Optimization of Perioperative Beta-Blockade in Patients Undergoing Operation for Peripheral Vascular Disease

Introduction

The emergence of vascular surgery as a multidisciplinary specialty in its own regard has allowed significant advances in the diagnosis, medical management and operative techniques applied to patients with peripheral occlusive and aneurysmal vascular disease. However, its increasing effectiveness in the treatment of circulatory disorders continues to be tempered by the fact that functional status and longevity after successful intervention are often determined by coronary co-morbidity.¹ Indeed, the inherent cardiac stress induced by surgery may provoke ischemic events perioperatively that markedly affect overall outcome. The 30-day postoperative mortality rates for elective vascular surgery range between 2.1%² and 8%³, while perioperative myocardial infarction (MI) rates range between 3%⁴ and 17%.⁵ Furthermore, it has been shown that long-term outcomes are also significantly affected by perioperative events, with one study showing that an episode of myocardial ischemia within 48 hours of surgery is associated with a doubling of the risk of death over the next two years.⁶ Pre-operative cardiac assessment and optimization of patients scheduled for elective major vascular surgery, however, permits the opportunity to favorably address both immediate and long-term cardiac risk.⁷ Although the benefits of perioperative b-blockade in high-risk patients undergoing major non-cardiac vascular surgery have now been clearly established by prospective cohort studies^5,8,9, it remains underutilized as a cardioprotective strategy with only 40% using it routinely in clinical practice.^10–12 This is somewhat surprising considering the fact that surgical stress can invoke myocardial ischemia and result in high levels of early cardiac morbidity and mortality^13–15 has been a major driving factor in the development of endovascular surgical approaches. The underlying reasons for this may relate both to an under-appreciation of the positive effects of b-blockers as well as to traditional concerns over supposed contraindications. This concern leads to a lack of clarity over harm:benefit ratios on an individualized basis. This article aims to clarify and dispel some of the concerns relating to these issues. As implementation rates are not necessarily improved by anesthetic pre-assessment (despite awareness)^16,17 and patients benefit from a period of pre-treatment with this medication prior to intervention, it behooves all physicians involved in the care of patients with peripheral vascular disease (PVD) to be actively aware in this regard.

Why Should Beta-Blockade be Instituted Perioperatively?

Approximately 40% of vascular surgical patients have significant ischemic episodes during their procedure, with the average duration of these events exceeding 10% of the total operative time.¹⁸ While traditional cardiac risk factors (hypertension, hypercholesterolemia, smoking and diabetes mellitus) all require redress prior to scheduling elective surgery, minimization of cardiac stress perioperatively is being increasingly recognized as an important means for avoiding cardiac ischemia and infarction. Although the effects of various medications, including a-2 antagonists, nitrates and calcium channel blockers have been proposed to reduce perioperative cardiac morbidity and mortality, perioperative cardioselective b-blockade has emerged as the most effective agent to date. Recently, Poldermans et al. have demonstrated a 91% drop in the perioperative risk of MI or death from cardiac causes in high-risk patients (i.e., those with inducible ischemia preoperatively) undergoing vascular procedure.⁵ The benefits due to prolonged b-blockade in this study persisted over the first two postoperative years. The results of another randomized study also support the long-term effects of b-blockade usage in the perioperative period,¹⁹ while early beneficial effects on myocardial ischemia and infarction rates as well as mortality have been endorsed by a recent meta-analysis.²⁰ Therefore, consideration of all patients for initiation or augmentation of b-blocker therapy prior to operation should now be standard practice in vascular surgical units.

How Do b-Blockers Modulate Perioperative Risk?

Effective b-blockade provides perioperative cardioprotection by exerting both direct hemodynamic effects (i.e., controlling the tachycardia which may be provoked by general anesthesia and surgery by such stresses as endotracheal intubation and extubation^21,22, perioperative pain, hypovolemia, hypothermia and hypoxia) and indirect effects on shear stress forces in circulatory flow as well on inflammatory responses affected by catecholamine release and sympathetic tone. The reduction in heart rate facilitates ventricular filling as well as diastolic perfusion time, so coronary oxygen delivery is improved while reduced contractile effort diminishes myocardial demand. The autonomic effects on flow dynamics may promote plaque stability and alter the incidence and significance of plaque rupture. Furthermore, b-blockers may augment collateral flow (although this is controversial) and act to limit arrhythmic tendencies that may be potentiated by myocardial stress. Lastly, the lipophilic quality of b-blockers may allow for their penetration through the blood-brain barrier, allowing the exertion of central nervous effects that may allow reduced amount of anesthetic agent and so promote postoperative recovery.^23,24

Who Should Receive b-Blockade Perioperatively?

