Publications by authors named "Konrad Meissner"

42 Publications

How relevant is stereoselectivity to the side-effects of ketamine?

Br J Anaesth 2021 May 5. Epub 2021 May 5.

Department of Anesthesiology, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.

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http://dx.doi.org/10.1016/j.bja.2021.03.017DOI Listing
May 2021

Gene Expression-Based Diagnosis of Infections in Critically Ill Patients-Prospective Validation of the SepsisMetaScore in a Longitudinal Severe Trauma Cohort.

Crit Care Med 2021 Apr 21. Epub 2021 Apr 21.

Division of Biomedical Informatics Research, Department of Medicine, Stanford University School of Medicine, Stanford, CA. Department of Anesthesiology, University Medical Centre, Georg August University, Goettingen, Germany. Center of Anesthesiology and Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Department of Anesthesiology and Intensive Care Medicine, Klinikum Region Hannover, Hannover, Germany. Department of Trauma Surgery, Orthopedics and Plastic Surgery, University Medical Center, Georg August University, Goettingen, Germany. Division of Biomedical Informatics, Stanford Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA. Department of Anesthesiology, Asklepios Hospitals Schildautal, Seesen, Germany.

Objectives: Early diagnosis of infections is pivotal in critically ill patients. Innovative gene expression-based approaches promise to deliver precise, fast, and clinically practicable diagnostic tools to bedside. This study aimed to validate the SepsisMetaScore, an 11-gene signature previously reported by our study group, in a representative longitudinal cohort of trauma patients.

Design: Prospective observational cohort study.

Setting: Surgical ICUs of the University Medical Center Goettingen, Germany.

Patients: Critically ill patients with severe traumatic injuries.

Interventions: None.

Measurements And Main Results: Paired box gene (PAXgene) RNA blood tubes were drawn at predefined time points over the course of disease. The performance of the SepsisMetaScore was tested using targeted polymerase chain reaction and compared with Procalcitonin using area under the receiver operating characteristics analyses. The SepsisMetaScore showed significant differences between infected and noninfected patients (n = 52). It was able to accurately discriminate infectious from noninfectious acute inflammation with an area under the receiver operating characteristics of 0.92 (95% CI, 0.85-0.99) and significantly outperformed Procalcitonin (area under the receiver operating characteristics curve = 0.53; 95% CI, 0.42-0.64) early in the course of infection (p = 0.014).

Conclusions: We demonstrated the clinical utility for diagnosis of infections with higher accuracy using the SepsisMetaScore compared with Procalcitonin in a prospective cohort of severe trauma patients. Future studies should assess whether the SepsisMetaScore may substantially improve clinical practice by accurate differentiation of infections from sterile inflammation and identification of patients at risk for sepsis. Our results support further investigation of the SepsisMetaScore for the development of tailored precision treatment of critically ill patients.
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http://dx.doi.org/10.1097/CCM.0000000000005027DOI Listing
April 2021

End-tidal to arterial PCO ratio: a bedside meter of the overall gas exchanger performance.

Intensive Care Med Exp 2021 Apr 19;9(1):21. Epub 2021 Apr 19.

Department of Anesthesiology, University Medical Center Göttingen, Robert Koch Straße 40, 37075, Göttingen, Germany.

Background: The physiological dead space is a strong indicator of severity and outcome of acute respiratory distress syndrome (ARDS). The "ideal" alveolar PCO, in equilibrium with pulmonary capillary PCO, is a central concept in the physiological dead space measurement. As it cannot be measured, it is surrogated by arterial PCO which, unfortunately, may be far higher than ideal alveolar PCO, when the right-to-left venous admixture is present. The "ideal" alveolar PCO equals the end-tidal PCO (PCO) only in absence of alveolar dead space. Therefore, in the perfect gas exchanger (alveolar dead space = 0, venous admixture = 0), the PCO/PaCO is 1, as PCO, PCO and PaCO are equal. Our aim is to investigate if and at which extent the PCO/PaCO, a comprehensive meter of the "gas exchanger" performance, is related to the anatomo physiological characteristics in ARDS.

Results: We retrospectively studied 200 patients with ARDS. The source was a database in which we collected since 2003 all the patients enrolled in different CT scan studies. The PCO/PaCO, measured at 5 cmHO airway pressure, significantly decreased from mild to mild-moderate moderate-severe and severe ARDS. The overall populations was divided into four groups (~ 50 patients each) according to the quartiles of the PCO/PaCO (lowest ratio, the worst = group 1, highest ratio, the best = group 4). The progressive increase PCO/PaCO from quartile 1 to 4 (i.e., the progressive approach to the "perfect" gas exchanger value of 1.0) was associated with a significant decrease of non-aerated tissue, inohomogeneity index and increase of well-aerated tissue. The respiratory system elastance significantly improved from quartile 1 to 4, as well as the PaO/FiO and PaCO. The improvement of PCO/PaCO was also associated with a significant decrease of physiological dead space and venous admixture. When PEEP was increased from 5 to 15 cmHO, the greatest improvement of non-aerated tissue, PaO and venous admixture were observed in quartile 1 of PCO/PaCO and the worst deterioration of dead space in quartile 4.

Conclusion: The ratio PCO/PaCO is highly correlated with CT scan, physiological and clinical variables. It appears as an excellent measure of the overall "gas exchanger" status.
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http://dx.doi.org/10.1186/s40635-021-00377-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054233PMC
April 2021

A Potential Role of the Renin-Angiotensin-System for Disturbances of Respiratory Chemosensitivity in Acute Respiratory Distress Syndrome and Severe Acute Respiratory Syndrome.

Front Physiol 2020 20;11:588248. Epub 2021 Jan 20.

Universitätsmedizin Göttingen, Klinik für Anästhesiologie, Georg-August-Universität, Göttingen, Germany.

Acute respiratory distress syndrome (ARDS) represents an acute diffuse inflammation of the lungs triggered by different causes, uniformly leading to a noncardiogenic pulmonary edema with inhomogeneous densities in lung X-ray and lung CT scan and acute hypoxemia. Edema formation results in "heavy" lungs, inducing loss of compliance and the need to spend more energy to "move" the lungs. Consequently, an ARDS patient, as long as the patient is breathing spontaneously, has an increased respiratory drive to ensure adequate oxygenation and CO removal. One would expect that, once the blood gases get back to "physiological" values, the respiratory drive would normalize and the breathing effort return to its initial status. However, in many ARDS patients, this is not the case; their respiratory drive appears to be upregulated and fully or at least partially detached from the blood gas status. Strikingly, similar alteration of the respiratory drive can be seen in patients suffering from SARS, especially SARS-Covid-19. We hypothesize that alterations of the renin-angiotensin-system (RAS) related to the pathophysiology of ARDS and SARS are involved in this dysregulation of chemosensitive control of breathing.
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http://dx.doi.org/10.3389/fphys.2020.588248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857271PMC
January 2021

The impact of ventilation-perfusion inequality in COVID-19: a computational model.

