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Preliminary results of the Multicenter Observational Study with Enoximone in Cardiac surgery (MOSEC)
IJCA-26738; No of Pages 5 International Journal of Cardiology xxx (2018) xxx–xxx
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Preliminary results of the Multicenter Observational Study with Enoximone in Cardiac surgery (MOSEC)☆ Emiliano Angeloni a,⁎,1, Giovanni Melina a,1, Francesco Federici b, Francesca Pischedda b, Walter Vignaroli a, Monica Rocco b, Riccardo Sinatra a, on behalf of the MOSEC Investigators 2 a b
Department of Cardiac Surgery, Sapienza University of Rome, Policlinico Sant'Andrea, Roma, Italy Department of Anaesthesiology, Sapienza University of Rome, Policlinico Sant'Andrea, Roma, Italy
a r t i c l e
i n f o
Article history: Received 23 May 2018 Received in revised form 4 July 2018 Accepted 13 July 2018 Available online xxxx Keywords: Cardiac surgery Cardio-pulmonary bypass Inotropes
a b s t r a c t Background: Perioperative administration of Enoximone has been shown to improve hemodynamics, organ function, and inflammatory response. Aim of the present study was to evaluate the effects of Enoximone after on-pump cardiac surgery. Methods: A protocol for a multicenter observational study was reviewed and approved by local ethic committee. This preliminary report involves the first 29 patients enrolled, in whom Enoximone was perioperatively administered in the context of on-pump cardiac surgery. All patients enrolled were propensity-matched 1:1 with controls not receiving Enoximone, renal function was evaluated in terms of estimated glomerular filtration rate (eGFR) with the CKD-EPI equation. Results: After propensity matching, the two cohorts of patients receiving Enoximone or not did not show any significant differences among baseline characteristics. Patients receiving Enoximone showed a progressive improvement of eGFR at each time-point of follow-up: roughly +4.3, +10.0, and +12.3 mL/min/1.73 m2 on postoperative days 2, 7, and 30; respectively. Consistently, maximum difference versus baseline was +12.6 mL/min/1.73 m2 (or +19.3%) among Enoximone patients vs +3.3 mL/min/1.73 m2 (or +4.4%) among controls (p = 0.02). Multivariable regression analysis (R2-adjusted 0.47) showed only age (β −0.53; p = 0.01), preoperative eGFR (β −0.39; p = 0.02), diabetes (β 2.1; p = 0.01), cardio-pulmonary bypass duration (β 0.08; p = 0.05), and Enoximone administration (β −0.74; p = 0.05) to be independently correlated with delta eGFR variation on day 30. Conclusion: These preliminary results show that perioperative Enoximone administration improved renal function in patients undergoing on-pump cardiac surgery. Further studies are needed to confirm these findings. © 2018 Elsevier B.V. All rights reserved.
1. Introduction Recent life expectancy models in “high-income” countries show an increase of at least 65% in women and 85% in men by year 2030 which translates into a careful planning for health and social services [1]. ☆ Each of the above authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ⁎ Corresponding author at: Department of Cardiac Surgery, Sapienza Università di Roma, Policlinico Sant'Andrea, Via di Grottarossa 1035, 00189 Roma, Italy. E-mail address: [email protected] (E. Angeloni). 1 Contributed equally. 2 MOSEC Investigators: Pasquale Mastroroberto and Filiberto Serraino (AOU Mater Domini, Catanzaro); Giulio Baio, Roberto Bianchini, Domitilla Brancadoro, Benedetta Basili, Gisella Capua, Fabio Capuao, Federica Cialone, Giuseppe D'Arista, Piero David, Elia Forte, Federica Giorgi, Elisabetta Giorni, Antonio Liardo, Domenico Massullo, Maria Grazia Monina, Miriam Pafundi, Ettore Riva, Atonino Roscitano, Paolo Sgarlata, Pierpaolo Spitaleri, Euclide Tonelli, Giulia Zampetti (Policlinico Sant'Andrea, Sapienza, University of Rome).
In this scenario, patients undergoing cardiac surgery are increasingly older with multiple risk factors. Cardio-pulmonary bypass (CPB), which is commonly used in the setting of cardiac surgery, may increase morbidity and mortality in such a higher risk population. Indeed, the well-known systemic inflammatory response due to CPB, with its possible sequelae, may play a role in determining postoperative outcomes. Specifically, the non-physiological perfusion along with blood contact with non-endothelial surfaces both activate coagulation, promote endothelial layer modifications, and trigger the expression of leukocyte adhesion molecules, which may lead to postCPB target-organ damage [2]. In particular, postoperative renal failure (RF) is a major issue affecting outcomes of cardiac surgery, and it has been clearly demonstrated to be strongly correlated with the use and length of CPB [3]. As a result, RF is an established significant cause of morbidity and mortality after cardiac surgery; thus it has been found to increase short- and longterm mortality, the incidence of post-operative complications such as
https://doi.org/10.1016/j.ijcard.2018.07.071 0167-5273/© 2018 Elsevier B.V. All rights reserved.
Please cite this article as: E. Angeloni, et al., Preliminary results of the Multicenter Observational Study with Enoximone in Cardiac surgery (MOSEC), Int J Cardiol (2018), https://doi.org/10.1016/j.ijcard.2018.07.071
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E. Angeloni et al. / International Journal of Cardiology xxx (2018) xxx–xxx accepted when p ≤ 0.05. Continuous variables are shown as mean with standard deviation. All categorical data were displayed as percentages. Differences in baseline characteristics and postoperative data were compared using the chi-square test for categorical variables and t-test for continuous variables. In order to control the efficacy of Enoximone for other important, clinically wellknown factors associated with postoperative RF after cardiac surgery [16], a multivariable logistic regression analysis (significance level p = 0.05) was manually performed forcing clinically relevant variables into the model (age, preoperative eGFR, diabetes, recent myocardial infarction, preoperative chronic obstructive pulmonary disease, preoperative NYHA functional class, preoperative cardiogenic shock, previous cardiac surgery, and type of surgical intervention). A second multivariable logistic model (significance level p = 0.05) was used to correct for other inotropic drugs administered during the perioperative period. Goodness-of-fit of the logistic models was checked with the Coefficient of determination R2 adjusted for entered variables.
respiratory infections, sepsis, and gastrointestinal bleeding, and intensive care unit and hospital lengths of stay [3,4]. Because of the latter, in the last decades many efforts have been made to avoid CPB (e.g. off-pump techniques, percutaneous valve procedures) or to manipulate the inflammatory process associated with CPB; including the introduction of miniaturized CPB, and the use of corticosteroids or other specific inhibitors of inflammatory mediators [5–8]. Enoximone is a selective inhibitor of Phosphodiesterase (PDE) III, known to modulate hemodynamics and phlogosis [9]; indeed, recent studies have shown that perioperative administration of Enoximone results in beneficial effects on hemodynamic status, organ function, inflammatory response, and endothelial integrity [9–11]. In order to evaluate the effects of Enoximone in patients undergoing cardiac surgery, we designed a multicenter prospective observational study.
