Martin Sauer

The influence of residual neuromuscular block on the incidence of critical respiratory events. A randomised, prospective, placebo-controlled trial.

Context Residual paralysis is associated with post-operative pulmonary complications, including critical respiratory events. Objective We determined the incidence of critical respiratory events, such as hypoxaemia, in patients with minimal residual neuromuscular blockade and compared these data with those from patients with full recovery of blockade. Design Randomised, prospective, placebo-controlled trial. Setting Single centre; Rostock, Germany, from January 2007 to February 2008. Patients One hundred and thirty-two adult patients, aged 18–80 years, with the American Society of Anesthesiology I–III physical status, undergoing orthopaedic surgery under general anaesthesia, including rocuronium to produce neuromuscular blockade; 114 patients were randomised to one of two groups: neostigmine group (neostigmine 20 &mgr;g kg−1) or placebo group (saline). Interventions In the patients in the neostigmine group, the tracheal tube was removed at a train-of-four (TOF) ratio of 1.0; in the patients in the placebo group, the trachea was extubated at a TOF ratio less than 1.0, but without fade in TOF and double-burst stimulation (DBS). Neuromuscular monitoring was assessed simultaneously with qualitative TOF/DBS monitoring, and with quantitative calibrated acceleromyography. Critical respiratory events, such as hypoxaemia, were assessed in the post-anaesthesia care unit. Main outcome measures Forty-five patients (39.5%) became hypoxaemic (SaO2 < 93%); there was a significant difference between the groups (29 patients in the placebo group versus 16 in the neostigmine group; P = 0.021). Results In the neostigmine group, all patients were extubated at a TOF ratio of 1.0. In the placebo group, the median TOF ratio was 0.7 (range: 0.46–0.9; P < 0.001). The median time for spontaneous recovery in the placebo group was 16 min (range 3–49 min). Neostigmine 20 &mgr;g kg−1 was effective in antagonising rocuronium-induced blockade without fade in TOF and DBS. Conclusion In this randomised, prospective, placebo-controlled trial, minimal residual block was associated with hypoxaemia in the post-anaesthesia care unit. Neostigmine 20 &mgr;g kg−1 was effective in antagonising rocuronium-induced (minimal) blockade.

Extracorporeal cell therapy with granulocytes in a pig model of Gram-positive sepsis.

Objectives:Granulocyte transfusions have been used to treat immune cell dysfunction in sepsis. As granulocyte transfusions can trigger tissue injury via local effects of neutrophils, we hypothesized that extracorporeal treatment of plasma using granulocytes would prove beneficial while having less side effects. Design:Prospective controlled three-armed animal study. Setting:Research laboratory. Subjects:Twenty-one female immature pigs (7.5–12 kg, 7–9 weeks old). Interventions:Three groups of spontaneously breathing, sedated pigs (n = 7 each) received an intravenous lethal dose of live Staphylococcus aureus over 1 hour. Although group I had no specific treatment (control), group II and III were subsequently treated for 4 hours with an extracorporeal device containing either no cells (sham control, group II) or human cell line-derived granulocytic cells (group III). Survival time and physiologic, biochemical, and hematologic parameters were monitored for 7 days. Measurements and Main Results:All animals of group I died during the observation time (mean survival time: 70 hours). In group II, two of seven and in group III, six of seven animals survived the observation time (mean survival: 75 and 168 hours, respectively). Survival differences were significant between group I and III (p < 0.001) and between group II and III (p < 0.05) but not between group I and II (p = 0.43). Furthermore, group differences in bacterial blood concentrations, differential blood count, blood gases, lactate, and interleukins were observed. The extracorporeal cell treatment was well tolerated by the animals. Conclusions:Extracorporeal therapy with granulocytic cells significantly improved survival in a pig model of sepsis. Further studies with this approach are encouraged.

Plasma separation by centrifugation and subsequent plasma filtration: impact on survival in a pig model of sepsis.

The impact on survival of a combination of plasma separation by centrifugation and subsequent plasma filtration was tested in a bacterial sepsis model in pigs. In this animal study 19 pigs were included. Groups II and III received an intravenous lethal dose of live Staphylococcus aureus over 1 h; group I received saline (non‐septic control—NC). Groups I and II were treated by an extracorporeal circuit consisting of online centrifugation and subsequent plasma filtration (group II: treated group—TG) for 4 h; group III had no specific treatment (septic control, SC). The observation time was 7 days. All animals of group I (NC) and group II (TG) survived, while all animals of group III (SC) died during the observation time. Extracorporeal therapy with online centrifugation and plasma filtration significantly improved survival in a pig model of sepsis. Further studies with this approach are encouraged.

Safety evaluation for a cell-based immune support system in an ex vivo rat model of gram-negative sepsis.

