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1.  Inhaled nitric oxide improves transpulmonary blood flow and clinical outcomes after prolonged cardiac arrest: a large animal study 
Critical Care  2015;19(1):328.
The probability to achieve a return of spontaneous circulation (ROSC) after cardiac arrest can be improved by optimizing circulation during cardiopulomonary resuscitation using a percutaneous left ventricular assist device (iCPR). Inhaled nitric oxide may facilitate transpulmonary blood flow during iCPR and may therefore improve organ perfusion and outcome.
Ventricular fibrillation was electrically induced in 20 anesthetized male pigs. Animals were left untreated for 10 minutes before iCPR was attempted. Subjects received either 20 ppm of inhaled nitric oxide (iNO, n = 10) or 0 ppm iNO (Control, n = 10), simultaneously started with iCPR until 5 hours following ROSC. Animals were weaned from the respirator and followed up for five days using overall performance categories (OPC) and a spatial memory task. On day six, all animals were anesthetized again, and brains were harvested for neurohistopathologic evaluation.
All animals in both groups achieved ROSC. Administration of iNO markedly increased iCPR flow during CPR (iNO: 1.81 ± 0.30 vs Control: 1.64 ± 0.51 L/min, p < 0.001), leading to significantly higher coronary perfusion pressure (CPP) during the 6 minutes of CPR (25 ± 13 vs 16 ± 6 mmHg, p = 0.002). iNO-treated animals showed significantly lower S-100 serum levels thirty minutes post ROSC (0.26 ± 0.09 vs 0.38 ± 0.15 ng/mL, p = 0.048), as well as lower blood glucose levels 120–360 minutes following ROSC. Lower S-100 serum levels were reflected by superior clinical outcome of iNO-treated animals as estimated with OPC (3 ± 2 vs. 5 ± 1, p = 0.036 on days 3 to 5). Three out of ten iNO-treated, but none of the Control animals were able to successfully participate in the spatial memory task. Neurohistopathological examination of vulnerable cerebral structures revealed a trend towards less cerebral lesions in neocortex, archicortex, and striatum in iNO-treated animals compared to Controls.
In pigs resuscitated with mechanically-assisted CPR from prolonged cardiac arrest, the administration of 20 ppm iNO during and following iCPR improved transpulmonary blood flow, leading to improved clinical neurological outcomes.
PMCID: PMC4570752  PMID: 26369409
2.  Emergence times and airway reactions in general laryngeal mask airway anesthesia: study protocol for a randomized controlled trial 
Trials  2015;16:316.
The use of a laryngeal mask airway (LMA) in appropriate patients supports fast-track anesthesia with a lower incidence of postoperative airway-connected adverse events. Data on the most favorable anesthetic in this context, with the lowest rate of upper airway complications and fast emergence times, are controversial and limited. Desflurane seems to match these criteria best, but large randomized controlled trials (RCTs) with a standardized study protocol are lacking. Therefore, we aim to compare desflurane with other commonly used anesthetics, sevoflurane and propofol, in a sufficiently powered RCT. We hypothesize that desflurane is noninferior regarding the frequency of upper airway events and superior regarding the emergence times to sevoflurane and propofol.
A total of 351 patients undergoing surgery with an LMA will be included in this prospective, randomized, double-blind controlled, multicenter clinical trial. The patients will be randomly assigned to the three treatment arms: desflurane (n = 117), sevoflurane (n = 117), and propofol (n = 117). The emergence time (time to state the date of birth) will be the primary endpoint of this study. The secondary endpoints include further emergence times, such as time to open eyes, to remove LMA, to respond to command and to state name. Additionally, we will determine the frequency of cough and laryngospasm, measured intraoperatively and at emergence. We will assess the postoperative recovery on the first postoperative day via the Postoperative Quality Recovery Scale.
Despite increasing importance of cost-effective and safe anesthesia application, we lack proof for the most advantageous anesthetic agent, when an LMA is used. There are only a few RCTs comparing desflurane to other commonly used anesthetics (sevoflurane, propofol and isoflurane) in patients with LMA. These RCTs were conducted with small sample sizes, huge interstudy variability, and some also showed strong biases. The present multicenter RCT will provide results from a large sample size with a standardized study protocol and minimized bias, which is feasible in the clinical routine. Furthermore, we will expand our knowledge regarding the most favorable recovery on the first postoperative day, which impacts patients’ comfort after surgery.
