Physical activity is increased by a 12-week semiautomated telecoaching programme in patients with COPD: a multicentre randomised controlled trial.

RATIONALE: Reduced physical activity (PA) in patients with COPD is associated with a poor prognosis. Increasing PA is a key therapeutic target, but thus far few strategies have been found effective in this patient group. OBJECTIVES: To investigate the effectiveness of a 12-week semiautomated telecoaching intervention on PA in patients with COPD in a multicentre European randomised controlled trial. METHODS: 343 patients from six centres, encompassing a wide spectrum of disease severity, were randomly allocated to either a usual care group (UCG) or a telecoaching intervention group (IG) between June and December 2014. This 12-week intervention included an exercise booklet and a step counter providing feedback both directly and via a dedicated smartphone application. The latter provided an individualised daily activity goal (steps) revised weekly and text messages as well as allowing occasional telephone contacts with investigators. PA was measured using accelerometry during 1 week preceding randomisation and during week 12. Secondary outcomes included exercise capacity and health status. Analyses were based on modified intention to treat. MAIN RESULTS: Both groups were comparable at baseline in terms of factors influencing PA. At 12 weeks, the intervention yielded a between-group difference of mean, 95% CI (lower limit - upper limit; ll-ul) +1469, 95% CI (971 to 1965) steps/day and +10.4, 95% CI (6.1 to 14.7) min/day moderate PA; favouring the IG (all p≤0.001). The change in 6-min walk distance was significantly different (13.4, 95% CI (3.40 to 23.5) m, p<0.01), favouring the IG. In IG patients, an improvement could be observed in the functional state domain of the clinical COPD questionnaire (p=0.03) compared with UCG. Other health status outcomes did not differ. CONCLUSIONS: The amount and intensity of PA can be significantly increased in patients with COPD using a 12-week semiautomated telecoaching intervention including a step counter and an application installed on a smartphone. TRIAL REGISTRATION NUMBER: NCT02158065.

Klotho and smoking--An interplay influencing the skeletal muscle function deficits that occur in COPD.

BACKGROUND: Klotho is an 'anti-ageing' hormone and transmembrane protein; Klotho deficient mice develop a similar ageing phenotype to smokers including emphysema and muscle wasting. The objective of this study was to evaluate skeletal muscle and circulating Klotho protein in smokers and COPD patients and to relate Klotho levels to relevant skeletal muscle parameters. We sought to validate our findings by undertaking complimentary murine studies. METHODS: Fat free mass, quadriceps strength and spirometry were measured in 87 participants (61 COPD, 13 'healthy smokers' and 13 never smoking controls) in whom serum and quadriceps Klotho protein levels were also measured. Immunohistochemistry was performed to demonstrate the location of Klotho protein in human skeletal muscle and in mouse skeletal muscle in which regeneration was occurring following injury induced by electroporation. In a separate study, gastrocnemius Klotho protein was measured in mice exposed to 77 weeks of smoke or sham air. RESULTS: Quadriceps Klotho levels were lower in those currently smoking (p = 0.01), irrespective of spirometry, but were not lower in patients with COPD. A regression analysis identified current smoking status as the only independent variable associated with human quadriceps Klotho levels, an observation supported by the finding that smoke exposed mice had lower gastrocnemius Klotho levels than sham exposed mice (p = 0.005). Quadriceps Klotho levels related to local oxidative stress but were paradoxically higher in patients with established muscle wasting or weakness; the unexpected relationship with low fat free mass was the only independent association. Within locomotor muscle, Klotho localized to the plasma membrane and to centralized nuclei in humans and in mice with induced muscle damage. Serum Klotho had an independent association with quadriceps strength but did not relate to quadriceps Klotho levels or to spirometric parameters. CONCLUSIONS: Klotho is expressed in skeletal muscle and levels are reduced by smoking. Despite this, quadriceps Klotho protein expression in those with established disease appears complex as levels were paradoxically elevated in COPD patients with established muscle wasting. Whilst serum Klotho levels were not reduced in smokers or COPD patients and were not associated with quadriceps Klotho protein, they did relate to quadriceps strength.

Physiological responses to Tai Chi in stable patients with COPD.

