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Effect of Age on Bronchodilator Response
Effect of Age on Bronchodilator Response* Wayne A. Kradjan, Pharm.D.; NancyK.JJriesner; Pharm.D.; Tammy H. Abuan, R.N.; Gayle Emmick, R.N.; and Robert B. Schoene, M.D., F.G.G.R
Study Objective: Our objective was to compare the differential effects of age and drug type on bronchodilator response. Design: The design was an unblinded, randomized crossover study. Setting: An ambulatory pulmonary drug study unit was the setting. Patienta: Nineteen young (18 to 25 yr) and 17 elderly (>65 yr) stable asthmatic subjects were studied. Interventions and MeaBUrement8: A1buterol or ipratropium was given on two separate mornings using an MDI with extender. Subjects inhaled two puffs initially and then one puffevery 30 min to a total of six puffs. Pulmonary function, blood pressure, and pulse were measured at baseline and every 30 min for 3 h. Haults: All subjects had a greater than 15 percent increase in FEV. with one or both drugs. More patients responded to a1buterol than to ipratropium in both age groups. The maximum percentage of change from baseline was greater (p
young; 31.2 percent in old) in both groups. These differences remain significant after correction for baseline differences using area-under-the-curve analysis of the percent of maximum improvement; however, the differences between age groups for the same drug were not statistically significant by either index of change. There were also no differences between drugs or between age groups for time (or number of puffs) to reach maximum improvement (mean, 2.0 to 2.2 h for albuterol and 1.6 to 1.7 h for ipratropium). The changes in FVC and FEF25-75% were similar to FEV•. Changes in blood pressure and pulse were not significant. Three subjects stopped therapy with albuterol with side effects. Conclmiona: Both drugs are effective bronchodilators in young and old asthmatic subjects, but albuterol results in a greater magnitude of response in both age groups. Age is not a predictor of response to either drug. (Chest 1992; 101:1545-51)
agonists and anticholinergics are both indicated for use as bronchodilators in patients with reversible obstructive lung disease. Be~-agonists act primarily to dilate small-diameter airways and are more effective than anticholinergics in the treatment of asthma. 1.2 Conversely, anticholinergic drugs may preferentially dilate larger airways and are often more effective in treating patients with chronic obstructive pulmonary disease (COPD) complicated by emphysema or bronchitis (or both);3-6 however, these differences are not universally accepted. 7 .8 Generalities of superiority of one drug vs another in various patient groups is complicated by a number of factors because COPD is a heterogeneous disease and is thus difficult to characterize as a single patient group. Since neither emphysema nor bronchitis has a reversible component, patients with COPD who re-
spond to a bronchodilator must have an underlying asthmatic component to their disease. Additionally, within any group, individual patients will demonstrate one of several patterns. Some will respond equally well to both drugs, others will clearly have a better response to either a ~2-adrenergic agonist or an anticholinergic, and still others will show additive responses when the two drugs are used together. One variable that has not been fully explored when differentiating bronchodilator response is the effect of age on sympathetic and cholinergic actions in the lung. There is evidence from several cardiovascular studies that the activity of the adrenergic system is blunted with age.9-14 For instance, responsiveness to isoproterenol and propranolol in the elderly is decreased; however, the effects of age on pulmonary ~-adrenergic receptors is unknown. If a similar blunting of response occurs in the lung, it might be postulated that the differing bronchodilator responses in asthmatic patients (who are often young) and in patients with COPD who have emphysema (who are typically older) may be related to age and not disease. If this is true, older subjects may require increased doses of sympathomimetics, compared to anticholinergic bronchodilators, to obtain maximal bronchodilatory response. Whether such age-related differences
Bet~-adrenergiC
*From the Division of Pulmonary and Critical Care Medicine, Department of Medicine, and the Department of Pharmacy Practice, University of Washington Schools of Pharmacy and Medicine, and the Department of Pulmonary and Clinical Care Medicine, Harborview Medical Center, Seattle. Supported in part by a gift from the Schering Corp., Kenilworth,
NJ.
Manuscript received June 24; revision accepted September 12. Reprint requests: Dr. Kradjan, Department of Pharmacy Practice, University ofWashington, Seattw 98195
AVC = area under the curve; CRC = Clinical Research Center; MAP mean arterial pressure; MDI metered-dose inhaler
=
=
CHEST I 101 I 6 I JUNE, 1992
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also occur in cholinergic responses is less well defined. It has been postulated that the atropine-like effect for bronchodilation remains constant with advancing age, further supporting the premise that ipratropium may be more effective than albuterol in elderly subjects. 15 This study was undertaken to evaluate the effects of age on bronchodilator response to albuterol (a pi-agonist) and ipratropium (an anticholinergic) in asthmatic patients. Specifically, the study identified and compared the time and dose required to achieve maximum bronchodilator response, and the magnitude ofthe maximum bronchodilator response for both drugs in young and elderly asthmatic patients. Our hypotheses to be tested were that (1) maximum bronchodilation is equal after ~-agonists and anticholinergics within age groups, (2) young subjects require smaller doses of p-agonists to reach maximum bronchodilation than do elderly subjects, and (3) responses to ipratropium are either unaffected by age or increased in the elderly population. MATERIALS AND METHODS
Using age as the major criterion, we recruited two populations of otherwise health~ stable asthmatic patients.. Group 1 consisted of 21 young adults aged 18 to 25 yr, and group 2 was 20 elderly patients over the age of 60 yr. Admission to the study required a diagnosis of asthma as defined by the criteria of the American Thoracic Society18 and at least a 15 percent reversibility in FEV1after either albuterol or ipratropium. Criteria for exclusion included a history of emphysema, bronchitis, other acute or chronic pulmonary disorders, hypertension, cardiac arrhythmias, unstable angina, or other significant cardiovascular diseases. Those with a history of tobacco use for a sustained period of time during their life or exposure to hazardous fumes were also excluded. Long-acting theophylline products were withheld 24 h before each study da~ and p-agonists or anticholinergics were withheld from midnight on each study da~ The study was approved by the institutions review board, and informed consent was obtained from all participants. The study followed an unblinded, randomized crossover design. The subjects reported to the pulmonary