ICU- and ventilator-free days with isoflurane or propofol as a primary sedative - A post- hoc analysis of a randomized controlled trial.

PURPOSE: To compare ICU-free (ICU-FD) and ventilator-free days (VFD) in the 30 days after randomization in patients that received isoflurane or propofol without receiving the other sedative. MATERIALS AND METHODS: A recent randomized controlled trial (RCT) compared inhaled isoflurane via the Sedaconda® anaesthetic conserving device (ACD) with intravenous propofol for up to 54 h (Meiser et al. 2021). After end of study treatment, continued sedation was locally determined. Patients were eligible for this post-hoc analysis only if they had available 30-day follow-up data and never converted to the other drug in the 30 days from randomization. Data on ventilator use, ICU stay, concomitant sedative use, renal replacement therapy (RRT) and mortality were collected. RESULTS: Sixty-nine of 150 patients randomized to isoflurane and 109 of 151 patients randomized to propofol were eligible. After adjusting for potential confounders, the isoflurane group had more ICU-FD than the propofol group (17.3 vs 13.8 days, p = 0.028). VFD for the isoflurane and propofol groups were 19.8 and 18.5 respectively (p = 0.454). Other sedatives were used more frequently (p < 0.0001) and RRT started in a greater proportion of patients in the propofol group (p = 0.011). CONCLUSIONS: Isoflurane via the ACD was not associated with more VFD but with more ICU-FD and less concomitant sedative use.

The first German Helicopter Medical Evacuation Mission in World War 2.

Since 1936, the German aviation industry developed various helicopters. These helicopters were technically advanced, but because of the Allied air offensive, series production could no longer take place. We report on the first (and only) air rescue operation by a German helicopter in World War II.

Nano-in-Microparticles for Aerosol Delivery of Antibiotic-Loaded, Fucose-Derivatized, and Macrophage-Targeted Liposomes to Combat Mycobacterial Infections: In Vitro Deposition, Pulmonary Barrier Interactions, and Targeted Delivery.

Nontuberculous mycobacterial infections rapidly emerge and demand potent medications to cope with resistance. In this context, targeted loco-regional delivery of aerosol medicines to the lungs is an advantage. However, sufficient antibiotic delivery requires engineered aerosols for optimized deposition. Here, the effect of bedaquiline-encapsulating fucosylated versus nonfucosylated liposomes on cellular uptake and delivery is investigated. Notably, this comparison includes critical parameters for pulmonary delivery, i.e., aerosol deposition and the noncellular barriers of pulmonary surfactant (PS) and mucus. Targeting increases liposomal uptake into THP-1 cells as well as peripheral blood monocyte- and lung-tissue derived macrophages. Aerosol deposition in the presence of PS, however, masks the effect of active targeting. PS alters antibiotic release that depends on the drug's hydrophobicity, while mucus reduces the mobility of nontargeted more than fucosylated liposomes. Dry-powder microparticles of spray-dried bedaquiline-loaded liposomes display a high fine particle fraction of >70%, as well as preserved liposomal integrity and targeting function. The antibiotic effect is maintained when deposited as powder aerosol on cultured Mycobacterium abscessus. When treating M. abscessus infected THP-1 cells, the fucosylated variant enabled enhanced bacterial killing, thus opening up a clear perspective for the improved treatment of nontuberculous mycobacterial infections.

Distinct Patterns of Blood Cytokines Beyond a Cytokine Storm Predict Mortality in COVID-19.

