Aortic cross-clamp time and cardiopulmonary bypass time: prognostic implications in patients operated on for infective endocarditis

Aortic cross-clamp time and cardiopulmonary bypass time: prognostic implications in patients... Abstract OBJECTIVES Prolonged aortic cross-clamp (XCT) and cardiopulmonary bypass time (CPBT) are associated with increased morbidity and mortality following cardiac surgery. The aim of this study was to assess the predictors of mortality and other severe postoperative complications in patients undergoing surgery for infective endocarditis (IE), focusing in particular on the role of prolonged XCT and CPBT. METHODS A retrospective single-centre study was conducted from January 2000 to January 2017, including all patients undergoing valvular surgery for IE. The primary end point was early postoperative mortality. The main secondary end point was a composite end point for severe postoperative complications. RESULTS During the study period, 264 patients were included. Early postoperative mortality was 14%. Prolonged CPBT [odds ratio (OR) 1.008, 95% confidence intervals (CIs) 1.003–1.01; P = 0.009] and increasing age (OR 1.04, 95% CI 1.01–1.07; P = 0.02) independently predicted mortality, while an inverse association was observed for left ventricular ejection fraction (OR 0.93, 95% CI 0.89–0.97; P = 0.0007). The best mortality cut-offs were >72 min for XCT and >166 min for CPBT. Prolonged CPBT also predicted severe complications, along with age, stroke, preoperative mechanical ventilation and reduced left ventricular ejection fraction. When XCT was included in the multivariable models instead of CPBT, it was associated with both mortality and severe complications. CONCLUSIONS Prolonged XCT and CPBT are associated with mortality and development of severe complications after valvular surgery for IE. Further validation of safe limits for XCT and CPBT might provide novel insights on how to improve intraoperative and postoperative outcomes of patients with IE. Cardiopulmonary bypass , Endocarditis , Heart valves , Inflammation INTRODUCTION Prolonged aortic cross-clamp (XCT) and cardiopulmonary bypass time (CPBT) are associated with increased morbidity and mortality following cardiac surgery, conceivably in view of the myocardial damage and inflammatory response associated with cardioplegic cardiac arrest and cardiopulmonary bypass [1–6]. Infective endocarditis (IE) is a systemic infectious disease, as evidenced by the increase in systemic inflammatory markers, and might require valvular surgery [7–9]. From this standpoint, the underlying preoperative inflammatory state might theoretically heighten the detrimental effect of a prolonged XCT and CPBT. However, up to date the magnitude of the unfavourable impact of prolonged XCT and CPBT on clinical outcomes has been extensively described in patients undergoing coronary artery bypass surgery (CABG) or aortic valve replacement (AVR) [1, 4, 10], but not in patients operated on for IE. The aim of this study was therefore to assess the predictors of in-hospital mortality and other severe postoperative complications in patients undergoing surgery for IE, focusing in particular on the role of prolonged XCT and CPBT. METHODS Study design From January 2000 to January 2017, data of patients undergoing valvular surgery for IE at the San Martino University Hospital were included in a prospectively collected database. Patients in whom cardiopulmonary bypass and cardioplegic cardiac arrest were employed during surgery were retrospectively identified in the database and included in the present study. For each patient, baseline demographic and clinical data were collected at the time of the first surgical procedure. Study end points The primary end point was early postoperative mortality. The main secondary end point was a composite endpoint of severe complications within 30 days after surgery (i.e. mortality, intensive care unit (ICU) stay ≥5 days, stroke, or denovo haemodialysis, postoperative use of intra-aortic balloon pump (IABP), whichever came first [6]). Other secondary end points were prolonged XCT and prolonged CPBT. Definitions and procedures The presence of IE was defined according to the modified Duke’s criteria [11, 12]. All other patients who did not fulfil the modified Duke’s criteria preoperatively were retrospectively included if the positive culture of vegetation and/or abscess and/or tissue histology collected at the time of surgery confirmed infection. Patient comorbidities and postoperative complications were defined according to the joint AATS/EACTS/STS Guidelines for Reporting Mortality and Morbidity After Cardiac Valve Interventions in adult cardiac surgery [13]. Early postoperative mortality was defined as death during the hospital stay or within 30 days after surgery. Urgent-emergent surgery priorities were defined as surgery performed immediately or within the current admission for medical reasons according to European System for Cardiac Operative Risk Evaluation II (EuroSCORE II) definitions [14]. Myocardial protection was achieved by means of antegrade administration of warm blood cardioplegia associated with topical ventricular cooling or hypothermic (31°C) Custodiol Histidine Tryptophan Ketoglutarate solution. Data collected for the analysis The following baseline variables were collected: gender, age (collected as a continuous variable), hypertension, diabetes [any preoperative diagnosis of diabetes mellitus requiring treatment (diet, oral drugs and/or insulin therapy)], obesity (body mass index > 30), chronic obstructive pulmonary disease (defined as long term use of bronchodilators or steroids for lung disease), stroke (any preoperative focal or global neurological syndrome caused by ischaemia or haemorrhage not resolving within 24 h), previous cardiac surgery, peripheral vascular disease (1 or more of the following: claudication, carotid occlusion or >50% stenosis, amputation for arterial disease, previous or planned intervention on the abdominal aorta, limb arteries or carotids), preoperative insertion of IABP, chronic kidney disease (baseline serum creatinine >200 µmol/l), solid organ cancer, preoperative mechanical ventilation, myocardial infarction <3 months, New York Heart Association (NYHA) class, EuroSCORE II (calculated retrospectively using the on-line calculator available at http://www.euroscore.org/calc.html) [14], STS Endocarditis Score (STS-IE) calculated retrospectively [15], PALSUSE score calculated retrospectively [16], status priority, critical preoperative state, left ventricular ejection fraction (LVEF; all defined according to EuroSCORE II definitions), endocarditis characteristics [native valve endocarditis (NVE) or prosthetic valve endocarditis (PVE), cerebrovascular embolic events in the setting of IE, active endocarditis (defined as admission before or within the first 30 days of antimicrobial treatment)]; causative organisms (identified in positive blood, vegetation or abscess cultures by means of the VITEK 2 automated system, bioMérieux, Marcy l’Etoile, France), 2-dimensional echocardiographic data (presence of vegetation, abscess, paravalvular leak, LVEF, valve diseases, pulmonary hypertension), atrioventricular block on the electrocardiogram, and operative findings. The collected postoperative complications included resternotomy for bleeding; prolonged mechanical ventilation (>48 h); ICU stay (days); acute kidney injury (a peak serum creatinine ≥50% above baseline within 5 days postoperatively); renal replacement therapy; postoperative stroke, atrial fibrillation; new onset of atrioventricular block; sternal wound infection; respiratory insufficiency (any of hypoxemic respiratory failure with a PaO2/FiO2 ratio less than 300 while on supplemental oxygen or acute hypercapnic respiratory failure, defined as a significantly elevated PaCO2 to 50 mmHg or more and a pH <7.35); sepsis (according to international definitions [17]); multiorgan failure [defined as multiple organ dysfunction within the context of Systemic Inflammatory Response Syndrome (SIRS)]; reoperation for new endocarditis event (novel evidence of valve endocarditis after discharge); and postoperative IABP placement. Statistical analysis Categorical data were presented as frequencies and percentages and compared using the χ2 test or the Fisher’s exact test where appropriate. Continuous variables were expressed as mean and standard deviation (SD) and compared using 2-tailed t-test or Mann–Whitney test. Kruskal–Wallis test was used for group comparisons. To identify factors associated with early postoperative mortality and with the composite outcome of severe complications, demographic and clinical characteristics of patients (including length of XCT and CPBT) were compared between survivors and non-survivors and between patients who experienced the composite severe complications end point and those who did not by means of the univariable logistic regression models. Then, to assess the independent role of potential predictors, variables associated with the pertinent outcome in the univariable analyses (P < 0.05) were included in a stepwise backward multivariable logistic regression model employing the R algorithm based on the Akaike information criterion at each step. The reliability of the regression models was assessed with the C-statistic and the Hosmer–Lemeshow’s test. The Youden’s test was used to identify the best cut-off values of XCT and CPBT in predicting early mortality. A P-value <0.05 was considered statistically significant. The discriminatory performance and the calibration of risk scores (EuroSCORE II, STS-IE and PALSUSE) with regard to mortality was evaluated using the C-statistic and the Hosmer–Lemeshow’s test, respectively. To identify risk factors for prolonged XCT and CPBT, exhaustive search for the best subsets of independent variables to include for predicting prolonged XCT and CPBT in multiple linear regression was undertaken [18]. All the analyses were performed using the R Statistical Software (version 3.2.2; R Foundation for Statistical Computing, Vienna, Austria). RESULTS Of the 274 consecutive patients operated on for IE from January 2000 to January 2017, 264 patients underwent valvular repair\substitution with the use of cardiopulmonary bypass and cardioplegic cardiac arrest. Ten patients who were operated on for an infected pacemaker lead removal were excluded from the study. Their mean age was 62 years [SD ± 15.2] and 196 were males (74%). The complete demographic and clinical characteristics of the patients included are shown in Table 1. NVE and PVE accounted for 81% and 19% of the cases, respectively. The proportion of active IE was 68%. Aortic (145/264, 55%) and mitral valve (128/264, 48%) were mostly involved; 18% of the diseased mitral valves were repaired (17 of 97 patients). The tricuspid valve was involved in 10 (4%) patients, and the pulmonary valve in 1 (<1%) patient. Forty-nine patients had multiple valve disease (19%). Table 1: Preoperative clinical and operative characteristics and their impact on early postoperative mortality according to univariable and multivariable logistic regression analyses Variables  n = 264 (%)  Survivors (n = 228)  Non-survivors (n = 36)  Univariable logistic regression OR (95% CI), P-value  Multivariable logistic regression OR (95% CI), P-value  Female gender  68 (26)  54 (24)  14 (39)  2.05 (0.96–4.25), 0.06    Age (years)  62 ± 15.2  61.45 ± 15.1  67.2 ± 14.7  1.03 (1.00–1.06), 0.04  1.04 (1.01–1.07), 0.02  Hypertension  114 (43)  96 (42)  18 (50)  1.38 (0.68–2.79), 0.37    Diabetes  35 (13)  31 (14)  4 (11)  0.79 (0.23–2.18), 0.68    BMI >30 (kg/m2)  47 (18)  41 (18)  6 (17)  0.91 (0.33–2.20), 0.85    COPD  24 (9)  19 (8)  5 (14)  1.77 (0.56–4.79), 0.28    Stroke  28 (11)  23 (10)  5 (14)  1.44 (046–3.80), 0.49    Previous cardiac surgery  62 (23)  51 (22)  11 (31)  1.53 (0.68–3.25), 0.28    Peripheral vascular disease  26 (10)  20 (9)  6 (17)  2.08 (0.71–5.34), 0.15    Critical preoperative status  18 (7)  14 (6)  4 (11)  1.91 (0.52–5.72), 0.28    Preoperative IABP  2 (1)  2 (1)  0  NA, 0.99    Chronic kidney disease  46 (17)  36 (16)  10 (28)  2.05 (0.88–4.52), 0.08    Solid organ cancer  7 (3)  7 (3)  0  NA, 0.99    Preoperative mechanical ventilation  10 (4)  9 (4)  1 (3)  0.70 (0.04–3.87), 0.73    Myocardial infarction <3 months  8 (3)  7 (3)  1 (3)  0.90 (0.05–5.29), 0.92    NYHA  185 (70)  158 (69)  27 (75)  1.32 (0.61–3.13), 0.49     I–II             III–IV  79 (30)  70 (31)  9 (25)  0.75 (0.32–1.63), 0.49    EuroSCORE II  6.68 ± 9.85  5.89 ± 8.76  11.59 ± 14.22  1.04 (1.01–1.07), 0.005    STS-IE score  22.13 ± 10.45  21.7 ± 1.09  24.83 ± 13.65  1.03 (0.99–1.06), 0.10    PALSUSE score  2.11 ± 1.45  2.01 ± 1.42  2.72 ± 1.52  1.40 (1.10–1.82), 0.007    Endocarditis characteristics             NVE  213 (81)  187 (82)  26 (72)  0.57 (0.26–1.32), 0.17     PVE  51 (19)  41 (18)  10 (28)  1.75 (0.75–3.83), 0.17     Active endocarditis  179 (68)  158 (69)  21 (58)  0.62 (0.30–1.29), 0.19     Embolic event  11 (4)  11 (5)  0  NA, 0.99     Causative organisma        0.07      Staphylococcus spp.  70 (27)  63 (28)  7 (19)  1 (Reference)      Streptococcus spp.  41 (16)  39 (17)  2 (6)  0.46 (0.07–2.03)      Enterococcus spp.  25 (9)  20 (9)  5 (14)  2.25 (0.61–7.85)      Candida spp.  5 (2)  4 (2)  1 (3)  2.25 (0.11–18.16)      Other  8 (3)  8 (4)  0  NA     Negative culture  115 (44)  94 (41)  21 (58)  2.01 (0.84–5.36)    Echocardiogram and electrocardiogram findings             Vegetation >1 cm  33 (4)  30 (13)  3 (8)  0.60 (0.14–1.71), 0.42     Abscess  11 (4)  7 (3)  4 (11)  3.95 (0.99–13.84), 0.04     Paravalvular leak  40 (15)  