Jens-Christian Schewe

Cellular Pathology of Hilar Neurons in Ammon's Horn Sclerosis

In addition to functionally affected neuronal signaling pathways, altered axonal, dendritic, and synaptic morphology may contribute to hippocampal hyperexcitability in chronic mesial temporal lobe epilepsies (MTLE). The sclerotic hippocampus in Ammons horn sclerosis (AHS)‐associated MTLE, which shows segmental neuronal cell loss, axonal reorganization, and astrogliosis, would appear particularly susceptible to such changes. To characterize the cellular hippocampal pathology in MTLE, we have analyzed hilar neurons in surgical hippocampus specimens from patients with MTLE. Anatomically well‐preserved hippocampal specimens from patients with AHS (n = 44) and from patients with focal temporal lesions (non‐AHS; n = 20) were studied using confocal laser scanning microscopy (CFLSM) and electron microscopy (EM). Hippocampal samples from three tumor patients without chronic epilepsies and autopsy samples were used as controls. Using intracellular Lucifer Yellow injection and CFLSM, spiny pyramidal, multipolar, and mossy cells as well as non‐spiny multipolar neurons have been identified as major hilar cell types in controls and lesion‐associated MTLE specimens. In contrast, none of the hilar neurons from AHS specimens displayed a morphology reminiscent of mossy cells. In AHS, a major portion of the pyramidal and multipolar neurons showed extensive dendritic ramification and periodic nodular swellings of dendritic shafts. EM analysis confirmed the altered cellular morphology, with an accumulation of cytoskeletal filaments and increased numbers of mitochondria as the most prominent findings. To characterize cytoskeletal alterations in hilar neurons further, immunohistochemical reactions for neurofilament proteins (NFP), microtubule‐associated proteins, and tau were performed. This analysis specifically identified large and atypical hilar neurons with an accumulation of low weight NFP. Our data demonstrate striking structural alterations in hilar neurons of patients with AHS compared with controls and non‐sclerotic MTLE specimens. Such changes may develop during cellular reorganization in the epileptogenic hippocampus and are likely to contribute to the pathogenesis or maintenance of temporal lobe epilepsy. J. Comp. Neurol. 414:437–453, 1999.

Induction of Bim and Bid gene expression during accelerated apoptosis in severe sepsis

IntroductionIn transgenic animal models of sepsis, members of the Bcl-2 family of proteins regulate lymphocyte apoptosis and survival of sepsis. This study investigates the gene regulation of pro-apoptotic and anti-apoptotic members of the Bcl-2 family of proteins in patients with early stage severe sepsis.MethodsIn this prospective case-control study, patients were recruited from three intensive care units (ICUs) in a university hospital. Sixteen patients were enrolled when they fulfilled the criteria of severe sepsis. Ten critically ill but non-septic patients and 11 healthy volunteers served as controls. Blood samples were immediately obtained at inclusion. To confirm the presence of accelerated apoptosis in the patient groups, caspase-3 activation and phosphatidylserine externalisation in CD4+, CD8+ and CD19+ lymphocyte subsets were assessed using flow cytometry. Specific mRNAs of Bcl-2 family members were quantified from whole blood by real-time PCR. To test for statistical significance, Kruskal-Wallis testing with Dunns multiple comparison test for post hoc analysis was performed.ResultsIn all lymphocyte populations caspase-3 (p < 0.05) was activated, which was reflected in an increased phosphatidylserine externalisation (p < 0.05). Accordingly, lymphocyte counts were decreased in early severe sepsis. In CD4+ T-cells (p < 0.05) and B-cells (p < 0.001) the Bcl-2 protein was decreased in severe sepsis. Gene expression of the BH3-only Bim was massively upregulated as compared with critically ill patients (p < 0.001) and 51.6-fold as compared with healthy controls (p < 0.05). Bid was increased 12.9-fold compared with critically ill patients (p < 0.001). In the group of mitochondrial apoptosis inducers, Bak was upregulated 5.6-fold, while the expression of Bax showed no significant variations. By contrast, the pro-survival members Bcl-2 and Bcl-xl were both downregulated in severe sepsis (p < 0.001 and p < 0.05, respectively).ConclusionsIn early severe sepsis a gene expression pattern with induction of the pro-apoptotic Bcl-2 family members Bim, Bid and Bak and a downregulation of the anti-apoptotic Bcl-2 and Bcl-xl proteins was observed in peripheral blood. This constellation may affect cellular susceptibility to apoptosis and complex immune dysfunction in sepsis.

