Role of Postoperative Use of Adrenergic Drugs in Occurrence of Atrial Fibrillation after Cardiac Surgery

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1 Clin. Cardiol. 28, (2005) Role of Postoperative Use of Adrenergic Drugs in Occurrence of Atrial Fibrillation after Cardiac Surgery VIKRANT SALARIA, M.D., NIRAV J. MEHTA, M.D., SYED ABDUL-AZIZ, M.D., SYED M. MOHIUDDIN, M.D., FACC, IJAZ A. KHAN, M.D., FACC* Division of Cardiology, Creighton University School of Medicine, Omaha, Nebraska, and *Division of Cardiology, University of Maryland School of Medicine, Baltimore, Maryland, USA Summary Background: Use of adrenergic (inotropic and vasopressor) drugs is common after cardiac surgery. Hypothesis: The study was undertaken to evaluate the role of postoperative adrenergic drug use as a predictor of postoperative (AF) after cardiac surgery. Methods: The study population consisted of 199 patients post cardiac surgery. Postoperative adrenergic drug use and the baseline and clinical variables were analyzed as possible predictors of postoperative AF. Results: Of 199 patients, postoperative AF occurred in 59 patients (incidence 30%). The adrenergic drugs were used in 127 (64%) patients. Postoperative AF occurred in 49 of the 127 patients (39%) with and in 10 of the 72 patients (14%) without adrenergic drug use (p < 0.01). By univariate analyses, postoperative adrenergic drug use, age, left ventricular hypertrophy, left atrial size, valve surgery, aortic valve replacement, cross clamp time, bypass time, postoperative ventricular pacing, and hours in intensive care unit were predictors of development of postoperative AF. Atrial pacing was a predictor of freedom from developing AF. By multivariate logistic regression analysis, adrenergic drug use was an independent predictor of postoperative AF (odds ratio [OR] 3.35, 95% confidence interval [CI] , p = 0.016). Two other independent predictors were valve surgery (OR 2.88, 95% CI , p = 0.002) and age (OR 13, 95% CI , p = Address for reprints: Ijaz A. Khan, M.D., FACC Division of Cardiology University of Maryland School of Medicine 22 South Greene Street - S3B06 Baltimore, MD 21201, USA ikhan@medicine.umaryland.edu Received: vember 29, 2004 Accepted with revision: January 18, ). Adrenergic drug use, valve surgery, ventricular pacing, and age were predictors of time duration from surgery to the occurrence of AF. Drugs with predominantly 1 -adrenergic receptor affinity were associated with a higher incidence of postoperative AF (dopamine 44%, dobutamine 41% vs. phenylepherine 20%, p = 0.001). Conclusion: Use of adrenergic drugs is an independent predictor of postoperative AF after cardiac surgery. Key words: heart surgery, postoperative, adrenergic, vasopressor, inotropic, cardiac arrhythmia, atrial arrhythmia, adrenergic receptor agonists Introduction Atrial fibrillation (AF) is the most common postoperative arrhythmia after cardiac surgery, with an incidence ranging from 15 to 50%. 1, 2 Postoperative AF could result in prolonged hospital stay, increased resource utilization, postoperative stroke, hemodynamic compromise, and, perhaps, higher mortality. 1 5 Age, atrial ischemia, intraoperative elements, postoperative fluctuations in autonomic tone, and postoperative sympathetic activation are the factors suggested as predictors of AF development after cardiac surgery. 1 7 Adrenergic drugs are used commonly after cardiac surgery to improve cardiac output and to raise blood pressure. The use of these drugs sets a higher catecholamine stage, which, theoretically, may trigger postoperative AF. Clinically, it is not known whether the use of adrenergic drugs after cardiac surgery is a predictor of occurrence of postoperative AF. The purpose of this study was to examine this hypothesis. Methods Study Population All patients aged > 18 years who underwent cardiac surgery at Creighton University Medical Center between June

