PD Dr. med. Joerg C. Schefold

Abstract: This study sought to assess the effects of ursodeoxycholic acid (UDCA) on endothelial function and inflammatory markers in patients with chronic heart failure (CHF).

Abstract: Obesity is a common and increasing condition in Western countries and seems to be associated with increased carcinogenesis and tumor invasiveness. We evaluated operative and clinical outcome in patients operated to treat primary epithelial ovarian cancer (EOC) according to their body mass index (BMI).

Abstract: We hypothesised that assessment of plasma C-terminal pro-endothelin-1 (CT-proET-1), a stable endothelin-1 precursor fragment, is of prognostic value in patients with chronic heart failure (CHF), beyond other prognosticators, including N-terminal pro-B-type natriuretic peptide (NT-proBNP).

Abstract: Mild hypothermia treatment (32-34°C) in survivors after cardiac arrest (CA) is clearly recommended by the current guidelines. The effects of cooling procedure towards QT interval have not been evaluated so far outside of case series. In a prospective study 34 consecutive survivors after cardiac arrest were continuously monitored with Holter ECG over the first 48 h.

Abstract: Sepsis is associated with failure of multiple organs, including failure of the immune system. The resulting 'sepsis-associated immunosuppression' resembles a state of immunological anergy that is characterized by repeated 'infectious hits', prolonged multiple-organ failure, and death. As a consequence, adjunctive treatment approaches using measures of immunostimulation with colony-stimulating factors (CSFs) were tested in animal experiments and clinical trials. Herein, data from randomized clinical trials will be discussed in the context of a recently published meta-analysis investigating the effects of granulocyte- and granulocyte-macrophage colony-stimulating factor therapy in patients with severe sepsis and septic shock.

Abstract: Infection-induced inflammation triggers catabolism of proteins and amino acids. Phenylalanine and tryptophan are 2 amino acids related to infections that regulate immune responses. Polyomavirus BK (BKV) and cytomegalovirus (CMV) are important pathogens after kidney transplantation. We investigated the clinical relevance of phenylalanine, tryptophan, and tryptophan metabolites (kynurenine and quinolinic acid) plasma levels in kidney transplant recipients with active CMV (BKV(-)CMV(+), n = 12) or BK virus infection (BKV(+)CMV(-), n = 37). Recipients without active viral infections (CMV(-)BKV(-), n = 28) and CMV(-)BKV(-) healthy individuals (HCs, n = 50) served as controls. In contrast to BKV infection, activated CMV infection is tightly linked to increased phenylalanine and tryptophan metabolite plasma levels (p ≤ 0.002). The association of phenylalanine (cutoff 50 μmol/L) with CMV infection demonstrates high sensitivity (100%) and specificity (94%). By contrast, kynurenine (p = 0.029) and quinolinic acid (p = 0.003) values reflect the severity of CMV infection. In this early proof-of-concept trial, evidence indicates that activated CMV infection is strongly associated with increased phenylalanine as well as kynurenine and quinolinic acid plasma levels. Moreover, tryptophan metabolite levels correlate with disease severity. Measurement of these amino acids is an inexpensive and fast method expected to complete conventional diagnostic assays.

Abstract: Induction of tryptophan catabolism is mediated by inflammatory mechanisms including up-regulation of the immunoregulatory enzyme indoleamine-2,3-dioxygenase (IDO). This leads to the formation of mediators collectively referred to as kynurenines. Kynurenines are involved in various diseases such as renal failure, sepsis and cancer. We aimed to investigate whether systemic levels of kynurenines are induced in primary cervical cancer (PCC).

Abstract: A well-balanced immunological interaction between mother and the semi-allogenic embryo is of particular importance. The objective of the present study was to analyse mechanisms of immune tolerance in bovine pregnancy during peri-implantation. Simmental heifers inseminated with either cryopreserved spermatozoa or seminal plasma were killed 12, 15 or 18 days after oestrus. Uteri were flushed for the recovery of conceptuses and the ipsilateral intercaruncular endometrium was sampled for gene expression analysis. Indoleamine 2,3-dioxygenase (IDO) mRNA, coding for the initial enzyme of the kynurenine pathway, was 18-fold (P < 0.001) more abundant in the endometrium of Day 18 pregnant v. non-pregnant animals. Tandem mass spectrometry revealed a decrease of endometrial l-tryptophan (P = 0.0008), but an increase of l-kynurenine concentration (P = 0.005) from Day 12 to Day 18, suggesting increasing IDO activity (P < 0.03). An in vitro coculture model of endometrial cells showed an induction of IDO expression following interferon-Ï„ exposure primarily in stroma cells, which was confirmed by in situ hybridisation localising IDO mRNA mainly in deep stroma cells. Immunohistochemical analysis revealed fewer CD45-positive leucocytes in the zona basalis of pregnant animals. Elevated IDO activity may reduce the presence of leucocytes in the pregnant endometrium, providing a possible mechanism for protecting the semi-allogenic conceptus from maternal rejection.

Abstract: It has recently been shown that an increased plasma level of the tryptophan catabolite kynurenine is an early indicator for the development of sepsis in major trauma patients. We examined the predictive value of kynurenine pathway activity for ongoing sepsis in patients being admitted to a surgical intensive care unit for different reasons. In addition, we asked whether an accumulation of kynurenines in patients' plasma depends on reduced renal clearance. We conducted a prospective observational study including 100 consecutive patients and monitored laboratory variables, physiological and adverse events, sepsis and outcome. Using tandem mass spectrometry, we quantified the five indoleamines tryptophan, serotonin (5-HT), kynurenine, quinolinic acid and kynurenic acid at baseline and twice a week during the intensive care unit stay. Among the patients enrolled, 50 did not develop sepsis in the intensive care unit (non-septic), 18 patients did not have sepsis at baseline but developed sepsis later on (pre-septic) and 32 patients already fulfilled the criteria of severe sepsis and septic shock at baseline (septic). In general, non-septic critically ill patients showed activation of the kynurenine pathway, but septic shock coincided with an exacerbation of kynurenine pathway activity even in the absence of renal failure. Importantly, plasma concentrations of quinolinic acid (area under the curve 0.832 [95% confidence interval 0.710 to 0.954]) and the Quin/Trp ratio (area under the curve 0.835 [95% confidence interval; 0.719 to 0.952]) showed the best discrimination between non-septic and pre-septic patients at baseline. These findings open new avenues for further investigations on the pathophysiology of sepsis.

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Abstract: BACKGROUND AND OBJECTIVES: We evaluated the outcome of pelvic exenteration in women with locally advanced primary or recurrent gynecological malignancies. METHODS: All pelvic exenteration procedures performed between 01/2003 and 06/2009 were evaluated. Extent of surgical radicality, operative techniques, and outcome were evaluated. Kaplan-Meier curves were calculated for Overall (OS) and progression-free survival (PFS). RESULTS: Forty-seven patients (median age: 52.5 years) were evaluated. Ten of 47 patients (21.3%) had a primary and 37(78.7%) a relapsed cancer. Most common (80.8%) site of origin was the cervix. Patients (80.8%) had undergone previous pelvic irradiation. A total exenteration was performed in 32/47 patients (68%). A complete tumor resection was obtained in 23 patients (49%). Thirty-three patients (70.2%) had at least one major complication, including ileus (8.5%), intestinal-fistula (29.8%), ureteral anastomotic insufficiency (6.4%), abscess (6.4%), and cardiothrombotic events (23.4%). At a median follow-up of 7 months (range: 1-42), 22/47 patients (46.8%) died and 22/47 (46.8%) experienced a relapse. Median OS was 4 months (range: 0.1-16) and 22 months (range: 6-42) for patients with versus without postoperative tumor residuals, respectively (P = 0.0006), while median PFS was 4 months (range:0.1-16) versus 12 months (range: 6-42) (P < 0.0001). CONCLUSIONS: Radical pelvic exenteration due to advanced pelvic malignancies may be associated with a high morbidity. Complete tumor resection is associated with a significantly higher overall and PFS.

