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1.  Neuroprotective Effect of Dexmedetomidine on Hyperoxia-Induced Toxicity in the Neonatal Rat Brain 
Dexmedetomidine is a highly selective agonist of α2-receptors with sedative, anxiolytic, analgesic, and anesthetic properties. Neuroprotective effects of dexmedetomidine have been reported in various brain injury models. In the present study, we investigated the effects of dexmedetomidine on neurodegeneration, oxidative stress markers, and inflammation following the induction of hyperoxia in neonatal rats. Six-day-old Wistar rats received different concentrations of dexmedetomidine (1, 5, or 10 µg/kg bodyweight) and were exposed to 80% oxygen for 24 h. Sex-matched littermates kept in room air and injected with normal saline or dexmedetomidine served as controls. Dexmedetomidine pretreatment significantly reduced hyperoxia-induced neurodegeneration in different brain regions of the neonatal rat. In addition, dexmedetomidine restored the reduced/oxidized glutathione ratio and attenuated the levels of malondialdehyde, a marker of lipid peroxidation, after exposure to high oxygen concentration. Moreover, administration of dexmedetomidine induced downregulation of IL-1β on mRNA and protein level in the developing rat brain. Dexmedetomidine provides protections against toxic oxygen induced neonatal brain injury which is likely associated with oxidative stress signaling and inflammatory cytokines. Our results suggest that dexmedetomidine may have a therapeutic potential since oxygen administration to neonates is sometimes inevitable.
doi:10.1155/2015/530371
PMCID: PMC4310240  PMID: 25653737
2.  Voluntary peer review as innovative tool for quality improvement in the intensive care unit – a retrospective descriptive cohort study in German intensive care units 
GMS German Medical Science  2014;12:Doc17.
Introduction: Quality improvement and safety in intensive care are rapidly evolving topics. However, there is no gold standard for assessing quality improvement in intensive care medicine yet. In 2007 a pilot project in German intensive care units (ICUs) started using voluntary peer reviews as an innovative tool for quality assessment and improvement. We describe the method of voluntary peer review and assessed its feasibility by evaluating anonymized peer review reports and analysed the thematic clusters highlighted in these reports.
Methods: Retrospective data analysis from 22 anonymous reports of peer reviews. All ICUs – representing over 300 patient beds – had undergone voluntary peer review. Data were retrieved from reports of peers of the review teams and representatives of visited ICUs. Data were analysed with regard to number of topics addressed and results of assessment questionnaires. Reports of strengths, weaknesses, opportunities and threats (SWOT reports) of these ICUs are presented.
Results: External assessment of structure, process and outcome indicators revealed high percentages of adherence to predefined quality goals. In the SWOT reports 11 main thematic clusters were identified representative for common ICUs. 58.1% of mentioned topics covered personnel issues, team and communication issues as well as organisation and treatment standards. The most mentioned weaknesses were observed in the issues documentation/reporting, hygiene and ethics. We identified several unique patterns regarding quality in the ICU of which long-term personnel problems und lack of good reporting methods were most interesting
Conclusion: Voluntary peer review could be established as a feasible and valuable tool for quality improvement. Peer reports addressed common areas of interest in intensive care medicine in more detail compared to other methods like measurement of quality indicators.
doi:10.3205/000202
PMCID: PMC4270273  PMID: 25587245
peer review; critical care; patient safety; quality improvement; quality management
3.  Early administration of levosimendan is associated with improved kidney function after cardiac surgery – a retrospective analysis 
Background
Several animal studies suggest beneficial effects on kidney function upon administration of levosimendan. As recent data from clinical studies are heterogeneous, we sought to investigate whether levosimendan is associated with improved postoperative kidney function in cardiac surgery patients with respect to timing of its administration.
Methods
Retrospective, single centre, observational analysis at a university hospital in Berlin, Germany. All adult patients without preoperative renal dysfunction that underwent coronary artery bypass grafting and/or valve reconstruction/replacement between 01/01/2007 and 31/12/2011 were considered for analyses.
Results
Out of 1.095 included patients, 46 patients were treated with levosimendan due to a severely reduced left ventricular systolic function preoperatively (LVEF < 35%) and/or clinical signs of a low cardiac output syndrome. Sixty-one percent received the drug whilst in the OR, 39% after postoperative intensive care unit admission. When levosimendan was given immediately after anaesthesia induction, creatinine plasma levels (p = 0.009 for nonparametric analysis of longitudinal data in a two-factorial design) and incidence of postoperative renal dysfunction (67.9% vs. 94.4%; p = 0.033) were significantly reduced in contrast to a later start of treatment. In addition, duration of renal replacement therapy was significantly shorter (79 [35;332] vs. 272 [132;703] minutes; p = 0.046) in that group.
Conclusions
Postoperative kidney dysfunction is a common condition in patients under going cardiac surgery. Patients with severely reduced left ventricular function and/or clinical signs of a low cardiac output syndrome who preoperatively presented with a normal kidney function may benefit from an early start of levosimendan administration, i.e. immediately after anaesthesia.
