Airway smooth muscle area to predict steroid responsiveness in COPD patients receiving triple therapy (HISTORIC): a randomised, placebo-controlled, double-blind, investigator-initiated trial.

BACKGROUND: Although inhaled corticosteroids (ICS) are highly effective in asthma, they provide significant, but modest, clinical benefit in COPD. Here, we tested the hypothesis that high bronchial airway smooth muscle cell (ASMC) area in COPD is associated with ICS responsiveness. METHODS: In this investigator-initiated and -driven, double-blind, randomised, placebo-controlled trial (HISTORIC), 190 COPD patients, Global Initiative for Chronic Obstructive Lung Disease stage B-D, underwent bronchoscopy with endobronchial biopsy. Patients were divided into groups A and B, with high ASMC area (HASMC: >20% of the bronchial tissue area) and low ASMC area (LASMC: ≤20% of the bronchial tissue area), respectively, and followed a run-in period of 6 weeks on open-label triple inhaled therapy with aclidinium (ACL)/formoterol (FOR)/budesonide (BUD) (400/12/400 µg twice daily). Subsequently, patients were randomised to receive either ACL/FOR/BUD or ACL/FOR/placebo and followed for 12 months. The primary end-point of the study was the difference in post-bronchodilator forced expiratory volume in 1 s (FEV1) over 12 months between patients with LASMC and HASMC receiving or not receiving ICS. RESULTS: In patients with LASMC, ACL/FOR/BUD did not significantly improve FEV1 over 12 months, as compared to ACL/FOR/placebo (p=0.675). However, in patients with HASMC, ACL/FOR/BUD significantly improved FEV1, as compared to ACL/FOR/placebo (p=0.020). Over 12 months, the difference of FEV1 change between the ACL/FOR/BUD group and the ACL/FOR/placebo group was 50.6 mL·year-1 within the group of patients with LASMC and 183.0 mL·year-1 within the group of patients with HASMC. CONCLUSION: COPD patients with ΗASMC respond better to ICS than patients with LASMC, suggesting that this type of histological analysis may predict ICS responsiveness in COPD patients receiving triple therapy.

Oxygen desaturation during flexible bronchoscopy with propofol sedation is associated with sleep apnea: the PROSA-Study.

BACKGROUND: Obstructive sleep apnea (OSA) is characterized by repetitive episodes of complete or partial obstruction of the upper airways during sleep. Conscious sedation for flexible bronchoscopy (FB) places patients in a sleep-like condition. We hypothesize that oxygen desaturation during flexible bronchoscopy may help to detect undiagnosed sleep apnea. METHODS: Single-centre, investigator-initiated and driven study including consecutive patients undergoing FB for clinical indication. Patients completed the Epworth Sleepiness Scale (ESS), Lausanne NoSAS score, STOP-BANG questionnaire and the Berlin questionnaire and underwent polygraphy within 7 days of FB. FB was performed under conscious sedation with propofol. Oxygen desaturation during bronchoscopy was measured with continuous monitoring of peripheral oxygen saturation with ixTrend (ixellence GmbH, Germany). RESULTS: 145 patients were included in the study, 62% were male, and the average age was 65.8 ± 1.1 years. The vast majority of patients (n = 131, 90%) proved to fulfill OSA criteria based on polygraphy results: 52/131 patients (40%) had mild sleep apnea, 49/131 patients (37%) moderate sleep apnea and 30/131 patients (23%) severe sleep apnea. Patients with no oxygen desaturation had a significantly lower apnea-hypopnea index than patients with oxygen desaturation during bronchoscopy (AHI 11.94/h vs 21.02/h, p = 0.011). This association remained significant when adjusting for the duration of bronchoscopy and propofol dose (p = 0.023; 95% CI 1.382; 18.243) but did not hold when also adjusting for age and BMI. CONCLUSION: The severity of sleep apnea was associated to oxygen desaturation during flexible bronchoscopy under conscious sedation. Patients with oxygen desaturation during bronchoscopy might be considered for sleep apnea screening. TRIAL REGISTRATION: The Study was approved by the Ethics Committee northwest/central Switzerland, EKNZ (EK 16/13) and was carried out according to the Declaration of Helsinki and Good Clinical Practice guidelines. Due to its observational character, the study did not require registration at a clinical trial registry.

Time-course of upper respiratory tract viral infection and COPD exacerbation.

