Amiodarone was initially developed to alleviate angina pectoris in patients with coronary artery disease . Clinical evaluation of amiodarone as an antiarrhythmic drug revealed its efficacy for the treatment of supraventricular and ventricular tachyarrhythmia . Amiodarone was also found to exert other pharmacological effects beneficial for patients with congestive heart failure . Amiodarone possessed an antisympathetic effect on both alpha-adrenergic and beta-adrenergic receptors in response to sympathetic stimulation and circulating plasma catecholamines, which attenuated left ventricular afterload . Amiodarone also inhibited presynaptic release of neurotransmitter from adrenergic neurons and modulated the activity of the autonomic nervous system in acute and chronic heart failure.
Amiodarone, an iodinated benzofuran compound, has a cationic amphiphilic molecular structure that is composed of polar water-soluble and nonpolar lipidsoluble moieties similar to the molecular structure of phospholipids found in cell membranes . Amiodarone accumulates within the cell membrane phospholipids of target organs . The volume of distribution is approximately 5000 L because of avid tissue sequestration of amiodarone . Tissue concentration can exceed plasma concentration of amiodarone more than 100-fold . The half-life of elimination of plasma amiodarone has been estimated to be as long as 61 days, and tissue stores can last longer .
Amiodarone has been reported to cause skin discoloration, corneal microdeposits, abnormal liver enzymes, renal insufficiency, abnormal thyroid function, and neuromuscular symptoms . Pulmonary fibrosis and amiodarone pulmonary toxicity are among the most well documented serious complications of chronic therapy with amiodarone . Several studies reported an increased incidence of acute organ dysfunction, including acute respiratory distress syndrome (ARDS) and cardiac dysfunction after surgery in patients receiving amiodarone [8-22] (Table 1). These reports recommended discontinuation of amiodarone therapy for several weeks before surgery to reduce postoperative morbidity in patients who are also at high-risk of suffering a life-threatening arrhythmia [15,19,21,22]. However, subsequent studies did not observe any additional increase in the incidence of acute organ dysfunction from amiodarone in the critically ill or after cardiac surgery [23-26] (Table 1).
The exact etiologic role of amiodarone in the development of acute organ dysfunction after cardiac surgery remains controversial. Previous studies enrolled patients with severe underlying cardiopulmonary disease who underwent high-risk surgical procedures. The nature of the underlying disease, in addition to the type of surgical procedures and perioperative events, obscured the potential contribution of amiodarone for the development of acute organ dysfunction after cardiac surgery . To determine the contribution of preoperative therapy with amiodarone on the incidence of acute organ dysfunction after cardiac surgery, we designed a pairwise-matched (1:1) case-control study. The matching criteria of the study cohort were demographic characteristics and perioperative risk factors that were reported to influence the development of acute organ dysfunction after cardiac surgery .
All admissions (11,950 patients) for cardiac surgery between January 1, 1993 and June 30, 1996 at a single tertiary care institution were eligible for the study. A pairwise-matched (1:1) case-control study was performed. The cases (amiodarone group) were 220 patients treated with amiodarone before and at the time of cardiac surgery. The amiodarone maintenance dose was 200-600 mg per day, and the duration of therapy was longer than 1 week. The controls (control group) were the remaining patients who had not received amiodarone before or during hospitalization and who satisfied the matching criteria. The study was approved by the institutional review committee for human research.
The controls were selected according to predefined preoperative and operative matching criteria known to influence the incidence of acute organ dysfunction after cardiac surgery . Preoperative matching criteria were the day of surgery (+/-3 days), source of admission (inpatient or outpatient), age (within 5 yr), gender, body mass index (within 5 kg/m2), and placement of intraaortic balloon pump before surgery. Operative matching criteria were repeat operation, emergency surgery, and surgical procedures on thoracic aorta or other procedures. Repeat operation implied a prior operation on the heart or thoracic aorta. Emergency surgery was performed for one of the following conditions: unstable angina, cardiac shock, ischemic valvular dysfunction that could not be controlled medically, leaking or dissection of thoracic aortic aneurysms, complications of routine cardiac catheterization, or percutaneous transluminal coronary angioplasty. The selection for the best control was performed in a stepwise fashion to obtain a pairwise-matched (1:1) case-control cohort. Each of the case-control pair was matched for at least 8 of the 10 selected matching variables.
