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1.  SodiUm SeleniTe Adminstration IN Cardiac Surgery (SUSTAIN CSX-trial): study design of an international multicenter randomized double-blinded controlled trial of high dose sodium-selenite administration in high-risk cardiac surgical patients 
Trials  2014;15(1):339.
Cardiac surgery has been shown to result in a significant decrease of the antioxidant selenium, which is associated with the development of multiorgan dysfunction and increased mortality. Thus, a large-scale study is needed to investigate the effect of perioperative selenium supplementation on the occurrence of postoperative organ dysfunction.
We plan a prospective, randomized double-blind, multicenter controlled trial, which will be conducted in North and South America and in Europe. In this trial we will include 1,400 high-risk patients, who are most likely to benefit from selenium supplementation. This includes patients scheduled for non-emergent combined and/or complex procedures, or with a predicted operative mortality of ≥5% according to the EuroSCORE II. Eligible patients will be randomly assigned to either the treatment group (bolus infusion of 2,000 μg sodium selenite immediately prior to surgery, followed by an additional dosage of 2,000 μg at ICU admission, and a further daily supplementation of 1,000 μg up to 10 days or ICU discharge) or to the control group (placebo administration at the same time points).
The primary endpoint of this study is a composite of 'persistent organ dysfunction’ (POD) and/or death within 30 days from surgery (POD + death). POD is defined as any need for life-sustaining therapies (mechanical ventilation, vasopressor therapy, mechanical circulatory support, continuous renal replacement therapy, or new intermittent hemodialysis) at any time within 30 days from surgery.
The SUSTAIN-CSX™ study is a multicenter trial to investigate the effect of a perioperative high dosage sodium selenite supplementation in high-risk cardiac surgical patients.
Trial registration
This trial was registered at (identifier: NCT02002247) on 28 November 2013.
Electronic supplementary material
The online version of this article (doi:10.1186/1745-6215-15-339) contains supplementary material, which is available to authorized users.
PMCID: PMC4247649  PMID: 25169040
Selenium; Inflammatory response; Oxidative stress; Antioxidant capacity; Myocardial ischemia/reperfusion; Postoperative organ failure
2.  The Importance of Intraoperative Selenium Blood Levels on Organ Dysfunction in Patients Undergoing Off-Pump Cardiac Surgery: A Randomised Controlled Trial 
PLoS ONE  2014;9(8):e104222.
Cardiac surgery is accompanied by an increase of oxidative stress, a significantly reduced antioxidant (AOX) capacity, postoperative inflammation, all of which may promote the development of organ dysfunction and an increase in mortality. Selenium is an essential co-factor of various antioxidant enzymes. We hypothesized a less pronounced decrease of circulating selenium levels in patients undergoing off-pump coronary artery bypass (OPCAB) surgery due to less intraoperative oxidative stress.
In this prospective randomised, interventional trial, 40 patients scheduled for elective coronary artery bypass grafting were randomly assigned to undergo either on-pump or OPCAB-surgery, if both techniques were feasible for the single patient. Clinical data, myocardial damage assessed by myocard specific creatine kinase isoenzyme (CK-MB), circulating whole blood levels of selenium, oxidative stress assessed by asymmetric dimethylarginine (ADMA) levels, antioxidant capacity determined by glutathionperoxidase (GPx) levels and perioperative inflammation represented by interleukin-6 (IL-6) levels were measured at predefined perioperative time points.
At end of surgery, both groups showed a comparable decrease of circulating selenium concentrations. Likewise, levels of oxidative stress and IL-6 were comparable in both groups. Selenium levels correlated with antioxidant capacity (GPx: r = 0.720; p<0.001) and showed a negative correlation to myocardial damage (CK-MB: r = −0.571, p<0.001). Low postoperative selenium levels had a high predictive value for the occurrence of any postoperative complication.
OPCAB surgery is not associated with less oxidative stress and a better preservation of the circulating selenium pool than on-pump surgery. Low postoperative selenium levels are predictive for the development of complications.
Trial registration NCT01409057
PMCID: PMC4132095  PMID: 25118980
3.  What Is the Significance of Perioperative Release of Macrophage Migration Inhibitory Factor in Cardiac Surgery? 
Antioxidants & Redox Signaling  2013;19(3):231-239.