Trial registration
EudraCT Identifier: 2014-003810-96, 5 September 2014 NCT02322502, December 2014
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-015-0855-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4515321  PMID: 26210907
laryngeal mask airway; emergence time; airway reaction; anesthesia
3.  Recombinant Factor VIIa Reduces Bleeding after Blunt Liver Injury in a Pig Model of Dilutional Coagulopathy under Severe Hypothermia 
PLoS ONE  2015;10(6):e0113979.
Recombinant factor VIIa (rFVIIa) is registered for use in haemophilia with inhibitors and other rare bleeding disorders, but has also been used in various other clinical conditions to terminate life-threatening bleeding. Underlying conditions (e.g. coagulopathy) and dosing may affect treatment efficacy. The objective of the present study was to evaluate the impact of increasing doses of rFVIIa on blood loss and coagulation assays in haemodiluted and hypothermic pigs undergoing blunt liver injury.
A grade III blunt liver injury was induced in 28 pigs after 70% haemodilution and cooling to 32.6–33.4°C. Ten minutes after trauma, animals randomly received placebo or 90, 180 or 360 μg/kg rFVIIa. Global coagulation parameters, thromboelastometry (TEM) and plasma thrombin generation (TG) were determined at different time points during the observation period of 120 minutes.
Total blood loss was significantly lower following 90 μg/kg rFVIIa (1206 [1138–1470] mL) relative to placebo (2677 [2337–3068] mL; p<0.05), with no increased effect with higher dose levels of rFVIIa. Following trauma and haemodilution, coagulation was impaired relative to baseline in both TEM and TG analysis. At 60 and 120 minutes after trauma, TEM variables improved in the rFVIIa-treated animals compared with the placebo group. Similarly, rFVIIa improved coagulation kinetics in TG. As was observed with blood loss, no significant effect between different rFVIIa dose levels was found in TEM or TG. Macro- and microscopic post-mortem examination did not reveal any signs of thromboembolic events.
Early administration of 90 μg/kg rFVIIa reduced blood loss in pigs undergoing blunt liver injury even after severe haemodilution and hypothermia, with no further effect of higher dose levels. Coagulation assays showed impaired coagulation in coagulopathic animals, with a dose-independent improvement in animals treated with rFVIIa.
PMCID: PMC4476676  PMID: 26098426
4.  CONSORT Item Reporting Quality in the Top Ten Ranked Journals of Critical Care Medicine in 2011: A Retrospective Analysis 
PLoS ONE  2015;10(5):e0128061.
Reporting randomised controlled trials is a key element in order to disseminate research findings. The CONSORT statement was introduced to improve the reporting quality. We assessed the adherence to the CONSORT statement of randomised controlled trials published 2011 in the top ten ranked journals of critical care medicine (ISI Web of Knowledge 2011, Thomson Reuters, London UK).
Design. We performed a retrospective cross sectional data analysis. Setting. This study was executed at the University Hospital of RWTH, Aachen. Participants. We selected the following top ten listed journals according to ISI Web of Knowledge (Thomson Reuters, London, UK) critical care medicine ranking in the year 2011: American Journal of Respiratory and Critical Care Medicine, Critical Care Medicine, Intensive Care Medicine, CHEST, Critical Care, Journal of Neurotrauma, Resuscitation, Pediatric Critical Care Medicine, Shock and Minerva Anestesiologica. Main outcome measures. We screened the online table of contents of each included journal, to identify the randomised controlled trials. The adherence to the items of the CONSORT Checklist in each trial was evaluated. Additionally we correlated the citation frequency of the articles and the impact factor of the respective journal with the amount of reported items per trial.
We analysed 119 randomised controlled trials and found, 15 years after the implementation of the CONSORT statement, that a median of 61,1% of the checklist-items were reported. Only 55.5% of the articles were identified as randomised trials in their titles. The citation frequency of the trials correlated significantly (rs = 0,433; p<0,001 and r = 0,331; p<0,001) to the CONSORT statement adherence. The impact factor showed also a significant correlation to the CONSORT adherence (r = 0,386; p<0,001).
The reporting quality of randomised controlled trials in the field of critical care medicine remains poor and needs considerable improvement.
PMCID: PMC4447424  PMID: 26020246
5.  Experimental Subarachnoid Hemorrhage in Rats: Comparison of Two Endovascular Perforation Techniques with Respect to Success Rate, Confounding Pathologies and Early Hippocampal Tissue Lesion Pattern 
PLoS ONE  2015;10(4):e0123398.
