Regional Gas Exchange Measured by 129 Xe Magnetic Resonance Imaging Before and After Combination Bronchodilators Treatment in Chronic Obstructive Pulmonary Disease.

BACKGROUND: Hyperpolarized 129 Xe magnetic resonance imaging (MRI) provides a non-invasive assessment of regional pulmonary gas exchange function. This technique has demonstrated that chronic obstructive pulmonary disease (COPD) patients exhibit ventilation defects, reduced interstitial barrier tissue uptake, and poor transfer to capillary red blood cells (RBCs). However, the behavior of these measurements following therapeutic intervention is unknown. PURPOSE: To characterize changes in 129 Xe gas transfer function following administration of an inhaled long-acting beta-agonist/long-acting muscarinic receptor antagonist (LABA/LAMA) bronchodilator. STUDY TYPE: Prospective. POPULATION: Seventeen COPD subjects (GOLD II/III classification per Global Initiative for Chronic Obstructive Lung Disease criteria) were imaged before and after 2 weeks of LABA/LAMA therapy. FIELD STRENGTH/SEQUENCES: Dedicated ventilation imaging used a multi-slice 2D gradient echo sequence. Three-dimensional images of ventilation, barrier uptake, and RBC transfer used an interleaved, radial, 1-point Dixon sequence. Imaging was acquired at 3 T. ASSESSMENT: 129 Xe measurements were quantified before and after LABA/LAMA treatment by ventilation defect + low percent (vendef + low ) and by barrier uptake and RBC transfer relative to a healthy reference population (bar%ref and RBC%ref ). Pulmonary function tests, including diffusing capacity of the lung for carbon monoxide (DLCO ), were also performed before and after treatment. STATISTICAL TESTS: Paired t-test, Pearson correlation coefficient (r). RESULTS: Baseline vendef + low was 57.8 ± 8.4%, bar%ref was 73.2 ± 19.6%, and RBC%ref was 36.5 ± 13.6%. Following treatment, vendef + low decreased to 52.5 ± 10.6% (P < 0.05), and improved in 14/17 (82.4%) of subjects. However, RBC%ref decreased in 10/17 (58.8%) of subjects. Baseline measurements of bar%ref and DLCO were correlated with the degree of post-treatment change in vendef + low (r = -0.49, P < 0.05 and r = -0.52, P < 0.05, respectively). CONCLUSION: LABA/LAMA therapy tended to preferentially improve ventilation in subjects whose 129 Xe barrier uptake and DLCO were relatively preserved. However, newly ventilated regions often revealed RBC transfer defects, an aspect of lung function opaque to spirometry. These microvasculature abnormalities must be accounted for when assessing the effects of LABA/LAMA therapy. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 4.

Evaluation of a novel endotracheal tube suctioning system incorporating an inflatable sweeper.

INTRODUCTION: Accumulation of secretions in an endotracheal tube can increase the resistance to flow resulting in an increased patient work of breathing when the patient is interacting with the ventilator. Retained secretions can also serve as an infection risk. Standard suction catheters are limited in their ability to keep the lumen of the endotracheal tube clear. A novel closed-suction catheter has been introduced that incorporates a balloon at its distal end that, when inflated, physically scrapes secretions out of the endotracheal tube (CleanSweep catheter (CSC), Teleflex, Morrisville NC). We hypothesized that the CSC would be more efficient at removing secretions from inside the endotracheal tube than a standard suction catheter (SSC). METHODS: We performed a bench study examining resistive pressures across different sizes of endotracheal tubes when cleaned by the CSC as compared with an SSC. This study was followed by a prospective crossover study again comparing the CSC with an SSC in intubated intensive care unit patients receiving mechanical ventilation and requiring frequent suctioning. RESULTS: For the bench study the CSC was significantly better in reducing airway resistive pressures (P < 0.001). In the prospective crossover study the CSC over 2 h also removed significantly more secretions than the SSC (P < 0.05). CONCLUSION: Both our bench and crossover clinical study demonstrated improved clearance of secretions with the CSC vs an SSC. Further research is needed to ascertain the clinical outcome benefits of enhanced secretion removal.

Chronic hypersensitivity pneumonitis in the southeastern United States: an assessment of how clinicians reached the diagnosis.

