Effect of salbutamol on lung function and chest wall volumes at rest and during exercise in COPD

BACKGROUND: Inhaled bronchodilators can increase exercise capacity in chronic obstructive pulmonary disease (COPD) by reducing dynamic hyperinflation, but treatment is not always effective. This may reflect the degree to which the abdomen allows dynamic hyperinflation to occur.Method: A double blind, randomised, crossover trial of the effect of 5 mg nebulised salbutamol or saline on endurance exercise time was conducted in 18 patients with COPD of mean (SD) age 67.1 (6.3) years and mean (SD) forced expiratory volume in 1 second (FEV1) of 40.6 (15.0)% predicted. Breathing pattern, metabolic variables, dyspnoea intensity, and total and regional chest wall volumes were measured non-invasively by optoelectronic plethysmography (OEP) at rest and during exercise. RESULTS: Salbutamol increased FEV1, forced vital capacity (FVC) and inspiratory capacity and reduced functional residual capacity (FRC) and residual volume significantly. OEP showed the change in resting FRC to be mainly in the abdominal compartment. Although the mean (SE) end expiratory chest wall volume was 541 (118) ml lower (p<0.001) at the end of exercise, the endurance time was unchanged by the bronchodilator. Changes in resting lung volumes were smaller when exercise duration did not improve, but FEV1 still rose significantly after active drug. After the bronchodilator these patients tried to reduce the end expiratory lung volume when exercising, while those exercising longer continued to allow end expiratory abdominal wall volume to rise. The change to a more euvolumic breathing pattern was associated with a lower oxygen pulse and a significant fall in endurance time with higher isotime levels of dyspnoea. CONCLUSIONS: Nebulised salbutamol improved forced expiratory flow in most patients with COPD, but less hyper-nflated patients tried to reduce the abdominal compartmental volume after active treatment and this reduced their exercise capacity. Identifying these patients has important therapeutic implications, as does an understanding of the mechanisms that control chest wall muscle recruitment.     

Effect of salmeterol on respiratory muscle activity during exercise in poorly reversible COPD

BACKGROUND: Some patients with irreversible chronic obstructive pulmonary disease (COPD) experience subjective benefit from long acting bronchodilators without change in forced expiratory volume in 1 second (FEV(1)). Dynamic hyperinflation is an important determinant of exercise induced dyspnoea in COPD. We hypothesised that long acting bronchodilators improve symptoms by reducing dynamic hyperinflation and work of breathing, as measured by respiratory muscle pressure-time products. METHODS: Sixteen patients with "irreversible" COPD (<10% improvement in FEV(1) following a bronchodilator challenge; mean FEV(1) 31.1% predicted) were recruited into a randomised, double blind, placebo controlled, crossover study of salmeterol (50 micro g twice a day). Treatment periods were of 2 weeks duration with a 2 week washout period. Primary outcome measures were end exercise isotime transdiaphragmatic pressure-time product and dynamic hyperinflation as measured by inspiratory capacity. RESULTS: Salmeterol significantly reduced the transdiaphragmatic pressure-time product (294.5 v 348.6 cm H(2)O/s/min; p = 0.03), dynamic hyperinflation (0.22 v 0.33 litres; p = 0.002), and Borg scores during endurance treadmill walk (3.78 v 4.62; p = 0.02). There was no significant change in exercise endurance time. Improvements in isotime Borg score were significantly correlated to changes in tidal volume/oesophageal pressure swings, end expiratory lung volume, and inspiratory capacity, but not pressure-time products. CONCLUSIONS: Despite apparent "non-reversibility" in spirometric parameters, long acting bronchodilators can cause both symptomatic and physiological improvement during exercise in severe COPD.     

