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On-line version ISSN 1806-907X
Rev. Bras. Anestesiol. vol.54 no.4 Campinas July/Aug. 2004
Peri-operative management of amiodarone patients*
Manoseo peri-operatorio del paciente en uso de amiodarona
Gilson Ramos, TSA, M.D.I; José Ramos Filho, M.D.II; Edisio Pereira, TSA, M.D.III; Salustiano Gabriel Neto, M.D.IV; Enio Chaves, M.D.V
IDoutorando da UnB; Diretor Clínico
do Hospital Samaritano de Goiânia; Clínico do Hospital da Unimed
de Goiânia, GO
IIProfessor Doutor Titular e Responsável pela Disciplina de Cardiologia do Curso de Medicina da Universidade São Francisco, Bragança Paulista, SP
IIIProfessor Doutor do Curso de Pós-graduação da Faculdade de Ciências da Saúde da Universidade de Brasília, UnB
IVCirurgião do Aparelho Digestivo; Professor Assistente de Técnica Operatória da Faculdade de Medicina da UFG, GO
VCirurgião do Aparelho Digestivo do Pronto Socorro da Faculdade de Medicina da UFG, GO; Doutorando da USP, Ribeirão Preto, SP
BACKGROUND AND OBJECTIVES:
Amiodarone is quite an effective anti-arrhythmic drug indicated for controlling
ventricular and supra-ventricular arrhythmias, and it is being widely administered
in clinical practice. However, its chronic use may be associated to severe side
effects which may be worsened by anesthetic-surgical acts, thus increasing the
risk of such procedures. This study aimed at reviewing major amiodarone effects
and relating them to anesthetic procedures.
CONTENTS: The study covers major amiodarone properties, its clinical use, as well as major adverse effects, which may increase patient's surgical risk.
CONCLUSIONS: Amiodarone, although normally safe and effective, may present adverse effects, especially on cardiovascular system, during anesthetic-surgical procedures. This is possibly due to interactions between this drug and anesthetic agents mainly related to general anesthesia. There are reports on severe, treatment - resistant bradycardias as well as on different degrees of atrioventricular block (AVB). Patients should be carefully monitored, especially during major procedures, and vasoactive drugs (isoproterenol) and temporary artificial pacemaker, should be available because they may be critical during the adverse effects treatment.
Key Words: COMPLICATIONS: arrhythmias, hypotension, liver toxicity, respiratory, thyroidal; DRUGS: amiodarone
JUSTIFICATIVA Y OBJETIVOS:
La amiodarona es un antidisrítmico bastante eficaz y indicado en el tratamiento
de disritmias ventriculares y supraventriculares, motivo por el cual viene siendo
extensamente administrada en la práctica clínica. Entretanto, su uso
crónico puede estar asociado con serios efectos colaterales, que pueden
ser agravados por actos anestésico-cirúgicos, aumentando el riesgo
de los procedimientos. El presente estudio objetiva revisar los principales
efectos de la amiodarona y asociarlos a la práctica clínica del anestesista.
CONTENIDO: Se trató de las principales propiedades de la amiodarona, su uso clínico, bien como los más importantes efectos adversos que pueden aumentar el riesgo quirúrgico de los pacientes en uso de este antidisrítmico.
CONCLUSIONES: La amiodarona, a pesar de habitualmente segura y eficiente, puede presentar efectos adversos exacerbados, especialmente para el aparato cardiovascular, durante procedimientos anestésico-cirúgicos. Esto se debe posiblemente a las interacciones entre ese fármaco y agentes anestésicos, asociados principalmente a la anestesia general. Hay relatos de bradicárdias graves y resistentes a la terapéutica, bien como bloqueo atrioventricular (BAV) en grados variados. El paciente debe ser rigurosamente monitorizado, especialmente en los procedimientos de grande porte, y el anestesista debe estar amparado en el peri-operatorio con drogas vasoactivas (isoproterenol) y marcapaso cardíaco artificial temporario, que pueden ser fundamentales durante el procedimiento.
