Beta-blockers in anesthesiology: clinical and pharmacological aspects

Abstracts

JUSTIFICATIVA E OBJETIVOS: Informações experimentais e clínicas têm sugerido que os b-bloqueadores apresentam efeitos hemodinâmicos importantes e protetores durante o ato anestésico-cirúrgico. O objetivo deste trabalho é revisar as informações farmacológicas e clínicas dos b-bloqueadores para sua utilização adequada na medicina per-operatória. CONTEÚDO: Os b-bloqueadores seletivos inibem preferencialmente os b1-receptores reduzindo a freqüência e inotropismo cardíacos e determinando redução no consumo de oxigênio do miocárdio. Os b-bloqueadores não seletivos inibem também os b2-receptores, aumentando a resistência bronquiolar e vascular periférica. Alguns b-bloqueadores são, também, vasodilatadores. O tratamento prolongado com os b-bloqueadores aumenta a densidade dos b-receptores na membrana celular, o que pode explicar a hiperatividade simpática que pode ocorrer durante a parada do tratamento desses medicamentos. Em cirurgia não cardíaca, os efeitos benéficos do b-bloqueadores em pacientes hipertensos ou nos que apresentam doença coronariana têm sido demonstrados, com redução da incidência de isquemia miocárdica no pós-operatório e da mortalidade durante o período de dois anos que se segue à operação. CONCLUSÕES: O tratamento com b-bloqueadores deve ser mantido até o período da manhã da operação, exceto nos pacientes com sinais de intolerância à droga, como hipotensão ou bradicardia importante. Os b-bloqueadores exercem efeito benéfico na recuperação pós-operatória de pacientes com doenças cardiovasculares ou nos que apresentam fatores de risco. Por isso, o emprego desses medicamentos é importante na medicina per-operatória e deve ser ampliado.

DROGAS, Interação

REVIEW ARTICLE

Beta-blockers in anesthesiology: clinical and pharmacological aspects^*

Beta-bloqueadores en anestesiologia: aspectos farmacológicos y clínicos

Fabiana Aparecida Penachi Bosco, M.D.^I; José Reinaldo Cerqueira Braz, TSA, M.D.^II

^IME₂ do CET/SBA do Departamento de Anestesiologia da FMB da UNESP, SP

^IIProfessor Titular do CET/SBA do Departamento de Anestesiologia da FMB da UNESP, SP

Correspondence

SUMMARY

BACKGROUND AND OBJECTIVES: Experimental and clinical data have suggested b-blockers protective hemodynamic effects during anesthesia and surgery. This study aimed at reviewing pharmacological and clinical information needed to prescribe b-blockers in perioperative medicine.

CONTENTS: Selective b-blockers inhibit preferentially b₁-receptors, decreasing heart rate and inotropism leading to less myocardial oxygen consumption. Non-selective b-blockers also inhibit b₂-receptors, increasing bronchial and peripheral vascular resistance. Some b-blockers are also vasodilators. Prolonged treatment with b-blockers increases cell membrane b-receptors density, which may explain sympathetic hyperactivity observed during treatment interruption. In non-cardiac surgeries, beneficial effects of b-blockers have been observed in hypertensive patients and in patients with coronary artery disease, with a decrease in postoperative myocardial ischemia and overall two-year mortality.

CONCLUSIONS: Continued administration of b-blockers until anesthesia induction has been encouraged except in patients with signs of intolerance such as hypotension or significant bradycardia. b-blockers have been shown to have beneficial effects on postoperative outcomes in patients with cardiovascular disease or risk factors. Hence, their more widespread use in perioperative medicine is encouraged.

Key words: DRUGS, Interaction: beta-blockers

RESUMEN

JUSTIFICATIVA Y OBJETIVOS: Informaciones experimentales y clínicas han sugerido que os b-bloqueadores presentan efectos hemodinámicos importantes y protectores durante el acto anestésico-cirúgico. El objetivo de este trabajo es revisar las Informaciones farmacológicas y clínicas de los b-bloqueadores para su utilización adecuada en la medicina per-operatoria.

