Anja Meyer

Propofol versus combined sedation in flexible bronchoscopy: a randomised non-inferiority trial

Combined sedation with a benzodiazepine and an opiate has been proposed as standard sedation for bronchoscopy. Propofol is a sedative–hypnotic with a rapid onset of action and fast recovery time, but carries the potential risk of respiratory failure. Consecutive patients (n = 200) were randomly allocated to receive either the combination midazolam and hydrocodone or intravenous propofol. The primary end-points were the mean lowest arterial oxygen saturation during bronchoscopy and the readiness-for-discharge score 1 h after the procedure. The mean lowest arterial oxygen saturation during bronchoscopy did not differ across treatment groups (p = 0.422), and the number of patients recording an arterial oxygen saturation of ≤90% on at least one occasion was similar in both groups (p = 0.273). The median (interquartile range) readiness-for-discharge score 1 h after the procedure was significantly higher in the propofol group than in the combined sedation group (8 (6–9) versus 7 (5–9); p = 0.035). Patients assigned propofol exhibited less tachycardia during bronchoscopy and for ≥1 h after the examination. Minor procedural complications were noted in 71 (35.5%) patients and exhibited a similar incidence in both treatment arms (p = 0.460). Propofol is as effective and safe as combined sedation in patients undergoing flexible bronchoscopy, thus representing an appealing option if timely discharge is a priority.

Ceramide-1-phosphate inhibits cigarette smoke-induced airway inflammation

Sphingolipids are involved in the pathogenesis of inflammatory diseases. The central molecule is ceramide, which can be converted into ceramide-1-phosphate (C1P). Although C1P can exert anti- and pro-inflammatory effects, its influence on cigarette smoke (CS)-induced lung inflammation is unknown. We aimed to clarify the role of C1P in the pathogenesis of CS-triggered pulmonary inflammation and emphysema in humans and mice. The effects of C1P were addressed on CS-induced lung inflammation in C57BL/6 mice, CS extract-triggered activation of human airway epithelial cells (AECs) and neutrophils from patients with chronic obstructive pulmonary disease. Differential cell counts in bronchoalveolar lavage fluid were determined by flow cytometry and pro-inflammatory cytokines were measured by ELISA. Expression and DNA binding of nuclear factor (NF)-κB and neutral sphingomyelinase (nSMase) were quantified by PCR, electrophoretic mobility shift and fluorometric assays. C1P reduced CS-induced acute and chronic lung inflammation and development of emphysema in mice, which was associated with a reduction in nSMase and NF-κB activity in the lungs. nSMase activity in human serum correlated negatively with forced expiratory volume in 1 s % predicted. In human AECs and neutrophils, C1P inhibited CS-induced activation of NF-κB and nSMase, and reduced pro-inflammatory cytokine release. Our results suggest that C1P is a potential target for anti-inflammatory treatment in CS-induced lung inflammation. Ceramide-1-phosphate, a potential target for anti-inflammatory treatment in cigarette smoke-induced lung inflammation http://ow.ly/E7tUS

MicroRNA‐155 modulates P2R signaling and Th2 priming of dendritic cells during allergic airway inflammation in mice

Dendritic cells (DCs) are the professional antigen‐presenting cells (APCs) in the lung. They are known to be key players in the induction and maintenance of allergic asthma by cross‐linking innate and adaptive immune responses. MicroRNAs (miRNAs) are known to influence cell fate and function by translational suppression or induction of messenger RNA (mRNA) degradation. miR‐155 has been shown to be a crucial regulator of the immune system. However, its function in the pathogenesis of allergic airway inflammation (AAI) is not completely elucidated yet.