Granulocyte dysfunction is a central component of immunodeficiency in septic patients. Granulocyte transfusions appear to be pathophysiologically useful; however, they cause unwanted side‐effects in the lungs and other organs. This study evaluates the safety of an extracorporeal immune support system with granulocytic cells in a rat model of Gram‐negative sepsis. Three groups of male CD rats received either saline (control group, I), a dose of Escherichia coli O7:K1 lethal to 90% of the animals (LD90) (septic group, II), or an LD90 dose of E. coli that was incubated with the human promyelocytic leukemia cell line (HL‐60) (differentiated into the granulocytic direction) for 20 min prior to infusion (second septic group, III). The animals were observed for seven days. Pre‐treatment with HL‐60 cells resulted in no adverse effects in the group III animals. Significantly lower bacterial counts and endotoxin levels in the plasma were detected after 24 h as compared to group II (P < 0.05). Group III animals had better weight gain and more stable hemodynamics than group II animals (P < 0.01). Seven day survival was 0/8 in group II, 6/8 in group III, and 8/9 in group I (log–rank test: II–III: P < 0.001). The data suggest that extracorporeal use of granulocytes allows the therapeutic use of these cells while avoiding unwanted effects resulting from direct contact to internal organs.

Treatment of the First Acute Relapse Following Therapeutic Plasma Exchange in Formerly Glucocorticosteroid-Unresponsive Multiple Sclerosis Patients—A Multicenter Study to Evaluate Glucocorticosteroid Responsiveness

Therapeutic options to treat multiple sclerosis (MS) relapses comprise glucocorticosteroids (GCS) as first-line and therapeutic plasma exchange (TPE) as second-line treatments in GCS-unresponsive patients. No guidelines exist for the treatment of another relapse following TPE. We retrospectively analyzed the responsiveness to GCS in a subsequent relapse following TPE in previously GCS-unresponsive MS patients. Thirty-seven patients with GCS-unresponsive MS relapses received TPE (relapse A). All patients developed another relapse after the completion of TPE and received GCS again (relapse B). The primary study endpoint was the clinical response to GCS and TPE. Marked improvement was defined as clinically significant improvement in function, moderate improvement as a definite change of symptoms without significant impact on function, no effect comprised unchanged symptoms, and deterioration a worsening of symptoms or new deficits. The secondary endpoint was an improvement in expanded disability status scale (EDSS) scoring. All patients were GCS-unresponsive during relapse A and received TPE. During GCS treatment of relapse B, marked improvement was observed in 10, moderate improvement in 24, and no effect in three patients. The EDSS decreased in 15 patients. GCS might remain the first-line relapse treatment following TPE in formerly GCS-unresponsive MS patients.

Hepatotoxicity of Antimycotics Used for Invasive Fungal Infections: In Vitro Results

Purpose. Drug-induced liver injury (DILI) is the most common cause of liver injury and a serious clinical problem; antimycotics are involved in approximately 3% of all DILI cases. The hepatotoxicity of many drugs, including the antimycotics, is poorly screened in human models. Methods. In a standardized assay the cytotoxicity on hepatocytes of different concentrations (Cmax, 5x Cmax, and 10x Cmax) of the antimycotics used for systemic infections was tested. Anidulafungin (ANI), liposomal amphotericerin B (L-AmB), caspofungin (CASPO), fluconazole (FLUCO), and voriconazole (VORI) were incubated with HepG2/C3A cells. After incubation, the viability of cells (XTT test, LDH release, trypan blue staining), the synthesis of albumin, the cytochrome 1A2 activity, and the cell death (DNA fragmentation) were determined. Kruskal-Wallis and Mann–Whitney tests were used for statistical analyses. Results. L-AmB, ANI, and CASPO showed a mild hepatotoxicity in the Cmax concentrations. Higher concentrations of anidulafungin led to a severe impairment of hepatocyte viability and function. The azoles FLUCO and VORI had a higher hepatotoxic potential in all concentrations. Conclusion. Antimycotics, especially azoles, used for systemic infections should be given with caution in patient with liver insufficiency or liver failure or high risk for this; therefore, therapeutic drug monitoring should be used. Further studies with this approach are encouraged.

Rocuronium is more hepatotoxic than succinylcholine in vitro.

BACKGROUND The development of liver failure is a major problem in critically ill patients. The hepatotoxicity of many drugs, as one important reason for liver failure, is poorly screened for in human models. Rocuronium and succinylcholine are neuromuscular blocking agents used for tracheal intubation and for rapid-sequence induction. OBJECTIVE We used an in-vitro test with a permanent cell line and compared rocuronium and succinylcholine for hepatotoxicity. DESIGN In-vitro study. SETTING A basic science laboratory, University Hospital Rostock, Germany. MATERIAL/(PATIENTS) The basic test compound is the permanent human liver cell line HepG2/C3A. In a standardised microtitre plate assay the toxicity of different concentrations of rocuronium, succinylcholine and plasma control was tested. INTERVENTIONS After two incubation periods of 3 days, the viability of cells (XTT test, lactate dehydrogenase release and trypan blue staining), micro-albumin synthesis and the cytochrome 1A2 activity (metabolism of ethoxyresorufin) were measured. MAIN OUTCOME MEASURES Differences between rocuronium and succinylcholine were assessed using the Kruskal–Wallis one-way test and two-tailed Mann–Whitney U test. RESULTS Rocuronium, but not succinylcholine, led to a significant dose-dependent decrease of viability, albumin synthesis and cytochrome 1A2 activity of test cells. CONCLUSION An in-vitro test with a cell line showed hepatotoxicity of rocuronium that was dose-dependent. Further studies are needed to investigate the underlying mechanisms of the effects of rocuronium on hepatic cellular integrity. TRIAL REGISTRATION Not suitable.