Trial registration
Clinicaltrials.gov-ID: NCT01918618.
doi:10.1186/s13019-014-0167-8
PMCID: PMC4240807  PMID: 25399779
Levosimendan; Kidney function; Renal effects; Cardiac surgery; Left ventricular ejection fraction
4.  Delirium, Sedation and Analgesia in the Intensive Care Unit: A Multinational, Two-Part Survey among Intensivists 
PLoS ONE  2014;9(11):e110935.
Analgesia, sedation and delirium management are important parts of intensive care treatment as they are relevant for patients' clinical and functional long-term outcome. Previous surveys showed that despite this fact implementation rates are still low. The primary aim of the prospective, observational multicenter study was to investigate the implementation rate of delirium monitoring among intensivists. Secondly, current practice concerning analgesia and sedation monitoring as well as treatment strategies for patients with delirium were assesed. In addition, this study compares perceived and actual practice regarding delirium, sedation and analgesia management. Data were obtained with a two-part, anonymous survey, containing general data from intensive care units in a first part and data referring to individual patients in a second part. Questionnaires from 101 hospitals (part 1) and 868 patients (part 2) were included in data analysis. Fifty-six percent of the intensive care units reported to monitor for delirium in clinical routine. Fourty-four percent reported the use of a validated delirium score. In this respect, the survey suggests an increasing use of delirium assessment tools compared to previous surveys. Nevertheless, part two of the survey revealed that in actual practice 73% of included patients were not monitored with a validated score. Furthermore, we observed a trend towards moderate or deep sedation which is contradicting to guideline-recommendations. Every fifth patient was suffering from pain. The implementation rate of adequate pain-assessment tools for mechanically ventilated and sedated patients was low (30%). In conclusion, further efforts are necessary to implement guideline recommendations into clinical practice. The study was registered (ClinicalTrials.gov identifier: NCT01278524) and approved by the ethical committee.
doi:10.1371/journal.pone.0110935
PMCID: PMC4232258  PMID: 25398099
5.  Intravenous Lormetazepam during Sedation Weaning in a 26-Year-Old Critically Ill Woman 
Case Reports in Critical Care  2014;2014:372740.
Recent evidence revealed that sedation is related to adverse outcomes including a higher mortality. Despite this fact, patients sometimes require deep sedation for a limited period of time to control, for example, intracranial hypertension. In particular in these cases, weaning from sedation is often challenging due to emerging agitation, stress, and delirium. The submitted research letter reports a rare case of severe and persisting agitation that was unresponsive to all available treatments. Ultimately, lormetazepam which has recently become available for intravenous use in Germany resolved the problem by stress-reduction and anxiolysis without leading to measurable sedation.
doi:10.1155/2014/372740
PMCID: PMC4206932  PMID: 25374699
6.  Wake up your patients! 
doi:10.5935/0103-507X.20140050
PMCID: PMC4304458  PMID: 25607259
7.  Evaluation of medical research performance – position paper of the Association of the Scientific Medical Societies in Germany (AWMF) 
GMS German Medical Science  2014;12:Doc11.
Objective: The evaluation of medical research performance is a key prerequisite for the systematic advancement of medical faculties, research foci, academic departments, and individual scientists’ careers. However, it is often based on vaguely defined aims and questionable methods and can thereby lead to unwanted regulatory effects. The current paper aims at defining the position of German academic medicine toward the aims, methods, and consequences of its evaluation.
Methods: During the Berlin Forum of the Association of the Scientific Medical Societies in Germany (AWMF) held on 18 October 2013, international experts presented data on methods for evaluating medical research performance. Subsequent discussions among representatives of relevant scientific organizations and within three ad-hoc writing groups led to a first draft of this article. Further discussions within the AWMF Committee for Evaluation of Performance in Research and Teaching and the AWMF Executive Board resulted in the final consented version presented here.
Results: The AWMF recommends modifications to the current system of evaluating medical research performance. Evaluations should follow clearly defined and communicated aims and consist of both summative and formative components. Informed peer reviews are valuable but feasible in longer time intervals only. They can be complemented by objective indicators. However, the Journal Impact Factor is not an appropriate measure for evaluating individual publications or their authors. The scientific “impact” rather requires multidimensional evaluation. Indicators of potential relevance in this context may include, e.g., normalized citation rates of scientific publications, other forms of reception by the scientific community and the public, and activities in scientific organizations, research synthesis and science communication. In addition, differentiated recommendations are made for evaluating the acquisition of third-party funds and the promotion of junior scientists.
Conclusions: With the explicit recommendations presented in the current position paper, the AWMF suggests enhancements to the practice of evaluating medical research performance by faculties, ministries and research funding organizations.
doi:10.3205/000196
PMCID: PMC4071625  PMID: 24971044
8.  Standard operating procedures for antibiotic therapy and the occurrence of acute kidney injury: a prospective, clinical, non-interventional, observational study 
Critical Care  2014;18(3):R120.
Introduction
Acute kidney injury (AKI) occurs in 7% of hospitalized and 66% of Intensive Care Unit (ICU) patients. It increases mortality, hospital length of stay, and costs. The aim of this study was to investigate, whether there is an association between adherence to guidelines (standard operating procedures (SOP)) for potentially nephrotoxic antibiotics and the occurrence of AKI.
