Perioperative Beta-blockers for Major Noncardiac Surgery: Primum Non Nocere

REVIEW

Perioperative Beta-blockers for Major Noncardiac Surgery: Primum Non Nocere Vineet Chopra, MD,a Benjamin Plaisance, MD,a Erdal Cavusoglu, MD,b Scott A. Flanders, MD,a Kim A. Eagle, MDc a Division of General Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor; bDivision of Cardiology, Department of Medicine, State University of New York Downstate Medical Center, Brooklyn; cDivision of Cardiovascular Medicine, Department of Medicine, University of Michigan Health System, Ann Arbor.

ABSTRACT Recent studies have called into question the benefit of perioperative beta blockade, especially in patients at low to moderate risk of cardiac events. Once considered standard of care, the role of beta-blocker therapy now lies mired in conflicting data that are difficult to apply to the at-risk patient. We provide an overview of the evolution of perioperative beta blockade, beginning with the physiology of the adrenergic system, with emphasis on the biologic rationale for the perioperative implementation of beta-blockers. Although initial studies were small in size and statistically limited, early data showed cardiac benefit with the use of perioperative beta-blockers. However, larger, more recent studies now suggest a lack of benefit and potential harm from this practice. This paradigm holds true especially in those at low-to-moderate cardiovascular risk profiles. Potential explanations for these paradoxical results are discussed, stressing the key differences between earlier and current studies that may explain these divergent outcomes. We conclude by commenting on performance measures as they relate to perioperative beta-blockers and make recommendations for the continued safe implementation of this practice. © 2009 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2009) 122, 222-229 KEYWORDS: Beta-blockers; Noncardiac surgery; Perioperative risk reduction; POISE

The story of beta-blockers as risk-reducing agents in perioperative medicine is a tale of progressive scientific inquiry. For instance, it was once theorized that blockade of the beta-receptor suppressed protective mechanisms geared to prevent cardiovascular collapse during periods of surgical stress. This theory was so widely accepted that the routine discontinuation of beta-blockers before elective cardiac surgery was embraced by the scientific community in the 1970s.1 The hypothesis that beta-blockers actually improve cardiovascular outcomes during surgery was tested in a 1973 trial, the results of which showed a decrease in myocardial ischemia, ventricular arrhythmia, and blunting of the

Funding: None; no funding received. Conflicts of Interest: There are no conflicts of interest for any of the authors. Authorship: All authors had access to the data and a role in writing the manuscript. Requests for reprints should be addressed to Vineet Chopra, MD, University of Michigan Health System, 3119 Taubman Center, 1500 E, Medical Ctr Dr., SPC 5376, Ann Arbor, MI 48109. E-mail address: [email protected]

0002-9343/$ -see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2008.11.004

hypertensive response on intubation associated with this therapy.2 As clinical data accumulated, beta-blockers quickly became first-line therapy in acute myocardial infarction, stable coronary artery disease, and systolic heart failure.3-5 Their use also grew in the perioperative treatment of patients undergoing vascular surgery with coronary ischemia,6 ultimately leading to a Class I recommendation (evidence that a given procedure is useful and effective) in the 2002 American Heart Association/American College of Cardiology Joint Guidelines.7 A Class IIa recommendation (conflicting evidence in favor of usefulness) was provided for patients with either untreated hypertension, coronary artery disease, or the presence of risk factors for coronary artery disease. The medical community thus began to enthusiastically implement these agents, extending their use to populations not shown to derive benefit; namely, patients at low/moderate cardiovascular risk and those undergoing nonvascular surgery.8 A number of seminal trials published over the past decade have demonstrated a lack of benefit in the peri-

