Intraoperative hemoadsorption in patients with native mitral valve infective endocarditis

Journal Pre-proof Intraoperative hemoadsorption in patients with native mitral valve infective endocarditis Zaki Haidari, MD, Daniel Wendt, MD, PhD, Matthias Thielmann, MD, PhD, Malwina Mackowiak, M.Sc., Markus Neuhäuser, PhD, Heinz Jakob, MD, PhD, Arjang Ruhparwar, MD, PhD, Mohamed El-Gabry, MD PII:

S0003-4975(20)30188-0

DOI:

https://doi.org/10.1016/j.athoracsur.2019.12.067

Reference:

ATS 33468

To appear in:

The Annals of Thoracic Surgery

Received Date: 16 May 2019 Revised Date:

4 December 2019

Accepted Date: 26 December 2019

Please cite this article as: Haidari Z, Wendt D, Thielmann M, Mackowiak M, Neuhäuser M, Jakob H, Ruhparwar A, El-Gabry M, Intraoperative hemoadsorption in patients with native mitral valve infective endocarditis, The Annals of Thoracic Surgery (2020), doi: https://doi.org/10.1016/ j.athoracsur.2019.12.067. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 by The Society of Thoracic Surgeons

Intraoperative hemoadsorption in patients with native mitral valve infective endocarditis Running Head: Effect of Cytosorb on Postoperative Sepsis in Cardiac Surgery

Zaki Haidari MD1, Daniel Wendt MD, PhD1, Matthias Thielmann, MD, PhD1, Malwina Mackowiak, M.Sc.2, Markus Neuhäuser, PhD2, Heinz Jakob MD, PhD1, Arjang Ruhparwar MD, PhD1, Mohamed El-Gabry MD1

1

Department of Thoracic and Cardiovascular Surgery, West-German Heart and Vascular

Centre, University Hospital Essen, Essen, Germany 2

Department of Mathematics and Technique, Koblenz University of Applied Science,

RheinAhrCampus Remagen, Remagen, Germany

Presented at the 68th International Congress of the European Society of CardioVascular and Endovascular Surgery (ESCVS), Groningen, The Netherlands, 22-25 May, 2019 Keywords: infective endocarditis, mitral valve surgery, hemoadsorption, sepsis

Word count: 4495

Address for correspondence and reprints: Zaki Haidari, MD, Department of Thoracic and Cardiovascular Surgery, Hufelandstrasse 55, 45147 Essen, Germany. E-Mail: [email protected]

Abstract Background: Cardiac surgery in patients with infective endocarditis is associated with high mortality due to postoperative septic multiorgan failure. Hemoadsorption therapy may improve surgical outcomes by reducing the circulating cytokines. We aimed to evaluate the clinical effects of intraoperative hemoadsorption in patients with mitral valve endocarditis. Methods: Eligible candidates were patients with infective endocarditis of the native mitral valve undergoing cardiac surgery between January 2014 and July 2018. Patients with intraoperative hemoadsorption (hemoadsorption) were compared with surgery without hemoadsorption (control). The endpoints were the incidence of postoperative sepsis, sepsisassociated death and 30-day mortality. Furthermore, postoperative need for epinephrine and norepinephrine and systemic vascular resistance were evaluated. Results: 58 consecutive patients were included, 30 patients in the hemoadsorption group and 28 patients in the control group. Postoperative sepsis occurred in five patients in the hemoadsorption group and in 11 patients in the control group (p=0.05). No sepsis-associated death occurred in the hemoadsorption group, while five septic patients in the control group died (p=0.02). 30-day-mortality was 10% in the hemoadsorption group versus 18% in the control group, p=0.39. On ICU-admission, the cumulative need for epinephrine and norepinephrine was 0.15 versus 0.24 µg/kgBW/min, p=0.01 and the median systemic vascular resistance was 1413 versus 1010 dyn·s·cm-5, p=0.02 in the hemoadsorption versus control group, respectively. Conclusions: Intraoperative hemoadsorption might reduce the incidence of postoperative sepsis and sepsis-related death. Additionally, patients with intraoperative hemoadsorption showed

greater

hemodynamic

stability.