Amiodarone is derived from benzoflurane and is classified as type III anti-arrhythmic drug according to Vaughan-Williams criteria1. Due to its coronary vasodilating properties, it has been firstly introduced in the clinical practice to treat angina pectoris. Its anti-arrhythmic properties were shown after 1974 and it is currently the most important and complete anti-arrhythmic available for clinical use. Although widely administered and very effective to manage arrhythmias, its use may lead to different and even severe systemic side effects, which may be lethal if not promptly detected and treated. For this reason, cardiac patients under amiodarone presenting for surgeries, especially under general anesthesia, may be exposed to higher risk, which may be attenuated by direct anesthesiologist's intervention looking for and treating morbidities associated to this drug.
This review aimed at presenting amiodarone's pharmacological principles, major amiodarone-related side effects and anesthesiologists' care to surgical patients under this anti-arrhythmic drug in the preoperative period.
ELECTROPHYSIOLOGICAL AND PHARMACOKINETIC PROPERTIES
Amiodarone's electrophysiological effects include: a) prolonged action potential by widening phases 2 and 3; b) decreased cell automatism by shortening phase 4; c) frequency-dependent blockade of fast sodium channels (similar to group I anti-arrythmics but less intensive); d) anti-adrenergic effect (mild and non-competitive b-blocker); e) calcium channels antagonist. These properties allow for amiodarone to be included in groups I, II, III and IV according to Vaughan-Williams1,2.
Amiodarone plasma peak is observed 3 to 7 hours after single oral dose administration and its gastrointestinal absorption is approximately 50%. More than 96% of circulating drug are bound to plasma proteins3,4. This drug undergoes gradual tissue storage, especially in myocardium and fatty tissue, from which it is slowly released. This has impaired the pharmacokinetic study of such agent. Orally, amiodarone onset is variable, however arrhythmia suppression is observed around the 5th day. Its excretion is slow and influenced by dose and length of use. Its excretion half-life is 29 days when chronically administered and its pharmacological effects remain for at least 45 days. Residues due to prolonged use may be found up to six months after is withdrawal5. When intravenously administered its onset is fast and effective, being observed in up to 15 minutes. Its action is short with the advantage of not presenting major side effects, more often observed with chronic administration.
CLINICAL INDICATIONS AND DOSE
Amiodarone is effective for most ventricular arrhythmias, such as ventricular and supra-ventricular tachycardia, paroxysmal tachycardia and atrial fibrillation. Initial oral dose is 800 mg.day-1 for 7 to 10 days, followed by 600 mg.day-1 for one to three weeks. Thereafter, 200 to 400 mg.day-1 are indicated. Intravenous bolus dose is 5 to 10 mg.kg-1 with 5 to 10-minute intervals between doses. One may also add 450 mg amiodarone to 150 mL crystalloid solution and intravenously infuse 30 to 40 drops.min-1. Priming parenteral dose is 10 mg.kg-1 for 3 to 5 days6. A different schedule proposed for perioperative emergencies is intravenous 150 mg in 15 minutes (it may be repeated 15 minutes after if there is no arrhythmia reversion), followed by 1 mg.min-1 in 6 hours, and 0.5 mg.min-1 thereafter until a maximum dose of 1000 mg in 24 hours7.
As in every preoperative period, patients under amiodarone should be systematically evaluated by a or clinical exam. In general, these are patients with one or more major cardiologic risk factors, such as: acute coronary syndromes; uncontrolled cardiac heart failure (CHF); arrhythmias or severe valve disease. Special attention however should be given to co-morbidities caused by amiodarone undesirable or side effects, which are divided into cardiac and extra-cardiac effects. The latter affect thyroid, lungs and GI tract and peripheral neuromuscular system. Coexisting preoperative affections in these tissues are of major concern for the anesthesiologist; there are often dermatological manifestations and corneal deposits and more seldom neuropathy or optic neuritis. These effects are dose-dependent and tend to disappear with decreased dose or treatment withdrawal8.