Cardiac surgery is associated with release of the pleiotropic cytokine macrophage migration inhibitory factor (MIF). The trigger for MIF release has not yet been elucidated. Owing to its intrinsic antioxidative activity, MIF might reduce oxidative stress and protect from myocardial ischemia and reperfusion (I/R) injury. In the present study, patients scheduled for elective cardiac surgery (n=46) were randomized to undergo coronary artery bypass grafting either conventionally with cardiopulmonary bypass and cardioplegic arrest-induced I/R (cCABG) or in an off-pump procedure (OPCAB) with minimized I/R. We report that only patients who underwent cCABG exhibited a postoperative increase of MIF (p=0.024), while both groups showed an increase in interleukin-6. MIF release appears to be primarily mediated by I/R and to a lesser extent by inflammation. Endogenous peroxidase activity (p=0.021) and serum levels of thioredoxin (p=0.003) were significantly higher in patients who underwent cCABG after surgery. Interestingly, perioperative MIF release was associated with an enhanced antioxidant capacity and a significantly reduced postoperative incidence of atrial fibrillation (p=0.018) and acute kidney injury (p=0.048). The present study highlights the role of MIF increase during cardiac surgery in response to oxidative stress. Based on current observations, we hypothesize that intraoperative MIF secretion is due to I/R and enhances the antioxidant capacity in patients during cardiac surgery. Antioxid. Redox Signal. 19, 231–239.
PMCID: PMC3691912  PMID: 23157710
4.  Oxygenated shunting from right to left: a feasibility study of minimized atrio-atrial extracorporeal membrane oxygenation for mid-term lung assistance in an acute ovine model†‡ 
Right ventricular failure is often the final phase in acute and chronic respiratory failure. We combined right ventricular unloading with extracorporeal oxygenation in a new atrio-atrial extracorporeal membrane oxygenation (ECMO).
Eleven sheep (65 kg) were cannulated by a 28-Fr inflow cannula to the right atrium and a 25-Fr outflow cannula through the lateral left atrial wall. Both were connected by a serial combination of a microaxial pump (Impella Elect®, Abiomed Europe, Aachen, Germany) and a membrane oxygenator (Novalung®—iLA membrane oxygenator; Novalung GmbH, Hechingen, Germany). In four animals, three subsequent states were evaluated: normal circulation, apneic hypoxia and increased right atrial after load by pulmonary banding. We focused on haemodynamic stability and gas exchange.
All animals reached the end of the study protocol. In the apnoea phase, the decrease in PaO2 (21.4 ± 3.6 mmHg) immediately recovered (179.1 ± 134.8 mmHg) on-device in continuous apnoea. Right heart failure by excessive after load decreased mean arterial pressure (59 ± 29 mmHg) and increased central venous pressure and systolic right ventricular pressure; PaO2 and SvO2 decreased significantly. On assist, mean arterial pressure (103 ± 29 mmHg), central venous pressure and right ventricular pressure normalized. The SvO2 increased to 89 ± 3% and PaO2 stabilized (129 ± 21 mmHg).
We demonstrated the efficacy of a miniaturized atrio-atrial ECMO. Right ventricular unloading was achieved, and gas exchange was well taken over by the Novalung. This allows an effective short- to mid-term treatment of cardiopulmonary failure, successfully combining right ventricular and respiratory bridging. The parallel bypass of the right ventricle and lung circulation permits full unloading of both systems as well as gradual weaning. Further pathologies (e.g. ischaemic right heart failure and acute lung injury) will have to be evaluated.
PMCID: PMC3686368  PMID: 23543405
Respiratory insufficiency; Right ventricular dysfunction; Membrane oxygenators; Heart-assist devices
5.  Interatrial conduction disturbance in postoperative atrial fibrillation: a comparative study of P-wave dispersion and Doppler myocardial imaging in cardiac surgery 
Disturbances of interatrial conduction have been proposed as one of the contributing mechanisms of postoperative atrial fibrillation (AF). P-wave dispersion has been recognized as a sensitive tool for detecting interatrial conduction disturbances. Doppler myocardial imaging (DMI) has been validated as a non-invasive tool to indirectly reflect electrical atrial activation and therefore is used in this study to detect possible interatrial electromechanical disturbances after cardiac surgery.
