Breathing In Chronic Obstructive Pulmonary Disease Research Articles

Capnography-Assisted Learned, Monitored (CALM) breathing therapy for dysfunctional breathing in COPD: A bridge to pulmonary rehabilitation

BackgroundAlthough dyspnea is a primary symptom of chronic obstructive pulmonary disease (COPD), its treatment is suboptimal. In both COPD and acute anxiety, breathing patterns become dysregulated, contributing to abnormal CO2, dyspnea, and inefficient recovery from breathing challenges. While pulmonary rehabilitation (PR) improves dyspnea, only 1–2% of patients access it. Individuals with anxiety who use PR have worse outcomes. MethodsWe present the protocol of a randomized controlled trial designed to determine the feasibility and acceptability of a new, four-week mind-body intervention that we developed, called “Capnography-Assisted Learned, Monitored (CALM) Breathing,” as an adjunct to PR. Eligible participants are randomized in a 1:1 ratio to either CALM Breathing program or Usual Care. CALM Breathing consists of 10 core, slow breathing exercises combined with real time biofeedback (of end-tidal CO2, respiratory rate, and airflow) and motivational interviewing. CALM Breathing promotes self-regulated breathing, linking CO2 changes to dyspnea and anxiety symptoms and targeting breathing efficiency and self-efficacy in COPD. Participants are randomized to CALM Breathing or a Usual Care control group. ResultsPrimary outcomes include feasibility and acceptability metrics of recruitment efficiency, participant retention, intervention adherence and fidelity, PR facilitation, patient satisfaction, and favorable themes from interviews. Secondary outcomes include breathing biomarkers, symptoms, health-related quality of life, six-minute walk distance, lung function, mood, physical activity, and PR utilization and engagement. ConclusionBy disrupting the cycle of dyspnea and anxiety, and providing a needed bridge to PR, CALM Breathing may address a substantive gap in healthcare and optimize treatment for patients with COPD.

Lung Deposition Using the Respimat® Soft Mist™ Inhaler Mono and Fixed-Dose Combination Therapies: An In Vitro/In Silico Analysis

Tiotropium and olodaterol are mainstay treatments for chronic obstructive pulmonary disease (COPD) and yield important clinical improvements, especially when used in fixed-dose combination. Whilst previous studies have shown consistent delivery of tiotropium to the lungs with the Respimat® inhaler, no such study has been carried out for olodaterol or the components of their fixed-dose combination (TIO/OLO). Combining in vitro and in silico models, we measured the amount of drug retained in the mouth–throat area, entering the trachea and reaching the lung periphery. We applied a hybrid deposition model that considered the experimentally determined output of an Alberta throat model (in vitro – dose to lung) combined with a computational fluid dynamic model of the lungs (in silico). Regardless of the COPD breathing pattern, ≥50% of the nominal dose of either tiotropium, olodaterol, or TIO and OLO in the fixed-dose combination reached the lung. Of the dose reaching the lungs, greater than 50% is deposited in the lung periphery (from generation 8 onwards). Our study demonstrated that aerosol delivery via the Respimat inhaler achieved high deposition deep into the lung periphery with all formulations evaluated.

Sleep disordered breathing and chronic obstructive pulmonary disease: a narrative review on classification, pathophysiology and clinical outcomes.

Chronic obstructive pulmonary disease (COPD) causes load-capacity-drive imbalance in both wakefulness and sleep, principally driven by expiratory flow limitation and hyperinflation. Sleep imposes additional burdens to the respiratory muscle pump, driven by changes in respiratory muscle tone, neural respiratory drive and consequences of the supine position. COPD patients are therefore at higher risk of decompensation during sleep, which may manifest as altered sleep architecture, isolated nocturnal desaturation, sleep hypoventilation and restless legs. Each form of sleep disordered breathing in COPD is associated with adverse clinical and patient-reported outcomes, including increased risk of exacerbations, hospitalisation, cardiovascular events, reduced survival and poorer quality of life. COPD-obstructive sleep apnoea (OSA) overlap syndrome represents a distinct clinical diagnosis, in which clinical outcomes are significantly worse than in either disease alone, including increased mortality, risk of cardiovascular events, hospitalisation and exacerbation frequency. Sleep disordered breathing is under-recognised by COPD patients and their clinicians, however early diagnosis and management is crucial to reduce the risk of adverse clinical outcomes. In this narrative review, we describe the pathophysiology of COPD and physiological changes that occur during sleep, manifestations and diagnosis of sleep disordered breathing in COPD and associated clinical outcomes.