Major cardiac side effects after prolonged amiodarone therapy are sinusal bradycardia, more frequently seen, and atrioventricular block (AVB), which is less common9. These effects may be worsened by anesthetics inhibiting sinoatrial node (SAN) automatism, such as halothane and lidocaine, which should be avoided in such patients for the increased possibility of sinoatrial block10. Digitalis, in addition to interfering with SAN, decrease atrioventricular conduction increasing the risk for AVB when combined with amiodarone, fact which is also observed in vitro11 when this anti-arrhythmic is associated to volatile anesthetics (enflurane, halothane or isoflurane). High fentanyl doses, such as those administered for heart surgery, may promote bradycardia. Substantial hemodynamic instability has been ascribed to the perioperative association of fentanyl and amiodarone12,13. However, this opioid may be safely administered to amiodarone-impregnated patients14.
Amiodarone arrhythmic effects are uncommon but there may be Torsade de Pointes, a special type of tachycardia characterized by heart rate between 180 and 250 bpm. This arrhythmia is developed by prolonged ventricular repolarization and is manifested by long QT interval at ECG. Patients under amiodarone with long QT associated or not to the use of digitalis and in the presence of hydroelectrolytic disorders (especially hypokalemia) are more prone to develop this tachy-arrhythmia, which some times, in addition to adequate electrolytes correction and isoproterenol, requires temporary artificial pacemaker to control arrhythmia and prevent death15.
Anti-adrenergic (alpha and beta) effect is related to amiodarone's anti-arrhythmic and therapeutic action and cannot be considered a side effect. However, due to this property, perioperative bradycardias may be difficult to treat since they do not respond to atropine and have limited response to catecholamines, including isoproterenol. In addition, general anesthesia may increase amiodarone's anti-adrenergic effects with perioperative manifestations of sinoatrial block (SAB), atrioventricular block (AVB) and hypotension, with low cardiac output10. So, after considering the risk-benefit ratio of the procedure in patients with preoperative AVB degree II or severe bradycardia and depending on surgical length and under general anesthesia, invasive cardiac monitoring is recommended, including pulmonary artery catheterization, in addition to considering the implant of temporary pacemaker16,17. Similarly, and in similar clinical situations where this device was preoperatively ruled out, it should be available in the operating room for perioperative emergencies.
Fearing AVB associated to brady-arrhythmias affecting cardiac output, preoperative withdrawal of amiodarone has been questioned18. It is worth stressing, however, that the main intraoperative complication responds well to symptomatic treatment17. In addition and when indicated, artificial pacemakers are available. These are highly effective devices assuring the safe operative handling of cardiac patients under amiodarone. On the other hand, for having a long excretion half-life, preoperative amiodarone withdrawal could make patients vulnerable to malignant arrhythmias and, depending on the surgical disease; prolonged surgical postponement could worsen patients' prognosis or threaten their lives. Finally, some authors19 have reported that cardiac patients in whom amiodarone is maintained in the preoperative period are protected against postoperative arrhythmias.
Arterial hypotension is another side effect caused by the negative inotropic and vasodilating property of amiodarone, which is more apparent intravenously and minor during chronic oral administration. By both routes, amiodarone is well tolerated by patients with ventricular dysfunction who are, in fact, the target population for the benefits of this anti-arrhythmic drug. Lab experience9 indicates additive and potentially severe cardiac depression effects of the association of amiodarone and volatile anesthetics, which are more evident with enflurane, followed by halothane and isoflurane, reason why the latter would be the volatile anesthetic of choice to be combined with amiodarone.
Amiodarone's side effects on thyroid are caused by the high iodine concentration of this drug and include hyperthyroidism, the most frequent, or hypothyroidism20,21. The incidence of thyroid involvement varies 2% to 10%22. There is the prevention of peripheral conversion of T4 into T3 by 5'-deiodinase enzyme inhibition by amiodarone. Different factors are involved in hypothyroidism, among them family history of this disease and the presence of anti-thyroid antibodies. Lab changes are present in 50% of cases without clinical manifestations and tend to disappear after four months of therapy. For this reason, periodic plasma dosage of T3, T4 and TSH is unnecessary and would only be justified in the presence of symptoms. Hypothyroidism is confirmed by positive clinical data and when free T4 is decreased with increased TSH, moment in which thyroid hormone should be replaced. Similarly, hyperthyroidism is confirmed by clinical suspicion, increased T3 and T4 and decreased TSH. Treatment involves anti-thyroidism drugs, steroids, b-blockers and thyroidectomy23-25.
