Minimally invasive extracorporeal circulation improves quality of life after coronary artery bypass grafting

European Journal of Cardio-Thoracic Surgery 50 (2016) 1196 1203 doi:10.1093/ejcts/ezw210 Advance Access publication 14 June 2016 ORIGINAL ARTICLE Cite this article as: Anastasiadis K, Antonitsis P, Kostarellou G, Kleontas A, Deliopoulos A, Grosomanidis V et al. Minimally invasive extracorporeal circulation improves quality of life after coronary artery bypass grafting. Eur J Cardiothorac Surg 2016;50:1196 203. Minimally invasive extracorporeal circulation improves quality of life after coronary artery bypass grafting Kyriakos Anastasiadis, Polychronis Antonitsis*, Georgia Kostarellou, Athanassios Kleontas, Apostolos Deliopoulos, Vassilios Grosomanidis and Helena Argiriadou Cardiothoracic Department, AHEPA University Hospital, Thessaloniki, Greece * Corresponding author. Cardiothoracic Department, AHEPA University Hospital, S. Kyriakidi 1, 54636 Thessaloniki, Greece. Tel: +30-2310-994845; fax: +30-2310-994814; e-mail: antonits@auth.gr; antonits@otenet.gr (P. Antonitsis). Received 27 December 2015; received in revised form 2 May 2016; accepted 8 May 2016 Abstract OBJECTIVES: The effect on postoperative health-related quality of life (HRQoL) after coronary artery bypass grafting (CABG) surgery with conventional cardiopulmonary bypass (ccpb) and off-pump surgery has been investigated extensively; however, there are no studies focusing on HRQoL after surgery with minimally invasive extracorporeal circulation (MiECC). Therefore, we sought to prospectively investigate the effect of MiECC on postoperative HRQoL when compared with ccpb in patients undergoing CABG over a short-term (3-month) follow-up period. METHODS: Sixty patients scheduled for elective CABG surgery were randomly assigned into two groups: those who had surgery on MiECC system (n = 30) and those who underwent CABG using ccpb (n = 30). Quality-of-life assessment was performed preoperatively (baseline- T0), at first postoperative month (T1) and at 3-month follow-up (T3). The RAND SF-36 scale was used for data collection, which included both sociodemographic and clinical characteristics of patients. The primary outcome of the study was quantitative measurement of postoperative HRQoL at 3-month follow-up. RESULTS: Both groups were balanced in terms of demographic, socio-economic and operative characteristics. At 3-month follow-up, mean SF-36 component and summary scores in each group were higher in absolute values than the respective mean baseline scores, apart from role-physical score in patients operated with ccpb. Patients operated on MiECC showed uniformly significantly higher values in all individual and summary domains, whereas patients operated on ccpb showed significant improvement in 6/8 individual domains. Patients operated on MiECC showed a more pronounced increase in SF-36 individual domain scores from the first to the third postoperative month when compared with ccpb, which was statistically significant regarding physical functioning (P = 0.001), role-physical (P < 0.001), vitality (P = 0.01) and role-emotional (P = 0.004). This resulted in a significant improvement in physical (P = 0.002) and mental (P = 0.01) summary scores. CONCLUSIONS: The current study proves that MiECC significantly improves HRQoL after coronary surgery compared with ccpb. This finding, combined with results from large-scale studies showing superior clinical outcomes from its use, enhances the role of MiECC as a dominant technique in coronary revascularization surgery. Keywords: Minimally invasive extracorporeal circulation Cardiopulmonary bypass Coronary artery bypass grafting Quality of life INTRODUCTION Minimally invasive extracorporeal circulation (MiECC) has been developed in an attempt to integrate all advances in cardiopulmonary bypass (CPB) technology in one closed circuit that shows improved biocompatibility and minimizes systemic detrimental effects of CPB [1]. Large-scale cohort studies and multiple meta-analyses have proved that MiECC is associated with superior results in terms of reducing morbidity and mortality rates in patients operated for coronary artery bypass grafting (CABG) when compared with conventional CPB (ccpb) or off-pump coronary revascularization (OPCAB) [2]. These objective