30 patients (23 men, age 62 ± 1 years) admitted for coronary bypass surgery with no prior history of AF were included in this investigation. Echocardiography and electrocardiograms (ECG) were obtained on the day before and after surgery. In addition to standard echocardiography, DMI-loops were acquired from the apical window. The following time intervals were derived off-line from the free right atrial (RA), left atrial (LA) lateral and LA posterior wall: onset P-wave to start (P to A’start), to peak (P to A’peak) and to end of atrial deformation (total electromechanical activity). These intervals were compared to each other and to P-wave dispersion derived from the recorded ECGs.
All patients were in sinus rhythm during their postoperative assessment, but 11 patients presented episodes of AF within the first three postoperative days. Atrial electromechanical activation was earliest in the RA and latest in the lateral LA. In patients with AF, P-wave dispersion was significantly prolonged postoperatively (mean: +18.6 ms; 95% confidence interval (CI): 12.1–25.2 ms; p < 0.001) compared to non-AF patients (mean: -2.4 ms; CI: -6.6–1.9 ms). P dispersion was closely correlated to P to A’start intervals (from RA to LA lat.: preop.: rho = 0.74, postop.: rho = 0.87; p < 0.001). Prolonged right to left conduction interval was associated with an elevated risk for AF (from RA to LA lat.: odds ratio 1.13 (CI:1.03-1.24); p: 0.007.
DMI enabled detection of interatrial conduction disturbances in concordance to findings of prolonged postoperative P-wave dispersion. Equally effective to P-wave dispersion, this simple and reproducible tool might help to early identify the risk for postoperative AF, thus extending the informative value of routine postoperative echocardiography.
PMCID: PMC4082174  PMID: 24957051
Electrophysiology; Echocardiography; Atrial fibrillation; CABG
6.  The Role of Macrophage Migration Inhibitory Factor in Anesthetic-Induced Myocardial Preconditioning 
PLoS ONE  2014;9(3):e92827.
Anesthetic-induced preconditioning (AIP) is known to elicit cardioprotective effects that are mediated at least in part by activation of the kinases AMPK and PKCε as well as by inhibition of JNK. Recent data demonstrated that the pleiotropic cytokine macrophage migration inhibitory factor (MIF) provides cardioprotection through activation and/or inhibition of kinases that are also known to mediate effects of AIP. Therefore, we hypothesized that MIF could play a key role in the AIP response.
Cardiomyocytes were isolated from rats and subjected to isoflurane preconditioning (4 h; 1.5 vol. %). Subsequently, MIF secretion and alterations in the activation levels of protective kinases were compared to a control group that was exposed to ambient air conditions. MIF secretion was quantified by ELISA and AIP-induced activation of protein kinases was assessed by Western blotting of cardiomyocyte lysates after isoflurane treatment.
In cardiomyocytes, preconditioning with isoflurane resulted in a significantly elevated secretion of MIF that followed a biphasic behavior (30 min vs. baseline: p = 0.020; 24 h vs. baseline p = 0.000). Moreover, quantitative polymerase chain reaction demonstrated a significant increase in MIF mRNA expression 8 h after AIP. Of note, activation of AMPK and PKCε coincided with the observed peaks in MIF secretion and differed significantly from baseline.
These results suggest that the pleiotropic mediator MIF is involved in anesthetic-induced preconditioning of cardiomyocytes through stimulation of the protective kinases AMPK and PKCε.
PMCID: PMC3965449  PMID: 24667295
7.  Recovery of Diaphragm Function following Mechanical Ventilation in a Rodent Model 
PLoS ONE  2014;9(1):e87460.
Mechanical ventilation (MV) induces diaphragmatic muscle fiber atrophy and contractile dysfunction (ventilator induced diaphragmatic dysfunction, VIDD). It is unknown how rapidly diaphragm muscle recovers from VIDD once spontaneous breathing is restored. We hypothesized that following extubation, the return to voluntary breathing would restore diaphragm muscle fiber size and contractile function using an established rodent model.
Following 12 hours of MV, animals were either euthanized or, after full wake up, extubated and returned to voluntary breathing for 12 hours or 24 hours. Acutely euthanized animals served as controls (each n = 8/group). Diaphragmatic contractility, fiber size, protease activation, and biomarkers of oxidative damage in the diaphragm were assessed.