CONTENIDO: Los b-bloqueadores selectivos inhiben preferencialmente los b₁-receptores reduciendo la frecuencia e inotropismo cardíacos y determinando reducción en el consumo de oxígeno del miocardio. Los b-bloqueadores no selectivos inhiben también los b₂-receptores, aumentando la resistencia bronquiolar y vascular periférica. Algunos b-bloqueadores son, también, vasodilatadores. El tratamiento prolongado con los b-bloqueadores aumenta la densidad de los b-receptores en la membrana celular, lo que puede explicar la hiperatividad simpática que puede ocurrir durante la parada del tratamiento de eses medicamentos. En cirugía no cardíaca, han sido demostrados los efectos benéficos de los b-bloqueadores en pacientes hipertensos o en los que presentan enfermedad coronariana, con reducción de la incidencia de isquemia miocárdica en el pós-operatorio y de la mortalidad durante el período de dos años que se siguen a la operación.

CONCLUSIONES: El tratamiento con b-bloqueadores debe ser mantenido hasta el período de la mañana de la operación, excepto en los pacientes con señales de intolerancia a la droga, como hipotensión o bradicardia importante. Los b-bloqueadores ejercen efecto benéfico en la recuperación pós-operatoria de pacientes con enfermedades cardiovasculares o en los que presentan factores de riesgo. Por eso, el empleo de esos medicamentos es importante en la medicina per-operatoria y debe ser ampliado.

INTRODUCTION

Beta-adrenergic receptor antagonists (b-blockers) (Figure 1) have been studied by anesthesiologists for minimizing circulating catecholamine effects by blocking their binding to receptors. They are peri and postoperatively used for preventing or treating tachycardia, hypertensive crises, ischemic cardiopathy and arrhythmias, mainly supraventricular arrhythmias ^1,2. Several studies have also shown the efficacy of such drugs in decreasing postoperative morbidity and mortality ^3-5. Preanesthetic evaluations often reveal patients in chronic use of b-blockers.

Brazilian Journal of Anesthesiology, 2001; 51: 5: 431-447

Beta-blockers in anesthesiology: clinical and pharmacological aspects

Fabiana Aparecida Penachi Bosco; José Reinaldo Cerqueira Braz

The interest in b-blockers in Anesthesiology has increased with the recent introduction of a very short half-life molecule, namely esmolol. So, it is necessary to know the pharmacology of such agents to use them in perioperative medicine ^1,6,7.

b -BLOCKERS FUNDAMENTAL PHARMACOLOGICAL ASPECTS

Action Mechanism

Norepinephrine is the neurotransmitter responsible for most sympathetic nervous system adrenergic activity. It is synthesized in the axoplasm and stored in post-ganglionary sympathetic fiber vesicles. Adrenergic receptors are often classified in three major groups: alpha and beta-adrenergics and dopaminergics (Chart I), which are divided in sub-types a₁ and a₂, b₁ and b₂, dopa₁ and dopa₂, respectively. Visceral membrane b-receptors are stimulated by catecholamines released by sympathetic post-ganglionary neurons and the medulla of the adrenal gland. Such stimulation results in the activation of stimulating proteins (protein Gs), which trigger adenylate cyclase activation promoting the conversion of adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cyclic-AMP).The latter phosphorilates the proteic component of voltage-dependent calcium channels increasing the number of open channels during depolarization and calcium transfer to cytoplasm, which is responsible for intracellular activation ⁸.

Brazilian Journal of Anesthesiology, 2001; 51: 5: 431-447

Beta-blockers in anesthesiology: clinical and pharmacological aspects

Fabiana Aparecida Penachi Bosco; José Reinaldo Cerqueira Braz

An opposite situation is observed when there is a decreased agonist stimulation or receptor blockade ^6,9. The action mechanism may explain "rebound" events when beta-blockers are abruptly withdrawn.

