Risk Factors for Postoperative Pulmonary Complications Leading to Increased Morbidity and Mortality in Patients Undergoing Thoracic Surgery for Pleural Empyema.

OBJECTIVES: Surgery for pleural empyema carries a high burden of morbidity and mortality. The authors investigated the incidence of postoperative pulmonary complications (PPCs) and their effects on perioperative morbidity and mortality. Patient-specific, preoperative, procedural, and postoperative risk factors for PPCs were analyzed. DESIGN: Retrospective observational study. SETTING: A single, large university hospital. PARTICIPANTS: A total of 250 adult patients were included who underwent thoracic surgery for pleural empyema between January 2017 and December 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 250 patients with pleural empyema underwent thoracic surgery by video-assisted thoracoscopic surgery (49%; n = 122) or open thoracotomy (51%; n = 128). A proportion (42% [105]) of patients had ≥1 PPCs; 28% (n = 70) had to undergo resurgery; and 10% (n = 25) were re-admitted unexpectedly to the ICU. Preoperative respiratory failure (odds ratio [OR]: 5.8, 95% CI: 2.4-13.1), general anesthesia without regional analgesia techniques (OR: 2.9, 95% CI: 1.4-5.8), open thoracotomy and subsequent resurgery (OR: 3.9, 95% CI 1.5-9.9), surgery outside the regular working hours (OR: 3.1, 95% CI 1.2-8.2), and postoperative sepsis (OR: 2.6, 95% CI 1.1-6.8) were identified as independent risk factors for PPCs. Postoperative pulmonary complications were independent factors for unplanned intensive care unit admission (OR: 10.5, 95% CI 2.1-51 for >1 PPC), death within 360 days (OR: 4.5, 95% CI 2.2-12.3 for ≥2 PPCs), and death within 30 days for ≥1 PPCs (OR: 1.2, 95% CI 1.1-1.3). CONCLUSIONS: The incidence of PPCs is a significant risk factor for morbidity and mortality after surgery for pleural empyema. Targeting the risk factors identified in this study could improve patient outcomes.

The Impact of Postoperative Pulmonary Complications on Perioperative Outcomes in Patients Undergoing Pneumonectomy: A Multicenter Retrospective Cohort Study of the German Thorax Registry.

Postoperative pulmonary complications have a deleterious impact in regards to thoracic surgery. Pneumonectomy is associated with the highest perioperative risk in elective thoracic surgery. The data from 152 patients undergoing pneumonectomy in this multicenter retrospective study were extracted from the German Thorax Registry database and presented after univariate and multivariate statistical processing. This retrospective study investigated the incidence of postoperative pulmonary complications (PPCs) and their impact on perioperative morbidity and mortality. Patient-specific, preoperative, procedural, and postoperative risk factors for PPCs and in-hospital mortality were analyzed. A total of 32 (21%) patients exhibited one or more PPCs, and 11 (7%) died during the hospital stay. Multivariate stepwise logistic regression identified a preoperative FEV1 < 50% (OR 9.1, 95% CI 1.9-67), the presence of medical complications (OR 7.4, 95% CI 2.7-16.2), and an ICU stay of more than 2 days (OR 14, 95% CI 3.9-59) as independent factors associated with PPCs. PPCs (OR 13, 95% CI 3.2-52), a preoperative FEV1 < 60% in patients with previous pulmonary infection (OR 21, 95% CI 3.2-52), and continued postoperative mechanical ventilation (OR 8.4, 95% CI 2-34) were independent factors for in-hospital mortality. Our data emphasizes that PPCs are a significant risk factor for morbidity and mortality after pneumonectomy. Intensified perioperative care targeting the underlying risk factors and effects of PPCs, postoperative ventilation, and preoperative respiratory infections, especially in patients with reduced pulmonary reserve, could improve patient outcomes.

Risk Factors for Postoperative Pulmonary Complications Leading to Increased In-Hospital Mortality in Patients Undergoing Thoracotomy for Primary Lung Cancer Resection: A Multicentre Retrospective Cohort Study of the German Thorax Registry.