BACKGROUND: Chronic hypersensitivity pneumonitis (cHP) is a disease caused by exposure to inhaled environmental antigens. Diagnosis of cHP is influenced by the awareness of the disease prevalence, which varies significantly in different regions, and how clinicians utilize relevant clinical information. We conducted a retrospective study to evaluate how clinicians in the Southeast United States, where the climate is humid favoring mold growth, diagnosed cHP using items identified in the international modified Delphi survey of experts, i.e., environmental exposure, CT imaging and lung pathology, METHODS: We searched Duke University Medical Center database for patients over the age of 18 with a diagnosis of cHP (ICD-9 code: 495) between Jan. 1, 2008 to Dec. 31, 2013 using a query tool, Duke Enterprise Data Unified Content Explorer (DEDUCE). RESULTS: Five hundred patients were identified and 261 patients had cHP confirmed in clinic notes by a pulmonologist or an allergist. About half of the patients lived in the Research Triangle area where our medical center is located, giving an estimated prevalence rate of 6.5 per 100,000 persons. An exposure source was mentioned in 69.3% of the patient. The most common exposure sources were environmental molds (43.1%) and birds (26.0%). We used Venn diagram to evaluate how the patients met the three most common cHP diagnostic criteria: evidence of environmental exposures (history or precipitin) (E), chest CT imaging (C) and pathology from lung biopsies (P). Eighteen patients (6.9%) met none of three criteria. Of the remaining 243 patients, 135 patients (55.6%) had one (E 35.0%, C 3.3%, P 17.3%), 81 patients (33.3%) had two (E + C 12.3%, E + P 17.3%, C + P 4.9%), and 27 patients (11.1%) had all three criteria (E + C + P). Overall, 49.4% of patients had pathology from lung biopsy compared to 31.6% with CT scan. CONCLUSIONS: Environmental mold was the most common exposure for cHP in the Southeast United States. Lung pathology was available in more than half of cHP cases in our tertiary care center, perhaps reflecting the complexity of referrals. Differences in exposure sources and referral patterns should be considered in devising future diagnostic pathways or guidelines for cHP.

Hyperpolarized 129 Xe gas transfer MRI: the transition from 1.5T to 3T.

PURPOSE: Hyperpolarized 129 Xe MRI depicting 3D ventilation, interstitial barrier uptake, and transfer to red blood cells (RBCs) has emerged as a powerful new means of detecting pulmonary disease. However, given the challenging susceptibility environment of the lung, such gas transfer imaging has, thus far, only been implemented at 1.5T. Here, we seek to demonstrate the feasibility of Dixon-based 129 Xe gas transfer MRI at 3T. METHODS: Seven healthy subjects and six patients with pulmonary disorders were recruited to characterize 129 Xe spectral structure, optimize acquisition parameters, and acquire representative images. Imaging used randomized, gradient-spoiled 3D-radial encoding of 1000 gas (0.5° flip) and dissolved (20° flip) views, reconstructed into 3-mm isotropic voxels. The center of k-space was sampled when barrier and RBC compartments were 90° out of phase (TE90 ). A single dissolved phase spectrum was appended to the sequence to measure the global RBC-barrier ratio for Dixon-based decomposition. RESULTS: A 0.69 ms sinc was found to generate minimal off-resonance gas-phase excitation (3.0 ± 0.3% of the dissolved-phase), yielding a TE90 = 0.47 ± 0.02 ms. The RBC and barrier resonance frequencies were shifted by 217.6 ± 0.6 ppm and 197.8 ± 0.2 ppm. The RBC T 2 * was estimated to be ∼1.1 ms, and therefore each read-out was limited to 1.3 ms. 129 Xe gas and dissolved-phase images have sufficient SNR to produce gas transfer maps of similar quality and sensitivity to pathology, as previously obtained at 1.5T. CONCLUSIONS: Despite short dissolved-phase T 2 * , 129 Xe gas transfer MRI is feasible at 3T.

Non-malignant respiratory disease among workers in industries using styrene-A review of the evidence.