Association of daily physical activity volume and intensity with COPD severity

PURPOSE The purpose of this study was to assess whether daily walking activity is indicative of disease severity in patients with COPD. METHODS Daily activity was measured by accelerometry in 107 COPD: GOLD II (N=28), GOLD III (N=51), and GOLD IV (N=25). Steps per day and times (min/day) spent passively, actively, walking (WLK, 0-5 km/h), and fast walking (FWLK, >5 km/h) were analyzed. Total walking time (TWT) was computed. RESULTS Times spent WLK (P=0.031), FWLK (P=0.001), TWT (P=0.021), and steps per day (P=0.013) differed significantly between GOLD stages. There was a significant negative correlation between TWK and GOLD stage (R=-0.35; P<0.0001), BODE index (R=-0.58; P<0.0001), and MMRC dyspnea scale (R=-0.65; P<0.0001). Logistic regression analysis showed that both TWT and FWLK were independently and significantly associated with BODE index ≥ 6 (P=0.029 and P=0.040, respectively). The corresponding AUC-value with 95% CI for TWT was 0.80 (95% CI: 0.70 to 0.90) and 0.87 (95% CI: 0.81 to 0.94) for FWLK. The corresponding optimal cut-off value for TWT was 33.3 min/day (sensitivity: 86%; specificity 70%) and FWLK was 0.10 min/day (sensitivity: 93%; specificity 76%). CONCLUSION Daily walking activity, in particular walking intensity, is significant predictor of disease severity in patients with COPD. Objective measures of habitual activity might provide additive value in assessing the likelihood of poor prognosis in this patient cohort.

Mortality risk prediction in COPD by a prognostic biomarker panel

Chronic obstructive pulmonary disease (COPD) is a complex disease with various phenotypes. The simultaneous determination of multiple biomarkers reflecting different pathobiological pathways could be useful in identifying individuals with an increased risk of death. We derived and validated a combination of three biomarkers (adrenomedullin, arginine vasopressin and atrial natriuretic peptide), assessed in plasma samples of 385 patients, to estimate mortality risk in stable COPD. Biomarkers were analysed in combination and defined as high or low. In the derivation cohort (n = 142), there were 73 deaths during the 5-year follow-up. Crude hazard ratios for mortality were 3.0 (95% CI 1.8–5.1) for one high biomarker, 4.8 (95% CI 2.4–9.5) for two biomarkers and 9.6 (95% CI 3.3–28.3) for three high biomarkers compared with no elevated biomarkers. In the validation cohort (n = 243), 87 individuals died. Corresponding hazard ratios were 1.9 (95% CI 1.1–3.3), 3.1 (95% CI 1.8–5.4) and 5.4 (95% CI 2.5–11.4). Multivariable adjustment for clinical variables as well as the BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity) index and stratification by the Global Initiative for Chronic Obstructive Lung Disease stages provided consistent results. The addition of the panel of three biomarkers to the BODE index generated a net reclassification improvement of 57.9% (95% CI 21.7–92.4%) and 45.9% (95% CI 13.9–75.7%) at 3 and 5 years, respectively. Simultaneously elevated levels of adrenomedullin, arginine vasopressin and atrial natriuretic peptide are associated with increased risk of death in patients with stable COPD. Simultaneously elevated levels of ADM, AVP and ANP are associated with increased risk of death in COPD http://ow.ly/yt9GA

Predictors of Success for Smoking Cessation at the Workplace: A Longitudinal Study

Background: The effectiveness of worksite interventions to reduce smoking is debatable. Objectives: A comprehensive smoking cessation intervention was implemented in a community of more than 17,000 employees at three different health care companies. The primary endpoint was abstinence at 24 months (self-reported and confirmed by exhaled carbon monoxide ≤6 parts per million). Predictors of long-term abstinence were analysed by multivariable regression analysis. Methods: The study was designed as an investigator-initiated and investigator-driven, open, multicentre, cohort study; 887 smokers were enrolled in the programme. The intervention included intensive individual counselling as well as nicotine replacement and/or bupropion according to individual preferences. Re-interventions for relapse were offered during the 24-month follow-up. Results: The abstinence rate was 37% at 24 months and did not differ among the various medication groups (p > 0.05 for all). Predictors of successful cessation were higher age (odds ratio, OR 1.47, 95% confidence interval, CI 1.08-2.00, p < 0.01), breathlessness on exertion (OR 2.26, 95% CI 1.1-4.9, p = 0.03), and a higher educational level (OR 1.81, 95% CI 1.06-3.09, p = 0.03). Higher Fagerström (OR 0.76, 95% CI 0.59-0.97, p < 0.01) and craving scores (OR 0.75, 95% CI 0.63-0.89, p < 0.01), chronic sputum production (OR 0.52, 95% CI 0.31-0.87, p = 0.01) and use of antidepressants (OR 0.54, 95% CI 0.32-0.91, p = 0.02) were associated with ongoing smoking. Conclusion: A comprehensive smoking cessation intervention at the workplace achieves high, stable, long-term abstinence rates. Elderly, well-educated employees with breathlessness on exertion have higher odds of quitting smoking. In contrast, those with high physical dependency and more intense craving, and those reporting use of antidepressant medication or sputum production have poorer chances to quit.

Associations of daily walking activity with biomarkers related to cardiac distress in patients with chronic obstructive pulmonary disease

Background: The prevalence of cardiovascular mortality is high in Chronic Obstructive Pulmonary Disease (COPD) and the identification of clinical parameters to improve risk stratification is of great interest. Objectives: This study aims to assess the predictive strength of daily walking activity on expression of cardiac biomarkers in patients with COPD. Methods: One hundred and five patients with COPD (66.1 ± 8.7 years of age) were prospectively analyzed. Daily walking activity was measured by means of accelerometry. Stepwise multivariate regression analyses were employed with either midregional proatrial natriuretic peptide (MRproANP) or plasma proadrenomedullin (MRproADM) as dependent variables, and age, age-adjusted Charlson score, Modified Medical Research Council Dyspnea Scale (MMRC), Saint Georges Respiratory Questionnaire total score and either total walk, steps per day or fast walk as covariates. Results: Independent predictors of MRproANP included age (p = 0.015) and either total walk or steps per day (both p < 0.0001). Total walk or steps per day were the only independent predictors of MRproADM (p < 0.0001). There was a significant negative correlation between fast walk and MMRC (R = -0.70; p < 0.001) and fast walk was only independently predictive of MRproANP but not MRproADM once MMRC was excluded from the list of covariates (p = 0.023 and p = 0.057, respectively). Conclusions: Daily walking activity independently predicts levels of circulating MRproANP and MRproADM in stable COPD patients, two prognostic biomarkers of cardiac distress associated with long-term survival upon exacerbation of COPD. Employing activity monitors in the stable state might simplify risk stratification in daily living.

NTPDase1/CD39 and aberrant purinergic signalling in the pathogenesis of COPD.

Purinergic receptor activation via extracellular ATP is involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). Nucleoside triphosphate diphosphohydrolase-1/CD39 hydrolyses extracellular ATP and modulates P2 receptor signalling. We aimed to investigate the expression and function of CD39 in the pathogenesis of cigarette smoke-induced lung inflammation in patients and preclinical mouse models. CD39 expression and soluble ATPase activity were quantified in sputum and bronchoalveolar lavage fluid (BALF) cells in nonsmokers, smokers and COPD patients or mice with cigarette smoke-induced lung inflammation. In mice, pulmonary ATP and cytokine concentrations, inflammation and emphysema were analysed in the presence or absence of CD39. Following acute cigarette smoke exposure CD39 was upregulated in BALF cells in smokers with further increases in COPD patients. Acute cigarette smoke exposure induced CD39 upregulation in murine lungs and BALF cells, and ATP degradation was accelerated in airway fluids. CD39 inhibition and deficiency led to augmented lung inflammation; treatment with ATPase during cigarette smoke exposure prevented emphysema. Pulmonary CD39 expression and activity are increased in COPD. CD39 deficiency leads to enhanced emphysema in mice, while external administration of a functional CD39 analogue partially rescues the phenotype. The compensatory upregulation of pulmonary CD39 might serve as a protective mechanism in cigarette smoke-induced lung damage. The upregulation of pulmonary ATPase is a protective mechanism in cigarette smoke-induced lung inflammation http://ow.ly/S5YcC