A MIF haplotype is associated with the outcome of patients with severe sepsis: a case control study.

BackgroundMacrophage migration inhibitory factor (MIF) plays an important regulatory role in sepsis. In the promoter region a C/G single nucleotide polymorphism (SNP) at position -173 (rs755622) and a CATT5-8 microsatellite at position -794 are related to modified promoter activity. The purpose of the study was to analyze their association with the incidence and outcome of severe sepsis.MethodsGenotype distributions and allele frequencies in 169 patients with severe sepsis, 94 healthy blood donors and 183 postoperative patients without signs of infection or inflammation were analyzed by real time PCR and Sequence analysis. All included individuals were Caucasians.ResultsGenotype distribution and allele frequencies of severe sepsis patients were comparable to both control groups. However, the genotype and allele frequencies of both polymorphisms were associated significantly with the outcome of severe sepsis. The highest risk of dying from severe sepsis was detectable in patients carrying a haplotype with the alleles -173 C and CATT7 (p = 0.0005, fisher exact test, RR = 1,806, CI: 1.337 to 2.439).ConclusionThe haplotype with the combination of the -173 C allele and the -794 CATT7 allele may not serve as a marker for susceptibility to sepsis, but may help identify septic patients at risk of dying.

Effects of spinal anaesthesia versus epidural anaesthesia for caesarean section on postoperative analgesic consumption and postoperative pain

Background and objective Regional anaesthesia is commonly used for elective caesarean section. The aim of this study was to investigate whether there is a positive effect of either spinal or epidural anaesthesia on postoperative analgesic requirements and pain relief. Methods The analgesic effect of either spinal or epidural induction of perispinal anaesthesia have been compared in 132 women (ASA I or II) scheduled for elective caesarean section, all having epidural catheterization for perioperative anaesthesia and postoperative analgesia. The patients were randomized into two groups. To achieve a sensory block height to the level of the sixth thoracic dermatome, the parturients received isobaric bupivacaine 0.5% and 5 μg sufentanil intrathecally or ropivacaine 0.75% and 10 μg sufentanil epidurally. For postoperative analgesia, all patients used patient-controlled epidural analgesia at identical settings [bolus of ropivacaine 0.133% (11–15 mg according to patients height), lock-out time 1 h]. Intraoperative and postoperative pain was recorded using a visual analogue pain score as well as analgesic requirements over the first 24 h after surgery. Results One hundred and twenty-five patients completed the study. There were no differences in patient-controlled epidural analgesic requirements between groups. During surgery, the pain score on a visual analogue scale was more intense with epidural anaesthesia than with spinal anaesthesia (P < 0.05). For the whole 24 h observation period, the area under the curve for pain was lower with spinal anaesthesia (P < 0.0005). At almost all postoperative time points, visual analogue scale scores at rest and during mobilization were lower with spinal anaesthesia (P < 0.05), which was accompanied by less motor blockade and lower frequency of adverse effects. More patients with epidural anaesthesia received supplemental analgesic medication. Conclusion In parturients undergoing elective caesarean section, postoperative use of epidural ropivacaine via patient-controlled epidural analgesia is similar after spinal and epidural anaesthesia. Spinal anaesthesia is, however, accompanied with less postoperative pain, use of additional analgesics and side-effects.

Cytokine Promoter Polymorphisms in Severe Sepsis

The need to develop individualized risk profiles and drug therapy regimens motivates interest in genetic studies of critically ill patients. Gene promoter variants may predict interindividual variability in response to inflammatory stimuli, such as infection and trauma. Genomic variations also may affect gene expression profiles, as well as the structure and production of proteins. The genes involved in inflammation are numerous, as are genomic variations within most of those genes. Cytokine genes involved in inflammatory cascades are important candidate genes that may determine the extent of a persons response to injury. Understanding the genetic determination of the inflammatory process includes the possibility of developing valuable diagnostic tools and new therapeutic approaches in severe sepsis. To date, specific patterns of markers of genomic variation reliably indicating at-risk populations do not exist. Evaluation of possible genomic markers for risk stratification of patients with sepsis and persons at high risk of developing organ failure has begun at a level of well-powered genetic epidemiological research. Cytokine promoter variants may contribute substantially to studies of genetic predisposition of sepsis because they operate in a gene region of high regulatory activity.