parameters are widely accepted and have been traditionally used for assessing the safety and effectiveness of any operative procedure. However, it has been recognized that CABG, despite improving survival and relieving angina even in an increasingly elderly and high-risk population, may not always lead to a better satisfaction with life [3]. Coronary surgery is still hampered by significant major morbidity and mortality rates affecting 13% of operated patients over a 12-month follow-up period [4]. These complications greatly influence patients subjective perception of the utility of CABG, sense of well-being, physical and mental functional capacity, which is defined as health-related quality of life (HRQoL) [5, 6], comprising one of the major indicators of their medical outcome. Modern The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

K. Anastasiadis et al. / European Journal of Cardio-Thoracic Surgery 1197 cardiac surgeons have become more attuned to the patients perception of the operation and its effect on HRQoL post surgery [7]. Consequently, the major goal of CABG is now focused on not just increasing survival and relieving symptoms, but also on improving patients postoperative functional level. Particularly in older age, when the life expectancy is naturally limited, the expected HRQoL after surgery becomes the most important indicator in deciding to perform CABG rather than considering less invasive percutaneous coronary intervention or medical treatment [8]. The effect on postoperative HRQoL after CABG surgery with ccpb and OPCAB has been investigated extensively [4, 9]; however, there are no studies focusing on HRQoL after surgery with MiECC. Therefore, we sought to prospectively investigate the effect of MiECC on postoperative HRQoL when compared with ccpb in patients undergoing CABG over a short-term (3-month) follow-up period. MATERIALS AND METHODS We conducted a single-centre prospective randomized study on 60 patients scheduled for elective CABG surgery at AHEPA University Hospital between January and December 2014. The study adhered to the Consolidated Standards of Reporting Trials (CONSORT) statement [10]. The CONSORT flow diagram is presented in Fig. 1. The study was approved by the institutional research ethics committee and all patients gave written informed consent. Registration at ClinicalTrials.gov was completed (NCT02000544). Patients were randomly assigned into two groups using computer-generated random allocations in a 1 : 1 randomization: those who had surgery on MiECC system (Group A) and those who underwent CABG using ccpb (Group B). The research group, the nursing staff and the patients were blinded to the allocated treatment. Eligible patients were 18 years old or greater, and referred for CABG according to the existing guidelines [11]. Exclusion criteria were emergency surgery, history of acute myocardial infarction with ST elevation <14 days old, critical preoperative state (inotropic support or intra-aortic balloon pump), concomitant valve surgery other than mitral valve repair for ischaemic mitral regurgitation, prior cardiac surgery, previous psychiatric illness (for example depression, schizophrenia) and inability to undergo a proper quality-of-life assessment (for example due to language difficulties or poor educational status). Perfusion technology Minimally invasive extracorporeal circulation group. The MiECC system used in MiECC group was a modular type IV circuit according to the classification scheme proposed by Anastasiadis et al. [12]. It consisted of a standard and a standing-by accessory circuit. Components of the standard circuit included: aortic cannula, three-stage venous cannula, coated tubing (Carmeda BioActive Surface, Medtronic Inc., Minnesota, USA), a centrifugal pump (Affinity CP pump, Medtronic Inc.), a new-generation membrane oxygenator with integrated arterial filter (Affinity Fusion, Medtronic Inc.), a venous air removal device (Medtronic Inc.), a soft coated bag and pulmonary artery as well as aortic root vent. Priming volume of the system was 500 ml, whereas retrograde autologous priming was utilized in all patients. In addition, there was a standby hard-shell reservoir in parallel to the venous line, so as to convert the closed ADULT CARDIAC Figure 1: The CONSORT flowchart by treatment group.

