Patients were divided into two groups depending upon the change in the degree of density dependence of the MEFV curve in response to isoproterenol. Patients showing a decrease in density dependence as measured by a more than 15 percent rise in VisoV and/or a similar fall in the percentage ratio of Vmaxso breathing-Helox to that breathing air (Vmax5o Helox/air) were assigned to group 1. Subjects showing an increase in density dependence of airflow after administration of isoproterenol, manifested by a fall in VisoV and/or a rise in Vmax5o Helox/air were placed in group 2 (Fig 1).
The peak expiratory flow (Vmax) with Helox was higher than with air in all subjects. Changes in VisoV and in Vmaxso Helox/air were in opposite directions in all instances, but there was no quantitative correlation between the two measurements. In three subjects, the change in VisoV was less than 15 percent, and the change in Vmaxso Helox/air was above 40 percent. In another three subjects, the change in Vmaxso Helox/air was < 15 percent, but the change in VisoV was > 20 percent. Therefore, by considering the change in both VisoV and Vmax-so Helox/air, an increase or decrease in the D/MEF after isoproterenol could always be precisely determined even when the change in VisoV or in Vmax5o Helox/air alone gave equivocal results.
Table 1 summarizes the selected clinical data in subjects belonging to group 1 (decrease in D/ MEF), and 2 (increase in D/MEF). The subjects were all adults with asthma, as defined elsewhere, who had the disease for a mean of 18 ±: 17 SD, and 20 =h 17 SD years in groups 1 and 2 respectively. Eighteen (75 percent) subjects had chronic cough with expectoration and 22 (92 percent) had persistent wheezing. No subject was asymptomatic at the time of study. Group 2 subjects had a higher prevalence of identifiable allergies and seasonal exacerbation of symptoms although the difference was not statistically significant (x2 < 3.71, P > .05).
Table 2 shows the data on selected pulmonary function tests before and 15 minutes after isoproterenol inhalation. Although the subjects in group 2 appear to have milder disease and a greater reversibility of airway obstruction after isoproterenol, the differences fail to attain statistical significance. In all other measurements, the two groups are similar.
Tables 3 and 4 show the results of pulmonary function tests used to evaluate the response to isoproterenol in comparison to atropine in individual subjects responding better to isoproterenol (IR) and to atropine (AR) respectively. A better response to one drug as compared to another was indicated by at least 10 percent greater FEVi and/ or 15 percent greater Vmax5o, in 22 subjects. In two other subjects, the difference in FEVi or Vmaxso after the use of one drug versus another, was less than above and in these subjects a better response was indicated by a more than 10 percent difference in at least three of the four parameters used (Tables 3 and 4). In no instance were the changes in FEVi or Vmaxso opposite the changes in these other parameters. In 21 of the 24 subjects, their own assessment of the efficacy of the two drugs based upon symptomatic improvement was in agreement with the response shown by pulmonary function tests. In three patients, the best objective response and the subjective improvement were obtained with different drugs.
Use of either isoproterenol or atropine for one week resulted in improvement in pulmonary function measurements compared to the baseline values in all subjects. However, there was a significant difference in the relative response to isoproterenol and atropine between the two groups (Table 5). Of the 11 subjects in group 1, ten responded better to isoproterenol and only one to atropine, while of the 13 subjects in group 2, ten responded better to atropine and only three to isoproterenol (*2 with Yates correction = 8.48, P<.0Q5). Considering both groups together, 11 subjects responded better to atropine than to isoproterenol (AR) and 13 responded better to isoproterenol than to atropine (IR). Ten (77 percent) of the IR and only one (9 percent) of the AR belonged to group 1, a significant difference (*2 with Yates correction = 8.48, P<.0G5).
Table 6 summarizes the distribution, severity and the nature of the side effects. Seven subjects, three of the group 2 and four of the group 1, had no side effects throughout the study. Five subjects experienced side effects from both isoproterenol and atropine. Nine subjects had side effects from atropine, but not from isoproterenol, while three subjects had side effects from isoproterenol but not from atropine. One quit the study because of severe side effects, five reduced the dosage of atropine sulphate to 0.04 mg/kg twice daily, and two had to reduce dosage of the drug to 0.04 mg/kg four times a day. The difference in response to atropine and isoproterenol between the two groups remains highly significant (x2 = 8.24, P<.005) even if these seven subjects (two from group 1, five from group 2) are eliminated from the analysis. In the remaining eight subjects, the side effects were not severe enough for the patients to make any adjustments in the dosage.