Preoperative chronic disease process data were also recorded for the study cohort. History of smoking, diabetes mellitus (insulin- and noninsulin-dependent), cerebral vascular disease (previous stroke or carotid artery surgery), peripheral vascular disease (history of vascular surgery, dilation, or claudication), hypertension, and previous myocardial infarction was recorded. Chronic obstructive pulmonary disease or asthma was documented by history and requirement of bronchodilator therapy. Pulmonary vascular hypertension was defined by preoperative mean pulmonary arterial pressure of 25 mm Hg or higher. History of congestive heart failure was documented by history or active symptoms of shortness of breath on exertion, paroxysmal nocturnal dyspnea, orthopnea, or peripheral edema.
Hematocrit, blood urea nitrogen, serum creatinine, albumin, and total serum bilirubin levels were measured during preoperative evaluation. Preoperative systemic and pulmonary hemodynamic variables were measured or calculated before the induction of anesthesia. Severe left ventricular dysfunction was diagnosed by angiography ventriculogram, which generally corresponded to an ejection fraction of less than 35% and was present in 133 (79%) patients with a history of congestive heart failure.
The surgical procedures performed were classified as coronary artery bypass graft (CABG) isolated or combined with valve surgery, isolated valve repair or replacement surgery, thoracic aorta surgery, and other procedures. Return to the operating room for reexploration was indicated for persistent postoperative bleeding, tamponade, or revision of vascular grafts. Total duration of cardiopulmonary bypass, aortic cross-clamp and circulatory arrest (if applicable), transfusion of blood products during the operation, and placement of an intraaortic balloon pump after surgery or in the intensive care unit (ICU) were also recorded. Systemic hemodynamic variables, hematocrit, arterial blood gas tensions, core body temperature, plasma glucose levels, infusions of inotropes (amrinone, milrinone, and dobutamine), vasopressors (dopamine, norepinepherine, epinephrine, phenylephrine), and nitrodilators (nitroprusside and nitroglycerine) were recorded on admission to the ICU. Hematological, biochemical, and microbiological data were obtained during ICU stay. Clinical outcome was defined as the incidence of acute organ dysfunction, duration of mechanical ventilation, length of stay in the ICU, and death after cardiac surgery, as described previously .
All continuous variables were presented as mean +/- SD and were analyzed by using Student's t-test or Wilcoxon's rank sum test when appropriate. Repeated-measures analysis of variance for continuous variables was used to examine the interaction between amiodarone and surgery. A nonparametric test of the median (number of points above median) compared time variables such as days of mechanical ventilation or length of stay in the ICU. Categorical variables were expressed as actual numbers as well as percentages and compared by using chi squared or Fisher's exact test. The Cochran-Mantel-Haenszel test and multiple regression analysis were used to examine the effect of amiodarone on clinical outcome variables. All statistical tests were two-tailed, and significance was accepted at P < 0.05. Statistical analysis was performed using JMP Statistical software version 3.5.1 (SAS Institute Inc., Cary, NC).
The perioperative matching criteria for the control and amiodarone groups are depicted in Table 2. Source of admission, age, gender, body mass index, preoperative placement of intraaortic balloon pump, repeat operations, emergency surgery, thoracic aorta surgery, and other surgical procedures were matched in both groups. History of smoking (63% vs 63%), diabetes mellitus (23% vs 20%), hypertension (48% vs 50%), myocardial infarction (44% vs 45%), chronic obstructive pulmonary disease (8% vs 9%), pulmonary vascular hypertension (13% vs 14%), and cardiac shock (2% vs 1%) was similar in the control and amiodarone groups. However, cerebral and peripheral vascular disease, history of congestive heart failure, severe left ventricular dysfunction, and preoperative therapy with digoxin and angiotensin I-converting enzyme inhibitors were more prevalent in the amiodarone group (Table 3). beta-blockers (24% vs 17%) and calcium channel blockers (27% vs 20%) were used with similar frequency in the two groups.
Preoperative hematocrit, serum albumin, and total bilirubin levels were similar in the control and amiodarone groups. The blood urea nitrogen and serum creatinine levels were significantly higher in the amiodarone group. Although the preoperative heart rate was slower in the amiodarone group, other systemic and pulmonary hemodynamic variables were similar to those of the control group. Systemic oxygen delivery was slightly lower in the amiodarone group (Table 3). Operative characteristics, including ischemic times, operating times, transfusion of blood products, and return to the operating room for reexploration, were similar in both groups. There were more patients with CABG and valve surgery and fewer CABG alone in the amiodarone group.
