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1.  What Is the Significance of Perioperative Release of Macrophage Migration Inhibitory Factor in Cardiac Surgery? 
Antioxidants & Redox Signaling  2013;19(3):231-239.
Abstract
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.
doi:10.1089/ars.2012.5015
PMCID: PMC3691912  PMID: 23157710
2.  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.
doi:10.1186/cc12579
PMCID: PMC3672629  PMID: 23635083
3.  The Role of Macrophage Migration Inhibitory Factor in Anesthetic-Induced Myocardial Preconditioning 
PLoS ONE  2014;9(3):e92827.
Introduction
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1371/journal.pone.0092827
PMCID: PMC3965449  PMID: 24667295
4.  Smartphone Apps for Cardiopulmonary Resuscitation Training and Real Incident Support: A Mixed-Methods Evaluation Study 
Background
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.
Objective
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.2196/jmir.2951
PMCID: PMC3978555  PMID: 24647361
basic life support (BLS); cardiopulmonary resuscitation (CPR); external chest compression (ECC); smartphone apps; mobile phone; mobile health
5.  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.
doi:10.1364/BOE.5.001075
PMCID: PMC3986002  PMID: 24761290
(040.3060) Infrared; (170.1610) Clinical applications; (170.2655) Functional monitoring and imaging
6.  Milrinone Relaxes Pulmonary Veins in Guinea Pigs and Humans 
PLoS ONE  2014;9(1):e87685.
Introduction
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).
Results
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.
Discussion
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.
doi:10.1371/journal.pone.0087685
PMCID: PMC3909212  PMID: 24498166
7.  Recovery of Diaphragm Function following Mechanical Ventilation in a Rodent Model 
PLoS ONE  2014;9(1):e87460.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1371/journal.pone.0087460
PMCID: PMC3903648  PMID: 24475293
8.  Levosimendan limits reperfusion injury in a rat middle cerebral artery occlusion (MCAO) model 
BMC Neurology  2013;13:106.
Background
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.
Methods
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.
Results
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.
Conclusions
Levosimendan demonstrated significant neuroprotective properties in a rat model of transient brain ischemia by reducing reperfusion injury.
doi:10.1186/1471-2377-13-106
PMCID: PMC3750823  PMID: 23937651
Experimental stroke; Postconditioning; Levosimendan; Cerebral reperfusion injury
9.  Prolonged Mechanical Ventilation Alters the Expression Pattern of Angio-neogenetic Factors in a Pre-Clinical Rat Model 
PLoS ONE  2013;8(8):e70524.
Objective
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1371/journal.pone.0070524
PMCID: PMC3738548  PMID: 23950950
10.  Implementation phase of a multicentre prehospital telemedicine system to support paramedics: feasibility and possible limitations 
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1186/1757-7241-21-54
PMCID: PMC3710491  PMID: 23844941
Telemedicine; Teleconsultation; Telepresence; Emergency medical service; Analgesia
11.  Accuracy of the Masimo Pronto-7® system in patients with left ventricular assist device 
Background
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).
Methods
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).
Results
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.
Conclusion
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.
doi:10.1186/1749-8090-8-159
PMCID: PMC3776432  PMID: 23800231
Perioperative care; Circulatory assist devices; Blood transfusion; Emergency; Patient safety
12.  Levosimendan Relaxes Pulmonary Arteries and Veins in Precision-Cut Lung Slices - The Role of KATP-Channels, cAMP and cGMP 
PLoS ONE  2013;8(6):e66195.
Introduction
Levosimendan is approved for left heart failure and is also used in right heart failure to reduce right ventricular afterload. Despite the fact that pulmonary arteries (PAs) and pulmonary veins (PVs) contribute to cardiac load, their responses to levosimendan are largely unknown.
Materials and Methods
Levosimendan-induced vasorelaxation of PAs and PVs was studied in precision-cut lung slices from guinea pigs by videomicroscopy; baseline luminal area was defined as 100%. Intracellular cAMP- and cGMP-levels were measured by ELISA and NO end products were determined by the Griess reaction.
