Christian Kleber

Critical illness myopathy and GLUT4 - significance of insulin and muscle contraction

RATIONALE Critical illness myopathy (CIM) has no known cause and no treatment. Immobilization and impaired glucose metabolism are implicated. OBJECTIVES We assessed signal transduction in skeletal muscle of patients at risk for CIM. We also investigated the effects of evoked muscle contraction. METHODS In a prospective observational and interventional pilot study, we screened 874 mechanically ventilated patients with a sepsis-related organ-failure assessment score greater than or equal to 8 for 3 consecutive days in the first 5 days of intensive care unit stay. Thirty patients at risk for CIM underwent euglycemic-hyperinsulinemic clamp, muscle microdialysis studies, and muscle biopsies. Control subjects were healthy. In five additional patients at risk for CIM, we performed corresponding analyses after 12-day, daily, unilateral electrical muscle stimulation with the contralateral leg as control. MEASUREMENTS AND MAIN RESULTS We performed successive muscle biopsies and assessed systemic insulin sensitivity and signal transduction pathways of glucose utilization at the mRNA and protein level and glucose transporter-4 (GLUT4) localization in skeletal muscle tissue. Skeletal muscle GLUT4 was trapped at perinuclear spaces, most pronounced in patients with CIM, but resided at the sarcolemma in control subjects. Glucose metabolism was not stimulated during euglycemic-hyperinsulinergic clamp. Insulin signal transduction was competent up to p-Akt activation; however, p-adenosine monophosphate-activated protein kinase (p-AMPK) was not detectable in CIM muscle. Electrical muscle stimulation increased p-AMPK, repositioned GLUT4, locally improved glucose metabolism, and prevented type-2 fiber atrophy. CONCLUSIONS Insufficient GLUT4 translocation results in decreased glucose supply in patients with CIM. Failed AMPK activation is involved. Evoked muscle contraction may prevent muscle-specific AMPK failure, restore GLUT4 disposition, and diminish protein breakdown. Clinical trial registered with http://www.controlled-trials.com (registration number ISRCTN77569430).

Requirement for a structured algorithm in cardiac arrest following major trauma: epidemiology, management errors, and preventability of traumatic deaths in Berlin.

BACKGROUND Despite continuous innovation in trauma care, fatal trauma remains a significant medical and socioeconomic problem. Traumatic cardiac arrest (tCA) is still considered a hopeless situation, whereas management errors and preventability of death are neglected. We analyzed clinical and autopsy data from tCA patients in an emergency-physician-based rescue system in order to reveal epidemiologic data and current problems in the successful treatment of tCA. MATERIAL AND METHODS Epidemiological and autopsy data of all unsuccessful tCPR cases in a one-year-period in Berlin, Germany (n=101, Group I) and clinical data of all cases of tCPR in a level 1 trauma centre in an 6-year period (n=52, Group II) were evaluated. Preventability of traumatic deaths in autopsy cases (n=22) and trauma-management failures were prospectively assessed. RESULTS In 2010, 23% of all traumatic deaths in Berlin received tCPR. Death after tCPR occurred predominantly prehospital (PH;74%) and only 26% of these patients were hospitalized. Of 52 patients (Group II), 46% required tCPR already PH and 81% in the emergency department (ED). In 79% ROSC was established PH and 53% in the ED. The survival rate after tCPR was 29% with 27% good neurological outcome. Management errors occurred in 73% PH; 4 cases were judged as potentially or definitive preventable death. CONCLUSION Trauma CPR is beyond routine with the need for a tCPR-algorithm, including chest/pericardial decompression, external pelvic stabilization and external bleeding control. The prehospital trauma management has the highest potential to improve tCPR and survival. Therefore, we suggested a pilot prehospital tCPR-algorithm.

Early type II fiber atrophy in intensive care unit patients with nonexcitable muscle membrane