Regional chest wall volumes during exercise in chronic obstructive pulmonary disease

BACKGROUND: Dynamic hyperinflation of the lungs impairs exercise performance in chronic obstructive pulmonary disease (COPD). However, it is unclear which patients are affected by dynamic hyperinflation and how the respiratory muscles respond to the change in lung volume. METHODS: Using optoelectronic plethysmography, total and regional chest wall volumes were measured non-invasively in 20 stable patients with COPD (mean (SD) forced expiratory volume in 1 second 43.6 (11.6)% predicted) and dynamic hyperinflation was tracked breath by breath to test if this was the mechanism of exercise limitation. Resting ventilation, breathing pattern, symptoms, rib cage and abdominal volumes were recorded at rest and during symptom limited cycle ergometry. Pleural, abdominal, and transdiaphragmatic pressures were measured in eight patients. RESULTS: End expiratory chest wall volume increased by a mean (SE) of 592 (80) ml in 12 patients (hyperinflators) but decreased by 462 (103) ml in eight (euvolumics). During exercise, tidal volume increased in euvolumic patients by reducing end expiratory abdominal volume while in hyperinflators tidal volume increased by increasing end inspiratory abdominal and rib cage volumes. The maximal abdominal pressure was 22.1 (9.0) cm H(2)O in euvolumic patients and 7.6 (2.6) cm H(2)O in hyperinflators. Euvolumic patients were as breathless as hyperinflators but exercised for less time and reached lower maximum workloads (p<0.05) despite having better spirometric parameters and a greater expiratory flow reserve. CONCLUSIONS: Dynamic hyperinflation is not the only mechanism limiting exercise performance in patients with stable COPD. Accurate measurement of chest wall volume can identify the different patterns of respiratory muscle activation during exercise.     

Physiopathology of acute respiratory failure in COPD and asthma

Asthma and chronic obstructive pulmonary diseases (COPD) lead to functional obstruction of airways, identified by increased inspiratory and expiratory resistances. Increased expiratory resistances cause, in turn, a reduction in expiratory flow. The analysis of flow-volume loops shows that, as the disease progresses, the flow generated during expiration of a tidal volume becomes very close to the flow generated during forced maximal expiration. In such condition, where there is little or no reserve of expiratory flow, higher tidal volumes need to be reached in order to increase the expiratory flow, and hyperinflation inevitably occurs. Hyperinflation, a key feature in COPD pathophysiology, is generated by two mechanisms: reduction of elastic recoil of the lung (static hyperinflation) and interruption of expiration at lung volumes still higher than FRC, due to reduction of expiratory flow (dynamic hyperinflation). When dynamic hyperinflation occurs, a residual positive pressure remains in the alveoli, which is defined as intrinsic positive end-expiratory pressure (PEEPi). Hyperinflation carries several consequences: 1) Respiratory mechanics: at lung volumes close to total lung capacity, lung compliance is physiologically reduced, and elastic work required to generate the same inspiratory volume is therefore increased; 2) Respiratory muscles: contractile properties of diaphragm deteriorate when the dome is pushed downward by an increased lung volume, inspiration is mainly performed by inspiratory muscles, and expiration becomes active; 3) Circulation: pulmonary vascular resistances increase due to compression exerted by hyperinflation on alveolar vessels and to hypoxic vasoconstriction; right ventricle afterload increases and right sided hypertrophy and dilation ensue; left ventricular afterload may increase due to increased negative intrapleural pressure which translates into an increased transmural pressure which needs to be overcome by ventricular contraction. Ventilatory support of COPD patients should decrease work of breathing and improve gas exchange without increasing hyperinflation. This target can be achieved during assisted ventilation by applying a positive pressure both during inspiration and expiration; the level of PEEP should equal PEEPi. During mechanical ventilation in sedated paralyzed patients hyperinflation should be limited by decreasing minute volume and by increasing expiratory time, eventually choosing controlled hypercapnia.     

Decreased mechanical efficiency in clinically stable patients with COPD

BACKGROUND: It has recently been reported that total daily energy expenditure (TDE) is increased in patients with chronic obstructive pulmonary disease (COPD) and it was hypothesised that these patients may have a decreased mechanical efficiency during activities. The purpose of the present study was to measure the mechanical efficiency of submaximal leg exercise, and to characterise patients with a potentially low efficiency in terms of body composition, resting energy expenditure, lung function, and symptom limited exercise performance. METHODS: Metabolic and ventilatory variables were measured breath by breath during submaximal cycle ergometry exercise performed at 50% of symptom limited achieved maximal load in 33 clinically stable patients with COPD (23 men) with forced expiratory volume in one second (FEV1) of 40 (12)% predicted. Net mechanical efficiency was calculated adjusting for resting energy expenditure (REE). RESULTS: Median mechanical efficiency was 15.5% and ranged from 8.5% to 22.7%. Patients with an extremely low mechanical efficiency (< 17%, n = 21) demonstrated an increased VO2/VE compared with those with a normal efficiency (median difference 4.7 ml/l, p = 0.005) during submaximal exercise. There was no difference between the groups differentiated by mechanical efficiency in blood gas tensions at rest, airflow obstruction, respiratory muscle strength, hyperinflation at rest, resting energy expenditure or body composition. There was a significant difference in total airways resistance (92% predicted, p = 0.03) between the groups differentiated by mechanical efficiency. CONCLUSIONS: It is concluded that many patients with severe COPD have decreased mechanical efficiency. Furthermore, based on the results of this study it is hypothesised that an increased oxygen cost of breathing during exercise contributes to the decreased mechanical efficiency.