Postoperative arterial bicarbonate, pH, PCO2, positive end-expiratory pressure, fraction of inspired oxygen concentration (FIO2), PaO2/FIO2 ratio, and core body temperature on admission to the ICU were similar in the amiodarone and control groups (Table 4). Systemic hemodynamic variables were similar in both groups, except for a slower heart rate and higher stroke volume index in the amiodarone group. There was no significant interaction between amiodarone and surgery on any of the systemic hemodynamic variables. Although the requirement for inotropes and vasopressors was greater in the amiodarone group, the difference from the control group was not significant after adjustment for congestive heart failure (Cochran-Mantel-Haenszel test P = 0.15 and P = 0.25, respectively). Hematocrit and plasma glucose concentration (on admission to ICU) and lowest hematocrit, maximal blood lactate, maximal serum total bilirubin, and minimal platelet counts were also similar in both groups during ICU stay (Table 4). Serum creatinine levels on the first postoperative day and the maximal value during ICU stay were significantly higher in the amiodarone group than in the control group (Table 4). There was no significant interaction between amiodarone and surgery on serum creatinine (repeatedmeasure analysis of variance P = 0.3).
Clinical outcomes are summarized in Table 5. The incidence of postoperative cardiac, pulmonary, renal, gastrointestinal, hepatic and neurologic dysfunction, and coagulopathy was similar in both groups. The incidence of bradyarrythmia or asystole that required pacing after surgery was more frequent in the amiodarone group (Table 5). The incidence of postoperative nosocomial infections, especially pneumonia, was significantly higher in the amiodarone group. However, the increased incidence of nosocomial infections and pneumonia in the amiodarone group was not significantly different from that of the control group after adjustment for congestive heart failure (Cochran-Mantel-Haenszel test P = 0.16 and P = 0.10, respectively). The duration of mechanical ventilation, length of stay in the ICU, and incidence of death were similar in both groups.
Multivariate analysis indicated that therapy with amiodarone and peripheral vascular disease was associated with elevated serum creatinine before surgery (Table 6). The elevation of preoperative blood urea nitrogen was associated with amiodarone, history of congestive heart failure, peripheral vascular disease, and therapy with angiotensin I-converting enzyme inhibitors (Table 6).
Opinions concerning the safety of amiodarone administration and the incidence of organ dysfunction after surgery are diverse (Table 1). In a case-control cohort, the current study found no evidence to substantiate that amiodarone increased the incidence of acute organ dysfunction or death after cardiac surgery. Treatment with amiodarone was associated with a slower heart rate and renal insufficiency (as indicated by elevated serum creatinine and blood urea nitrogen levels) before surgery, compared with controls. The increased requirement for inotropes and vasopressors and the incidence of nosocomial infections (especially pneumonia and elevated serum creatinine after cardiac surgery) may be attributed not only to preoperative congestive heart failure but also to renal insufficiency and therapy with angiotensin I-converting enzymes inhibitors.
The study examined the contribution of preoperative therapy with amiodarone on postoperative organ dysfunction after matching for demographic characteristics and perioperative events that influence the incidence of organ dysfunction after cardiac surgery. Peripheral and cerebral vascular disease, congestive heart failure, and renal insufficiency were more prevalent in amiodarone-treated patients. A bias in clinical practice for treating high-risk cardiac patients with underlying vascular disease and heart failure with amiodarone could explain the association with amiodarone. A similar bias for selecting high-risk cardiac patients was also noted in a comparative analysis of previous studies reporting adverse effects from therapy with amiodarone .
Preoperative therapy with amiodarone has been blamed for acute postoperative pulmonary and organ dysfunction in several studies (Table 1). However, many of the patients enrolled in these studies had progressive underlying cardiopulmonary and diffuse arterial disease, which frequently result in renal and other end-organ insufficiency . This study found an association between amiodarone and renal insufficiency before surgery. However, amiodarone did not seem to increase the incidence of postoperative renal dysfunction after cardiac surgery. Long-term treatment with amiodarone has been reported to contribute to renal insufficiency in cardiac patients . Congestive heart failure, arterial vascular disease, and medications with angiotension I-enzyme inhibitors were additional risk factors for the development of renal insufficiency in the study cohort before surgery.