Abstract: OBJECTIVE: To systematically assess the metastatic pattern of intermediate- and high-risk endometrial cancer in pelvic and para-aortic lymph-nodes and to evaluate risk factors for lymph-node metastases. STUDY DESIGN: Between 01/2005 and 01/2009 62 consecutive patients with intermediate- and high-risk endometrial cancer who underwent a systematic surgical staging including pelvic and para-aortic lymphadenectomy were enrolled into this study. Patients' characteristics, histological findings, lymph-node localization and involvement, surgical morbidity and relapse data were analyzed. Univariate analysis was performed to define risk factors for lymph-node metastasis. RESULTS: Of the 13 patients (21%) with positive lymph-nodes (N1), 8 (61.5%) had both pelvic and para-aortic lymph-nodes affected, 2 (15.4%) only para-aortic and 3 (23%) only pelvic lymph-node metastases. Overall, 54% of the N1-patients had positive lymph-nodes above the inferior mesenteric artery (IMA) to the level of the renal veins. Univariate analysis revealed lymph vascular space invasion (p-value: <0.001), vascular-space-invasion (p-value: <0.001) and incomplete tumor resection (p-value: 0.008) as significant risk factors for N1-status. Overall and progression-free survival was not significantly different between N1- and N0-patients. CONCLUSIONS: Since the proportion of N1-endometrial cancer patients with positive para-aortic lymph-nodes is, at 76%, considerably high, and more than half of them have affected lymph-nodes above the IMA-level, lymphadenectomy for endometrial cancer should be extended up to the renal veins, when indicated. The therapeutic impact of systematic lymphadenectomy on overall and progression-free survival has still to be evaluated in future prospective randomized studies.

Abstract: BACKGROUND: Acute heart failure is associated with a poor prognosis. It is important to identify patients at increased risk of adverse events. The presence of anaemia could help in this regard. METHODS AND RESULTS: Admission charts of 627 patients (325 female) with acute heart failure were analysed; 182 patients (29%) fulfilled the World Health Organization criteria of anaemia [haemoglobin (Hb) < 13.0 in men, <12.0 g/dl in women], 87 (48%) of them were female. Anaemic patients were older than non-anaemics (p = 0.04), had lower systolic and diastolic blood pressure (both p < 0.05), had higher creatinine (p < 0.01), and stayed longer in hospital (p = 0.0005). Patients were followed-up for a mean of 61 months or until death. A total of 387 patients (61.7%) died during follow-up. Anaemia was an independent predictor of death in this cohort. Patients with moderate or severe anaemia (Hb < 12 in men or <11 g/dl in women) had a significantly increased 12-month mortality after adjusting for age, New York Heart Association class, systolic and diastolic blood pressure, and creatinine (hazard ratio 1.5, 95% confidence interval 1.1-2.0, p = 0.01). CONCLUSION: Anaemia is a frequent co-morbidity in patients with acute heart failure. Moderate to severe anaemia is an independent predictor of death in these patients.

Abstract: Neuron specific enolase (NSE) has been proven effective in predicting neurological outcome after cardiac arrest with a current cut off recommendation of 33 microg/l. However, most of the corresponding studies were conducted before the introduction of mild therapeutic hypothermia (MTH). Therefore we conducted a study investigating the association between NSE and neurological outcome in patients treated with MTH.

Abstract: The immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) controls tryptophan metabolism and is induced by pro-inflammatory stimuli. We investigated whether immunostimulatory treatment with granulocyte-macrophage colony-stimulating factor (GM-CSF) influences IDO activity and tryptophan metabolism in sepsis. Thirty-six patients with severe sepsis/septic shock and sepsis-associated immunosuppression (assessed using monocytic human leukocyte antigen-DR (mHLA-DR) expression) were assessed in a controlled trial of GM-CSF or placebo treatment for 8 days. Using tandem mass spectrometry, levels of tryptophan, kynurenine, kynurenic acid, quinolinic acid, 5-hydroxytryptophan, serotonin, and estimated IDO activity were determined in a blinded fashion over a 9-day interval. At baseline, tryptophan and metabolite levels did not differ between the study groups. Although tryptophan levels were unchanged in both groups over the treatment interval (all p>0.8), IDO activity was markedly reduced after GM-CSF treatment (35.4 +/- 21.0 vs 21.6 +/-9.9 (baseline vs day 9), p = 0.02). IDO activity differed significantly between the 2 groups after therapy (p = 0.03). Metabolites downstream of IDO (kynurenine, quinolinic acid, kynurenic acid) were all induced in sepsis and declined in the GM-CSF group, but not in controls. Serotonin pathway metabolites remained unchanged in both groups (all p>0.15). Moreover, IDO activity correlated with procalcitonin (p< 0.0001, r = 0.56) and mHLA-DR levels (p = 0.005, r = -0.28) in the overall samples group. Thus, GM-CSF therapy is associated with decreased IDO activity and reduced kynurenine pathway catabolites in sepsis. This may be due to an improved antibacterial defence.

Abstract: BACKGROUND: Therapeutic hypothermia has been proven to be effective in improving neurological outcome in patients after cardiac arrest due to ventricular fibrillation (VF). Data concerning the effect of hypothermia treatment on long-term survival however is limited. MATERIALS AND METHODS: Clinical and outcome data of 107 consecutive patients undergoing therapeutic hypothermia after cardiac arrest due to VF were compared with 98 historical controls. Neurological outcome was assessed at ICU discharge according to the Pittsburgh cerebral performance category (CPC). A Kaplan-Meier analysis of follow-up data concerning mortality after 24 months as well as a Cox-regression to adjust for confounders were calculated. RESULTS: Neurological outcome significantly improved after mild hypothermia treatment (hypothermia group CPC 1-2 59.8%, control group CPC 1-2 24.5%; p < 0.01). In Kaplan-Meier survival analysis hypothermia treatment was also associated with significantly improved 2-year probability for survival (hypothermia 55% vs. control 34%; p = 0.029). Cox-regression analysis revealed hypothermia treatment (p = 0.031) and age (p = 0.013) as independent predictors of 24-month survival. CONCLUSIONS: Our study demonstrates that the early survival benefit seen with therapeutic hypothermia persists after two years. This strongly supports adherence to current recommendations regarding postresuscitation care for all patients after cardiac arrest due to VF and maybe other rhythms as well.

Abstract: Objective Prehospital induction of therapeutic hypothermia after cardiac arrest may require temperature monitoring in the field. Tympanic temperature is non-invasive and frequently used in clinical practice. Nevertheless, it has not yet been evaluated in patients undergoing mild therapeutic hypothermia (MTH). Therefore, a prospective observational study was conducted comparing three different sites of temperature monitoring during therapeutic hypothermia. Methods Ten consecutive patients admitted to our medical intensive care unit after out-of-hospital cardiac arrest were included in this study. During MTH, tympanic temperature was measured using a digital thermometer. Simultaneously, oesophageal and bladder temperatures were recorded in a total of 558 single measurements. Results Compared with oesophageal temperature, bladder temperature had a bias of 0.019 degrees C (limits of agreement +/-0.61 degrees C (2SD)), and tympanic measurement had a bias of 0.021 degrees C (+/-0.80 degrees C). Correlation analysis revealed a high relationship for tympanic versus oesophageal temperature (r=0.95, p<0.0001) and also for tympanic versus bladder temperature (r=0.96, p<0.0001). Conclusions That tympanic temperature accurately indicates both oesophageal and bladder temperatures with a very small discrepancy in patients undergoing MTH after cardiac arrest is demonstrated in this study. Although our results were obtained in the hospital setting, these findings may be relevant for the prehospital application of therapeutic hypothermia as well. In this case, tympanic temperature may provide an easy and non-invasive method for temperature monitoring.

Abstract: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide-dependent vasodilation. In 113 patients with chronic heart failure (CHF) and 26 controls, ADMA level was studied in relation to peripheral blood flow and vasodilator capacity. Further, the effects of allopurinol on concentrations of reactive oxygen species (ROS) and ADMA and peripheral vasodilator capacity were tested in a double-blind design. ADMA level was found to be elevated in CHF patients as compared with controls and increased in parallel with New York Heart Association (NYHA) class and exercise capacity (all P < 0.0001). The level of ADMA predicted resting blood flow (P < 0.05) and postischemic vasodilator capacity (P < 0.001). Sixty eight patients died during the follow-up period. The level of ADMA predicted survival after multivariable adjustment (P = 0.04). Allopurinol reduced uric acid (UA) concentration (P < 0.001) and decreased ROS concentration (allantoin, P < 0.01). Allopurinol lowered ADMA concentration (P = 0.02); postischemic vasodilation as well as endothelium-dependent vasodilation (both P < 0.05) improved. ADMA may be a pathophysiologic factor that is modulated by ROS accumulation and contributes to impaired vascular regulation in CHF.

