Publications by authors named "Markus Roessler"

37 Publications

Impact of perceived inappropiate cardiopulmonary resuscitation on emergency clinicians' intention to leave the job: Results from a cross-sectional survey in 288 centres across 24 countries.

Resuscitation 2021 Jan 20;158:41-48. Epub 2020 Nov 20.

Department of Intensive Care Medicine, Ghent University Hospital, Ghent, Belgium.

Introduction: Cardiopulmonary resuscitation (CPR) in patients with a poor prognosis increases the risk of perception of inappropriate care leading to moral distress in clinicians. We evaluated whether perception of inappropriate CPR is associated with intention to leave the job among emergency clinicians.

Methods: A cross-sectional multi-centre survey was conducted in 24 countries. Factors associated with intention to leave the job were analysed by conditional logistic regression models. Results are expressed as odds ratios with 95% confidence intervals.

Results: Of 5099 surveyed emergency clinicians, 1836 (36.0%) were physicians, 1313 (25.7%) nurses, 1950 (38.2%) emergency medical technicians. Intention to leave the job was expressed by 1721 (33.8%) clinicians, 3403 (66.7%) often wondered about the appropriateness of a resuscitation attempt, 2955 (58.0%) reported moral distress caused by inappropriate CPR. After adjustment for other covariates, the risk of intention to leave the job was higher in clinicians often wondering about the appropriateness of a resuscitation attempt (1.43 [1.23-1.67]), experiencing associated moral distress (1.44 [1.24-1.66]) and who were between 30-44 years old (1.53 [1.21-1.92] compared to <30 years). The risk was lower when the clinician felt valued by the team (0.53 [0.42-0.66]), when the team leader acknowledged the efforts delivered by the team (0.61 [0.49-0.75]) and in teams that took time for debriefing (0.70 [0.60-0.80]).

Conclusion: Resuscitation attempts perceived as inappropriate by clinicians, and the accompanying moral distress, were associated with an increased likelihood of intention to leave the job. Interprofessional collaboration, teamwork, and regular interdisciplinary debriefing were associated with a lower risk of intention to leave the job.; No.: NCT02356029.
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January 2021

Cardiopulmonary Resuscitation in Adults Over 80: Outcome and the Perception of Appropriateness by Clinicians.

J Am Geriatr Soc 2020 01 15;68(1):39-45. Epub 2019 Dec 15.

Department of Geriatric Medicine, Ghent University Hospital, Ghent, Belgium.

Objectives: To determine the prevalence of clinician perception of inappropriate cardiopulmonary resuscitation (CPR) regarding the last out-of-hospital cardiac arrest (OHCA) encountered in an adult 80 years or older and its relationship to patient outcome.

Design: Subanalysis of an international multicenter cross-sectional survey (REAPPROPRIATE).

Setting: Out-of-hospital CPR attempts registered in Europe, Israel, Japan, and the United States in adults 80 years or older.

Participants: A total of 611 clinicians of whom 176 (28.8%) were doctors, 123 (20.1%) were nurses, and 312 (51.1%) were emergency medical technicians/paramedics.

Results And Measurements: The last CPR attempt among patients 80 years or older was perceived as appropriate by 320 (52.4%) of the clinicians; 178 (29.1%) were uncertain about the appropriateness, and 113 (18.5%) perceived the CPR attempt as inappropriate. The survival to hospital discharge for the "appropriate" subgroup was 8 of 265 (3.0%), 1 of 164 (.6%) in the "uncertain" subgroup, and 2 of 107 (1.9%) in the "inappropriate" subgroup (P = .23); 503 of 564 (89.2%) CPR attempts involved non-shockable rhythms. CPR attempts in nursing homes accounted for 124 of 590 (21.0%) of the patients and were perceived as appropriate by 44 (35.5%) of the clinicians; 45 (36.3%) were uncertain about the appropriateness; and 35 (28.2%) perceived the CPR attempt as inappropriate. The survival to hospital discharge for the nursing home patients was 0 of 107 (0%); 104 of 111 (93.7%) CPR attempts involved non-shockable rhythms. Overall, 36 of 543 (6.6%) CPR attempts were undertaken despite a known written do not attempt resuscitation decision; 14 of 36 (38.9%) clinicians considered this appropriate, 9 of 36 (25.0%) were uncertain about its appropriateness, and 13 of 36 (36.1%) considered this inappropriate.

Conclusion: Our findings show that despite generally poor outcomes for older patients undergoing CPR, many emergency clinicians do not consider these attempts at resuscitation to be inappropriate. A professional and societal debate is urgently needed to ensure that first we do not harm older patients by futile CPR attempts. J Am Geriatr Soc 68:39-45, 2019.
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January 2020

Key questions about the future of laboratory medicine in the next decade of the 21st century: A report from the IFCC-Emerging Technologies Division.

Clin Chim Acta 2019 Aug 28;495:570-589. Epub 2019 May 28.

Department of Pathology & Lab. Medicine, University of Pennsylvania Medical Center, Philadelphia, PA, USA.

This review advances the discussion about the future of laboratory medicine in the 2020s. In five major topic areas: 1. the "big picture" of healthcare; 2. pre-analytical factors; 3. Analytical factors; 4. post-analytical factors; and 5. relationships, which explores a next decade perspective on laboratory medicine and the likely impact of the predicted changes by means of a number of carefully focused questions that draw upon predictions made since 2013. The "big picture" of healthcare explores the effects of changing patient populations, the brain-to-brain loop, direct access testing, robots and total laboratory automation, and green technologies and sustainability. The pre-analytical section considers the role of different sample types, drones, and biobanks. The analytical section examines advances in point-of-care testing, mass spectrometry, genomics, gene and immunotherapy, 3D-printing, and total laboratory quality. The post-analytical section discusses the value of laboratory medicine, the emerging role of artificial intelligence, the management and interpretation of omics data, and common reference intervals and decision limits. Finally, the relationships section explores the role of laboratory medicine scientific societies, the educational needs of laboratory professionals, communication, the relationship between laboratory professionals and clinicians, laboratory medicine financing, and the anticipated economic opportunities and outcomes in the 2020's.
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August 2019

Perception of inappropriate cardiopulmonary resuscitation by clinicians working in emergency departments and ambulance services: The REAPPROPRIATE international, multi-centre, cross sectional survey.