Although many patients presenting for vascular surgery may already have an obvious cardiac indication for b-blocker therapy (e.g., prior MI), only approximately 30% of such patients are actually already prescribed this medication.¹⁰ Therefore, considering the institution of the drug first requires assessment of the patient’s known past medical history. For those without a pre-existing indication, the decision to operate should prompt consideration of this as a “de novo” indication for b-blockade. Currently, the available evidence only definitively supports the efficacy of b-blockade in those at high-risk of coronary artery disease (CAD).^9,25,26 However, it may be difficult to accurately select such patients preoperatively. Exercise electrocardiogram (ECG) testing only detects an underlying tendency to stress-invoked myocardial ischemia with a sensitivity of 88% and specificity of 66% and additional practical limitations often undermine its utility. The patient must be ambulatory and capable of reaching maximum exercise (often difficult in the setting of PVD and concurrent obstructive airways disease) or the sensitivity of this investigation is markedly reduced. Exercise stress testing specificity is impaired if a resting ECG shows evidence of prior ischemic changes (in particular ST segment and T wave changes) or if the patient is on digoxin medication. Despite initial favorable data, dipyridamole thalium stress testing is also now known to have limited clinical value. Its sensitivity and specificity in moderate-risk patients in whom two or more reversible perfusion defects are identified are only in the region of 11% and 90%, respectively.²⁷ While dobutamine stress echocardiography is a promising investigation in predicting cardiac risk, its widespread use is not yet fully validated.²⁸ Even though selected patients who undergo pre-operative percutaneous transluminal coronary angioplasty and coronary artery bypass grafting have improved postoperative outcomes,^29,30 the indications for the use of coronary angiography in pre-operative assessment and optimization remain controversial. Furthermore, as the greatest benefits tend to accrue to those patients who had had the procedure performed more than three months prior to their surgical intervention, such revascularization may not be a useful means of improving cardiac risk in the short term. Therefore, the use of coronary revascularization in the pre-operative period should be individualized to each patient, as efficacy on a broader level is not yet clear. Six risk factors predictive of adverse perioperative cardiac events specific for patients undergoing vascular surgery have, however, been elucidated using multivariate analysis by Eagle et al.³⁰ Adverse cardiac events occur at a rate of 3.1%, 15.5% and 50% in patients with up to 3 or more risk factors. In addition to such patient-defined risk assignment, certain vascular operations have different operative risk of adverse cardiac events. Carotid endarterectomy is assigned an intermediate risk, while all open surgery on the aorta is deemed high risk for cardiac events. However, measures aimed at more exactly quantifying an individual’s risk remain limited, therefore, identifying every single patient likely to benefit from beta blockade is problematic. Nonetheless, it is reasonable to assume all patients with PVD possess a significant degree of underlying cardiac artery disease (whether occult or manifest). Indeed, this stance is supported by the Joint British Recommendations for the Prevention of Coronary Heart Disease statement that recommends that patients with PVD should be managed in a similar way to those with CAD. In this regard, it is well established that b-blockade in patients with known coronary disease is likely to be beneficial or is at worst neutral. Additionally, while a non-selective strategy of b-blockade prior to intervention may theoretically provoke or exacerbate symptoms in certain patients, selective withholding of this therapy necessarily exposes some patients to potentially avoidable intraoperative cardiac ischemia and perhaps infarction. It is with this in mind that some experts advise that b-blocker therapy be administered to all patients with one or more risk factors correlated with increased risk of cardiac complication.³¹

Who Should Not Receive b-Blockade Perioperatively?

Although definite contraindications do exist for the use of b-blockers (in particular brittle diabetic control, strongly reactive airway disease and heart block in the absence of a cardiac pacemaker), some misperceptions persist. Indeed, many physicians still allow the possibility of a theoretical side-effect of the medication to dissuade them from effectively reducing perioperative ischemia with b-blockade. This seems particularly true for those with mild to moderate chronic obstructive pulmonary disease (COPD), because traditional teaching cautions that b-blockers may precipitate bronchospasm in these groups. However, concern also exists in patients with severe peripheral vascular disease that unopposed a-adrenergic vasoconstriction may increase PVD. Furthermore, it remains unclear how the perioperative institution of b-blockade may affect the categorization of a patient’s symptom severity, operative risk and postoperative outcome as both pulmonary function testing and ankle/brachial index measurement are a standard part of selection and assessment for operative intervention^32,33, as well as to aid in the selection of the most appropriate management strategy (i.e., whether surgery or medical management is appropriate as well as whether open or endovascular techniques are preferable). Publications aiming to dispel some of these historical concerns are increasing in number. Recent, small prospective studies have shown, however, that beta blockers are safe in patients with moderate COPD34 as well as in those with COPD and concomitant CAD³⁵, while a large meta-analysis has shown that these medications are well tolerated in the majority of patients overall with COPD (although careful titration may be required in certain patients). A meta-analysis of five studies concluded that b-blockers have no effect on pain-free walking distance and perfusion of calf muscles of patients with PVD³⁷, while Ubbink et al. demonstrated that b-blockade does not appear to affect the microcirculation of patients with PVD.³⁸ Recently, our group has reinforced these findings by demonstrating that neither a significant drop in forced expiratory volume1 nor in ankle and brachial index occurs in patients prescribed a b-blocker in the perioperative period.

How Should Perioperative b-Blockade Be Instituted

Cardioselective b-antagonists are routinely advocated in order to minimize the incidence of adverse effects outside the cardiovascular system (although no such agent has proven to be entirely b1 specific). While bisoprolol was the initial agent studied, metoprolol is now considered more suitable as its short half life allows quicker dose titration. However, there is no compelling evidence to select one b-blocker in preference to another,⁹ and a variety of protocols have been determined to be cost-effective.³⁹ Preoperative doses may need to be adjusted to keep the resting heart rate less than 60 beats per minute (diastolic perfusion time is intimately related to heart rate in an inverse fashion). The medication should be commenced at least seven days prior to surgery (preferable as soon as surgery is considered necessary) and discontinued approximately 30 days following surgery in those without ongoing indications. Oral therapy should be discontinued in a tapered fashion as hyperadrenergic rebound can occur on withdrawal. In conclusion, consideration of implementation of b-blockade perioperative in all patients with vascular disease enables appropriate care of the entire patient and leads to a more favorable outcome after site-specific surgery. Although the decision to institute such therapy in certain patients may require a tailored approach, institutional guidelines and protocols should be established to promote and facilitate adoption of this efficacious strategy.