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Background Ketamine is a potent sedative drug that helps to maintain upper‐airway patency, due to its higher upper‐airway dilator muscular activity and higher level of duty cycle, as seen in rats. However, no clinical trials have tested passive upper‐airway collapsibility and changes in the inspiratory duty cycle against partial upper‐airway obstruction in humans. The present study evaluated both the passive mechanical upper‐airway collapsibility and compensatory response against acute partial upper‐airway obstruction using three different sedative drugs in a crossover trial. Methods Eight male volunteers entered this nonblinded, randomized crossover study. Upper‐airway collapsibility (passive critical closing pressure) and inspiratory duty cycle were measured under moderate sedation with ketamine, propofol, and dexmedetomidine. Propofol, dexmedetomidine, and ketamine anesthesia were induced to obtain adequate, same‐level sedation, with a BIS value of 50–70 and the OAA/S score of 2–3 and RASS score of −3. Results The median passive critical closing pressure of 0.08 [−5.51 to 1.20] cm H2O was not significantly different compared to that of propofol sedation (−0.32 [−1.41 to −0.19] cm H2O) and of dexmedetomidine sedation (−0.28 [−0.95 to −0.03] cm H2O) (p = .045). The median passive RUS for ketamine 54.35 [32.00 to 117.50] cm H2O/L/s was significantly higher than that for propofol 5.50 [2.475 to 19.60] cm H2O/L/s; (mean difference, 27.50; 95% CI 9.17 to 45.83) (p = .009) and for dexmedetomidine 19.25 [4.125 to 22.05] cm H2O/L/s; (mean difference, 22.88; 95% CI 4.67 to 41.09) (p = .021). The inspiratory duty cycle increased significantly as the inspiratory airflow decreased in passive conditions for each sedative drug, but behavior differed among the three sedative drugs. Conclusion Our findings demonstrate that ketamine sedation may have an advantage of both maintained passive upper‐airway collapsibility and a compensatory respiratory response, due to both increase in neuromuscular activity and the increased duty cycle, to acute partial upper‐airway obstruction. ketamine sedation may have an advantage of both maintained passive upper‐airway collapsibility and a compensatory respiratory response, due to the increased duty cycle, to acute partial upper‐airway obstruction.

To determine the safety and clinical efficacy of an innovative integrated airway system (AnapnoGuard™ 100 system) that continuously monitors and controls the cuff pressure (Pcuff), while facilitating the aspiration of subglottic secretions (SS). This was a prospective, single centre, open-label, randomized, controlled feasibility and safety trial. The primary endpoint of the study was the rate of device related adverse events (AE) and serious AE (SAE) as a result of using AnapnoGuard (AG) 100 during mechanical ventilation. Secondary endpoints were: (1) mechanical complications rate (2) ICU staff satisfaction; (3) VAP occurrence; (4) length of mechanical ventilation; (5) length of Intensive Care Unit stay and mortality; (6) volume of evacuated subglottic secretions. Sixty patients were randomized to be intubated with the AG endotracheal-tube (ETT) and connected to the AG 100 system allowing Pcuff adjustment and SS aspiration; or with an ETT combined with SS drainage and Pcuff controlled manually. No difference in adverse events rate was identified between the groups. The use of AG system was associated with a significantly higher incidence of Pcuff determinations in the safety range (97.3% vs. 71%; p<0.01) and a trend to a greater volume of aspirated SS secretions: (192.0[64-413] ml vs. 150[50-200], p = 0.19 (total)); (57.8[20-88.7] ml vs. 50[18.7-62] ml, p = 0.11 (daily)). No inter-group difference was detected using AG system vs. controls in terms of post-extubation throat pain level (0 [0-2] vs. 0 [0-3]; p = 0.7), hoarseness (42.9% vs. 75%; p = 0.55) and tracheal mucosa oedema (16.7% vs. 10%; p = 0.65). Patients enrolled in the AG group had a trend to reduced VAP risk of ventilator-associated pneumonia(VAP) (14.8% vs. 40%; p = 0.06), which were more frequently monomicrobial (25% vs. 70%; p = 0.03). No statistically significant difference was observed in duration of mechanical ventilation, ICU stay, and mortality. The use AG 100 system and AG tube in critically ill intubated patients is safe and effective in Pcuff control and SS drainage. Its protective role against VAP needs to be confirmed in a larger randomized trial. ClinicalTrials.gov NCT01550978. Date of registration: February 21, 2012.

Susceptibility to chronic obstructive pulmonary disease (COPD) beyond cigarette smoking is incompletely understood, although several genetic variants associated with COPD are known to regulate airway branch development. We demonstrate that in vivo central airway branch variants are present in 26.5% of the general population, are unchanged over 10 y, and exhibit strong familial aggregation. The most common airway branch variant is associated with COPD in two cohorts (n = 5,054), with greater central airway bifurcation density, and with emphysema throughout the lung. The second most common airway branch variant is associated with COPD among smokers, with narrower airway lumens in all lobes, and with genetic polymorphisms within the FGF10 gene. We conclude that central airway branch variation, readily detected by computed tomography, is a biomarker of widely altered lung structure with a genetic basis and represents a COPD susceptibility factor.

