A double-blind evaluation of the use of nebulired metaproterenol and isoproterenol in hospitalized asthmatic children and adolescents

Brian Garra, M.D., Gail G. Shapiro, M.D., Carol S. Dorsett, B.A., F. Estelle R. Simons, M.D., William E. Pierson, M.D., and C. Warren Bierman, M.D. Seattle Wash., and Winnipeg, Manitoba, Canada

This study compared two beta-adrenergic agents in the treatment of severe asthma of children and adolescents. Thirty patients admitted to Children’s Orthopedic Hospital and Medical Center with acute asthma were treated with either isoproterenol 0.05% (iso) or metaproterenol 0.5% (meta) nebulized in physiologic saline and delivered with 02 in addition to intravenous hydration, aminophylline, and corticosteroids. Vital signs, blood gases, and pulmonary function were monitored frequently. No adverse reactions to the study drugs were encountered. Pulse rates increased similarly after treatments with both drugs. Patients treated with meta had somewhat higher rates than those treated with iso. Diastolic blood pressure decreased significantly from admission in the meta group compared to the iso group. For FVC and FEVt, the meta group had greater percentage increases from admission than the iso group at all times, with the difference being signiJcant (p < 0.05) at I and 12 hr. The same trend occurred for FEF25%-75~. Though iso seemed to cause greater increases in Jlow immediately after administrations, these changes were transient compared to improvement caused by meta. Thus, meta seemed to be more effective than iso in reversing bronchospasm as measured by certain pulmonary function parameters.

Administration of nebulized isoproterenol is a standard part of therapy for the patient hospitalized with acute asthma.‘, 2 Recently, several new adrener- gic bronchodilators with longer duration of action and greater specificity for bronchial smooth muscle have been introduced. Metaproterenol is one of the newer bronchodilators and differs from isoproterenol only in the shift of one of the hydroxyl groups on the catechol proterenol ring from the ortho to the meta position. It is claimed to have greater specificity for B2 receptors and a longer half-life than isoproterenol. The bronchial and cardiac effects of metaproterenol have been compared to those of isoproterenol in laboratory animals33 4 and in human clinical trials,4-13

From the Division of Allergy, Children’s Orthopedic Hospital and Medical Center, the Department of Pediatrics, University of Washington, and the Department of Pediatrics, University of Manitoba, Winnipeg, Manitoba, Canada.

Supported in part by a grant from A.S.T.H.M.A., Inc. Received for publication Jan. 17, 1977. Accepted for publication May 17, 1977. Reprint requests to: Gail G. Shapiro, M.D., Department of Pediat-

rics, University of Washington School of Medicine, Seattle, Wash. 98195.

but most studies of aerosolized metaproterenol have utilized hand nebulizers with freon propellant in am- bulatory asthmatics who avoided methylxanthines during the study period. This study compares the ef- fectiveness of isoproterenol and metaproterenol ad- ministered by aerosol in the treatment of children and adolescents hospitalized with acute asthma.

PATIENTS AND METHODS

The study group consisted of 30 patients admitted to Children’s Orthopedic Hospital and Medical Center, Seat- tle, Washington, for severe acute asthma between June, 1974, and June, 1975. This group includes all patients ad- mitted to the hospital with acute asthma during that time interval who were able to cooperate for pulmonary function testing and from whom personal and familial informed con- sent could be obtained, except for those who had used sym- pathomimetic inhalers as part of their outpatient asthma therapy. Each patient had failed to respond to sym- pathomimetic agents: either three IO-min treatments with nebulized 0.05% isoproterenol, three 0.01 cc/kg injections of 1: 1,000 aqueous epinephrine (up to 0.3 cc per injection), or some combination of the two therapies.

