Indacaterol and glycopyrronium versus indacaterol on body plethysmography measurements in COPD-a randomised controlled study.

BACKGROUND: Dual bronchodilator therapy is recommended for symptomatic patients with chronic obstructive pulmonary disease (COPD). There are limited data on effects of a combination of two long-acting bronchodilators on lung function including body plethysmography. METHODS: This multicentre, randomised, double-blind, single-dose, cross-over, placebo-controlled study evaluated efficacy and safety of the free combination of indacaterol maleate (IND) and glycopyrronium bromide (GLY) versus IND alone on spirometric and body plethysmography parameters, including inspiratory capacity (IC), forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), total lung capacity (TLC) and airway resistance (Raw) in moderate-to-severe COPD patients. RESULTS: Seventy-eight patients with FEV1 % pred. (mean ± SD) 56 ± 13% were randomised. The combination of IND + GLY versus IND presented a numerically higher peak-IC (Δ = 0.076 L, 95% confidence interval [CI]: -0.010 - 0.161 L; p = 0.083), with a statistically significant difference in mean IC over 4 h (Δ = 0.054 L, 95%CI 0.022 - 0.086 L; p = 0.001). FEV1, FVC and Raw, but not TLC, were consistently significantly improved by IND + GLY compared to IND alone. Safety profiles of both treatments were comparable. CONCLUSION: The free combination of IND + GLY improved lung function parameters as evaluated by spirometry and body plethysmography, with a similar safety profile compared to IND alone. TRIAL REGISTRATION: NCT01699685.

Rhinitis in Swiss adults is associated with asthma and early life factors, but not second hand tobacco smoke or obesity.

BACKGROUND: Second hand tobacco smoke (SHS) and overweight/obesity are risk factors for asthma and lower airway respiratory symptoms. We investigated whether SHS or overweight/obesity were also associated with allergic or non-allergic rhinitis. METHODS: Cross-sectional data were obtained during the second SAPALDIA Study. Interviewer administered questionnaires were completed by 8047 participants from 8 communities in Switzerland. Blood was collected from 5841 participants and tested for allergen specific IgE. Allergic rhinitis was defined as nasal symptoms with detectable IgE. Data were analysed by multinomial logistic regression with four outcome categories defined according to the presence or absence of rhinitis and/or atopy. RESULTS: The prevalence of allergic rhinitis was 885 (15.2%) and non-allergic rhinitis 323 (5.5%). The risk of allergic rhinitis was increased in subjects with physician diagnosed asthma (Relative Risk Ratio 6.81; 95%CI 5.39, 8.6), maternal atopy (1.56; 1.27, 1.92) and paternal atopy (1.41; 1.11, 1.79). Older subjects were at lower risk (0.96; 0.95,0.97 per year), as were those raised on a farm (0.64; 0.49,0.84), with older siblings (0.92; 0.86,0.97 per sib) or from rural areas. The risk of non-allergic rhinitis was also increased in subjects with physician diagnosed asthma (4.02; 2.86, 5.67), reduced in males (0.59; 0.46, 0.77), but not associated with upbringing on a farm or older siblings. There were no significant associations of SHS or overweight/obesity with either form of rhinitis. CONCLUSIONS: Allergic and non-allergic rhinitis have different risk factors apart from asthma. There are significant regional variations within Switzerland, which are not explained by the factors examined.

Oxidative stress in hypobaric hypoxia and influence on vessel-tone modifying mediators.