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operative application of beta blockade. In fact, a recent demonstrate heightened vasomotor reactivity, rupture of large randomized study showed potential for harm in the vulnerable coronary plaques, and thrombus formation, ultiform of increased rates of stroke and overall mortality.9 mately leading to vessel occlusion and cardiac events. These In addition, several trials have reported intraoperative “culprit” lesions are difficult to detect, rendering preoperacomplications in patients on beta-blocker therapy.10,11 tive intervention difficult and subjective.14 Finally, increases Thus, mounting evidence has in circulating coagulation factors, called into question ubiquitous reduced fibrinolytic activity, and perioperative beta blockade. The heightened systemic inflammatory CLINICAL SIGNIFICANCE clinical dilemma faced by toresponses interplay to produce a day’s practitioner consequently hazardous perioperative milieu.15 ● A biological rationale for benefit from lies in identifying which patients It is thus not surprising that perioperative beta-blockers exists. might benefit and which might cardiovascular complications after ● Initial trials supporting perioperative be harmed by this intervention. noncardiac surgery range from 2.5 beta blockade suffered small construct to 10 in every 100 patients.16 In and limited design, and thus cannot dethe specific subgroup of patients PHYSIOLOGY AND with known coronary artery distermine current practice. PHARMACOLOGY OF BETAease, the most important predic● Recent studies suggest caution with ADRENERGIC RECEPTORS tors of morbidity remain periobeta blockade, especially in low/moderperative ischemia and nonfatal AND THEIR BLOCKERS ate cardiovascular risk profiles. myocardial infarction. PostoperaBeta-adrenergic blockers are a tive ischemia has been shown to class of medications targeted at ● Differences in trial design and drug regaccount for a 9-fold increase in the blockade of postsynaptic betaimen explain divergent study outcomes. the odds of cardiovascular death, adrenergic receptors. These recep● Authorities may have perpetuated broamyocardial infarction, or unstable tors are cell surface-specific and der implementation of perioperative beta angina, and thus forms an imporare found throughout various tisblockade than was supported by the availtant target for remediation in the sues. Several sub-types of beta preoperative setting.17 able science. receptors exist, including beta-1 Numerous properties of beta(found in the myocardium, kidblockers make them ideal therapy ney, eye), beta-2 (adipose tissue, in this situation. Beta-blockers limit pancreas, liver, smooth and skeleand attenuate both sympathetic and neuroendocrine responses tal muscle), and beta-3 (involved with metabolic regulation 18 to stress during surgery. In individuals with preexisting and lipolytic pathways). On a molecular level, they are cardiovascular disease, beta-blockers reduce perioperative linked to G-coupled proteins activating adenylyl cyclase, ischemia by balancing myocardial oxygen supply and deinitiating intracellular events via cyclic adenosine monomand mismatch.19 They prevent ventricular arrhythmias phosphate. Interruption of this pathway prevents activation and attenuate perioperative inflammatory markers and free of excitatory channels, leading to the benefits associated radicals, variables associated with precipitation of acute with this class of drugs. coronary syndromes.20 On a cellular level, beta-blockers Beta-blockers differ considerably in their pharmacokisuppress intracellular lipolysis, reducing myocardial oxygen netic and pharmacodynamic profiles. For example, bisoproconsumption via promotion of glucose metabolism over lol and atenolol are long acting (t/2 10-11 hours vs 6 hours, fatty acids.21 They increase the stability of atherosclerotic respectively), whereas metoprolol is relatively short acting plaque and suppress catecholamine production during the (t/2 3.5 hours). A longer-acting preparation of metoprolol first 48 hours after surgery.22 Thus, due to their multifaceted (t/2 of 24 hours) is available and was used in the POISE 9 effects, beta-blockers mitigate cardiovascular stress from study. Beta-blockers also differ in their affinity for target surgery. receptors, mediating selective clinical and hemodynamic effects through variable receptor agonism.