1198 K. Anastasiadis et al. / European Journal of Cardio-Thoracic Surgery system to an open one. This accessory component serves as a safety net in the unlikely event of an unexpected scenario (massive air entrainment into the circuit, significant blood loss) [13]. Conventional cardiopulmonary bypass group. A standard open CPB circuit was used, consisting of uncoated PVC tubing, a hard-shell venous reservoir, a microporous membrane oxygenator (Dideco, Mirandola, Italy) and a roller pump (Stöckert S3, Munich, Germany). The circuit contained an arterial line blood filter (Dideco) and it was primed with 1500 ml of a balanced crystalloid/ colloid solution (1000 ml of Ringer s solution, 200 ml of mannitol 20% and 300 ml of hydroxyethyl starch 6%) [14]. Cardiotomy and sump sucker were integrated to the circuit. Shed blood was collected in both groups with a cell-saving device (autolog Autotransfusion System, Medtronic Inc.). The extracorporeal flow rate for both systems was set at 2.4 l/min/m 2.Perfusionpressure was kept at a minimum of 60 mmhg. Anticoagulation in the ccpb group was attained by the administration of 300 IU/kg heparin to achieve an activated clotting time (ACT) of longer than 450 s. In the MiECC group, 150 IU/kg heparin was administered with a target ACT level of 300 s. Calafiore warm blood cardioplegia was used in all patients and was instilled antegrade to the ascending aorta, whereas both groups were operated on normothermia (35 C). Surgical technique A standard surgical pattern with the use of the left internal mammary artery grafted to the left anterior descending artery and saphenous vein grafts for the other target coronary vessels was implemented in all patients. After completing distal anastomoses, the aortic cross-clamp was removed and the proximal anastomoses were constructed using a single side-clamp on the aorta. All procedures were performed by the same group of surgeons. Anaesthetic and haemodynamic monitoring All patients received a standardized anaesthetic protocol. General anaesthesia was induced with 1 3 mg midazolam,5 10 μg/kg fentanyl and 2 3 mg/kg propofol. Tracheal intubation was facilitated with 1 mg/kg rocuronium, which was also employed for intraoperative neuromuscular blockade as necessary. Analgesia was maintained with fentanyl and anaesthesia with propofol (40 100 μg/kg/min) used as continuous infusion. Propofol was targeted to achieve a bispectral index of 40 45. No volatile agents were used. A thermodilutional pulmonary artery catheter (Swan-Ganz CCOmbo CCO/SvO 2, Edwards Lifesciences LLC, Irvine, CA) for continuous cardiac output and mixed venous oxygen saturation monitoring was inserted into the right internal jugular vein via a 9.0 Fr introducer (AVA HF, Edwards Lifesciences LLC). All patients were monitored with nearinfrared spectroscopy during the entire procedure. In-line monitoring of patient s parameters was used for obtaining optimal cerebral perfusion, indicative of end-organ protection; this was maintained throughout the procedure. Episodes of cerebral desaturation were managed with a standardized protocol analysed elsewhere [14]. Quality-of-life assessment The RAND SF-36 scale was used for data collection, which included both sociodemographic and clinical characteristics of patients. The SF-36 Health Survey is one of the most extensive standardized, self-administered, generic questionnaires for measuring both the physical and mental health of a patient. It was developed to assess the functional status and well-being of patients. It appears to be a suitable instrument to evaluate changes in health status following CABG and the main determinant factor in these changes [15]. The SF-36 provides quantified information (on a scale from 0 to 100 with higher scores indicating better health) in 8 domains of health: physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional and mental health. Two summary scores are extracted to summarize the patients physical [Physical Component Summary (PCS)] and mental [Mental Component Summary (MCS) score] [16]. Quality-of-life assessment was performed preoperatively (baseline-t0), at 1-month (T1) and at 3-month follow-up postoperatively (T3). Testing would commence only after a clear indication that instructions were completely understood. Evaluation was conducted with a personal interview in a quiet environment without extraneous distractions by independent clinical researchers that were blinded to the patients allocated management (MiECC or ccpb). Only patients who adhered to the pre-defined protocol were included in the final analysis. To ensure that patients had completely understood the instructions for completing the questionnaire and to exclude bias attributed to third-body reporting, we decided not to send any questionnaires by post to the patients who were unable to have a proper on-site HRQoL evaluation. The version of the SF-36 questionnaire