Increased pulmonary artery pressure is a well-known phenomenon of hypoxia and is seen in patients with chronic pulmonary diseases, and also in mountaineers on high altitude expedition. Different mediators are known to regulate pulmonary artery vessel tone. However, exact mechanisms are not fully understood and a multimodal process consisting of a whole panel of mediators is supposed to cause pulmonary artery vasoconstriction. We hypothesized that increased hypoxemia is associated with an increase in vasoconstrictive mediators and decrease of vasodilatators leading to a vasoconstrictive net effect. Furthermore, we suggested oxidative stress being partly involved in changement of these parameters. Oxygen saturation (Sao2) and clinical parameters were assessed in 34 volunteers before and during a Swiss research expedition to Mount Muztagh Ata (7549 m) in Western China. Blood samples were taken at four different sites up to an altitude of 6865 m. A mass spectrometry-based targeted metabolomic platform was used to detect multiple parameters, and revealed functional impairment of enzymes that require oxidation-sensitive cofactors. Specifically, the tetrahydrobiopterin (BH4)-dependent enzyme nitric oxide synthase (NOS) showed significantly lower activities (citrulline-to-arginine ratio decreased from baseline median 0.21 to 0.14 at 6265 m), indicating lower NO availability resulting in less vasodilatative activity. Correspondingly, an increase in systemic oxidative stress was found with a significant increase of the percentage of methionine sulfoxide from a median 6% under normoxic condition to a median level of 30% (p<0.001) in camp 1 at 5533 m. Furthermore, significant increase in vasoconstrictive mediators (e.g., tryptophan, serotonin, and peroxidation-sensitive lipids) were found. During ascent up to 6865 m, significant altitude-dependent changes in multiple vessel-tone modifying mediators with excess in vasoconstrictive metabolites could be demonstrated. These changes, as well as highly significant increase in systemic oxidative stress, may be predictive for increase in acute mountain sickness score and changes in Sao2.

Population-based reference values for the 1-min sit-to-stand test.

OBJECTIVES: To determine reference values for the 1-min sit-to-stand (STS) test in an adult population. METHODS: Cross-sectional study nested within a nationwide health promotion campaign in Switzerland. Adults performed the STS test and completed questions on demographics and health behavior. RESULTS: 6,926 out of 7,753 (89.3 %) adults were able to complete the STS test. The median number of repetitions ranged from 50/min (25-75th percentile 41-57/min) in young men and 47/min (39-55/min) in young women aged 20-24 years to 30/min (25-37/min) in older men and 27/min (22-30/min) in older women aged 75-79 years. CONCLUSIONS: The reference values support the interpretation of 1-min STS test performance and identification of subjects with decreased lower body muscular strength and endurance.

Cognitive performance in high-altitude climbers: a comparative study of saccadic eye movements and neuropsychological tests.

Impairment of cognitive performance during and after high-altitude climbing has been described in numerous studies and has mostly been attributed to cerebral hypoxia and resulting functional and structural cerebral alterations. To investigate the hypothesis that high-altitude climbing leads to cognitive impairment, we used of neuropsychological tests and measurements of eye movement (EM) performance during different stimulus conditions. The study was conducted in 32 mountaineers participating in an expedition to Muztagh Ata (7,546 m). Neuropsychological tests comprised figural fluency, line bisection, letter and number cancellation, and a modified pegboard task. Saccadic performance was evaluated under three stimulus conditions with varying degrees of cortical involvement: visually guided pro- and anti-saccades, and visuo-visual interaction. Typical saccade parameters (latency, mean sequence, post-saccadic stability, and error rate) were computed off-line. Measurements were taken at a baseline level of 440 m and at altitudes of 4,497, 5,533, 6,265, and again at 440 m. All subjects reached 5,533 m, and 28 reached 6,265 m. The neuropsychological test results did not reveal any cognitive impairment. Complete eye movement recordings for all stimulus conditions were obtained in 24 subjects at baseline and at least two altitudes and in 10 subjects at baseline and all altitudes. Measurements of saccade performances showed no dependence on any altitude-related parameter and were well within normal limits. Our data indicates that acclimatized climbers do not seem to suffer from significant cognitive deficits during or after climbs to altitudes above 7,500 m. We demonstrated that investigation of EMs is feasible during high-altitude expeditions.

Nocturnal periodic breathing during acclimatization at very high altitude at Mount Muztagh Ata (7,546 m).