J Appl Physiol (1985) 2021 03 13;130(3):865-876. Epub 2021 Jan 13.

Department of Anesthesiology, Intensive Care and Emergency Medicine, University Medical Center of Göttingen, Göttingen, Germany.

COVID-19 infection may lead to acute respiratory distress syndrome (CARDS) where severe gas exchange derangements may be associated, at least in the early stages, only with minor pulmonary infiltrates. This may suggest that the shunt associated to the gasless lung parenchyma is not sufficient to explain CARDS hypoxemia. We designed an algorithm (VentQ), based on the same conceptual grounds described by J.B. West in 1969. We set 498 ventilation-perfusion (V/Q) compartments and, after calculating their blood composition (PO, PCO, and pH), we randomly chose 10 combinations of five parameters controlling a bimodal distribution of blood flow. The solutions were accepted if the predicted PaO and PaCO were within 10% of the patient's values. We assumed that the shunt fraction equaled the fraction of non-aerated lung tissue at the CT quantitative analysis. Five critically-ill patients later deceased were studied. The PaO/FiO was 91.1 ± 18.6 mmHg and PaCO 69.0 ± 16.1 mmHg. Cardiac output was 9.58 ± 0.99 L/min. The fraction of non-aerated tissue was 0.33 ± 0.06. The model showed that a large fraction of the blood flow was likely distributed in regions with very low V/Q (Q = 0.06 ± 0.02) and a smaller fraction in regions with moderately high V/Q. Overall LogSD, Q was 1.66 ± 0.14, suggestive of high V/Q inequality. Our data suggest that shunt alone cannot completely account for the observed hypoxemia and a significant V/Q inequality must be present in COVID-19. The high cardiac output and the extensive microthrombosis later found in the autopsy further support the hypothesis of a pathological perfusion of non/poorly ventilated lung tissue. Hypothesizing that the non-aerated lung fraction as evaluated by the quantitative analysis of the lung computed tomography (CT) equals shunt (V/Q = 0), we used a computational approach to estimate the magnitude of the ventilation-perfusion inequality in severe COVID-19. The results show that a severe hyperperfusion of poorly ventilated lung region is likely the cause of the observed hypoxemia. The extensive microthrombosis or abnormal vasodilation of the pulmonary circulation may represent the pathophysiological mechanism of such V/Q distribution.
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http://dx.doi.org/10.1152/japplphysiol.00871.2020DOI Listing
March 2021

Accuracy of zero-heat-flux thermometry and bladder temperature measurement in critically ill patients.

Sci Rep 2020 12 10;10(1):21746. Epub 2020 Dec 10.

Department of Anesthesiology, University Medical Center Göttingen, Robert-Koch Strasse 40, 37099, Göttingen, Germany.

Core temperature (T) monitoring is essential in intensive care medicine. Bladder temperature is the standard of care in many institutions, but not possible in all patients. We therefore compared core temperature measured with a zero-heat flux thermometer (T) and with a bladder catheter (T) against blood temperature (T) as a gold standard in 50 critically ill patients in a prospective, observational study. Every 30 min T, T and T were documented simultaneously. Bland-Altman statistics were used for interpretation. 7018 pairs of measurements for the comparison of T with T and 7265 pairs of measurements for the comparison of T with T could be used. T represented T more accurate than T. In the Bland Altman analyses the bias was smaller (0.05 °C vs. - 0.12 °C) and limits of agreement were narrower (0.64 °C to - 0.54 °C vs. 0.51 °C to - 0.76 °C), but not in clinically meaningful amounts. In conclusion the results for zero-heat-flux and bladder temperatures were virtually identical within about a tenth of a degree, although T tended to underestimate T. Therefore, either is suitable for clinical use.German Clinical Trials Register, DRKS00015482, Registered on 20th September 2018, http://apps.who.int/trialsearch/Trial2.aspx?TrialID=DRKS00015482 .
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http://dx.doi.org/10.1038/s41598-020-78753-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730188PMC
December 2020

Physiological and quantitative CT-scan characterization of COVID-19 and typical ARDS: a matched cohort study.

Intensive Care Med 2020 12 21;46(12):2187-2196. Epub 2020 Oct 21.

Department of Anesthesiology, Intensive Care and Emergency Medicine, Medical University of Göttingen, Robert-Koch Straße 40, Göttingen, Germany.

Purpose: To investigate whether COVID-19-ARDS differs from all-cause ARDS.

Methods: Thirty-two consecutive, mechanically ventilated COVID-19-ARDS patients were compared to two historical ARDS sub-populations 1:1 matched for PaO/FiO or for compliance of the respiratory system. Gas exchange, hemodynamics and respiratory mechanics were recorded at 5 and 15 cmHO PEEP. CT scan variables were measured at 5 cmHO PEEP.

Results: Anthropometric characteristics were similar in COVID-19-ARDS, PaO/FiO-matched-ARDS and Compliance-matched-ARDS. The PaO/FiO-matched-ARDS and COVID-19-ARDS populations (both with PaO/FiO 106 ± 59 mmHg) had different respiratory system compliances (Crs) (39 ± 11 vs 49.9 ± 15.4 ml/cmHO, p = 0.03). The Compliance-matched-ARDS and COVID-19-ARDS had similar Crs (50.1 ± 15.7 and 49.9 ± 15.4 ml/cmHO, respectively) but significantly lower PaO/FiO for the same Crs (160 ± 62 vs 106.5 ± 59.6 mmHg, p < 0.001). The three populations had similar lung weights but COVID-19-ARDS had significantly higher lung gas volume (PaO/FiO-matched-ARDS 930 ± 644 ml, COVID-19-ARDS 1670 ± 791 ml and Compliance-matched-ARDS 1301 ± 627 ml, p < 0.05). The venous admixture was significantly related to the non-aerated tissue in PaO/FiO-matched-ARDS and Compliance-matched-ARDS (p < 0.001) but unrelated in COVID-19-ARDS (p = 0.75), suggesting that hypoxemia was not only due to the extent of non-aerated tissue. Increasing PEEP from 5 to 15 cmHO improved oxygenation in all groups. However, while lung mechanics and dead space improved in PaO/FiO-matched-ARDS, suggesting recruitment as primary mechanism, they remained unmodified or worsened in COVID-19-ARDS and Compliance-matched-ARDS, suggesting lower recruitment potential and/or blood flow redistribution.

