1Department of Anesthesiology, University Hospital Zurich, Rämistrasse 100, CH-8091 Zurich, Switzerland. 2Institute of Pharmacology and Toxicology, University of Zurich, Switzerland. 3Department of Anesthesiology, University Hospital Lausanne, Switzerland*Corresponding author
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Abstract |
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Br J Anaesth 2002; 88: 10123
Keywords: sympathetic nervous system, adrenergic block; complications, side-effects; heart, heart rate, perioperative; heart, cardioprotection; sympathetic nervous system, beta-adrenergic receptor
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Choice of literature |
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Clinical uses of perioperative ß-adrenergic antagonists |
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In spite of this overwhelming evidence, ß-AAs are underused in current clinical practice, and physicians prescribe ß-AAs only to approximately 50% of patients qualifying for this therapy.21 122 130 242 Notably, medical contraindications do not appear to explain the low use of ß-AAs, and it has been speculated that pharmaceutical industry competitiveness may have contributed to it by leading to exaggeration of the side-effects of ß-AAs (harmful lipid profile, decreased sexual function, potential for precipitating congestive heart failure, decreased exercise performance).112 210 The proof of the concept of ß-adrenergic antagonism in cardioprotection, however, is now also firmly established in patients with coexisting disease states that were traditionally considered as contraindications. Particularly, patients older than 80 yr with heart failure (ejection fraction less than 20%), non-Q-wave infarction, diabetes or chronic obstructive pulmonary disease have a disproportionate high benefit from postinfarction ß-adrenergic antagonism.74 205 Therefore, anaesthetists should assume the role of primary caregivers and initiate treatment with ß-AAs in surgical patients with well-defined indications for ß-AAs who are admitted to the hospital without proper treatment.78 232
Because gaining control over the autonomous nervous system constitutes a significant part of perioperative medicine,59 184 ß-adrenergic antagonism has been used traditionally to maintain blood pressure and heart rate within baseline values in various perioperative settings. In particular, ß-AAs were successfully used to blunt haemodynamic responses to intubation,44 154 at the time of emergence caused by decreasing anaesthetic depth,67 and during electroconvulsive therapy.46 262 High-dose ß-AA treatment is used to maintain deliberate hypotensive anaesthesia,105 219 and has been used most recently to enable multiple-vessel coronary artery bypass grafting (CABG) on the beating heart.170 152 Esmolol-enriched normothermic blood also resulted in better myocardial protection compared with crystalloid cardioplegia in patients undergoing CABG surgery.19 In addition, perioperative ß-AAs reduce the incidence of atrial fibrillation after cardiac surgery,94 191 as well as after thoracotomy for lung resection.100 Nonetheless, it was not until the late 1970s that it became generally accepted that patients taking ß-AAs preoperatively should be continued on ß-AA treatment perioperatively. In one study, Slogoff and colleagues202 reported pre-bypass ischaemia in patients undergoing CABG surgery in 26% of patients with propranolol treatment continued in full dosage until operation, in 50% of patients with propranolol withdrawal and in 70% of patients with no ß-AA treatment.
Administration of perioperative ß-AAs controls haemodynamic variables and successfully decreases the incidence of ischaemic events in patients with or at risk of coronary artery disease. This is particularly relevant as patients with perioperative ischaemia have a nine-fold increase in the risk of developing a serious adverse cardiac outcome during hospitalization and more than a two-fold increase in the risk of dying prematurely over the first 6 months after surgery.140 Patients with a postoperative in-hospital myocardial infarction have a 28-fold increase in the rate of subsequent cardiac complications within 6 months, a 15-fold increase within 1 yr and a 14-fold increase within 2 yr. Stone and colleagues212 administered a single oral preoperative dose of one of three different ß-AAs (labetalol, oxprenolol, atenolol) to patients with mild uncontrolled hypertension undergoing non-cardiac surgery. The incidence of myocardial ischaemia was 28% in the untreated controls compared with 2% in the ß-AA-treated patients, based on ECG criteria (P<0.001). Wallace and colleagues231 administered i.v. atenolol preoperatively and i.v. and oral atenolol for up to 7 days postoperatively in patients with or at risk of coronary artery disease. Myocardial ischaemia was assessed by continuous three-lead Holter monitoring. Intraoperative myocardial ischaemia was reported to be 12% in each of the control and atenolol-treated groups. Conversely, the incidence of myocardial ischaemia was reported to be 34% in the control vs 17% in the treated patients in the first 48 h after surgery (P<0.008) and 39 vs 24% over days 07 (P<0.029). More recent studies by Raby and colleagues179 and Urban and colleagues225 confirm the powerful anti-ischaemic effect of perioperative ß-adrenergic antagonism and re-emphasize the importance of stress-induced increases in heart rate in the pathogenesis of perioperative myocardial ischaemia. The association between the occurrence of perioperative myocardial ischaemic events, perioperative tachycardia and an adverse long-term cardiac outcome led to therapeutic trials with ß-AAs. However, it should be noted at this point that the association between postoperative myocardial ischaemia and adverse cardiac events does not necessarily imply a causal relationship and that postoperative myocardial ischaemia may represent only a manifestation of the underlying cardiac disease. Factors other than reduced ischaemia