Continuous infusion of physostigmine in patients with perioperative septic shock: A pharmacokinetic/pharmacodynamic study with population pharmacokinetic modeling

Background In the context of the cholinergic anti-inflammatory pathway, the clinical trial Anticholium® per Se (EudraCT Number: 2012-001650-26, ClinicalTrials.gov NCT03013322) addressed the possibility of taking adjunctive physostigmine salicylate treatment in septic shock from bench to bedside. Pharmacokinetics (PK) are likely altered in critically ill patients; data on physostigmine PK and target concentrations are sparse, particularly for continuous infusion. Our objective was to build a population PK (popPK) model for physostigmine, and further evaluate pharmacodynamics (PD) and concentration-response relationship in this setting. Methods In the randomized, double-blind, placebo-controlled trial, 20 patients with perioperative septic shock either received an initial dose of 0.04 mg/kg physostigmine salicylate, followed by continuous infusion of 1 mg/h for up to 120 h, or equivalent volumes of 0.9% sodium chloride (placebo group). Physostigmine plasma concentrations and acetylcholinesterase (AChE) activity were measured; concentration-response associations were evaluated, and popPK and PD modeling was performed with NONMEM. Results Steady state physostigmine plasma concentrations reached 7.60 ± 2.81 ng/mL (mean ± standard deviation [SD]). PK was best described by a two-compartment model with linear clearance. Significant covariate effects were detected for body weight and age on clearance, as well as a high inter-individual variability of the central volume of distribution. AChE activity was significantly reduced to 30.5%–50.6% of baseline activity during physostigmine salicylate infusion. A sigmoidal direct effect PD model best described enzyme inhibition by physostigmine, with an estimated half maximal effective concentration (EC50) of 5.99 ng/mL. Conclusions PK of physostigmine in patients with septic shock displayed substantial inter-individual variability with body weight and age influencing the clearance. Physostigmine inhibited AChE activity with a sigmoidal concentration-response effect

Helical Nanographenes Containing an Azulene Unit : Synthesis, Crystal Structures, and Properties

Three unprecedented helical nanographenes (1, 2, and 3) containing an azulene unit are synthesized. The resultant helical structures are unambiguously confirmed by X-ray crystallographic analysis. The embedded azulene unit in 2 possesses a record-high twisting degree (16.1°) as a result of the contiguous steric repulsion at the helical inner rim. Structural analysis in combination with theoretical calculations reveals that these helical nanographenes manifest a global aromatic structure, while the inner azulene unit exhibits weak antiaromatic character. Furthermore, UV/Vis-spectral measurements reveal that superhelicenes 2 and 3 possess narrow energy gaps (2: 1.88 eV; 3: 2.03 eV), as corroborated by cyclic voltammetry and supported by density functional theory (DFT) calculations. The stable oxidized and reduced states of 2 and 3 are characterized by in-situ EPR/Vis–NIR spectroelectrochemistry. Our study provides a novel synthetic strategy for helical nanographenes containing azulene units as well as their associated structures and physical properties. © 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA

Two years later: Is the SARS-CoV-2 pandemic still having an impact on emergency surgery? An international cross-sectional survey among WSES members

BACKGROUND: The SARS-CoV-2 pandemic is still ongoing and a major challenge for health care services worldwide. In the first WSES COVID-19 emergency surgery survey, a strong negative impact on emergency surgery (ES) had been described already early in the pandemic situation. However, the knowledge is limited about current effects of the pandemic on patient flow through emergency rooms, daily routine and decision making in ES as well as their changes over time during the last two pandemic years. This second WSES COVID-19 emergency surgery survey investigates the impact of the SARS-CoV-2 pandemic on ES during the course of the pandemic. METHODS: A web survey had been distributed to medical specialists in ES during a four-week period from January 2022, investigating the impact of the pandemic on patients and septic diseases both requiring ES, structural problems due to the pandemic and time-to-intervention in ES routine. RESULTS: 367 collaborators from 59 countries responded to the survey. The majority indicated that the pandemic still significantly impacts on treatment and outcome of surgical emergency patients (83.1% and 78.5%, respectively). As reasons, the collaborators reported decreased case load in ES (44.7%), but patients presenting with more prolonged and severe diseases, especially concerning perforated appendicitis (62.1%) and diverticulitis (57.5%). Otherwise, approximately 50% of the participants still observe a delay in time-to-intervention in ES compared with the situation before the pandemic. Relevant causes leading to enlarged time-to-intervention in ES during the pandemic are persistent problems with in-hospital logistics, lacks in medical staff as well as operating room and intensive care capacities during the pandemic. This leads not only to the need for triage or transferring of ES patients to other hospitals, reported by 64.0% and 48.8% of the collaborators, respectively, but also to paradigm shifts in treatment modalities to non-operative approaches reported by 67.3% of the participants, especially in uncomplicated appendicitis, cholecystitis and multiple-recurrent diverticulitis. CONCLUSIONS: The SARS-CoV-2 pandemic still significantly impacts on care and outcome of patients in ES. Well-known problems with in-hospital logistics are not sufficiently resolved by now; however, medical staff shortages and reduced capacities have been dramatically aggravated over last two pandemic years