Objective: Intensive care unit-acquired weakness indicates increased morbidity and mortality. Nonexcitable muscle membrane after direct muscle stimulation develops early and predicts intensive care unit-acquired weakness in sedated, mechanically ventilated patients. A comparison of muscle histology at an early stage in intensive care unit-acquired weakness has not been done. We investigated whether nonexcitable muscle membrane indicates fast-twitch myofiber atrophy during the early course of critical illness. Design: Prospective observational study. Setting: Two intensive care units at Charité University Medicine, Berlin. Patients: Patients at increased risk for development of intensive care unit-acquired weakness, indicated by Sepsis-related Organ Failure Assessment scores ≥8 on 3 of 5 consecutive days within their first week in the intensive care unit. Interventions: None. Measurements and Main Results: Electrophysiological compound muscle action potentials after direct muscle stimulation and muscle biopsies were obtained at median days 7 and 5, respectively. Patients with nonexcitable muscle membranes (n = 15) showed smaller median type II cross-sectional areas (p < .05), whereas type I muscle fibers did not compared with patients with preserved muscle membrane excitability (compound muscle action potentials after direct muscle stimulation ≥3.0 mV; n = 9). We also observed decreased mRNA transcription levels of myosin heavy chain isoform IIa and a lower densitometric ratio of fast-to-slow myosin heavy chain protein content. Conclusion: We suggest that electrophysiological nonexcitable muscle membrane predicts preferential type II fiber atrophy in intensive care unit patients during early critical illness.

Emergency medicine techniques and the forensic autopsy

Emergency medicine measures often have to be carried out under suboptimal conditions in emergency situations and require invasive patient treatment. In the case of a fatal outcome these measures have to be evaluated at autopsy, regarding indications, correct implementation and possible complications. As well, alongside the more familiar procedures—such as endotracheal intubation, insertion of chest drains, external cardiac massage and cannulation of central and peripheral veins—there are alternative techniques being increasingly applied, that include new tools for the management of hemorrhagic shock, drug delivery and alternative airway management devices. On the one hand, all of these measures are essential for the survival and appropriate treatment of the injured and/or sick patient, but on the other hand they can damage the patient and thus contain a significant risk of both medical and forensic relevance for the patient and the physician. In the following review we provide an overview of established, new and alternative techniques for emergency airway management, administration of drugs and management of hemorrhagic shock. The aim is to facilitate the understanding and autopsy evaluation of current emergency medicine techniques.

Results of in-hospital triage in 17 mass casualty trainings: Underestimation of life-threatening injuries and need for re-triage

BACKGROUND In-hospital triage is the key factor for successful management of an overwhelming number of patients in lack of treatment capacity. The main goal of in-hospital triage is to identify casualties with life-threatening injuries and to allocate immediate medical aid. For the first time, we evaluate the quality of in-hospital triage in the German capital Berlin. METHODS In this prospective observational study of 17 unheralded external mass casualty trainings for Berlin disaster hospitals in 2010/2011, we analyzed the in-hospital triage of 601 rouged casualty actors. Evaluation was performed by structured external survey and interview of the casualty actors after the disaster training. In 93 percent (n = 558), complete data were available and suitable for statistical analysis. RESULTS The primary triage category was allocated correctly to 61 percent (n = 338) of the simulated injury severity. The following measurements were performed: anamnesis in 77 percent, physical examination 71 percent, blood pressure in 68 percent, heart rate in 61 percent, and oxygen saturation in 25 percent. Additive radiological diagnostics were used: 38 percent X-ray, 16 percent computer tomography, and 7 percent ultrasound. On an average, 1.6 ± 1.2 diagnostic tools were used to allocate injury severity to rouged casualties. Of all the rouged casualties, 24 percent overtriage and 16 percent undertriage were observed. Overtriage was significantly infrequent in level I trauma centers (p = 0.03). Of the patients with life-threatening injuries, 18 percent was undertriaged. Of the 62 percent with secondary right allocation to triage category, re-triage was only used in 4 percent. CONCLUSION The accuracy of in-hospital triage is low (61 percent). Predominately, the problem of overtriage (24 percent) due to insufficient triage training in contrast to undertriage (16 percent) occurs. The diagnostic triage adjuncts, ultrasound and re-triage, should be routinely used to lower the rate of undetected life threat in mass casualty incidents. Furthermore, a standardized training program and triage algorithm for in-hospital triage should be established.