Viral respiratory tract infections have been implicated as the predominant risk factor for acute exacerbations of chronic obstructive pulmonary disease (AECOPD). We aimed to evaluate, longitudinally, the association between upper respiratory tract infections (URTI) caused by viruses and AECOPD.Detection of 18 viruses was performed in naso- and orοpharyngeal swabs from 450 COPD patients (Global Initiative for Chronic Obstructive Lung Disease stages 2-4) who were followed for a mean of 27 months. Swabs were taken during stable periods (n=1909), at URTI onset (n=391), 10 days after the URTI (n=356) and during an AECOPD (n=177) and tested using a multiplex nucleic acid amplification test.Evidence of at least one respiratory virus was significantly higher at URTI onset (52.7%), 10 days after the URTI (15.2%) and during an AECOPD (38.4%), compared with the stable period (5.3%, p<0.001). During stable visits, rhinovirus accounted for 54.2% of all viral infections, followed by coronavirus (20.5%). None of the viruses were identified in two consecutive stable visits. Patients with a viral infection at URTI onset did not have a higher incidence of exacerbation than patients without viral infection (p=0.993). Τhe incidence of any viral infection during an AECOPD was similar between URTI-related AECOPD and non-URTI-related AECOPD (p=0.359). Only 24% of the patients that had a URTI-related AECOPD had the same virus at URTI onset and during an AECOPD. Detection of parainfluenza 3 at URTI onset was associated with a higher risk of an AECOPD (p=0.003). Rhinovirus and coronavirus were the most frequently detected viruses during AECOPD visits, accounting for 35.7% and 25.9% of all viral infections, respectively.The prevalence of viral infection during the stable period of COPD was low. The risk of exacerbation following the onset of URTI symptoms depends on the particular virus associated with the event and was significant only for parainfluenza 3.

Comprehensive biomarker profiling in patients with obstructive sleep apnea.

OBJECTIVES: The pathophysiological links between obstructive sleep apnea syndrome (OSAS) and cardiovascular mortality are incompletely understood. We aimed to contribute to a better characterization by using comprehensive biomarker profiling quantifying hemodynamic cardiac stress, cardiomyocyte injury, inflammation, endothelial function, matrix turnover and metabolism. DESIGN AND METHODS: In 65 patients with moderate or severe OSAS [apnea-hypopnea index (AHI) 39±20/h] and 33 patients with no or mild OSAS (AHI 8+4/h), B-type natriuretic peptide (BNP), N-terminal-pro-BNP (NT-proBNP), high-sensitivity cardiac troponin I (hs-cTnI), interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9), and insulin were measured before and after sleep. In a subgroup measurements were repeated in a second night with continuous positive airway pressure (CPAP). RESULTS: Patients with moderate/severe OSAS had higher insulin before sleep [median (interquartile range), 36.4 (21.9-52.1) vs. 20.8 (10.6-32.8)mU/mL; p=0.006], higher IL-6 after sleep [1.00 (0.73-1.58) vs. 0.72 (0.48-0.94)pg/mL; p=0.005], and larger relative overnight reduction in BNP [-9 (-35-0) vs. -3 (-21-13)%; p=0.04] than those with mild/no OSAS. Insulin before sleep was the only independent predictor of moderate/severe OSAS. Insulin before and IL-6 after sleep were independent predictors of severe OSAS, and when combined provided high diagnostic accuracy for severe OSAS (area under the receiver operator characteristic curve 0.80; 95%-confidence interval 0.69-0.91). In contrast, there were no significant differences in NT-proBNP, hs-cTnI, VEGF, and MMP-9 between moderate/severe and mild/no OSAS. Short-term CPAP had no impact on biomarker concentrations before and after sleep. CONCLUSIONS: Significant OSAS is characterized by a distinct biomarker profile including high insulin before and high IL-6 after sleep.

The circadian regulation of sleep: impact of a functional ADA-polymorphism and its association to working memory improvements.

