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1.  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
2.  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
3.  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
4.  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
5.  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)
6.  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

Results 1-6 (6)