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Sympatho-modulatory therapies in perioperative medicine

2004; Elsevier BV; Volume: 93; Issue: 1 Linguagem: Inglês

10.1093/bja/aeh158

1471-6771

Michael Zaugg, Christian Schulz, J. Wacker, Marcus Schaub,

Anesthesia and Sedative Agents

With increasing life expectancy and improved surgical technology an ever-larger number of elderly patients with cardiovascular disease, or significant cardiovascular risk factors will undergo major surgery. More than 5% of an unselected surgical population undergoing non-cardiac surgery will suffer from perioperative cardiovascular complications including myocardial infarction and cardiac death. The incidence of adverse cardiac events may even reach 30% in high-risk patients undergoing vascular surgery causing a substantial financial burden of perioperative health care costs.59Poldermans D Boersma E Bax JJ et al.The effect of bisoprolol on perioperative mortality and myocardial infarction in high‐risk patients undergoing vascular surgery. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group.N Engl J Med. 1999; 341: 1789-1794Crossref PubMed Scopus (1364) Google Scholar Thus, all therapeutic measures should be undertaken to reach the challenging goal of a lower incidence of perioperative cardiovascular complications. Gaining control over sympathetic nervous system activity, that is blunting the adrenergic response to the surgical trauma, traditionally represents an important aspect of anaesthetic practice.21Ebert TJ. Is gaining control of the autonomic nervous system important to our specialty?.Anesthesiology. 1999; 90: 651-653Crossref PubMed Scopus (12) Google Scholar Anaesthesiology has been regarded as the ‘practice of autonomic nervous system medicine’. While variable and moderate changes in sympathetic nervous system activity function as a servo-control mechanism and are even required to maintain and optimize cardiac performance, undue liberation of excitotoxic substances such as catecholamines and inflammatory cytokines, particularly during emergence from anaesthesia and the painful postoperative period, facilitates the occurrence of cardiovascular complications.83Zaugg M Schaub MC Pasch T Spahn DR. Modulation of β‐adrenergic receptor subtype activities in perioperative medicine: mechanisms and sites of action.Br J Anaesth. 2002; 88: 101-123Crossref PubMed Scopus (93) Google Scholar 84Zaugg M Tagliente T Lucchinetti E et al.Beneficial effects from β‐adrenergic blockade in elderly patients undergoing noncardiac surgery.Anesthesiology. 1999; 91: 1674-1686Crossref PubMed Scopus (204) Google Scholar At this point, the life-supporting adrenergic drive (‘fight-or-flight-response’) turns into a potentially hazardous life-threatening maladaptation. In support of this concept, the beneficial effects of anti-adrenergic treatment regimens in perioperative medicine have been confirmed, in observational studies, meta- analyses5Beattie W Badner N Choi P. Epidural analgesia reduces postoperative myocardial infarction: a meta‐analysis.Anesth Analg. 2001; 93: 853-858Crossref PubMed Scopus (434) Google Scholar 51Nishina K Mikawa K Uesugi T et al.Efficacy of clonidine for prevention of perioperative myocardial ischemia. A critical appraisal and meta‐analysis of the literature.Anesthesiology. 2002; 96: 323-329Crossref PubMed Scopus (119) Google Scholar 66Rodgers A Walker N McKee A et al.Reduction of postoperative mortality and morbidity with epidural or spinal anaesthesia: results from overview of randomised trials.BMJ. 2000; 321: 1-12Crossref PubMed Google Scholar and randomized controlled clinical trials.43Mangano DT Layug EL Wallace A Tateo I Multicenter Study of Perioperative Ischemia Research Group Effects of atenolol on mortality and cardiovascular morbidity after noncardiac surgery.N Engl J Med. 1996; 335: 1713-1720Crossref PubMed Scopus (1558) Google Scholar 54Oliver MF Goldman L Julian DG Holme I. Effects of mivazerol on perioperative cardiac complications during non‐cardiac surgery in patients with coronary heart disease: the European Mivazerol Trial (EMIT).Anesthesiology. 