Results
Levosimendan relaxed control PVs (116%) and those pre-constricted with an endothelinA-receptor agonist (119%). PAs were only relaxed if pre-constricted (115%). Inhibition of KATP-channels (glibenclamide), adenyl cyclase (SQ 22536) and protein kinase G (KT 5823) largely attenuated the levosimendan-induced relaxation in control PVs, as well as in pre-constricted PAs and PVs. Inhibition of BKCa2+-channels (iberiotoxin) and Kv-channels (4-aminopyridine) only contributed to the relaxant effect of levosimendan in pre-constricted PAs. In both PAs and PVs, levosimendan increased intracellular cAMP- and cGMP-levels, whereas NO end products remained unchanged. Notably, basal NO-levels were higher in PVs. The KATP-channel activator levcromakalim relaxed PAs dependent on cAMP/PKA/PKG and increased cAMP-levels in PAs.
Discussion
Levosimendan initiates complex and divergent signaling pathways in PAs and PVs. Levosimendan relaxes PAs and PVs primarily via KATP-channels and cAMP/cGMP; in PAs, BKCa2+- and Kv-channels are also involved. Our findings with levcromakalim do further suggest that in PAs the activation of KATP-channels leads to the production of cAMP/PKA/PKG. In conclusion, these results suggest that levosimendan might reduce right ventricular afterload by relaxation of PAs as well as pulmonary hydrostatic pressure and pulmonary edema by relaxation of PVs.
doi:10.1371/journal.pone.0066195
PMCID: PMC3688856  PMID: 23824760
13.  Xenon consumption during general surgery: a retrospective observational study 
Medical Gas Research  2013;3:12.
Background
High costs still limits the widespread use of xenon in the clinical practice. Therefore, we evaluated xenon consumption of different delivery modes during general surgery.
Methods
A total of 48 patients that underwent general surgery with balanced xenon anaesthesia were retrospectively analysed according to the mode of xenon delivery during maintenance phase (ECO mode, AUTO mode or MANUAL mode).
Results
Xenon consumption was highest during the wash-in phase (9.4 ± 2.1l) and further decreased throughout maintenance of anaesthesia. Comparison of different xenon delivery modes revealed significant reduced xenon consumption during ECO mode (18.5 ± 3.7L (ECO) vs. 24.7 ± 11.5L (AUTO) vs. 29.6 ± 14.3L (MANUAL); p = 0.033). No differences could be detected with regard to anaesthetic depth, oxygenation or performance of anaesthesia.
Conclusion
The closed-circuit respirator Felix Dual offers effective reduction of xenon consumption during general surgery when ECO mode is used.
doi:10.1186/2045-9912-3-12
PMCID: PMC3733954  PMID: 23758970
Anaesthesia; Xenon; Closed-circuit respirator
14.  Thrombin Generation Capacity of Prothrombin Complex Concentrate in an In Vitro Dilutional Model 
PLoS ONE  2013;8(5):e64100.
Background
The use of PCC for the treatment of trauma-induced coagulopathy potentially increase the risk of thromboembolism and disseminated intravascular coagulation, which is addressed to an imbalance of both pro- and anticoagulants. As PCCs differ in composition, we used an in vitro dilutional approach to assess the overall thrombin generation of five different PCCs through various laboratory assays.
Methods
The vitamin K-dependent coagulation factors, heparin, and antithrombin were assessed in five commercially available PCCs. The procoagulant potential of the PCCs was assessed in plasma and whole blood from 4 healthy donors by means of classical coagulation assays, thrombin generation assay and thromboelastometry. In order to reflect coagulopathy, whole blood was diluted to 80, 60, 40, and 20% with Ringer’s lactate solution.
Results
The five different PCCs were characterised by comparable levels of factors II, VII, IX and X (all around 20–30 IU/mL), whereas the heparin (0 to 17.6 IU/mL) and antithrombin (0.06 to 1.29 IU/mL) levels were remarkably different between manufactures. In vitro dilution of blood induced a prolongation of the PT and aPTT, and attenuation of thrombin generation and ExTem induced thromboelastometry. Overall, non- or low-heparin containing PCCs restored the in vitro dilutional coagulopathy, whereas PCCs containing heparin have an anticoagulant effect. The thrombin generation assay showed to be the most sensitive method for assessment of PCC effects.