We compared the physiological work, judged by oxygen uptake, esophageal pressure swing and diaphragm electromyography, elicited by Tai Chi compared with that elicited by constant rate treadmill walking at 60% of maximal load in eleven patients with COPD (Mean FEV1 61% predicted, FEV1/FVC 47%). Dynamic hyperinflation was assessed by inspiratory capacity and twitch quadriceps tension (TwQ) elicited by supramaximal magnetic stimulation of the femoral nerve was also measured before and after both exercises. The EMGdi and esophageal pressure at the end of exercise were similar for both treadmill exercise and Tai Chi (0.109±0.047 mV vs 0.118±0.061 mV for EMGdi and 22.3±7.1 cmH2O vs 21.9±8.1 cmH2O for esophageal pressure). Moreover the mean values of oxygen uptake during Tai Chi and treadmill exercise did not differ significantly: 11.3 ml/kg/min (51.1% of maximal oxygen uptake derived from incremental exercise) and 13.4 ml/kg/min (52.5%) respectively, p>0.05. Respiratory rate during Tai Chi was significantly lower than that during treadmill exercise. Both Tai Chi and treadmill exercise elicited a fall in IC at end exercise, indicating dynamic hyperinflation, but this was statistically significant only after treadmill exercise. TwQ decreased significantly after Tai Chi but not after treadmill. We conclude that Tai Chi constitutes a physiologically similar stimulus to treadmill exercise and may therefore be an acceptable modality for pulmonary rehabilitation which may be culturally more acceptable in some parts of the world.

Dynamic laryngeal narrowing during exercise: a mechanism for generating intrinsic PEEP in COPD?

INTRODUCTION: Patients with COPD commonly exhibit pursed-lip breathing during exercise, a strategy that, by increasing intrinsic positive end-expiratory pressure, may optimise lung mechanics and exercise tolerance. A similar role for laryngeal narrowing in modulating exercise airways resistance and the respiratory cycle volume-time course is postulated, yet remains unstudied in COPD. The aim of this study was to assess the characteristics of laryngeal narrowing and its role in exercise intolerance and dynamic hyperinflation in COPD. METHODS: We studied 19 patients (n=8 mild-moderate; n=11 severe COPD) and healthy age and sex matched controls (n=11). Baseline physiological characteristics and clinical status were assessed prior to an incremental maximal cardiopulmonary exercise test with continuous laryngoscopy. Laryngeal narrowing measures were calculated at the glottic and supra-glottic aperture at rest and peak exercise. RESULTS: At rest, expiratory laryngeal narrowing was pronounced at the glottic level in patients and related to FEV1 in the whole cohort (r=-0.71, p<0.001) and patients alone (r=-0.53, p=0.018). During exercise, glottic narrowing was inversely related to peak ventilation in all subjects (r=-0.55, p=0.0015) and patients (r=-0.71, p<0.001) and peak exercise tidal volume (r=-0.58, p=0.0062 and r=-0.55, p=0.0076, respectively). Exercise glottic narrowing was also inversely related to peak oxygen uptake (% predicted) in all subjects (r=-0.65, p<0.001) and patients considered alone (r=-0.58, p=0.014). Exercise inspiratory duty cycle was related to exercise glottic narrowing for all subjects (r=-0.69, p<0.001) and patients (r=-0.62, p<0.001). CONCLUSIONS: Dynamic laryngeal narrowing during expiration is prevalent in patients with COPD and is related to disease severity, respiratory duty cycle and exercise capacity.

Increased expression of GDF-15 may mediate ICU-acquired weakness by down-regulating muscle microRNAs.