1999; 91: 951-961Crossref PubMed Scopus (182) Google Scholar 59Poldermans D Boersma E Bax JJ et al.The effect of bisoprolol on perioperative mortality and myocardial infarction in high‐risk patients undergoing vascular surgery. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group.N Engl J Med. 1999; 341: 1789-1794Crossref PubMed Scopus (1364) Google Scholar 63Raby 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: 477-482Crossref PubMed Google Scholar 80Urban 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: 1257-1261Crossref PubMed Scopus (185) Google Scholar 84Zaugg M Tagliente T Lucchinetti E et al.Beneficial effects from β‐adrenergic blockade in elderly patients undergoing noncardiac surgery.Anesthesiology. 1999; 91: 1674-1686Crossref PubMed Scopus (204) Google Scholar However, the seemingly established concept of ‘sympatholysis’ as an effective cardioprotective treatment modality needs considerable refinement in the light of the many new experimental and clinical findings. The parlance of ‘sympatholytic’ protection erroneously equates annihilation of any type of adrenergic stimulation with cardioprotection and should be replaced by ‘sympatho-modulatory’protection. The present review summarizes findings from large-scale heart failure trials and discusses basic and clinical aspects of individual sympatho-modulatory therapies, as currently used in perioperative medicine, including β-adrenergic antagonism, α2-agonism, and regional anaesthetic techniques. For limitation of space, reviews will often be cited where further references to the primary literature may be found. Over several decades, the basic ideas on the role of the sympathetic nervous system in healthy and diseased myocardium have required repeated re-evaluation. In 1960, Braunwald and colleagues at the National Institutes of Health reported for the first time on adrenergic dysfunction in the failing heart. Based on reduced noradrenaline levels in failing myocardial tissue and the adverse short-term effects of high doses of anti-adrenergic agents,25Gaffney TE Braunwald EB. Importance of the adrenergic nervous system in the support of circulatory function in patients with congestive heart failure.Am J Med. 1963; 34: 320-324Abstract Full Text PDF PubMed Scopus (145) Google Scholar it became widely accepted that sufficient and—in the case of heart failure—supportive adrenergic drive would be needed to ensure normal cardiac function. Fifteen years later in the late 1970s, this therapeutic concept was challenged by the following findings summarized in reference13Bristow MR. Beta‐adrenergic receptor blockade in chronic heart failure.Circulation. 2000; 101: 558-569Crossref PubMed Scopus (936) Google Scholar. First, chronically administered β-adrenergic antagonists (β-AAs) exhibited beneficial effects in idiopathic dilated cardiomyopathies. Secondly, β-adrenergic receptor (β-AR) down-regulation was detected in failing myocardium as a consequence of excessive adrenergic drive. Thirdly, despite decreased noradrenaline stores in failing myocardial tissue, coronary sinus blood exhibited increased noradrenaline release. These findings led to a new ‘counterintuitive’ therapeutic strategy whereby anti-adrenergic treatment was considered beneficial in the failing heart. This concept has dominated therapeutic thinking in cardiology for almost 20 years. However, most recent results from basic science and clinical studies again questioned this ‘dogma’ and called for further refinement of the concept.12Bristow MR. Antiadrenergic therapy of chronic heart failure. Surprises and new opportunities.Circulation. 2003; 107: 1100-1102Crossref PubMed Scopus (79) Google Scholar First, moxonidine, a centrally active imidazoline agonist, which lowers noradrenaline spill-over in myocardial tissue and even reverses catecholamine-induced remodelling in the myocardium, increased mortality by more than 50% in the Moxonidine Congestive Heart Failure Trial (MOXCON).17Coats AJ. Heart failure 99; the MOXCON story.Int J Cardiol. 1999; 71: 109-111Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar This is in accordance with experimental results from a canine heart failure model where dopamine β-hydroxylase inhibition resulting in decreased noradrenaline levels did not improve left ventricular function.69Sabbah HN Stanley WC Sharov VG et al.Effects of dobutamine beta‐hydroxylase inhibition with nepicastat on the progression of left ventricular dysfunction and remodeling in dogs with chronic heart failure.Circulation. 