Mechanisms of improvement of respiratory failure in patients with COPD treated with NIV

Annabel H Nickol1,2, Nicholas Hart1,3, Nicholas S Hopkinson1, Carl-Hugo Hamnegård4, John Moxham5, Anita Simonds1, Michael I Polkey11Respiratory Muscle Laboratory, Royal Brompton Hospital, London, UK; 2Oxford Centre for Respiratory Medicine, Churchill Hospital, Oxford, UK; 3The Lane Fox Unit, St Thomas’ Hospital, London, UK; 4Department of Pulmonary Medicine and Clinical Physiology, Sahlgrenska University, Gotenborg, Sweden; 5Respiratory Muscle Laboratory, King’s College London School of Medicine, King’s College Hospital, London, UKBackground: Noninvasive ventilation (NIV) improves gas-exchange and symptoms in selected chronic obstructive pulmonary disease (COPD) patients with hypercapnic respiratory failure. We hypothesized NIV reverses respiratory failure by one or all of increased ventilatory response to carbon-dioxide, reduced respiratory muscle fatigue, or improved pulmonary mechanics.Methods: Nineteen stable COPD patients (forced expiratory volume in one second 35% predicted) were studied at baseline (D0), 5–8 days (D5) and 3 months (3M) after starting NIV.Results: Ventilator use was 6.2 (3.7) hours per night at D5 and 3.4 (1.6) at 3M (p = 0.12). Mean (SD) daytime arterial carbon-dioxide tension (PaCO2) was reduced from 7.4 (1.2) kPa to 7.0 (1.1) kPa at D5 and 6.5 (1.1) kPa at 3M (p = 0.001). Total lung capacity decreased from 107 (28) % predicted to 103 (28) at D5 and 103 (27) % predicted at 3M (p = 0.035). At D5 there was an increase in the hypercapnic ventilatory response and some volitional measures of inspiratory and expiratory muscle strength, but not isolated diaphragmatic strength whether assessed by volitional or nonvolitional methods.Conclusion: These findings suggest decreased gas trapping and increased ventilatory sensitivity to CO2 are the principal mechanism underlying improvements in gas-exchange in patients with COPD following NIV. Changes in some volitional but not nonvolitional muscle strength measures may reflect improved patient effort.Keywords: COPD; hypercapnic respiratory failure; NIV; pulmonary mechanics; ventilatory driv

The effects of inspiratory muscle training in older adults

Purpose: Declining inspiratory muscle function and structure and systemic low-level inflammation and oxidative stress may contribute to morbidity and mortality during normal ageing. Therefore, we examined the effects of inspiratory muscle training (IMT) in older adults on inspiratory muscle function and structure and systemic inflammation and oxidative stress, and re-examined the reported positive effects of IMT on respiratory muscle strength, inspiratory muscle endurance, spirometry, exercise performance, physical activity levels (PAL) and quality of life (QoL). Methods: Thirty-four healthy older adults (68 ± 3 years) with normal spirometry, respiratory muscle strength and physical fitness were divided equally into a pressure-threshold IMT or sham-hypoxic placebo group. Before and after an 8 week intervention, measurements were taken for dynamic inspiratory muscle function and inspiratory muscle endurance using a weighted plunger pressure-threshold loading device, diaphragm thickness using B-mode ultrasonography, plasma cytokine concentrations using immunoassays, DNA damage levels in peripheral blood mononuclear cells (PBMC) using Comet Assays, spirometry, maximal mouth pressures, exercise performance using a six minute walk test, PAL using a questionnaire and accelerometry, and QoL using a questionnaire

