Effect of Disodium Cromoglycate on Exercise-induced Asthma

In eight patients with exercise-induced asthma, disodium cromoglycate was found to produce a definite inhibition of the post-exercise fall in forced expiratory volume in one second. This effect may be part of the cause for the subjective improvement experienced with this drug.     

Effect of Alpha-receptor Blocking Drugs and Disodium Cromoglycate on Histamine Hypersensitivity in Bronchial Asthma

Twenty patients with extrinsic type bronchial asthma are shown to have a significant fall in vital capacity (V.C.) and forced expiratory volume in 1 second (F.E.V.₁) after an intravenous infusion of 50μg. of histamine dihydrochloride. In 10 of these subjects the fall in V.C. and F.E.V.₁ produced by intravenous histamine is inhibited by the alpha-receptor blocking drugs phentolamine and phenoxybenzamine injected before the histamine test. The inhalation of disodium cromoglycate in 10 subjects is also shown to inhibit the fall in V.C. and F.E.V.₁ produced by the intravenous infusion of histamine. It is suggested that bronchial smooth muscle in asthmatic subjects has alpha-adrenergic receptor sites, and that a possible mechanism for the action of disodium cromoglycate is that it stabilizes the cell membrane, thereby altering calcium ion transport.     

Changes in lung mechanics during asthma induced by exercise.

Pulmonary and airway mechanics were assessed in seven asthmatic patients in remission, when asthma was induced by exercise and again after spontaneous recovery or bronchodilator treatment. After exercise there was a sustained fall in forced expiratory volume in 1 s (FEV 1.0) in all patients, varying from 30 to 80 percent of the initial value. Total lung capacity (TLC) increased significantly in four of the seven patients. In one of the four patients the increase in TLC was associated with an increase in static transpulmonary pressure at full inflation but in the remaining three patients it was associated with a parallel shift of the pressure-volume curve of the lung without change in its slope. In all patients residual volume increased, regardless of change in TLC; both pressure-volume and maximum expiratory flow-volume curves suggested that widespread airway closure (or virtual closure) occurred at positive transpulmonary pressures when asthma was induced. Loss of lung recoli pressure sometimes contributed to the reduction in maximum expiratory flow but diffuse airway narrowing was probably the dominant abnormality. When air-flow obstruction became more severe the ratio of expiratory to inspiratory time was increased and although expiratory flow limitation was present excessive expiratory pressures were not generated.     

Disodium Cromoglycate in the Prevention of Induced Asthma

In 13 patients with allergic asthma disodium cromoglycate protected fully only two from an allergen-induced asthmatic attack.Inhalation of disodium cromoglycate did not improve lung function in five patients with long-standing chronic asthma.Previous clinical trials do not show convincing evidence that this drug improves bronchial asthma in a high percentage of cases, but it seems to help a small minority of patients.     

Exercise-induced bronchodilation in natural and induced asthma: effects on ventilatory response and performance.

We studied whether bronchodilatation occurs with exercise during the late asthmatic reaction (LAR) to allergen (group 1, n = 13) or natural asthma (NA; group 2, n = 8) and whether this is sufficient to preserve maximum ventilation (VE(max)), oxygen consumption (VO(2 max)), and exercise performance (W(max)). In group 1, partial forced expiratory flow at 30% of resting forced vital capacity increased during exercise, both at control and LAR. W(max) was slightly reduced at LAR, whereas VE(max), tidal volume, breathing frequency, and VO(2 max) were preserved. Functional residual capacity and end-inspiratory lung volume were significantly larger at LAR than at control. In group 2, partial forced expiratory flow at 30% of resting forced vital capacity increased greatly with exercise during NA but did not attain control values after appropriate therapy. Compared with control, W(max) was slightly less during NA, whereas VO(2 max) and VE(max) were similar. Functional residual capacity, but not end-inspiratory lung volume at maximum load, was significantly greater than at control, whereas tidal volume decreased and breathing frequency increased. In conclusion, remarkable exercise bronchodilation occurs during either LAR or NA and allows VE(max) and VO(2 max) to be preserved with small changes in breathing pattern and a slight reduction in W(max).     