2002; 102: 1990-1995Crossref Scopus (47) Google Scholar Secondly, in the β-Blocker Evaluation of Survival Trial (BEST), bucindolol increased mortality disproportionately in black NYHA Class IV patients, although the overall benefit of bucindolol still prevailed in the whole bucindolol cohort when compared with placebo.6BEST Trial Investigators A trial of the beta‐adrenergic blocker bucindolol in patients with advanced heart failure.N Engl J Med. 2001; 344: 1659-1667Crossref PubMed Scopus (977) Google Scholar It was speculated that pronounced β2-AR antagonism, which excessively decreases pre-synaptic noradrenaline release, in conjunction with unopposed α1-block could be responsible for the observed adverse effects. Collectively, these findings seriously challenged the overly simple dogma of ‘sympatholytic equals beneficial’. Irreversible removal of adrenergic support with the inability to recruit compensatory adrenergic drive when required to maintain adequate cardiac function is obviously detrimental. Moreover, these observations highlight the fundamentally differential biological consequences between ‘unselective inhibition of adrenergic drive’, which may be achieved by central inhibition of the sympathetic tone vs selective peripheral receptor-targeted block. Hyperadrenergic drive is a hallmark of the perioperative stress response. Maladaptive alterations in the autonomic nervous system, such as down-regulation of adrenergic receptors and autonomic imbalance, persist for weeks after surgery.1Amar D Fleisher M Oantuck CB et al.Persistent alterations of the autonomic nervous system after noncardiac surgery.Anesthesiology. 1998; 89: 30-42Crossref PubMed Scopus (50) Google Scholar Activation of the sympathetic nervous system, particularly β-ARs dramatically increases heart rate and oxygen consumption, and plays a central role in the development of perioperative ischaemia. Patients with coronary artery disease, risk factors for coronary artery disease or specific genetic polymorphisms may be particularly sensitive to catecholamine toxicity and prone to perioperative ischaemia and cardiac complications. Current knowledge suggests significant protection from maladaptive adrenergic activity by selective inhibition and/or activation of specific β/α-AR subtypes.83Zaugg M Schaub MC Pasch T Spahn DR. Modulation of β‐adrenergic receptor subtype activities in perioperative medicine: mechanisms and sites of action.Br J Anaesth. 2002; 88: 101-123Crossref PubMed Scopus (93) Google Scholar Identification of patients with critical genetic polymorphisms associated with adverse outcome as part of perioperative risk assessment may directly improve patient management by adequate timely pharmacological interventions and decrease perioperative mortality. Unfortunately, at present the pharmacological armamentarium is still limited with respect to receptor-subtype selectivity. Pan-adrenergic inhibition of the sympathetic nervous system may not represent the optimal cardioprotective treatment modality in perioperative medicine. Irreversible removal of adrenergic support with the inability to maintain adequate cardiac function may be detrimental. Basic mechanisms and cardiovascular effects α2-Agonists exert their cardioprotective effects predominantly by attenuation of catecholamine release and thus inhibition of stress-induced tachycardia. The hypotensive effect of this class of drugs is achieved by lowering central sympathetic tone via activation of α2A-ARs and the pharmacologically less well-defined imidazoline1 receptors. This is consistent with the notion that clonidine is ineffective in controlling increased arterial pressure in hypertensive tetraplegic patients.44Mathias CJ Wing LM Frankel HL Christensen NJ. Antihypertensive effects of clonidine in tetraplegic subjects devoid of central sympathetic control.Clin Sci. 1979; 57: 425-428Crossref PubMed Google Scholar In contrast, bradycardic effects are elicited by vagomimetic effects, and are preserved in tetraplegic patients.64Reid JL Wing LM Mathias CJ Frankel HL Neill E. The central hypotensive effects of clonidine—studies in tetraplegic subjects.Clin Pharmacol Ther. 1977; 21: 375-381Crossref PubMed Scopus (77) Google Scholar Apart from their haemodynamic effects, α2-agonists may induce analgesia (particularly for sympathetically maintained pain), anxiolysis, and sedation.32Kamibayashi T Maze M. Clinical uses of alpha2‐adrenergic agonists.Anesthesiology. 