Conclusions: COVID-19-ARDS is a subset of ARDS characterized overall by higher compliance and lung gas volume for a given PaO/FiO, at least when considered within the timeframe of our study.
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http://dx.doi.org/10.1007/s00134-020-06281-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577365PMC
December 2020

Mobilizing Carbon Dioxide Stores. An Experimental Study.

Am J Respir Crit Care Med 2021 02;203(3):318-327

Department of Anesthesiology and Intensive Care, Medical University of Göttingen, Göttingen, Germany.

Understanding the physiology of CO stores mobilization is a prerequisite for intermittent extracorporeal CO removal (ECCOR) in patients with chronic hypercapnia. To describe the dynamics of CO stores. Fifteen pigs (61.7 ± 4.3 kg) were randomized to 48 hours of hyperventilation (group "Hyper,"  = 4); 48 hours of hypoventilation (group "Hypo,"  = 4); 24 hours of hypoventilation plus 24 hours of normoventilation (group "Hypo-Baseline,"  = 4); or 24 hours of hypoventilation plus 24 hours of hypoventilation plus ECCOR (group "Hypo-ECCOR,"  = 3). Forty-eight hours after randomization, the current [Formula: see text]e was reduced by 50% in every pig. We evaluated [Formula: see text]co, [Formula: see text]o, and metabolic [Formula: see text]co ([Formula: see text]o times the metabolic respiratory quotient). Changes in the CO stores were calculated as [Formula: see text]co - metabolic V̇co. After 48 hours, the CO stores decreased by 0.77 ± 0.17 l kg in group Hyper and increased by 0.32 ± 0.27 l kg in group Hypo ( = 0.030). In group Hypo-Baseline, they increased by 0.08 ± 0.19 l kg, whereas in group Hypo-ECCOR, they decreased by 0.32 ± 0.24 l kg ( = 0.197). In the second 24-hour period, in groups Hypo-Baseline and Hypo-ECCOR, the CO2 stores decreased by 0.15 ± 0.09 l kg and 0.51 ± 0.06 l kg, respectively ( = 0.002). At the end of the experiment, the 50% reduction of [Formula: see text]e caused a Pa rise of 9.3 ± 1.1, 32.0 ± 5.0, 16.9 ± 1.2, and 11.7 ± 2.0 mm Hg h in groups Hyper, Hypo, Hypo-Baseline, and Hypo-ECCOR, respectively ( < 0.001). The Pa rise was inversely related to the previous CO stores mobilization ( < 0.001). CO from body stores can be mobilized over 48 hours without reaching a steady state. This provides a physiological rationale for intermittent ECCOR in patients with chronic hypercapnia.
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http://dx.doi.org/10.1164/rccm.202005-1687OCDOI Listing
February 2021

The baby lung and the COVID-19 era.

Intensive Care Med 2020 Jul 25;46(7):1438-1440. Epub 2020 May 25.

Regions Hospital, St. Paul, MN, USA.

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http://dx.doi.org/10.1007/s00134-020-06103-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246291PMC
July 2020

Development of the Greifswald questionnaire for the measurement of interprofessional attitudes.

GMS J Med Educ 2020 17;37(1):Doc7. Epub 2020 Feb 17.

Universität Greifswald, Institut für Psychologie, Greifswald, Germany.

The implementation of interprofessional education (IPE) could be a potential approach to dealing with increasing complexity in health care. And thus, encouraging interprofessional collaborations to minimize errors in patient care. However, empirical evidence regarding the effectiveness of IPE is inconclusive. One reason for this is a lack of valid and reliable evaluation instruments. This study aims to illustrate the first steps of the development and validation of a German evaluation instrument for the measurement of interprofessional attitudes. To achieve high psychometric quality, we first selected relevant attitude dimensions and specified criteria for the wording of the items. The a priori developed factor structure was evaluated via factor analysis and the internal consistencies of the scales were analysed in a sample of medical students and nursing trainees, both participants of an IPE course (n=338). Stability was evaluated in an additional sample of nursing trainees (n=14). The Factor analysis revealed three dimensions. Whereby, the two factors "Relevance of learning interprofessional communicational techniques" (German: Wichtigkeit Techniken interprofessioneller Kommunikation zu lernen) (α=.85) and "Doubts, dismissal and perceived barriers" (German: Zweifel, Ablehnung und wahrgenommene Barrieren) (α=.73) revealed good to acceptable internal consistency. Third-factor "Attitude towards another profession" (German: Einstellung zur anderen Berufsgruppe) (α=.62) remained below a desired internal consistency of α>.70. Factors "Doubts, dismissal and perceived barriers", as well as "Attitude towards another profession" showed sufficient stability for pre-/post-measurements. The Greifswald Questionnaire for the Measurement of Interprofessional Attitudes is the first version of a three-dimensional tool to evaluate IPE in German-speaking countries. Results showed insufficient item difficulty in the tested sample, which resulted in an insufficient internal consistency, and retest reliability for some factors. Further studies are required to investigate item difficulty, internal consistency and retest reliability in a postgraduate sample.
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http://dx.doi.org/10.3205/zma001300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105766PMC
October 2020

Favorable 90-Day Mortality in Obese Caucasian Patients with Septic Shock According to the Sepsis-3 Definition.

J Clin Med 2019 Dec 24;9(1). Epub 2019 Dec 24.

Department of Anesthesiology, University Medical Center, Georg August University, D-37075 Goettingen, Germany.

Septic shock is a frequent life-threatening condition and a leading cause of mortality in intensive care units (ICUs). Previous investigations have reported a potentially protective effect of obesity in septic shock patients. However, prior results have been inconsistent, focused on short-term in-hospital mortality and inadequately adjusted for confounders, and they have rarely applied the currently valid Sepsis-3 definition criteria for septic shock. This investigation examined the effect of obesity on 90-day mortality in patients with septic shock selected from a prospectively enrolled cohort of septic patients. A total of 352 patients who met the Sepsis-3 criteria for septic shock were enrolled in this study. Body-mass index (BMI) was used to divide the cohort into 24% obese (BMI ≥ 30 kg/m) and 76% non-obese (BMI < 30 kg/m) patients. Kaplan-Meier survival analysis revealed a significantly lower 90-day mortality (31% vs. 43%; = 0.0436) in obese patients compared to non-obese patients. Additional analyses of baseline characteristics, disease severity, and microbiological findings outlined further statistically significant differences among the groups. Multivariate Cox regression analysis estimated a significant protective effect of obesity on 90-day mortality after adjustment for confounders. An understanding of the underlying physiologic mechanisms may improve therapeutic strategies and patient prognosis.
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http://dx.doi.org/10.3390/jcm9010046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019854PMC
December 2019

Integrating cross-border emergency medicine systems: Securing future preclinical medical workforce for remote medical services.