Recently aside from the “classic” endovascular monofilament perforation technique to induce experimental subarachnoid hemorrhage (SAH) a modification using a tungsten wire advanced through a guide tube has been described. We aim to assess both techniques for their success rate (induction of SAH without confounding pathologies) as primary endpoint. Further, the early tissue lesion pattern as evidence for early brain injury will be analyzed as secondary endpoint. Sprague Dawley rats (n=39) were randomly assigned to receive either Sham surgery (n=4), SAH using the “classic” technique (n=18) or using a modified technique (n=17). Course of intracranial pressure (ICP) and regional cerebral blood flow (rCBF) was analyzed; subsequent pathologies were documented either 6 or 24 h after SAH. Hippocampal tissue samples were analyzed via immunohistochemistry and western blotting. SAH-induction, regardless of confounding pathologies, was independent from type of technique (p=0.679). There was no significant difference concerning case fatality rate (classic: 40%; modified: 20%; p=0.213). Successful induction of SAH without collateral ICH or SDH was possible in 40% with the classic and in 86.7% with the modified technique (p=0.008). Peak ICP levels differed significantly between the two groups (classic: 94 +/- 23 mmHg; modified: 68 +/- 19 mmHg; p=0.003). Evidence of early cellular stress response and activation of apoptotic pathways 6 h after SAH was demonstrated. The extent of stress response is not dependent on type of technique. Both tested techniques successfully produce SAH including activation of an early stress response and apoptotic pathways in the hippocampal tissue. However, the induction of SAH with less confounding pathologies was more frequently achieved with the modified tungsten wire technique.
PMCID: PMC4395040  PMID: 25867893
6.  Cortisol and alpha-amylase as stress response indicators during pre-hospital emergency medicine training with repetitive high-fidelity simulation and scenarios with standardized patients 
In emergency medicine, the benefits of high-fidelity simulation (SIM) are widely accepted and standardized patients (SP) are known to mimic real patients accurately. However, only limited data are available concerning physicians’ stress markers within these training environments.
The aim of this pilot study was to investigate repetitive stress among healthcare professionals in simulated pre-hospital emergency scenarios using either SIM or SPs.
Teams with one emergency medical services (EMS) physician and two paramedics completed three SIM scenarios and two SP scenarios consecutively. To evaluate stress, salivary cortisol and alpha-amylase were measured in saliva samples taken before, during and after the scenarios.
A total of 14 EMS physicians (29% female; mean age: 36.8 ± 5.0 years; mean duration of EMS-experience: 9.1 ± 5.8 years) and 27 paramedics (11% female; age: 30.9 ± 6.9 years; EMS experience: 8.1 ± 6.0 years) completed the study. Alpha-amylase and cortisol levels did not differ significantly between the two professions. Cortisol values showed a gradual and statistically significant reduction over time but little change was observed in response to each scenario. In contrast, alpha-amylase activity increased significantly in response to every SIM and SP scenario, but there was no clear trend towards an overall increase or decrease over time.
Increases in salivary alpha-amylase activity suggest that both SIM and SP training produce stress among emergency healthcare professionals. Corresponding increases in salivary cortisol levels were not observed. Among physicians in the emergency setting, it appears that alpha-amylase provides a more sensitive measure of stress levels than cortisol.
PMCID: PMC4393871  PMID: 25887044
Stress response; Salivary alpha-amylase; Salivary cortisol; High-fidelity simulation; Standardized patients; Post-graduate medical education
7.  Doubling survival and improving clinical outcomes using a left ventricular assist device instead of chest compressions for resuscitation after prolonged cardiac arrest: a large animal study 
Critical Care  2015;19(1):123.
Despite improvements in pre-hospital and post-arrest critical care, sudden cardiac arrest (CA) remains one of the leading causes of death. Improving circulation during cardiopulmonary resuscitation (CPR) may improve survival rates and long-term clinical outcomes after CA.
In a porcine model, we compared standard CPR (sCPR; n =10) with CPR using an intravascular cardiac assist device without additional chest compressions (iCPR; n =10) following 10 minutes of electrically induced ventricular fibrillation (VF). In a separate crossover experiment, 10 additional pigs were subjected to 10 minutes of VF and 6 minutes of sCPR; the iCPR device was then implanted if a return of spontaneous circulation (ROSC) was not achieved using sCPR. Animals were evaluated in respect to intra- and post-arrest hemodynamics, survival, functional outcome and cerebral and myocardial lesions following CPR. We hypothesized that iCPR would result in more frequent ROSC and better functional recovery than sCPR.