drug study unit at approximately 9 AM each study day. On the first da~ subjects were randomized to receive either albuterol (Proventil; 9O..,g per pufI) or ipratropium bromide (Atrovent; 18..,g per puft) as the initial drug, followed by the alternate drug on day 2. Commercially available MDls fitted with a spacer device (Aerochamber) were used for administration of both drugs. Subjects were instructed to exhale to the end of a tidal breath and then to actuate the MDI, followed by a slow inhalation to vital capacity. The initial dose of each drug was two inhalations from the MDi, separated by 5 min. All subsequent doses were single inhalations at 3O-min intervals to a cumulative maximum of six doses at 2 h (540..,g of albuterol; IOB..,g of ipratropium). A spirometer (Cybermedic PC-JR) was used to measure baseline pulmonary function (FVC; FEV1; FEF25-75%) prior to drug administration. Spirometry was repeated 30 min after inhalation of the initial dose and 30 min after each subsequent dose. An additional measurement was taken 1 h after the last dose (time = 3 h). All pulmonary function tests were performed in duplicate, with the better effort used for reporting purposes. Pulse rate and blood pressure were measured prior to each battery of pulmonary function tests. The patients were queried to ascertain the development of adverse reactions prior to each dose of the test medication. The trial for each subject ended when either
1546
a maximum of six doses had been administered or the subject requested discontinuation of the study due to side effects or increasing respiratory distress. Results of pulmonary function tests for each subject were visually inspected follOwing each drug to identify the highest value achieved (maximum bronchodilator response). The results of pulmonary function testing were calculated as percentage of change relative to baseline and as percentage ofpossible improvement by the following equations: Percentage of change = [(observed - base)/base] x 100 Percentage of possible improvement = [(observed - base)/maximum - base)] x 100 where observed is the postbronchodilator value, base is the baseline value on the day of testing, and maximum is the maximum postbronchodilator value achieved at any time by an individual patient with either drug during the 2-day study period. The latter calculation, as advocated by Weber and co-workers, 17 allows for a more accurate comparison of response between two populations with different baseline pulmonary function. Response expressed as percentage of change from baseline may be misleading in persons with lower baseline function compared to subjects with higher baseline values. Primary variables examined were the maximum increase (percentage of improvement and percentage of possible improvement) in FEV., FVC, and FEF25-75% for each subject after each drug; the time and dose required to achieve maximum improvement; and the area under the curve (AUC) of percentage of possible improvement vs time during the 3-h observation period. This latter variable, calculated by the trapezoidal method, expresses response both as a function of magnitude and duration. The effects of ipratropium and albuterol on pulse and blood pressure were evaluated by assessing the change in these parameters from baseline. Blood pressure is reported as the mean arterial pressure (MAP) calculated as follows: (systolic blood pressure + 2[diastolic blood pressure])/3. The mean and SD for each variable was calculated for both drugs in each age group. Statistical analysis was performed using analysis ofvariance (ANOVA) with post hoc testing between groups applying paired and unpaired two-tailed Studenfs t-tests. A p value of less than 0.05 was considered significant. RESULTS
Nineteen young (mean age, 22 ± 3 yr; 6 men and 13 women) and 17 elderly (mean age, 67 ± 5 yr; 7 men and 10 women) subjects completed the study and are included in the final evaluation. The average weight was 67.8±3.1 kg in the young and 73.0± 16.2 kg in the older group. Two other young and three elderly subjects were also studied, but are not included in the final analysis because they failed to achieve 15 percent reversibility with either of the two study drugs. One additional elderly subject completed one arm of the stud~ but was excluded before the second day as a result of a nonstudy-related injury. The order of drug administration and baseline pulmonary function on both study days are included in Tables 1 and 2. Albuterol was received first in 11 young and 9 elderly subjects. The remaining eight young and eight elderly subjects received ipratropium on the first study day. The mean baseline FEV1 was significantly higher in the young subjects than in the older patients (p<0.05), averaging 2.52 L and 1.29 L, respectively: Effect of AIJ8 on Bronchodilator Response (Kradjan et 81)
Table I-Order of Drug Administration and 8aBeUne FEV. on Day 1 VB Day 2 Group and Subject· Young 101 103 105 106 107 108 109 110 III
112 113 114 115 116 117 118 119 120 121 Mean SD Old 202
203 204 205 206
9JJ7 208 209 211 212 213 214 215 218 219 220 221 Mean SD
FEV.,L
.
Absolute Ipra- Difference, Percent tropium L Differencet
Drug on Day 1
Albuterol
Ipratropium Ipratropium Albuterol Albuterol Ipratropium Albuterol Ipratropium Ipratropium Albuterol Albuterol Ipratropium Albuterol Ipratropium Albuterol Ipratropium Albuterol Albuterol Albuterol Albuterol
2.00 2.10 2.83 1.79 0.54 2.86 2.97 2.84 3.02 1.76 1.89 2.02 3.18 2.18 3.57 2.72 2.83 3.83 2.48 2.50 ±0.74
Albuterol Ipratropium Ipratropium Albuterol Ipratropium Ipratropium Albuterol Ipratropium Albuterol Albuterol Ipratropium Ipratropium Albuterol Albuterol Ipratropium Albuterol Albuterol
1.63 1.50 0.65 0.80 1.24 1.54 0.94 0.88 0.82 0.98 1.04 1.35 1.14 1.27 1.35 1.25 1.03 1.04 1.11 1.22 2.57 2.30 1.36 1.44 2.10 1.98 1.62 1.83 0.62 0.47 1.02 0.94 1.35 1.34 1.27* 1.30* ±0.48 ±0.44
1.76 2.31 3.06 1.93 0.54 2.99 2.92 2.74 2.99 2.02 1.66 2.04 3.20 2.10 3.60 2.89 2.96 3.87 2.77 2.54 ±0.76
0.24 0.21 0.23 0.14 0.0 0.13 0.05 0.10 0.03 0.26 0.23 0.02 0.02 0.08 0.03 0.17 0.13 0.04 0.29 0.13 ±0.08
12.0 9.1 7.5 7.3 0.0 4.3 1.7 3.5 1.0 12.9 12.2 1.0 0.6 3.7 0.8 5.9 4.4 1.0 10.5 5.2 ±4.3
0.13 0.15 0.30 0.06 0.16 0.31 0.13 0.10 0.01 0.11 0.27 0.08 0.12 0.21 0.15 0.08 0.01 0.14 ±0.07
8.0 18.8 19.5 6.4 16.3 23.0 10.2 7.4 1.0 9.0 10.5 5.6 5.7 11.5 24.2 7.8 0.7 10.9 ±6.9
*Two young subjects (102 and 104) and three older subjects (201,
210, and 217) are not listed because they failed to demonstrate 15 percent reversibility with either drug. Subject 216 is not included because of inability to participate in second study day for personal reasons. tPercentage of difference calculated as: (highest observed valuelowest observed value)/highest observed value. elderly subjects with greater than 15 percent variability in baseline between study days are dropped (203, 204, 206, 207, and 219) mean baseline after albuterol is 1.44 ± 0.47 L, and mean baseline after ipratropium is 1.42±0.41 L, with average of only 7.2± 1.6 percent variability in percent difference.
*1£
For individual young subjects, baseline values for FEV. were relatively constant between the two study days, the largest difference being 12.9 percent (Table 1).