administered had already been normed on the Greek population [17]. Although the surgeons allocated to the intervention group were aware of the allocated arm, outcome assessors and data analysts were kept blinded to the allocation. The primary outcome of the study was quantitative measurement of postoperative HRQoL at 3-month follow-up. Secondary endpoints included HRQoL at 1 month postoperatively and the incidence of major adverse events during the 3-month follow-up period defined as the composite outcome of: (i) postoperative myocardial infarction (CK-MB levels >125 IU/l during the first 72 h plus new pathological Q waves or left bundle branch block), (ii) postoperative renal failure (serum creatinine levels of >2 mg/dl or doubling of preoperative levels), (iii) postoperative stroke (neurological deficit of abrupt onset persisting >24 h) and (iv) all-cause mortality during the index hospitalization or up to 30 days postoperatively. Assessment of the primary and secondary outcomes was conducted blindly to patient management and group allocation. Sample size calculation and statistical analysis Under the assumption based on previously published data investigating HRQoL in patients undergoing CABG [3] of a reference value of 60/100 with a standard deviation (SD) of 20, a sample size of 60 patients was calculated to detect a minimum difference of 10% in the treatment (MiECC) group with a statistical power of 0.8 (β risk) and a two-sided 5% significance level (α = 0.05). Continuous variables are expressed as mean values ± SD. Categorical variables are expressed as numbers and percentages. Demographic characteristics, perioperative variables and calculated values were compared using independent samples non-parametric Mann Whitney U-test for continuous variables and the χ 2 test or Fisher s exacttest (when one or more cells had an expected frequency of five or less) for categorical variables. Differences within a treatment group of SF-36 questionnaire scores were identified using a paired Student s t-test. For each patient, the preoperative score was considered as

K. Anastasiadis et al. / European Journal of Cardio-Thoracic Surgery 1199 baseline score, and changes from baseline were calculated by subtracting the baseline score from the scores at 1 and 3 months, respectively. Differences between groups in scores from baseline were identified using repeated-measures analysis of variance, including treatment group and time as factors. The standard set of assumptions associated with an ordinary analysis of variance was extended to the matrix case: multivariate normality, homogeneity of covariance matrices and independence. Additionally, the assumption of sphericity (Mauchly s sphericity test) was also tested using transformed-dependent variables, to examine the form of the common covariance matrix. For all tests, a P-value of <0.05 (twosided) was considered statistically significant. All statistical analyses were performed using the SPSS statistical software (IBM SPSS Statistics, version 19). RESULTS Eighty patients in total were screened during the preoperative evaluation. Sixty-six patients of these were randomized into two groups of 33 patients in each cohort. The overall compliance of follow-up protocol was similar between the two groups with 30/33 patients (91%) completing the 3-month follow-up and included in the analysis. All preoperative and operative characteristics were balanced and are presented in Table 1. Preoperative risk stratification according to EuroSCORE II was similar in both groups. Moreover, both groups were balanced in socio-economic and education parameters. Operative details and postoperative clinical parameters are presented in Table 2. Total CPB and cross-clamp times were similar between groups. Conversion to an open circuit was not required in any patient. Complete revascularization was performed in both groups. MiECC surgery was associated with a significant reduction in haemodilution, as evidenced with higher postoperative haematocrit (30.4 ± 3.8 vs 24.9 ± 3.9, P < 0.001). Postoperative course, as described with the duration of mechanical ventilation, intensive care unit and total hospital length of stay, was similar between groups. Three patients experienced acute postoperative renal failure (2 operated on MiECC and 1 with ccpb), whereas there was 1 in-hospital mortality due to low cardiac output syndrome postoperatively in a patient with reduced preoperative left ventricular ejection fraction operated on ccpb (Table 2). The absolute SF-36 scores in all domains by treatment group are presented in Table 3. No differences were observed in preoperative (baseline) mean scores between groups for individual SF-36 health domain scores or for the summary scores PCS and MCS. At 3-month follow-up period, mean SF-36 component and summary scores in each group were higher in absolute values than the respective mean baseline scores, apart