iCPR produced a mean flow of 1.36 ± 0.02 L/min, leading to significantly higher coronary perfusion pressure (CPP) values during the early period of CPR (22 ± 10 mmHg vs. 9 ± 5 mmHg, P ≤0.01, 1 minute after start of CPR; 20 ± 11 mmHg vs. 10 ± 7 mmHg, P =0.03, 2 minutes after start of CPR), resulting in high ROSC rates (100% in iCPR vs. 50% in sCPR animals; P =0.03). iCPR animals showed significantly lower serum S100 levels at 10 and 30 minutes following ROSC (3.5 ± 0.6 ng/ml vs. 7.4 ± 3.0 ng/ml 30 minutes after ROSC; P ≤0.01), as well as superior clinical outcomes based on overall performance categories (2.9 ± 1.0 vs. 4.6 ± 0.8 on day 1; P ≤0.01). In crossover experiments, 80% of animals required treatment with iCPR after failed sCPR. Notably, ROSC was still achieved in six of the remaining eight animals (75%) after a total of 22.8 ± 5.1 minutes of ischemia.
In a model of prolonged cardiac arrest, the use of iCPR instead of sCPR improved CPP and doubled ROSC rates, translating into improved clinical outcomes.
PMCID: PMC4407317  PMID: 25886909
8.  Prothrombin complex concentrates and a specific antidote to dabigatran are effective ex-vivo in reversing the effects of dabigatran in an anticoagulation/liver trauma experimental model 
Critical Care  2014;18(1):R27.
New oral anticoagulants are effective alternatives to warfarin. However, no specific reversal agents are available for life-threatening bleeding or emergency surgery. Using a porcine model of trauma, this study assessed the ability of prothrombin complex concentrate (PCC), activated PCC (aPCC), recombinant FVIIa (rFVIIa) and a specific antidote to dabigatran (aDabi-Fab) to reverse the anticoagulant effects of dabigatran.
Dabigatran etexilate (DE) was given orally for 3 days (30 mg/kg bid) and intravenously on day 4 to achieve consistent, supratherapeutic concentrations of dabigatran. Blood samples were collected at baseline, after oral DE, after intravenous dabigatran, and 60 minutes post-injury. PCC (30 and 60 U/kg), aPCC (30 and 60 U/kg), rFVIIa (90 and 180 μg/kg) and antidote (60 and 120 mg/kg) were added to blood samples ex-vivo. Coagulation was assessed by thromboelastometry, global coagulation assays and diluted thrombin time.
Plasma concentrations of dabigatran were 380 ± 106 ng/ml and 1423 ± 432 ng/ml after oral and intravenous administration, respectively, and all coagulation parameters were affected by dabigatran. Both PCCs and aDabi-Fab, but not rFVIIa, reversed the effects of dabigatran on thromboelastometry parameters and prothrombin time. In contrast, aPTT was only normalised by aDabi-Fab. Plasma concentration (activity) of dabigatran remained elevated after PCC and rFVIIa therapy, but was not measureable after aDabi-Fab.
In conclusion, PCC and aPCC were effective in reducing the anticoagulant effects of dabigatran under different conditions, while aDabi-Fab fully corrected all coagulation measures and decreased the plasma concentration of dabigatran below the limit of detection. No significant effects were observed with rFVIIa.
PMCID: PMC4059479  PMID: 24499559
9.  Interstitial lactate, lactate/pyruvate and glucose in rat muscle before, during and in the recovery from global hypoxia 
Hypoxia results in an imbalance between oxygen supply and oxygen consumption. This study utilized microdialysis to monitor changes in the energy-related metabolites lactate, pyruvate and glucose in rat muscle before, during and after 30 minutes of transient global hypoxia. Hypoxia was induced in anaesthetised rats by reducing inspired oxygen to 6% O2 in nitrogen.
Basal values for lactate, the lactate/pyruvate ratio and glucose were 0.72 ± 0.04 mmol/l, 10.03 ± 1.16 and 3.55 ± 0.19 mmol/l (n = 10), respectively. Significant increases in lactate and the lactate/pyruvate ratio were found in the muscle after the induction of hypoxia. Maximum values of 2.26 ± 0.37 mmol/l for lactate were reached during early reperfusion, while the lactate/pyruvate ratio reached maximum values of 35.84 ± 7.81 at the end of hypoxia. Following recovery to ventilation with air, extracellular lactate levels and the lactate/pyruvate ratio returned to control levels within 30–40 minutes. Extracellular glucose levels showed no significant difference between hypoxia and control experiments.