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Table 1—Clinical Characteristics of Subjects
| Group 1 | Group 2 | |
| No. | 11 | 13 |
| Age (years, mean ± 1SD | 46.6 ±12.4 46.6 ±10.3 | |
| Duration of asthma (years, mean ± 1SD) | 17.9 ±17.6 | 20.2 ±16.8 |
| Age at onset of asthma (years, mean ± 1SD) | 28.7 ±20.5 | 26.2 ±17.1 |
| No. subjects with | ||
| identified allergies | 3 (27.2) | 8(61.5) |
| Seasonal exacerbations | 2 (18.2) | 7 (53.8) |
| Family history of asthma | 2 (18.2) | 4 (30.8) |
| Chronic cough and expectoration | 8 (72.7) | 10 (76.9) |
| Wheezing on ausculation | 10 (90.9) | 12 (92.3) |
| Eosinophil count (mean ± 1SD) | 448 ±398 | 375 ±341 |
Table 2—Selected Pulmonary Function Measurements
| Group 1 | Group 2 | |
| No. | 11 | 13 |
| FVC (liters) | 3.5 ± 1.2 | 4.0 ± 1.2 |
| FEVi (liters) | 2.2 ± .9 | 2.3 ± .9 |
| FEVi/FVC% | 61.4 ± 8.9 | 57.5 ±11.2 |
| Gaw/VL (cm HsO/L/Sec/L) | .09 ± .06 | .08 ± .04 |
| FRC (liters) | 4.0 ± 1.8 | 4.36 ± 1.2 |
| Vmax 50air (liters/Sec) | 1.5± 1.4 | 1.5 ± 1.0 |
| Vmax 25air (liters/Sec) | .5± .2 | .6± .3 |
| Vmax 50Helox/Vmax 50air% | 148 ±38.2 | 127.5 ±20.6 |
| VisoV% | 23.2 ±15.0 | 25.9 ±12.1 |
| Percentage of change after administration of isoproterenol in | ||
| FEVi | 11.1 ±12.0 | 25.2 ±33.3 |
| Gaw/VL | 43.2 ±52.0 | 42.1 ±65.9 |
| FRC | -7.7 ±17.1 | -16.4 ±18.0 |
| Vmax 50air | 34.6 ±42.8 | 42.2 ±55.1 |
| VisoV | 45.0 ±31.2 | -39.2 ±30.0 |
| Vmax 50Helox/Vmax 50air% | -33.1 ±24.2 | 105.4 ±119 |
Table 3—Comparison of Selected Pulmonary Function Tests in Individual IR Subjects after One Week of Treatment with Isoproterenol versus Atropine
| No. | Isoproterenol (I) | Atropine (A)A | ||||||||||
| FEVi | MMEF | Vmax | Vmax50 | Gaw/VL | FRC | FEV, | MMEF | Vmax | Vmax50 | Gaw/VL | FRC | |
| 1 | 1.3 | 0.75 | 1.95 | 0.4 | — | — | 0.8 | 0.3 | 1.7 | 0.2 | — | — |
| 2 | 2.4 | 1.5 | 4.1 | 2.0 | 0.12 | 3.0 | 2.3 | 1.5 | 3.8 | 1.5 | 0.11 | 3.0 |
| 3 | 3.6 | 2.4 | 5.2 | 3.0 | 0.09 | 2.0 | 2.8 | 1.4 | 5.0 | 2.2 | 0.1 | 3.2 |
| 4 | 1.7 | 0.7 | 4.0 | 0.9 | 0.07 | 5.0 | 1.6 | 0.7 | 3.2 | 0.6 | 0.06 | 5.1 |
| 5 | 1.8 | 1.4 | 5.3 | 1.5 | 0.11 | 2.1 | 1.8 | 1.2 | 3.9 | 1.5 | 0.09 | 2.2 |
| 6 | 3.2 | 1.7 | 6.8 | 1.6 | 0.08 | 4.0 | 3.0 | 1.6 | 6.1 | 1.2 | 0.08 | 4.5 |
| 7 | 3.1 | 1.5 | 6.7 | 2.0 | 0.11 | 4.3 | 2.7 | 1.5 | 6.0 | 1.6 | 0.10 | 4.7 |
| 8 | 2.7 | 1.8 | 7.0 | 1.7 | 0.12 | 3.3 | 2.6 | 1.1 | 6.4 | 1.8 | 0.10 | 4.5 |
| 9 | 4.0 | 4.6 | 10.1 | 4.8 | 0.11 | 3.1 | 3.1 | 2.5 | 8.1 | 3.8 | 0.08 | 3.8 |
| 10 | 1.6 | 0.6 | 3.5 | 1.1 | 0.05 | 5.8 | 1.4 | 0.5 | 2.8 | 0.4 | 0.06 | 5.9 |
| 11 | 3.3 | 1.9 | 8.0 | 2.8 | 0.08 | 4.3 | 3.2 | 1.8 | 7.3 | 2.4 | 0.07 | 4.1 |
| 12 | 1.2 | 0.6 | 4.1 | 0.6 | 0.04 | 5.2 | 1.1 | 0.5 | 2.8 | 0.4 | 0.04 | 5.3 |
| 13 | 2.6 | 3.1 | 5.9 | 2.9 | 0.2 | 2.9 | 2.4 | 2.8 | 5.5 | 2.2 | 0.15 | 4.2 |
| Mean | 2.5 | 1.7 | 5.6 | 1.95 | 0.1 | 3.75 | 2.2 | 1.3 | 4.8 | 1.5 | 0.09 | 4.2 |