Postoperative pulmonary complications (PPCs) represent the most frequent complications after lung surgery, and they increase postoperative mortality. This study investigated the incidence of PPCs, in-hospital mortality rate, and risk factors leading to PPCs in patients undergoing open thoracotomy lung resections (OTLRs) for primary lung cancer. The data from 1426 patients in this multicentre retrospective study were extracted from the German Thorax Registry and presented after univariate and multivariate statistical processing. A total of 472 patients showed at least one PPC. The presence of two PPCs was associated with a significantly increased mortality rate of 7% (p < 0.001) compared to that of patients without or with a single PPC. Three or more PPCs increased the mortality rate to 33% (p < 0.001). Multivariate stepwise logistic regression analysis revealed male gender (OR 1.4), age > 60 years (OR 1.8), and current or previous smoking (OR 1.6), while the pre-operative risk factors were still CRP levels > 3 mg/dl (OR 1.7) and FEV1 < 60% (OR 1.4). Procedural independent risk factors for PPCs were: duration of surgery exceeding 195 min (OR 1.6), the amount of intraoperative blood loss (OR 1.6), partial ligation of the pulmonary artery (OR 1.5), continuing invasive ventilation after surgery (OR 2.9), and infusion of intraoperative crystalloids exceeding 6 mL/kg/h (OR 1.9). The incidence of PPCs was significantly lower in patients with continuous epidural or paravertebral analgesia (OR 0.7). Optimising perioperative management by implementing continuous neuroaxial techniques and optimised fluid therapy may reduce the incidence of PPCs and associated mortality.

Inhalative as well as Intravenous Administration of H2S Provides Neuroprotection after Ischemia and Reperfusion Injury in the Rats' Retina.

BACKGROUND: Neuronal ischemia-reperfusion injury (IRI), such as it can occur in glaucoma or strokes, is associated with neuronal cell death and irreversible loss of function of the affected tissue. Hydrogen sulfide (H2S) is considered a potentially neuroprotective substance, but the most effective route of application and the underlying mechanism remain to be determined. METHODS: Ischemia-reperfusion injury was induced in rats by a temporary increase in intraocular pressure (1 h). H2S was then applied by inhalation (80 ppm at 0, 1.5, and 3 h after reperfusion) or by intravenous administration of the slow-releasing H2S donor GYY 4137. After 24 h, the retinas were harvested for Western blotting, qPCR, and immunohistochemical staining. Retinal ganglion cell survival was evaluated 7 days after ischemia. RESULTS: Both inhalative and intravenously delivered H2S reduced retinal ganglion cell death with a better result from inhalative application. H2S inhalation for 1.5 h, as well as GYY 4137 treatment, increased p38 phosphorylation. Both forms of application enhanced the extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, and inhalation showed a significant increase at all three time points. H2S treatment also reduced apoptotic and inflammatory markers, such as caspase-3, intracellular adhesion molecule 1 (ICAM-1), vascular endothelial growth factor (VEGF), and inducible nitric oxide synthase (iNOS). The protective effect of H2S was partly abolished by the ERK1/2 inhibitor PD98059. Inhalative H2S also reduced the heat shock response including heme oxygenase (HO-1) and heat shock protein 70 (HSP-70) and the expression of radical scavengers such as superoxide dismutases (SOD1, SOD2) and catalase. CONCLUSION: Hydrogen sulfide acts, at least in part, via the mitogen-activated protein kinase (MAPK) ERK1/2 to reduce apoptosis and inflammation. Both inhalative H2S and intravenous GYY 4137 administrations can improve neuronal cell survival.

Standardized Colon Ascendens Stent Peritonitis in Rats - a Simple, Feasible Animal Model to Induce Septic Acute Kidney Injury.