Methods
This study was carried out as a prospective, clinical, non-interventional, observational study. Data collection was performed over a total of 170 days in three ICUs at Charité – Universitaetsmedizin Berlin. A total of 675 patients were included; 163 of these had therapy with vancomycin, gentamicin, or tobramycin; were >18 years; and treated in the ICU for >24 hours. Patients with an adherence to SOP >70% were classified into the high adherence group (HAG) and patients with an adherence of <70% into the low adherence group (LAG). AKI was defined according to RIFLE criteria. Adherence to SOPs was evaluated by retrospective expert audit. Development of AKI was compared between groups with exact Chi2-test and multivariate logistic regression analysis (two-sided P <0.05).
Results
LAG consisted of 75 patients (46%) versus 88 HAG patients (54%). AKI occurred significantly more often in LAG with 36% versus 21% in HAG (P = 0.035). Basic characteristics were comparable, except an increased rate of soft tissue infections in LAG. Multivariate analysis revealed an odds ratio of 2.5-fold for LAG to develop AKI compared with HAG (95% confidence interval 1.195 to 5.124, P = 0.039).
Conclusion
Low adherence to SOPs for potentially nephrotoxic antibiotics was associated with a higher occurrence of AKI.
Trial registration
Current Controlled Trials ISRCTN54598675. Registered 17 August 2007.
doi:10.1186/cc13918
PMCID: PMC4095670  PMID: 24923469
9.  Inflammation-Induced Acute Phase Response in Skeletal Muscle and Critical Illness Myopathy 
PLoS ONE  2014;9(3):e92048.
Objectives
Systemic inflammation is a major risk factor for critical-illness myopathy (CIM) but its pathogenic role in muscle is uncertain. We observed that interleukin 6 (IL-6) and serum amyloid A1 (SAA1) expression was upregulated in muscle of critically ill patients. To test the relevance of these responses we assessed inflammation and acute-phase response at early and late time points in muscle of patients at risk for CIM.
Design
Prospective observational clinical study and prospective animal trial.
Setting
Two intensive care units (ICU) and research laboratory.
Patients/Subjects
33 patients with Sequential Organ Failure Assessment scores ≥8 on 3 consecutive days within 5 days in ICU were investigated. A subgroup analysis of 12 patients with, and 18 patients without CIM (non-CIM) was performed. Two consecutive biopsies from vastus lateralis were obtained at median days 5 and 15, early and late time points. Controls were 5 healthy subjects undergoing elective orthopedic surgery. A septic mouse model and cultured myoblasts were used for mechanistic analyses.
Measurements and Main Results
Early SAA1 expression was significantly higher in skeletal muscle of CIM compared to non-CIM patients. Immunohistochemistry showed SAA1 accumulations in muscle of CIM patients at the early time point, which resolved later. SAA1 expression was induced by IL-6 and tumor necrosis factor-alpha in human and mouse myocytes in vitro. Inflammation-induced muscular SAA1 accumulation was reproduced in a sepsis mouse model.
Conclusions
Skeletal muscle contributes to general inflammation and acute-phase response in CIM patients. Muscular SAA1 could be important for CIM pathogenesis.
Trial Registration
ISRCTN77569430.
doi:10.1371/journal.pone.0092048
PMCID: PMC3961297  PMID: 24651840
10.  Inhibition of Acetylcholinesterase Modulates NMDA Receptor Antagonist Mediated Alterations in the Developing Brain 
Exposure to N-methyl-d-aspartate (NMDA) receptor antagonists has been demonstrated to induce neurodegeneration in newborn rats. However, in clinical practice the use of NMDA receptor antagonists as anesthetics and sedatives cannot always be avoided. The present study investigated the effect of the indirect cholinergic agonist physostigmine on neurotrophin expression and the extracellular matrix during NMDA receptor antagonist induced injury to the immature rat brain. The aim was to investigate matrix metalloproteinase (MMP)-2 activity, as well as expression of tissue inhibitor of metalloproteinase (TIMP)-2 and brain-derived neurotrophic factor (BDNF) after co-administration of the non-competitive NMDA receptor antagonist MK801 (dizocilpine) and the acetylcholinesterase (AChE) inhibitor physostigmine. The AChE inhibitor physostigmine ameliorated the MK801-induced reduction of BDNF mRNA and protein levels, reduced MK801-triggered MMP-2 activity and prevented decreased TIMP-2 mRNA expression. Our results indicate that AChE inhibition may prevent newborn rats from MK801-mediated brain damage by enhancing neurotrophin-associated signaling pathways and by modulating the extracellular matrix.
doi:10.3390/ijms15033784
PMCID: PMC3975367  PMID: 24595240
developing brain; NMDA receptor; MK801; acetylcholinesterase; extracellular matrix; BDNF; neuroprotection
11.  Anesthesiology residents’ perspective about good teaching – a qualitative needs assessment 
GMS German Medical Science  2014;12:Doc05.
Background: Germany, like many other countries, will soon have a shortage of qualified doctors. One reason for the dissatisfaction amongst medical residents are the relatively unstructured residency training programs despite increasing importance of outcome-based education. The aim of our study was to identify characteristics and requirements for good teaching during anesthesiology residency training from the resident’s point of view.