3. Results
2. Materials and methods
3.1. Overall data
2.1. Patients and variables
Finally, the study population consisted of 58 patients (mean age 65.6 ± 8.4; with 39 or 78% being male) with a mean EuroSCORE II of 6.6 ± 2.5%, which reflects the increased-risk profile of those patients. There were no hospital deaths, whilst cumulative incidence of postoperative RF was 8.6% (5/58), with no patient requiring RRT. After propensity matching, the two cohorts of patients receiving Enoximone (Group A, n = 29) or not (Group B, n = 29) did not show any significant differences among baseline characteristics (Table 1).
The MOSEC is a Multicenter Observational Study of Enoximone in Cardiac surgery involving 2 Italian centers, with other 4 awaiting for ethic committee approval. The study was initially approved by the Ethics Committee of “Sapienza” University of Rome (EC Ref. no. 4116_2016, MOSEC Protocol no. 110SA_2016, authorized June 09th 2016). Informed consent was obtained from each patient and the study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution's human research committee. We prospectively enrolled patients scheduled for on-pump cardiac surgery for whom anticipated prolonged CPB and/or comorbidities preoperatively suggested the use of Enoximone. Exclusion criteria were: off-pump interventions, non-hypothermic CPB, preoperative severe renal failure, preoperative liver disease, preoperative infection, and history of pathological alcohol consumption. The decision to include the individual was shared by the anaesthesiologist and the surgeon in charge for the case, and every patient, after being provided with full information about the study, gave his written informed consent. Renal function was evaluated by means of glomerular filtration rate (GFR) estimated with the CKD-EPI equation [12]. Diagnosis of severe preoperative renal disease was made [13,14] because of previous renal replacement therapy (RRT) or because of eGFR b 15 mL/min/1.73 m2 (CKD-EPI class V). Subsequently, postoperative RF was defined as a decline of ≥50% in GFR relative to baseline or need for renal replacement therapy. The rationale for the latter was the strong association shown by such defined values and operative mortality in previously published studies dealing with cardiac surgery cohorts [13,14]. In those patients included, Enoximone was administered from the weaning from CPB to 48–72 h postoperatively; the administration was performed with a starting bolus of 0.5 mg/kg followed by continuous infusion at 3 μg/kg/min. Other drugs used perioperatively in the whole study population included epinephrine, norepinephrine, dopamine, dobutamine, and levosimendan; aprotinin and vasopressin have been used in no patient. Primary end-point was renal function, assessed as described above. Secondary endpoints were operative mortality, length of stay, blood drainage in the first 24 h, and need for transfusions. For the latter two, too few data were available in order to make a statistical comparison in this preliminary report. End-points were assessed at baseline, postoperatively at the arrival in the intensive care unit (ICU), and on day 2, 7, and 30 postoperatively. Thirty-day follow-up data were collected at the time of outpatient visits at each Institution. 2.2. Statistical analysis For the purpose of the study, patients receiving Enoximone were compared with similar patients operated in the same period (June 2016–December 2017) without the use of Enoximone and to control for selection bias, a propensity score [15] was calculated. To obtain a semi-saturated model, continuous and binary variables were used for a total of 32 preoperative and intraoperative variables, including: age, gender, body mass index, diabetes mellitus, hypertension, smoking history, chronic obstructive pulmonary disease (COPD), peripheral vascular disease, previous cerebro-vascular accident, preoperative left ventricular ejection fraction (LVEF), preoperative systolic pulmonary artery pressure, preoperative New York Heart Association (NYHA) functional class, preoperative eGFR, preoperative C-reactive protein level, preoperative hemoglobin level, preoperative myocardial infarction, preoperative medications, elective surgery, reinterventional surgery, type of surgical procedure, miniaturized extra-corporeal circulation devices usage, aortic cross-clamp time, CPB time and post-operative transfusions. After a perfect 1:1 propensity-matching process, two balanced cohorts of 29 patients each were obtained. The final propensity model showed a satisfactory goodness of fit (c-statistic 0.81; p b 0.0001). All statistical analyses were performed using the Statistical Package for the Social Sciences, version 11.0 (SPSS, Chicago, IL). Variables were checked for normality by means of the Kolmogorov-Smirnov test for normal distribution and normality was
3.2. Comparison of groups The fair comparison of propensity-matched groups showed that patients who received perioperative Enoximone had a lower incidence of postoperative RF: 0% (0/29) versus 17.2% (6/29) in those who did not (p b 0.0001). Furthermore, patients receiving Enoximone showed a progressive improvement of eGFR at each time-point of follow-up: roughly +4.3, +10.0, and +12.3 mL/min/1.73 m2 on postoperative days 2, 7, and 30; respectively (Table 2). That slight amelioration of renal function was not seen among controls; with significant differences favoring patients treated with Enoximone on postoperative days 2 and 30 (Table 2). Consistently, maximum difference versus first value was +12.6 (95% CI: +7.9 to +17.3 mL/min/1.73 m2) among Enoximone patients versus +3.3 (95% CI: −5.1 to +11.7 mL/min/1.73 m2) among controls (p = 0.04). Given that, best proportional amelioration of Table 1 Baseline characteristics stratified for treatment groups. Variables
Group A Enoxinone (n = 29)
Group B No Enoximone (n = 29)
p value
Age, years Gender male BMI, kg/m2 CAD Hgb, g/dL WBC, 103/mm3 HR, bpm SBP, mm Hg DBP, mm Hg eGFR, mL/min/1.73 m2 CKD-EPI class CPB duration, mins Type of intervention Aortic (arch/ascending) ± CABG Multiple valve procedure CABG + valve procedure
70.3 ± 8.1 18 (62.1) 25.7 ± 4.5 20 (69.0) 12.5 ± 3.7 5337.6 ± 3133.5 72.2 ± 8.8 119.5 ± 20.5 61.9 ± 14.9 74.1 ± 16.2 2.1 ± 0.7 134.4 ± 41.1
69.2 ± 11.4 18 (62.1) 25.3 ± 3.7 19 (65.5) 12.7 ± 4.3 5919.1 ± 3874.9 71.6 ± 15.1 118.6 ± 22.7 64.6 ± 14.9 75.0 ± 15.2 2.0 ± 0.6 133.4 ± 31.5
0.35 0.99 0.70 0.92 0.83 0.51 0.54 0.41 0.37 0.61 0.76 0.39
11 (38.0) 6 (21.0) 12 (41.0)
11 (38.0) 8 (27.6) 10 (34.4)
0.66 0.36 0.29
BMI, body mass index; CAD, coronary artery disease; Hgb, hemoglobin; WBC, white blood cells; HR, heart rate; SBP, systolic blood pressure; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; CABG, coronary artery bypass grafting. Continuous variables are shown as mean ± standard deviation, categorical variables as absolute number (percentage).