BACKGROUND: Asthma and obliterative bronchiolitis (OB) cases have occurred among styrene-exposed workers. We aimed to investigate styrene as a risk factor for non-malignant respiratory disease (NMRD). METHODS: From a literature review, we identified case reports and assessed cross-sectional and mortality studies for strength of evidence of positive association (i.e., strong, intermediate, suggestive, none) between styrene exposure and NMRD-related morbidity and mortality. RESULTS: We analyzed 55 articles and two unpublished case reports. Ten OB cases and eight asthma cases were identified. Six (75%) asthma cases had abnormal styrene inhalation challenges. Thirteen (87%) of 15 cross-sectional studies and 12 (50%) of 24 mortality studies provided at least suggestive evidence that styrene was associated with NMRD-related morbidity or mortality. Six (66%) of nine mortality studies assessing chronic obstructive pulmonary disease-related mortality indicated excess mortality. CONCLUSIONS: Available evidence suggests styrene exposure is a potential risk factor for NMRD. Additional studies of styrene-exposed workers are warranted. Am. J. Ind. Med. 60:163-180, 2017. © 2016 Wiley Periodicals, Inc.

Global perspectives of emerging occupational and environmental lung diseases.

PURPOSE OF REVIEW: New technologies continue to be introduced into the workplace and the environment. These novel technologies also bring in new hazards leading to evolving patterns of established occupational and environmental diseases, as well as novel conditions never before encountered. RECENT FINDINGS: Many of these emerging conditions have appeared in media outlets or in the literature as case reports. These sentinel cases often serve as a warning sign for subsequent outbreaks. This review will discuss environmental and occupational lung diseases and exposures from a global perspective. These diseases and exposures include environmental exposure to asbestos and lung diseases, accelerated silicosis in sandblasting jean workers, coal worker's pneumoconiosis in surface coal miners, health effects of indoor air pollution from burning of biomass fuels and exposures to heavy metals and potential health effects from hydraulic fracturing (fracking). Other emerging conditions are also discussed, including smog in developing countries, sand storms in Asia and the Middle East and respiratory illnesses from nanoparticles and man-made fibres. SUMMARY: Clinicians must remain vigilant for potential occupational and environmental exposures, especially when evaluating patients with unusual and unique presentation, so that occupational and environmental risk factors may be identified, and monitoring and preventive measures can be implemented early.

TD-19, an erlotinib derivative, induces epidermal growth factor receptor wild-type nonsmall-cell lung cancer apoptosis through CIP2A-mediated pathway.

Some patients with nonsmall-cell lung cancer (NSCLC) without epidermal growth factor receptor (EGFR) mutations still respond to gefitinib and erlotinib, suggesting that there may be a mechanism(s) other than the EGFR pathway that mediates the tumoricidal effects. In the current study, we tested the efficacy of TD-19, a novel compound chemically modified from erlotinib, which has more potent apoptotic effects than erlotinib in EGFR wild-type NSCLC cell lines. TD-19 induced significant cell death and apoptosis in H358, H441, H460, and A549 cells, as evidenced by increased caspase-3 activity and cleavage of procaspase-9 and poly (ADP-ribose) polymerase. The apoptotic effect of TD-19 in H460 cells, which were resistant to erlotinib, was associated with downregulation of cancerous inhibitor of protein phosphatase 2A (CIP2A), increased protein phosphatase 2A (PP2A) activity, and decreased AKT phosphorylation, but minimal effects on EGFR phosphorylation. Overexpression of CIP2A partially protected the H460 cells from TD-19-induced apoptosis. Okadaic acid, a known PP2A inhibitor, significantly reduced TD-19-induced apoptosis, while forskolin, which increased PP2A activity, increased the apoptotic effect of TD-19. TD-19 inhibited the growth of H460 xenograft tumors by ∼80%. We conclude that TD-19 exerted tumoricidal effects on NSCLC cells. TD-19 provides proof that the CIP2A pathway may be a novel target for the treatment of EGFR wild-type NSCLC.

Health effects associated with faulty application of spray polyurethane foam in residential homes.