Alterations in plasma soluble vascular endothelial growth factor receptor-1 (sFlt-1) concentrations during coronary artery bypass graft surgery: relationships with post-operative complications

<p>Abstract</p> <p>Background</p> <p>Plasma concentrations of sFlt-1, the soluble form of the vascular endothelial growth factor receptor (VEGF), markedly increase during coronary artery bypass graft (CABG) surgery with extracorporeal circulation (ECC). We investigated if plasma sFlt-1 values might be related to the occurrence of surgical complications after CABG.</p> <p>Methods</p> <p>Plasma samples were collected from the radial artery catheter before vascular cannulation and after opening the chest, at the end of ECC just before clamp release, after cross release, after weaning from ECC, at the 6^thand 24^thpost-operative hour. Thirty one patients were investigated. The presence of cardiovascular, haematological and respiratory dysfunctions was prospectively assessed. Plasma sFlt-1 levels were measured with commercially ELISA kits.</p> <p>Results</p> <p>Among the 31 investigated patients, 15 had uneventful surgery. Patients with and without complications had similar pre-operative plasma sFlt-1 levels. Lowered plasma sFlt-1 levels were observed at the end of ECC in patients with haematological (p = 0.001, ANOVA) or cardiovascular (p = 0.006) impairments, but not with respiratory ones (p = 0.053), as compared to patients with uneventful surgery.</p> <p>Conclusion</p> <p>These results identify an association between specific post-CABG complication and the lower release of sFlt-1 during ECC. sFlt-1-induced VEGF neutralisation might, thus, be beneficial to reduce the development of post-operative adverse effects after CABG.</p

Acute cholecystitis – early laparoskopic surgery versus antibiotic therapy and delayed elective cholecystectomy: ACDC-study

<p>Abstract</p> <p>Background</p> <p>Acute cholecystitis occurs frequently in the elderly and in patients with gall stones. Most cases of severe or recurrent cholecystitis eventually require surgery, usually laparoscopic cholecystectomy in the Western World. It is unclear whether an initial, conservative approach with antibiotic and symptomatic therapy followed by delayed elective surgery would result in better morbidity and outcome than immediate surgery. At present, treatment is generally determined by whether the patient first sees a surgeon or a gastroenterologist. We wish to investigate whether both approaches are equivalent. The primary endpoint is the morbidity until day 75 after inclusion into the study.</p> <p>Design</p> <p>A multicenter, prospective, randomized non-blinded study to compare treatment outcome, complications and 75-day morbidity in patients with acute cholecystitis randomized to laparoscopic cholecystectomy within 24 hours of symptom onset or antibiotic treatment with moxifloxacin and subsequent elective cholecystectomy. For consistency in both arms moxifloxacin, a fluorquinolone with broad spectrum of activity and high bile concentration is used as antibiotic. Duration: October 2006 – November 2008</p> <p>Organisation/Responsibility</p> <p>The trial was planned and is being conducted and analysed by the Departments of Gastroenterology and General Surgery at the University Hospital of Heidelberg according to the ethical, regulatory and scientific principles governing clinical research as set out in the Declaration of Helsinki (1989) and the Good Clinical Practice guideline (GCP).</p> <p>Trial Registration</p> <p>ClinicalTrials.gov NCT00447304</p

An initial evaluation of newly proposed biomarker of zinc status in humans - linoleic acid: dihomo-y-linolenic acid (LA:DGLA) ratio

Background: Zinc is an essential micronutrient for humans with important physiological functions. A sensitive and specific biomarker for assessing Zn status is still needed. Objective: The major aim of this study was to examine if the changes in the content of plasma phospholipid LA, DGLA and LA: DGLA ratio can be used to efficiently predict the dietary Zn intake and plasma Zn status of humans. Methods: The study was performed on healthy human volunteers, 25-55 years of age. The dietary Zn intake was assessed using 24 h recall questionnaires. Plasma phospholipid fatty acid analysis was done by gas chromatography, and plasma analysis of minerals by atomic absorption spectrometry. Biochemical, anthropometrical and hematological parameters were assessed. Results: No significant relationship was found between the dietary and plasma zinc status (r = 0.07; p = 0.6). There was a statistically significant correlation between DGLA and plasma Zn (r = 0.39, p = 0.00). No relationship was observed between the linoleic acid and plasma Zn, while there was a significant negative correlation between LA: DGLA ratio and plasma Zn status (r = 0.35, p = 0.01). Similarly, there were statistically significant difference in DGLA status (p = 0.004) and LA: DGLA ratio (p = 0.042) between the Zn formed groups. Conclusions: This study is an initial step in evaluating LA: DGLA ratio as a biomarker of Zn status in humans. The results are encouraging as they show that concentration of DGLA is decreased and LA: DGLA ratio increased in people with lower dietary Zn intake. However, additional studies are needed to fully examine the sensitivity of this biomarker

