Johannes Zimmermann

Meta‐analysis of standard, restrictive and supplemental fluid administration in colorectal surgery

Optimal fluid therapy for colorectal surgery remains uncertain.

Infrahepatic inferior vena cava clamping for reduction of central venous pressure and blood loss during hepatic resection: a randomized controlled trial.

Objective:To evaluate the effectiveness and safety of infrahepatic inferior vena cava (IVC) clamping for reduction of central venous pressure (CVP) and blood loss during hepatic resection. Background:Low CVP during parenchymal transection has been widely accepted to reduce intraoperative hemorrhage via the hepatic veins and is commonly achieved by anesthesiological interventions such as fluid restriction. We hypothesized that infrahepatic clamping of the IVC may lower the intraoperative blood loss more effectively and, moreover, prevent potential adverse effects of fluid restriction such as hemodynamic instability. Methods:Patients scheduled for elective hepatic resection were enrolled and allocated randomly to CVP reduction by infrahepatic IVC clamping or anesthesiological interventions including primarily fluid restriction with additional use of diuretics, nitro compounds, and opioids (control group). The primary efficacy endpoint was total intraoperative blood loss. Analyses were done following intention-to-treat principles. The protocol was submitted to the clinicaltrials.gov registry (NCT00732979). Results:From April 2007 to December 2009, a total of 152 patients were randomized and 128 were eligible for final analyses. Baseline data were similar between both study groups. Despite higher CVP values during resection (4.0 ± 3.2 vs. 2.6 ± 1.8 mm Hg; P = 0.003), infrahepatic IVC clamping significantly reduced total intraoperative blood loss [550 (350.0–1150) mL vs. 900 (500–1500) mL; P = 0.02] and blood loss during parenchymal transection [150 (85–500) mL vs. 400 (200–700) mL; P = 0.006] compared with the control group. Postoperative mortality [4 (6.1%) vs. 2 (3.2%); P = 0.42] and total morbidity rates [38 (58.5%) vs. 37 (58.7%); P = 0.97] were comparable between both study groups. Although intraoperative hemodynamic instability occurred less frequently in patients with infrahepatic IVC clamping [0 vs. 4 (6.3%); P = 0.04], the incidence of pulmonary embolism was increased in this study arm [4 (6.1%) vs. 0; P = 0.04]. Conclusions:Infrahepatic IVC clamping is associated with significantly less intraoperative blood loss and may reduce the incidence of intraoperative hemodynamic instability. The potential association with postoperative pulmonary embolism represents a significant concern.

Soluble TREM-1 is not suitable for distinguishing between systemic inflammatory response syndrome and sepsis survivors and nonsurvivors in the early stage of acute inflammation.

Background and objective To evaluate plasma levels of soluble TREM-1 (sTREM-1) in patients with systemic inflammatory response syndrome (SIRS), severe sepsis, and septic shock and to determine whether plasma sTREM-1 could be used as a diagnostic and prognostic marker in sepsis in the surgical ICU. Methods The study was designed as an observational noninterventional clinical study in a surgical ICU of a university hospital. For this, 65 intensive care patients were enrolled within the first 24 h after onset of SIRS (n = 11), severe sepsis (n = 39) or septic shock (n = 15). In addition, 21 healthy volunteers served as controls. At days 0, 1, and 3 after diagnosis, plasma sTREM-1 was measured by ELISA. Results Plasma sTREM-1 concentrations in healthy controls did not significantly differ from those in patients with SIRS, severe sepsis, or septic shock at days 0, 1, and 3. Survivors were defined as septic patients surviving for at least 28 days. There were no differences in plasma sTREM-1 levels between survivors (n = 22) and nonsurvivors (n = 27) on any day. Conclusions In this study in patients with SIRS, severe sepsis, or septic shock, plasma sTREM-1 levels were not elevated as compared with healthy controls. Measurement of plasma sTREM-1 did not distinguish between patients with SIRS, severe sepsis, or septic shock or between survivors and nonsurvivors. The suggested role of sTREM-1 as a diagnostic and prognostic marker in sepsis should be carefully verified.