32 (14)  8 (22)  1.75 (0.73–4.18), 0.20     Severe stenosis  38 (14)  32 (14)  6 (17)  1.14 (0.44–2.97), 0.75     Severe regurgitation  163 (62)  148 (65)  15 (42)  0.51 (0.25–1.04), 0.07     LVEF (%)  53.7 ± 8.9  54.56 ± 8.85  48.47 ± 8.21  0.93 (0.89–0.97), 0.0003  0.93 (0.89–0.97), 0.0007   PAPS >60 mmHg  35 (13)  31 (14)  4 (11)  0.79 (0.23–2.18), 0.68     Atrioventricular block  10 (4)  8 (4)  2 (6)  1.62 (0.24–6.79), 0.55    Surgical procedure             Isolated AVR  108 (41)  98 (43)  20 (56)  0.51 (0.24–1.11), 0.08     Isolated MV surgery  97 (37)  86 (38)  11 (31)  0.72 (0.34–1.55), 0.41     Multiple valve procedure  49 (19)  37 (16)  12 (33)  2.58 (1.16–5.54), 0.02  2.19 (0.92–5.06), 0.07   Concomitant CABG  8 (3)  5 (2)  3 (8)  4.05 (0.80–17.32), 0.06     Concomitant procedure on thoracic (ascending) aorta  15 (6)  13 (6)  2 (6)  0.97 (0.15–3.73), 0.97     Urgent-emergent  103 (39)  87 (38)  16 (44)  1.30 (0.63–2.63), 0.47     Blood cardioplegia with topical ventricular cooling  166 (63)  144 (63)  22 (61)  0.91 (0.45–1.92), 0.81     Custodiol cardioplegia  98 (37)  84 (37)  14 (39)  1.09 (0.52–2.23), 0.81     CPBT  128.8 ± 89.2  121.72 ± 48.81  173.69 ± 151.42  1.01 (1.00–1.01), 0.003  1.01 (1.00–1.01), 0.009   XCT  89.6 ± 38.4  94.36 ± 39.63  105.69 ± 52.31  1.01 (1.00–1.02), 0.01  b  Variables  n = 264 (%)  Survivors (n = 228)  Non-survivors (n = 36)  Univariable logistic regression OR (95% CI), P-value  Multivariable logistic regression OR (95% CI), P-value  Female gender  68 (26)  54 (24)  14 (39)  2.05 (0.96–4.25), 0.06    Age (years)  62 ± 15.2  61.45 ± 15.1  67.2 ± 14.7  1.03 (1.00–1.06), 0.04  1.04 (1.01–1.07), 0.02  Hypertension  114 (43)  96 (42)  18 (50)  1.38 (0.68–2.79), 0.37    Diabetes  35 (13)  31 (14)  4 (11)  0.79 (0.23–2.18), 0.68    BMI >30 (kg/m2)  47 (18)  41 (18)  6 (17)  0.91 (0.33–2.20), 0.85    COPD  24 (9)  19 (8)  5 (14)  1.77 (0.56–4.79), 0.28    Stroke  28 (11)  23 (10)  5 (14)  1.44 (046–3.80), 0.49    Previous cardiac surgery  62 (23)  51 (22)  11 (31)  1.53 (0.68–3.25), 0.28    Peripheral vascular disease  26 (10)  20 (9)  6 (17)  2.08 (0.71–5.34), 0.15    Critical preoperative status  18 (7)  14 (6)  4 (11)  1.91 (0.52–5.72), 0.28    Preoperative IABP  2 (1)  2 (1)  0  NA, 0.99    Chronic kidney disease  46 (17)  36 (16)  10 (28)  2.05 (0.88–4.52), 0.08    Solid organ cancer  7 (3)  7 (3)  0  NA, 0.99    Preoperative mechanical ventilation  10 (4)  9 (4)  1 (3)  0.70 (0.04–3.87), 0.73    Myocardial infarction <3 months  8 (3)  7 (3)  1 (3)  0.90 (0.05–5.29), 0.92    NYHA  185 (70)  158 (69)  27 (75)  1.32 (0.61–3.13), 0.49     I–II             III–IV  79 (30)  70 (31)  9 (25)  0.75 (0.32–1.63), 0.49    EuroSCORE II  6.68 ± 9.85  5.89 ± 8.76  11.59 ± 14.22  1.04 (1.01–1.07), 0.005    STS-IE score  22.13 ± 10.45  21.7 ± 1.09  24.83 ± 13.65  1.03 (0.99–1.06), 0.10    PALSUSE score  2.11 ± 1.45  2.01 ± 1.42  2.72 ± 1.52  1.40 (1.10–1.82), 0.007    Endocarditis characteristics             NVE  213 (81)  187 (82)  26 (72)  0.57 (0.26–1.32), 0.17     PVE  51 (19)  41 (18)  10 (28)  1.75 (0.75–3.83), 0.17     Active endocarditis  179 (68)  158 (69)  21 (58)  0.62 (0.30–1.29), 0.19     Embolic event  11 (4)  11 (5)  0  NA, 0.99     Causative organisma        0.07      Staphylococcus spp.  70 (27)  63 (28)  7 (19)  1 (Reference)      Streptococcus spp.  41 (16)  39 (17)  2 (6)  0.46 (0.07–2.03)      Enterococcus spp.  25 (9)  20 (9)  5 (14)  2.25 (0.61–7.85)      Candida spp.  5 (2)  4 (2)  1 (3)  2.25 (0.11–18.16)      Other  8 (3)  8 (4)  0  NA     Negative culture  115 (44)  94 (41)  21 (58)  2.01 (0.84–5.36)    Echocardiogram and electrocardiogram findings             Vegetation >1 cm  33 (4)  30 (13)  3 (8)  0.60 (0.14–1.71), 0.42     Abscess  11 (4)  7 (3)  4 (11)  3.95 (0.99–13.84), 0.04     Paravalvular leak  40 (15)  32 (14)  8 (22)  1.75 (0.73–4.18), 0.20     Severe stenosis  38 (14)  32 (14)  6 (17)  1.14 (0.44–2.97), 0.75     Severe regurgitation  163 (62)  148 (65)  15 (42)  0.51 (0.25–1.04), 0.07     LVEF (%)  53.7 ± 8.9  54.56 ± 8.85  48.47 ± 8.21  0.93 (0.89–0.97), 0.0003  0.93 (0.89–0.97), 0.0007   PAPS >60 mmHg  35 (13)  31 (14)  4 (11)  0.79 (0.23–2.18), 0.68     Atrioventricular block  10 (4)  8 (4)  2 (6)  1.62 (0.24–6.79), 0.55    Surgical procedure             Isolated AVR  108 (41)  98 (43)  20 (56)  0.51 (0.24–1.11), 0.08     Isolated MV surgery  97 (37)  86 (38)  11 (31)  0.72 (0.34–1.55), 0.41     Multiple valve procedure  49 (19)  37 (16)  12 (33)  2.58 (1.16–5.54), 0.02  2.19 (0.92–5.06), 0.07   Concomitant CABG  8 (3)  5 (2)  3 (8)  4.05 (0.80–17.32), 0.06     Concomitant procedure on thoracic (ascending) aorta  15 (6)  13 (6)  2 (6)  0.97 (0.15–3.73), 0.97     Urgent-emergent  103 (39)  87 (38)  16 (44)  1.30 (0.63–2.63), 0.47     Blood cardioplegia with topical ventricular cooling  166 (63)  144 (63)  22 (61)  0.91 (0.45–1.92), 0.81     Custodiol cardioplegia  98 (37)  84 (37)  14 (39)  1.09 (0.52–2.23), 0.81     CPBT  128.8 ± 89.2  121.72 ± 48.81  173.69 ± 151.42  1.01 (1.00–1.01), 0.003  1.01 (1.00–1.01), 0.009   XCT  89.6 ± 38.4  94.36 ± 39.63  105.69 ± 52.31  1.01 (1.00–1.02), 0.01  b  Continuous variables are reported as mean and standard deviation. Categorical variables are reported as absolute number and percentages. Area under the ROC curve for multivariable model 0.77, Hosmer–Lemeshow’s test: P = 0.91. a Staphylococcus aureus (n = 41), coagulase-negative staphylococci (n = 29), viridans group streptococci (not further specified, n = 20), Streptococcus gallolyticus (n = 10), Streptococcus mutans (n = 5), Streptococcus mitis (n = 1), Streptococcus salivarius (n = 1), Streptococcus pyogenes (n = 1), Streptococcus pneumoniae (n = 1), Streptococcus agalactiae (n = 1), Streptococcus dysgalactiae (n = 1), Enterococcus faecalis (n = 24), Enterococcus faecium (n = 1) and Candida albicans (n = 5). Other: Granulicatella adiacens (n = 3); Proteus mirabilis (n = 3); Corynebacterium striatum (n = 2). b A multivariable model forcing into XCT instead of CPBT was included as Supplementary Material. AVR: aortic valve replacement; BMI: body mass index; CABG: coronary artery bypass grafting; CI: confidence interval; COPD: chronic obstructive pulmonary disease; CPBT: cardiopulmonary bypass time; IABP: intra-aortic balloon pump; LVEF: left ventricular ejection fraction; MV: mitral valve; NA: not applicable; NVE: native valve endocarditis; NYHA: New York Heart Association; OR: odds ratio; PAPS: pulmonary artery systolic pressure; PVE: prosthetic valve endocarditis; XCT: aortic cross-clamp time. Table 1: Preoperative clinical and operative characteristics and their impact on early postoperative mortality according to univariable and multivariable logistic regression analyses Variables  n = 264 (%)  Survivors (n = 228)  Non-survivors (n = 36)  Univariable logistic regression OR (95% CI), P-value  Multivariable logistic regression OR (95% CI), P-value  Female gender  68 (26)  54 (24)  14 (39)  2.05 (0.96–4.25), 0.06    Age (years)  62 ± 15.2  61.45 ± 15.1  67.2 ± 14.7  1.03 (1.00–1.06), 0.04  1.04 (1.01–1.07), 0.02  Hypertension  114 (43)  96 (42)  18 (50)  1.38 (0.68–2.79), 0.37    Diabetes  35 (13)  31 (14)  4 (11)  0.79 (0.23–2.18), 0.68    BMI >30 (kg/m2)  47 (18)  41 (18)  6 (17)  0.91 (0.33–2.20), 0.85    COPD  24 (9)  19 (8)  5 (14)  1.77 (0.56–4.79), 0.28    Stroke  28 (11)  23 (10)  5 (14)  1.44 (046–3.80), 0.49    Previous cardiac surgery  62 (23)  51 (22)  11 (31)  1.53 (0.68–3.25), 0.28    Peripheral vascular disease  26 (10)  20 (9)  6 (17)  2.08 (0.71–5.34), 0.15    Critical preoperative status  18 (7)  14 (6)  4 (11)  1.91 (0.52–5.72), 0.28    Preoperative IABP  2 (1)  2 (1)  0  NA, 0.99    Chronic kidney disease  46 (17)  36 (16)  10 (28)  2.05 (0.88–4.52), 0.08    Solid organ cancer  7 (3)  7 (3)  0  NA, 0.99    Preoperative mechanical ventilation  10 (4)  9 (4)  1 (3)  0.70 (0.04–3.87), 0.73    Myocardial infarction <3 months  8 (3)  7 (3)  1 (3)  0.90 (0.05–5.29), 0.92    NYHA  185 (70)  158 (69)  27 (75)  1.32 (0.61–3.13), 0.49     I–II             III–IV  79 (30)  70 (31)  9 (25)  0.75 (0.32–1.63), 0.49    EuroSCORE II  6.68 ± 9.85  5.89 ± 8.76  11.59 ± 14.22  1.04 (1.01–1.07), 0.005    STS-IE score  22.13 ± 10.45  21.7 ± 1.09  24.83 ± 13.65  1.03 (0.99–1.06), 0.10    PALSUSE score  2.11 ± 1.45  2.01 ± 1.42  2.72 ± 1.52  1.40 (1.10–1.82), 0.007    Endocarditis characteristics             NVE  213 (81)  187 (82)  26 (72)  0.57 (0.26–1.32), 0.17     PVE  51 (19)  41 (18)  10 (28)  1.75 (0.75–3.83), 0.17     Active endocarditis  179 (68)  158 (69)  21 (58)  0.62 (0.30–1.29), 0.19     Embolic event  11 (4)  11 (5)  0  NA, 0.99     Causative organisma        0.07      Staphylococcus spp.  70 (27)  63 (28)  7 (19)  1 (Reference)      Streptococcus spp.  41 (16)  39 (17)  2 (6)  0.46 (0.07–2.03)      Enterococcus spp.  25 (9)  20 (9)  5 (14)  2.25 (0.61–7.85)      Candida spp.  5 (2)  4 (2)  1 (3)  2.25 (0.11–18.16)      Other  8 (3)  8 (4)  0  NA     Negative culture  115 (44)  94 (41)  21 (58)  2.01 (0.84–5.36)    Echocardiogram and electrocardiogram findings             Vegetation >1 cm  33 (4)  30 (13)  3 (8)  0.60 (0.14–1.71), 0.42     Abscess  11 (4)  7 (3)  4 (11)  3.95 (0.99–13.84), 0.04     Paravalvular leak  40 (15)  32 (14)  8 (22)  1.75 (0.73–4.18), 0.20     Severe stenosis  38 (14)  32 (14)  6 (17)  1.14 (0.44–2.97), 0.75     Severe regurgitation  163 (62)  148 (65)  15 (42)  0.51 (0.25–1.04), 0.07     LVEF (%)  53.7 ± 8.9  54.56 ± 8.85  48.47 ± 8.21  0.93 (0.89–0.97), 0.0003  0.93 (0.89–0.97), 0.0007   PAPS >60 mmHg  35 (13)  31 (14)  4 (11)  0.79 (0.23–2.18), 0.68     Atrioventricular block  10 (4)  8 (4)  2 (6)  1.62 (0.24–6.79), 0.55    Surgical procedure             Isolated AVR  108 (41)  98 (43)  20 (56)  0.51 (0.24–1.11), 0.08     Isolated MV surgery  97 (37)  86 (38)  11 (31)  0.72 (0.34–1.55), 0.41     Multiple valve procedure  49 (19)  37 (16)  12 (33)  2.58 (1.16–5.54), 0.02  2.19 (0.92–5.06), 0.07   Concomitant CABG  8 (3)  5 (2)  3 (8)  4.05 (0.80–17.32), 0.06     Concomitant procedure on thoracic (ascending) aorta  15 (6)  13 (6)  2 (6)  0.97 (0.15–3.73), 0.97     Urgent-emergent  103 (39)  87 (38)  16 (44)  1.30 (0.63–2.63), 0.47     Blood cardioplegia with topical ventricular cooling  166 (63)  144 (63)  22 (61)  0.91 (0.45–1.92), 0.81     Custodiol cardioplegia  98 (37)  84 (37)  14 (39)  1.09 (0.52–2.23), 0.81     CPBT  128.8 ± 89.2  121.72 ± 48.81  173.69 ± 151.42  1.01 (1.00–1.01), 0.003  1.01 (1.00–1.01), 0.009   XCT  89.6 ± 38.4  94.36 ± 39.63  105.69 ± 52.31  1.01 (1.00–1.02), 0.01  b  Variables  n = 264 (%)  Survivors (n = 228)  Non-survivors (n = 36)  Univariable logistic regression OR (95% CI), P-value  Multivariable logistic regression OR (95% CI), P-value  Female gender  68 (26)  54 (24)  14 (39)  2.05 (0.96–4.25), 0.06    Age (years)  62 ± 15.2  61.45 ± 15.1  67.2 ± 14.7  1.03 (1.00–1.06), 0.04  1.04 (1.01–1.07), 0.02  Hypertension  114 (43)  96 (42)  18 (50)  1.38 (0.68–2.79), 0.37    Diabetes  35 (13)  31 (14)  4 (11)  0.79 (0.23–2.18), 0.68    BMI >30 (kg/m2)  47 (18)  41 (18)  6 (17)  0.91 (0.33–2.20), 0.85    COPD  24 (9)  19 (8)  5 (14)  1.77 (0.56–4.79), 0.28    Stroke  28 (11)  23 (10)  5 (14)  1.44 (046–3.80), 0.49    Previous cardiac surgery  62 (23)  51 (22)  11 (31)  1.53 (0.68–3.25), 0.28    Peripheral vascular disease  26 (10)  20 (9)  6 (17)  2.08 (0.71–5.34), 0.15    Critical preoperative status  18 (7)  14 (6)  4 (11)  1.91 (0.52–5.72), 0.28    Preoperative IABP  2 (1)  2 (1)  0  NA, 0.99    Chronic kidney disease  46 (17)  36 (16)  10 (28)  2.05 (0.88–4.52), 0.08    Solid organ cancer  7 (3)  7 (3)  0  NA, 0.99    Preoperative mechanical ventilation  10 (4)  9 (4)  1 (3)  0.70 (0.04–3.87), 0.73    Myocardial infarction <3 months  8 (3)  7 (3)  1 (3)  0.90 (0.05–5.29), 0.92    NYHA  185 (70)  158 (69)  27 (75)  1.32 (0.61–3.13), 0.49     I–II             III–IV  79 (30)  70 (31)  9 (25)  0.75 (0.32–1.63), 0.49    EuroSCORE II  6.68 ± 9.85  5.89 ± 8.76  11.59 ± 14.22  1.04 (1.01–1.07), 0.005    STS-IE score  22.13 ± 10.45  21.7 ± 1.09  24.83 ± 13.65  1.03 (0.99–1.06), 0.10    PALSUSE score  2.11 ± 1.45  2.01 ± 1.42  2.72 ± 1.52  1.40 (1.10–1.82), 0.007    Endocarditis characteristics             NVE  213 (81)  187 (82)  26 (72)  0.57 (0.26–1.32), 0.17     PVE  51 (19)  41 (18)  10 (28)  1.75 (0.75–3.83), 0.17     Active endocarditis  179 (68)  158 (69)  21 (58)  0.62 (0.30–1.29), 0.19     Embolic event  11 (4)  11 (5)  0  NA, 0.99     Causative organisma        0.07      Staphylococcus spp.  70 (27)  63 (28)  7 (19)  1 (Reference)      Streptococcus spp.  41 (16)  39 (17)  2 (6)  0.46 (0.07–2.03)      Enterococcus spp.  25 (9)  20 (9)  5 (14)  2.25 (0.61–7.85)      Candida spp.  5 (2)  4 (2)  1 (3)  2.25 (0.11–18.16)      Other  8 (3)  8 (4)  0  NA     Negative culture  115 (44)  94 (41)  21 (58)  2.01 (0.84–5.36)    Echocardiogram and electrocardiogram findings             Vegetation >1 cm  33 (4)  30 (13)  3 (8)  0.60 (0.14–1.71), 0.42     Abscess  11 (4)  7 (3)  4 (11)  3.95 (0.99–13.84), 0.04     Paravalvular leak  40 (15)  32 (14)  8 (22)  1.75 (0.73–4.18), 0.20     Severe stenosis  38 (14)  32 (14)  6 (17)  1.14 (0.44–2.97), 0.75     Severe regurgitation  163 (62)  148 (65)  15 (42)  0.51 (0.25–1.04), 0.07     LVEF (%)  53.7 ± 8.9  54.56 ± 8.85  48.47 ± 8.21  0.93 (0.89–0.97), 0.0003  0.93 (0.89–0.97), 0.0007   PAPS >60 mmHg  35 (13)  31 (14)  4 (11)  0.79 (0.23–2.18), 0.68     Atrioventricular block  10 (4)  8 (4)  2 (6)  1.62 (0.24–6.79), 0.55    Surgical procedure             Isolated AVR  108 (41)  98 (43)  20 (56)  0.51 (0.24–1.11), 0.08     Isolated MV surgery  97 (37)  86 (38)  11 (31)  0.72 (0.34–1.55), 0.41     Multiple valve procedure  