Abstract: Sepsis presents a major health care problem and remains one of the leading causes of death within the intensive care unit (ICU). Therapeutic approaches against severe sepsis and septic shock focus on early identification. Adequate source control, administration of antibiotics, preload optimization by fluid resuscitation and further hemodynamic stabilisation using vasopressors whenever appropriate are considered pivotal within the early-golden-hours of sepsis. However, organ dysfunction develops frequently in and represents a significant comorbidity of sepsis. A considerable amount of patients with sepsis will show signs of severe muscle wasting and/or ICU-acquired weakness (ICUAW), which describes a frequently observed complication in critically ill patients and refers to clinically weak ICU patients in whom there is no plausible aetiology other than critical illness. Some authors consider ICUAW as neuromuscular organ failure, caused by dysfunction of the motor unit, which consists of peripheral nerve, neuromuscular junction and skeletal muscle fibre. Electrophysiologic and/or biopsy studies facilitate further subclassification of ICUAW as critical illness myopathy, critical illness polyneuropathy or critical illness myoneuropathy, their combination. ICUAW may protract weaning from mechanical ventilation and impede rehabilitation measures, resulting in increased morbidity and mortality. This review provides an insight on the available literature on sepsis-mediated muscle wasting, ICUAW and their potential pathomechanisms.

Abstract: BACKGROUND: High-mobility group box-1 (HMGB-1) protein is released during "late sepsis" by activated monocytes. We investigated whether systemic HMGB-1 levels are associated with indices of monocytic activation/function in patients with sepsis-induced immunosuppression. METHODOLOGY: 36 patients (31 male, 64 +/- 14 years) with severe sepsis/septic shock and monocytic deactivation (reduced mHLA-DR expression and TNF-alpha release) were assessed in a subanalysis of a placebo-controlled immunostimulatory trial using GM-CSF. HMGB-1 levels were assessed over a 9-day treatment interval. Data were compared to standardized biomarkers of monocytic immunity (mHLA-DR expression, TNF-alpha release). PRINCIPLE FINDINGS: HMGB-1 levels were enhanced in sepsis but did not differ between treatment and placebo groups at baseline (14.6 +/- 13.5 versus 12.5 +/- 11.5 ng/ml, P = .62). When compared to controls, HMGB-1 level increased transiently in treated patients at day 5 (27.8 +/- 21.7 versus 11.0 +/- 14.9, P = .01). Between group differences were not noted at any other point of assessment. HMGB-1 levels were not associated with markers of monocytic function or clinical disease severity. CONCLUSIONS: GM-CSF treatment for sepsis-induced immunosuppression induces a moderate but only transient increase in systemic HMGB-1 levels. HMGB-1 levels should not be used for monitoring of monocytic function in immunostimulatory trials as they do not adequately portray contemporary changes in monocytic immunity.

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Abstract: BACKGROUND: Overproduction of pro-inflammatory cytokines is a well established factor in the progression of chronic heart failure (CHF). Changes in cellular immunity have not been widely studied, and the impact of standard medication is uncertain. Here we investigate whether a leukocyte redistribution occurs in CHF and whether this effect is influenced by beta-blocker therapy. METHODOLOGY: We prospectively studied 75 patients with systolic CHF (age: 68+/-11 years, left ventricular ejection fraction 32+/-11%, New York Heart Association class 2.5+/-0.7) and 20 age-matched healthy control subjects (age: 63+/-10 years). We measured the response of cells to endotoxin exposure in vitro, analysed subsets of lymphocytes using flow cytometry, and assessed plasma levels of the pro-inflammatory markers interleukin 1, 6, tumor necrosis factor-alpha, and soluble tumor necrosis factor receptors 1 and 2. PRINCIPAL FINDINGS: While no differences in the number of leukocytes were noted between patients with CHF and healthy controls, we detected relative lymphopenia in patients with CHF (p<0.001 vs. control), mostly driven by reductions in T helper cells and B cells (both p<0.05). The number of neutrophils was increased (p<0.01). These effects were pronounced in patients who were beta-blocker naïve (32% of all patients with CHF). Increased plasma levels of soluble tumor necrosis receptor-1 correlated with the relative number of lymphocyte subsets. CONCLUSIONS: In patients with CHF, we detected a redistribution of leukocyte subsets, i.e. an increase in neutrophils with relative lymphopenia. These effects were pronounced in patients who were beta-blocker naïve. The underlying mechanism remains to be elucidated.

Abstract: BACKGROUND: Renal transplantation (RTx) restitutes the function of the failing organ and induces convalescence of the entire organism. Our study investigates whether this is accompanied by improvements in cardiovascular function and structural changes. METHODS: A total of 25 Caucasian patients (14 male, median age 44.2 +/- 9.2 years, BMI 23.7 +/- 4.0 kg/m(2)) were assessed in a prospective trial before, 1, 3 and 12 months after RTx from living donors by clinical examination, cardiopulmonary exercise testing, dual X-ray absorptiometry (DEXA) and analysis of plasma indices. RESULTS: Creatinine clearance improved from 8.0 +/- 3.1 to 60.9 +/- 18.1 mL/min at 1 month, but declined at 3 (51.6 +/- 16.3 mL/min) and 12 months (53.6 +/- 20.8 mL/min, P = 0.04 versus month 1). Body composition shifted from lean towards fat tissue (25.8 +/- 12.5-31.2 +/- 11.2% body fat content, P = 0.0001). Only baseline lean weight correlated with fat increase over time (r(2) = 0.28, P = 0.008). Patients with fat content above median (n = 13) had a 3-fold increased hazard ratio of infection (CI 1.04-9.41, P = 0.042) and overall hospitalization (hazard ratio 2.95, CI 1.10-7.93, P = 0.03). PeakVO(2) decreased over RTx (23.2 +/- 6.0- 17.6 +/- 5.1 mL/kg/min) and returned to baseline levels not until 1 year later (P < 0.001). After an initial decline, muscle oxidative capacity (peakVO(2)/lean mass) improved from 33.6 +/- 10.1 to 35.0 +/- 8.2 mL/kg/min at 12 months after RTx (P < 0.001). CONCLUSIONS: After RTx, body composition shifted continuously towards fat tissue, and baseline lean weight significantly correlated with fat increase over time. Both severe infections and hospitalizations are associated with a higher fat content before RTx. Exercise capacity (peakVO(2)) worsened after RTx and restitutes during follow-up, with muscle quality (peakVO(2)/lean) even exceeding baseline levels after 12 months.

Abstract: BACKGROUND: In chronic heart failure (CHF), impaired insulin sensitivity (Si) is frequently observed. It is associated with symptomatic status and poor prognosis suggesting an intrinsic role of Si within CHF pathophysiology. HOmeostasis Model Assessment (HOMA), Fasting Insulin Resistance Index (FIRI), and QUick Insulin CheCK Index (QUICKI) are based on single-time fasting glucose and insulin assessment. Their value and discriminatory power in comparison to dynamic range assessment of Si by minimal modelling are not well established. METHODS AND RESULTS: In 105 patients with stable CHF (mean age 62+/-1years, peak VO(2) 18.2+/-0.7mL/kg/min, LVEF 28+/-2%, mean+/-SEM) Si was assessed by minimal modelling. HOMA, FIRI, and QUICKI were calculated from single-time point fasting glucose and insulin measurements. Detailed body composition was analyzed using dual-energy X-ray absorptiometry. All assessment methods showed impaired Si in CHF patients compared to healthy controls (n=25). Yet, only minimal model-derived Si differentiated between NYHA classes (p=0.0007). Further, minimal modelling was the only method to be directly associated with peak oxygen uptake and skeletal muscle strength. Model-derived Si predicted survival independently of established prognostic markers in CHF (RR 0.30 [95%CI 0.14-0.63]; p=0.0016). In contrast, HOMA, FIRI and QUICKI did not show any of these qualities. CONCLUSION: HOMA, FIRI and QUICKI are surrogate estimates of Si with reduced discriminatory power in patients with CHF. While they are suitable to semi-quantitatively categorize impaired Si compared to normal values, the dynamic range assessment of Si by minimal modelling is superior for quantitative assessment of Si in pathophysiological studies.

