Sustained bronchoprotection, bronchodilatation, and symptom control during regular formoterol use in asthma of moderate or greater severity. The Canadian FO/OD1 Study Group.

BACKGROUND: Recent studies have raised concern that regular inhalation of beta2 -agonists may cause a worsening of asthma control compared with on-demand dosing regimens. OBJECTIVE: The objective of this study was to compare the effect of twice daily formoterol (Foradil), 4 times daily albuterol, and on-demand albuterol on bronchial hyperresponsiveness (BHR), lung function measurements, symptoms, and other indicators of disease control over 6 months inpatients with asthma of moderate or greater severity receiving concomitant inhaled corticosteroids. We also looked for occurrence of rebound BHR on discontinuation of treatment. METHODS: This was a multicenter, parallel-group, double-blind, clinical trial. Methacholine PC20 was the primary outcome variable. Other outcome variables included symptom scores, use of rescue medication, morning peak expiratory flow (PEF), serial FEV1 measurements, and asthma exacerbations. RESULTS: Of the 271 randomized patients, 217 completed the study. Formoterol was significantly superior to on-demand albuterol with regard to methacholine PC20, FEV1, PEF, symptom scores, and use of rescue medication at each measured time point/interval. Regular albuterol was superior to on-demand albuterol with regard to PC20 and FEV1, but not PEF or various clinical scores. After a small drop in the magnitude of bronchoprotection and bronchodilatation occurring shortly after randomization, there was no evidence of progressive tolerance to either regular treatment for any of the measured variables or of rebound increase in BHR 2 days after the end of treatment. The formoterol group had the lowest number of exacerbation days, as defined by high intake of rescue bronchodilator and/or symptom scores, whereas the number of exacerbations requiring increased corticosteroid coverage was similar in the 3 groups. CONCLUSION: In patients with asthma of moderate or greater severity receiving inhaled corticosteroids, formoterol taken twice daily resulted in superior bronchoprotection, bronchodilatation, and clinical control compared with on-demand albuterol over 6 months. Four times daily albuterol was superior to on-demand albuterol for only some of the end points. Progressive tolerance and a rebound increase in BHR on discontinuation of beta-agonists were not found

Prediction of heart rate and oxygen uptake during incremental and maximal exercise in healthy adults.

Measurement of heart rate and oxygen uptake during incremental exercise and at maximal exercise is useful in evaluating mechanisms responsible for exercise limitation in patients with cardiopulmonary disease. Presently used prediction equations are based on relatively small groups of subjects in whom there was an uneven distribution of subjects with regard to age and sex or based on equations that were from extrapolated data. Our prediction equations are based on data from 231 men and women equally divided within decades between 20 and 80 years. Patients exercised to a symptom-limited maximum on a cycle ergometer while measurements of heart rate and oxygen uptake were recorded. The relationship between heart rate and oxygen uptake throughout exercise (HR:VO2) was determined using a statistical technique that included each data point from each subject. The HR:VO2 throughout incremental exercise was best described by separate equations for women younger than 50 years and older than 50 years and for men younger than 70 years and older than 70 years. Prediction equations for maximal heart rate (HRmax) and maximal oxygen uptake (VO2max) were developed by linear regression and were selected from all possible combinations of parameters. The HRmax was most accurately predicted by age alone for both sexes. Unlike the HR:VO2 relationship, the slope of the line relating heart rate to age was not different for the older women compared with the younger women so that a single equation was derived to predict HRmax. A single equation for the men was also sufficient since the slope of heart rate to age was the same for all ages. To most accurately predict VO2max, a separate equation was required for both the women and men that included age, height, and weight.

Comparison of effects of exercise and hyperventilation on leukocyte kinetics in humans.

