Matthias Gründling

Effect of Empirical Treatment With Moxifloxacin and Meropenem vs Meropenem on Sepsis-Related Organ Dysfunction in Patients With Severe Sepsis: A Randomized Trial

CONTEXT Early appropriate antimicrobial therapy leads to lower mortality rates associated with severe sepsis. The role of empirical combination therapy comprising at least 2 antibiotics of different mechanisms remains controversial. OBJECTIVE To compare the effect of moxifloxacin and meropenem with the effect of meropenem alone on sepsis-related organ dysfunction. DESIGN, SETTING, AND PATIENTS A randomized, open-label, parallel-group trial of 600 patients who fulfilled criteria for severe sepsis or septic shock (n = 298 for monotherapy and n = 302 for combination therapy). The trial was performed at 44 intensive care units in Germany from October 16, 2007, to March 23, 2010. The number of evaluable patients was 273 in the monotherapy group and 278 in the combination therapy group. INTERVENTIONS Intravenous meropenem (1 g every 8 hours) and moxifloxacin (400 mg every 24 hours) or meropenem alone. The intervention was recommended for 7 days and up to a maximum of 14 days after randomization or until discharge from the intensive care unit or death, whichever occurred first. MAIN OUTCOME MEASURE Degree of organ failure (mean of daily total Sequential Organ Failure Assessment [SOFA] scores over 14 days; score range: 0-24 points with higher scores indicating worse organ failure); secondary outcome: 28-day and 90-day all-cause mortality. Survivors were followed up for 90 days. RESULTS Among 551 evaluable patients, there was no statistically significant difference in mean SOFA score between the meropenem and moxifloxacin group (8.3 points; 95% CI, 7.8-8.8 points) and the meropenem alone group (7.9 points; 95% CI, 7.5-8.4 points) (P = .36). The rates for 28-day and 90-day mortality also were not statistically significantly different. By day 28, there were 66 deaths (23.9%; 95% CI, 19.0%-29.4%) in the combination therapy group compared with 59 deaths (21.9%; 95% CI, 17.1%-27.4%) in the monotherapy group (P = .58). By day 90, there were 96 deaths (35.3%; 95% CI, 29.6%-41.3%) in the combination therapy group compared with 84 deaths (32.1%; 95% CI, 26.5%-38.1%) in the monotherapy group (P = .43). CONCLUSION Among adult patients with severe sepsis, treatment with combined meropenem and moxifloxacin compared with meropenem alone did not result in less organ failure. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00534287.

Activated protein C improves intestinal microcirculation in experimental endotoxaemia in the rat

IntroductionSuccessful treatment of severe sepsis and septic shock remains a major challenge in critical care medicine. The recently introduced recombinant human activated protein C (APC) remarkably improved the outcome of septic patients. The influence of APC on intestinal circulation is still poorly understood. Therefore, the present study aimed to investigate the effects of APC on intestinal microcirculation during experimental endotoxaemia in rats by using intravital microscopy.MethodsA total of 44 male Lewis rats were randomly assigned to receive intravenous injections of 15 mg/kg lipopolysaccharide alone (LPS) (n = 11) or LPS followed by subsequent injection of 2 mg/kg recombinant human APC (LPS + APC) (n = 11), whereas control animals received either APC (n = 11) or saline (n = 11). Animals underwent observations of functional capillary density and leucocyte adherence on venular endothelium in the microcirculation of the intestinal wall by means of intravital fluorescence microscopy. Indicators of macrocirculation as well as plasma levels of tumour necrosis factor-α, interleukin (IL)-1β, IL-6, and IL-10 were measured.ResultsAlthough APC administration of both LPS-treated and control rats did not change macrocirculation or release of inflammatory cytokines, it increased mucosal and muscular functional capillary density (p < 0.001 and p < 0.05, respectively) and reduced the number of firmly adhering leucocytes in intestinal submucosal V1 and V3 venules (p < 0.01) in LPS + APC-treated compared with LPS-treated animals, which did not receive APC. No remarkable differences that could be attributed to APC treatment were observed between the two control groups.ConclusionAPC administration during experimental endotoxaemia improved intestinal microcirculation by protecting functional capillary density as a measure of microvascular perfusion and exerted anti-inflammatory effects by reducing leucocyte adherence to the endothelium in submucosal venules. Therefore, beneficial effects of APC in septic patients might be due, in part, to improved intestinal microcirculation.

