Impact of minimal invasive extracorporeal circulation on atrial fibrillation after coronary artery bypass surgery

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(1)UEF//eRepository DSpace Rinnakkaistallenteet. https://erepo.uef.fi Terveystieteiden tiedekunta. 2020. Impact of minimal invasive extracorporeal circulation on atrial fibrillation after coronary artery bypass surgery Ellam, Sten Wiley Tieteelliset aikakauslehtiartikkelit © 2020 International Center for Artificial Organs and Transplantation and Wiley Periodicals LLC All rights reserved http://dx.doi.org/10.1111/aor.13756 https://erepo.uef.fi/handle/123456789/23695 Downloaded from University of Eastern Finland's eRepository.

(2) Accepted Article. DR. STEN ELLAM (Orcid ID : 0000-0002-0077-7245). Article type. : Main Text. Impact of minimal invasive extracorporeal circulation on atrial fibrillation after coronary artery bypass surgery. Sten Ellam MD1, Juha Hartikainen MD, PhD2, Pekka Korvenoja MD3, Otto Pitkänen, MD, PhD1, Esko Tyrväinen MD1, Antti Valtola, MD2, Jari Halonen MD, PhD2 1Department. of Anesthesiology and Operative Services, Kuopio University Hospital, Kuopio,. Finland. 2Heart. Center, Kuopio University Hospital, and School of Medicine, University of Eastern. Finland, Kuopio, Finland. 3Acute. Care, South Karelia Central Hospital, Lappeenranta, Finland.. Running Head: Minimal invasive Extracorporeal Circulation and Atrial Fibrillation. Funding Source: This study was supported by research grant for Dr. Halonen from Government Research Foundation of Finland. Conflict of Interest Statement: The authors have no conflict of interest that would impact this study’s design, data collection, analysis and interpretation. ClinicalTrials.gov Identifier: NCT01160393 Correspondence to: This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/AOR.13756 This article is protected by copyright. All rights reserved.

(3) Accepted Article. Sten Ellam, MD Department of Anesthesiology and Operative Services Kuopio University Hospital PO Box 100, FI-70029 KYS, Finland E-mail: sten.ellam@kuh.fi Fax: +358-17-173443; Phone: +358-17-173311 Received: April 14, 2020 Revised: June 2, 2020. This article is protected by copyright. All rights reserved.

(4) Accepted Article. ABSTRACT Objectives: Postoperative atrial fibrillation (POAF) is the most common arrhythmia after cardiac surgery with an incidence between 15-50 % and pathophysiology not fully known. By choosing the method of extracorporeal circulation with focus on the reduction of systemic inflammatory response, one can potentially decrease the risk of POAF. In this prospective, randomized trial, we compared minimal invasive extracorporeal circulation (MiECC) with conventional extracorporeal circulation (CECC) in the prevention of POAF after coronary artery bypass surgery (CABG). Methods: A total of 240 patients who were scheduled for their first on-pump CABG, were randomized to MiECC or CECC. The primary outcome measure was the incidence of first POAF during the first 84 hours after surgery. Results:. POAF occurred in 42/120 (35.0 %) MiECC patients and 43/120 (35.8%) CECC patients with nonsignificant difference between the groups (OR 1.043, 95% CI 0.591-1.843, p=0.884). The first postoperative creatine kinase-MB mass (CK-MBm) value was lower in the MiECC group, 13.95 [10.5-16.7] (median [IQR]) than in the CECC group, 15.30 [11.4-18.9] (p=0.036) whereas the use of perioperative dobutamine was higher in the MiECC group, 18/120 (15.0%), than in the CECC group 8/120 (6.7%) (p=0.038). The incidence of a stroke, perioperative myocardial infarction and resternotomy caused by bleeding did not differ in the MiECC and CECC groups. Age (OR 1.08, 95% CI 1.04-1.13, p=0.000) and peak postoperative CK-MBm (OR 1.57, 95% CI 1.06-2.37, p=0.026) were independent predictors of POAF. Conclusion: MiECC compared to CECC was not effective in reducing the incidence of POAF in patients undergoing CABG. Key Words: minimal invasive extracorporeal circulation; miecc; mecc; atrial fibrillation; postoperative atrial fibrillation; coronary artery bypass surgery.. This article is protected by copyright. All rights reserved.