from role-physical score in patients operated with ccpb which showed a significant decrease at 1 month that almost reached baseline values at 3 months. Within-group analysis revealed that at 3 months postoperatively patients operated on MiECC showed uniformly significantly higher values in all individual and summary domains, whereas patients operated on ccpb showed significant improvement in 6/8 individual domains (role-physical and role-emotional were similar to baseline) as well as on both physical and mental summary scores. Between-group analysis at 1-month follow-up revealed that patients operated on MiECC showed statistically significant higher values regarding physical functioning (73.5 ± 15.9 vs 52.6 ± 22.3, P < 0.001), role-physical (23.3 ± 30.7 vs 4.16 ± 18.6, P < 0.01), Table 1: Parameter Patients demographic and preoperative data MiECC (n = 30) ccpb (n = 30) P-value Age (years) 64.8 ± 7.9 67.8 ± 10 0.2 Gender (male/female) 28/2 23/7 0.1 Body mass index 2 ± 0.4 2.1 ± 0.3 0.9 Education level Elementary 15 (50%) 17 (57%) 0.2 Intermediate 10 (33%) 9 (30%) Higher 5 (17%) 4 (13%) Professional activity Civil servant 6 (20%) 1 (3%) 0.2 Private sector employee 6 (20%) 8 (27%) Employer and own account 6 (20%) 6 (20%) worker Farmer 2 (7%) 1 (3%) Housekeeping 1 (3%) 5 (17%) Other 2 (7%) 0 Retired 7 (23%) 9 (30%) Annual income level ( ) <10 000 16 (53%) 22 (73%) 0.2 10 000 19 999 9 (30%) 6 (20%) 20 000 29 999 2 (7%) 2 (7%) 30 000 3 (10%) 0 LV ejection fraction (%) 42.3 ± 6.9 44.2 ± 7.4 0.6 EuroSCORE II 3.1 ± 1.8 2.9 ± 2.1 0.7 Diabetes mellitus (%) 9 (30%) 6 (20%) 0.7 Hypertension (%) 24 (80%) 25 (83%) 0.8 Smoking history 25 (83%) 23 (77%) 0.9 Medications pre-intervention ACE inhibitors 10 (33%) 8 (27%) 0.7 Angiotensin II blockers 6 (20%) 8 (27%) 0.7 β-blockers 30 (100%) 30 (100%) 1 Nitrates 29 (97%) 28 (93%) 0.9 Values are presented as mean ± standard deviation. ACE: angiotensin converting enzyme; ccpb: conventional cardiopulmonary bypass; LV: left ventricular; MiECC: minimally invasive extracorporeal circulation. Table 2: Operative and postoperative characteristics Parameter MiECC (n = 30) ccpb (n = 30) P-value CPB time (min) 86.8 ± 45.1 96.6 ± 25.2 0.7 Cross-clamp time (min) 55.2 ± 29.6 61.2 ± 14.3 0.6 Number of grafts 3.2 ± 0.9 3 ± 0.8 0.9 RBC transfusion (units) 2.1 ± 2.2 3.1 ± 2.9 0.3 Haematocrit post-cpb (%) 30.4 ± 3.8 24.9 ± 3.9 <0.001 Mechanical ventilation (h) 5.8 ± 4.1 8.9 ± 6.7 0.3 ICU stay (days) 2.3 ± 0.4 2.6 ± 0.7 0.2 Hospital stay (days) 7.8 ± 1.1 8.1 ± 1.8 0.5 Major adverse events 0.2 Acute renal failure 1 (3%) 2 (7%) Mortality 0 1 (3%) Statistically significant differences (P < 0.05) are denoted in bold. ccpb: conventional cardiopulmonary bypass; ICU: intensive care unit; MiECC: minimally invasive extracorporeal circulation; RBC: red blood cells. vitality (59.3 ± 16.2 vs 41.3 ± 17.5, P < 0.001) and role-emotional (54.4 ± 30.9 vs 33.3 ± 24.9, P < 0.01) when compared with ccpb counterparts, which resulted in significantly higher physical ADULT CARDIAC

1200 K. Anastasiadis et al. / European Journal of Cardio-Thoracic Surgery Table 3: Results of SF-36 domains in absolute values Domain Preoperative (T0) 1-Month (T1) ccpb MiECC ccpb P-value MiECC ccpb P-value MiECC 3-Month (T3) P-value Physical functioning 58 ± 26.4 52.8 ± 25 0.44 73.5 ± 15.9* 52.6 ± 22.3 <0.001 92 ± 6.9* 78.3 ± 11.6* <0.001 Role-physical 24.1 ± 38.5 26.6 ± 39.8 0.806 23.3 ± 30.7 4.2 ± 18.6* 0.005 70 ± 24* 20 ± 27.3 <0.001 Bodily pain 58 ± 32 56.4 ± 32.2 0.85 80.8 ± 23.8* 73.5 ± 28* 0.279 94.6 ± 10.8* 88.5 ± 17.7* 0.115 General health 67.6 ± 18.2 60.5 ± 22 0.175 77.3 ± 17.1* 72.3 ± 20.2* 0.305 80.3 ± 18* 73.8 ± 19.6* 0.187 Vitality 38.0 ± 23.2 43.0 ± 30.2 0.476 59.3 ± 16.2* 41.3 ± 17.5 <0.001 79.8 ± 10.7* 60.5 ± 15.1* <0.001 Social functioning 52.9 ± 31.9 48.7 ± 36.3 0.639 54.1 ± 22.5 47.0 ± 21.9 0.223 86.2 ± 15.8* 70.8 ± 20.8* 0.002 Role-emotional 51.1 ± 33.6 49.9 ± 36.8 0.903 54.4 ± 30.9 33.3 ± 24.9* 0.003 88.8 ± 25.2* 59.9 ± 43.3 <0.001 Mental health 57.8 ± 21.4 58.8 ± 19.7 0.862 65.6 ± 18.4* 64.6 ± 15.8 0.835 79.6 ± 11.9* 70.8 ± 14.8* 0.014 Summary scores Physical Component Summary 51.9 ± 19.5 49.1 ± 22.0 0.598 63.7 ± 16.4* 50.6 ± 16.5 0.003 84.2 ± 10.7* 65.1 ± 14.8* <0.001 Score (PCS) Mental Component Summary Score (MCS) 49.9 ± 20.4 50.1 ± 25.2 0.978 58.3 ± 16.4* 46.6 ± 12.4 0.003 83.6 ± 12.6* 65.5 ± 17.2* <0.001 Statistically significant differences (P < 0.05) are denoted in bold. *Statistically significant (P < 0.05) within-group difference when compared with baseline (T0) values. Figure 2: Change from baseline in SF-36 individual health domain scores by period and treatment group. P-value indicates between-group difference from a repeated-measure analysis of covariance. A positive change shows an improvement (T1 = 1 month postoperatively; T3 = 3 months postoperatively). MiECC: minimally invasive extracorporeal circulation; ccpb: conventional cardiopulmonary