Diagnose und Therapie der Sepsis: S-2 Leitlinien der Deutschen Sepsis-Gesellschaft e.V. (DSG) und der Deutschen Interdisziplinären Vereinigung für Intensiv- und Notfallmedizin (DIVI)*

SummaryA recent survey conducted by the publicly funded Competence Network Sepsis (Sep- Net) reveals that severe sepsis and/or septic shock occurs in 75,000 inhabitants (110 out of 100,000) and sepsis in 79,000 inhabitants (116 out of 100,000) in Germany annually. This illness is responsible for approx. 60,000 deaths and ranges as the third most frequent cause of death after acute myocardial infarction. Direct costs for the intensive care of patients with severe sepsis alone amount to approx. 1.77 billion euros, which means that about 30% of the budget in intensive care is used to treat severe sepsis. However, until now German guidelines for the diagnosis and therapy of severe sepsis did not exist. Therefore, the German Sepsis Society initiated the development of guidelines which are based on international recommendations by the International Sepsis Forum (ISF) and the Surviving Sepsis Campaign (SSC) and take into account the structure and organisation of the German health care system. Priority was given to the following guideline topics: a) diagnosis, b) prevention, c) causative therapy, d) supportive therapy, e) adjunctive therapy. The guidelines development process was carefully planned and strictly adhered to according to the requirements of the Working Group of Scientific Medical Societies (AWMF).ZusammenfassungNach neuesten Erhebungen des vom BMBF geförderten Kompetenznetzwerkes Sepsis (SepNet) erkranken in Deutschland pro Jahr 75 000 Einwohner (110 von 100 000) an einer schweren Sepsis bzw. septischem Schock und 79 000 (116 von 100 000) an einer Sepsis. Mit ca. 60 000 Todesfällen stellen septische Erkrankungen die dritthäufigste Todesursache nach dem akuten Myokardinfarkt dar. Die direkten anteiligen Kosten, die allein für die intensivmedizinische Behandlung von Patienten mit schwerer Sepsis anfallen, liegen bei ca. 1,77 Milliarden Euro. Ca. 30% des Budgets für Intensivmedizin werden damit in die Behandlung der Sepsis investiert. Im Kontrast hierzu, existierten bisher jedoch keine deutsche Leitlinien zur Diagnose und Therapie der schweren Sepsis. Auf Initiative der Deutschen Sepsis-Gesellschaft wurden daher in Anlehnung an die internationalen Empfehlungen des International Sepsis Forum (ISF) und der Surviving Sepsis Campaign (SSC) Leitlinien erarbeitet, welche die Versorgungsstrukturen im deutschen Gesundheitssystem berücksichtigen. Folgende Leitlinienthemen wurden als vorrangig eingestuft: a) Diagnose, b) Prävention, c) kausale Therapie, d) supportive Therapie, e) adjunktive Therapie. Die Leitlinien sind nach einem sorgfältig geplanten und streng eingehaltenen Prozess nach den Vorgaben der Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF) entstanden.

Propranolol selectively blocks the enhanced parietal old/new effect during long-term recollection of unpleasant pictures: A high density ERP study

Evidence from both animal and human research suggests that the formation of emotional memories is triggered by the beta-adrenergic system. To confirm whether modulation of central beta-adrenergic transmission is specifically involved in the neural signature of memory performance, the pre-encoding effect of propranolol (80 mg) on event-related potentials (ERPs) was measured in a placebo-controlled, double-blind, parallel-group study in 46 male healthy subjects using high density EEG and source imaging analysis during encoding and retrieval (after 1 week) of IAPS pictures of unpleasant, neutral and pleasant contents; for recognition 90 old pictures were randomly mixed with 90 new pictures. During retrieval correctly remembered old pictures elicited a significantly larger positive voltage change over the centro-parietal cortex than new pictures. Propranolol significantly reduced this old/new difference of the mean ERP amplitudes (500-800 ms) for unpleasant but not for neutral and pleasant memories. This effect correlated with salivary alpha-amylase activity, a surrogate for central adrenergic stimulation. In conclusion, propranolol selectively blocked the neural signature of unpleasant memories by mechanisms in which the parietal cortex seems to be specifically involved.

