Klinik und Poliklinik für Anästhesiologie (ab 2004)
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- EMBL Mouse Biology Unit, Monterotondo, Italien (1)
- Interdisziplinäres Zentrum für Klinische Forschung (ZIKF), Würzburg (1)
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- Krankenhaushygiene und Antimicrobial Stewardship (1)
- Krankenhaushygiene und Antimicrobial Stewardship, Universitätsklinikum Würzburg (1)
Objective
In this abridged version of the recently published Cochrane review on antiemetic drugs, we summarize its most important findings and discuss the challenges and the time needed to prepare what is now the largest Cochrane review with network meta-analysis in terms of the number of included studies and pages in its full printed form.
Methods
We conducted a systematic review with network meta-analyses to compare and rank single antiemetic drugs and their combinations belonging to 5HT₃-, D₂-, NK₁-receptor antagonists, corticosteroids, antihistamines, and anticholinergics used to prevent postoperative nausea and vomiting in adults after general anesthesia.
Results
585 studies (97 516 participants) testing 44 single drugs and 51 drug combinations were included. The studies’ overall risk of bias was assessed as low in only 27% of the studies. In 282 studies, 29 out of 36 drug combinations and 10 out of 28 single drugs lowered the risk of vomiting at least 20% compared to placebo. In the ranking of treatments, combinations of drugs were generally more effective than single drugs. Single NK1 receptor antagonists were as effective as other drug combinations. Of the 10 effective single drugs, certainty of evidence was high for aprepitant, ramosetron, granisetron, dexamethasone, and ondansetron, while moderate for fosaprepitant and droperidol. For serious adverse events (SAEs), any adverse event (AE), and drug-class specific side effects evidence for intervention effects was mostly not convincing.
Conclusions
There is high or moderate evidence for at least seven single drugs preventing postoperative vomiting. However, there is still considerable lack of evidence regarding safety aspects that does warrant investigation.
Background
Evidence concerning combined general anesthesia (GA) and thoracic epidural analgesia (EA) is controversial and the procedure appears heterogeneous in clinical implementation. We aimed to gain an overview of different approaches and to unveil a suspected heterogeneity concerning the intraoperative management of combined GA and EA.
Methods
This was an anonymous survey among Members of the Scientific working group for regional anesthesia within the German Society of Anaesthesiology and Intensive Care Medicine (DGAI) conducted from February 2020 to August 2020.
Results
The response rate was 38%. The majority of participants were experienced anesthetists with high expertise for the specific regimen of combined GA and EA. Most participants establish EA in the sitting position (94%), prefer early epidural initiation (prior to skin incision: 80%; intraoperative: 14%) and administer ropivacaine (89%) in rather low concentrations (0.2%: 45%; 0.375%: 30%; 0.75%: 15%) mostly with an opioid (84%) in a bolus-based mode (95%). The majority reduce systemic opioid doses intraoperatively if EA works sufficiently (minimal systemic opioids: 58%; analgesia exclusively via EA: 34%). About 85% manage intraoperative EA insufficiency with systemic opioids, 52% try to escalate EA, and only 25% use non-opioids, e.g. intravenous ketamine or lidocaine.
Conclusions
Although, consensus seems to be present for several aspects (patient's position during epidural puncture, main epidural substance, application mode), there is considerable heterogeneity regarding systemic opioids, rescue strategies for insufficient EA, and hemodynamic management, which might explain inconsistent results of previous trials and meta-analyses.
Background
Coronavirus disease 2019 (COVID-19) associated coagulopathy (CAC) leads to thromboembolic events in a high number of critically ill COVID-19 patients. However, specific diagnostic or therapeutic algorithms for CAC have not been established. In the current study, we analyzed coagulation abnormalities with point-of-care testing (POCT) and their relation to hemostatic complications in patients suffering from COVID-19 induced Acute Respiratory Distress Syndrome (ARDS). Our hypothesis was that specific diagnostic patterns can be identified in patients with COVID-19 induced ARDS at risk of thromboembolic complications utilizing POCT.
Methods
This is a single-center, retrospective observational study. Longitudinal data from 247 rotational thromboelastometries (Rotem®) and 165 impedance aggregometries (Multiplate®) were analysed in 18 patients consecutively admitted to the ICU with a COVID-19 induced ARDS between March 12th to June 30th, 2020.
Results
Median age was 61 years (IQR: 51–69). Median PaO2/FiO2 on admission was 122 mmHg (IQR: 87–189), indicating moderate to severe ARDS. Any form of hemostatic complication occurred in 78 % of the patients with deep vein/arm thrombosis in 39 %, pulmonary embolism in 22 %, and major bleeding in 17 %. In Rotem® elevated A10 and maximum clot firmness (MCF) indicated higher clot strength. The delta between EXTEM A10 minus FIBTEM A10 (ΔA10) > 30 mm, depicting the sole platelet-part of clot firmness, was associated with a higher risk of thromboembolic events (OD: 3.7; 95 %CI 1.3–10.3; p = 0.02). Multiplate® aggregometry showed hypoactive platelet function. There was no correlation between single Rotem® and Multiplate® parameters at intensive care unit (ICU) admission and thromboembolic or bleeding complications.