     

Patterns of dynamic hyperinflation during exercise and recovery in patients with severe chronic obstructive pulmonary disease

BACKGROUND: Not all patients with severe chronic obstructive pulmonary disease (COPD) progressively hyperinflate during symptom limited exercise. The pattern of change in chest wall volumes (Vcw) was investigated in patients with severe COPD who progressively hyperinflate during exercise and those who do not. METHODS: Twenty patients with forced expiratory volume in 1 second (FEV(1)) 35 (2)% predicted were studied during a ramp incremental cycling test to the limit of tolerance (Wpeak). Changes in Vcw at the end of expiration (EEVcw), end of inspiration (EIVcw), and at total lung capacity (TLCVcw) were computed by optoelectronic plethysmography (OEP) during exercise and recovery. RESULTS: Two significantly different patterns of change in EEVcw were observed during exercise. Twelve patients had a progressive significant increase in EEVcw during exercise (early hyperinflators, EH) amounting to 750 (90) ml at Wpeak. In contrast, in all eight remaining patients EEVcw remained unchanged up to 66% Wpeak but increased significantly by 210 (80) ml at Wpeak (late hyperinflators, LH). Although at the limit of tolerance the increase in EEVcw was significantly greater in EH, both groups reached similar Wpeak and breathed with a tidal EIVcw that closely approached TLCVcw (EIVcw/TLCVcw 93 (1)% and 93 (3)%, respectively). EEVcw was increased by 254 (130) ml above baseline 3 minutes after exercise only in EH. CONCLUSIONS: Patients with severe COPD exhibit two patterns during exercise: early and late hyperinflation. In those who hyperinflate early, it may take several minutes before the hyperinflation is fully reversed after termination of exercise.     

Cardiovascular collapse associated with extreme iatrogenic PEEPi in patients with obstructive airways disease

Chronic obstructive pulmonary disease (COPD) is commonly associated with positive alveolar pressure at end-expiration (intrinsic PEEP or PEEPi) caused by a prolonged expiratory time constant. Positive pressure ventilation (PPV) with large tidal volumes and high ventilatory frequencies may cause pulmonary hyperinflation, with increases in intrathoracic pressure and cardiopulmonary effects. We report two cases, one of fatal pulseless electrical activity, the other of life-threatening hypotension, both during vigorous manual PPV, in patients with severe COPD. This phenomenon has been well-recognized by intensivists but is reported poorly more widely.      

Association of anxiety with perception of histamine induced bronchoconstriction in patients with asthma

BACKGROUND: The perception of bronchoconstriction varies among patients with asthma and this perception may be related to the covariation of sensory and affective aspects of dyspnoea. A study was performed to evaluate whether there are differences in the perception of histamine induced bronchoconstriction between anxious and non-anxious perceivers and whether anxious perception of bronchoconstriction can be predicted by higher levels of baseline anxiety. METHODS: Seventy eight asthmatic subjects referred for a histamine challenge test undertook baseline measures for anxiety symptomatology and forced expiratory volume in one second (FEV1) followed by perceived breathlessness (Borg scale), anxiety (SUDS), and FEV1 measurement before and during induced bronchoconstriction. Based on the correlation between Borg and SUDS scores, the patients were divided into anxious and non-anxious perceivers. RESULTS: Forty one patients reported no anxiety during the challenge test. The anxious perceivers (n = 20) had higher levels of perceived breathlessness and anxiety at 20% fall in FEV1 and were more accurate in their perception of airways obstruction than non-anxious perceivers (n = 58). However, they did not report higher baseline levels of anxiety symptomatology. CONCLUSIONS: Anxiety experienced during bronchial challenge testing may result from the accurate perception of physiological changes and further direct attention to airways obstruction.


