Prolonged, physiologically relevant nicotine concentrations in the airways of smokers.

Nicotine from cigarette smoke is a biologically active molecule that has pleiotropic effects in the airway, which could play a role in smoking-induced lung disease. However, whether nicotine and its metabolites reach sustained, physiologically relevant concentrations on airway surfaces of smokers is not well defined. To address these issues, concentrations of nicotine, cotinine, and hydroxycotinine were measured by mass spectrometry (MS) in supernatants of induced sputum obtained from participants in the subpopulations and intermediate outcome measures in COPD study (SPIROMICS), an ongoing observational study that included never smokers, former smokers, and current smokers with and without chronic obstructive pulmonary disease (COPD). A total of 980 sputum supernatants were analyzed from 77 healthy never smokers, 494 former smokers (233 with COPD), and 396 active smokers (151 with COPD). Sputum nicotine, cotinine, and hydroxycotinine concentrations corresponded to self-reported smoking status and were strongly correlated to urine measures. A cutoff of ∼8-10 ng/mL of sputum cotinine distinguished never smokers from active smokers. Accounting for sample dilution during processing, active smokers had airway nicotine concentrations in the 70-850 ng/mL (∼0.5-5 µM) range, and concentrations remained elevated even in current smokers who had not smoked within 24 h. This study demonstrates that airway nicotine and its metabolites are readily measured in sputum supernatants and can serve as biological markers of smoke exposure. In current smokers, nicotine is present at physiologically relevant concentrations for prolonged periods, supporting a contribution to cigarette-induced airway disease.

Forced Expiratory Flow at 25%-75% Links COPD Physiology to Emphysema and Disease Severity in the SPIROMICS Cohort.

BACKGROUND: Forced expiratory volume in 1 second (FEV1) is central to the diagnosis of chronic obstructive pulmonary disease (COPD) but is imprecise in classifying disease burden. We examined the potential of the maximal mid-expiratory flow rate (forced expiratory flow rate between 25% and 75% [FEF25%-75%]) as an additional tool for characterizing pathophysiology in COPD. OBJECTIVE: To determine whether FEF25%-75% helps predict clinical and radiographic abnormalities in COPD. STUDY DESIGN AND METHODS: The SubPopulations and InteRediate Outcome Measures In COPD Study (SPIROMICS) enrolled a prospective cohort of 2978 nonsmokers and ever-smokers, with and without COPD, to identify phenotypes and intermediate markers of disease progression. We used baseline data from 2771 ever-smokers from the SPIROMICS cohort to identify associations between percent predicted FEF25%-75% (%predFEF25%-75%) and both clinical markers and computed tomography (CT) findings of smoking-related lung disease. RESULTS: Lower %predFEF25-75% was associated with more severe disease, manifested radiographically by increased functional small airways disease, emphysema (most notably with homogeneous distribution), CT-measured residual volume, total lung capacity (TLC), and airway wall thickness, and clinically by increased symptoms, decreased 6-minute walk distance, and increased bronchodilator responsiveness (BDR). A lower %predFEF25-75% remained significantly associated with increased emphysema, functional small airways disease, TLC, and BDR after adjustment for FEV1 or forced vital capacity (FVC). INTERPRETATION: The %predFEF25-75% provides additional information about disease manifestation beyond FEV1. These associations may reflect loss of elastic recoil and air trapping from emphysema and intrinsic small airways disease. Thus, %predFEF25-75% helps link the anatomic pathology and deranged physiology of COPD.

Ratio of FEV1/Slow Vital Capacity of < 0.7 Is Associated With Clinical, Functional, and Radiologic Features of Obstructive Lung Disease in Smokers With Preserved Lung Function.