In our study, the complete post-hypoxic recovery of metabolite levels suggests that metabolic enzymes of the skeletal muscle and their related cellular components may be able to tolerate severe hypoxic periods without prolonged damage. The consumption of glucose in the muscle in relation to its delivery seems to be unaffected.
PMCID: PMC4234838  PMID: 25391249
Hypoxia; Microdialysis; Muscle; Recovery; Lactate; Glucose; Metabolism
10.  Argon: Systematic Review on Neuro- and Organoprotective Properties of an “Inert” Gas 
Argon belongs to the group of noble gases, which are regarded as chemically inert. Astonishingly some of these gases exert biological properties and during the last decades more and more reports demonstrated neuroprotective and organoprotective effects. Recent studies predominately use in vivo or in vitro models for ischemic pathologies to investigate the effect of argon treatment. Promising data has been published concerning pathologies like cerebral ischemia, traumatic brain injury and hypoxic ischemic encephalopathy. However, models applied and administration of the therapeutic gas vary. Here we provide a systematic review to summarize the available data on argon’s neuro- and organoprotective effects and discuss its possible mechanism of action. We aim to provide a summary to allow further studies with a more homogeneous setting to investigate possible clinical applications of argon.
PMCID: PMC4227210  PMID: 25310646
argon; neuroprotection; organoprotection; inert gas; hypoxia; ischemia; cytoprotection
11.  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;15:339.
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
12.  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
13.  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
14.  Expression analysis following argon treatment in an in vivo model of transient middle cerebral artery occlusion in rats 
Medical Gas Research  2014;4:11.
Argon treatment following experimental neurotrauma has been found neuroprotective in an array of in vivo and in vitro models. The inherent cellular and molecular mechanisms are still unknown. We seeked to shed light on these processes by examinig the cellular distribution and the expression of inflammatory markers and growth factors in argon treated brain tissue.
Male adult Sprague-Dawley rats were randomly assigned to one of the study groups: sham surgery + placebo, sham surgery + argon, tMCAO + placebo, and tMCAO + argon. Animals underwent 2 h-transient middle cerebral artery occlusion (tMCAO) using the endoluminal thread model or sham surgery without tMCAO. After the first hour of tMCAO or sham surgery a 1 h inhalative argon (50% argon/50% O2) or placebo (50% N2/50% O2) treatment was performed. Brains were removed and evaluated after 24 h. RealTime-PCR was performed from biopsies of the penumbra and contralateral corresponding regions. Paraffin sections were immunostained with antibodies against GFAP, NeuN, and Iba1. Cell counts of astrocytes, neurons and microglia in different cortical regions were performed in a double-blinded manner.
Fifteen animals per tMCAO group and twelve sham + placebo respectively eleven sham + argon animals completed the interventional procedure. We identified several genes (IL-1β, IL-6, iNOS, TGF-β, and NGF) whose transcription was elevated 24 h after the study intervention, and whose expression levels significantly differed between argon treatment and placebo following tMCAO. Except for the core region of ischemia, cell numbers were comparable between different treatment groups.
In our study, we found an elevated expression of several inflammatory markers and growth factors following tMCAO + argon compared to tMCAO + placebo. Although conflicting the previously described neuroprotective effects of argon following experimental ischemia, these findings might still be associated with each other. Further studies will have to evaluate their relevance and potential relationship.
PMCID: PMC4322493  PMID: 25671080
Argon; Noble gas; MCAO; Ischemia; Neuroprotection
15.  The STOP the Bleeding Campaign 
Critical Care  2013;17(2):136.
According to the World Health Organization, traumatic injuries worldwide are responsible for over 5 million deaths annually. Post-traumatic bleeding caused by traumatic injury-associated coagulopathy is the leading cause of potentially preventable death among trauma patients. Despite these facts, awareness of this problem is insufficient and treatment options are often unclear. The STOP the Bleeding Campaign therefore aims to increase awareness of the phenomenon of post-traumatic coagulopathy and its appropriate management by publishing European guidelines for the management of the bleeding trauma patient, by promoting and monitoring the implementation of these guidelines and by preparing promotional and educational material, organising activities and developing health quality management tools. The campaign aims to reduce the number of patients who die within 24 hours after arrival in the hospital due to exsanguination by a minimum of 20% within the next 5 years.
PMCID: PMC3672629  PMID: 23635083
16.  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
17.  Smartphone Apps for Cardiopulmonary Resuscitation Training and Real Incident Support: A Mixed-Methods Evaluation Study 
No systematic evaluation of smartphone/mobile apps for resuscitation training and real incident support is available to date. To provide medical, usability, and additional quality criteria for the development of apps, we conducted a mixed-methods sequential evaluation combining the perspective of medical experts and end-users.