Detection and diagnosis of large airway collapse: a systematic review

Large airway collapse (LAC) is a frequently encountered clinical problem, caused by tracheobronchomalacia +/− excessive dynamic airway collapse, yet there are currently no universally accepted diagnostic criteria. We systematically reviewed studies reporting a diagnostic approach to LAC in healthy adults and patients, to compare diagnostic modalities and criteria used. Electronic databases were searched for relevant studies between 1989 and 2019. Studies that reported a diagnostic approach using computed tomography (CT), magnetic resonance imaging or flexible fibreoptic bronchoscopy were included. Random effects meta-analyses were performed to estimate the prevalence of LAC in healthy subjects and in patients with chronic obstructive airway diseases. We included 41 studies, describing 10 071 subjects (47% female) with a mean±sd age of 59±9 years. Most studies (n=35) reported CT findings, and only three studies reported bronchoscopic findings. The most reported diagnostic criterion was a ≥50% reduction in tracheal or main bronchi calibre at end-expiration on dynamic expiratory CT. Meta-analyses of relevant studies found that 17% (95% CI: 0–61%) of healthy subjects and 27% (95% CI: 11–46%) of patients with chronic airways disease were classified as having LAC, using this threshold. The most reported approach to diagnose LAC utilises CT diagnostics, and at a threshold used by most clinicians (i.e.≥50%) may classify a considerable proportion of healthy individuals as being abnormal and having LAC in a quarter of patients with chronic airways disease. Future work should focus on establishing more precise diagnostic criteria for LAC, relating this to relevant physiological and disease sequelae

Detection and diagnosis of large airway collapse: a systematic review

Large airway collapse (LAC) is a frequently encountered clinical problem, caused by tracheobronchomalacia +/− excessive dynamic airway collapse, yet there are currently no universally accepted diagnostic criteria. We systematically reviewed studies reporting a diagnostic approach to LAC in healthy adults and patients, to compare diagnostic modalities and criteria used. Electronic databases were searched for relevant studies between 1989 and 2019. Studies that reported a diagnostic approach using computed tomography (CT), magnetic resonance imaging or flexible fibreoptic bronchoscopy were included. Random effects meta-analyses were performed to estimate the prevalence of LAC in healthy subjects and in patients with chronic obstructive airway diseases. We included 41 studies, describing 10 071 subjects (47% female) with a mean±sd age of 59±9 years. Most studies (n=35) reported CT findings, and only three studies reported bronchoscopic findings. The most reported diagnostic criterion was a ≥50% reduction in tracheal or main bronchi calibre at end-expiration on dynamic expiratory CT. Meta-analyses of relevant studies found that 17% (95% CI: 0–61%) of healthy subjects and 27% (95% CI: 11–46%) of patients with chronic airways disease were classified as having LAC, using this threshold. The most reported approach to diagnose LAC utilises CT diagnostics, and at a threshold used by most clinicians (i.e.≥50%) may classify a considerable proportion of healthy individuals as being abnormal and having LAC in a quarter of patients with chronic airways disease. Future work should focus on establishing more precise diagnostic criteria for LAC, relating this to relevant physiological and disease sequelae

Physical Activity Characteristics across GOLD Quadrants Depend on the Questionnaire Used

BACKGROUND:The GOLD multidimensional classification of COPD severity combines the exacerbation risk with the symptom experience, for which 3 different questionnaires are permitted. This study investigated differences in physical activity (PA) in the different GOLD quadrants and patient's distribution in relation to the questionnaire used. METHODS:136 COPD patients (58±21% FEV1 predicted, 34F/102M) completed COPD assessment test (CAT), clinical COPD questionnaire (CCQ) and modified Medical Research Council (mMRC) questionnaire. Exacerbation history, spirometry and 6MWD were collected. PA was objectively measured for 2 periods of 1 week, 6 months apart, in 5 European centres; to minimise seasonal and clinical variation the average of these two periods was used for analysis. RESULTS:GOLD quadrants C+D had reduced PA compared with A+B (3824 [2976] vs. 5508 [4671] steps.d-1, p<0.0001). The choice of questionnaire yielded different patient distributions (agreement mMRC-CAT κ = 0.57; CCQ-mMRC κ = 0.71; CCQ-CAT κ = 0.72) with different clinical characteristics. PA was notably lower in patients with an mMRC score ≥2 (3430 [2537] vs. 5443 [3776] steps.d-1, p <0.001) in both the low and high risk quadrants. CONCLUSIONS:Using different questionnaires changes the patient distribution and results in different clinical characteristics. Therefore, standardization of the questionnaire used for classification is critical to allow comparison of different studies using this as an entry criterion. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov NCT01388218

Effects of acute fatigue on the volitional and magnetically-evoked electromechanical delay of the knee flexors in males and females