Regulation of Ventilation and Perceived Effort of Breathing by Locomotor Muscle Metaboreceptor Afferents in Patients with Chronic Obstructive Pulmonary Disease

Exercise intolerance in chronic obstructive pulmonary disease (COPD) is greater for lower limb locomotor exercise as compared to upper limb exercise, presumably due to greater ventilatory constraint and sense of breathing effort (the main component of dyspnea sensation) in the former. Muscle afferent signaling has been proposed to be involved on dysfunctional ventilatory and perceptual responses to exercise in COPD. However, ventilatory responses to muscle metaboreflex activation in locomotor muscles remain uninvestigated. Moreover, regardless of exercise mode, the effect of muscle metaboreflex activation on perceived effort of breathing has never been explored. Therefore, we investigated the effect of locomotor muscle metaboreflex activation on ventilation and perceived effort of breathing in COPD. Nine patients with moderate‐to‐severe COPD and nine age‐ and sex‐matched controls (CON) performed constant work rate cycle ergometry using both lower limbs. Workload was set at 75% of maximal for 4 min. Then subjects recovered at rest for 2 min either with or without unilateral lower limb circulatory occlusion. After a 30‐min interval, subjects were crossed over to the other experimental trial. On another visit, patients were submitted to the cold pressor test (CPT; hand immersion on iced water).The CPT was used to provoke a stress response independently from muscle afferents activation. In contrast to free flow recovery, recovery with circulatory occlusion increased systolic and diastolic arterial pressures, increased pulmonary ventilation, increased respiratory frequency and decreased expiratory time similarly in COPD and CON. Circulatory occlusion did not change tidal volume in both groups. Of note, circulatory occlusion decreased inspiratory time (mean±SD; COPD: occlusion = 0.90±0.27 vs free flow = 1.00±0.20 units; P < 0.01; CON: occlusion = 1.24±0.37 vs free flow = 1.22±0.29 units; P = 0.66) and increased inspiratory flow (COPD: occlusion = 1.09 ± 0.25 vs free flow = 0.90 ± 0.10 L/s; P < 0.01; CON: occlusion = 0.95 ± 0.27 vs free flow = 0.92 ± 0.23 L/s; P = 0.61), a surrogate of the inspiratory drive, only in COPD. On the other hand, circulatory occlusion increased perceived effort of breathing only in CON (COPD: occlusion = 1.4±0.9 vs free flow = 1.1±0.9 units; P = 0.53; CON: occlusion = 4.3±2.3 vs free flow = 1.9±1.1 units; P < 0.001). CPT increased arterial pressure, but did not change pulmonary ventilation, respiratory pattern and perceived effort of breathing in COPD. In conclusion, locomotor muscle metaboreflex activation stimulated pulmonary ventilation and inspiratory drive without affecting perceived effort of breathing in patients with COPD. Such responses were specific to the muscle metaboreflex activation and suggest that the muscle metaboreflex per se is not linked with the origin of COPD exertional dyspnea.Support or Funding InformationThe study was funded by (FAPESP: 2017/07771‐3). L.C.A. and T.O.F received CAPES scholarships. I.C.R received a FAPESP scholarship.