BACKGROUND: COVID-19 comprises several severity stages ranging from oligosymptomatic disease to multi-organ failure and fatal outcomes. The mechanisms why COVID-19 is a mild disease in some patients and progresses to a severe multi-organ and often fatal disease with respiratory failure are not known. Biomarkers that predict the course of disease are urgently needed. The aim of this study was to evaluate a large spectrum of established laboratory measurements. PATIENTS AND METHODS: Patients from the prospective PULMPOHOM and CORSAAR studies were recruited and comprised 35 patients with COVID-19, 23 with conventional pneumonia, and 28 control patients undergoing elective non-pulmonary surgery. Venous blood was used to measure the serum concentrations of 79 proteins by Luminex multiplex immunoassay technology. Distribution of biomarkers between groups and association with disease severity and outcomes were analyzed. RESULTS: The biomarker profiles between the three groups differed significantly with elevation of specific proteins specific for the respective conditions. Several biomarkers correlated significantly with disease severity and death. Uniform manifold approximation and projection (UMAP) analysis revealed a significant separation of the three disease groups and separated between survivors and deceased patients. Different models were developed to predict mortality based on the baseline measurements of several protein markers. A score combining IL-1ra, IL-8, IL-10, MCP-1, SCF and CA-9 was associated with significantly higher mortality (AUC 0.929). DISCUSSION: Several newly identified blood markers were significantly increased in patients with severe COVID-19 (AAT, EN-RAGE, myoglobin, SAP, TIMP-1, vWF, decorin) or in patients that died (IL-1ra, IL-8, IL-10, MCP-1, SCF, CA-9). The use of established assay technologies allows for rapid translation into clinical practice.

Inhaled isoflurane via the anaesthetic conserving device versus propofol for sedation of invasively ventilated patients in intensive care units in Germany and Slovenia: an open-label, phase 3, randomised controlled, non-inferiority trial.

BACKGROUND: Previous studies indicate that isoflurane could be useful for the sedation of patients in the intensive care unit (ICU), but prospective studies evaluating isoflurane's efficacy have been small. The aim of this study was to test whether the sedation with isoflurane was non-inferior to sedation with propofol. METHODS: This phase 3, randomised, controlled, open-label non-inferiority trial evaluated the efficacy and safety of up to 54 h of isoflurane compared with propofol in adults (aged ≥18 years) who were invasively ventilated in ICUs in Germany (21 sites) and Slovenia (three sites). Patients were randomly assigned (1:1) to isoflurane inhalation via the Sedaconda anaesthetic conserving device (ACD; Sedana Medical AB, Danderyd, Sweden; ACD-L [dead space 100 mL] or ACD-S [dead space 50 mL]) or intravenous propofol infusion (20 mg/mL) for 48 h (range 42-54) using permuted block randomisation with a centralised electronic randomisation system. The primary endpoint was percentage of time in Richmond Agitation-Sedation Scale (RASS) range -1 to -4, assessed in eligible participants with at least 12 h sedation (the per-protocol population), five or more RASS measurements, and no major protocol violations, with a non-inferiority margin of 15%. Key secondary endpoints were opioid requirements, spontaneous breathing, time to wake-up and extubation, and adverse events. Safety was assessed in all patients who received at least one dose. The trial is complete and registered with EudraCT, 2016-004551-67. FINDINGS: Between July 2, 2017, and Jan 12, 2020, 338 patients were enrolled and 301 (89%) were randomly assigned to isoflurane (n=150) or propofol (n=151). 146 patients (97%) in each group completed the 24-h follow-up. 146 (97%) patients in the isoflurane group and 148 (98%) of patients in the propofol group were included in the per-protocol analysis of the primary endpoint. Least-squares mean percentage of time in RASS target range was 90·7% (95% CI 86·8-94·6) for isoflurane and 91·1% (87·2-95·1) for propofol. With isoflurane sedation, opioid dose intensity was 29% lower than with propofol for the overall sedation period (0·22 [0·12-0·34] vs 0·32 [0·21-0·42] mg/kg per h morphine equivalent dose, p=0·0036) and spontaneous breathing was more frequent on day 1 (odds ratio [OR] 1·72 [1·12-2·64], generalised mixed linear model p=0·013, with estimated rates of 50% of observations with isoflurane vs 37% with propofol). Extubation times were short and median wake-up was significantly faster after isoflurane on day 2 (20 min [IQR 10-30] vs 30 min [11-120]; Cox regression p=0·0011). The most common adverse events by treatment group (isoflurane vs propofol) were: hypertension (ten [7%] of 150 vs two [1%] of 151), delirium (eight [5%] vs seven [5%]), oliguria (seven [5%] vs six [4%]), and atrial fibrillation (five [3%] vs four [3%]). INTERPRETATION: These results support the use of isoflurane in invasively ventilated patients who have a clinical need for sedation. FUNDING: Sedana Medical AB.

A pulmonary mucus surrogate for investigating antibiotic permeation and activity against Pseudomonas aeruginosa biofilms.