AKI in septic patients is associated with increased mortality and poor outcome despite major efforts to refine the understanding of its pathophysiology. Here, an in vivo model is presented that combines a standardized septic focus to induce AKI and an intensive care (ICU) setup to provide an advanced hemodynamic monitoring and therapy comparable in human sepsis. Sepsis is induced by standardized colon ascendens stent peritonitis (sCASP). AKI is investigated functionally by measurement of blood and urine samples as well as histologically by evaluation of histopathological scores. Furthermore, the advanced hemodynamic monitoring and the possibility of repetitive blood gas sampling enable a differentiated analysis of severity of induced sepsis. The sCASP method is a standardized, reliable and reproducible method to induce septic AKI. The intensive care setup, continuous hemodynamic and gas exchange monitoring, low mortality rate as well as the opportunity of detailed analyses of kidney function and impairments are advantages of this setup. Therefore, the described method may serve as a new standard for experimental investigations of septic AKI.

Diagnosing capillary leak in critically ill patients: development of an innovative scoring instrument for non-invasive detection.

BACKGROUND: The concomitant occurrence of the symptoms intravascular hypovolemia, peripheral edema and hemodynamic instability is typically named Capillary Leak Syndrome (CLS) and often occurs in surgical critical ill patients. However, neither a unitary definition nor standardized diagnostic criteria exist so far. We aimed to investigate common characteristics of this phenomenon with a subsequent scoring system, determining whether CLS contributes to mortality. METHODS: We conducted this single-center, observational, multidisciplinary, prospective trial in two separately run surgical ICUs of a tertiary academic medical center. 200 surgical patients admitted to the ICU and 30 healthy volunteers were included. Patients were clinically diagnosed as CLS or No-CLS group (each N = 100) according to the grade of edema, intravascular hypovolemia, hemodynamic instability, and positive fluid balance by two independent attending physicians with > 10 years of experience in ICU. We performed daily measurements with non-invasive body impedance electrical analysis, ultrasound and analysis of serum biomarkers to generate objective diagnostic criteria. Receiver operating characteristics were used, while we developed machine learning models to increase diagnostic specifications for our scoring model. RESULTS: The 30-day mortility was increased among CLS patients (12 vs. 1%, P = 0.002), while showing higher SOFA-scores. Extracellular water was increased in patients with CLS with higher echogenicity of subcutaneous tissue [29(24-31) vs. 19(16-21), P < 0.001]. Biomarkers showed characteristic alterations, especially with an increased angiopoietin-2 concentration in CLS [9.9(6.2-17.3) vs. 3.7(2.6-5.6)ng/mL, P < 0.001]. We developed a score using seven parameters (echogenicity, SOFA-score, angiopoietin-2, syndecan-1, ICAM-1, lactate and interleukin-6). A Random Forest prediction model boosted its diagnostic characteristics (AUC 0.963, P < 0.001), while a two-parameter decision tree model showed good specifications (AUC 0.865). CONCLUSIONS: Diagnosis of CLS in critically ill patients is feasible by objective, non-invasive parameters using the CLS-Score. A simplified two-parameter diagnostic approach can enhance clinical utility. CLS contributes to mortality and should, therefore, classified as an independent entity. TRIAL REGISTRATION: German Clinical Trials Registry (DRKS No. 00012713), Date of registration 10/05/2017, www.drks.de.

Hydrogen Sulfide Reduces Ischemia and Reperfusion Injury in Neuronal Cells in a Dose- and Time-Dependent Manner.