PERIOPERATIVE BETA-ADRENERGIC BLOCKADE: AN IDEAL TARGET Following surgery, a number of protective physiologic responses are activated (Figure). For example, a significant catecholamine surge occurs after surgery, producing important sympathetic effects, including measurable elevations in heart rate and blood pressure.12 In the perioperative setting, such responses are potentially deleterious and can precipitate cardiovascular events.13 Experimental perioperative models

INITIAL CLINICAL STUDIES SUPPORTING PERIOPERATIVE BETA BLOCKADE As a plausible physiologic mechanism of benefit exists for perioperative beta-blockers, initial clinical studies sought to demonstrate this fact. Among the first of these studies was published by Stone et al in 1988.23 These investigators conducted a trial with hypertensive patients monitored via Holter for ischemia during anesthesia and surgery. The study randomized 128 patients to treatment with a single oral preoperative dose of labetalol, atenolol,

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Figure

The physiologic basis for perioperative cardiovascular events.

or oxprenolol. The study reported myocardial ischemia in 11 of 39 control subjects versus 2 of 89 study patients (28% vs 2%, P ⬍.001). Although small and unblinded, the authors concluded that a single dose of preoperative beta-blocker prevented ischemia by limiting heart rate accelerations in hypertensive patients. In 1996, Mangano et al24 performed the first randomized controlled trial on perioperative beta blockade, comparing atenolol to placebo in 200 patients with known coronary artery disease undergoing noncardiac surgery. Analyses at study completion showed that overall mortality was 55% lower in the atenolol group than the placebo group. Although no difference in immediate perioperative cardiac events was observed, the benefit of beta blockade was evident at 6-month follow-up, where the rate of cardiac events was 0 in the study group versus 12 in the placebo group (P ⬍.001). Further, the time to first event was 6 days for placebo (vs 158 days for atenolol), indicating an acute increase in events in those untreated with beta-blockers. Like Stone et al,23 the authors noted that controlling heart rate prevented postoperative ischemia. The trial has been criticized, however, due to significant discrepancies in the 2 study groups and exclusion of deaths in the immediate postoperative period, which (if included at endpoint analyses), would have negated the outcome of the study.25 Nonetheless, the article remains frequently cited as it offered a

novel, inexpensive means of preventing perioperative cardiac death. Poldermans et al26 followed the Mangano study with the Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echo (DECREASE) trial, which involved 112 high-risk patients (clinical markers of risk and inducible myocardial ischemia on dobutamine echocardiography) randomized to either bisoprolol or placebo before major vascular surgery. Importantly, the study protocol called for the initiation of bisoprolol at least 1 week before surgery (mean ⫽ 37 days) with titration of the drug to achieve a heart rate of 60/min. The study was stopped prematurely when interim analyses revealed a 10-fold reduction in the incidence of perioperative cardiac death and myocardial infarction versus placebo (3.4% vs 34%; P ⬍.001). The study thus reaffirmed the value of perioperative beta-blockers in a high-risk cohort. A systematic review published by Auerbach and Goldman unified the findings of these initial studies.27 When examining myocardial ischemia, the authors found “modest” numbers needed to treat of 2.5-6.7, with the greatest benefit evident in high-risk patients. The review concluded that the benefits of beta blockade were “without known adverse effect.” It is pertinent to note that many of these initial studies were small in size and insufficiently powered to address

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Size, Design, Endpoints and Limitations of Early Perioperative ␤-Blocker Trials

Table 1

Study/Reference 23

Stone et al

Mangano et al24

Wallace et al18

Poldermans et al26

Zaugg et al41

Urban et al42

Boersma et al43

Brady et al28

(n)