2 132 Clin. Cardiol. Vol. 28, March and December 2000 were evaluated for inclusion in the study. Patients with a previous history of AF and those on antiarrhythmic drugs (except beta blockers) in pre- or postoperative periods were excluded. Of 400 patients who underwent cardiac surgery during the selected time period, 201 were excluded based on these two exclusion criteria, and the other 199 patients comprised the study population. The study protocol was approved by the Institutional Review Board of Creighton University. Data Collection Atrial fibrillation was defined as irregular heart rate without any P waves either on 12-lead electrocardiogram or continuous rhythm monitoring. Postoperative AF was defined as development of AF any time after surgery during the index hospitalization. The occurrence of postoperative AF was determined. The data were collected and tabulated on following variables: postoperative adrenergic drug use, age, gender, hypertension, smoking, preoperative echo parameters (left atrial size, left ventricular [LV] function, LV hypertrophy), type of cardiac surgery, cardioplegia used, cross clamp time, bypass time, perioperative beta-blocker use, postoperative cardiac pacing, postoperative serum magnesium, occurrence of postoperative transient attack/stroke, and stay in intensive care unit. These variables were examined for the prediction of postoperative AF. The adrenergic drugs were used postoperatively on as needed basis at surgeons discretion. The data collection was retrospective. Statistical Analysis Continuous variables were expressed as means ± standard deviation (SD) and analyzed by using Student s unpaired t- test. Categorical variables were expressed as n (%) and analyzed using chi-square statistics. Stepwise logistic regression analysis was used to determine the independent predictors for occurrence of postoperative AF, and Cox regression analysis was used to determine predictors of time from surgery to the occurrence of AF. A p value of 0.05 was considered significant. Computer software Statistical Package for Social Sciences 7.0 (SPSS Inc., Chicago, Ill., USA) was used for statistical analyses. Results Of 199 patients, postoperative AF occurred in 59 with an incidence of 30%. Adrenergic drugs were used in 127 (64%) patients. Postoperative AF occurred in 49 of the 127 patients (39%) with adrenergic drug use and 10 of the 72 patients (14%) without adrenergic drug use (p < 0.01). Baseline and clinical characteristics with univariate analyses are given in Table I. By univariate analyses, postoperative adrenergic drug use (p = ), age (p = ), LV hypertrophy (p = 0.03), left atrial size (p = 0.01), valve surgery (p = ), aortic valve replacement (p = 0.01), cross clamp time (p = 0.009), bypass time (0.01), postoperative ventricular pacing (p = ), and hours in intensive care unit (0.004) were predictors of development of postoperative AF (Table I). Atrial pacing was a predictor of freedom from developing AF (p = ). Similarly, perioperative beta-blocker use was higher in the group that did not develop AF, but the difference did not reach statistical significance. According to stepwise logistic regression analysis (Table II), adrenergic drug use was an independent predictor of postoperative AF (odds ratio [OR] 3.35, 95% confidence interval [CI] , p = 0.016). Two other independent predictors were valve surgery (OR 2.88, 95% CI , p = 0.002) and age (OR 13, 95% CI , p = ). By Cox regression analysis (Table III), adrenergic drug use (p = 0.003), valve surgery (p = 0.007), ventricular pacing (0.0001), and age (p = 0.001) were predictors of time duration from surgery to the occurrence of AF. The cumulative freedom from AF after surgery was lower with adrenergic drug use, valve surgery, and ventricular pacing (Figs. 1 3). Among various adrenergic drugs, use of those with predominantly 1 -adrenergic affinity was associated with a higher incidence of postoperative AF (dopamine 44% and dobutamine 41% vs. phenylepherine 20%, p = 0.001) (Table IV). Discussion Adrenergic drugs are used after cardiac surgery to maintain both cardiac index and blood pressure within reasonable limits. Our study demonstrated that the use of adrenergic drugs is an independent predictor of development of AF after cardiac surgery. Second, with the use of these drugs the cumulative freedom from AF after surgery is reduced. Third, the incidence of postoperative AF is higher with the use of predominantly 1 -adrenergic receptor agonists than with the use of a predominantly -adrenergic receptor agonist. This is the first study evaluating the role of adrenergic drug use in the development of postoperative AF after cardiac surgery. The autonomic nervous system is well known to be involved in the initiation and continuation of AF. Catecholamines enhance triggered activity and automaticity, the triggers for the initiation of AF. 8 In addition, catecholamines shorten atrial refractoriness in a nonhomogeneous pattern favoring the continuation of AF. 8 The postoperative state is clearly a hyperadrenergic condition resulting from multiple factors including operative trauma and stay in intensive care unit. A significant association has been shown between postoperative mixed venous norepinephrine levels after cardiac surgery and development of postoperative AF, suggesting that sympathetic activation may be an important factor in a majority of such patients. 