BACKGROUND: Pulmonary infections associated with Pseudomonas aeruginosa can be life-threatening for patients suffering from chronic lung diseases such as cystic fibrosis. In this scenario, the formation of biofilms embedded in a mucus layer can limit the permeation and the activity of anti-infectives. OBJECTIVES: Native human pulmonary mucus can be isolated from endotracheal tubes, but this source is limited for large-scale testing. This study, therefore, aimed to evaluate a modified artificial sputum medium (ASMmod) with mucus-like viscoelastic properties as a surrogate for testing anti-infectives against P. aeruginosa biofilms. METHODS: Bacterial growth in conventional broth cultures was compared with that in ASMmod, and PAO1-GFP biofilms were imaged by confocal microscopy. Transport kinetics of three antibiotics, tobramycin, colistin, and ciprofloxacin, through native mucus and ASMmod were studied, and their activity against PAO1 biofilms grown in different media was assessed by determination of metabolic activity and cfu. RESULTS: PAO1(-GFP) cultured in human pulmonary mucus or ASMmod showed similarities in bacterial growth and biofilm morphology. A limited permeation of antibiotics through ASMmod was observed, indicating its strong barrier properties, which are comparable to those of native human mucus. Reduced susceptibility of PAO1 biofilms was observed in ASMmod compared with LB medium for tobramycin and colistin, but less for ciprofloxacin. CONCLUSIONS: These findings underline the importance of mucus as a biological barrier to antibiotics. ASMmod appears to be a valuable surrogate for studying mucus permeation of anti-infectives and their efficacy against PAO1 biofilms.

Microfluidics as tool to prepare size-tunable PLGA nanoparticles with high curcumin encapsulation for efficient mucus penetration.

Great challenges still remain to develop drug carriers able to penetrate biological barriers (such as the dense mucus in cystic fibrosis) and for the treatment of bacteria residing in biofilms, embedded in mucus. Drug carrier systems such as nanoparticles (NPs) require proper surface chemistry and small size to ensure their permeability through the hydrogel-like systems. We have employed a microfluidic system to fabricate poly(lactic-co-glycolic acid) (PLGA) nanoparticles coated with a muco-penetrating stabilizer (Pluronic), with a tunable hydrodynamic diameter ranging from 40 nm to 160 nm. The size dependence was evaluated by varying different parameters during preparation, namely polymer concentration, stabilizer concentration, solvent nature, the width of the focus mixing channel, flow rate ratio and total flow rate. Furthermore, the influence of the length of the focus mixing channel on the size was evaluated in order to better understand the nucleation-growth mechanism. Surprisingly, the channel length was revealed to have no effect on particle size for the chosen settings. In addition, curcumin was loaded (EE% of ≈68%) very efficiently into the nanoparticles. Finally, the permeability of muco-penetrating PLGA NPs through pulmonary human mucus was assessed; small NPs with a diameter of less than 100 nm showed fast permeation, underlining the potential of microfluidics for such pharmaceutical applications.

Macro- and Microrheological Properties of Mucus Surrogates in Comparison to Native Intestinal and Pulmonary Mucus.

Mucus is a complex hydrogel that acts as a protective barrier in various parts of the human body. Both composition and structural properties play a crucial role in maintaining barrier properties while dictating diffusion of molecules and (nano)materials. In this study, we compare previously described mucus surrogates with the native human airway and pig intestinal mucus. Oscillatory shear rheology was applied to characterize mucus on the bulk macrorheological level, revealing that the artificial airway surrogate deviates from the elastic-dominant behavior of native mucus samples. We circumvented this limitation through the addition of a cross-linking polymer to the surrogate, adjusting the rheological properties closer to those of native mucus. Applying particle tracking microrheology, we further demonstrated that the mechanical properties at the microscale differ significantly between artificial and native mucus. We conclude that proper characterization of mucus and its surrogates is vital for a reliable investigation of nanoparticle-based mucosal drug delivery.

Farnesylated Glycol Chitosan as a Platform for Drug Delivery: Synthesis, Characterization, and Investigation of Mucus-Particle Interactions.