     

Breathing pattern and carbon dioxide retention in severe chronic obstructive pulmonary disease.

BACKGROUND: The factors leading to chronic hypercapnia and rapid shallow breathing in patients with severe chronic obstructive pulmonary disease (COPD) are not completely understood. In this study the interrelations between chronic carbon dioxide retention, breathing pattern, dyspnoea, and the pressure required for breathing relative to inspiratory muscle strength in stable COPD patients with severe airflow obstruction were studied. METHODS: Thirty patients with COPD in a clinically stable condition with forced expiratory volume in one second (FEV1) of < 1 litre were studied. In each patient the following parameters were assessed: (1) dyspnoea scale rating, (2) inspiratory muscle strength by measuring minimal pleural pressure (PPLmin), and (3) tidal volume (VT), flow, pleural pressure swing (PPLsw), total lung resistance (RL), dynamic lung elastance (ELdyn), and positive end expiratory alveolar pressure (PEEPi) during resting breathing. RESULTS: Arterial carbon dioxide tension (PaCO2) related directly to RL/PPLmin, and ELdyn/PPLmin, and inversely to VT and PPLmin. There was no relationship between PaCO2 and functional residual capacity (FRC), total lung capacity (TLC), or minute ventilation. PEEPi was similar in eucapnic and hypercapnic patients. Expressing PaCO2 as a combined function of VT and PPLmin (stepwise multiple regression analysis) explained 71% of the variance in PaCO2. Tidal volume was directly related to inspiratory time (TI), and TI was inversely related to the pressure required for breathing relative to inspiratory muscle strength (PPLsw, %PPLmin). There was an association between the severity of dyspnoea and both the increase in PPLsw (%PPLmin) and the shortening in TI. CONCLUSIONS: The results indicate that, in stable patients with COPD with severe airflow obstruction, hypercapnia is associated with shallow breathing and inspiratory muscle weakness, and rapid and shallow breathing appears to be linked to both a marked increase in the pressure required for breathing relative to inspiratory muscle strength and to the severity of the breathlessness.     

Inspiratory muscle strength and endurance during hyperinflation and histamine induced bronchoconstriction.

BACKGROUND: This study investigated whether the inspiratory muscles are susceptible to fatigue during acute airway narrowing because of increased airway resistance and hyperinflation. METHODS: Asthmatic subjects performed up to four series (on separate days) of 18 maximal static inspiratory efforts of 10 seconds' duration with 10 second rest intervals (50% duty cycle; total duration six minutes): at functional residual capacity (FRC) (control); after histamine induced bronchoconstriction, which decreased forced expiratory volume in one second (FEV1) to a mean of 55% (SD 11%) of the initial value; at a voluntarily increased lung volume (initial volume held at 140% control); and after inhalation of histamine at a voluntarily increased lung volume. RESULTS: For the group of subjects the mean (SD) maximal inspiratory pressure (MIP) in the control experiments was 114 (22) cmH2O and the initial volume was 3.5 (1.2) 1. After histamine inhalation the initial lung volume for contractions increased to 118% (5%) of the control volume. In the high lung volume experiments initial volumes were 140% (12%) of the control (volume without histamine) and 140% (15%) (with histamine). The relation between MIP and initial absolute lung volume was determined for each subject before fatigue developed. When the inspiratory pressures for each contraction in the endurance test were normalised to the pressure expected for that lung volume, no significant differences were found between the four experimental conditions for MIP, or between pressures sustained over the 18 contractions. CONCLUSIONS: Histamine induced bronchoconstriction and hyperinflation had no detectable effect on inspiratory muscle strength or endurance in these asthmatic subjects.     

Effects of cessation of terbutaline treatment on airway obstruction and responsiveness in patients with chronic obstructive pulmonary disease.