Resuscitation 2018 11 12;132:112-119. Epub 2018 Sep 12.

Department of Intensive Care Medicine, Ghent University Hospital, Ghent, Belgium.

Introduction: Cardiopulmonary resuscitation (CPR) is often started irrespective of comorbidity or cause of arrest. We aimed to determine the prevalence of perception of inappropriate CPR of the last cardiac arrest encountered by clinicians working in emergency departments and out-of-hospital, factors associated with perception, and its relation to patient outcome.

Methods: A cross-sectional survey was conducted in 288 centres in 24 countries. Factors associated with perception of CPR and outcome were analyzed by Cochran-Mantel-Haenszel tests and conditional logistic models.

Results: Of the 4018 participating clinicians, 3150 (78.4%) perceived their last CPR attempt as appropriate, 548 (13.6%) were uncertain about its appropriateness and 320 (8.0%) perceived inappropriateness; survival to hospital discharge was 370/2412 (15.3%), 8/481 (1.7%) and 8/294 (2.7%) respectively. After adjusting for country, team and clinician's characteristics, the prevalence of perception of inappropriate CPR was higher for a non-shockable initial rhythm (OR 3.76 [2.13-6.64]; P < .0001), a non-witnessed arrest (2.68 [1.89-3.79]; P < .0001), in older patients (2.94 [2.18-3.96]; P < .0001, for patients >79 years) and in case of a "poor" first physical impression of the patient (3.45 [2.36-5.05]; P < .0001). In accordance, non-shockable and non-witnessed arrests were both associated with lower survival to hospital discharge (0.33 [0.26-0.41]; P < 0.0001 and 0.25 [0.15-0.41]; P < 0.0001, respectively), as were older patient age (0.25 [0.14-0.44]; P < 0.0001 for patients >79 years) and a "poor" first physical impression (0.26 [0.19-0.35]; P < 0.0001).

Conclusions: The perception of inappropriate CPR increased when objective indicators of poor prognosis were present and was associated with a low survival to hospital discharge. Factoring clinical judgment into the decision to (not) attempt CPR may reduce harm inflicted by excessive resuscitation attempts.
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November 2018

The 10 fundamental principles of lay resuscitation: Recommendations by the German Resuscitation Council.

Eur J Anaesthesiol 2018 10;35(10):721-723

From the Department of Anaesthesiology and Intensive Care Medicine, University Hospital of Cologne, Cologne (BWB, SW), GRC (German Resuscitation Council) Ulm (BD), DLRG (German Lifesaving Association), Bad Nenndorf (UJ), Department of Anaesthesiology, University Hospital, LMU Munich, Munich (UK), German Red Cross eV, Berlin (SO), Department of Anaesthesiology, University Medicine Göttingen, Göttingen (MR) and Department of Cardiology and Intensive Care Medicine, St. Bernward Krankenhaus Hildesheim, Hildesheim, Germany (KHS).

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October 2018

Prehospital ultrasound-guided nerve blocks improve reduction-feasibility of dislocated extremity injuries compared to systemic analgesia. A randomized controlled trial.

PLoS One 2018 2;13(7):e0199776. Epub 2018 Jul 2.

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

Background: Out-of-hospital analgosedation in trauma patients is challenging for emergency physicians due to associated complications. We compared peripheral nerve block (PNB) with analgosedation (AS) as an analgetic approach for patients with isolated extremity injury, assuming that prehospital required medical interventions (e.g. reduction, splinting of dislocation injury) using PNB are less painful and more feasible compared to AS.

Methods: Thirty patients (aged 18 or older) were randomized to receive either ultrasound-guided PNB (10 mL prilocaine 1%, 10 mL ropivacaine 0.2%) or analgosedation (midazolam combined with s-ketamine or with fentanyl). Reduction-feasibility was classified (easy, intermediate, impossible) and pain scores were assessed using numeric rating scales (NRS 0-10).

Results: Eighteen patients were included in the PNB-group and twelve in the AS-group; 15 and 9 patients, respectively, suffered dislocation injury. In the PNB-group, reduction was more feasible (easy: 80.0%, impossible: 20.0%) compared to the AS-group (easy: 22.2%, intermediate: 22.2%, impossible: 55.6%; p = 0.01). During medical interventions, 5.6% [1/18] of the PNB-patients and 58.3% [7/12] of the AS-patients experienced pain (p<0.01). Recorded pain scores were significantly lower in the PNB-group during prehospital medical intervention (median[IQR] NRS PNB: 0[0-0]) compared to the AS-group (6[0-8]; p<0.001) as well as on first day post presentation (NRS PNB: 1[0-5], AS: 5[5-7]; p = 0.050). All patients of the PNB-group would recommend their analgesic technique (AS: 50.0%, p<0.01).

Conclusions: Prehospital ultrasound-guided PNB is rapidly performed in extremity injuries with high success. Compared to the commonly used AS in trauma patients, PNB significantly reduces pain intensity and severity.
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January 2019

Pre-hospital transthoracic echocardiography for early identification of non-ST-elevation myocardial infarction in patients with acute coronary syndrome.

Crit Care 2018 02 7;22(1):29. Epub 2018 Feb 7.

Department of Anesthesiology, Emergency and Intensive Care Medicine, University Medical Center, University of Goettingen, Robert-Koch Str. 40, 37075, Göttingen, Germany.

Background: Non-ST elevation myocardial infarction (NSTEMI) is a common manifestation of acute coronary syndrome (ACS), but delayed diagnosis can increase mortality. In this proof of principle study, the emergency physician performed transthoracic echocardiography (TTE) on scene to determine whether NSTEMI could be correctly diagnosed pre-hospitalization. This could expedite admission to the appropriate facility and reduce the delay until initiation of correct therapy.

Methods: Pre-hospital TTE was performed on scene by the emergency physician in patients presenting with ACS but without ST-elevation in the initial 12-lead electrocardiography (ECG) (NSTE-ACS). A presumptive NSTEMI diagnosis was made if regional wall motion abnormalities (RWMA) were detected. These patients were admitted directly to a specialist cardiac facility. Patient characteristics and pre-admission and post-admission clinical, pre-hospital TTE data, and therapeutic measures were recorded.

