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Eur J Cardiothorac Surg 2004;25:224-230
© 2004 Elsevier Science NL

Supraventricular tachyarrythmia prophylaxis after coronary artery surgery in chronic obstructive pulmonary disease patients (early amiodarone prophylaxis trial)

Erkan Kuralaya*, Faruk Cingöza, Selim Kiliçb, Cengiz Bolcala, Celalettin Günaya, Ufuk Demirkiliça, Harun Tatara

a GATA Cardiovascular Surgery Department, Gülhane Military Medical Academy, Yazanlar sokak No. 31/11, Asagi Ayranci, Ankara 06540, Turkey
b Department of Public Health and Epidemiology, Etlik, Ankara, Turkey

Received 19 July 2003; received in revised form 30 October 2003; accepted 11 November 2003.

* Corresponding author. Tel.: +90-312-468-1773; fax: +90-312-232-3038
e-mail: ekural{at}gata.edu.tr


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 References
 
Objective: Supraventricular tachyarrhythmias (SVT) is common after coronary artery bypass grafting in chronic obstructive pulmonary disease (COPD). Preoperative FEV1 is the major predetermining factor of mortality, morbidity and SVT. Methods: Patients were divided into two groups according to their preoperative FEV1 values. FEV1 is <75% of predicted value in group 1 (no. 200), and >=75% of predicted value in group 2 (no. 100). Group 1 is divided into two subgroups. SVT prophylaxis was not done in A subgroup (no. 100) whereas arrhythmia prophylaxis was done with amiodarone in all B subgroups (no. 100) in the early postoperative period. Results: Atrial fibrillation developed in 28 patients in group 1A, whereas it developed in 12 in group 1B (P=0.005). Atrial flutter developed in 10 patients in group 1A but in 3 patients in group 1B (P=0.045). Multifocal atrial tachycardia developed in 13 patients in group 1A and in 4 in group 1B (P=0.022). Multivariate analysis identified ejection fraction (P<0.002, odds ratio (OR) 0.93), inotropy requirement (P<0.001, OR 3.98) amiodarone (P<0.001, OR 0.18), and FEV1<75% of predicted value (P<0.048, OR 1.84) as predictor of SVT. There were statistically significant differences between A and B subgroups of group 1 for hospital (P<0.001) and intensive care unit (ICU) stay (P<0.001). There was also statistically significant difference between groups 1A and 2 comparison for ICU (P<0.001; 6.4±3.4 versus 1.4±0.6 days) and hospital stay (P<0.001; 17.6±8.2 versus 6.9±0.6 days). Conclusions: Early prophylactic amiodarone not only significantly reduces SVT but also reduces SVT-related hospital and ICU stay. We strongly recommend prophylactic early use of amiodarone in COPD patients.

Key Words: Amiadarone • Supraventricular tachycardia • Coronary artery bypass


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 References
 
Coronary artery bypass grafting (CABG) is a safe and effective surgical intervention that is performed successfully with advanced technological methods and distinctive strategies for a wide range of patients. Recently CABG has been performed even on elderly patients with co-morbid medical problems such as chronic obstructive pulmonary disease (COPD) [1]. COPD has been considered as a risk factor for early mortality in patients undergoing CABG, and forced expiratory volume in the first minute (FEV1) has been shown to be an independent risk factor for early mortality [2]. Vital capacity, functional residual capacity, total lung capacity and pulmonary diffusion capacity are all reduced after open heart operation and return of these variables to their preoperative levels takes up to approximately 4 months [3,4]. Postoperative complications such as respiratory failure, re-intubation, sternal dehiscence, prolonged mechanical ventilation and atrial fibrillation (AF) are very common after CABG in COPD patients. Atrial arrhythmias, especially AF, present an important but probably benign morbidity after coronary artery surgery. Usually, most of the AF rapidly self-recovers and cannot cause embolic attacks and serious hemodynamic disturbance. The incidence of AF in the early postoperative period varies between 15 and 40%. The most common postoperative atrial arrhythmias are transient and cause little morbidity [1–6]. But the profile of AF is relatively different in COPD patients. If any treatment protocol is not administered supraventricular tachyarrhythmias (SVT) may persist and sustain for a long time in COPD patients [7]. These SVT [commonly AF and multifocal atrial tachycardia (MAT)] may cause hypotension, congestive heart failure (CHF) or subjective discomfort and anxiety, lengthen the period of postoperative hospitalization, necessitate posthospital medications and increase the total cost of medical care. Systemic embolization during the arrhythmia is another and the most feared complication in COPD patients. There have been several studies done on the necessity of prophylaxis of AF in early postoperative and long-term period. There is no consensus about the necessity of AF prophylaxis in early period [4,5]. Yilmaz and co-workers [8] had advocated that long-term drug prophylaxis is not necessary in some patients. FEV1<75% of predicted value and age are some of the strong predictors of mortality after CABG surgery. The relationship between FEV1 and mortality in COPD patients was shown by Samuels et al. [9] to be 50% mortality in patients over 75 years of age and FEV1<75%. In this study, we attempted to answer the question of whether the prophylaxis of SVT is necessary or not in COPD patients.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 References
 