RATIONALE: Quantitative data on ventilation during acclimatization at very high altitude are scant. Therefore, we monitored nocturnal ventilation and oxygen saturation in mountaineers ascending Mt. Muztagh Ata (7,546 m). OBJECTIVES: To investigate whether periodic breathing persists during prolonged stay at very high altitude. METHODS: A total of 34 mountaineers (median age, 46 yr; 7 women) climbed from 3,750 m within 19-20 days to the summit at 7,546 m. During ascent, repeated nocturnal recordings of calibrated respiratory inductive plethysmography, pulse oximetry, and scores of acute mountain sickness were obtained. MEASUREMENTS AND MAIN RESULTS: Nocturnal oxygen saturation decreased, whereas minute ventilation and the number of periodic breathing cycles increased with increasing altitude. At the highest camp (6,850 m), median nocturnal oxygen saturation, minute ventilation, and the number of periodic breathing cycles were 64%, 11.3 L/min, and 132.3 cycles/h. Repeated recordings within 5-8 days at 4,497 m and 5,533 m, respectively, revealed increased oxygen saturation, but no decrease in periodic breathing. The number of periodic breathing cycles was positively correlated with days of acclimatization, even when controlled for altitude, oxygen saturation, and other potential confounders, whereas symptoms of acute mountain sickness had no independent effect on periodic breathing. CONCLUSIONS: Our field study provides novel data on nocturnal oxygen saturation, breathing patterns, and ventilation at very high altitude. It demonstrates that periodic breathing increases during acclimatization over 2 weeks at altitudes greater than 3,730 m, despite improved oxygen saturation consistent with a progressive increase in loop gain of the respiratory control system. Clinical trial registered with www.clinicaltrials.gov (NCT00514826).

New insights into changes in corneal thickness in healthy mountaineers during a very-high-altitude climb to Mount Muztagh Ata.

OBJECTIVE: To investigate the effect of very high altitude and different ascent profiles on central corneal thickness (CCT). METHODS: Twenty-eight healthy mountaineers were randomly assigned to 2 different ascent profiles during a medical research expedition to Mount Muztagh Ata (7546 m) in western China. Group 1 was allotted a shorter acclimatization time prior to ascent to 6265 m. The main outcome measure was CCT. Secondary outcome measures were oxygen saturation (SpO(2)) and symptom assessments of acute mountain sickness (cerebral acute mountain sickness score). Examinations were performed at 490, 4497, 5533, and 6265 m. RESULTS: Central corneal thickness increased in both groups with increasing altitude and decreased after descent. In group 1 (with the shorter acclimatization), mean CCT increased from 537 to 572 microm. Mean CCT in group 2 increased from 534 to 563 microm (P = .048). The amount of decrease in SpO(2) paralleled the increase in CCT. There was no significant decrease in visual acuity. There was a significant correlation between CCT and cerebral acute mountain sickness score when controlled for SpO(2) and age. CONCLUSIONS: Corneal swelling during high-altitude climbs is promoted by low SpO(2). Systemic delivery of oxygen to the anterior chamber seems to play a greater role in corneal oxygenation than previously thought. Adhering to a slower ascent profile results in less corneal edema. Visual acuity in healthy corneas is not adversely affected by edema at altitudes of up to 6300 m. Individuals with more acute mountain sickness-related symptoms had thicker corneas, possibly due to their higher overall susceptibility to hypoxia.

Effect of ascent protocol on acute mountain sickness and success at Muztagh Ata, 7546 m.