Inducibility of the endogenous antibiotic peptide β-defensin 2 is impaired in patients with severe sepsis

IntroductionThe potent endogenous antimicrobial peptide human β-defensin 2 (hBD2) is a crucial mediator of innate immunity. In addition to direct antimicrobial properties, different effects on immune cells have been described. In contrast to the well-documented epithelial β-defensin actions in local infections, little is known about the leukocyte-released hBD2 in systemic infectious disorders. This study investigated the basic expression levels and the ex vivo inducibility of hBD2 mRNA in peripheral whole blood cells from patients with severe sepsis in comparison to non-septic critically ill patients and healthy individuals.MethodsThis investigation was a prospective case-control study performed at a surgical intensive care unit at a university hospital. A total of 34 individuals were tested: 16 patients with severe sepsis, 9 critically ill but non-septic patients, and 9 healthy individuals. Serial blood samples were drawn from septic patients, and singular samples were obtained from critically ill non-septic patients and healthy controls. hBD2 mRNA levels in peripheral white blood cells were quantified by real-time polymerase chain reaction in native peripheral blood cells and following ex vivo endotoxin stimulation. Defensin plasma levels were quantified by enzyme-linked immunosorbent assay.ResultsEndotoxin-inducible hBD2 mRNA expression was significantly decreased in patients with severe sepsis compared to healthy controls and non-septic critically ill patients (0.02 versus 0.95 versus 0.52, p < 0.05, arbitrary units). hBD2 plasma levels in septic patients were significantly higher compared to healthy controls and critically ill non-septic patients (541 versus 339 versus 295 pg/ml, p < 0.05).ConclusionIn contrast to healthy individuals and critically ill non-septic patients, ex vivo inducibility of hBD2 in peripheral blood cells from septic patients is reduced. Impaired hBD2 inducibility may contribute to the complex immunological dysfunction in patients with severe sepsis.

Monitoring of cerebral oxygen saturation during resuscitation in out-of-hospital cardiac arrest: a feasibility study in a physician staffed emergency medical system

BackgroundDespite recent advances in resuscitation algorithms, neurological injury after cardiac arrest due to cerebral ischemia and reperfusion is one of the reasons for poor neurological outcome. There is currently no adequate means of measuring cerebral perfusion during cardiac arrest. It was the aim of this study to investigate the feasibility of measuring near infrared spectroscopy (NIRS) as a potential surrogate parameter for cerebral perfusion in patients with out-of-hospital resuscitations in a physician-staffed emergency medical service.MethodsAn emergency physician responding to out-of-hospital emergencies was equipped with a NONIN cerebral oximetry device. Cerebral oximetry values (rSO2) were continuously recorded during resuscitation and transport. Feasibility was defined as >80% of total achieved recording time in relation to intended recording time.Results10 patients were prospectively enrolled. In 89.8% of total recording time, rSO2 values could be recorded (213 minutes and 20 seconds), thus meeting feasibility criteria. 3 patients experienced return of spontaneous circulation (ROSC). rSO2 during manual cardiopulmonary resuscitation (CPR) was lower in patients who did not experience ROSC compared to the 3 patients with ROSC (31.6%, ± 7.4 versus 37.2% ± 17.0). ROSC was associated with an increase in rSO2. Decrease of rSO2 indicated occurrence of re-arrest in 2 patients. In 2 patients a mechanical chest compression device was used. rSO2 values during mechanical compression were increased by 12.7% and 19.1% compared to manual compression.ConclusionsNIRS monitoring is feasible during resuscitation of patients with out-of-hospital cardiac arrest and can be a useful tool during resuscitation, leading to an earlier detection of ROSC and re-arrest. Higher initial rSO2 values during CPR seem to be associated with the occurrence of ROSC. The use of mechanical chest compression devices might result in higher rSO2. These findings need to be confirmed by larger studies.