Conclusions
Rotem® and Multiplate® results indicate hypercoagulability and hypoactive platelet dysfunction in COVID-19 induced ARDS but were all in all poorly related to hemostatic complications..
Background
Acute respiratory distress syndrome (ARDS) is a complex clinical diagnosis with various possible etiologies. One common feature, however, is pulmonary permeability edema, which leads to an increased alveolar diffusion pathway and, subsequently, impaired oxygenation and decarboxylation. A novel inhaled peptide agent (AP301, solnatide) was shown to markedly reduce pulmonary edema in animal models of ARDS and to be safe to administer to healthy humans in a Phase I clinical trial. Here, we present the protocol for a Phase IIB clinical trial investigating the safety and possible future efficacy endpoints in ARDS patients.
Methods
This is a randomized, placebo-controlled, double-blind intervention study. Patients with moderate to severe ARDS in need of mechanical ventilation will be randomized to parallel groups receiving escalating doses of solnatide or placebo, respectively. Before advancing to a higher dose, a data safety monitoring board will investigate the data from previous patients for any indication of patient safety violations. The intervention (application of the investigational drug) takes places twice daily over the course of 7 days, ensued by a follow-up period of another 21 days.
Discussion
The patients to be included in this trial will be severely sick and in need of mechanical ventilation. The amount of data to be collected upon screening and during the course of the intervention phase is substantial and the potential timeframe for inclusion of any given patient is short. However, when prepared properly, adherence to this protocol will make for the acquisition of reliable data. Particular diligence needs to be exercised with respect to informed consent, because eligible patients will most likely be comatose and/or deeply sedated at the time of inclusion.
Trial registration
This trial was prospectively registered with the EU Clinical trials register (clinicaltrialsregister.eu). EudraCT Number: 2017-003855-47.
This work investigated phenotypes of complex regional pain syndrome (CRPS) with special interest in sensory abnormalities. Quantitative sensory testing (QST) was used to assess sensory function. In addition, clinical and sensory differences of fracture and CRPS patients were addressed. Finally, the longitudinal outcome of CRPS patients was part of this thesis.
Clinical trials of novel therapeutics for Alzheimer’s Disease (AD) have consumed a significant amount of time and resources with largely negative results. Repurposing drugs already approved by the Food and Drug Administration (FDA), European Medicines Agency (EMA), or Worldwide for another indication is a more rapid and less expensive option. Therefore, we apply the scaffold searching approach based on known amyloid-beta (Aβ) inhibitor tramiprosate to screen the DrugCentral database (n = 4,642) of clinically tested drugs. As a result, menadione bisulfite and camphotamide substances with protrombogenic and neurostimulation/cardioprotection effects were identified as promising Aβ inhibitors with an improved binding affinity (ΔGbind) and blood-brain barrier permeation (logBB). Finally, the data was also confirmed by molecular dynamics simulations using implicit solvation, in particular as Molecular Mechanics Generalized Born Surface Area (MM-GBSA) model. Overall, the proposed in silico pipeline can be implemented through the early stage rational drug design to nominate some lead candidates for AD, which will be further validated in vitro and in vivo, and, finally, in a clinical trial.
Background: Proportions of patients dying from the coronavirus disease-19 (COVID-19) vary between different countries. We report the characteristics; clinical course and outcome of patients requiring intensive care due to COVID-19 induced acute respiratory distress syndrome (ARDS).
Methods: This is a retrospective, observational multicentre study in five German secondary or tertiary care hospitals. All patients consecutively admitted to the intensive care unit (ICU) in any of the participating hospitals between March 12 and May 4, 2020 with a COVID-19 induced ARDS were included.
Results: A total of 106 ICU patients were treated for COVID-19 induced ARDS, whereas severe ARDS was present in the majority of cases. Survival of ICU treatment was 65.0%. Median duration of ICU treatment was 11 days; median duration of mechanical ventilation was 9 days. The majority of ICU treated patients (75.5%) did not receive any antiviral or anti-inflammatory therapies. Venovenous (vv) ECMO was utilized in 16.3%. ICU triage with population-level decision making was not necessary at any time. Univariate analysis associated older age, diabetes mellitus or a higher SOFA score on admission with non-survival during ICU stay.
Conclusions: A high level of care adhering to standard ARDS treatments lead to a good outcome in critically ill COVID-19 patients.