There was more variability in baseline values for the older subjects, averaging 10.9 percent, with five subjects having more than a 15 percent difference. The correctiQ~,: for percentage of possible improvement helps to'minimize the influence of this variability in baseline on the analysis of reversibility; however, to further correct for these differences, the results from the elderly subjects are reported both in terms of the 17 subjects who demonstrated reversibility with at least one of the drugs and again after deleting the five subjects who had a large variability in baseline FEV•. The pulse and MAP were higher at baseline in the elderly, as compared to the young, but these differences were not significantly different (Table 3). All evaluable subjects in both age groups were able to tolerate all six doses of ipratropium, while two of the young subjects and one elderly subject had to stop the study prematurely secondary to side effects after receiving albuterol. Table 2 summarizes the pertinent mean pulmonary function data for each study group. Overall, more subjects responded to albuterol than to ipratropium. Seven (37 percent) of the young and 12 (71 percent) of the older patients had a greater than 15 percent improvement in FEV. with both drugs. Nine young subjects showed reversibility only after albuterol, and three responded only to ipratropium. For the elderly, five subjects had reversibility only after albuterol, and none responded solely to ipratropium. These results are consistent with previous experience that p-agonists are more effective than anticholinergics in asthmatic patients. Figure 1 compares the means ofthe maximum response for FEV. in each treated group expressed as percentage change from baseline. Two differences are noted when evaluating these data. First, the maximum response after albuterol is significantly greater than that after ipratropium in both age groups (p
1547
Table i-Pulmonary Function 1lm Summary· Young Test FEV, Baseline, Lt Maximum percentage ofchange from baselineUIl Percent possible improvement AUC, h'percentUIl TIme to maximum improvement, h,·· FVC Baseline, Lt Maximum percentage ofchange from baselineUlitUt Percent possible improvement AUe, h'percentUlltt TIme to maximum improvement, h,"
Albuterol
Ipratropium
Albuterol
Ipratropium
2.50±0.76 4O.1±29.2 199.4±60.9 2.2±0.7
2.54±0.78 21.2±14.0 122.0±72.0 1.7±0.7
1.27 ± O.50U 6O.5±48.3U 216.7±49.6§§ 2.0±0.7
1.30±O.45U 31.2 ±28.0§§ 121.1 ± 115.8§§ 1.6±0.9
2.02±0.60 49.1±33.1 210.5±47.2 2.1 ±0.6
2.07 ± 0.55 26.3±22.8 IOS.7 ± 121.8 1.4±0.7
0.87±0.65 75.8 ± 68.3 153.8± 10fl.8 2.2±0.8
0.84±0.54 45.0 ± 35.5 117.6±90.8 1.8±0.9
3.60±0.87 21.4±20.2 143.2± 116.9 2.1± 1.0
FEF25-75~
Baseline, Usect Maximum percentage ofchange from baselineUIl Percent possible improvement AUe, h'percentU TIme to maximum improvement, h,··
Old
3.67±0.91 12.8± 15.5 36.3±183.8 1.8±0.8
1.95±0.85 86.7±57.5 202.2±45.5 2.4±0.6
2.00±0.93 42.8±23.0 126.2 ± 85.4 1.8±0.8
·Values are given as means ± SD. tpO.OS (no significant difference). ••Assuming that maximum response occurs 0.5 h after last dose, peale at 0.5 h is equivalent to two puftS of MDI; 1 h = three puffs; 1.5 h = four puftS; 2 h = five puffs; and 2.5 h = six puffs. Also observed at 3 h, equivalent to 1 h after last dose (maximum of six puftS). ttp
difference in baseline FEV. are deleted. For the 12 remaining subjects, the maximum percentage of change from baseline decreases to 44.1 percent after albuterol and 25.9 percent after ipratropium. Interestingly, deleting these subjects does not change the mean calculated AUC for percentage of possible improvement (see Table 2, last footnote). Table 3-Blood Preaure and PtJ.e EffectYoung Characteristic Albuterol Ipratropium
Old Albuterol
MAP Baseline, 87.7±7.5 86.32 ± 6.45 101.6±8.1 mmHg No. with 4 3 0 rise· No. with 4 3 drop· Pulse 71.6±8.3 72.2±8.8 79.8±8.8 Baseline, beats per min No. with 2 riset 2 No. with 3 5 dropt ·Rise or drop of more than 10 mm Hg. tRise or drop of more than 10 beats per min.
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The changes in FVC and FEF25-75% were similar to those observed in FEV. with the following exceptions: FVC was the only pulmonary function test that showed statistically different age-related changes, with the elderly having a greater maximum change after albuterol (p =0.006) and ipratropium (p =0.049), compared to younger subjects. These differences retain 120
Ipratropium
, chanaa
110 100
aD
98.3±7.5
80
0
80
2
70 50 40 30
74.1±4.5
20 10
o 5
Yt chino- • (obi .. Hal) I
be,.
F.CURE 1. Maximum percentage of change in FEV, (mean ± SD) in young and older subjects following albuterol and ipratropium. Single aaterlsk indicates p
AUC (hr ,,)
::f 200
150 100 50
o
'/bung Ilbu'-rol
'/bung Iprllroplulll
Old Ilbullrol
Old Iprltroplulll
.. pOI· (obi - b..ll/lblll-b..11
FIGURE 2. Change in FEV, (mean ± SD) in young and older subjects following a1buterol and ipratropium, expressed as area under response curve (AUe) from time zero to 3 h for percentage of possible improvement. Single asterisk indicates p
statistical significance for albuterol (p =0.039), but not for ipratropium, after correction for baseline differences between age groups and after deleting the five elderly subjects with the highest baseline variability. Analysis for ipratropium was complicated by 4 of the 19 young subjects having worsening of FVC values after ipratropium, resulting in a low mean value and a large SO. With FEF25-75%, the greater response to a1buterol, compared to ipratropium, for maximum percentage of change from baseline remained statistically significant only in the young subjects (p =0.005). After correcting for percentage of possible improvement, there were no age-related differences detected by FEF25-75% analysis, while a greater response to albuterol over ipratropium was seen in the young (p =0.003). Observation of the time and dose required to achieve maximum improvement in FEV I (Table 1) 100 80 80 . ·G
%
..•.......
40
20
..... :::::::::::::::::~
······8
DISCUSSION .................•. .
'G"
;:".
Time (hr)
• • • • •
Otl----'-----'-----'-----'-------'----'
o
0.5
1
1.6
revealed a trend for a faster response and a lower dosage requirement (number of puffs) for ipratropium in both age groups, but the differences were not statistically significant. When comparing the young to the elderly, there were no age-related differences in the time or dose required to achieve maximum bronchodilator effect with either drug. There were similar trends in FVC and FEF25-75%, but none of the differences was statistically significant. Simply looking at the mean time to maximum response does not give a full appreciation for the time of onset after each drug, since there is wide variability in time to maximum response among the four groups. Moreover, 80 percent ofthe maximum response was usually between 0.5 to 1 h (two to three puffs) in all groups. This is illustrated by Figure 3, which shows that the initial response to the bronchodilator was curvilinear, with the greatest change occurring after the initial treatment. The cardiovascular effects were highly variable within subjects. Table 3 shows the number of patients who had an increase or decrease of more than 10 mm Hg in MAP or an increase or decrease of greater than 10 beats per minute in pulse rate. Generally, the pulse rate tended to decrease after albuterol in both age groups and after ipratropium in the young while it increased after ipratropium in the elderly. The results for MAP were highly variable among the study participants. One elderly subject complained of shortness of breath with ipratropium. Conversely, four subjects in the young group and four in the elderly population complained of side effects with albuterol. The side effects reported include shakiness (four), dry mouth (one), headache (one), cough (one), and nausea (one). Two young subjects stopped the study prematurely after two and four doses of albuterol secondary to headache and cough, respectively; while one elderly subject stopped after the third dose of albuterol with a complaint of shakiness.
2
....... '/bung. Ilbu'-,ol
..•.
-e- old. Ilbu.'ol
·G·· old.lp'llroplulIl
2.5
3
""un.. Ipra'tOplu",
.. pOI· (Obi - b..I)llblll - blill
FIGURE 3. Percentage of possible improvement in FEV, (mean ± SD) vs time from baseline to 3 h follOwing increasing doses of a1buterol (solid lines) and ipratropium (dotted lines) in young (asterisks) and older (boxes) asthmatic subjects. Arrows indicate time of dosing (2 MOl puffs at time 0 and one puff thereafter). obs = Observed.