Inspiratory pre‐motor potentials during quiet breathing in ageing and chronic obstructive pulmonary disease

A cortical contribution to breathing, as indicated by a Bereitschaftspotential (BP) in averaged electroencephalographic signals, occurs in healthy individuals when external inspiratory loads are applied. Chronic obstructive pulmonary disease (COPD) is a condition where changes in the lung, chest wall and respiratory muscles produce an internal inspiratory load. These changes also occur in normal ageing, although to a lesser extent. In the present study, we determined whether BPs are present during quiet breathing and breathing with an external inspiratory load in COPD compared to age-matched and young healthy controls. We demonstrated that increased age, rather than COPD, is associated with a cortical contribution to quiet breathing. A cortical contribution to inspiratory loading is associated with more severe dyspnoea (i.e. the sensation of breathlessness). We propose that cortical mechanisms may be engaged to defend ventilation in ageing with dyspnoea as a consequence. A cortical contribution to breathing is determined by the presence of a Bereitschaftspotential, a low amplitude negativity in the averaged electroencephalographic (EEG) signal, which begins ∼1s before inspiration. It occurs in healthy individuals when external inspiratory loads to breathing are applied. In chronic obstructive pulmonary disease (COPD), changes in the lung, chest wall and respiratory muscles produce an internal inspiratory load. We hypothesized that there would be a cortical contribution to quiet breathing in COPD and that a cortical contribution to breathing with an inspiratory load would be linked to dyspnoea, a major symptom of COPD. EEG activity was analysed in 14 participants with COPD (aged 57-84years), 16 healthy age-matched (57-87years) and 15 young (18-26years) controls during quiet breathing and inspiratory loading. The presence of Bereitschaftspotentials, from ensemble averages of EEG epochs at Cz and FCz, were assessed by blinded assessors. Dyspnoea was rated using the Borg scale. The incidence of a cortical contribution to quiet breathing was significantly greater in participants with COPD (6/14) compared to the young (0/15) (P=0.004) but not the age-matched controls (6/16) (P=0.765). A cortical contribution to inspiratory loading was associated with higher Borg ratings (P=0.007), with no effect of group (P=0.242). The data show that increased age, rather than COPD, is associated with a cortical contribution to quiet breathing. A cortical contribution to inspiratory loading is associated with more severe dyspnoea. We propose that cortical mechanisms may be engaged to defend ventilation with dyspnoea as a consequence.

Dynamic change in respiratory resistance during inspiratory and expiratory phases of tidal breathing in patients with chronic obstructive pulmonary disease

Background and objectiveChronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation consisting of airway obstruction and parenchymal emphysema, with loss of elastic recoil. The forced oscillation technique can detect impairment of lung function by measuring lung impedance during normal tidal breathing. Respiratory resistance (Rrs) in COPD has been well-studied, but the differences in Rrs in the inspiratory and expiratory phases between mild and moderate COPD remain poorly understood. Since airway obstruction in COPD is known to change dynamically during tidal breathing and might affect Rrs, the differences in Rrs during tidal breathing between mild and moderate COPD were evaluated.MethodsMild (n = 13) and moderate (n = 13) COPD patients were recruited at Tokyo University Hospital (Tokyo, Japan). Rrs was measured using MostGraph-01 (Chest MI, Inc, Tokyo, Japan), which depicted Rrs in a frequency-and respiratory cycle-dependent manner in three-dimensional graphics. Rrs was evaluated at 4–35 Hz during tidal breathing.ResultsRrs changed dynamically during tidal breathing in COPD. The mean Rrs values were significantly greater in the moderate COPD group than in the mild group. The maximal and minimal Rrs values at higher frequencies in the respiratory cycle were significantly greater in moderate COPD. In inspiratory–expiratory breath analysis, the maximal and minimal Rrs values at 20 Hz and 35 Hz were significantly greater in the moderate group, whereas at 4 Hz they did not differ significantly between the groups.ConclusionRrs changed dynamically during tidal breathing in patients with COPD. The Rrs values at higher frequencies were greater in moderate COPD than in mild COPD. Rrs at higher frequencies might reflect the degree of airway obstruction in tidal breathing in patients with COPD and might be a useful marker for evaluation of airway obstruction at an early stage of COPD.