2.1. Study design
This prospective study was done between June 1997 and January 2002. The aim of our study was to investigate the effect of amiadorane for reducing both supraventricular and ventricular arrhythmia among patients with COPD who underwent coronary artery bypass surgery. We recognized a patient with COPD who has positive physical examination findings and has <75% predicted value of FEV1. During our study period, the number of COPD patients who underwent coronary artery bypass surgery was 200. These patients were divided into two groups (A and B subgroups). Each group included 100 patients. We decided to give amiadorane to the odd-numbered patients and not to give the medication to the even-numbered patients. The decision as to which group (odd-numbered or even-numbered) would take the amiadorane was determined by drawing lots at the beginning of the procedure and amiadorane was decided to be given to the odd-numbered patients. We had a hypothesis that patients with COPD had more frequent arrhythmias with respect to the normal group. To evaluate this hypothesis for every two COPD patients, we selected one patient who had normal respiratory functions with FEV1>=75% of predicted value during the same period (group 2; no. 100). Arrhythmia prophylaxis with amiodarone was done in the intensive care unit (ICU) just after operation in all B subgroups (no. 100). Amiodarone loading (1200 mg/day) dose was given intravenously and then 600 mg/day oral amiodarone was administered to extubated patients. If the patient was intubated, 400 mg/day amiodarone was infused. Amiadarone was administered 600 mg/day in 10 days after loading dose (1200 mg/day). The dose gradually tapered to 400 mg/day over the following 10 days. Then a 200 mg/day single dose of amiadarone was administered for at least 4 months. Patients' characteristics in the preoperative period and the operations performed are summarized in Table 1. Corticosteroids were not administered in both patient groups. Methylxantine and ß2-mimetics therapies were routinely administered in the postoperative periods. Blood gases and oxygen saturation were routinely followed in the postoperative periods. Low flow nasal oxygen was administered intermittently in the postoperative ward after ICU therapy was completed. Nasotracheal aspirations were done when necessary. Amiadarone administration just after operation without any evidence of arrhythmia is not a standard protocol in our department. For this reason informed consent was obtained from the B subgroup patients. Low molecular weight heparin was used in all patients during AF or atrial flutter for prophylaxis of stroke. All procedures were done with cardiopulmonary bypass (CPB). CPB was established with a roller pump non-pulsatile flow after anticoagulation with bovine lung heparin (3 mg/kg) and activated clotting time was maintained for more than 480 s. Membrane oxygenators (Capiox-E Terumo Corp, Tokyo, Japan) were used in all cases. Heparin was reversed by protamine (3.5 mg/kg) at the end of the CPB. All distal anastomosis was done in a single cross-clamp period.


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  		Table 1. Patients characteristics and operative variables

 
2.2. Exclusion criteria
All re-operative and off-pump procedures were excluded from the study. Ejection fraction (EF) <25% and concomitant valvular operations were excluded. Rhythm disorders such as AF and atrial flutter in preoperative period and patients with antiarrhythmic drugs were also excluded.

2.3. Arrhythmia analysis
Continuous rhythm monitoring was done in the ICU. Rhythm analysis was also done by using a telemetry system (Hewlett-Packard Telemetry system) on the postoperative ward. Patients were also examined for any time symptoms suggestive of the occurrence of arrhythmias such as palpitation or dizziness. Radial pulse was taken at least six times a day by medical assistants and family members.

2.4. Operative characteristics
All patients in all groups had elective or urgent operations. All were in hemodynamically stable condition when brought to the operating room. All patients underwent primary coronary re-vascularization. CPB was done in all patients with single venous and aortic cannula. Moderate hypothermia to 26 °C and topical cooling with iced saline slush were used in all patients. Myocardial preservation was accomplished with the intermittent use of both antegrade and retrograde St Thomas II solution. St Thomas II solution was infused antegradely via aortic root needle just after cross-clamp insertion then cardioplegia infused retrogradely for every 20 min.

2.5. Sample size
According to our previous clinical observations, SVT developed in 45% of the COPD patients. We predicted 20% reduction of SVT in the COPD patients with amiodarone prophylaxis. To detect this difference with 95% confidence limits and power of 80% we needed to enter at least 96 patients into each group [10].

