Endothelin receptor-antagonists suppress lipopolysaccharide-induced cytokine release from alveolar macrophages of non-smokers, smokers and COPD subjects.

Smoking-induced COPD is characterized by chronic airway inflammation, which becomes enhanced by bacterial infections resulting in accelerated disease progression called exacerbation. Alveolar macrophages (AM) release endothelin-1 (ET-1), IL-6, CCL-2 and MMP-9, all of which are linked to COPD pathogenesis and exacerbation. ET-1 signals via ETA- and ETB-receptors (ETAR, ETBR). This is blocked by endothelin receptor antagonists (ERAs), like bosentan, which targets both receptors, ETAR-selective ambrisentan and ETBR-specific BQ788. Therefore, ERAs could have anti-inflammatory potential, which might be useful in COPD and other inflammatory lung diseases. We hypothesized that ERAs suppress cytokine release from AM of smokers and COPD subjects induced by lipopolysaccharide (LPS), the most important immunogen of gram-negative bacteria. AM were isolated from the broncho-alveolar lavage (BAL) of n=29 subjects (11 non-smokers, 10 current smokers without COPD, 8 smokers with COPD), cultivated and stimulated with LPS in the presence or absence of ERAs. Cytokines were measured by ELISA. Endothelin receptor expression was investigated by RT-PCR and western blot. AM expressed ETAR and ETBR mRNA, but only ETBR protein was detected. LPS and ET-1 both induced IL-6, CCL-2 and MMP-9. LPS-induced IL-6 release was increased in COPD versus non-smokers and smokers. Bosentan, ambrisentan and BQ788 all partially reduced all cytokines without differences between cohorts. Specific ETBR inhibition was most effective. LPS induced ET-1, which was exclusively blocked by BQ788. In conclusion, LPS induces ET-1 release in AM, which in turn leads to CCL-2, IL-6 and MMP-9 expression rendering AM sensitive for ERAs. ERAs could have anti-inflammatory potential in smoking-induced COPD.

Impact of lung diseases on morbidity and mortality after transcatheter aortic valve implantation: insights from spirometry and body plethysmography.

BACKGROUND: The study aims to determine the impact of different lung diseases on morbidity and mortality after transcatheter aortic valve implantation (TAVI). METHODS: Transcatheter aortic valve implantation was performed transfemoral or transaxillary with CoreValve prosthesis or Edwards SAPIEN prosthesis in patients with symptomatic severe aortic valve stenosis and high surgical risk. Examinations comprised spirometry, body plethysmography echocardiography, and x-ray before TAVI. The primary study end point was death from any cause after TAVI. RESULTS: During follow-up of 750 ± 538 days, 63 of 212 patients died. Logistic European System for Cardiac Operative Risk Evaluation (hazard risk [HR] 1.032, P < .001), aortic mean gradient (HR 0.96, P < .001), chronic obstructive pulmonary disease (COPD; each degree of COPD: HR 1.436, P = .001), restrictive ventilatory disease (HR 2.252, P = .002), oxygen dependency (HR 3.291, P = .004), and noninvasive ventilation (HR 3.799, P = .005) were independent predictors of long-term mortality. Restrictive ventilatory disease was associated with lower left ventricular ejection fraction, higher B-type natriuretic peptide levels, and pulmonary edema. CONCLUSION: In patients undergoing TAVI, lung diseases are an independent predictor of all-cause mortality. In particular, oxygen dependency patients and patients with severe COPD and noninvasive ventilation indicate a dismal prognosis. Transcatheter aortic valve implantation seems to have a dubious prognostic benefit in these patients.

Difficult intubation and outcome after out-of-hospital cardiac arrest: a registry-based analysis.

BACKGROUND: Airway management during resuscitation attempts is pivotal for treating hypoxia, and endotracheal intubation is the standard procedure. This German Resuscitation Registry analysis investigates the influence of airway management on primary outcomes after out-of-hospital cardiac arrest, in a physician-based emergency system. METHODS: A total of 8512 patients recorded in the German Resuscitation Registry (2007-2011) were analyzed. The Return of Spontaneous Circulation After Cardiac Arrest (RACA) score was used to compare observed return of spontaneous circulation (ROSC) rates with the ROSC predicted by the score and to analyze factors influencing the primary outcome. Patients were classified into three groups: difficult intubation, impossible intubation, and a control group with normal airways. RESULTS: The observed ROSC matched the predicted ROSC in the group with difficult airways. The impossible intubation group had lower ROSC rates (31.3% vs. 40.5%; P < 0.05). Impossible intubation was more frequent in men (OR 2.28; 95% CI, 1.43-3.63; P = 0.001), young patients (OR 2.18; 95% CI, 1.26-3.76; P = 0.005) and those with trauma (OR 2.22; 95% CI, 1.01-4.85; P = 0.046). Fewer impossible intubations were reported when the emergency physicians were anesthesiologists (OR 0.65; 95% CI, 0.44-0.96; P = 0.028). If a supraglottic airway device was not used in the impossible intubation group, the observed ROSC (18.0%; 95% CI, 7.4-28.6%) was poorer than predicted (38.2%) (P < 0.05). CONCLUSIONS: Outcomes after resuscitation attempts are poorer when endotracheal intubation is not possible. Predictive factors for impossible intubation are male gender, younger age, and trauma. Supraglottic airway devices should be used at an early stage whenever these negative factors are present.

Short-term effects of oral theophylline in addition to CPAP in mild to moderate OSAS.

Theophylline is effective in the treatment of central apneas and periodic breathing. In obstructive sleep apnea syndrome (OSAS), results of pharmacological monotherapy with theophylline are inconsistent. The present study investigates whether additional theophylline in patients with OSAS and continuous positive airway pressure (CPAP) therapy might improve ventilation, lower effective CPAP pressure levels or affect sleep architecture. Patients with mild to moderate OSAS (mean apnea index [AI] 12.8+/-11.7) and CPAP therapy (Autoset system; n=16, all male) received either 900 mg of oral sustained-release theophylline (T) or placebo (P) on two separate nights, 3 days apart, using a randomized double-blind crossover study design. There was no change in AI (T: 0.7+/-1.4 vs. P: 0.7+/-0.6/h; P=0.3) or apnea-hypopnea index (AHI; T: 4.3+/-3.3 vs. P: 4.5+/-3.7/h; P=0.84) when theophylline was added to CPAP therapy. We observed no difference in mean CPAP pressure (T: 6.9+/-2.1 vs. P: 6.7+/-1.9 cm H2O; P=0.7) or 95% pressure percentiles (T: 9.7+/-2.7 vs. P: 9.3+/-2.1cm H2O; P=0.3) when nights with theophylline were compared to placebo nights. Theophylline reduced significantly total sleep time (T: 290.6+/-58.9 vs. P: 338.0+/-40.1 min; P=0.02) and thus sleep efficiency (SE; T: 70.5+/-14.9%, P: 82.0+/-70.5%; P=0.005). Rapid eye movement and slow wave sleep were not affected. Oral theophylline did not show any additional effects on ventilation parameters or pressures in patients with mild to moderate OSAS once CPAP therapy has been successfully installed. SE was reduced with theophylline with unchanged sleep architecture. The role of oral theophylline may be in patients with predominately central apneas not eligible for ventilation therapy or severe cases.