BACKGROUND: Spray polyurethane foam (SPF) has become a popular form of home insulation in the United States, but there have been adverse health effects reported by home owners. METHODS: We summarized adverse health effects in 13 adults from 10 households (age: 33-82) whose homes were improperly retrofitted with SPF. Subjects either were not asked to leave the premise or were told to return too early. In some cases, proper ventilation was not used or the foams were sprayed using the improper mixing technique. We correlated symptoms with volatile organic compounds (VOCs) in indoor air samples. RESULTS: All subjects reported fishy odors and developed acute watery and burning eyes, burning nose, sinus congestion, throat irritation, cough, dyspnea and chest tightness. Twelve subjects (92.3%) reported acute neuropsychiatric symptoms, including headache, dizziness, forgetfulness, difficulty in concentrating and insomnia. Three subjects (23.0%) had nausea, vomiting and abdominal cramps and three (23.0%) developed skin rash. Subjects continued to experience symptoms long after SPF was done. These symptoms subsided after they left homes, but recurred upon returning. All subjects eventually vacated their homes. The methacholine challenge test was negative in 5 of 7 patients. Analysis of indoor air and headspace gas from the foams showed increased concentrations of VOCs derived from SPF and common indoor air pollutants. The levels of VOCs decreased after SPF was completely removed. CONCLUSIONS: Faulty application of SPF was associated with acute and persistent pulmonary and extra-pulmonary symptoms. These symptoms may be associated with SPF-derived compounds as well as increased concentrations of indoor VOCs.

Host and environmental factors affect pulmonary responses measured in bronchoalveolar lavage.

CONTEXT: Bronchoscopy with bronchoalveolar lavage (BAL) is used to measure pulmonary effects in inhalational exposure studies. OBJECTIVES: To determine how host and background environmental factors may affect pulmonary responses in BAL. MATERIALS AND METHODS: We retrospectively analyzed 77 healthy non-smoking volunteers (38 males and 39 females, age 18-35) who participated in a bronchoscopy study to donate cells for in vitro studies. BAL was performed by lavaging one subsegment of both the lingular segment of the left upper lobe and the right middle lobe with 250 ml of sterile normal saline each. We obtained temperature, relative humidity, ambient O3, PM2.5 and PM10 levels from monitor stations in Durham area in North Carolina. We correlated concentrations of leptin, adiponectin, monocyte chemotactic protein-1 (MCP-1), interleukin (IL)-8, ferritin and total lavaged cells in BAL samples with body mass index (BMI), age, ambient O3, PM2.5, PM10, temperature and relative humidity. RESULTS: Increased BMI was associated with higher lavage leptin. Males had higher MCP-1 and total lavaged cells than females. Average PM2.5, PM10 and O3 concentrations before bronchoscopy were 13.7 µg/m(3), 21.2 µg/m(3) and 0.029 ppm, respectively. Using stepwise multiple linear regression, we found positive associations of MCP-1 with BMI, and of total lavaged cells with humidity and O3. There were inverse associations of IL-8 and total lavaged cells with temperature. DISCUSSION AND CONCLUSIONS: Background environmental and host factors may affect some pulmonary responses to ambient pollutants. Interpretation of pulmonary effects in inhalational exposure studies may need to consider the effects of some host and environmental factors.

Development and evaluation of a computerized algorithm for the interpretation of pulmonary function tests.

Pulmonary function tests (PFTs) are usually interpreted by clinicians using rule-based strategies and pattern recognition. The interpretation, however, has variabilities due to patient and interpreter errors. Most PFTs have recognizable patterns that can be categorized into specific physiological defects. In this study, we developed a computerized algorithm using the python package (pdfplumber) and validated against clinicians' interpretation. We downloaded PFT reports in the electronic medical record system that were in PDF format. We digitized the flow volume loop (FVL) and extracted numeric values from the reports. The algorithm used FEV1/FVC<0.7 for obstruction, TLC<80%pred for restriction and <80% or >120%pred for abnormal DLCO. The algorithm also used a small airway disease index (SADI) to quantify late expiratory flattening of the FVL to assess small airway dysfunction. We devised keywords for the python Natural Language Processing (NLP) package (spaCy) to identify obstruction, restriction, abnormal DLCO and small airway dysfunction in the reports. The algorithm was compared to clinicians' interpretation in 6,889 PFTs done between March 1st, 2018, and September 30th, 2020. The agreement rates (Cohen's kappa) for obstruction, restriction and abnormal DLCO were 94.4% (0.868), 99.0% (0.979) and 87.9% (0.750) respectively. In 4,711 PFTs with FEV1/FVC≥0.7, the algorithm identified 190 tests with SADI < lower limit of normal (LLN), suggesting small airway dysfunction. Of these, the clinicians (67.9%) also flagged 129 tests. When SADI was ≥ LLN, no clinician's reports indicated small airway dysfunction. Our results showed the computerized algorithm agreed with clinicians' interpretation in approximately 90% of the tests and provided a sensitive objective measure for assessing small airway dysfunction. The algorithm can improve efficiency and consistency and decrease human errors in PFT interpretation. The computerized algorithm works directly on PFT reports in PDF format and can be adapted to incorporate a different interpretation strategy and platform.