Bloch, Konrad E., Alexander J. Turk, Marco Maggiorini, Thomas Hess, Tobias Merz, Martina M. Bosch, Daniel Barthelmes, Urs Hefti, Jacqueline Pichler, Oliver Senn, and Otto D. Schoch. Effect of ascent protocol on acute mountain sickness and success at Muztagh Ata, 7546 m. High Alt. Med. Biol. 10:25-32, 2009.-Data on acclimatization during expedition-style climbing to > 5000 m are scant. We evaluated the hypothesis that minor differences in ascent protocol influence acute mountain sickness (AMS) symptoms and mountaineering success in climbers to Muztagh Ata (7546 m), Western China. We performed a randomized, controlled trial during a high altitude medical research expedition to Muztagh Ata. Thirty-four healthy mountaineers (mean age 45 yr, 7 women) were randomized to follow one of two protocols, ascending within 15 or 19 days to the summit of Muztagh Ata at 7546 m, respectively. The main outcome measures, AMS symptom scores and the number of proceeding climbers, were assessed daily. Mean +/- SD AMS-C scores of 16 climbers randomized to slow ascent were 0.06 +/- 0.18, 0.26 +/- 0.08, 0.41 +/- 0.45, 0.53 +/- 0.77 at camps I (5533 m), II (6265 m), III (6865 m), and the summit (7546 m), respectively. Corresponding values in 18 climbers randomized to fast ascent were significantly higher: 0.17 +/- 0.23, 0.43 +/- 0.75, 0.49 +/- 0.36, and 0.69 +/- 0.54 (p < 0.008, vs. slow ascent in regression analysis accounting for weather-related protocol deviation). Climbers randomized to slow ascent were able to ascend according to the protocol without AMS for significantly more days than climbers randomized to fast ascent (p = 0.04, Kaplan-Meier analysis). More climbers randomized to slow ascent were successful in reaching the highest camp at 6865 m without AMS (odds ratio 9.5; 95% confidence interval 1.02 to 89). In climbers ascending to very high altitudes, differences of a few days in acclimatization have a significant impact on symptom severity, the prevalence of AMS, and mountaineering success. ClinicalTrials.gov Identifier NCT00603122.

[When the throug is reached]. / Wenn die Talsohle erreicht ist.

The only option for a patient suffering from severe chronic obstructive pulmonary disease (COPD) despite fully developed medical therapy inclusive eventually supplemental oxygen is either lung transplantation or lung-volume-reduction surgery (LVRS). Indication for LVRS is based on the results of a large prostective controlled clinical trial and patients are selected for this intervention based on particular functional and radiomorphologic criteria. We report a patient with far advanced COPD, no longer able to walk to the toilette without support. Based on clinical reasoning and our experience with other unique cases the patient underwent unilateral LVRS despite a lack of scientific evidence that she might profit from this intervention. Luckily, the perioperative course was uneventful and she experienced an impressive subjective and objective improvement. This case illustrates, that in desperate situations it may be necessary to reach a therapeutic decision outside scientifically based evidence.

High incidence of optic disc swelling at very high altitudes.

OBJECTIVES: To determine the incidence of optic disc swelling as a possible indicator of cerebral edema in a large group of healthy mountaineers exposed to very high altitudes and to correlate these findings with various clinical and environmental factors and occurrence of acute mountain sickness and high-altitude cerebral edema. METHODS: This multidisciplinary, prospective, observational cohort study was performed in 2005 within the scope of a medical research expedition to Muztagh Ata (7546 m [24,751 ft]) in Western Xinjiang Province, China. Twenty-seven healthy mountaineers aged 26 to 62 years participated. Medical examinations were performed in Switzerland 1 month before and 4 1/2 months after the expedition. Ophthalmologic examinations were performed at 4 high camps (maximum elevation, 6865 m [22,517 ft]). Optic disc status was documented using digital photography. Further assessments included arterial oxygen saturation and cerebral acute mountain sickness scores. RESULTS: Sixteen of 27 study subjects (59%) exhibited optic disc swelling during their stay at high altitudes, with complete regression on return to lowlands. Significant correlation was noted between optic disc swelling and lower arterial oxygen saturation (odds ratio, 0.86 per percentage of arterial oxygen saturation; 95% confidence interval, 0.81-0.92; P < .001), younger age (odds ratio, 0.95 per year; 95% confidence interval, 0.90-0.99; P = .03), and higher cerebral acute mountain sickness scores (odds ratio, 2.32 per 0.1 point; 95% confidence interval, 1.48-3.63; P < .001). CONCLUSION: Optic disc swelling occurs frequently in high-altitude climbers and is correlated with peripheral oxygen saturation and symptoms of acute mountain sickness. It is most likely the result of hypoxia-induced brain volume increase.