Procalcitonin Impairs Liver Cell Viability and Function In Vitro: A Potential New Mechanism of Liver Dysfunction and Failure during Sepsis?

Purpose. Liver dysfunction and failure are severe complications of sepsis and result in poor outcome and increased mortality. The underlying pathologic mechanisms of hepatocyte dysfunction and necrosis during sepsis are only incompletely understood. Here, we investigated whether procalcitonin, a biomarker of sepsis, modulates liver cell function and viability. Materials and Methods. Employing a previously characterized and patented biosensor system evaluating hepatocyte toxicity in vitro, human hepatocellular carcinoma cells (HepG2/C3A) were exposed to 0.01–50 ng/mL procalcitonin for 2 × 72 h and evaluated for proliferation, necrosis, metabolic activity, cellular integrity, microalbumin synthesis, and detoxification capacity. Acetaminophen served as positive control. For further standardization, procalcitonin effects were confirmed in a cellular toxicology assay panel employing L929 fibroblasts. Data were analyzed using ANOVA/Tukeys test. Results. Already at concentrations as low as 0.25 ng/mL, procalcitonin induced HepG2/C3A necrosis (P < 0.05) and reduced metabolic activity, cellular integrity, synthesis, and detoxification capacity (all P < 0.001). Comparable effects were obtained employing L929 fibroblasts. Conclusion. We provide evidence for procalcitonin to directly impair function and viability of human hepatocytes and exert general cytotoxicity in vitro. Therapeutical targeting of procalcitonin could thus display a novel approach to reduce incidence of liver dysfunction and failure during sepsis and lower morbidity and mortality of septic patients.

Role of different replacement fluids during extracorporeal treatment in a pig model of sepsis.

In an extracorporeal combination therapy, the impact of different replacement fluids on survival was tested in a bacterial sepsis model in pigs. In an animal study 19 pigs, weighing 7.5–11.1 kg, were included. All groups received an intravenous lethal dose of live Staphylococcus aureus over 1 h. The animals were treated by an extracorporeal circuit consisting of online centrifugation and subsequent plasma filtration for 4 h. The extracorporeal circuit was pre‐filled with 400 mL replacement fluid. In the P0 group 100% hydroxyethyl starch 130/0.4 was used as replacement fluid; in the P30 group 30% pig plasma and 70% hydroxyethyl starch; and in the P100 group 100% pig plasma. The observation time was 7 days. All animals of the group P100 survived, while all animals of group P0 and five out of seven animals of the P30 group died during the observation time. Extracorporeal therapy consisting of online centrifugation and plasma filtration with 100% pig plasma as replacement fluid significantly improved survival in a pig model of sepsis. Further studies with this approach are encouraged.

Adaptive FE-Meshfree-Modelling for Impacts of Liquid Filled Vessels on Thin Walled Structures

A principal approach to simulate the airplane impact and the collapse of World Trade Center North Tower has been shown by Quan and Birnbaum [4]. Using the general purpose hydrocode AUTODYN the impact damage, fire induced strength reduction and progressive collapse were investigated. Both for the fuel propagation after tank break up and the thermodynamic burn processes assumptions have been taken. It is the aim of this paper to focus on the numerical aspects of simulating the fluid propagation after vessel break up. The release of a fluid out of a broken vessel after impact is not easily represented in a numerical simulation as the fluid flow and its interaction with structures can not be modelled using Lagrangian type element formulations. These elements, typically applied for structural analyses, fail under massive deformation and usually need then to be taken out of the simulation. Typical fluid dynamic discretization methods, so called Eulerian grids, would have to cover the whole space potentially being reached by the fluid flow and are therefore inefficient in a large three dimensional simulation. As an alternative method a coupled discretization using Lagrange elements and Lagrange type meshfree methods is proposed here. Meshfree methods have been introduced to structural dynamics more then ten years ago specifically to simulate processes including large deformation [1]. Originally developed as pure meshfree code, the EMI SOPHIA [3] provides now a new form of adaptivity that allows for more efficiency and accuracy. This is achieved by the use of finite elements as long as deformation is capable for the elements. At definable strain or failure thresholds any element can be transformed into one or more meshfree particles. This way, mass and volume of the original elements are conserved. As the particles interact with each other as well as with the remaining elements, all physical processes can be modelled continuously. The purpose of this study was to contribute to numerical simulation of the airplane impacts into the World Trade Center. It includes impact simulations of cylindrical vessels filled with water against thin walled rectangular shaped bars. It shows that coupled discretizations and specifically an adaptive FE-meshfree discretization offer the flexibility needed to gain both accuracy and efficiency in the simulation.Copyright