may contribute significantly to the improvements in outcome observed after administration of ß-AAs. These will be discussed extensively in this article. Using preoperative (1 h before surgery) and postoperative (until 7 days after surgery) atenolol (Table 1), Mangano and colleagues142 demonstrated in a well-designed study a significant reduction in postoperative myocardial ischaemia in patients with or at risk of coronary artery disease. This reduction in ischaemic events was associated with a 55% decrease in overall mortality and a 65% decrease in cardiac mortality at 2 yr for the atenolol-treated patients. The protective effects of atenolol were evident in these patients 6 months after surgery (overall mortality 0 vs 8%, P<0.001) and were preserved over the 2-yr follow-up period (overall mortality 10 vs 21%, P<0.019). Recently, Poldermans and colleagues173 randomized patients undergoing vascular surgery with mild to moderate positive stress echocardiography to preoperative (from 1 week before surgery) and postoperative (until 30 days after surgery) bisoprolol treatment or placebo (Table 1). After the inclusion of 112 patients, this study was halted for ethical reasons associated with large differences in morbidity and mortality rates between the placebo and bisoprolol arms of the study. Notably, the study reports a 10-fold decrease in the 30-day perioperative incidence of death from cardiac causes and non-fatal myocardial infarction in bisoprolol-treated patients (3.4 vs 34%, P<0.001). A critical evaluation of these studies has been published recently in the British Journal of Anaesthesia and can be recommended as additional reading.96 Taken together, these data indicate that ß-adrenergic antagonism remains the sole proven pharmacological means of reducing perioperative cardiovascular short- and long-term cardiac morbidity and mortality in patients with or at risk of coronary artery disease. In the light of the benefits of perioperative ß-AAs and the exceptionally low complication rate associated with the perioperative use of ß-AAs, future trials have to clarify whether the cumulative morbidity and mortality associated with sophisticated and expensive preoperative testing can be justified in high-risk cardiac patients undergoing surgery.128 144 190
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The present armamentarium of ß-adrenergic antagonists |
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Mechanisms and sites of action |
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Cardiac considerations
Bradycardia, the link to many cardioprotective effects of ß-adrenergic antagonists
Elevated heart rate is a well-established independent predictor of coronary artery disease and cardiovascular morbidity and mortality.168 Also, delayed decrease in heart rate after graded exercise predicts cardiovascular mortality.38 Bradycardia is suggested to be one important mechanism of cardioprotection elicited by ß-AAs. Importantly, a negative chronotropic response to ß-AAs is preserved among diabetic patients with progressive autonomic dysfunction.111
In the perioperative period, increased heart rate is strongly associated with myocardial ischaemia.141 143 Accordingly, myocardial oxygen balance is closely related to heart rate and must be examined on a beat-to-beat basis (Fig. 004F2). Increased heart rate results in elevated myocardial oxygen demand via the Bowditch effect, which is, however, nearly offset by decreased oxygen demand caused by the lower ventricular wall tension at higher heart rates. Because increased heart rate is usually accompanied by increased inotropy and the length of diastole is significantly decreased in tachycardia, myocardial oxygen balance can deteriorate seriously at higher heart rates in patients with coronary artery disease. Increased left ventricular stiffness further exacerbates impairment of ventricular filling. Importantly, the heart rate at which patients are considered at risk of developing ischaemia is not absolute and must be individualized. Patients with severe angiographic narrowing of the coronary arteries show a gradual decrease in cross-sectional area by 32% when heart rate reaches 90 beats min1.160 Therefore, it is not surprising that patients with coronary artery disease and a heart rate greater than 100 beats min1 almost inevitably develop myocardial ischaemia.69
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The institution of bradycardia was recently found to cause restoration of contractile function in a canine model of mitral regurgitation-induced left ventricular dysfunction.161 In this model, optimized myocardial Ca2+ handling and bioenergetics are direct consequences of bradycardia and are suggested to be responsible for the observed improvement in contractility.257
At the cellular level, rapid electrical stimulation of contraction reduces the density of ß-ARs and their responsiveness,116 which appears to be associated with disassembly of microtubules secondary to undue micromechanical stress.248
Cardioprotective effects of ß-adrenergic antagonists not apparently associated with bradycardia
Stangeland and colleagues207 addressed the important question of whether decreased heart rate is the only mechanism responsible for cardioprotection elicited by ß-AAs. They treated anaesthetized cats with alinidine (a clonidine analogue that decreases heart rate independently of ß-ARs) or timolol. Heart rate was similarly reduced by 40 beats min1 in the treatment groups compared with the control group, and regional ischaemia was induced by occluding the left descending coronary artery. After 6 h of ischaemia, the necrotic tissue was measured and expressed as a percentage of necrotic tissue in the area at risk. Notably, alinidine significantly decreased necrosis from 87% present in the control group to 77% (P<0.01), whereas timolol decreased necrosis to 65% (P<0.001). This observation clearly indicates that mechanisms other than decreased heart rate contribute substantially to cardioprotection by ß-AAs.