Results: Patients with NSTE-ACS (n = 53; 72.5 ± 13.4 years of age; 23 female) were studied. The 20 patients with pre-hospital RWMA and presumptive NSTEMI, and two without RWMA were conclusively diagnosed with NSTEMI in hospital. Percutaneous coronary intervention was performed in 50% of the patients presumed to have NSTEMI immediately after admission. The RWMA seen before hospital TTE corresponded with the in-hospital ECG findings and/or the supply regions of the occluded coronary vessels seen during PCI in 85% of the cases. The diagnostic sensitivity of pre-hospital TTE for NSTEMI was 90.9% with 100% specificity.

Conclusions: Pre-hospital transthoracic echocardiography by the emergency physician can correctly diagnose NSTEMI in more than 90% of cases. This can expedite the initiation of appropriate therapy and could thereby conceivably reduce morbidity and mortality.

Trial Registration: Deutsche Register klinischer Studien, DRKS00004919 . Registered on 29 April 2013.
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February 2018

Recommended practice for out-of-hospital emergency anaesthesia in adults: Statement from the Out-of-Hospital Emergency Anaesthesia Working Group of the Emergency Medicine Research Group of the German Society of Anaesthesiology and Intensive Care.

Eur J Anaesthesiol 2016 Dec;33(12):881-897

From the Department of Anaesthesiology and Intensive Care Medicine, Section Emergency Medicine, Armed Forces Hospital, Ulm (BH); Department of Anaesthesiology, Intensive Care Medicine, Emergency Medicine, Pain Service, ASKLEPIOS Hospital St. Georg, Hamburg (BB); Department of Anaesthesiology and Intensive Care Medicine, University Hospital of Cologne, Cologne (BWB, JH); City of Münster Fire Department, Münster (AB); Department of Anaesthesiology, Intensive Care Medicine, Emergency Medicine, Pain Service, Hospital Am Eichert, Goeppingen (MF); Department of Emergency Medicine, University of Schleswig-Holstein, Kiel (J-TG); Department of Emergency Medicine, University of Giessen and Marburg, Campus Marburg (CK); Department of Anesthesiology, University Medical Center, Johannes Gutenberg-University of Mainz, Mainz (CL); Department of Anesthesiology, University of Heidelberg, Heidelberg (EP); Department of Anesthesiology, University Medical Center Göttingen, Göttingen (MR); Department of Anaesthesiologie and Intensive Care Medicine University of Giessen and Marburg, Campus Giessen, Germany (AS); Department of Anesthesiology and Critical Care Medicine, Innsbruck Medical University, Innsbruck, Austria (VW); Emergency Department, University of Leipzig, Leipzig, Germany (MB).

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December 2016

The pre-hospital administration of tranexamic acid to patients with multiple injuries and its effects on rotational thrombelastometry: a prospective observational study in pre-hospital emergency medicine.

Scand J Trauma Resusc Emerg Med 2016 Oct 10;24(1):122. Epub 2016 Oct 10.

Department for Anaesthesiology, University Medical Centre, University of Göttingen, Robert-Koch-Straße 40, 37075, Göttingen, Germany.

Background: Hyperfibrinolysis (HF) is a major contributor to coagulopathy and mortality in trauma patients. This study investigated (i) the rate of HF during the pre-hospital management of patients with multiple injuries and (ii) the effects of pre-hospital tranexamic acid (TxA) administration on the coagulation system.

Methods: From 27 trauma patients with pre-hospital an estimated injury severity score (ISS) ≥16 points blood was obtained at the scene and on admission to the emergency department (ED). All patients received 1 g of TxA after the first blood sample was taken. Rotational thrombelastometry (ROTEM) was performed for both blood samples, and the results were compared. HF was defined as a maximum lysis (ML) >15 % in EXTEM.

Results: The median (min-max) ISS was 17 points (4-50 points). Four patients (15 %) had HF diagnosed via ROTEM at the scene, and 2 patients (7.5 %) had HF diagnosed via ROTEM on admission to the ED. The median ML before TxA administration was 11 % (3-99 %) vs. 10 % after TxA administration (4-18 %; p > 0.05). TxA was administered 37 min (10-85 min) before ED arrival. The ROTEM results before and after TxA administration did not significantly differ. No adverse drug reactions were observed after TxA administration.

Discussion: HF can be present in severely injured patients during pre-hospital care. Antifibrinolytic therapy administered at the scene is a significant time saver. Even in milder trauma fibrinogen can be decreased to critically low levels. Early administration of TxA cannot reverse or entirely stop this decrease.

Conclusions: The pre-hospital use of TxA should be considered for severely injured patients to prevent the worsening of trauma-induced coagulopathy and unnecessarily high fibrinogen consumption.

Trial Registration: ID NCT01938768 (Registered 5 September 2013).
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October 2016

Use of the GlideScope®-Ranger for pre-hospital intubations by anaesthesia trained emergency physicians - an observational study.

BMC Emerg Med 2016 Jan 29;16. Epub 2016 Jan 29.

Department of Anaesthesiology, University Hospital Göttingen, 370799, Göttingen, Germany.

Background: Pre-hospital endotracheal intubation is more difficult than in the operating room (OR). Therefore, enhanced airway management devices such as video laryngoscopes may be helpful to improve the success rate of pre-hospital intubation. We describe the use of the Glidescope®-Ranger (GS-R) as an alternative airway tool used at the discretion of the emergency physician (EP) in charge.

Methods: During a 3.5 year period, the GS-R was available to be used either as the primary or backup tool for pre-hospital intubation by anaesthesia trained EP with limited expertise using angulated videolaryngoscopes.

Results: During this period 672 patients needed pre-hospital intubation of which the GS-R was used in 56 cases. The overall GS-R success rate was 66 % (range of 34-100 % among EP). The reasons for difficulties or failure included inexperience of the EP with the GS-R, impaired view due to secretion, vomitus, blood or the inability to see the screen in very bright environment due to sunlight.