Best Pract Res Clin Anaesthesiol 2018 Mar 13;32(1):39-46. Epub 2018 Apr 13.

Klinik für Anästhesiologie, Universitätsmedizin Greifswald, Greifswald, Germany. Electronic address:

The European Union intends to enable its citizens to interact across borders in relevant areas of society and culture to further integrate neighboring regions. Medicine has not been at the core of recent EU-funded efforts in central Europe, partially due to significant differences in health care administration, delivery, reimbursement, and culture. However, impeding changes in social structure and centralization of specialized care warrant changes in preclinical administration of medical care, which are already transforming practices across developed countries in central Europe. Moreover, demographic and social changes are transforming not only patients but also health care providers, thus leading to an increased need for specialized medical personnel, particularly in regions close to formerly secluding borders. The EU-funded cooperation project presented in this article is located in the Euroregion Pomerania, which consists of northeastern Germany and northwestern Poland. This project emerged because of the need to solve practical emergency medicine-related problems for many years, which brought partners together. Unfortunately, administrative and medical interaction has not become significantly easier with Poland joining the Schengen area in 2007 and, subsequently, initial international contracts regarding, among other things, emergency medicine being negotiated and signed thereafter. Three different interdependent areas of cooperation within the project deal with key aspects of an improved and eventually integrated cooperation. An accepted clarification of administrative and legal foundations - or the lack and thus the need thereof - needs to be defined. Specialized language and simulation-based education and practice sessions employing modern technology throughout will be introduced to the entire region. Finally, the pre-existing and developing acceptance and sustainability aspects of personnel involved in the aforementioned actions and stakeholders on both sides of the border will be evaluated. In essence, the project focuses on a multimodal improvement of professional cooperation of key providers of emergency medicine services in the Euroregion Pomerania. Thereby, it aims to improve infrastructure; interpersonal and professional skills of involved personnel, administrative, and cultural relations; and eventually identification of specialized personnel with their workplace and region to secure and retain important medical workforce in an otherwise remote area on both sides of a formerly secluded border.
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http://dx.doi.org/10.1016/j.bpa.2018.04.004DOI Listing
March 2018

Vitamin C in sepsis.

Curr Opin Anaesthesiol 2018 Feb;31(1):55-60

Department of Anesthesiology, University of Colorado Denver, Aurora, Colorado, USA.

Purpose Of Review: This narrative review summarizes recent insights into the role of vitamin C in sepsis.

Recent Findings: Septic shock remains a major source of morbidity and mortality in critically ill patients. Although many nutritional supplements have previously been tested unsuccessfully, vitamins are still being explored as a therapeutic option in septic patients. In particular, vitamin C-containing regimens as adjunctive therapy in sepsis have received much attention.

Summary: In-vitro evidence supports a critical role for vitamin C in cellular mechanisms relevant to the pathophysiology of sepsis. However, whether this justifies therapeutic use of vitamin C in septic patients remains uncertain.
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http://dx.doi.org/10.1097/ACO.0000000000000549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5996765PMC
February 2018

Morphine and the blood-brain barrier: diffusion, uptake, or efflux?

Can J Anaesth 2017 10 18;64(10):997-1001. Epub 2017 Jul 18.

Klinik für Anästhesiologie, Universitätsmedizin Greifswald, Greifswald, Germany.

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http://dx.doi.org/10.1007/s12630-017-0932-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005186PMC
October 2017

Timeliness of Operating Room Case Planning and Time Utilization: Influence of First and To-Follow Cases.

Front Med (Lausanne) 2017 27;4:49. Epub 2017 Apr 27.

Klinik für Anästhesiologie, Universitätsmedizin Greifswald, Greifswald, Germany.

Resource and cost constraints in hospitals demand thorough planning of operating room schedules. Ideally, exact start times and durations are known in advance for each case. However, aside from the first case's start, most factors are hard to predict. While the role of the start of the first case for optimal room utilization has been shown before, data for to-follow cases are lacking. The present study therefore aimed to analyze all elective surgery cases of a university hospital within 1 year in search of visible patterns. A total of 14,014 cases scheduled on 254 regular working days at a university hospital between September 2015 and August 2016 underwent screening. After eliminating 112 emergencies during regular working hours, 13,547 elective daytime cases were analyzed, out of which 4,346 ranked first, 3,723 second, and 5,478 third or higher in the daily schedule. Also, 36% of cases changed start times from the day before to 7:00 a.m., with half of these (52%) resulting in a delay of more than 15 min. After 7:00 a.m., 87% of cases started more than 10 min off schedule, with 26% being early and 74% late. Timeliness was 15 ± 72 min (mean ± SD) for first, 21 ± 84 min for second, and 25 ± 93 min for all to-follow cases, compared to preoperative day planning, and 21 ± 45, 23 ± 61, and 19 ± 74 min compared to 7:00 a.m. status. Start time deviations were also related to procedure duration, with cases of 61-90 min duration being most reliable (deviation 9.8 ± 67 min compared to 7:00 a.m.), regardless of order. In consequence, cases following after 61-90 min long cases had the shortest deviations of incision time from schedule (16 ± 66 min). Taken together, start times for elective surgery cases deviate substantially from schedule, with first and second cases falling into the highest mean deviation category. Second cases had the largest deviations from scheduled times compared to first and all to-follow cases. While planned vs. actual start times differ among specialties, cases of 61-90 min duration had the most reliable start times, with neither shorter nor longer cases seeming to improve timeliness of start times.
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http://dx.doi.org/10.3389/fmed.2017.00049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5406398PMC
April 2017

Electric Nerve Stimulation Does Not Correctly Predict Needle-Nerve Distance and Potential Local Anesthetic Spread for Interscalene Brachial Plexus Blockade.

Anesth Analg 2017 08;125(2):632-634

From the *Klinik für Anästhesiologie und Intensivmedizin; †Klinik für Orthopädie, Dietrich Bonhoeffer Klinikum Neubrandenburg, Neubrandenburg, Germany; and ‡Klinik für Anästhesiologie, Universitätsmedizin Greifswald, Greifswald, Germany.