We found no age-related differences in either the magnitude of response or in the time and dose required to reach peak effect following either drug, indicating that the elderly patients were not less responsive to either drug compared to the young. The magnitude of response should be greater for albuterol in the young and for ipratropium in the elderly if agerelated differences are present that affect the balance between adrenergic and cholinergic responses. The differential response to ipratropium and a1buterol (salbutamol) was found to be positively correlated to age by Ullah and colleagues,15 with subjects greater than 40 yr of age exhibiting a greater response to ipratropium and subjects less than 40 yr of age CHEST I 101 I 6 I JUNE, 1992
1548
demonstrating a greater response to albuterol. Furthermore, albuterol has been shown to be more effective in asthmatic subjects, while ipratropium has been found to be more effective in patients with COPD.8.18 The differential response seen in these two disease states may be related to the fact that asthmatic patients are typically young, while patients with COPD are typically older. The magnitude ofeffect was assessed by two factors in the present study: maximum response and AUC for percentage ofpossible improvement. When evaluating the maximum percentage of change from baseline in FEV1, there was a statistically greater response to albuterol than to ipratropium in both age groups. The greatest response (60.5 percent ± 48.3 percent) was seen after albuterol in the elderly subjects; however, these results must be interpreted with caution, as the elderly had lower and more variable baseline values for pulmonary function. Several studies have shown that the degree ofimprovement in pulmonary function is directly related to the amount of airflow obstruction. 19.!O Therefore, we adjusted our method of assessment by calculating the AUC for the percentage of possible improvement in FEV., which corrects for changes among groups in baseline pulmonary function. With this correction, we were unable to show a significant difference between the groups with respect to age, while the statistically greater response to albuterol compared to ipratropium within age groups remained. These conclusions are unchanged after dropping the elderly subjects with high variability in baseline function between study days from the final analysis. Thus, our results do not substantiate the premise that the elderly have a greater response to ipratropium compared to albuterol, or that the elderly have a lower response to albuterol compared to young subjects, further refuting the hypothesis that elderly subjects have a loss of ~-receptors in the lung. The results of FEF25-75% data parallel the FEV. data for magnitude of response, again showing no agerelated differences. Only the FVC data revealed a possible difference between age groups, with a statistically greater percentage of change from baseline occurring after both albuterol and ipratropium in the elderly compared to the young. The differences remained significant only for albuterol after correcting for the percent possible improvement and baseline variabili~ The reason for these differences for FVC are not readily explainable and are opposite what had been predicted. In an attempt to determine if age differences in response are present, it is important to look at the time and dose required to reach peak effect. If pulmonary responses are blunted with age as they are in cardiac tissue, either a slower response or the requirement for larger doses would be expected to 1550
reach the same magnitude of response in young vs elderly subjects. This has been demonstrated in the cardiovascular system with higher doses of isoproterenol or propranolol required in elderly subjects to produce the same degree of change in heart rate as in young subjects. 9 Interestingly, there was a nonsignificant trend for the time and dose required to achieve maximum bronchodilator effect for FEV 1 to be greater for albuterol than for ipratropium in both age groups; however, the maximum response obtained was always greater for albuterol compared to ipratropium in both age groups. Both groups may have responded with a lower number ofpuffs after ipratropium than albuterol because ofdifferences in dose equivalency for the two drugs. Other investigators have reported the dose required to produce maximum increases in pulmonary function tests for these two drugs as 40"",g to 80"",g for ipratropium and BOOJLg for a1buterol. R By this ratio, it would require two to four puffs of ipratropium (18JLg per pufl) vs eight puffs of a1buterol (90"",g per puff) to reach maximum effect. We compared one puff of ipratropium to one puff of albuterol, so the dose to produce a maximum change in FEV 1 might theoretically have been achieved with fewer puffs of ipratropium. Although comparison of the number of puffs may not accurately reflect differences in efficacy for these two drugs, it does help establish the fact that there are no age-related differences in the time and dose ofeach drug required to achieve maximum effect. Therefore, blunting of the ~-adrenergic system was not apparent in our population with increasing age. The effect of both drugs on MAP and pulse were insignificant. Interestingl~ the pulse tended to decrease in all groups except the elderly after ipratropium. Anticholinergics and ~-agonists would be expected to increase the pulse rate; however, it was noted that most study participants were short ofbreath at the beginning of the study and anxious secondary to moderate respiratory distress. The effect of the drugs may have decreased their anxiety, with resultant decreases in pulse rate. Additionally, the ability to tolerate ipratropium was superior to albuterol in this stud): Eight subjects complained of side effects with albuterol, compared to only one subject with ipratropium. CONCLUSION
Asthmatic patients generally have a greater response and quicker onset of action to ~2-agonists. Our population followed this pattern, with a greater magnitude of response to albuterol compared to ipratropium within age groups; however, no statistically significant differences between age groups were seen. The time and dose required to achieve maximum bronchodilator effect was less for ipratropium than albuterol, although Effect of Age on Bronchodilator Response (Kradjan et 8/)
this probably reflects the fact that equivalent doses were not used; however, the concern over a decrease in the number or responsiveness of p-receptors in the lung with age does not appear to be app~ntcUnicall~ as no age-related differences in the magnitude of response or the time and dose required to achieve maximum response were found in this stud)'. Both anticholinergics and p-agonists are effective bronchodilators in young and elderly asthmatic subjects, and we found that age is not a predictor of response to either drug. REFERENCES 1 Barnes PJ, Basbaum CD, Nael JA. Autoradiographic localization of autonomic receptors in airway smooth muscle: marked differences between large and small airways. Am Rev Respir Dis 1983; 127:758-62 2 Ruffin RE, Fitzgerald JD, Rebuck AS. A comparison of the bronchodilator activity of Sch 1000 and salbutamol. J Allergy Coo Immunol1977; 59:139-41 3 Gross NJ, Skorodin MS. Anticholinergic, antimuscarinic bronchodilators. Am Rev Respir Dis 1984; 129:856-70 4 Gross N. Ipratropium bromide. N Engl J Moo 1988; 319:48694
5 Gross N, Skorodin MS. Role of the parasympathetic system in airway obstruction due to emphysema. N Engl J Moo 1984; 311:421-25 6 Storms ~ Bodman S, Nathan R, Busse ~ Bush R, Falliers C, et ale Use ofipratropium bromide in asthma. Am J Moo 1986; 81(suppl 5A):61-5 7 Mollio M, Benzaray S, Lidji M, Karasik A, Steir S, Baum GL. Salbutamol versus atropine: site of bronchodilation in asthmatic patients. Respiration 1987; 51:26-34 8 Easton ~ Jadue C, Dhingra S, Anthonisen NR. A comparison of the bronchodilating effects of a beta-2 adrenergic agent (albuterol) and an anticholinergic agent (ipratropium bromide) given by aerosol alone or in sequence. N Engl J Moo 1986; 315:
735-39 9 Vestal RE, Wood AJ, Shand DG. Reduced beta adrenoreceptor sensitivity in the elderly. Clin Pharmacol Ther 1979; 26;181-86 10 Barnes R, Raskind M, Gumbrecht G, Halter J. The effects of age~ on ·the plasma catecholamine response to mental stress in man. J Clio Endocrinol Metab 1982; 54:64-9 11 Saar N, Gordon R. Variability of plasma catecholamine levels: age, posture, and time of da~ Br J Clio Phannacoll979; 8:35358 12 Rowe J, Troen B. Sympathetic nervous system and aging in man. Endocrinol Rev 1980; 1:167-78 13 Buehler F, Kiowski ~ Van Brummelen ~ Amann ~ Bertel 0, Landmann R, et ale Plasma catecholamines and cardiac, renal and peripheral vascular adrenoreceptor-mediated responses in different age groups of normal and hypertensive men. Clin Exp Hypertension 1980; 2:409-26 14 Klein C, Hiatt ~ Gerber G, Nies A. The balance between vascular alpha and beta adrenoreceptors is not changed in the elderl~ Clio Phannacol Ther 1987; 42:260-64 15 Ullah M, Newman GB, Saunders IeB. InHuence of age on respon$e to ipratropium and salbutamol in asthma. Thorax 1981; 36:523-29 16 American Thoracic Socie~ Statement by the committee on diagnostic standards for nontuberculous respiratory diseases: definitions and classifications of chronic bronchitis, asthma, and pulmonary emphysema. Am Rev Respir Dis 1962; 85:762 17 Weber ~ Petty WE, Nelson HS. Aerosolized terbutaline in asthmatics. J Allergy Clio Immuno11979; 63:116-21 18 Tashkin D~ Ashutosh Ie, Bleecker ER, James Britt E, Cugell D~ Cummiskey JM, et ale Comparison of the anticholinergic bronchodilator ipratropium bromide with metaproterenol in chronic obstructive pulmonary disease. Am J Moo 1986; 81 (suppl 5A):81-90 19 Rebuck A, Chapman Ie, Abboud R, Pare PD, Kreisman H, Wolkove N, et ale Nebulized anticholinergic and sympathomimetic treatment of asthma and chronic obstructive airways disease in the emergency room. Am J Med 1987; 82:59-64 20 Braun SR, McKenzie WN, Copeland C. A comparison of the effect of ipratropium and albuterol in the treatment of chronic obstructive airway disease. Arch Intern Med 1989; 149:544