ß-Adrenergic signal transduction in cardiomyocytes. Biological responses mediated by ß-ARs involve positive chronotropy, dromotropy, inotropy and cardiomyocyte growth and death (Fig. 004F3). ß-ARs are members of the G-protein-coupled superfamily, which share the characteristic feature of the seven-transmembrane-spanning domains. In healthy mammalian cardiomyocytes, ß1-ARs constitute around 7080% of the ß-ARs in human and rat hearts.52 236 In many disease states with heightened sympathetic drive, ß1-ARs are down-regulated by phosphorylation (desensitization), translocation (sequestration) and finally by degradation of the receptor.88 Conversely, ß2-ARs do not decrease in number; however, they show some loss of contractile response to agonist stimulation as a result of the up-regulation of ß-AR kinases (ß-ARK) and Gi proteins (Table 4).26 In the failing human heart, ß2-ARs represent 40% of ß-ARs and are of great importance in mediating inotropic and chronotropic responses.25 Key steps in signal transduction of ß1- and ß2-ARs involve coupling to G-proteins and activation of the cAMP/protein kinase A (PKA) pathway, which leads to phosphorylation of target proteins such as phospholamban, the ryanodine receptor, troponin I and L-type Ca2+ channels.209 244 However, apart from changes in myocardial contractile function, ß-ARs exert important effects on cellular metabolism, growth and death (gene expression) through the activation of PKA and protein kinase C (PKC).90 Because the ß1-AR and the ß2-AR share only 54% of amino acid sequences overall, it is possible that ß-AR subtypes couple to distinct signal transduction pathways.243 245 Although both ß1- and ß2-ARs increase the contractile response and hasten relaxation in ventricular myocytes, several striking differences with respect to G-protein binding characteristics and signal transduction downstream from the receptor have been revealed. In contrast to ß1-ARs, ß2-ARs exhibit dual coupling to Gs and Gi that can completely negate Gs-mediated responses. Also characteristic of ß2-mediated signalling is the exceptionally modest increase in cAMP and the compartmentalized increase in PKA activity, which is restricted to the vicinity of L-type Ca2+ channels.124 260 Finally, ß2-ARs may also bind to Gq-activating phospholipase C (Fig. 004F3). These data indicate that ß-AR subtypes differentially modulate cardiac function and cardiomyocyte phenotype. Therefore, the subtype specificity of various ß-AAs affects biological responses significantly.
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Cell death signalling: apoptosis and necrosis. Catecholamines, although beneficial in the short-term cardiovascular response, exert significant cardiac toxicity. The toxic effects of catecholamines on cardiomyocytes have been known since the beginning of the 20th century.82 However, necrotic and apoptotic cell death has been closely related to enhanced ß-adrenergic signalling only recently.145 Apoptotic cardiomyocyte death by activation of the ß-adrenergic signalling pathway was reported in norepinephrine-stimulated adult rat ventricular myocytes.39 Zaugg and colleagues255 further demonstrated that apoptotic cardiomyocyte cell death is dissociated from ß2-ARs and selectively mediated by ß1-ARs in adult ventricular myocytes (Fig. 004F4). This is in line with clinical observations that cardiac lesions associated with massive catecholamine bursts were prevented with atenolol in patients with subarachnoid haemorrhage.43 Communal and colleagues40 and Chesley and colleagues36 further showed that ß2-AR stimulation may protect cardiomyocytes from apoptosis-inducing stimuli. The abilities of ß-AR stimulation and tachycardia to induce cardiomyocyte apoptosis were addressed by Shizukuda and colleagues200 in an in vivo rat model. Rats were treated with placebo or isoproterenol to establish whether catecholamines per se in the absence of significant increases in systolic load and tachycardia induce myocardial damage via apoptosis. After only 24 h of isoproterenol treatment, a significant increase in apoptotic events was detected. Animals exposed to ventricular pacing to induce tachycardia equivalent to that produced by isoproterenol treatment did not show an increase in apoptosis. The authors concluded that apoptotic cardiomyocyte death resulting from isoproterenol treatment may not be explained by increased heart rate alone. Conversely, in a canine model, rapid ventricular pacing per se increased apoptotic cell death and led to cardiac myopathy.136 Importantly, decreased apoptosis has been reported in carvedilol- and propranolol-pretreated rabbit hearts subjected to ischaemiareperfusion injury.252 Because apoptotic cell death occurs in only a few hours, apoptosis may be an important mechanism for loss of viable cardiomyocytes and myocardial dysfunction in the immediate perioperative period.253
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Mechanical unloading and modulation of gene expression. ß-AAs allow the heart to rest by emulating a state of ventricular unloading. Accordingly, the expression of tumour necrosis factor (TNF-
), an indicator of increased mechanical load, is similarly reduced by ß-AAs and by mechanical circulatory support.174 221 High-dose atenolol also prevents angiotensin II- and tachycardia-induced activation of metalloproteinases and diastolic stiffening.195 Changes in gene expression caused by ß-AAs also involve a decrease in endothelin-168 and sarcoplasmic reticulum proteins217 and an increase in atrial natriuretic factor.250 Furthermore, carvedilol decreases Fas receptor expression (cell death signalling receptor) after ischaemiareperfusion injury, which leads to decreased apoptotic cell death.252 Taken together, these observations suggest altered gene expression as a potential site of cardioprotection by ß-AAs.