(5) Accepted Article. INTRODUCTION Postoperative atrial fibrillation (POAF) is the most common arrhythmia after cardiac surgery. The incidence of POAF has been reported to range from 15% to 50% after coronary artery bypass surgery (CABG), with a peak incidence occurring between the second and fourth postoperative days. [1-4]. POAF is associated with complications, including increased risk of stroke, need of additional treatment, as well as prolonged hospital stay and increased costs [4-8]. The pathophysiology of POAF is not fully understood. Open-heart surgery and extracorporeal circulation are known to be associated with systemic inflammation which is a possible mechanism responsible for POAF [9, 10]. In addition to directs effects on the heart, systemic inflammation may cause diminished visceral blood flow resulting in mucosal ischemia, oedema and impaired mucosal transport. Evolution of the cardiopulmonary bypass has emerged new techniques such as miniaturized extracorporeal circulation (MiECC). The concept behind MiECC is to reduce hemodilution and blood-artificial material contact as well as eliminate blood-air contact by using centrifugal pump driven, coated, closed and minimized circuit without an open venous reservoir. Despite the theoretical benefits of MiECC and evidence supporting its use [11] the effect of MiECC on the occurrence of POAF has not been evaluated in a prospective randomized set-up. To test the hypothesis, that MiECC is effective in the prevention of POAF after CABG surgery, we performed a prospective, randomized, open labelled clinical study to compare whether MiECC is superior to CECC in preventing POAF after CABG surgery. METHODS Patients. A total of 240 patients, aged 39-82 years, scheduled to undergo their first CABG at Kuopio University Hospital between February 2010 and August 2014 were enrolled. Patients with a history of episodes of atrial fibrillation or flutter, sick sinus syndrome, II-or III-degree atrioventricular block, heart failure, corticosteroid or immunosuppressive medication, thyroid disease as well as patients, who were scheduled for redo- or emergency surgery or were enrolled to another study, were excluded. Also, we excluded patients with unexpected conversion to offpump surgery due to atheromatous ascending aorta revealed by routine perioperative epiaortic scanning. The study flow diagram is shown in Figure 1.. This article is protected by copyright. All rights reserved.

(6) Accepted Article. Study protocol Patients underwent on-pump elective CABG surgery with MiECC or CECC method assigned by computer-generated randomisation list. The anesthetic management was the same in the both groups: propofol infusion, sufentanil and pancuronium boluses. Pulmonary artery catheter was used in all patients. The mean arterial pressure target was above 60 mmHg, and phenylephrine boluses or norepinephrine infusion were used if needed. Cardiac index target was above 2,0 l/min/m2, and dobutamine infusion (2-10. µg/kg/min) was applied when appropriate. Hemoglobin level below 80 g/l was the red blood cell transfusion trigger during the whole study period. After surgery, the patients were followed in the intensive care unit (ICU) and were weaned off ventilator when they fulfilled the following criteria: hemodynamic stability, peripheral temperature of more than 32°C, cooperativity, and no major bleeding. Chest drains were removed on the first postoperative day and patients were referred to the surgical ward. Patients in both study groups received per oral metoprolol of 50 mg x 3 from the first postoperative day. If the heart rate was lower than 60 beats per minute, dose was reduced to 25 mg x 3. Patients were connected to 3-lead ward monitors for continuous electrocardiographic monitoring for the 84-hour study period. The ward monitor stored electrocardiographic recordings for subsequent analysis. 12-lead electrocardiographic recording was performed if necessary and physician confirmed the rhythm and diagnosis. Ethics Committee of University of Eastern Finland approved the study protocol and all patients gave written informed consent. The study complies with the Declaration of Helsinki. ClinicalTrials.gov Identifier: NCT01160393. MiECC. The MiECC used is a type III system [12] built around HL 20 short console or Cardiohelp console (Maquet, Rastatt, Germany) including centrifugal pump, online monitoring of hemoglobin, hematocrit, temperature, and venous oxygen saturation. The type III set (Maquet) is customized. This article is protected by copyright. All rights reserved.