The role of in vitro gene expression profiling in particulate matter health research.

Exposure to particulate matter (PM) is consistently associated with increased morbidity and mortality rate. The mechanisms for these adverse health effects have been vigorously investigated for many years, but remain uncertain, in part due to the complex interactions between host and exposure. Over the past decade, the use of global gene expression profiling has increased to investigate molecular changes in an attempt to gain more insight into the complex mechanisms that underlie the adverse health effects induced by PM. These experiments have been performed mostly in cell cultures, in part due to the easy availability and maneuverability of different cell types. Whether or not the results obtained from these in vitro experiments are relevant to human exposure is unclear. In this study, cell culture studies were reviewed that used microarray technology to measure global gene expression in response to PM and the findings discussed in the context of global gene expression results obtained from animal and human exposure studies. Ten in vitro studies were identified from PubMed that reported global gene expression results in response to PM exposure. Despite difference in cell types, microarray platforms, incubation time, and PM sources and doses, these experiments showed commonality in the expression of genes and pathways, especially xenobiotic metabolism, oxidative stress, and inflammation. These gene expression profiles were consistent with results from animal and human controlled exposure experiments. The in vitro experiments also uncovered novel biological mechanisms that may be important in PM-induced health effects reported in epidemiological studies. Data indicate that in vitro microarray experiments complement animal and human exposure studies and allow the PM-associated health research to focus on the "toxic" components in PM and novel mechanisms, and may enhance risk assessment beyond the current mass-based standards.

Impact of diagnostic guidelines on the diagnosis of hypersensitivity pneumonitis.

Introduction: Hypersensitivity pneumonitis (HP) is an immune-mediated interstitial lung disease from exposure to environmental antigens. Diagnosing HP could be challenging. The American College of Chest Physicians (CHEST) and American Thoracic Society/Japanese Respiratory Society/and Asociación Latinoamericana del Tórax (ATS/JRS/ALAT) have published diagnostic guidelines in 2021 and 2020 respectively. The CHEST guideline uses four grades of confidence: confident (>90%), provisional high (70-89%), provisional low (51-69%), and unlikely (≤50%). The ATS/JRS/ALAT guideline uses five grades of confidence: definite (>90%), high (80-89%), moderate (70-79%), low (51-69%) and not excluded (≤50%). In this study, we determined how these two guidelines could have affected the diagnosis of HP made before the guidelines. Methods: Two hundred and fifty-nine adult patients from a previous cohort with HP (ICD-9:495) made between Jan. 1, 2008, and Dec. 31, 2013, at Duke University Medical Center were included. We simplified the diagnostic confidence into three categories so we could compare the guidelines: high (≥90%), intermediate (51-89%), and low (≤50%). Results: There were 156 female and 103 male. Mean age was 58 (range: 20-90). 68.8% of the patients had restrictive defects (FVC < 80% pred) and 48.6% had lung biopsy. The CHEST guideline classified 33.6% of the patients into high, 59.5% into intermediate and 6.9% into low confidence categories. The ATS/JRS/ALAT guideline classified 29.7% of the patients into high, 21.2% into intermediate and 49.0% into low confidence categories (p < 0.0001 vs. CHEST). Cohen's kappa was 0.331. In patients with identifiable inciting agents (IAs) (N = 168), the CHEST guideline classified 32.1% of the patients into high, 64.3% into intermediate and 3.6% into low confidence categories. The ATS/JRS/ALAT guideline classified 29.2% of the patients into high, 20.8% into intermediate, and 50.0% into low confidence categories. Cohen's kappa was 0.314. Discussion: In our HP cohort with two-thirds of the patients with restrictive defects, we found the two guidelines had fair agreement in diagnosing HP with or without identifiable IAs. They agreed more when the diagnostic confidence was high. When the diagnostic confidence was lower, however, the ATS/JRS/ALAT guideline was more stringent. Clinicians should be aware of the differences between the two guidelines when evaluating patients suspicious of HP.

