Quadriceps strength relates to exercise capacity and prognosis in chronic obstructive pulmonary disease (COPD). We wanted to quantify the prevalence of quadriceps weakness in COPD and hypothesised ...that it would not be restricted to patients with severe airflow obstruction or dyspnoea. Predicted quadriceps strength was calculated using a regression equation (incorporating age, sex, height and fat-free mass), based on measurements from 212 healthy subjects. The prevalence of weakness (defined as observed values 1.645 standardised residuals below predicted) was related to Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage and Medical Research Council (MRC) dyspnoea score in two cohorts of stable COPD outpatients recruited from the UK (n = 240) and the Netherlands (n = 351). 32% and 33% of UK and Dutch COPD patients had quadriceps weakness. A significant proportion of patients in GOLD stages 1 and 2, or with an MRC dyspnoea score of 1 or 2, had quadriceps weakness (28 and 26%, respectively). These values rose to 38% in GOLD stage 4, and 43% in patients with an MRC Score of 4 or 5. Quadriceps weakness was demonstrable in one-third of COPD patients attending hospital respiratory outpatient services. Quadriceps weakness exists in the absence of severe airflow obstruction or breathlessness.
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.
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.
Adults and children with neuromuscular disease exhibit weak cough and are susceptible to recurrent chest infections, a major cause of morbidity and mortality. Mechanical insufflation/exsufflation may ...improve cough efficacy by increasing peak cough flow. It was hypothesised that mechanical insufflation/exsufflation would produce a greater increase in peak cough flow than other modes of cough augmentation. The acceptability of these interventions was also compared. Twenty-two patients aged 10-56 yrs (median 21 yrs) with neuromuscular disease and 19 age-matched controls were studied. Spirometry was performed and respiratory muscle strength measured. Peak cough flow was recorded during maximal unassisted coughs, followed in random order by coughs assisted by physiotherapy, noninvasive ventilation, insufflation and exsufflation, and exsufflation alone. Subjects rated strength of cough, distress and comfort on a visual analogue scale. In the neuromuscular disease group, mean +/- SD forced expiratory volume in one second was 0.8 +/- 0.6 L x s(-1), forced vital capacity 0.9 +/- 0.8 L, maximum inspiratory pressure 25 +/- 16 cmH2O, maximum expiratory pressure 26 +/- 22 cmH2O and unassisted peak cough flow 169 +/- 90 L x min(-1). The greatest increase in peak cough flow was observed with mechanical insufflation/exsufflation at 235 +/- 111 L x min(-1) (p<0.01). All techniques showed similar patient acceptability. Mechanical insufflation/exsufflation produces a greater increase in peak cough flow than other standard cough augmentation techniques in adults and children with neuromuscular disease.
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.
To investigate the effectiveness of a 12-week semiautomated telecoaching intervention on PA in patients with COPD in a multicentre European randomised controlled trial.
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.
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.
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.
NCT02158065.
Quadriceps weakness and loss of muscle mass predict mortality in chronic obstructive pulmonary disease (COPD). It was hypothesised that a reduced quadriceps cross-sectional area could be detected by ...ultrasound in patients with COPD compared with healthy subjects, and that measurements relate to strength and fat-free mass (FFM).
Rectus femoris muscle cross-sectional area (RF(CSA)) was measured by ultrasound and whole-body FFM estimated using electrical bioimpedance. Quadriceps strength was measured by maximum voluntary contraction and twitch tension (TwQ) following magnetic femoral nerve stimulation.
26 healthy volunteers of mean (SD) age 63 (9) years and 30 patients with COPD of mean (SD) age 67 (9) years and percentage predicted forced expiratory volume in 1 s (FEV(1)) 48.0 (20.8)% with a similar FFM (46.9 (9.3) kg vs 46.1 (7.3) kg, p = 0.193) participated in the study. Mean RF(CSA) was reduced in patients with COPD by 25% of the mean value in healthy subjects(-115 mm(2); 95% CI -177 to -54, p = 0.001) and was related to MRC dyspnoea scale score, independent of FFM or sex. Maximum voluntary contraction strength was linearly related to RF(CSA) in patients with COPD (r = 0.78, p<0.001). TwQ force per unit of RF(CSA) was similar in both healthy individuals and those with COPD (mean (SD) 17 (4) g/mm(2) vs 18 (3) g/mm(2), p = 0.657). Voluntary contraction strength per unit of RF(CSA) was dependent on central quadriceps activation and peripheral oxygen saturation in COPD.