Study Design

Primary Endpoint

Limiting Factors Identified

Small study cohort Unblinded design Type(s) of surgery unidentified No baseline demographic data reported Less CAD in beta-blocker group 200 More ACE-I usage in beta-blocker group Placebo arm 1 patients with DM and prior MI Excluded deaths in the immediate postoperative period which would have changed study findings at 2 years 200 Oral atenolol 0, 50, or 100 Incidence of myocardial 1 Pre-existing HTN in beta-blocker mg vs placebo ischemia during the first week group of surgery Control had beta-blocker withdrawn if already on this Rx, possibly precipitating withdrawal and changing outcomes Unblinded study 112 Oral bisoprolol (titrated to Cardiac death Nonfatal MI Patients already on beta-blockers were heart rate) before excluded surgery (⬇37 days) vs 8 patients with extensive ischemia placebo were excluded 63 Intra and post-op atenolol Measurement of catecholamine Argues against blunting of stress10-20 mg vs standard stress response hormones catecholamine surge as a protective care mechanism of beta blockade Unexpected low rate of post operative Incidence of ST segment 107 IV esmolol on day of MI in placebo changes surgery followed by 25 Did not prove beta-blockers 2 cardiac Incidence of adverse cardiac mg BID metoprolol vs morbidity outcomes (death, MI) placebo 1/3 of placebo group concomitantly received beta-blockers Cardiac death and nonfatal MI Retrospective study-design 1351 Follow-up study to within 30 days of surgery Unblinded Poldermans—oral Low observed event rates vs expected bisoprolol vs standard care 103 Oral metoprolol 50 mg BID Cardiac death and nonfatal MI High rate of CV events (33%) preoperatively ⫹ 7 day within 30 days of surgery and uncharacteristic postop. LOS Randomization arms uneven 128

Incidence of Holter Documented Preoperative single dose Ischemia of oral labetolol, atenolol, olprenolol vs placebo Oral atenolol 0, 50, or 100 All-cause mortality, cardiac death and postoperative mg at time of ischemia anesthesia vs placebo

Abbreviations: CAD ⫽ coronary artery disease; ACE-I ⫽ angiotensin-converting enzyme inhibitor; DM ⫽ diabetes mellitus; MI ⫽ myocardial infarction; HTN ⫽ hypertension; BID ⫽ twice a day; CV ⫽ cardiovascular; LOS ⫽ length of stay.

effects on cardiovascular outcomes. In addition, some of these studies used surrogate endpoints (eg, electrocardiogram ischemia) to show benefit. Thus, limitation in study design and the potential for bias might have led to error in the interpretation and implementation of data from these trials (Table 1).

ORIGINS OF CONCERN: MORE RECENT STUDIES Recent clinical trials have reported adverse effects from the use of perioperative beta-blockers, particularly in patients at low to moderate risk of cardiac events. These studies have raised concern in the broad endorsement of this practice.

The 2006 Metoprolol after Vascular Surgery (MaVS) study sought to answer whether perioperative administration of metoprolol was associated with a reduction in cardiac events in patients undergoing vascular surgery.10 The trial randomized 496 patients without known ischemic heart disease in a double-blinded manner to placebo (n ⫽ 250) or perioperative metoprolol (n ⫽ 246) dosed according to patient body weight (ⱖ75 kg: 100 mg; 40-75 kg: 50 mg; ⱕ40 kg: 25 mg). Metoprolol was given 2 hours preoperatively and was continued for 5 days or until hospital discharge. Mean follow-up was 6 months, with analysis for the composite endpoint of cardiac death, nonfatal myocardial in-

