Effect of Dexamethasone on Atrial Fibrillation After Cardiac Surgery: Prospective, Randomized, Double-Blind, Placebo-Controlled Trial Jean-Pierre Yared, MD,* Mohamed H. Bakri, MD, PhD,* Serpil C. Erzurum, MD,†‡ Christine S. Moravec, PhD,§ Daniel M. Laskowski, BS, RPFT,†‡ David R. Van Wagoner, PhD,§ Edward Mascha, PhD, and Julie Thornton, MS Objective: The purpose of this study was to assess the effect of preoperative dexamethasone (DEX) on the occur- rence of postoperative atrial fibrillation (AF). Design: Prospective, randomized, double-blind, placebo- controlled clinical trial. Setting: Tertiary referral center. Participants: Seventy-eight adult patients undergoing combined valve and coronary artery bypass graft (CABG) surgery were randomized to receive either DEX or placebo. Interventions: The DEX group received dexamethasone, 0.6 mg/kg, after induction of anesthesia, and the placebo group received an equal volume of normal saline. Interleukin (IL)-6, -8, and -10; tumor necrosis factor ; and endothelin (ET)-1 were measured preoperatively and on postoperative days (POD) 1, 2, and 3. Complement (C-4) and C-reactive protein (CRP) were measured preoperatively and on POD 2. Exhaled nitric oxide (NO) was measured preoperatively, 15 minutes after aortic unclamping, and 1 hour after intensive care unit admission. Measurements and Main Results: No significant difference in the incidence of AF was found between the placebo (41%) and DEX groups (30%) (95% confidence interval [11%, 34%); p  0.31). DEX significantly reduced at least 1 postop- erative level of IL-6, IL-8, IL-10, CRP, and exhaled NO. DEX did not affect ET-1 or C-4 levels. IL-10 on POD 3 was posi- tively correlated with postoperative hospital length of stay (r  0.30, p  0.01). Increased levels of IL-8 and IL-10 on POD 1 were positively correlated with the intubation time (r  0.31, p  0.01; r  0.30, p  0.01, respectively). Conversely, C-4 on POD 2 was negatively correlated with the intubation time and intensive care unit length of stay (r 0.32, p  0.006; r 0.30, p  0.01, respectively). Conclusions: DEX did not affect the incidence of AF in patients undergoing combined CABG and valve surgery. However, it did modulate the release of several inflamma- tory and acute-phase response mediators that are associ- ated with adverse outcomes. © 2007 Elsevier Inc. All rights reserved. KEY WORDS: dexamethasone, atrial fibrillation, cardiopul- monary bypass, cytokines A N ESTIMATED 400,000 adults in the United States un- dergo coronary artery bypass graft (CABG) surgery an- nually. 1 Atrial fibrillation (AF) develops in up to 41.6% of patients after CABG surgery 2 and in over 60% of patients after combined CABG and valve surgery. 3 AF after CABG remains a major problem that is likely to increase in frequency because the typical patient undergoing CABG surgery today is older and has more left ventricular dysfunction than the typical patient decades ago. 4 With physicians and hospitals facing increasing pressure to control costs, the future of therapy for this condition lies in prophylaxis. The cumulative cost of AF care will exceed that of any other complication. Any reduction in its occurrence may result in enormous savings. Hravnak and colleagues 5 found that the economic impact of AF after CABG surgery was underes- timated in most previous reports. However, a recent report by Connolly et al 6 found that AF did not increase total costs. Further understanding of the pathophysiology of AF at the cellular and the molecular levels may provide more specific targets for prevention and treatment. 7 Cardiopulmonary bypass (CPB) triggers an inflammatory response and release of several mediators that may affect outcome after cardiac surgery. 8 Inflammatory markers includ- ing C-reactive protein (CRP), endothelin-1 (ET-1), comple- ment, and interleukin (IL)-6 have been associated with an increased incidence of AF. 9-12 The effect of CPB on the inflam- matory system may stem from circulatory and metabolic de- rangement and myocardial injury, 13-15 and this derangement may play a role in the pathogenesis of postoperative AF. 11 IL-6 and tumor necrosis factor  (TNF-) may contribute to myo- cardial dysfunction and hemodynamic instability after CPB. 16,17 Indeed, the myocardium is the major source of IL-8 during reperfusion after an extended period of ischemia or after acute myocardial infarction. 18 Anti-inflammatory cytokines such as IL-10 are released during CPB and may play a protec- tive role by suppressing the production of proinflammatory cytokines. 18,19 Cytokines and chemokines as well as exhaled nitric oxide (NO) have been used as markers of inflammation and may indicate the effectiveness of anti-inflammatory ther- apy. 20-22 The authors previously reported as an incidental finding that dexamethasone (DEX) reduced the incidence of new-onset AF from 52.6% to 18.2% after combined CABG and valve sur- gery. 23 This finding served as a hypothesis generator, and the present study was designed so that the dose and timing of DEX would be similar to the ones used in the original study. The previous study was designed to assess the effect of DEX on postoperative shivering, but AF was not looked at prospectively (post hoc analysis). The present study was designed to verify whether this incidental finding could be confirmed prospec- tively. The objective of this study was to evaluate the ability of From the Departments of *Cardiothoracic Anesthesiology, †Patho- biology, ‡Pulmonary, Allergy and Critical Care Medicine, §Cardio- vascular Medicine, and Quantitative Health Sciences, Cleveland Clinic Foundation, Cleveland, OH. Supported in part by core services provided by the Public Health Service Research Grant M01 RR018390. S.C.E. and D.M.L. were funded by HL 60917 and HL 04265. D.R.V. was supported by RO1 HL-65412 (Oxidative Stress and Atrial Fibrillation). Address reprint requests to Jean-Pierre Yared, MD, Cleveland Clinic Foundation, Department of Cardiothoracic Anesthesiology, 9500 Euclid Avenue, G5, Cleveland, OH 44195. E-mail: yaredj@ccf.org © 2007 Elsevier Inc. All rights reserved. 1053-0770/07/2101-0013$32.00/0 doi:10.1053/j.jvca.2005.10.014 68 Journal of Cardiothoracic and Vascular Anesthesia, Vol 21, No 1 (February), 2007: pp 68-75