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Ann Thorac Surg 2003;76:535-541
© 2003 The Society of Thoracic Surgeons

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Original article: cardiovascular

Acute circulatory actions of intravenous amiodarone loading in cardiac surgical patients

^a department of Departments of Anesthesiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA,
^b department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA

^* Address reprint requests to Dr Cheung, University of Pennsylvania, 3400 Spruce St, Ravdin 4 Courtyard, Philadelphia, PA, USA 19104-4283
e-mail: cheunga{at}uphs.upenn.edu

Accepted for publication March 4, 2003.

	Abstract

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BACKGROUND: The duration, severity, and cause of hypotension after intravenous amiodarone has not been well characterized in anesthetized cardiac surgical patients. Because amiodarone is tolerated in patients with advanced cardiac disease, we hypothesized that left ventricular systolic performance is preserved despite hypotension during amiodarone loading.

METHODS: In a prospective double-blind trial, 30 patients undergoing coronary artery bypass graft (CABG) surgery were randomly assigned to receive intravenous amiodarone (n = 15) or placebo (n = 15). Cardiac output (CO), mixed venous oxygen saturation (SVO), arterial blood pressure (systolic blood pressure [SBP], diastolic blood pressure [DBP], mean arterial pressure [MAP]), pulmonary artery pressure, and central venous pressure (CVP) were recorded. Transesophageal echocardiographic left ventricular end-diastolic area (EDA), end-systolic area (ESA), fractional area change (FAC), and end-systolic wall stress (ESWS) were measured every 5 minutes.

RESULTS: Mean arterial pressure, SBP, and DBP decreased over time after drug administration in both groups (p < 0.05). At 6 minutes, amiodarone decreased the MAP by 14 mm Hg (p = 0.004) and placebo decreased the MAP by 4 mm Hg. The change in MAP, SBP, and DBP between groups was statistically different for the first 15 minutes after drug administration. Hypotension requiring intervention occurred in 3 of 15 after amiodarone and 0 of 15 after placebo (p = 0.22). The mean heart rate was 11.5 beats per minute less after amiodarone (p < 0.02), but pulmonary artery pressure, CVP, SVO, and FAC were not different between groups.

CONCLUSIONS: Intravenous amiodarone decreased heart rate and caused a significant, but transient decrease in arterial pressure in the first 15 minutes after administration. Left ventricular performance was maintained suggesting that selective arterial vasodilation was the primary cause of drug-induced hypotension.

	Introduction

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Intravenous amiodarone is an antiarrhythmic with wide-ranging activity [1]. Intravenous amiodarone was recommended in the Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care consensus for the treatment of rapid atrial arrhythmias, ventricular tachycardia, ventricular fibrillation, and wide-complex tachycardia of uncertain origin [2]. Although the Guidelines 2000 stated that intravenous amiodarone was preferable to other antiarrhythmic agents in patients with severely impaired heart function, the guidelines warn that major adverse effects of intravenous amiodarone were hypotension and bradycardia [2].

Hypotension was the most frequent adverse event related to intravenous amiodarone in clinical trials. The incidence of hypotension in trials ranged from 15% to 26% [3–6]. In some cases, hypotension after drug administration was reported to contribute to cardiogenic shock [7], increased vasopressor requirements [3, 6], the need for mechanical circulatory assist [6], or even to death [3]. In the amiodarone for out-of-hospital resuscitation of refractory sustained ventricular tachyarrhythmias (ARREST) trial, patients who received intravenous amiodarone during resuscitation had significantly lower blood pressure, lower heart rate, and increased need for vasopressor drugs [7].

The etiology, magnitude, and duration of hypotension after intravenous amiodarone in clinical trials were difficult to determine because the drug was administered typically to patients with severe heart disease who were hemodynamically unstable. Determining the precise magnitude, duration, and mechanism of hypotension caused by intravenous amiodarone could potentially increase the safety of drug administration to critically ill patients. The objective was to characterize the acute cardiovascular actions of an intravenous loading dose of amiodarone administered using echocardiographic and hemodynamic measurements. Because chronic amiodarone was well tolerated in patients with heart failure [8], it was hypothesized that hypotension associated with intravenous amiodarone was caused by vasodilation instead of myocardial depression.