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farction, unstable angina, congestive heart failure, or arrhythmia requiring treatment, performed at 30 days. The study reported that while the postoperative heart rate was lower in the metoprolol group (69.4 vs 79.1 beats per minute, P ⬍.001), the rate of intraoperative complications, including hypotension requiring treatment (46.3% vs 33.6%, P ⬍.001) and bradycardia requiring treatment (21.5% vs 7.6%, P ⬍.001), was significantly higher. This mirrored the results of prior studies,11,28 casting a shadow on the risk:benefit profile of beta-blockers. Importantly, MaVS showed no difference in cardiac events in patients receiving perioperative beta-blockers versus those receiving placebo (10.2% vs 12%, P ⫽ .57), thus demonstrating no benefit, but potential harm from this practice. The findings of MaVS were similar to those of 2 other studies: Diabetic Post Operative Mortality and Morbidity (DIPOM) and the Perioperative Beta-Blockade studies (POBBLE).11,28 Comparable in construct to MaVS, DIPOM assessed the benefit of metoprolol in 921 diabetic patients without coronary artery disease undergoing vascular surgery. Results showed that perioperative metoprolol failed to reduce cardiac events but did cause intraoperative hypotension and bradycardia. Similarly, POBBLE randomized 103 patients undergoing vascular surgery to 50 mg metoprolol twice a day or placebo, starting ⬍24 hours before surgery and continued 7 days after. Results from POBBLE also did not show benefit in cardiovascular outcomes, with events occurring in 32% vs. 34% in the metoprolol and placebo arms, respectively. MaVS, DIPOM, and POBBLE thus suggested caution in the use of beta-blockers in patients without defined preoperative ischemia. In a landmark review, Lindenauer et al29 performed a retrospective cohort study analyzing the effects of beta-blockers according to preexisting cardiac risk defined by Lee’s Revised Cardiac Risk Index (Table 2). This approach was unique in that it attempted to identify risk categories that may benefit or be harmed by beta-blockers. The study reviewed 782,969 patients, of whom 122,338 (16%) received beta blockade during the first 2 days of hospitalization. Within this study cohort, 14% had a Revised Cardiac Risk Index score of 0, portending low cardiovascular risk, whereas 44% had a score of 4 or higher, suggestive of high risk. Analysis of results revealed that

Table 2

Lee’s Revised Cardiac Risk Index (RCRI)

Clinical Parameter

RCRI Point

Prior TIA or CVA Diabetes mellitus requiring insulin therapy Serum creatinine ⱖ2 mg/dL History of coronary artery disease High-risk surgery (chest, abdominal or suprainguinal vascular surgery)

1 1 1 1 1

Abbreviations: TIA ⫽ transient ischemic attack; CVA ⫽ cardiovascular accident. Low risk ⫽ 0-1; moderate risk ⫽ 2; high risk ⱖ3. Event rates increase as RCRI score increases.

the relationship between perioperative beta blockade and the risk of death varied directly with cardiac risk; thus, individuals at high risk showed the greatest benefit from beta blockade, whereas those in the low to moderate risk categories showed a trend toward harm from this practice owing to bradycardia and hypotension.29 The Perioperative Ischemic Evaluation (POISE) study published in 2008 remains the largest randomized controlled trial examining the role of beta-blockers in the perioperative setting.9 The study prospectively randomized 8351 patients with or at risk for coronary artery disease scheduled to undergo noncardiac surgery into 2 arms receiving either oral extendedrelease metoprolol succinate (n ⫽ 4174) or placebo (n ⫽ 4177). The trial protocol called for administration of 100 mg of the study drug 2-4 hours before surgery, with a second dose 6 hours after surgery if prespecified hemodynamic parameters remained acceptable. Patients were then given 200 mg extended-release metoprolol 12 hours after their postoperative dose, with this regimen continued for 30 days. Results from POISE showed cardiac benefit. Fewer patients in the metoprolol group reached the primary endpoint of death, nonfatal myocardial infarction, or nonfatal cardiac arrest (244 [5.8%] vs 290 [6.9%]) than in the placebo group (hazard ratio 0.84, 95% confidence interval, 0.70-0.99, P ⫽ .0399). Additionally, fewer patients in the metoprololtreated group had a myocardial infarction (176 [4.2%] vs 239 [5.7%], hazard ratio 0.73, 95% confidence interval, 0.60-0.89, P ⫽ .0017). However, there were more deaths in the metoprolol group (129 vs 97) than placebo. Subgroup analyses indicated that the major contributor to mortality in the beta-blocker group were noncardiac deaths. In addition, significantly more patients in the metoprolol group developed ischemic stroke (41 vs 19) compared with placebo. Predictably, clinically significant hypotension and bradycardia was noted in the metoprolol group (15% and 6.6%, respectively). POISE thus demonstrated that there is significant risk in the assumption that a perioperative beta-blocker regimen has benefit without harm, illustrating that for every 1200 patients treated, metoprolol would prevent 15 myocardial infarctions at a cost of 8 excess deaths and 5 disabling strokes. In a recent meta-analysis, Devereaux et al30 reviewed 22 trials randomizing 2437 patients and reported that perioperative beta-blockers were not associated with statistically significant benefits on either individual or composite cardiovascular outcomes. Importantly, this article did confirm an increased risk of bradycardia and hypotension, and showed that the evidence for perioperative beta blockade was “insufficient and inconclusive,” especially in those at low to moderate risk of adverse cardiovascular outcomes.