2000; 93: 1345-1349Crossref PubMed Scopus (633) Google Scholar 34Khan ZP Ferguson CN Jones RM. Alpha‐2 and imidazoline receptor agonists.Anaesthesia. 1999; 54: 146-165Crossref PubMed Scopus (539) Google Scholar Post-junctional α2B-ARs mediate the short-term hypertensive response seen with these drugs via stimulation of L-type Ca2+ channels in smooth muscle cells of resistance vessels. Recently, etomidate was found to activate α2B-ARs thereby eliciting its well-known stabilizing cardiovascular effect.55Paris A Philipp M Tonner PH et al.Activation of α2B‐adrenoceptors mediates the cardiovascular effects of etomidate.Anesthesiology. 2003; 99: 889-895Crossref PubMed Scopus (73) Google Scholar Pre-junctional α2A-ARs have anti-adrenergic effects, and post-junctional α2A-ARs have anaesthetic effects via inhibition of L-type Ca2+ channels in neurons localized in the locus coeruleus and nucleus reticularis lateralis. Decreased ganglionic transmission and a concomitant increase of the counterregulatory vagal tone can further enhance the central effects of α2-agonist.45McCallum JB Boban N Hogan Q Schmeling WT Kampine JP Bosnjak ZJ. The mechanism of alpha2‐adrenergic inhibition of sympathetic ganglionic transmission.Anesth Analg. 1998; 87: 503-510PubMed Google Scholar Interestingly, the anti-arrhythmic effects of α2-agonists are completely mediated via the vagal nerve, as anti-arrhythmic effects are totally abolished by vagotomy.30Hayashi Y Maze M. Drugs affecting adrenoceptors: alpha2‐agonists.in: Bowdle TA Horita A Kharasch ED The Pharmacologic Basis of Anaesthesiology. Churchill Livingstone, New York1994: 602-623Google Scholar One of the potential advantages of central inhibition of sympathetic tone over peripheral receptor block is that the release of co-transmitters such as neuropeptide-Y, a major contributor to coronary vascular resistance, is equally suppressed. On the other hand, these neurotransmitters may exert trophic effects on cardiomyocytes. All α2-agonists interact with imidazoline receptors because of their imidazole ring. Although the novel α2-agonist moxonidine was developed to preferentially interact with imidazoline binding sites, it requires the α2-AR to lower arterial pressure as no hypotensive effects in response to moxonidine were observed in α2-AR knockout mice.78Tan CM Wilson MH MacMillan LB Kobilka BK Limbird LE. Heterozygous alpha2A‐adrenergic receptor mice unveil unique therapeutic benefits of partial agonists.Proc Natl Acad Sci USA. 2002; 99: 12471-12476Crossref PubMed Scopus (58) Google Scholar As with β-ARs, α-ARs can be up- or down-regulated.74Smiley RM Kwatra MM Schwinn DA. New developments in cardiovascular adrenergic receptor pharmacology: molecular mechanisms and clinical relevance.J Cardiothorac Vasc Anesth. 1998; 12: 80-95Abstract Full Text PDF PubMed Scopus (32) Google Scholar However, their regulation and the subsequent physiological consequences are poorly understood. Unfortunately, there are no subtype-selective agonists clinically available. At present, the most commonly used α2-agonists are clonidine and dexmedetomidine. Their relative receptor specificities as compared with other α2-agonists are listed in Table 1.Table 1α2-Agonists and specific properties. +=effect present; I1*=centrally located imidazoline receptor-1; /=not knownDrugSelectivity ratio of α2/α1Selectivity ratio of α2/I1*Plasma half-lifeLipid solubilityClearanceSpecialClonidine40169 h+Hepatic/renal }SedativeMivazerol4002154 h+Hepatic/renalAnalgesicDexmedetomidine1600302 h+Hepatic/renalAnti-shiveringMoxonidine/702 h+Hepatic/renalAnti-sialogueNeuromuscular blocking agents Open table in a new tab Clinical aspects and considerations A recent meta-analysis on the efficacy of clonidine for the prevention of perioperative myocardial ischaemia included seven studies and concluded that clonidine reduces cardiac ischaemic events in patients who either have or are at risk of coronary artery disease, without increasing the incidence of bradycardia.51Nishina K Mikawa K Uesugi T et al.Efficacy of clonidine for prevention of perioperative myocardial ischemia. A critical appraisal and meta‐analysis of the literature.Anesthesiology. 