Methods: A consensus workshop with residents from all medical universities in Germany was held. Participants were allocated to one of the three topics, chosen based on a 2009 nationwide evaluation of residency. The three topics were (A) characteristics of helpful/good teachers, (B) characteristics of helpful/good conditions and (C) characteristics of helpful/good curricular structure. Each group followed a nominal group technique consensus process to define and rank characteristics for a good residency.
Results: 31 (79.5%) resident representatives were present. The consented results put emphasis on the importance of structured curricula including transparent goals and objectives, in training formative assessments and quality assurance measures for the program. Residents further long for trained trainers with formal teaching qualifications and protected teaching time.
Conclusions: Good residency training requires careful consideration of all stakeholders’ needs. Results reflect and extend previous findings and are at least to some degree easily implemented. These findings are an important step to establish a broader consensus within the discipline.
doi:10.3205/000190
PMCID: PMC3935158  PMID: 24574941
residents; curriculum development; needs assessment; anesthesiology; consensus
12.  A Modified Approach to Induce Predictable Congestive Heart Failure by Volume Overload in Rats 
PLoS ONE  2014;9(1):e87531.
The model of infrarenal aortocaval fistula (ACF) has recently gained new interest in its use to investigate cardiac pathophysiology. Since in previous investigations the development of congestive heart failure (CHF) was inconsistent and started to develop earliest 8–10 weeks after fistula induction using a 18G needle, this project aimed to induce a predictable degree of CHF within a definite time period using a modified approach. An aortocaval fistula was induced in male Wistar rats using a 16G needle as a modification of the former 18G needle-technique described by Garcia and Diebold. Results revealed within 28±2 days of ACF significantly increased heart and lung weight indices in the ACF group accompanied by elevated filling pressure. All hemodynamic parameters derived from a pressure-volume conductance-catheter in vivo were significantly altered in the ACF consistent with severe systolic and diastolic left ventricular dysfunction. This was accompanied by systemic neurohumoral activation as demonstrated by elevated rBNP-45 plasma concentrations in every rat of the ACF group. Furthermore, the restriction in overall cardiac function was associated with a β1- and β2-adrenoreceptor mRNA downregulation in the left ventricle. In contrast, β3-adrenoreceptor mRNA was upregulated. Finally, electron microscopy of the left ventricle of rats in the ACF group showed signs of progressive subcellular myocardial fragmentation. In conclusion, the morphometric, hemodynamic and neurohumoral characterization of the modified approach revealed predictable and consistent signs of congestive heart failure within 28±2 days. Therefore, this modified approach might facilitate the examination of various questions specific to CHF and allow for pharmacological interventions to determine pathophysiological pathways.
doi:10.1371/journal.pone.0087531
PMCID: PMC3909118  PMID: 24498127
13.  Prediction of Long-Term Mortality by Preoperative Health-Related Quality-of-Life in Elderly Onco-Surgical Patients 
PLoS ONE  2014;9(1):e85456.
Objective
Aim of this study was to evaluate the association between preoperative health-related quality of life (HRQoL) and mortality in a cohort of elderly patients (>65 years) with gastrointestinal, gynecological and genitourinary carcinomas.
Design
Prospective cohort pilot study.
Setting
Tertiary university hospital in Germany.
Patients
Between June 2008 and July 2010 and after ethical committee approval and written informed consent, 126 patients scheduled for onco-surgery were included. Prior to surgery as well as 3 and 12 months postoperatively all participants completed the EORTC-QLQ-C30 questionnaire (measuring self-reported health-related quality of life). Additionally, demographic and clinical data including the Mini Mental State Examination (MMSE) were collected. Surgery and anesthesia were conducted according to the standard operating procedures. Primary endpoint was the cumulative mortality rate over 12 months after one year. Changes in Quality of life were considered as secondary outcome.
Results
Mortality after one year was 28%. In univariable and multivariable logistic regression analysis baseline HRQoL self-reported cognitive function (OR per point: 0.98; CI 95% 0.96–0.99; p = 0.024) and higher symptom burden for appetite loss (per point: OR 1.02; CI 95% 1.00–1.03; p = 0.014) were predictive for long-term mortality. Additionally the MMSE as an objective measure of cognitive impairment (per point: OR 0.69; CI 95% 0.51–0.96; p = 0.026) as well as severity of surgery (OR 0.31; CI 95% 0.11–0.93; p = 0.036) were predictive for long-term mortality. Global health status 12 months after surgery was comparable to the baseline levels in survivors despite moderate impairments in other domains.
Conclusion
This study showed that objective and self-reported cognitive functioning together with appetite loss were prognostic for mortality in elderly cancer patients. In addition, impaired cognitive dysfunction and severity of surgery were predictive for one-year mortality whereas in this selected population scheduled for surgery age, gender, cancer site and metastases were not.
doi:10.1371/journal.pone.0085456
PMCID: PMC3896375  PMID: 24465568
14.  Dysfunction of alveolar macrophages after cardiac surgery and postoperative pneumonia? - an observational study 
Critical Care  2013;17(6):R285.
