Anesth Analg 1999;89:585
© 1999 International Anesthesia Research Society
CARDIOVASCULAR ANESTHESIA
An Assessment of the Safety of Short-Term Amiodarone Therapy in Cardiac Surgical Patients with Fentanyl-Isoflurane Anesthesia
C. Michael White, PharmD
,§,
Alisha Dunn, PharmD,§,
James Tsikouris, PharmD,§,
Witold Waberski, MD
,
Kathy Felton, RN*,
Linda Freeman-Bosco, RN*,
Satyendra Giri, MD*, and
Jeffrey Kluger, MD*,||
*Division of Cardiology and Departments of
Pharmacy and
Anesthesiology, Hartford Hospital, Hartford; and Schools of
§Pharmacy and
||Medicine, University of Connecticut, Storrs and Farmington, Connecticut
Address correspondence and reprint requests to Jeffrey Kluger, MD, Hartford Hospital, 80 Seymour St., Hartford, CT 06102-5037. Address e-mail to jkluger{at}harthosp.org
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Abstract
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In previously published case reports and a retrospective study, investigators have noted that amiodarone may cause substantial hemodynamic instability when combined with fentanyl-containing anesthesia regimens. We performed the present study to evaluate the safety of short-term amiodarone therapy when combined with a fentanyl-containing anesthesia regimen in a randomized, double-blinded, placebo-controlled format. After institutional approval and written informed consent, patients scheduled to undergo coronary artery bypass grafting or valvular surgery were randomly allocated to receive amiodarone (3.4 g over 5 days or 2.2 g over 24 hours) or placebo before surgery. Four indicators for hemodynamic instability were assessed: 1) a net increase in fluid balance during surgery of >2 L; 2) use of dopamine at a rate >10 µg · kg-1 · min-1; 3) use of other vasopressive catecholamines; and 4) use of a phosphodiesterase inhibitor or intraaortic balloon pump. Systolic, diastolic, and central venous pressures were measured before fentanyl administration, before cardiopulmonary bypass (CPB), and after separation from CPB. Overall, 84 patients (45 patients in the amiodarone group, 39 in the placebo group) were enrolled and completed the study. There were no significant differences between the two groups in any indicator for hemodynamic instability or the indicators of instability combined. After CPB, there was a significantly lower systolic blood pressure in the amiodarone group compared with the placebo group (112 ± 12 vs 117 ± 14 mm Hg;
P = 0.049). However, there was a trend toward smaller IV fluid requirements during surgery in the amiodarone group compared with the placebo group (438 ± 867 vs 907 ± 1640 mL; P = 0.09). We found no increased risk of hemodynamic compromise after short-term amiodarone therapy among patients receiving a fentanyl-containing anesthesia regimen during open heart surgery.
Implications: In previous retrospective studies and case reports, investigators have identified a possible risk of hemodynamic compromise when patients receiving chronic amiodarone therapy are given anesthesia regimens containing fentanyl. We performed a prospective, randomized, double-blinded study to evaluate the hemodynamic effects of short-term amiodarone therapy during fentanyl-isoflurane anesthesia for open heart surgery. No adverse hemodynamic effects of amiodarone were identified.
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Introduction
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Amiodarone is an iodinated benzofuran derivative classified as a Vaughn-Williams class III antiarrhythmic drug and is commonly used to suppress ventricular and supraventricular tachyarrhythmias. Amiodarone also has a noncompetitive antiadrenergic effect, and it was initially developed as an antianginal drug (1). In case reports, investigators have found an association between chronic amiodarone use and atrioventricular blockade, symptomatic bradycardia, sinus arrest, and severe hypotension resistant to 
1-adrenoceptor agonists when amiodarone is combined with anesthesia (2–4). In four of the five referenced cases, fentanyl-containing anesthesia regimens were used (2–4). In another case report, the systemic vascular resistance of a patient receiving chronic amiodarone therapy decreased from 2200 to 1400 dynes · s · cm-5 30 min after fentanyl was administered (5). This case may be important because fentanyl was the only drug used within or before that time period. The authors of a retrospective review reported a 67% incidence of bradyarrhythmias when patients receiving amiodarone were given anesthesia during surgery. They also reported a 50% incidence of hypotension or low cardiac output state that required intraarterial balloon counterpulsation (6). The events in the retrospective review and the case reports all occurred during the intraoperative period, usually after separation from cardiopulmonary bypass (CPB). All 16 of the patients had received anesthesia regimens containing fentanyl (6). This prompted one standardized textbook (7) to report an amiodarone-fentanyl interaction as having level 1 (i.e., critical) significance. A retrospective study of patients receiving amiodarone undergoing heart transplantation also demonstrated a significant increase in the dose of norepinephrine and milrinone used versus historical controls. The investigators, however, did not report the anesthesia regimen used (8).