bypass. (63.7 ± 16.4 vs 50.6 ± 16.5, P < 0.01) and mental (58.3 ± 16.4 vs 46.6 ± 12.4, P < 0.01) summary scores. The same trend was evidenced at 3-month follow-up, when MiECC was associated with significantly higher values in all individual health domains, excluding bodily pain and general health, as well as in both physical and mental summary scores (84.2 ± 10.7 vs 65.1 ± 14.8, P < 0.001 and 83.6 ± 12.6 vs 65.5 ± 17.2, P < 0.001, respectively). The dynamic of treatment effect through time in each cohort is better understood by analysing the mean change from baseline values regarding the various health domains, as presented in Fig. 2. Patients operated on MiECC showed a more pronounced increase in SF-36 individual domain scores from the first to the third postoperative month when compared with ccpb, which was statistically significant regarding physical functioning (P = 0.001), role-physical (P < 0.001), vitality (P = 0.01) and role-emotional (P = 0.004). This resulted in a significant improvement in physical (P = 0.002) and mental (P = 0.01) summary scores in patients operated on MiECC (Fig. 3), which reflect an overall improvement in HRQoL. No correlation was evidenced between reduced need for blood transfusion (2.1 ± 2.2 vs 3.1 ± 2.9, P = 0.3) observed in patients operated on MiECC and improvement in HRQoL (Pearson s correlation coefficient = 0.139, P = 0.37 and 0.092,

K. Anastasiadis et al. / European Journal of Cardio-Thoracic Surgery 1201 Figure 3: Change from baseline in SF-36 physical (A) and mental (B) summary scores by period and treatment group. P-value indicates between-group difference from a repeated-measure analysis of covariance. Error bars indicate standard errors. A positive change shows an improvement (T1 = 1 month postoperatively; T3 = 3 months postoperatively). MCS: Mental Component Summary; PCS: Physical Component Summary; MiECC: minimally invasive extracorporeal circulation; ccpb: conventional cardiopulmonary bypass. P = 0.552 for PCS score at 1 and 3 months, respectively; Pearson s correlation coefficient = 0.204, P = 0.184 and 0.059, P = 0.706 for MCS score at 1 and 3 months, respectively). DISCUSSION To the best of our knowledge, this is the first reported prospective clinical trial investigating the impact of MiECC on HRQoL in patients undergoing CABG. The results of our study clearly indicate that: (i) both techniques used offer an improvement in HRQoL over a shortterm 3-month period of follow-up, (ii) MiECC, when compared with ccpb, is associated with significantly higher values in all major health domains indicative of an overall better HRQoL during this period of time. This finding is more likely attributed to the more physiological perfusion during surgery with MiECC ultimately resulting in a smoother postoperative recovery period [12]. This randomized study was designed to prospectively assess the net effect of CPB circuit on HRQoL after CABG surgery. All randomized patients were operated by the same surgical team to exclude bias attributed to the surgeon s preference of one technique over the other. Moreover, the researchers carrying out the SF-36 administration as well as the patients were blinded to the surgical technique. The issue on when to perform the HRQoL assessment remains of critical importance. The majority of studies are non-randomized and extend from a period of 6 months up to 12 months after CABG [8, 9]. While some studies find improvements in physical function between post-event to 6 months, others failed to show any improvement occurring between 3 and 6 months or later [3]. Other prospective non-randomized studies that extended from 6 to 12 months after surgery suggested that improved HRQoL after CABG is unrelated to the use of CPB [7, 18]. This can be explained by the fact that successful myocardial revascularization, regardless of the technique utilized, produces at the 6-month interval substantial functional recovery and improvement in HRQoL [7]. Our understanding on HRQoL after cardiac surgery follows the trajectory of neurocognitive outcome of the patients, as evidenced by Le Grande et al. and Kiessling et al. [19, 20]. It has been recognized that the pathogenesis of early (within 3 months of operation) neurocognitive, and subsequently HRQoL, changes is most likely different from late (from 3 months to 5 years). Early cognitive decline that could significantly impair HRQoL occurs in a considerable proportion of patients after cardiac surgery and is predominantly related to a combination of operative factors. These include the surgical technique, the effect of general anaesthesia and the overall effect of CPB, mainly the systemic inflammatory response. On the contrary, late determinants of HRQoL are more likely influenced by the patients age, comorbidities, progression of atheromatous disease as well as socio-economic factors. This hypothesis has been tested by Selnes in a prospective