BACKGROUND: The ischemia-reperfusion injury (IRI) of neuronal tissue, such as the brain and retina, leads to possible cell death and loss of function. Current treatment options are limited, but preliminary observations suggest a protective effect of hydrogen sulfide (H2S). However, the dosage, timing, and mechanism of inhaled H2S treatment after IRI requires further exploration. METHODS: We investigated possible neuroprotective effects of inhaled H2S by inducing retinal ischemia-reperfusion injury in rats for the duration of 1 h (120 mmHg), followed by the administration of hydrogen sulfide (H2S) for 1 h at different time points (0, 1.5, and 3 h after the initiation of reperfusion) and at different H2S concentrations (120, 80, and 40 ppm). We quantified the H2S effect by conducting retinal ganglion cell counts in fluorogold-labeled animals 7 days after IRI. The retinal tissue was harvested after 24 h for molecular analysis, including qPCR and Western blotting. Apoptotic and inflammatory mediators, transcription factors, and markers for oxidative stress were investigated. Histological analyses of the retina and the detection of inflammatory cytokines in serum assays were also performed. RESULTS: The effects of inhaled H2S were most evident at a concentration of 80 ppm administered 1.5 h after IRI. H2S treatment increased the expression of anti-apoptotic Bcl-2, decreased pro-apoptotic Bax expression, reduced the release of the inflammatory cytokines IL-1ß and TNF-α, attenuated NF-κB p65, and enhanced Akt phosphorylation. H2S also downregulated NOX4 and cystathionine ß-synthase. Histological analyses illustrated a reduction in TNF-α in retinal ganglion cells and lower serum levels of TNF-α in H2S-treated animals after IRI. CONCLUSION: After neuronal IRI, H2S mediates neuroprotection in a time- and dose-dependent manner. The H2S treatment modulated transcription factor NF-κB activation and reduced retinal inflammation.

Incidence of gastric insufflation at high compared with low laryngeal mask cuff pressure: A randomised controlled cross-over trial.

BACKGROUND: The success of ventilation with a laryngeal mask depends crucially on the seal between the mask and the periglottic tissue. Increasing the laryngeal mask's cuff volume is known to reduce oral air leakage but may lead to gastric insufflation. OBJECTIVE: We hypothesised that a lower cuff pressure would result in less gastric insufflation. We sought to compare gastric insufflation with laryngeal mask cuff pressures of 20 cmH2O (CP20) and 60 cmH2O (CP60) during increasing peak airway pressures in a randomised controlled double-blind cross-over study. We also evaluated the incidence of gastric insufflation at the recommended peak airway pressure of 20 cmH2O or less and during both intermittent positive airway pressure and continuous positive airway pressure. METHODS: After obtaining ethics approval and written informed consent, 184 patients ventilated via laryngeal mask received a stepwise increase in peak airway pressure from 15 to 30 cmH2O with CP20 and CP60 in turn. Gastric insufflation was determined via real-time ultrasound and measurement of the cross-sectional area of the gastric antrum. The primary endpoint was the incidence of gastric insufflation at the different laryngeal mask cuff pressures. RESULTS: Data from 164 patients were analysed. Gastric insufflation occurred less frequently at CP20 compared with CP60 (P < 0.0001). Gastric insufflation was detected in 35% of cases with CP20 and in 48% with CP60 at a peak airway pressure of 20 cmH2O or less. Gastric insufflation occurred more often during continuous than during intermittent positive airway pressures (P < 0.01). CONCLUSION: A laryngeal mask cuff pressure of 20 cmH2O may reduce the risk of gastric insufflation during mechanical ventilation. Surprisingly, peak airway pressure of 20 cmH2O or less may already induce significant gastric insufflation. Continuous positive airway pressure should be avoided due to an increased risk of gastric insufflation. CLINICAL TRIAL REGISTRATION: The study was registered in the German Clinical Trials Register (DRKS00010583) https://www.drks.de.

Early Postoperative Use of Diuretics After Kidney Transplantation Showed Increase in Delayed Graft Function.

PURPOSE: In acute renal injury, diuretics are widely considered to be harmful. Nevertheless, they are used frequently after kidney transplantation. We hypothesized that diuretics administered in the early postoperative treatment after kidney transplantation increase the incidence of delayed graft function (DGF). METHODS: In this monocentric, retrospective cohort analysis, we screened the closed files of all consecutive patients who underwent kidney transplantation from 2011 to 2017. The outcome variable was DGF, defined as at least 1 hemodialysis within 7 days postoperatively. To stratify for baseline characteristics such as waiting time or cold ischemic period, we employed a propensity score-matched analysis. Further statistical processing included basic descriptive statistics, Mann-Whitney U test, and binary logistic regression analysis. RESULTS: The unmatched cohort included 445 patients and showed a significantly increased rate of DGF for patients who received either furosemide or mannitol or a combination of both (5% vs 25%; P < .001). Mannitol (odds ratio [OR]: 4.094) and furosemide (OR: 2.915) showed a significant correlation with DGF in the multivariate regression analysis. Propensity score-based matching resulted in a matched cohort of 214 patients with balanced baseline risk variables. In this matched cohort, the rate of DGF was significantly increased in patients who received diuretics in the early postoperative treatment (7% vs 16%; P = .031). CONCLUSION: Our results show that postoperatively administered diuretics are associated with an increased rate of DGF even in a cohort with balanced preoperative risk variables. This study supports recently published reviews, which call diuretics in the transplantation process into question.