Please cite this article as: E. Angeloni, et al., Preliminary results of the Multicenter Observational Study with Enoximone in Cardiac surgery (MOSEC), Int J Cardiol (2018), https://doi.org/10.1016/j.ijcard.2018.07.071
E. Angeloni et al. / International Journal of Cardiology xxx (2018) xxx–xxx Table 2 Postoperative renal function stratified for treatment groups. Variables
Group A Enoxinone (n = 29)
Group B No Enoximone (n = 29)
p value
eGFR day 2 Delta eGFR day 2 Delta CKD-EPI class day 2 eGFR day 7 Delta eGFR day 7 Delta CKD-EPI class day 7 eGFR day 30 Delta eGFR day 30 Delta CKD-EPI class day 30
78.4 ± 17.6 +4.3 ± 9.8 −0.17 ± 0.5 84.1 ± 17.4 +10.0 ± 11.1 −0.35 ± 0.62 84.7 ± 15.9 +12.3 ± 10.2 −0.5 ± 0.6
74.9 ± 18.8 −0.28 ± 15.8 +0.12 ± 0.6 82.9 ± 21.6 +8.0 ± 16.3 −0.17 ± 0.64 82.2 ± 22.3 +7.6 ± 10.5 0.1 ± 0.0
0.14 0.04 0.05 0.17 0.59 0.05 0.15 0.05 b0.0001
eGFR, estimated glomerular filtration rate; CABG, coronary artery bypass grafting. eGFR and its deltas are shown as mL/min/1.73 m2.
eGFR from baseline was +19.3% (95% CI: +11.4 to +27.1%) for Enoximone patients, and +4.4% (95% CI: −6.6 to +15.5%) for controls (p = 0.02). Even comparing CKD-EPI class variations, patients belonging to the Enoximone group showed a 30-day half class improvement, with respect to no variation among controls (p b 0.0001, Table 2). Length of stay was similar between groups, both if comparing ICU stay (1.7 ± 0.7 vs. 1.8 ± 0.8 days; p = 0.88) or cumulative postoperative stay (7.2 ± 1.5 vs. 7.1 ± 1.7 days; p = 0.84), respectively for patients treated or not with Enoximone. 3.3. Multivariable analysis The multivariable regression analysis (R2-adjusted 0.47) showed only age (β −0.53; p = 0.01), preoperative eGFR (β −0.39; p = 0.02), diabetes (β 2.1; p = 0.01), CPB duration (β 0.08; p = 0.05), and Enoximone administration (β −0.74; p = 0.05) to be independently correlated with delta eGFR variation on day 30 (Table 3). A second multivariable regression model was built to control for the administration of other inotropic drugs, such as Epinephrine, Norepinephrine, Dopamine, Dobutamine, and Levosimendan. Only Enoximone (β −0.81; p = 0.02) and the administration of no inotropic drug (β −0.84; p b 0.0001) were found to be independently correlated with delta eGFR variation on day 30. 4. Discussion The main finding of this study is that the perioperative administration of Enoximone significantly improves postoperative eGFR and CKD-EPI class with respect to controls, regardless of age, duration of CPB, other inotropic drugs used, and other baseline characteristics. We have previously reported on a retrospective consecutive series of patients from a single Institution undergoing on-pump cardiac surgery between 2004 and 2010, showing similar results on renal function [11]. The present study is a multicenter prospective investigation which started in 2017; the preliminary results reported here not only confirm
Table 3 Multivariable regression analysis with Delta eGFR on day 30 as dependent variable. Variables
β coefficient
SE
p value
Year of age BMI Gender male Diabetes Preoperative eGFR CPB minutes Enoximone
−0.53 0.01 0.71 2.1 −0.39 0.08 −0.74
0.27 0.57 4.86 0.43 0.16 0.05 0.76
0.01 0.98 0.88 0.01 0.02 0.05 0.05
SE, standard error; BMI, body mass index; eGFR, estimated glomerular filtration rate; CPB, cardio-pulmonary bypass.