	Material and methods

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The study was a randomized double-blind, placebo-controlled trial. Eligible patients were enrolled into an Institutional Review Board–approved (June 1999 to January 2002) protocol after obtaining written informed consent. Inclusion criteria were age 18 years or older, nonemergent coronary artery bypass grafting (CABG) requiring cardiopulmonary bypass (CPB), and stable hemodynamic function after separation from CPB defined by a systolic arterial pressure (SBP) of at least 90 mm Hg, mixed venous oxygen saturation (SVO) 60% or greater, and heart rate between 50 and 115 beats per minute. Patients were excluded if they had hemodynamically significant valvular heart disease, required mechanical circulatory assist, received amiodarone intravenously (IV) or lidocaine IV for cardiac arrhythmias, had uncontrolled bleeding after CPB, or had an allergy or previous adverse reaction to amiodarone.

General anesthesia consisted of midazolam 0.05 to 0.15 mg/kg IV, fentanyl 15 to 75 µg/kg IV, pancuronium 0.15 to 0.35 mg/kg IV, and inhaled isoflurane 0.4 to 1.0 vol % in oxygen. Operations were performed with moderate hypothermic cardiopulmonary bypass and intermittent antegrade hypothermic (4°C) oxygenated crystalloid or blood cardioplegia. Epinephrine 1.0 µg/min to 4.0 µg/min intravenous infusion was administered as the first line vasopressor agent to facilitate separation from cardiopulmonary bypass in patients with hypotension or left ventricular dysfunction at the termination of cardiopulmonary bypass. To ensure that both test and control groups had a uniform distribution of subjects with normal and abnormal left ventricular function, subjects were stratified according to preoperative left ventricular ejection fraction (LVEF) before randomization. Subjects with a preoperative LVEF of 30% or less and those with LVEF more than 30% were randomized separately. Subjects in the test group (group A) were administered amiodarone 150 mg IV (Cordarone I.V.; Wyeth-Ayerst, Radnor, PA) diluted in 100 mL normal saline over 10 minutes by a programmable intravenous drug delivery pump after sternal closure at the start of skin closure. Subjects in the control group (group B) were administered 100 mL of normal saline infused intravenously over 10 minutes. The inspired concentration of isoflurane was kept constant, vasoactive drug infusions were kept constant, and no additional intravenous anesthetic drugs were administered within 15 minutes before and 30 minutes after the start of study drug. The rate of intravenous fluid administration was adjusted to maintain central venous pressure (CVP) constant before study drug administration then changed only if necessary during the period of study.

Lead II of the electrocardiogram, the radial arterial pressure (Jelco 20 g 1-3/4 in catheter; Johnson and Johnson Medical, Arlington, TX), pulmonary arterial pressure (Baxter Swan-Ganz CCOmbo; Baxter, Irvine, CA), CVP, thermodilution cardiac output (CO), oximetric SVO and were recorded continuously by a 128 Hz computerized data acquisition system. Pressure transducers (Sorenson 47616-10; Abbott Laboratories, Chicago, IL) were zeroed at the level of the midaxillary line with the patient in a level supine position.

Transesophageal echocardiography (TEE) was performed using a 5.0 to 6.2 MHz TEE ultrasound transducer (Sonos 5500, Omniplane 2; Agilent Technologies, Andover, MA). The left ventricle was imaged continuously from the transgastric window in short-axis at the midpapillary muscle level beginning 90 seconds before and for at least 30 minutes after start of study drug. Cardiac cycles were acquired as digital cine loops at base line and every 5 minutes for 30 minutes after start of study drug. Off-line analysis of TEE images was performed by manual planimetry of the stored images (Enconcert; Agilent Technologies, Andover, MA). The cross sectional area of papillary muscle bodies within the left ventricular cavity was considered to be part of the blood pool. The left ventricular end-diastolic cross sectional cavity area (EDA) was used as a TEE index of left ventricular preload [9]. The fractional area change (FAC) and left ventricular end-systolic cross sectional cavity area (ESA) were used as TEE indexes of global systolic performance [10]. The left ventricular end-systolic meridional wall stress (ESWS) was used as a TEE index of left ventricular afterload [10].