2002; 96: 323-329Crossref PubMed Scopus (119) Google Scholar Interestingly, this meta-analysis found a reduction in myocardial ischaemia by clonidine in cardiac and non-cardiac surgery, but only in the oral (mostly preoperative), but not the i.v. administration group. Mortality associated with myocardial ischaemia was not evaluated in this meta-analysis because of the expected low number of myocardial infarctions and cardiac deaths. Another recent meta-analysis included studies with all α2-agonists claimed a lower cardiac morbidity in high-risk patients undergoing vascular and major surgery.82Wijeysundera DN Naik JS Beattie WS. Alpha‐2 adrenergic agonists to prevent perioperative cardiovascular complications: a meta‐analysis.Am J Med. 2003; 114: 742-744Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar Clonidine has also been found to decrease anaesthetic-induced impairment of the baroreflex responses and thus to attenuate arterial pressure lability (smaller haemodynamic fluctuations around a lower basal arterial pressure).57Parlow JL Bégou G Sagnard P et al.Cardiac baroreflex during the postoperative period in patients with hypertension.Anesthesiology. 1999; 90: 681-692Crossref PubMed Scopus (40) Google Scholar Similarly, perioperative mivazerol has been reported to decrease the occurrence of perioperative ischaemic events, and recently to decrease cardiac death (9.5 vs 14% in placebo, P=0.02), but not myocardial infarction, in patients with coronary artery disease undergoing vascular surgery.54Oliver MF Goldman L Julian DG Holme I. Effects of mivazerol on perioperative cardiac complications during non‐cardiac surgery in patients with coronary heart disease: the European Mivazerol Trial (EMIT).Anesthesiology. 1999; 91: 951-961Crossref PubMed Scopus (182) Google Scholar However, there was no effect of mivazerol on the incidence of all-cause deaths, cardiac deaths, or myocardial infarctions in the whole cohort of study patients (undergoing all types of surgery). There is currently less evidence for α2-agonists than β-AA to decrease perioperative cardiovascular mortality. However, apart from their cardiovascular effects, α2-agonists may exert indirect beneficial cardiac effects by their non-ceiling analgesic, anti-shivering, and sedative effects. Sudden discontinuation should be avoided because of the risk of withdrawal syndrome.83Zaugg M Schaub MC Pasch T Spahn DR. Modulation of β‐adrenergic receptor subtype activities in perioperative medicine: mechanisms and sites of action.Br J Anaesth. 2002; 88: 101-123Crossref PubMed Scopus (93) Google Scholar Theoretically, α2-agonists can jeopardize coronary flow reserve, as intracoronary application of α2-antagonist yohimbine was shown to attenuate inhibition of coronary flow in patients undergoing coronary culprit lesion stenting.27Gregorini L Marco J Farah B et al.Effects of alpha1‐ and alpha2‐adrenergic blockade on coronary flow reserve after coronary stenting.Circulation. 2002; 106: 2901-2909Crossref PubMed Scopus (72) Google Scholar Conversely, α-adrenergic vasoconstriction reduces systolic retrograde coronary blood flow maintaining sufficient perfusion in subendocardial myocardium during adrenergic stimulation.48Morita K Mori H Tsujioka K et al.Alpha‐adrenergic vasoconstriction reduces systolic retrograde coronary blood flow.Am J Physiol. 1997; 273 (2H2755): 2H2746Google Scholar Bradycardia as a side-effect should be primarily treated with atropine, but higher doses of clonidine can markedly blunt the effect of atropine.49Nishikawa T Dohi S. Oral clonidine blunts the heart rate response to intravenous atropine in humans.Anesthesiology. 1991; 75: 217-222Crossref PubMed Scopus (34) Google Scholar Conversely, clonidine may significantly potentiate the pressor effects of catecholamines.50Nishikawa T Kimura T Taguchi N Dohi S. Oral clonidine preanesthetic medication augments the pressor response to intravenous ephedrine in awake or anesthetized patients.Anesthesiology. 