Following admission to the Intensive Care Unit, all pa- tients were managed according to a standard protocol given

Vol. 60, No. 1, pp. 63-68

64 Garra et al. J. ALLERGY CLIN. IMMUNOL. JULY 1977

TABLE 1. Mean heart rates for the two groups at various times is indicated; mean percent change represents the mean of the percent change for each patient; mean percent change from admission is significantly different for metaproterenol compared to isoproterenol (p < 0.05) at 3 and 21 hr

Isoproterenol Mean 5 SEM Maximum Minimum Mean percent change

Metaproterenol Mean * SEM Maximum Minimum Mean percent change

Isoproterenol Mean ? SEM Maximum Minimum Mean percent change

Metaproterenol Mean ? SEM Maximum Minimum Mean percent change

Admission 30 min 1 hr

Pre- Post- Pre- Post-

132.4 2 4.6 134.5 k 5.1 151.2 t 6.9 133.5 + 5.1 143.7 +- 7.5 160 178 200 184 200 100 116 116 100 96

+2.19 + 1.37

124.5 f 5.1 123.2 k 3.5 142.3 k 5.6 127.1 2 4.1 145.2 ? 5.7 160 140 172 160 172 100 104 100 108 108

+2.26 +5.65

6 hr

Pre- Post- 7 hr 9 hr 11 hr

122.1 ? 6.4 131.7 2 4.8 122.7 -c 5.7 115.0 * 4.5 116.7 I 6.1 180 160 164 I48 I80 92 104 84 84 88

-6.51 -7.93 - 12.73 -9.08

124.4 _’ 4.4 137 * 4.3 127.2 2 3.0 117.8 t 5.0 II3 * 3.7 142 160 I50 140 132 80 100 116 80 88

+5.00 +3.00 -3.71 -9.75

in the Appendix. Each patient was given a study number and was assigned to receive either isoproterenol or metapro- terenol according to that number by the hospital pharmacist, using a previously generated random assignment list. The bronchodilator that each patient received was known only to the pharmacist until the study was completed. The bron- chodilators were administered and evaluated according to the following schedule.

Viral signs: Pulse, respiratory rate, and blood pressure monitored every hour for 12 hr, then every 3 hr for 12 hr.

Blood gases: From arterialized capillary samples taken with the patient in room air at 1 hr, 3 hr, and 24 hr after therapy was begun.

Respiratory therapy: Unlabeled brown vials containing either 0.05% isoproterenol or 0.5% metaproterenol were delivered by the pharmacist to the respiratory therapist for administration to the patient as an aerosolized mist with oxygen. The aerosolized mist was delivered from a Puritan No. 126055 wall nebulizer by means of disposable plastic tubing and face mask. The bronchodilator aerosol was ad- ministered for 5 min at the following intervals after admis- sion: 30 min, 60 min, 90 min, 2 hr, 3 hr, 4 hr, 5 hr, 6 hr, 12 hr, 24 hr, and every 2 hr as needed between 6 hr and 24 hr. Administration was stopped if the pulse rate reached 200 beats per minute. Actual determination of amount of drug consumed, which would require radioactive tagging stud- ies, could not be incorporated into the protocol.

Pulmonary function testing: Pulse was measured and a spirogram was obtained by an experienced respiratory therapist using a portable spirometer (Vitalor) before and after the administration of aerosolized bronchodilator at 30 min, 1 hr, 3 hr, 4 hr, 5 hr, 6 hr, 12 hr, and 24 hr after admission. FVC, FEVl, and FEFz~%.~~% were measured from the spirograms.

Mean percentage change from admission was calculated for the pulse and pulmonary function data. Vital signs and pulmonary data obtained just prior to bronchodilator admin- istration were used for times when bronchodilator mist was given. Thus spirometry obtained 30 min after admission represents an interval prior to study drug administration while the 1 -hr determination is a measurement 30 min after study drug and immediately prior to the I-hr study drug administration.

RESULTS

There were 18 males and 12 females in the study who ranged from 4.9 yr to 19.8 yr in age, with an average of 10.1 yr. Fifteen patients received each drug. The isoproterenol and metaproterenol groups had similar age and sex distributions. Mean duration of asthma and number of previous hospitalizations for asthma were similar for the two groups.