(7) Accepted Article. containing Quadrox-i adult microporous membrane oxygenator with integrated arterial filter, venous bubble trap (VBT), reservoir (with a possibility to give blood back to the venous line), and tubing. All elements of the system have Softline coating (Maquet). The circuit prime consists of 1,000 mL of Ringer-Acetate solution (Baxter Oy, Helsinki, Finland) and 10,000 IU heparin (Leo, Ballerup, Denmark). Air removal is possible from venting system, VBT, and arterial filter. Both venous and arterial sides have bubble alarms, additionally a level sensor on VBT. Closed venting was performed from the aortic root and/or from pulmonary artery via a drip chamber to the venous line, driven by negative pressure on the venous side. Calafiore-type warm blood cardioplegia was chosen to minimize hemodilution effect and administered at 34°C, driven by arterial line positive pressure without separate pump. Standalone flow/volume meter (Sono TT; Emtec GmbH, Finning, Germany) was used on the cardioplegia line to ensure cardioplegia flow and to measure volume. Initial antegrade dose and repeated boluses after 15-25 minutes, depending on the phase of procedure, were used. Closed circuit configuration was maintained in all cases throughout perfusion, no conversions to open system were made. CECC. For the CECC procedures S3 or S5 (LivaNova, Mirandola, Italy), heart-lung machines with roller pumps were used. Customized perfusion set from Maquet (open hard-shell venous reservoir, Quadrox-i adult microporous membrane oxygenator with integrated arterial filter and tubing, with all elements of circuit Softline-coated) was used. Circuit prime consists of 2,000 mL RingerAcetate solution + 10,000 IU heparin and 3.0 g of tranexamic acid. Buckberg-type tepid blood cardioplegia (4:1and 8:1 ratios) was used at 23°C via Plegiox (Maquet) heat exchanger and separate double-head roller pump. Initial antegrade dose and repeated boluses after 15-25 minutes, depending on the phase of procedure, were used. The suction system was the same in both extracorporeal circulation methods. Patients were cooled to 34°C and rewarmed to 36°C before decannulation. All patients received 3.0 g of tranexamic acid intravenously and another 3.0 g of tranexamic acid was added to perfusion set priming solution in the CECC group. Hepcon (Medtronic, Minneapolis, MN, USA) protocol was used, with activated coagulation time (ACT) target of 480 seconds in both MiECC and CECC groups. Heparin concentration level was controlled at 20- to 30-minute. This article is protected by copyright. All rights reserved.

(8) Accepted Article. intervals, and appropriate heparin concentration was maintained during the perfusion. At the end of the procedure, heparin was reversed with protamine according to the Hepcon calculation. After surgery, patients were transferred to intensive care unit for at least overnight. Outcome measures The primary outcome measure of the study was the occurrence of the first POAF episode after ICU arrival with duration of > 30 minutes or completion of the 84-hour study protocol. The rhythm was defined as atrial fibrillation when there were no consistent P waves before each QRS complex and ventricular rate was irregular. The secondary endpoints were perioperative use of vasoactive agents, perioperative myocardial infarction (defined as an increase of creatine kinase-MB mass (CK-MB) (normal value 7.0 mg/L) by more than five times (>35.0 mg/L) associated with new Q-waves or new LBBB or coronary new artery occlusion or new infarction scar in the cardiac imaging, CT or MRI), first postoperative CK-MBm at ICU arrival, peak postoperative CK-MBm, stroke (defined as a new neurological symptom verified by correlative changes in the computer tomography) and resternotomy caused by bleeding.. Sample size The sample size determination was based on the assumption that the incidence of POAF can be reduced from 30% (CECC) to 15% with MiECC method [13]. At a level of  .05 with a power of more than 80%, the sample size calculation was 120 patients in each group. Statistical analysis Continuous variables were analyzed with the Student’s t-test and Mann-Whitney U test when appropriate. Categorical variables were compared using the chi-square test or Fisher’s exact test. Normally distributed data were expressed as mean ± standard deviation (SD) and non-normal distributed data were expressed as median with interquartile range [IQR]. Multivariate logistic regression analysis with adjustment for previously reported risk factors of POAF (age, sex, extracorporeal circulation method, left ventricular ejection fraction, unstable angina pectoris, chronic obstructive pulmonary disease, and right coronary artery bypass) was used to compare the. This article is protected by copyright. All rights reserved.