Amphiphilic polymer-based drug delivery systems hold potential in enhancing pharmacokinetics and therapeutic efficacy due to their ability to simultaneously codeliver different drugs in a controlled manner. We propose here a facile method for synthesizing a new amphiphilic polymer, farnesylated glycol chitosan (FGC), which self-assembles into nanoparticles upon being dispersed in aqueous media. The characteristics of FGC nanoparticles, in particular the size, could be tuned in a range from 200 to 500 nm by modulating the degree of farnesylation and the pH and polymer concentration during particle preparation. Carrier capacity, release kinetics, and surface modification of the established system were investigated using different model compounds. The colloids were biocompatible and stable at biologically relevant pH values. The interactions between the carriers and human mucus were examined by multiple particle tracking, which revealed that ∼80% of the particles remain immobilized within the mucus matrix. These results postulate FGC as a versatile drug delivery platform.

Human airway mucus alters susceptibility of Pseudomonas aeruginosa biofilms to tobramycin, but not colistin.

Objectives: In the context of cystic fibrosis, Pseudomonas aeruginosa biofilms often develop in the vicinity of airway mucus, which acts as a protective physical barrier to inhaled matter. However, mucus can also adsorb small drug molecules administered as aerosols, including antibiotics, thereby reducing their bioavailability. The efficacy of antibiotics is typically assessed by determining the MIC using in vitro assays. This widespread technique, however, does not consider either bacterial biofilm formation or the influence of mucus, both of which may act as diffusion barriers, potentially limiting antibiotic efficacy. Methods: We grew P. aeruginosa biofilms in the presence or absence of human tracheal mucus and tested their susceptibility to tobramycin and colistin. Results: A significant reduction of tobramycin efficacy was observed when P. aeruginosa biofilms were grown in the presence of mucus compared with those grown in the absence of mucus. Diffusion of tobramycin through mucus was reduced; however, this reduction was more pronounced in biofilm/mucus mixtures, suggesting that biofilms in the presence of mucus respond differently to antibiotic treatment. In contrast, the influence of mucus on colistin efficacy was almost negligible and no differences in mucus permeability were observed. Conclusions: These findings underline the important role of mucus in the efficacy of anti-infective drugs.

Characterization of the seven-day course of pulmonary response following unilateral lung acid injury in rats.

BACKGROUND: Aspiration of gastric acid is an important cause of acute lung injury. The time course of the pulmonary response to such an insult beyond the initial 48 hours is incompletely characterized. The purpose of this study was to comprehensively describe the pulmonary effects of focal lung acid injury over a seven day period in both directly injured and not directly injured lung tissue. METHODS: Male Wistar rats underwent left-endobronchial instillation with hydrochloric acid and were sacrificed at 4, 24, 48, 96 or 168 h after the insult. Healthy non-injured animals served as controls. We assessed inflammatory cell counts and cytokine levels in right and left lung lavage fluid and blood, arterial oxygen tension, alterations in lung histology, lung wet-to-dry weight ratio and differential lung perfusion. RESULTS: Lung acid instillation induced an early strong inflammatory response in the directly affected lung, peaking at 4-24 hours, with only partial resolution after 7 days. A less severe response with complete resolution after 4 days was seen in the opposite lung. Alveolar cytokine levels, with exception of IL-6, only partially reflected the localization of lung injury and the time course of the functional and histologic alterations. Alveolar leucocyte subpopulations exhibited different time courses in the acid injured lung with persistent elevation of alveolar lymphocytes and macrophages. After acid instillation there was an early transient decrease in arterial oxygen tension and lung perfusion was preferentially distributed to the non-injured lung. CONCLUSION: These findings provide a basis for further research in the field of lung acid injury and for studies exploring effects of mechanical ventilation on injured lungs. Incomplete recovery in the directly injured lung 7 days after acid instillation suggests that increased vulnerability and susceptibility to further noxious stimuli are still present at that time.

Tracing molecular and structural changes upon mucolysis with N-acetyl cysteine in human airway mucus.

The conducting airways of the human lungs are lined by mucus, which lubricates the lung epithelium and provides a first-line protection against airborne threats. As a novel approach for visualization of the human mucus microstructure, we applied confocal Raman microscopy as a label-free and chemically selective technique. We were successfully able to chemically resolve the pulmonary surfactant from the mucus matrix and show its spatial distribution, as well as to visualize the structural changes within the freeze-dried mucus mesh upon chemical mucolysis. Subsequently, we performed rheological measurements before and after mucolysis and correlated morphology and chemical structure of the mucus with its rheological characteristics. These results do not only enrich the knowledge about the mucus microstructure, but can also, significantly contribute to rational development of future lung therapeutics.