Abstract: INTRODUCTION: As patients after cardiac arrest suffer from the consequences of global ischemia reperfusion, we aimed to establish the incidence of acute kidney injury (AKI) in these patients, and to investigate its possible association to severe hypoxic brain damage. METHODS: One hundred and seventy-one patients (135 male, mean age 61.6 +/- 15.0 years) after cardiac arrest were included in an observational cohort study. Serum creatinine was determined at admission and 24, 48 and 72 hours thereafter. Serum levels of neuron-specific enolase (NSE) were measured 72 hours after admission as a marker of hypoxic brain damage. Clinical outcome was assessed at intensive care unit (ICU) discharge using the Pittsburgh cerebral performance category (CPC). RESULTS: AKI as defined by AKI Network criteria occurred in 49% of the study patients. Patients with an unfavourable prognosis (CPC 3-5) were affected significantly more frequently (P = 0.013). Whilst serum creatinine levels decreased in patients with good neurological outcome (CPC 1 or 2) over the ensuing 48 hours, it increased in patients with unfavourable outcome (CPC 3-5). ROC analysis identified DeltaCrea24 <-0.19 mg/dl as the value for prediction with the highest accuracy. The odds ratio for an unfavourable outcome was 3.81 (95% CI 1.98-7.33, P = 0.0001) in cases of unchanged or increased creatinine levels after 24 hours compared to those whose creatinine levels decreased during the first 24 hours. NSE levels were found to correlate with the change in serum creatinine in the first 24 hours both in simple and multivariate regression (both r = 0.24, P = 0.002). CONCLUSIONS: In this large cohort of patient after cardiac arrest, we found that AKI occurs in nearly 50% of patients when the new criteria are applied. Patients with unfavourable neurological outcome are affected more frequently. A significant association between the development of AKI and NSE levels indicating hypoxic brain damage was observed. Our data show that changes in serum creatinine may contribute to the prediction of outcome in patients with cardiac arrest. Whereas a decline in serum creatinine (> 0.2 mg/dL) in the first 24 hours after cardiac arrest indicates good prognosis, the risk of unfavourable outcome is markedly elevated in patients with constant or increasing serum creatinine.

Abstract: OBJECTIVE: Borderline ovarian tumors (BOTs) are rare entities with excellent prognosis depending on tumor stage and presence of invasive implants. There are limited data regarding the intraoperative tumor pattern, the actual base of optimal treatment planning. We conducted a systematic evaluation of the macroscopic and microscopic tumor spreads in patients with BOTs with special focus on the diagnosis of invasive and noninvasive lesions. METHODS: Between January 2001 and July 2008, data of patients with BOTs were evaluated using a systematic and validated documentation tool (intraoperative mapping of ovarian cancer). Surgical outcome and pathological findings were analyzed. RESULTS: Fifty-one patients underwent surgery for BOT. Mean (SD) age was 47.76 (15.9) years. In 6 patients (11.8%), surgery was performed for recurrence. Complete tumor resection was achieved in 47 patients (92.15%), whereas mean (SD) operative time was 126.34 (73.4) minutes. Pathologic evaluation identified 12 patients (23.53%) with mucinous and 39 patients (76.47%) with serous histologic diagnoses. Twenty-nine (56.86%) and 22 patients (43.13%) were found to have unilateral and bilateral ovarian involvements, respectively. Sixteen patients (31.37%) presented extraovarian involvement into the peritoneum (23.5%), omentum (17.7%), uterus (7.84%), sigmoid (7.8%), lymph nodes (7.8%), ileum (3.9%), mesentery (5.9%), and appendix (1.96%). Twenty patients (39.2%) had implants; of those, 9 (17.64%) and 11 patients (21.6%) have invasive and noninvasive lesions, respectively. Eight of the 9 patients with positive peritoneal cytology were associated with the presence of peritoneal implants; 3 of them with invasive character. CONCLUSIONS: Borderline ovarian tumors require a systematic surgical evaluation to verify or exclude extrapelvic tumor lesions and allow further clinical relevant differentiation between invasive and noninvasive implants.

Abstract: Chronic heart failure is viewed as a state of chronic inflammation. Many inflammatory markers have been shown to be up-regulated in patients who have this condition, but the markers' roles in clinical decision making have not yet been fully elucidated. A panel of biomarkers is likely to have a strong impact on patient management. Inflammatory biomarkers are interesting candidates that could answer specific clinical questions on their own or complement a multi-marker approach. This article provides a broad overview of several inflammatory biomarkers, including the pro-inflammatory cytokines tumor necrosis factor-alpha, interleukin (IL)-6, IL-1, IL-18, and the soluble receptors TNFR-1, TNFR-2, IL-6R, and gp130. In addition to these acute phase reactants, several adhesion molecules, and lipopolysaccharide-signaling pathways are discussed.

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Abstract: INTRODUCTION: A rare side effect of antipsychotic medication is neuroleptic malignant syndrome, mainly characterized by hyperthermia, altered mental state, haemodynamic dysregulation, elevated serum creatine kinase and rigor. There may be multi-organ dysfunction including renal and hepatic failure as well as serious rhabdomyolysis, acute respiratory distress syndrome and disseminated intravascular coagulation. The prevalence of neuroleptic malignant syndrome is between 0.02% and 2.44% for patients taking neuroleptics and it is not necessary to fulfil all cardinal features characterizing the syndrome to be diagnosed with neuroleptic malignant syndrome. Because of other different life-threatening diseases matching the various clinical findings, the correct diagnosis can sometimes be hard to make. A special problem of intensive care treatment is the management of severe hyperthermia. Lowering of body temperature, however, may be a major clinical problem because hyperthermia in neuroleptic malignant syndrome is typically unresponsive to antipyretic agents while manual cooling proves difficult due to peripheral vasoconstriction. CASE PRESENTATION: A 22-year-old Caucasian man was admitted unconscious with a body temperature of 42 degrees C, elevated serum creatine phosphokinase, tachycardia and hypotonic blood pressure. In addition to intensive care standard therapy for coma and shock, a non-invasive cooling device (Arctic Sun 2000((R)), Medivance Inc., USA), originally designed to induce mild therapeutic hypothermia in patients after cardiopulmonary resuscitation, was used to lower body temperature. After successful treatment it became possible to obtain information from the patient about his recent ambulant treatment with Olanzapin (Zyprexa(R)) for schizophrenia. CONCLUSION: Numerous case reports have been published about patients who developed neuroleptic malignant syndrome due to Olanzapin (Zyprexa(R)) medication. Frequently hyperthermia has been observed in these cases with varying outcomes. In our case the only residual impairment for the patient is dysarthria with corresponding symmetric cerebellar pyramidal cell destruction demonstrated by increased signal intensity in T2-weighted magnetic resonance imaging, most likely caused by the excessive hyperthermia.

Abstract: ABSTRACT: INTRODUCTION: Patients with sepsis often demonstrate severely impaired immune responses. The hallmark of this state of "immunoparalysis" is monocytic deactivation characterized by decreased human leukocyte antigen (HLA)-DR expression and reduced production of pro-inflammatory cytokines. Recently, diminished numbers of dendritic cells (DC) were reported in patients with sepsis. However, little is known about DC phenotype and function in human sepsis. We therefore compared phenotypic and functional changes in monocyte and DC subsets in patients with sepsis and immunoparalysis. METHODS: In a prospective observational analysis, 16 consecutive patients with severe sepsis and septic shock (age 59.2+/-9.7 years, 13 male, SOFA score 6.1+/-2.7) and immunoparalysis (monocytic HLA-DR expression <5,000 Ab/cell) and 16 healthy volunteers were included. Peripheral blood DC counts, HLA-DR expression and ex vivo cytokine production were evaluated in comparison with monocyte subsets over time. RESULTS: At baseline, a profound reduction in the numbers of myeloid DCs (MDC), plasmacytoid DCs (PDC), and CD14dimCD16positive monocytes was observed in sepsis whereas CD14brightCD16negative and CD14brightCD16positive monocyte numbers were increased. HLA-DR expression was reduced on all monocyte and DC subsets. Production of pro-inflammatory cytokines and intracellular cytokine staining in response to lipopolysaccharide and lipoteichoic acid was impaired in monocyte subsets and MDCs, whereas interleukin-10 (IL-10) secretion was increased. Interferon-alpha response by stimulated PDCs was significantly decreased compared to controls. At day 28, HLA-DR expression and cytokine production of DC and monocyte subsets remained lower in septic patients compared to controls. CONCLUSIONS: In sepsis, long-lasting functional deactivation is common to all circulating monocyte and DC subsets. In addition to decreased peripheral blood DC counts, functional impairment of antigen-presenting cells may contribute to an impaired antimicrobial defence in sepsis.