(9) Accepted Article. incidence of POAF in MiECC and CECC groups [1] as well as preoperative and perioperative variables that differed between MiECC and CECC groups was used to compare the incidence of POAF in MiECC and CECC groups. The results are expressed as odds ratios with 95% confidence interval. IBM SPSS statistics software package version 22 was used for statistical analyses. A pvalue < 0.05 was considered statistically significant. RESULTS With respect to all preoperative characteristics, MiECC and CECC groups were well matched with no significant differences between the groups (Table 1). Perioperative characteristics are shown in Table 2. MiECC and CECC groups did not differ with respect to aortic cross clamp time, perfusion time, number of peripheral anastomoses or vessel bypassed (Table 2). The use of dobutamine perioperatively was higher in the MiECC group compared to CECC group (15.0% vs. 6.7%, p=0.038, respectively). In the whole study population, POAF developed in 85 (35.4%) patients. POAF occurred in 42 (35.0%) MiECC patients and in 43 (35.8%) CECC patients, with no difference between the groups (OR 1.04, 95% CI 0.59-1.84, p=0.884) (Tables 3, 4). The first postoperative CK-MBm value was lower in the MECC group than in the CECC group (13.95 [10.5-16.7] mg/L vs. 15.30 [11.4-18.9] mg/L, p=0.036, respectively). There was also a trend to lower in peak postoperative CK-MBm value in the MiECC group (p=0.074). The incidence of perioperative myocardial infarction, stroke and resternotomy due to bleeding, did not differ between the MiECC and CECC groups (Table 3). Mortality during the first 84 postoperative hours was zero in both groups. Multivariate logistic regression model did reveal statistically significant association between age (OR 1.08, 95% CI 1.04-1.13, p=0.000), peak postoperative CK-MBm (OR 1.57, 95% CI 1.062.37, p=0.026) and incidence of POAF. The use of dobutamine tended to reduce the risk of POAF, but failed to demonstrate a statistically significant difference (OR 0.41, 95% CI 0.14-1.06, p=0.075). Other preoperative and perioperative risk factors, including extracorporeal circulation method, did not show associations with POAF (Table 4).. This article is protected by copyright. All rights reserved.

(10) Accepted Article. DISCUSSION The main finding of our randomized, controlled trial was that MiECC type III configuration compared to CECC was not effective in reducing the incidence of POAF in patients undergoing CABG. To our knowledge, our study is first to study the effect of MiECC with POAF as the primary endpoint. POAF is the most common complication after cardiac surgery with reported incidence of 15-50 % after CABG and even higher after concomitant valve surgery [1-4, 14]. POAF is clinically significant, because it increases the risk of stroke, heart failure, prolongs hospital stay, readmissions, and increases costs [8]. Inflammatory response caused by cardiopulmonary bypass has been considered as major contributor of POAF after cardiac surgery. MiECC represents a novel cardiopulmonary bypass circuit aiming to reduce the inflammatory response and postoperative complications, such as POAF. Fromes et al. [15], Immer et al. [16] and Remadi et al. [17] have reported reduced inflammatory response in MiECC patients versus CECC patients undergoing CABG surgery. In an early retrospective study by Wiesenack et al. MiECC reduced the incidence of POAF from 33% to 12% compared to the standard CECC [13]. However, since then meta-analyses as well as prospective randomized trials have addressed this issue with somewhat contradictory results. The meta-analyses by Zangrillo et al. and Biancari et al. found no difference in the incidence of POAF between patients treated with MiECC or CECC [18, 19]. On the other hand, Anastasiadis et al. reported in their large meta-analysis of 24 studies and c. 2800 patients that MiECC reduced the occurrence of POAF from 27.6 % to 19.2 % [20]. Correspondingly, of the four randomized trials comparing MiECC and CECC, two reported that MiECC was associated with 33-38 % reduction in the development of POAF [21, 22]. In the study by El-Essawi the incidence of POAF reduced from 24.2 % to 16.3 %, and in the study by Anastasiadis from 53.3 % to 33.3 %. However, in line with us, two other randomized trials reported that MiECC was not superior to CECC with respect to the incidence of POAF [17, 23]. The contradictory results of the benefits of MiECC reported in earlier studies, including our study, may be due to differences in the definition of POAF. In our study, as well as in all the aforementioned studies patients undergoing CABG with no additional surgery were studied. In spite of this, the incidence of POAF in the reference group (CECC) has ranged considerably, from. This article is protected by copyright. All rights reserved.

