Comparison of Isoproterenol and Isoproterenol-Phenylephrine Aerosols

Comparison of Isoproterenol and Isoproterenol-Phenylephrine Aerosols· Joseph L. Grant, M.D.; Norman Werfelman; Milton R. Cook, M.S.; and William Metherall, B.S.

Thirty patients witb chronic obsttuctive pulmonary disease bad their vital c. pacity (VC) and forced expiratory volume in one second (FEV 1) measured before, one-ball boor after, and two and a ball bours after they breathed aerosols of isoproterenol (cartridge M), isoproterenol with pbenylephrine (c.-tridge D), or a placebo. The placebo had negligible mean effects. Thirty minutes after each isoproterenol cartridge there was a rise in mean VC and FEV1 whicb was statlstically significant compared to the change 30 minutes after the placebo. Tbtl"e was no significant difference between the two aerosols in effect on VC or FEV 1 at 30 minutes. Two and one-balf bours after the inhalations, there was no signUicandy greater persistent effect on VC or FEV 1 after cartridge D than after cartridge M. Cartridge M bad greater effects on VC than D wben used Initially; wben used as a second dose its etfects were balved, possibly because iD tbe study it w. given after tolerance to isoproterenol bad developed after the administration of cartridge D.

ephrine and isoproterenol more effective and longer lasting than isoproterenol alone in decreasing airway resistance.

Despite reports':" of the limitations of aerosolized isoproterenol in asthma, it remains in common use in obstructive bronchitis and emphysema. The present study compares the effect on vital capacity and forced expiratory volume of two widely marketed Freon-powered aerosol cartridges, one of which, M,·· contains isoproterenol alone, and the other, D,t isoproterenol in combination with phenylephrine. Isoproterenol stimulates ,8-receptor sites in sympathetic effector cells, and thereby ·causes relaxation of bronchial musculature.f Phenylephrine stimulates a-receptor sites, causing vasoconstriction in both the systemic and pulmonary circulation," But has little direct effect on bronchial muscle. Phenylephrine has been thought to potentiate the effect of isoproterenol by slowing its absorption from respiratory epithelium, thereby allowing it to remain at receptor sites for longer periods of time. Cohen and Hale 7 have found the combination of phenyl-

METHODS

Thirty male patients with chronic obstructive pulmonary disease, whose ward physicians wished to know to what extent their obstruction might be reversed by isoproterenol, reported to the pulmonary function laboratory in the morning, after taking no bronchodilators for eight hours. Control measurements of vital capacity (VC) and forced expiratory volume (FEV.) were made on a 13-liter Collins spirometer. One of the investigators then selected at random one of the cartridges and coached the patient in its proper use. Under supervision, the patient held it in his open mouth and took one deep inspiration while pressing the plunger. Two minutes later, he took another such breath, inhaling another dose of either of two test cartridges (designated M or D) or of a placebo cartridge (P). The M cartridges contain isoproterenol hydrochloride alone in a dilution of 1:400 with 33 percent alcohol, and each press on the plunger releases about 125 p.g, so that 250 p.g of isoproterenol were inhaled in two minutes by subjects given M cartridges. The D cartridges contain isoproterenol hydrochloride and phenylephrine bitartrate in a suspension of inert particles. Each press on the plunger delivers 137 p.g of isoproterenol and 126 p.g of phenylephrine, so that 275 p.g of isoproterenol and 250 p.g of phenylephrine were inhaled in two minutes by subjects

°From the Medical and Pharmacy Services, Veterans Administration Hospital, White River Junction, Vermont and the Dartmouth Medical School, Hanover, New Hampshire. oOIsuprel Mistometer1 Winthrop Laboratories, New York, NY. tDuo-Medihaler, Riker Laboratories, Northridge, Calif.