The study aims to assess the quality of current mobile apps for cardiopulmonary resuscitation (CPR) training and real incident support from expert as well as end-user perspective.
Two independent medical experts evaluated the medical content of CPR apps from the Google Play store and the Apple App store. The evaluation was based on pre-defined minimum medical content requirements according to current Basic Life Support (BLS) guidelines. In a second phase, non-medical end-users tested usability and appeal of the apps that had at least met the minimum requirements. Usability was assessed with the System Usability Scale (SUS); appeal was measured with the self-developed ReactionDeck toolkit.
Out of 61 apps, 46 were included in the experts’ evaluation. A consolidated list of 13 apps resulted for the following layperson evaluation. The interrater reliability was substantial (kappa=.61). Layperson end-users (n=14) had a high interrater reliability (intraclass correlation 1 [ICC1]=.83, P<.001, 95% CI 0.75-0.882 and ICC2=.79, P<.001, 95% CI 0.695-0.869). Their evaluation resulted in a list of 5 recommendable apps.
Although several apps for resuscitation training and real incident support are available, very few are designed according to current BLS guidelines and offer an acceptable level of usability and hedonic quality for laypersons. The results of this study are intended to optimize the development of CPR mobile apps. The app ranking supports the informed selection of mobile apps for training situations and CPR campaigns as well as for real incident support.
PMCID: PMC3978555  PMID: 24647361
basic life support (BLS); cardiopulmonary resuscitation (CPR); external chest compression (ECC); smartphone apps; mobile phone; mobile health
18.  Contact-free monitoring of circulation and perfusion dynamics based on the analysis of thermal imagery 
Biomedical Optics Express  2014;5(4):1075-1089.
Acute circulatory disorders are commonly associated with systemic inflammatory response (SIRS) and sepsis. During sepsis, microcirculatory perfusion is compromised leading to tissue hypoperfusion and potentially to multiple organ dysfunction. In the present study, acute lung injury (ALI), one of the major causes leading to SIRS and sepsis, was experimentally induced in six female pigs. To investigate the progress of body temperature distribution, measurements with a long-wave infrared camera were carried out. Temperature centralization was evidenced during ALI owing to impairments of peripheral perfusion. In addition, statistical analysis demonstrated strong correlations between (a) standard deviation of the skin temperature distribution (SD) and shock index (SI) (p<0.0005), (b) SD and mean arterial pressure (MAP) (p<0.0005), (c) ΔT/Δx and SI (p<0.0005), as well as between (d) ΔT/Δx and MAP (p<0.0005). For clarification purposes, ΔT/Δx is a parameter implemented to quantify the spatial temperature gradient. This pioneering study created promising results. It demonstrated the capacity of infrared thermography as well as of the indexes, SD and ΔT/Δx, to detect impairments in both circulation and tissue perfusion.
PMCID: PMC3986002  PMID: 24761290
(040.3060) Infrared; (170.1610) Clinical applications; (170.2655) Functional monitoring and imaging
19.  Accuracy and precision of calibrated arterial pulse contour analysis in patients with subarachnoid hemorrhage requiring high-dose vasopressor therapy: a prospective observational clinical trial 
Critical Care  2014;18(1):R25.
Calibrated arterial pulse contour analysis has become an established method for the continuous monitoring of cardiac output (PCCO). However, data on its validity in hemodynamically instable patients beyond the setting of cardiac surgery are scarce. We performed the present study to assess the validity and precision of PCCO-measurements using the PiCCO™-device compared to transpulmonary thermodilution derived cardiac output (TPCO) as the reference technique in neurosurgical patients requiring high-dose vasopressor-therapy.
A total of 20 patients (16 females and 4 males) were included in this prospective observational clinical trial. All of them suffered from subarachnoid hemorrhage (Hunt&Hess grade I-V) due to rupture of a cerebral arterial aneurysm and underwent high-dose vasopressor therapy for the prevention/treatment of delayed cerebral ischemia (DCI). Simultaneous CO measurements by bolus TPCO and PCCO were obtained at baseline as well as 2 h, 6 h, 12 h, 24 h, 48 h and 72 h after inclusion.