Lung disease in people with cystic fibrosis (CF) is initiated by defective host defense that predisposes airways to bacterial infection. Advanced CF is characterized by a deficit in mucociliary transport (MCT), a process that traps and propels bacteria out of the lungs, but whether this deficit occurs first or is secondary to airway remodeling has been unclear. To assess MCT, we tracked movement of radiodense microdisks in airways of newborn piglets with CF. Cholinergic stimulation, which elicits mucus secretion, substantially reduced microdisk movement. Impaired MCT was not due to periciliary liquid depletion; rather, CF submucosal glands secreted mucus strands that remained tethered to gland ducts. Inhibiting anion secretion in non-CF airways replicated CF abnormalities. Thus, impaired MCT is a primary defect in CF, suggesting that submucosal glands and tethered mucus may be targets for early CF treatment.

The role of excessive airway constriction in the hyperresponsiveness to nebulized methacholine in mice with experimental asthma is still contentious. Yet, there have been very few studies investigating whether the increased in vivo response to methacholine caused by experimental asthma is associated with a corresponding increase in ex vivo airway constriction. Herein, the responses to nebulized methacholine in vivo and airway constriction in lung slices ex vivo were studied in 8‐ to 10‐week‐old male mice of two strains, BALB/c and C57BL/6. Experimental asthma was induced by administering house dust mites (HDM) intranasally, once daily, for 10 consecutive days. Complementary ex vivo studies were conducted with excised tracheas to measure and compare isometric force. As expected, the in vivo response to methacholine, and especially the hyperresponsiveness caused by HDM, was greater in BALB/c than in C57BL/6 mice. In contrast, there were no differences in maximal airway constriction between mouse strains, and the hyperresponsiveness to nebulized methacholine caused by HDM in both mouse strains was not associated with a corresponding increase in ex vivo airway constriction. The experiments with excised tracheas demonstrated no differences in isometric force between strains and between mice with and without experimental asthma. It is concluded that the hyperresponsiveness to nebulized methacholine in an acute mouse model of asthma induced by repeated HDM exposures is not associated with excessive airway constriction ex vivo. What is the central question of this study? In this study, we investigated the association between the in vivo response of the respiratory system to nebulized methacholine and the ex vivo responsiveness of airways in two mouse strains with and without experimental asthma induced by repetitive intranasal exposures to house dust mites. The ex vivo assays included measurements of airway constriction in lung slices and measurements of isometric force with excised tracheas. What is the main finding and its importance? Although striking differences in the in vivo response to methacholine were observed between mouse strains and between mice with and without experimental asthma, these changes were not matched by corresponding changes in ex vivo airway responsiveness.

Inhalation injury, a critical complication in patients with severe burns, contributes substantially to morbidity and mortality. Current diagnostic practices suffer from subjectivity and lack quantitative metrics. Enhanced diagnostic accuracy is imperative for improving treatment outcomes. Our objective was to develop normalized cross-sectional compliance (nCsC) of the airway wall, as measured by anatomical optical coherence tomography (aOCT), to reflect the severity of trachea inhalation injury. We employed a customized aOCT system that incorporates an intraluminal pressure probe to assess nCsC in pigs subjected to steam-induced inhalation injuries. Multiple steam intensity levels of injury were induced, and nCsC was measured from the carina to the larynx at time points up to 6 h using aOCT. Histological analysis was performed post-mortem. We revealed that airway wall nCsC decreased initially after injury but exhibited recovery at 4 h. This is supported by ANOVA results showing that nCsC was significantly influenced by time ( ). Linear regression indicated that nCsC was negatively correlated with anatomical position ( ), whereas histological injury grade was positively correlated with position ( ). In other words, nCsC decreased and injury grading increased when closer to the site of steam introduction. Airway wall nCsC is a promising quantitative metric for assessing inhalation injury. Future translation of this aOCT-based technology to humans may potentially enhance clinical management of inhalation injuries.

Mounting evidence suggests that nematode infection can protect against disorders of immune dysregulation. Administration of live parasites or their excretory/secretory (ES) products has shown therapeutic effects across a wide range of animal models for immune disorders, including asthma. Human clinical trials of live parasite ingestion for the treatment of immune disorders have produced promising results, yet concerns persist regarding the ingestion of pathogenic organisms and the immunogenicity of protein components. Despite extensive efforts to define the active components of ES products, no small molecules with immune regulatory activity have been identified from nematodes. Here we show that an evolutionarily conserved family of nematode pheromones called ascarosides strongly modulates the pulmonary immune response and reduces asthma severity in mice. Screening the inhibitory effects of ascarosides produced by animal-parasitic nematodes on the development of asthma in an ovalbumin (OVA) murine model, we found that administration of nanogram quantities of ascr#7 prevented the development of lung eosinophilia, goblet cell metaplasia, and airway hyperreactivity. Ascr#7 suppressed the production of IL-33 from lung epithelial cells and reduced the number of memory-type pathogenic Th2 cells and ILC2s in the lung, both key drivers of the pathology of asthma. Our findings suggest that the mammalian immune system recognizes ascarosides as an evolutionarily conserved molecular signature of parasitic nematodes. The identification of a nematode-produced small molecule underlying the well-documented immunomodulatory effects of ES products may enable the development of treatment strategies for allergic diseases.