(11) Accepted Article. 19% to 53% [17, 21-24]. This most probably depicts different definition of POAF used in these trials. The earlier trials were not primarily designed to address the incidence of POAF, but the activation of inflammatory and coagulation pathways and recovery from cardiac surgery. Therefore, none of them has reported the definition of POAF. AF episodes with duration of few seconds to minutes and hours are observed after cardiac surgery. Thus, to address the question of incidence of POAF as the primary endpoint, one needs to define the method to diagnose AF (monitoring or 12-lead ECG) as well as the duration of AF that is counted as POAF. It is likely that the difference in the POAF incidence between the earlier trials and our result is, at least partly, due to different definitions of POAF. In our study, the incidence of POAF was the primary endpoint and thus, patient were on continuous ECG monitoring for the whole study period, a 12lead ECG was performed if needed to confirm the rhythm and POAF was defined as AF with duration of > 30 minutes. The differences between our results and the earlier randomized studies may also mirror differences in patient characteristics, particularly, preoperative history of AF [17, 21-23]. In the earlier trials patients with preoperative paroxysmal of persistent AF were not excluded, whereas in our study only patients without a history of atrial fibrillation were included. In spite is this, in our study the incidence of POAF was rather high (35%-36 %). Dobutamine has been associated with increased risk of POAF in cardiac surgery patients undergoing CECC [25]. On the other hand, in the randomized study by El-Essawi et al. comparing MiECC and CECC, the lower incidence of POAF in MiECC patients was not related to dobutamine use [22]. In our study, MiECC patients were more often treated with perioperative dobutamine. However, multivariate logistic regression model showed that dobutamine tended to be associated (albeit non-significantly) with lower POAF incidence. Thus, it is unlikely that dobutamine would explain the lack of benefit with respect of POAF in MiECC treated patients. Cardiopulmonary bypass results in inflammatory response characterized by activation of cytokines and complements and contributing myocardial damage, cardiac dysfunction and development of POAF [23]. In our study, the first postoperative creatine kinase-MB mass, a marker of perioperative myocardial injury, was significantly lower in the MiECC group than in the CECC. This article is protected by copyright. All rights reserved.

(12) Accepted Article. group, which is in accordance with Remadi et al., El-Essawi et al. and Farag et al. [17, 22, 26]. However, this, obviously beneficial issue was not mirrored by lower incidence of POAF. One year of age increased the risk of POAF by 8%,which complies with published literature [1]. This, however, does not explain the lack of MiECC to prevent PAOF, since age in MiECC and CECC groups did not differ from each other. Classification of a MiECC systems to distinctive types was first published by Anastasiadis et al. in 2015 [12]. Our study was conducted between 2010-2014 and designed even before that. Customized MiECC set that we used for the study complies with the definition of MiECC type III. In our MiECC group, closed circuit configuration, including venting, was maintained in all cases throughout perfusion and no conversions to open system were made. We acknowledge some limitations of our study. We used different cardioplegia methods between the MiECC and CECC groups. Buckberg-type tepid blood cardioplegia is the routine method in our clinic for CECC. Calafiore-type warm blood cardioplegia is used routinely for MiECC to avoid excessive hemodilution and achieve mandatory cardioplegia concentrate volume reduction, which, is a conceptual choice for minimized perfusion circuit. However, it is unlikely that the difference in the cardioplegia method would explain our results. Namely, Falcoz et al. in their prospective randomized study with 70 patients, comparing tepid and warm blood cardioplegia, found no statistical difference between the groups, concerning POAF [27]. In addition, to minimize the effect of different perfusion methods, both types of extracorporeal circulation sets were from the same manufacturer, with the same coating and same oxygenator. In our study, the postoperative follow-up was 84 hours. According to our hospital practice, patients with uncomplicated recovery are discharged back to the referral hospital on the 4th postoperative day. In earlier studies, the incidence of AF has been highest 24-72 hours after the operation [1, 28]. This period was well covered in our study. Our study result was very clear and the trend to either side cannot be observed. Thus, with high a confidence, we can state that the study sample size was sufficient to draw solid conclusion;. This article is protected by copyright. All rights reserved.