Release of soluble vascular endothelial growth factor receptor-1 (sFlt-1) during coronary artery bypass surgery

<p>Abstract</p> <p>Background</p> <p>This study was conducted to follow plasma concentrations of sFlt-1 and sKDR, two soluble forms of the vascular endothelial growth factor (VEGF) receptor in patients undergoing coronary artery bypass graft (CABG) surgery with extracorporeal circulation (ECC).</p> <p>Methods</p> <p>Plasma samples were obtained before, during and after surgery in 15 patients scheduled to undergo CABG. Levels of sFlt-1 and KDR levels were investigated using specific ELISA.</p> <p>Results</p> <p>A 75-fold increase of sFlt-1 was found during cardiac surgery, sFlt-1 levels returning to pre-operative values at the 6^thpost-operative hour. In contrast sKDR levels did not change during surgery. The ECC-derived sFlt-1 was functional as judge by its inhibitory effect on the VEGF mitogenic response in human umbilical vein endothelial cells (HUVECs). Kinetic experiments revealed sFlt-1 release immediately after the beginning of ECC suggesting a proteolysis of its membrane form (mFlt-1) rather than an elevated transcription/translation process. Flow cytometry analysis highlighted no effect of ECC on the shedding of mFlt-1 on platelets and leukocytes suggesting vascular endothelial cell as a putative cell source for the ECC-derived sFlt-1.</p> <p>Conclusion</p> <p>sFlt-1 is released during CABG with ECC. It might be suggested that sFlt-1 production, by neutralizing VEGF and/or by inactivating membrane-bound Flt-1 and KDR receptors, might play a role in the occurrence of post-CABG complication.</p

Comparison of balance assessment modalities in emergency department elders: a pilot cross-sectional observational study

<p>Abstract</p> <p>Background</p> <p>More than one-third of US adults 65 and over fall every year. These falls may cause serious injury including substantial long-term morbidity (due declines in activities of daily living) and death. The emergency department (ED) visit represents an opportunity for identifying high risk elders and potentially instituting falls-related interventions. The unique characteristic of the ED environment and patient population necessitate that risk-assessment modalities be validated in this specific setting. In order to better identify elders at risk of falls, we examined the relationship between patient-provided history of falling and two testing modalities (a balance plate system and the timed up-and-go [TUG] test) in elder emergency department (ED) patients.</p> <p>Methods</p> <p>We conducted a cross-sectional observational study of patients ≥ 60 years old being discharged from the ED. Patient history of falls in the past week, month, 6 months, and year was obtained. Balance plate center of pressure excursion (COP) measurements and TUG testing times were recorded. COP was recorded under four conditions: normal stability eyes open (NSEO) and closed (NSEC), and perturbed stability eyes open and closed. Correlation between TUG and COP scores was measured. Univariate logistic regression was used to identify the relationship between patient-provided falls history and the two testing modalities. Proportions, likelihood ratios, and receiver-operating-characteristic (ROC) curves for prediction of previous falls were reported.</p> <p>Results</p> <p>Fifty-three subjects were enrolled, 11% had fallen in the previous week and 42% in the previous year. There was no correlation between TUG and any balance plate measurements. In logistic regression, neither testing modality was associated with prior history of falls (<it>p </it>> 0.05 for all time periods). Balance plate NSEO and NSEC testing cutoffs could be identified which were 83% sensitive and had a negative likelihood ratio (LR-) of 0.3 for falls in the past week. TUG testing was not useful for falls in the past week, but performed best for more distant falls in the past month, 6 months, or year. TUG cutoffs with sensitivity over 80% and LR(-) of 0.17-0.32 could be identified for these time periods.</p> <p>Conclusion</p> <p>Over 40% of community-dwelling elder ED patients report a fall within the past year. Balance plate and TUG testing were feasibly conducted in an ED setting. There is no relationship between scores on balance plate and TUG testing in these patients. In regression analysis, neither modality was significantly associated with patient provided history of falls. These modalities should not be adopted for screening purposes in elders in the ED setting without validation in future studies or as part of multi-factorial risk assessment.</p