Epidural analgesia and avoidance of blood transfusion are associated with reduced mortality in patients with postoperative pulmonary complications following thoracotomic esophagectomy: a retrospective cohort study of 335 patients.

BACKGROUND: Postoperative pulmonary complications (PPCs) represent the most frequent complications after esophagectomy. The aim of this study was to identify modifiable risk factors for PPCs and 90-days mortality related to PPCs after esophagectomy in esophageal cancer patients. METHODS: This is a single center retrospective cohort study of 335 patients suffering from esophageal cancer who underwent esophagectomy between 1996 and 2014 at a university hospital center. Statistical processing was conducted using univariate and multivariate stepwise logistic regression analysis of patient-specific and procedural risk factors for PPCs and mortality. RESULTS: The incidence of PPCs was 52% (175/335) and the 90-days mortality rate of patients with PPCs was 8% (26/335) in this study cohort. The univariate and multivariate analysis revealed the following independent risk factors for PPCs and its associated mortality. ASA score ≥ 3 was the only independent patient-specific risk factor for the incidence of PPCs and 90-days mortality of patients with an odds ratio for PPCs being 1.7 (1.1-2.6 95% CI) and an odds ratio of 2.6 (1.1-6.2 95% CI) for 90-days mortality. The multivariate approach depicted two independent procedural risk factors including transfusion of packed red blood cells (PRBCs) odds ratio of 1.9 (1.2-3 95% CI) for PPCs and an odds ratio of 5.0 (2.0-12.6 95% CI) for 90-days mortality; absence of thoracic epidural anesthesia (TEA) revealed the highest odds ratio 2.0 (1.01-3.8 95% CI) for PPCs and an odds ratio of 3.9 (1.6-9.7 95% CI) for 90-days mortality. CONCLUSION: In esophageal cancer patients undergoing esophagectomy via thoracotomy, epidural analgesia and the avoidance of intraoperative blood transfusion are significantly associated with a reduced 90-days mortality related to PPCs.

Modifiable Risk Factors for Delayed Graft Function After Deceased Donor Kidney Transplantation.

PURPOSE: Delayed graft function is a major complication after kidney transplantation affecting patients' long-term outcome. The aim of this study was to identify modifiable risk factors for delayed graft function after deceased donor kidney transplantation. METHODS: This is a single-center retrospective cohort study of a university transplantation center. Univariate and multivariate step-wise logistic regression analysis of patient-specific and procedural risk factors were conducted. RESULTS: We analyzed 380 deceased donor kidney transplantation patients between October 30, 2008 and December 30, 2017. The incidence of delayed graft function was 15% (58/380). Among the patient-specific risk factors recipient diabetes (2.8 [1.4-5.9] odds ratio [OR] [95% confidence interval [CI]]), American Society of Anesthesiologist score of 4 (2.7 [1.2-6.5] OR [95% CI]), cold ischemic time >13 hours (2.8 [1.5-5.3] OR [95% CI]) and donor age >55 years (1.9 [1.01-3.6] OR [95% CI]) revealed significance. The significant intraoperative, procedural risk factors included the use of colloids (3.9 [1.4-11.3] OR [95% CI]), albumin (3.0 [1.2-7.5] OR [95% CI]), crystalloids >3000 mL (3.1 [1.2-7.5] OR [95% CI]) and mean arterial pressure <80 mm Hg at the time of reperfusion (2.4 [1.2-4.8] OR [95% CI]). CONCLUSION: Patients undergoing deceased donor kidney transplantation with a mean arterial pressure >80 mm Hg at the time of transplant reperfusion without requiring excessive fluid therapy in terms of colloids, albumin or crystalloids >3000 mL are less likely to develop delayed graft function.