(13) Accepted Article. prevention of the POAF with the MiECC method still remains controversial and is a promising field for further studies. CONCLUSION There was no difference in the incidence of postoperative atrial fibrillation after cardiac surgery between the MiECC with type III configuration and CECC groups. More prospective, randomized studies are needed to establish potentially useful methods in the prevention of postoperative atrial fibrillation in cardiac surgery patients.. This article is protected by copyright. All rights reserved.

(14) Accepted Article. Acknowledgements The authors thank biostatistician Tuomas Selander, MSc, and study nurse Petri Toroi, RN, for excellent contribution. Also, we thank the perfusionists Mika Niiranen, RN, Heikki Miettinen, RN, Tuomas Lukkari, RN, Niko Luostarinen, RN and Petteri Mustakallio, RN, for their enthusiasm to develop minimal invasive extracorporeal circulation method in our clinic. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding This study was supported by the research grant from the Government Research Foundation of Finland.. Author contributions All authors contributed to study design, data collection, drafting, revising and approving the article. Pitkänen, Ellam, Hartikainen and Halonen performed statistical analysis.. This article is protected by copyright. All rights reserved.

(15) Accepted Article. REFERENCES 1. Aranki SF, Shaw DP, Adams DH, et al. Predictors of atrial fibrillation after coronary artery surgery. Circulation 1996;94:390–397.. 2. Svedjeholm R, Håkanson E. Predictors of atrial fibrillation in patients undergoing surgery for ischemic heart disease. Scand Cardiovasc J 2000;34:516 –521.. 3. Mahoney EM, Thompson TD, Veledar E, et al. Cost-effectiveness of targeting patients undergoing cardiac surgery for therapy with intravenous amiodarone to prevent atrial fibrillation. J Am Coll Cardiol 2002;40:737–745.. 4. Hakala T, Pitkänen O, Hippeläinen M. Feasibility of predicting the risk of atrial fibrillation after coronary artery bypass surgery with logistic regression model. Scand J Surg 2002;91:339–344.. 5. Almassi GH, Schowalter T, Nicolosi AC, et al. Atrial fibrillation after cardiac surgery. A major morbid event? Ann Surg 1997;226: 501–513.. 6. Creswell LL, Schuessler RB, Rosenbloom M, et al. Hazards of postoperative atrial arrhythmias. Ann Thorac Surg 1993;56:539–549.. 7. Lahtinen J, Biancari F, Salmela E, et al. Postoperative atrial fibrillation is a major cause of stroke after on-pump coronary artery bypass surgery. Ann Thorac Surg 2004;77:12411244.. 8. LaPar DJ, Speir AM, Crosby IK, et al. Investigators for the Virginia Cardiac Surgery Quality Initiative. Postoperative Atrial Fibrillation Significantly Increases Mortality, Hospital Readmission, and Hospital Costs. Ann Thorac Surg 2014;98:527–33.. 9. Hall RI, Smith MS, Rocker G. The systemic inflammatory response to cardiopulmonary bypass: pathophysiological, therapeutic, and pharmacological considerations. Anesth Analg 1997;85:766-782.. 10. Wan S, LeClerc JL, Vincent JL. Inflammatory response to cardiopulmonary bypass: mechanisms involved and possible therapeutic strategies. Chest 1997; 112:676-692.. 11. Anastasiadis K, Murkin J, Antonitsis P, et al. Use of minimal invasive extracorporeal circulation in cardiac surgery: principles, definitions and potential benefits: a position paper from the Minimal invasive ExtraCorporeal Technologies international Society (MiECTiS). Interact Cardiovasc Thorac Surg 2016; 22: 647–662.. This article is protected by copyright. All rights reserved.