9 This is further substantiated by the observation that postoperative AF usually resolves spontaneously once the provocative hyperadrenergic state is no longer present. Use of adrenergic drugs would further enhance the already present hyperadrenergic postoperative state and result in a higher chance for development of AF. The longer cross-clamp and bypass times, reported in the group with AF in the present study, may result in

3 V. Salaria et al.: Postoperative 133 TABLE I Atrial fibrillation after cardiac surgery Atrial fibrillation Variables (n = 59) (n = 140) p Value Postoperative adrenergic drug used (%) 49 (83) 78 (56%) Age (years) 74.3 ± ± Gender (M/F) (%) 36/23 (61/39) 90/50 (64/36) NS Hypertension (%) 49 (83) 104 (74) NS LV hypertrophy (%) 34 (58) 58 (41) 0.03 LV ejection fraction (%) 47.6 ± ± 12.9 NS LA size (mm) 44.9 ± ± Valve surgery (%) 28 (47) 27 (19) Aortic valve replacement (%) 18 (31) 20 (14) 0.01 Mitral valve replacement or repair (%) 10 (17) 6 (4) NS Tricuspid valve repair (%) ne 1 (1) NS On-pump CABG (%) 20 (34) 68 (49) NS Off-pump CABG (%) 10 (17) 33 (24) NS Septal myomectomy ne 1 (1) NS Aortic root replacement (%) 1 (2) 2 (1) NS Thoracic aortic aneurysm repair (%) ne 3 (2) NS LV septum repair (%) ne 3 (2) NS ASD repair (%) ne 3 (2) NS Cardioplegia used (%) 58 (98) 136 (97) NS Cross-clamp time (min) 98.6 ± ± Bypass time (min) ± ± Perioperative beta-blocker use (%) 49 (83) 122 (87) NS Postoperative atrial pacing (%) 48 (81) 139 (99) Postoperative ventricular pacing (%) 11 (19) ne Postoperative cardiac index 2.67 ± ± 7 NS Postoperative serum magnesium (meq/l) 1.96 ± ± 0.3 NS Hours in ICU ± ± Number of patients unless specified otherwise. Abbreviations: M = male, F = female, ASD = atrial septal defect, CABG = coronary artery bypass graft, ICU = intensive care unit, LA = left atrium, LV = left ventricular. TABLE II Prediction of after cardiac surgery Standard error Odds 95% Confidence interval Variables B of B ratio of odds ratio p Value Adrenergic drug use Valve surgery Ventricular pacing E Age TABLE III Predictors of time duration from surgery to occurrence of Variables B Standard error of B p Value Adrenergic drug used Valve surgery Ventricular pacing Age Cox regression analysis was used to model the effect of multiple covariates on time-to-. The final model included use of adrenergic drugs, valve surgery, ventricular pacing, and age. The final model significance was

4 134 Clin. Cardiol. Vol. 28, March 2005 Adrenergic drug use FIG. 1 after cardiac surgery with and without postoperative adrenergic drug use. Valve surgery FIG. 2 after cardiac surgery with and without valve surgery. Ventricular pacing FIG. 3 after cardiac surgery with and without postoperative ventricular pacing. TABLE IV Incidence of by adrenergic drug Incidence of AF Drugs used within Adrenergic drug within drug use AF group ne (%) 10/72 (14) 10/59 (17) Dopamine (%) 15/34 (44) a 15/59 (25) Dobutamine (%) 30/73 (41) a 30/59 (51) Phenylepherine (%) 4/20 (20) a 4/59 (7) a p = (dopamine vs. phenylepherine and dobutamine vs. phenylepherine) from Pearson s chi-square test. Abbreviation: AF =. study substantiates these findings. The greater risk of AF in cases of valve surgery is believed to result from atrial fibrosis and enlargement from valvular disease, higher atrial pressures, and higher ischemia-reperfusion injury from longer cardiopulmonary bypass time. 10, 11 Age-related structural and hemodynamic changes including atrial dilation, changes in atrial substrate, and higher atrial pressures due to age-related slow ventricular relaxation could be the plausible mechanisms of a higher incidence of postoperative AF in older patients. 12 In addition, aging is associated with increased sympathetic outflow and higher levels of circulating norepinephrine. 