129

GRANT ET AL

130 Table l--Order 01 .4dmini.'ralion Morning D M p D p M M D

Afternoon M

D

D P M P M

D

01 Cartrid«e•• No. of Patients 9

Table 2-Yital Stali.lic•• Patient

Age

1

46 58 53 53

8 3 2 3 2 2 1

given D cartridges. Placebo cartridges (P) indistinguishable from the D cartridges contain only the propellant gases." Onehalf hour later, VC and FEV t were repeated. Two hours later, in the afternoon, the vital capacity and FEV t were again measured, as a control for the second test cartridge, and the patient reported to a different investigator who selected a cartridge at random and had him inhale in exactly the same way as before. The investigator who selected the afternoon cartridge did not know which cartridge had been given in the morning. Half an hour later the VC and FEV 1 were done again. The technician who measured the VC and FEV t also did not know which cartridge had been given. After the entire group had been studied, it was revealed that, apparently entirely by chance, the aerosols had been given in the order shown in Table 1. From this it can be seen that, in all, 24 patients inhaled cartridge M, and 23 inhaled cartridge D. Since nine inhaled D in the morning and M in the afternoon and eight reversed the order, if any effects of medication persisted two hours they were about equally divided between D and M. The effect of the placebo was measured in ten patients of whom six breathed it in the morning. In the four who breathed it in the afternoon, any persisting medication effect would have been evenly divided since two had breathed cartridge D in the morning and the other two had breathed M. A comparison of the effects of 0 and M used in the same patient could be derived from 17 patients, of whom nine used 0 first. The effects on VC and FEV 1 in 12 patients two and one-half hours after cartridge D could be compared with those in 12 patients two and one-half hours after cartridge M. The effects of cartridge M, used as an initial dose (considering the effects of P negligible) in 15 patients, could be compared with its use as a second dose of isoproterenol in 11, with the effects of the initial use of cartridge D in 15, and with D as a second dose in nine patients. Statistical analysis has been carried out, using Student's "t' test for non paired data, to compare each of these changes after cartridge D with those after M, and with those after P, and to compare M with P. In each such analysis, two groups were compared. Statistical significance was attached to differences between groups where values of "p" were less than 0.05. In the tables, the mean results are presented as percent change from the control after each cartridge, plus or minus the standard deviation.

2 3

4

5

6 7 8 9

10

11 12 13 14 15

16

17

18

19 20

21

22

23 24 25

45 54 51 56 71 72 74 40

62

51 55 43 72 53 63

54 47 51 72 64

27 28 29 30

59 81 37 42 71 63

Mean

57

26

• Kindly supplied by Riker Laboratories.

(Kg)

63 61 67 69 97 59 102 90 78 59 53 74 52 41 89 72 59 61 66 63 65 51 65 53

62 79

Height

Vital capacity

(Cm)

172 172 184 180 ISO 170 168 178 164 166

4.02 4.35 4.76 3.89 4.42 3.28 3.14 1.98 1.89 2.26 2.38 2.81

162 160 164

2.21

168

1.67 3.55 3.74 2.05

172 ISO

162 160

1.84

162

2.28 4.08 2.65

170

178 162 175

1.95

2.82 2.50 3.61 3.07 4.10 3.18

170 170

182

86 72 57 42

166 166 168 167

67

170

FEV,.o

183

2.26

2.70 1.73 3.50 .87 1.73 1.23 .97 1.18 .76 1.52 .92 .59 1.67 3.07 1.07 .81 1.25 1.35 1.93

.86

1.73

1.19 .97 2.43 1.94 3.12 2.39 .60

2.91

1.56

1.24

.54

3.03 liter ).10 Table 3 compares the change in VC and FEV 1 one-half hour after cartridges D and M to the change after the placebo. Vital capacity rose by a mean of 16.75 percent after cartridge M, and 12.6 percent after cartridge D. FEV 1 rose 23.3 percent after cartridge M and 15.3 percent after cartridge D. These effects were all statistically significantly greater than the negligible mean changes after the placebo cartridge (p < .05). Table 4 shows a comparison of the effects of cartridges M and D used in the same patients. Excluding the ten who received placebo cartridges and three who had repeated doses of the same Table 3-.4, 30 Minu,e., Effect. 01 Cartrid«ea M and D Compared Placebo.

'0

RESULTS

Table 2 presents vital statistics and baseline pulmonary function studies. All subjects were men. The average age was 57, range 37 to 81. The average height was 170 em, range 160 to 184. The mean vital capacity was 2.91 liter (predicted 3.65 liter) and the mean FEV 1 was 1.56 liter (predicted

Weight

n*

% change VC FEV,

Placebo

Cartridge M

Cartridge D

10

24

23

-1.3 ±8.1 +16.75 ± 11.1 +12.6 ± 11.1 +2.9 ±12

+23.3

±19.5 +15.3 ±13.3

*n= number of patients. For the changes in both VC and FEV 1, separate comparison of both cartridge M and cartridge D with the placebo gave values of p less than .05.