Effects of dopexamine on the intestinal microvascular blood flow and leucocyte activation in a sepsis model in rats

IntroductionDopexamine may be a therapeutic option to improve hepatosplanchnic perfusion in sepsis. To investigate this possibility, we administered dopexamine in an experimental sepsis model in rats.MethodsThis prospective, randomized, controlled laboratory study was conducted in 42 Wistar rats. The animals were divided into three groups. Group 1 served as the control group (CON group). The animals in both groups 2 (LPS group) and 3 (DPX group) received an endotoxin (lipopolysaccharide from Escherichia coli – LPS) infusion (20 mg/kg for 15 minutes). DPX group additionally received dopexamine (0.5 μg/kg per minute over four hours). One half of the animals in each group underwent studies of intestinal microvascular blood flow (IMBF) using laser Doppler fluxmetry. In the other half an intravital microscopic evaluation of leucocyte-endothelial cell interaction in intestinal microcirculation was conducted. Functional capillary density (FCD) in the intestinal mucosa and in the circular as well as longitudinal muscle layer was estimated.ResultsOne hour after endotoxin challenge, IMBF decreased significantly in LPS group to 51% compared with baseline (P < 0.05). In DPX group (endotoxin plus dopexamine) we found IMBF values significantly higher than those in LPS group (approximately at the level of controls). The impaired FCD following endotoxin challenge was improved by dopexamine in the longitudinal muscle layer (+33% in DPX group versus LPS group; P < 0.05) and in the circular muscle layer (+48% in DPX group versus LPS group; P < 0.05). In DPX group, dopexamine administration reduced the number of firmly adherent leucocytes (-31% versus LPS group; P < 0.05). Plasma levels of tumour necrosis factor-α were reduced by dopexamine infusion (LPS group: 3637 ± 553 pg/ml; DPX group: 1933 ± 201 pg/ml) one hour after endotoxin challenge.ConclusionDopexamine administration improved IMBF and FCD (markers of intestinal microcirculation) and reduced leucocyte activation (a marker of inflammation) in experimental sepsis.

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

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.

Effects of coagulation factor XIII on intestinal functional capillary density, leukocyte adherence and mesenteric plasma extravasation in experimental endotoxemia

IntroductionThe objective of this study was to determine the effects of the administration of the coagulation factor XIII (F XIII) on intestinal functional capillary density, leukocyte adherence and mesenteric plasma extravasation during experimental endotoxemia.MethodsIn a prospective, randomized, controlled animal study 42 male Wistar rats were divided into three groups. Group 1 served as the control group. Groups 2 (lipopolysaccharide (LPS) group) and 3 (F XIII group) received endotoxin infusions (2.5 mg/kg/h for 2 hours). In group 3, 50 U/kg body weight F XIII was continuously administered during the first 30 minutes of endotoxemia. F XIII levels were measured in all animals. One half of the animals of each group were studied for intestinal functional capillary density (FCD) and leukocyte adherence on venular endothelium by intravital fluorescence microscopy (IVM). In the other half of each group, mesenteric plasma extravasation (FITC-albumin) was determined by IVM.ResultsThe F XIII level was significantly increased in the F XIII treatment group. In the LPS group, endotoxemia led to a significant reduction of mucosal FCD (-18.5%; p < 0.01 versus control group). F XIII administration in the F XIII group attenuated the decrease in mucosal FCD (-3.7% compared to control; p < 0.05 versus LPS group). During endotoxemia, a significant increase of leukocyte adherence at the endothelium could be noted in the LPS group compared to the control group. Leukocyte adherence at the endothelium and plasma extravasation in the F XIII group did not differ significantly from the LPS group.ConclusionFactor XIII protected mucosal capillary perfusion against endotoxin-induced impairment in an experimental sepsis model in rats, whereas leukocyte adherence and plasma extravasation remained unchanged.

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

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·kg−1 lipopolysaccharideiv), APC (2 mg·kg−1 APCiv), 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-α, IL-1β, 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 andP=0.0004, respectively). Interleukin-1β release was also significantly reduced by APC treatment (2567.4 ± 320.9 pg·mL−1 in the LPS groupvs 1626.1 ± 427.2 pg·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-1β 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.RésuméObjectif: La protéine C activée (PCA) est le premier médicament anti-inflammatoire à être approuvé pour le traitement des septicémies sévères. Cependant, les mécanismes sous-jacents de cette protéine ne sont pas encore complètement compris. C’est pourquoi notre étude avait pour but d’évaluer les effets de la PCA sur la microcirculation (interaction mésentérique leucocytaire-endothéliale, extravasation plasmatique) en utilisant la microscopie intravitale (IVM) ainsi que ses effets sur la libération de cytokines pendant une endotoxémie expérimentale chez les rats.Méthode: Nous avons randomisé quarante rats Lewis mâles en quatre groupes (n=10 par groupe) : témoin, LPS (15 mg·kg−1 lipopolysaccharide iv), PCA (2 mg·kg−1 PCA iv), et LPS+PCA. Nous avons évalué les interactions mésentériques leucocytaires-endothéliales et l’extravasation plasmatique à zéro, une et deux heures après l’administration de LPS et de PCA par MIV. Les niveaux plasmatiques de facteur onconécrosant-α, d’IL-1β, d’interleukine (IL)-6, et d’IL-10 ont été mesurés à zéro et deux heures.Résultats: L’adhérence leucocytaire (−74 %) et l’extravasation plasmatique (−28 %) pendant l’endotoxémie ont été significativement réduites après un traitement avec PCA, par rapport aux animaux LPS non traités (P=0,0001 et P=0,0004, respectivement). La libération d’interleukine-1β était également réduite de façon significative par le traitement avec PCA (2567,4 ± 320,9 pg·mL−1 dans le groupe LPS vs 1626,1 ± 427,2 pg·mL−1 dans le groupe LPS+PCA ; P=0,001).Conclusion: Ces expériences sur les rongeurs ont montré que le traitement à base de PCA atténuait de manière significative la détérioration de la microcirculation mésentérique ainsi que la libération systémique d’IL-1β provoquées par le choc endotoxique. En raison du rôle primordial de la microcirculation dans la pathogenèse continue de la septicémie et dans le syndrome de défaillance multisystémique, ces effets pourraient avoir une importance clinique.