BACKGROUND: Mild expiratory flow limitation may not be recognized using traditional spirometric criteria based on the ratio of FEV1/FVC. RESEARCH QUESTION: Does slow vital capacity (SVC) instead of FVC increase the sensitivity of spirometry to identify patients with early or mild obstructive lung disease? STUDY DESIGN AND METHODS: We included 854 current and former smokers from the Subpopulations and Intermediate Outcome Measures in COPD Study cohort with a postbronchodilator FEV1/FVC ≥ 0.7 and FEV1 % predicted of ≥ 80% at enrollment. We compared baseline characteristics, chest CT scan features, exacerbations, and progression to COPD (postbronchodilator FEV1/FVC, < 0.7) during the follow-up period between 734 participants with postbronchodilator FEV1/SVC of ≥ 0.7 and 120 with postbronchodilator FEV1/SVC < 0.7 at the enrollment. We performed multivariate linear and logistic regression models and negative binomial and interval-censored proportion hazards regression models adjusted for demographics and smoking exposure to examine the association of FEV1/SVC < 0.7 with those characteristics and outcomes. RESULTS: Participants with FEV1/SVC < 0.7 were older and had lower FEV1 and more emphysema than those with FEV1/SVC ≥ 0.7. In adjusted analysis, individuals with postbronchodilator FEV1/SVC < 0.7 showed a greater percentage of emphysema by 0.45% (95% CI, 0.09%-0.82%), percentage of gas trapping by 2.52% (95% CI, 0.59%-4.44%), and percentage of functional small airways disease based on parametric response mapping by 2.78% (95% CI, 0.72%-4.83%) at baseline than those with FEV1/SVC ≥ 0.7. During a median follow-up time of 1,500 days, an FEV1/SVC < 0.7 was not associated with total exacerbations (incident rate ratio [IRR], 1.61; 95% CI, 0.97-2.64), but was associated with severe exacerbations (IRR, 2.60; 95% CI, 1.04-4.89). An FEV1/SVC < 0.7 was associated with progression to COPD during a 3-year follow-up even after adjustment for demographics and smoking exposure (hazard ratio, 3.93; 95% CI, 2.71-5.72). We found similar results when we examined the association of prebronchodilator FEV1/SVC < 0.7 or FEV1/SVC less than the lower limit of normal with chest CT scan features and progression to COPD. INTERPRETATION: Low FEV1 to SVC in current and former smokers with normal spirometry results can identify individuals with CT scan features of COPD who are at risk for severe exacerbations and is associated with progression to COPD in the future. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01969344T4; URL: www.clinicaltrials.gov.

Actigraphy to Measure Physical Activity in the Intensive Care Unit: A Systematic Review.

OBJECTIVE: In the intensive care unit (ICU), prolonged inactivity is common, increasing patients' risk for adverse outcomes, including ICU-acquired weakness. Hence, interventions to minimize inactivity are gaining popularity, highlighting actigraphy, a measure of activity involving a wristwatch-like accelerometer, as a method to inform these efforts. Therefore, we performed a systematic review of studies that used actigraphy to measure patient activity in the ICU setting. DATA SOURCES: We searched PubMed, EMBASE, CINAHL, Cochrane Library, and ProQuest from inception until December 2016. STUDY SELECTION: Two reviewers independently screened studies for inclusion. A study was eligible for inclusion if it was published in a peer-reviewed journal and used actigraphy to measure activity in ≥5 ICU patients. DATA EXTRACTION: Two reviewers independently performed data abstraction and risk of bias assessment. Abstracted actigraphy-based activity data included total activity time and activity counts. RESULTS: Of 16 studies (607 ICU patients) identified, 14 (88%) were observational, 2 (12%) were randomized control trials, and 5 (31%) were published after 2009. Mean patient activity levels per 15 to 60 second epoch ranged from 25 to 37 daytime and 2 to 19 nighttime movements. Actigraphy was evaluated in the context of ICU and post-ICU outcomes in 11 (69%) and 5 (31%) studies, respectively, and demonstrated potential associations between actigraphy-based activity levels and delirium, sedation, pain, anxiety, time to extubation, and length of stay. CONCLUSION: Actigraphy has demonstrated that patients are profoundly inactive in the ICU with actigraphy-based activity levels potentially associated with important measures, such as delirium, sedation, and length of stay. Larger and more rigorous studies are needed to further evaluate these associations and the overall utility of actigraphy in the ICU setting.

Clinical Significance of Bronchodilator Responsiveness Evaluated by Forced Vital Capacity in COPD: SPIROMICS Cohort Analysis.