RATIONALE: The molecular mechanisms underlying the muscle atrophy of intensive care unit-acquired weakness (ICUAW) are poorly understood. We hypothesised that increased circulating and muscle growth and differentiation factor-15 (GDF-15) causes atrophy in ICUAW by changing expression of key microRNAs. OBJECTIVES: To investigate GDF-15 and microRNA expression in patients with ICUAW and to elucidate possible mechanisms by which they cause muscle atrophy in vivo and in vitro. METHODS: In an observational study, 20 patients with ICUAW and seven elective surgical patients (controls) underwent rectus femoris muscle biopsy and blood sampling. mRNA and microRNA expression of target genes were examined in muscle specimens and GDF-15 protein concentration quantified in plasma. The effects of GDF-15 on C2C12 myotubes in vitro were examined. MEASUREMENTS AND MAIN RESULTS: Compared with controls, GDF-15 protein was elevated in plasma (median 7239 vs 2454 pg/mL, p=0.001) and GDF-15 mRNA in the muscle (median twofold increase p=0.006) of patients with ICUAW. The expression of microRNAs involved in muscle homeostasis was significantly lower in the muscle of patients with ICUAW. GDF-15 treatment of C2C12 myotubes significantly elevated expression of muscle atrophy-related genes and down-regulated the expression of muscle microRNAs. miR-181a suppressed transforming growth factor-ß (TGF-ß) responses in C2C12 cells, suggesting increased sensitivity to TGF-ß in ICUAW muscle. Consistent with this suggestion, nuclear phospho-small mothers against decapentaplegic (SMAD) 2/3 was increased in ICUAW muscle. CONCLUSIONS: GDF-15 may increase sensitivity to TGF-ß signalling by suppressing the expression of muscle microRNAs, thereby promoting muscle atrophy in ICUAW. This study identifies both GDF-15 and associated microRNA as potential therapeutic targets.

Bronchoscopic lung volume reduction with endobronchial valves for patients with heterogeneous emphysema and intact interlobar fissures (the BeLieVeR-HIFi trial): study design and rationale.

Although lung volume reduction surgery improves survival in selected patients with emphysema, there has been ongoing interest in developing and evaluating bronchoscopic approaches to try to reduce lung volumes with less morbidity and mortality. The placement of endobronchial valves is one such technique, and although some patients have had a significant improvement, responses have been inconsistent because collateral ventilation prevents lobar atelectasis. We describe the protocol of a trial (ISRCTN04761234) aimed to show that a responder phenotype, patients with heterogeneous emphysema and intact interlobar fissures on CT scanning, can be identified prospectively, leading to a consistent benefit in clinical practice.

Respiratory motor output during an inspiratory capacity maneuver is preserved despite submaximal exercise.

It is unknown whether respiratory motor output is constrained during exhaustive exercise in healthy adults. We hypothesised that neural inhibition did occur; to test this hypothesis we measured diaphragm EMG from a maximal inspiratory capacity maneuver (EMG(di)-IC) at rest and during exercise. EMG(di)-IC was measured before and after the amplitude of the diaphragm EMG entered a plateau phase in eleven healthy adults undertaking exercise at 60% and 80% of maximal workload achieved from incremental exercise. The mean EMG(di)-IC at rest was 65 ± 16% of the maximum that could be obtained from a battery of inspiratory tasks. Before and after the plateau phase of diaphragm EMG, EMG(di)-IC was 68 ± 13% and 72 ± 12% (p > 0.05) during 60% of the maximum workload, and was 70 ± 13% and 78 ± 13% (p > 0.05) during 80% of the maximum workload achieved on an incremental test. A further sub-study in which 5 participants exercised at 90% of the maximum workload also showed that EMG(di)-IC was not diminished during exercise. Our data show that exercise condition does not reduce the magnitude of EMG(di)-IC. This argues against neural inhibition as feature of submaximal exercise in healthy adults.

Molecular mechanisms of intensive care unit-acquired weakness.

Intensive care unit-acquired weakness (ICUAW) is an increasingly recognised and important clinical consequence of critical illness. It is associated with significant morbidity and mortality. The aetiology of this disease is not well understood. The purpose of this article is to review our understanding of the molecular pathogenesis of ICUAW in the context of current knowledge of clinical risk factors and aetiology. Key features of the disease are loss of muscle mass resulting from a shift in the dynamic balance of muscle protein synthesis and breakdown and a reduction in force-generating capacity. These alternations are secondary to neuropathy, disruption of the myofilament structure and function, a disrupted sarcoplasmic reticulum, electrical inexcitability and bioenergenetic failure. As knowledge and understanding of ICUAW grows, potential therapeutic targets will be identified, hopefully leading to multiple strategies for prevention and treatment of this important condition.

Atelectasis and survival after bronchoscopic lung volume reduction for COPD.