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(17) Accepted Article. 23. Sakwa MP, Emery RW, Shannon FL, et al. Coronary artery bypass grafting with a minimized cardiopulmonary bypass circuit: a prospective, randomized trial. J Thorac Cardiovasc Surg 2009; 137: 481–485.. 24. Halonen J, Hakala T, Auvinen T, et al. Intravenous administration of metoprolol is more effective than peroral administration in the prevention of atrial fibrillation after cardiac surgery. Circulation 2006; 114(suppl):I1-I4.. 25. Feneck RO, Sherry KM, Withington PS, et al. Comparison of the hemodynamic effects of milrinone with dobutamine in patients after cardiac surgery. J Cardiothorac Vasc Anesth. 2001 Jun;15(3):306-15.. 26. Farag M, Patil NP, Sabashnikov A. Comparison of Two Miniaturized Cardiopulmonary Bypass Systems Regarding Inflammatory Response. Artif Organs. 2017 Feb;41(2):139145.. 27. Falcoz P-E, Kaili D, Chocron S, et al. Warm and tepid cardioplegia: Do they provide equal myocardial protection? Ann Thorac Surg 2002;74: 2156-2160.. 28. Halonen J, Halonen P, Järvinen O, et al. Corticosteroids for the Prevention of Atrial Fibrillation After Cardiac Surgery: A Randomized Controlled Trial. JAMA 2007;297(14):1562–1567.. This article is protected by copyright. All rights reserved.

(18) Accepted Article. Table 1. Preoperative clinical characteristics. MiECC n = 120. CECC n = 120. p-value. Age (years). 65.1 ± 8.2. 64.8 ± 9.3. 0.791. Body surface area (m2). 2.0 ± 0.2. 2.0 ± 0.2. 0.472. LVEF (%). 56.9 ± 13.4. 55.6 ± 10.3. 0.280. Sex (male). 98 (81.6). 97 (80.8). 0.869. COPD. 13 (10.8). 6 (5.0). 0.138. Diabetes mellitus. 27 (22.5). 32 (26.6). 0.123. Left main stenosis. 45 (37.5). 45 (37.5). 1.000. Unstable angina pectoris. 34 (28.3). 39 (32.5). 0.196. CCS/NYHA class. 0.869. 1. 2 (1.7). 1 (0.8). 2. 35 (29.1). 26 (1.7). 3. 50 (49.6). 54 (44.5). 4. 33 (27.6). 39 (32.5). B-blocker. 90 (75.0). 89 (74.2). 1.000. Nitroglycerin. 71 (59.2). 69 (57.5). 0.896. Ca-antagonists. 22 (18.3). 23 (19.2). 1.000. ACE inhibitors/ARB. 63 (52.5). 74 (61.7). 0.192. Statins. 117 (97.5). 110 (91.7). 0.084. Diuretics. 26 (21.7). 19 (15.8). 0.321. Clopidogrel. 3 (2.5). 4 (3.3). 1.000. Warfarin. 3 (2.5). 2 (1.7). 1.000. Low molecular weight heparin. 27 (22.5). 33 (27.5). 0.456. Hemoglobin (g/l). 143.9 ± 13.0. 140.3 ± 15.7. 0.051. The values are n (%) or mean ± SD. MiECC = minimal invasive extracorporeal circulation; CECC = conventional extracorporeal circulation; ACE = angiotensin convertase enzyme; ARB =. angiotensin receptor blocker; LVEF = left ventricular ejection fraction; COPD = chronic obstructive pulmonary disease; CCS = Canadian Cardiovascular Society score; NYHA = New York Heart Association classification score; SD = Standard deviation.. This article is protected by copyright. All rights reserved.