Thioredoxin in human and experimental sepsis

Introduction: Thioredoxin (TRX) is assumed to be beneficial in acute inflammatory diseases because of its potent antioxidant properties and an inhibitory effect on neutrophil evasion into sites of inflammation. Objective: To compare plasma levels of thioredoxin in septic patients and to investigate the role of thioredoxin in a polymicrobial septic mouse model. Design and Interventions: A combined single-center noninterventional clinical observation study and randomized controlled experimental investigation. Setting: Intensive care unit of a university hospital and laboratories of four university hospitals. Measurements and Main Results: To evaluate the role of TRX in sepsis, we measured TRX in plasma of septic patients and compared its levels in survivors and patients who did not survive sepsis. In addition, we examined the effect of neutralization of endogenous TRX as well as of treatment with recombinant TRX in a mouse peritonitis model of cecal ligation and puncture (CLP). We found that the serum plasma levels of TRX were significantly higher in patients with sepsis compared with healthy individuals. Furthermore, nonsurvivors showed even higher TRX levels than survivors of sepsis. The CLP septic mouse model revealed that neutralization of endogenous TRX impaired survival of septic mice, whereas treatment with recombinant TRX after CLP strongly enhanced the survival of mice. Conclusions: Our results therefore demonstrate a critical role for TRX in the septic inflammatory response and suggest TRX as a potential therapeutic target for septic shock.

IVC CLAMP: infrahepatic inferior vena cava clamping during hepatectomy - a randomised controlled trial in an interdisciplinary setting

BackgroundIntraoperative haemorrhage is a known predictor for perioperative outcome of patients undergoing hepatic resection. While anaesthesiological lowering of central venous pressure (CVP) by fluid restriction is known to reduce bleeding during transection of the hepatic parenchyma its potential side effects remain poorly investigated. In theory it may have negative effects on kidney function and tissue perfusion and bears the risk to result in severe haemodynamic instability in case of profound intraoperative blood loss. The present randomised controlled trial evaluates efficacy and safety of infrahepatic inferior vena cava (IVC) clamping as an alternative surgical technique to reduce CVP during hepatic resection.Methods/DesignThe proposed IVC CLAMP trial is a single-centre randomised controlled trial with a two-group parallel design. Patients and outcome-assessors are blinded for the treatment intervention. Patients undergoing elective hepatic resection due to any reason are enrolled in IVC CLAMP. All patients admitted to the Department of General-, Visceral-, and Transplant Surgery, University of Heidelberg for elective hepatic resection are consecutively screened for eligibility and written informed consent is obtained on the day before surgery. The primary objective of this trial is to assess and compare the amount of blood loss during hepatic resection in patients receiving surgical CVP reduction by clamping of the IVC as compared to anaesthesiological CVP without infrahepatic IVC clamping reduction. In addition to blood loss a set of general as well as surgical variables are analysed.DiscussionThis is a randomised controlled patient and observer blinded two-group parallel trial designed to assess efficacy and safety of infrahepatic IVC clamping during elective hepatectomy.Trial registrationClinicalTrials NCT00732979

Biodegradable Polycaprolactone as Ion Solvating Polymer for Solution-Processed Light-Emitting Electrochemical Cells.

In this work, we demonstrate the use of the biodegradable polymer polycaprolactone (PCL) as the ion solvating polymer in solution-processed light-emitting electrochemical cells (LEC). We show that the inclusion of PCL in the active layer yields higher ionic conductivities and thus contributes to a rapid formation of the dynamic p-i-n junction and reduction of operating voltages. PCL shows no phase separation with the emitter polymer and reduces film roughness. The devices show light-emission at voltages as low as 3.2 V and lifetimes on the order of 30 h operating above 150 cd m−2 with turn-on times <20 s and current and luminous efficacies of 3.2 Cd A−1 and 1.5 lm W−1 respectively.