Bronchoscopic therapies to reduce lung volumes in chronic obstructive pulmonary disease are intended to avoid the risks associated with lung volume reduction surgery (LVRS) or to be used in patient groups in whom LVRS is not appropriate. Bronchoscopic lung volume reduction (BLVR) using endobronchial valves to target unilateral lobar occlusion can improve lung function and exercise capacity in patients with emphysema. The benefit is most pronounced in, though not confined to, patients where lobar atelectasis has occurred. Few data exist on their long-term outcome. 19 patients (16 males; mean±sd forced expiratory volume in 1 s 28.4±11.9% predicted) underwent BLVR between July 2002 and February 2004. Radiological atelectasis was observed in five patients. Survival data was available for all patients up to February 2010. None of the patients in whom atelectasis occurred died during follow-up, whereas eight out of 14 in the nonatelectasis group died (Chi-squared p=0.026). There was no significant difference between the groups at baseline in lung function, quality of life, exacerbation rate, exercise capacity (shuttle walk test or cycle ergometry) or computed tomography appearances, although body mass index was significantly higher in the atelectasis group (21.6±2.9 versus 28.4±2.9 kg·m(-2); p<0.001). The data in the present study suggest that atelectasis following BLVR is associated with a survival benefit that is not explained by baseline differences.

Screening for sleep-disordered breathing in neuromuscular disease using a questionnaire for symptoms associated with diaphragm paralysis.

Patients with neuromuscular disease (NMD) are at risk of developing sleep-disordered breathing (SDB) following respiratory muscle involvement. We hypothesised that a questionnaire based on clinical symptoms and signs of diaphragm weakness can be used to screen for SDB in such patients. We developed a self-administered multiple choice questionnaire containing five questions (Sleep-Disordered Breathing in Neuromuscular Disease Questionnaire (SiNQ)-5), scoring 0-10 points. 125 patients were enrolled: 32 with respiratory muscle weakness, 35 subjects with normal respiratory muscle strength and 58 patients with obstructive sleep apnoea (OSA). All subjects underwent full polysomnography. NMD patients with involvement of the respiratory muscles scored mean ± sd 6.8 ± 2.3 out of 10 points, significantly higher than both OSA patients 2.5 ± 2.3 and normal subjects 1.0 ± 2.0 (p < 0.001). A score of five or more points in the SiNQ-5 had a sensitivity of 86.2%, specificity of 88.5%, positive predictive value of 69.4% and a negative predictive value of 95.5% to identify NMD with combined SDB. A short self-administered questionnaire, the SiNQ-5, based on clinical symptoms can reliably screen for SDB in patients with diaphragm weakness. However, comorbidities, such as heart failure, that have symptoms influenced by posture could alter diagnostic accuracy.

Acute ischaemic hemispheric stroke is associated with impairment of reflex in addition to voluntary cough.

Cough function is impaired after stroke; this may be important for protection against chest infection. Reflex cough (RC) intensity indices have not been described after stroke. RC, voluntary cough (VC) and respiratory muscle strength were studied in patients within 2 weeks of hemispheric infarct. The null hypotheses were that patients with cortical hemisphere stroke would show the same results as healthy controls on: 1) objective indices of RC and VC intensity; and 2) respiratory muscle strength tests. Peak cough flow rate (PCFR) and gastric pressure (P(ga)) were measured during maximum VC and RC. Participants also underwent volitional and nonvolitional respiratory muscle testing. Nonvolitional expiratory muscle strength was assessed by measuring P(ga) increase after magnetic stimulation over the T10 nerve roots (twitch T10 P(ga)). Stroke severity was scored using the National Institutes of Health Stroke Scale (NIHSS; maximum = 31). 18 patients (mean ± sd age 62 ± 15 yrs and NIHSS score 14 ± 8) and 20 controls (56 ± 16 yrs) participated. VC intensity was impaired in patients (PCFR 287 ± 171 versus 497 ± 122 L·min⁻¹) as was VC P(ga) (98.5 ± 61.6 versus 208.5 ± 61.3 cmH2O; p < 0.001 for both). RC PCFR was reduced in patients (204 ± 111 versus 379 ± 110 L·min⁻¹; p < 0.001), but RC P(ga) was not significantly different from that of controls (179.0 ± 78.0 versus 208.0 ± 77.4 cmH2O; p = 0.266). Patients exhibited impaired volitional respiratory muscle tests, but twitch T10 P(ga) was normal. VC and RC are both impaired in hemispheric stroke patients, despite preserved expiratory muscle strength. Cough coordination is probably cortically modulated and affected by hemispheric stroke.