13 Another important observation of this study is that the use of adrenergic drugs is a predictor of time duration from surgery to the occurrence of AF with a reduced freedom from AF at any time postoperatively during hospital stay. The other factors that reduced the chances of freedom from AF were valve surgery, postoperative ventricular pacing, and age. It is interesting that ventricular pacing was not an independent predictor of postoperative AF but was a predictor of the time duration from surgery to the occurrence of AF. Due to loss of atrioventricular synchrony, ventricular pacing results in a marked hemodynamic change in the atria, resulting in higher atrial pressures, especially if the patient is in sinus rhythm, as atrial contraction against closed atrioventricular valve will result in an acute rise in atrial pressure. The acute hemodynamic changes in the atria can trigger AF, and this might explain how ventricular pacing is a predictor of the time duration from surgery to the occurrence of AF. Atrial pacing, on the other hand, was a predictor of freedom from developing AF, which is in accordance with previous observations. 14, 15 The incidence of postoperative AF was higher with the use of dopamine and dobutamine, both of which are predominantly 1 -adrenergic receptor agonists, compared with phenylepherine, which in therapeutic doses is predominantly an agonist of -adrenergic receptors and lacks direct stimulatory effects on atrial myocardium. In fact, the prevalence of AF in patients in whom phenylepherine was used was similar to those in whom no adrenergic drug was used. a substrate for AF by causing greater reperfusion injury and/or atrial ischemia. Both valve surgery and age have been consistently shown as independent predictors of postoperative AF, 1, 2 and the present Conclusions Adrenergic drug use is an independent predictor of postoperative AF after cardiac surgery. Patients who have undergone

5 V. Salaria et al.: Postoperative 135 cardiac surgery and who receive adrenergic drugs postoperatively have a higher chance of developing AF with less cumulative freedom from this arrhythmia in the postoperative period. The incidence of postoperative AF is higher with the use of 1 -adrenergic receptor agonists. Therefore, judicious postoperative use of adrenergic drugs with careful selection may reduce the incidence of AF after cardiac surgery. References 1. Funk M, Richards SB, Desjardins J, Bebon C, Wilcox H: Incidence, timing, symptoms, and risk factors for after cardiac surgery. Am J Crit Care 2003;12: Mathew JP, Fontes ML, Tudor IC, Ramsay J, Duke P, Mazer CD, Barash PG, Hsu PH, Mangano DT: A multicenter risk index for after cardiac surgery. J Am Med Assoc 2004;291: Tamis JE, Steinberg JS: Atrial fibrillation independently prolongs hospital stay after coronary artery bypass surgery. Clin Cardiol 2000;23: Creswell LL, Schuessler RB, Rosenbloom M, Cox JL: Hazards of postoperative atrial arrhythmias. Ann Thorac Surg 1993;56: Villareal RP, Hariharan R, Liu BC, Kar B, Lee VV, Elayda M, Lopez JA, Rasekh A, Wilson JM, Massumi A: Postoperative and mortality after coronary artery bypass surgery. J Am Coll Cardiol 2004;43: Crosby LH, Pifalo WB, Woll KR, Burkholder JA: Risk factors for after coronary artery bypass grafting. Am J Cardiol 1990;66: Kolvekar S, D Souza A, Akhatar P, Reek C, Garratt C, Spyt T: Role of atrial ischemia in development of following coronary artery bypass surgery. Eur J Cardiothorac Surg 1997;11: Waldo AL: Mechanisms of, atrial flutter, and ectopic atrial tachycardia. Circulation 1987;75(suppl 3): Kalman JM, Munawar M, Howes LG, Louis WJ, Buxton BF, Gutteridge G, Tonkin AM: Atrial fibrillation after coronary artery bypass grafting is associated with sympathetic activation. Ann Thorac Surg 1995;60: Asher CR, Miller DP, Grimm RA, Cosgrove DM III, Chung MK: Analysis of risk factors for development of early after cardiac valvular surgery. Am J Cardiol 1998;82: Bruins P, te Velthuis H, Yazdanbakhsh AP, Jansen PG, van Hardevelt FW, de Beaumont EM, Wildevuur CR, Eijsman L, Trouwborst A, Hack CE: Activation of the complement system during and after cardiopulmonary bypass surgery: Postsurgery activation involves C-reactive protein and is associated with postoperative arrhythmia. Circulation 1997;96: Manyari DE, Patterson C, Johnson D, Melendez L, Kostuk WJ, Cape RD: Atrial and ventricular arrhythmias in asymptomatic active elderly subjects: Correlation with left atrial size and left ventricular mass. Am Heart J 1990; 119: Hoeldtke RD, Cilmi KM: Effects of aging on catecholamine metabolism. J Clin Endocrinol Metab 1985;60: Greenberg MD, Katz NM, Iuliano S, Tempesta BJ, Solomon AJ: Atrial pacing for the prevention of after cardiovascular surgery. J Am Coll Cardiol 2000;35: Blommaert D, Gonzalez M, Mucumbitsi J, Gurne O, Evrard P, Buche M, Louagie Y, Eucher P, Jamart J, Installe E, De Roy L: Effective prevention of by continuous atrial overdrive pacing after coronary artery bypass surgery. J Am Coll Cardiol 2000;35: