Volatile sedation in sepsis: a promising therapeutic approach or a venture doomed to fail?

Preclinical strategies targeting sepsis often had a single target and could not be translated into the clinical setting. Volatile sedation modulates multiple aspects of inflammation and improves sepsis-related survival in animal models. Whether a similar effect can be achieved in humans is unclear. Only a prospective clinical trial will be able to answer this question. The implementation of such a study in times when volatile anaesthetics are the focus of attention because of their greenhouse effect and their carbon dioxide emission will be a challenge, even though the alternative, i.v. sedation, is still insufficiently investigated in this respect

Effects of sevoflurane and its metabolite hexafluoroisopropanol on hypoxia/reoxygenation-induced injury and mitochondrial bioenergetics in murine cardiomyocytes

Background The volatile anaesthetic sevoflurane protects cardiac tissue from reoxygenation/reperfusion. Mitochondria play an essential role in conditioning. We aimed to investigate how sevoflurane and its primary metabolite hexafluoroisopropanol (HFIP) affect necrosis, apoptosis, and reactive oxygen species formation in cardiomyocytes upon hypoxia/reoxygenation injury. Moreover, we aimed to describe the similarities in the mode of action in a mitochondrial bioenergetics analysis. Methods Murine cardiomyocytes were exposed to hypoxia (0.2% O2 for 6 h), followed by reoxygenation (air with 5% CO2 for 2 h) in the presence or absence sevoflurane 2.2% or HFIP 4 mM. Lactate dehydrogenase (LDH) release (necrosis), caspase activation (apoptosis), reactive oxygen species, mitochondrial membrane potential, and mitochondrial function (Seahorse XF analyser) were measured. Results Hypoxia/reoxygenation increased cell death by 44% (+31 to +55%, P<0.001). Reoxygenation in the presence of sevoflurane 2.2% or HFIP 4 mM increased LDH release only by +18% (+6 to +30%) and 20% (+7 to +32%), respectively. Apoptosis and reactive oxygen species formation were attenuated by sevoflurane and HFIP. Mitochondrial bioenergetics analysis of the two substances was profoundly different. Sevoflurane did not influence oxygen consumption rate (OCR) or extracellular acidification rate (ECAR), whereas HFIP reduced OCR and increased ECAR, an effect similar to oligomycin, an adenosine triphosphate (ATP) synthase inhibitor. When blocking the metabolism of sevoflurane into HFIP, protective effects of sevoflurane – but not of HFIP – on LDH release and caspase were mitigated. Conclusion Together, our data suggest that sevoflurane metabolism into HFIP plays an essential role in cardiomyocyte postconditioning after hypoxia/reoxygenation injury

Video-assisted versus macintosh direct laryngoscopy for intubation of obese patients: a meta-analysis of randomized controlled trials

INTRODUCTION: We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to compare the usefulness of video-assisted (VL) approaches with the Macintosh direct laryngoscope for endotracheal intubation of obese patients. MATERIAL AND METHODS: Studies were obtained via a systematic search of SCOPUS, Medline, Web of Science, CINAHL, and the Cochrane Central databases. The polled relative risks (RRs) odds ratios (ODs) or standard mean differences (SMD) with 95% confidence intervals (CIs) were calculated with a random–effects model. Subgroup analyses were performed to evaluate the influence of VL types on the association. RESULTS: First intubation attempt success rate in VL and DL group varied and amounted to 94.7% vs 89.5% respectively (OR = 2.04; 95% CI: 1.21–3.42; p = 0.007) and overall intubation success rate was 99.0% vs 97.5% respectively (OR = 2.20; 95% CI: 0.45–10.67; p = 0.33). Intubation time which was 48.0 ± 37.7 for VL and 48.4 ± 37.5 seconds for DL (SMD = 0.14; 95% CI: –0.33–0.61; p = 0.56). Cormack-Lehane 1 or 2 grade during intubation using VL was observed in 95.9% of cases and was statistically significantly higher than in the case of direct laryngoscopy (79.6%; OR = 6.68; 95% CI: 3.32–13.42; p < 0.001). CONCLUSIONS: Our meta-analysis suggests that video-assisted intubation may be superior to conventional intubation in an obese patient population due to a higher first–attempt success rate, better glottis visibility, and a lower rate of intubation-related injuries. Keywords - video-laryngoscope, direct-laryngoscope, endotracheal intubation, obese, intubation attempt, intubation time, meta-analysi

Non-Feasibility to Estimate the Need for Reversal of Neuromuscular Relaxation from the Applied Rocuronium Dosing Pattern: A Retrospective Analysis of Anaesthesia Records