These

data

suggest

that

intraoperative

hemoadsorption may improve surgical outcome in patients with mitral valve endocarditis.

Word count: 248

An important cause of in-hospital mortality in patients undergoing cardiac surgery for infective endocarditis is postoperative multiorgan failure (1-4). Postoperative multiorgan failure in cardiac surgical patients is mostly a consequence of sepsis resulting from a severe systemic inflammatory reaction with the use of cardiopulmonary bypass (5-7). Although the pathophysiologic mechanisms of postoperative sepsis are not fully understood, the role of cytokines as messengers and the so-called ‘cytokine storm’ has been shown to play a key role (8). A possible way to reduce postoperative multiorgan failure is to reduce the proinflammatory circulating cytokines by blood purification. Up to now, several blood purification techniques have been described and evaluated. However, to date, the clinical outcomes of these techniques have been disappointing. A new form of blood purification called hemoadsorption is currently an emerging technology that has been showing promising results (9). This novel hemoadsorption device, Cytosorb (Cytosorbents®, Monmouth Junction, NJ, USA), is in clinical use and increasingly investigated. Beside the Jafron HA 330 device (Jafron Biomedical Co., Zhuhai City, China), Cytosorb is a CE approved cytokine adsorption device. The aim of this study was to evaluate the clinical effects of intraoperative hemoadsorption in patients with native mitral valve infective endocarditis undergoing cardiac surgery.

Patients and Methods Patients Eligible candidates for this retrospective and non-randomized study were patients with infective endocarditis of the native mitral valve undergoing surgical therapy between January 2014 and July 2018. The diagnosis was made according the modified Duke criteria (10). Exclusion criteria were infective endocarditis affecting valves other than the mitral valve, and previous mitral valve operation. The institutional ethics committee approved the study and written informed consent was collected from all patients before inclusion.

Operation techniques All patients underwent general anesthesia and orotracheal intubation. Preoperative transesophageal echocardiography was performed to evaluate cardiac and valvular function. Standard aortic and bicaval cannulation were applied. The decision to apply intraoperative hemoadsorption was made by the operating surgeon on clinical grounds on the day of surgery or intraoperatively at latest depending on the following criteria: (1) fever or (2) severely elevated inflammatory parameters (3) and/or hemodynamic instability requiring very high inotropic support. In patients selected for intraoperative hemoadsorption, a hemoadsorption device Cytosorb (Cytosorbents®, Monmouth Junction, NJ, USA) was installed in the cardiopulmonary bypass (CPB) machine using a side arm coming from the venous cannula and pumped back to the reservoir (Figure 1). Cardioplegic arrest was achieved by cold crystalloid Bretschneider cardioplegia (Custodiol, Dr. Franz Koehler Chemie, Bensheim, Germany). The operative strategy on the mitral valve consisted of eradication of all infected tissue and subsequent evaluation as to whether a valve repair was possible or valve replacement was needed. In patients with additional cardiac pathology, concomitant procedures were performed accordingly.

Hemoadsorption therapy Hemoadsorption therapy with CytoSorb (Cytosorbents®, Monmouth Junction, NJ, USA) is based on extracorporeal blood purification that effectively reduces excessive levels of inflammatory mediators with the aim to specifically modulate the overshooting immune response, mitigate the cytotoxic effects of elevated cytokine levels and increase the chances for recovery. The cartridge, which can safely and easily be integrated into various extracorporeal circuits, such as e.g. continuous renal replacement therapy, CPB and extracorporeal membrane oxygenation, is filled with highly biocompatible, porous polymer beads covered with a divinylbenzen coating. Each polymer bead is between 300 and 800 µm in size and has pores and channels, giving it a large (40,000 m2) effective surface area for binding hydrophobic small and middle molecules.

Postoperative care Postoperatively, all patients were transferred to a cardiac surgical intensive care unit (ICU). Postoperative care consisted of invasive hemodynamic monitoring and guideline directed antibiotic therapy. Standard invasive monitoring consisted of an arterial line for invasive blood pressure measurement, central venous line for the evaluation of central venous pressure and oxygen saturation and pulmonary artery catheter for cardiac output measurement by thermodilution. Furthermore, pulmonary and systemic vascular resistances were calculated from data derived from invasive monitoring (11). Additionally, routinely measured lactate levels were used for the evaluation of the metabolic state and course of sepsis. Catecholamine therapy (epinephrine and norepinephrine) was guided by several factors, including blood pressure, heart rhythm, preoperative cardiac function, systemic vascular resistance and metabolic parameters such as lactate measured by arterial blood gas analysis. Laboratory measurements included, among others, daily white blood counts (WBC) by fluorescent flow cytometry using the XN-1000 (Sysmex, Germany), C-reactive protein (CRP) concentration with the ADVIA Clinical Chemistry (Siemens, Germany) and procalcitonin (PCT) measurement using the chemiluminescent assay on the Advia Centaur BRAHMS PCT (Thermo Fisher Scientific, B·R·A·H·M·S GmbH, Germany), according to manufacturer’s instructions.

Endpoints The primary endpoints were the incidence of sepsis as defined by the third international consensus definitions for sepsis and septic shock (12) and sepsis-related death. The rationale behind this was that intraoperative hemoadsorption only focuses on the reduction of the occurrence of sepsis (13-14). In addition, sepsis is an important cause of increased mortality and morbidity for patients undergoing surgery for infective endocarditis (15). Secondary endpoints included all-cause mortality (30 days) and duration of ICU-stay. Additionally, the need for epinephrine and norepinephrine and systemic vascular resistance

(on ICU-arrival and postoperative day 1) as well as the postoperative course of inflammatory and metabolic parameters (PCT, CRP, WBC and lactate) were evaluated.

Statistical analysis Data was analyzed using SPSS software version 25 (SPSS Inc., Chicago, IL, USA). Continuous variables were expressed as mean and median with standard deviation (SD) and interquartile range (IQR), respectively, and compared using Student’s t-test or the MannWhitney test. Categorical data were expressed as number of patients and frequencies, and compared using the chi-square test. Univariate and multivariable logistic regression analyses were performed to identify preoperative independent risk factors for sepsis, sepsis-related death and 30-day mortality. Variables identified by the univariate analysis with a p value < 0.05 were added to the multivariable model.

Results Baseline characteristics Preoperative baseline characteristics of patients are outlined in Table 1. In total, 58 consecutive patients were included. 30 patients received intraoperative hemoadsorption and 28 patients without hemoadsorption therapy served as control group. Mean age at the time of operations was 60±14 and 64% of the patients were male. There were no statistically significant differences between the two groups in terms of baseline demographics. Nine patients were intubated and seven patients needed catecholamine therapy already before induction of anesthesia. Hemodynamic and pulmonary instability and the levels of preoperative inflammatory parameters did not differ between the two groups. Preoperative echocardiography showed preserved left ventricular function in 48 patients (83%) and 69% of the patients had severe mitral valve regurgitation. Concomitant aortic or tricuspid valve disease (other than infective endocarditis) requiring additional valve procedures was present in 24% of the patients. The most commonly identified causative pathogen was

staphylococcus species in 20 patients (35%) of which 15 patients had staphylococcus aureus.