Lower rate of delayed graft function is observed when epidural analgesia for living donor nephrectomy is administered.

BACKGROUND: The beneficial effects of epidural analgesia (EDA) in terms of pain control and postoperative convalescence are widely known and led to a frequent use for patients who underwent living donor kidney nephrectomy. The objective of this study was to determine whether general anesthesia (GA) plus EDA compared to GA only, administered for living donor nephrectomy has effects on postoperative graft function in recipients. METHODS: In this monocentric, retrospective cohort analysis we analyzed the closed files of all consecutive donor- recipient pairs who underwent living donor kidney transplantations from 2008 to 2017. The outcome variable was delayed graft function (DGF), defined as at least one hemodialysis within seven days postoperatively, once hyperacute rejection, vascular or urinary tract complications were ruled out. Statistical analyses of continuous variables were calculated using the two-tail Student's t test and Fisher exact test for categorical variables with a significance level of p < 0.05, respectively. RESULTS: The study enclosed 291 consecutive living donor kidney transplantations. 99 kidney donors received epidural analgesia whereas 192 had no epidural analgesia. The groups showed balanced pretransplantational characteristics and comparable donors´ and recipients' risk factors. 9 out of all 291 recipients needed renal replacement therapy (RRT) during the first 7 days due to delayed graft function; none of these donors received EDA. The observed rate of DGF in recipients whose kidney donors received epidural analgesia was significantly lower (0% vs. 4.6%; p = 0.031). CONCLUSIONS: In our cohort we observed a significantly lower rate of DGF when epidural analgesia for donor nephrectomy was administered. Due to restrictions of the study design this observation needs further confirmation by prospective studies.

Evaluation of hemodynamic goal-directed therapy to reduce the incidence of bone cement implantation syndrome in patients undergoing cemented hip arthroplasty - a randomized parallel-arm trial.

BACKGROUND: The bone cement implantation syndrome (BCIS) is a frequent and potentially disastrous intraoperative complication in patients undergoing cemented hip arthroplasty. Several risk factors have been identified, however randomized controlled trials to reduce the incidence of BCIS are still pending. We hypothesized that goal-directed hemodynamic therapy guided by esophageal Doppler monitoring (EDM) may reduce the incidence of BCIS in a randomized, controlled parallel-arm trial. METHODS: After approval of the local ethics committee, 90 patients scheduled for cemented hip arthroplasty at the Medical Center - University of Freiburg were randomly assigned to either standard hemodynamic management or goal-directed therapy (GDT) guided by an esophageal Doppler monitoring-based algorithm. The primary endpoint was the incidence of overall BCIS including grade 1-3 after cementation of the femoral stem. Secondary endpoints included cardiac function, length of hospital stay and postoperative complications. RESULTS: Ninety patients were finally analyzed. With regards to the primary endpoint, the overall incidence of BCIS showed no difference between the GDT and control group. Compared to the control group, patients of the GDT group showed a higher cardiac index before and after bone cement implantation (2.7 vs. 2.2 [l●min- 1●m- 2]; 2.8 vs. 2.4 [l●min- 1●m- 2]; P = 0.003, P = 0.042), whereas intraoperative amount of fluids and mean arterial pressure did not differ. CONCLUSIONS: The implementation of a specific hemodynamic goal-directed therapy did not reduce the overall incidence of BCIS in patients undergoing cemented hip arthroplasty. TRIAL REGISTRATION: This randomized clinical two-arm parallel study was approved by the local Ethics Committee, Freiburg, Germany [EK 160/15, PI: U. Goebel] and registered in the German Clinical Trials Register ( DRKS No. 00008778 , 16th of June, 2015).

Balanced Hydroxyethylstarch (HES 130/0.4) Impairs Kidney Function In-Vivo without Inflammation.