49 (19)  37 (16)  12 (33)  2.58 (1.16–5.54), 0.02  2.19 (0.92–5.06), 0.07   Concomitant CABG  8 (3)  5 (2)  3 (8)  4.05 (0.80–17.32), 0.06     Concomitant procedure on thoracic (ascending) aorta  15 (6)  13 (6)  2 (6)  0.97 (0.15–3.73), 0.97     Urgent-emergent  103 (39)  87 (38)  16 (44)  1.30 (0.63–2.63), 0.47     Blood cardioplegia with topical ventricular cooling  166 (63)  144 (63)  22 (61)  0.91 (0.45–1.92), 0.81     Custodiol cardioplegia  98 (37)  84 (37)  14 (39)  1.09 (0.52–2.23), 0.81     CPBT  128.8 ± 89.2  121.72 ± 48.81  173.69 ± 151.42  1.01 (1.00–1.01), 0.003  1.01 (1.00–1.01), 0.009   XCT  89.6 ± 38.4  94.36 ± 39.63  105.69 ± 52.31  1.01 (1.00–1.02), 0.01  b  Continuous variables are reported as mean and standard deviation. Categorical variables are reported as absolute number and percentages. Area under the ROC curve for multivariable model 0.77, Hosmer–Lemeshow’s test: P = 0.91. a Staphylococcus aureus (n = 41), coagulase-negative staphylococci (n = 29), viridans group streptococci (not further specified, n = 20), Streptococcus gallolyticus (n = 10), Streptococcus mutans (n = 5), Streptococcus mitis (n = 1), Streptococcus salivarius (n = 1), Streptococcus pyogenes (n = 1), Streptococcus pneumoniae (n = 1), Streptococcus agalactiae (n = 1), Streptococcus dysgalactiae (n = 1), Enterococcus faecalis (n = 24), Enterococcus faecium (n = 1) and Candida albicans (n = 5). Other: Granulicatella adiacens (n = 3); Proteus mirabilis (n = 3); Corynebacterium striatum (n = 2). b A multivariable model forcing into XCT instead of CPBT was included as Supplementary Material. AVR: aortic valve replacement; BMI: body mass index; CABG: coronary artery bypass grafting; CI: confidence interval; COPD: chronic obstructive pulmonary disease; CPBT: cardiopulmonary bypass time; IABP: intra-aortic balloon pump; LVEF: left ventricular ejection fraction; MV: mitral valve; NA: not applicable; NVE: native valve endocarditis; NYHA: New York Heart Association; OR: odds ratio; PAPS: pulmonary artery systolic pressure; PVE: prosthetic valve endocarditis; XCT: aortic cross-clamp time. Predictors of early postoperative mortality The crude early postoperative mortality was 14% (36 of 264 patients). The mortality rate was not significantly different after surgery for isolated aortic valve endocarditis versus isolated mitral valve IE [10/108 (9%) vs 11/97 (11%), P = 0.65] or for NVE versus PVE [26/213 (12%) vs 10/51 (19%), P =0.16]. On the contrary, it was significantly different for multiple valve procedures vs single valve procedures [12/49 (24%) vs 24/215 (11%), P = 0.014]. No difference in early postoperative mortality was observed between patients operated during the 1st vs 2nd half of the study period [12.6% (15 of 119 patients) from 2000 to 2008 vs 14.5% (21 of 145 patients) from 2009 to 2016, χ2 statistic = 0.20; P = 0.66]. The distribution of mortality rates according to quartiles of XCT and CPBT is shown in Fig. 1, while Table 1 shows the results of univariable and multivariable analyses of mortality predictors. Figure 1: View largeDownload slide Distribution of early postoperative mortality and increasing OR for mortality according to quartiles of aortic cross-clamp (A) and cardiopulmonary bypass time (B). CI: confidence interval; OR: odds ratio. Figure 1: View largeDownload slide Distribution of early postoperative mortality and increasing OR for mortality according to quartiles of aortic cross-clamp (A) and cardiopulmonary bypass time (B). CI: confidence interval; OR: odds ratio. At univariable analysis, age, EuroSCORE II, PALSUSE score, presence of abscess, LVEF, multiple valve procedures, increasing XCT and increasing CPBT showed a statistically significant association with the outcome. Of note, increasing XCT [odds ratio (OR) 3.21, 95% confidence interval (CI) 1.32–8.14; P = 0.01, area under the ROC curve 0.62, Hosmer–Lemeshow’s test: P = 0.45] and increasing CPBT (OR 3.20, 95% CI 1.45–7.36; P = 0.005, area under the ROC curve 0.60, Hosmer–Lemeshow’s test: P = 0.15) predicted early postoperative mortality also when logarithmically transformed. In multivariable analysis (Hosmer–Lemeshow’s test: P = 0.9, area under the ROC curve 0.77), increasing CPBT (OR 1.008, 95% CI 1.003–1.01; P = 0.009) was retained in the final model and confirmed as an independent predictor of early postoperative mortality, along with increasing age (OR 1.04, 95% CI 1.01–1.07; P = 0.02) and reduced LVEF (OR 0.93, 95% CI 0.89–0.97; P = 0.0007). Since a statistically significant correlation was present between increasing XCT and increasing CPBT (Spearman test, rho: 0.94, P < 0.0001), an additional variant of the final multivariable model was built by forcing inclusion of XCT instead of CPBT. The results of the additional model confirmed the existence of an independent association between increasing XCT and mortality (Supplementary Material, Table S1). The best prognostic cut-off for predicting early postoperative mortality in our cohort were > 72 min for XCT (ROC curve: 0.61, 95% CI 0.52–0.71; sensitivity 83%, specificity 38%, Adjusted OR 3.03, 95% CI 1.29–8.33; P = 0.02) and >166 min for CPBT (ROC curve: 0.60, 95% CI 0.50–0.70; sensitivity 36%, specificity 83%; Adjusted OR 2.91, 95% CI 1.33–6.22; P = 0.006), as depicted on the respective prognostic ROC curves (Fig. 2A and B). The highest rates of early postoperative mortality in our cohort were observed when both XCT and CPBT were beyond their prognostic cut-offs (Fig. 3). Figure 2: View largeDownload slide ROC curves for the best prognostic cut-off of XCT (A) and CPBT (B) values in predicting early postoperative mortality. AUC: area under the curve; CPBT: cardiopulmonary bypass time; XCT: aortic cross-clamp time. Figure 2: View largeDownload slide ROC curves for the best prognostic cut-off of XCT (A) and CPBT (B) values in predicting early postoperative mortality. AUC: area under the curve; CPBT: cardiopulmonary bypass time; XCT: aortic cross-clamp time. Figure 3: View largeDownload slide Postoperative mortality rates related to prognostic cut-offs of XCT and CPBT. CPBT: cardiopulmonary bypass time; XCT: aortic cross-clamp time. Figure 3: View largeDownload slide Postoperative mortality rates related to prognostic cut-offs of XCT and CPBT. CPBT: cardiopulmonary bypass time; XCT: aortic cross-clamp time. The discriminatory performance of risk scores, evaluated using the AUC, resulted in 0.643 for EuroSCORE II (95% CI 0.541–0.744), 0.639 for PALSUSE (95% CI 0.545–0.733) and 0.559 for STS-IE (95% CI 0.445–0.672). The calibration was adequate (Hosmer–Lemeshow test; P = 0.47, P = 0.51 and P = 0.09 for EuroSCORE II, PALSUSE and STS-IE, respectively). Predictors of postoperative severe complications The rate of occurrence of the combined severe complications end point (in-hospital mortality, ICU stay ≥5 days, stroke, postoperative haemodialysis, and postoperative use of IABP) was 32% (84 of 264). At univariable logistic regression analysis, prolonged XCT, prolonged CPBT, increasing age, stroke, reduced LVEF, preoperative mechanical ventilation, pulmonary hypertension with pulmonary artery systolic pressure >60 mmHg, critical preoperative status, EuroSCORE II, STS-IE score PALSUSE score, peripheral vascular disease, chronic kidney disease, previous cardiac surgery, urgent or emergent operation, NYHA I–II, NYHA III–IV and multiple valve procedure were associated with the composite outcome (Supplementary Material, Table S2). As shown in Table 2, multivariable logistic regression analysis confirmed CPBT (OR 1.02, 95% CI 1.006–1.04; P = 0.002) as an independent predictor of severe complications along with increasing age (OR 1.03, 95% CI 1.009–1.07; P = 0.008), stroke (OR 3.54, 95% CI 1.29–9.97; P = 0.01), preoperative mechanical ventilation (OR 44.96, 95% CI 4.83–1098.54; P = 0.003) and LVEF (OR 0.93, 95% CI 0.90–0.96; P < 0.0001). Table 2: Multivariable logistic regression for the composite end point severe complications   Complications (n = 84)  No-complications (n = 180)  Multivariable logistic regression OR (95% CI), P-value  Age (years)  65.85 ± 17.16  60.54 ± 15.22  1.03 (1.01–1.07), 0.008  Stroke  17 (20)  11 (6)  3.54 (1.29–9.97), 0.009  Preoperative mechanical ventilation  9 (11)  1 (1)  44.96 (4.83–1098.54), 0.003  EuroSCORE II  11.70 ± 16.05  4.33 ± 5.87  1.04 (1.0005–1.08), 0.06  LVEF  50.13 ± 10.14  55.41 ± 8.54  0.93 (0.90–0.96), <0.0001  Multiple valve procedure  24 (29)  25 (14)  1.83 (0.82–4.04), 0.13  CPBT  157.04 ± 50.83  115.64 ± 47.18  1.02 (1.006–1.04), 0.002  XCT  101.51 ± 43.30  83.99 ± 34.32  0.98 (0.96–1.006), 0.49a    Complications (n = 84)  No-complications (n = 180)  Multivariable logistic regression OR (95% CI), P-value  Age (years)  65.85 ± 17.16  60.54 ± 15.22  1.03 (1.01–1.07), 0.008  Stroke  17 (20)  11 (6)  3.54 (1.29–9.97), 0.009  Preoperative mechanical ventilation  9 (11)  1 (1)  44.96 (4.83–1098.54), 0.003  EuroSCORE II  11.70 ± 16.05  4.33 ± 5.87  1.04 (1.0005–1.08), 0.06  LVEF  50.13 ± 10.14  55.41 ± 8.54  0.93 (0.90–0.96), <0.0001  Multiple valve procedure  24 (29)  25 (14)  1.83 (0.82–4.04), 0.13  CPBT  157.04 ± 50.83  115.64 ± 47.18  1.02 (1.006–1.04), 0.002  XCT  101.51 ± 43.30  83.99 ± 34.32  0.98 (0.96–1.006), 0.49a  Continuous variables are reported as mean and standard deviation. Categorical variables are reported as absolute number and percentages. Area under the ROC curve for multivariable model 0.72, Hosmer–Lemeshow’s test: P = 0.74. See Supplementary Material, Table S2 for detailed univariable and multivariable logistic regression analyses. a A multivariable model forcing into XCT instead of CPBT was included as Supplementary Material, Table S3. CI: confidence interval; CPBT: cardiopulmonary bypass time; LVEF: left ventricular ejection fraction; OR: odds ratio; XCT: aortic cross-clamp time. Table 2: Multivariable logistic regression for the composite end point severe complications   Complications (n = 84)  No-complications (n = 180)  Multivariable logistic regression OR (95% CI), P-value  Age (years)  65.85 ± 17.16  60.54 ± 15.22  1.03 (1.01–1.07), 0.008  Stroke  17 (20)  11 (6)  3.54 (1.29–9.97), 0.009  Preoperative mechanical ventilation  9 (11)  1 (1)  44.96 (4.83–1098.54), 0.003  EuroSCORE II  11.70 ± 16.05  4.33 ± 5.87  1.04 (1.0005–1.08), 0.06  LVEF  50.13 ± 10.14  55.41 ± 8.54  0.93 (0.90–0.96), <0.0001  Multiple valve procedure  24 (29)  25 (14)  1.83 (0.82–4.04), 0.13  CPBT  157.04 ± 50.83  115.64 ± 47.18  1.02 (1.006–1.04), 0.002  XCT  101.51 ± 43.30  83.99 ± 34.32  0.98 (0.96–1.006), 0.49a    Complications (n = 84)  No-complications (n = 180)  Multivariable logistic regression OR (95% CI), P-value  Age (years)  65.85 ± 17.16  60.54 ± 15.22  1.03 (1.01–1.07), 0.008  Stroke  17 (20)  11 (6)  3.54 (1.29–9.97), 0.009  Preoperative mechanical ventilation  9 (11)  1 (1)  44.96 (4.83–1098.54), 0.003  EuroSCORE II  11.70 ± 16.05  4.33 ± 5.87  1.04 (1.0005–1.08), 0.06  LVEF  50.13 ± 10.14  55.41 ± 8.54  0.93 (0.90–0.96), <0.0001  Multiple valve procedure  24 (29)  25 (14)  1.83 (0.82–4.04), 0.13  CPBT  157.04 ± 50.83  115.64 ± 47.18  1.02 (1.006–1.04), 0.002  XCT  101.51 ± 43.30  83.99 ± 34.32  0.98 (0.96–1.006), 0.49a  Continuous variables are reported as mean and standard deviation. Categorical variables are reported as absolute number and percentages. Area under the ROC curve for multivariable model 0.72, Hosmer–Lemeshow’s test: P = 0.74. See Supplementary Material, Table S2 for detailed univariable and multivariable logistic regression analyses. a A multivariable model forcing into XCT instead of CPBT was included as Supplementary Material, Table S3. CI: confidence interval; CPBT: cardiopulmonary bypass time; LVEF: left ventricular ejection fraction; OR: odds ratio; XCT: aortic cross-clamp time. As observed earlier with regard to early postoperative mortality, an additional variant of the multivariable model forcing inclusion of XCT instead of CPBT confirmed an independent association between increasing XCT and postoperative severe complications (Supplementary Material, Table S3). For descriptive purposes, Table 3 shows a stratification of all postoperative adverse events (both included and not included in the composite outcome) according to the XCT and CPBT mortality cut-offs (>72 min and >166 min, respectively). Table 3: Outcomes   XCT ≤72 min; CPBT ≤166 min (n = 96)  XCT >72 min; CPBT ≤166 min (n = 119)  XCT >72 min; CPBT >166 min (n = 49)  P-value  Resternotomy for bleeding*  8 (8.3)  13 (10.9)  12 (24.5)  0.02  Acute kidney injury  6 (6.2)  8 (6.7)  2 (4.1)  0.80  Renal replacement therapy  3 (3.1)  3 (2.5)  1 (2.0)  0.92  Stroke  3 (3.1)  1 (0.8)  0  0.24  Atrial fibrillation  4 (4.2)  6 (2.1)  4 (8.2)  0.58  New onset atrioventricular block  1 (1.0)  1 (0.8)  0  0.78  Sternal wound infection  1 (1.0)  1 (0.8)  1 (2.0)  0.79  Postoperative use of IABP  1 (1.0)  1 (0.8)  0  0.78  Prolonged mechanical ventilation (>48 h)  15 (15.6)  29 (24.4)  12 (24.5)  0.24  Respiratory insufficiency  4 (4.2)  5 (4.2)  2 (4.1)  0.99  Sepsis  7 (7.3)  9 (7.6)  2 (4.1)  0.71  Multiorgan failure  1 (1.0)  4 (2.1)  1 (2.0)  0.52  Reoperation for new endocarditis event  1 (1.0)  2 (1.7)  0  0.64  ICU stay (days)**  3.2 ± 5.4  6.2 ± 18.6  5.6 ± 6.2  0.35    XCT ≤72 min; CPBT ≤166 min (n = 96)  XCT >72 min; CPBT ≤166 min (n = 119)  XCT >72 min; CPBT >166 min (n = 49)  P-value  Resternotomy for bleeding*  8 (8.3)  13 (10.9)  12 (24.5)  0.02  Acute kidney injury  6 (6.2)  8 (6.7)  2 (4.1)  0.80  Renal replacement therapy  3 (3.1)  3 (2.5)  1 (2.0)  0.92  Stroke  3 (3.1)  1 (0.8)  0  0.24  Atrial fibrillation  4 (4.2)  6 (2.1)  4 (8.2)  0.58  New onset atrioventricular block  1 (1.0)  1 (0.8)  0  0.78  Sternal wound infection  1 (1.0)  1 (0.8)  1 (2.0)  0.79  Postoperative use of IABP  1 (1.0)  1 (0.8)  0  0.78  Prolonged mechanical ventilation (>48 h)  15 (15.6)  29 (24.4)  12 (24.5)  0.24  Respiratory insufficiency  4 (4.2)  5 (4.2)  2 (4.1)  0.99  Sepsis  7 (7.3)  9 (7.6)  2 (4.1)  0.71  Multiorgan failure  1 (1.0)  4 (2.1)  1 (2.0)  0.52  Reoperation for new endocarditis event  1 (1.0)  2 (1.7)  0  0.64  ICU stay (days)**  3.2 ± 5.4  6.2 ± 18.6  5.6 ± 6.2  0.35  Categorical variables are reported as counts and percentages (in parentheses). Continuous variables are reported as mean and standard deviation. For descriptive purposes, variables were compared by means of the Fisher’s exact test, the χ2 test or the Kruskal–Wallis test. * P < 0.01 ‘XCT >72 min + CPBT >166 min’ vs ‘XCT <72 min + CPBT  <166 min’. ** P < 0.05 ‘XCT >72 min + CPBT >166 min’ vs ‘XCT <72 min + CPBT <166 min’. CPBT: cardiopulmonary bypass time; IABP: intra-aortic balloon pump; ICU: intensive care unit; XCT: aortic cross-clamp time. Table 3: Outcomes   XCT ≤72 min; CPBT ≤166 min (n = 96)  XCT >72 min; CPBT ≤166 min (n = 119)  XCT >72 min; CPBT >166 min (n = 49)  P-value  Resternotomy for bleeding*  8 (8.3)  13 (10.9)  12 (24.5)  0.02  Acute kidney injury  6 (6.2)  8 (6.7)  2 (4.1)  0.80  Renal replacement therapy  3 (3.1)  3 (2.5)  1 (2.0)  0.92  Stroke  3 (3.1)  1 (0.8)  0  0.24  Atrial fibrillation  4 (4.2)  6 (2.1)  4 (8.2)  0.58  New onset atrioventricular block  1 (1.0)  1 (0.8)  0  0.78  Sternal wound infection  1 (1.0)  1 (0.8)  1 (2.0)  0.79  Postoperative use of IABP  1 (1.0)  1 (0.8)  0  0.78  Prolonged mechanical ventilation (>48 h)  15 (15.6)  29 (24.4)  12 (24.5)  0.24  Respiratory insufficiency  4 (4.2)  5 (4.2)  2 (4.1)  0.99  Sepsis  7 (7.3)  9 (7.6)  2 (4.1)  0.71  Multiorgan failure  1 (1.0)  4 (2.1)  1 (2.0)  0.52  Reoperation for new endocarditis event  1 (1.0)  2 (1.7)  0  0.64  ICU stay (days)**  3.2 ± 5.4  6.2 ± 18.6  5.6 ± 6.2  0.35    XCT ≤72 min; CPBT ≤166 min (n = 96)  XCT >72 min; CPBT ≤166 min (n = 119)  XCT >72 min; CPBT >166 min (n = 49)  P-value  Resternotomy for bleeding*  8 (8.3)  13 (10.9)  12 (24.5)  0.02  Acute kidney injury  6 (6.2)  8 (6.7)  2 (4.1)  0.80  Renal replacement therapy  3 (3.1)  3 (2.5)  1 (2.0)  0.92  Stroke  3 (3.1)  1 (0.8)  0  0.24  Atrial fibrillation  4 (4.2)  6 (2.1)  4 (8.2)  0.58  New onset atrioventricular block  1 (1.0)  1 (0.8)  0  0.78  Sternal wound infection  1 (1.0)  1 (0.8)  1 (2.0)  0.79  Postoperative use of IABP  1 (1.0)  1 (0.8)  0  0.78  Prolonged mechanical ventilation (>48 h)  15 (15.6)  29 (24.4)  12 (24.5)  0.24  Respiratory insufficiency  4 (4.2)  5 (4.2)  2 (4.1)  0.99  Sepsis  7 (7.3)  9 (7.6)  2 (4.1)  0.71  Multiorgan failure  1 (1.0)  4 (2.1)  1 (2.0)  0.52  Reoperation for new endocarditis event  1 (1.0)  2 (1.7)  0  0.64  ICU stay (days)**  3.2 ± 5.4  6.2 ± 18.6  5.6 ± 6.2  0.35  Categorical variables are reported as counts and percentages (in parentheses). Continuous variables are reported as mean and standard deviation. For descriptive purposes, variables were compared by means of the Fisher’s exact test, the χ2 test or the Kruskal–Wallis test. * P < 0.01 ‘XCT >72 min + CPBT >166 min’ vs ‘XCT <72 min + CPBT  <166 min’. ** P < 0.05 ‘XCT >72 min + CPBT >166 min’ vs ‘XCT <72 min + CPBT <166 min’. CPBT: cardiopulmonary bypass time; IABP: intra-aortic balloon pump; ICU: intensive care unit; XCT: aortic cross-clamp time. Predictors of prolonged aortic cross-clamp and cardiopulmonary bypass time The selection process of demographic and clinical variables to be included in multivariable models for predicting prolonged XCT and CPBT is shown in Supplementary Material, Fig. S1. In the first multivariable model (dependent variable = XCT), age, diabetes, previous cardiac surgery, Custodiol cardioplegia, PVE, multiple valve procedures, concomitant procedures on thoracic aorta were independently associated with prolonged XCT. In the second multivariable model (dependent variable = CPBT), EuroSCORE II, presence of abscess, critical preoperative state, Custodiol cardioplegia, PVE, multiple valve procedures and concomitant procedures on thoracic aorta were independently associated with prolonged CPBT (Table 4). Table 4: Predictors of prolonged XCT and CPBT XCT   CPBT   Independent variables  Beta  t  P-value  Independent variables  Beta  t  P-value  Age (years)  −0.25  −1.96  0.05  Age  −0.51  −1.92  0.06  Diabetes  13.21  2.31  0.02  EuroSCORE II  1.65  3.00  0.003  Embolic event  16.70  1.74  0.08  Presence of abscess  44.72  2.26  0.02  Previous cardiac surgery  36.74  2.36  0.02  Critical preoperative state  −40.13  −2.08  0.04  Custodiol cardioplegia  12.20  3.04  0.003  Custodiol cardioplegia  17.19  2.14  0.03  PVE  34.57  7.05  <0.0001  PVE  45.28  4.21  <0.0001  Multiple valve procedures  32.01  6.39  <0.0001  Multiple valve procedures  37.48  10.21  0.0003  Concomitant procedure on thoracic (ascending) aorta  45.76  5.46  <0.0001  Concomitant procedure on thoracic (ascending) aorta  85.02  5.05  <0.0001  R2 = 0.38; R2 adjusted = 0.36; SE = 30.7  R2 = 0.33; R2 adjusted = 0.31; SE = 61.36  XCT   CPBT   Independent variables  Beta  t  P-value  Independent variables  Beta  t  P-value  Age (years)  −0.25  −1.96  0.05  Age  −0.51  −1.92  0.06  Diabetes  13.21  2.31  0.02  EuroSCORE II  1.65  3.00  0.003  Embolic event  16.70  1.74  0.08  Presence of abscess  44.72  2.26  0.02  Previous cardiac surgery  36.74  2.36  0.02  Critical preoperative state  −40.13  −2.08  0.04  Custodiol cardioplegia  12.20  3.04  0.003  Custodiol cardioplegia  17.19  2.14  0.03  PVE  34.57  7.05  <0.0001  PVE  45.28  4.21  <0.0001  Multiple valve procedures  32.01  6.39  <0.0001  Multiple valve procedures  37.48  10.21  0.0003  Concomitant procedure on thoracic (ascending) aorta  45.76  5.46  <0.0001  Concomitant procedure on thoracic (ascending) aorta  85.02  5.05  <0.0001  R2 = 0.38; R2 adjusted = 0.36; SE = 30.7  R2 = 0.33; R2 adjusted = 0.31; SE = 61.36  Beta: standardized regression coefficient; CPBT: cardiopulmonary bypass time; PVE: prosthetic valve endocarditis; SE: standard error; XCT: aortic cross-clamping time. Table 4: Predictors of prolonged XCT and CPBT XCT   CPBT   Independent variables  Beta  t  P-value  Independent variables  Beta  t  P-value  Age (years)  −0.25  −1.96  0.05  Age  −0.51  −1.92  0.06  Diabetes  13.21  2.31  0.02  EuroSCORE II  1.65  3.00  0.003  Embolic event  16.70  1.74  0.08  Presence of abscess  44.72  2.26  0.02  Previous cardiac surgery  36.74  2.36  0.02  Critical preoperative state  −40.13  −2.08  0.04  Custodiol cardioplegia  12.20  3.04  0.003  Custodiol cardioplegia  17.19  2.14  0.03  PVE  34.57  7.05  <0.0001  PVE  45.28  4.21  <0.0001  Multiple valve procedures  32.01  6.39  <0.0001  Multiple valve procedures  37.48  10.21  0.0003  Concomitant procedure on thoracic (ascending) aorta  45.76  5.46  <0.0001  Concomitant procedure on thoracic (ascending) aorta  85.02  5.05  <0.0001  R2 = 0.38; R2 adjusted = 0.36; SE = 30.7  R2 = 0.33; R2 adjusted = 0.31; SE = 61.36  XCT   CPBT   Independent variables  Beta  t  P-value  Independent variables  Beta  t  P-value  Age (years)  −0.25  −1.96  0.05  Age  −0.51  −1.92  0.06  Diabetes  13.21  2.31  0.02  EuroSCORE II  1.65  3.00  0.003  Embolic event  16.70  1.74  0.08  Presence of abscess  44.72  2.26  0.02  Previous cardiac surgery  36.74  2.36  0.02  Critical preoperative state  −40.13  −2.08  0.04  Custodiol cardioplegia  12.20  3.04  0.003  Custodiol cardioplegia  17.19  2.14  0.03  PVE  34.57  7.05  <0.0001  PVE  45.28  4.21  <0.0001  Multiple valve procedures  32.01  6.39  <0.0001  Multiple valve procedures  37.48  10.21  0.0003  Concomitant procedure on thoracic (ascending) aorta  45.76  5.46  <0.0001  Concomitant procedure on thoracic (ascending) aorta  85.02  5.05  <0.0001  R2 = 0.38; R2 adjusted = 0.36; SE = 30.7  R2 = 0.33; R2 adjusted = 0.31; SE = 61.36  Beta: standardized regression coefficient; CPBT: cardiopulmonary bypass time; PVE: prosthetic valve endocarditis; SE: standard error; XCT: aortic cross-clamping time. DISCUSSION In our cohort of 264 patients undergoing valvular surgery for IE, increasing XCT and CBPT were associated with poor short-term outcomes, namely early postoperative mortality and a composite outcome of severe postoperative complications within 30 days after surgery (mortality, ICU stay ≥5 days, stroke, postoperative haemodialysis or postoperative use of IABP). The unfavourable impact of prolonged XCT and CPBT has been previously explored, although not specifically in patients with IE [2–6, 10]. Our study confirms these findings in a cohort composed exclusively of patients undergoing valvular surgery for IE and also underlys an alarmingly high postoperative mortality especially in patients presenting with complicated IE [19–21]. Indeed, early postoperative mortality was as high as 14% in our study, a worrisome rate albeit in line with other series [19–22]. In this perspective, the identification of safe limits for XCT and CPBT might help to plan, and if possible to limit the surgical strategy to improve overall outcomes. For this purpose, the prognostic cut-offs found in our study (≤72 and ≤166 min for XCT and CPBT, respectively) might represent desirable intraoperative targets. Of note, our cut-offs were slightly lower than those identified by other authors in cohorts unrestricted to IE patients (<90–150 and <240 min for XCT and CPBT, respectively) [2, 4, 6]. We speculated that this result could be explained by the impairment in heart rate regulation and the damage of mitochondrial function by inflammatory mediators that occurs more frequently in IE than in non-infectious surgical conditions and which might enhance the unfavourable prognostic impact of prolonged XCT and CPBT [23–26]. This intriguing possibility still deserves confirmation through dedicated preclinical models and should be considered with caution pending further investigation. In our opinion, another point worthy of further investigation might be the use, in some selected patients, of new generation prostheses, such as sutureless or rapid deployment valves [27], which could help in reducing XCT and CBPT, and in turn improving the prognosis of IE patients. In our study, the unfavourable impact of prolonged XCT and CPBT is further testified by their association with the composite outcome of severe complications. A similar association was already described by Nissinen et al. [6] in a heterogeneous cohort of patients of whom less than 1% had active endocarditis. In this regard, it is worth noting that in our study, the composite outcome had a frequency of 32%, far higher than that of 11% described by Nissinen et al. [6], thus making the challenge of impacting the postoperative outcome by means of reducing CPBT and XCT even more attractive and worthy of further investigation. Increased XCT and CPBT were not the only predictors of in-hospital mortality and severe complications found in our study. Indeed, reduced LVEF and older age also unfavourably influenced outcomes, with preoperative stroke and preoperative mechanical ventilation being further independent predictors of the composite outcome of severe complications. These results comply with previous literature and highlight the fact that risk assessment in patients undergoing valvular surgery for IE is a challenging task [6, 27–29]. In this regard, our study suggests that prolonged XCT and CPBT might provide additional information about postoperative risks that cannot be intercepted by classical preoperative risk scores used in patients with IE [22, 30]. Finally, we observed that diabetes, previous cardiac surgery, Custodiol cardioplegia, PVE, multiple valve procedures, and concomitant procedures on the thoracic aorta were associated with prolonged XCT, while EuroSCORE II, presence of abscess, critical preoperative state, Custodiol cardioplegia, PVE, multiple valve procedures and concomitant procedures on thoracic aorta predicted prolonged CPBT. In our opinion, these findings reflect the critical importance of baseline comorbidities, acute phase conditions and extension of the infections process in influencing XCT and CPBT, and, in turn, postoperative outcomes. Consequently, all these factors should be considered when planning ahead a surgical procedure for IE in order to lessen the operative risk. Limitations Our study has some important limitations. First, information on the anatomical factors that might have influenced outcomes were not recorded. Second, incomplete information on the appropriateness of antibiotic therapy might have also affected the outcomes, as well as any possible impact of inflammation/activity of endocarditis. Finally, the collected procedures were performed over 17 years by different surgical teams using a variety of techniques that might have influenced the results. CONCLUSION In conclusion, prolonged XCT and CPBT are associated with mortality and development of severe complications after valvular surgery for IE. Provided that their prognostic role is validated in confirmatory studies, the safe limits of 72 min for XCT and 166 min for CPBT found in our study might be considered as factors to be weighed when planning the best surgical strategy to improve intraoperative and postoperative outcomes of IE patients. SUPPLEMENTARY MATERIAL Supplementary material is available at ICVTS online. Conflict of interest: none declared. 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This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Interactive CardioVascular and Thoracic Surgery Oxford University Press

Aortic cross-clamp time and cardiopulmonary bypass time: prognostic implications in patients operated on for infective endocarditis