CHEST I 101 I 6 I JUNE. 1992
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Study Objective: Our objective was to compare the differential effects of age and drug type on bronchodilator response. Design: The design was an unblinded, randomized crossover study. Setting: An ambulatory pulmonary drug study unit was the setting. Patienta: Nineteen young (18 to 25 yr) and 17 elderly (>65 yr) stable asthmatic subjects were studied. Interventions and MeaBUrement8: A1buterol or ipratropium was given on two separate mornings using an MDI with extender. Subjects inhaled two puffs initially and then one puffevery 30 min to a total of six puffs. Pulmonary function, blood pressure, and pulse were measured at baseline and every 30 min for 3 h. Haults: All subjects had a greater than 15 percent increase in FEV. with one or both drugs. More patients responded to a1buterol than to ipratropium in both age groups. The maximum percentage of change from baseline was greater (p
young; 31.2 percent in old) in both groups. These differences remain significant after correction for baseline differences using area-under-the-curve analysis of the percent of maximum improvement; however, the differences between age groups for the same drug were not statistically significant by either index of change. There were also no differences between drugs or between age groups for time (or number of puffs) to reach maximum improvement (mean, 2.0 to 2.2 h for albuterol and 1.6 to 1.7 h for ipratropium). The changes in FVC and FEF25-75% were similar to FEV•. Changes in blood pressure and pulse were not significant. Three subjects stopped therapy with albuterol with side effects. Conclmiona: Both drugs are effective bronchodilators in young and old asthmatic subjects, but albuterol results in a greater magnitude of response in both age groups. Age is not a predictor of response to either drug. (Chest 1992; 101:1545-51)
agonists and anticholinergics are both indicated for use as bronchodilators in patients with reversible obstructive lung disease. Be~-agonists act primarily to dilate small-diameter airways and are more effective than anticholinergics in the treatment of asthma. 1.2 Conversely, anticholinergic drugs may preferentially dilate larger airways and are often more effective in treating patients with chronic obstructive pulmonary disease (COPD) complicated by emphysema or bronchitis (or both);3-6 however, these differences are not universally accepted. 7 .8 Generalities of superiority of one drug vs another in various patient groups is complicated by a number of factors because COPD is a heterogeneous disease and is thus difficult to characterize as a single patient group. Since neither emphysema nor bronchitis has a reversible component, patients with COPD who re-
spond to a bronchodilator must have an underlying asthmatic component to their disease. Additionally, within any group, individual patients will demonstrate one of several patterns. Some will respond equally well to both drugs, others will clearly have a better response to either a ~2-adrenergic agonist or an anticholinergic, and still others will show additive responses when the two drugs are used together. One variable that has not been fully explored when differentiating bronchodilator response is the effect of age on sympathetic and cholinergic actions in the lung. There is evidence from several cardiovascular studies that the activity of the adrenergic system is blunted with age.9-14 For instance, responsiveness to isoproterenol and propranolol in the elderly is decreased; however, the effects of age on pulmonary ~-adrenergic receptors is unknown. If a similar blunting of response occurs in the lung, it might be postulated that the differing bronchodilator responses in asthmatic patients (who are often young) and in patients with COPD who have emphysema (who are typically older) may be related to age and not disease. If this is true, older subjects may require increased doses of sympathomimetics, compared to anticholinergic bronchodilators, to obtain maximal bronchodilatory response. Whether such age-related differences
Bet~-adrenergiC
*From the Division of Pulmonary and Critical Care Medicine, Department of Medicine, and the Department of Pharmacy Practice, University of Washington Schools of Pharmacy and Medicine, and the Department of Pulmonary and Clinical Care Medicine, Harborview Medical Center, Seattle. Supported in part by a gift from the Schering Corp., Kenilworth,
NJ.
Manuscript received June 24; revision accepted September 12. Reprint requests: Dr. Kradjan, Department of Pharmacy Practice, University ofWashington, Seattw 98195
AVC = area under the curve; CRC = Clinical Research Center; MAP mean arterial pressure; MDI metered-dose inhaler
=
=
CHEST I 101 I 6 I JUNE, 1992
1545
also occur in cholinergic responses is less well defined. It has been postulated that the atropine-like effect for bronchodilation remains constant with advancing age, further supporting the premise that ipratropium may be more effective than albuterol in elderly subjects. 15 This study was undertaken to evaluate the effects of age on bronchodilator response to albuterol (a pi-agonist) and ipratropium (an anticholinergic) in asthmatic patients. Specifically, the study identified and compared the time and dose required to achieve maximum bronchodilator response, and the magnitude ofthe maximum bronchodilator response for both drugs in young and elderly asthmatic patients. Our hypotheses to be tested were that (1) maximum bronchodilation is equal after ~-agonists and anticholinergics within age groups, (2) young subjects require smaller doses of p-agonists to reach maximum bronchodilation than do elderly subjects, and (3) responses to ipratropium are either unaffected by age or increased in the elderly population. MATERIALS AND METHODS
Using age as the major criterion, we recruited two populations of otherwise health~ stable asthmatic patients.. Group 1 consisted of 21 young adults aged 18 to 25 yr, and group 2 was 20 elderly patients over the age of 60 yr. Admission to the study required a diagnosis of asthma as defined by the criteria of the American Thoracic Society18 and at least a 15 percent reversibility in FEV1after either albuterol or ipratropium. Criteria for exclusion included a history of emphysema, bronchitis, other acute or chronic pulmonary disorders, hypertension, cardiac arrhythmias, unstable angina, or other significant cardiovascular diseases. Those with a history of tobacco use for a sustained period of time during their life or exposure to hazardous fumes were also excluded. Long-acting theophylline products were withheld 24 h before each study da~ and p-agonists or anticholinergics were withheld from midnight on each study da~ The study was approved by the institutions review board, and informed consent was obtained from all participants. The study followed an unblinded, randomized crossover design. The subjects reported to the pulmonary drug study unit at approximately 9 AM each study day. On the first da~ subjects were randomized to receive either albuterol (Proventil; 9O..,g per pufI) or ipratropium bromide (Atrovent; 18..,g per puft) as the initial drug, followed by the alternate drug on day 2. Commercially available MDls fitted with a spacer device (Aerochamber) were used for administration of both drugs. Subjects were instructed to exhale to the end of a tidal breath and then to actuate the MDI, followed by a slow inhalation to vital capacity. The initial dose of each drug was two inhalations from the MDi, separated by 5 min. All subsequent doses were single inhalations at 3O-min intervals to a cumulative maximum of six doses at 2 h (540..,g of albuterol; IOB..,g of ipratropium). A spirometer (Cybermedic PC-JR) was used to measure baseline pulmonary function (FVC; FEV1; FEF25-75%) prior to drug administration. Spirometry was repeated 30 min after inhalation of the initial dose and 30 min after each subsequent dose. An additional measurement was taken 1 h after the last dose (time = 3 h). All pulmonary function tests were performed in duplicate, with the better effort used for reporting purposes. Pulse rate and blood pressure were measured prior to each battery of pulmonary function tests. The patients were queried to ascertain the development of adverse reactions prior to each dose of the test medication. The trial for each subject ended when either
1546