Abstract: BACKGROUND: Tryptophan (Trp) is catabolized by indoleamine 2,3-dioxygenase (IDO). Changes in Trp metabolism and IDO activity in chronic kidney disease (CKD) have not been widely studied, and the impact of haemodialysis is uncertain. Here we investigate Trp catabolism, IDO activity and the role of inflammation in moderate to very severe CKD and haemodialysis. METHODS: Eighty individuals were included in a prospective blinded endpoint analysis. Using tandem mass spectrometry, serum levels of Trp, kynurenine (Kyn), kynurenic-acid (Kyna), quinolinic-acid (Quin), 5-hydroxytryptophan (OH-Trp), serotonin (5-HT), estimated IDO activity and inflammatory markers were assessed in 40 CKD patients (age 57 +/- 14 years, 21 male, creatinine 4.5 +/- 2.7, n = 17 receiving haemodialysis), and in 40 healthy controls (age 34 +/- 9 years, 26 male). RESULTS: Trp levels were unchanged in CKD (P = 0.78 versus controls). Serum levels of Kyn, Kyna and Quin increased with CKD severity (stages 4, 5 versus controls all P </= 0.01). IDO activity was significantly induced in CKD and correlated with disease severity (stages 3-5 versus controls, all P </= 0.01) and inflammatory markers [high-sensitivity C-reactive protein (hsCRP), soluble TNF-receptor-1 (sTNFR-I); both P </= 0.03]. IDO products (Kyn, Kyna, Quin) correlated also with hsCRP and sTNFR-I (all P </= 0.04). Haemodialysis did not influence IDO activity (P = 0.26) and incompletely removed Kyn, Kyna, Quin, OH-Trp and 5-HT by 22, 26, 50, 44 and 34%, respectively. In multiple regression, IDO activity correlated with hsCRP and sTNFR-I (both P </= 0.03) independent of serum creatinine, age and body weight. CONCLUSIONS: IDO activity and serum levels of tryptophan catabolites of the kynurenine pathway increase with CKD severity. In CKD, induction of IDO may primarily be a consequence of chronic inflammation.

Abstract: Abdominal infections are associated with significant morbidity and mortality. Nearly all bacteria causing abdominal infections are derived from the endogenous flora of the alimentary tract. The resulting infection is typically polymicrobial and comprised of both aerobic and anaerobic microbes. They can be classified by their severity as uncomplicated and complicated or by their origin as community or hospital acquired. Escherichia coli and Bacteroides fragilis are the most frequently isolated bacteria in community-acquired abdominal infections. Nosocomial infections typically involve a more resistant flora (e.g. Pseudomonas spp., Acinetobacter spp., Gram-negative bacilli producing extended-spectrum beta-lactamases [ESBL], vancomycin-resistant enterococci [VRE] and methicillin-resistant Staphylococcus aureus [MRSA]). Antimicrobial therapy should be guided by microbiological testing and frequently requires other interventions as well. In uncomplicated infections antimicrobial prophylaxis for < 24h may be considered. Patients with underlying or acquired immunodeficiency, i.e. organ transplant recipients and other patients on complex immunosuppressant regimens require special attention and antimicrobial coverage. We discuss the relevant microbiota, a rational diagnostic and therapeutic approach including strategies to handle challenging infections. The application of novel compounds and/or drug classes for abdominal infections such as glycylcyclines (i.e. tigecycline), glycopeptides (i.e. dalbavancin, telavancin, oritavancin), carbapenems (i.e. doripenem), and forth generation cephalosporins (i.e. ceftaroline, ceftobiprole) as well as patents on metalloproteinase and caspase inhibitors, interleukin antagonists, fusion proteins and nitric oxide donators is critically reviewed. The information is summarized in flow charts and algorithms for use in daily clinical practice and the review article also shows the useful information of the patents for the treatment of abdominal infections.

Abstract: PURPOSE: To prospectively analyse the pharmacokinetics of lamotrigine (LTG) during pregnancy and lactation in a consecutive series of epileptic pregnant women. METHODS: Nine women on LTG-monotherapy were studied during pregnancy, delivery and lactation, until a mean of 3 weeks postpartum. Maternal blood samples were available from all trimesters as well as umbilical cord blood samples of the newborn 24 and/or 48h postpartum. In 4 cases we additionally determined the LTG-concentration in breast milk. RESULTS: The median LTG-clearance was elevated by 197% during the first trimester, 236% and 248% during the second and third trimester respectively. A maximum of 264% was reached at delivery. An average LTG-dose increase by 250% had to be undertaken in order to obtain therapeutic serum levels. In puerperium LTG-clearance decreased again to reach the initial concentrations approximately at the third week postpartum. The median LTG-concentration ratio of the umbilical cord blood to maternal serum was 1.01 (range: 0.56-1.42), while the median LTG-concentration ratio of breast milk to maternal serum was 0.59 (range: 0.35-0.86). DISCUSSION: Our study confirms the therapeutic relevant changes of LTG-clearance during pregnancy and lactation in women on LTG-monotherapy. Since LTG crosses the placenta, a close monitoring of both mother and newborn is indispensable.

Abstract: ABSTRACT: INTRODUCTION: A rare side effect of antipsychotic medication is neuroleptic malignant syndrome, mainly characterized by hyperthermia, altered mental state, haemodynamic dysregulation, elevated serum creatine kinase and rigor. There may be multi-organ dysfunction including renal and hepatic failure as well as serious rhabdomyolysis, acute respiratory distress syndrome and disseminated intravascular coagulation. The prevalence of neuroleptic malignant syndrome is between 0.02% and 2.44% for patients taking neuroleptics and it is not necessary to fulfil all cardinal features characterizing the syndrome to be diagnosed with neuroleptic malignant syndrome. Because of other different life-threatening diseases matching the various clinical findings, the correct diagnosis can sometimes be hard to make. A special problem of intensive care treatment is the management of severe hyperthermia. Lowering of body temperature, however, may be a major clinical problem because hyperthermia in neuroleptic malignant syndrome is typically unresponsive to antipyretic agents while manual cooling proves difficult due to peripheral vasoconstriction. CASE PRESENTATION: A 22-year-old Caucasian man was admitted unconscious with a body temperature of 42degreesC, elevated serum creatine phosphokinase, tachycardia and hypotonic blood pressure. In addition to intensive care standard therapy for coma and shock, a non-invasive cooling device (Arctic Sun 2000(R), Medivance Inc., USA), originally designed to induce mild therapeutic hypothermia in patients after cardiopulmonary resuscitation, was used to lower body temperature. After successful treatment it became possible to obtain information from the patient about his recent ambulant treatment with Olanzapin (Zyprexa(R)) for schizophrenia. CONCLUSION: Numerous case reports have been published about patients who developed neuroleptic malignant syndrome due to Olanzapin (Zyprexa(R)) medication. Frequently hyperthermia has been observed in these cases with varying outcomes. In our case the only residual impairment for the patient is dysarthria with corresponding symmetric cerebellar pyramidal cell destruction demonstrated by increased signal intensity in T2-weighted magnetic resonance imaging, most likely caused by the excessive hyperthermia.

Abstract: BACKGROUND: With the recent introduction of therapeutic hypothermia the application of sedation becomes necessary in cardiac arrest patients. We therefore analysed the usefulness of the Glasgow coma score (GCS) for outcome prediction in survivors of cardiac arrest treated with therapeutic hypothermia. PATIENTS AND METHODS: In a prospective observational study we identified 72 comatose patients admitted to our intensive care unit after cardiac arrest. All patients were treated with therapeutic hypothermia. After sedation stop the Glasgow coma scale (GCS) was recorded until day 4. Neurological outcome was assessed using the Pittsburgh cerebral performance category (CPC) score. RESULTS: Forty-four of 72 patients (61%) were discharged with a favourable neurological outcome (CPC 1+2). GCS was significantly higher in patients with good outcome compared to patients with unfavourable outcome at every point in time after sedation stop (p<0.001). The value for prediction of good outcome with the highest accuracy was a GCS>4 at the first day after sedation stop (sensitivity 61%, PPV 90% and AUC 0.808) and GCS>6 in the following days (sensitivity 84%, PPV 92.5% and AUC 0.921 at day 4). In particular a score of >3 on the motor component of the GCS predicted good outcome with a specificity of 100% (sensitivity 43%) at the first day. CONCLUSIONS: Our results indicate that monitoring of the GCS is a simple and reliable method for clinical outcome assessment in patients treated with therapeutic hypothermia. Thus, GCS monitoring remains a powerful tool to predict outcome of patients treated with therapeutic hypothermia.