longitudinal study which evaluated 6-year neurocognitive outcome in four different patient categories: patients who underwent CABG with standard CPB, patients operated without CPB, patients with stable coronary artery disease treated medically and healthy individuals [21]. The results from the study showed that there is uniform decline in cognitive performance over the 6-year period without any significant difference among the groups. This finding ultimately rules out any selective effect attributable to the type of operation or the use of CPB. In our study, we focused on the status of HRQoL during the first 3 months postoperatively, which has not been investigated thoroughly by other studies. This time frame represents the most vulnerable period for the patient after surgery and is more likely to be affected by the type of extracorporeal circulation and the surgical technique. This was also the rationale for performing the first postoperative HRQoL evaluation at 1-month follow-up, when the patients subjective assessment of the treatment s outcome more likely reflects the effect from surgery and the immediate postoperative course. Various instruments have been used to measure HRQoL in CABG patients, most commonly the Nottingham Health Profile (NPH), the Medical Outcomes Study Short Form (SF-36), RAND 36-Item Health Survey (RAND-36) or EuroQol (EQ-5D) [8]. In the present study, we used the SF-36, which has been shown to be a valid, feasible tool that shows higher sensitivity than diseasespecific measures to assess HRQoL in cardiac patients. As proved by Rumsfeld et al. [5], low scores in the physical function domain of the SF-36 are independent predictors of mortality at 6 months following CABG. Results of the present study showed a significant improvement in the HRQoL of CABG patients during the first 3 months after surgery, confirming the reported evidence that CABG patients ADULT CARDIAC

1202 K. Anastasiadis et al. / European Journal of Cardio-Thoracic Surgery experience a significant improvement in their HRQoL quite soon after surgery [5, 9]. This finding more likely reflects successful course of the operation and fulfilment of expectations for each individual patient recovering mostly without any major complications or adverse events. However, the most important observation of this prospective randomized study is that MiECC exerts a significantly beneficial effect in HRQoL when compared with ccpb, starting from the first and extending up to the third postoperative month. This was reflected in physical functioning, role-physical, vitality and role-emotional as well as in physical and mental summary scores, which reflect overall HRQoL. Physical functioning, which is the most well-studied HRQoL variable after CABG, typically shows a nadir during the first 2 6 weeks postoperatively and then gradually improves [3]. This trend applied to ccpb patients in our study, whereas those operated on MiECC experienced a steady and consistent abatement of their physical symptoms following surgery translated into improved self-assessed physical functioning over the follow-up period of 3 months. In contrast to physical functioning, mental health typically remains stable or deteriorates at 6 weeks after CABG [19]. This is mainly attributed to postoperative cognitive decline, especially in elderly and high-risk patients [21]. In our study, mental health followed a steady improvement in patients operated with MiECC from the first to the third postoperative month, as opposed to ccpb that showed an improvement only at 3-month evaluation. This finding could be interpreted in the light of improved neurocognitive performance that was evidenced in patients operated on MiECC extending from discharge up to 3 months after CABG [14]. Attenuation of neurocognitive impairment explains the pattern in role-emotional observed in our study. Patients operated with ccpb showed significantly reduced absolute values at 1 month that returned to baseline at 3 months, whereas in the MiECC counterparts, there was a steady improvement in role-emotional that became significant at 3 months. According to Immer et al., this facet of HRQoL assesses problems occurring during daily activity. These subtle impairments in the person s normal everyday role usually reflect neuropsychological deficits [9]. As expected, domains not directly related to the type of extracorporeal circulation, such as bodily pain or general health perception, were similar between groups at all time points, adding to the validity of the study. These outcomes are obviously not related to the type of perfusion but the surgery per se. The reason for the significantly improved HRQoL after surgery on MiECC compared with ccpb should be attributed mainly to the beneficial properties of MiECC system. It is a closed, autoregulated, heparin-coated and short-tubing circuit, integrating a centrifugal pump and an air-removing