Introduction
Patients undergoing cardiac surgery have an increased risk of postoperative pneumonia. Pulmonary immune dysfunction might be a contributing factor. We therefore determined changes of the surface molecules on alveolar macrophages (AMs). To characterize modulation in patients with pneumonia we correlated these changes to the development of postoperative pneumonia.
Methods
After ethical approval and written informed consent, 33 patients undergoing elective coronary bypass grafting surgery were included in this observational study. Peripheral blood cells and alveolar lavage fluid were collected directly after induction of anesthesia and two hours after separation from cardiopulmonary bypass (CPB). Human leukocyte antigen-DR (HLA-DR) and toll-like receptors (TLR) 2/4 expression on monocytes and AM were assessed by flow cytometry. A total of three patients developed postoperative pneumonia determined according to the criteria of the Center of Disease Control. Statistical analysis was performed with the Mann–Whitney-U test and Wilcoxon test.
Results
We found significant changes of phenotypic and functional immune markers on AMs after cardiac surgery. HLA-DR expression on peripheral blood monocytes and AMs was significantly reduced compared to baseline in all patients (each approximately 30%). After surgery patients who developed postoperative pneumonia revealed a trend of stronger reduction of HLA-DR expression (83.7% versus 27.1%) and TLR4 expression on AMs (46.1% versus 9.9%) compared to patients without pneumonia. Already before surgery, the baseline of TLR2 expression on AM was significantly lower (27.7%) in patients who developed postoperative pneumonia.
Conclusions
As far as we know this is the first study that shows an early impairment of lung cellular immune response after cardiac surgery. These findings can help to understand the role of cell-mediated immunosuppression and its association to the development of postoperative pneumonia.
doi:10.1186/cc13148
PMCID: PMC4056566  PMID: 24321282
16.  The German quality indicators in intensive care medicine 2013 – second edition 
GMS German Medical Science  2013;11:Doc09.
Quality indicators are key elements of quality management. The quality indicators for intensive care medicine of the German Interdisciplinary Society of Intensive Care Medicine (DIVI) from the year 2010 were recently evaluated when their validity time expired after two years. Overall one indicator was replaced and further three were in part changed. The former indicator I “elevation of head of bed” was replaced by the indicator “Daily multi-professional ward rounds with the documentation of daily therapy goals” and added to the indicator IV “Weaning and other measures to prevent ventilator associated pneumonias (short: Weaning/VAP Bundle)” (VAP = ventilator-associated pneumonia) which aims at the reduction of VAP incidence. The indicator VIII “Documentation of structured relative-/next-of-kin communication” was refined. The indicator X “Direction of the ICU by a specially trained certified intensivist with no other clinical duties in a department” was also updated according to recent study results. These updated quality indicators are part of the Peer Review in intensive care medicine. The next update of the quality indicators is due in 2016.
doi:10.3205/000177
PMCID: PMC3728642  PMID: 23904823
quality management; intensive care medicine; quality indicators; peer review
17.  Immediate Outcome Indicators in Perioperative Care: A Controlled Intervention Study on Quality Improvement in Hospitals in Tanzania 
PLoS ONE  2013;8(6):e65428.
Introduction
Outcome assessment is the standard for evaluating the quality of health services worldwide. In this study, outcome has been divided into immediate and final outcome. Aim was to compare an intervention hospital with a Continuous Quality Improvement approach to a control group using benchmark assessments of immediate outcome indicators in surgical care. Results were compared to final outcome indicators.
Method
Surgical care quality in six hospitals in Tanzania was assessed from 2006–2011, using the Hospital Performance Assessment Tool. Independent observers assessed structural, process and outcome quality using checklists based on evidence-based guidelines. The number of surgical key procedures over the benchmark of 80% was compared between the intervention hospital and the control group. Results were compared to Case Fatality Rates.
Results
In the intervention hospital, in 2006, two of nine key procedures reached the benchmark, one in 2009, and four in 2011. In the control group, one of nine key procedures reached the benchmark in 2006, one in 2009, and none in 2011. Case Fatality Rate for all in-patients in the intervention hospital was 5.5% (n = 12,530) in 2006, 3.5% (n = 21,114) in 2009 and 4.6% (n = 18,840) in 2011. In the control group it was 3.1% (n = 17,827) in 2006, 4.2% (n = 13,632) in 2009 and 3.8% (n = 17,059) in 2011.
Discussion
Results demonstrated that quality assurance improved performance levels in both groups. After the introduction of Continuous Quality Improvement, performance levels improved further in the intervention hospital while quality in the district hospital did not. Immediate outcome indicators appeared to be a better steering tool for quality improvement compared to final outcome indicators. Immediate outcome indicators revealed a need for improvement in pre- and postoperative care.
Conclusion
Quality assurance programs based on immediate outcome indicators can be effective if embedded in Continuous Quality Improvement. Nevertheless, final outcome indicators cannot be neglected.
doi:10.1371/journal.pone.0065428
PMCID: PMC3680445  PMID: 23776482
18.  Acetylcholinesterase Inhibitors Reduce Neuroinflammation and -Degeneration in the Cortex and Hippocampus of a Surgery Stress Rat Model 
PLoS ONE  2013;8(5):e62679.