This study evaluated electric nerve stimulation as a nerve location tool. After eliciting motor response in 43 patients undergoing shoulder surgery, the needle tip's position, distance from the closest nerve, and spread of saline were evaluated using ultrasound imaging. The needle's tip resided 1 to 4 mm from the closest nerve in 21, in direct contact with it in 7, and 6 to 18 mm away in 15 patients. In 21 patients, subsequent saline dissection did not reach the brachial plexus. Thus, the success rate of electric nerve stimulation for correct needle-nerve distance identification was 48.8%, with correct fluid spread reached in only 51.2% of patients.
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http://dx.doi.org/10.1213/ANE.0000000000001982DOI Listing
August 2017

Fluid Resuscitation in Sepsis: "Get the Balance Right".

Crit Care Med 2017 03;45(3):555-556

Department of Anesthesiology University Medicine of Greifswald Greifswald, Germany.

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http://dx.doi.org/10.1097/CCM.0000000000002244DOI Listing
March 2017

Quality Improvement Initiative for Severe Sepsis and Septic Shock Reduces 90-Day Mortality: A 7.5-Year Observational Study.

Crit Care Med 2017 Feb;45(2):241-252

1Department of Anesthesiology, University Hospital of Greifswald, Greifswald, Germany. 2Department of Mathematics and Computer Science, University of Greifswald, Greifswald, Germany. 3Department of Internal Medicine, University Hospital of Greifswald, Greifswald, Germany. 4Department of Microbiology, University Hospital of Greifswald, Greifswald, Germany.

Objective: To investigate the impact of a quality improvement initiative for severe sepsis and septic shock focused on the resuscitation bundle on 90-day mortality. Furthermore, effects on compliance rates for antiinfective therapy within the recommended 1-hour interval are evaluated.

Design: Prospective observational before-after cohort study.

Setting: Tertiary university hospital in Germany.

Patients: All adult medical and surgical ICU patients with severe sepsis and septic shock.

Intervention: Implementation of a quality improvement program over 7.5 years.

Measurements: The primary endpoint was 90-day mortality. Secondary endpoints included ICU and hospital mortality rates and length of stay, time to broad-spectrum antiinfective therapy, and compliance with resuscitation bundle elements.

Main Results: A total of 14,115 patients were screened. The incidence of severe sepsis and septic shock was 9.7%. Ninety-day mortality decreased from 64.2% to 45.0% (p < 0.001). Hospital length of stay decreased from 44 to 36 days (p < 0.05). Compliance with resuscitation bundle elements was significantly improved. Antibiotic therapy within the first hour after sepsis onset increased from 48.5% to 74.3% (p < 0.001). Multivariate analysis revealed blood cultures before antibiotic therapy (hazard ratio, 0.60-0.84; p < 0.001), adequate calculated antibiotic therapy (hazard ratio, 0.53-0.75; p < 0.001), 1-2 L crystalloids within the first 6 hours (hazard ratio 0.67-0.97; p = 0.025), and greater than or equal to 6 L during the first 24 hours (hazard ratio, 0.64-0.95; p = 0.012) as predictors for improved survival.

Conclusions: The continuous quality improvement initiative focused on the resuscitation bundle was associated with increased compliance and a persistent reduction in 90-day mortality over a 7.5-year period. Based on the observational study design, a causal relationship cannot be proven, and respective limitations need to be considered.
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http://dx.doi.org/10.1097/CCM.0000000000002069DOI Listing
February 2017

Interprofessional Learning - Development and Implementation of Joint Medical Emergency Team Trainings for Medical and Nursing Students at Universitätsmedizin Greifswald.

GMS J Med Educ 2016 29;33(2):Doc32. Epub 2016 Apr 29.

Universitätsmedizin Greifswald, Körperschaft des öffentlichen Rechts, Klinik für Anästhesiologie, Greifswald, Germany.

Introduction: Interprofessional collaboration is of great importance in clinical practice, particularly in the field of emergency medicine. The professions involved in providing emergency care must work hand in hand, and tasks and routines must be coordinated effectively. However, medical and nursing students have only few opportunities to experience interprofessional cooperation during their formal training. Addressing this situation, the Department of Anesthesiology and the Vocational School of Greifswald University Medical School initiated a project to increase patient safety by integrating interprofessional human factor training into the curriculum of both health professions. This manuscript addresses how an interprofessional course module focusing on clinical emergency medicine can be taught with an emphasis on competency and problem-solving. In addition, it was important to identify suitable instruments for systematic quality development and assurance of this teaching and learning format.

Project Description: The aim of the project, which took place from October 2013 to September 2015, was the development, implementation and evaluation of a simulation-based, interprofessional course module on clinical emergency medicine. Target groups were medical and nursing students. Modern pedagogical models and methods were applied to the design and teaching of the course content. The project was carried out in separate phases: definition, planning, practical implementation, evaluation and documentation. The project was accompanied by systematic quality development. Established guidelines for quality-centered school development were applied to quality development, assurance and evaluation.

Results: Over two years, a 16 credit-hour course module was developed and then taught and evaluated during the 2014 and 2015 summer semesters. A total of 120 medical students and 120 nursing students participated in the course module. Eighteen teachers from medicine and nursing were trained as instructors and assisted by 12 student tutors. Regular evaluations focused on different aspects of the project, using instruments for empirical educational research. Excellent ratings given to the course by the attendees indicate a high degree of satisfaction in both participating professions regarding course design and content, as well as the quality of teaching.

Discussion: In a position paper, the GMA committee on Interprofessional Education in Health Professions issued recommendations for interprofessional education. The recommendations given for teaching and quality assurance are drawn upon here, and relevant examples from the course concept presented.

Conclusion: The design of the course corresponds to the recommendations of the GMA committee on Interprofessional Education in the Health Professions. Based on these, and considering the satisfactory evaluations, both continuation and further development of this interprofessional teaching format are justified.
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http://dx.doi.org/10.3205/zma001031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4895854PMC
March 2018

Simulation in preclinical emergency medicine.

Best Pract Res Clin Anaesthesiol 2015 Mar 28;29(1):61-8. Epub 2015 Jan 28.

Universitätsmedizin Greifswald, Klinik für Anästhesiologie, Intensivmedizin, Notfallmedizin und Schmerzmedizin, Ferdinand-Sauerbruch-Str., D-17475 Greifswald, Germany.