The effect of traumatic brain injury on bone healing: an experimental study in a novel in vivo animal model

INTRODUCTION Among many factors determining the outcome of complex fractures in polytrauma patients, the role of traumatic brain injury (TBI) remains only partly understood. The aim of the present study was to examine the effect of traumatic brain injury on bone healing through the establishment of a novel standardised animal model that sequentially combines traumatic brain injury (TBI) with a long bone injury. MATERIALS AND METHODS Thirty-six female twelve-week old C57/BL6 mice were randomised in two groups (fracture (Fx)-group and combined-trauma (Fx/TBI) group). The methods of the Control Cortical Impact Injury for induction of TBI and of the femoral osteotomy, fixed with an external fixator for the simulation of the long bone fracture, were combined. No TBI was induced in the Fx-group. Bone healing was examined using in vivo micro-CT measurements over a period of three weeks. RESULTS The severity of the TBI was sufficient to stimulate a significantly increased callus formation in the Fx/TBI-group with an acceptable mortality rate. The micro-CT analysis of fracture healing displayed a significantly increased callus volume in the Fx/TBI-group already from the second postoperative week. This difference remained significant throughout the entire study period. DISCUSSION The successful and standardised combination of TBI and fracture in a mouse model allows systematic and quantitative in vivo analysis of underlying pathways that trigger the mutual interaction between musculoskeletal trauma and brain injury, as well as, corresponding differences in fracture healing using micro-CT methods. CONCLUSION The present study offers three new aspects: a standardised model for combined injury of TBI and femoral osteotomy; direct and serial in vivo imaging and quantification of fracture healing response using micro-CT; testing of potentially beneficial therapeutic regimens for fracture treatment in presence of TBI. Thus this model provides a valuable basic approach for the study of the amplifying effect of TBI on callus formation seen in patients with craniocerebral injury and concomitant skeletal trauma.

Komplikationsmanagement bei infizierter Osteosynthese

ZusammenfassungHintergrundPeriimplantäre Infektionen (PII) zählen zu den häufigsten postoperativen Komplikationen und erfordern in der Regel ein kombiniertes chirurgisches und antibiotisches Vorgehen. In diesem Übersichtsartikel stellen wir die aktuellen Kenntnisse bezüglich der Pathogenese, Klassifikation, Diagnose und Therapie osteosyntheseassoziierter Infektionen vor. Ziel der Arbeit ist es, die rationalen Hintergründe und die Evidenz der einzelnen chirurgischen Maßnahmen zu erläutern und konkrete Therapieempfehlungen auszuarbeiten.Material und MethodenAnhand der aktuellen relevanten Fachliteratur wurden Informationen zur Diagnostik, Therapie und Prävention kritisch interpretiert. Aufgrund dieser Daten wurde ein abgestimmtes kombiniertes chirurgisches und antibiotisches Behandlungskonzept vorgestellt.ErgebnisseMit einem konsequenten, interdisziplinären Vorgehen können hohe Heilungsraten mit Elimination der PII erzielt werden. Bei akuten PII kann das Osteosynthesematerial meist erhalten werden (vorausgesetzt die Weichteile lassen dies zu), während bei einer chronischen PII das Implantat in der Regel ein- oder zweizeitig gewechselt werden muss (abhängig von Weichteilen, Knochen, Erreger).DiskussionWissenschaftliche Erkenntnisse und klinische Daten führen zu neuen Behandlungskonzepten mit verbessertem Outcome, Verminderung der Morbidität und verkürztem Krankenhausaufenthalt. Systemische Antibiotika sind ein wichtiger Bestandteil der wirksamen Behandlung akuter und chronischer PII. Die lokale Anwendung von Antibiotika und der Einsatz von Knochenersatzmaterialien stellen weitere Behandlungsoptionen dar, deren genauer Stellenwert muss jedoch noch ermittelt werden.AbstractBackgroundPeri-implant infections (PII) are one of the most frequent postoperative complications and require an individualized combined surgical and antibiotic management. In this review article we provide up to date scientific knowledge regarding the pathogenesis, classification, diagnosis and therapy of PII. The aim of this article is to explain the rational background and evidence of individual treatment options in order to elaborate concrete management recommendations.Material and methodsThe relevant scientific publications were critically reviewed for diagnostics, therapy and prevention of PII. Based on these data we present a combined surgical and antibiotic treatment algorithm for PII.ResultsWith a consistent interdisciplinary action high healing rates with eradication of PII can be achieved. In acute PII (< 6 weeks) the implant can normally be retained but this is dependent on the soft tissue conditions, while in chronic PII (> 6 weeks) the implant generally has to be removed in a one or two step exchange, depending on the soft tissue, bone defects and pathogen.ConclusionScientific knowledge and clinical data have led to new treatment algorithms for PII with improved outcome, decreased morbidity and shortened hospitalization. Systemic individualized antimicrobial therapy, radical septic and plastic surgery are the cornerstones for successful treatment of acute and chronic PII. The local use of antibiotics and application of bone substitute materials are other techniques for treatment but the exact importance must still be determined.BACKGROUND Peri-implant infections (PII) are one of the most frequent postoperative complications and require an individualized combined surgical and antibiotic management. In this review article we provide up to date scientific knowledge regarding the pathogenesis, classification, diagnosis and therapy of PII. The aim of this article is to explain the rational background and evidence of individual treatment options in order to elaborate concrete management recommendations. MATERIAL AND METHODS The relevant scientific publications were critically reviewed for diagnostics, therapy and prevention of PII. Based on these data we present a combined surgical and antibiotic treatment algorithm for PII. RESULTS With a consistent interdisciplinary action high healing rates with eradication of PII can be achieved. In acute PII (< 6 weeks) the implant can normally be retained but this is dependent on the soft tissue conditions, while in chronic PII (> 6 weeks) the implant generally has to be removed in a one or two step exchange, depending on the soft tissue, bone defects and pathogen. CONCLUSION Scientific knowledge and clinical data have led to new treatment algorithms for PII with improved outcome, decreased morbidity and shortened hospitalization. Systemic individualized antimicrobial therapy, radical septic and plastic surgery are the cornerstones for successful treatment of acute and chronic PII. The local use of antibiotics and application of bone substitute materials are other techniques for treatment but the exact importance must still be determined.