Hypotension after study drug was defined as a SBP of 85 mm Hg or less and treated initially by discontinuing intravenous vasodilator therapy if the patient was receiving vasodilator during the study. If the SBP remained at 85 mm Hg or less after discontinuing vasodilator, phenylephrine 100 µg IV increments were administered into the CVP port until a SBP more than 85 mm Hg was achieved. Acute intravascular volume expansion was not used to treat drug-induced hypotension. Bradycardia was defined as a heart rate less than 60 beats per minute and treated by epicardial pacing. Telemetry until hospital discharge was used to detect postoperative cardiac arrhythmias.

Hemodynamic and echocardiographic data were treated as continuous variables. Base line hemodynamic values were averaged over 90 seconds before study drug administration. The CO, SVO, and TEE measurements were analyzed at 5 intervals for the first 30 minutes after study drug administration while the patient was in the operating room. Hemodynamic and heart rate data were analyzed at 1-minute intervals for the first 15 minutes, 5-minute intervals for the next 15 minutes, then every 60 minutes for the next 4 hours after the patient was transferred to the intensive care unit. One-way analysis of variance (ANOVA) for repeated measures was used to test if measured variables changed with respect to time after study drug. Repeated measures ANOVA with treatment as the grouping factor was used to test for differences in the hemodynamic responses to amiodarone and placebo. Student’s t test or Fisher’s exact test was used to test for differences in base line demographics and the incidence of hypotension, or arrhythmias in the two groups. A p value less than 0.05 was considered to be significant.

	Results

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All 30 patients enrolled completed the protocol with 15 patients randomly assigned to amiodarone (group A) and 15 patients randomly assigned to control (group B). Patient age, weight, height, sex, and preoperative LVEF (range 0.15 to 0.85) were not different in the two groups (Table 1). All patients were in sinus rhythm. The base line heart rate, SBP, diastolic blood pressure (DBP), mean arterial pressure (MAP), pulmonary artery systolic pressure (PAS), pulmonary artery diastolic pressure (PAD), CVP, CO, SVO, and TEE indicators of left ventricular size and function were not different in the two groups before study drug administration (Table 2). Nasopharyngeal temperature during cardiopulmonary bypass and at the time of study drug administration was not different in the two groups (Table 1). Epinephrine infusion was administered for separation from CPB and continued during the study period in 10 of 15 (67%) patients in group A and 7 of 15 (47%) patients in group B (p = 0.46). The mean (±SD) dose of epinephrine administered in group A was 2.2 ± 0.9 µg/min (median, 2.0 µg/min; range, 1.0 to 4.0 µg/min) and in group B it was 2.0 ± 0.0 µg/min (median, 2.0 µg/min), and was not different in the two groups (p = 0.23).

View larger version (27K): [in this window] [in a new window]   Fig 1. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) after study drug administration (mean ± SEM). Analysis of variance for repeated measures demonstrated a significant time and group interaction on the changes in SBP (p < 0.005), DBP (p < 0.003), and MAP (p < 0.004) over time in the first 15 minutes after drug administration. The group effect was not significant beyond 15 minutes after drug administration. (Solid circles and triangles = group A, amiodarone; open circles and triangles = group B, control.)

View larger version (34K): [in this window] [in a new window]   Fig 2. Heart rate, pulmonary artery systolic pressure (PAS), pulmonary artery diastolic pressure (PAD), and central venous pressure (CVP) after study drug administration (mean ± SEM). Analysis of variance for repeated measures demonstrated a significant group effect on the changes in heart rate (p = 0.024) over the entire period of study after drug administration. There was no significant group effect on the changes in PAS (p = 0.18), PAD (p = 0.08), and CVP (p = 0.87) over the period of study. (Solid circles and triangles = group A, amiodarone; open circles and triangles = group B, control.)

View larger version (18K): [in this window] [in a new window]   Fig 3. Cardiac output (CO) and mixed venous oxygen saturation (SVO) after study drug administration (mean ± SEM). Analysis of variance for repeated measures detected a significant group effect on the changes in CO (p = 0.03). There was no significant group effect on the changes in SVO (p = 0.20) over the period of study. (Solid circles = group A, amiodarone; open circles = group B, control.)