Conclusion: Special expertise and substantial training is needed to successfully accomplish tracheal intubation with the GS-R in the pre-hospital setting. Providers inexperienced with DL as well as video-assisted intubation should not expect to be able to perform tracheal intubation easily just because a videolaryngoscope is available. Additionally, indirect laryngoscopy might be difficult or even impossible to achieve in the pre-hospital setting due to impeding circumstances such as blood, secretions or bright sun-light. Therefore, videolaryngoscopes, here the GS-R, should not be considered as the "Holy Grail" of endotracheal intubation, neither for the experts nor for inexperienced providers.
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January 2016

Exposure and Tumor Fn14 Expression as Determinants of Pharmacodynamics of the Anti-TWEAK Monoclonal Antibody RG7212 in Patients with Fn14-Positive Solid Tumors.

Clin Cancer Res 2016 Feb 7;22(4):858-67. Epub 2015 Oct 7.

Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. Department of Pharmaceutical Sciences, Science Faculty, Utrecht University, Utrecht, the Netherlands.

Purpose: The TWEAK-Fn14 pathway represents a novel anticancer target that is being actively investigated. Understanding the relationship between pharmacokinetics of anti-TWEAK therapeutics and tumor pharmacodynamics is critical. We investigated exposure-response relationships of RG7212, an anti-TWEAK mAb, in patients with Fn14-expressing tumors.

Experimental Design: Patients with Fn14-positive tumors (IHC ≥ 1+) treated in a phase I first-in-human study with ascending doses of RG7212 were the basis for this analysis. Pharmacokinetics of RG7212 and dynamics of TWEAK were determined, as were changes in tumor TWEAK-Fn14 signaling in paired pre- and posttreatment tumor biopsies. The objectives of the analysis were to define exposure-response relationships and the relationship between pretreatment tumor Fn14 expression and pharmacodynamic effect. Associations between changes in TWEAK-Fn14 signaling and clinical outcome were explored.

Results: Thirty-six patients were included in the analysis. RG7212 reduced plasma TWEAK to undetectable levels at all observed RG7212 exposures. In contrast, reductions in tumor Fn14 and TRAF1 protein expression were observed only at higher exposure (≥ 300 mg*h/mL). Significant reductions in tumor Ki-67 expression and early changes in serum concentrations of CCL-2 and MMP-9 were observed exclusively in patients with higher drug exposure who had high pretreatment tumor Fn14 expression. Pretreatment tumor Fn14 expression was not associated with outcome, but a trend toward longer time on study was observed with high versus low RG7212 exposure.

Conclusions: RG7212 reduced tumor TWEAK-Fn14 signaling in a systemic exposure-dependent manner. In addition to higher exposure, relatively high Fn14 expression might be required for pharmacodynamic effect of anti-TWEAK monoclonal antibodies.
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February 2016

Blood-sampling collection prior to surgery may have a significant influence upon biomarker concentrations measured.

Clin Proteomics 2015 31;12(1):19. Epub 2015 Jul 31.

Translational Research Unit (STF), Thoraxklinik, University of Heidelberg, Amalienstr. 5, 69126 Heidelberg, Germany ; Translational Lung Research Centre Heidelberg (TLRC-H), German Centre for Lung Research (DZL), Heidelberg, Germany.

Background: Biomarkers can be subtle tools to aid the diagnosis, prognosis and monitoring of therapy and disease progression. The validation of biomarkers is a cumbersome process involving many steps. Serum samples from lung cancer patients were collected in the framework of a larger study for evaluation of biomarkers for early detection of lung cancer. The analysis of biomarker levels measured revealed a noticeable difference in certain biomarker values that exhibited a dependence of the time point and setting of the sampling. Biomarker concentrations differed significantly if taken before or after the induction of anesthesia and if sampled via venipuncture or arterial catheter.

Methods: To investigate this observation, blood samples from 13 patients were drawn 1-2 days prior to surgery (T1), on the same day by venipuncture (T2) and after induction of anesthesia via arterial catheter (T3). The biomarkers Squamous Cell Carcinoma antigen (CanAG SCC EIA, Fujirebio Diagnostics, Malvern, USA), Carcinoembrionic Antigen (CEA), and CYFRA 21-1 (Roche Diagnostics GmbH, Mannheim, Germany) were analyzed.

Results: SCC showed a very strong effect in relation to the sampling time and procedure. While the first two points in time (T1; T2) were highly comparable (median fold-change: 0.84; p = 0.7354; correlation ρ = 0.883), patients showed a significant increase (median fold-change: 4.96; p = 0.0017; correlation ρ = -0.036) in concentration when comparing T1 with the sample time subsequent to anesthesia induction (T3). A much weaker increase was found for CYFRA 21-1 at T3 (median fold-change: 1.40; p = 0.0479). The concentration of CEA showed a very small, but systematic decrease (median fold-change: 0.72; p = 0.0039).

Conclusions: In this study we show the unexpectedly marked influence of blood withdrawal timing (before vs. after anesthesia) and procedure (venous versus arterial vessel puncture) has on the concentration of the protein biomarker SCC and to a less extent upon CYFRA21-1. The potential causes for these effects remain to be elucidated in subsequent studies, however these findings highlight the importance of a standardized, controlled blood collection protocol for biomarker detection.
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August 2015

A phase I monotherapy study of RG7212, a first-in-class monoclonal antibody targeting TWEAK signaling in patients with advanced cancers.

Clin Cancer Res 2015 Jan 11;21(2):258-66. Epub 2014 Nov 11.

Ottawa Hospital Cancer Center, Ottawa, Ontario, Canada.

Purpose: Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible molecule 14 (Fn14) are a ligand-receptor pair frequently overexpressed in solid tumors.

Tweak: Fn14 signaling regulates multiple oncogenic processes through MAPK, AKT, and NFκB pathway activation. A phase I study of RG7212, a humanized anti-TWEAK IgG1κ monoclonal antibody, was conducted in patients with advanced solid tumors expressing Fn14.

Experimental Design: Dose escalations, over a 200- to 7,200-mg range, were performed with patients enrolled in weekly (QW), bi-weekly (Q2W), or every-three-week (Q3W) schedules. Primary objectives included determination of dose and safety profile. Secondary endpoints included assessments related to inhibition of

Tweak: Fn14 signaling, tumor proliferation, tumor immune cell infiltration, and pharmacokinetics.