Volume therapy is a standard procedure in daily perioperative care, and there is an ongoing discussion about the benefits of colloid resuscitation with hydroxyethylstarch (HES). In sepsis HES should be avoided due to a higher risk for acute kidney injury (AKI). Results of the usage of HES in patients without sepsis are controversial. Therefore we conducted an animal study to evaluate the impact of 6% HES 130/0.4 on kidney integrity with sepsis or under healthy conditions Sepsis was induced by standardized Colon Ascendens Stent Peritonitis (sCASP). sCASP-group as well as control group (C) remained untreated for 24 h. After 18 h sCASP+HES group (sCASP+VOL) and control+HES (C+VOL) received 50 ml/KG balanced 6% HES (VOL) 130/0.4 over 6 h. After 24 h kidney function was measured via Inulin- and PAH-Clearance in re-anesthetized rats, and serum urea, creatinine (crea), cystatin C and Neutrophil gelatinase-associated lipocalin (NGAL) as well as histopathology were analysed. In vitro human proximal tubule cells (PTC) were cultured +/- lipopolysaccharid (LPS) and with 0.1-4.0% VOL. Cell viability was measured with XTT-, cell toxicity with LDH-test. sCASP induced severe septic AKI demonstrated divergent results regarding renal function by clearance or creatinine measure focusing on VOL. Soleley HES (C+VOL) deteriorated renal function without sCASP. Histopathology revealed significantly derangements in all HES groups compared to control. In vitro LPS did not worsen the HES induced reduction of cell viability in PTC cells. For the first time, we demonstrated, that application of 50 ml/KG 6% HES 130/0.4 over 6 hours induced AKI without inflammation in vivo. Severity of sCASP induced septic AKI might be no longer susceptible to the way of volume expansion.

Phosphodiesterase-4 inhibition with rolipram attenuates hepatocellular injury in hyperinflammation in vivo and in vitro without influencing inflammation and HO-1 expression.

OBJECTIVE: To investigate the impact of the phophodiesterase-4 inhibition (PD-4-I) with rolipram on hepatic integrity in lipopolysaccharide (LPS) induced hyperinflammation. MATERIALS AND METHODS: Liver microcirculation in rats was obtained using intravital microscopy. Macrohemodynamic parameters, blood assays, and organs were harvested to determine organ function and injury. Hyperinflammation was induced by LPS and PD-4-I rolipram was administered intravenously one hour after LPS application. Cell viability of HepG2 cells was measured by EZ4U-kit based on the dye XTT. Experiments were carried out assessing the influence of different concentrations of tumor necrosis factor alpha (TNF-α) and LPS with or without PD-4-I. RESULTS: Untreated LPS-induced rats showed significantly decreased liver microcirculation and increased hepatic cell death, whereas LPS + PD-4-I treatment could improve hepatic volumetric flow and cell death to control level whithout influencing the inflammatory impact. In HepG2 cells TNF-α and LPS significantly reduced cell viability. Coincubation with PD-4-I increased HepG2 viability to control levels. The heme oxygenase 1 (HO-1) pathway did not induce the protective effect of PD-4-I. CONCLUSION: Intravenous PD-4-I treatment was effective in improving hepatic microcirculation and hepatic integrity, while it had a direct protective effect on HepG2 viability during inflammation.

Phosphodiesterase 4 inhibition dose dependently stabilizes microvascular barrier functions and microcirculation in a rodent model of polymicrobial sepsis.