Hemorrhage under veno-venous extracorporeal membrane oxygenation in acute respiratory distress syndrome patients: a retrospective data analysis

Background Despite being still invasive and challenging, technical improvement has resulted in broader and more frequent application of extracorporeal membrane oxygenation (ECMO), to prevent hypoxemia and to reduce invasiveness of mechanical ventilation (MV). Heparin-coated ECMO-circuits are currently standard of care, in addition to heparin based anticoagulation (AC) regimen guided by activated clotting time (ACT) or activated partial thromboplastin time (aPTT). Despite these advances, a reliable prediction of hemorrhage is difficult and the risk of hemorrhagic complication remains unfortunately high. We hypothesized, that there are coagulation parameters that are indices for a higher risk of hemorrhage under veno-venous (VV)-ECMO therapy. Methods Data from 36 patients with severe respiratory failure treated with VV-ECMO at a University Hospital intensive care unit (ICU) were analyzed retrospectively. Patients were separated into two groups based on severity of hemorrhagic complications and transfusion requirements. The following data were collected: demographics, hemodynamic data, coagulation samples, transfusion requirements, change of ECMO-circuit during treatment and adverse effects, including hemorrhage and thrombosis. Results In this study 74 hemorrhagic events were observed, one third of which were severe. Patients suffering from severe hemorrhage had a lower survival rate on VV-ECMO (43% vs. 91%; P=0.002) and in ICU (36% vs. 86%; P=0.002). SAPS II, factor VII and X were different between mild and severe hemorrhage group. Conclusions Severe hemorrhage under VV-ECMO is associated with higher mortality. Only factor VII and X differed between groups. Further clinical studies are required to determine the timing of initiation and targets for AC therapies during VV-ECMO.

Medical emergency teams in hospitals

ZusammenfassungHintergrundDer innerklinische Notfall stellt eine zunehmende Herausforderung für das Risikomanagement eines Krankenhauses dar und bislang gibt es in Deutschland keine allgemein verbindlichen Empfehlungen für ein innerklinisches Notfallmanagement. Die Zeitverzögerung bei der Erkennung und Behandlung des kritisch Kranken auf den Bettenstationen führt häufig zu schwerwiegenden Zwischenfällen. Das Konzept der traditionellen Reanimationsteams greift regelhaft zu kurz, da sie erst nach Eintritt einer akuten Verschlechterung bzw. des Herz-Kreislauf-Stillstands aktiviert werden.ZielsetzungDie Einführung eines Rapid-response-Systems mit präventivem Ansatz basierend auf einem medizinischen Notallteam (MET) stellt eine unverzichtbare Verbesserung des innerklinischen Notfallmanagements dar. Dafür genügt nicht allein die Umbenennung und Umstrukturierung des bisherigen Reanimationsteams zu einem MET. Vielmehr bedarf es der Einführung standardisierter präventiver Alarmierungskriterien und strukturierter Abläufe, einer Standardisierung der Ausbildung und der Notfallausrüstung in der Klinik sowie der Bereitstellung eines an die Intensivstation angebundenen MET. SchlussfolgerungFür ein Krankenhaus mit bisher etabliertem Reanimationsteam bedeutet dies einen grundlegenden Paradigmenwechsel mit einem nachhaltigen, interdisziplinären und institutionalisierten Prozess des Umdenkens und Reorganisierens. Ein klares Bekenntnis und andauernde gemeinsame Anstrengungen des Krankenhausträgers und aller Klinikmitarbeiter ist hierfür Voraussetzung.AbstractBackgroundIn-hospital emergencies represent an increasing challenge with regard to risk management in hospitals and until now, no binding recommendations for in-hospital emergency management are available in Germany. Time delays in the detection and treatment of critically ill patients on the wards often lead to serious adverse events. The concept of traditional resuscitation teams is not adequate, because they are initiated only after acute deterioration or cardiac arrest has already occurred.ObjectiveThe introduction of a rapid response system with a preventive approach based on a medical emergency team (MET) represents an essential improvement in the management of in-hospital emergencies. However, it is not sufficient to simply rename and restructure the existing resuscitation team to a MET. Rather, the introduction of standardized preventive alarm criteria and structured processes, standardization of training and emergency equipment in the clinic, and the provision of a MET associated with the intensive care unit are required.ConclusionFor a hospital with an already established resuscitation team, this represents a fundamental paradigm shift to a sustainable, interdisciplinary, and institutionalized process of rethinking and reorganizing. A clear commitment and ongoing joint efforts of the hospital management and all hospital staff are prerequisite for this.BACKGROUND In-hospital emergencies represent an increasing challenge with regard to risk management in hospitals and until now, no binding recommendations for in-hospital emergency management are available in Germany. Time delays in the detection and treatment of critically ill patients on the wards often lead to serious adverse events. The concept of traditional resuscitation teams is not adequate, because they are initiated only after acute deterioration or cardiac arrest has already occurred. OBJECTIVE The introduction of a rapid response system with a preventive approach based on a medical emergency team (MET) represents an essential improvement in the management of in-hospital emergencies. However, it is not sufficient to simply rename and restructure the existing resuscitation team to a MET. Rather, the introduction of standardized preventive alarm criteria and structured processes, standardization of training and emergency equipment in the clinic, and the provision of a MET associated with the intensive care unit are required. CONCLUSION For a hospital with an already established resuscitation team, this represents a fundamental paradigm shift to a sustainable, interdisciplinary, and institutionalized process of rethinking and reorganizing. A clear commitment and ongoing joint efforts of the hospital management and all hospital staff are prerequisite for this.