View larger version (20K): [in this window] [in a new window]   Fig 4. Left ventricular fractional area change (FAC) and end-systolic meridional wall stress (ESWS) were measured using the transesophageal echocardiography transgastric left ventricular short-axis view at 5-minute intervals after study drug administration (mean ± SEM). There was no significant group or time effect on the changes in FAC (p = 0.34) and ESWS (p = 0.47). (Solid circles = group A, amiodarone; open circles = group B, control.)

View larger version (20K): [in this window] [in a new window]   Fig 5. Left ventricular end-diastolic area (EDA) and end-systolic area (ESA) were measured using the transesophageal echocardiography transgastric left ventricular short-axis view at 5-minute intervals after study drug administration (mean ± SEM). There was a significant group effect on the changes in EDA (p = 0.01). The ESA was greater after drug administration in the amiodarone group, but the group effect was not quite significant (p = 0.08). (Solid circles = group A, amiodarone; open circles = group B, control.) (LVSAX = left ventricular short-axis.)

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Intravenous amiodarone caused a decrease in arterial pressure during drug loading. Hypotension requiring treatment occurred in 20% of patients receiving amiodarone, a frequency that was similar to that observed in clinical trials of intravenous amiodarone for treating ventricular arrhythmias [3–6]. The maximum decrease in arterial pressure occured at 6 minutes and resolved by 15 minutes after the start of drug loading. The decrease in arterial pressure after intravenous amiodarone was not associated with decreased CO, left ventricular systolic performance, or cardiac preload indicating that the decrease in arterial pressure was a consequence of arterial vasodilation.

The magnitude and duration of drug-induced hypotension in the study may underestimate the changes that may be expected in a clinical setting. Safety concerns mandated that arterial pressure be controlled within strict limits. Patients were monitored continuously and hypotension defined as a SBP less than 85 mm Hg was treated immediately, thereby limiting the maximum drug-induced decrease in arterial pressure. The early treatment of hypotension by discontinuing vasodilators or administering phenylephrine may have contributed to the rebound in arterial pressure observed at 10 to 15 minutes after amiodarone in group A. Another explanation for the relatively minor hemodynamic difference between groups was the use of pulmonary catheter and TEE data to optimize the hemodynamic condition of patients before drug administration. It is possible that the magnitude or duration of drug-induced hypotension may be more severe and less predictable in hemodynamically compromised patients in a less intensely monitored setting. Only a standard recommended loading dose of intravenous amiodarone was tested. Administering a greater loading dose of amiodarone or administering the loading dose more rapidly may magnify drug-induced hemodynamic changes.

No evidence of significant myocardial depression accompanied the decrease in arterial pressure after intravenous amiodarone. The absence of detectable changes in CVP and pulmonary artery pressures together with no detectable decreases in CO, SVO, and FAC indicated that drug-induced hypotension was caused primarily by arterial vasodilation. The small increase in EDA and ESA shortly after drug administration was consistent with increased left ventricular preload and may have reflected increased rates of intravenous fluid administration to patients manifesting greater decreases in arterial pressure after drug administration even though volume expansion was not used to treat hypotension according to the study protocol. Increased left ventricular preload may also explain the slightly greater CO in the amiodarone group. Studies have demonstrated that TEE could detect changes in systolic function in the range of 5% to 20% caused by hypovolemia or intraaortic balloon counterpulsation [9, 10]. Selective arterial vasodilation should have normally increased CO and FAC because of decreased left ventricular afterload and reflex activation of sympathetic nervous system tone. These predicted responses to arterial hypotension may have been attenuated by the drug-induced decrease in heart rate, the effects of general anesthesia, or the prompt treatment of hypotension. It was possible that the absence of a detectable increase in CO, increase in FAC, and decrease in ESWS in response to the decreased arterial pressure may have been caused by drug-induced myocardial depression. If drug-induced myocardial depression occurred, the effect was small.