Breathing during exercise in subjects with mild-to-moderate airflow obstruction: effects of physical training.

In this study we explored the effects of physical training on the response of the respiratory system to exercise. Eight subjects with irreversible mild-to-moderate airflow obstruction [forced expiratory volume in 1 s of 85 +/- 14 (SD) % of predicted and ratio of forced expiratory volume in 1 s to forced vital capacity of 68 +/- 5%] and six normal subjects with similar anthropometric characteristics underwent a 2-mo physical training period on a cycle ergometer three times a week for 31 min at an intensity of approximately 80% of maximum heart rate. At this work intensity, tidal expiratory flow exceeded maximal flow at control functional residual capacity [FRC; expiratory flow limitation (EFL)] in the obstructed but not in the normal subjects. An incremental maximum exercise test was performed on a cycle ergometer before and after training. Training improved exercise capacity in all subjects, as documented by a significant increase in maximum work rate in both groups (P < 0.001). In the obstructed subjects at the same level of ventilation at high workloads, FRC was greater after than before training, and this was associated with an increase in breathing frequency and a tendency to decrease tidal volume. In contrast, in the normal subjects at the same level of ventilation at high workloads, FRC was lower after than before training, so that tidal volume increased and breathing frequency decreased. These findings suggest that adaptation to breathing under EFL conditions does not occur during exercise in humans, in that obstructed subjects tend to increase FRC during exercise after experiencing EFL during a 2-mo strenuous physical training period.     

Exercise Asthma and Disodium Cromoglycate

Exercise-induced asthma (defined as a fall in PEF of at least 25% of the pre-exercise value) was studied in adult patients with uncomplicated asthma. This was found to occur in 22 out of 52 patients. Pre-exercise inhalation of disodium cromoglycate reduced the mean fall in PEF after maximal exercise from 50% of the pre-exercise value to 23% (open assessment in 11 cases). After submaximal exercise for eight minutes the reduction was from 18% to 10% (double-blind crossover study in 28 cases). It is concluded that disodium cromoglycate partly inhibits the increase of airways resistance after exercise in asthmatic patients.     

Changes in blood gas tensions and functional residual capacity in chronic asthmatics treated with disodium cromoglycate

Twenty chronic asthmatic subjects were treated with disodium cromoglycate in open trial. Although in the group as a whole spirometric findings improved, some patients showed a significant increase in arterial oxygen tension or a significant fall in functional residual capacity without any appreciable changes in spirometry. These changes may partly explain the clinical efficacy of this drug.     

Effect of Disodium Cromoglycate on Exacerbations of Asthma Produced by Hyperventilation

The prophylactic inhalation of disodium cromoglycate lessens the exacerbations which occur in some asthmatic patients after voluntary hyperventilation. Reasons are given for considering this to be a possible mechanism for certain types of emotional exacerbation of the disease and for disodium cromoglycate giving sypmtomatic relief of asthma disproportionate to the improvement in routine measurements of ventilatory capacity. It is suggested that one clinical indication for giving disodium cromoglycate is to observe whether a fall in FEV₁ occurs after two minutes hyperventilation.     

Effects of expiratory threshold loading during steady-state exercise.