a maximum of six doses had been administered or the subject requested discontinuation of the study due to side effects or increasing respiratory distress. Results of pulmonary function tests for each subject were visually inspected follOwing each drug to identify the highest value achieved (maximum bronchodilator response). The results of pulmonary function testing were calculated as percentage of change relative to baseline and as percentage ofpossible improvement by the following equations: Percentage of change = [(observed - base)/base] x 100 Percentage of possible improvement = [(observed - base)/maximum - base)] x 100 where observed is the postbronchodilator value, base is the baseline value on the day of testing, and maximum is the maximum postbronchodilator value achieved at any time by an individual patient with either drug during the 2-day study period. The latter calculation, as advocated by Weber and co-workers, 17 allows for a more accurate comparison of response between two populations with different baseline pulmonary function. Response expressed as percentage of change from baseline may be misleading in persons with lower baseline function compared to subjects with higher baseline values. Primary variables examined were the maximum increase (percentage of improvement and percentage of possible improvement) in FEV., FVC, and FEF25-75% for each subject after each drug; the time and dose required to achieve maximum improvement; and the area under the curve (AUC) of percentage of possible improvement vs time during the 3-h observation period. This latter variable, calculated by the trapezoidal method, expresses response both as a function of magnitude and duration. The effects of ipratropium and albuterol on pulse and blood pressure were evaluated by assessing the change in these parameters from baseline. Blood pressure is reported as the mean arterial pressure (MAP) calculated as follows: (systolic blood pressure + 2[diastolic blood pressure])/3. The mean and SD for each variable was calculated for both drugs in each age group. Statistical analysis was performed using analysis ofvariance (ANOVA) with post hoc testing between groups applying paired and unpaired two-tailed Studenfs t-tests. A p value of less than 0.05 was considered significant. RESULTS
Nineteen young (mean age, 22 ± 3 yr; 6 men and 13 women) and 17 elderly (mean age, 67 ± 5 yr; 7 men and 10 women) subjects completed the study and are included in the final evaluation. The average weight was 67.8±3.1 kg in the young and 73.0± 16.2 kg in the older group. Two other young and three elderly subjects were also studied, but are not included in the final analysis because they failed to achieve 15 percent reversibility with either of the two study drugs. One additional elderly subject completed one arm of the stud~ but was excluded before the second day as a result of a nonstudy-related injury. The order of drug administration and baseline pulmonary function on both study days are included in Tables 1 and 2. Albuterol was received first in 11 young and 9 elderly subjects. The remaining eight young and eight elderly subjects received ipratropium on the first study day. The mean baseline FEV1 was significantly higher in the young subjects than in the older patients (p<0.05), averaging 2.52 L and 1.29 L, respectively: Effect of AIJ8 on Bronchodilator Response (Kradjan et 81)
Table I-Order of Drug Administration and 8aBeUne FEV. on Day 1 VB Day 2 Group and Subject· Young 101 103 105 106 107 108 109 110 III
112 113 114 115 116 117 118 119 120 121 Mean SD Old 202
203 204 205 206
9JJ7 208 209 211 212 213 214 215 218 219 220 221 Mean SD
FEV.,L
.
Absolute Ipra- Difference, Percent tropium L Differencet
Drug on Day 1
Albuterol
Ipratropium Ipratropium Albuterol Albuterol Ipratropium Albuterol Ipratropium Ipratropium Albuterol Albuterol Ipratropium Albuterol Ipratropium Albuterol Ipratropium Albuterol Albuterol Albuterol Albuterol
2.00 2.10 2.83 1.79 0.54 2.86 2.97 2.84 3.02 1.76 1.89 2.02 3.18 2.18 3.57 2.72 2.83 3.83 2.48 2.50 ±0.74
Albuterol Ipratropium Ipratropium Albuterol Ipratropium Ipratropium Albuterol Ipratropium Albuterol Albuterol Ipratropium Ipratropium Albuterol Albuterol Ipratropium Albuterol Albuterol
1.63 1.50 0.65 0.80 1.24 1.54 0.94 0.88 0.82 0.98 1.04 1.35 1.14 1.27 1.35 1.25 1.03 1.04 1.11 1.22 2.57 2.30 1.36 1.44 2.10 1.98 1.62 1.83 0.62 0.47 1.02 0.94 1.35 1.34 1.27* 1.30* ±0.48 ±0.44
1.76 2.31 3.06 1.93 0.54 2.99 2.92 2.74 2.99 2.02 1.66 2.04 3.20 2.10 3.60 2.89 2.96 3.87 2.77 2.54 ±0.76
0.24 0.21 0.23 0.14 0.0 0.13 0.05 0.10 0.03 0.26 0.23 0.02 0.02 0.08 0.03 0.17 0.13 0.04 0.29 0.13 ±0.08
12.0 9.1 7.5 7.3 0.0 4.3 1.7 3.5 1.0 12.9 12.2 1.0 0.6 3.7 0.8 5.9 4.4 1.0 10.5 5.2 ±4.3
0.13 0.15 0.30 0.06 0.16 0.31 0.13 0.10 0.01 0.11 0.27 0.08 0.12 0.21 0.15 0.08 0.01 0.14 ±0.07
8.0 18.8 19.5 6.4 16.3 23.0 10.2 7.4 1.0 9.0 10.5 5.6 5.7 11.5 24.2 7.8 0.7 10.9 ±6.9
*Two young subjects (102 and 104) and three older subjects (201,
210, and 217) are not listed because they failed to demonstrate 15 percent reversibility with either drug. Subject 216 is not included because of inability to participate in second study day for personal reasons. tPercentage of difference calculated as: (highest observed valuelowest observed value)/highest observed value. elderly subjects with greater than 15 percent variability in baseline between study days are dropped (203, 204, 206, 207, and 219) mean baseline after albuterol is 1.44 ± 0.47 L, and mean baseline after ipratropium is 1.42±0.41 L, with average of only 7.2± 1.6 percent variability in percent difference.
*1£
For individual young subjects, baseline values for FEV. were relatively constant between the two study days, the largest difference being 12.9 percent (Table 1).
There was more variability in baseline values for the older subjects, averaging 10.9 percent, with five subjects having more than a 15 percent difference. The correctiQ~,: for percentage of possible improvement helps to'minimize the influence of this variability in baseline on the analysis of reversibility; however, to further correct for these differences, the results from the elderly subjects are reported both in terms of the 17 subjects who demonstrated reversibility with at least one of the drugs and again after deleting the five subjects who had a large variability in baseline FEV•. The pulse and MAP were higher at baseline in the elderly, as compared to the young, but these differences were not significantly different (Table 3). All evaluable subjects in both age groups were able to tolerate all six doses of ipratropium, while two of the young subjects and one elderly subject had to stop the study prematurely secondary to side effects after receiving albuterol. Table 2 summarizes the pertinent mean pulmonary function data for each study group. Overall, more subjects responded to albuterol than to ipratropium. Seven (37 percent) of the young and 12 (71 percent) of the older patients had a greater than 15 percent improvement in FEV. with both drugs. Nine young subjects showed reversibility only after albuterol, and three responded only to ipratropium. For the elderly, five subjects had reversibility only after albuterol, and none responded solely to ipratropium. These results are consistent with previous experience that p-agonists are more effective than anticholinergics in asthmatic patients. Figure 1 compares the means ofthe maximum response for FEV. in each treated group expressed as percentage change from baseline. Two differences are noted when evaluating these data. First, the maximum response after albuterol is significantly greater than that after ipratropium in both age groups (p
1547
Table i-Pulmonary Function 1lm Summary· Young Test FEV, Baseline, Lt Maximum percentage ofchange from baselineUIl Percent possible improvement AUC, h'percentUIl TIme to maximum improvement, h,·· FVC Baseline, Lt Maximum percentage ofchange from baselineUlitUt Percent possible improvement AUe, h'percentUlltt TIme to maximum improvement, h,"
Albuterol
Ipratropium
Albuterol
Ipratropium
2.50±0.76 4O.1±29.2 199.4±60.9 2.2±0.7
2.54±0.78 21.2±14.0 122.0±72.0 1.7±0.7
1.27 ± O.50U 6O.5±48.3U 216.7±49.6§§ 2.0±0.7
1.30±O.45U 31.2 ±28.0§§ 121.1 ± 115.8§§ 1.6±0.9
2.02±0.60 49.1±33.1 210.5±47.2 2.1 ±0.6
2.07 ± 0.55 26.3±22.8 IOS.7 ± 121.8 1.4±0.7
0.87±0.65 75.8 ± 68.3 153.8± 10fl.8 2.2±0.8
0.84±0.54 45.0 ± 35.5 117.6±90.8 1.8±0.9
3.60±0.87 21.4±20.2 143.2± 116.9 2.1± 1.0
FEF25-75~
Baseline, Usect Maximum percentage ofchange from baselineUIl Percent possible improvement AUe, h'percentU TIme to maximum improvement, h,··
Old
3.67±0.91 12.8± 15.5 36.3±183.8 1.8±0.8
1.95±0.85 86.7±57.5 202.2±45.5 2.4±0.6
2.00±0.93 42.8±23.0 126.2 ± 85.4 1.8±0.8
·Values are given as means ± SD. tp
difference in baseline FEV. are deleted. For the 12 remaining subjects, the maximum percentage of change from baseline decreases to 44.1 percent after albuterol and 25.9 percent after ipratropium. Interestingly, deleting these subjects does not change the mean calculated AUC for percentage of possible improvement (see Table 2, last footnote). Table 3-Blood Preaure and PtJ.e EffectYoung Characteristic Albuterol Ipratropium
Old Albuterol
MAP Baseline, 87.7±7.5 86.32 ± 6.45 101.6±8.1 mmHg No. with 4 3 0 rise· No. with 4 3 drop· Pulse 71.6±8.3 72.2±8.8 79.8±8.8 Baseline, beats per min No. with 2 riset 2 No. with 3 5 dropt ·Rise or drop of more than 10 mm Hg. tRise or drop of more than 10 beats per min.