Any uncertainty about clinical findings should be clarified in the preoperative period of cardiac patients under amiodarone, even with thyroid lab tests. Elective situations require clinical and lab compensation, both for hypo and hyperthyroidism patients. If thyroid hypo or hyperfunction is detected in patients treated and compensated, preanesthetic care includes those related to thyroid patients and drugs to compensate them, such as steroids and b-blockers. Amiodarone is an additional risk factor for thyrotoxicosis, which may be severe with heart failure and can be difficult and refractory to treat with indication for thyroidectomy20,26. In such situation, patients may be decompensated and the procedure should be performed under local anesthesia, although general anesthesia may be successfully administered with selected anesthetic agents27. Iopanoic acid, a radio-opaque iodinized compound used as contrast for colecystography has been successfully used in these cases, clinically compensating patients for further thyroidectomy28.
Pulmonary toxicity is amiodarone's most fearful and severe side effect with an incidence of 5% to 10%29 and appearing 2 weeks to 30 months after the beginning of administration. It seems that pulmonary effects are more related to treatment duration and drug's cumulative effect than to the dose. Elderly patients with abnormal pulmonary diffusion capacity tests seem to be at greater risk30, together with patients with pre-existing pulmonary diseases31, although previous radiological changes are not considered risk factors. Similarly, spirometry does not identify individuals at risk. First clinical complaints are fever, dyspnea and cough. Late manifestations include productive cough with pleural pain and respiratory failure3,23. Radiological findings are varied and spirometry may reveal severe restrictive respiratory failure. Pulmonary biopsy reveals foamy cytoplasm inclusions, intra-alveolar hemorrhage and nonspecific interstitial pneumonitis. The presence of macrophages with lipid-containing lipossomal inclusion bodies confirms the diagnosis. Treatment consists of amiodarone withdrawal and introduction of steroids23, when necessary. Pulmonary toxicity-induced mortality may reach 10% if the drug is not discontinued4. When anesthetic-surgical procedures cannot be postponed, preoperative planning involves all possible care not to worsen respiratory symptoms and/or induce respiratory failure. Whenever possible, local-regional blockade should be used, avoiding general anesthesia. Efficient postoperative analgesia should be provided, including epidural catheters, especially in surgeries close to the diaphragm. Laparoscopic techniques should be thought of to replace conventional surgeries.
Among gastrointestinal effects, the most important is liver involvement. Liver toxicity may manifest as hepatomegaly although liver clinical propedeutics is normal in most cases32. High plasma alkaline phosphatase and transaminase levels, the latter with an incidence of 15% to 20%, are usually observed in patients impregnated with amiodarone for a long period. In general, prothrombin time and plasma bilirubin levels are normal. Amiodarone-induced hepatitis is uncommon but may be lethal33 and, in the presence of cholestasis or hepatomegaly with increased transaminases, drug withdrawal should be though of. Of course, elective surgery should be postponed in the presence of liver failure, however patients with cardiopathy under amiodarone may present for surgery with clinically normal GI tract but with increased lab liver markers. To the date of this review, no scientific publication was found that would evidence liver damage with increased lab liver markers, with the association of volatile anesthetics and amiodarone. However, it is prudent in these cases to select anesthetic techniques, anesthetic or any other drugs with the least possible liver toxicity. So, local-regional blocks are preferred to volatile agents. Although uncommon, halogenate-induced hepatitis, especially halothane, may be observed. Risk factors for such complication are genetic predisposition, repeated exposure to halothane, female gender, age, obesity, enzymatic induction and intra-hepatic hypoxia34. Nevertheless, one should have in mind that, although more uncommon, safe anesthetic agents such as isoflurane may lead to lethal liver necrosis35. The extent to which amiodarone-induced liver morbidity may be worsened by volatile agents should be subjected to further studies.