Sleep is regulated in a time-of-day dependent manner and profits working memory. However, the impact of the circadian timing system as well as contributions of specific sleep properties to this beneficial effect remains largely unexplored. Moreover, it is unclear to which extent inter-individual differences in sleep-wake regulation depend on circadian phase and modulate the association between sleep and working memory. Here, sleep electroencephalography (EEG) was recorded during a 40-h multiple nap protocol, and working memory performance was assessed by the n-back task 10 times before and after each scheduled nap sleep episode. Twenty-four participants were genotyped regarding a functional polymorphism in adenosine deaminase (rs73598374, 12 G/A-, 12 G/G-allele carriers), previously associated with differences in sleep-wake regulation. Our results indicate that genotype-driven differences in sleep depend on circadian phase: heterozygous participants were awake longer and slept less at the end of the biological day, while they exhibited longer non rapid eye movement (NREM) sleep and slow wave sleep concomitant with reduced power between 8-16 Hz at the end of the biological night. Slow wave sleep and NREM sleep delta EEG activity covaried positively with overall working memory performance, independent of circadian phase and genotype. Moreover, REM sleep duration benefitted working memory particularly when occurring in the early morning hours and specifically in heterozygous individuals. Even though based on a small sample size and thus requiring replication, our results suggest genotype-dependent differences in circadian sleep regulation. They further indicate that REM sleep, being under strong circadian control, boosts working memory performance according to genotype in a time-of-day dependent manner. Finally, our data provide first evidence that slow wave sleep and NREM sleep delta activity, majorly regulated by sleep homeostatic mechanisms, is linked to working memory independent of the timing of the sleep episode within the 24-h cycle.

Insights into behavioral vulnerability to differential sleep pressure and circadian phase from a functional ADA polymorphism.

Sleep loss affects human behavior in a nonuniform manner, depending on the cognitive domain and also the circadian phase. Besides, evidence exists about stable interindividual variations in sleep loss-related performance impairments. Despite this evidence, only a few studies have considered both circadian phase and neurobehavioral domain when investigating trait-like vulnerability to sleep manipulation. By applying a randomized, crossover design with 2 sleep pressure conditions (40 h sleep deprivation vs. 40 h multiple naps), we investigated the influence of a human adenosine deaminase (ADA) polymorphism (rs73598374) on several behavioral measures throughout nearly 2 circadian cycles. Confirming earlier studies, we observed that under sleep deprivation the previously reported vulnerable G/A-allele carriers felt overall sleepier than G/G-allele carriers. As expected, this difference was no longer present when sleep pressure was reduced by the application of multiple naps. Concomitantly, well-being was worse in the G/A genotype under sleep loss when compared to the nap protocol, and n-back working memory performance appeared to be specifically susceptible to sleep-wake manipulation in this genotype. When considering psychomotor vigilance performance, however, a higher sensitivity to sleep-wake manipulation was detected in homozygous participants, but specifically at the end of the night and only for optimal task performance. Although these data are based on a small sample size and hence require replication (12 G/A- and 12 G/G-allele carriers), they confirm the assumption that interindividual differences regarding the effect of sleep manipulation highly depend on the cognitive task and circadian phase, and thus emphasize the necessity of a multimethodological approach. Moreover, they indicate that napping might be suitable to counteract endogenously heightened sleep pressure depending on the neurobehavioral domain.

Enhanced didactic methods of smoking cessation training for medical students--a randomized study.

BACKGROUND: It is essential that medical students are adequately trained in smoking cessation. A web-based tobacco abstinence training program might supplement or replace traditional didactic methods. METHODS: One-hundred and forty third-year medical students were all provided access to a self-directed web-based learning module on smoking cessation. Thereafter, they were randomly allocated to attend 1 of 4 education approaches: (a) web-based training using the same tool, (b) lecture, (c) role playing, and (d) supervised interaction with real patients. RESULTS: Success of the intervention was measured in an objective structured clinical examination. Scores were highest in Group 4 (35.9 ± 8.7), followed by Groups 3 (35.7 ± 6.5), 2 (33.5 ± 9.4), and 1 (28.0 ± 9.6; p = .007). Students in Groups 4 (60.7%) and 3 (57.7%) achieved adequate counseling skills more frequently than those in Groups 2 (34.8%) and 1 (30%; p = .043). There was no difference in the scores reflecting theoretical knowledge (p = .439). Self-assessment of cessation skills and students' satisfaction with training was significantly better in Groups 3 and 4 as compared with 1 and 2 (p < .001 and p = .006, respectively). CONCLUSIONS: Role playing and interaction with real patients are equally efficient and both more powerful learning tools than web-based learning with or without a lecture.

Recurrent bilateral pneumothorax.