Platelet aggregability and coagulation. The adrenergic system influences coagulation and fibrinolysis, particularly during episodes of heightened adrenergic drive, but contributes much less to baseline levels of coagulatory and fibrinolytic function. Epidemiological studies revealed a significant morning increase in the incidences of infarction, sudden cardiac death and transient myocardial ischaemia, which appears to be related to increased morning catecholamine levels and coagulation.158 238 Perioperatively, increased catecholamine levels and tissue damage greatly increase the propensity to coagulation. Propranolol decreases thromboxane synthesis and platelet aggregation in patients receiving long-term propranolol treatment.32 One study evaluating the effect of metoprolol on platelet function did not find any inhibitory effect,239 whereas another study reports decreased platelet aggregability in patients with stable angina being tested for exercise stress.241 Metoprolol also prevents stress-induced endothelial injury by increasing prostacyclin biosynthesis75 and decreasing epinephrine-induced increases in von Willebrand factor antigen.126 Esmolol has in vivo inhibitory action on neutrophil superoxide generation and platelet aggregation in a canine model of myocardial ischaemiareperfusion.186 ß-AAs also decrease the affinity of low-density lipoprotein to arterial proteoglycans and endothelial wall damage by reducing plasminogen activator inhibitor-1.216 Conversely, increased platelet aggregability and decreased platelet cAMP production were reported after timolol treatment.240
ß-Adrenergic receptor down-regulation and target protein hyperphosphorylation. Prolonged and intensive perioperative agonist stimulation leads to desensitization and down-regulation of ß-ARs, which may seriously impair cardiac function.28 29 Conversely, down-regulation of the sensitivity and number of receptors may be beneficial with respect to arrhythmogenicity.251 Tachycardia,116 free oxygen radicals133 and increased serum levels of TNF-,79 which are, notably, all factors significantly affected by ß-AAs, were further implicated in the down-regulation of ß-ARs and the subsequent attenuated cardiovascular response. Importantly, down-regulation occurs after only a few hours of agonist stimulation.88 At the molecular level, the process involves uncoupling of the ß-AR from Gs-proteins by PKA and ß-adrenergic receptor kinase 1 (ß-ARK) and binding of inhibiting arrestin to the receptor, which is followed by internalization and degradation or resensitization of the receptor (Fig. 004F3B). Early uncoupling and late down-regulation of myocardial ß-ARs were reported after cardiopulmonary bypass.72 193 Similarly, persistent down-regulation and desensitization of ß-ARs were reported after thoracotomy or laparotomy throughout the first week after surgery.5 Hyperphosphorylation of channels and regulatory proteins such as the sarcoplasmic ryanodine receptor (RYR) may occur, resulting in hypersensitivity to cytosolic Ca2+.147 148 ß-AAs potentially prevent hyperphosphorylation in the perioperative period, which is similar to their effects in congestive heart failure.91
Anti-arrhythmic effects. Sustained arrhythmias may be haemodynamically relevant and may affect the outcome adversely.13 Almost half of all high-risk cardiac patients undergoing non-cardiac surgery have ventricular ectopic beats or some sort of ventricular tachycardia.166 Patients undergoing cardiac surgery have a high risk of developing new-onset atrial fibrillation.6 From a mechanistic point of view, sympathetic tone plays an important role in most ventricular as well as atrial arrhythmias.192 ß-AAs shift the autonomic balance towards a higher vagal and lower sympathetic tone.224 Studies on infarctions in pigs clearly showed that ß-adrenergic mechanisms play a major role in ventricular fibrillation threshold during experimental coronary occlusion.119 This is consistent with the notion that ß-AAs prevent sudden electrical cardiac death.62 112 Regarding atrial arrhythmias, ß-AAs may be superior to newer class-III anti-arrhythmic drugs in the treatment of perioperative atrial fibrillation, as these drugs carry the risk of drug-induced polymorphic ventricular tachycardia. Notably, ß-AAs also counteract epinephrine-induced hypokalaemia, which significantly predisposes to arrhythmias.