Obesity is a major risk factor for obstructive sleep apnea. Although greater dimensional changes in the upper airway during wake respiration have been noted in patients with apnea compared with control subjects, whether these differences remain in the presence of obesity is unknown. To evaluate upper airway anatomic characteristics and airway compliance (distensibility) in obese subjects with obstructive sleep apnea compared with obese control subjects. Dynamic magnetic resonance imaging was performed in 157 obese subjects with apnea and 46 obese control subjects during wakefulness in the midsagittal and three axial upper airway regions (retropalatal, retroglossal, epiglottal). Differences in measurements between subjects with apnea and control subjects, and correlations with apnea-hypopnea index among subjects with apnea, were examined. Measurements included airway areas and linear dimensions. Subject-specific coefficients of variation were calculated to examine variability in airway size. Controlling for covariates, the retropalatal area during respiration was significantly smaller in subjects with apnea than control subjects, based on the average (P = 0.003), maximum (P = 0.004), and minimum (P = 0.001) airway area. Airway narrowing was observed in anteroposterior and lateral dimensions (adjusted P < 0.05). Results were similar in an age, sex, and body mass index-matched subsample. There were significant correlations between apnea-hypopnea index and dynamic measures of airway caliber in the retropalatal and retroglossal regions among subjects with apnea. Upper airway caliber during respiration was significantly narrower in obese subjects with apnea than obese control subjects in the retropalatal region. These findings provide further evidence that retropalatal airway narrowing plays an important role in the pathogenesis of obstructive sleep apnea in obese subjects.

Abstract Rationale The mechanisms underlying cystic fibrosis (CF) lung disease pathogenesis are unknown. Objectives To establish mechanisms linking anion transport with the functional microanatomy, we evaluated normal and CF piglet trachea as well as adult swine trachea in the presence of selective anion inhibitors. Methods We investigated airway functional microanatomy using microoptical coherence tomography, a new imaging modality that concurrently quantifies multiple functional parameters of airway epithelium in a colocalized fashion. Measurements and Main Results Tracheal explants from wild-type swine demonstrated a direct link between periciliary liquid (PCL) hydration and mucociliary transport (MCT) rates, a relationship frequently invoked but never experimentally confirmed. However, in CF airways this relationship was completely disrupted, with greater PCL depths associated with slowest transport rates. This disrupted relationship was recapitulated by selectively inhibiting bicarbonate transport in vitro and ex vivo. CF mucus exhibited increased viscosity in situ due to the absence of bicarbonate transport, explaining defective MCT that occurs even in the presence of adequate PCL hydration. Conclusions An inherent defect in CF airway surface liquid contributes to delayed MCT beyond that caused by airway dehydration alone and identifies a fundamental mechanism underlying the pathogenesis of CF lung disease in the absence of antecedent infection or inflammation.

Epidemiologic studies have linked gestational vitamin D deficiency to respiratory diseases, although mechanisms have not been defined. We hypothesized that antenatal vitamin D deficiency would impair airway development and alveolarization in a mouse model. We studied the effect of antenatal vitamin D deficiency by inducing it in pregnant mice and then compared lung development and function in their offspring to littermate controls. Postnatal vitamin D deficiency and sufficiency models from each group were also studied. We developed a novel tracheal ultrasound imaging technique to measure tracheal diameter in vivo. Histological analysis estimated tracheal cartilage total area and thickness. We found that vitamin D–deficient pups had reduced tracheal diameter with decreased tracheal cartilage minimal width. Vitamin D deficiency increased airway resistance and reduced lung compliance, and led to alveolar simplification. Postnatal vitamin D supplementation improved lung function and radial alveolar count, a parameter of alveolar development, but did not correct tracheal narrowing. We conclude that antenatal vitamin D deficiency impairs airway and alveolar development and limits lung function. Reduced tracheal diameter, cartilage irregularity, and alveolar simplification in vitamin D–deficient mice may contribute to increased airways resistance and diminished lung compliance. Vitamin D supplementation after birth improved lung function and, potentially, alveolar simplification, but did not improve defective tracheal structure. This mouse model offers insight into the mechanisms of vitamin D deficiency–associated lung disease and provides an in vivo model for investigating preclinical preventive and therapeutic strategies.