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what we have shown previously but are more robust in terms of study design and technical improvement considering the time-frame. In addition, renal function was estimated by means of the CKD-EPI equation [12] whilst in our previous report we used the MDRD formula. It has been shown that the CKD-EPI equation is more accurate to categorize the risk for mortality and end-stage renal dysfunction than the MDRD Study equation across a broad range of populations [17], exception made for kidney transplant recipients [18]. 4.1. Mechanisms of action of Enoximone The consensus conference of the acute dialysis quality initiative [19] identified five subgroups of cardio-renal syndromes, and the postoperative occurrence of RF configures in two possible patterns of those five: type 1 (acute cardio-renal syndrome) or type 3 (acute reno-cardiac syndrome). The latter includes those with a primitive acute kidney injury further determining cardiac events (e.g. arrhythmias), whilst type 1 involves instead patients with left ventricular impairment determining target organ dysfunction. It has to be preliminary disclosed that beneficial effects of Enoximone may apply to both those clinical scenarios of post-operative renal dysfunction. Indeed, Enoximone enhances hemodynamic, attenuates inflammation and ameliorates microperfusion. In particular, the positive inotropic and vascular relaxant actions of Enoximone may be correlated with selective inhibitory effects on the cyclic Adenosine MonoPhosphate (cAMP)-specific and cyclic Guanosine MonoPhosphate (cGMP)-inhibited form of PDE [19]. In addition, the inflammatory process is beneficially modulated by this elevation in intracellular cAMP and cGMP, which determine blockade of the production and release of pro-inflammatory cytokines (e.g., TNF-α, IL-6), attenuated lipopolysaccharide-induced leukocyte-endothelial adhesion and emigration, and macromolecular extravasation [19]. Additionally, increased intracellular cAMP concentrations result in direct inhibition of neutrophils' secretory function [19]. Finally, the increase in microperfusion secondary to PDE III inhibition [5] may exert particular benefit in the elderly because microcirculatory deficits are common after CPB and may induce organ dysfunction. Following initial promises, trials investigating the oral administration of Enoximone in the settings of heart failure did not show significantly improved clinical outcomes, even if oral Enoximone was found useful to wean from intravenous inotropic support a modest percentage of patients [20,21]. These findings were consistent with the positive inotropic, lusitropic, and vasodilatory effect shown by Enoximone [10,11] and could explain the benefit resulting from Enoximone administration in type 1 cardio-renal syndrome. Instead, in the context of type 3 reno-cardiac syndrome benefits deriving from the perioperative administration of Enoximone could be explained by its inflammatory-modulation effect. Given the independent correlation between Enoximone and ameliorated renal outcomes found in our analysis, it is reasonable to assume that both pathways (positive inotropism/lusitropism and inflammatory modulation) play a contemporary and synergic role after on-pump cardiac surgery, since findings are not influenced neither by CPB times nor by other inotropic agents administered. In addition, the inflammatory modulation exerted by Enoximone may be beneficial not only for vessels and circulation functions (thereby for target organ perfusion), but even in those cases where extracorporeal circulation and/or cardioplegia trigger transient myocardial oedema or ventricular dysfunction. 4.2. Modulation of the inflammatory response In the settings of heart failure, Enoximone improves cardiac output and lowers pulmonary pressures better than dobutamine does [22]; therefore, a growing interest raises towards the beneficial effects of Enoximone in the surgical settings. Endothelial cell activation commonly occurs during CPB [23], and the expression of endothelial cell
Please cite this article as: E. Angeloni, et al., Preliminary results of the Multicenter Observational Study with Enoximone in Cardiac surgery (MOSEC), Int J Cardiol (2018), https://doi.org/10.1016/j.ijcard.2018.07.071
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E. Angeloni et al. / International Journal of Cardiology xxx (2018) xxx–xxx
adhesion molecules is believed to play a key role in the inflammatory process in these patients undergoing on-pump cardiac surgery [24]. Expression of adhesion molecules is up-regulated during CPB and some of the soluble adhesion molecules measured in the circulating blood appear to be excellent markers of endothelial damage [25]. In different studies [26] plasma levels of all measured soluble adhesion molecules (e.g., sE-selectin; s-vascular cell adhesion molecule 1; s-intercellular adhesion molecule 1) were significantly more elevated in the untreated control than in the Enoximone-treated patients; leading to the evidence of reduced inflammatory response in patients receiving perioperative Enoximone infusion. In our study, no severe side effects were observed with the use of Enoximone at any time during the study period and the incidence of arrhythmias was similar between groups, despite previous study reported increased ectopics with the use of Enoximone [22]. 4.3. Limitations The resulting evidence of reduced postoperative incidence of RF in patients receiving Enoximone seems to be particularly robust because it was confirmed using two different discrete and continuous variables (eGFR and CKD-EPI class variation). Furthermore, even adjusting the analysis for covariates such as age, duration of CPB, baseline characteristics, and other inotropes usage, the correlation between Enoximone administration and lower postoperative renal impairment stay statistically significant. Of particular interest is the fact that in the present study Enoximone resulted as the only inotropic agent yielding to improved postoperative renal outcome, whereas only the administration of no inotropic drug was associated with the latter results. It has to be pointed out that dopamine, despite a positive trend, did not show better renal outcomes; maybe because its usage is widely extended to many patients just because of renal impairment. This means that the group of patients receiving dopamine includes cases of overt renal failure treated with dopamine and other agents, and this fact implies the different trend of eGFR observed in such cohort. On the other hand, inotropes such epinephrine, norepinephrine, and levosimendan showed a slight negative impact on renal outcome. This can be explained by the fact that patients receiving these drugs where obviously patients with a low cardiac output, which are at higher risk of organ dysfunction because of suboptimal perfusion. Contrariwise, patients receiving no inotropic drugs showed better postoperative renal function maybe as a result of the fact that patients not needing pharmacologic inotropic support have more steady, regular and straightforward course following surgery, which results in improved outcomes. Main limitation of the present report is represented by the lack of randomization and, to date, the small sample size. Forthcoming reports will include data from other Institutes participating this multicenter study, thus strengthening present results. In addition, being the present a prospective multicenter trial, we believe this gives additional strength to our investigation also in terms of avoiding the so called “Hawthorne effect”. 