Increases in functional residual capacity (FRC) decrease inspiratory muscle efficiency; the present experiments were designed to determine the effect of FRC change on the ventilatory response to exercise. Six well-trained adults were exposed to expiratory threshold loads (ETL) ranging from 5 to 40 cmH2O during steady-state exercise on a bicycle ergometer at 40-95% VO2max. Inspiratory capacity (IC) was measured and changes of IC interpreted as changes of FRC. ETL did not consistently limit exercise performance. At heavy work (greater than 92% VO2max) minute ventilation decreased with increasing ETL; at moderate work (less than 58% VO2max) it did not. Decreases in ventilation were due to decreases in respiratory frequency with prolongation of the duration of expiration being the most consistent change in breathing pattern. At moderate work levels, FRC increased with ETL; at maximum work it did not. Changes in FRC were dictated by constancy of tidal volume and a fixed maximum end-inspiratory volume of 80-90% of the inspiratory capacity. When tidal volume was such that end-inspiratory volume was less than this value, FRC increased with ETL. Mouth pressure measured during the first 0-1 s of inspiratory effort against an occluded airway (P0-1) was increased by ETL equals 30 cmH2O, in spite of the fact that ventilation was decreased. We concluded that changes in FRC due to ETL had no effect on the ventilatory response to exercise and that changes in P0-1 induced by ETL did not reflect changes of inspiratory drive so much as changes of the pattern of inspiration.     

Mechanism of action of ozone on the human lung

Fourteen healthy normal volunteers were randomly exposed to air and 0.5 ppm of ozone (O3) in a controlled exposure chamber for a 2-h period during which 15 min of treadmill exercise sufficient to produce a ventilation of approximately 40 l/min was alternated with 15-min rest periods. Before testing an esophageal balloon was inserted, and lung volumes, flow rates, maximal inspiratory (at residual volume and functional residual capacity) and expiratory (at total lung capacity and functional residual capacity) mouth pressures, and pulmonary mechanics (static and dynamic compliance and airway resistance) were measured before and immediately after the exposure period. After the postexposure measurements had been completed, the subjects inhaled an aerosol of 20% lidocaine until response to citric acid aerosol inhalation was abolished. All of the measurements were immediately repeated. We found that the O3 exposure 1) induced a significant mean decrement of 17.8% in vital capacity (this change was the result of a marked fall in inspiratory capacity without significant increase in residual volume), 2) significantly increased mean airway resistance and specific airway resistance but did not change dynamic or static pulmonary compliance or viscous or elastic work, 3) significantly reduced maximal transpulmonary pressure (by 19%) but produced no changes in inspiratory or expiratory maximal mouth pressures, and 4) significantly increased respiratory rate (in 5 subjects by more than 6 breaths/min) and decreased tidal volume.(ABSTRACT TRUNCATED AT 250 WORDS)     

Long-term Trial of Disodium Cromoglycate and Isoprenaline in Children with Asthma

A year-long double-blind trial was carried out in 53 asthmatic children with severe perennial symptoms who were not receiving corticosteroids or corticotrophin. The treatment group were given disodium cromoglycate with isoprenaline (Intal Co.) while the placebo group were given lactose with isoprenaline four times daily. The groups were closely matched for clinical, physiological, and immunological features. Evaluation was based on the use of a diary and clinical and physiological investigations, including exercise tests.After one year 71% of the treatment group were still well controlled while 76% of the placebo group had dropped out because of inadequate control of symptoms. There was no rise in the rate of failure towards the end of the trial period and there were no seasonal variations in the failure rate. No important toxic effects were noted. It was impossible to predict the outcome of the trial in any given patient from his clinical, physiological, or immunological status at the beginning. However, the prevention of exercise-induced asthma by premedication with disodium cromoglycate in a laboratory exercise test did correlate well with the satisfactory clinical response to the drug.     

A double-blind trial of disodium cromoglycate (Intal) in the treatment of bronchial asthma

The result of a double-blind crossover trial with disodium cromoglycate (Intal) in 22 patients, nine with extrinsic asthma and 13 with intrinsic asthma, is reported. While eight extrinsic asthmatics showed considerable symptomatic improvement, only five of the intrinsic group improved while on disodium cromoglycate. Twelve out of 13 patients with symptomatic improvement had associated decrease in airway obstruction as measured by the FEV₁.It is concluded that disodium cromoglycate is useful in the treatment of asthma, particularly of the extrinsic type.     