Temporal profile of inflammatory response to fracture and hemorrhagic shock: Proposal of a novel long-term survival murine multiple trauma model

Hemorrhagic shock (hS) interacts with the posttraumatic immune response and fracture healing in multiple trauma. Due to the lack of a long‐term survival multiple trauma animal models, no standardized analysis of fracture healing referring the impact of multiple trauma on fracture healing was performed. We propose a new long‐term survival (21 days) murine multiple trauma model combining hS (microsurgical cannulation of carotid artery, withdrawl of blood and continuously blood pressure measurement), femoral (osteotomy/external fixation) and tibial fracture (3‐point bending technique/antegrade nail). The posttraumatic immune response was measured via IL‐6, sIL‐6R ELISA. The hS was investigated via macrohemodynamics, blood gas analysis, wet‐dry lung ration and histologic analysis of the shock organs. We proposed a new murine long‐term survival (21 days) multiple trauma model mimicking clinical relevant injury patterns and previously published human posttraumatic immune response. Based on blood gas analysis and histologic analysis of shock organs we characterized and standardized our murine multiple trauma model. Furthermore, we revealed hemorrhagic shock as a causative factor that triggers sIL‐6R formation underscoring the fundamental pathophysiologic role of the transsignaling mechanism in multiple trauma.

[Complication management of infected osteosynthesis: Therapy algorithm for peri-implant infections].