5. Conclusion Finally, as cardiac surgery is being offered to an increasing number of elderly patients, and our understanding of the CPB-related complications has improved in recent years, the development of therapies focused on reducing the inflammatory response and improving postoperative organ function plays a key role in determining surgical results. Organ function reserve is often reduced in cardiac surgery patients, and especially renal failure is a complication leading to poorer outcomes that can be prevented by the surgeon only avoiding long times of CPB. Because of this, protective pharmacological interventions are of crucial
matter to grant better surgical results. In these settings, our study showed that Enoximone exerts significant beneficial effects on renal function after on-pump cardiac surgery. The mechanisms underlying these beneficial effects remain to be elucidated. Further investigations are needed to confirm our findings. Disclosures None. References [1] V. Kostis, J.E. Bennet, C.D. Mathers, G. Li, K. Foreman, M. Ezzati, Future life expectancy in 35 industrialised countries: projections with a Bayesian model ensemble, Lancet 389 (2017) 1323–1335. [2] J.H. Levy, K.A. Tanaka, Inflammatory response to cardiopulmonary bypass, Ann. Thorac. Surg. 75 (2003) S715–S720. [3] P. Kolh, Renal insufficiency after cardiac surgery: a challenging clinical problem, Eur. Heart J. 30 (2009) 1824–1827. [4] C.E. Hobson, S. Yavas, M.S. Segal, et al., Acute kidney injury is associated with increased long-term mortality after cardiothoracic surgery, Circulation 119 (2009) 2444–2453. [5] R. Bellomo, C. Ronco, J.A. 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Please cite this article as: E. Angeloni, et al., Preliminary results of the Multicenter Observational Study with Enoximone in Cardiac surgery (MOSEC), Int J Cardiol (2018), https://doi.org/10.1016/j.ijcard.2018.07.071
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Preliminary results of the Multicenter Observational Study with Enoximone in Cardiac surgery (MOSEC)☆ Emiliano Angeloni a,⁎,1, Giovanni Melina a,1, Francesco Federici b, Francesca Pischedda b, Walter Vignaroli a, Monica Rocco b, Riccardo Sinatra a, on behalf of the MOSEC Investigators 2 a b
Department of Cardiac Surgery, Sapienza University of Rome, Policlinico Sant'Andrea, Roma, Italy Department of Anaesthesiology, Sapienza University of Rome, Policlinico Sant'Andrea, Roma, Italy
a r t i c l e
i n f o
Article history: Received 23 May 2018 Received in revised form 4 July 2018 Accepted 13 July 2018 Available online xxxx Keywords: Cardiac surgery Cardio-pulmonary bypass Inotropes
a b s t r a c t Background: Perioperative administration of Enoximone has been shown to improve hemodynamics, organ function, and inflammatory response. Aim of the present study was to evaluate the effects of Enoximone after on-pump cardiac surgery. Methods: A protocol for a multicenter observational study was reviewed and approved by local ethic committee. This preliminary report involves the first 29 patients enrolled, in whom Enoximone was perioperatively administered in the context of on-pump cardiac surgery. All patients enrolled were propensity-matched 1:1 with controls not receiving Enoximone, renal function was evaluated in terms of estimated glomerular filtration rate (eGFR) with the CKD-EPI equation. Results: After propensity matching, the two cohorts of patients receiving Enoximone or not did not show any significant differences among baseline characteristics. Patients receiving Enoximone showed a progressive improvement of eGFR at each time-point of follow-up: roughly +4.3, +10.0, and +12.3 mL/min/1.73 m2 on postoperative days 2, 7, and 30; respectively. Consistently, maximum difference versus baseline was +12.6 mL/min/1.73 m2 (or +19.3%) among Enoximone patients vs +3.3 mL/min/1.73 m2 (or +4.4%) among controls (p = 0.02). Multivariable regression analysis (R2-adjusted 0.47) showed only age (β −0.53; p = 0.01), preoperative eGFR (β −0.39; p = 0.02), diabetes (β 2.1; p = 0.01), cardio-pulmonary bypass duration (β 0.08; p = 0.05), and Enoximone administration (β −0.74; p = 0.05) to be independently correlated with delta eGFR variation on day 30. Conclusion: These preliminary results show that perioperative Enoximone administration improved renal function in patients undergoing on-pump cardiac surgery. Further studies are needed to confirm these findings. © 2018 Elsevier B.V. All rights reserved.
1. Introduction Recent life expectancy models in “high-income” countries show an increase of at least 65% in women and 85% in men by year 2030 which translates into a careful planning for health and social services [1]. ☆ Each of the above authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ⁎ Corresponding author at: Department of Cardiac Surgery, Sapienza Università di Roma, Policlinico Sant'Andrea, Via di Grottarossa 1035, 00189 Roma, Italy. E-mail address: [email protected] (E. Angeloni). 1 Contributed equally. 2 MOSEC Investigators: Pasquale Mastroroberto and Filiberto Serraino (AOU Mater Domini, Catanzaro); Giulio Baio, Roberto Bianchini, Domitilla Brancadoro, Benedetta Basili, Gisella Capua, Fabio Capuao, Federica Cialone, Giuseppe D'Arista, Piero David, Elia Forte, Federica Giorgi, Elisabetta Giorni, Antonio Liardo, Domenico Massullo, Maria Grazia Monina, Miriam Pafundi, Ettore Riva, Atonino Roscitano, Paolo Sgarlata, Pierpaolo Spitaleri, Euclide Tonelli, Giulia Zampetti (Policlinico Sant'Andrea, Sapienza, University of Rome).
In this scenario, patients undergoing cardiac surgery are increasingly older with multiple risk factors. Cardio-pulmonary bypass (CPB), which is commonly used in the setting of cardiac surgery, may increase morbidity and mortality in such a higher risk population. Indeed, the well-known systemic inflammatory response due to CPB, with its possible sequelae, may play a role in determining postoperative outcomes. Specifically, the non-physiological perfusion along with blood contact with non-endothelial surfaces both activate coagulation, promote endothelial layer modifications, and trigger the expression of leukocyte adhesion molecules, which may lead to postCPB target-organ damage [2]. In particular, postoperative renal failure (RF) is a major issue affecting outcomes of cardiac surgery, and it has been clearly demonstrated to be strongly correlated with the use and length of CPB [3]. As a result, RF is an established significant cause of morbidity and mortality after cardiac surgery; thus it has been found to increase short- and longterm mortality, the incidence of post-operative complications such as
https://doi.org/10.1016/j.ijcard.2018.07.071 0167-5273/© 2018 Elsevier B.V. All rights reserved.