Bioenergetics. ß-AAs are known to reduce NADH oxidase activity in mitochondria, which may lead to an energy-sparing effect.177 Also, ß-AAs shift cellular metabolism from fatty acid oxidation to glucose utilization, which effectively reduces the myocardial oxygen requirement.22 Recently, oxidative metabolism was evaluated in patients with ventricular dysfunction using C-11-acetate positron emission tomography. The results of this study showed a significant reduction in cellular oxidative metabolism under metoprolol treatment.10 Accordingly, in patients undergoing cardiopulmonary bypass, chronic propranolol treatment reduces oxygen consumption.108 Interestingly, patients receiving chronic ß-AA treatment compensate for reduced arterial oxygen content by increases in cardiac output and oxygen extraction, whereas patients not receiving ß-AA treatment demonstrate only an increase in oxygen extraction.206 Reduced production of lactate during exercise and increased oxygen extraction as a result of decreased cardiac output were reported previously under ß-adrenergic antagonism.175 ß-AAs also prevent the decrease in mitochondrial CK activity after myocardial infarction.97
Neuroendocrine stress response. There is a reduction in renin activity by selective as well as non-selective ß-AAs mediated by antagonizing ß-ARs, and some studies have even reported decreased catecholamine release after initiation of ß-adrenergic antagonism.157 Most studies, however, did not observe a decrease in catecholamine serum levels254 but rather an increase.93 One study in pigs reported decreased neuropeptide Y serum levels associated with increased heart rate variability after treatment with metoprolol.1
Preconditioning. Theoretically, ß-AAs may prevent preconditioning of the heart, which renders it more resistant to subsequent sustained ischaemia. However, metoprolol does not neutralize the favourable effects of preconditioning.237 On the contrary, nipradilol, a nitric oxide-generating ß-AA, clearly induces preconditioning by itself.95
Non-cardiac considerations
Effects of ß-adrenergic antagonism on core components of an anaesthetic regimen
Anaesthetic and analgesic requirements. Previous studies focused on the anti-ischaemic properties of peri- and intraoperative ß-adrenergic antagonism. Recently, it was shown that esmolol can potentiate the reduction in the minimum alveolar concentration (MAC) for isoflurane (26% at esmolol 250 µg kg1 min1) and decrease anaesthetic requirements for skin incision during propofol/nitrous oxide/morphine anaesthesia (27% at esmolol 250 µg kg1 min1).102 103 Esmolol also decreases nociception in a variety of experimental settings, suggesting the potential to decrease the intraoperative anaesthetic requirements.47 Altered distribution and decreased metabolism of opioids by ß-AAs may underlie this anaesthetic-sparing effect.182 Furthermore, although ß-AAs per se do not provide analgesia or hypnosis, they are known to have central nervous system modulating activities and anxiolytic effects.76 146 158 ß-AAs potentially affect central nervous system pathways, which include neurones in the hypothalamus, hippocampus and cerebral cortex.120 234 Accordingly, the favourable changes in heart rate variability after ß-AA treatment are ascribed to lower activity of the central sympathetic nervous system. In mice and rats, the locus coeruleus-associated noradrenergic system participates in arousal, and ß-adrenergic antagonism within this region reduces forebrain electroencephalographic activity.16 Similarly, amphetamine-induced activation of the rat forebrain is clearly inhibited by timolol, and in humans norepinephrine is known to enhance the responsiveness of the cerebral cortex to excitatory neuronal transmission.15 181 Notably, pure ß-adrenergic antagonism is crucial for the observed anaesthetic-sparing effect because labetalol increases the anaesthetic requirement.47 Even though esmolol and atenolol are hydrophilic ß-AAs, they produce the same plasma/cerebrospinal fluid ratio as lipophilic ß-AAs, thereby affecting the centrally located surface ß-ARs.120 Another mechanism that may significantly contribute to the anaesthetic-sparing effect elicited by ß-AAs involves decreased excitatory stimulation of central nervous effector sites of hypnosis and somatic response. In this case, peripheral interruption of centripetal ß-adrenergic autonomic pathways, like spinal and epidural anaesthesia, decreases afferent input and anaesthetic requirement.163
Memory storage. ß-AAs also possess attenuating effects on memory storage. Effects of opioids on memory are known to be mediated through noradrenergic influences.98 Importantly, propranolol was reported to impair memory storage of particularly emotional events in humans.31 Also, ß-AAs impair arousal-induced enhancement of working memory in elderly patients.165 As intraoperative recall and subconscious processing of information is particularly increased for emotionally charged information,132 it is tempting to speculate that ß-AAs, as anaesthetic adjuvants, might actually decrease the risk of intraoperative awareness and recall. However, this may be different for haemodynamically compromised patients with concomitant cardiovascular medication. Nonetheless, adequate depth of anaesthesia, as indicated by the bispectral index, was achieved in a group of elderly patients using high-dose intraoperative atenolol and a restricted amount of anaesthetic.254
Recovery. Faster recovery from anaesthesia was reported in patients receiving propranolol or metoprolol101 208 and in patients receiving intra- or perioperative atenolol.254 Titration of anaesthetics to heart rate and blood pressure without administration of ß-AAs may lead to prolonged recovery from anaesthesia as a result of relative overdosing with administered anaesthetics (MACBAR> MACAWAKE).183 Furthermore, specific properties of ß-AAs may alleviate recovery from anaesthesia. In cats receiving atenolol, waking times were significantly prolonged,92 and human sleep disturbance is a well-known side-effect of ß-AAs.159
Immune response and ß-adrenergic antagonism
The perioperative stress response impairs immune competence, particularly natural killer cell cytotoxic activity.220 In the experimental setting, reduction of natural killer cell cytotoxicity was achieved by electrical stimulation of the splanchnic nerve in rats, and was completely antagonized by nadolol.109 Recently, Ben-Eliyahu and colleagues14 reported that hypothermia in barbiturate-anaesthetized rats suppresses natural killer cell cytotoxic activity and thereby accelerates the spread of tumour cells. Interestingly, nadolol attenuated the effect of hypothermia on natural killer cells and increased resistance to tumour metastasis.