Beta-Receptors

The most important b₁-receptors are located in post-synaptic heart membranes. Their stimulation results in increase atrioventricular stimulus conduction, myocardial contractility and heart rate.

b₂-receptors are post-synaptic adrenoreceptors located in bronchi, vessels, uterus, bladder and intestine smooth muscles. Their stimulation causes bronchodilation, vasodilation and uterus, bladder and intestine relaxation, respectively. It also determines glucogenolysis, neoglucogenesis, insulin secretion stimulation and Na⁺/K⁺ pump activation and may lead to hypokalemia and cardiac arrhythmias ^9,10.

Chart I shows major types, location and primary actions of adrenergic receptors.

Properties

Ahlquist's ¹¹ hypothesis that catecholamine effects are mediated by the action of different a and b-adrenergic receptors has triggered b-blockers study, synthesis and pharmacological evaluation. Further efforts resulted in compounds with a relative differentiated affinity to b₁ and b₂ receptors, presence or not of intrinsic sympatheticomimetic activity and presence or absence of membrane stabilizing effects (Table I).

Brazilian Journal of Anesthesiology, 2001; 51: 5: 431-447

Beta-blockers in anesthesiology: clinical and pharmacological aspects

Fabiana Aparecida Penachi Bosco; José Reinaldo Cerqueira Braz

Beta-adrenergic receptor antagonists are classified as selective and non-selective, according to their affinity to b₁ and b₂ receptors. So, methoprolol is a very selective molecule for b₁-receptors only being beaten by bisoprolol, while atenolol, esmolol and acebutolol are less selective. Propranolol, pindolol, sotalol and timolol, on the other hand, have equivalent affinity to b₁ and b₂ receptors. They are also classified as pure or partial antagonists, depending on the presence or absence of intrinsic sympatheticomimetic activity, which may be related only to b₁ receptors, as it is the case of acebutolol, to b₂ receptors, or even to both, as with pindolol ¹². Intrinsic sympatheticomimetic activity antagonists are less effective in decreasing heart rate and cause less myocardial contractility depression. So, partial antagonists may be better tolerated by patients with poor left ventricular function.

Some beta-adrenergic antagonists, such as propranolol, may produce some degree of membrane stabilization, similar to quinidine or local anesthetics, which are anti-arrhythmic agents class I. However, such effect can only be observed when plasma concentrations above those needed for an adequate blockade are reached. So, myocardial depression and bradycardia produced by beta-blockers are due to sympathetic nervous system blockade and not to membrane stabilization ^9,10.

Some beta-blockers, such as labetalol, are also vasodilators and prevent the increase in systemic vascular resistance by acting as alfa₁-adrenergic antagonist in arterial circulation ¹⁴.

Beta-blockers are anti-arrhythmic agents class II, according to Vaughan-Williams' classification. They are effective in treating arrhythmias caused by increased sympathetic activity and myocardial ischemia ¹⁴. Catecholamines are important for conduction velocity during the refractory period and in fibrillation vulnerability. Beta-blockers decrease diastolic depolarization velocity (phase 4) and are effective in decreasing ectopic arrhythmias, especially in the atrium. In the presence of fibrillation or atrial flutter, the increase in refractory period and nodus atrioventricularis velocity controls the ventricular rate and may interrupt re-entry-induced tachi-arrhythmias ¹⁵.

Pharmacological Effects

Beta-blockers efficiency for coronary failure is attributed to the decrease in myocardial oxygen consumption (MVO₂), which is preceded by negative chronotropic effects, especially when exercising, and negative inotropic effects. Before increasing total peripheral resistance by blocking vascular b₂-receptors and decreasing cardiac output, propranolol decreases blood pressure by decreasing heart rate and myocardial contractility and, probably, plasma rennin activity ¹⁰.

On the other hand, beta-blockers do not act on coronary spasm and may even favor it ¹⁶. Beta blockers-induced bradycardia and decreased inotropism increase systolic ejection time and left ventricle end diastolic volume, which may increase MVO₂, especially during exercise ¹⁰.