The Effects of Automatic Inspiratory Rise Time and Flow Termination on Operation of Closed-Loop Ventilation.

BACKGROUND: Adaptive ventilation mode (AVM) is a automated mode of mechanical ventilation. AVM is comprable to adaptive support ventilation (ASV). Both recommend a tidal volume (VT) and breathing frequency (f) combination based on lung mechanics, but AVM also automatically adjusts rise time and flow termination of pressure support breaths. How these added features of AVM affect VT and f recommendations compared to ASV is not clear. The present study compared these 2 modes in a test lung with obstructive and restrictive mechanics. METHODS: The experiment was performed in a simulated lung model in which the compliance (C) and resistance (R) could be altered independently. The ventilatory parameters at different minute volumes (MinVol%) in AVM or ASV mode were recorded. RESULTS: When MinVol% was set at 100%, AVM provided a similar VT and f combination compared to ASV with decreasing compliance or increasing resistance. However, when MinVol% was increased to 250% simulating hyperventilation, for the severely obstructive lung (C60, R70) model, AVM provided a significantly higher f (26 ± 0.6 breaths/min vs 7.00 ± 0 breaths/min in ASV) and lower VT (240 ± 80 mL vs 491 ± 131 mL in ASV). CONCLUSIONS: The addition of automatic control of rise time and flow termination functions did not affect recommended ventilator settings in AVM in the noncompliant or obstructive lung when minute ventilation (V̇E) was low. At higher V̇E, AVM compared to ASV recommended a ventilatory strategy with lower VT and higher f. These results need to be validated in patients.

Pollutant particles induce arginase II in human bronchial epithelial cells.

Exposure to particulate matter (PM) is associated with adverse pulmonary effects, including induction and exacerbation of asthma. Recently arginase was shown to play an important role in the pathogenesis of asthma. In this study, it was postulated that PM exposure might induce arginase. Human bronchial epithelial cells (HBEC) obtained from normal individuals by endobronchial brushings cultured on an air-liquid interface were incubated with fine Chapel Hill particles (PM2.5, 100 µg/ml) for up to 72 h. Arginase activity, protein expression, and mRNA of arginase I and arginase II were measured. PM2.5 increased arginase activity in a time-dependent manner. The rise was primarily due to upregulation of arginase II. PD153035 (10 µM), an epidermal growth factor (EGF) receptor antagonist, attenuated the PM2.5-induced elevation in arginase activity and arginase II expression. Treatment of HBEC with human EGF increased arginase activity and arginase II expression. Pretreatment with catalase (200 U/ml), superoxide dismutase (100 U/ml), or apocynin (5 µg/ml), an NAD(P)H oxidase inhibitor, did not markedly affect arginase II expression. Treatment of HBEC with arginase II siRNA inhibited the expression of arginase II by 60% and increased IL-8 release induced by PM2.5. These results indicate that PM exposure upregulates arginase II activity and expression in human bronchial epithelial cells, in part via EGF-dependent mechanisms independent of oxidative stress. The elevated arginase II activity and expression may be a mechanism underlying adverse effects induced by PM exposure in asthma patients.

Synergistic effects of exposure to concentrated ambient fine pollution particles and nitrogen dioxide in humans.

CONTEXT: Exposure to single pollutants e.g. particulate matter (PM) is associated with adverse health effects, but it does not represent a real world scenario that usually involves multiple pollutants. OBJECTIVES: Determine if simultaneous exposure to PM and NO2 results in synergistic interactions. MATERIALS AND METHODS: Healthy young volunteers were exposed to clean air, nitrogen dioxide (NO2, 0.5 ppm), concentrated fine particles from Chapel Hill air (PM(2.5)CAPs, 89.5 ± 10.7 µg/m³), or NO2+PM(2.5)CAPs for 2 h. Each subject performed intermittent exercise during the exposure. Parameters of heart rate variability (HRV), changes in repolarization, peripheral blood endpoints and lung function were measured before and 1 and 18 h after exposure. Bronchoalveolar lavage (BAL) was performed 18 h after exposure. RESULTS: NO2 exposure alone increased cholesterol and HDL 18 h after exposure, decreased high frequency component of HRV one and 18 h after exposure, decreased QT variability index 1 h after exposure, and increased LDH in BAL fluid. The only significant change with PM(2.5)CAPs was an increase in HDL 1 h after exposure, likely due to the low concentrations of PM(2.5)CAPs in the exposure chamber. Exposure to both NO2 and PM(2.5)CAPs increased BAL α1-antitrypsin, mean t wave amplitude, the low frequency components of HRV and the LF/HF ratio. These changes were not observed following exposure to NO2 or PM(2.5)CAPs alone, suggesting possible interactions between the two pollutants. DISCUSSION AND CONCLUSIONS: NO2 exposure may produce and enhance acute cardiovascular effects of PM(2.5)CAPs. Assessment of health effects by ambient PM should consider its interactions with gaseous copollutants.