PCCO- and TPCO-measurements were obtained at baseline as well as 2 h, 6 h, 12 h, 24 h, 48 h and 72 h after inclusion. Patients received vasoactive support with (mean ± standard deviation, SD) 0.57 ± 0.49 μg · kg-1 · min-1 norepinephrine resulting in a mean arterial pressure of 103 ± 13 mmHg and a systemic vascular resistance of 943 ± 248 dyn · s · cm-5. 136 CO-data pairs were analyzed. TPCO ranged from 5.2 to 14.3 l · min-1 (mean ± SD 8.5 ± 2.0 l · min-1) and PCCO ranged from 5.0 to 14.4 l · min-1 (mean ± SD 8.6 ± 2.0 l · min-1). Bias and limits of agreement (1.96 SD of the bias) were −0.03 ± 0.82 l · min-1 and 1.62 l · min-1, resulting in an overall percentage error of 18.8%. The precision of PCCO-measurements was 17.8%. Insufficient trending ability was indicated by concordance rates of 74% (exclusion zone of 15% (1.29 l · min-1)) and 67% (without exclusion zone), as well as by polar plot analysis.
In neurosurgical patients requiring extensive vasoactive support, CO values obtained by calibrated PCCO showed clinically and statistically acceptable agreement with TPCO-measurements, but the results from concordance and polar plot analysis indicate an unreliable trending ability.
PMCID: PMC4057342  PMID: 24499533
20.  Milrinone Relaxes Pulmonary Veins in Guinea Pigs and Humans 
PLoS ONE  2014;9(1):e87685.
The phosphodiesterase-III inhibitor milrinone improves ventricular contractility, relaxes pulmonary arteries and reduces right ventricular afterload. Thus, it is used to treat heart failure and pulmonary hypertension (PH). However, its action on pulmonary veins (PVs) is not defined, although particularly PH due to left heart disease primarily affects the pulmonary venous bed. We examined milrinone-induced relaxation in PVs from guinea pigs (GPs) and humans.
Material and Methods
Precision-cut lung slices (PCLS) were prepared from GPs or from patients undergoing lobectomy. Milrinone-induced relaxation was studied by videomicroscopy in naïve PVs and in PVs pre-constricted with the ETA-receptor agonist BP0104. Baseline luminal area was defined as 100%. Intracellular cAMP was measured by ELISA and milrinone-induced changes of segmental vascular resistances were studied in the GP isolated perfused lung (IPL).
In the IPL (GP), milrinone (10 µM) lowered the postcapillary resistance of pre-constricted vessels. In PCLS (GP), milrinone relaxed naïve and pre-constricted PVs (120%) and this relaxation was attenuated by inhibition of protein kinase G (KT 5823), adenyl cyclase (SQ 22536) and protein kinase A (KT 5720), but not by inhibition of NO-synthesis (L-NAME). In addition, milrinone-induced relaxation was dependent on the activation of KATP-, BKCa2+- and Kv-channels. Human PVs also relaxed to milrinone (121%), however only if pre-constricted.
Milrinone relaxes PVs from GPs and humans. In GPs, milrinone-induced relaxation is based on KATP-, BKCa2+- and Kv-channel-activation and on cAMP/PKA/PKG. The relaxant properties of milrinone on PVs lead to reduced postcapillary resistance and hydrostatic pressures. Hence they alleviate pulmonary edema and suggest beneficial effects of milrinone in PH due to left heart disease.
PMCID: PMC3909212  PMID: 24498166
21.  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
22.  Levosimendan limits reperfusion injury in a rat middle cerebral artery occlusion (MCAO) model 
BMC Neurology  2013;13:106.
Neuroprotective strategies in ischemic stroke are an important challenge in clinical and experimental research as an adjunct to reperfusion therapy that may reduce neurologic injury and improve outcome. The neuroprotective properties of levosimendan in traumatic brain injury in vitro, transient global brain ischemia and focal spinal cord ischemia suggest the potential for similar effects in transient brain ischemia.
Transient brain ischemia was induced for 60 min by intraluminal occlusion of the middle cerebral artery in 40 male Wistar rats under general anesthesia with s-ketamine and xylazine and with continuous monitoring of their blood pressure and cerebral perfusion. Five minutes before inducing reperfusion, a levosimendan bolus (24 μg kg -1) was administered over a 20 minute period. Infarct size, brain swelling, neurological function and the expression of inflammatory markers were quantified 24 hours after reperfusion.
Although levosimendan limited the infarct size and brain swelling by 40% and 53%, respectively, no effect on neurological outcome or mortality could be demonstrated. Upregulation of tumor necrosis factor α and intercellular adhesion molecule 1 was significantly impeded. Cerebral blood flow during reperfusion was significantly reduced as a consequence of sustained autoregulation.