Local circulations are affected by beta-blockers in a different manner. So, systemic vascular resistance is increased by those lacking intrinsic sympatheticomimetic activity, mainly the non selective beta-blockers. The same is not true for those with such activity. The same is true for renal ¹⁷ and brain circulation. Propranolol decreases hepatic artery and portal vein blood flow in liver circulation. Most bronchioli have b₂-adrenergic receptors which, when stimulated cause bronchodilation. Beta-blockers are bronchoconstrictors, especially in asthma patients. Beta₁ selectivity and intrinsic sympatheticomimetic activity decrease beta-blockers bronchoconstrictor activity ¹⁸.

The action of beta-blockers on the renal function is a function of direct and indirect effects and may increase or decrease diuresis ¹⁷.

Beta-blockers decrease intraocular pressure in glaucoma patients ¹⁹ and also decrease angiotensin and aldosterone plasma levels, glucagon secretion in response to physiological hypoglycemia and to glucogenolysis. Beta₁ selectivity and intrinsic sympatheticomimetic activity decrease such effects.

Pharmacokinetics

Hydrosoluble beta-blockers, such as atenolol and nadolol, are absorbed by the GI tract and are weakly or not metabolized and excreted by the urine. Conversely, liposoluble compounds, such as propranolol, pindolol and methoprolol, are almost totally absorbed by the GI tract and suffer the first liver passage effect because they are metabolized in the liver, sometimes giving origin to active metabolites, such as propranolol. The knowledge of their metabolic pathways allows for dose adjustments according to patients renal and liver function (Table II).

Brazilian Journal of Anesthesiology, 2001; 51: 5: 431-447

Beta-blockers in anesthesiology: clinical and pharmacological aspects

Fabiana Aparecida Penachi Bosco; José Reinaldo Cerqueira Braz

Some authors propose preoperative isoproterenol tests to determine an effective blockade with beta-blockers, since it seems not to be a satisfactory correlation between plasma concentration and therapeutic effects ²⁰. Beta-blockers may also change the metabolism of other drugs by decreasing liver output and/or oxidative metabolism. As an example, propranolol decreases lidocaine clearance in 30% ²¹and diazepam in 17% ²².

Propranolol also decreases lung fentanyl clearance ²³. This reflects the property of a basic lypophylic amine (propranolol) of inhibiting lung re-intake of a second lipophylic amine. As a result, two to four times more fentanyl enter circulation after injection.

On the other hand, drugs changing liver microsomal functions alter the metabolism of liposoluble beta-blockers. So, enzyme inducers, such as barbiturates, decrease propranolol, timolol and methoprolol plasma rates, while drugs decreasing microsomal activity, such as cimetidine, decrease liver extraction and increase b-blockers plasma levels ^9,13.

MAJOR BETA-ADRENERGIC BLOCKERS USED IN ANESTHESIOLOGY

There is a wide spectrum of beta-blockers available for daily use. In anesthesiology, cardioselectivity, action time and intravenous formulation are important factors to be considered (Table III).

Brazilian Journal of Anesthesiology, 2001; 51: 5: 431-447

Beta-blockers in anesthesiology: clinical and pharmacological aspects

Fabiana Aparecida Penachi Bosco; José Reinaldo Cerqueira Braz

Esmolol

Although with clinical relevance proven for several years, only recently is esmolol being more widely used in anesthesia. Due to its pharmacokinetics and short action time it is the best intravenous beta-blocker for continuous infusion.

Its short duration is due to the fast hydrolytic metabolism through plasma estearases, resulting in an inactive metabolite and negligible amounts of methanol. Plasma estearases responsible for its metabolization are different from plasma pseudocholinesterases ²⁵. So, succinylcholine has no prolonged effect in patients treated with esmolol. Its distribution half-life is approximately two minutes, elimination half-life is nine minutes with 55% protein binding and high clearance rate of 20 L.kg^-1.h^-1. Esmolol plasma concentrations are undetectable 15 minutes after withdrawal. Its low liposolubility limits its passage through the blood-brain or placental barrier.

Esmolol has been used during pheochromocytoma resection in association with alpha-blockers ^26,27, to treat thyrotoxicosis-induced hypertension ²⁸ and cardiovascular toxicity caused by epinephrine or cocaine. It can also be used as an alternative to cardioplegia in coronary surgery ²⁹, in controlled hypotension ³⁰, as an adjuvant for electroconvulsive therapy ³¹ and rigid bronchoscopy, and in controlling tachiarhythmias and arterial and intra-ocular hypertension, among others ^6,10,13,32.