Pulmonary and ventilatory responses to pregnancy, immersion, and exercise

To examine the effects of pregnancy, immersion, and exercise during immersion on pulmonary function and ventilation, 12 women were studied at 15, 25, and 35 wk of pregnancy and 8-10 wk postpartum. Pulmonary function and ventilation were measured under three experimental conditions: after 20 min of rest on land (LR), after 20 min of rest during immersion to the level of the xiphoid (IR), and after 20 min of exercise during immersion at 60% of predicted maximal capacity (IE). Forced vital capacity remained relatively constant, except for a decrease at 15 wk, for the duration of pregnancy. Expiratory reserve volume decreased with a change in the pregnancy status and with the duration of pregnancy. However, the forced vital capacity was maintained by an increase in the inspiratory capacity during pregnancy. Forced expiratory volume for 1 s, expressed as percent of forced vital capacity, did not differ significantly between conditions or as a result of pregnancy. Forced vital capacity was lower during the IR trial compared with LR and IE trials. The decreased forced vital capacity of the IR trials was mediated by a decrease in the expiratory reserve volume. Whereas the inspiratory capacity increased during IR and IE compared with LR, the increase was not large enough to offset the decrease in the expiratory reserve volume. Resting immersion resulted in a significant decrease in maximal voluntary ventilation as did pregnancy. Pregnancy resulted in significant increases in minute ventilation (VE), which were related to increases in the O2 consumption.(ABSTRACT TRUNCATED AT 250 WORDS)     

Calcium antagonists in exercise-induced asthma.

Ten patients with exercise-induced asthma participated in a single-blind trial comparing the protective effects of inhaled verapamil (estimated dose 3 mg) and sodium cromoglycate (estimated dose 12 mg). Saline was used as control. Effects were assessed from the mean maximal percentage fall in forced expiratory volume in one second (FEV1) after running on a treadmill for eight minutes. There was no significant change in baseline FEV1 values after each agent. In the exercise periods, however, FEV1 fell by 45.4% (SEM 4.0) after saline inhalation, 18.4% (5.1) after sodium cromoglycate, and 16.7% (4.3) after verapamil. The inhibitory effects of sodium cromoglycate and verapamil were comparable and significantly different from saline (p less than 0.02 and p less than 0.01 respectively). Nevertheless, considerable intrasubject variability was observed. The findings suggest that mediator release, which is calcium dependent, may play an important part in exercise-induced asthma, and calcium antagonists may inhibit post-exercise bronchoconstriction by their blocking effect on calcium channels.     

Exercise hyperpnea in chronic heart failure: relationships to lung stiffness and expiratory flow limitation.

The changes in breathing pattern and lung mechanics in response to incremental exercise were compared in 14 subjects with chronic heart failure and 15 normal subjects. In chronic heart failure subjects, exercise hyperpnea was achieved by increasing breathing frequency more than tidal volume. The rate of increase in breathing frequency with carbon dioxide output was inversely correlated (r = -0.61, P < 0.05) with dynamic lung compliance measured at rest, but not with static lung compliance either at rest or at maximum exercise. Although decrease in expiratory flow reserve near functional residual capacity in chronic heart failure occurred earlier with exercise than in the normal subjects (P < 0.01), it was not correlated with changes in breathing pattern or occurrence of tachypnea. Tachypnea was achieved in chronic heart failure subjects with an increase in duty cycle because of a greater than normal decrease in expiratory time with exercise. We conclude that in chronic heart failure preexisting increase in lung stiffness plays a significant role in causing tachypnea during exercise. The results of the present study do not support the hypothesis that dynamic compression of the airways downstream from the flow-limiting segment occurring during exercise contributes to hyperpnea.     