Conclusions
This study shows that most available PCCs are not balanced regarding their pro- and anticoagulants. The effect of measured differences in thrombin generation among different PCCs requires further investigations to elaborate the clinical meaning of this finding in the treatment of trauma induced coagulopathy.
doi:10.1371/journal.pone.0064100
PMCID: PMC3656958  PMID: 23696866
15.  Management of bleeding and coagulopathy following major trauma: an updated European guideline 
Critical Care  2013;17(2):R76.
Introduction
Evidence-based recommendations are needed to guide the acute management of the bleeding trauma patient. When these recommendations are implemented patient outcomes may be improved.
Methods
The multidisciplinary Task Force for Advanced Bleeding Care in Trauma was formed in 2005 with the aim of developing a guideline for the management of bleeding following severe injury. This document represents an updated version of the guideline published by the group in 2007 and updated in 2010. Recommendations were formulated using a nominal group process, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) hierarchy of evidence and based on a systematic review of published literature.
Results
Key changes encompassed in this version of the guideline include new recommendations on the appropriate use of vasopressors and inotropic agents, and reflect an awareness of the growing number of patients in the population at large treated with antiplatelet agents and/or oral anticoagulants. The current guideline also includes recommendations and a discussion of thromboprophylactic strategies for all patients following traumatic injury. The most significant addition is a new section that discusses the need for every institution to develop, implement and adhere to an evidence-based clinical protocol to manage traumatically injured patients. The remaining recommendations have been re-evaluated and graded based on literature published since the last edition of the guideline. Consideration was also given to changes in clinical practice that have taken place during this time period as a result of both new evidence and changes in the general availability of relevant agents and technologies.
Conclusions
A comprehensive, multidisciplinary approach to trauma care and mechanisms with which to ensure that established protocols are consistently implemented will ensure a uniform and high standard of care across Europe and beyond.
Please see related letter by Morel et alhttp://ccforum.com/content/17/4/442
doi:10.1186/cc12685
PMCID: PMC4056078  PMID: 23601765
16.  Prehospital digital photography and automated image transmission in an emergency medical service – an ancillary retrospective analysis of a prospective controlled trial 
Background
Still picture transmission was performed using a telemedicine system in an Emergency Medical Service (EMS) during a prospective, controlled trial. In this ancillary, retrospective study the quality and content of the transmitted pictures and the possible influences of this application on prehospital time requirements were investigated.
Methods
A digital camera was used with a telemedicine system enabling encrypted audio and data transmission between an ambulance and a remotely located physician. By default, images were compressed (jpeg, 640 x 480 pixels). On occasion, this compression was deactivated (3648 x 2736 pixels). Two independent investigators assessed all transmitted pictures according to predefined criteria. In cases of different ratings, a third investigator had final decision competence. Patient characteristics and time intervals were extracted from the EMS protocol sheets and dispatch centre reports.
Results
Overall 314 pictures (mean 2.77 ± 2.42 pictures/mission) were transmitted during 113 missions (group 1). Pictures were not taken for 151 missions (group 2). Regarding picture quality, the content of 240 (76.4%) pictures was clearly identifiable; 45 (14.3%) pictures were considered “limited quality” and 29 (9.2%) pictures were deemed “not useful” due to not/hardly identifiable content. For pictures with file compression (n = 84 missions) and without (n = 17 missions), the content was clearly identifiable in 74% and 97% of the pictures, respectively (p = 0.003). Medical reports (n = 98, 32.8%), medication lists (n = 49, 16.4%) and 12-lead ECGs (n = 28, 9.4%) were most frequently photographed. The patient characteristics of group 1 vs. 2 were as follows: median age – 72.5 vs. 56.5 years, p = 0.001; frequency of acute coronary syndrome – 24/113 vs. 15/151, p = 0.014. The NACA scores and gender distribution were comparable. Median on-scene times were longer with picture transmission (26 vs. 22 min, p = 0.011), but ambulance arrival to hospital arrival intervals did not differ significantly (35 vs. 33 min, p = 0.054).