Objective: Bronchodilator responsiveness (BDR) is prevalent in COPD, but its clinical implications remain unclear. We explored the significance of BDR, defined by post-bronchodilator change in FEV1 (BDRFEV1) as a measure reflecting the change in flow and in FVC (BDRFVC) reflecting the change in volume. Methods: We analyzed 2974 participants from a multicenter observational study designed to identify varying COPD phenotypes (SPIROMICS). We evaluated the association of BDR with baseline clinical characteristics, rate of prospective exacerbations and mortality using negative binomial regression and Cox proportional hazards models. Results: A majority of COPD participants exhibited BDR (52.7%). BDRFEV1 occurred more often in earlier stages of COPD, while BDRFVC occurred more frequently in more advanced disease. When defined by increases in either FEV1 or FVC, BDR was associated with a self-reported history of asthma, but not with blood eosinophil counts. BDRFVC was more prevalent in subjects with greater emphysema and small airway disease on CT. In a univariate analysis, BDRFVC was associated with increased exacerbations and mortality, although no significance was found in a model adjusted for post-bronchodilator FEV1. Conclusion: With advanced airflow obstruction in COPD, BDRFVC is more prevalent in comparison to BDRFEV1 and correlates with the extent of emphysema and degree of small airway disease. Since these associations appear to be related to the impairment of FEV1, BDRFVC itself does not define a distinct phenotype nor can it be more predictive of outcomes, but it can offer additional insights into the pathophysiologic mechanism in advanced COPD. Clinical trials registration: ClinicalTrials.gov: NCT01969344T4.

Spelunking Meckel Cave: A 31-Year-Old With Diplopia and Loss of Taste and Smell.

CASE PRESENTATION: A 31-year-old woman presented to the ED with a loss of taste and smell of 2 months' duration and a frontal headache, bilateral facial numbness, photophobia, and horizontal diplopia that was worse with far vision of 2 weeks' duration. A review of systems revealed mild nausea and decreased appetite without weight loss. She denied any cardiopulmonary symptoms, specifically no cough or shortness of breath. Her medical history was notable for arthralgias. The patient was diagnosed with ankylosing spondylitis, for which she had been taking etanercept for several months. She consumed minimal alcohol and had no history of tobacco or drug use or recent travel. Her family history was unremarkable.

Actigraphy to Evaluate Sleep in the Intensive Care Unit. A Systematic Review.

RATIONALE: Poor sleep quality is common in the intensive care unit (ICU) and may be associated with adverse outcomes. Hence, ICU-based efforts to promote sleep are gaining attention, motivating interest in methods to measure sleep in critically ill patients. Actigraphy evaluates rest and activity by algorithmically processing gross motor activity data, usually collected by a noninvasive wristwatch-like accelerometer device. In critically ill patients, actigraphy has been used as a surrogate measure of sleep; however, its use has not been systematically reviewed. OBJECTIVES: To conduct a systematic review of ICU-based studies that used actigraphy as a surrogate measure of sleep, including its feasibility, validity, and reliability as a measure of sleep in critically ill patients. METHODS: We searched PubMed, EMBASE, CINAHL, Proquest, and Web of Science for studies that used actigraphy to evaluate sleep in five or more patients in an ICU setting. RESULTS: Our search yielded 4,869 citations, with 13 studies meeting eligibility criteria. These 13 studies were conducted in 10 countries, and eight (62%) were published since 2008. Across the 13 studies, the mean total sleep time of patients in the ICU, as estimated using actigraphy, ranged from 4.4 to 7.8 hours at nighttime and from 7.1 to 12.1 hours over a 24-hour period, with 1.4 to 49.0 mean nocturnal awakenings and a sleep efficiency of 61 to 75%. When compared side-by-side with other measures of sleep (polysomnography, nurse assessments, and patient questionnaires), actigraphy consistently yielded higher total sleep time and sleep efficiency, fewer nighttime awakenings (vs. polysomnography), and more overall awakenings (vs. nurse assessment and patient questionnaires). None of the studies evaluated the association between actigraphy-based measures of sleep and outcomes of patients in the ICU. CONCLUSIONS: In critically ill patients, actigraphy is being used more frequently as a surrogate measure of sleep; however, because actigraphy only measures gross motor activity, its ability to estimate sleep is limited by the processing algorithm used. Prior ICU-based studies involving actigraphy were heterogeneous and lacked data regarding actigraphy-based measures of sleep and patient outcomes. Larger, more rigorous and standardized studies are needed to better understand the role of actigraphy in evaluating sleep and sleep-related outcomes in critically ill patients.