Intravenous amiodarone decreased the average heart rate by 12 beats per minute beginning within minutes after drug administration. The negative chronotropic effect of amiodarone was similar to the 11 to 12 beats per minute decrease observed in other clinical trials but no patients in the study required treatment for drug-induced bradycardia [7]. In contrast to the decrease in arterial pressure, the drug-induced decrease in heart rate persisted for at least 4 hours after drug administration. Although the frequency of postoperative atrial fibrillation was greater in the control group, amiodarone was not dosed appropriately for the treatment of atrial fibrillation nor was the study powered to test the antiarrhythmic actions of amiodarone.

It has not been established with certainty whether intravenous amiodarone depresses myocardial contractility. Most experimental studies indicated that amiodarone decreased left ventricular dP/dt [11–15]. In many of these studies, the negative inotropic action of amiodarone was observed only at concentrations that exceeded those encountered in clinical settings [11, 13, 14]. Clinical studies of chronic or long-term oral amiodarone therapy have demonstrated that LVEF remained unchanged or even increased [8, 16, 17]. In contrast, clinical studies of intravenous amiodarone has been observed to increase left ventricular end-diastolic pressure and decrease cardiac index leading investigators to believe that it caused myocardial depression [18–22]. Only one previous clinical study assessed the effect of intravenous amiodarone on left ventricular function directly by echocardiography and demonstrated increased left ventricular systolic performance associated with the decrease in blood pressure [23]. It was possible that the negative chronotropic actions of amiodarone complicated the interpretation of drug-induced changes in ventricular performance when cardiac output was dependent on heart rate. In the study by Bellotti and colleagues [19] it was noted that left ventricular stroke volume was preserved despite the decrease in cardiac index following amiodarone administration.

The acute circulatory actions of polysorbate 80 and benzyl alcohol in the drug delivery vehicle may also explain the different hemodynamic responses to oral and intravenous amiodarone. Both experimental and clinical studies comparing the actions of intravenous amiodarone formulated with or without polysorbate 80 demonstrated that only formulations containing polysorbate 80 caused significant decreases in arterial pressure [22, 24]. Acute hypotension without myocardial depression during intravenous amiodarone loading was consistent with an experimental study that showed neither amiodarone nor polysorbate 80 altered myocardial contractile force [25]. The dichotomy between the arterial pressure and heart rate responses to intravenous amiodarone also suggested different pharmacologic mechanisms. The short duration of hypotension during drug infusion was not consistent with the long duration of action of amiodarone. In contrast, the long duration of the negative chronotropic response to amiodarone was consistent with the known pharmacologic characteristics of the drug. Examining the hemodynamic responses to new formulations of intravenous amiodarone that do not contain polysorbate 80 or benzyl alcohol may help establish whether hypotension during intravenous amiodarone administration can be attributed to the independent actions of the drug delivery vehicle.

A potential limitation of the study was distinguishing drug-induced circulatory changes from inherent changes in the clinical setting of surgery. The timing of drug administration was chosen to avoid many of the hemodynamic changes caused by acute separation from cardiopulmonary bypass, manipulation of the heart, sternal closure, and surgical stimulation. In addition, anesthetic technique was standardized. The control group provided an additional means to isolate drug effects from usual circulatory changes after sternal closure. The protocol-dictated interventions to treat hypotension may have attenuated the magnitude of drug-induced hypotension that would be observed normally in untreated patients, but provided information on the consequences of treating hypotension with vasopressor therapy. The incidence of hypotension requiring treatment between groups was different, but not statistically different because the study was powered to detect differences in hemodynamic responses over time rather than the incidence of events between groups. A heterogeneous population was chosen for study to provide results that would be representative of a typical clinical mix of patients. In contrast to an earlier clinical study, amiodarone-induced hypotension did not selectively affect patients with low LVEF [20].

	Acknowledgments

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The study was supported in part by a research grant from Wyeth-Ayerst Laboratories. The authors wish to acknowledge Joseph E. Bavaria, MD, Michael A. Acker, MD, Robert C. Gorman, MD, Bruce R. Rosengard, MD, and Alberto Pochettino, MD, Division of Cardiothoracic Surgery, for their support and assistance in conducting this study.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Timothy J. Gardner Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cheung, A. T. Articles by Gardner, T. J. Search for Related Content PubMed PubMed Citation Articles by Cheung, A. T. Articles by Gardner, T. J. Related Collections Electrophysiology - arrhythmias