Conclusions
Picture transmission was used frequently and resulted in an acceptable picture quality, even with compressed files. In most cases, previously existing “paper data” was transmitted electronically. This application may offer an alternative to other modes of ECG transmission. Due to different patient characteristics no conclusions for a prolonged on-scene time can be drawn. Mobile picture transmission holds important opportunities for clinical handover procedures and teleconsultation.
doi:10.1186/1757-7241-21-3
PMCID: PMC3568016  PMID: 23324531
Telemedicine; Teleconsultation; Digital image; Emergency medical service; Picture transmission; Photo transmission
17.  The Hip Fracture Surgery in Elderly Patients (HIPELD) study: protocol for a randomized, multicenter controlled trial evaluating the effect of xenon on postoperative delirium in older patients undergoing hip fracture surgery 
Trials  2012;13:180.
Background
Strategies to protect the brain from postoperative delirium (POD) after hip fracture are urgently needed. The development of delirium often is associated with the loss of independence, poor functional recovery, and increased morbidity, as well as increases in length of hospital stay, discharges to nursing facilities, and healthcare costs. We hypothesize that xenon may reduce the burden of POD, (i) by avoiding the need to provide anesthesia with a drug that targets the γ-amino-butyric acid (GABA)A receptor and (ii) through beneficial anesthetic and organ-protective effects.
Methods and design
An international, multicenter, phase 2, prospective, randomized, blinded, parallel group and controlled trial to evaluate the incidence of POD, diagnosed with the Confusion Assessment Method (CAM), in older patients undergoing hip fracture surgery under general anesthesia with xenon or sevoflurane, for a period of 4 days post surgery (primary outcome) is planned. Secondary objectives are to compare the incidence of POD between xenon and sevoflurane, to evaluate the incidence of POD from day 5 post surgery until discharge from hospital, to determine the time to first POD diagnosis, to evaluate the duration of POD, to evaluate the evolution of the physiological status of the patients in the postoperative period, to evaluate the recovery parameters, to collect preliminary data to evaluate the economical impact of POD in the postoperative period and to collect safety data. Patients are eligible if they are older aged (≥ 75 years) and assigned to a planned hip fracture surgery within 48 h after the hip fracture. Furthermore, patients need to be willing and able to complete the requirements of this study including the signature of the written informed consent. A total of 256 randomized patients in the 10 participating centers will be recruited, that is, 128 randomized patients in each of the 2 study groups (receiving either xenon or sevoflurane).
Trial registration
EudraCT Identifier: 2009-017153-35; ClinicalTrials.gov Identifier: NCT01199276
doi:10.1186/1745-6215-13-180
PMCID: PMC3488510  PMID: 23016882
Hip fracture; Postoperative delirium; Xenon
18.  The effects of levosimendan on brain metabolism during initial recovery from global transient ischaemia/hypoxia 
BMC Neurology  2012;12:81.
Backround
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1186/1471-2377-12-81
PMCID: PMC3492141  PMID: 22920500
Levosimendan; Cerebral ischaemia; Hypoxia; Microdialysis
19.  Acute Pain Therapy in Postanesthesia Care Unit Directed by Skin Conductance: A Randomized Controlled Trial 
PLoS ONE  2012;7(7):e41758.
Background
After surgery, effective and well-directed acute pain therapy is a necessary and integral part of the overall treatment plan. Generally, the assessment of pain intensity depends on a patient’s self-evaluation using scoring systems such as numeric rating scales (NRS, 0 to 10). Recently, a “Pain Monitor” was commercially provided which is based on measurements of fluctuations of skin conductance (NFSC). In this randomized, controlled, single-blind trial, possible benefits of this certain device were studied.