BACKGROUND: Cessation of regular therapy with inhaled beta 2 agonists in patients with asthma may lead to a temporary deterioration of lung function and airway responsiveness. Few such studies have been reported in patients with chronic obstructive pulmonary disease (COPD), so an investigation was carried out to determine whether rebound airway responsiveness and rebound bronchoconstriction also occurs in COPD and if there is any relationship with the dose of beta 2 agonist being used. METHODS: Lung function (forced expiratory volume in one second (FEV1) and peak expiratory flow (PEF)), airway responsiveness (PC20 methacholine (PC20)) and symptoms were assessed in a double blind, placebo controlled crossover study during and after cessation of two weeks regular treatment with placebo, and low dose (250 micrograms) and high dose (1000 micrograms) inhaled terbutaline via a dry powder inhaler (Turbohaler) all given three times a day. Sixteen non-allergic patients with COPD of mean (SD) age 58.7 (6.5) years, FEV1 57.1 (12.8)% of predicted, and reversibility on 1000 micrograms terbutaline of 4.5 (3.5)% predicted were studied. PC20 and FEV1 were measured 10, 14, 34 and 82 hours after the last inhalation of terbutaline or placebo. Measurements performed at 10, 14, and 34 hours were expressed relative to 82 hour values in each period, transformed into an area under the curve (AUC) value and analysed by ANOVA. RESULTS: Mean morning and evening PEF increased during terbutaline treatment. PC20 and FEV1 did not change after cessation of terbutaline treatment. CONCLUSIONS: Cessation of regular treatment with both low and high dose inhaled terbutaline does not result in a rebound bronchoconstriction and rebound airway responsiveness in patients with COPD.     

Which spirometric indices best predict subsequent death from chronic obstructive pulmonary disease?

BACKGROUND: Previous epidemiological studies have related mortality from chronic obstructive pulmonary disease (COPD) to forced expiratory volumes (FEV(1) or FEV(0.75)) and it is unknown whether other spirometric indices might have greater predictive power. METHODS: A case-control study of fatal COPD was conducted within a cohort of London civil servants who performed forced expiratory spirograms in 1967-9 and were followed up for mortality over 20 years. The spirograms of 143 men who died of COPD (ICD8 491, 492 or 519.8) were compared with those of 143 controls individually matched for age, height, and smoking habit who survived longer than their matched case. Flow rates in different parts of the spirogram were compared within case-control pairs and analysed as predictors of fatal COPD by conditional logistic regression. RESULTS: Within pair case:control ratios of FEV(1), mid expiratory flow rates (e.g. FEF(50-75)) and FEF(75-85) were highly intercorrelated (r>0.7) but correlations with FEF(85-95) were weaker (r<0.5). All indices except the FEV(1)/FVC ratio were stronger predictors of death from COPD within the first 10 years than of later deaths (15-19 years). After adjustment for FEV(1), mid expiratory flow rates independently predicted fatal COPD but end expiratory flow rates did not. The FEV(1) adjusted mortality ratios associated with a 10% decrement in each index were 2.24 (95% CI 1.54 to 3.76) for FEF(50-75), 1.20 (95% CI 1.00 to 1.42) for FEF(75-85), and 1.10 (95% CI 0.96 to 1.26) for FEF(85-95). CONCLUSION: This study confirms FEV(1) and mid expiratory flow rates as powerful predictors of mortality from COPD, and suggests that measurement of end expiratory flow rates would add little extra predictive information.     

Abnormalities of chest wall motion in patients with chronic airflow obstruction

Forty patients with severe chronic stable airflow obstruction and hyperinflation were studied to assess patterns of abnormal chest wall motion and their frequency. Dimensional changes were measured during tidal breathing, four pairs of magnetometers being used to record anteroposterior diameters of ribcage and abdomen and two lateral diameters of the ribcage. Chest wall movements were qualitatively normal in only five patients. Three main types of abnormality were found and 13 subjects had two or more abnormal patterns. Lateral ribcage paradox was present in 31 of the 40 patients and was recognised clinically in all except one. Inspiratory indrawing of the lower sternum was recorded in 12 patients, paradoxical inspiratory motion of the abdomen was present in four patients and in six there was a biphasic expiratory pattern of abdominal movement. Analysis of variance showed no significant group differences in severity of airflow obstruction or hyperinflation between the patients with qualitatively normal motion and those with different types of abnormal motion. Relationships between the tidal displacement of each dimension and severity of airflow obstruction and hyperinflation were examined. In general, patients with more severe hyperinflation showed less abdominal movement and those with severe airflow obstruction had less lateral expansion of the ribcage, but the correlations were weak. It is concluded that abnormal motion of the chest wall is very common in patients with airflow obstruction and hyperinflation, that clinical recognition of abnormal motion other than lateral ribcage paradox is easily overlooked, and that quantitative relationships between abnormal motion and disease severity are weak.     