DECIPHERING DIVERGENT STUDY RESULTS: EXPLANATIONS FOR CONFLICTING DATA Several aspects help explain the conflicting evidence for perioperative beta-blocker use (Table 3). First, the preoperative timing of beta blockade may have influenced study

Chopra et al Table 3

Perioperative Beta-blockers for Noncardiac Surgery

Studies Grouped According to Outcomes associated with Perioperative ␤-Blockers

Studies Showing Benefit with Perioperative ␤-Blockade Year 1988 1996 1999 1999 2000 2001

227

Investigators 23

Stone et al Mangano et al24 Raby et al44 Poldermans et al26 Urban et al42 Boersma et al43

Design R NB R DB R DB R NB R NB RP

PCT PCT PCT PCT PCT

Studies Showing Harm with Perioperative ␤-Blockade Size (n) 128 200 26 112 107 1351

Year 1988 2005 2005 2005 2008 2008

Investigators 23

Stone et al Devereaux et al30 Lindenauer et al29 DIPOM11 MaVS10 POISE9

Design

Size (n)

Nature of Harm

R NB PCT RV MA RP PCT A R DB PCT R DB PCT R DB PCT

128 2437 119,632 921 496 8351

Bradycardia requiring Rx Bradycardia requiring Rx Bradycardia and HypoTN 1 Intra-operative HypoTN 1 Intra-operative HypoTN 1 Death and 1 Stroke

Abbreviations: A ⫽ analyses; R ⫽ randomized; RP ⫽ retrospective; RV ⫽ review; NB ⫽ nonblinded; DB ⫽ double blinded; MA ⫽ meta-analyses; PCT ⫽ placebo controlled trial; Rx ⫽ treatment.

outcomes. For example, the Mangano protocol24 called for beta-blockers at induction of anesthesia, while Poldermans et al26 initiated bisoprolol at an average of 37 days before surgery. The importance of time of initiation lies in the fact that acute effects of beta blockade (decreased heart rate, systolic pressure, and reduced myocardial ischemia) may not fully explain the benefit of perioperative therapy, as anti-inflammatory and plaque-stabilizing properties take days to develop.22 Secondly, the type of beta-blocker used may have led to different study outcomes. The perioperative benefit from beta blockade is thought to arise primarily via the negative ino- and chronotropic effects through beta-1 blockade. Dual beta-1 and beta-2 receptor inhibition is unwelcome in the hyperadrenergic perioperative environment, as it would lead to unopposed alpha stimulation. This may explain why bisoprolol (highly beta-1 selective) has been associated with better results, whereas metoprolol and atenolol (moderately beta-1 selective) are associated with mixed results in clinical trials. Other drug properties such as degree of absorption, volume of distribution, plasma protein binding, and drug half-life might also contribute to study outcomes, as longer-acting agents show greater cardioprotection than short-acting agents.31 An important parameter in perioperative beta-blocker studies remains the balance between dose adjustments of drug to achieve target heart rates in relation to drug side effects. This is graphically illustrated in POISE, where the increased rate of ischemic stroke in combination with intraoperative bradycardia and hypotension suggest an overtreatment effect.32 Conversely, recent studies33,34 and a large meta-analysis35 have confirmed that heart rate control with beta-blockers avoiding hypotension is associated with improved cardiovascular outcomes. Finally, estimating baseline cardiac risk remains an important parameter in determining benefit of beta blockade. As confirmed by Lindenauer et al,29 the data have shown that beta-blockers do benefit patients with high cardiovascular risk, while harm may occur to low-risk patients. This paradigm may explain the adverse findings of MAVS, DIPOM, and POBBLE, as these patients were among the low to moderate