Methods
Postoperative patients (n = 44) were randomly assigned to a test or a control group during their stay in the postanesthesia care unit (PACU). All patients were treated and monitored according to internal hospital standards. Whereas all patients systematically evaluated their pain each 15 min, test group patients were additionally addressed when NFSC exceeded a predefined level. In cases of NRS≥5 during a routine elevation or in between, pain relief was achieved by standard procedures irrespective of group allocation.
Results
During their stay in PACU, both test and control groups experienced a significant decrease in NRS as a consequence of pain therapy. No significant differences in mean NRS or in NFSC values were found between the test and control groups. No correlation was observed between NRS and NFSC.
Conclusion
Postoperative patients experience diverse stressors, such as anxiety, disorientation, shivering, sickness and pain. Although the application of continuous pain monitoring would be meaningful in this clinical setting, the tested device failed to distinguish pain from other stressors in postoperative adult patients.
Trial Registration
German Clinical Trials Register DRKS00000755.
doi:10.1371/journal.pone.0041758
PMCID: PMC3407175  PMID: 22848592
20.  Evaluation of a newly developed media-supported 4-step approach for basic life support training 
Objective
The quality of external chest compressions (ECC) is of primary importance within basic life support (BLS). Recent guidelines delineate the so-called 4“-step approach” for teaching practical skills within resuscitation training guided by a certified instructor. The objective of this study was to evaluate whether a “media-supported 4-step approach” for BLS training leads to equal practical performance compared to the standard 4-step approach.
Materials and methods
After baseline testing, 220 laypersons were either trained using the widely accepted method for resuscitation training (4-step approach) or using a newly created “media-supported 4-step approach”, both of equal duration. In this approach, steps 1 and 2 were ensured via a standardised self-produced podcast, which included all of the information regarding the BLS algorithm and resuscitation skills. Participants were tested on manikins in the same mock cardiac arrest single-rescuer scenario prior to intervention, after one week and after six months with respect to ECC-performance, and participants were surveyed about the approach.
Results
Participants (age 23 ± 11, 69% female) reached comparable practical ECC performances in both groups, with no statistical difference. Even after six months, there was no difference detected in the quality of the initial assessment algorithm or delay concerning initiation of CPR. Overall, at least 99% of the intervention group (n = 99; mean 1.5 ± 0.8; 6-point Likert scale: 1 = completely agree, 6 = completely disagree) agreed that the video provided an adequate introduction to BLS skills.
Conclusions
The “media-supported 4-step approach” leads to comparable practical ECC-performance compared to standard teaching, even with respect to retention of skills. Therefore, this approach could be useful in special educational settings where, for example, instructors’ resources are sparse or large-group sessions have to be prepared.
doi:10.1186/1757-7241-20-37
PMCID: PMC3461483  PMID: 22647148
Basic Life Support (BLS); Cardiopulmonary resuscitation (CPR); External chest compressions (ECC); Training; Media; 4-step approach
21.  Feasibility of Prehospital Teleconsultation in Acute Stroke – A Pilot Study in Clinical Routine 
PLoS ONE  2012;7(5):e36796.
Background
Inter-hospital teleconsultation improves stroke care. To transfer this concept into the emergency medical service (EMS), the feasibility and effects of prehospital teleconsultation were investigated.
Methodology/Principal Findings
Teleconsultation enabling audio communication, real-time video streaming, vital data and still picture transmission was conducted between an ambulance and a teleconsultation center. Pre-notification of the hospital was carried out with a 14-item stroke history checklist via e-mail-to-fax. Beside technical assessments possible influences on prehospital and initial in-hospital time intervals, prehospital diagnostic accuracy and the transfer of stroke specific data were investigated by comparing telemedically assisted prehospital care (telemedicine group) with local regular EMS care (control group). All prehospital stroke patients over a 5-month period were included during weekdays (7.30 a.m. –4.00 p.m.). In 3 of 18 missions partial dropouts of the system occurred; neurological co-evaluation via video transmission was conducted in 12 cases. The stroke checklist was transmitted in 14 cases (78%). Telemedicine group (n = 18) vs. control group (n = 47): Prehospital time intervals were comparable, but in both groups the door to brain imaging times were longer than recommended (median 59.5 vs. 57.5 min, p = 0.6447). The prehospital stroke diagnosis was confirmed in 61% vs. 67%, p = 0.8451. Medians of 14 (IQR 9) vs. 5 (IQR 2) stroke specific items were transferred in written form to the in-hospital setting, p<0.0001. In 3 of 10 vs. 5 of 27 patients with cerebral ischemia thrombolytics were administered, p = 0.655.