In contrast, a small randomized study of 19 patients undergoing open heart surgery who received 3 wk of amiodarone (10 g) or no therapy did not demonstrate an increased risk of bradyarrhythmias or hypotension when a fentanyl-containing anesthesia regimen was used in patients receiving amiodarone (9).
Administering short-term amiodarone therapy to patients before open heart surgery has been shown to decrease the risk of postoperative atrial fibrillation (10,11). However, the authors of these studies did not identify the anesthesia regimen or the intraoperative safety of therapy. Before amiodarone can be commonly used to prevent atrial fibrillation in patients undergoing Coronary Artery Bypass Graft (CABG) or valvular surgery, a comprehensive assessment of amiodarone's intraoperative safety when combined with anesthesia is needed. If substantial hemodynamic compromise occurs after short-term amiodarone therapy, alternative anesthetics or antiarrhythmics will need to be identified.
The purpose of this study was to investigate whether there is an increase in hemodynamic compromise when an anesthesia regimen containing fentanyl is administered to elderly patients receiving short-term amiodarone therapy before CABG or valvular surgery.
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Methods
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This prospective, randomized, double-blinded, placebo-controlled trial was conducted at a tertiary care teaching hospital. Enrollment began February 1, 1998 and continued until October 1, 1998. Patients >60 yr old who were electively scheduled for open heart surgery (>12 h away) were screened for eligibility. Patients with current atrial fibrillation or flutter, moderate to severe liver disease, sinus bradycardia without a pacemaker, second- or third-degree heart block, or an implantable cardiac defibrillator, and patients currently taking class I or III antiarrhythmic drugs, cimetidine, phenytoin, cholestyramine, or cyclosporin were excluded. Patients who did not give their written, informed consent were also excluded. The study protocol was approved by our institutional review board.
At our hospital, patients are usually scheduled for surgery no more than 6 days in advance. Patients enrolled at least 5 days before surgery were randomly allocated to receive a 5-day loading dose and dose on the morning of surgery or to receive a matching placebo. Patients scheduled <5 days but >24 h before surgery were randomly allocated to receive a 1-day oral loading regimen on Preoperative Day 1 and a dose on the morning of surgery or to receive a matching placebo. The 5-day oral regimen consisted of amiodarone of 200 mg three times a day for 5 days (3 g total) with a dose of 400 mg on the morning of surgery. The 1-day regimen consisted of amiodarone 400 mg four times a day for 1 day (1600 mg total) with a 600-mg dose on the morning of surgery.
Preoperative demographic data, such as patient gender, surgery type (valvular surgery versus nonvalvular surgery), age, and left ventricular ejection fraction, were collected. Intraoperative demographic data, such as aortic cross-clamp time; total CPB time; dose of fentanyl, midazolam, and pancuronium; and the total number of capsules actually ingested before surgery, were also collected.
The primary objective was to compare the occurrence of hemodynamic compromise between patients randomized to amiodarone or placebo during surgery. Hemodynamic compromise was defined as a net increase in fluid status (fluid administered minus fluid lost during surgery) of >2 L, the use of >10 µg · kg-1 · min-1 dopamine, the need for additional vasopressor catecholamines (epinephrine, norepinephrine, or phenylephrine), the need for a phosphodiesterase inhibitor (amrinone or milrinone), or the use of an intraaortic balloon pump. Dopamine was routinely administered in small to moderate doses unless hemodynamic compromise occurred.
Systolic blood pressure (SBP), diastolic blood pressure (DBP), and central venous pressure (CVP) were recorded at three times. The initial recording of these variables occurred in the operating room before the induction of anesthesia (prefentanyl). In this phase, 2 mg of midazolam was given before pulmonary artery catheter placement and readings were taken. Anesthesia was then induced with midazolam and fentanyl and maintained at a bispectral array electroencephalogram level of 30–70 with isoflurane (0.2%–1.5% via an endotracheal tube), midazolam, and fentanyl. Pancuronium was used to prevent movement during the open heart procedures. Immediately before CPB, the SBP, DBP, and CVP were recorded again (pre-CPB). At this point, the heart was cannulated and CPB was initiated. After CPB weaning, the SBP, DBP, and CVP were measured again.
The SBP, DBP, and CVP were compared prefentanyl (after the induction of anesthesia but before fentanyl administration), immediately before CPB, and immediately after CPB between the amiodarone and placebo groups. In a similar manner, the heart rates were compared prefentanyl and after CPB for the amiodarone and placebo groups. The aortic cross-clamp and total CPB times were also compared.
We compared the subgroup receiving the 5-day amiodarone loading regimen with the subgroup receiving the 1-day amiodarone loading regimen, and both of these groups were compared with the total placebo group. All of the study variables in the primary analysis were evaluated for the subgroups.