CHEST, VOL. 60, NO.2, AUGUST 1971

COMPARISON OF ISOPROTERENOL AND ISOPROTERENOL-PHENYLEPHRINE AEROSOLS Table 4--A' 30 Minu'e. Mi.'ome'er .,. Duo-medihaler uaed in .ame paden' (n = 17).

% change in

VC

Cartridge M

Cartridge D

12.4

13.2

p*

± 11

± 13.9

<.8(NS)

% change in FEV 1.0

18.8

p*

± 18.6

15

±12.8

<.4(NS)

"P values indicate significance of difference between drugs. Mistometer was used first in eight instances and DuoMedihaler in nine. NS= not significant.

cartridge, 17 patients received both test cartridges. The mean changes after each were very similar. Table 5 shows that in 12 patients after two and one-half hours there was a negligible difference between the small persisting increases in vital capacity after the two test cartridges. The persisting increase in FEV 1 was greater after M than after D, but not significantly so. To explore further the effects of the order in which the aerosols were given, Table 6 presents the changes in VC and FEV 1 after cartridges M and D, listed according to whether they were given as initial medication (either as a morning dose or in the afternoon after a placebo had been given in the morning) or as an afternoon medication after an isoproterenol cartridge had been given in the morning. M had significantly greater (p < .05) effects on VC and FEV 1 when given initially than when given as a second dose, while D had more effect as a second dose than as a first one. Table 7 presents p values for the diHerence between the effects of doses of M and D given either first or second. When M was given as an initial dose, it had a significantly greater effect on VC than D had (p < .05), while D, given second, had 'significantly greater effects on VC than M given second. These results contrast with the over-all effects of M and D since, as Tables 1, 3, and 4 show, the mean effects of M and D on VC and FEV 1 in all patients who inhaled it in the morning or afternoon were not significantly different. Table 5--Pereen, Chan«e in Mean Yi,al Capaeity and FEY} 2~ Hour. aller Inhalation 01 Car'ridge. M and D in 12 Potien,., eaela. Cartridge

% Change VC

FEV 1

M

+4.6

±9.8

+13.7

± 16.9

D

+2.8

±9.2

6.8

± 15.7

p*

>O.4(NS)*

Table 6-Mean Pereen'age Riae in YC and FEY 1 eompared to Controla, 30 Minu'e. al'er Car1rid«e. M and D by Order 01 Adming'ration. VC M first

n= 15

16.6

M second

n= 11

D first D second

CHEST, VOL. 60, NO.2, AUGUST 1971

FEVl,o

±11

23

±19

8

± 9.4

13.5

± 14

n= 15

11.5

±10.6

17

±15

n= 9

16

±15

19

±15

DISCUSSION

Out of a total of 60 cartridge administrations, the placebo cartridge, P, was given ten times, while M and D were given 26 and 24 times, respectively. The probability that cartridges M and D would be given that much more often than the placebo, by chance alone, is less than one in ten. This makes it likely that the investigators who selected the cartridges during the study had an unconscious bias toward using an isoproterenol-containing cartridge rather than a placebo. Nevertheless, the placebo group was large enough, and the placebo effects small enough, to make statistical comparisons valid at the 95 percent confidence level. The study reveals few differences between aerosolized isoproterenol in alcohol and aerosolized isoproterenol with phenylephrine in particulate form, in effects on the vital capacity and first second forced expiratory volume of patients with chronic obstructive pulmonary disease. The mean change after cartridge M in 30 minutes, (17 percent rise in VC, 23 percent rise in FEV 1, Table 3) is comparable to that found by Cohen and Hale 7 after 15 minutes of administration of aerosolized isoproterenol by an intermittent positive pressure breathing apparatus. Their subjects, studied also with a volume displacement body plethysmograph, showed a 32 percent drop in airway resistance after cartridge M, and 38 percent drop after cartridge D. These effects persisted so that at two hours there remained a 25 percent change in resistance in their group given cartridge M, and a 35 percent change in their group given cartridge D. The doses they Table 7-P Yalue. lor Differenee in EffeeJ of CarJrid.e. M and D Aecordin« to Order 01 Adminiatralion.

M First VC FEVl M first VCFEV1-

D First VC FEVl

M Second VC FEVl

D Second VC FEVl

<.025

<.005 >0.5 >0.05 <.001 D first VC >0.1 >0.1 FEVl >0.5

>0.2 >0.5

M second VC <0.025' FEV1 • >0.2

>O.I(NS)

NS*= Not significant.