Conclusions
Teleconsultation was feasible but technical performance and reliability have to be improved. The approach led to better stroke specific information; however, a superiority over regular EMS care was not found and in-hospital time intervals were unacceptably long in both groups. The feasibility of prehospital tele-stroke consultation has future potential to improve emergency care especially when no highly trained personnel are on-scene.
Trial Registration
International Standard Randomised Controlled Trial Number Register (ISRCTN) ISRCTN83270177 83270177.
doi:10.1371/journal.pone.0036796
PMCID: PMC3356340  PMID: 22629331
22.  High Postoperative Blood Levels of Macrophage Migration Inhibitory Factor Are Associated with Less Organ Dysfunction in Patients after Cardiac Surgery 
Molecular Medicine  2012;18(1):843-850.
Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine that exerts protective effects during myocardial ischemia/reperfusion injury. We hypothesized that elevated MIF levels in the early postoperative time course might be inversely associated with postoperative organ dysfunction as assessed by the simplified acute physiology score (SAPS) II and sequential organ failure assessment (SOFA) score in patients after cardiac surgery. A total of 52 cardiac surgical patients (mean age [± SD] 67 ± 10 years; EuroScore: 7 [2–11]) were enrolled in this monocenter, prospective observational study. Serum levels of MIF and clinical data were obtained after induction of anesthesia, at admission to the intensive care unit (ICU), 4 h after admission and at the first and second postoperative day. To characterize the magnitude of MIF release, we compared blood levels of samples from cardiac surgical patients with those obtained from healthy volunteers. We assessed patient outcomes using the SAPS II at postoperative d 1 and SOFA score for the first 3 d of the eventual ICU stay. Compared to healthy volunteers, patients had already exhibited elevated MIF levels prior to surgery (64 ± 50 versus 13 ± 17 ng/mL; p < 0.05). At admission to the ICU, MIF levels reached peak values (107 ± 95 ng/mL; p < 0.01 versus baseline) that decreased throughout the observation period and had already reached preoperative values 4 h later. Postoperative MIF values were inversely correlated with SAPS II and SOFA scores during the early postoperative stay. Moreover, MIF values on postoperative d 1 were related to the calculated cardiac power index (r = 0.420, p < 0.05). Elevated postoperative MIF levels are inversely correlated with organ dysfunction in patients after cardiac surgery.
doi:10.2119/molmed.2012.00071
PMCID: PMC3409286  PMID: 22526918
23.  Dexmedetomidine is neuroprotective in an in vitro model for traumatic brain injury 
BMC Neurology  2012;12:20.
Background
The α2-adrenoreceptor agonist dexmedetomidine is known to provide neuroprotection under ischemic conditions. In this study we investigated whether dexmedetomidine has a protective effect in an in vitro model for traumatic brain injury.
Methods
Organotypic hippocampal slice cultures were subjected to a focal mechanical trauma and then exposed to varying concentrations of dexmedetomidine. After 72 h cell injury was assessed using propidium iodide. In addition, the effects of delayed dexmedetomidine application, of hypothermia and canonical signalling pathway inhibitors were examined.
Results
Dexmedetomidine showed a protective effect on traumatically injured hippocampal cells with a maximum effect at a dosage of 1 μM. This effect was partially reversed by the simultaneous administration of the ERK inhibitor PD98059.
Conclusion
In this TBI model dexmedetomidine had a significant neuroprotective effect. Our results indicate that activation of ERK might be involved in mediating this effect.
doi:10.1186/1471-2377-12-20
PMCID: PMC3350422  PMID: 22494498
Neuroprotection; Traumatic brain injury; Dexmedetomidine
24.  Blood Levels of Macrophage Migration Inhibitory Factor after Successful Resuscitation from Cardiac Arrest 
PLoS ONE  2012;7(4):e33512.