Emergency medicine has been a stronghold of simulation-based training ever since high-fidelity simulators became available. The preclinical setting differs remarkably from any in-hospital environment in both available technology and resources, and thus stress levels of the health-care professionals involved in patient care – ideal factors for the simulation-based teaching approach. This review reports on the current status of the method for teaching preclinical scenarios from an educational and practical perspective. Particular attention is given to contents, formats, and evaluation of success.
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http://dx.doi.org/10.1016/j.bpa.2015.01.001DOI Listing
March 2015

Cyclosporine-inhibitable cerebral drug transport does not influence clinical methadone pharmacodynamics.

Anesthesiology 2014 Dec;121(6):1281-91

From the Department of Anesthesiology, Universitätsmedizin Greifswald, Greifswald, Germany (K.M.); and Departments of Anesthesiology (K.M., J.B., A.M.F., V.Y., E.D.K.) and of Biochemistry and Molecular Biophysics (E.D.K.), Washington University in St. Louis, St. Louis, Missouri.

Background: Interindividual variability and drug interaction studies suggest that blood-brain barrier drug transporters mediate human methadone brain biodistribution. In vitro and animal studies suggest that methadone is a substrate for the efflux transporter P-glycoprotein, and that P-glycoprotein-mediated transport influences brain access and pharmacologic effect. This investigation tested whether methadone is a transporter substrate in humans [corrected].

Methods: Healthy volunteers received oral (N=16) or IV (N=12) methadone in different crossover protocols after nothing (control) or the validated P-glycoprotein inhibitor cyclosporine (4.5 mg/kg orally twice daily for 4 days, or 5 mg/kg IV over 2 h). Plasma and urine methadone and metabolite concentrations were measured by mass spectrometry. Methadone effects were measured by miosis and thermal analgesia (maximally tolerated temperature and verbal analog scale rating of discreet temperatures).

Results: Cyclosporine marginally but significantly decreased methadone plasma concentrations and apparent oral clearance, but had no effect on methadone renal clearance or on hepatic N-demethylation. Cyclosporine had no effect on miosis or on R-methadone concentration-miosis relationships after either oral or IV methadone. Peak miosis was similar in controls and cyclosporine-treated subjects after oral methadone (1.4±0.4 and 1.3±0.5 mm/mg, respectively) and IV methadone (3.1±1.0 and 3.2±0.8 mm, respectively). Methadone increased maximally tolerated temperature, but analgesia testing was confounded by cyclosporine-related pain.

Conclusions: Cyclosporine did not affect methadone pharmacodynamics. This result does not support a role for cyclosporine-inhibitable transporters mediating methadone brain access and biodistribution.
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http://dx.doi.org/10.1097/ALN.0000000000000391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562501PMC
December 2014

Cohort profile: Greifswald approach to individualized medicine (GANI_MED).

J Transl Med 2014 May 23;12:144. Epub 2014 May 23.

Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Ellernholzstraße 1-2, Greifswald 17475, Germany.

Background: Individualized Medicine aims at providing optimal treatment for an individual patient at a given time based on his specific genetic and molecular characteristics. This requires excellent clinical stratification of patients as well as the availability of genomic data and biomarkers as prerequisites for the development of novel diagnostic tools and therapeutic strategies. The University Medicine Greifswald, Germany, has launched the "Greifswald Approach to Individualized Medicine" (GANI_MED) project to address major challenges of Individualized Medicine. Herein, we describe the implementation of the scientific and clinical infrastructure that allows future translation of findings relevant to Individualized Medicine into clinical practice.

Methods/design: Clinical patient cohorts (N > 5,000) with an emphasis on metabolic and cardiovascular diseases are being established following a standardized protocol for the assessment of medical history, laboratory biomarkers, and the collection of various biosamples for bio-banking purposes. A multi-omics based biomarker assessment including genome-wide genotyping, transcriptome, metabolome, and proteome analyses complements the multi-level approach of GANI_MED. Comparisons with the general background population as characterized by our Study of Health in Pomerania (SHIP) are performed. A central data management structure has been implemented to capture and integrate all relevant clinical data for research purposes. Ethical research projects on informed consent procedures, reporting of incidental findings, and economic evaluations were launched in parallel.
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http://dx.doi.org/10.1186/1479-5876-12-144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4040487PMC
May 2014

Cyclosporine-inhibitable blood-brain barrier drug transport influences clinical morphine pharmacodynamics.

Anesthesiology 2013 Oct;119(4):941-53

* Associate Professor of Anesthesiology, Universitätsmedizin Greifswald, Klinik für Anästhesiologie und Intensivmedizin, Greifswald, Germany, and Department of Anesthesiology, Division of Clinical and Translational Research, Washington University in St. Louis, St. Louis, Missouri. † Associate Professor of Anesthesiology, Department of Anesthesiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois. ‡ Research Technician, § Clinical Research Coordinator, ‖ Head Research Nurse, Department of Anesthesiology, Washington University in St. Louis. # Russell D. and Mary B. Shelden Professor of Anesthesiology, Professor of Biochemistry and Molecular Biophysics, Vice-Chancellor for Research, Departments of Anesthesiology and Biochemistry and Molecular Biophysics, Division of Clinical and Translational Research, Washington University in St. Louis.

Background: The blood-brain barrier is richly populated by active influx and efflux transporters influencing brain drug concentrations. Morphine, a drug with delayed clinical onset, is a substrate for the efflux transporter P-glycoprotein in vitro and in animals. This investigation tested whether morphine is a transporter substrate in humans.

Methods: Fourteen healthy volunteers received morphine (0.1 mg/kg, 1-h IV infusion) in a crossover study without (control) or with the infusion of validated P-glycoprotein inhibitor cyclosporine (5 mg/kg, 2-h infusion). Plasma and urine morphine and morphine glucuronide metabolite concentrations were measured by mass spectrometry. Morphine effects were measured by miosis and analgesia.

Results: Cyclosporine minimally altered morphine disposition, increasing the area under the plasma morphine concentration versus time curve to 100 ± 21 versus 85 ± 24 ng/ml·h (P < 0.05) without changing maximum plasma concentration. Cyclosporine enhanced (3.2 ± 0.9 vs. 2.5 ± 1.0 mm peak) and prolonged miosis, and increased the area under the miosis-time curve (18 ± 9 vs. 11 ± 5 mm·h), plasma effect-site transfer rate constant (k(e0), median 0.27 vs. 0.17 h(-1)), and maximum calculated effect-site morphine concentration (11.5 ± 3.7 vs. 7.6 ± 2.9 ng/ml; all P < 0.05). Analgesia testing was confounded by cyclosporine-related pain.