12 hours of MV induced VIDD. Compared to controls diaphragm contractility remained significantly depressed at 12 h after extubation but rebounded at 24 h to near control levels. Diaphragmatic levels of oxidized proteins were significantly elevated after MV (p = 0.002) and normalized at 24 hours after extubation.
These findings indicate that diaphragm recovery from VIDD, as indexed by fiber size and contractile properties, returns to near control levels within 24 hours after returning to spontaneous breathing. Besides the down-regulation of proteolytic pathways and oxidative stress at 24 hours after extubation further repairing mechanisms have to be determined.
PMCID: PMC3903648  PMID: 24475293
8.  Accuracy of the Masimo Pronto-7® system in patients with left ventricular assist device 
The Masimo Pronto-7® calculates hemoglobin (Hb) values using the pulsoximetry technique and a variety of mathematical algorithms analyzing the pulse waveform. Although this system has demonstrated a high level of accuracy in average patients, the performance might be altered in special patient populations. Regarding patients with left ventricular cardiac failure, a rotary blood pump generates a constant, continuous, non-pulsatile flow to improve effective cardiac output. Due to this alteration in both, blood flow and arterial blood pressure we hypothesized a reduced accuracy of the Masimo Pronto-7® to detect Hb in patients with left ventricular cardiac failure. To test our hypothesis, we evaluated the Pronto-7®SpHb system in outpatients after continuous-flow-left ventricular assist device (cf-LVAD) implantation (HeartMate II, Thoratec).
21 cf-LVAD outpatients from the Clinic for Cardiac, Thoracic and Vascular Surgery were investigated during routine follow up examinations. After venous blood samples were drawn, the Pronto-7® sensor was attached to one randomly selected finger of one hand. The collected SpHb data were compared with Hb values measured by our central laboratory. The difference between the methods was determined using Bland – Altman analysis. The study was registered in the DRKS (DRKS00004415).
In all cf-LVAD patients evaluated, the Pronto-7® successfully detected SpHb values. Using Bland – Altman analysis, a bias of 0.14 g/dl (95% upper and lower limits of agreement ± 2.76 g/dl) was calculated.
The Pronto-7® overestimated the actual Hb value in cf-LVAD outpatients with the HeartMate II. Due to this, we conclude that the system is suitable for screening in routine examinations and further analysis can be performed if needed. However, its use as an emergency tool is questionable because of the increased inaccuracy when Hb values are critically low.
PMCID: PMC3776432  PMID: 23800231
Perioperative care; Circulatory assist devices; Blood transfusion; Emergency; Patient safety
9.  EuroScore 2 for identification of patients for transapical aortic valve replacement - a single center retrospective in 206 patients 
Operative risk scoring algorithms identify patients with severe AS for transcatheter valve implantation in whom the anticipated operative mortality for conventional surgery would be considered prohibitive. We compared the three risk scores EuroScore 1 (LES), society of thoracic surgeons’ (STS) score and ACEF (age-creatinine-ejection fraction score) to the readjusted EuroScore 2 recently presented.
We reviewed all consecutive patients receiving either isolated conventional aortic valve replacement (cAVR) or transapical aortic valve implantation (TA-TAVI) in a two-year period (n = 206). 30-days mortality was considered as primary endpoint.
TA-TAVI was performed in 76 patients, isolated cAVR in 130 patients. Overall mortality was 4.4% (TA-TAVI: 7.9%; cAVR: 2.3%). EuroScore 2 showed a good estimation for the entire population as well as within the subgroups: 4,02 ± 5,36% (TA-TAVI: 6.16 ± 7.14%, cAVR: 2.77 ± 3.42%). Predicted mortalities as assessed by LES were largely overestimated (TA-TAVI: 27.4 ± 20.9% cAVR: 10.6 ± 10.6%, sensitivity: 0.89, specificity: 0.71). STS predicted mortality was 6.3 ± 4.4% for TA-TAVI patients as to 3.2 ± 3.1% for cAVR patients (sens.: 0.22, spec.: 0.96) and ACEF predicted a mortality of 1.16 ± 0.36% for cAVR and 1.58 ± 0.59% for TA-TAVI patients (sens.: 0.78, spec.: 0.89).
The newly refined EuroScore 2 showed a good correlation within the studied population. For the individual patient, new cut-offs will have to be defined to triage patients for TAVI procedure. A drawback for complex score systems such as EuroScore and STS is the lack of recalibration to smaller populations as encountered in even large single centers.