Methoprolol

Methoprolol is a selective beta-adrenergic blocker without intrinsic sympatheticomimetic activity. In high doses it may act upon b₁ and b₂ receptors. It is available for intravenous administration and is perioperatively used to control hypertension and tachiarhytmias.

After intravenous administration, its peak of action occurs in approximately ten minutes and its elimination half-life is 3 to 4 hours. It has a high distribution volume of 5 to 6 L.kg^-1, suffers liver metabolization and its inactive metabolites are excreted by urine and feces. Hemodynamic effects are negative chronotropism and inotropism without significant vascular resistance changes ⁶. b₁-blocker recovery pharmacodynamics is prolonged and may last more than 12 hours after excessive doses.

Propranolol

Propranolol interacts with b₁ and b₂ receptors, does not block a receptors and has no intrinsic sympatheticomimetic activity.

It is highly lipophylic and after oral absorption suffers an intense first passage effect; only 10% to 25% of the initial dose reach systemic circulation. In spite of its basic character, it has high protein binding (90%), especially acid a₁-glucoproteins. Its liver biotransformation is by cytochrome P450 and most metabolites are excreted by the urine. Hydroxypropranolol, with antagonist activity, is one of its metabolites with an elimination half-life shorter than the original drug. Its plasma clearance depends on blood flow and liver function. Its elimination half-life is 3 to 6 hours ^6,10,13,32.

Labetalol

Labetalol is seldom used in Brazil, but in other countries it is often used for acting on a₁ and b-adrenergic receptors with beta blockade much more potent than alfa. The alfa1 blockade is selective and the beta blockade is non-selective. It is weakly lipophylic and 55% of the drug are bound to plasma proteins. It has a 5-minute onset, short distribution half-life and distribution volume from 9 to 16 L.kg^-1. It is conjugated to glucuronic acid in the liver and excreted by urine and feces. Its elimination half-life is 5 to 8 hours ³³. It has minor effects on uterine and cerebral flows ³⁴. Its anti-hypertensive effects result from systemic vascular resistance, heart rate and myocardial contractility decrease. It does not increase heart rate after vasodilation and blood pressure decrease ³³ being widely used in pheochromocytoma surgeries.

Atenolol

Atenolol is a selective b₁ blocker. This drug causes less side-effects than propranolol because it is less liposoluble. It is the most selective b₁ blocker among all adrenergic agonists and is widely used in preventing recurrent supraventricular arrhythmias and in controlling hypertension and stable angina. Approximately 50% are orally absorbed with low binding to plasma proteins (10%). It suffers minor liver metabolization and 85% to 100% of the drug are excreted unaltered by the urine. It has a 2 ml.min^-1.kg^-1 clearance and a very low apparent distribution volume of 1 L.kg^-1.

The prophylactic use of perioperative atenolol in cardiac patients submitted to non-cardiac surgeries has been recommended because it decreases medium and long term mortality and has few side-effects ^35,36. So it is recommended for cardiac patients or patients at risk of coronary disease presenting two or more risk factors, more than 65 years of age, systemic hypertension, smokers, serum cholesterol above 240 mg.dl^-1 or diabetes ^37,38.

Atenolol does not exacerbate insulin-induced hypoglycemia and may be cautiously administered to diabetes patients whose hypertension was not controlled with other drugs. It administration requires heart rate to be equal to or higher than 55 bpm and systolic pressure to be equal to or higher than 100 mmHg, with no signs of heart failure or bronchospasm. It should be slowly injected in 5 mg intravenous bolus 30 minutes before surgery and the dose should be repeated immediately after surgery. Postoperatively, patients are maintained with oral 100 mg.day^-1 if heart rate is equal to or higher than 65 bpm, or 50 mg.day^-1 if it is equal to or higher than 55 bpm. If the patient is unable to receive oral medication, intravenous doses of 5 mg are administered every 12 hours for no longer than 7 days ^6,36.