Neuromuscular performance capabilities, including those measured by evoked responses, may be adversely affected by fatigue; however, the capability of the neuromuscular system to initiate muscle force rapidly under these circumstances is yet to be established. Sex-differences in the acute responses of neuromuscular performance to exercise stress may be linked to evidence that females are much more vulnerable to ACL injury than males. Optimal functioning of the knee flexors is paramount to the dynamic stabilisation of the knee joint, therefore the aim of this investigation was to examine the effects of acute maximal intensity fatiguing exercise on the voluntary and magnetically-evoked electromechanical delay in the knee flexors of males and females. Knee flexor volitional and magnetically-evoked neuromuscular performance was assessed in seven male and nine females prior to and immediately after: (i) an intervention condition comprising a fatigue trial of 30-seconds maximal static exercise of the knee flexors, (ii) a control condition consisting of no exercise. The results showed that the fatigue intervention was associated with a substantive reduction in volitional peak force (PFV) that was greater in males compared to females (15.0%, 10.2%, respectively, p < 0.01) and impairment to volitional electromechanical delay (EMDV) in females exclusively (19.3%, p < 0.05). Similar improvements in magnetically-evoked electromechanical delay in males and females following fatigue (21%, p < 0.001), however, may suggest a vital facilitatory mechanism to overcome the effects of impaired voluntary capabilities, and a faster neuromuscular response that can be deployed during critical times to protect the joint system

Respiratory muscle strength as a predictive biomarker for survival in amyotrophic lateral sclerosis

Rationale: Biomarkers for survival in amyotrophic lateral sclerosis (ALS) would facilitate the development of novel drugs. Although respiratory muscle weakness is a known predictor of poor prognosis, a comprehensive comparison of different tests is lacking. Objectives: To compare the predictive power of invasive and noninvasive respiratory muscle strength assessments for survival or ventilator-free survival, up to 3 years. Methods: From a previously published report respiratory muscle strength measurements were available for 78 patients with ALS. Time to death and/or ventilation were ascertained. Receiver operating characteristic analysis was used to determine the cutoff point of each parameter. Measurements and Main Results: Each respiratory muscle strength assessment individually achieved statistical significance for prediction of survival or ventilator-free survival. In multivariate analysis sniff trans-diaphragmatic and esophageal pressure, twitch trans-diaphragmatic pressure (Tw Pdi), age, and maximal static expiratory mouth pressure were significant predictors of ventilation-free survival and Tw Pdi and maximal static expiratory mouth pressure for absolute survival. Although all measures had good specificity, there were differing sensitivities. All cutoff points for the VC were greater than 80% of normal, except for prediction of 3-month outcomes. Sequential data showed a linear decline for direct measures of respiratory muscle strength, whereas VC showed little to no decline until 12 months before death/ventilation. Conclusions: The most powerful biomarker for mortality stratification was Tw Pdi, but the predictive power of sniff nasal inspiratory pressure was also excellent. A VC within normal range suggested a good prognosis at 3 months but was of little other value

Validity and responsiveness of the Daily- and Clinical visit-PROactive Physical Activity in COPD (D-PPAC and C-PPAC) instruments

BACKGROUND: The Daily-PROactive and Clinical visit-PROactive Physical Activity (D-PPAC and C-PPAC) instruments in chronic obstructive pulmonary disease (COPD) combines questionnaire with activity monitor data to measure patients' experience of physical activity. Their amount, difficulty and total scores range from 0 (worst) to 100 (best) but require further psychometric evaluation. OBJECTIVE: To test reliability, validity and responsiveness, and to define minimal important difference (MID), of the D-PPAC and C-PPAC instruments, in a large population of patients with stable COPD from diverse severities, settings and countries. METHODS: We used data from seven randomised controlled trials to evaluate D-PPAC and C-PPAC internal consistency and construct validity by sex, age groups, COPD severity, country and language as well as responsiveness to interventions, ability to detect change and MID. RESULTS: We included 1324 patients (mean (SD) age 66 (8) years, forced expiratory volume in 1 s 55 (17)% predicted). Scores covered almost the full range from 0 to 100, showed strong internal consistency after stratification and correlated as a priori hypothesised with dyspnoea, health-related quality of life and exercise capacity. Difficulty scores improved after pharmacological treatment and pulmonary rehabilitation, while amount scores improved after behavioural physical activity interventions. All scores were responsive to changes in self-reported physical activity experience (both worsening and improvement) and to the occurrence of COPD exacerbations during follow-up. The MID was estimated to 6 for amount and difficulty scores and 4 for total score. CONCLUSIONS: The D-PPAC and C-PPAC instruments are reliable and valid across diverse COPD populations and responsive to pharmacological and non-pharmacological interventions and changes in clinically relevant variables