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
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1569-9293
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1569-9285
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10.1093/icvts/ivy085
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Abstract

Abstract OBJECTIVES Prolonged aortic cross-clamp (XCT) and cardiopulmonary bypass time (CPBT) are associated with increased morbidity and mortality following cardiac surgery. The aim of this study was to assess the predictors of mortality and other severe postoperative complications in patients undergoing surgery for infective endocarditis (IE), focusing in particular on the role of prolonged XCT and CPBT. METHODS A retrospective single-centre study was conducted from January 2000 to January 2017, including all patients undergoing valvular surgery for IE. The primary end point was early postoperative mortality. The main secondary end point was a composite end point for severe postoperative complications. RESULTS During the study period, 264 patients were included. Early postoperative mortality was 14%. Prolonged CPBT [odds ratio (OR) 1.008, 95% confidence intervals (CIs) 1.003–1.01; P = 0.009] and increasing age (OR 1.04, 95% CI 1.01–1.07; P = 0.02) independently predicted mortality, while an inverse association was observed for left ventricular ejection fraction (OR 0.93, 95% CI 0.89–0.97; P = 0.0007). The best mortality cut-offs were >72 min for XCT and >166 min for CPBT. Prolonged CPBT also predicted severe complications, along with age, stroke, preoperative mechanical ventilation and reduced left ventricular ejection fraction. When XCT was included in the multivariable models instead of CPBT, it was associated with both mortality and severe complications. CONCLUSIONS Prolonged XCT and CPBT are associated with mortality and development of severe complications after valvular surgery for IE. Further validation of safe limits for XCT and CPBT might provide novel insights on how to improve intraoperative and postoperative outcomes of patients with IE. Cardiopulmonary bypass , Endocarditis , Heart valves , Inflammation INTRODUCTION Prolonged aortic cross-clamp (XCT) and cardiopulmonary bypass time (CPBT) are associated with increased morbidity and mortality following cardiac surgery, conceivably in view of the myocardial damage and inflammatory response associated with cardioplegic cardiac arrest and cardiopulmonary bypass [1–6]. Infective endocarditis (IE) is a systemic infectious disease, as evidenced by the increase in systemic inflammatory markers, and might require valvular surgery [7–9]. From this standpoint, the underlying preoperative inflammatory state might theoretically heighten the detrimental effect of a prolonged XCT and CPBT. However, up to date the magnitude of the unfavourable impact of prolonged XCT and CPBT on clinical outcomes has been extensively described in patients undergoing coronary artery bypass surgery (CABG) or aortic valve replacement (AVR) [1, 4, 10], but not in patients operated on for IE. The aim of this study was therefore to assess the predictors of in-hospital mortality and other severe postoperative complications in patients undergoing surgery for IE, focusing in particular on the role of prolonged XCT and CPBT. METHODS Study design From January 2000 to January 2017, data of patients undergoing valvular surgery for IE at the San Martino University Hospital were included in a prospectively collected database. Patients in whom cardiopulmonary bypass and cardioplegic cardiac arrest were employed during surgery were retrospectively identified in the database and included in the present study. For each patient, baseline demographic and clinical data were collected at the time of the first surgical procedure. Study end points The primary end point was early postoperative mortality. The main secondary end point was a composite endpoint of severe complications within 30 days after surgery (i.e. mortality, intensive care unit (ICU) stay ≥5 days, stroke, or denovo haemodialysis, postoperative use of intra-aortic balloon pump (IABP), whichever came first [6]). Other secondary end points were prolonged XCT and prolonged CPBT. Definitions and procedures The presence of IE was defined according to the modified Duke’s criteria [11, 12]. All other patients who did not fulfil the modified Duke’s criteria preoperatively were retrospectively included if the positive culture of vegetation and/or abscess and/or tissue histology collected at the time of surgery confirmed infection. Patient comorbidities and postoperative complications were defined according to the joint AATS/EACTS/STS Guidelines for Reporting Mortality and Morbidity After Cardiac Valve Interventions in adult cardiac surgery [13]. Early postoperative mortality was defined as death during the hospital stay or within 30 days after surgery. Urgent-emergent surgery priorities were defined as surgery performed immediately or within the current admission for medical reasons according to European System for Cardiac Operative Risk Evaluation II (EuroSCORE II) definitions [14]. Myocardial protection was achieved by means of antegrade administration of warm blood cardioplegia associated with topical ventricular cooling or hypothermic (31°C) Custodiol Histidine Tryptophan Ketoglutarate solution. Data collected for the analysis The following baseline variables were collected: gender, age (collected as a continuous variable), hypertension, diabetes [any preoperative diagnosis of diabetes mellitus requiring treatment (diet, oral drugs and/or insulin therapy)], obesity (body mass index > 30), chronic obstructive pulmonary disease (defined as long term use of bronchodilators or steroids for lung disease), stroke (any preoperative focal or global neurological syndrome caused by ischaemia or haemorrhage not resolving within 24 h), previous cardiac surgery, peripheral vascular disease (1 or more of the following: claudication, carotid occlusion or >50% stenosis, amputation for arterial disease, previous or planned intervention on the abdominal aorta, limb arteries or carotids), preoperative insertion of IABP, chronic kidney disease (baseline serum creatinine >200 µmol/l), solid organ cancer, preoperative mechanical ventilation, myocardial infarction <3 months, New York Heart Association (NYHA) class, EuroSCORE II (calculated retrospectively using the on-line calculator available at http://www.euroscore.org/calc.html) [14], STS Endocarditis Score (STS-IE) calculated retrospectively [15], PALSUSE score calculated retrospectively [16], status priority, critical preoperative state, left ventricular ejection fraction (LVEF; all defined according to EuroSCORE II definitions), endocarditis characteristics [native valve endocarditis (NVE) or prosthetic valve endocarditis (PVE), cerebrovascular embolic events in the setting of IE, active endocarditis (defined as admission before or within the first 30 days of antimicrobial treatment)]; causative organisms (identified in positive blood, vegetation or abscess cultures by means of the VITEK 2 automated system, bioMérieux, Marcy l’Etoile, France), 2-dimensional echocardiographic data (presence of vegetation, abscess, paravalvular leak, LVEF, valve diseases, pulmonary hypertension), atrioventricular block on the electrocardiogram, and operative findings. The collected postoperative complications included resternotomy for bleeding; prolonged mechanical ventilation (>48 h); ICU stay (days); acute kidney injury (a peak serum creatinine ≥50% above baseline within 5 days postoperatively); renal replacement therapy; postoperative stroke, atrial fibrillation; new onset of atrioventricular block; sternal wound infection; respiratory insufficiency (any of hypoxemic respiratory failure with a PaO2/FiO2 ratio less than 300 while on supplemental oxygen or acute hypercapnic respiratory failure, defined as a significantly elevated PaCO2 to 50 mmHg or more and a pH <7.35); sepsis (according to international definitions [17]); multiorgan failure [defined as multiple organ dysfunction within the context of Systemic Inflammatory Response Syndrome (SIRS)]; reoperation for new endocarditis event (novel evidence of valve endocarditis after discharge); and postoperative IABP placement. Statistical analysis Categorical data were presented as frequencies and percentages and compared using the χ2 test or the Fisher’s exact test where appropriate. Continuous variables were expressed as mean and standard deviation (SD) and compared using 2-tailed t-test or Mann–Whitney test. Kruskal–Wallis test was used for group comparisons. To identify factors associated with early postoperative mortality and with the composite outcome of severe complications, demographic and clinical characteristics of patients (including length of XCT and CPBT) were compared between survivors and non-survivors and between patients who experienced the composite severe complications end point and those who did not by means of the univariable logistic regression models. Then, to assess the independent role of potential predictors, variables associated with the pertinent outcome in the univariable analyses (P < 0.05) were included in a stepwise backward multivariable logistic regression model employing the R algorithm based on the Akaike information criterion at each step. The reliability of the regression models was assessed with the C-statistic and the Hosmer–Lemeshow’s test. The Youden’s test was used to identify the best cut-off values of XCT and CPBT in predicting early mortality. A P-value <0.05 was considered statistically significant. The discriminatory performance and the calibration of risk scores (EuroSCORE II, STS-IE and PALSUSE) with regard to mortality was evaluated using the C-statistic and the Hosmer–Lemeshow’s test, respectively. To identify risk factors for prolonged XCT and CPBT, exhaustive search for the best subsets of independent variables to include for predicting prolonged XCT and CPBT in multiple linear regression was undertaken [18]. All the analyses were performed using the R Statistical Software (version 3.2.2; R Foundation for Statistical Computing, Vienna, Austria). RESULTS Of the 274 consecutive patients operated on for IE from January 2000 to January 2017, 264 patients underwent valvular repair\substitution with the use of cardiopulmonary bypass and cardioplegic cardiac arrest. Ten patients who were operated on for an infected pacemaker lead removal were excluded from the study. Their mean age was 62 years [SD ± 15.2] and 196 were males (74%). The complete demographic and clinical characteristics of the patients included are shown in Table 1. NVE and PVE accounted for 81% and 19% of the cases, respectively. The proportion of active IE was 68%. Aortic (145/264, 55%) and mitral valve (128/264, 48%) were mostly involved; 18% of the diseased mitral valves were repaired (17 of 97 patients). The tricuspid valve was involved in 10 (4%) patients, and the pulmonary valve in 1 (<1%) patient. Forty-nine patients had multiple valve disease (19%). Table 1: Preoperative clinical and operative characteristics and their impact on early postoperative mortality according to univariable and multivariable logistic regression analyses Variables  n = 264 (%)  Survivors (n = 228)  Non-survivors (n = 36)  Univariable logistic regression OR (95% CI), P-value  Multivariable logistic regression OR (95% CI), P-value  Female gender  68 (26)  54 (24)  14 (39)  2.05 (0.96–4.25), 0.06    Age (years)  62 ± 15.2  61.45 ± 15.1  67.2 ± 14.7  1.03 (1.00–1.06), 0.04  1.04 (1.01–1.07), 0.02  Hypertension  114 (43)  96 (42)  18 (50)  1.38 (0.68–2.79), 0.37    Diabetes  35 (13)  31 (14)  4 (11)  0.79 (0.23–2.18), 0.68    BMI >30 (kg/m2)  47 (18)  41 (18)  6 (17)  0.91 (0.33–2.20), 0.85    COPD  24 (9)  19 (8)  5 (14)  1.77 (0.56–4.79), 0.28    Stroke  28 (11)  23 (10)  5 (14)  1.44 (046–3.80), 0.49    Previous cardiac surgery  62 (23)  51 (22)  11 (31)  1.53 (0.68–3.25), 0.28    Peripheral vascular disease  26 (10)  20 (9)  6 (17)  2.08 (0.71–5.34), 0.15    Critical preoperative status  18 (7)  14 (6)  4 (11)  1.91 (0.52–5.72), 0.28    Preoperative IABP  2 (1)  2 (1)  0  NA, 0.99    Chronic kidney disease  46 (17)  36 (16)  10 (28)  2.05 (0.88–4.52), 0.08    Solid organ cancer  7 (3)  7 (3)  0  NA, 0.99    Preoperative mechanical ventilation  10 (4)  9 (4)  1 (3)  0.70 (0.04–3.87), 0.73    Myocardial infarction <3 months  8 (3)  7 (3)  1 (3)  0.90 (0.05–5.29), 0.92    NYHA  185 (70)  158 (69)  27 (75)  1.32 (0.61–3.13), 0.49     I–II             III–IV  79 (30)  70 (31)  9 (25)  0.75 (0.32–1.63), 0.49    EuroSCORE II  6.68 ± 9.85  5.89 ± 8.76  11.59 ± 14.22  1.04 (1.01–1.07), 0.005    STS-IE score  22.13 ± 10.45  21.7 ± 1.09  24.83 ± 13.65  1.03 (0.99–1.06), 0.10    PALSUSE score  2.11 ± 1.45  2.01 ± 1.42  2.72 ± 1.52  1.40 (1.10–1.82), 0.007    Endocarditis characteristics             NVE  213 (81)  187 (82)  26 (72)  0.57 (0.26–1.32), 0.17     PVE  51 (19)  41 (18)  10 (28)  1.75 (0.75–3.83), 0.17     Active endocarditis  179 (68)  158 (69)  21 (58)  0.62 (0.30–1.29), 0.19     Embolic event  11 (4)  11 (5)  0  NA, 0.99     Causative organisma        0.07      Staphylococcus spp.  70 (27)  63 (28)  7 (19)  1 (Reference)      Streptococcus spp.  41 (16)  39 (17)  2 (6)  0.46 (0.07–2.03)      Enterococcus spp.  25 (9)  20 (9)  5 (14)  2.25 (0.61–7.85)      Candida spp.  5 (2)  4 (2)  1 (3)  2.25 (0.11–18.16)      Other  8 (3)  8 (4)  0  NA     Negative culture  115 (44)  94 (41)  21 (58)  2.01 (0.84–5.36)    Echocardiogram and electrocardiogram findings             Vegetation >1 cm  33 (4)  30 (13)  3 (8)  0.60 (0.14–1.71), 