Neuromodulatory Effect of Endogenous Opioids on the Intensity and Unpleasantness of Breathlessness during Resistive Load Breathing in COPD

Background: Endogenous opioids are naturally occurring peptides released by the brain in response to noxious stimuli. Although these naturally occurring peptides modulate pain, it is unknown whether endogenous opioids affect the perception of breathlessness associated with a specific respiratory challenge. The hypothesis is that intravenous administration of naloxone, used to block opioid signaling and inhibit neural pathways, will increase ratings of breathlessness during resistive load breathing (RLB) in patients with chronic obstructive pulmonary disease (COPD). Methods: Fourteen patients with COPD (age, 64 ± 9 years) inspired through resistances during practice sessions to identify an individualized target load that caused ratings of intensity and/or unpleasantness of breathlessness ≥ 50 mm on a 100 mm visual analog scale. At two intervention visits, serum beta-endorphins were measured, naloxone (10 mg/25 ml) or normal saline (25 ml) was administered intravenously, and patients rated the two dimensions of breathlessness each minute during RLB. Results: Patient ratings of intensity (p = 0.0004) and unpleasantness (p = 0.024) of breathlessness were higher with naloxone compared with normal saline. Eleven patients (79%) reported that it was easier to breathe during RLB with normal saline (p = 0.025). RLB led to significant increases in serum beta-endorphin immunoreactivity and decreases in inspiratory capacity. There were no significant differences in physiological responses between interventions. Conclusions: Endogenous opioids modulate the intensity and the unpleasantness of breathlessness in patients with COPD. Differences in breathlessness ratings between interventions were clinically relevant based on the patients’ global assessment.

Patterns of chest wall kinematics during volitional pursed-lip breathing in COPD at rest

Analysis of chest wall kinematics can contribute to identifying the reasons why some patients benefit from pursed-lip breathing (PLB). We evaluated the displacement of the chest wall and its compartments, the rib cage and abdomen, by optoelectronic plethysmography (OEP), during supervised PLB maneuver in 30 patients with mild to severe chronic obstructive pulmonary disease (COPD). OEP showed two different patterns. A first pattern characterized the 19 most severely obstructed and hyperinflated patients in whom PLB decreased end-expiratory volumes of the chest wall and abdomen, and increased end-inspiratory volumes of the chest wall and rib cage. Deflation of the abdomen and inflation of the rib cage contributed to increasing tidal volume of the chest wall. The second pattern characterized 11 patients in whom, compared to the former group, PLB resulted in the following: (i) increased end-expiratory volume of the rib cage and chest wall, (ii) greater increase in end-inspiratory volume of the rib cage and abdomen, and (iii) lower tidal volume of the chest wall. In the patients as a whole changes in end-expiratory chest wall volume were related to change in Borg score (r(2)=0.5, p<0.00002). OEP helps identifying the reason why patients with COPD may benefit from PLB at rest.

Passive properties of the diaphragm in COPD

Structural adaptations that occur in the diaphragm muscle of patients with chronic obstructive pulmonary disease (COPD), namely an increase in type I fibers and a decrease in type II fibers, have been explored in terms of the active contractile properties of the diaphragm. The aim of this study was to test the passive properties of the diaphragm by measuring the force response of relaxed diaphragm muscle fibers to stretching to determine the effect of COPD on these properties. Costal diaphragm biopsies were taken from patients with COPD and from controls with normal pulmonary function. From these biopsies, titin expression was assessed in diaphragm homogenates by gel electrophoresis, and the restoring force was measured by incremental stretching of single fibers in the relaxed state and measuring the force response to stretching. A quadratic model was used to illustrate the relationship between restoring force and muscle fiber length, and it revealed that COPD fibers generate significantly lower restoring forces than control fibers as judged by the area under the force-length curve. Furthermore, this finding applies to both type I and type II fibers. Gel electrophoresis revealed different titin isoforms in COPD and controls, consistent with the conclusion that COPD results not only in a change in muscle fiber-type distribution but in a structural change in the titin molecule in all muscle fiber types within the diaphragm. This may assist the muscle with the energetic changes in the length of the diaphragm required during breathing in COPD.

