We conclude that TNF-alpha overexpression causes pathologic changes consistent with both emphysema and pulmonary fibrosis combined with a general lung inflammation, and consequently does not model any single human disease. Our study thus confirms the pleiotropic effects of TNF-alpha, which has been implicated in multiple inflammatory disorders, and underscores the necessity of using a wide range of investigative techniques to link gene expression and phenotype in animal models of disease.

Reopening the injured lung with deep inflation (DI) and positive end-expiratory pressure (PEEP) likely depends on the duration and severity of acute lung injury (ALI), key features of which include increased alveolar permeability and fibrin accumulation. We hypothesized that the response to DI and PEEP would worsen as ALI evolves and that this would correspond with increasing accumulation of alveolar fibrin. C57BL/6 mice were anesthetized and aspirated 75 microl of HCl (pH 1.8) or buffered normal saline. Subgroups were reanesthetized 4, 14, 24, and 48 h later. Following DI, tissue damping (G) and elastance (H) were measured periodically at PEEP of 1, 3, and 6 cmH(2)O, and air within the lung (thoracic gas volume) was quantified by microcomputed tomography. Following DI, G and H increased with time during progressive lung derecruitment, the latter confirmed by microcomputed tomography. The rise in H was greater in acid-injured mice than in controls (P < 0.05) and also increased from 4 to 48 h after acid aspiration, reflecting progressively worsening injury. The rise in H was reduced by PEEP, but this effect was significantly blunted by 48 h (P < 0.05), also confirmed by thoracic gas volume. Lung permeability and alveolar fibrin also increased over the 48-h study period, accompanied by increasing levels and transcription of the fibrinolysis inhibitor plasminogen activator inhibitor-1. Lung injury worsens progressively in mice during the 48 h following acid aspiration. This injury manifests as progressively increasing alveolar instability, likely due to surfactant dysfunction caused by increasing levels of alveolar protein and fibrin.

The role of gastroesophageal reflux and micro-aspiration as a trigger of airways hyperresponsiveness (AHR) in patients with asthma is controversial. The role of acid reflux and aspiration as a direct cause of AHR in normal subjects is also unclear. We speculated that aspiration of a weak acid with a pH (1.8) equivalent to the upper range of typical gastric contents would lead to AHR in naive mice. We further speculated that modest reductions in aspirate acidity to a level expected during gastric acid suppression therapy (pH 4.0) would impede aspiration-induced AHR. BALB/c female mice were briefly anesthetized with isoflurane and allowed to aspirate 75 microl of saline with HCl (pH 1.8, 4.0, or 7.4) or underwent sham aspiration. Mice were re-anesthetized 2 or 24 h later, underwent tracheostomy, and were coupled to a mechanical ventilator. Forced oscillations were used to periodically measure respiratory impedance (Zrs) following aerosol delivery of saline and increasing doses of methacholine to measure for AHR. Values for elastance (H), airways resistance (R(N)), and tissue damping (G) were derived from Zrs. Aspirate pH of 1.8 led to a significant overall increase in peak R(N), G, and H compared with pH 4.0 and 7.4 at 2 and 24 h. Differences between pH 7.4 and 4.0 were not significant. In mice aspirating pH 1.8 compared with controls, airway lavage fluid contained more neutrophils, higher protein, and demonstrated higher permeability. We conclude that acid aspiration triggers an acute AHR, driven principally by breakdown of epithelial barrier integrity within the airways.

In select cases where additional tissue may be needed, sampling with a 19-G EBUS needle following standard aspiration with a 22-G needle results in an increase in diagnostic yield.

Background: Robotic assisted bronchoscopy (RAB) is designed to increase bronchoscopic accessibility for difficult to reach pulmonary lesions. One limitation to success of RAB is computed tomography (CT) to body divergence. Real time imaging with cone beam CT is increasingly utilized for confirmation of correct navigation and tool-in-lesion during RAB. O-arm CT is a 3-dimensional imaging modality, which has not previously been described for use with RAB. Our purpose is to display the feasibility, ease of use, and high rate of confirmation of tool-in-lesion when using O-arm CT during RAB.Methods: Single center, retrospective review of 75 patients undergoing RAB with intraprocedural use of O-arm CT.Results: Median patient age was 65 years. Forty-nine percent of cases involved nodules ≤ 2 cm. Bronchus sign was absent in 44% of cases. Median procedure time was 80 minutes. Median number of O-arm CT runs per case was 2. The median effective dose of radiation was 7.2 millisieverts. Tool-in-lesion was confirmed in 97% (77 of 79) of cases. Definitive diagnosis was reached in 61 to 68 of 79 cases (77% to 86%). There were 2 cases of pneumothorax (2.5%), one of which needed intervention with tube thoracostomy.Conclusions: O-arm CT is an effective, and convenient alternative to other 3-dimensional imaging modalities for intraprocedural confirmation of tool-in-lesion during RAB.

We have previously measured thoracic gas volume (VTG) in spontaneously breathing mice using a whole body plethysmograph and have now extended our technique to allow for V(TG) measurements during paralysis. BALB/c mice were anesthetized and placed in a body-box and ventilated via a tracheostomy cannula through the box wall. Box pressure (Pb) and tracheal pressure (Pao) were measured during spontaneous breathing, and again after paralysis while mechanically compressing the chest. V(TG) was much larger after paralysis (0.49+/-0.06 ml, positive end-expiratory pressure = 2 cmH2O) when compared with spontaneous breathing (0.31+/-0.01 ml). External chest compression produced looping in the plots of Pb versus Pao that was attributable to gradual changes in Pb upon release of the mechanical chest compression and had the character of thermal transients. Under the assumption that the rate of heating of the air in the chamber was proportional to the pressure applied to the animal's chest, and that any increase in air temperature was dissipated by heat absorption by the chamber walls, we developed an algorithm that corrected for the thermal events. This yielded similar results for V(TG) (0.30+/-0.02 ml) as obtained during spontaneous efforts. Our method may prove particularly useful when paralysis is required for the precise measurement of lung mechanics.

Background: The utility of vitamin D (VITD) supplementation during critical illness and whether it may alter outcomes, including mortality and ventilator-free days, is unclear. We performed a retrospective cohort study in a generalizable population to investigate this question. Methods: We included all mechanically ventilated adults admitted to the medical intensive care unit (ICU) service at a tertiary center from 2009 to 2012 who were in the ICU for at least 72 hours. Patients were grouped as having received or not received VITD at any time during the first 7 days of their ICU stay, and we adjusted for the following covariates with multivariable analyses: simplified acute physiology score, age, gender, admission diagnosis, race/ethnicity, admission season, admission day of the week, and VITD supplementation prior to admission. Results: Among the 610 included patients, 281 received VITD, and 329 did not. There were no differences in outcomes between these groups. However, we did find significantly more ventilator-free days (21.0±2.6 [adjusted mean days±standard error] vs 17.6±2.4, P=0.04) and ICU-free days (18.5±2.5 vs 16.3±2.3, P=0.03) in patients who were taking VITD prior to admission (n=91) vs those who were not (n=519). No patients who were taking VITD before admission died vs 34.5% of those who were not (estimated odds ratio=4.9×10 −7 , 95% CI=3.1×10 −7 to 7.5×10 −7 , P<0.0001). Conclusion: These results suggest that VITD supplementation during critical illness may not provide benefit and that further research investigating potential supplementation in ambulatory patients at high risk of ICU admission (eg, severe underlying chronic disease) is warranted. (JPEN J Parenter Enteral Nutr. 2019;43:1037-1043

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