Heart rates and mean percentage changes in heart

VOLUME 60 NUMBER 1

Metaproterenol and isoproterenol in asthma 65

Pre-

3 hr

Post- Pre-

4 hr

Post- Pre-

5 hr

Post-

121.9 rt 5.9 133.2 t 5.5 122.5 + 5.6 137.6 + 6.9 123.4 ‘- 5.6 139.0 + 6.7 160 165 172 180 163 200 84 90 79 83 96 II2

-8.50 -6.71 -6.02

129.1 -+ 4.5 148.6 + 4.0 127.1 -+ 3.7 I41 + 5.6 124.9 2 3.7 140.7 rt 4.3 I64 168 144 174 144 160 100 I08 90 100 90 98

+ 10.05 15.75 +3.27

12 hr 24 hr

Pre- Post- 15 hr 18 hr 21 hr Pre- Post-

114.1 * 5.3 120.9 + 6.4 104 k 5.2 112.8 2 6.4 110.1 r 6.1 114.4 4 5.1 133.0 + 9.0 164 168 142 170 156 154 190 94 86 64 96 84 90 85

- 13.06 -21.39 13.32 16.92 - - - 12.05

113.4 k 4.9 123.3 4 6.0 114.5 2 5.5 114.1 !I 4.6 121.3 k 4.0 115.4 2 3.9 127.7 t 5.0 140 160 142 140 140 144 160 80 80 80 80 100 80 96

-9.44 -9.21 -7.32 -1.69 -5.59

rate from admission are listed in Table I. Patients treated with metaproterenol had somewhat higher rates than those treated with isoproterenol. The mean percentage decrease in heart rate from admission was greater for the isoproterenol group than for the meta- proterenol group. Those treated with metaproterenol had increased heart rates during the first 7 hr of ther- apy, while those treated with isoproterenol had rates less than on admission after 3 hr. Both isoproterenol and metaproterenol produced similar elevations in heart rate immediately following each administration. There was no difference in pulse elevation in small children compared to large children, indicating that the amount of study preparation consumed per child was proportional to size. Only one patient had pulse elevation requiring cessation of drug administration for a specific time interval. This patient developed premature ventricular contractions after administra- tion of bronchodilator. Her code was broken and she was found to be receiving isoproterenol. Subsequent hospital admissions for status asthmaticus during which the patient was not treated with adrenergic agents showed the PVCs to be a response to severe asthma with normal cardiac rhythm returning when her respiratory function improved. No further adverse

effects became apparent during bronchodilator ther- apy in patients receiving either drug.

The mean systolic blood pressure on admission was 116 t 5 mm Hg for those treated with isoproterenol and 108 -t 5 mm Hg for those treated with meta- proterenol. No significant changes in systolic blood pressure occurred in any patient during the 24-hr study period.

The mean diastolic blood pressure on admission for the isoproterenol group was 72.9 ? 2.5 mm Hg, while that of the metaproterenol group was 7 1.7 + 3.1 mm Hg. The mean diastolic blood pressure of the metaproterenol group fell below the admis- sion value by 1 hr, while that of the isoproterenol group did not fall below the admission value for 11 hr. In general, patients treated with metaproterenol had lower mean diastolic blood pressures than those receiving isoproterenol during the study period. This difference was significant (p < 0.05) at 5 hr. Blood pressures remained, nevertheless, within the normal range.

The mean respiratory rates on admission of the isoproterenol and the metaproterenol groups were 38.29 + 3.3 per min and 33.87 -+ 3.2 per min, re- spectively. Both of these groups demonstrated similar

66 Garra et al. J. ALLERGY CLIN. IMMUNOL.

JULY 1977

-1soproterenol O---Q Metaproterenol

Hours from admission

FIG. 1. Arterialized capillary blood gas results for the iso- proterenol and metaproterenol groups.

TABLE II. Comparison of study groups at time of admission

IS0 Meta (mean 2 (mean f

SEMI SEMI

Age (yr) Height (cm) Weight (kg)

FVC (cc) % predicted FEVl (cc) % predicted FEFzw-m,

(L/min) % predicted

10.0 2 1.1 10.1 ‘- 1.1 131.1 t 4.4 131 e 4.2 30.0 ? 3.1 28.5 k 2.6

813.9 -I- 159.9 687.5 2 188.3 O.psl 44.2 2 6.4 34.2 t 6.7 0.29

421.4 t 69.6 390.0 k 99.1 0.80 30.3 2 3.4 24.8 -c 4.4 0.33

244.1 +- 31.8 286.5 + 45.0 0.44

11.8 ? 1.6 15.3 t 2.6 0.26

decreases in mean respiratory rate with time. Arterlialized blood gas determinations are shown in

Fig. 1. Both groups of patients had a mile respiratory alkalosis throughout the study period, with mean pOz values ranging from 60 to 75 mm Hg. The group receiving metaproterenol had a significantly higher mean p0, (p < 0.5) 1 hr after admission than did the group receiving isoproterenol. At no other time dur- ing the study period did the two groups differ in mean pH, mean pOz, or mean pCOz.