Preventive use of noninvasive ventilation after extubation: a prospective, multicenter randomized controlled trial.

BACKGROUND: The effectiveness of noninvasive ventilation (NIV) after extubation in preventing post-extubation respiratory failure is still controversial. METHODS: We conducted a prospective, multicenter randomized controlled study involving patients on mechanical ventilation for > 48 hours who tolerated a 2-hour spontaneous breathing trial and were subsequently extubated. The patients were randomized to NIV or standard medical therapy. Re-intubation rate within 72 hours was the primary outcome measure. Multivariable logistic regression analysis was used to determine predictors for extubation failure. RESULTS: We randomized 406 patients to either NIV (no. = 202) or standard medical therapy (no. = 204). The 2 groups had similar baseline clinical characteristics. There were no differences in extubation failure (13.2% in control and 14.9% in NIV), intensive care unit or hospital mortality. Cardiac failure was a more common cause of extubation failure in control than in NIV. There was no difference in rapid shallow breathing index (RSBI) in extubation failure patients between control (80) and NIV (73). When using data from all patients, we found Acute Physiology and Chronic Health Evaluation (APACHE II) scores (odds ratio [OR] 1.13, 95% CI 1.07-1.20, P < .001), maximal inspiratory pressure (OR 1.04, 95% CI 1.00-1.08, P = .03), and RSBI (OR 1.03, 95% CI 1.02-1.05, P < .001) to be predictors of extubation failure. Abundant secretions were the most common reason (35.1%) for extubation failure identified by attending physicians. CONCLUSIONS: Preventive use of NIV after extubation in patients who passed spontaneous breathing trial did not show benefits in decreasing extubation failure rate or the mortality rate.

Development and Evaluation of a Small Airway Disease Index Derived From Modeling the Late-Expiratory Flattening of the Flow-Volume Loop.

Excessive decrease in the flow of the late expiratory portion of a flow volume loop (FVL) or "flattening", reflects small airway dysfunction. The assessment of the flattening is currently determined by visual inspection by the pulmonary function test (PFT) interpreters and is highly variable. In this study, we developed an objective measure to quantify the flattening. We downloaded 172 PFT reports in PDF format from the electronic medical records and digitized and extracted the expiratory portion of the FVL. We located point A (the point of the peak expiratory flow), point B (the point corresponding to 75% of the expiratory vital capacity), and point C (the end of the expiratory portion of the FVL intersecting with the x-axis). We did a linear fitting to the A-B segment and the B-C segment. We calculated: 1) the AB-BC angle (∠ABC), 2) BC-x-axis angle (∠BCX), and 3) the log ratio of the BC slope over the vertical distance between point A and x-axis [log (BC/A-x)]. We asked an expert pulmonologist to assess the FVLs and separated the 172 PFTs into the flattening and the non-flattening groups. We defined the cutoff value as the mean minus one standard deviation using data from the non-flattening group. ∠ABC had the best concordance rate of 80.2% with a cutoff value of 149.7°. We then asked eight pulmonologists to evaluate the flattening with and without ∠ABC in another 168 PFTs. The Fleiss' kappa was 0.320 (lower and upper confidence intervals [CIs]: 0.293 and 0.348 respectively) without ∠ABC and increased to 0.522 (lower and upper CIs: 0.494 and 0.550) with ∠ABC. There were 147 CT scans performed within 6 months of the 172 PFTs. Twenty-six of 55 PFTs (47.3%) with ∠ABC <149.7° had CT scans showing small airway disease patterns while 44 of 92 PFTs (47.8%) with ∠ABC ≥149.7° had no CT evidence of small airway disease. We concluded that ∠ABC improved the inter-rater agreement on the presence of the late expiratory flattening in FVL. It could be a useful addition to the assessment of small airway disease in the PFT interpretation algorithm and reporting.