The indicators for hemodynamic instability were compared between the amiodarone and placebo groups by using a 
2 or Fisher's exact test (depending on numbers in each cell). The patient's age, left ventricular ejection fraction, heart rate, SBP, DBP, CVP, amount of fluid given, and dopamine administration rate were reported as means ± SDs. Student's t-tests were used to compare characteristics of the amiodarone and placebo groups and to compare the subgroups based on the length of the loading dose. A P value <0.05 was considered statistically significant.
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Results
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Overall, 84 patients were enrolled into the study; 45 received amiodarone and 39 received placebo. There were no significant differences between the amiodarone and placebo groups in any of the patient characteristics (Table 1). In the amiodarone group, two patients (4.4%) had a net increase in fluid status of >2 L, compared with four patients (10.3%) in the placebo group (P = 0.202). No patient in either group received >10 µg · kg-1 · min-1 dopamine or required the use of an intraaortic balloon pump. Eight amiodarone-treated patients (17.8%) required epinephrine, norepinephrine, or phenylephrine during surgery, compared with five patients (12.8%) in the placebo group (P = 0.746). One patient (2.2%) required milrinone therapy in the amiodarone group, compared with two patients (5.1%) in the placebo group (P = 0.595). When the indicators of hemodynamic instability were combined, no differences were noted between the amiodarone (24.4%) and the placebo (28.2%) groups (P = 0.887).
The SBP, DBP, CVP, heart rates, total fluid administered, and total net increase in fluid status are reported in Table 2. The prefentanyl SBP was significantly lower in the amiodarone group than in the placebo group (P = 0.018). After separation from CPB, the SBP was again significantly lower in the amiodarone group than in the placebo group (P = 0.049). There were no differences in the DBP, CVP, or heart rate at any point evaluated in the study for either group. There were also no differences in the average administration rate of dopamine for either group. The amiodarone group tended to receive less fluid and exhibit a lower net increase in fluid status during surgery than the placebo group, although statistical significance was not reached (P = 0.13 and P = 0.09, respectively).
When the two amiodarone subgroups were compared for all study variables, no significant differences were noted (Table 3).
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Discussion
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We assessed the safety of short-term amiodarone therapy among patients undergoing open heart surgery who received fentanyl-isoflurane anesthesia. We performed this study in a randomized, double-blinded, and placebo-controlled manner. With studies showing that short-term amiodarone therapy can reduce the incidence of postoperative atrial fibrillation after open heart surgery, it was important to evaluate the safety of short-term amiodarone therapy in this population (6,7).
We could find no increase in the incidence of hemodynamic compromise in the group receiving amiodarone compared with those receiving placebo. The SBP was lower in the amiodarone group than in the placebo group after CPB, although the SBP in the amiodarone group still averaged 112 mm Hg, which is within the normal range. This effect on SBP was not unexpected, as amiodarone was originally developed as an antianginal and antihypertensive (12). The lower SBP in the amiodarone group before anesthetic induction with fentanyl (prefentanyl) suggests that the effect is that of amiodarone itself and not amiodarone and surgery or amiodarone and fentanyl. No differences in the DBP, CVP, or heart rate were observed after CPB in either group. The amiodarone group received less fluid during surgery than the placebo group, but the variability among patients in each group was large; thus, the two groups did not differ significantly.
We wanted to assess the effect of preoperative loading time and preoperative loading dose on hemodynamics. We postulated that the duration of amiodarone therapy and the dose might have been important in the initiation of the hemodynamic compromise. The duration of amiodarone therapy before surgery was theoretically important, as longer loading times increase the accumulation of amiodarone's active metabolite, desethylamiodarone (12). We found no differences in the indicators for hemodynamic compromise and no differences in the blood pressure or heart rate variables between the one-day and the five-day subgroups.
Our study does not exclude the possibility that long-term amiodarone therapy may increase the risk of hemodynamic compromise in patients receiving an anesthetic regimen containing fentanyl and undergoing open heart surgery. However, the hemodynamic compromise described in the previous cases and retrospective studies may be due to the underlying life-threatening co-morbid conditions for which amiodarone is used. Because the control patients in the previous retrospective studies did not have the same indications for antiarrhythmic therapy as the amiodarone group, the co-morbid conditions themselves could have caused the hemodynamic compromise during open heart surgery (3). In our study, the patients were randomized into treatment groups, and we excluded patients currently receiving antiarrhythmic drugs. Hence, the hemodynamic compromise after long-term amiodarone therapy may be due to a fentanyl interaction, anesthesia interaction in general, or underlying disease. Future studies of long-term amiodarone therapy are required to evaluate this supposition.
In summary, we found no increase in adverse hemodynamic effects after short-term amiodarone therapy among patients receiving fentanyl-isoflurane anesthesia for CABG or valvular surgery. The hemodynamic effects are not changed by increasing the loading regimen from one to five days or by increasing the loading dose from 2.2 to 3.4 g of amiodarone.
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Footnotes
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This study was sponsored by an open competition grant from the Hartford Hospital Research Foundation.
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References
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Accepted for publication May 14, 1999.
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Abstract
Introduction