Abstract: Despite substantial advances in our understanding of the pathogenesis of sepsis, the mortality of patients with severe sepsis/septic shock is unacceptably high. The potential role of extracorporeal therapies in the adjunctive treatment of sepsis is highly controversial. The present article reviews the current status of clinical research in this area. Conventional 'renal dose' continuous and discontinuous renal replacement technologies fail to achieve a biologically relevant reduction of target molecules. This may be accomplished by modified approaches, e.g. using high-dose protocols, high cut-off membranes, or (selective or unselective) adsorption techniques; however, their clinical value remains to be established by prospective studies using clinical end points.

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Abstract: Despite numerous advances in intensive care medicine, sepsis remains a deadly disease. Today, conventional therapeutic approaches and mainstream scientific research mostly focus on symptomatic early goal directed organ support therapy. This includes fluid resuscitation, choice and timing of antibiotics and vasopressors, mechanical ventilation, and renal replacement strategies. Furthermore, great effort has been undertaken to investigate whether tightly controlled blood glucose levels, the application of corticosteroids, and early medication using activated protein C improves survival. However, most of these mainstream approaches have recently been shown unsuccessful in large-scale clinical trials. Current data now suggest that besides giving fluids, antibiotics, and symptomatic organ support, little - if at all - can be done to improve mortality from sepsis. This might be due to the fact that in the presence of modern intensive care medicine, most patients with severe sepsis or septic shock will survive the early "shock phase" of the disease. Mounting evidence suggests that in the course of the disease, most septic patients are then subjected to a secondary phase, which is characterised by a failure of cell-mediated immunity. This leads to repeated and uncontrolled infections, "chronic" multiple organ failure, and death in a large number of cases. Here we hypotheses that in order to profoundly influence survival from sepsis, future therapeutic efforts in the field should concentrate on this later "hypo-immune" stage of sepsis, associated immune phenomena, and novel immunomodulatory strategies. This may lead to the development of advanced immunomodulatory therapies available for widespread clinical use. Today, in the era of antibiotics and advanced organ system support therapy, it is not the bug that kills you- survival has become a matter of whether your cellular immune system can cope.

Abstract: BACKGROUND: The aim of the study was to report the impact of our hypothermia protocol on survival and neurological outcome. Furthermore, we were interested in the risk of bleeding complications in patients with acute myocardial infarction (AMI) being treated with percutaneous coronary revascularisation (PCI) and therapeutic hypothermia. METHODS AND RESULTS: In a prospective observational study we identified 31 comatose patients (25 male, age 65+/-13 years) admitted to our intensive care unit with out-of-hospital cardiac arrest due to AMI who were treated with hypothermia. They were compared to 31 historical age- and gender-matched controls (25 male, age 65+/-12 years) admitted after out-of-hospital cardiac arrest due to AMI in the era prior to hypothermia treatment. Peak creatinine kinase-MB was 118 U/L (94-248) in the hypothermia group and 131 U/L (98-257) in controls (p=0.51). In the hypothermia group, 19 patients were discharged with a favourable neurological outcome, whereas in controls, such outcome was observed in only six patients (p=0.002). In both groups, haemoglobin values and platelet counts declined during the first 48 h (all p<0.001). No differences regarding bleeding complications (p=1.0), transfusion requirements (p=1.0), and the number of transfusions (p=0.9) were observed between the groups. CONCLUSIONS: A major improvement in neurological outcome was observed in patients treated with hypothermia. Our results indicate that the combination of reperfusion strategies and the application of hypothermia do not carry an excessive risk of bleeding complications. Patients with AMI and out-of-hospital cardiac arrest should receive the optimal therapy for both conditions, that is, either thrombolysis or PCI and therapeutic hypothermia.

Abstract: Early optimization of fluid status is of central importance in the treatment of critically ill patients. This study aims to investigate whether inferior vena cava (IVC) diameters correlate with invasively assessed hemodynamic parameters and whether this approach may thus contribute to an early, non-invasive evaluation of fluid status. Thirty mechanically ventilated patients with severe sepsis or septic shock (age 60 +/- 15 years; APACHE-II score 31 +/- 8; 18 male) were included. IVC diameters were measured throughout the respiratory cycle using transabdominal ultrasonography. Consecutively, volume-based hemodynamic parameters were determined using the single-pass thermal transpulmonary dilution technique. This was a prospective study in a tertiary care academic center with a 24-bed medical intensive care unit (ICU) and a 14-bed anesthesiological ICU. We found a statistically significant correlation of both inspiratory and expiratory IVC diameter with central venous pressure (p = 0.004 and p = 0.001, respectively), extravascular lung water index (p = 0.001, p < 0.001, respectively), intrathoracic blood volume index (p = 0.026, p = 0.05, respectively), the intrathoracic thermal volume (both p < 0.001), and the PaO(2)/FiO(2) oxygenation index (p = 0.007 and p = 0.008, respectively). In this study, IVC diameters were found to correlate with central venous pressure, extravascular lung water index, intrathoracic blood volume index, the intrathoracic thermal volume, and the PaO(2)/FiO(2) oxygenation index. Therefore, sonographic determination of IVC diameter seems useful in the early assessment of fluid status in mechanically ventilated septic patients. At this point in time, however, IVC sonography should be used only in addition to other measures for the assessment of volume status in mechanically ventilated septic patients.

Abstract: BACKGROUND: Intrathecal interleukin (IL)-6 is considered to be a proinflammatory biomarker for cerebral inflammatory response. This is of clinical importance for the prediction of vasospasm after subarachnoid haemorrhage (SAH). We evaluated a bedside technique for the quantitative measurement of IL-6 in the cerebrospinal fluid (CSF). MATERIAL/METHODS: 32 samples of CSF and serum were taken from 11 patients suffering from SAH on day 3, 4 and 5 after bleeding. A lateral flow immunoassay chip-test (POC-Test) was used for bedside testing and the results were compared to the standard chemiluminescence-based ELISA (Immulite) performed in a specialized laboratory. RESULTS: For CSF analysis Immulite and POC-Test show linear correlation (r2=0.81). The high IL-6 values found in SAH are depicted more easily by the POC-Test, because it has a working range of up to 10.000 pg/ml instead of up to 1000 pg/ml for Immulite. Serum IL-6 values were clearly lower, suggesting CNS inflammation in SAH. CONCLUSIONS: The new chip-test provides a handy tool for the neurosurgical intensive care unit, analysing CSF IL-6 concentrations within 20 minutes. This is the first time a point-of care test for IL-6 in CSF was evaluated. The test results match the values achieved by the standard Immulite technique. Therefore a tool for clinical routine interleukin-6 investigation is provided which could find use in a broad variety of neurosurgical and neurological diseases.

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Abstract: OBJECTIVES: Interleukin-6 (IL-6) is involved in inflammatory diseases, provides prognostical information, and allows the early identification and monitoring of septic patients. We investigated whether IL-6 can be assessed using a new densitometric point-of-care (POC) bedside assay. DESIGN AND METHODS: 392 samples were prospectively collected from 57 intensive care unit patients (38 male, age: 45.2 +/- 16.9years, APACHE II score: 25.4 +/- 4.8). Blinded IL-6 measurements were performed using conventional semiautomatic enzyme-linked immunosorbent assays (ELISA) and the POC test. RESULTS: Mean IL-6 levels were 102.9 +/- 388.6pg/mL (ELISA) and 97.0 +/- 535.5 (POC). A significant correlation was found (p < 0.0001, r = 0.92). The sensitivity/specificity for sepsis was 82.6%/86.5% (ELISA, AUC: 0.881), and 76.4%/95.0% (POC, AUC: 0.868). CONCLUSIONS: Here we demonstrate significant correlations of IL-6 levels determined using a POC test and semiautomatic ELISA. ROC analyses revealed no significant differences between the two tests. With a turn-around time of 20min, the bedside IL-6 test is a new tool that may help to initiate early goal-directed therapy.