1991; 74: 705-710Crossref PubMed Scopus (52) Google Scholar At higher concentrations, α2-agonists may promote coagulation.79Theodorou AE Mistry H Davies SL Yamaguchi Y Horton RW. Platelet alpha2‐adrenoceptor binding and function during the menstrual cycle.J Psychiatr Res. 1987; 21: 163-169Abstract Full Text PDF PubMed Scopus (17) Google Scholar Although detrimental cardiac effects were reported after long-term use of α2-agonists in heart failure patients, the short-term use of α2-agonists at moderate doses (thrombotic complications are possible with high doses) in perioperative medicine can be advocated. Nonetheless, more selective modulation of α2-ARs would be highly desirable. Basic mechanisms and cardiovascular effects Although some effects of β-AAs may be caused by central actions,72Shyong EQ Lucchinetti E Tagliente TM Hossain S Silverstein JH Zaugg M. Interleukin balance and early recovery from anesthesia in elderly surgical patients exposed to beta‐adrenergic antagonism.J Clin Anesth. 2003; 15: 170-178Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar 85Zaugg M Tagliente T Silverstein JH Lucchinetti E. Atenolol may not modify anesthetic depth indicators in elderly patients—a second look at the data.Can J Anesth. 2003; 50: 638-642Crossref PubMed Scopus (21) Google Scholar β-AAs in principle mediate their effects directly at the end-organ receptor level by decreasing β-AR signalling. This is fundamentally different from most of the α2-agonist-mediated effects. Important mechanisms responsible for β-AA-mediated perioperative cardioprotection are:83Zaugg M Schaub MC Pasch T Spahn DR. Modulation of β‐adrenergic receptor subtype activities in perioperative medicine: mechanisms and sites of action.Br J Anaesth. 2002; 88: 101-123Crossref PubMed Scopus (93) Google Scholar •Blunting of stress-induced increases in heart rate optimizing myocardial oxygen balance and stabilizing atherosclerotic plaques.•Improved Ca2+ handling and bioenergetics shifting ATP production from oxidation of free fatty acid to less oxygen consuming glucose oxidation.•Prevention of target protein hyperphosphorylation leading to decreased receptor desensitization and diastolic Ca2+ leackage by the ryanodine receptor.•Inhibition of β1-AR-mediated cytotoxicity (altered gene expression, mechanical unloading, apoptosis, necrosis).•Anti-arrhythmic effects. In contrast to α2-agonists, untoward peripheral effects of β-AAs can be offset by counter-regulatory production of endogenous catecholamines explaining the good tolerability of this class of drugs.26Gottlieb SS Fisher ML Kjekshus J et al.Tolerability of beta‐blocker initiation and titration in the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT‐HF).Circulation. 2002; 105: 1182-1188Crossref PubMed Scopus (75) Google Scholar 43Mangano DT Layug EL Wallace A Tateo I Multicenter Study of Perioperative Ischemia Research Group Effects of atenolol on mortality and cardiovascular morbidity after noncardiac surgery.N Engl J Med. 1996; 335: 1713-1720Crossref PubMed Scopus (1558) Google Scholar 59Poldermans D Boersma E Bax JJ et al.The effect of bisoprolol on perioperative mortality and myocardial infarction in high‐risk patients undergoing vascular surgery. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group.N Engl J Med. 1999; 341: 1789-1794Crossref PubMed Scopus (1364) Google Scholar 84Zaugg M Tagliente T Lucchinetti E et al.Beneficial effects from β‐adrenergic blockade in elderly patients undergoing noncardiac surgery.Anesthesiology. 1999; 91: 1674-1686Crossref PubMed Scopus (204) Google Scholar On the other hand, direct receptor block may be more cytoprotective under supramaximal autonomic stimulation (flat part of the sigmoid dose–response curve) than simply lowering catecholamine levels as observed with α2-agonist treatment. Finally, selective inhibition of the β1-AR-mediated toxic effects leaves the beneficial effects of moderate β2-AR-stimulation unaffected and thus may further improve haemodynamic tolerance.83Zaugg M Schaub MC Pasch T Spahn DR. Modulation of β‐adrenergic receptor subtype activities in perioperative medicine: mechanisms and sites of action.Br J Anaesth. 