2.6. Statistical analyses
Statistical analysis was performed with SPSS software version 10.0 (SPSS Inc., Chicago, IL). Clinical data were expressed as mean values±standard deviation. Differences were analysed with Fisher's exact test, {chi}2-test, unpaired Student's t-test and Mann–Whitney test. We investigated the effects of the variables on supraventricular arrhythmias by calculating odds ratios (OR) in univariate analyses for all COPD patients. Variables for which the unadjusted P-value was <=0.20 in logistic regression analysis were identified as potential risk markers and included in the full model. We conducted stepwise multivariate analyses by using logistic regression. We reduced the model by using backward elimination and we eliminated potential risk markers by using likelihood ratio tests.


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
References
 
All patients were successfully weaned from CPB. Inotropy was required in 97 patients and intra-aortic balloon counterpulsation (IABP) in 28 patients during the weaning from CPB. Average cross-clamp and CPB time are summarized in Table 2. Re-intubation was done in 34 patients, among whom 14 required tracheostomy. Air leakage was found from chest tube drains in 85 patients. Sternal dehiscence was developed in 39 patients. Three of these patients required re-operation and sternum was re-wired in re-operation. External chest support (Heart Hugger-Sternum Support Harness) was used for another 36 patients. Superficial wound infection on the sternotomy incision occurred in 53 patients. Transient ischemic attack (TIA) developed in five patients and stroke developed in six COPD patients. TIA did not develop in the control group but stroke developed in one patient in the control group. Hospital mortality was developed in 16 patients in COPD patients but only one hospital mortality was developed in the non-COPD group (P=0.013). There were statistically significant differences between A and B subgroups of group 1 for hospital (P<0.001) and ICU stay (P<0.001). There was statistically significant difference between groups 1A and 2 comparison for ICU (P<0.001; 6.4±3.4 versus 1.4±0.6 days) and hospital stay (P<0.001; 17.6±8.2 versus 6.9±0.6 days). Average ICU stay in group 1B was 4.4±2.2 and 1.4±0.6 days in group 2 (P=0.014). Average hospital stay was 14.5±6.3 in group 1B and 6.9±0.6 in group 2 (P=0.001). Detailed postoperative variables are summarized in Table 2.


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  		Table 2. Perioperative and postoperative variables

 
3.1. Arrhythmia profile
AF developed in 28 patients in group 1A, whereas it developed in 12 patients in group 1B (P=0.005). AF developed in 17 patients in group 2. Atrial flutter developed in 10 patients in group 1A but 3 patients in group 1B (P=0.045). Atrial flutter developed in 6 patients in group 2. MAT developed in 13 patients in group 1A but in 4 patients in group 1B (P=0.022). MAT did not develop in any group 2 patient. There was statistically significant difference between groups 1A and 1B based on total supraventricular tachycardia (SVT) (P<0.001). There was also statistically significant difference between groups 1A and 1B for ventricular arrhythmias. Ventricular premature beat (VPB) was detected in 12 patients in group 1A, but 4 patients in group 1B (P=0.037). VPB was detected in 7 patients in group 2. Ventricular tachycardia developed in 6 patients in group 1A, 1 patient in group 1B (P=0.12), and 1 patient in group 2. Ventricular fibrillation developed in 3 patients in group 1A and 1 patient in group 2. There was statistically significant difference between groups 1A and 1B based on total ventricular arrhythmias (P=0.001). Postoperative arrhythmia profile of groups is summarized in Table 3.


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  		Table 3. Postoperative arrhythmia profile

 
3.2. Average onset and duration of SVT
Average onset of SVT in group 1A was 14.3±5.2 h postoperation, but 66.1±7.6 h for group 1B (P<0.001). Average onset of SVT in group 2 was 52.1±14.4 h. There was also statistically significant difference between groups 1A and 2 comparison (P<0.001). But there was no statistically significant difference between groups 1B and 2 comparison (P=0.065) for onset of SVT. Average duration of SVT was 37.4±11.7 h in group 1A but 7.4±3.1 h in group 1B (P<0.001). Average duration of SVT was 4.2±1.4 h in group 2. There was also statistically significant difference between both groups 1A and 2 (P<0.001), and between groups 1B and 2 (P=0.042) comparisons for duration of SVT.

3.3. Predictors of supraventricular tachyarrhythmias
Data for all groups were combined and 15 variables were subjected to statistical analysis as a predictor of SVT. As shown in Table 4 univariate analysis identified inotropy requirement (P<0.001, OR 3.32), EF (P=0.003, OR 0.95), cross-clamp time (P=0.028, OR 0.98), tracheostomy (P=0.026, OR 3.56), re-intubation (P<0.001, OR 4.70), amiodarone (P<0.001, OR 0.35), LITA (P=0.003, OR 0.46) and FEV1<75% of predicted value (P<0.005, OR 2.12) as predictor of SVT. Stepwise multivariate analysis confirmed the significance of some of the above-mentioned variables as a predictor of SVT. The value of -2 log likelihood of multivariate analyses was 426.701. These were EF (P<0.002, OR 0.93), inotropy requirement (P<0.001, OR 3.98), amiodarone (P<0.001, OR 0.18), and FEV1<75% of predicted value (P<0.048, OR 1.84). The effects of operative and patients' variables on SVT by univariate and multivariate logistic regression analyses are shown in Table 4.