Comparison of gene expression profiles induced by coarse, fine, and ultrafine particulate matter.

Coarse, fine, and ultrafine particulate matter (PM) fractions possess different physical properties and chemical compositions and may produce different adverse health effects. Studies were undertaken to determine whether or not gene expression patterns may be used to discriminate among the three size fractions. Airway epithelial cells obtained from 6 normal individuals were exposed to Chapel Hill coarse, fine or ultrafine PM (250 µg/ml) for 6 and 24 h (n=3 different individuals each). RNA was isolated and hybridized to Affymetrix cDNA microarrays. Significant genes were identified and mapped to canonical pathways. Expression of selected genes was confirmed by reverse-transcription polymerase chain reaction (RT-PCR). The numbers of genes altered by coarse, fine, and ultrafine PM increased from 0, 6, and 17 at 6 h to 1281, 302, and 455 at 24 h, respectively. The NRF2-mediated oxidative stress response, cell cycle:G2/M DNA damage checkpoint regulation, and mitotic roles of polo-like kinase were the top three pathways altered by all three fractions. Fine and ultrafine PM displayed more similar gene expression patterns. One example was the increased expression of metallothionein isoforms, reflecting the higher zinc content associated with fine and ultrafine fractions. A set of 10 genes was identified that could discriminate fine and ultrafine PM from coarse PM. These results indicate that common properties shared by the three size fractions as well as size-specific factors, e.g., compositions, may determine the effects on gene expression. Genomic markers may be used to discriminate coarse from fine and ultrafine PM.

Effects of implementing adaptive support ventilation in a medical intensive care unit.

BACKGROUND: Adaptive support ventilation (ASV) facilitates ventilator liberation in postoperative patients in surgical intensive care units (ICU). Whether ASV has similar benefits in patients with acute respiratory failure is unclear. METHODS: We conducted a pilot study in a medical ICU that manages approximately 600 mechanically ventilated patients a year. The ICU has one respiratory therapist who manages ventilators twice during the day shift (8:00 am to 5:00 pm). No on-site respiratory therapist was present at night. We prospectively enrolled 79 patients mechanically ventilated for ≥ 24 hours on pressure support of ≥ 15 cm H(2)O, with or without synchronized intermittent mandatory ventilation, F(IO(2)) ≤ 50%, and PEEP ≤ 8 cm H(2)O. We switched the ventilation mode to ASV starting at a "%MinVol" setting of 80-100%. We defined spontaneous breathing trial (SBT) readiness as a frequency/tidal-volume ratio of < 105 (breaths/min)/L on pressure support of ≤ 8 cm H(2)O and PEEP of ≤ 5 cm H(2)O for at least 2 h, and all spontaneous breaths. The T-piece SBT was considered successful if the frequency/tidal-volume ratio remained below 105 (breaths/min)/L for 30 min, and we extubated after successful SBT. The control group consisted of 70 patients managed with conventional ventilation modes and a ventilator protocol during a 6-month period immediately before the ASV study period. RESULTS: Extubation was attempted in 73% of the patients in the ASV group, and 80% of the patients in the non-ASV group. The re-intubation rates in the ASV and non-ASV groups were 5% and 7%, respectively. In the ASV group, 20% of the patients achieved extubation readiness within 1 day, compared to 4% in the non-ASV group (P = <.001). The median time from the enrollment to extubation readiness was 1 day for the ASV group and 3 days for the non-ASV group (P = .055). Patients switched to ASV were more likely to be liberated from mechanical ventilation at 3 weeks (P = .04). Multiple logistic regression analysis showed that, of the independent factors in the model, only ASV was associated with shorter time to extubation readiness (P = .048 via likelihood ratio test). CONCLUSIONS: Extubation readiness may not be recognized in a timely manner in at least 15% of patients recovering from respiratory failure. ASV helps to identify these patients and may improve their weaning outcomes.