Modelling the bronchial barrier in pulmonary drug delivery: A human bronchial epithelial cell line supplemented with human tracheal mucus.

The airway epithelium together with the mucus layer coating it forms a protective system that efficiently filters and removes potentially harmful particles contained in inhaled air. The same mechanism, however, serves to entrap particulate drug carriers, precluding their interaction with their target. The mucus barrier is often neglected in in vitro testing setups employed for the assessment of pulmonary drug delivery strategies. Therefore, our aim was to more accurately model the bronchial barrier, by developing an in vitro system comprising a tight epithelial cell layer which may be optionally supplemented with a layer of human tracheal mucus. To form the epithelium in vitro, we used the cystic fibrosis cell line CFBE41o-, which can be grown as monolayers on Transwell® supports, expressing tight junctions as well as relevant transport proteins. In contrast to the cell line Calu-3, however, CFBE41o- does not produce mucus. Therefore, native human mucus, obtained from tracheal tubes of patients undergoing elective surgery, was used as a supplement. The compatibility of CFBE41o- cells with the human mucus was addressed with the MTT assay, and confirmed by fluorescein diacetate/propidium iodide live/dead staining. Moreover, the CFBE41o- cells retained their epithelial barrier properties after being supplemented with mucus, as evidenced by the high trans-epithelial electrical resistance values (∼1000Ωcm2) together with a continued low level of paracellular transport of sodium fluorescein. Fluorescently-labeled chitosan-coated PLGA nanoparticles (NP, ∼168nm) were used as a model drug delivery system to evaluate the suitability of this in vitro model for studying mucus permeation and cell uptake. Comparing CFBE41o- cell monolayers with and without mucus, resp., showed that the NP uptake was dramatically reduced in the presence of mucus. This model may therefore be used as a tool to study potential mucus interactions of aerosolized drugs, and more specifically NP-based drug delivery systems designed to exert their effect in the bronchial region.

Impact of compliance with infection management guidelines on outcome in patients with severe sepsis: a prospective observational multi-center study.

INTRODUCTION: Current sepsis guidelines recommend antimicrobial treatment (AT) within one hour after onset of sepsis-related organ dysfunction (OD) and surgical source control within 12 hours. The objective of this study was to explore the association between initial infection management according to sepsis treatment recommendations and patient outcome. METHODS: In a prospective observational multi-center cohort study in 44 German ICUs, we studied 1,011 patients with severe sepsis or septic shock regarding times to AT, source control, and adequacy of AT. Primary outcome was 28-day mortality. RESULTS: Median time to AT was 2.1 (IQR 0.8 - 6.0) hours and 3 hours (-0.1 - 13.7) to surgical source control. Only 370 (36.6%) patients received AT within one hour after OD in compliance with recommendation. Among 422 patients receiving surgical or interventional source control, those who received source control later than 6 hours after onset of OD had a significantly higher 28-day mortality than patients with earlier source control (42.9% versus 26.7%, P <0.001). Time to AT was significantly longer in ICU and hospital non-survivors; no linear relationship was found between time to AT and 28-day mortality. Regardless of timing, 28-day mortality rate was lower in patients with adequate than non-adequate AT (30.3% versus 40.9%, P < 0.001). CONCLUSIONS: A delay in source control beyond 6 hours may have a major impact on patient mortality. Adequate AT is associated with improved patient outcome but compliance with guideline recommendation requires improvement. There was only indirect evidence about the impact of timing of AT on sepsis mortality.

Susceptibility to ventilator induced lung injury is increased in senescent rats.