Objective: Some anaesthetists are convinced that a long interval since the last relaxant dose may be sufficient to recover from anaesthesia without a pharmacological reversal. We intended to demonstrate that the dosing pattern of rocuronium could not predict the necessity of reversal. Methods: In a cohort analysis, we retrospectively analysed 180 anaesthesia records of adult patients who underwent elective surgical interventions in general anaesthesia and tracheal intubation with rocuronium-induced neuromuscular blockade. The extracted records were divided to 3 post hoc groups of 60 each, according to the reversal method employed at the end of anaesthesia: group N with neostigmine, group S with sugammadex and group Z without pharmacological reversal. All cases were terminated after achieving a train of four ratio of 0.9. Dosing patterns of rocuronium were compared by applying a novel pharmacometric calculation method, residual drug activity coefficient (RDAC), which employs both the administered individual drug doses in mg kg-1 and the timing of each drug administration in relation to the time of extubation. The rocuronium dosing pattern was correlated with the employed method of neuromuscular blockade reversal. Results: The dosing for rocuronium in patients without pharmacological reversal was lower than that in both reversal agent groups (n=0.58±0.21, S=0.58±0.17 and Z=0.47±0.17), but there was still a large overlap in the RDAC. Conclusion: The dosage profile of rocuronium alone cannot predict the possibility to refrain from pharmacological reversal

Rat model of the associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) procedure

Recent clinical data support an aggressive surgical approach to both primary and metastatic liver tumors. For some indications, like colorectal liver metastases, the amount of liver tissue left behind after liver resection has become the main limiting factor of resectability of large or multiple liver tumors. A minimal amount of functional tissue is required to avoid the severe complication of post-hepatectomy liver failure, which has high morbidity and mortality. Inducing liver growth of the prospective remnant prior to resection has become more established in liver surgery, either in the form of portal vein embolization by interventional radiologists or in the form of portal vein ligation several weeks prior to resection. Recently, it was shown that liver regeneration is more extensive and rapid, when the parenchymal transection is added to portal vein ligation in a first stage and then, after only one week of waiting, resection performed in a second stage (Associating Liver Partition and Portal vein ligation for Staged hepatectomy = ALPPS). ALPPS has rapidly become popular across the world, but has been criticized for its high perioperative mortality. The mechanism of accelerated and extensive growth induced by this procedure has not been well understood. Animal models have been developed to explore both the physiological and molecular mechanisms of accelerated liver regeneration in ALPPS. This protocol presents a rat model that allows mechanistic exploration of accelerated regeneration

Brugada syndrome and fever: Genetic and molecular characterization of patients carrying SCN5A mutations

Objective: Brugada syndrome (BrS) is characterized by ventricular tachyarrhythmias leading to sudden cardiac death and is caused, in part, by mutations in the SCN5A gene encoding the sodium channel Nav1.5. Fever can trigger or exacerbate the clinical manifestations of BrS. The aim of this work was to characterize the genetic and molecular determinants of fever-dependent BrS. Methods: Four male patients with typical BrS ST-segment elevation in V1-V3 or ventricular arrhythmias during fever were screened for mutations in the SCN5A gene. Wild-type (WT) and mutant Nav1.5 channels were expressed in HEK293 cells. The sodium currents (INa) were analysed using the whole-cell patch clamp technique at various temperatures. Protein expression of WT and mutant channels was studied by Western blot experiments. Results: Two mutations in SCN5A, L325R and R535X, were identified. Expression of the two mutant Nav1.5 channels in HEK293 cells revealed in each case a severe loss-of-function. Upon the increase of temperature up to 42 °C, we observed a pronounced acceleration of Nav1.5 activation and fast inactivation kinetics. Cardiac action potential modelling experiments suggest that in patients with reduced INa, fever could prematurely shorten the action potential by virtue of its effect on WT channels. Further experiments revealed that L325R channels are likely misfolded, since their function could be partially rescued by mexiletine or curcumin. In co-expression experiments, L325R channels interfered with the proper function of WT channels, suggesting that a dominant negative phenomenon may underlie BrS triggered by fever. Conclusions: The genetic background of BrS patients sensitive to fever is heterogeneous. Our experimental data suggest that the clinical manifestations of fever-exacerbated BrS may not be mutation specifi

Inhaled Sedation in Patients with COVID-19-Related Acute Respiratory Distress Syndrome: An International Retrospective Study