Intravenous free and dipeptide-bound glutamine maintains intestinal microcirculation in experimental endotoxemia.

OBJECTIVE The administration of glutamine (Gln), which is depleted in critical illness, is associated with an improvement of gut metabolism, structure, and function. The aim of the present study was to evaluate the effects of intravenous Gln and its galenic formulation, l-alanyl-l-glutamine dipeptide (AlaGln), on the intestinal microcirculation during experimental endotoxemia using intravital fluorescence microscopy. Gln or AlaGln administration was performed as pretreatment or post-treatment, respectively. To identify further the underlying mechanisms, amino acid levels were studied. METHODS Sixty male Lewis rats were randomly divided into six groups (n = 10/group): control, LPS (lipopolysaccharide 5 mg/kg intravenously), Gln/LPS (LPS animals pretreated with Gln 0.75 g/kg Gln intravenously), AlaGln/LPS (LPS animals pretreated with AlaGln intravenously, 0.75 g/kg Gln content), LPS/Gln (LPS animals post-treated with Gln 0.75 g/kg intravenously), and LPS/AlaGln (LPS animals post-treated with AlaGln intravenously, 0.75 g/kg Gln content). Two hours after the endotoxin challenge, the microcirculation of the terminal ileum was studied using intravital fluorescence microscopy. Blood samples were drawn at the beginning, during, and the end of the experiment to determine the amino acid levels. RESULTS The Gln and AlaGln pre- and post-treatment, respectively, prevented the LPS-induced decrease in the functional capillary density of the intestinal muscular and mucosal layers (P < 0.05). The number of adherent leukocytes in the submucosal venules was significantly attenuated after the Gln and AlaGln pre- and post-treatment (P < 0.05). CONCLUSION The Gln and AlaGln administrations improved the intestinal microcirculation by increasing the functional capillary density of the intestinal wall and decreasing the submucosal leukocyte activation.

Infection prevention during anaesthesia ventilation by the use of breathing system filters (BSF): Joint recommendation by German Society of Hospital Hygiene (DGKH) and German Society for Anaesthesiology and Intensive Care (DGAI).

An interdisciplinary working group from the German Society of Hospital Hygiene (DGKH) and the German Society for Anaesthesiology and Intensive Care (DGAI) worked out the following recommendations for infection prevention during anaesthesia by using breathing system filters (BSF). The BSF shall be changed after each patient. The filter retention efficiency for airborne particles is recommended to be >99% (II). The retention performance of BSF for liquids is recommended to be at pressures of at least 60 hPa (=60 mbar) or 20 hPa above the selected maximum ventilation pressure in the anaesthetic system. The anaesthesia breathing system may be used for a period of up to 7 days provided that the functional requirements of the system remain unchanged and the manufacturer states this in the instructions for use. The breathing system and the manual ventilation bag are changed immediately after the respective anaesthesia if the following situation has occurred or it is suspected to have occurred: Notifiable infectious disease involving the risk of transmission via the breathing system and the manual bag, e.g. tuberculosis, acute viral hepatitis, measles, influenza virus, infection and/or colonisation with a multi-resistant pathogen or upper or lower respiratory tract infections. In case of visible contamination e.g. by blood or in case of defect, it is required that the BSF and also the anaesthesia breathing system is changed and the breathing gas conducting parts of the anaesthesia ventilator are hygienically reprocessed. Observing of the appropriate hand disinfection is very important. All surfaces of the anaesthesia equipment exposed to hand contact must be disinfected after each case.