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  		Table 4. Effects of various variables on the supraventricular arrhythmias based on univariate and multivariate logistic regression analyses

 
3.4. Discussion
Recent studies strongly proved development of lung injury after CPB, even preoperatively in completely normal functioning lung [11,12]. Lung injury becomes more prominent after surgery in COPD patients. Pulmonary variables returned to their preoperative levels in approximately 4 months in COPD patients [3,4]. Several studies have been made to establish COPD as a risk factor for mortality in patients undergoing CABG [1,11–14]. The Society of Thoracic Surgeons established COPD as an operative risk factor and Cleveland Clinic score has allotted COPD a value of 1 [12]. The Veterans Administration showed patients undergoing CABG with an FEV1<1.25 l to have significantly higher acute mortality rate [2]. Detailed quantitative analysis of the influence of COPD on patients undergoing CABG has not been done. The association of COPD with an increased incidence of ventricular and supraventricular arrhythmias is well established. Especially supraventricular arrhythmias are common after CABG in patients with COPD patients [15,16]. Hospitalized patients with COPD have as high an incidence of arrhythmias as 89%. Poor ventilatory mechanics and atelectasis of the lung in the postoperative period will aggravate ventilation perfusion (V/Q) mismatch and hypoxia. AF decreases the cardiac output and leads to further deterioration of hypoxemia that can be fatal if not corrected. COPD patients have frequent premature atrial contraction that predisposes them to AF [17,18]. The COPD proved to be predictor of AF. A similar association between COPD and AF was found by Leitch et al. [19] in their retrospective review of 5807 patients who underwent CABG in an earlier era. Our study is also confirmed by all the above-mentioned studies. Univariate (P=0.005, OR 2.12) and multivariate (P=0.048, OR 1.84) studies identified COPD as a predictor of SVT in this study. FEV1<75% of predicted value, is the main predictor of SVT. Supraventricular arrhythmias after CABG are usually benign and of short duration in the normal population. But SVT after CABG in COPD patients persists for rather longer periods of time and causes both hemodynamic compromise and embolic complication [7]. Average onset of SVT was on postoperative 14.3±5.2 h in group 1A but 66.1±7.6 h in group 1B (P<0.001). Average onset of SVT in group 2 was 52.1±14.4 h. Average duration of SVT was 37.4±11.7 h in group 1A but 7.4±3.1 h in group 1B (P<0.001). Average duration of SVT was 4.2±1.4 h in group 2. This profile of SVT is attributable to several factors such as hypoxemia, hypercapnia and medications for COPD (methylxantine and ß2-mimetics therapy). Some studies have shown benefits of prophylactic oral amiodarone for SVT in the normal population [8,20]. Cohen et al. [7] recommended prophylaxis against both SVT and also ventricular arrhythmias in both early and late postoperative periods in COPD patients. There was statistically significant difference between groups 1A and 1B for AF (P=0.005), atrial flutter (P=0.045) incidence, ICU (P<0.001) and hospital stay (P<0.001) in our early amiadarone prophylaxis trial in COPD patients. Borzak and colleagues [21] showed that AF is strongly associated with prolonged hospital stay, and it appears to be attributable to the rhythm itself. The reasons for the prolonged hospital stay attributable to AF were examined by Aranki and colleagues [22]. They found that patients with AF had an increased incidence of pneumonia, prolonged mechanical ventilation, and other respiratory complications as well as renal failure and more serious ventricular arrhythmias and hemodynamic compromise. Long-time AF can also increase the risk of stroke, so we routinely used low molecular weight heparin just after onset of AF. There are lots of amiadarone prophylaxis protocols in the literature [23–25]. Our amiadarone prophylaxis is similar to Guarnieri protocols. Usually long-term prevention of SVT is not necessary in the normal population [8,23–25]. A COPD patient constitutes more specific subgroups. SVT is much more common in this subgroup patients. Hemodynamic compromise because of arrhythmias in this group was a major cause of morbidity and mortality [7]. Cohen [7] suggests arrhythmia prophylaxis after CABG and maintenance of antiarrhythmic drugs indefinitely.

3.5. Conclusion
There is a strong relation between FEV1 and AF. Multivariate analyses confirmed FEV1<75 of predicted value as a predictor of SVT. Early prophylaxis of SVT in COPD patients with amiodarone not only reduces SVT but also reduces SVT-related ICU and hospital stay. We strongly recommend early prophylactic use of amiodarone in COPD patients.


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 References
 

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