Exogenous stress like tissue damage and pathogen invasion during surgical trauma could lead to a peripheral inflammatory response and induce neuroinflammation, which can result in postoperative cognitive dysfunction (POCD). The cholinergic anti-inflammatory pathway is a neurohumoral mechanism that plays a prominent role by suppressing the inflammatory response. Treatments with acetylcholinesterase inhibitors enhance cholinergic transmission and may therefore act as a potential approach to prevent neuroinflammation. In the presence or absence of acetylcholinesterase inhibitors, adult Wistar rats underwent surgery alone or were additionally treated with lipopolysaccharide (LPS). Physostigmine, which can overcome the blood-brain barrier or neostigmine acting only peripheral, served as acetylcholinesterase inhibitors. The expression of pro- and anti-inflammatory cytokines in the cortex, hippocampus, spleen and plasma was measured after 1 h, 24 h, 3 d and 7 d using Real-Time PCR, western blot analysis or cytometric bead array (CBA). Fluoro-Jade B staining of brain slices was employed to elucidate neurodegeneration. The activity of acetylcholinesterase was estimated using a spectrofluorometric method. Surgery accompanied by LPS-treatment led to increased IL-1beta gene and protein upregulation in the cortex and hippocampus but was significantly reduced by physostigmine and neostigmine. Furthermore, surgery in combination with LPS-treatment caused increased protein expression of IL-1, TNF-alpha and IL-10 in the spleen and plasma. Physostigmine and neostigmine significantly decreased the protein expression of IL-1 and TNF-alpha. Neuronal degeneration and the activity of acetylcholinesterase were elevated after surgery with LPS-treatment and reduced by physostigmine and neostigmine. Along with LPS-treatment, acetylcholinesterase inhibitors reduce the pro-inflammatory response as well as neurodegeneration after surgery in the cortex and hippocampus. This combination may represent a tool to break the pathogenesis of POCD.
doi:10.1371/journal.pone.0062679
PMCID: PMC3643957  PMID: 23671623
19.  Persistence of Psychological Distress in Surgical Patients with Interest in Psychotherapy: Results of a 6-Month Follow-Up 
PLoS ONE  2012;7(12):e51167.
Objectives
This prospective observational study investigated whether self-reported psychological distress and alcohol use problems of surgical patients change between preoperative baseline assessment and postoperative 6-month follow-up examination. Patients with preoperative interest in psychotherapy were compared with patients without interest in psychotherapy.
Methods
A total of 1,157 consecutive patients from various surgical fields completed a set of psychiatric questionnaires preoperatively and at 6 months postoperatively, including Patient Health Questionnaire-4 (PHQ-4), Brief Symptom Inventory (BSI), Center for Epidemiologic Studies Depression Scale (CES-D), World Health Organization 5-item Well-Being Index (WHO-5), and Alcohol Use Disorder Identification Test (AUDIT). Additionally, patients were asked for their interest in psychotherapy. Repeated measure ANCOVA was used for primary data analysis.
Results
16.7% of the patients were interested in psychotherapy. Compared to uninterested patients, they showed consistently higher distress at both baseline and month 6 regarding all of the assessed psychological measures (p’s between <0.001 and 0.003). At 6-month follow-up, neither substantial changes over time nor large time x group interactions were found. Results of ANCOVA’s controlling for demographic variables were confirmed by analyses of frequencies of clinically significant distress.
Conclusion
In surgical patients with interest in psychotherapy, there is a remarkable persistence of elevated self-reported general psychological distress, depression, anxiety, and alcohol use disorder symptoms over 6 months. This suggests high and chronic psychiatric comorbidity and a clear need for psychotherapeutic and psychiatric treatment rather than transient worries posed by facing surgery.
doi:10.1371/journal.pone.0051167
PMCID: PMC3515556  PMID: 23227250
20.  Managing End-Of-Life Decision Making in Intensive Care Medicine – A Perspective from Charité Hospital, Germany 
PLoS ONE  2012;7(10):e46446.
Introduction
End-of-life-decisions (EOLD) have become an important part of modern intensive care medicine. With increasing therapeutic possibilities on the one hand and many ICU-patients lacking decision making capacity or an advance directive on the other the decision making process is a major challenge on the intensive care unit (ICU). Currently, data are poor on factors associated with EOLD in Germany. In 2009, a new law on advance directives binding physicians and the patient´s surrogate decision makers was enacted in Germany. So far it is unknown if this law influenced proceedings of EOLD making on the ICU.
Methods
A retrospective analysis was conducted on all deceased patients (n = 224) in a 22-bed surgical ICU of a German university medical center from 08/2008 to 09/2010. Patient characteristics were compared between patients with an EOLD and those without an EOLD. Patients with an EOLD admitted before and after change of legislation were compared with respect to frequencies of EOLD performance as well as advance directive rates.
Results
In total, 166 (74.1%) of deaths occurred after an EOLD. Compared to patients without an EOLD, comorbidities, ICU severity scores, and organ replacement technology did not differ significantly. EOLDs were shared within the caregiverteam and with the patient´s surrogate decision makers. After law enacting, no differences in EOLD performance or frequency of advance directives (8.9% vs. 9.9%; p = 0.807) were observed except an increase of documentation efforts associated with EOLDs (18.7% vs. 43.6%; p<0.001).