Extracellular ATP is a danger signal activating P2X7 Receptor in a LPS mediated inflammation (ARDS/ALI)

Acute respiratory distress syndrome (ARDS) is a life-threating lung condition resulting from a direct and indirect injury to the lungs [1, 2]. Pathophysiologically it is characterized by an acute alveolar damage, an increased permeability of the microvascular-barrier, leading to protein-rich pulmonary edema and subsequent impairment of arterial oxygenation and respiratory failure [1]. This study examined the role of extracellular ATP in recruiting inflammatory cells to the lung after induction of acute lung injury with lipopolysaccharide (LPS). However, the precise mechanism is poorly understood. Our objective was to investigate the functional role of the P2X7 receptor in the pathogenesis of acute respiratory distress syndrome (ARDS/ acute lung injury (ALI)) in vitro and in vivo. We show that intratracheally applied LPS causes an acute accumulation of ATP in the BALF (bronchoalveolar lavage) and lungs of mice. Prophylactic and therapeutic inhibition of P2X7R signalling by a specific antagonist and knock-out experiments was able to ameliorate the inflammatory response demonstrated by reduced ATP-levels, number of neutrophils and concentration of pro-inflammatory cytokine levels in the BALF. Experiments with chimeric mice showed that P2X7R expression on immune cells was responsible for the observed effect. Consistently, the inflammatory response is diminished only by a cell-type specific knockdown of P2X7 receptor on non-stationary immune cells. Since the results of BALF from patients with acute ARDS or pneumonia simulated the in vivo data after LPS exposure, the P2X7 receptor may be a new therapeutic target for treatment in acute respiratory distress syndrome (ARDS/ALI).

Inert Gas Washout in Bronchiolitis Obliterans Following Hematopoietic Cell Transplantation

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) is a leading cause of chronic graft‐vs‐host disease (cGvHD) and is associated with mortality after allogeneic hematopoietic stem cell transplantation (alloHSCT). The nitrogen multiple breath washout test (N2‐MBW) measures ventilation inhomogeneity, a biomarker of central and peripheral airway obstruction. The aim of this study was to examine ventilation inhomogeneity according to cGvHD score and histologically defined bronchiolitis obliterans (BO). METHODS: This single‐center prospective cross‐sectional study included 225 adults (mean age, 52.8 years; median, 5.4 years [interquartile range, 2.0–11 years]) after alloHSCT. Outcomes were global (lung clearance index [LCI]) and acinar ventilation inhomogeneity index (SACIN) from N2‐MBW. Patients were categorized into five groups: (1) no cGvHD and no obstruction (cGvHD overall score 0 and FEV1/FVC ≥ 70) (2) cGvHD and no obstruction (cGvHD overall score 1–3 and FEV1/FVC ≥ 70), (3) BOS with or without cGvHD (if available, no BO on histologic examination, and FEV1/FVC < 70), (4) histologically proven BO, and (5) diffuse parenchymal lung disease other than BO. RESULTS: The LCI and SACIN differed significantly between groups (P < .001) and increased progressively according to cGvHD score. In BO, the LCI and SACIN were elevated in 95.5% and 81.8% of patients, respectively, whereas FEV1/FVC was abnormal in only 56.5% of patients, respectively. CONCLUSIONS: N2‐MBW is highly sensitive for detecting abnormal lung function in patients following alloHSCT. LCI and SACIN seem to be promising biomarkers of lung involvement in cGvHD.