Operative characteristics Median time between definitive diagnosis of mitral valve infective endocarditis and surgery was 12 (6-22) and 6 (1-20) days in the hemoadsorption and the control group, respectively (Table 2). Isolated mitral valve surgery was performed in 30 patients (51.7%). 35 patients (60.3%) underwent mitral valve repair and 23 patients (39.7%) received mitral valve replacement. Concomitant coronary artery bypass grafting and aortic and/or tricuspid valve surgery was necessary in 13 and 14 patients, respectively. A clear difference between the groups were the larger number of concomitant procedures and subsequent longer CPB and aortic cross clamp (ACC) times in the control group, however these differences did not reach statistical significance. No device-related adverse events occurred. Intraoperatively, the use of heparin and post-CPB administered protamine did not differ between both groups (p=1.00). None of the patients received postoperative hemoadsorption therapy.

Endpoints The endpoints are summarized in Table 3. The incidence of postoperative sepsis in the whole cohort was 16 (27.6%), of which 5 (16.7%) patients in the hemoadsorption and 11 patients (39.3%) in the control group (p=0.05). All septic patients who received intraoperative hemoadsorption

survived,

however

five

patients

(17.9%)

without

intraoperative

hemoadsorption died due to sepsis; p=0.02. All sepsis-related deaths were secondary to therapy refractory septic shock. Overall in-hospital mortality was 13.8%, 10% in patients with intraoperative hemoadsorption and 17.9% in patients without intraoperative hemoadsorption, p=0.39. Other causes of death included one brain herniation due to preoperative stroke, one pulmonary failure due to preoperative unknown pulmonary fibrosis and one unknown cause.

Postoperative hemodynamic stability was primarily achieved by the catecholamines epinephrine and norepinephrine. On ICU-admission, the median need for epinephrine and norepinephrine (Figure 2A) was 0.15 µg/kgBW/min (IQR 0.08-0.21) in the hemoadsorption group and 0.24 µg/kgBW/min (IQR 0.12-0.50) in the control group, p=0.01. On postoperative day 1, the median need for epinephrine and norepinephrine decreased to 0.00 µg/kgBW/min (IQR 0.00-0.06) in the hemoadsorption group and 0.05 µg/kgBW/min (IQR 0.00-0.31) in the control group, p=0.05. None of the patients have been treated by vasopressin. Furthermore, a systemic vascular resistance (Figure 2B) of 1413 dyn·s·cm-5 (1098-1682) in the hemoadsorption group versus 1010 dyn·s·cm-5 (IQR 786-1442) in the control group was observed on ICU-admission, p=0.02. On postoperative day 1, the systemic vascular resistance increased to 1421 dyn·s·cm-5 (800-1727) in the hemoadsorption group and the systemic vascular resistance in the control group decreased to 872 dyn·s·cm-5 (752-1113), p=0.05. No adverse side effects from hemoadsorption have been observed (e.g. postoperative acute liver failure).

Inflammatory parameters (Figure 3) increased postoperatively in both groups in a comparable fashion. Procalcitonin levels (Figure 3A) increased abruptly and peaked on the first postoperative day. C-reactive protein (Figure 3B) and white blood count (Figure 3C) increased more slowly and peaked on postoperative day 3 and 2, respectively. Although not significant, a faster recovery of all three inflammatory parameters was evident in patients with intraoperative hemoadsorption compared to patients without hemoadsorption therapy. Postoperative course of lactate (Figure 3D) levels showed no significant differences between the two groups. Furthermore, postoperative platelet count and the need for platelet transfusion did not differ between the two groups. The duration of ICU-stay was 5 days in both groups.

Regression analysis

In order to evaluate independent predictors for sepsis-related death, a logistic regression model was constructed. Several univariate indicators were found to predict for sepsis-related death as shown in Table 4. Hemoadsorption therapy showed a significant benefit in the univariate analysis (P=0.015). However, only the EuroSCORE-II remained significant (p=0.03) in the multivariate regression model in regard to sepsis-related death.

Comment This study is the first comparative analysis of intraoperative hemoadsorption versus controls in a homogeneous population of patients with infective endocarditis of the native mitral valve undergoing cardiac surgery with cardiopulmonary bypass. These data suggest that intraoperative hemoadsorption might reduce the incidence of postoperative sepsis and sepsis-related deaths in this population. This is further supported by the favorable hemodynamic stability and the faster recovery of the inflammatory parameters. Although a relevant difference in overall in-hospital mortality is found, however this did not reach statistical significance.