Results: In 192 treatment cycles administered to 54 patients, RG7212 was well-tolerated with no dose-limiting toxicities observed. More than 95% of related adverse events were limited to grade 1/2. Pharmacokinetics were dose proportional for all cohorts, with a t1/2 of 11 to 12 days. Pharmacodynamic changes included clearance of free and total TWEAK ligand and reductions in tumor Ki-67 and TRAF1. A patient with BRAF wild-type melanoma who received 36 weeks of RG7212 therapy had tumor regression and pharmacodynamic changes consistent with antitumor effects. Fifteen patients (28%) received 16 or more weeks of RG7212 treatment.

Conclusion: RG7212 demonstrated excellent tolerability and favorable pharmacokinetics. Pharmacodynamic endpoints were consistent with reduced

Tweak: Fn14 signaling. Tumor regression was observed and prolonged stable disease was demonstrated in multiple heavily pretreated patients with solid tumors. These encouraging results support further study of RG7212. Clin Cancer Res; 21(2); 258-66. ©2014 AACR.
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January 2015

Prehospital noninvasive ventilation for acute respiratory failure: systematic review, network meta-analysis, and individual patient data meta-analysis.

Acad Emerg Med 2014 Sep;21(9):960-70

The School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK.

Objectives: This meta-analysis aimed to determine the effectiveness of prehospital continuous positive airway pressure (CPAP) or bilevel inspiratory positive airway pressure (BiPAP) in acute respiratory failure.

Methods: Fourteen electronic databases and research registers were searched from inception to August 2013. Randomized or quasi-randomized controlled trials that reported mortality or intubation rate for prehospital CPAP or BiPAP were selected and compared to a relevant comparator in patients with acute respiratory failure. An aggregate data network meta-analysis was used to jointly estimate intervention effects relative to standard care. A network meta-analysis using a mixture of individual patient-level data and aggregate data was carried out to assess potential treatment effect modifiers.

Results: Eight randomized and two quasi-randomized controlled trials (six CPAP, four BiPAP, sample sizes 23 to 207) were identified. The aggregate data network meta-analysis suggested that CPAP was the most effective treatment in terms of mortality (probability = 0.989) and intubation rate (probability = 0.639) and reduced both mortality (odds ratio [OR] = 0.41; 95% credible interval [CrI] = 0.20 to 0.77) and intubation rate (OR = 0.32; 95% CrI = 0.17 to 0.62), compared to standard care. The effect of BiPAP on mortality (OR = 1.94; 95% CrI = 0.65 to 6.14) and intubation rate (OR = 0.40; 95% CrI = 0.14 to 1.16) was uncertain. The network meta-analysis using individual patient-level data and aggregate data suggested that sex was a modifier of the effect of treatment on mortality.

Conclusions: Prehospital CPAP can reduce mortality and intubation rates compared to standard care, while the effectiveness of prehospital BiPAP is uncertain.
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September 2014

A prospective, blinded evaluation of a video-assisted '4-stage approach' during undergraduate student practical skills training.

BMC Med Educ 2014 May 22;14:104. Epub 2014 May 22.

Department of Anaesthesiology, University Hospital Göttingen, Göttingen 37075, Germany.

Background: The 4-stage approach (4-SA) is used as a didactic method for teaching practical skills in international courses on resuscitation and the structured care of trauma patients. The aim of this study was to evaluate objective and subjective learning success of a video-assisted 4-SA in teaching undergraduate medical students.

Methods: The participants were medical students learning the principles of the acute treatment of trauma patients in their multidiscipline course on emergency and intensive care medicine. The participants were quasi- randomly divided into two groups. The 4-SA was used in both groups. In the control group, all four steps were presented by an instructor. In the study group, the first two steps were presented as a video. At the end of the course a 5-minute objective, structured clinical examination (OSCE) of a simulated trauma patient was conducted. The test results were divided into objective results obtained through a checklist with 9 dichotomous items and the assessment of the global performance rated subjectively by the examiner on a Likert scale from 1 to 6.

Results: 313 students were recruited; the results of 256 were suitable for analysis. The OSCE results were excellent in both groups and did not differ significantly (control group: median 9, interquantil range (IQR) 8-9, study group: median 9, IQR 8-9; p = 0.29). The global performance was rated significantly better for the study group (median 1, IQR 1-2 vs. median 2, IQR 1-3; p < 0.01). The relative knowledge increase, stated by the students in their evaluation after the course, was greater in the study group (85% vs. 80%).

Conclusion: It is possible to employ video assistance in the classical 4-SA with comparable objective test results in an OSCE. The global performance was significantly improved with use of video assistance.
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May 2014

The effect of changing the sequence of cuff inflation and device fixation with the LMA-Supreme® on device position, ventilatory complications, and airway morbidity: a clinical and fiberscopic study.

BMC Anesthesiol 2014 Jan 4;14. Epub 2014 Jan 4.

Department of Anaesthesiology, Emergency and Intensive Care Medicine, University of Göttingen Medical School, Robert-Koch Str, 40, 37075 Göttingen, Germany.

Background: The conventional sequence when using supraglottic airway devices is insertion, cuff inflation and fixation. Our hypothesis was that a tighter fit of the cuff and tip could be achieved with a consequently lower incidence of air leak, better separation of gastrointestinal and respiratory tracts and less airway morbidity if the device were first affixed and the cuff then inflated.

Methods: Our clinical review board approved the study (public registry number DRKS00003174). An LMA Supreme® was inserted into 184 patients undergoing lower limb arthroscopy in propofol-remifentanil anaesthesia who were randomly assigned to either the control (inflation then fixation; n = 92) or study group (fixation then inflation; n = 92). The cuff was inflated to 60 cmH2O. The patients' lungs were ventilated in pressure-controlled mode with 5 cmH2O PEEP, Pmax to give 6 ml kg-1 tidal volume, and respiratory rate adjusted to end-tidal CO2 of 4.8 and 5.6 kPa. Correct cuff and tip position were determined by leak detection, capnometry trace, oropharyngeal leak pressure, suprasternal notch test, and lube-tube test. Bowl and cuff position and the presence of glottic narrowing were assessed by fiberscopic examination. Postoperative dysphagia, hoarseness and sore throat were assessed with a questionnaire. Ventilatory impairment was defined as a tidal volume < 6 ml kg-1 with Pmax at oropharyngeal leak pressure, glottic narrowing was defined as an angle between the vocal cords under 16 degrees.