2002; 88: 101-123Crossref PubMed Scopus (93) Google Scholar Notably, β1-AR antagonism enhances inotropic response to β2-AR stimulation.29Hall JA Kaumann AJ Brown MJ. Selective α1‐adrenoceptor blockade enhances positive inotropic responses to endogenous catecholamines mediated through β2‐adrenoceptors in human atrial myocardium.Circ Res. 1990; 66: 1610-1623Crossref PubMed Scopus (156) Google Scholar β1-AR-block may increase post-ischaemic and pharmacologic coronary flow velocity reserve.7Billinger M Seiler C Fleisch M Eberli FR Meier B Hess OM. Do beta‐adrenergic blocking agents increase coronary flow reserve?.J Am Coll Cardiol. 2001; 38: 1866-1871Crossref PubMed Scopus (54) Google Scholar Although many ancillary properties of individual β-AAs are thought to be linked to clinical effectiveness and tolerability,75Soriano JB Hoes AW Meems L Grobbee DE. Increased survival with β‐blockers: importance of ancillary properties.Prog Cardiovasc Dis. 1997; 39: 445-456Abstract Full Text PDF PubMed Scopus (73) Google Scholar their significance in perioperative medicine needs to be elucidated. The selection of a specific agent over another on the basis of individual drug profiles may be advantageous in specific clinical situations (Table 2). As with clonidine, β-AAs improve the baroreflex sensitivity in elderly hypertensive patients, thus stabilizing arterial pressure.16Cleophas TJ Grabowsky I Niemeyer MG Mäkel WM van der Wall EE Nebivolol Follow‐Up Study Group Paradoxical pressor effects of beta‐blockers in standing elderly patients with mild hypertension. A beneficial side effect.Circulation. 2002; 105: 1669-1671Crossref PubMed Scopus (29) Google ScholarTable 2β-AAs and ancillary properties. NO, nitric oxide; +=effect present; –=effect absent; ?=still under debateDrugSelectivity ratio of β1/β2Membrane stabilizing activityIntrinsic sympatho-mimetic activityLipid solubilityClearanceSpecialPropranolol2.1+–+++HepaticInverse agonistMetoprolol74––+Hepatic stereoselectiveInverse agonist-ARAtenolol75–––Renal–Esmolol70–––Erythrocyte esterase–Bisoprolol119––(+)Hepatic/renal–Celiprolol≈300–β2+–Hepatic/renalβ2-agonistNebivolol293––+HepaticNO-release bronchodilationCarvedilol7.2–β1+(?)+Hepatic, stereo-selectiveAnti-oxidant, anti-adhesive. α1-antagonist, β-AR↓Bucindolol1.4–+ (?)+Hepaticα1-antagonist Open table in a new tab Clinical aspects and considerations The evidence for the effectiveness of β-AAs in reducing perioperative cardiac events has been extensively reviewed.2Auerbach AD Goldman L. Beta‐blockers and reduction of cardiac events in noncardiac surgery.JAMA. 2002; 287: 1435-1447Crossref PubMed Google Scholar 62Priebe HJ. Perioperative beta‐blocker therapy.Anesth Analg. 2003; (Review Course Lectures Supplement): 60-65Google Scholar Based on the clinical evidence of mainly two well-designed randomized clinical trials,43Mangano DT Layug EL Wallace A Tateo I Multicenter Study of Perioperative Ischemia Research Group Effects of atenolol on mortality and cardiovascular morbidity after noncardiac surgery.N Engl J Med. 1996; 335: 1713-1720Crossref PubMed Scopus (1558) Google Scholar 59Poldermans D Boersma E Bax JJ et al.The effect of bisoprolol on perioperative mortality and myocardial infarction in high‐risk patients undergoing vascular surgery. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group.N Engl J Med. 1999; 341: 1789-1794Crossref PubMed Scopus (1364) Google Scholar the perioperative use of β-AAs has been firmly supported in the updated (2002) guidelines on perioperative evaluation of patients undergoing non-cardiac surgery of the American Heart Association (AHA).20Eagle KA Berger PB Calkins H et al.ACC/AHA guideline up‐date on perioperative cardiovascular evaluation for noncardiac surgery: a report of the ACC/AHA Task Force on Practice Guidelines (Committee to Update the 1996 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery).Circulation. 2002; 105: 1257-1267Crossref PubMed Scopus (79) Google Scholar Mangano and colleagues showed in a cohort of elderly male patients with coronary artery disease or at risk of coronary artery disease undergoing major surgery (predominantly abdominal and vascular) that perioperative atenolol administration decrea