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Tolerability of perioperative administration of ß-adrenergic antagonists |
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Haemodynamics
Excessive sympatholysis is undesirable in patients who depend heavily on central sympathetic tone for adequate circulatory function. While chronic administration of ß-AAs improves systolic and diastolic function in heart failure patients,73 115 228 acute exposure to ß-AAs may lead to intolerable bradycardia and arterial hypotension and potentially result in an adverse outcome.215 Accordingly, eye-drops with ß-AAs were implicated in the progression of ischaemic optic nerve disorders and the progression of visual loss attributable to recurrent nocturnal hypotensive episodes.89 Therefore, patients with advanced conduction defects or symptomatic bradycardia should not receive ß-AAs without concomitant pacemaker therapy. However, patients with a resting heart rate below 60 beats min1 may receive therapy with caution. One study evaluating the tolerability of ß-AA titration in patients with idiopathic dilated cardiomyopathy found that generally accepted measures of the severity of heart failure were not predictive of problematic up-titration of ß-AAs.7 A low systolic blood pressure (<120 mmHg) was the strongest predictor of complications. The mechanisms underlying the good tolerability of initiation of ß-AAs in patients with heart failure was previously investigated by Halpern and colleagues81 (Fig. 004F5). Acute effects of metoprolol on systolic and diastolic function as well as on ventriculoarterial coupling were evaluated using volumepressure loops. The results of these studies indicate that decreased afterload, as assessed by arterial elastance and the preservation of ventriculoarterial coupling and passive ventricular properties, explain the excellent tolerance of ß1-AR antagonists in heart failure patients (Fig. 004F5). Notably, ß1-AR antagonists also leave inotropic responses to ß2-AR receptors intact and thereby produce less cardiac depression and vasoconstriction. Conversely, studies using a pulmonary artery catheter technique showed an increase in systemic vascular resistance (SVR) after metoprolol administration in chronically treated, mostly NYHA III heart-failure patients.123 Similarly, acute graded administration of esmolol in patients with severe ventricular dysfunction increased SVR to compensate for the decrease in cardiac output.99 Intraoperatively, SVR decreases significantly during undisturbed anaesthesia, but increases markedly under surgical stimulation in metoprolol as well as placebo-treated patients.139 However, SVR depends on loading conditions and contractility, which were not measured in all these studies. Therefore, SVR may not properly reflect the effects of ß-AAs on distension in the arterial system, i.e. afterload. Accordingly, in mitral regurgitation-induced left ventricular dysfunction ß-AAs decrease left atrial hypertension independently of changes in heart rate, which is thought to result from decreased afterload.33 228
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Coronary vascular resistance
Sympathetic nerve stimulation in the presence of propranolol was reported to increase diastolic coronary resistance by 30%.64 This coronary vasoconstriction is less likely to occur after administration of ß1-AR antagonists.2 More importantly, in a study that measured simultaneously total coronary flow (sinus outflow) and local tissue flow (heated thermocouples), sympathetic stimulation after ß-AA administration resulted in a decrease in sinus outflow but an increase in the nutritional microcirculatory flow.107 This implies that a reduction in total coronary outflow does not necessarily parallel a decrease in tissue flow at the microcirculatory level. Also, the mechanism of the reduction in blood flow after administration of ß-AAs is likely to be a result of decreased myocardial oxygen demand. This is strongly supported by the notion that atenolol decreases myocardial blood flow by 16% and increases coronary vascular resistance by 23%.211 At the same time, however, the myocardial arteriovenous oxygen difference remains unaltered. Furthermore, when paced at the pre-atenolol heart rate, there is no decrease in coronary blood flow or increase in vascular resistance under atenolol treatment, which again clearly indicates that the observed decreases in coronary flow can be ascribed solely to decreased left ventricular work and myocardial oxygen demand. Adverse effects of ß-AAs on feed-forward coronary vasodilation (mediated by ß2-ARs) clearly do not occur. Importantly, even in patients with vasospastic angina, administration of propranolol does not precipitate coronary spasms.51
Strategies to treat bradycardia and hypotension caused by ß-adrenergic antagonists
In general, untoward circulatory effects can be treated easily with vagolytic drugs (atropine) or can be overcome pharmacologically with inotropic agents. If atropine is not effective in treating bradycardia, i.v. glucagon 2.5 µg kg1 may be administered.137 187 The haemodynamic improvements after glucagon treatment result mainly from its pronounced chronotropic effect. Importantly, ß-adrenergic agonists are not the inotropic agents of choice in treating cardiac decompensation from ß-adrenergic antagonism.138 In the presence of fully established ß-adrenergic antagonism, high doses of catecholamines, which significantly increase afterload and pulmonary artery pressure, have to be administered to overcome the receptor antagonism.137 138 222 In metoprolol-treated patients, the response to phospho diesterase III inhibitor (PDE3I) is superior to the response to dobutamine. Milrinone 25 µg kg1 given over 10 min is well tolerated in patients with heart failure under carvedilol treatment and significantly improves the cardiac index with virtually no changes in heart rate and mean arterial pressure. PDE3Is retain their full haemodynamic effects in the face of ß-adrenergic antagonism, because their site of action is beyond ß-ARs. PDE3Is act specifically on the phospho diesterase III isoenzyme, which is anchored to the sarcoplasmic reticulum.246 Inhibitory