Please cite this article as: E. Angeloni, et al., Preliminary results of the Multicenter Observational Study with Enoximone in Cardiac surgery (MOSEC), Int J Cardiol (2018), https://doi.org/10.1016/j.ijcard.2018.07.071
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E. Angeloni et al. / International Journal of Cardiology xxx (2018) xxx–xxx accepted when p ≤ 0.05. Continuous variables are shown as mean with standard deviation. All categorical data were displayed as percentages. Differences in baseline characteristics and postoperative data were compared using the chi-square test for categorical variables and t-test for continuous variables. In order to control the efficacy of Enoximone for other important, clinically wellknown factors associated with postoperative RF after cardiac surgery [16], a multivariable logistic regression analysis (significance level p = 0.05) was manually performed forcing clinically relevant variables into the model (age, preoperative eGFR, diabetes, recent myocardial infarction, preoperative chronic obstructive pulmonary disease, preoperative NYHA functional class, preoperative cardiogenic shock, previous cardiac surgery, and type of surgical intervention). A second multivariable logistic model (significance level p = 0.05) was used to correct for other inotropic drugs administered during the perioperative period. Goodness-of-fit of the logistic models was checked with the Coefficient of determination R2 adjusted for entered variables.
respiratory infections, sepsis, and gastrointestinal bleeding, and intensive care unit and hospital lengths of stay [3,4]. Because of the latter, in the last decades many efforts have been made to avoid CPB (e.g. off-pump techniques, percutaneous valve procedures) or to manipulate the inflammatory process associated with CPB; including the introduction of miniaturized CPB, and the use of corticosteroids or other specific inhibitors of inflammatory mediators [5–8]. Enoximone is a selective inhibitor of Phosphodiesterase (PDE) III, known to modulate hemodynamics and phlogosis [9]; indeed, recent studies have shown that perioperative administration of Enoximone results in beneficial effects on hemodynamic status, organ function, inflammatory response, and endothelial integrity [9–11]. In order to evaluate the effects of Enoximone in patients undergoing cardiac surgery, we designed a multicenter prospective observational study.
3. Results
2. Materials and methods
3.1. Overall data
2.1. Patients and variables
Finally, the study population consisted of 58 patients (mean age 65.6 ± 8.4; with 39 or 78% being male) with a mean EuroSCORE II of 6.6 ± 2.5%, which reflects the increased-risk profile of those patients. There were no hospital deaths, whilst cumulative incidence of postoperative RF was 8.6% (5/58), with no patient requiring RRT. After propensity matching, the two cohorts of patients receiving Enoximone (Group A, n = 29) or not (Group B, n = 29) did not show any significant differences among baseline characteristics (Table 1).
The MOSEC is a Multicenter Observational Study of Enoximone in Cardiac surgery involving 2 Italian centers, with other 4 awaiting for ethic committee approval. The study was initially approved by the Ethics Committee of “Sapienza” University of Rome (EC Ref. no. 4116_2016, MOSEC Protocol no. 110SA_2016, authorized June 09th 2016). Informed consent was obtained from each patient and the study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution's human research committee. We prospectively enrolled patients scheduled for on-pump cardiac surgery for whom anticipated prolonged CPB and/or comorbidities preoperatively suggested the use of Enoximone. Exclusion criteria were: off-pump interventions, non-hypothermic CPB, preoperative severe renal failure, preoperative liver disease, preoperative infection, and history of pathological alcohol consumption. The decision to include the individual was shared by the anaesthesiologist and the surgeon in charge for the case, and every patient, after being provided with full information about the study, gave his written informed consent. Renal function was evaluated by means of glomerular filtration rate (GFR) estimated with the CKD-EPI equation [12]. Diagnosis of severe preoperative renal disease was made [13,14] because of previous renal replacement therapy (RRT) or because of eGFR b 15 mL/min/1.73 m2 (CKD-EPI class V). Subsequently, postoperative RF was defined as a decline of ≥50% in GFR relative to baseline or need for renal replacement therapy. The rationale for the latter was the strong association shown by such defined values and operative mortality in previously published studies dealing with cardiac surgery cohorts [13,14]. In those patients included, Enoximone was administered from the weaning from CPB to 48–72 h postoperatively; the administration was performed with a starting bolus of 0.5 mg/kg followed by continuous infusion at 3 μg/kg/min. Other drugs used perioperatively in the whole study population included epinephrine, norepinephrine, dopamine, dobutamine, and levosimendan; aprotinin and vasopressin have been used in no patient. Primary end-point was renal function, assessed as described above. Secondary endpoints were operative mortality, length of stay, blood drainage in the first 24 h, and need for transfusions. For the latter two, too few data were available in order to make a statistical comparison in this preliminary report. End-points were assessed at baseline, postoperatively at the arrival in the intensive care unit (ICU), and on day 2, 7, and 30 postoperatively. Thirty-day follow-up data were collected at the time of outpatient visits at each Institution. 2.2. Statistical analysis For the purpose of the study, patients receiving Enoximone were compared with similar patients operated in the same period (June 2016–December 2017) without the use of Enoximone and to control for selection bias, a propensity score [15] was calculated. To obtain a semi-saturated model, continuous and binary variables were used for a total of 32 preoperative and intraoperative variables, including: age, gender, body mass index, diabetes mellitus, hypertension, smoking history, chronic obstructive pulmonary disease (COPD), peripheral vascular disease, previous cerebro-vascular accident, preoperative left ventricular ejection fraction (LVEF), preoperative systolic pulmonary artery pressure, preoperative New York Heart Association (NYHA) functional class, preoperative eGFR, preoperative C-reactive protein level, preoperative hemoglobin level, preoperative myocardial infarction, preoperative medications, elective surgery, reinterventional surgery, type of surgical procedure, miniaturized extra-corporeal circulation devices usage, aortic cross-clamp time, CPB time and post-operative transfusions. After a perfect 1:1 propensity-matching process, two balanced cohorts of 29 patients each were obtained. The final propensity model showed a satisfactory goodness of fit (c-statistic 0.81; p b 0.0001). All statistical analyses were performed using the Statistical Package for the Social Sciences, version 11.0 (SPSS, Chicago, IL). Variables were checked for normality by means of the Kolmogorov-Smirnov test for normal distribution and normality was
3.2. Comparison of groups The fair comparison of propensity-matched groups showed that patients who received perioperative Enoximone had a lower incidence of postoperative RF: 0% (0/29) versus 17.2% (6/29) in those who did not (p b 0.0001). Furthermore, patients receiving Enoximone showed a progressive improvement of eGFR at each time-point of follow-up: roughly +4.3, +10.0, and +12.3 mL/min/1.73 m2 on postoperative days 2, 7, and 30; respectively (Table 2). That slight amelioration of renal function was not seen among controls; with significant differences favoring patients treated with Enoximone on postoperative days 2 and 30 (Table 2). Consistently, maximum difference versus first value was +12.6 (95% CI: +7.9 to +17.3 mL/min/1.73 m2) among Enoximone patients versus +3.3 (95% CI: −5.1 to +11.7 mL/min/1.73 m2) among controls (p = 0.04). Given that, best proportional amelioration of Table 1 Baseline characteristics stratified for treatment groups. Variables
Group A Enoxinone (n = 29)
Group B No Enoximone (n = 29)
p value
Age, years Gender male BMI, kg/m2 CAD Hgb, g/dL WBC, 103/mm3 HR, bpm SBP, mm Hg DBP, mm Hg eGFR, mL/min/1.73 m2 CKD-EPI class CPB duration, mins Type of intervention Aortic (arch/ascending) ± CABG Multiple valve procedure CABG + valve procedure
70.3 ± 8.1 18 (62.1) 25.7 ± 4.5 20 (69.0) 12.5 ± 3.7 5337.6 ± 3133.5 72.2 ± 8.8 119.5 ± 20.5 61.9 ± 14.9 74.1 ± 16.2 2.1 ± 0.7 134.4 ± 41.1
69.2 ± 11.4 18 (62.1) 25.3 ± 3.7 19 (65.5) 12.7 ± 4.3 5919.1 ± 3874.9 71.6 ± 15.1 118.6 ± 22.7 64.6 ± 14.9 75.0 ± 15.2 2.0 ± 0.6 133.4 ± 31.5
0.35 0.99 0.70 0.92 0.83 0.51 0.54 0.41 0.37 0.61 0.76 0.39
11 (38.0) 6 (21.0) 12 (41.0)
11 (38.0) 8 (27.6) 10 (34.4)
0.66 0.36 0.29
BMI, body mass index; CAD, coronary artery disease; Hgb, hemoglobin; WBC, white blood cells; HR, heart rate; SBP, systolic blood pressure; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; CABG, coronary artery bypass grafting. Continuous variables are shown as mean ± standard deviation, categorical variables as absolute number (percentage).