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Abstract: BACKGROUND: Animal studies suggest that the induction of therapeutic hypothermia in patients after cardiac arrest should be initiated as soon as possible after ROSC to achieve optimal neuroprotective benefit. A "gold standard" for the method of inducing hypothermia quickly and safely has not yet been established. In order to evaluate the feasibility of a hypothermia cap we conducted a study for the prehospital setting. METHODS AND RESULTS: The hypothermia cap was applied to 20 patients after out-of-hospital cardiac arrest with a median of 10 min after ROSC (25/75 IQR 8-15 min). The median time interval between initiation of cooling and hospital admission was 28 min (19-40 min). The median tympanic temperature before application of the hypothermia cap was 35.5 degrees C (34.8-36.3). Until hospital admission we observed a drop of tympanic temperature to a median of 34.4 degrees C (33.6-35.4). This difference was statistically significant (P < 0.001). We could not observe any side effects related to the hypothermia cap. 25 patients who had not received prehospital cooling procedures served as a control group. Temperature at hospital admission was 35.9 degrees C (35.3-36.4). This was statistically significant different compared to patients treated with the hypothermia cap (P < 0.001). CONCLUSIONS: In summary we demonstrated that the prehospital use of hypothermia caps is a safe and effective procedure to start therapeutic hypothermia after cardiac arrest. This approach is rapidly available, inexpensive, non-invasive, easy to learn and applicable in almost any situation.

Abstract: INTRODUCTION: Persistent coma is a common finding after cardiac arrest and has profound ethical and economic implications. Evidence suggests that therapeutic hypothermia improves neurological outcome in these patients. In this analysis, we investigate whether therapeutic hypothermia influences the length of intensive care unit (ICU) stay and ventilator time in patients surviving out-of-hospital cardiac arrest. METHODS: A prospective observational study with historical controls was conducted at our medical ICU. Fifty-two consecutive patients (median age 62.6 years, 43 males, 34 ventricular fibrillation) submitted to therapeutic hypothermia after out-of-hospital cardiac arrest were included. They were compared with a historical cohort (n = 74, median age 63.8 years, 53 males, 43 ventricular fibrillation) treated in the era prior to hypothermia treatment. All patients received the same standard of care. Neurological outcome was assessed using the Pittsburgh cerebral performance category (CPC) score. Univariate analyses and multiple regression models were used. RESULTS: In survivors, therapeutic hypothermia and baseline disease severity (Acute Physiology and Chronic Health Evaluation II [APACHE II] score) were both found to significantly influence ICU stay and ventilator time (all P < 0.01). ICU stay was shorter in survivors receiving therapeutic hypothermia (median 14 days [interquartile range (IQR) 8 to 26] versus 21 days [IQR 15 to 30] in the control group; P = 0.017). ICU length of stay and time on ventilator were prolonged in patients with CPC 3 or 4 compared with patients with CPC 1 or 2 (P = 0.003 and P = 0.034, respectively). Kaplan-Meier analysis showed improved probability for 1-year survival in the hypothermia group compared with the controls (log-rank test P = 0.013). CONCLUSION: Therapeutic hypothermia was found to significantly shorten ICU stay and time of mechanical ventilation in survivors after out-of-hospital cardiac arrest. Moreover, profound improvements in both neurological outcome and 1-year survival were observed.

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Abstract: OBJECTIVE: To report on the recurrent release of charcoal from an intrapulmonary cavern in a case of acute respiratory failure after charcoal aspiration. DESIGN: Case report. SETTING: Anaesthesiological ICU, university hospital. PATIENT: An 18-year-old ethanol intoxicated comatose patient regurgitated and aspirated activated charcoal during orotracheal intubation. TREATMENT: After 2 days of mechanical ventilation, the patient was transferred to a tertiary care university hospital. On admission, acute respiratory distress syndrome with bilateral pulmonary infiltrations was diagnosed. The patient's recovery was hampered by recurrent release of charcoal from an intrapulmonary cavern. Sophisticated ventilatory support, prone positioning, secretolytics, repetitive bronchoscopy, and antibiotic therapy may have facilitated bronchoalveolar clearance and weaning after 18 days. CONCLUSION: Aspiration may be a dramatic complication if charcoal is administered in comatose patients without airway protection. In this case report, advanced intensive care measures were necessary to tackle the special feature of charcoal release from an intrapulmonary cavern.

Abstract: Warm water bathing is a popular recreational activity and is frequently used in rehabilitation medicine. Although well tolerated in most cases, there are reports indicating an increased risk of thrombotic events after hot tub bathing. The effects of a 45 min thermoneutral bath followed by a 50 min bath with increasing water temperature (maximum 41 degrees C) until reaching a body core temperature of 39 degrees C on factors of blood coagulation and fibrinolysis were studied in eight healthy male volunteers. Blood was obtained after a 45-min resting period as control and after the thermoneutral and hyperthermic bath as well as after another 45 min recovery period at the end of the study. Hyperthermic immersion (HI) lead to a shortening of activated partial thromboplastin time (aPTT) (P < 0.05). Fibrinogen concentration decreased immediately after HI (P < 0.05) but increased during recovery (P < 0.05). Plasminogen activator inhibitor (PAI) activity decreased during HI (P < 0.05), D-dimer concentration was not found to change. Thrombocyte count increased (P < 0.05) during HI. The increases in tissue-type plasminogen activator concentration as well as leucocyte count during HI were due to haemoconcentration. Prothrombin time, PAI-activity and granulocyte count decreased during thermoneutral immersion (P < 0.05). Warm water bathing leads to haemoconcentration and minimal activation of coagulation. The PAI-1 activity is decreased. A marked risk for thrombotic or bleeding complications during warm water bathing in healthy males could not be ascertained.

Abstract: BACKGROUND: Various diagnostic methods are applied preoperatively in patients with suspected and histologically proven endometrial cancer, but no standard diagnostic tool exists for the accurate preoperative evaluation of tumor spread and staging. The aim of this study was to evaluate the diagnostic value of transvaginal sonography (TVS) as a staging tool, by determining tumor size and infiltration of the adjacent organs and correlating sonographic results to the respective intraoperative findings. PATIENTS AND METHODS: Overall, thirty patients with endometrial cancer were included in the study prospectively. Systematic staging regarding tumor size (T), infiltration of the cervix (Cx) and ovaries (OV), peritoneal carcinomatosis (PC), bladder invasion (BI), intestinal invasion (II) and ascites (A) was assessed using TVS. Findings of B-mode ultrasound imaging were compared to intraoperative findings and histopathological results. RESULTS: Preoperative diagnosis was correctly made by TVS in 93.4% of the patients [95% confidence interval (CI): 84%-100%]. Preoperative staging was correctly achieved by TVS for T in 73.3% [95% CI: 58%-89%], for Cx in 16.7% [95% CI: 13%-46%], for OV in 100%, for BI in 97% [95% CI: 90%-100%], for II in 97% [95% CI: 90%-100%], for PC in 90% [95% CI: 79%-100%] and for A in 100%. CONCLUSION: TVS is a sensitive and non-invasive method for preoperative diagnosis of suspected endometrial cancer. Of the tumors, 73% were correctly classified regarding size, whereas the detection rate of tumor spread in the ovaries and of ascites were high. Accuracy and sensitivity for the description of the infiltration of other adjacent organs, such as the bladder, intestine and peritoneal layers, were low. Further studies on the value of the combination of TVS and magnetic resonance imaging in the preoperative setting of patients with endometrial cancer are warranted.

Abstract: The pathophysiologic understanding of chronic heart failure has made significant advances over the last decades. Counterintuitively, high levels of plasma cholesterol are associated with better survival, perhaps because plasma lipoproteins are able to scavenge lipopolysaccharide, a cell-wall component from gram-negative bacteria. A number of similar features are present in patients who have sepsis. This article explores the cholesterol paradox in patients who have chronic heart failure and extends this view to patients who have sepsis. Also discussed is the potential of statins, which might be able to exert beneficial effects in both clinical conditions, despite lowering plasma cholesterol values.