Pulmonary function in normal subjects following exercise at cold ambient temperatures

We measured pulmonary function in 12 healthy volunteers before and at 5-min intervals for 30 min following treadmill exercise of 30 min duration performed under control (20 degrees C) and cold (-11 degrees C) ambient temperatures. Post-run changes in forced vital capacity (FVC), residual volume (RV) and peak expiratory flow rate were similar between the two temperature conditions. FVC decreased slightly but significantly 5 min post-run (-0.25 +/- 0.20 l and -0.21 +/- 0.20 l, for control and cold conditions respectively) and returned to baseline by 30 min. RV increased significantly post-exercise (+0.07 +/- 0.09 l and +0.14 +/- 0.1 l, control and cold respectively) and remained elevated for 30 min. Forced expired volume in 1 s was not significantly different following either run. Post-exercise, maximum mid-expiratory flow rate and flows at 50% and 25% of vital capacity were not significantly different between warm and cold conditions. These data suggest that changes in lung volumes following exercise under cold ambient conditions are similar to changes seen following warm exercise of similar duration. In non-asthmatics, moderate exertion under cold ambient conditions does not appear to cause clinically significant decreases in expiratory flow rates as compared to similar exertion under warm conditions.     

Ventilatory Tests and Pulmonary Conductance in Hospitalized Patients

In a series of 49 patients, including individuals with varying lung pathology and some older patients with no lung disease, the usual excellent correlation between first-second forced expiratory volume and maximum breathing capacity was found (coefficient of correlation=0.88). The first-second forced expiratory volume and maximum mid-expiratory flow rate were also seen to be closely related (coefficient of correlation=0.87). The relationship between these ventilatory tests and direct mechanical measurements of pulmonary resistance, however, was not as striking. Reduction in pulmonary compliance not due to loss or removal of pulmonary tissue did not affect the interrelationships between these tests. First-second forced expiratory volume, expressed as a percentage of the predicted vital capacity, was more closely related to the expression “% of predicted maximum breathing capacity” than the first-second forced expiratory volume, expressed as a percentage of the actual vital capacity (p<.05).     

Trachea and lung dimensions in nonsmoking twins: morphological and functional studies

To compare genetic and environmental factors that determine lung function and dimensions, chest radiographs and pulmonary function were measured in 17 pairs of nonsmoking twin adolescent boys (12 monozygotic pairs and 5 dizygotic pairs). Genetic factors dominated in tracheal width and lung dimensions (height, width, and apicofissural and fissurodiaphragmatic distances) at residual volume. Genetic factors also affected forced vital capacity, functional residual capacity, forced expiratory volume in 1 s, maximum expiratory flow at 25% vital capacity, and maximum flow at 50% vital capacity-to-forced vital capacity ratio. Peak expiratory flow correlated with tracheal width at residual volume. Age correlated with lung dimensions (width and depth) but not with tracheal width. These results indicate that genetic factors determine the dimensions and function of central airways, peripheral airways, and lung parenchyma in adolescent males. The effects of genetic factors on some functional measurements (airway resistance, closing volume-to-vital capacity ratio, and phase III in single-breath N2 washout) may be masked because of poor reproducibility of the tests.     

Influence of expiratory flow on closing capacity at low expiratory flow rates.

Single-breath oxygen (SBO2) tests at expiratory flow rates of 0.2, 0.5, and 1.01/s were performed by 10 normal subjects in a body plethysmograph. Closing capacity (CC)--the absolute lung volume at which phase IV began--increased significantly with increases in flow. Five subjects were restudied with a 200-ml bolus of 100% N2 inspired from residual volume after N2 washout by breathing 100% O2 and similar results were obtained. An additional five subjects performed SBO2 tests in the standing, supine, and prone positions; closing volume (CV)--the lung volume above residual volume at which phase IV began--also increased with increases of expiratory flow. The observed increase in CC with increasing flow did not appear to result from dependent lung regions reaching some critical "closing volume" at a higher overall lung volume. In normal subjects, the phase IV increase in NI concentration may be caused by the asynchronous onset of flow limitation occurring initially in dependent regions.