INTRODUCTION: The principal mechanisms of ventilator induced lung injury (VILI) have been investigated in numerous animal studies. However, prospective data on the effect of old age on VILI are limited. Under the hypothesis that susceptibility to VILI is increased in old age, we investigated the pulmonary and extrapulmonary effects of mechanical ventilation with high tidal volume (VT) in old compared to young adult animals. INTERVENTIONS: Old (19.1±3.0 months) and young adult (4.4±1.3 months) male Wistar rats were anesthetized and mechanically ventilated (positive end-expiratory pressure 5 cmH2O, fraction of inspired oxygen 0.4, respiratory rate 40/minute) with a tidal volume (VT) of either 8, 16 or 24 ml/kg for four hours. RESULTS: Compared to young adult animals, high VT (24 ml/kg body weight) caused more lung injury in old animals as indicated by decreased oxygenation (arterial oxygen tension (PaO2): 208±3 vs. 131±20 mmHg; P<0.05), increased lung wet-to-dry-weight ratio (5.61±0.29 vs. 7.52±0.27; P<0.05), lung lavage protein (206±52 mg/l vs. 1,432±101; P<0.05) and cytokine (IL-6: 856±448 vs. 3,283±943 pg/ml; P<0.05) concentration. In addition, old animals ventilated with high VT had more systemic inflammation than young animals (IL-1ß: 149±44 vs. 272±36 pg/ml; P<0.05--young vs. old, respectively). CONCLUSIONS: Ventilation with unphysiologically large tidal volumes is associated with more lung injury in old compared to young rats. Aggravated pulmonary and systemic inflammation is a key finding in old animals developing VILI.

Oxygenation during one-lung ventilation with propofol or sevoflurane.

60 patients, ASA I-III, underwent one-lung ventilation for open or video-assisted thoracic surgery randomized either with intravenous anesthesia with propofol or with inhalational anesthesia with 1 MAC sevoflurane. Propofol was titrated during one-lung ventilation to achieve a mean arterial pressure of 75-80 mmHg. Blood gas analyses, hemodynamic and respiratory parameters were measured during two-lung ventilation at the beginning of the surgical procedure and 10 min, 20 min and 30 min after start of one-lung ventilation. At all time points, hemodynamic and respiratory parameters were comparable in both groups. Oxygenation did not differ between groups at comparable mean arterial blood pressures.

Students insert the laryngeal tube quicker and more often successful than the esophageal-tracheal combitube in a manikin.

BACKGROUND: Endotracheal intubation remains the standard of airway management. Because intubation skills are difficult to acquire, for medical students teaching of easier to learn techniques should be considered. METHODS: We retrospectively analyzed data that were collected in a University teaching facility. 264 medical students were taught how to use laryngeal tube (LT) and Esophageal Tracheal Combitube((R)) (ETC) in a manikin. The students underwent one of two different types of extraglottic airway management training consisting of either long lecture (30min) and intensive training (2h) (group IT, n=48), or brief (10min) lecture and 20min of training (group BT, n=216). Both groups underwent a test 6 weeks after training, group IT had an additional test 24h after training. RESULTS: After 24h students in group IT were faster using the LT than the ETC (31.7s+/-2.1 vs. 51.9s+/-5.8, p<0.001). Up to 6 weeks after training students were able to place the LT significantly faster than the ETC in both groups (26.5s+/-2.1 vs. 53.9s+/-5.8 group IT and 43.4s+/-1.6 vs. 103.8s+/-4.4 group BT, p<0.001). At 24h and 6 weeks following intensive training, there was no statistical difference in the time required for insertion of either device. CONCLUSION: Following different training scenarios in a manikin, students were able to place the LT much faster than the ETC. Even brief training was sufficient to generate short insertion times for the LT.

Hypoxemia during one-lung ventilation: prediction, prevention, and treatment.

When switching from two-lung to one-lung ventilation (OLV), shunt fraction increases, oxygenation is impaired, and hypoxemia may occur. Hypoxemia during OLV may be predicted from measurements of lung function, distribution of perfusion between the lungs, whether the right or the left lung is ventilated, and whether the operation will be performed in the supine or in the lateral decubitus position. Hypoxemia during OLV may be prevented by applying a ventilation strategy that avoids alveolar collapse while minimally impairing perfusion of the dependent lung. Choice of anesthesia does not influence oxygenation during clinical OLV. Hypoxemia during OLV may be treated symptomatically by increasing inspired fraction of oxygen, by ventilating, or by using continuous positive airway pressure in the nonventilated lung. Hypoxemia during OLV may be treated causally by correcting the position of the double-lumen tube, clearing the main bronchi of the ventilated lung from secretions, and improving the ventilation strategy.