1548
The changes in FVC and FEF25-75% were similar to those observed in FEV. with the following exceptions: FVC was the only pulmonary function test that showed statistically different age-related changes, with the elderly having a greater maximum change after albuterol (p =0.006) and ipratropium (p =0.049), compared to younger subjects. These differences retain 120
Ipratropium
, chanaa
110 100
aD
98.3±7.5
80
0
80
2
70 50 40 30
74.1±4.5
20 10
o 5
Yt chino- • (obi .. Hal) I
be,.
F.CURE 1. Maximum percentage of change in FEV, (mean ± SD) in young and older subjects following albuterol and ipratropium. Single aaterlsk indicates p
AUC (hr ,,)
::f 200
150 100 50
o
'/bung Ilbu'-rol
'/bung Iprllroplulll
Old Ilbullrol
Old Iprltroplulll
.. pOI· (obi - b..ll/lblll-b..11
FIGURE 2. Change in FEV, (mean ± SD) in young and older subjects following a1buterol and ipratropium, expressed as area under response curve (AUe) from time zero to 3 h for percentage of possible improvement. Single asterisk indicates p
statistical significance for albuterol (p =0.039), but not for ipratropium, after correction for baseline differences between age groups and after deleting the five elderly subjects with the highest baseline variability. Analysis for ipratropium was complicated by 4 of the 19 young subjects having worsening of FVC values after ipratropium, resulting in a low mean value and a large SO. With FEF25-75%, the greater response to a1buterol, compared to ipratropium, for maximum percentage of change from baseline remained statistically significant only in the young subjects (p =0.005). After correcting for percentage of possible improvement, there were no age-related differences detected by FEF25-75% analysis, while a greater response to albuterol over ipratropium was seen in the young (p =0.003). Observation of the time and dose required to achieve maximum improvement in FEV I (Table 1) 100 80 80 . ·G
%
..•.......
40
20
..... :::::::::::::::::~
······8
DISCUSSION .................•. .
'G"
;:".
Time (hr)
• • • • •
Otl----'-----'-----'-----'-------'----'
o
0.5
1
1.6
revealed a trend for a faster response and a lower dosage requirement (number of puffs) for ipratropium in both age groups, but the differences were not statistically significant. When comparing the young to the elderly, there were no age-related differences in the time or dose required to achieve maximum bronchodilator effect with either drug. There were similar trends in FVC and FEF25-75%, but none of the differences was statistically significant. Simply looking at the mean time to maximum response does not give a full appreciation for the time of onset after each drug, since there is wide variability in time to maximum response among the four groups. Moreover, 80 percent ofthe maximum response was usually between 0.5 to 1 h (two to three puffs) in all groups. This is illustrated by Figure 3, which shows that the initial response to the bronchodilator was curvilinear, with the greatest change occurring after the initial treatment. The cardiovascular effects were highly variable within subjects. Table 3 shows the number of patients who had an increase or decrease of more than 10 mm Hg in MAP or an increase or decrease of greater than 10 beats per minute in pulse rate. Generally, the pulse rate tended to decrease after albuterol in both age groups and after ipratropium in the young while it increased after ipratropium in the elderly. The results for MAP were highly variable among the study participants. One elderly subject complained of shortness of breath with ipratropium. Conversely, four subjects in the young group and four in the elderly population complained of side effects with albuterol. The side effects reported include shakiness (four), dry mouth (one), headache (one), cough (one), and nausea (one). Two young subjects stopped the study prematurely after two and four doses of albuterol secondary to headache and cough, respectively; while one elderly subject stopped after the third dose of albuterol with a complaint of shakiness.
2
....... '/bung. Ilbu'-,ol
..•.
-e- old. Ilbu.'ol
·G·· old.lp'llroplulIl
2.5
3
""un.. Ipra'tOplu",
.. pOI· (Obi - b..I)llblll - blill
FIGURE 3. Percentage of possible improvement in FEV, (mean ± SD) vs time from baseline to 3 h follOwing increasing doses of a1buterol (solid lines) and ipratropium (dotted lines) in young (asterisks) and older (boxes) asthmatic subjects. Arrows indicate time of dosing (2 MOl puffs at time 0 and one puff thereafter). obs = Observed.