Reduced Cl\(^{-}\) conductance causes inhibited muscle relaxation after forceful voluntary contraction due to muscle membrane hyperexcitability. This represents the pathomechanism of myotonia congenita. Due to the prevailing data suggesting that an increased potassium level is a main contributor, we studied the effect of a modulator of a big conductance Ca\(^{2+}\)- and voltage-activated K\(^{+}\) channels (BK) modulator on contraction and relaxation of slow- and high-twitch muscle specimen before and after the pharmacological induction of myotonia. Human and murine muscle specimens (wild-type and BK\(^{-/-}\)) were exposed to anthracene-9-carboxylic acid (9-AC) to inhibit CLC-1 chloride channels and to induce myotonia in-vitro. Functional effects of BK-channel activation and blockade were investigated by exposing slow-twitch (soleus) and fast-twitch (extensor digitorum longus) murine muscle specimens or human musculus vastus lateralis to an activator (NS1608) and a blocker (Paxilline), respectively. Muscle-twitch force and relaxation times (T\(_{90/10}\)) were monitored. Compared to wild type, fast-twitch muscle specimen of BK\(^{-/-}\) mice resulted in a significantly decreased T\(_{90/10}\) in presence of 9-AC. Paxilline significantly shortened T\(_{90/10}\) of murine slow- and fast-twitch muscles as well as human vastus lateralis muscle. Moreover, twitch force was significantly reduced after application of Paxilline in myotonic muscle. NS1608 had opposite effects to Paxilline and aggravated the onset of myotonic activity by prolongation of T\(_{90/10}\). The currently used standard therapy for myotonia is, in some individuals, not very effective. This in vitro study demonstrated that a BK channel blocker lowers myotonic stiffness and thus highlights its potential therapeutic option in myotonia congenital (MC).
In my thesis, I characterized aGPCRs Adgrl1 and Adgrl3, tight junction proteins and the blood-DRG-barrier in rats’ lumbar dorsal root ganglions after traumatic neuropathy. In contrast to the otherwise tightly sealed barriers shielding neural tissues, the dorsal root ganglion’s neuron rich region is highly permeable in its healthy state. Furthermore, the DRG is a source of ectopic signal generation during neuropathy; the exact origin of which is still unclear. I documented expression of Adgrl1 and Adgrl3 in NF200 + , CGRP + and IB4 + neurons. One week after CCI, I observed transient downregulation of Adgrl1 in non-peptidergic nociceptors (IB4+). In the context of previous data, dCirl deletion causing an allodynia-like state in Drosophila, our research hints to a possible role of Adgrl1 nociceptive signal processing and pain resolution in neuropathy. Furthermore, I demonstrated similar claudin-1, claudin-12, claudin-19, and ZO-1 expression of the dorsal root ganglion’s neuron rich and fibre rich region. Claudin-5 expression in vessels of the neuron rich region was lower compared to the fibre rich region. Claudin-5 expression was decreased one week after nerve injury in vessels of the neuron rich region while permeability for small and large injected molecules remained unchanged. Nevertheless, we detected more CD68+ cells in the neuron rich region one week after CCI. As clinically relevant conclusion, we verified the high permeability of the neuron rich regions barrier as well as a vessel specific claudin-5 downregulation after CCI. We observed increased macrophage invasion into the neuron rich region after CCI. Furthermore, we identified aGPCR as potential target for further research and possible treatments for neuropathy, which should be easily accessible due to the blood-DRG-barriers leaky nature. Its precise function in peripheral tissues, its mechanisms of activation, and its role in pain resolution should be evaluated further.
Physical and mental well-being during the COVID-19 pandemic is typically assessed via surveys, which might make it difficult to conduct longitudinal studies and might lead to data suffering from recall bias. Ecological momentary assessment (EMA) driven smartphone apps can help alleviate such issues, allowing for in situ recordings. Implementing such an app is not trivial, necessitates strict regulatory and legal requirements, and requires short development cycles to appropriately react to abrupt changes in the pandemic. Based on an existing app framework, we developed Corona Health, an app that serves as a platform for deploying questionnaire-based studies in combination with recordings of mobile sensors. In this paper, we present the technical details of Corona Health and provide first insights into the collected data. Through collaborative efforts from experts from public health, medicine, psychology, and computer science, we released Corona Health publicly on Google Play and the Apple App Store (in July 2020) in eight languages and attracted 7290 installations so far. Currently, five studies related to physical and mental well-being are deployed and 17,241 questionnaires have been filled out. Corona Health proves to be a viable tool for conducting research related to the COVID-19 pandemic and can serve as a blueprint for future EMA-based studies. The data we collected will substantially improve our knowledge on mental and physical health states, traits and trajectories as well as its risk and protective factors over the course of the COVID-19 pandemic and its diverse prevention measures.