Postoperative sepsis in cardiac surgical patients is a known complication with an incidence of between 0.4% and 14.5%, with an increased risk of mortality compared to patients without postoperative sepsis (16-20). In patients with infective endocarditis, the risk of postoperative sepsis and sepsis-related death is significantly higher (21-23). In the treatment arsenal of patients with sepsis, several blood purification techniques have been investigated, but clinical results have been disappointing thus far (24). Currently, a novel hemoadsorption device, Cytosorb (Cytosorbents®, Monmouth Junction, NJ, USA), is in clinical use and increasingly investigated. Many of the key inflammatory mediators involved in sepsis, such as IL-1β, IL-6, IL-8, TNF-α, IL-10, pathogen- and damage-associated molecular patterns and bacterial endotoxins are irreversibly removed in an concentration dependent fashion (14).

Recent clinical research has focused on the use of the hemoadsorption therapy in cardiac surgery. A case series of 16 patients undergoing cardiopulmonary bypass with hemoadsorption and renal replacement therapy demonstrated decreased serum levels of circulating cytokines, improved organ function and improved hemodynamic stability (25). A randomized controlled trial showed a significant reduction of serum cytokines and improved cardiac index. However, these differences were minor and of short duration (26). Moreover, one should visualize oneself, that also dialysis (pre- and postoperatively) might remove additional inflammatory mediators. Recently, Poli et. al performed a randomized pilot study including elective cardiac surgical patients who were deemed at high risk due to expected long cardiopulmonary bypass time. In this small study, there were no differences found in cytokine levels, coagulation factors and clinical outcome in terms of in-hospital mortality, hemodynamic stability, duration of mechanical ventilation, acute kidney injury and ICU- and hospital stay (27). In another randomized controlled clinical trial in 37 patients with postcardiopulmonary bypass systemic inflammatory response syndrome, there were no significant differences in cytokine removal, vasopressor dependence or 30-day mortality with hemoadsorption therapy (28). Altogether, hemoadsorption therapy so far has shown variable and non-equivocal results in cardiac surgical patients with cardiopulmonary bypass with no benefit on survival. However, the studies are limited in number and sample size, and were focused on patients with a low to medium risk profile and consequently low inflammatory responses. Furthermore, the focus was mostly on cytokine levels and less on clinically relevant outcome measures. It is known that cytokine levels in patients with infective endocarditis are much higher than in the previously published studies (29) and cytokine removal with Cytosorb is concentration-dependent. It is therefore plausible to expect better results from hemoadsorption therapy in patients with infective endocarditis undergoing cardiac surgery with CPB.

Clinical research of hemoadsorption in patients with infective endocarditis undergoing cardiac surgery is currently limited to one retrospective study of 39 patients (30).

Intraoperative hemoadsorption showed a reduction in serum cytokines and lactate levels and improvement in hemodynamic stability. In the current study, a better hemodynamic stability in patients treated with hemoadsorption was also observed. Furthermore, the postoperative course of inflammatory parameters in our hemoadsorption group showed a faster trend towards recovery. The current findings are consistent with the previous study. However, other factors such as study population and operative characteristics could also explain the results. In the current study, only patients with native mitral valve infective endocarditis were included as we aimed to evaluate only one entity to avoid further bias. It is well known that surgical outcome in patients with infective endocarditis of more than one valve or prosthetic valve is worse compared to single or native valve infective endocarditis (31). Furthermore, the longer cardiopulmonary bypass and aortic cross-clamp times in the control group could also have played a role in favorable outcome in hemoadsorption group. However, CPB- and ACC-times showed no statistical significant differences.