Please cite this article as: E. Angeloni, et al., Preliminary results of the Multicenter Observational Study with Enoximone in Cardiac surgery (MOSEC), Int J Cardiol (2018), https://doi.org/10.1016/j.ijcard.2018.07.071
E. Angeloni et al. / International Journal of Cardiology xxx (2018) xxx–xxx Table 2 Postoperative renal function stratified for treatment groups. Variables
Group A Enoxinone (n = 29)
Group B No Enoximone (n = 29)
p value
eGFR day 2 Delta eGFR day 2 Delta CKD-EPI class day 2 eGFR day 7 Delta eGFR day 7 Delta CKD-EPI class day 7 eGFR day 30 Delta eGFR day 30 Delta CKD-EPI class day 30
78.4 ± 17.6 +4.3 ± 9.8 −0.17 ± 0.5 84.1 ± 17.4 +10.0 ± 11.1 −0.35 ± 0.62 84.7 ± 15.9 +12.3 ± 10.2 −0.5 ± 0.6
74.9 ± 18.8 −0.28 ± 15.8 +0.12 ± 0.6 82.9 ± 21.6 +8.0 ± 16.3 −0.17 ± 0.64 82.2 ± 22.3 +7.6 ± 10.5 0.1 ± 0.0
0.14 0.04 0.05 0.17 0.59 0.05 0.15 0.05 b0.0001
eGFR, estimated glomerular filtration rate; CABG, coronary artery bypass grafting. eGFR and its deltas are shown as mL/min/1.73 m2.
eGFR from baseline was +19.3% (95% CI: +11.4 to +27.1%) for Enoximone patients, and +4.4% (95% CI: −6.6 to +15.5%) for controls (p = 0.02). Even comparing CKD-EPI class variations, patients belonging to the Enoximone group showed a 30-day half class improvement, with respect to no variation among controls (p b 0.0001, Table 2). Length of stay was similar between groups, both if comparing ICU stay (1.7 ± 0.7 vs. 1.8 ± 0.8 days; p = 0.88) or cumulative postoperative stay (7.2 ± 1.5 vs. 7.1 ± 1.7 days; p = 0.84), respectively for patients treated or not with Enoximone. 3.3. Multivariable analysis The multivariable regression analysis (R2-adjusted 0.47) showed only age (β −0.53; p = 0.01), preoperative eGFR (β −0.39; p = 0.02), diabetes (β 2.1; p = 0.01), CPB duration (β 0.08; p = 0.05), and Enoximone administration (β −0.74; p = 0.05) to be independently correlated with delta eGFR variation on day 30 (Table 3). A second multivariable regression model was built to control for the administration of other inotropic drugs, such as Epinephrine, Norepinephrine, Dopamine, Dobutamine, and Levosimendan. Only Enoximone (β −0.81; p = 0.02) and the administration of no inotropic drug (β −0.84; p b 0.0001) were found to be independently correlated with delta eGFR variation on day 30. 4. Discussion The main finding of this study is that the perioperative administration of Enoximone significantly improves postoperative eGFR and CKD-EPI class with respect to controls, regardless of age, duration of CPB, other inotropic drugs used, and other baseline characteristics. We have previously reported on a retrospective consecutive series of patients from a single Institution undergoing on-pump cardiac surgery between 2004 and 2010, showing similar results on renal function [11]. The present study is a multicenter prospective investigation which started in 2017; the preliminary results reported here not only confirm
Table 3 Multivariable regression analysis with Delta eGFR on day 30 as dependent variable. Variables
β coefficient
SE
p value
Year of age BMI Gender male Diabetes Preoperative eGFR CPB minutes Enoximone
−0.53 0.01 0.71 2.1 −0.39 0.08 −0.74
0.27 0.57 4.86 0.43 0.16 0.05 0.76
0.01 0.98 0.88 0.01 0.02 0.05 0.05
SE, standard error; BMI, body mass index; eGFR, estimated glomerular filtration rate; CPB, cardio-pulmonary bypass.