(19) Accepted Article. Table 2. Perioperative clinical characteristics. MiECC n = 120. CECC n = 120. p-value. Aortic cross clamp time, (min). 80.3 ± 25.8. 77.7 ± 23.8. 0.420. Perfusion time, (min). 93.7 ± 30.4. 89.5 ± 28.5. 0.267. Number of peripheral anastomoses. 3.9 ± 1.1. 3.9 ± 1.0. 0.667. LAD region. 1.5 ± 0.6. 1.6 ± 0.6. 0.214. LCX region. 1.5 ± 0.7. 1.3 ± 0.7. 0.100. RCA region. 1.0 ± 0.7. 1.1 ± 0.6. 0.225. Dobutamine use. 18 (15.0). 8 (6.7). 0.038. Norepinephrine use. 29 (24.2). 20 (16.7). 0.150. The values are mean + SD or n (%). MiECC = Minimal invasive extracorporeal circulation; CECC = conventional extracorporeal circulation; LAD region = Left anterior descending artery and diagonal branches; LCX region = Circumflex artery and marginal branches; RCA region = Right coronary artery and marginal branches; SD = standard deviation.. This article is protected by copyright. All rights reserved.

(20) Accepted Article. Table 3. Postoperative clinical characteristics. MiECC n = 120. CECC n = 120. p-value. POAF (first postoperative 84 hours) 42 (35). 43 (35.8). 0.884. Perioperative myocardial infarction. 3 (2.5). 1.000. First postoperative CK-MBm (mg/L) 14.0 [10.5-16.7]. 15.3 [11.4-18.9]. 0.036. Peak postoperative CK-MBm (mg/L) 11.15 [14.3-18.4]. 11.83 [15.6-21.5]. 0.074. Stroke. 2 (1.7). 1 (0.8). 0.513. Resternotomy. 4 (3.3). 7 (5.8). 0.539. 2 (1.7). The values are n (%) or median [IQR]. MiECC = Minimal invasive extracorporeal circulation; CECC = conventional extracorporeal circulation; POAF = Postoperative atrial fibrillation; CKMBm = creatine kinase-MB mass; [IQR] = interquartile range.. This article is protected by copyright. All rights reserved.

(21) Accepted Article. Table 4. Risk factors and postoperative atrial fibrillation in multivariate logistic regression model.. Odds ratio. 95% CI. p-value. Age. 1.08. 1.04-1.13. 0.000. Sex. 1.08. 0.53-2.18. 0.838. Extracorporeal circulation method. 1.04. 0.59-1.84. 0.884. Left ventricular ejection fraction. 1.00. 0.97-1.03. 0.953. Unstable angina pectoris. 1.11. 0.60-2.04. 0.750. Chronic obstructive pulmonary disease0.55. 0.18-1.73. 0.308. Right coronary artery bypass. 1.53. 0.74-3.15. 0.249. Dobutamine use. 0.41. 0.14-1.06. 0.075. Peak postoperative CK-MBm. 1.57. 1.06-2.37. 0.026. CI = Confidence interval; CK-MBm = creatine kinase-MB mass.. This article is protected by copyright. All rights reserved.

(22) Accepted Article. Figure 1. Study flow diagram.. Total of 1885 CABG patients between February 2010 and August 2014.. 243 patients enrolled for randomization.. 122 patients randomized to MiECC group.. 2 patients excluded due to unexpected conversion to off-pump surgery.. 120 patients to final analysis in the MiECC group.. Excluded patients with previous episodes of atrial fibrillation or flutter, sick sinus syndrome, II-or III-degree atrioventricular block, heart failure, corticosteroid or immunosuppressive medication, thyroid disease, redo- or emergency surgery and participation in another study. 121 patients randomized to CECC group.. 1 patient excluded due to unexpected conversion to off-pump surgery.. 120 patients to final analysis in the CECC group.. CABG = coronary artery bypass surgery; MiECC = minimal invasive extracorporeal circulation; CECC = conventional extracorporeal circulation..

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