Conclusions: Morphine is a transporter substrate at the human blood-brain barrier. Results suggest a role for P-glycoprotein or other efflux transporters in brain morphine access, although the magnitude of the effect is small, and unlikely to be a major determinant of morphine clinical effects. Efflux may explain some variability in clinical morphine effects.
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http://dx.doi.org/10.1097/ALN.0b013e3182a05bd3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3823830PMC
October 2013

Selective regulation of cardiac organic cation transporter novel type 2 (OCTN2) in dilated cardiomyopathy.

Am J Pathol 2011 Jun;178(6):2547-59

Department of Pharmacology, Ernst-Moritz-Arndt University, Greifswald, Germany.

Organic cation transporters (OCT1-3 and OCTN1/2) facilitate cardiac uptake of endogenous compounds and numerous drugs. Genetic variants of OCTN2, for example, reduce uptake of carnitine, leading to heart failure. Whether expression and function of OCTs and OCTNs are altered by disease has not been explored in detail. We therefore studied cardiac expression, heart failure-dependent regulation, and affinity to cardiovascular drugs of these transporters. Cardiac transporter mRNA levels were OCTN2>OCT3>OCTN1>OCT1 (OCT2 was not detected). Proteins were localized in vascular structures (OCT3/OCTN2/OCTN1) and cardiomyocytes (OCT1/OCTN1). Functional studies revealed a specific drug-interaction profile with pronounced inhibition of OCT1 function, for example, carvedilol [half maximal inhibitory concentration (IC₅₀), 1.4 μmol/L], diltiazem (IC₅₀, 1.7 μmol/L), or propafenone (IC₅₀, 1.0 μmol/L). With use of the cardiomyopathy model of coxsackievirus-infected mice, Octn2mRNA expression was significantly reduced (56% of controls, 8 days after infection). Accordingly, in endomyocardial biopsy specimens OCTN2 expression was significantly reduced in patients with dilated cardiomyopathy, whereas the expression of OCT1-3 and OCTN1 was not affected. For OCTN2 we observed a significant correlation between expression and left ventricular ejection fraction (r = 0.53, P < 0.0001) and the presence of cardiac CD3⁺ T cells (r = -0.45, P < 0.05), respectively. OCT1, OCT3, OCTN1, and OCTN2 are expressed in the human heart and interact with cardiovascular drugs. OCTN2 expression is selectively reduced in dilated cardiomyopathy patients and predicts the impairment of cardiac function.
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http://dx.doi.org/10.1016/j.ajpath.2011.02.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3124333PMC
June 2011

Genetic and environmental determinants of plasma total homocysteine levels: impact of population-wide folate fortification.

Pharmacogenet Genomics 2011 Jul;21(7):426-31

Department of Anesthesiology, Washington University School of Medicine, St Louis, Missouri, USA.

Objectives: Folate metabolism is an important target for drug therapy. Drug-induced inhibition of folate metabolism often causes an elevation of plasma total homocysteine (tHcy). Plasma tHcy levels are influenced by several nongenetic (e.g. folate intake, age, smoking) as well as genetic factors. Over the last decade, several countries have implemented a nationwide folate fortification program of all grain products. This investigation sought to determine the impact of folate fortification on the relative contribution of environmental and genetic factors to the variability of plasma tHcy.

Methods: Two cohorts were compared in this study, one from the United States (with folate fortification, n=281) and one from Austria (without folate fortification, n=139). Several environmental factors as well as previously identified gene variants important for tHcy levels (MTHFR C677T, MTHFR A1298C, MTRR A66G) were examined for their ability to predict plasma tHcy in a multiple linear regression model.

Results: Nongenetic, environmental factors had a comparable influence on plasma tHcy between the two cohorts (R: approximately 0.19). However, after adjusting for other covariates, the tested gene variants had a substantially smaller impact among patients from the folate-fortified cohort (R=0.021) compared with the nonfolate-fortified cohort (R=0.095). The MTHFR C677T polymorphism was the single most important genetic factor. Male sex, smoking, and folate levels were important predictors for nonfolate-fortified patients; age was for folate-fortified patients.

Conclusion: Population wide folate fortification had a significant effect on the variability of plasma tHcy and reduced the influence of genetic factors, most importantly the MTHFR 677TT genotype, and may be an important confounder for a personalized drug therapy.
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http://dx.doi.org/10.1097/FPC.0b013e32834741ffDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116052PMC
July 2011

Automated radiosynthesis of [11C]morphine for clinical investigation.

Appl Radiat Isot 2011 Feb 11;69(2):431-5. Epub 2010 Nov 11.

Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Blvd. St. Louis, MO 63110, USA.

To meet a multiple-dose clinical evaluation of the P-gp modulation of [(11)C]morphine delivery into the human brain, radiosynthesis of [(11)C]morphine was accomplished on an automated system by N-methylation of normorphine with [(11)C]CH(3)I. A methodology employing optimized solid phase extraction of the HPLC eluent was developed. Radiosynthesis took 45 min with a radiochemical yield ranging from 45% to 50% and specific activity ranging from 20 to 26 Ci/μmol (decay corrected to end-of-bombardment); radiochemical and chemical purities were >95% (n=28).
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http://dx.doi.org/10.1016/j.apradiso.2010.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3026438PMC
February 2011

Acute high-dose sodium selenite administration improves intestinal microcirculation without affecting cytokine release in experimental endotoxemia.

J Trace Elem Med Biol 2009 20;23(2):138-43. Epub 2008 Nov 20.

Klinik und Poliklinik für Anästhesiologie und Intensivmedizin, Ernst-Moritz- Arndt-Universität, Greifswald, Germany.

We evaluated the effects of acute high-dose sodium selenite (SEL) administration on the intestinal microcirculation and the release of the cytokines TNF-alpha, IL-1beta, IL-6 and IL-10 in experimental endotoxemia (induced by lipopolysaccharide-LPS). Three groups of animals (n=30) were studied: control group, endotoxemic group (15 mg kg(-1) i.v. LPS from E. coli) and SEL-treated LPS group (100 microg kg(-1) SEL i.v.). SEL treatment resulted in a significant reduced number of firmly adhering leukocytes in intestinal submucosal venules and reduced significantly the impairment of the intestinal functional capillary density. Despite of the improvement of microcirculatory parameters, we did not detect any changes in the pattern of cytokine release. In conclusion, administration of high-dose sodium SEL attenuates leukocyte adhesion and improves capillary perfusion within the intestinal microcirculation without affecting release of the cytokines TNF-alpha, IL-1beta, IL-6 and IL-10 in experimental endotoxemia.
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http://dx.doi.org/10.1016/j.jtemb.2008.09.003DOI Listing
July 2009

Successful transtracheal lung ventilation using a manual respiration valve: an in vitro and in vivo study.