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what we have shown previously but are more robust in terms of study design and technical improvement considering the time-frame. In addition, renal function was estimated by means of the CKD-EPI equation [12] whilst in our previous report we used the MDRD formula. It has been shown that the CKD-EPI equation is more accurate to categorize the risk for mortality and end-stage renal dysfunction than the MDRD Study equation across a broad range of populations [17], exception made for kidney transplant recipients [18]. 4.1. Mechanisms of action of Enoximone The consensus conference of the acute dialysis quality initiative [19] identified five subgroups of cardio-renal syndromes, and the postoperative occurrence of RF configures in two possible patterns of those five: type 1 (acute cardio-renal syndrome) or type 3 (acute reno-cardiac syndrome). The latter includes those with a primitive acute kidney injury further determining cardiac events (e.g. arrhythmias), whilst type 1 involves instead patients with left ventricular impairment determining target organ dysfunction. It has to be preliminary disclosed that beneficial effects of Enoximone may apply to both those clinical scenarios of post-operative renal dysfunction. Indeed, Enoximone enhances hemodynamic, attenuates inflammation and ameliorates microperfusion. In particular, the positive inotropic and vascular relaxant actions of Enoximone may be correlated with selective inhibitory effects on the cyclic Adenosine MonoPhosphate (cAMP)-specific and cyclic Guanosine MonoPhosphate (cGMP)-inhibited form of PDE [19]. In addition, the inflammatory process is beneficially modulated by this elevation in intracellular cAMP and cGMP, which determine blockade of the production and release of pro-inflammatory cytokines (e.g., TNF-α, IL-6), attenuated lipopolysaccharide-induced leukocyte-endothelial adhesion and emigration, and macromolecular extravasation [19]. Additionally, increased intracellular cAMP concentrations result in direct inhibition of neutrophils' secretory function [19]. Finally, the increase in microperfusion secondary to PDE III inhibition [5] may exert particular benefit in the elderly because microcirculatory deficits are common after CPB and may induce organ dysfunction. Following initial promises, trials investigating the oral administration of Enoximone in the settings of heart failure did not show significantly improved clinical outcomes, even if oral Enoximone was found useful to wean from intravenous inotropic support a modest percentage of patients [20,21]. These findings were consistent with the positive inotropic, lusitropic, and vasodilatory effect shown by Enoximone [10,11] and could explain the benefit resulting from Enoximone administration in type 1 cardio-renal syndrome. Instead, in the context of type 3 reno-cardiac syndrome benefits deriving from the perioperative administration of Enoximone could be explained by its inflammatory-modulation effect. Given the independent correlation between Enoximone and ameliorated renal outcomes found in our analysis, it is reasonable to assume that both pathways (positive inotropism/lusitropism and inflammatory modulation) play a contemporary and synergic role after on-pump cardiac surgery, since findings are not influenced neither by CPB times nor by other inotropic agents administered. In addition, the inflammatory modulation exerted by Enoximone may be beneficial not only for vessels and circulation functions (thereby for target organ perfusion), but even in those cases where extracorporeal circulation and/or cardioplegia trigger transient myocardial oedema or ventricular dysfunction. 4.2. Modulation of the inflammatory response In the settings of heart failure, Enoximone improves cardiac output and lowers pulmonary pressures better than dobutamine does [22]; therefore, a growing interest raises towards the beneficial effects of Enoximone in the surgical settings. Endothelial cell activation commonly occurs during CPB [23], and the expression of endothelial cell
Please cite this article as: E. Angeloni, et al., Preliminary results of the Multicenter Observational Study with Enoximone in Cardiac surgery (MOSEC), Int J Cardiol (2018), https://doi.org/10.1016/j.ijcard.2018.07.071
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E. Angeloni et al. / International Journal of Cardiology xxx (2018) xxx–xxx
adhesion molecules is believed to play a key role in the inflammatory process in these patients undergoing on-pump cardiac surgery [24]. Expression of adhesion molecules is up-regulated during CPB and some of the soluble adhesion molecules measured in the circulating blood appear to be excellent markers of endothelial damage [25]. In different studies [26] plasma levels of all measured soluble adhesion molecules (e.g., sE-selectin; s-vascular cell adhesion molecule 1; s-intercellular adhesion molecule 1) were significantly more elevated in the untreated control than in the Enoximone-treated patients; leading to the evidence of reduced inflammatory response in patients receiving perioperative Enoximone infusion. In our study, no severe side effects were observed with the use of Enoximone at any time during the study period and the incidence of arrhythmias was similar between groups, despite previous study reported increased ectopics with the use of Enoximone [22]. 4.3. Limitations The resulting evidence of reduced postoperative incidence of RF in patients receiving Enoximone seems to be particularly robust because it was confirmed using two different discrete and continuous variables (eGFR and CKD-EPI class variation). Furthermore, even adjusting the analysis for covariates such as age, duration of CPB, baseline characteristics, and other inotropes usage, the correlation between Enoximone administration and lower postoperative renal impairment stay statistically significant. Of particular interest is the fact that in the present study Enoximone resulted as the only inotropic agent yielding to improved postoperative renal outcome, whereas only the administration of no inotropic drug was associated with the latter results. It has to be pointed out that dopamine, despite a positive trend, did not show better renal outcomes; maybe because its usage is widely extended to many patients just because of renal impairment. This means that the group of patients receiving dopamine includes cases of overt renal failure treated with dopamine and other agents, and this fact implies the different trend of eGFR observed in such cohort. On the other hand, inotropes such epinephrine, norepinephrine, and levosimendan showed a slight negative impact on renal outcome. This can be explained by the fact that patients receiving these drugs where obviously patients with a low cardiac output, which are at higher risk of organ dysfunction because of suboptimal perfusion. Contrariwise, patients receiving no inotropic drugs showed better postoperative renal function maybe as a result of the fact that patients not needing pharmacologic inotropic support have more steady, regular and straightforward course following surgery, which results in improved outcomes. Main limitation of the present report is represented by the lack of randomization and, to date, the small sample size. Forthcoming reports will include data from other Institutes participating this multicenter study, thus strengthening present results. In addition, being the present a prospective multicenter trial, we believe this gives additional strength to our investigation also in terms of avoiding the so called “Hawthorne effect”. 5. Conclusion Finally, as cardiac surgery is being offered to an increasing number of elderly patients, and our understanding of the CPB-related complications has improved in recent years, the development of therapies focused on reducing the inflammatory response and improving postoperative organ function plays a key role in determining surgical results. Organ function reserve is often reduced in cardiac surgery patients, and especially renal failure is a complication leading to poorer outcomes that can be prevented by the surgeon only avoiding long times of CPB. Because of this, protective pharmacological interventions are of crucial
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Please cite this article as: E. Angeloni, et al., Preliminary results of the Multicenter Observational Study with Enoximone in Cardiac surgery (MOSEC), Int J Cardiol (2018), https://doi.org/10.1016/j.ijcard.2018.07.071