Conclusions
In our ICU EOLD proceedings were performed patient-individually. But EOLDs follow a standard of shared decision making within the caregiverteam and the patient´s surrogate decision makers. Enacting a law on advance directives has not affected the decision making-process in EOLDs nor has it affected population´s advance care planning habits. However, it has led to increased EOLD-associated documentation on the ICU.
Trail Registration
ClinicalTrials.gov NCT01294189.
doi:10.1371/journal.pone.0046446
PMCID: PMC3462175  PMID: 23049701
21.  Mortality after surgery in Europe: a 7 day cohort study 
Lancet  2012;380(9847):1059-1065.
Summary
Background
Clinical outcomes after major surgery are poorly described at the national level. Evidence of heterogeneity between hospitals and health-care systems suggests potential to improve care for patients but this potential remains unconfirmed. The European Surgical Outcomes Study was an international study designed to assess outcomes after non-cardiac surgery in Europe.
Methods
We did this 7 day cohort study between April 4 and April 11, 2011. We collected data describing consecutive patients aged 16 years and older undergoing inpatient non-cardiac surgery in 498 hospitals across 28 European nations. Patients were followed up for a maximum of 60 days. The primary endpoint was in-hospital mortality. Secondary outcome measures were duration of hospital stay and admission to critical care. We used χ2 and Fisher's exact tests to compare categorical variables and the t test or the Mann-Whitney U test to compare continuous variables. Significance was set at p<0·05. We constructed multilevel logistic regression models to adjust for the differences in mortality rates between countries.
Findings
We included 46 539 patients, of whom 1855 (4%) died before hospital discharge. 3599 (8%) patients were admitted to critical care after surgery with a median length of stay of 1·2 days (IQR 0·9–3·6). 1358 (73%) patients who died were not admitted to critical care at any stage after surgery. Crude mortality rates varied widely between countries (from 1·2% [95% CI 0·0–3·0] for Iceland to 21·5% [16·9–26·2] for Latvia). After adjustment for confounding variables, important differences remained between countries when compared with the UK, the country with the largest dataset (OR range from 0·44 [95% CI 0·19–1·05; p=0·06] for Finland to 6·92 [2·37–20·27; p=0·0004] for Poland).
Interpretation
The mortality rate for patients undergoing inpatient non-cardiac surgery was higher than anticipated. Variations in mortality between countries suggest the need for national and international strategies to improve care for this group of patients.
Funding
European Society of Intensive Care Medicine, European Society of Anaesthesiology.
doi:10.1016/S0140-6736(12)61148-9
PMCID: PMC3493988  PMID: 22998715
22.  Effects of intensivist coverage in a post-anaesthesia care unit on surgical patients' case mix and characteristics of the intensive care unit 
Critical Care  2012;16(4):R126.
Introduction
There is an increasing demand for intensive care in hospitals, which can lead to capacity limitations in the intensive care unit (ICU). Due to postponement of elective surgery or delayed admission of emergency patients, outcome may be negatively influenced. To optimize the admission process to intensive care, the post-anaesthesia care unit (PACU) was staffed with intensivist coverage around the clock. The aim of this study is to demonstrate the impact of the PACU on the structure of ICU-patients and the contribution to overall hospital profit in terms of changes in the case mix index for all surgical patients.
Methods
The administrative data of all surgical patients (n = 51,040) 20 months prior and 20 months after the introduction of a round-the-clock intensivist staffing of the PACU were evaluated and compared.
Results
The relative number of patients with longer length of stay (LOS) (more than seven days) in the ICU increased after the introduction of the PACU. The average monthly number of treatment days of patients staying less than 24 hours in the ICU decreased by about 50% (138.95 vs. 68.19 treatment days, P <0.005). The mean LOS in the PACU was 0.45 (± 0.41) days, compared to 0.27 (± 0.2) days prior to the implementation. The preoperative times in the hospital decreased significantly for all patients. The case mix index (CMI) per hospital day for all surgical patients was significantly higher after the introduction of a PACU: 0.286 (± 0.234) vs. 0.309 (± 0.272) P <0.001 CMI/hospital day.
Conclusions
The introduction of a PACU and the staffing with intensive care staff might shorten the hospital LOS for surgical patients. The revenues for the hospital, as determined by the case mix index of the patients per hospital day, increased after the implementation of a PACU and more patients can be treated in the same time, due to a better use of resources.
doi:10.1186/cc11428
PMCID: PMC3580709  PMID: 22809294
23.  Thawed solvent/detergent-treated plasma: too precious to be wasted after 6 hours? 
Blood Transfusion  2012;10(3):360-367.
Background.
Coagulopathy associated with trauma and bleeding requires early administration of haemostatic agents. Solvent/detergent-treated plasma (S/D-plasma) requires thawing and its availability for clinical use is, therefore, delayed. The long-term stability of clotting factors in thawed S/D-plasma has not been thoroughly investigated. The purpose of this study was to evaluate stability of clotting factors and inhibitors in thawed S/D-plasma stored at 4 °C for 6 days.
Materials and methods.