Results: The incidence of incorrect device position (18% vs. 21%), failed ventilation (10% vs. 9%), leak pressure (24.8 vs. 25.2 cmH2O, p = 0.63), failed lube-tube test (16.3% vs. 17.6%) and glottic narrowing (19.3% vs. 14.1%, p = 0.35) was similar in both groups (control vs. study, resp.). When glottic narrowing occurred, it was more frequently associated with ventilatory impairment in the control group (77% vs. 39%; p = 0.04). Airway morbidity was more common in the control group (33% vs. 19%; p < 0.05).

Conclusions: Altering the sequence of cuff inflation and device fixation does not affect device position, oropharyngeal leak pressures or separation of gastrointestinal and respiratory tracts. It reduces the incidence of glottic narrowing with impaired ventilation and also perioperative airway morbidity.
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January 2014

Bioenergetics of the moderately halophilic bacterium Halobacillus halophilus: composition and regulation of the respiratory chain.

Appl Environ Microbiol 2013 Jun 12;79(12):3839-46. Epub 2013 Apr 12.

Molecular Microbiology & Bioenergetics, Institute of Molecular Biosciences, Johann Wolfgang Goethe University, Frankfurt, Germany.

In their natural environments, moderately halophilic bacteria are confronted not only with high salinities but also with low oxygen tensions due to the high salinities. The growth of H. halophilus is strictly aerobic. To analyze the dependence of respiration on the NaCl concentration and oxygen availability of the medium, resting cell experiments were performed. The respiration rates were dependent on the NaCl concentration of the growth medium, as well as on the NaCl concentration of the assay buffer, indicating regulation on the transcriptional and the activity level. Respiration was accompanied by the generation of an electrochemical proton potential (Δμ(H+)) across the cytoplasmic membrane whose magnitude was dependent on the external pH. Genes encoding proteins involved in respiration and Δμ(H+) generation, such as a noncoupled NADH dehydrogenase (NDH-2), complex II, and complex III, were identified in the genome. In addition, genes encoding five different terminal oxidases are present. Inhibitor profiling revealed the presence of NDH-2 and complex III, but the nature of the oxidases could not be resolved using this approach. Expression analysis demonstrated that all the different terminal oxidases were indeed expressed, but by far the most prominent was cta, encoding cytochrome caa3 oxidase. The expression of all of the different oxidase genes increased at high NaCl concentrations, and the transcript levels of cta and qox (encoding cytochrome aa3 oxidase) also increased at low oxygen concentrations. These data culminate in a model of the composition and variation of the respiratory chain of H. halophilus.
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June 2013

Accuracy of prehospital diagnoses by emergency physicians: comparison with discharge diagnosis.

Eur J Emerg Med 2012 Oct;19(5):292-6

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

Objective: A correct prehospital diagnosis of emergency patients is crucial as it determines initial treatment, admitting specialty, and subsequent treatment. We evaluated the diagnostic accuracy of emergency physicians.

Methods: All patients seen by six emergency physicians staffing the local emergency ambulance and rescue helicopter services during an 8-month period were studied. The ambulance and helicopter physicians had 3 and 4 years, respectively, training in anesthesia and intensive care medicine. The admission diagnoses were compared with the discharge diagnoses for agreement. Time of day of the emergency call, patients' age, and sex, living conditions, and presenting symptoms were evaluated as contributing factors.

Results: Three hundred and fifty-five ambulance and 241 helicopter deployment protocols were analyzed. The overall degree of agreement between initial and discharge diagnoses was 90.1% with no difference attributable to years of experience. The lowest agreement rate was seen in neurological disorders (81.5%), with a postictal state after an unobserved seizure often being diagnosed as a cerebrovascular accident. Inability to obtain a complete medical history (e.g. elderly patients, patients in nursing homes, neurological impairment) was associated with a lower agreement rate between initial and discharge diagnoses (P<0.05).

Conclusion: Medical history, physical examination, ECG, and blood glucose enabled a correct diagnosis in most cases, but some were impossible to resolve without further technical and laboratory investigations. Only a few were definitively incorrect. A detailed medical history is essential. Neurological disorders can present with misleading symptoms and when the diagnosis is not clear it is better to assume the worst case.
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October 2012

Early out-of-hospital non-invasive ventilation is superior to standard medical treatment in patients with acute respiratory failure: a pilot study.

Emerg Med J 2012 May 27;29(5):409-14. Epub 2011 Sep 27.

Department of Anaesthesiology, Emergency and Intensive Care Medicine, University Medicine, Georg-August-University, Goettingen, Germany.

Objective: To assess in patients with acute respiratory failure (ARF) whether out-of-hospital (OOH) non-invasive ventilation (NIV) is feasible, safe and more effective compared with standard medical therapy (SMT).

Patients And Interventions: Patients with OOH ARF were randomly assigned to receive either SMT or NIV.

Measurements And Results: Fifty-one patients were enrolled, 26 of whom were randomly assigned to SMT and 25 of whom received NIV. Two patients were excluded because of protocol violations. OOH NIV was safe and effective in all patients. In the SMT group, treatment was not effective in five of 25 patients who required OOH mechanical ventilation (p=0.05). Patients in the SMT group were admitted to an intensive care unit (ICU) more frequently (n=17) (p<0.05) and for longer periods (3.7±6.4 days) (p=0.03) compared with patients in the NIV group (n=9, 1.3±2.6 days). Six patients in the SMT group required subsequent inhospital intubation and invasive ventilation during their hospital stays; only one patient in the NIV group required intubation (p=0.10). In contrast, patients in the NIV group received NIV more frequently (n=14) in hospital compared with patients in the SMT group (n=5) (p<0.01).

Conclusions: OOH NIV proved to be feasible, safe and more effective for the treatment of ARF compared with SMT. OOH NIV promotes inhospital treatment with NIV and may reduce the frequency and length of ICU stays. Because the risks of OOH emergency intubation can be avoided, NIV should be the first-line treatment in OOH ARF if no contraindications are present.
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May 2012

Intra-arrest transnasal evaporative cooling: a randomized, prehospital, multicenter study (PRINCE: Pre-ROSC IntraNasal Cooling Effectiveness).

