denver.
Corresponding author and reprints: Craig H. Selzman, MD, Division of
Cardiothoracic Surgery, Box C-310, University of Colorado Health Sciences
Center, 4200 E Ninth Ave, Denver, CO 80262.
This study was supported by grants from the
Pacific Vascular Research Foundation (Dr Selzman) and by grants GM49222 and
GM08315 from the National Institutes of Health, Bethesda, Md (Dr Harken).
1.
Mangano DT, Goldman L.
Preoperative assessment of patients with known or suspected coronary disease.
N Engl J Med.
1995;333:1750-1756.
MEDLINE
2.
Goldman L, Caldera DL, Nussbaum SR, et al.
Multifactorial index of cardiac risk in noncardiac surgical procedures.
N Engl J Med.
1977;297:845-850.
MEDLINE
3.
Eagle KA, Froehlich JB.
Reducing cardiovascular risk in patients undergoing noncardiac surgery.
N Engl J Med.
1996;335:1761-1763.
MEDLINE
4.
Krupski WC, Nehler MR, Whitehill TA, Lawson RC, Strecker PK, Hiatt WR.
Negative impact of cardiac evaluation before vascular surgery.
Vasc Med.
2000;5:3-9.
MEDLINE
5.
McFalls EO, Ward HB, Krupski WC, et al, for the Veterans Affairs Cooperative
Study Group on Coronary Artery Revascularization Prophylaxis for Elective
Vascular Surgery.
Prophylactic coronary artery revascularization for elective vascular surgery:
study design.
Control Clin Trials.
1999;20:297-308.
MEDLINE
6.
Sametz W, Metzler H, Gries M, et al.
Perioperative catecholamine changes in cardiac risk patients.
Eur J Clin Invest.
1999;29:582-587.
MEDLINE
7.
Mangano DT, Browner WS, Hollenberg M, London MJ, Tubau JF, Tateo IM, for the
Study of Perioperative Ischemia Research Group.
Association of perioperative myocardial ischemia with cardiac morbidity and
mortality in men undergoing noncardiac surgery.
N Engl J Med.
1990;323:1781-1788.
MEDLINE
8.
Braunwald E.
Thirteenth Bowditch Lecture: the determinants of myocardial oxygen consumption.
Physiologist.
1969;12:65-94.
MEDLINE
9.
Stone JG, Foex P, Sear JW, Johnson LL, Khambatta HJ, Triner L.
Myocardial ischemia in untreated hypertensive patients: effect of a single
small oral dose of a -adrenergic
blocking agent.
Anesthesiology.
1988;68:495-500.
MEDLINE
10.
Smulyan H, Weinberg SE, Howanitz PJ.
Continous propranolol infusion following abdominal surgery.
JAMA.
1982;247:2539-2542.
MEDLINE
11.
Hammon JW Jr, Wood AJ, Prager RL, Wood M, Muirhead JJ, Bender HW.
Perioperative blockade with
propranolol: reduction in myocardial oxygen demands and incidence of atrial and
ventricular arrhythmias.
Ann Thorac Surg.
1984;38:363-367.
MEDLINE
12.
Pasternack PF, Grossi EA, Baumann FG, et al.
Beta blockade to decrease silent myocardial ischemia during peripheral vascular
surgery.
Am J Surg.
1989;158:113-116.
MEDLINE
13.
Yeager RA, Moneta GL, Edwards JM, Taylor LM Jr, McConnell DB, Porter JM.
Reducing perioperative myocardial infarction following vascular surgery: the
potential role of -blockade.
Arch Surg.
1995;130:869-872.
MEDLINE
14.
Mangano DT, Layug EL, Wallace A, Tateo I, for the Multicenter Study of
Perioperative Ischemia Research Group.
Effect of atenolol on mortality and cardiovascular morbidity after noncardiac
surgery.
N Engl J Med.
1996;335:1713-1720.
MEDLINE
15.
Poldermans D, Boersma E, Bax JJ, et al, for the Dutch Echocardiographic Cardiac
Risk Evaluation Applying Stress Echocardiography Study Group.
The effect of bisoprolol on perioperative mortality and myocardial infarction
in high-risk patients undergoing vascular surgery.
N Engl J Med.
1999;341:1789-1794.
MEDLINE
16.
Urban MK, Markowitz SM, Gordon MA, et al.
Postoperative prophylactic administration of -adrenergic
blockers in patients at risk for myocardial ischemia.
Anesth Analg.
2000;90:1257-1261.
MEDLINE
17.
Wallace A, Layug B, Tateo I, et al, for the McSPI Research Group.
Prophylactic atenolol reduces postoperative myocardial ischemia.
Anesthesiology.
1998;88:7-17.
MEDLINE
18.
Tafreshi MJ, Weinacker AB.
Beta-adrenergic-blocking agents in bronchospastic diseases: a therapeutic
dilemma.
Pharmacotherapy.
1999;19:974-978.
MEDLINE
19.
Bristow MR.
-Adrenergic
receptor blockade in chronic heart failure.
Circulation.
2000;101:558-569.
MEDLINE
20.
Warltier DC, Pagel PS, Kersten JR.
Approaches to the prevention of perioperative myocardial ischemia.
Anesthesiology.
2000;92:253-259.
MEDLINE
21.
Thomson IR, Mutch WA, Culligan JD.
Failure of intravenous nitroglycerin to prevent intraoperative myocardial
ischemia during fentanyl-pancuronium anesthesia.
Anesthesiology.
1984;61:385-393.
MEDLINE
22.
Eagle KA, Brundage BH, Chaitman BR, et al.
Guidelines for perioperative cardiovascular evaluation for noncardiac surgery.
Circulation.
1996;93:1278-1317.
Edward
E. Rylander,M.D.
D.A.B.F.P. AND D.A.B.P.M.