risk category. The 2007 American College of Cardiology/ American Heart Association Update on Perioperative Risk Reduction highlight this fact, restricting their Class I indication to those already on beta-blockers and to those with known ischemia undergoing high-risk surgery.

PERIOPERATIVE BETA-BLOCKERS: NOT QUITE READY FOR A QUALITY REVOLUTION Based on the positive results of preliminary studies, numerous regulatory agencies were quick to endorse perioperative beta blockade. The Leapfrog Group for Patient Safety, for example, promoted perioperative beta blockade as a patient safety measure in their annual report. Subsequently, the National Quality Forum, Surgical Care Improvement Project, and the Agency for Healthcare Research and Quality also issued statements of support for this measure, identifying the perioperative implementation of beta-blockers as a “clear opportunity for safety improvement in surgical outcomes.”36,37 It is well known that performance measures can serve as a catalyst for implementing quality improvement efforts.38 Thus, health care institutions have faced increased pressure in not only reporting, but also implementing perioperative beta blockade. As has been argued with the rapid implementation of other performance metrics,39 regulatory agencies may have inadvertently helped perpetuate a far wider implementation of perioperative beta blockade than was supported by the available science. We are thus reminded that performance metrics must be based on both the highest level of clinical evidence and affirmative effect on patient outcomes. Such was not the case with perioperative beta blockade. Importantly, several agencies have revised their stance on this issue.40

CONCLUSION Cumulative data over the past decade have shown that there is danger in extending the original narrow indication of perioperative beta blockade. We summarize vital clinical recommendations for the ongoing use of perioperative beta blockade in Table 4. The literature has summarily revealed

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Table 4

Clinical Recommendations for Implementing ␤-blockers in the Perioperative Setting

Recommendation

Description and Rationale

Monitor perioperative heart rate and blood pressure

Serially assess hemodynamic measures at prespecified intervals Withhold or administer beta-blocker according to preset thresholds/criteria Such an approach may help detection of issues such as hypovolemia, infection, sepsis Initiate therapy at least 7 days before operative intervention Allows for both acute (hemodynamic) and delayed (anti-inflammatory) effects of beta-blockers Promotes early recognition of adverse effects (eg, bradycardia, hypotension, bronchospasm) Heart rate control remains the major mechanism of beta-blocker benefit Helps identify and prevent perioperative bradycardia and intraoperative hypotension Can require variable doses of drug and thus allows for individualization of therapy Short vs long-acting agents, varying clinical effects based on receptor agonism IV vs PO route of administration important as IV route can rapidly precipitate side effects Tailor therapy to maintain same agent/dose(s) as in the preoperative setting Sudden withdrawal of beta-blockers known to cause upregulated beta-receptor state Class I ACC/AHA recommendation, especially if an original indication already exists Strive to maintain same agent as the preoperative setting

Implement a “run-in” phase for perioperative beta blockade

Adjust dose to achieve a target heart-rate of 60 beats per minute, avoiding hypotension

Recognize that beta-blockers differ considerably

Continue beta-blockers if already on this therapy

Abbreviations: IV ⫽ intravenous; PO ⫽ by mouth; ACC/AHA ⫽ American College of Cardiology/American Heart Association.

that attention to both patient risk and beta-blocker profile is critical to the safe and effective implementation of this therapy. Although there remains an overwhelming need for further study in this area, our best approach is captured by the truism Primum Non Nocere. First, do no harm.

11.

12.

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