PMCID: PMC3485095  PMID: 22998666
Risk models; Transapical valve replacement; Valve disease
10.  Prevention of sternal dehiscence with the Sternum External Fixation (Stern-E-Fix) corset – a randomized trial in 750 patients 
The main objective of this study will be to determine the effects of a new advanced sternum external fixation (Stern-E-Fix) corset on prevention of sternal instability and mediastinitis in high-risk patients.
This prospective, randomized study (January 2009 – June 2011) comprised 750 male patients undergoing standard median sternotomy for cardiac procedures (78% CABG). Patients were divided in two randomized groups (A, n = 380: received a Stern-E-Fix corset postoperatively for 6 weeks and B, n = 370: control group received a standard elastic thorax bandage). In both groups, risk factors for sternal dehiscence and preoperative preparations were similar.
Wound infections occurred in n = 13 (3.42%) pts. in group A vs. n = 35 (9.46%) in group B. In group A, only 1 patient presented with sternal dehiscence vs. 22 pts. in group B. In all 22 patients, sternal rewiring followed by antibiotic therapy was needed. Mediastinitis related mortality was none in A versus two in B. Treatment failure in group B was more than five times higher than in A (p = 0.01); the mean length of stay in hospital was 12.5 ± 7.4 days (A) versus 18 ± 15.1 days (B) (p=0.002). Re-operation for sternal infection was 4 times higher in group B. Mean ventilation time was relatively longer in B (2.5 vs. 1.28 days) (p = 0.01). The mean follow-up period was 8 weeks (range 6 – 12 weeks).
We demonstrated that using an external supportive sternal corset (Stern-E-Fix) yields a significantly better and effective prevention against development of sternal dehiscence and secondary sternal infection in high-risk poststernotomy patients.
PMCID: PMC3579734  PMID: 22958313
Cardiac surgery; Sternal dehiscence; Mediastinitis; Sternum external fixation corset (Stern-E-Fix)
11.  The effects of levosimendan on brain metabolism during initial recovery from global transient ischaemia/hypoxia 
BMC Neurology  2012;12:81.
Neuroprotective strategies after cardiopulmonary resuscitation are currently the focus of experimental and clinical research. Levosimendan has been proposed as a promising drug candidate because of its cardioprotective properties, improved haemodynamic effects in vivo and reduced traumatic brain injury in vitro. The effects of levosimendan on brain metabolism during and after ischaemia/hypoxia are unknown.
Transient cerebral ischaemia/hypoxia was induced in 30 male Wistar rats by bilateral common carotid artery clamping for 15 min and concomitant ventilation with 6% O2 during general anaesthesia with urethane. After 10 min of global ischaemia/hypoxia, the rats were treated with an i.v. bolus of 24 μg kg-1 levosimendan followed by a continuous infusion of 0.2 μg kg-1 min-1. The changes in the energy-related metabolites lactate, the lactate/pyruvate ratio, glucose and glutamate were monitored by microdialysis. In addition, the effects on global haemodynamics, cerebral perfusion and autoregulation, oedema and expression of proinflammatory genes in the neocortex were assessed.
Levosimendan reduced blood pressure during initial reperfusion (72 ± 14 vs. 109 ± 2 mmHg, p = 0.03) and delayed flow maximum by 5 minutes (p = 0.002). Whereas no effects on time course of lactate, glucose, pyruvate and glutamate concentrations in the dialysate could be observed, the lactate/pyruvate ratio during initial reperfusion (144 ± 31 vs. 77 ± 8, p = 0.017) and the glutamate release during 90 minutes of reperfusion (75 ± 19 vs. 24 ± 28 μmol·L-1) were higher in the levosimendan group. The increased expression of IL-6, IL-1ß TNFα and ICAM-1, extend of cerebral edema and cerebral autoregulation was not influenced by levosimendan.
Although levosimendan has neuroprotective actions in vitro and on the spinal cord in vivo and has been shown to cross the blood–brain barrier, the present results showed that levosimendan did not reduce the initial neuronal injury after transient ischaemia/hypoxia.
PMCID: PMC3492141  PMID: 22920500
Levosimendan; Cerebral ischaemia; Hypoxia; Microdialysis

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