Background and objectives: The coronavirus disease 2019 (COVID-19) pandemic and the shortage of intravenous sedatives has led to renewed interest in inhaled sedation for patients with acute respiratory distress syndrome (ARDS). We hypothesized that inhaled sedation would be associated with improved clinical outcomes in COVID-19 ARDS patients. Methods: Retrospective international study including mechanically ventilated patients with COVID-19 ARDS who required sedation and were admitted to 10 European and US intensive care units. The primary endpoint of ventilator-free days through day 28 was analyzed using zero-inflated negative binomial regression, before and after adjustment for site, clinically relevant covariates determined according to the univariate results, and propensity score matching. Results: A total of 196 patients were enrolled, 78 of whom died within 28 days. The number of ventilator-free days through day 28 did not differ significantly between the patients who received inhaled sedation for at least 24 h (n = 111) and those who received intravenous sedation only (n = 85), with medians of 0 (interquartile range [IQR] 0–8) and 0 (IQR 0–17), respectively (odds ratio for having zero ventilator-free days through day 28, 1.63, 95% confidence interval [CI], 0.91–2.92, p = 0.10). The incidence rate ratio for the number of ventilator-free days through day 28 if not 0 was 1.13 (95% CI, 0.84–1.52, p = 0.40). Similar results were found after multivariable adjustment and propensity matching. Conclusion: The use of inhaled sedation in COVID-19 ARDS was not associated with the number of ventilator-free days through day 28. Keywords: coronavirus disease 2019; acute respiratory distress syndrome; inhaled sedation; sevoflurane; isofluran

APETALA2 control of barley internode elongation

Many plants dramatically elongate their stems during flowering, yet how this response is coordinated with the reproductive phase is unclear. We demonstrate that microRNA (miRNA) control of APETALA2 (AP2) is required for rapid, complete elongation of stem internodes in barley, especially of the final 'peduncle' internode directly underneath the inflorescence. Disrupted miR172 targeting of AP2 in the Zeo1.b barley mutant caused lower mitotic activity, delayed growth dynamics and premature lignification in the peduncle leading to fewer and shorter cells. Stage- and tissue-specific comparative transcriptomics between Zeo1.b and its parent cultivar showed reduced expression of proliferation-associated genes, ectopic expression of maturation-related genes and persistent, elevated expression of genes associated with jasmonate and stress responses. We further show that applying methyl jasmonate (MeJA) phenocopied the stem elongation of Zeo1.b, and that Zeo1.b itself was hypersensitive to inhibition by MeJA but less responsive to promotion by gibberellin. Taken together, we propose that miR172-mediated restriction of AP2 may modulate the jasmonate pathway to facilitate gibberellin-promoted stem growth during flowering

Variability in Avian Eggshell Colour: A Comparative Study of Museum Eggshells

Background: The exceptional diversity of coloration found in avian eggshells has long fascinated biologists and inspired a broad range of adaptive hypotheses to explain its evolution. Three main impediments to understanding the variability of eggshell appearance are: (1) the reliable quantification of the variation in eggshell colours; (2) its perception by birds themselves, and (3) its relation to avian phylogeny. Here we use an extensive museum collection to address these problems directly, and to test how diversity in eggshell coloration is distributed among different phylogenetic levels of the class Aves. Methodology and Results: Spectrophotometric data on eggshell coloration were collected from a taxonomically representative sample of 251 bird species to determine the change in reflectance across different wavelengths and the taxonomic level where the variation resides. As many hypotheses for the evolution of eggshell coloration assume that egg colours provide a communication signal for an avian receiver, we also modelled reflectance spectra of shell coloration for the avian visual system. We found that a majority of species have eggs with similar background colour (long wavelengths) but that striking differences are just as likely to occur between congeners as between members of different families. The region of greatest variability in eggshell colour among closely related species coincided with the medium-wavelength sensitive region around 500 nm. Conclusions: The majority of bird species share similar background eggshell colours, while the greatest variability among species aligns with differences along a red-brown to blue axis that most likely corresponds with variation in the presence and concentration of two tetrapyrrole pigments responsible for eggshell coloration. Additionally, our results confirm previous findings of temporal changes in museum collections, and this will be of particular concern for studies testing intraspecific hypotheses relating temporal patterns to adaptation of eggshell colour. We suggest that future studies investigating the phylogenetic association between the composition and concentration of eggshell pigments, and between the evolutionary drivers and functional impacts of eggshell colour variability will be most rewarding.Phillip Cassey, Steven J. Portugal, Golo Maurer, John G. Ewen, Rebecca L. Boulton, Mark E. Hauber and Tim M. Blackbur