INTERACTIONS OF BETA-BLOCKERS AND ANESTHESIA

Several studies have shown that treating patients with beta-blockers until the day of the surgery, in addition to not significantly changing hemodynamic balance during general anesthesia, decreases heart rate, blood pressure and blocked pulmonary artery pressure increase and ischemia related to noxious stimuli of tracheal intubation and surgery ^39-43.

Beta-blockers should also be maintained until the day of the surgery for spinal or epidural anesthesia. In these situations, however, all relative perioperative hypovolemia should be recognized and treated ⁴⁴.

To control perioperative blood pressure and heart rate some authors propose the preanesthetic administration of beta-blockers in patients not using such drugs ⁴¹. In those cases, liposoluble beta-blockers, such as methoprolol, pindolol and labetalol, which are mostly metabolized during the first liver passage, should not be used and hydrosoluble beta blockers, such as atenolol and nadolol should be preferred.

Another possibility is to use esmolol and other intravenous beta-blockers immediately before anesthetic induction. In such situation, esmolol has shown to be useful in decreasing heart rate and blood pressure during tracheal intubation and anesthesia ^45,46.

For preanesthetic medication, beta-blockers should only be used after assuring that the patient has a good left ventricular function at clinical evaluation and, if needed, at additional tests such as ecocardiography and angioscintigraphy which provide objective and reliable data on ventricular function ¹.

Interactions of b-blockers with anesthetic agents do not favor perioperative hemodynamic complications. Several studies have shown that cardiac effects of b-blockers and opioids are additive without exacerbation ¹.

Halothane and enflurane decrease sympathetic adrenergic activity. However, beta-blockers effect in decreasing sympathetic activity is a function of the baseline sympathetic tone level and their effects are limited in the absence of stimuli ^1,10. Conversely, tachycardia, arrhythmias and hypertension during laryngoscopy, intubation and surgical painful stimuli may be prevented by beta-blockers ^10,32, thus avoiding an increase in cardiac oxygen consumption, especially in patients with coronary artery disease.

Among halogenate agents, only enflurane and halothane seem to exacerbate negative chronotropic and inotropic effects of some beta-blockers, but only in concentrations higher than 1.5 times minimum alveolar concentration (MAC) ¹. So, in patients adequately beta-blocked they should only be used in low concentrations ¹⁰. The same caveat is true for other halogenate agents, especially when there are high beta-blockers plasma levels, to decrease the risk for drug interaction ⁴⁰.

Cardiovascular effects of neuromuscular blockers may also be changed by beta-blockers. In patients with coronary artery disease, preoperative propranolol (180 mg in 24 hours) may minimize pancuronium-induced heart rate, blood pressure and cardiac output increase ⁴⁷. However, care must be taken during reversion of the neuromuscular block with neostigmine because there may be prolonged bradycardia ⁴⁸.

Beta-blockers are well tolerated by anesthetized patients with acute hypovolemia ⁴⁹.

Hypercabia has a negative inotropic effect, in general compensated by sympathetic hyper-reactivity. In the presence of beta-blockers, such compensation is impossible. It is recommended, then, to avoid hypercabia during anesthesia in beta-blockers users ⁵⁰.

Bradycardia is frequent during regional blocks so prophylactic beta-blockers are, in general, not needed. It must be taken into consideration that during spinal or epidural blocks beta-blockers cardiovascular effects may add to the effects of sympathetic block and local anesthetics when there is an overdose of such agents. However, their perioperative use during regional blocks, such as isolated or combined thoracic epidural and general anesthesia is considered safe ^7,51. Regional anesthesia in beta-blocked patients requires special attention for correcting hypovolemia and hypotension with vasoactive agents and bradycardia with atropine. One must bear in mind that after the test dose with epinephrine and local anesthetics for epidural anesthesia there may be no heart rate increase in patients under b-blockers although blood pressure increase may be seen ⁵².