Pulmonary function values on admission and the relationship of these to normal predicted values are shown in Table II. The iso and meta groups had com- parable degrees of bronchospasm as evidenced by no significant difference between them in percent pre- dicted by FVC, FEVl, or FEF25%-75% at admission. The mean FVC of both groups increased with time as shown by rising mean percentage increases in FVC from admission (Fig. 2). The metaproterenol group

had greater percentage increases from admission than the isoproterenol group did at all times with the dif- ference being significant (p < 0.05) at 1 hr and 12 hr. A similar pattern appears in the FEVl results. The trend of the mean percentage change values indicates that the mean FEVl increased in both groups during the study period, with the metaproterenol group con- sistently showing the greater improvement (Fig. 3). This difference was significant at 1 hr and 12 hr (p < 0.05). The FEF25%.75% values for each group of patients also increased from admission. Meta- proterenol-treated patients had a greater mean per- centage increase in FEF~s%-,~% than did those treated with isoproterenol, but the difference was not statistically significant.

On comparing pulmonary function before and after bronchodilator administration, those patients treated with isoproterenol had a greater response to inhaled drug than did the metaproterenol group as measured both by mean percent increase in FEV, and by mean percent increase in FEF25%-75% (Figs. 4 and 5). Dif- ference between the two groups in FEVl were significant (p < 0.05) at 1 and 6 hr, while differences between the two groups in FEF25%.75% were sig- nificant (p < 0.05) at 5 hr. There was no signif- icant difference between the mean percentage FVC increases of the two groups.

DISCUSSION

Studies in both animals3 and humans73 8, lo have shown that isoproterenol aerosol is 4 to 15 times more potent than metaproterenol. A preliminary open trial study by the authors in children with acute asthma confirmed a IO-fold potency difference between the two drugs. Accordingly, the metaproterenol adminis- tered in this study was 10 times more concentrated than the isoproterenol used.

Engelhardt and others3 studied metaproterenol in dogs and concluded that the drug was less active than isoproterenol in causing cardiac (B 1) stimilation when given at equipotent doses for bronchodilation. Studies in humans by Shanks and co-workers caused him to conclude that metaproterenol was 10 to 40 times less potent a cardiac stimulator than isoproterenol. Other clinical trial+ s, l1 have supported this contention, but at least two studies79 lo have shown little differ- ence between the two drugs in their effects on heart rate when given at equipotent doses for broncho- dilation.

In the present study, administration of meta- proterenol produced an elevation in heart rate very similar to that of isoproterenol. Such an effect may be due to direct B1 stimulation by the bronchodilator and/or to a reflex response to Bz-induced vasodilation and lowered blood pressure. Since heart rate occa-

VOLUME 60 NUMBER 1

I T

Metaproterenol and isoproterenol in asthma 67

R Isoproterenol

0 Metaproterenol

30 I 2 3 4 5 6 12 24 mln Hours from admIssIon

FIG. 2. Mean percent change in forced vital capacity (FVC) from admission.

0 Isoproterenol group

q Metaproterenol group

ml” Hours from admission

FIG. 3. Mean percent change from admission in forced expiratory volume in one second (FEV,).

Cl lsoproterenol group

0 Metapmterenol group I-SEM

ml” Hours from admwon

FIG. 4. Comparison of FEV, before and after bron- chodilator administration at various times after admis- sion.

sionally rose to near 200 per minute with both drugs, heart rate should be monitored closely while giving either agent. In addition, patients treated with meta- proterenol had persistently elevated heart rates be- tween aerosol treatments, indicating its increased serum half-life relative to isoproterenol. The in- creased half-life of metaproterenol compared to iso- proterenol arises from its resistance to degradation by catechol-o-methyltransferase in the body. Another important aspect of metaproterenol’s more prolonged activity may be attributed to the fact that the portion of nebulized metaproterenol which is swallowed re- tains pharmacologic activity since, unlike isoprotere- nol, it is resistant to enzymatic degradation in the gut.