Clotting factor levels and bacterial contamination were investigated using 20 units of S/D-plasma. Fibrinogen, factor (F) II, FV, FVII, FVIII, FIX, FX, FXI, FXII, FXIII, antithrombin, von Willebrand antigen (VWF-Ag), plasmin inhibitor, protein C and free protein S were analysed over time.
Results.
After 6 days of storage the results were as follows: fibrinogen 270 mg/dL (−10 mg/dL, p=0.0204), FII 75% (−5%, p<0.0001), FV 88% (−14%, p<0.0001), FVII 81% (−24%, p<0.0001), FVIII 70% (−16%, p<0.0001), FIX 96% (−8, p<0.0001), FX 92% (−1%, p<0.0001), FXI 119% (−4%, p=0.3666), FXII 94% (−2%, p=0.3602), FXIII 89% (−1%, p 0.0019), free protein S 76% (−4%, p<0.0001), protein C 96% (+1%, p=0.0371), antithrombin 92% (−3%, p<0.0001), plasmin inhibitor 29% (−4%, p<0.0299), VWF-Ag 137% (+2%, p=0.2205). FVII and FVIII showed a critical drop of more than 20% or approached the lower quality assurance threshold after storage for more than 24 hours. No S/D-plasma showed bacterial contamination.
Conclusion.
All clotting factors in thawed S/D plasma remained stable for up to 24 hours when stored at 4 °C. Storage of thawed S/D plasma may improve the availability of this product in emergency situations.
doi:10.2450/2012.0092-11
PMCID: PMC3417736  PMID: 22507858
S/D-plasma; massive transfusion; plasma storage; clotting factors
24.  The paediatric Confusion Assessment Method for the Intensive Care Unit (pCAM-ICU): Translation and cognitive debriefing for the German-speaking area 
GMS German Medical Science  2012;10:Doc07.
Purpose: To date there are only a few studies published, dealing with delirium in critically ill patients. The problem with these studies is that prevalence rates of delirium could only be estimated because of the lack of validated delirium assessment tools for the paediatric intensive care unit (PICU). The paediatric Confusion Assessment Method for the Intensive Care Unit (pCAM-ICU) was specifically developed and validated for the detection of delirium in PICU patients. The purpose of this study was the translation of the English pCAM-ICU into German according to international validated guidelines.
Methods: The translation process was performed according to the principles of good practice for the translation and cultural adaptation process for patient reported outcomes measures: From three independently created German forward-translation versions one preliminary German version was developed, which was then retranslated to English by a certified, state-approved translator. The back-translated version was submitted to the original author for evaluation. The German translation was evaluated by clinicians and specialists anonymously (German grades) in regards to language and content of the translation.
Results: The results of the cognitive debriefing revealed good to very good results. After that the translation process was successfully completed and the final version of the German pCAM-ICU was adopted by the expert committee.
Conclusion: The German version of the pCAM-ICU is a result of a translation process in accordance with internationally acknowledged guidelines. Particularly, with respect to the excellent results of the cognitive debriefing, we could finalise the translation and cultural adaptation process for the German pCAM-ICU.
doi:10.3205/000158
PMCID: PMC3334933  PMID: 22557940
delirium; paediatric; pCAM-ICU; intensive care unit; translation
25.  Gastrointestinal function in intensive care patients: terminology, definitions and management. Recommendations of the ESICM Working Group on Abdominal Problems 
Intensive Care Medicine  2012;38(3):384-394.
Purpose
Acute gastrointestinal (GI) dysfunction and failure have been increasingly recognized in critically ill patients. The variety of definitions proposed in the past has led to confusion and difficulty in comparing one study to another. An international working group convened to standardize the definitions for acute GI failure and GI symptoms and to review the therapeutic options.
Methods
The Working Group on Abdominal Problems (WGAP) of the European Society of Intensive Care Medicine (ESICM) developed the definitions for GI dysfunction in intensive care patients on the basis of the available evidence and current understanding of the pathophysiology.
Results
Definitions for acute gastrointestinal injury (AGI) with its four grades of severity, as well as for feeding intolerance syndrome and GI symptoms (e.g. vomiting, diarrhoea, paralysis, high gastric residual volumes) are proposed. AGI is a malfunctioning of the GI tract in intensive care patients due to their acute illness. AGI grade I = increased risk of developing GI dysfunction or failure (a self-limiting condition); AGI grade II = GI dysfunction (a condition that requires interventions); AGI grade III = GI failure (GI function cannot be restored with interventions); AGI grade IV = dramatically manifesting GI failure (a condition that is immediately life-threatening). Current evidence and expert opinions regarding treatment of acute GI dysfunction are provided.
Conclusions
State-of-the-art definitions for GI dysfunction with gradation as well as management recommendations are proposed on the basis of current medical evidence and expert opinion. The WGAP recommends using these definitions for clinical and research purposes.
Electronic supplementary material
The online version of this article (doi:10.1007/s00134-011-2459-y) contains supplementary material, which is available to authorized users.
doi:10.1007/s00134-011-2459-y
PMCID: PMC3286505  PMID: 22310869
Gastrointestinal function; Failure; Symptoms; Feeding intolerance; Intensive care; Definitions; Classification

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