Introduction
Ischemia-reperfusion injury following cardiopulmonary resuscitation (CPR) is associated with a systemic inflammatory response, resulting in post-resuscitation disease. In the present study we investigated the response of the pleiotropic inflammatory cytokine macrophage migration inhibitory factor (MIF) to CPR in patients admitted to the hospital after out-of-hospital cardiac arrest (OHCA). To describe the magnitude of MIF release, we compared the blood levels from CPR patients with those obtained in healthy volunteers and with an aged- and gender-matched group of patients undergoing cardiac surgery with the use of extracorporeal circulation.
Methods
Blood samples of 17 patients with return of spontaneous circulation (ROSC) after OHCA were obtained upon admission to the intensive care unit, and 6, 12, 24, 72 and 96 h later. Arrest and treatment related data were documented according to the Utstein style.
Results
In patients after ROSC, MIF levels at admission (475.2±157.8 ng/ml) were significantly higher than in healthy volunteers (12.5±16.9 ng/ml, p<0.007) and in patients after cardiac surgery (78.2±41.6 ng/ml, p<0.007). Six hours after admission, MIF levels were decreased by more than 50% (150.5±127.2 ng/ml, p<0.007), but were not further reduced in the subsequent time course and remained significantly higher than the values observed during the ICU stay of cardiac surgical patients. In this small group of patients, MIF levels could not discriminate between survivors and non-survivors and were not affected by treatment with mild therapeutic hypothermia.
Conclusion
MIF shows a rapid and pronounced increase following CPR, hence allowing a very early assessment of the inflammatory response. Further studies are warranted in larger patient groups to determine the prognostic significance of MIF.
Trial Registration
ClinicalTrials.gov NCT01412619
doi:10.1371/journal.pone.0033512
PMCID: PMC3323606  PMID: 22506003
25.  Does a 4 diagram manual enable laypersons to operate the laryngeal mask supreme®? A pilot study in the manikin 
Background
Bystander resuscitation plays an important role in lifesaving cardiopulmonary resuscitation (CPR). A significant reduction in the "no-flow-time", quantitatively better chest compressions and an improved quality of ventilation can be demonstrated during CPR using supraglottic airway devices (SADs). Previous studies have demonstrated the ability of inexperienced persons to operate SADs after brief instruction. The aim of this pilot study was to determine whether an instruction manual consisting of four diagrams enables laypersons to operate a Laryngeal Mask Supreme® (LMAS) in the manikin.
Methods
An instruction manual of four illustrations with speech bubbles displaying the correct use of the LMAS was designed. Laypersons were handed a bag containing a LMAS, a bag mask valve device (BMV), a syringe prefilled with air and the instruction sheet, and were asked to perform and ventilate the manikin as displayed. Time to ventilation was recorded and degree of success evaluated.
Results
A total of 150 laypersons took part. Overall 145 participants (96.7%) inserted the LMAS in the manikin in the right direction. The device was inserted inverted or twisted in 13 (8.7%) attempts. Eight (5.3%) individuals recognized this and corrected the position. Within the first 2 minutes 119 (79.3%) applicants were able to insert the LMAS and provide tidal volumes greater than 150 ml (estimated dead space). Time to insertion and first ventilation was 83.2 ± 29 s. No significant difference related to previous BLS training (P = 0.85), technical education (P = 0.07) or gender could be demonstrated (P = 0.25).
Conclusion
In manikin laypersons could insert LMAS in the correct direction after onsite instruction by a simple manual with a high success rate. This indicates some basic procedural understanding and intellectual transfer in principle. Operating errors (n = 91) were frequently not recognized and corrected (n = 77). Improvements in labeling and the quality of instructional photographs may reduce individual error and may optimize understanding.
doi:10.1186/1757-7241-20-21
PMCID: PMC3375204  PMID: 22453060

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