Several risk factors for acute pulmonary dysfunction such as age, body mass index, chronic obstructive pulmonary disease or asthma, pulmonary vascular disease, and smoking were equally prevalent in both the amiodarone and control groups. The study found that amiodarone did not increase the incidence of acute pulmonary dysfunction or the duration of mechanical ventilation after cardiac surgery. This finding is in contrast to previous studies, which concluded that amiodarone was a causal factor for the onset of acute pulmonary dysfunction after surgical procedures (Table 1). Amiodarone was reported to increase the incidence of ARDS to 50% in a small series of patients undergoing cardiac surgical procedures for malignant arrhythmia . This report was contradicted by a subsequent study of patients after cardiac transplantation, which documented no effect from amiodarone on the incidence of acute pulmonary dysfunction, ARDS, or the length of mechanical ventilation . The diverse conclusions on the role of amiodarone in precipitating acute lung injury could be explained by other hemodynamic and perioperative events related to surgery. Acute lung injury was reported in combination with circulatory shock, infusion of angiographic dyes, high inspired oxygen concentration, one-lung ventilation, and pulmonary resection concurrent with therapy with amiodarone [11,17,18,21]. Extensive surgical trauma to pulmonary tissue, massive blood loss and transfusion of blood products, ventilator pressure and volume trauma during independent lung ventilation, generalized inflammatory response to intraoperative ischemia, etc., can induce acute lung injury after surgery . It is noteworthy that the current study found no adverse interaction between amiodarone and a high concentration of inspired oxygen (median FIO2 = 0.6) on the incidence of acute pulmonary dysfunction, as suggested in a previous case report .
The study observed that amiodarone was associated with an increased incidence of nosocomial infections, especially pneumonia after cardiac surgery. The incidence of postoperative pneumonia was related to preexisting congestive heart failure, a predisposing factor for recurrent pulmonary infections in cardiac patients . A slight increase in the incidence of pulmonary infections after long-term therapy with amiodarone was previously reported in patients with underlying chronic obstructive pulmonary disease and congestive heart failure . Amiodarone was postulated to alter the lymphocyte subpopulations in bronchial alveolar fluid, which increased susceptibility to pulmonary infections and subsequent inflammatory reaction to pathogens .
Therapy with amiodarone was also reported to increase the incidence of low cardiac output syndrome, peripheral vascular failure, and exacerbation of congestive heart failure after cardiac surgery (Table 1) [10,13]. This study found that preoperative therapy with amiodarone was associated with higher requirements for inotropes and vasopressor support after cardiac surgery. The requirement for inotropic and vasopressor support was related to underlying severe left ventricular dysfunction and congestive heart failure. Angiotensin I enzyme inhibitors were also prevalent in the study cohort. Angiotensin I enzyme inhibitors caused systemic vasodilation and increased the incidence of systemic hypotension after cardiac surgery . Systemic vasodilation could be secondary to concurrent therapy with arteriolar vasodilators and/or the release of inflammatory mediators after surgery. In fact, a small study of patients undergoing uncomplicated valvular surgery confirmed that amiodarone given before surgery did not affect postoperative cardiac function or the control of arterial blood pressure after separation from cardiopulmonary bypass .
Several surgical factors responsible for early onset of acute organ dysfunction after cardiac procedures were not previously examined in conjunction with amiodarone. Intraaortic balloon counterpulsation, cardiopulmonary bypass time, circulatory arrest, blood loss, transfusion of blood products, splanchnic ischemia, and systemic thromboembolism from the thoracic aorta are recognized risk factors for the development of organ dysfunction after cardiac surgery . When surrogate operative characteristics (e.g., repeat operations, emergency surgery, thoracic aortic surgery, and other surgical procedures) were eliminated as confounding factors in this study, therapy with amiodarone did not seem to increase the incidence of acute organ dysfunction after cardiac surgery. Preoperative therapy with amiodarone was ascribed to increase the incidence of combined cardiovascular, pulmonary, and hepatic dysfunction after cardiac surgery [15,20]. Several of the surgical risk factors were present in those patients also received amiodarone and developed acute organ dysfunction after surgery.
We conclude that preoperative therapy with amiodarone does not increase the incidence of acute organ dysfunction or death after cardiac surgery. Amiodarone was associated with a slower heart rate and renal insufficiency before surgery, compared with those of controls. The severity of the underlying cardiac disease rather than amiodarone therapy contributed to the increased requirement for inotropes and vasopressors support and the higher incidence of nosocomial infections, especially pneumonia, after cardiac surgery. The practice of discontinuation of amiodarone treatment before surgery to reduce the incidence of acute organ dysfunction should be critically reevaluated.
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