Levosimendan demonstrated significant neuroprotective properties in a rat model of transient brain ischemia by reducing reperfusion injury.
PMCID: PMC3750823  PMID: 23937651
Experimental stroke; Postconditioning; Levosimendan; Cerebral reperfusion injury
23.  Prolonged Mechanical Ventilation Alters the Expression Pattern of Angio-neogenetic Factors in a Pre-Clinical Rat Model 
PLoS ONE  2013;8(8):e70524.
Mechanical ventilation (MV) is a life saving intervention for patients with respiratory failure. Even after 6 hours of MV, diaphragm atrophy and dysfunction (collectively referred to as ventilator-induced diaphragmatic dysfunction, VIDD) occurs in concert with a blunted blood flow and oxygen delivery. The regulation of hypoxia sensitive factors (i.e. hypoxia inducible factor 1α, 2α (HIF-1α,–2α), vascular endothelial growth factor (VEGF)) and angio-neogenetic factors (angiopoietin 1–3, Ang) might contribute to reactive and compensatory alterations in diaphragm muscle.
Male Wistar rats (n = 8) were ventilated for 24 hours or directly sacrificed (n = 8), diaphragm and mixed gastrocnemius muscle tissue was removed. Quantitative real time PCR and western blot analyses were performed to detect changes in angio-neogenetic factors and inflammatory markers. Tissues were stained using Isolectin (IB 4) to determine capillarity and calculate the capillary/fiber ratio.
MV resulted in up-regulation of Ang 2 and HIF-1α mRNA in both diaphragm and gastrocnemius, while VEGF mRNA was down-regulated in both tissues. HIF-2α mRNA was reduced in both tissues, while GLUT 4 mRNA was increased in gastrocnemius and reduced in diaphragm samples. Protein levels of VEGF, HIF-1α, -2α and 4 did not change significantly. Additionally, inflammatory cytokine mRNA (Interleukin (IL)-6, IL-1β and TNF α) were elevated in diaphragm tissue.
The results demonstrate that 24 hrs of MV and the associated limb disuse induce an up-regulation of angio-neogenetic factors that are connected to HIF-1α. Changes in HIF-1α expression may be due to several interactions occurring during MV.
PMCID: PMC3738548  PMID: 23950950
24.  Implementation phase of a multicentre prehospital telemedicine system to support paramedics: feasibility and possible limitations 
Legal regulations often limit the medical care that paramedics can provide. Telemedical solutions could overcome these limitations by remotely providing expert support. Therefore, a mobile telemedicine system to support paramedics was developed. During the implementation phase of this system in four German emergency medical services (EMS), the feasibility and possible limitations of this system were evaluated.
After obtaining ethical approval and providing a structured training program for all medical professionals, the system was implemented on three paramedic-staffed ambulances on August 1st, 2012. Two more ambulances were included subsequently during this month. The paramedics could initiate a consultation with EMS physicians at a teleconsultation centre. Telemedical functionalities included audio communication, real-time vital data transmission, 12-lead electrocardiogram, picture transmission on demand, and video streaming from a camera embedded into the ceiling of each ambulance. After each consultation, telephone-based debriefings were conducted. Data were retrieved from the documentation protocols of the teleconsultation centre and the EMS.
During a one month period, teleconsultations were conducted during 35 (11.8%) of 296 emergency missions with a mean duration of 24.9 min (SD 12.5). Trauma, acute coronary syndromes, and circulatory emergencies represented 20 (57%) of the consultation cases. Diagnostic support was provided in 34 (97%) cases, and the administration of 50 individual medications, including opioids, was delegated by the teleconsultation centre to the paramedics in 21 (60%) missions (range: 1–7 per mission). No medical complications or negative interpersonal effects were reported. All applications functioned as expected except in one case in which the connection failed due to the lack of a viable mobile network.
The feasibility of the telemedical approach was demonstrated. Teleconsultation enabled early initiation of treatments by paramedics operating under the real-time medical direction. Teleconsultation can be used to provide advanced care until the patient is under a physician’s care; moreover, it can be used to support the paramedics who work alone to provide treatment in non-life-threatening cases. Non-availability of mobile networks may be a relevant limitation. A larger prospective controlled trial is needed to evaluate the rate of complications and outcome effects.
PMCID: PMC3710491  PMID: 23844941
Telemedicine; Teleconsultation; Telepresence; Emergency medical service; Analgesia
25.  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

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