Defective exercise-related expiratory muscle recruitment in patients with PHOX2B mutations: A clue to neural determinants of the congenital central hypoventilation syndrome.

INTRODUCTION AND OBJECTIVES: The human congenital central hypoventilation syndrome (CCHS) is caused by mutations in the PHOX2B (paired-like homeobox 2B) gene. Genetically engineered PHOX2B rodents exhibit defective development of the brainstem retrotrapezoid nucleus (RTN), a carbon dioxide sensitive structure that critically controls expiratory muscle recruitment. This has been linked to a blunted exercise ventilatory response. Whether this can be extrapolated to human CCHS is unknown and represents the objective of this study. MATERIALS AND METHODS: Thirteen adult CCHS patients and 13 healthy participants performed an incremental symptom-limited cycle cardiopulmonary exercise test. Responses were analyzed using guideline approaches (ventilation V'E, tidal volume VT, breathing frequency, oxygen consumption, carbon dioxide production) complemented by a breathing pattern analysis (i.e. expiratory and inspiratory reserve volume, ERV and IRV). RESULTS: A ventilatory response occurred in both study groups, as follows: V'E and VT increased in CCHS patients until 40 W and then decreased, which was not observed in the healthy participants (p<0.001). In the latter, exercise-related ERV and IRV decreases attested to concomitant expiratory and inspiratory recruitment. In the CCHS patients, inspiratory recruitment occurred but there was no evidence of expiratory recruitment (absence of any ERV decrease, p<0.001). CONCLUSIONS: Assuming a similar organization of respiratory rhythmogenesis in humans and rodents, the lack of exercise-related expiratory recruitment observed in our CCHS patients is compatible with a PHOX2B-related defect of a neural structure that would be analogous to the rodents' RTN. Provided corroboration, ERV recruitment could serve as a physiological outcome in studies aiming at correcting breathing control in CCHS.

Evaluation of acute bronchodilator reversibility in patients with symptoms of GOLD stage I COPD.

BACKGROUND: Patients with symptoms of GOLD stage I chronic obstructive pulmonary disease (COPD) can have significant abnormalities of ventilatory mechanics with greater exertional symptoms and exercise limitation than age-matched healthy subjects. In such patients the impact of bronchodilator therapy remains unknown and is difficult to evaluate. METHODS: The acute effects of nebulised ipratropium bromide 500 microg (IB) on resting pulmonary function and on dyspnoea and ventilatory parameters during symptom-limited constant work rate cycle exercise were measured. In a randomised double-blind crossover study, 16 patients with COPD (mean (SD) post-bronchodilator forced expiratory volume in 1 s (FEV(1)) 90 (7)% predicted, FEV(1)/forced vital capacity (FVC) 59 (7)%) with a significant smoking history (mean (SD) 44 (16) pack-years) inhaled either IB or placebo on each of two separate visits. Pulmonary function tests and cycle exercise at 80-85% of each subject's maximal work capacity were performed 2 h after dosing. RESULTS: Compared with placebo, FEV(1) increased 5 (9)% predicted, residual volume decreased 12 (20)% predicted and specific airway resistance decreased 81 (93)% predicted (all p<0.05) after IB. At a standardised time during exercise, dynamic inspiratory capacity and tidal volume significantly increased in tandem by 0.12 and 0.16 litres, respectively (each p<0.05), dyspnoea fell by 0.9 (1.8) Borg units (p = 0.07) and dyspnoea/ventilation ratios fell significantly (p<0.05). The fall in dyspnoea intensity at higher submaximal ventilations correlated with the concurrent decrease in end-expiratory lung volume (p<0.05). CONCLUSION: In patients with symptoms of GOLD stage I COPD, IB treatment is associated with modest but consistent improvements in airway function, operating lung volumes and dyspnoea intensity during exercise. These results provide a physiological rationale for a trial of bronchodilator therapy in selected patients with milder but symptomatic COPD.

[Pulmonary function testing of dyspnea complaint by the pulmonologist]. / Investigation fonctionnelle respiratoire de la dyspnée chronique par le pneumologue.