Efficacy of inhaled salmeterol in the management of smokers with chronic obstructive pulmonary disease: a single centre randomised, double blind, placebo controlled, crossover study.

BACKGROUND--The acute response to bronchodilators in patients with chronic obstructive pulmonary disease (COPD) is modest; it has, however, been suggested that these patients may benefit from long term treatment. METHODS--To investigate the efficacy of salmeterol in smokers with moderate to severe COPD a double blind, randomised, crossover comparison was performed between salmeterol (50 micrograms twice daily) and placebo in 63 patients with stable COPD (mean age 65 years). Prior to inclusion, all patients had a forced expiratory volume in one second (FEV1) of < 60% of predicted and an improvement in FEV1 of < 15% following 400 micrograms inhaled salbutamol. Patients received four weeks of therapy with each of the treatment regimens. Assessment of efficacy was made with recording of morning and evening peak expiratory flow rates (PEF), respiratory symptoms, and use of rescue salbutamol. FEV1 was measured before and after nebulised salbutamol prior to randomisation and at the end of each treatment period. RESULTS--Morning PEF values were higher during the salmeterol than during the placebo period, although the mean treatment difference was small (12 l/min (95% confidence limits 6 to 17)). No difference in mean evening PEF values was found. Diurnal variation in PEF, assessed as the difference between the morning PEF and that of the previous evening, was more pronounced during the placebo than during the salmeterol period. The mean spirometric values (including reversibility in FEV1) obtained at the end of the two treatment periods were similar. Compared with placebo, treatment with salmeterol was associated with lower daytime and night time symptom scores and less use of rescue salbutamol both during the day and the night. The patients rated the treatment with salmeterol better than treatment with placebo. CONCLUSIONS--This study shows that, compared with placebo, treatment with salmeterol produces an improvement in respiratory symptoms and morning PEF values in patients with moderate to severe COPD. Treatment with long acting beta agonists may therefore result in an improvement in functional status, even in patients suffering from apparently nonreversible obstructive pulmonary disease.     

Inhibition of allergen-induced airway obstruction and leukotriene generation in atopic asthmatic subjects by the leukotriene biosynthesis inhibitor BAYx 1005

BACKGROUND: Leukotriene receptor antagonists significantly blunt allergen-induced bronchoconstriction in asthmatic subjects. Inhibitors of leukotriene synthesis should theoretically provide similar protection, but conflicting results have been obtained when synthesis inhibitors have been tested in allergen challenge. BAYx 1005, a new inhibitor of leukotriene synthesis, was therefore evaluated in an allergen bronchoprovocation study. METHODS: Ten men with mild allergic asthma and bronchial hyperresponsiveness to histamine were recruited. On two different occasions each subject inhaled a single dose of allergen, previously determined to cause at least a 20% fall in forced expiratory volume in one second (FEV1) four hours after ingestion of 750 mg BAYx 1005 or placebo in a double blind crossover design. Urinary excretion of leukotriene E4 was measured before and during the challenges. RESULTS: The mean (SE) maximal fall in FEV1 was 7.1 (1.7)% after BAYx 1005 and 21.0 (3.0)% after placebo (p < 0.001). The mean difference between treatments was 13.9 (95% CI 7.0 to 20.8) for the maximal fall in FEV1. All subjects were protected by BAYx 1005, the mean inhibition of the fall in FEV1 being 70.0 (7.0)%. The mean area under the curve (AUC) for urinary excretion of leukotriene E4 in the first two hours after the challenge was 1.7 (0.9) after placebo and 0.4 (0.6) after BAYx 1005 (difference = 1.3 (95% CI-0.1 to 2.7); p < 0.05). CONCLUSIONS: These results indicate that BAYx 1005 is a potent inhibitor of allergen-provoked leukotriene synthesis in asthmatic subjects and lend further support to the suggestion that leukotrienes are important mediators of allergen-induced bronchoconstriction.