131

·Underlinedvalues are lessthan 0.05.

132 administered from cartridge M and cartridge D were twice those given in our study, and they were administered over a I5-minute rather than a twominute period, which may account for these greater and longer-lasting effects. Their finding that airway resistance was decreased further and more persistently by the addition of phenylephrine to an isoproterenol aerosol cartridge was not borne out in our study since change in FEV 1 at 30 minutes was greater with cartridge M especially when it was used first (Table 3, 4, 6) and also remained greater after two and one-half hours (Table 5), though the latter change was not statistically significant. Tables 6 and 7 show that M had significantly greater effects than D on vital capacity when each was given as an initial dose. D, on the other hand, had significantly more effect on the vital capacity than M when given as a second dose. Since most of those who got M first had D second and vice versa, these results would lend themselves to the interpretation that the effects of M wore off more rapidly than D, permitting D as a second dose more effect, and M less, were it not that, as Table 5 shows, the two cartridges actually had about equally persistent effects on vital capacity at the end of two and onehalf hours. A possible interpretation may be that the reduced effects of M, given as a second dose after D, are due to the development of drug tolerance after D, which apparently failed to occur when D was given after M. A reduced effect with repeated doses is known to occur with sympathomimetic drugs," and it might have been more pronounced after the combination of isoproterenol and phenylephrine than after isoproterenol alone. That bronchodilator drugs may effectively increase ventilatory capacity without improving blood gas values has been shown by several authors. 2 - 5 The increase in ventilation may be only in areas which are already underperfused, or may otherwise lead to adverse local effects in the ventilationperfusion ratio. Isoproterenol administered over too long periods has also been found by Keighley--s to have adverse effects on ventilatory capacity itself. Therefore, though this study shows the short-term effectiveness of isoproterenol in increasing vital

GRANT ET AL

capacity and FEV 1, it does not necessarily imply either that it has a beneficial effect on blood gases, or that its effects will persist very long if it is used continuously. Taylor and Harris" found that mice rendered asphyxic inhaling Freons (the halogenated methane gases compressed in the cartridges to serve as propellants) developed bradycardia and 2: I atrioventricular block, while asphyxia alone produces tachycardia in mice. The cartridges in our study were charged with Freons identical to those in the Taylor and Harris study. Inhalations from placebo cartridges containing no bronchodilators had little effect on vital capacity or FEV 1, and no adverse cardiac effects were noted among our subjects. In view of the similar effects of cartridge M and cartridge D found in this study, we have, in practice, allowed the patient -to try each one and to choose the one that seemed to him most effective. REFERENCES

1 Keighley JF: Iatrogenic asthma associated with adrenergic aerosols. Ann Intern Med 65:985-989, 1966 2 Knudson RJ, Constantine HP: An effect of inhalation of isoproterenol on ventilation-perfusion in asthmatic versus normal subjects. J Appl PhysioI22:402-406, 1967 3 Rees HA, Millar JS, Donald KW: Adrenaline in bronchial asthma. Lancet 2: 1164-1167, 1967 4 Keighley JF: Refractory asthma and adrenergic aerosols. New York J Med 69:662-67, 1969 5 Ingram RH, Krumpe PE, Duffell GM, et a1: Ventilationperfusion changes after aerosolized isoproterenol in asthma. Amer Rev Resp Dis 101 :364-370, 1970 6 Goodwin LS, Gilman A: The Pharmacologic Basis of Therapeutics. New York, Macmillan, 1965:298, 497-498, 508-509 7 Cohen AA, Hale FC: Comparative effects of isoproterenol aerosols on airway resistance in obstructive pulmonary diseases. Amer J Med Sci 249:309-315, 1965 8 Snedecor GW: Statistical Methods. Ames, Iowa, Iowa State University Press, 1956, p 46 9 Taylor GJ IV, Harris WS: Cardiac toxicity of aerosol propellants. JAMA 214:81-85,1970 10 Baldwin E deF, Cournand A, Richards DW: Pulmonary insufficiency 1, physiologic classification, clinical methods of analysis, standard values in normal subjects. Medicine 27 :243-278, 1948 Reprint requests: Dr. Grant, VA Center, White River Junction. Vermont 05001

CHEST, VOL. 60, NO.2, AUGUST 1971