effects on degradation of cAMP remain compartmentalized and thereby lead selectively to increased activity of sarcoplasmic reticulum PKA, which preferentially improves systolic and diastolic function.129 Notably, the combination of glucagon and milrinone effectively restores cardiac output, but may increase heart rate excessively.187 Interestingly, the combination of PDE3I and ß-AA, administered on a short- or long-term basis, confers additive beneficial but subtractive adverse effects (Table 6).197 Accordingly, concomitant administration of PDE3Is was used to improve the tolerability of starting ß-adrenergic antagonism in patients with severe heart failure by counteracting the myocardial depressant effect of adrenergic withdrawal. The results of these studies suggest that the combined treatment may have beneficial effects beyond those produced by ß-AAs. Similarly, the use of prophylactic concomitant PDE3I administration may have the potential to facilitate the introduction of acute preoperative ß-adrenergic antagonism. Along with their favourable effects on cardiac function, PDE3Is also partially activate protein kinase G in bronchial smooth muscle, counteracting the bronchoconstriction of ß-AAs. In the future, adverse negative inotropic effects of ß-AAs may be reversed by the transient use of Ca2+ sensitizers, which are currently under investigation.194
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Drug interactions and the withdrawal phenomenon
Concurrent administration of ß-AAs with drugs that alter gastric, hepatic or renal function may affect the blood levels, duration of action and efficacy of ß-AAs. In general, doses of lipophilic ß-AAs must be reduced in the presence of liver dysfunction, whereas doses of hydrophilic ß-AAs need to be adjusted in renal dysfunction. Although lipophilic substances generally have larger volumes of distribution, they usually have shorter plasma elimination half-lives because of the greater capacity for drug clearance by the liver than the kidneys. Polymorphic metabolism of ß-AAs is of clinical relevance. In particular, lipophilic ß-AAs are metabolized by oxidative pathways and glucuronidation, and oxidative clearance is influenced by the debrisoquine hydroxylation gene.104 201 203 Poor metabolizers with polymorphic variants of cytochrome P450 may therefore have increased plasma levels. Also, changes in metabolism related to the genetic background appear to be responsible for decreased efficiency of ß-AAs in black patients. Notably, bisoprolol is independent of any genetic polymorphism of oxidation.131
Concomitant administration with Ca2+ channel blockers results in additive myocardial depression, and QT prolongation may occur with hypokalaemia, particularly if treatment with ß-AAs is associated with the use of diuretics.118 Sinus arrest and atrioventricular block were described under combined administration of diltiazem and ß-AAs, but this seems to occur only rarely.156 A combined infusion of nifedipine and metoprolol has been used successfully in patients undergoing CABG surgery.172 Importantly, sinus node dysfunction may be further enhanced by digoxin, guanidine, procainamide, disopyramide, methyldopa, reserpine, clonidine, cimetidine, lithium and lidocaine. The practice of concomitant amiodarone and ß-AA treatment is not hazardous.20 However, the potential for conduction abnormalities and arterial hypotension must be considered carefully.
In patients receiving ß-AAs, the duration of regional anaesthesia is prolonged by 3060% after administration of local anaesthetic containing epinephrine.256 Severe complications were reported in cancer patients receiving ß-AA treatment after administration of aminoglutethimide as a hormonal cancer therapy.85 Although the novel ultra-short-acting opioid remifentanil is metabolized by the same non-specific esterases in the blood as esmolol, there is no apparent pharmacokinetic interaction between remifentanil and esmolol in a rat model.83 Importantly, the use of non-steroidal anti-inflammatory drugs offsets the antihypertensive effects of ß-AAs.57 Carvedilol may increase plasma levels of digoxin by 15%. Conversely, the bioavailability of digoxin may be decreased after oral administration of talinolol, a ß1-AR antagonist, as a result of competition for intestinal P-glycoprotein between digoxin and talinolol.235 Interference of propofol and volatile anaesthetics with ß-adrenergic signal transduction has been reported and may modulate the response to ß-AAs.86 253 259
When combining 2-agonists and ß-AAs, the following issues need to be addressed. Concomitant administration of sotalol and clonidine produces an increase in blood pressure. Conversely, propranolol potentiates clonidine-induced decreases in blood pressure, which is even more pronounced with atenolol.135 Special caution must be used in treating withdrawal syndromes from
2-agonists, as
2-agonists and ß-AAs cannot be used interchangeably. Whereas clonidine successfully blunts ß-AA withdrawal, ß-AA substitution in clonidine withdrawal provokes hazardous hypertension.106 Abrupt autonomic changes occur with ß-AA withdrawal, and sudden cardiac death may occur.223 230 This withdrawal phenomenon is virtually absent in ß-AAs with intrinsic sympathetic activity. Importantly, inadvertent withdrawal, particularly from hydrophilic ß-AAs, must be considered after massive intraoperative transfusion. Although ACE inhibitors may induce catecholamine-resistant intraoperative hypotension, preoperative withdrawal of ACE inhibitors may lead to decreased ß-AR responsiveness and down-regulation.247
Renal function
In general, ß-AAs decrease renal blood flow and glomerular filtration rate as a result of decreased cardiac output.11 However, this is not of clinical significance, and most ß-AAs, particularly the ß1-AR antagonists, alter renal haemodynamics only slightly. ß-AAs reduce tubular reabsorption of fluid and electrolytes leading to reduced sodium and water retention, while renal function is well maintained.169 213 This effect is beneficial, particularly in the perioperative period. Very few cases of clinically evident deterioration in patients with already impaired renal function have been reported.