A 71-year-old male with a history of coronary artery bypass surgery 7 years ago underwent a transthoracic needle aspiration biopsy of a pulmonary nodule in the right lung. Three hours later, the patient complained of dyspnea and left sided thoracic pain. The chest x-ray showed bilateral apical pneumothoraces. A second chest x-ray two hours later showed an increase in pneumothorax size on the left side. An intercostal drainage tube (size 24 French) was inserted into the fourth intercostal space on the X side and continuous suction was applied with 20 cm H2O. One day later, the chest x-ray revealed resolution on both sides with only minimal residual bilateral pneumothoraces. There was no air leak and hence the chest tube was removed. Histology revealed a non small cell lung cancer and a lobectomy was performed. At the second postoperative day a chylothorax was diagnosed because of elevated triglycerides. Parenteral nutrition was begun and the quantity of drained effusion diminished. Nine days after successful lobectomy the patient accidentally removed the chest tube and bilateral pneumothoraces were seen in the x-ray again.

The impact of postoperative nasal packing on sleep-disordered breathing and nocturnal oxygen saturation in patients with obstructive sleep apnea syndrome.

Nasal septum surgery is frequently performed to establish a functional nasal airway. In these patients obstructive sleep apnea syndrome (OSAS) is frequently present. Although patients with OSAS are at increased risk for hypoxemia, the impact of postoperative nasal packing (PNP) on sleep-disordered breathing and oxygen desaturations in patients with OSAS is unknown. We consecutively investigated 40 patients undergoing endonasal surgery receiving PNP. Fifteen of these patients had previously diagnosed OSAS (Group 2) and 25 did not (Group 1). In the control group, 12 healthy patients underwent elective ear or neck surgery without PNP. During the preoperative and postoperative nights, we continuously measured oronasal flow, thoracoabdominal movements, and oxygen saturation. We calculated the apnea-hypopnea index (AHI) and the oxygen-desaturation index (ODI). Compared with the preoperative values, after the operation, neither AHI nor ODI changed in the control group. In contrast, in Group 1, AHI (from 11 [5-19] to 37 [22-49]) and ODI (from 4 [2-8] to 13 [6-21]) significantly increased (P < 0.05), whereas in Group 2, only AHI significantly increased (from 14 [10-21] to 39 [26-50]); ODI remained similar (13 [8-27] versus 11 [4-37]). Because ODI did not increase in patients with OSAS and PNP who received postoperative oxygen overnight, postoperative intensive care monitoring might not be necessary on a routine basis for all patients with PNP and OSAS.

Sedative drug requirements during flexible bronchoscopy.

BACKGROUND: There is a paucity of data comparing doses of sedative medication during bronchoscopy in immunosuppressed and non-immunosuppressed patients. OBJECTIVES: The aim of this study was to define the sedative medication doses used in specific patient groups during bronchoscopy. METHODS: Bronchoscopy was performed under local anesthesia, sedation with intermittent boluses of intravenous midazolam and intravenous hydrocodone 5 mg. Two hundred and thirty-nine consecutive bronchoalveolar lavage procedures were included. Procedures in non-immunosuppressed patients were classified as controls (n = 91). Procedures in immunosuppressed patients who received midazolam consisted of stem cell transplant (34), solid organ transplant (25), chemotherapy (33), HIV with drug abuse (10), HIV (5), prednisone (17) and immunosuppression for other diseases (12). Intravenous propofol was administered during 12 procedures due to inability to achieve optimal sedation with midazolam in a previous bronchoscopy (stem cell transplant recipient 1, lung transplant for cystic fibrosis 5) and during the same bronchoscopy due to inadequate sedation with a high dose of midazolam--renal transplant recipient 1, drug abuse (HIV 1, renal transplant recipient 1), bronchoscopy combined with gastroscopy (2) and a hypoxemic patient (1). The mean dose of propofol administered was 2.8 +/- 1.3 mg/kg. RESULTS: Midazolam requirement was significantly higher in patients with stem cell transplantation (0.09 +/- 0.05 mg/kg) compared with controls (0.06 +/- 0.03 mg/kg; p = 0.0002). In the HIV patients with drug abuse (0.12 +/- 0.10 mg/kg), there was a tendency for the need of a higher dose of midazolam compared with the control group (p = 0.0754). CONCLUSION: Stem cell transplant recipients and selected HIV patients with drug abuse need higher doses of midazolam for bronchoscopy.