0.42     Abscess  11 (4)  7 (3)  4 (11)  3.95 (0.99–13.84), 0.04     Paravalvular leak  40 (15)  32 (14)  8 (22)  1.75 (0.73–4.18), 0.20     Severe stenosis  38 (14)  32 (14)  6 (17)  1.14 (0.44–2.97), 0.75     Severe regurgitation  163 (62)  148 (65)  15 (42)  0.51 (0.25–1.04), 0.07     LVEF (%)  53.7 ± 8.9  54.56 ± 8.85  48.47 ± 8.21  0.93 (0.89–0.97), 0.0003  0.93 (0.89–0.97), 0.0007   PAPS >60 mmHg  35 (13)  31 (14)  4 (11)  0.79 (0.23–2.18), 0.68     Atrioventricular block  10 (4)  8 (4)  2 (6)  1.62 (0.24–6.79), 0.55    Surgical procedure             Isolated AVR  108 (41)  98 (43)  20 (56)  0.51 (0.24–1.11), 0.08     Isolated MV surgery  97 (37)  86 (38)  11 (31)  0.72 (0.34–1.55), 0.41     Multiple valve procedure  49 (19)  37 (16)  12 (33)  2.58 (1.16–5.54), 0.02  2.19 (0.92–5.06), 0.07   Concomitant CABG  8 (3)  5 (2)  3 (8)  4.05 (0.80–17.32), 0.06     Concomitant procedure on thoracic (ascending) aorta  15 (6)  13 (6)  2 (6)  0.97 (0.15–3.73), 0.97     Urgent-emergent  103 (39)  87 (38)  16 (44)  1.30 (0.63–2.63), 0.47     Blood cardioplegia with topical ventricular cooling  166 (63)  144 (63)  22 (61)  0.91 (0.45–1.92), 0.81     Custodiol cardioplegia  98 (37)  84 (37)  14 (39)  1.09 (0.52–2.23), 0.81     CPBT  128.8 ± 89.2  121.72 ± 48.81  173.69 ± 151.42  1.01 (1.00–1.01), 0.003  1.01 (1.00–1.01), 0.009   XCT  89.6 ± 38.4  94.36 ± 39.63  105.69 ± 52.31  1.01 (1.00–1.02), 0.01  b  Variables  n = 264 (%)  Survivors (n = 228)  Non-survivors (n = 36)  Univariable logistic regression OR (95% CI), P-value  Multivariable logistic regression OR (95% CI), P-value  Female gender  68 (26)  54 (24)  14 (39)  2.05 (0.96–4.25), 0.06    Age (years)  62 ± 15.2  61.45 ± 15.1  67.2 ± 14.7  1.03 (1.00–1.06), 0.04  1.04 (1.01–1.07), 0.02  Hypertension  114 (43)  96 (42)  18 (50)  1.38 (0.68–2.79), 0.37    Diabetes  35 (13)  31 (14)  4 (11)  0.79 (0.23–2.18), 0.68    BMI >30 (kg/m2)  47 (18)  41 (18)  6 (17)  0.91 (0.33–2.20), 0.85    COPD  24 (9)  19 (8)  5 (14)  1.77 (0.56–4.79), 0.28    Stroke  28 (11)  23 (10)  5 (14)  1.44 (046–3.80), 0.49    Previous cardiac surgery  62 (23)  51 (22)  11 (31)  1.53 (0.68–3.25), 0.28    Peripheral vascular disease  26 (10)  20 (9)  6 (17)  2.08 (0.71–5.34), 0.15    Critical preoperative status  18 (7)  14 (6)  4 (11)  1.91 (0.52–5.72), 0.28    Preoperative IABP  2 (1)  2 (1)  0  NA, 0.99    Chronic kidney disease  46 (17)  36 (16)  10 (28)  2.05 (0.88–4.52), 0.08    Solid organ cancer  7 (3)  7 (3)  0  NA, 0.99    Preoperative mechanical ventilation  10 (4)  9 (4)  1 (3)  0.70 (0.04–3.87), 0.73    Myocardial infarction <3 months  8 (3)  7 (3)  1 (3)  0.90 (0.05–5.29), 0.92    NYHA  185 (70)  158 (69)  27 (75)  1.32 (0.61–3.13), 0.49     I–II             III–IV  79 (30)  70 (31)  9 (25)  0.75 (0.32–1.63), 0.49    EuroSCORE II  6.68 ± 9.85  5.89 ± 8.76  11.59 ± 14.22  1.04 (1.01–1.07), 0.005    STS-IE score  22.13 ± 10.45  21.7 ± 1.09  24.83 ± 13.65  1.03 (0.99–1.06), 0.10    PALSUSE score  2.11 ± 1.45  2.01 ± 1.42  2.72 ± 1.52  1.40 (1.10–1.82), 0.007    Endocarditis characteristics             NVE  213 (81)  187 (82)  26 (72)  0.57 (0.26–1.32), 0.17     PVE  51 (19)  41 (18)  10 (28)  1.75 (0.75–3.83), 0.17     Active endocarditis  179 (68)  158 (69)  21 (58)  0.62 (0.30–1.29), 0.19     Embolic event  11 (4)  11 (5)  0  NA, 0.99     Causative organisma        0.07      Staphylococcus spp.  70 (27)  63 (28)  7 (19)  1 (Reference)      Streptococcus spp.  41 (16)  39 (17)  2 (6)  0.46 (0.07–2.03)      Enterococcus spp.  25 (9)  20 (9)  5 (14)  2.25 (0.61–7.85)      Candida spp.  5 (2)  4 (2)  1 (3)  2.25 (0.11–18.16)      Other  8 (3)  8 (4)  0  NA     Negative culture  115 (44)  94 (41)  21 (58)  2.01 (0.84–5.36)    Echocardiogram and electrocardiogram findings             Vegetation >1 cm  33 (4)  30 (13)  3 (8)  0.60 (0.14–1.71), 0.42     Abscess  11 (4)  7 (3)  4 (11)  3.95 (0.99–13.84), 0.04     Paravalvular leak  40 (15)  32 (14)  8 (22)  1.75 (0.73–4.18), 0.20     Severe stenosis  38 (14)  32 (14)  6 (17)  1.14 (0.44–2.97), 0.75     Severe regurgitation  163 (62)  148 (65)  15 (42)  0.51 (0.25–1.04), 0.07     LVEF (%)  53.7 ± 8.9  54.56 ± 8.85  48.47 ± 8.21  0.93 (0.89–0.97), 0.0003  0.93 (0.89–0.97), 0.0007   PAPS >60 mmHg  35 (13)  31 (14)  4 (11)  0.79 (0.23–2.18), 0.68     Atrioventricular block  10 (4)  8 (4)  2 (6)  1.62 (0.24–6.79), 0.55    Surgical procedure             Isolated AVR  108 (41)  98 (43)  20 (56)  0.51 (0.24–1.11), 0.08     Isolated MV surgery  97 (37)  86 (38)  11 (31)  0.72 (0.34–1.55), 0.41     Multiple valve procedure  49 (19)  37 (16)  12 (33)  2.58 (1.16–5.54), 0.02  2.19 (0.92–5.06), 0.07   Concomitant CABG  8 (3)  5 (2)  3 (8)  4.05 (0.80–17.32), 0.06     Concomitant procedure on thoracic (ascending) aorta  15 (6)  13 (6)  2 (6)  0.97 (0.15–3.73), 0.97     Urgent-emergent  103 (39)  87 (38)  16 (44)  1.30 (0.63–2.63), 0.47     Blood cardioplegia with topical ventricular cooling  166 (63)  144 (63)  22 (61)  0.91 (0.45–1.92), 0.81     Custodiol cardioplegia  98 (37)  84 (37)  14 (39)  1.09 (0.52–2.23), 0.81     CPBT  128.8 ± 89.2  121.72 ± 48.81  173.69 ± 151.42  1.01 (1.00–1.01), 0.003  1.01 (1.00–1.01), 0.009   XCT  89.6 ± 38.4  94.36 ± 39.63  105.69 ± 52.31  1.01 (1.00–1.02), 0.01  b  Continuous variables are reported as mean and standard deviation. Categorical variables are reported as absolute number and percentages. Area under the ROC curve for multivariable model 0.77, Hosmer–Lemeshow’s test: P = 0.91. a Staphylococcus aureus (n = 41), coagulase-negative staphylococci (n = 29), viridans group streptococci (not further specified, n = 20), Streptococcus gallolyticus (n = 10), Streptococcus mutans (n = 5), Streptococcus mitis (n = 1), Streptococcus salivarius (n = 1), Streptococcus pyogenes (n = 1), Streptococcus pneumoniae (n = 1), Streptococcus agalactiae (n = 1), Streptococcus dysgalactiae (n = 1), Enterococcus faecalis (n = 24), Enterococcus faecium (n = 1) and Candida albicans (n = 5). Other: Granulicatella adiacens (n = 3); Proteus mirabilis (n = 3); Corynebacterium striatum (n = 2). b A multivariable model forcing into XCT instead of CPBT was included as Supplementary Material. AVR: aortic valve replacement; BMI: body mass index; CABG: coronary artery bypass grafting; CI: confidence interval; COPD: chronic obstructive pulmonary disease; CPBT: cardiopulmonary bypass time; IABP: intra-aortic balloon pump; LVEF: left ventricular ejection fraction; MV: mitral valve; NA: not applicable; NVE: native valve endocarditis; NYHA: New York Heart Association; OR: odds ratio; PAPS: pulmonary artery systolic pressure; PVE: prosthetic valve endocarditis; XCT: aortic cross-clamp time. Table 1: Preoperative clinical and operative characteristics and their impact on early postoperative mortality according to univariable and multivariable logistic regression analyses Variables  n = 264 (%)  Survivors (n = 228)  Non-survivors (n = 36)  Univariable logistic regression OR (95% CI), P-value  Multivariable logistic regression OR (95% CI), P-value  Female gender  68 (26)  54 (24)  14 (39)  2.05 (0.96–4.25), 0.06    Age (years)  62 ± 15.2  61.45 ± 15.1  67.2 ± 14.7  1.03 (1.00–1.06), 0.04  1.04 (1.01–1.07), 0.02  Hypertension  114 (43)  96 (42)  18 (50)  1.38 (0.68–2.79), 0.37    Diabetes  35 (13)  31 (14)  4 (11)  0.79 (0.23–2.18), 0.68    BMI >30 (kg/m2)  47 (18)  41 (18)  6 (17)  0.91 (0.33–2.20), 0.85    COPD  24 (9)  19 (8)  5 (14)  1.77 (0.56–4.79), 0.28    Stroke  28 (11)  23 (10)  5 (14)  1.44 (046–3.80), 0.49    Previous cardiac surgery  62 (23)  51 (22)  11 (31)  1.53 (0.68–3.25), 0.28    Peripheral vascular disease  26 (10)  20 (9)  6 (17)  2.08 (0.71–5.34), 0.15    Critical preoperative status  18 (7)  14 (6)  4 (11)  1.91 (0.52–5.72), 0.28    Preoperative IABP  2 (1)  2 (1)  0  NA, 0.99    Chronic kidney disease  46 (17)  36 (16)  10 (28)  2.05 (0.88–4.52), 0.08    Solid organ cancer  7 (3)  7 (3)  0  NA, 0.99    Preoperative mechanical ventilation  10 (4)  9 (4)  1 (3)  0.70 (0.04–3.87), 0.73    Myocardial infarction <3 months  8 (3)  7 (3)  1 (3)  0.90 (0.05–5.29), 0.92    NYHA  185 (70)  158 (69)  27 (75)  1.32 (0.61–3.13), 0.49     I–II             III–IV  79 (30)  70 (31)  9 (25)  0.75 (0.32–1.63), 0.49    EuroSCORE II  6.68 ± 9.85  5.89 ± 8.76  11.59 ± 14.22  1.04 (1.01–1.07), 0.005    STS-IE score  22.13 ± 10.45  21.7 ± 1.09  24.83 ± 13.65  1.03 (0.99–1.06), 0.10    PALSUSE score  2.11 ± 1.45  2.01 ± 1.42  2.72 ± 1.52  1.40 (1.10–1.82), 0.007    Endocarditis characteristics             NVE  213 (81)  187 (82)  26 (72)  0.57 (0.26–1.32), 0.17     PVE  51 (19)  41 (18)  10 (28)  1.75 (0.75–3.83), 0.17     Active endocarditis  179 (68)  158 (69)  21 (58)  0.62 (0.30–1.29), 0.19     Embolic event  11 (4)  11 (5)  0  NA, 0.99     Causative organisma        0.07      Staphylococcus spp.  70 (27)  63 (28)  7 (19)  1 (Reference)      Streptococcus spp.  41 (16)  39 (17)  2 (6)  0.46 (0.07–2.03)      Enterococcus spp.  25 (9)  20 (9)  5 (14)  2.25 (0.61–7.85)      Candida spp.  5 (2)  4 (2)  1 (3)  2.25 (0.11–18.16)      Other  8 (3)  8 (4)  0  NA     Negative culture  115 (44)  94 (41)  21 (58)  2.01 (0.84–5.36)    Echocardiogram and electrocardiogram findings             Vegetation >1 cm  33 (4)  30 (13)  3 (8)  0.60 (0.14–1.71), 0.42     Abscess  11 (4)  7 (3)  4 (11)  3.95 (0.99–13.84), 0.04     Paravalvular leak  40 (15)  32 (14)  8 (22)  1.75 (0.73–4.18), 0.20     Severe stenosis  38 (14)  32 (14)  6 (17)  1.14 (0.44–2.97), 0.75     Severe regurgitation  163 (62)  148 (65)  15 (42)  0.51 (0.25–1.04), 0.07     LVEF (%)  53.7 ± 8.9  54.56 ± 8.85  48.47 ± 8.21  0.93 (0.89–0.97), 0.0003  0.93 (0.89–0.97), 0.0007   PAPS >60 mmHg  35 (13)  31 (14)  4 (11)  0.79 (0.23–2.18), 0.68     Atrioventricular block  10 (4)  8 (4)  2 (6)  1.62 (0.24–6.79), 0.55    Surgical procedure             Isolated AVR  108 (41)  98 (43)  20 (56)  0.51 (0.24–1.11), 0.08     Isolated MV surgery  97 (37)  86 (38)  11 (31)  0.72 (0.34–1.55), 0.41     Multiple valve procedure  49 (19)  37 (16)  12 (33)  2.58 (1.16–5.54), 0.02  2.19 (0.92–5.06), 0.07   Concomitant CABG  8 (3)  5 (2)  3 (8)  4.05 (0.80–17.32), 0.06     Concomitant procedure on thoracic (ascending) aorta  15 (6)  13 (6)  2 (6)  0.97 (0.15–3.73), 0.97     Urgent-emergent  103 (39)  87 (38)  16 (44)  1.30 (0.63–2.63), 0.47     Blood cardioplegia with topical ventricular cooling  166 (63)  144 (63)  22 (61)  0.91 (0.45–1.92), 0.81     Custodiol cardioplegia  98 (37)  84 (37)  14 (39)  1.09 (0.52–2.23), 0.81     CPBT  128.8 ± 89.2  121.72 ± 48.81  173.69 ± 151.42  1.01 (1.00–1.01), 0.003  1.01 (1.00–1.01), 0.009   XCT  89.6 ± 38.4  94.36 ± 39.63  105.69 ± 52.31  1.01 (1.00–1.02), 0.01  b  Variables  n = 264 (%)  Survivors (n = 228)  Non-survivors (n = 36)  Univariable logistic regression OR (95% CI), P-value  Multivariable logistic regression OR (95% CI), P-value  Female gender  68 (26)  54 (24)  14 (39)  2.05 (0.96–4.25), 0.06    Age (years)  62 ± 15.2  61.45 ± 15.1  67.2 ± 14.7  1.03 (1.00–1.06), 0.04  1.04 (1.01–1.07), 0.02  Hypertension  114 (43)  96 (42)  18 (50)  1.38 (0.68–2.79), 0.37    Diabetes  35 (13)  31 (14)  4 (11)  0.79 (0.23–2.18), 0.68    BMI >30 (kg/m2)  47 (18)  41 (18)  6 (17)  0.91 (0.33–2.20), 0.85    COPD  24 (9)  19 (8)  5 (14)  1.77 (0.56–4.79), 0.28    Stroke  28 (11)  23 (10)  5 (14)  1.44 (046–3.80), 0.49    Previous cardiac surgery  62 (23)  51 (22)  11 (31)  1.53 (0.68–3.25), 0.28    Peripheral vascular disease  26 (10)  20 (9)  6 (17)  2.08 (0.71–5.34), 0.15    Critical preoperative status  18 (7)  14 (6)  4 (11)  1.91 (0.52–5.72), 0.28    Preoperative IABP  2 (1)  2 (1)  0  NA, 0.99    Chronic kidney disease  46 (17)  36 (16)  10 (28)  2.05 (0.88–4.52), 0.08    Solid organ cancer  7 (3)  7 (3)  0  NA, 0.99    Preoperative mechanical ventilation  10 (4)  9 (4)  1 (3)  0.70 (0.04–3.87), 0.73    Myocardial infarction <3 months  8 (3)  7 (3)  1 (3)  0.90 (0.05–5.29), 0.92    NYHA  185 (70)  158 (69)  27 (75)  1.32 (0.61–3.13), 0.49     I–II             III–IV  79 (30)  70 (31)  9 (25)  0.75 (0.32–1.63), 0.49    EuroSCORE II  6.68 ± 9.85  5.89 ± 8.76  11.59 ± 14.22  1.04 (1.01–1.07), 0.005    STS-IE score  22.13 ± 10.45  21.7 ± 1.09  24.83 ± 13.65  1.03 (0.99–1.06), 0.10    PALSUSE score  2.11 ± 1.45  2.01 ± 1.42  2.72 ± 1.52  1.40 (1.10–1.82), 0.007    Endocarditis characteristics             NVE  213 (81)  187 (82)  26 (72)  0.57 (0.26–1.32), 0.17     PVE  51 (19)  41 (18)  10 (28)  1.75 (0.75–3.83), 0.17     Active endocarditis  179 (68)  158 (69)  21 (58)  0.62 (0.30–1.29), 0.19     Embolic event  11 (4)  11 (5)  0  NA, 0.99     Causative organisma        0.07      Staphylococcus spp.  70 (27)  63 (28)  7 (19)  1 (Reference)      Streptococcus spp.  41 (16)  39 (17)  2 (6)  0.46 (0.07–2.03)      Enterococcus spp.  25 (9)  20 (9)  5 (14)  2.25 (0.61–7.85)      Candida spp.  5 (2)  4 (2)  1 (3)  2.25 (0.11–18.16)      Other  8 (3)  8 (4)  0  NA     Negative culture  115 (44)  94 (41)  21 (58)  2.01 (0.84–5.36)    Echocardiogram and electrocardiogram findings             Vegetation >1 cm  33 (4)  30 (13)  3 (8)  0.60 (0.14–1.71), 0.42     Abscess  11 (4)  7 (3)  4 (11)  3.95 (0.99–13.84), 0.04     Paravalvular leak  40 (15)  32 (14)  8 (22)  1.75 (0.73–4.18), 0.20     Severe stenosis  38 (14)  32 (14)  6 (17)  1.14 (0.44–2.97), 0.75     Severe regurgitation  163 (62)  148 (65)  15 (42)  0.51 (0.25–1.04), 0.07     LVEF (%)  53.7 ± 8.9  54.56 ± 8.85  48.47 ± 8.21  0.93 (0.89–0.97), 0.0003  0.93 (0.89–0.97), 0.0007   PAPS >60 mmHg  35 (13)  31 (14)  4 (11)  0.79 (0.23–2.18), 0.68     Atrioventricular block  10 (4)  8 (4)  2 (6)  1.62 (0.24–6.79), 0.55    Surgical procedure             Isolated AVR  108 (41)  98 (43)  20 (56)  0.51 (0.24–1.11), 0.08     