Pulmonary function
Chronic obstructive pulmonary disease is not a contraindication for perioperative ß-adrenergic antagonism, and even patients with inactive stable asthmatic disease might be given a trial of a low dose of a highly selective ß-AA with appropriate ancillary properties [nebivolol (NO release), celiprolol (ß2 stimulation), bisoprolol].35 However, patients with active asthma and a demonstrable bronchodilator response should not receive ß-AAs. Celiprolol (200 mg day1) and atenolol (25 mg day1) can be used relatively safely in stable asthmatic patients, while metoprolol significantly increases airway resistance.214 Albuterol administered as four puffs before tracheal intubation blunts airway response significantly in patients with reactive airway disease and should be used prophylactically in these patients.149 Interestingly, ß-AAs increase hypoxic pulmonary vasoconstriction, which may be favourable in patients undergoing one-lung ventilation.24
Metabolic changes associated with ß-adrenergic antagonists
Several large studies indicate that there is some hyperglycaemic effect in patients receiving ß-AAs.77 However, as pointed out earlier, this is not a reason to withhold ß-AA treatment. Early treatment of myocardial infarction with ß-AAs results in a 13% reduction in mortality in all patients compared with a 37% reduction in diabetic patients.117 Similarly, reinfarction is reduced by 21% in patients without diabetes compared with 55% in diabetic patients.80 Nonetheless, ß-AAs impaired glucose tolerance and appeared to increase the risk of diabetes on a long-term basis by 28% in a recent study.77 Other studies (atenolol, acebutolol) did not show an increased risk of hyperglycaemia or diabetes in subjects taking long-term ß-AA treatment.162 188 Importantly, prolonged hypoglycaemia with delayed recovery may complicate ß-AA treatment in diabetic patients, particularly those with non-insulin-dependent diabetes mellitus.50 Sweating, but not tachycardia or palpitations, may be present in hypoglycaemic episodes.229 Also, diastolic blood pressure may be increased significantly as a result of unopposed epinephrine-induced -AR stimulation. Hypoglycaemia as a complication of ß-AA therapy is virtually absent with ß-AAs that have intrinsic sympathetic activity.
Although not of immediate concern in the perioperative period, unfavourable changes in lipid metabolism have been reported with ß-AA treatment. ß1-AR antagonists and labetalol do not increase triglycerides but may elevate very low density lipoproteins.49 Atenolol does not affect high-density lipoproteins, whereas metoprolol decreases them.185 However, total cholesterol, is largely unaffected by ß-AA treatment and a myriad of clinical and experimental studies document the anti-atherosclerotic effect of ß-AAs.
Cognitive dysfunction
The association between ß-adrenergic antagonism and depression remains controversial. More recent studies did not find any relationship between ß-AA use and depression or cognitive impairment.23 53 However, sleep disturbances, difficulty in falling asleep and vivid dreams with nightmares are clearly associated specifically with the use of lipophilic ß-AAs.
Vascular complications
Large studies on patients with peripheral occlusive artery disease do not show any adverse effects of ß-AAs on walking capacity or symptoms of intermittent claudication, even in patients with severe disease.180 Also, ß-AAs do not increase vascular complications in these patients.87 Because of epinephrine-induced effects mediated by the ß2-AR, the administration of ß1-AR antagonists may even result in decreased arterial resistance, which may increase nutritive blood flow.
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Using a retrospective and non-randomized approach, Boersma and colleagues264 investigated 1351 consecutive vascular patients to assess the relationship between clinical characteristics, dobutamine stress echocardiography, ß-AA therapy and perioperative cardiac events. The reported cardiac complication rates were greatly reduced in most patient categories (98% of patients) by ß-AA treatment. Only 2% of patients with three and more risk factors (age >70 yr, current angina, prior myocardial infarction, congestive heart failure, prior cerebrovascular accident, diabetes and renal failure) and extensive dobutamine stress echocardiography-induced ischaemia (at least five segments) would not profit from ß-AAs.
These studies thus support the conclusion that perioperative ß-adrenergic antagonism is likely to improve long-term outcome in selected groups of patients with or at risk of coronary artery disease.
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