Effects of Heliox Breathing on R-R Interval Variability at Rest and During Exercise in COPD

1454 Patients with non-hypoxemic chronic obstructive pulmonary disease (COPD) have, in addition to high airway resistance and low exercise tolerance, high parasympathetic nervous system activity. Airway resistance, however, is reduced with high inspired fractions of helium (Heliox: 20% oxygen, 80% helium) through less turbulent airflow. PURPOSE: To test whether autonomic system function might be altered with Heliox breathing in COPD during exercise. This might occur through a mechanism linked to reduced dynamic hyperinflation and – possibly – smaller intrathoracic pressure. METHODS: Autonomic nervous system function was assessed at rest and during 20 Watt constant work rate exercise in eight non-hypoxemic COPD patients (72 ± 10 yrs; FEV1% predicted: 36.6 ± 9.1). This was achieved by analysis of R-R interval variability, derived from the ECG signal, using an autoregressive method. Subjects inspired air or Heliox from a balloon. The low-to-high frequency ratio (LF/HF) and the high-to-total frequency ratio (HF/TOT) were calculated as indices of sympathetic and parasympathetic autonomic tone, respectively (HF: 0.15 – 0.50 Hz; LF: 0.04 – 0.15 Hz). RESULTS: Heliox breathing slightly increased heart rate at rest, compared with air (73.6 ± 10.7 vs 68.9 ± 9.1 min−1, P < 0.05). During exercise both heart rate (93.8 ± 13.9 vs. 89.9 ± 11.6 min−1, P< 0.05) and breathing frequency (24.9 ± 3.6 vs. 23.4 ± 3.2 min−1) were higher on Heliox. While at rest there was no significant difference in autonomic tone indices between air and Heliox breathing, during exercise the HF/TOT ratio (parasympathetic index) was significantly lower with Heliox than with air (0.09 ± 0.08 vs. 0.17 ± 0.08, respectively, P < 0.05). Autonomic tone balance did not change from rest to exercise with air breathing; in contrast, the HF/TOT ratio was significantly reduced (0.09 ± 0.08 vs. 0.24 ± 0.11, P < 0.05) and the LF/HF ratio (sympathetic index) was significantly increased (1.56 ± 0.81 vs. 0.70 ± 0.28, P < 0.05) with Heliox breathing. CONCLUSIONS: During exercise Heliox breathing reduces PNS activity and shifts the autonomic tone balance towards sympathetic dominance in nonhypoxemic COPD patients. This may be conducive to improved airway function.

Effects of Heliox Breathing on R-R Interval Variability at Rest and During Exercise in COPD

1454 Patients with non-hypoxemic chronic obstructive pulmonary disease (COPD) have, in addition to high airway resistance and low exercise tolerance, high parasympathetic nervous system activity. Airway resistance, however, is reduced with high inspired fractions of helium (Heliox: 20% oxygen, 80% helium) through less turbulent airflow. PURPOSE: To test whether autonomic system function might be altered with Heliox breathing in COPD during exercise. This might occur through a mechanism linked to reduced dynamic hyperinflation and – possibly – smaller intrathoracic pressure. METHODS: Autonomic nervous system function was assessed at rest and during 20 Watt constant work rate exercise in eight non-hypoxemic COPD patients (72 ± 10 yrs; FEV1% predicted: 36.6 ± 9.1). This was achieved by analysis of R-R interval variability, derived from the ECG signal, using an autoregressive method. Subjects inspired air or Heliox from a balloon. The low-to-high frequency ratio (LF/HF) and the high-to-total frequency ratio (HF/TOT) were calculated as indices of sympathetic and parasympathetic autonomic tone, respectively (HF: 0.15 – 0.50 Hz; LF: 0.04 – 0.15 Hz). RESULTS: Heliox breathing slightly increased heart rate at rest, compared with air (73.6 ± 10.7 vs 68.9 ± 9.1 min−1, P < 0.05). During exercise both heart rate (93.8 ± 13.9 vs. 89.9 ± 11.6 min−1, P< 0.05) and breathing frequency (24.9 ± 3.6 vs. 23.4 ± 3.2 min−1) were higher on Heliox. While at rest there was no significant difference in autonomic tone indices between air and Heliox breathing, during exercise the HF/TOT ratio (parasympathetic index) was significantly lower with Heliox than with air (0.09 ± 0.08 vs. 0.17 ± 0.08, respectively, P < 0.05). Autonomic tone balance did not change from rest to exercise with air breathing; in contrast, the HF/TOT ratio was significantly reduced (0.09 ± 0.08 vs. 0.24 ± 0.11, P < 0.05) and the LF/HF ratio (sympathetic index) was significantly increased (1.56 ± 0.81 vs. 0.70 ± 0.28, P < 0.05) with Heliox breathing. CONCLUSIONS: During exercise Heliox breathing reduces PNS activity and shifts the autonomic tone balance towards sympathetic dominance in nonhypoxemic COPD patients. This may be conducive to improved airway function.