Dyspnea results from an imbalance between ventilatory demand (linked to CO2 production, PaCO2 set-point and wasted ventilation-physiological dead space) and ventilatory capacity (linked to passive-compliance, resistance-and active-respiratory muscles-components of the respiratory system). Spirometry and static lung volumes investigate ventilatory capacity only. Ventilatory demand (increased for instance in all pulmonary vascular diseases due to increased physiological dead space) is not evaluated by these routine measurements. DLCO measurement, which evaluates both demand and capacity, depicts the best statistical correlation to dyspnea, for instance in obstructive and interstitial pulmonary diseases. Dyspnea has multiple domains and is inherently complex and weakly explained by resting investigations: explained variance is below 50%. The diagnostic strategy investigating dyspnea has to distinguish complaints related or not to exercise because dyspnea can occur independently from any effort. Cardiopulmonary exercise testing (V'O2, V'CO2, V'E and operating lung volumes measurements) allows the assessment of underlying pathophysiological mechanisms leading to functional impairment and can contribute to unmask potential underlying mechanisms of unexplained dyspnea although its "etiological diagnostic value" for dyspnea remains a challenging issue.

Mechanisms of exertional dyspnea in patients with cancer.

Exertional dyspnea is an important symptom in cancer patients, and, in many cases, its cause remains unexplained after careful clinical assessment. To determine mechanisms of exertional dyspnea in a variety of cancer types, we evaluated cancer outpatients with clinically important unexplained dyspnea (CD) at rest and during exercise and compared the results with age-, sex-, and cancer stage-matched control cancer (CC) patients and age- and sex-matched healthy control participants (HC). Participants (n = 20/group) were screened to exclude clinical cardiopulmonary disease and then completed dyspnea questionnaires, anthropometric measurements, muscle strength testing, pulmonary function testing, and incremental cardiopulmonary treadmill exercise testing. Dyspnea intensity was greater in the CD group at peak exercise and for a given ventilation and oxygen uptake (P < 0.05). Peak oxygen uptake was reduced in CD compared with HC (P < 0.05), and breathing pattern was more rapid and shallow in CD than in the other groups (P < 0.05). Reduced tidal volume expansion during exercise correlated with reduced inspiratory capacity, which, in turn, correlated with reduced inspiratory muscle strength. Patients with cancer had a relatively reduced diffusing capacity of the lung for carbon monoxide, reduced skeletal muscle strength, and lower ventilatory thresholds during exercise compared with HC (P < 0.05). There were no significant between-group differences in measurements of airway function, pulmonary gas exchange, or cardiovascular function during exercise. In the absence of evidence of airway obstruction or restrictive interstitial lung disease, the shallow breathing pattern suggests ventilatory muscle weakness as one possible explanation for increased dyspnea intensity at a given ventilation in CD patients.

Effect of tiotropium bromide on the cardiovascular response to exercise in COPD.

INTRODUCTION: Exercise limitation and exertional dyspnea are important symptoms of chronic obstructive pulmonary disease (COPD), which may be partially relieved by tiotropium. Although the mechanism of relief is multifactorial, improved dynamic ventilatory mechanics appear to be important. It is not however known whether tiotropium may also act by improving cardiovascular function during exercise. METHODS: We conducted a randomized, placebo-controlled crossover study in 18 COPD subjects with a FEV(1) 40+/-3% predicted (mean+/-SEM). Subjects inhaled either tiotropium 18 microg or placebo once daily for 7-10 days then the other intervention for a further 7-10 days after a 35-day washout period. Subjects performed constant work rate cycle exercise at 75% of maximum after each treatment period. Heart rate, blood pressure, oxygen uptake, operating lung volumes and breathing pattern were measured. RESULTS: Heart rate was 7 beats/min lower at rest and throughout exercise with tiotropium compared to placebo (p=0.001). Oxygen uptake was unchanged throughout exercise. Oxygen pulse on exercise was greater by 7.4% (p<0.01) and systolic blood pressure was lower by 7 mmHg (p=0.03). The cardiac rate pressure product was reduced by 7.6% (p<0.01) with tiotropium. Exercise endurance tended to be greater with tiotropium. Reduction in heart rate on exercise correlated with an increase in inspiratory reserve volume (r=-0.50, p=0.04). CONCLUSION: Tiotropium may improve cardiac as well as pulmonary function during exercise in COPD. We suggest that this effect may be due, in part, to improved cardiopulmonary interaction as a result of mechanical unloading of the ventilatory muscles however further study is required.

Exercise physiology in COPD.