Amiodarone effect on peripheral neuromuscular system is manifested by polineuropathy, which is observed in approximately 10% of cases and in general disappears some months after treatment withdrawal36. However and uncommonly, there might be clinical evolution even with therapy withdrawal37. The development of the disease seems to be independent of age and total drug dose38. Most common clinical manifestations are extremity paresthesias (feet and hands) followed or not by muscle weakness, which may impair daily activities such as walking. More severe cases, such as respiratory failure39, severe miolysis and kidney failure40 may be related to the use of such drug. Signs and symptoms magnitude determines treatment interruption. Electroneuromyographic pattern may be that of axonal or demielinizing neuropathy. Serum creatine kinase (CK) enzyme dosage is in general not increased, unless when there are more severe muscle fiber losses41. In more advanced cases, muscle biopsy shows liposomal inclusions with severe axonal degeneration32. Amiodarone-induced polineuromyopathy patients may need surgery. Anesthetic techniques less worsening neuromuscular changes, thus those preferred, would be local-regional blocks with low local anesthetic doses42. However, general anesthesia may be needed in several situations. Even not finding any scientific report on amiodarone-general anesthesia interaction triggering or worsening peripheral neuromyopathy, in theory there is this possibility which should be taken into consideration. Agents such as nondepolarizing neuromuscular blockers and glycocorticoids may trigger myopathies impairing skeletal contraction with difficult ventilatory weaning and prolonged tracheal extubation. Neuromuscular blocker monitor should be available in the perioperative period. Premedication with respiratory depressing agents should be avoided in the suspicion of respiratory muscles involvement to prevent restrictive respiratory problems42.
Major lab tests available aiming at topographic and etiologic diagnosis to be used in the preoperative period when there are questions about neuromuscular involvement are serum CK levels, electroneuromyography and muscle biopsy with histochemical study.
Other drug interactions involving amiodarone should be considered. Some of them are not uncommon in our daily practice and others are seldom observed. So, amiodarone may significantly increase midazolam duration43 and lidocaine toxicity44, even promoting seizures. Both situations seem to involve liver metabolic changes induced by amiodarone. Amiodarone increases oral anticoagulant free fractions increasing their plasma levels by competition with protein binding sites45. The result is increased anticoagulant activity requiring further care in the indication and induction of spinal blocks. In theory, the risk for neurological complications (extradural hematomas) in these cases seems to be increased. Thiazidic diuretics spoil potassium. Plasma decrease of this ion in patients treated with amiodarone makes them more prone to increased QT interval with a higher chance for severe arrhythmia (Torsade de Pointes). Some drugs also increasing QT interval, such as quinidine, procainamide, sotalol, phenothyazines and tricyclic antidepressants should be avoided in association with amiodarone for the same reasons. In addition, clinical indications justifying these associations are very uncommon and, when present, therapeutic alternatives should be considered. Calcium channel blockers tend to induce AVB and are negative inotropics, reason why they should be carefully used in association with amiodarone, for the higher risk for brady-arrhythmias and myocardial depression. The simultaneous use of b-blockers and amiodarone in full therapeutic doses may induce severe bradycardia with the risk for cardiac arrest46.
Although being usually safe and effective, amiodarone may induce several side effects, some of them severe, which may be further, worsened by anesthetic-surgical procedures. This is possibly due to interactions between this drug and anesthetic agents, especially associated to general anesthesia. There are reports on severe therapy-resistant bradycardia as well as AVB in different levels. Regional blocks are preferred in association to amiodarone. Patients should be closely monitored, especially during major procedures, and the anesthesiologist should have available vasoactive drugs, such as isoproterenol. In addition, emergency situations may require temporary artificial pacemaker, which may be critical for the success of the procedure.
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Dr. Gilson Ramos
Address: Rua 8, Nº 74/402 Setor Oeste
ZIP: 74115-100, City: Goiânia, Brazil
Submitted for publication February
Accepted for publication October 27, 2003
* Received from Serviço de Anestesiologia do Hospital Samaritano de Goiânia e da Disciplina de Cardiologia da Faculdade de Medicina da Universidade São Francisco, Bragança Paulista, SP