Circulation 2010 Aug 2;122(7):729-36. Epub 2010 Aug 2.

Department of Clinical Science and Education, Karolinska Institutet, Stockholm, Sweden.

Background: Transnasal evaporative cooling has sufficient heat transfer capacity for effective intra-arrest cooling and improves survival in swine. The aim of this study was to determine the safety, feasibility, and cooling efficacy of prehospital transnasal cooling in humans and to explore its effects on neurologically intact survival to hospital discharge.

Methods And Results: Witnessed cardiac arrest patients with a treatment interval
Conclusions: Prehospital intra-arrest transnasal cooling is safe and feasible and is associated with a significant improvement in the time intervals required to cool patients.
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August 2010

Initial ventilation through laryngeal tube instead of face mask in out-of-hospital cardiopulmonary arrest is effective and safe.

Eur J Emerg Med 2010 Feb;17(1):10-5

Department of Anaesthesiology, Emergency and Intensive Care Medicine, University Medical Centre, Göttingen, Germany.

Introduction: Bag-valve-mask ventilation is recommended as the initial airway management option for paramedics during cardiopulmonary resuscitation, although this technique requires considerable skill and is associated with the risk of stomach insufflation, regurgitation, and aspiration. The present two-phase study investigated the efficacy and safety of the laryngeal tube (LT-D) used by paramedics as the sole technique for ventilation in out-of-hospital cardiac arrest.

Methods: Paramedics staffing the emergency services' ambulances were selected for the study and trained in the use of the LT-D (phase I). They were then requested to use the device in patients requiring out-of-hospital cardiopulmonary resuscitation without prior bag-valve-mask ventilation. Patients were evaluated with regard to successful placement and effective ventilation using the airway. On arrival at the scene, the emergency physician replaced the LT-D with an endotracheal tube and assessed the incidence of regurgitation and injuries to the airways (phase II).

Results: Forty patients were enrolled into this study. One was excluded from analysis because of protocol violation. Insertion of the LT-D was successful and ventilation was effective in 33 patients (85%). Ventilation was not possible in six patients (15%) because of cuff rupture (n = 3) or massive regurgitation and aspiration before LT-D insertion (n = 3). No patient regurgitated after tube placement. No airway injuries were observed. The participants rated ventilation using the LT-D as effective.

Conclusion: The LT-D is feasible and effective for airway management and ventilation when used by paramedics in out-of-hospital cardiopulmonary resuscitation and can be recommended as the sole technique in such situations.
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February 2010

Characteristics and outcome of prehospital paediatric tracheal intubation attended by anaesthesia-trained emergency physicians.

Resuscitation 2009 Dec 4;80(12):1371-7. Epub 2009 Oct 4.

Department of Anaesthesiology, Emergency and Intensive Care Medicine, University Medical Centre, 37075 Göttingen, Germany.

Aim: To collect data regarding prehospital paediatric tracheal intubation by emergency physicians skilled in advanced airway management.

Methods: A prospective 8-year observational study of a single emergency physician-staffed emergency medical service. Self-reporting by emergency physicians of all children aged 0-14 years who had prehospital tracheal intubation and were attended by either anaesthesia-trained emergency physicians (group 1) or by a mixture of anaesthesia and non-anaesthesia-trained emergency physicians (group 2).

Results: Eighty-two out of 2040 children (4.0%) had prehospital tracheal intubation (58 in group 1). The most common diagnoses were trauma (50%; in school children, 73.0%), convulsions (13.4%) and SIDS (12.2%; in infants, 58.8%). The overall tracheal intubation success rate was 57 out of 58 attempts (98.3%). Compared to older children, infants had a higher number of Cormack-Lehane scores of 3 or 4, "difficult to intubate" status (both 3 out of 13; 23.1%) and a lower first attempt success rate for tracheal intubation (p=0.04). Among all 82 children 71 (86.6%) survived to hospital admission and 63 (76.8%) to discharge. Of the 63 survivors, 54 (85.7%) demonstrated a favourable or unchanged neurological outcome (PCPC 1-3). The survival and neurological outcomes of infants were inferior compared to older children (p<0.001). On average an emergency physician performed one prehospital tracheal intubation in 3 years in a child and one in 13 years in an infant.

Conclusions: Anaesthesia-trained emergency physicians working in our system report high success rates for prehospital tracheal intubation in children. Survival and neurological outcomes were considerably better than reported in previous studies.
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December 2009

The European Trauma Course (ETC) and the team approach: past, present and future.

Resuscitation 2009 Oct 24;80(10):1192-6. Epub 2009 Jul 24.

Birmingham Children's Hospital, Birmingham B4 6NH, United Kingdom.

The European Trauma Course (ETC) was officially launched during the international conference of the European Resuscitation Council (ERC) in 2008. The ETC was developed on behalf of ESTES (European Society of Trauma and Emergency Surgery), EuSEM (European Society of Emergency Medicine), the ESA (European Society of Anaesthesiology) and the ERC. The objective of the ETC is to provide an internationally recognised and certified life support course, and to teach healthcare professionals the key principles of the initial care of severely injured patients. Its core elements, that differentiates it from other trauma courses, are a strong focus on team training and a novel modular design that is adaptable to the differing regional European requirements. This article describes the lessons learnt during the European Trauma Course development and provides an outline of the planned future development.
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October 2009

Characteristics of out-of-hospital paediatric emergencies attended by ambulance- and helicopter-based emergency physicians.

Resuscitation 2009 Aug 10;80(8):888-92. Epub 2009 Jun 10.

Department of Anaesthesiology, Emergency and Intensive Care Medicine, University Medical Centre Göttingen, 37075 Gottingen, Germany.

Background: In Germany, as in many other countries, for the vast majority of cases, critical out-of-hospital (OOH) paediatric emergencies are attended by non-specialised emergency physicians (EPs). As it is assumed that this may lead to deficient service we aimed to gather robust data on the characteristics of OOH paediatric emergencies.

Methods: We retrospectively evaluated all OOH paediatric emergencies (0-14 years) within a 9-year period and attended by physician-staffed ground- or helicopter-based emergency medical service (EMS or HEMS) teams from our centre.