Multiple mechanisms contribute to exercise limitation in chronic obstructive pulmonary disease (COPD). The ability to increase ventilation during exercise is reduced; the more advanced the disease, the more impaired the exercise tolerance is. However, factors other than ventilatory limitation play an important role in reducing the exercise capacity in COPD. Data implicating peripheral muscle atrophy and muscle weakness as cofactors have been reported in individuals with advanced disease. At this stage daily activities are curtailed to avoid exertional respiratory discomfort. Recent studies have demonstrated that the muscle aerobic capacity of stable hypoxemic COPD patients is impaired; oxygen uptake (V'O2) kinetics and 31P magnetic resonance spectroscopy studies have shown that these patients rely heavily on non-aerobic energy sources even during moderate, sustained workloads. Finally, early occurrence of metabolic acidosis has been demonstrated in patients with mild to severe COPD during exercise. Inadequate tissue oxygenation appears to result from a defect in peripheral oxygen utilization rather than from a reduction in O2 bulk flow. Peripheral factors may include: a) impaired diffusive conductance for O2 between red cells and mitochondria; b) heterogeneous distribution of O2 bulk flow within the exercising muscle fibers; c) inertia of the oxidative processes at the cellular level; d) changes in distribution of muscle fibers, e) reduction in muscle aerobic enzymes; and f) poor nutritional status. Since muscle dysfunction has an important role in the development of exercise intolerance, physical rehabilitation is more and more used as part of the treatment of COPD. The aim of this review is to briefly discuss current views on the mechanisms responsible for the reduced ability to exercise and the rationale for exercise rehabilitation in COPD patients.

Role of hyperinflation vs. deflation on dyspnoea in severely to extremely obese subjects.

AIM: To test the hypothesis that obese individuals may either hyperinflate or deflate the lung when exercising. In both cases breathlessness is an inescapable consequence. METHODS: Ventilatory variables, end-expiratory lung volume and end-inspiratory lung volume, and dyspnoea score (Borg scale) were studied in 20 class II-III obese subjects and 14 healthy controls during incremental symptom-limited cycle exercise. RESULTS: Ventilation increased with increasing work rate, in obese and in control subjects; most obese subjects had to increase end-expiratory lung volume to escape from flow limitation; in contrast, like controls, a few subjects deflated the lung on heavy-to-peak exercise. Dyspnoea was equal in degree at anaerobic threshold and peak exercise in obese as in control subjects, and in obese who hyperinflated as in those who deflated the lung. In particular, end-expiratory lung volume at baseline (r = -0.84, P = 0.04) was negatively correlated with changes in Borg score in obese who did not hyperinflate: the lower the former the higher the latter. On the other hand, tidal volume (r = 0.54, P = 0.045) and decrease in inspiratory reserve volume (r = 0.59, P = 0.028) were positively correlated with the Borg score in obese subjects who hyperinflated. No other independent variable correlated with the Borg score. CONCLUSIONS: We conclude that not all obese subjects had to increase end-expiratory lung volume on heavy-to-peak exercise. Changes in dyspnoea for unit changes in ventilation were similar in obese who did hyperinflate as well as in those who did not, suggesting that the increase in respiratory neural drive, associated with an increase in ventilation, is an important source of dyspnoea in obese as well as in control subjects.

Mechanisms of dyspnoea and its language in patients with asthma.

This study hypothesises that regardless of the global score of dyspnoea intensity, different descriptors may be selected by asthmatic patients during short cardiopulmonary exercise test (sCPET) and methacholine (Mch) inhalation. It also examines whether different qualitative dyspnoea sensations can help explain the underlying mechanisms of the symptom. Minute ventilation (V'E), tidal volume (VT) and inspiratory capacity (IC) were measured in 22 stable asthmatic patients, and the sensation of dyspnoea during Mch inhalation and sCPET was quantitatively (Borg scale) and qualitatively (descriptors) assessed. The work rate and oxygen uptake (V'O2) were also measured during sCPET. Airway obstruction and hyperinflation, as measured by IC reduction, were the best correlates for dyspnoea with Mch. During sCPET, changes in WR, V'O2, V'E and VT significantly correlated with Borg score, with V'E being the best predictor of dyspnoea; IC decreased in eight patients. Furthermore, chest tightness (68%) was the highest reported descriptor during Mch inhalation, whereas work/effort (72%) was the highest during sCPET. In conclusion, obstruction/hyperinflation and work rate are highly reliable predictors of Borg rating of dyspnoea during methacholine inhalation and short cardiopulmonary exercise testing, respectively. Regardless of the global score of intensity dyspnoea, different descriptors may be selected by patients during short cardiopulmonary exercise testing and methacholine inhalation. Various qualities of dyspnoea result from different pathophysiological abnormalities.