ZusammenfassungHintergrundPeriimplantäre Infektionen (PII) zählen zu den häufigsten postoperativen Komplikationen und erfordern in der Regel ein kombiniertes chirurgisches und antibiotisches Vorgehen. In diesem Übersichtsartikel stellen wir die aktuellen Kenntnisse bezüglich der Pathogenese, Klassifikation, Diagnose und Therapie osteosyntheseassoziierter Infektionen vor. Ziel der Arbeit ist es, die rationalen Hintergründe und die Evidenz der einzelnen chirurgischen Maßnahmen zu erläutern und konkrete Therapieempfehlungen auszuarbeiten.Material und MethodenAnhand der aktuellen relevanten Fachliteratur wurden Informationen zur Diagnostik, Therapie und Prävention kritisch interpretiert. Aufgrund dieser Daten wurde ein abgestimmtes kombiniertes chirurgisches und antibiotisches Behandlungskonzept vorgestellt.ErgebnisseMit einem konsequenten, interdisziplinären Vorgehen können hohe Heilungsraten mit Elimination der PII erzielt werden. Bei akuten PII kann das Osteosynthesematerial meist erhalten werden (vorausgesetzt die Weichteile lassen dies zu), während bei einer chronischen PII das Implantat in der Regel ein- oder zweizeitig gewechselt werden muss (abhängig von Weichteilen, Knochen, Erreger).DiskussionWissenschaftliche Erkenntnisse und klinische Daten führen zu neuen Behandlungskonzepten mit verbessertem Outcome, Verminderung der Morbidität und verkürztem Krankenhausaufenthalt. Systemische Antibiotika sind ein wichtiger Bestandteil der wirksamen Behandlung akuter und chronischer PII. Die lokale Anwendung von Antibiotika und der Einsatz von Knochenersatzmaterialien stellen weitere Behandlungsoptionen dar, deren genauer Stellenwert muss jedoch noch ermittelt werden.AbstractBackgroundPeri-implant infections (PII) are one of the most frequent postoperative complications and require an individualized combined surgical and antibiotic management. In this review article we provide up to date scientific knowledge regarding the pathogenesis, classification, diagnosis and therapy of PII. The aim of this article is to explain the rational background and evidence of individual treatment options in order to elaborate concrete management recommendations.Material and methodsThe relevant scientific publications were critically reviewed for diagnostics, therapy and prevention of PII. Based on these data we present a combined surgical and antibiotic treatment algorithm for PII.ResultsWith a consistent interdisciplinary action high healing rates with eradication of PII can be achieved. In acute PII (< 6 weeks) the implant can normally be retained but this is dependent on the soft tissue conditions, while in chronic PII (> 6 weeks) the implant generally has to be removed in a one or two step exchange, depending on the soft tissue, bone defects and pathogen.ConclusionScientific knowledge and clinical data have led to new treatment algorithms for PII with improved outcome, decreased morbidity and shortened hospitalization. Systemic individualized antimicrobial therapy, radical septic and plastic surgery are the cornerstones for successful treatment of acute and chronic PII. The local use of antibiotics and application of bone substitute materials are other techniques for treatment but the exact importance must still be determined.BACKGROUND Peri-implant infections (PII) are one of the most frequent postoperative complications and require an individualized combined surgical and antibiotic management. In this review article we provide up to date scientific knowledge regarding the pathogenesis, classification, diagnosis and therapy of PII. The aim of this article is to explain the rational background and evidence of individual treatment options in order to elaborate concrete management recommendations. MATERIAL AND METHODS The relevant scientific publications were critically reviewed for diagnostics, therapy and prevention of PII. Based on these data we present a combined surgical and antibiotic treatment algorithm for PII. RESULTS With a consistent interdisciplinary action high healing rates with eradication of PII can be achieved. In acute PII (< 6 weeks) the implant can normally be retained but this is dependent on the soft tissue conditions, while in chronic PII (> 6 weeks) the implant generally has to be removed in a one or two step exchange, depending on the soft tissue, bone defects and pathogen. CONCLUSION Scientific knowledge and clinical data have led to new treatment algorithms for PII with improved outcome, decreased morbidity and shortened hospitalization. Systemic individualized antimicrobial therapy, radical septic and plastic surgery are the cornerstones for successful treatment of acute and chronic PII. The local use of antibiotics and application of bone substitute materials are other techniques for treatment but the exact importance must still be determined.

The E3 ubiquitin ligase TRIM62 and inflammation-induced skeletal muscle atrophy

IntroductionICU-acquired weakness (ICUAW) complicates the disease course of critically ill patients. Inflammation and acute-phase response occur directly within myocytes and contribute to ICUAW. We observed that tripartite motif-containing 62 (TRIM62), an E3 ubiquitin ligase and modifier of inflammation, is increased in the skeletal muscle of ICUAW patients. We investigated the regulation and function of muscular TRIM62 in critical illness.MethodsTwenty-six critically ill patients with Sequential Organ Failure Assessment scores ≥8 underwent two skeletal muscle biopsies from the vastus lateralis at median days 5 and 15 in the ICU. Four patients undergoing elective orthopedic surgery served as controls. TRIM62 expression and protein content were analyzed in these biopsies. The kinetics of Trim62, Atrogin1 and MuRF1 expression were determined in the gastrocnemius/plantaris and tibialis anterior muscles from mouse models of inflammation-, denervation- and starvation-induced muscle atrophy to differentiate between these contributors to ICUAW. Cultured myocytes were used for mechanistic analyses.ResultsTRIM62 expression and protein content were increased early and remained elevated in muscles from critically ill patients. In all three animal models, muscular Trim62 expression was early and continuously increased. Trim62 was expressed in myocytes, and its overexpression activated the atrophy-inducing activator protein 1 signal transduction pathway. Knockdown of Trim62 by small interfering RNA inhibited lipopolysaccharide-induced interleukin 6 expression.ConclusionsTRIM62 is activated in the muscles of critically ill patients. It could play a role in the pathogenesis of ICUAW by activating and maintaining inflammation in myocytes.Trial registrationCurrent Controlled Trials ID: http://www.controlled-trials.com/ISRCTN77569430 (registered 13 February 2008)