The circulating leukocyte (WBC) count increases with exercise, because WBCs enter the circulation from the marginated pool. The lung is a major source of the demarginating cells, but it is unclear whether this occurs because of increased ventilatory movements, increased cardiac output, or both. The present study examined the mechanical effect of ventilation (VE) in six healthy men with three different protocols on three separate occasions. First, the subjects cycled for 5-min intervals at 50, 100, 150, and 200 W, and we measured heart rate (HR), minute ventilation (VE), tidal volume (VT), respiratory rate, and end-tidal CO2. Second, each subject reproduced his exercise VE by matching VT, respiratory rate, and end-tidal CO2 on a circuit designed for isocapnic hyperpnea (matched VE). The subjects then performed a hyperventilation (hyper-VE) protocol with a minimum VT of 1.5 liters and a respiratory rate of 20 breaths/min. Blood samples were drawn at rest and throughout each protocol for measurement of WBCs, hematocrit, and band cells. During cycling, VE increased (9 +/- 1 to 66 +/- 7 l/min), HR increased (71 +/- 7 to 172 +/- 10 beats/min), and WBCs increased (5.5 +/- 0.9 to 7.8 +/- 1.3 x 10(9)/l). During matched VE, VE increased (11 +/- 2 to 69 +/- 11 l/min), but neither HR nor WBCs increased (67 +/- 13 to 78 +/- 12 beats/min and 5.3 +/- 1.6 to 5.7 +/- 1.5 x 10(9)/l, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Normal values and ranges for ventilation and breathing pattern at maximal exercise.

Assessment of the breathing pattern at maximal exercise in patients is limited because the range of ventilatory responses (minute ventilation; tidal volume; respiratory rate) at maximal exercise in normal humans is unknown. We studied 231 normal subjects (120 women; 111 men) equally distributed according to age from 20 to 80 years. Each subject performed a progressive incremental cycle ergometer exercise test to their symptom-limited maximum. Mean ventilation at the end of exercise (Vemax) was significantly higher in men (mean +/- SD, 97 +/- 25 L/min) than in women (69 +/- 22 L/min) (p less than 0.001). Minute ventilation at the end of exercise as a fraction of predicted maximal voluntary ventilation (Vemax/MVV) for all subjects was 0.61 +/- 0.14 (range, 0.28 to 1.02). There was no difference in Vemax/MVV between men (0.62 +/- 0.14) and women (0.59 +/- 0.14). Tidal volume at the end of exercise (Vtmax) was higher in men (2.70 +/- 0.48 L) than in women (1.92 +/- 0.41 L) (p less than 0.001). Any differences in Vtmax between men and women disappeared when Vtmax was corrected for baseline FVC. Respiratory rate at the end of exercise (RRmax) was 36.1 +/- 9.2 breaths per minute for all subjects. There was no difference in RRmax between men and women. The Vemax correlated best with carbon dioxide output at the end of exercise (r = 0.91; p less than 0.001) and with maximal oxygen uptake (r = 0.90; p less than 0.001) for all subjects. This study of a large group of subjects has demonstrated the wide range of possible breathing patterns which are adopted during exercise and has provided a wide range of "normal" responses which must be taken into consideration when maximal ventilatory data from exercise tests are analyzed.

Improved respiratory muscle endurance of highly trained cyclists and the effects on maximal exercise performance.

Insufficient respiratory muscle endurance (RME) may be one of the factors limiting ventilation during peak athletic performance. Our purpose was to determine whether the RME of highly trained cyclists could be enhanced and if so, to determine the effects of improved RME on their maximal exercise performance. Ten male cyclists (maximal oxygen consumption (VO2max) greater than 60 ml/kg-1) began the study by performing 3 tests. These were VO2max, RME measured as maximal sustainable ventilatory capacity (MSVC) and maximal exercise endurance (tlim) measured by an endurance cycling test to exhaustion at 90% of their maximal power output. Five subjects then completed 4 weeks of isocapnic hyperpnea training (16 session) and 5 subjects were controls. Following this training interval, each subject repeated the initial tests. After the RME training, the MSVC increased from 155 +/- 11 to 174 +/- 12 l/min (p = 0.004) for the training subjects while there was no change in the controls (155 +/- 26 and 150 +/- 34 l/min). There were no changes for any of the 10 subjects in either the maximal exercise performance (VO2max = 66.1 +/- 4.7 to 66.5 +/- 4.8 ml.kg-1) or the maximal exercise endurance (tlim = 335 +/- 79 to 385 +/- 158 sec). In conclusion, 4 weeks of respiratory muscle endurance training increased respiratory muscle endurance but had no effect on the maximal cycling performance of highly trained cyclists.

Respiratory muscle weakness and dyspnea in thyrotoxic patients.