We found no age-related differences in either the magnitude of response or in the time and dose required to reach peak effect following either drug, indicating that the elderly patients were not less responsive to either drug compared to the young. The magnitude of response should be greater for albuterol in the young and for ipratropium in the elderly if agerelated differences are present that affect the balance between adrenergic and cholinergic responses. The differential response to ipratropium and a1buterol (salbutamol) was found to be positively correlated to age by Ullah and colleagues,15 with subjects greater than 40 yr of age exhibiting a greater response to ipratropium and subjects less than 40 yr of age CHEST I 101 I 6 I JUNE, 1992
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demonstrating a greater response to albuterol. Furthermore, albuterol has been shown to be more effective in asthmatic subjects, while ipratropium has been found to be more effective in patients with COPD.8.18 The differential response seen in these two disease states may be related to the fact that asthmatic patients are typically young, while patients with COPD are typically older. The magnitude ofeffect was assessed by two factors in the present study: maximum response and AUC for percentage ofpossible improvement. When evaluating the maximum percentage of change from baseline in FEV1, there was a statistically greater response to albuterol than to ipratropium in both age groups. The greatest response (60.5 percent ± 48.3 percent) was seen after albuterol in the elderly subjects; however, these results must be interpreted with caution, as the elderly had lower and more variable baseline values for pulmonary function. Several studies have shown that the degree ofimprovement in pulmonary function is directly related to the amount of airflow obstruction. 19.!O Therefore, we adjusted our method of assessment by calculating the AUC for the percentage of possible improvement in FEV., which corrects for changes among groups in baseline pulmonary function. With this correction, we were unable to show a significant difference between the groups with respect to age, while the statistically greater response to albuterol compared to ipratropium within age groups remained. These conclusions are unchanged after dropping the elderly subjects with high variability in baseline function between study days from the final analysis. Thus, our results do not substantiate the premise that the elderly have a greater response to ipratropium compared to albuterol, or that the elderly have a lower response to albuterol compared to young subjects, further refuting the hypothesis that elderly subjects have a loss of ~-receptors in the lung. The results of FEF25-75% data parallel the FEV. data for magnitude of response, again showing no agerelated differences. Only the FVC data revealed a possible difference between age groups, with a statistically greater percentage of change from baseline occurring after both albuterol and ipratropium in the elderly compared to the young. The differences remained significant only for albuterol after correcting for the percent possible improvement and baseline variabili~ The reason for these differences for FVC are not readily explainable and are opposite what had been predicted. In an attempt to determine if age differences in response are present, it is important to look at the time and dose required to reach peak effect. If pulmonary responses are blunted with age as they are in cardiac tissue, either a slower response or the requirement for larger doses would be expected to 1550
reach the same magnitude of response in young vs elderly subjects. This has been demonstrated in the cardiovascular system with higher doses of isoproterenol or propranolol required in elderly subjects to produce the same degree of change in heart rate as in young subjects. 9 Interestingly, there was a nonsignificant trend for the time and dose required to achieve maximum bronchodilator effect for FEV 1 to be greater for albuterol than for ipratropium in both age groups; however, the maximum response obtained was always greater for albuterol compared to ipratropium in both age groups. Both groups may have responded with a lower number ofpuffs after ipratropium than albuterol because ofdifferences in dose equivalency for the two drugs. Other investigators have reported the dose required to produce maximum increases in pulmonary function tests for these two drugs as 40"",g to 80"",g for ipratropium and BOOJLg for a1buterol. R By this ratio, it would require two to four puffs of ipratropium (18JLg per pufl) vs eight puffs of a1buterol (90"",g per puff) to reach maximum effect. We compared one puff of ipratropium to one puff of albuterol, so the dose to produce a maximum change in FEV 1 might theoretically have been achieved with fewer puffs of ipratropium. Although comparison of the number of puffs may not accurately reflect differences in efficacy for these two drugs, it does help establish the fact that there are no age-related differences in the time and dose ofeach drug required to achieve maximum effect. Therefore, blunting of the ~-adrenergic system was not apparent in our population with increasing age. The effect of both drugs on MAP and pulse were insignificant. Interestingl~ the pulse tended to decrease in all groups except the elderly after ipratropium. Anticholinergics and ~-agonists would be expected to increase the pulse rate; however, it was noted that most study participants were short ofbreath at the beginning of the study and anxious secondary to moderate respiratory distress. The effect of the drugs may have decreased their anxiety, with resultant decreases in pulse rate. Additionally, the ability to tolerate ipratropium was superior to albuterol in this stud): Eight subjects complained of side effects with albuterol, compared to only one subject with ipratropium. CONCLUSION
Asthmatic patients generally have a greater response and quicker onset of action to ~2-agonists. Our population followed this pattern, with a greater magnitude of response to albuterol compared to ipratropium within age groups; however, no statistically significant differences between age groups were seen. The time and dose required to achieve maximum bronchodilator effect was less for ipratropium than albuterol, although Effect of Age on Bronchodilator Response (Kradjan et 8/)
this probably reflects the fact that equivalent doses were not used; however, the concern over a decrease in the number or responsiveness of p-receptors in the lung with age does not appear to be app~ntcUnicall~ as no age-related differences in the magnitude of response or the time and dose required to achieve maximum response were found in this stud)'. Both anticholinergics and p-agonists are effective bronchodilators in young and elderly asthmatic subjects, and we found that age is not a predictor of response to either drug. REFERENCES 1 Barnes PJ, Basbaum CD, Nael JA. Autoradiographic localization of autonomic receptors in airway smooth muscle: marked differences between large and small airways. Am Rev Respir Dis 1983; 127:758-62 2 Ruffin RE, Fitzgerald JD, Rebuck AS. A comparison of the bronchodilator activity of Sch 1000 and salbutamol. J Allergy Coo Immunol1977; 59:139-41 3 Gross NJ, Skorodin MS. Anticholinergic, antimuscarinic bronchodilators. Am Rev Respir Dis 1984; 129:856-70 4 Gross N. Ipratropium bromide. N Engl J Moo 1988; 319:48694
5 Gross N, Skorodin MS. Role of the parasympathetic system in airway obstruction due to emphysema. N Engl J Moo 1984; 311:421-25 6 Storms ~ Bodman S, Nathan R, Busse ~ Bush R, Falliers C, et ale Use ofipratropium bromide in asthma. Am J Moo 1986; 81(suppl 5A):61-5 7 Mollio M, Benzaray S, Lidji M, Karasik A, Steir S, Baum GL. Salbutamol versus atropine: site of bronchodilation in asthmatic patients. Respiration 1987; 51:26-34 8 Easton ~ Jadue C, Dhingra S, Anthonisen NR. A comparison of the bronchodilating effects of a beta-2 adrenergic agent (albuterol) and an anticholinergic agent (ipratropium bromide) given by aerosol alone or in sequence. N Engl J Moo 1986; 315:
735-39 9 Vestal RE, Wood AJ, Shand DG. Reduced beta adrenoreceptor sensitivity in the elderly. Clin Pharmacol Ther 1979; 26;181-86 10 Barnes R, Raskind M, Gumbrecht G, Halter J. The effects of age~ on ·the plasma catecholamine response to mental stress in man. J Clio Endocrinol Metab 1982; 54:64-9 11 Saar N, Gordon R. Variability of plasma catecholamine levels: age, posture, and time of da~ Br J Clio Phannacoll979; 8:35358 12 Rowe J, Troen B. Sympathetic nervous system and aging in man. Endocrinol Rev 1980; 1:167-78 13 Buehler F, Kiowski ~ Van Brummelen ~ Amann ~ Bertel 0, Landmann R, et ale Plasma catecholamines and cardiac, renal and peripheral vascular adrenoreceptor-mediated responses in different age groups of normal and hypertensive men. Clin Exp Hypertension 1980; 2:409-26 14 Klein C, Hiatt ~ Gerber G, Nies A. The balance between vascular alpha and beta adrenoreceptors is not changed in the elderl~ Clio Phannacol Ther 1987; 42:260-64 15 Ullah M, Newman GB, Saunders IeB. InHuence of age on respon$e to ipratropium and salbutamol in asthma. Thorax 1981; 36:523-29 16 American Thoracic Socie~ Statement by the committee on diagnostic standards for nontuberculous respiratory diseases: definitions and classifications of chronic bronchitis, asthma, and pulmonary emphysema. Am Rev Respir Dis 1962; 85:762 17 Weber ~ Petty WE, Nelson HS. Aerosolized terbutaline in asthmatics. J Allergy Clio Immuno11979; 63:116-21 18 Tashkin D~ Ashutosh Ie, Bleecker ER, James Britt E, Cugell D~ Cummiskey JM, et ale Comparison of the anticholinergic bronchodilator ipratropium bromide with metaproterenol in chronic obstructive pulmonary disease. Am J Moo 1986; 81 (suppl 5A):81-90 19 Rebuck A, Chapman Ie, Abboud R, Pare PD, Kreisman H, Wolkove N, et ale Nebulized anticholinergic and sympathomimetic treatment of asthma and chronic obstructive airways disease in the emergency room. Am J Med 1987; 82:59-64 20 Braun SR, McKenzie WN, Copeland C. A comparison of the effect of ipratropium and albuterol in the treatment of chronic obstructive airway disease. Arch Intern Med 1989; 149:544
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