Abstract: ABSTRACT: We report a case of fulminant multiple organ failure including the Acute Respiratory Distress Syndrome (ARDS), haemodynamic, and renal failure due to community-acquired methicillin-sensitive Panton Valentine Leukocidin (PVL) positive spa-type 284 (ST121) Staphylococcus aureus septic shock. The patient's first clinical symptom was necrotizing pneumonia. Despite organism-sensitive triple antibiotic therapy with linezolid, imipenem and clindamycin from the first day of treatment, progressive abscess formation in multiple skeletal muscles was observed. As a result, repeated surgical interventions became necessary. Due to progressive soft tissue infection, the anti-microbial therapy was changed to a combination of clindamycin and daptomycin. Continued surgical and antimicrobial therapy finally led to a stabilisation of the patients' condition. The clinical course of our patient underlines the existence of a "PVL-syndrome" which is independent of in vitro Staphylococcus aureus susceptibility. The PVL-syndrome should not only be considered in patients with soft tissue or bone infection, but also in patients with pneumonia. Such a condition, which may easily be mistaken for uncomplicated pneumonia, should be treated early, aggressively and over a long period of time in order to avoid relapsing infection.

Abstract: In sepsis, endotoxin, interleukin 6 (IL-6), and complement-activation product 5a (C5a) trigger inflammatory cascades resulting in monocytic deactivation. When this occurs, the outcome is often uncontrolled infection, multiple organ dysfunction, and death. We tested here whether simultaneous reduction of systemic endotoxin, IL-6, and C5a levels could be achieved via selective extracorporeal immunoadsorption (IA) and whether this would restore monocytic responsiveness and improve organ function. Therefore, 33 patients with severe sepsis or septic shock were enrolled in a prospective, 1:2 case-control matched, blinded endpoint evaluation trial. In addition to best supportive care, 11 of these patients (mean age, 57.8 +/- 2.2 years; Acute Physiology and Chronic Health Evaluation II score, 23.7 +/- 1.6) received simultaneous endotoxin IA, IL-6 IA, and C5a IA on 5 consecutive days for 7.5 h each. Our observational end points were the course of monocytic immunity (monocytic HLA-DR expression) and other indices of inflammation and disease severity. In patients receiving IA, the mean circulating level of IL-6 was reduced from 361.7 +/- 116.0 to 38.2 +/- 15.2 pg/mL (P = 0.02), and of C5a from 297.6 +/- 43.1 to 79.2 +/- 14.5 ng/mL (P < 0.001). Two indices of endotoxemia were reduced also. Treated patients had lower C-reactive protein and Acute Physiology and Chronic Health Evaluation II scores at day 7 (P = 0.004 and P = 0.0001, respectively). Monocytic HLA-DR improved in the treated patients but not in controls (P < 0.0001). Under treatment, HLA-DR was found to recover in all patients with immunoparalysis (4,993.6 +/- 1,162 to 15,295.3 +/- 2,197 molecules per cell; P = 0.002). Here, we demonstrate that simultaneously reducing circulating endotoxin, IL-6, and C5a levels by selective IA reverses monocytic deactivation and improves organ system functions. This novel strategy might open a new therapeutic avenue for an interventional extracorporeal treatment of patients with sepsis.

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Abstract: INTRODUCTION: In small bowel disease such as M. Crohn, the intestinal absorption of oxalate is increased. Severe calcium oxalate deposition in multiple organs as consequence of enteric hyperoxaluria may lead to severe organ dysfunction and chronic renal failure. The management of hemodialyzed patients with short bowel syndrome may be associated with vascular access problems and oxalate infiltration of the bone marrow leading to pancytopenia. Although the risk of recurrence of the disease is very high after renal transplantation, it may be the ultimate therapeutic alternative in secondary hyperoxaluria. CASE: Here, we report a patient with enteric oxalosis due to Crohn's disease. He developed end-stage renal disease, erythropoietin-resistant anemia, oxalate infiltration of the bone marrow and severe vascular access problems. Following high-urgency kidney transplantation, daily hemodiafiltration of 3 hours was performed for 2 weeks to increase oxalate clearance. Despite tubular and interstitial deposition of oxalate in the renal transplant, the patient did not require further hemodialysis and the hematocrit levels normalized. DISCUSSION: Early treatment of hyperoxaluria due to short bowel syndrome is essential to prevent renal impairment. Declining renal function leads to a further increase in oxalate accumulation and consecutive oxalate deposition in the bone marrow or in the vascular wall. If alternative treatments such as special diet or daily hemodialysis are insufficient, kidney transplantation may be a therapeutic alternative in severe cases of enteric oxalosis despite a possible recurrence of the disease.

Abstract: The transcription factor HIF-1alpha has been identified as a key regulator in the cellular and systemic response to hypoxia. Because hypoxia is frequently associated with acidosis, like in ischemia or tumour growth, we studied the impact of acidosis on the expression of the HIF-1alpha and HIF-2alpha proteins and that of the three HIF target genes carbonic anhydrase-9 (CA-9), glucose transporter-1 (Glut-1) and erythropoietin (EPO). Since the HIF-prolyl hydroxylases (PHD) modulate cellular HIF-alpha protein levels we also investigated changes in PHD mRNA expression under hypoxia and acidosis. HIF-1alpha immunoblots revealed, depending on the cell line investigated, a moderate induction of HIF-alpha protein levels by acidosis in normoxia (Hep3B cells) or hypoxia (HeLa cells). Concordantly, the activity of HIF-driven luciferase reporters was slightly enhanced at pH 7.0. In contrast, HIF target genes exhibited divergent responses to acidosis: basal and hypoxia-induced CA-9 mRNA levels were further increased, whereas hypoxic EPO mRNA induction was attenuated, and Glut-1 mRNA levels were not altered by acidosis. Except from a small increase of hypoxia-induced PHD3 mRNA levels in HeLa cells, there was also no significant effect of acidosis on PHD expression. In conclusion, albeit HIF protein levels slightly induced by acidosis and the inconsistent regulation of HIF target genes under acidosis suggest additional, yet unidentified pH-sensitive factors to be involved in the regulation of these genes.

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Abstract: Synopsis Acute kidney failure is an important clinical area in the intensive care unit setting. An estimated 5-20 percent of critically ill patients experience an episode of acute kidney failure during the course of their illness, and about 5 percent of patients admitted to an ICU will eventually require renal replacement therapy. In these patients, in-hospital mortality is extremely high, exceeding 50 percent. Thus, the early detection and causal treatment of acute kidney problems is vitally important for a successful outcome. Written by internationally renowned experts, this clinical reference offers helpful advice with the most recent information on the definition, epidemiology, pathophysiology, and clinical causes of acute kidney failure as a fundamental prerequisite for prevention of this disorder. Moreover, it also covers differential diagnostic approaches for patients with acute renal failure and provides a detailed outline of important measures for their clinical management. Finally, separate chapters are dedicated to various key aspects related to the adequate delivery of acute renal replacement therapy. It is intended as a helpful guide for all clinicians involved in the care of patients at risk of developing acute kidney problems.

Abstract: Das akute Nierenversagen ist eine häufige und schwerwiegende Komplikation in der Intensivmedizin und trägt in hohem Maße zu einer erhöhten Mortalität bei. Als Intensivmediziner sind Sie meist der Erste und im weiteren Verlauf häufig auch der Einzige, der für die Behandlung dieser Patienten verantwortlich ist. Sie müssen daher in der Lage sein, einem akuten Nierenversagen bei Risikopatienten vorzubeugen, sein Auftreten möglichst frühzeitig zu erkennen und eine optimale supportive oder, falls möglich, kausale Therapie einzuleiten. Beim manifesten Nierenversagen können Sie mit einer effizienten und zielgerichteten Nierenersatztherapie einen entscheidenden Beitrag zum Überleben schwerstkranker Patienten leisten. * Epidemiologie, Pathophysiologie und Differentialdiagnose * Präventionsmaßnahmen * Konservative Therapie * Extrakorporale Behandlungsoptionen: Darstellung und Kommentierung der verschiedenen Nierenersatzverfahren * Evidenzbasierte Antworten auf Fragen und Probleme des klinischen Alltags: von der Antikoagulation über Medikamentendosierungen bis hin zu Ernährung des Patienten. * Extrakorporale Blutreinigungsverfahren bei Vergiftungen, Sepsis oder Leberversagen

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