Real-time MR imaging of aortic flow: influence of breathing on left ventricular stroke volume in chronic obstructive pulmonary disease.

To assess real-time changes of left ventricular stroke volume (SV) in relation to the breathing pattern in healthy subjects and in patients with chronic obstructive pulmonary disease (COPD). Real-time magnetic resonance (MR) imaging flow measurements were performed in the ascending aorta of 10 healthy volunteers and nine patients with severe COPD. Breathing maneuvers were registered with an abdominal pressure belt, which was synchronized to the electrocardiographic signal and the flow measurement. Healthy subjects performed normal breathing, deep breathing, and the Valsalva maneuver. Patients with COPD performed spontaneous breathing. Paired two-tailed Student t tests were used in healthy volunteers to assess significant SV differences between normal breathing and deep breathing or the Valsalva maneuver. The results of measurements in the patients with COPD were compared with the results during normal breathing in healthy subjects with the unpaired two-tailed Student t test. In healthy subjects, SV decreased during inspiration and increased during expiration (r2 = 0.78, P <.05). When compared with the SV during normal breathing, mean SV did not change during deep breathing but declined during the Valsalva maneuver (P <.05). The difference between minimal and maximal SVs (ie, SV range) increased because of deep breathing or the Valsalva maneuver (P <.05). In normal and deep breathing, velocity of SV elevation and velocity of SV decrease were equal (which resulted in a ratio of 1), whereas during the Valsalva maneuver, this value increased (P <.05). Spontaneous breathing in COPD resulted in SV changes (P <.05) similar to those observed in healthy subjects who performed the Valsalva maneuver. Real-time MR imaging of aortic flow reveals physiologic flow alterations, which are dependent on variations in the breathing pattern.

Variability of inspired oxygen concentration with nasal cannulas.

The likely values of inspired oxygen concentration (FIO2) of patients with chronic obstructive pulmonary disease breathing via nasal cannulas have not been assessed previously. Seven patients with chronic obstructive lung disease and seven healthy subjects were studied while breathing oxygen via nasal cannulas or fixed performance (Venturi) or uncontrolled (MC) oxygen masks. Breath to breath values of FIO2 were calculated by extrapolation from expired oxygen and carbon dioxide concentrations on the basis of the oxygen-carbon dioxide relationship and on the assumption of a respiratory exchange ratio (R) of 0.8. In both groups of subjects the average values of FIO2 with nasal cannulas at 1 and 2 l min-1 were of a similar order to those achieved with 24.5% and 28% Venturi masks, but variations within and between subjects in both groups breathing via nasal cannulas were considerable and similar to those found with MC masks. In the seven patients with chronic obstructive lung disease breathing via nasal cannulas at 2 l min-1 the average FIO2 varied from 23.7% to 34.9%. "Typical" values of FIO2 quoted with nasal cannulas can mislead. The results confirm that this mode of oxygen delivery is unsatisfactory if precise control of inspired oxygen is desired.