In this study, the focus was on clinical effects of intraoperative hemoadsorption in patients with acute native mitral valve endocarditis undergoing surgery. Although this study is not a randomized clinical trial, the two groups of patients were comparable. Nevertheless, bias cannot be completely excluded. Despite the low incidence of the disease, as a referral center we have still a relatively large number of patients included. However, the sample size is still too small to draw definitive conclusions, which is also based on the fact, that the results of the present “pilot” study are preliminary. Due to clear selection of the study population, conclusions for patients with infective endocarditis other than the native mitral valve is not possible. Moreover, the timing (pre-, intra- and postoperative) and the length of hemoadsorption therapy might have an impact on outcome. However, no data on the timing and length of hemoadsorption therapy is available so far. In the univariate analysis, hemoadsorption therapy showed a significant benefit in sepsis-related survival, which was not the case in the multivariate analysis. It should be kept in mind however, that the independent variables for multivariate regression analyses have been arbitrarily chosen and

the confounding effects may vary by modifying the parameters. Yet, clinical outcomes in such a high-risk group of patients were multifactorial. Nevertheless, we strongly believe the ease of use of hemoadsorption therapy coming with no adverse side effects might be beneficial for such patients. Currently, the results of a large randomized controlled trial in patients with infective endocarditis undergoing cardiac surgery (REMOVE-Trial) with and without intraoperative hemoadsorption are expected to be published. We are looking forward to larger and randomized clinical trials with hard endpoints for further evaluation of intraoperative hemoadsorption in patients with infective endocarditis.

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8. Uhle, F, Chousterman, BG, Grützmann, R. Pathogenic, immunologic, and clinical aspects of sepsis – update 2016. Rev Anti Infect Ther 2016; 14: 917–927. 9. Honoré PM, De Bels D, Spapen HD et al. An update on membranes and cartridges for extracorporeal blood purification in sepsis and septic shock. Curr Opin Crit Care 2018; 24: 463-468. 10. Li JS, Sexton DJ, Mick N et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis 2000;30:633–638. 11. Connors AF, Speroff T, Dawson NV et al. The effectiveness of right heart catheterization in the initial care of critically ill patients. SUPPORT Investigators. JAMA. 1996; 276: 889-897. 12. Singer M, Deutschman CS, Seymour CW et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 2016; 315: 801–810. 13. Kogelmann K, Jarczak D, Scheller M. Hemoadsorption by CytoSorb in septic patients: a case series. Crit Care 2017; 21: 74-84. 14. Gruda MC, Ruggeberg KG, O'Sullivan P. Broad adsorption of sepsis related PAMP and DAMP molecules, mycotoxins, and cytokines from whole blood using CytoSorb® sorbent porous polymer beads. PLoS One 2018; 13: e0191676. 15. Howitt SH, Herring M, Malagon I, McCollum CN, Grant SW. Incidence and outcomes of sepsis after cardiac surgery as defined by the Sepsis-3 guidelines. Br J Anaesth 2018; 120: 509-516. 16. Oliveira DC, Oliveira Filho JB, Silva RF, et al. Sepsis in the postoperative period of cardiac surgery: problem description. Arq Bras Cardiol 2010; 94: 332e6 17. Michalopoulos A, Stavridis G, Geroulanos S. Severe sepsis in cardiac surgical patients. Eur J Surg 1998; 164: 217e22 18. Fowler VG, O’Brien SM, Muhlbaier LH, Corey GR, Ferguson TB, Peterson ED. Clinical predictors of major infections after cardiac surgery. Circulation 2005; 112. I358eI-365