| ±1SD | ±0.9 | ±1.1 | ±2.2 | ±1.2 | ±0.04 | ±1.2 | ±0.8 | ± .7 | ±1.9 | ±1.0 | ±0.03 | ±1.0 |
Table 4—Comparison of Selected Pulmonary Function Tests in Individual AR Subjects after One Week of Treatment ivith Isoproterenol versus Atropine
| No. | Isoproterenol (I) | Atropine (A) | ||||||||||
| FEVi | MMEF | Vmax | Vmax50 | Gaw/VL | FRC | FEV, | MMEF | Vmax | Vmax50 | Gaw/VL | FRC | |
| 14 | 2.2 | 1.4 | 4.6 | 1.4 | 0.07 | 3.2 | 2.5 | 1.8 | 4.6 | 1.6 | 0.09 | 2.6 |
| 15 | 4.3 | 2.6 | 7.7 | 2.1 | — | 4.7 | 4.9 | 4.0 | 7.6 | 3.6 | — | 3.3 |
| 16 | 2.2 | 0.6 | 4.8 | 0.9 | 0.13 | 5.2 | 2.7 | 0.9 | 5.5 | 1.4 | 0.12 | 4.5 |
| 17 | 3.7 | 2.2 | 5.6 | 1.8 | 0.06 | 4.0 | 3.9 | 2.2 | 7.8 | 2.6 | 0.14 | 4.1 |
| 18 | 2.3 | 1.0 | 5.4 | 1.2 | 0.07 | 4.7 | 2.6 | 1.0 | 5.5 | 1.2 | 0.09 | 4.4 |
| 19 | 2.5 | 1.6 | 5.0 | 1.9 | 0.15 | 2.5 | 2.6 | 1.9 | 5.5 | 2.3 | 0.23 | 1.9 |
| 20 | 3.0 | 1.7 | 6.2 | 2.1 | 0.09 | 4.0 | 4.1 | 30 | 7.5 | 3.0 | 0.11 | 4.5 |
| 21 | 0.8 | 0.3 | 2.4 | 0.2 | 0.04 | 5.7 | 1.0 | 0.3 | 2.9 | 0.45 | 0.04 | 5.0 |
| 22 | 1.3 | 0.6 | 2.3 | 0.6 | 0.06 | 5.4 | 2.2 | 1.0 | 5.0 | 1.1 | 0.08 | 5.4 |
| 23 | 1.3 | 0.5 | 3.0 | 0.4 | 0.05 | 6.0 | 1.4 | 0.6 | 3.2 | 0.8 | 0.05 | 5.2 |
| 24 | 2.9 | 1.5 | 3.2 | 1.2 | 0.04 | 7.2 | 3.0 | 1.8 | 6.5 | 2.0 | 0.04 | 4.4 |
| Mean | 2.4 | 1.3 | 4.6 | 1.25 | 0.08 | 4.8 | 2.8 | 1.7 | 5.6 | 1.8 | 1.0 | 4.1 |
| ±1SD | ±1.0 | ±0.7 | ±1.7 | ±0.7 | ±.04 | ±1.3 | ±1.1 | ±1.1 | ±1.7 | ±1.0 | ±0.06 | ±1.1 |
Table 5—Distribution of Subjects Responding better to Isoproterenol (IR) and to Atropine (AR) in Group 1 and 2
| Group 1 | Group 2 | Total | |
| Isoproterenol | 10 | 3 | 13 |
| Atropine | 1 | 10 | 11 |
| 11 | 13 | 24 | |
| x2=8.48, PC.005 |
Table 6—Side Effects Noted with Atropine (26 Subjects) and Isoproterenol (24 Subjects)
| Side Effects | Atropine | Isoproterenol |
| Total | 16 (61.5) | 8 (33.3) |
| Severe | 8 (30.8) | 1 (4.2) |
| Study discontinued because of side effects | 1 (3.9) | 0 |
| Dryness of mouth | 11 (42.3) | 2 (8.3) |
| Blurring of vision | 9 (34.6) | 2 (8.3) |
| Diplopia | 4 (15.4) | 0 |
| Difficulty in urination | 4 (15.4) | 1 (4.2) |
| Feeling of heat | 3 (11.5) | 1 (4.2) |
| Abnormal behavior, confusion | 3 (11.5) | 0 |
| Plugged nose | 2 (7.7) | 0 |
| Dizziness | 3 (11.5) | 3 (12.5) |
| Tremulousness | 4 (15.4) | 0 |
| Nausea, vomiting, GI upset | 2 (7.7) | 2 (8.3) |
| Persistent bad taste in mouth | 4 (15.4) | 0 |
| Headache | 3 (11.5) | 1 (4.2) |
| Anxiety, pain chest, skin rash | Each 1 (3.9) | Each 1 (4.2) |
| Palpitations | 1 (3.9) | 3 (12.5) |
| Insomnia | 2 (7.7) | 0 |
| Sore throat | 0 | 1 (4.2) |
Figure 1. Measurement of density dependence of maximum expiratory flow. Flow volume curves breathing air and Helox are superimposed on each other matched at the residual volume. The curves with higher peak flows are after breathing Helox. VisoV = VisoV/FVC X 100. Vmax50 Helox/air% = Vmax50 Helox/Vmax50 air X 100. A is before, and b after, isoproterenol inhalation.