     

Asynchrony and Hyperinflation in Patients With Chronic Obstructive Pulmonary Disease During Two Types of Upper Limbs Exercise

IntroductionOccurrence of dynamic hyperinflation during upper-limbs exercises in chronic obstructive pulmonary disease (COPD) patients is not well established. We hypothesized that dynamic hyperinflation and thoracoabdominal asynchrony occur in COPD patients accomplishing arms exercises. We assessed the occurrence and association of dynamic hyperinflation and thoracoabdominal asynchrony in COPD patients during the accomplishment of two arm exercises.Patients and methodsThis was a prospective study with 25 COPD patients. A maximal and a sub-maximal upper limbs exercise test with 50% load were performed with the diagonal technique and the arm cycle ergometer technique. Respiratory pattern, thoracoabdominal configuration and dynamic hyperinflation were assessed in the exercise tests.ResultsThirty per cent and 60% of patients hyperinflated at the end of the sub-maximum exercise tests with the diagonal and cycle ergometer techniques, respectively. Thoracoabdominal asynchrony occurred in 80% and 100% of patients who hyperinflated with the diagonal and cycle ergometer techniques, respectively. For both exercises we found enhancement of pulmonary ventilation, dyspnea, central respiratory drive and shortening of expiratory time (P<.05). Upper-limbs exercises with the diagonal technique presented less number of patients with these alterations.ConclusionsDynamic pulmonary hyperinflation and thoracoabdominal asynchrony association occurred in both upper-limbs exercises; however, the diagonal technique developed less dynamic hyperinflation and thoracoabdominal asynchrony in COPD patients than the arm cycle ergometer.     

Increased urinary excretion of LTE4 after exercise and attenuation of exercise-induced bronchospasm by montelukast, a cysteinyl leukotriene receptor antagonist

BACKGROUND: A study was undertaken to determine whether montelukast, a new potent cysteinyl leukotriene receptor antagonist, attenuates exercise-induced bronchoconstriction. The relationship between the urinary excretion of LTE4 and exercise-induced bronchoconstriction was also investigated. METHODS: Nineteen non-smoking asthmatic patients with a forced expiratory volume in one second (FEV1) of > or = 65% of the predicted value and a reproducible fall in FEV1 after exercise of at least 20% were enrolled. Subjects received placebo and montelukast 100 mg once daily in the evening or 50 mg twice daily, each for two days, in a three-period, randomised, double blind, crossover design. In the evening, approximately 20-24 hours after the once daily dose or 12 hours after the twice daily dose, a standardised exercise challenge was performed. Data from 14 patients were available for complete analysis. RESULTS: The mean (SD) maximal percentage decrease in FEV1 after exercise was 29.6 (16.0), 17.1 (8.2), and 14.0 (9.4) for placebo, once daily, and twice daily regimens, respectively. The mean (95% CI) percentage protection was 37 (15 to 59) for the group who received 50 mg twice daily and 50 (31 to 69) for those who received 100 mg once daily. Active treatments were not different from each other. The mean (SD) plasma concentrations of montelukast were higher after the twice daily regimen (1.27 (0.81) microgram/ml) than after the once daily regimen (0.12 (0.09) microgram/ml); there was no correlation between the percentage protection against exercise-induced bronchoconstriction and plasma concentrations. After exercise urinary excretion of LTE4 increased significantly during placebo treatment (from 34.3 to 73.7 pg/mg creatinine; p < 0.05) but did not correlate with the extent of exercise-induced bronchoconstriction. CONCLUSIONS: Montelukast protects similarly against exercise-induced bronchoconstriction between plasma concentrations of 0.12 and 1.27 micrograms/ml. The increase in the urinary excretion of LTE4 after exercise and the protection from exercise-induced bronchoconstriction with a cysteinyl leukotriene receptor antagonist provide further evidence of the role of leukotrienes in the pathogenesis of exercise-induced bronchoconstriction.