BACKGROUND: Breakdown of microvascular endothelial barrier functions contributes to disturbed microcirculation, organ failure, and death in sepsis. Increased endothelial cAMP levels by systemic application of phosphodiesterase 4 inhibitors (PD-4-I) have previously been demonstrated to protect microvascular barrier properties in a model of systemic inflammation (systemic inflammatory response syndrome) suggesting a novel therapeutic option to overcome this problem. However, in a clinically relevant model of polymicrobial sepsis long-term effects, immunomodulatory effects and effectivity of PD-4-I to stabilize microvascular barrier functions and microcirculation remained unexplored. METHODS: We induced polymicrobial sepsis using the colon ascendens stent peritonitis (CASP) model in which we performed macrohemodynamic and microhemodynamic monitoring with and without systemic intravenous application of different doses of PD-4-I rolipram in Sprague-Dawley rats over 26 h. RESULTS: All animals with CASP showed clinical and laboratory signs of sepsis and peritonitis. Whereas macrohemodynamic adverse effects were not evident, application of PD-4-I led to stabilization of endothelial barrier properties as revealed by reduced extravasation of fluorescein isothiocyanate-albumin. However, only low-dose application of 1 mg/kg body weight per hour of PD-4-I improved microcirculatory flow in the CASP model, whereas high-dose therapy of 3 mg/kg BW per hour PDI-4-I had adverse effects. Accordingly, sepsis-induced acute kidney injury and lung edema were prevented by PD-4-I treatment. Furthermore, PD-4-I showed immunomodulatory effects as revealed by decreased interleukin 1α (IL-1α), IL-1ß, IL-12, and tumor necrosis factor α levels following PD-4-I treatment, which appeared not to correlate with barrier-stabilizing effects of rolipram. CONCLUSIONS: These data provide further evidence that systemic application of PD-4-I could be suitable for therapeutic microvascular barrier stabilization and improvement of microcirculatory flow in sepsis.

Sepsis-induced acute kidney injury by standardized colon ascendens stent peritonitis in rats - a simple, reproducible animal model.

BACKGROUND: Up to 50% of septic patients develop acute kidney injury (AKI). The pathomechanism of septic AKI is poorly understood. Therefore, we established an innovative rodent model to characterize sepsis-induced AKI by standardized colon ascendens stent peritonitis (sCASP). The model has a standardized focus of infection, an intensive care set up with monitoring of haemodynamics and oxygenation resulting in predictable impairment of renal function, AKI parameters as well as histopathology scoring. METHODS: Anaesthetized rats underwent the sCASP procedure, whereas sham animals were sham operated and control animals were just monitored invasively. Haemodynamic variables and blood gases were continuously measured. After 24 h, animals were reanesthetized; cardiac output (CO), inulin and PAH clearances were measured and later on kidneys were harvested; and creatinine, urea, cystatin C and neutrophil gelatinase-associated lipocalin (NGAL) were analysed. Additional sCASP-treated animals were investigated after 3 and 9 days. RESULTS: All sCASP-treated animals survived, whilst ubiquitous peritonitis and significantly deteriorated clinical and macrohaemodynamic sepsis signs after 24 h (MAP, CO, heart rate) were obvious. Blood analyses showed increased lactate and IL-6 levels as well as leucopenia. Urine output, inulin and PAH clearance were significantly decreased in sCASP compared to sham and control. Additionally, significant increase in cystatin C and NGAL was detected. Standard parameters like serum creatinine and urea were elevated and sCASP-induced sepsis increased significantly in a time-dependent manner. The renal histopathological score of sCASP-treated animals deteriorated after 3 and 9 days. CONCLUSIONS: The presented sCASP method is a standardized, reliable and reproducible method to induce septic AKI. The intensive care set up, continuous macrohaemodynamic and gas exchange monitoring, low mortality rate as well as the opportunity of detailed analyses of kidney function and impairments are advantages of this setup. Thus, our described method may serve as a new standard for experimental investigations of septic AKI.

Superimposed linear lichen planopilaris: another polygenic disorder exemplifying a new genetic concept.

In a few cases, polygenic skin diseases show a segmental arrangement of the lesions and at the same time a milder non segmental involvement. This phenomenon has been described as superimposed segmental manifestation. Here, we report a patient who had developed itching papules on the right side of the trunk and neck together with a scarring alopecia of the scalp. Additionally, the patient showed perifollicular papules on the abdomen leading to truncal alopecia. The histopathological analyses of skin biopsies taken from the scalp and abdomen revealed a lichen planopilaris. Interestingly, the involvement of the scalp and the chest followed the lines of Blaschko, whereas the abdominal skin lesions did not show a segmental distribution, so that a superimposed lichen planopilaris could be diagnosed. This is to our knowledge the first described case of a superimposed lichen planopilaris.