Isolated MV surgery  97 (37)  86 (38)  11 (31)  0.72 (0.34–1.55), 0.41     Multiple valve procedure  49 (19)  37 (16)  12 (33)  2.58 (1.16–5.54), 0.02  2.19 (0.92–5.06), 0.07   Concomitant CABG  8 (3)  5 (2)  3 (8)  4.05 (0.80–17.32), 0.06     Concomitant procedure on thoracic (ascending) aorta  15 (6)  13 (6)  2 (6)  0.97 (0.15–3.73), 0.97     Urgent-emergent  103 (39)  87 (38)  16 (44)  1.30 (0.63–2.63), 0.47     Blood cardioplegia with topical ventricular cooling  166 (63)  144 (63)  22 (61)  0.91 (0.45–1.92), 0.81     Custodiol cardioplegia  98 (37)  84 (37)  14 (39)  1.09 (0.52–2.23), 0.81     CPBT  128.8 ± 89.2  121.72 ± 48.81  173.69 ± 151.42  1.01 (1.00–1.01), 0.003  1.01 (1.00–1.01), 0.009   XCT  89.6 ± 38.4  94.36 ± 39.63  105.69 ± 52.31  1.01 (1.00–1.02), 0.01  b  Continuous variables are reported as mean and standard deviation. Categorical variables are reported as absolute number and percentages. Area under the ROC curve for multivariable model 0.77, Hosmer–Lemeshow’s test: P = 0.91. a Staphylococcus aureus (n = 41), coagulase-negative staphylococci (n = 29), viridans group streptococci (not further specified, n = 20), Streptococcus gallolyticus (n = 10), Streptococcus mutans (n = 5), Streptococcus mitis (n = 1), Streptococcus salivarius (n = 1), Streptococcus pyogenes (n = 1), Streptococcus pneumoniae (n = 1), Streptococcus agalactiae (n = 1), Streptococcus dysgalactiae (n = 1), Enterococcus faecalis (n = 24), Enterococcus faecium (n = 1) and Candida albicans (n = 5). Other: Granulicatella adiacens (n = 3); Proteus mirabilis (n = 3); Corynebacterium striatum (n = 2). b A multivariable model forcing into XCT instead of CPBT was included as Supplementary Material. AVR: aortic valve replacement; BMI: body mass index; CABG: coronary artery bypass grafting; CI: confidence interval; COPD: chronic obstructive pulmonary disease; CPBT: cardiopulmonary bypass time; IABP: intra-aortic balloon pump; LVEF: left ventricular ejection fraction; MV: mitral valve; NA: not applicable; NVE: native valve endocarditis; NYHA: New York Heart Association; OR: odds ratio; PAPS: pulmonary artery systolic pressure; PVE: prosthetic valve endocarditis; XCT: aortic cross-clamp time. Predictors of early postoperative mortality The crude early postoperative mortality was 14% (36 of 264 patients). The mortality rate was not significantly different after surgery for isolated aortic valve endocarditis versus isolated mitral valve IE [10/108 (9%) vs 11/97 (11%), P = 0.65] or for NVE versus PVE [26/213 (12%) vs 10/51 (19%), P =0.16]. On the contrary, it was significantly different for multiple valve procedures vs single valve procedures [12/49 (24%) vs 24/215 (11%), P = 0.014]. No difference in early postoperative mortality was observed between patients operated during the 1st vs 2nd half of the study period [12.6% (15 of 119 patients) from 2000 to 2008 vs 14.5% (21 of 145 patients) from 2009 to 2016, χ2 statistic = 0.20; P = 0.66]. The distribution of mortality rates according to quartiles of XCT and CPBT is shown in Fig. 1, while Table 1 shows the results of univariable and multivariable analyses of mortality predictors. Figure 1: View largeDownload slide Distribution of early postoperative mortality and increasing OR for mortality according to quartiles of aortic cross-clamp (A) and cardiopulmonary bypass time (B). CI: confidence interval; OR: odds ratio. Figure 1: View largeDownload slide Distribution of early postoperative mortality and increasing OR for mortality according to quartiles of aortic cross-clamp (A) and cardiopulmonary bypass time (B). CI: confidence interval; OR: odds ratio. At univariable analysis, age, EuroSCORE II, PALSUSE score, presence of abscess, LVEF, multiple valve procedures, increasing XCT and increasing CPBT showed a statistically significant association with the outcome. Of note, increasing XCT [odds ratio (OR) 3.21, 95% confidence interval (CI) 1.32–8.14; P = 0.01, area under the ROC curve 0.62, Hosmer–Lemeshow’s test: P = 0.45] and increasing CPBT (OR 3.20, 95% CI 1.45–7.36; P = 0.005, area under the ROC curve 0.60, Hosmer–Lemeshow’s test: P = 0.15) predicted early postoperative mortality also when logarithmically transformed. In multivariable analysis (Hosmer–Lemeshow’s test: P = 0.9, area under the ROC curve 0.77), increasing CPBT (OR 1.008, 95% CI 1.003–1.01; P = 0.009) was retained in the final model and confirmed as an independent predictor of early postoperative mortality, along with increasing age (OR 1.04, 95% CI 1.01–1.07; P = 0.02) and reduced LVEF (OR 0.93, 95% CI 0.89–0.97; P = 0.0007). Since a statistically significant correlation was present between increasing XCT and increasing CPBT (Spearman test, rho: 0.94, P < 0.0001), an additional variant of the final multivariable model was built by forcing inclusion of XCT instead of CPBT. The results of the additional model confirmed the existence of an independent association between increasing XCT and mortality (Supplementary Material, Table S1). The best prognostic cut-off for predicting early postoperative mortality in our cohort were > 72 min for XCT (ROC curve: 0.61, 95% CI 0.52–0.71; sensitivity 83%, specificity 38%, Adjusted OR 3.03, 95% CI 1.29–8.33; P = 0.02) and >166 min for CPBT (ROC curve: 0.60, 95% CI 0.50–0.70; sensitivity 36%, specificity 83%; Adjusted OR 2.91, 95% CI 1.33–6.22; P = 0.006), as depicted on the respective prognostic ROC curves (Fig. 2A and B). The highest rates of early postoperative mortality in our cohort were observed when both XCT and CPBT were beyond their prognostic cut-offs (Fig. 3). Figure 2: View largeDownload slide ROC curves for the best prognostic cut-off of XCT (A) and CPBT (B) values in predicting early postoperative mortality. AUC: area under the curve; CPBT: cardiopulmonary bypass time; XCT: aortic cross-clamp time. Figure 2: View largeDownload slide ROC curves for the best prognostic cut-off of XCT (A) and CPBT (B) values in predicting early postoperative mortality. AUC: area under the curve; CPBT: cardiopulmonary bypass time; XCT: aortic cross-clamp time. Figure 3: View largeDownload slide Postoperative mortality rates related to prognostic cut-offs of XCT and CPBT. CPBT: cardiopulmonary bypass time; XCT: aortic cross-clamp time. Figure 3: View largeDownload slide Postoperative mortality rates related to prognostic cut-offs of XCT and CPBT. CPBT: cardiopulmonary bypass time; XCT: aortic cross-clamp time. The discriminatory performance of risk scores, evaluated using the AUC, resulted in 0.643 for EuroSCORE II (95% CI 0.541–0.744), 0.639 for PALSUSE (95% CI 0.545–0.733) and 0.559 for STS-IE (95% CI 0.445–0.672). The calibration was adequate (Hosmer–Lemeshow test; P = 0.47, P = 0.51 and P = 0.09 for EuroSCORE II, PALSUSE and STS-IE, respectively). Predictors of postoperative severe complications The rate of occurrence of the combined severe complications end point (in-hospital mortality, ICU stay ≥5 days, stroke, postoperative haemodialysis, and postoperative use of IABP) was 32% (84 of 264). At univariable logistic regression analysis, prolonged XCT, prolonged CPBT, increasing age, stroke, reduced LVEF, preoperative mechanical ventilation, pulmonary hypertension with pulmonary artery systolic pressure >60 mmHg, critical preoperative status, EuroSCORE II, STS-IE score PALSUSE score, peripheral vascular disease, chronic kidney disease, previous cardiac surgery, urgent or emergent operation, NYHA I–II, NYHA III–IV and multiple valve procedure were associated with the composite outcome (Supplementary Material, Table S2). As shown in Table 2, multivariable logistic regression analysis confirmed CPBT (OR 1.02, 95% CI 1.006–1.04; P = 0.002) as an independent predictor of severe complications along with increasing age (OR 1.03, 95% CI 1.009–1.07; P = 0.008), stroke (OR 3.54, 95% CI 1.29–9.97; P = 0.01), preoperative mechanical ventilation (OR 44.96, 95% CI 4.83–1098.54; P = 0.003) and LVEF (OR 0.93, 95% CI 0.90–0.96; P < 0.0001). Table 2: Multivariable logistic regression for the composite end point severe complications   Complications (n = 84)  No-complications (n = 180)  Multivariable logistic regression OR (95% CI), P-value  Age (years)  65.85 ± 17.16  60.54 ± 15.22  1.03 (1.01–1.07), 0.008  Stroke  17 (20)  11 (6)  3.54 (1.29–9.97), 0.009  Preoperative mechanical ventilation  9 (11)  1 (1)  44.96 (4.83–1098.54), 0.003  EuroSCORE II  11.70 ± 16.05  4.33 ± 5.87  1.04 (1.0005–1.08), 0.06  LVEF  50.13 ± 10.14  55.41 ± 8.54  0.93 (0.90–0.96), <0.0001  Multiple valve procedure  24 (29)  25 (14)  1.83 (0.82–4.04), 0.13  CPBT  157.04 ± 50.83  115.64 ± 47.18  1.02 (1.006–1.04), 0.002  XCT  101.51 ± 43.30  83.99 ± 34.32  0.98 (0.96–1.006), 0.49a    Complications (n = 84)  No-complications (n = 180)  Multivariable logistic regression OR (95% CI), P-value  Age (years)  65.85 ± 17.16  60.54 ± 15.22  1.03 (1.01–1.07), 0.008  Stroke  17 (20)  11 (6)  3.54 (1.29–9.97), 0.009  Preoperative mechanical ventilation  9 (11)  1 (1)  44.96 (4.83–1098.54), 0.003  EuroSCORE II  11.70 ± 16.05  4.33 ± 5.87  1.04 (1.0005–1.08), 0.06  LVEF  50.13 ± 10.14  55.41 ± 8.54  0.93 (0.90–0.96), <0.0001  Multiple valve procedure  24 (29)  25 (14)  1.83 (0.82–4.04), 0.13  CPBT  157.04 ± 50.83  115.64 ± 47.18  1.02 (1.006–1.04), 0.002  XCT  101.51 ± 43.30  83.99 ± 34.32  0.98 (0.96–1.006), 0.49a  Continuous variables are reported as mean and standard deviation. Categorical variables are reported as absolute number and percentages. Area under the ROC curve for multivariable model 0.72, Hosmer–Lemeshow’s test: P = 0.74. See Supplementary Material, Table S2 for detailed univariable and multivariable logistic regression analyses. a A multivariable model forcing into XCT instead of CPBT was included as Supplementary Material, Table S3. CI: confidence interval; CPBT: cardiopulmonary bypass time; LVEF: left ventricular ejection fraction; OR: odds ratio; XCT: aortic cross-clamp time. Table 2: Multivariable logistic regression for the composite end point severe complications   Complications (n = 84)  No-complications (n = 180)  Multivariable logistic regression OR (95% CI), P-value  Age (years)  65.85 ± 17.16  60.54 ± 15.22  1.03 (1.01–1.07), 0.008  Stroke  17 (20)  11 (6)  3.54 (1.29–9.97), 0.009  Preoperative mechanical ventilation  9 (11)  1 (1)  44.96 (4.83–1098.54), 0.003  EuroSCORE II  11.70 ± 16.05  4.33 ± 5.87  1.04 (1.0005–1.08), 0.06  LVEF  50.13 ± 10.14  55.41 ± 8.54  0.93 (0.90–0.96), <0.0001  Multiple valve procedure  24 (29)  25 (14)  1.83 (0.82–4.04), 0.13  CPBT  157.04 ± 50.83  115.64 ± 47.18  1.02 (1.006–1.04), 0.002  XCT  101.51 ± 43.30  83.99 ± 34.32  0.98 (0.96–1.006), 0.49a    Complications (n = 84)  No-complications (n = 180)  Multivariable logistic regression OR (95% CI), P-value  Age (years)  65.85 ± 17.16  60.54 ± 15.22  1.03 (1.01–1.07), 0.008  Stroke  17 (20)  11 (6)  3.54 (1.29–9.97), 0.009  Preoperative mechanical ventilation  9 (11)  1 (1)  44.96 (4.83–1098.54), 0.003  EuroSCORE II  11.70 ± 16.05  4.33 ± 5.87  1.04 (1.0005–1.08), 0.06  LVEF  50.13 ± 10.14  55.41 ± 8.54  0.93 (0.90–0.96), <0.0001  Multiple valve procedure  24 (29)  25 (14)  1.83 (0.82–4.04), 0.13  CPBT  157.04 ± 50.83  115.64 ± 47.18  1.02 (1.006–1.04), 0.002  XCT  101.51 ± 43.30  83.99 ± 34.32  0.98 (0.96–1.006), 0.49a  Continuous variables are reported as mean and standard deviation. Categorical variables are reported as absolute number and percentages. Area under the ROC curve for multivariable model 0.72, Hosmer–Lemeshow’s test: P = 0.74. See Supplementary Material, Table S2 for detailed univariable and multivariable logistic regression analyses. a A multivariable model forcing into XCT instead of CPBT was included as Supplementary Material, Table S3. CI: confidence interval; CPBT: cardiopulmonary bypass time; LVEF: left ventricular ejection fraction; OR: odds ratio; XCT: aortic cross-clamp time. As observed earlier with regard to early postoperative mortality, an additional variant of the multivariable model forcing inclusion of XCT instead of CPBT confirmed an independent association between increasing XCT and postoperative severe complications (Supplementary Material, Table S3). For descriptive purposes, Table 3 shows a stratification of all postoperative adverse events (both included and not included in the composite outcome) according to the XCT and CPBT mortality cut-offs (>72 min and >166 min, respectively). Table 3: Outcomes   XCT ≤72 min; CPBT ≤166 min (n = 96)  XCT >72 min; CPBT ≤166 min (n = 119)  XCT >72 min; CPBT >166 min (n = 49)  P-value  Resternotomy for bleeding*  8 (8.3)  13 (10.9)  12 (24.5)  0.02  Acute kidney injury  6 (6.2)  8 (6.7)  2 (4.1)  0.80  Renal replacement therapy  3 (3.1)  3 (2.5)  1 (2.0)  0.92  Stroke  3 (3.1)  1 (0.8)  0  0.24  Atrial fibrillation  4 (4.2)  6 (2.1)  4 (8.2)  0.58  New onset atrioventricular block  1 (1.0)  1 (0.8)  0  0.78  Sternal wound infection  1 (1.0)  1 (0.8)  1 (2.0)  0.79  Postoperative use of IABP  1 (1.0)  1 (0.8)  0  0.78  Prolonged mechanical ventilation (>48 h)  15 (15.6)  29 (24.4)  12 (24.5)  0.24  Respiratory insufficiency  4 (4.2)  5 (4.2)  2 (4.1)  0.99  Sepsis  7 (7.3)  9 (7.6)  2 (4.1)  0.71  Multiorgan failure  1 (1.0)  4 (2.1)  1 (2.0)  0.52  Reoperation for new endocarditis event  1 (1.0)  2 (1.7)  0  0.64  ICU stay (days)**  3.2 ± 5.4  6.2 ± 18.6  5.6 ± 6.2  0.35    XCT ≤72 min; CPBT ≤166 min (n = 96)  XCT >72 min; CPBT ≤166 min (n = 119)  XCT >72 min; CPBT >166 min (n = 49)  P-value  Resternotomy for bleeding*  8 (8.3)  13 (10.9)  12 (24.5)  0.02  Acute kidney injury  6 (6.2)  8 (6.7)  2 (4.1)  0.80  Renal replacement therapy  3 (3.1)  3 (2.5)  1 (2.0)  0.92  Stroke  3 (3.1)  1 (0.8)  0  0.24  Atrial fibrillation  4 (4.2)  6 (2.1)  4 (8.2)  0.58  New onset atrioventricular block  1 (1.0)  1 (0.8)  0  0.78  Sternal wound infection  1 (1.0)  1 (0.8)  1 (2.0)  0.79  Postoperative use of IABP  1 (1.0)  1 (0.8)  0  0.78  Prolonged mechanical ventilation (>48 h)  15 (15.6)  29 (24.4)  12 (24.5)  0.24  Respiratory insufficiency  4 (4.2)  5 (4.2)  2 (4.1)  0.99  Sepsis  7 (7.3)  9 (7.6)  2 (4.1)  0.71  Multiorgan failure  1 (1.0)  4 (2.1)  1 (2.0)  0.52  Reoperation for new endocarditis event  1 (1.0)  2 (1.7)  0  0.64  ICU stay (days)**  3.2 ± 5.4  6.2 ± 18.6  5.6 ± 6.2  0.35  Categorical variables are reported as counts and percentages (in parentheses). Continuous variables are reported as mean and standard deviation. For descriptive purposes, variables were compared by means of the Fisher’s exact test, the χ2 test or the Kruskal–Wallis test. * P < 0.01 ‘XCT >72 min + CPBT >166 min’ vs ‘XCT <72 min + CPBT  <166 min’. ** P < 0.05 ‘XCT >72 min + CPBT >166 min’ vs ‘XCT <72 min + CPBT <166 min’. CPBT: cardiopulmonary bypass time; IABP: intra-aortic balloon pump; ICU: intensive care unit; XCT: aortic cross-clamp time. Table 3: Outcomes   XCT ≤72 min; CPBT ≤166 min (n = 96)  XCT >72 min; CPBT ≤166 min (n = 119)  XCT >72 min; CPBT >166 min (n = 49)  P-value  Resternotomy for bleeding*  8 (8.3)  13 (10.9)  12 (24.5)  0.02  Acute kidney injury  6 (6.2)  8 (6.7)  2 (4.1)  0.80  Renal replacement therapy  3 (3.1)  3 (2.5)  1 (2.0)  0.92  Stroke  3 (3.1)  1 (0.8)  0  0.24  Atrial fibrillation  4 (4.2)  6 (2.1)  4 (8.2)  0.58  New onset atrioventricular block  1 (1.0)  1 (0.8)  0  0.78  Sternal wound infection  1 (1.0)  1 (0.8)  1 (2.0)  0.79  Postoperative use of IABP  1 (1.0)  1 (0.8)  0  0.78  Prolonged mechanical ventilation (>48 h)  15 (15.6)  29 (24.4)  12 (24.5)  0.24  Respiratory insufficiency  4 (4.2)  5 (4.2)  2 (4.1)  0.99  Sepsis  7 (7.3)  9 (7.6)  2 (4.1)  0.71  Multiorgan failure  1 (1.0)  4 (2.1)  1 (2.0)  0.52  Reoperation for new endocarditis event  1 (1.0)  2 (1.7)  0  0.64  ICU stay (days)**  3.2 ± 5.4  6.2 ± 18.6  5.6 ± 6.2  0.35    XCT ≤72 min; CPBT ≤166 min (n = 96)  XCT >72 min; CPBT ≤166 min (n = 119)  XCT >72 min; CPBT >166 min (n = 49)  P-value  Resternotomy for bleeding*  8 (8.3)  13 (10.9)  12 (24.5)  0.02  Acute kidney injury  6 (6.2)  8 (6.7)  2 (4.1)  0.80  Renal replacement therapy  3 (3.1)  3 (2.5)  1 (2.0)  0.92  Stroke  3 (3.1)  1 (0.8)  0  0.24  Atrial fibrillation  4 (4.2)  6 (2.1)  4 (8.2)  0.58  New onset atrioventricular block  1 (1.0)  1 (0.8)  0  0.78  Sternal wound infection  1 (1.0)  1 (0.8)  1 (2.0)  0.79  Postoperative use of IABP  1 (1.0)  1 (0.8)  0  0.78  Prolonged mechanical ventilation (>48 h)  15 (15.6)  29 (24.4)  12 (24.5)  0.24  Respiratory insufficiency  4 (4.2)  5 (4.2)  2 (4.1)  0.99  Sepsis  7 (7.3)  9 (7.6)  2 (4.1)  0.71  Multiorgan failure  1 (1.0)  4 (2.1)  1 (2.0)  0.52  Reoperation for new endocarditis event  1 (1.0)  2 (1.7)  0  0.64  ICU stay (days)**  3.2 ± 5.4  6.2 ± 18.6  5.6 ± 6.2  0.35  Categorical variables are reported as counts and percentages (in parentheses). Continuous variables are reported as mean and standard deviation. For descriptive purposes, variables were compared by means of the Fisher’s exact test, the χ2 test or the Kruskal–Wallis test. * P < 0.01 ‘XCT >72 min + CPBT >166 min’ vs ‘XCT <72 min + CPBT  <166 min’. ** P < 0.05 ‘XCT >72 min + CPBT >166 min’ vs ‘XCT <72 min + CPBT <166 min’. CPBT: cardiopulmonary bypass time; IABP: intra-aortic balloon pump; ICU: intensive care unit; XCT: aortic cross-clamp time. Predictors of prolonged aortic cross-clamp and cardiopulmonary bypass time The selection process of demographic and clinical variables to be included in multivariable models for predicting prolonged XCT and CPBT is shown in Supplementary Material, Fig. S1. In the first multivariable model (dependent variable = XCT), age, diabetes, previous cardiac surgery, Custodiol cardioplegia, PVE, multiple valve procedures, concomitant procedures on thoracic aorta were independently associated with prolonged XCT. In the second multivariable model (dependent variable = CPBT), EuroSCORE II, presence of abscess, critical preoperative state, Custodiol cardioplegia, PVE, multiple valve procedures and concomitant procedures on thoracic aorta were independently associated with prolonged CPBT (Table 4). Table 4: Predictors of prolonged XCT and CPBT XCT   CPBT   Independent variables  Beta  t  P-value  Independent variables  Beta  t  P-value  Age (years)  −0.25  −1.96  0.05  Age  −0.51  −1.92  0.06  Diabetes  13.21  2.31  0.02  EuroSCORE II  1.65  3.00  0.003  Embolic event  16.70  1.74  0.08  Presence of abscess  44.72  2.26  0.02  Previous cardiac surgery  36.74  2.36  0.02  Critical preoperative state  −40.13  −2.08  0.04  Custodiol cardioplegia  12.20  3.04  0.003  Custodiol cardioplegia  17.19  2.14  0.03  PVE  34.57  7.05  <0.0001  PVE  45.28  4.21  <0.0001  Multiple valve procedures  32.01  6.39  <0.0001  Multiple valve procedures  37.48  10.21  0.0003  Concomitant procedure on thoracic (ascending) aorta  45.76  5.46  <0.0001  Concomitant procedure on thoracic (ascending) aorta  85.02  5.05  <0.0001  R2 = 0.38; R2 adjusted = 0.36; SE = 30.7  R2 = 0.33; R2 adjusted = 0.31; SE = 61.36  XCT   CPBT   Independent variables  Beta  t  P-value  Independent variables  Beta  t  P-value  Age (years)  −0.25  −1.96  0.05  Age  −0.51  −1.92  0.06  Diabetes  13.21  2.31  0.02  EuroSCORE II  1.65  3.00  0.003  Embolic event  16.70  1.74  0.08  Presence of abscess  44.72  2.26  0.02  Previous cardiac surgery  36.74  2.36  0.02  Critical preoperative state  −40.13  −2.08  0.04  Custodiol cardioplegia  12.20  3.04  0.003  Custodiol cardioplegia  17.19  2.14  0.03  PVE  34.57  7.05  <0.0001  PVE  45.28  4.21  <0.0001  Multiple valve procedures  32.01  6.39  <0.0001  Multiple valve procedures  37.48  10.21  0.0003  Concomitant procedure on thoracic (ascending) aorta  45.76  5.46  <0.0001  Concomitant procedure on thoracic (ascending) aorta  85.02  5.05  <0.0001  R2 = 0.38; R2 adjusted = 0.36; SE = 30.7  R2 = 0.33; R2 adjusted = 0.31; SE = 61.36  Beta: standardized regression coefficient; CPBT: cardiopulmonary bypass time; PVE: prosthetic valve endocarditis; SE: standard error; XCT: aortic cross-clamping time. Table 4: Predictors of prolonged XCT and CPBT XCT   CPBT   Independent variables  Beta  t  P-value  Independent variables  Beta  t  P-value  Age (years)  −0.25  −1.96  0.05  Age  −0.51  −1.92  0.06  Diabetes  13.21  2.31  0.02  EuroSCORE II  1.65  3.00  0.003  Embolic event  16.70  1.74  0.08  Presence of abscess  44.72  2.26  0.02  Previous cardiac surgery  36.74  2.36  0.02  Critical preoperative state  −40.13  −2.08  0.04  Custodiol cardioplegia  12.20  3.04  0.003  Custodiol cardioplegia  17.19  2.14  0.03  PVE  34.57  7.05  <0.0001  PVE  45.28  4.21  <0.0001  Multiple valve procedures  32.01  6.39  <0.0001  Multiple valve procedures  37.48  10.21  0.0003  Concomitant procedure on thoracic (ascending) aorta  45.76  5.46  <0.0001  Concomitant procedure on thoracic (ascending) aorta  85.02  5.05  <0.0001  R2 = 0.38; R2 adjusted = 0.36; SE = 30.7  R2 = 0.33; R2 adjusted = 0.31; SE = 61.36  XCT   CPBT   Independent variables  Beta  t  P-value  Independent variables  Beta  t  P-value  Age (years)  −0.25  −1.96  0.05  Age  −0.51  −1.92  0.06  Diabetes  13.21  2.31  0.02  EuroSCORE II  1.65  3.00  0.003  Embolic event  16.70  1.74  0.08  Presence of abscess  44.72  2.26  0.02  Previous cardiac surgery  36.74  2.36  0.02  Critical preoperative state  −40.13  −2.08  0.04  Custodiol cardioplegia  12.20  3.04  0.003  Custodiol cardioplegia  17.19  2.14  0.03  PVE  34.57  7.05  <0.0001  PVE  45.28  4.21  <0.0001  Multiple valve procedures  32.01  6.39  <0.0001  Multiple valve procedures  37.48  10.21  0.0003  Concomitant procedure on thoracic (ascending) aorta  45.76  5.46  <0.0001  Concomitant procedure on thoracic (ascending) aorta  85.02  5.05  <0.0001  R2 = 0.38; R2 adjusted = 0.36; SE = 30.7  R2 = 0.33; R2 adjusted = 0.31; SE = 61.36  Beta: standardized regression coefficient; CPBT: cardiopulmonary bypass time; PVE: prosthetic valve endocarditis; SE: standard error; XCT: aortic cross-clamping time. DISCUSSION In our cohort of 264 patients undergoing valvular surgery for IE, increasing XCT and CBPT were associated with poor short-term outcomes, namely early postoperative mortality and a composite outcome of severe postoperative complications within 30 days after surgery (mortality, ICU stay ≥5 days, stroke, postoperative haemodialysis or postoperative use of IABP). The unfavourable impact of prolonged XCT and CPBT has been previously explored, although not specifically in patients with IE [2–6, 10]. Our study confirms these findings in a cohort composed exclusively of patients undergoing valvular surgery for IE and also underlys an alarmingly high postoperative mortality especially in patients presenting with complicated IE [19–21]. Indeed, early postoperative mortality was as high as 14% in our study, a worrisome rate albeit in line with other series [19–22]. In this perspective, the identification of safe limits for XCT and CPBT might help to plan, and if possible to limit the surgical strategy to improve overall outcomes. For this purpose, the prognostic cut-offs found in our study (≤72 and ≤166 min for XCT and CPBT, respectively) might represent desirable intraoperative targets. Of note, our cut-offs were slightly lower than those identified by other authors in cohorts unrestricted to IE patients (<90–150 and <240 min for XCT and CPBT, respectively) [2, 4, 6]. We speculated that this result could be explained by the impairment in heart rate regulation and the damage of mitochondrial function by inflammatory mediators that occurs more frequently in IE than in non-infectious surgical conditions and which might enhance the unfavourable prognostic impact of prolonged XCT and CPBT [23–26]. This intriguing possibility still deserves confirmation through dedicated preclinical models and should be considered with caution pending further investigation. In our opinion, another point worthy of further investigation might be the use, in some selected patients, of new generation prostheses, such as sutureless or rapid deployment valves [27], which could help in reducing XCT and CBPT, and in turn improving the prognosis of IE patients. In our study, the unfavourable impact of prolonged XCT and CPBT is further testified by their association with the composite outcome of severe complications. A similar association was already described by Nissinen et al. [6] in a heterogeneous cohort of patients of whom less than 1% had active endocarditis. In this regard, it is worth noting that in our study, the composite outcome had a frequency of 32%, far higher than that of 11% described by Nissinen et al. [6], thus making the challenge of impacting the postoperative outcome by means of reducing CPBT and XCT even more attractive and worthy of further investigation. Increased XCT and CPBT were not the only predictors of in-hospital mortality and severe complications found in our study. Indeed, reduced LVEF and older age also unfavourably influenced outcomes, with preoperative stroke and preoperative mechanical ventilation being further independent predictors of the composite outcome of severe complications. These results comply with previous literature and highlight the fact that risk assessment in patients undergoing valvular surgery for IE is a challenging task [6, 27–29]. In this regard, our study suggests that prolonged XCT and CPBT might provide additional information about postoperative risks that cannot be intercepted by classical preoperative risk scores used in patients with IE [22, 30]. Finally, we observed that diabetes, previous cardiac surgery, Custodiol cardioplegia, PVE, multiple valve procedures, and concomitant procedures on the thoracic aorta were associated with prolonged XCT, while EuroSCORE II, presence of abscess, critical preoperative state, Custodiol cardioplegia, PVE, multiple valve procedures and concomitant procedures on thoracic aorta predicted prolonged CPBT. In our opinion, these findings reflect the critical importance of baseline comorbidities, acute phase conditions and extension of the infections process in influencing XCT and CPBT, and, in turn, postoperative outcomes. Consequently, all these factors should be considered when planning ahead a surgical procedure for IE in order to lessen the operative risk. Limitations Our study has some important limitations. First, information on the anatomical factors that might have influenced outcomes were not recorded. Second, incomplete information on the appropriateness of antibiotic therapy might have also affected the outcomes, as well as any possible impact of inflammation/activity of endocarditis. Finally, the collected procedures were performed over 17 years by different surgical teams using a variety of techniques that might have influenced the results. CONCLUSION In conclusion, prolonged XCT and CPBT are associated with mortality and development of severe complications after valvular surgery for IE. Provided that their prognostic role is validated in confirmatory studies, the safe limits of 72 min for XCT and 166 min for CPBT found in our study might be considered as factors to be weighed when planning the best surgical strategy to improve intraoperative and postoperative outcomes of IE patients. SUPPLEMENTARY MATERIAL Supplementary material is available at ICVTS online. Conflict of interest: none declared. 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Interactive CardioVascular and Thoracic SurgeryOxford University Press

Published: Mar 22, 2018

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