     

Bronchial fenestration improves expiratory flow in emphysematous human lungs

BACKGROUND: The crippling effects of emphysema are due in part to dynamic hyperinflation, resulting in altered respiratory mechanics, an increased work of breathing, and a pervasive sense of dyspnea. Because of the extensive collateral ventilation present in emphysematous lungs, we hypothesize that placement of stents between pulmonary parenchyma and large airways could effectively improve expiratory flow, thus reducing dynamic hyperinflation. METHODS: Twelve human emphysematous lungs, removed at the time of lung transplantation, were placed in an airtight ventilation chamber with the bronchus attached to a tube traversing the chamber wall, and attached to a pneumotachometer. The chamber was evacuated to -10 cm H2O pressure for lung inflation. A forced expiratory maneuver was simulated by rapidly pressurizing the chamber to 20 cm H2O, while the expiratory volume was continuously recorded. A flexible bronchoscope was then inserted into the airway and a radiofrequency catheter (Broncus Technologies) was used to create a passage through the wall of three separate segmental bronchi into the adjacent lung parenchyma. An expandable stent, 1.5 cm in length and 3 mm in diameter, was then inserted through each passage. Expiratory volumes were then remeasured as above. In six experiments, two additional stents were then inserted and forced expiratory volumes again determined. RESULTS: The forced expiratory volume in 1 second (FEV1) increased from 245 +/- 107 mL at baseline to 447 +/- 199 mL after placement of three bronchopulmonary stents (p < 0.001). With two additional stents, the FEV1 increased to 666 +/- 284 mL (p < 0.001). CONCLUSIONS: Creation of extra-anatomic bronchopulmonary passages is a potential therapeutic option for emphysematous patients with marked hyperinflation and severe homogeneous pulmonary destruction.     

Peripheral muscle endurance and the oxidative profile of the quadriceps in patients with COPD

BACKGROUND: Based on previously reported changes in muscle metabolism that could increase susceptibility to fatigue, we speculated that patients with chronic obstructive pulmonary disease (COPD) have reduced quadriceps endurance and that this will be correlated with the proportion of type I muscle fibres and with the activity of oxidative enzymes. METHODS: The endurance of the quadriceps was evaluated during an isometric contraction in 29 patients with COPD (mean (SE) age 65 (1) years; forced expiratory volume in 1 second 37 (3)% predicted) and 18 healthy subjects of similar age. The electrical activity of the quadriceps was recorded during muscle contraction as an objective index of fatigue. The time at which the isometric contraction at 60% of maximal voluntary capacity could no longer be sustained was used to define time to fatigue (Tf). Needle biopsies of the quadriceps were performed in 16 subjects in both groups to evaluate possible relationships between Tf and markers of muscle oxidative metabolism (type I fibre proportion and citrate synthase activity). RESULTS: Tf was lower in patients with COPD than in controls (42 (3) v 80 (7) seconds; mean difference 38 seconds (95% CI 25 to 50), p<0.001). Subjects in both groups had evidence of electrical muscle fatigue at the end of the endurance test. In both groups significant correlations were found between Tf and the proportion of type I fibres and citrate synthase activity. CONCLUSION: Isometric endurance of the quadriceps muscle is reduced in patients with COPD and the muscle oxidative profile is significantly correlated with muscle endurance.     

COPD exacerbations . 3: Pathophysiology

Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with increased morbidity and mortality. The effective management of COPD exacerbations awaits a better understanding of the underlying pathophysiological mechanisms that shape its clinical expression. The clinical presentation of exacerbations of COPD is highly variable and ranges from episodic symptomatic deterioration that is poorly responsive to usual treatment, to devastating life threatening events. This underscores the heterogeneous physiological mechanisms of this complex disease, as well as the variation in response to the provoking stimulus. The derangements in ventilatory mechanics, muscle function, and gas exchange that characterise severe COPD exacerbations with respiratory failure are now well understood. Critical expiratory flow limitation and the consequent dynamic lung hyperinflation appear to be the proximate deleterious events. Similar basic mechanisms probably explain the clinical manifestations of less severe exacerbations of COPD, but this needs further scientific validation. In this review we summarise what we have learned about the natural history of COPD exacerbations from clinical studies that have incorporated physiological measurements. We discuss the pathophysiology of clinically stable COPD and examine the impact of acutely increased expiratory flow limitation on the compromised respiratory system. Finally, we review the chain of physiological events that leads to acute ventilatory insufficiency in severe exacerbations.