19. Howitt SH, Herring M, Malagon I, McCollum CN, Grant SW. Incidence and outcomes of sepsis after cardiac surgery as defined by the Sepsis-3 guidelines. Br J Anaesth 2018; 120: 509-516. 20. Kreuzer E, Kääb S, Pilz G, Werdan K. Early prediction of septic complications after cardiac surgery by APACHE II score. Eur J Cardiothorac Surg 1992; 6: 524-528. 21. Jenny Lourdes Rivas de Oliveira, Magaly Arrais dos Santos, Renato Tambellini Arnoni, Auristela Ramos, Dorival Della Togna, Samira Kaissar Ghorayeb, Roberto Tadeu Magro Kroll, Luiz Carlos Bento de Souza. Mortality Predictors in the Surgical Treatment of Active Infective Endocarditis. Braz J Cardiovasc Surg 2018; 33: 32–39. 22. Machado MN, Nakazone MA, Murad-Júnior JA, Maia LN. Surgical treatment for infective endocarditis and hospital mortality in a Brazilian single-center. Rev Bras Cir Cardiovasc 2013; 28: 29–35. 23. Gatti G, Benussi B, Gripshi F, Della Mattia A, Proclemer A, Cannatà A, et al. A risk factor analysis for in-hospital mortality after surgery for infective endocarditis and a proposal of a new predictive scoring system. Infection 2017; 45: 413–423. 24. Bonavia A, Groff A, Karamchandani K. Clinical Utility of Extracorporeal Cytokine Hemoadsorption Therapy: A Literature Review. Blood Purif 2018; 46: 337–349. 25. Trager K, Fritzler D, Fischer G. Treatment of post-cardiopulmonary bypass SIRS by hemoadsorption: a case series. Int J Artif Organs 2016; 39: 141–146. 26. Garau I, März A, Sehner S et al. Hemadsorption during cardiopulmonary bypass reduces interleukin 8 and tumor necrosis factor α serum levels in cardiac surgery: a randomized controlled trial. Minerva Anestesiol 2018 [Epub ahead of print] 27. Poli EC, Alberio L, Bauer-Doerries A et al. Cytokine clearance with CytoSorb® during cardiac surgery: a pilot randomized controlled trial. Crit Care 2019; 23: 108-119. 28. Bernardi

MH,

Rinoesl

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Dragosits

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cardiopulmonary bypass surgery - a blinded, randomized, controlled pilot study using a novel adsorbent. Crit Care 2016; 20: 96-109.

29. Araújo IR, Ferrari TC, Teixeira-Carvalho A et al. Cytokine Signature in Infective Endocarditis. PLoS One 2015; 10: e0133631 30. Trager K, Skrabal C, Fischer G et al. Hemoadsorption treatment of patients with acute infective endocarditis during surgery with cardiopulmonary bypass – a case series. Int J Artif Organs 2017; 40: 240–249. 31. Della Corte A, Di Mauro M, Actis Dato G et al. Surgery for prosthetic valve endocarditis: a retrospective study of a national registry. Eur J Cardiothorac Surg 2017; 52: 105-111.

Figure legends Figure 1. Hemoadsorption in cardiopulmonary bypass circuit.

Figure 2. Cumulative need of epinephrine and norepinephrine in µg/kgBW/min (A) and systemic vascular resistance in dyn·s·cm-5 (B). ICU: intensive care unit.

Figure 3. Levels of procalcitonin in ng/ml (A), C-reactive protein in mg/dl (B), white blood count x1000/ml (C) and lactate in mmol/l (D). POD: postoperative day.

Table 1 Baseline characteristics Hemoadsorption

Control

N=30

N=28

p

Age, years

59±14

61±14

0.49

BMI, kg/m2

25±5

25±7

0.78

21 (70.0)

16 (57.1)

0.31

Drug abuse

2 (6.7)

1 (3.6)

0.60

Coronary artery disease

9 (30.0)

9 (32.1)

0.86

Pulmonary disease

2 (6.7)

2 (7.1)

0.94

Dialysis

1 (3.3)

2 (7.1)

0.51

Liver disease

2 (6.7)

1 (3.6)

0.60

Peripheral vascular disease

5 (16.7)

4 (14.3)

0.80

Demographics

Gender, male

Previous CABG

-

2 (7.1)

0.14

1 (3.3)

1 (3.6)

0.96

-

2 (7.1)

0.14

3 (2-8)

3 (2-8)

0.12

NYHA III-IV

15 (50.0)