Dyspnea on exertion is a frequently reported symptom of thyrotoxicosis. In the majority of cases, there is no obvious cause of dyspnea, but as skeletal myopathy is also common in thyrotoxic patients, it has been postulated that increased dyspnea could be secondary to respiratory muscle weakness. We sought to determine whether thyrotoxic patients were in fact more dyspneic on exertion than age- and sex-matched controls, and if so, whether the increased dyspnea was secondary to respiratory muscle weakness. The study group consisted of 12 thyrotoxic patients and 12 control subjects matched for age and gender. We measured lung volumes, compliance, elastic recoil, respiratory muscle strength, maximal exercise performance, and the intensity of breathlessness (modified Borg scale) at various levels of exercise in all subjects. The respiratory muscles were weaker in patients than controls. This weakness improved in treated patients (p less than 0.05) with concomitant increases in VC, IC, and TLC (all p less than 0.05). Despite this, we found no differences in breathlessness intensity scores between patients and controls or in patients before and after successful antithyroid therapy.

Comparison of two-minute incremental threshold loading and maximal loading as measures of respiratory muscle endurance.

We performed a two-minute incremental threshold loading test (incremental test) in ten normal subjects on three occasions, and having ascertained the maximum load (max load) against which they could inspire for two minutes, measured how long this load could be tolerated by these same subjects on three further occasions (tlim test). We compared the reproducibility of the two tests. There were no significant differences found in the mean max loads in the three incremental tests, or in the endurance times in the three tlim tests. However, the intraindividual coefficients of variation of max load in the incremental test (0 to 14 percent) were much smaller than the intraindividual coefficients of variation of endurance time in the tlim test (20 to 65 percent). We found that the large variability in endurance time in our tlim tests was most likely accounted for by variability in breathing pattern, inspiratory flow rate and breath-by-breath mouth pressure generation. Differences in these parameters did not, however, explain why in the tlim test a given subject could tolerate for 19 minutes a load only 100 g less than that which he was unable to tolerate for two minutes in the incremental test. These findings emphasize the differences between these two tests of respiratory muscle endurance. Since there was less intraindividual variability in the two-minute incremental threshold loading test, we suggest that this test may be more useful than the tlim test.

The effect of breathing frequency on inspiratory muscle endurance during incremental threshold loading.

We tested whether there were differences in measures of respiratory muscle endurance between tests with spontaneously chosen breathing patterns and tests with fixed breathing rates in normal volunteers. Measures of respiratory muscle endurance-maximum load tolerated, mean mouth pressure at maximum load and peak pressure at maximum load were reproducible over three tests with the spontaneously chosen breathing pattern. There was no difference in these measurements between the three tests with fixed breathing frequency. There was no difference in tidal volume, inspiratory time, and the ratio of inspiratory time to total breath duration between the tests in which breathing pattern was spontaneously chosen; there was a difference in these measurements between the tests with a fixed breathing frequency. We conclude that regulation of breathing frequency is unnecessary in the two-minute threshold loading test to obtain reproducible results for measures of respiratory muscle endurance.

Cardiac output at rest and in exercise in elderly subjects.

We measured cardiac output (Q), at rest and during graded exercise, in 68 women and 41 men over the age of 55 yr, using a CO2 rebreathing method. Mean (+/- SD) age was 66 +/- 5 yr in women and 66 +/- 6 yr in men. Only subjects with no history or physical examination findings of pulmonary, cardiac, neuromuscular, or endocrine disease and normal electrocardiography and spirometry were studied. We found a linear relationship between Q and oxygen uptake (VO2) in males and females. The regression equation expressing this relationship in males was Q = 2.9 + 5 VO2 1.min-1 (SEE 2.8) and, in females, Q = 2.9 + 4.6 VO2 1.min-1 (SEE 2.8). This is similar to the relationship previously estimated for elderly males using the direct Fick method and concurs with other reports in the literature which show that, while the Q-VO2 relationship in the elderly has a slope similar to that in younger groups, the Q-VO2 intercept is lower. This means that the absolute level of cardiac output for a given level of work is lower in the elderly than in younger populations. This may reflect an age-related decrease in active metabolic tissue in the elderly and/or altered metabolic regulation with increased oxygen extraction from blood.

Prediction of maximal oxygen uptake and power during cycle ergometry in subjects older than 55 years of age.