Anesthesiology 2008 Aug;109(2):251-9

Department of Anesthesiology and Intensive Care Medicine, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany.

Background: Lung ventilation through a thin transtracheal cannula may be attempted in patients with laryngeal stenosis or "cannot intubate, cannot ventilate" situations. It may be impossible to achieve sufficient ventilation if the lungs are spontaneously emptying only through the thin transtracheal cannula, which imposes high resistance to airflow, resulting in dangerous hyperinflation. Therefore, the authors describe the use of a manual respiration valve that serves as a bidirectional pump providing not only inflation but also active deflation of the lungs in case of emergency transtracheal lung ventilation.

Methods: The effectiveness of such a valve was tested in vitro using mechanical lungs in combination with two different cannula sizes and various gas flows. The valve was then tested in five pigs using a transtracheal 16-gauge cannula with three different combinations of inspiratory/expiratory times and gas flows and an occluded upper airway.

Results: In the mechanical lungs, the valve permitted higher minute volumes compared with spontaneous lung emptying. In vivo, the arterial oxygen and carbon dioxide partial pressures increased initially and then remained stable over 1 h (arterial oxygen tension, 470.8 +/- 86.8; arterial carbon dioxide tension, 63.0 +/- 7.2 mmHg). The inspiratory pressures measured in the trachea remained below 10 cm H2O and did not substantially influence central venous and pulmonary artery pressures. Mean arterial pressure and cardiac output were unaffected by the ventilation maneuvers.

Conclusions: This study demonstrated in vitro and in vivo in adult pigs that satisfactory lung ventilation can be assured with transtracheal ventilation through a 16-gauge cannula for a prolonged period of time if combined with a bidirectional manual respiration valve.
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http://dx.doi.org/10.1097/ALN.0b013e31817f3de6DOI Listing
August 2008

Effects of activated protein C on the mesenteric microcirculation and cytokine release during experimental endotoxemia.

Can J Anaesth 2008 Mar;55(3):155-62

Department of Anesthesia, Dalhousie University, Halifax, Nova Scotia, Canada.

Purpose: Activated protein C (APC) is the first anti-inflammatory drug to be approved for the treatment of severe sepsis. However, the underlying mechanisms are not completely elucidated. Therefore, the aim of our study was to evaluate the effects of APC on the microcirculation (mesenteric leukocyte-endothelial interaction, plasma extravasation) using intravital microscopy (IVM) and on cytokine release during experimental endotoxemia in rats.

Methods: We divided forty, male, Lewis rats into four groups (n = 10 per group): Controls, LPS (15 mg x kg(-1) lipopolysaccharide iv), APC (2 mg x kg(-1) APC iv), and LPS+APC. We determined mesenteric leukocyte-endothelial interactions and plasma extravasation at zero, one and two hours following administration of LPS and APC by IVM. Plasma levels of tumour necrosis factor-alpha, IL-1beta, interleukin (IL)-6, and IL-10 were measured at zero and at two hours.

Results: Leukocyte adherence (-74%) and plasma extravasation (-28%) during endotoxemia were diminished significantly following APC treatment, compared to untreated LPS animals (P = 0.0001 and P = 0.0004, respectively). Interleukin-1ss release was also significantly reduced by APC treatment (2567.4 +/- 320.9 pg x mL(-1) in the LPS group vs 1626.1 +/- 427.2 pg x mL(-1) in the LPS+APC group; P = 0.001).

Conclusion: These rodent experiments showed that APC treatment significantly attenuated deterioration of the mesenteric microcirculation and systemic IL-1ss release caused by endotoxin challenge. Because of the crucial role of the microcirculation in ongoing sepsis pathogenesis and multiple organ dysfunction syndrome, these effects may be of clinical importance.
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http://dx.doi.org/10.1007/BF03016089DOI Listing
March 2008

Sepsis affects cardiac expression of multidrug resistance protein 5 (MRP5, ABCC5), an ABC-type CGMP export pump.

Shock 2007 Nov;28(5):564-9

Klinik für Anästhesiologie und Intensivmedizin, Ernst-Moritz-Arndt-Universität Greifswald, Greifswald, Germany.

One of the clinical characteristics associated with septic shock is heart failure. Several lines of evidence indicate that functional consequences of heart failure in septic shock are linked to the activated NO-cyclic guanosine monophosphate (NO-cGMP) pathway. We have previously shown that the high-affinity cGMP export transporter, multidrug resistance protein 5 (MRP5), is expressed in the heart, which modulates intracellular concentrations and, hence, the effects of cGMP. Thus, modified expression of cardiac MRP5 in septic shock can alter cGMP concentrations and contribute to the development of heart failure. We therefore investigated MRP5 expression in the heart using two established murine models of septic shock (intraperitoneal LPS injection and surgical implantation of a stent into the ascending colon, resulting in a multibacterial peritonitis [CASP, colon ascendens stent peritonitis] in C57BL/6N mice, respectively; n = 38). Cardiac MRP5 was assessed by quantitative polymerase chain reaction and immunofluorescence. The protein was localized in the endothelial wall, smooth muscle, and cardiac myocytes. MRP5 mRNA expression was significantly reduced compared with controls both in the LPS (31.9 +/- 16.8 x 10(-4) vs. 54.1 +/- 14.8 x 10(-4), P = 0.025) and CASP model (18.3 +/- 9.4 x 10(-4) vs. 42.8 +/- 12.1 x 10(-4), P = 0.009; MRP5/glyceraldehyde 3-phosphate dehydrogenase copy numbers, respectively). In parallel, IL-6 plasma levels were significantly increased in both models. Incubation of cultured murine cardiomyocytes (HL1) with 5 ng/mL IL-6 resulted in decreased expression of MRP5 (54% of control), as did incubation of the cells with serum from septic mice (LPS serum, 22% of control; CASP serum, 11% of control). In conclusion, cardiac expression of the cGMP export transporter MRP5 is decreased in two murine models of septic shock, most likely by a transcriptional mechanism. Reduced cGMP export as a consequence of decreased MRP5 expression can attenuate heart failure in sepsis.
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http://dx.doi.org/10.1097/shk.0b013e31804f5898DOI Listing
November 2007