Results: We identified 2271 paediatric emergencies, making up 6.3% of all cases (HEMS 8.5%). NACA scores IV-VII were assigned in 27.3% (HEMS 32.0%). The leading diagnosis groups were age dependent: respiratory disorders (infants 34.5%, toddlers 21.8%, school children 15.0%), convulsions (17.2%, 43.2%, and 16.0%, respectively), and trauma (16.0%, 19.5%, and 44.4%, respectively). Endotracheal intubation was performed in 4.2% (HEMS 7.6%) and intraosseous canulation in 0.7% (HEMS 1.0%) of children. Cardiopulmonary resuscitation (CPR) was commenced in 2.3% (HEMS 3.4%). Thoracocentesis, chest drain insertion and defibrillation were rarities. HEMS physicians attended a particularly high fraction of drowning (80.0%), head injury (73.9%) and SIDS (60.0%) cases, whereas 75.6% of all respiratory emergencies were attended by ground-based EPs.

Conclusions: Our data suggest that EPs need to be particularly confident with the care of children suffering respiratory disorders, convulsions, and trauma. The incidence of severe paediatric OOH emergencies requiring advanced interventions is higher in HEMS-attended cases. However, well-developed skills in airway management, CPR, and intraosseous canulation in children are essential for all EPs.
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August 2009

Out-of-hospital airway management with the LMA CTrach--a prospective evaluation.

Resuscitation 2008 Nov 8;79(2):212-8. Epub 2008 Aug 8.

Department of Anaesthesiology, Emergency and Intensive Care Medicine, University of Goettingen, 37099 Goettingen, Germany.

Aim Of The Study: Airway management in an out-of-hospital setting is a critical and demanding skill. Previous studies evaluated the intubating laryngeal mask airway (ILMA) as a valuable tool in this area. The LMA CTrach Laryngeal Mask Airway (CTrach) may increase intubation success. Therefore, we evaluated the CTrach as the primary tool for airway management in the out-of-hospital setting in adult patients.

Methods: From October 2006 until September 2007 EAN and SGR included all patients who needed advanced airway management during out-of-hospital emergency medicine service. Ventilation and intubation has been performed via the CTrach as the primary choice. Before intubation, visualization of the vocal cords was optimized under continuous ventilation via the CTrach. The time needed, manoeuvres to optimize vision, grades of vision and success rates have been documented.

Results: 16 patients have been included. Ventilation and intubation via the CTrach was possible in all patients. Ventilation was mostly established in less than 15s and was established in 15 of 16 (94%) patients at the first attempt. Intubation was successful in 15 of 16 (94%) patients on the first attempt. Visualization of the laryngeal structures was achieved in 69% of patients, while intubation without sight was performed in 31%, respectively.

Conclusion: In this study, ventilation and intubation via the CTrach was successful and could be rapidly established in all patients. Our data suggest that the use of the CTrach may be suitable for the out-of-hospital setting as it provides ventilation and facilitates intubation with a very high success rate.
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November 2008

[Introduction Course HEMS-Physician - from idea to course concept].

Anasthesiol Intensivmed Notfallmed Schmerzther 2008 May;43(5):404-7

Zentrum Anästhesiologie, Rettungsund Intensivmedizin der Universitätsmedizin Göttingen und Arztlicher Leiter RTH Christoph 44.

Physicians who take a role as flight physicians in a Helicopter Emergency Medical System (HEMS) will encounter more frequently certain emergencies - such as multiple trauma, mass casualties etc. - compared to physicians in a ground based Emergency Medical System (EMS). Furthermore EMS teams already present on scene have a variance of expectations towards HEMS-Physicians. Therefore HEMS-Physicians not only must have the capabilities to treat patients properly, especially under difficult circumstances. Particularly with regard to leadership and Crew Resource Management (CRM) they will be demanded. Not least HEMS-Physicians need to have knowledge of safety and technical aspects of rescue helicopters and of operation tactics as well. Since there has been no uniform or standardised training for physicians, who will take a role in a HEMS, a course concept has been developed to improve and standardise the preparation for this challenging task.
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May 2008

[Non-invasive ventilation in prehospital emergency medicine].

Markus Roessler

Anasthesiol Intensivmed Notfallmed Schmerzther 2008 Apr;43(4):264-6

Zentrum Anästhesiologie, Rettungs- und Intensivmedizinder Uniklinik Göttingen und Arztlicher.

Non-invasive ventilation has not yet been established in prehospital emergency medicine. This most likely due to missing technical prerequisites. Meanwhile emergency ventilators feasible for prehospital NIV are available. Recognizing the pathophysiology of acute respiratory insufficiency, treatment with NIV is superior in comparison to treatment with oxygen and medication only. The advantages of NIV may lead to reduced morbidity and mortality as long as attention is paid to possible contraindications.
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April 2008

Glutamate restores growth but not motility in the absence of chloride in the moderate halophile Halobacillus halophilus.

Extremophiles 2007 Sep 13;11(5):711-7. Epub 2007 Jun 13.

Molecular Microbiology and Bioenergetics, Institute of Molecular Biosciences, Goethe University, Max-von-Laue-Str. 9, 60438, Frankfurt am Main, Germany.

Halobacillus halophilus is a strictly chloride-dependent, moderately halophilic bacterium that synthesizes glutamate and glutamine as the major compatible solutes at intermediate NaCl concentrations. The key enzyme in production of the compatible solutes glutamine and glutamate, glutamine synthetase, is dependent on chloride on a transcriptional and activity level. This led us to ask whether exogenous supply of glutamate may relief the chloride dependence of growth of H. halophilus. Growth of H. halophilus in minimal medium at 1 M NaCl was stimulated by exogenous glutamate and transport experiments revealed a chloride-independent glutamate uptake by whole cells. Growth was largely impaired in the absence of chloride and, at the same time, glutamate and glutamine pools were reduced by 90%. Exogenous glutamate fully restored growth, and cellular glutamate and glutamine pools were refilled. Although glutamate could restore growth in the absence of chloride, another chloride-dependent process, flagellum synthesis and motility, was not restored by glutamate. The differential effect of glutamate on the two chloride-dependent processes, growth and motility, indicates that glutamate can not substitute chloride in general but apparently bypasses one function of the chloride regulon, the adjustment of pool sizes of compatible solutes.
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September 2007