One hundred twenty-eight healthy volunteers (81 women, 47 men) older than 55 yr of age were studied with an incremental progressive cycle ergometer test to a symptom-limited, maximal tolerable work load. Mean (+/- SD) age was 66 +/- 6 yr in women and 66 +/- 5 years in men. Subjects with a history of ischemic heart disease, diabetes, pulmonary disease, or neuromuscular disease were excluded. Smokers were included, but all subjects had normal FEV1 and FVC. The objective of the study was to compare measured values of VO2max and Wmax in this older population with previously published predicted values based on subjects of all ages. We found that Wmax observed exceeded Wmax predicted by 9.5 +/- 22% (mean +/- SD) and that VO2max observed exceeded VO2max predicted by 17.5 +/- 22%. Because of this systematic underestimate of VO2max and Wmax by the previous prediction equations, we constructed new prediction equations for use in subjects older than 55 yr of age using height, weight, age, and sex as variables. We conclude that these new prediction equations more accurately predict Wmax and VO2max in subjects older than 55 yr of age because they are based solely on subjects in this age group.

Long-term follow-up of symptoms, pulmonary function, respiratory muscle strength, and exercise performance after botulism.

Respiratory muscle weakness occurs commonly at presentation in patients with botulism. Although clinical improvement occurs over several months, symptoms such as fatigue and dyspnea persist in many patients in the long term. To determine whether continued respiratory muscle weakness might contribute to these symptoms, we compared lung function tests, respiratory muscle strength, and exercise performance in 13 patients 2 years after type B botulism. We found that residual symptoms including dyspnea and fatigue were common in botulism patients at 2 years postintoxication. Lung function tests had returned to normal in all patients. Maximal inspiratory and expiratory pressures were similar between botulism patients and control subjects. Evaluation of individual results showed evidence of inspiratory muscle weakness in four of 13 patients with botulism (Plmax less than 65% predicted). Maximal oxygen consumption and maximal workload during exercise were reduced in botulism patients in comparison to control subjects. During exercise, botulism patients had a more rapid and shallow breathing pattern and a higher dyspnea score at a given minute ventilation in comparison to control subjects. Reasons for premature exercise termination in botulism patients were multifactorial. Although respiratory muscle weakness may have been contributory in some patients, most appeared to be limited by reduced cardiovascular fitness, leg fatigue, or reduced motivation.

Maximal static respiratory pressures in the normal elderly.

To determine if a relationship exists between maximal static respiratory pressures measured at the mouth and age greater than 55 yr, and if so, whether regression equations can be derived that accurately reflect this, we measured maximal inspiratory (Plmax) and expiratory (PEmax) pressures in 64 normal women and 40 normal men older than 55 yr of age. We found no relationship between PImax and PEmax and age greater than 55 yr (all r squared values less than 0.14). We tested the reproducibility of our measurements of PImax and PEmax in 13 and 12 subjects, respectively, on three separate occasions. Repeated measures analysis showed no significant differences in these measurements. Using the measurements obtained in this large study, we calculated 95% confidence limits for PImax and PEmax values in men and women older than 55 yr of age. The 95% confidence limits for PImax in men were 55 to 161 cm H2O, and 26 to 124 cm H2O in women. The 95% confidence limits for PEmax in men were 90 to 256 cm H2O, and 46 to 184 cm H2O in women. We conclude that given the large interindividual variation, a cross-sectional study such as this or other previous studies may not be able to reveal age-dependent changes unless very large numbers are used, and even then potential for bias exists. However, with the small intraindividual coefficients of variation in repeated measurements of PImax and PEmax, a longitudinal study may provide more pertinent information.

Dietary supplementation and respiratory muscle performance in patients with COPD.

We studied the effects of oral nutritional supplementation on respiratory muscle (RM) performance in 25 ambulatory patients with severe chronic obstructive pulmonary disease (COPD). There was a relationship between body weight and anthropometric parameters of nutritional status (triceps skinfold thickness [r = 0.67; p less than 0.005], midarm muscle circumference (r = 0.53; p less than 0.005), but body weight did not correlate with daily caloric intake, serum albumin, transferrin, or blood lymphocyte count. None of these measurements of nutritional status correlated with any measure of RM strength or endurance. In a randomized observer-blinded crossover trial, patients were allocated to one of two groups. In the first eight weeks of the study, group A received nutritional supplementation, and patients in group B were control subjects. In the second eight weeks, patients in group A were control subjects, and group B received supplement. Mean daily caloric intake and body weight increased in both groups while receiving supplement (both p less than 0.05). Calories provided by the supplement were frequently substituted for normal dietary calories. Any increases in RM performance in the group receiving supplement were matched by increases (due to learning) in controls. We conclude that oral dietary supplements have no important effects on RM performance in ambulatory patients with COPD.