Preanesthetic administration of beta-blockers or during anesthesia may limit cardiac output adaptation to metabolic demand, especially during postanesthetic recovery, when it is markedly increased. So, it is desirable to decrease postoperative metabolic demand in beta-blocked patients, such as maintaining artificial ventilation until the patient is warm ¹.

PERIOPERATIVE BETA-BLOCKERS

Patients with coronary artery disease

Perioperative beta-blockers in coronary artery disease patients are administered whenever myocardial ischemia secondary to heart rate increase is to be avoided or treated. In the presence of tachycardia, two mechanisms are added to favor myocardial ischemia: oxygen consumption increase and myocardial oxygen uptake decrease due to a decrease in coronary diastolic filling time. Studies have shown that noxious effects of perioperative blood pressure decrease on the mechanism of the myocardial area where coronary stenosis is located will be more severe with high heart rates ⁵³.

Mean blood pressure and heart rate ratio (MBP/HR) is a good index when the goal is to avoid perioperative ischemia and it seems to always occur myocardial ischemia when such ratio is lower than one, that is, blood pressure, expressed in mmHg is lower than heart rate in beats per minute ⁵³.

So, intravenous peri or postoperative beta-blockers should be used in the following situations ¹:

1. To re-establish myocardial energetic balance if myocardial ischemia secondary to heart rate increase but with no significant blood pressure decrease is detected by ECG;

2. In patients with overt or latent coronary failure to reduce heart rate increases during tracheal intubation, surgery or anesthetic recovery. Perioperatively, it is important that depth of anesthesia matches the intensity of the surgical stimulus.

Heart Rate and Blood Pressure Limitations to Tracheal Intubation

Since intubation-induced hemodynamic changes have a short duration, ultra-short duration intravenous beta-blockers, such as esmolol, are preferred ^46,54. The benefit of beta-blockers for coronary artery disease patients before tracheal intubation is also result of a myocardial depressing effect of such drugs with potential to change ventricular function. Care must be taken with Prizmetal's angina patients because non-selective beta-blockers may cause myocardial ischemia ³². For those patients, calcium channel blockers and nitrates are the best indication.

Heart Rate Increase during Surgery

Inadequate anesthesia and/or analgesia are fundamental for the etiopathogeny of heart rate increases during surgery. So, whenever there is tachycardia during surgery after volume expansion, higher concentrations of halogenate anesthetics and/or opioids should be administered to deepen anesthesia. If after such measures heart rate is still high, intravenous beta-blockers are indicated.

Postoperative Heart Rate Increase

Heart rate increase favors postoperative myocardial ischemia. In a study by Mangano et al. (1990) ⁵⁵ (Figure 2), the incidence of ischemia was significantly higher in the postoperative period. This is easily explained by the fact that the thorough blood pressure and heart rate control during surgery was very often impossible after surgery in such studies, either because tachycardia was not detected or because the postoperative follow-up did not provide for a specific tachycardia treatment. In addition, in most studies, myocardial ischemia episodes were collected retrospectively and long time after surgery, from continuous electrocardiographic records obtained by Holter's method.

Brazilian Journal of Anesthesiology, 2001; 51: 5: 431-447

Beta-blockers in anesthesiology: clinical and pharmacological aspects

Fabiana Aparecida Penachi Bosco; José Reinaldo Cerqueira Braz

Several studies have proven the efficacy of peri and postoperative beta-blockers in decreasing myocardial ischemia and necrosis ^{3,4,35,38,56,57}. So, in patients under preoperative beta-blockers, the treatment must be restarted as soon as possible after surgery, in general in decreased doses for some days to prevent hypotension. Patients who received perioperative beta-blockers should continue to receive it after surgery and, when possible, orally. When using esmolol, it should be replaced, if possible, by other oral beta-blockers.

Treatment of Supraventricular Rhythm Changes

Perioperative paroxistic supraventricular rhythm changes are common. One may see atrial tachycardia (tachysystolis, tachyarrhythmias, atrial flutter) or junctional tachycardia.

In coronary patients or those with myocardial changes, it is important to decrease any ventricular rhythm increased by atrial rhythm changes. When stimulated at very fast rhythm, the ventricular myocardium often develops ventricular rhythm changes, such as extrasystole and tachycardia.