Ultrasound measurement of RF(CSA) is an effort-independent and radiation-free method of measuring quadriceps muscle cross-sectional area in patients with COPD that relates to strength.
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.
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.
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.
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-β (TGF-β) responses in C2C12 cells, suggesting increased sensitivity to TGF-β in ICUAW muscle. Consistent with this suggestion, nuclear phospho-small mothers against decapentaplegic (SMAD) 2/3 was increased in ICUAW muscle.
GDF-15 may increase sensitivity to TGF-β 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.
The load imposed on ventilation by increased body mass contributes to the respiratory symptoms caused by obesity. A study was conducted to quantify ventilatory load and respiratory drive in obesity ...in both the upright and supine postures.
Resting breathing when seated and supine was studied in 30 obese subjects (mean (SD) body mass index (BMI) 42.8 (8.6) kg/m(2)) and 30 normal subjects (mean (SD) BMI 23.6 (3.7) kg/m(2)), recording the electromyogram of the diaphragm (EMGdi, transoesophageal multipair electrode), gastric and oesophageal pressures.
Ventilatory load and neural drive were higher in the obese group as judged by the EMGdi (21.9 (9.0) vs 8.4 (4.0)%max, p<0.001) and oesophageal pressure swings (9.6 (2.9) vs 5.3 (2.2) cm H(2)O, p<0.001). The supine posture caused an increase in oesophageal pressure swings to 16.0 (5.0) cm H(2)O in obese subjects (p<0.001) and to 6.9 (2.0) cm H(2)O in non-obese subjects (p<0.001). The EMGdi increased in the obese group to 24.7 (8.2)%max (p<0.001) but remained the same in non-obese subjects (7.0 (3.4)%max, p = NS). Obese subjects developed intrinsic positive end-expiratory pressure (PEEPi) of 5.3 (3.6) cm H(2)O when supine. Applying continuous positive airway pressure (CPAP) in a subgroup of obese subjects when supine reduced the EMGdi by 40%, inspiratory pressure swings by 25% and largely abolished PEEPi (4.1 (2.7) vs 0.8 (0.4) cm H(2)O, p = 0.009).
Obese patients have substantially increased neural drive related to BMI and develop PEEPi when supine. CPAP abolishes PEEPi and reduces neural respiratory drive in these patients. These findings highlight the adverse respiratory consequences of obesity and have implications for the clinical management of patients, particularly where the supine posture is required.
Assessment of quadriceps endurance is of interest to investigators studying human disease. We hypothesized that repetitive magnetic stimulation (rMS) of the intramuscular branches of the femoral ...nerve could be used to induce and quantify quadriceps endurance. To test this hypothesis, we used a novel stimulating coil to compare the quadriceps endurance properties in eight normal humans and, to confirm that the technique could be used in clinical practice, in eight patients with advanced chronic obstructive pulmonary disease (COPD). To validate the method, we compared in vivo contractile properties of the quadriceps muscle with the fiber-type composition and oxidative enzyme capacity. We used a Magstim Rapid(2) magnetic nerve stimulator with the coil wrapped around the quadriceps. Stimuli were given at 30 Hz, a duty cycle of 0.4 (2 s on, 3 s off), and for 50 trains. Force generation and the surface electromyogram were measured throughout. Quadriceps twitch force, elicited by supramaximal magnetic stimulation of the femoral nerve, was measured before and after the protocol. Quadriceps muscle biopsies were analyzed for oxidative (citrate synthase, CS) and glycolytic (phosphofructokinase, PFK) enzyme activity and myosin heavy chain isoform protein expression. The time for force to fall to 70% of baseline (T(70)) was shorter in the COPD group than the control group: 55.6 +/- 26.0 vs. 121 +/- 38.7 s (P = 0.0014). Considering patients and controls together, positive correlations were observed between T(70) and the proportion of type I fibers (r = 0.68, P = 0.004) and CS-to-PFK ratio (CS/PFK) (r = 0.67, P = 0.005). We conclude that quadriceps endurance assessed using rMS is feasible in clinical studies.
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