device for enhanced safety. This design precludes blood air interaction as well as recirculation of shed blood directly to the system. MiECC is a blood-conserving circuit due to reduced haemodilution and subsequently less requirement for blood transfusion. Low anticoagulation protocols reduce endothelial activation, whereas there is a protective effect on coagulation integrity [22]. van Boven et al. [23] reported reduced myocardial oxidative stress when operating with MECC, which was attributed mainly to the attenuation of systemic inflammatory response. MiECC is associated with improved circulatory support and end-organ protection (renal, cerebral and lung), translated into improved clinical outcome in terms of morbidity and mortality, as confirmed by large-scale meta-analyses [2]. The pathophysiological mechanism responsible for the favourable clinical results of MiECC is improved peripheral perfusion due to higher mean arterial pressures at significantly reduced pump flows, obviating the need for vasoactive medication, as well as enhanced recovery of microvascular organ perfusion [12]. On the basis of these encouraging results, we proceeded in our institution to applying MiECC as a state-of-the-art technique to every cardiac surgical procedure. This requires a modular MiECC circuit that integrates a second open circuit with a venous reservoir and cardiotomy suction as a standing-by component (MiECC type IV), which provides a safety net in case air handling or volume management becomes problematic and it is compatible with all types of cardiac surgery [13]. Implementation of MiECC moved cardiac surgery towards a strategy that involves all disciplines of the surgical team (the cardiac surgeon, the perfusionist and the anaesthesiologist) aiming to a more physiological perfusion [12]. During the last two decades, minimally invasive cardiac surgery focused on OPCAB in an attempt to improve clinical outcomes and HRQoL by completely ameliorating the detrimental effects of CPB. However, this was not verified in large-scale studies [4, 9, 19]. An interesting network meta-analysis has recently been published by Kowalewski et al. [2] involving 22 778 patients comparing MiECC and OPCAB with ccpb. Detailed statistical analysis using the surface under the cumulative ranking (SUCRA) probabilities indicated that MiECC represented the safer and more effective intervention regarding all-cause mortality and protection from myocardial infarction, cerebral stroke, postoperative atrial fibrillation and renal dysfunction, when compared with OPCAB and ccpb. Further multicentre trials are required to delineate whether the superiority of MiECC regarding clinical outcomes translates to improved HRQoL. It should be emphasized that the observed clinical benefit is associated with costeffectiveness (lower cost and higher effectiveness) in coronary revascularization procedures at four different European healthcare settings, as evidenced in the economic analysis performed by Anastasiadis et al.[24]. Results obtained from our study should be interpreted in the light of the lack of a proper policy that promotes second-phase cardiac rehabilitation that starts 3 6 weeks after discharge from hospital and lasts ideally 3 5 months after CABG. In the present study, no outpatient cardiac rehabilitation programme for improving exercise capacity and HRQoL was applied in either patient. Family members took on care-giving responsibilities during this time. However, home-based exercise to engage in regular physical activity and achieve greater improvement was encouraged. In a systematic review study in 2012, Shepherd and While [25] reported that the HRQoL benefits of home-based cardiac rehabilitation are not inferior to those of centre-based programmes. The main limitation of the current study is that it is singleinstitutional with a relatively small number of recruited patients. An inherent limitation of the HRQoL assessment is that patients select responses relating to different aspects of their general health status over a fixed time period (at 1 and 3 months postoperatively in the current study), whereas the way the patients feel may vary on a day-to-day basis. It is obvious that major life events unrelated to the procedure may have taken place in the months between assessments [14]. The strength of the current study is the prospective randomized design, the quality of the randomization and the uniformity of both surgical technique and HRQoL evaluation. In conclusion, this prospective randomized study suggests that MiECC significantly improves HRQoL at 3 months after coronary surgery compared with ccpb. This finding further enhances the role of MiECC in performing coronary surgery. Considering improved HRQoL in the context of superior perioperative clinical outcomes evidenced by large-scale studies and meta-analyses [2], we

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