In the presence of atrial tachycardia, intravenous beta blockers drugs may rapidly and effectively control heart rate. They decrease nodal conduction, thus decreasing heart rate. Esmolol is the major short-duration beta blockers and is used in the doses of 50 to 150 µg.kg^-1.min^-1. In a clinical trial where esmolol was compared to verapamil, it was observed that both drugs decrease heart rate. However, blood pressure maintenance was better obtained with esmolol. Although the sinus rhythm return being not very frequent with both drugs, it was more frequent with esmolol (36% versus 12%). The efficacy of beta-receptors block should be first tested with esmolol and, after being proven, it might be replaced by other beta-blocker with longer half-life ².

Pheochromocytoma

Surgery preparation and intervention are performed under alpha-adrenergic blockade. However, the use of beta-blockers provides better hemodynamic stability. Associated infusions of esmolol and phentolamine or labetalol may be used ^26,27.

Controlled Hypotension

Labetalol is the most frequent beta-blocker used abroad for controlled hypotension because it determines blood pressure decrease by reducing systemic vascular resistance and prevents reflex tachycardia. This agent also promotes hypotension through a synergic effect with halogenate agents ⁵⁸. In our country, the experience has been the association of a-blockers with droperidol, and b-blockers with methoprolol ⁵⁹. Traditional beta-blockers still have an important role as adjuvants in controlled hypotension, but their medium and long half-life may limit the method. So, it is believed that esmolol, due to its short plasma half-life, will be more widely used for this technique ³⁰.

BETA-BLOCKERS USE PRECAUTIONS

Beta-blockers major adverse effects are hypotension, heart failure (counterindicated for patients class IV AHA) and bronchospasm.

Beta blocker-induced heart failure may be treated with diuretics and vasodilators, but frequently require inotropic support. In bronchial hyperactivity patients, non cardioselective beta-blockers may cause severe and even fatal bronch- spasms. Bronchospasm may be treated with sympatheticomimetic agents and aminophiline. In patients with chronic bronchial disease, there is a good respiratory tolerance for cardioselective beta-blockers ⁶⁰. In diabetes patients they intensify insulin-induced hypoglycemia by decreasing glucagon secretion and liver glyconeogenesis. Such effects are not evident with atenolol.

Beta-blockers are also counterindicated for patients with 2^nd and 3^rd degree atrioventricular blockade or with major bradycardia. Atropine may reestablish an adequate heart rate. In atropine-resistant bradycardia, one should consider the use of transcutaneous pacemaker, dopamine, epinephrine or isoproterenol infusion. To correct hypotension without bradycardia calcium chloride may be used (7 mg.kg^-1).

Beta-blockers adverse effects may be exacerbated when associated to drugs with similar effects, such as calcium channel antagonists, anti-hypertensive and anti-arrhythmic agents.

Beta-blocker effects may be exacerbated in elderly patients, probably due to high baseline levels of plasma catecholamines ⁵. For this patients, lower doses should be prescribed.

CONCLUSIONS

In patients under chronic use of beta-blockers, interactions between such drugs and intraoperative cardiovascular changes are particularly beneficial. So, the treatment with beta-blockers should be maintained until the day of the surgery. This is critical for the maintenance of hemodynamic balance both peri and postoperatively, in addition to decreasing postoperative cardiovascular complications. Due to their negative chronotropic effects, intravenous beta-blockers during surgery favor the preventive and even curative treatment of myocardial ischemia caused by heart rate increase. Those agents also allow for heart rate control if there is a change in atrial rhythm. The introduction in our country of a very short plasma half-life beta-blocker - esmolol - will certainly extend the use of such agents during and after surgery.

REFERENCES

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*

Recebido do CET/SBA do Departamento de Anestesiologia da Faculdade de Medicina de Botucatu (FMB) da UNESP, SP

Publication Dates

• Publication in this collection
  14 Mar 2011
• Date of issue
  Oct 2001

History

• Accepted
  14 Mar 2001
• Received
  19 Jan 2001