Medizinische Notfallteams im Krankenhaus

ZusammenfassungHintergrundDer innerklinische Notfall stellt eine zunehmende Herausforderung für das Risikomanagement eines Krankenhauses dar und bislang gibt es in Deutschland keine allgemein verbindlichen Empfehlungen für ein innerklinisches Notfallmanagement. Die Zeitverzögerung bei der Erkennung und Behandlung des kritisch Kranken auf den Bettenstationen führt häufig zu schwerwiegenden Zwischenfällen. Das Konzept der traditionellen Reanimationsteams greift regelhaft zu kurz, da sie erst nach Eintritt einer akuten Verschlechterung bzw. des Herz-Kreislauf-Stillstands aktiviert werden.ZielsetzungDie Einführung eines Rapid-response-Systems mit präventivem Ansatz basierend auf einem medizinischen Notallteam (MET) stellt eine unverzichtbare Verbesserung des innerklinischen Notfallmanagements dar. Dafür genügt nicht allein die Umbenennung und Umstrukturierung des bisherigen Reanimationsteams zu einem MET. Vielmehr bedarf es der Einführung standardisierter präventiver Alarmierungskriterien und strukturierter Abläufe, einer Standardisierung der Ausbildung und der Notfallausrüstung in der Klinik sowie der Bereitstellung eines an die Intensivstation angebundenen MET. SchlussfolgerungFür ein Krankenhaus mit bisher etabliertem Reanimationsteam bedeutet dies einen grundlegenden Paradigmenwechsel mit einem nachhaltigen, interdisziplinären und institutionalisierten Prozess des Umdenkens und Reorganisierens. Ein klares Bekenntnis und andauernde gemeinsame Anstrengungen des Krankenhausträgers und aller Klinikmitarbeiter ist hierfür Voraussetzung.AbstractBackgroundIn-hospital emergencies represent an increasing challenge with regard to risk management in hospitals and until now, no binding recommendations for in-hospital emergency management are available in Germany. Time delays in the detection and treatment of critically ill patients on the wards often lead to serious adverse events. The concept of traditional resuscitation teams is not adequate, because they are initiated only after acute deterioration or cardiac arrest has already occurred.ObjectiveThe introduction of a rapid response system with a preventive approach based on a medical emergency team (MET) represents an essential improvement in the management of in-hospital emergencies. However, it is not sufficient to simply rename and restructure the existing resuscitation team to a MET. Rather, the introduction of standardized preventive alarm criteria and structured processes, standardization of training and emergency equipment in the clinic, and the provision of a MET associated with the intensive care unit are required.ConclusionFor a hospital with an already established resuscitation team, this represents a fundamental paradigm shift to a sustainable, interdisciplinary, and institutionalized process of rethinking and reorganizing. A clear commitment and ongoing joint efforts of the hospital management and all hospital staff are prerequisite for this.BACKGROUND In-hospital emergencies represent an increasing challenge with regard to risk management in hospitals and until now, no binding recommendations for in-hospital emergency management are available in Germany. Time delays in the detection and treatment of critically ill patients on the wards often lead to serious adverse events. The concept of traditional resuscitation teams is not adequate, because they are initiated only after acute deterioration or cardiac arrest has already occurred. OBJECTIVE The introduction of a rapid response system with a preventive approach based on a medical emergency team (MET) represents an essential improvement in the management of in-hospital emergencies. However, it is not sufficient to simply rename and restructure the existing resuscitation team to a MET. Rather, the introduction of standardized preventive alarm criteria and structured processes, standardization of training and emergency equipment in the clinic, and the provision of a MET associated with the intensive care unit are required. CONCLUSION For a hospital with an already established resuscitation team, this represents a fundamental paradigm shift to a sustainable, interdisciplinary, and institutionalized process of rethinking and reorganizing. A clear commitment and ongoing joint efforts of the hospital management and all hospital staff are prerequisite for this.