16 (57.1)

0.59

Intubated

5 (16.7)

4 (14.3)

0.80

Catecholamine need

3 (10.0)

4 (14.3)

0.62

C-reactive protein, mg/dL

7.10 (2.45-12.23)

4.70 (1.08-9.23)

0.29

Procalcitonin, ng/ml

0.21 (0.05-0.41)

0.19 (0.10-0.85)

0.85

White blood count, 109/L

7.47 (6.02-13.09)

8.85 (7.09-11.52)

0.29

LVEF >50%

24 (80.0)

24 (85.7)

0.57

Severe MR

19 (63.3)

21 (75.0)

0.34

Concomitant AV/TV disease*

5 (16.7)

9 (32.1)

0.17

Previous PCI Previous AV/TV operation EuroSCORE II Clinical status

Inflammatory parameters

Echocardiographic parameters

Data are presented as mean±SD, median (IQR) or number (%); BMI, body mass index; CABG, coronary artery bypass grafting; PCI, percutaneous coronary intervention; AV, aortic valve; TV, tricuspid valve; EuroSCORE, European System for Cardiac Operative Risk Evaluation; NYHA, New York Heart Association; LVEF, left ventricular ejection fraction; MR, mitral regurgitation. *no infective endocarditis

Table 2 Operative characteristics Hemoadsorption

Control

N=30

N=28

p

Time between diagnosis and surgery, days

12 (6-22)

6 (1-20)

0.11

Isolated mitral valve surgery

18 (60.0)

12 (42.9)

0.19

Concomitant CABG

6 (20.0)

7 (25.0)

0.65

Concomitant AV/TV procedure

5 (16.7)

9 (32.1)

0.17

Cardiopulmonary bypass time, minutes

85 (74-106)

116 (79-149)

0.12

Aortic cross-clamp time, minutes

59 (45-78)

74 (49-106)

0.07

Data are presented as median (IQR) or number (%); CABG, coronary artery bypass grafting; AV, aortic valve; TV, tricuspid valve

Table 3 Postoperative outcomes Hemoadsorption

Control

N=30

N=28

p

5 (16.7)

11 (39.3)

0.05

-

5 (17.9)

0.02

3 (10.0)

5 (17.9)

0.39

178 (141-235)

181 (129-223)

0.99

0 (0)

1 (3.6)

0.48

Postoperative dialysis

20 (66.7)

14 (50.0)

0.20

Time on ventilator >24h

8 (26.6)

7 (25.0)

0.52

Primary Sepsis Sepsis-associated mortality Secondary 30-day mortality (all cause) Platelets count postoperative Postoperative IABP

Mediastinitis, n

1 (3.3)

1 (3.6)

1.00

APACHE II score

25.2±4.8

26.0±5.1

0.55

ICU-stay, days

5 (2-10)

5 (2-11)

0.77

15±8

18±10

0.33

Hospital stay, days

Data are presented as median (IQR), mean±SD or number (%); IABP, intraaortic balloonpump, ICU, intensive care unit.

Table 4 Regression analysis for dependent variables for sepsis-related death Univariate analysis

Multivariate analysis

CE (SE)

p

CE (SE)

p

Hemoadsorption therapy

-0.18 (0.07)

0.02

0.02 (0.15)

0.88

Dialysis

0.61 (0.15)

<0.01

-0.21 (0.30)

0.50

EuroSCORE II

0.01 (0.00)

<0.01

0.01 (0.01)

0.03

STS-Score

0.02 (0.00)

<0.01

-0.01 (0.01)

0.22

Redo surgery

-0.01 (0.52)

0.99

—

—

Preoperative leucocytes

0.02 (0.007)

<0.01

0.02 (0.02)

0.13

Preoperative PCT

0.15 (0.032)

<0.01

0.09 (0.08)

0.26

Data are presented as coefficient estimate (CE) with standard error (SE); STS, Society of Thoracic Surgeons, PCT, Procalcitonin.