Patients Suffering Due to Complicated Peritonitis May Not Benefit from Splenectomy: Clinical Data from a Retrospective Study

BACKGROUND In this retrospective observational study, we investigated the impact of prior splenectomy on the outcome of patients with complicated peritonitis. MATERIALS AND METHODS Of the 284 subjects with severe sepsis or septic shock due to intra-abdominal infection, 27 (9.5%) had undergone splenectomy before the development of that infection and 257 (90.5%) had not undergone splenectomy. The intra-abdominal source of infection was surgically confirmed (index operation). RESULTS The group of patients having undergone splenectomy and that of patients not having undergone the procedure were well balanced in age, gender concomitant disease, as well as medication (prior chemotherapy). Twenty-eight-day estimated mortality did not differ between groups (33.3 versus 25.7%; P = 0.39). Ninety-day estimated mortality did not differ either (57.2 versus 49.7%; P = 0.92). Overall survival was equal between the two groups. More patients having undergone splenectomy required dialysis for renal failure (74.0 versus 44.7%; P < 0.01). A Cox regression analysis left age, sepsis-related organ failure assessment (SOFA) score immediately following index-surgery, and need for administration of norepinephrine exceeding 0.1 μg/kg body weight/min as potential predictors of fatal outcome. CONCLUSIONS Our results did not support those of earlier reports suggesting that splenectomy protects against polymicrobial sepsis or septic shock. Regarding most effectiveness criteria (28- and 90-d estimated mortality, duration of mechanical ventilation, length of stay in ICU and in hospital), patients having undergone splenectomy fared as well as did those who had not undergone that procedure; regarding some (need for renal replacement), they fared worse. The effect of splenectomy is not large enough to be proven or ruled out with a limited number of cases.

Revival of physostigmine – a novel HPLC assay for simultaneous determination of physostigmine and its metabolite eseroline designed for a pharmacokinetic study of septic patients

Abstract Background: Physostigmine, commonly used as an antidote in anticholinergic poisoning, is reported to have additional pharmacological effects, such as activation of the cholinergic anti-inflammatory pathway in sepsis models. Due to the narrow therapeutic range of physostigmine and its metabolite eseroline, however, the plasma concentrations of these substances need to be determined so as to understand their effect and ensure safety in the treatment of septic patients. Methods: To determine physostigmine and its metabolite eseroline, a rapid and sensitive high performance liquid chromatography (HPLC) method has been developed and validated. Spiked plasma samples were cleaned up and concentrated using a simple liquid-liquid extraction (LLE) procedure with N-methylphysostigmine as internal standard. Separation was achieved using reversed-phase HPLC on a Kinetex C18 column with gradient elution and fluorescence detection (254 nm excitation/355 nm emission). Results: LLE produced clean extracts and a mean recovery of 80.3% for eseroline and 84.9% for physostigmine. The HPLC assay revealed a limit of detection (LOD) of 0.025 ng/mL and a lower limit of quantification (LLOQ) of 0.05 ng/mL for both analytes. Linearity was observed at 0.05–10.0 ng/mL (r2>0.999). Intra- and inter-day precision ranged from 0.7% to 6.6%, and intra- and inter-day accuracy 97.5%–110.0%. Conclusions: The presented method is useful for human drug level monitoring of physostigmine and eseroline in accordance with current guidelines. Remarkably low plasma concentrations can be quantified after LLE with gradient elution and fluorescence detection, making this a suitable method for pharmacokinetic studies in a clinical setting.

Tissue Phenomics for prognostic biomarker discovery in low- and intermediate-risk prostate cancer

Tissue Phenomics is the discipline of mining tissue images to identify patterns that are related to clinical outcome providing potential prognostic and predictive value. This involves the discovery process from assay development, image analysis, and data mining to the final interpretation and validation of the findings. Importantly, this process is not linear but allows backward steps and optimization loops over multiple sub-processes. We provide a detailed description of the Tissue Phenomics methodology while exemplifying each step on the application of prostate cancer recurrence prediction. In particular, we automatically identified tissue-based biomarkers having significant prognostic value for low- and intermediate-risk prostate cancer patients (Gleason scores 6–7b) after radical prostatectomy. We found that promising phenes were related to CD8(+) and CD68(+) cells in the microenvironment of cancerous glands in combination with the local micro-vascularization. Recurrence prediction based on the selected phenes yielded accuracies up to 83% thereby clearly outperforming prediction based on the Gleason score. Moreover, we compared different machine learning algorithms to combine the most relevant phenes resulting in increased accuracies of 88% for tumor progression prediction. These findings will be of potential use for future prognostic tests for prostate cancer patients and provide a proof-of-principle of the Tissue Phenomics approach.