The increased serum half-life of metaproterenol may also be responsible for the lower mean diastolic blood pressures of the metaproterenol group. While both drugs are known to cause vasodilation and reduc-

T 0 Isoproterenol group T T 17 Metaproterenol group

Kll” Hours from admission

FIG. 5. Comparison of FEF25%-,5% before and after bron- chodilator administration at various times after admis- sion.

tion in diastolic blood pressure,“, l2 repeated doses of metaproterenoi with its slower rate of degradation, may produce a greater serum concentration than iso- proterenol and thus greater reduction in diastolic blood pressure.

Although approximately equipotent doses of the two drugs were used, the percentage improvement in pulmonary function tests immediately after each dose was greatest for the isoproterenol group. Holmes has shown’ that metaproterenol achieves its greatest ef- fect on bronchi 60 min after inhalation vs 5 min for isoproterenol. This fact may explain the greater im- mediate response to isoproterenol since the post- bronchodilator spirogram was taken immediately after aerosol administration, i.e., at the peak of the isoproterenol response but before the peak of the metaproterenol response.

Studies”, 6, ‘* 9 have demonstrated that the bron-

66 Garra et al. J. ALLERGY CLIN. IMMUNOL. JULY 1977

chodilatory effect of metaproterenol is present 4 hr or more after inhalations of 1.3 to 4.5 mg of the drug. The effects of isoproterenol on the other hand are virtually gone by 2.5 hr after inhalation of 0.15 to 1.0 mg of drug. In our study, obstructed airways improved in patients treated with either drug, but the improvement was generally greater for the metaproterenol-treated patients. This result probably reflects the longer duration of bronchodilation pro- duced by metaproterenol and suggests that the slower elimination of metaproterenol and the possible addi- tion of active drug absorbed from the gastrointestinal tract, in addition to that part absorbed from the respi- ratory mucosa, may be advantageous in reversing bronchospasm in the hospitalized asthmatic patient.

The attentiveness of the respiratory therapy staff of Chil- dren’s Orthopedic Hospital and Medical Center directed by Ms. Fran Hopperstad, the pharmacy staff directed by Mr. Richard Marshall, and the housestaff of the University of Washington--Children’s Orthopedic Hospital and Medical Center is greatly appreciated.

REFERENCES

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

Falleroni, A. E.: Asthma management, in Patterson, R., editor, Allergic diseases-diagnosis and management, Phil- adelphia, 1972, J. B. Lippincott Co., p. 281. Bierman, C. W., and Pierson, W. E.: The pharmacologic management of status asthmaticus in children, Pediatrics S&245, 1974. Engelhardt, A., et al.: Pharmacology of the sympathomimetic amine drug I-(3,5dihydroxyphenyl)-10 hydroxy-2-isopro- pylaminoethane, Drugs Made in Germany 4~123, 1961. Shanks, R. G., et al.: Stimulation of adrenergic B receptors by orciprenaline, Br. Med. J. 1:610, 1967. Freedman, B. J., and Hill, G. B.: Comparative study of dura- tion of action and cardiovascular effects of bronchodilator aerosols, Thorax 26:46, 197 1. Pelz, H. H.: Metaproterenol, a new bronchodilator comparison with isoproterenol, Am. J. Med. Sci. 253~321, 1967. Holmes, T. H., and Morgan, B.: A comparative clinical trial of metaproterenol and isoproterenol as bronchodilator aerosols, Clin. Pharmacol. Ther. 9:615, 1968. Reilly, E. B., Rodgers, J. M., and Bickerman, H. A.: A comparison of the onset of bronchodilator activity of meta- proterenol and isoproterenol aerosols, Curr. Ther. Res. 16759, 1974. Choo-Kang, Y. F. J., Simpson, W. T., and Grant, 1. W. B.: Controlled comparison of the bronchodilator effects of three Padrenergic stimulant drugs administered by inhalation to pa- tients with asthma, Br. Med. J. 2:287, 1969. Milner, A. D., and Ingram, D.: Bronchodilator and cardiac

11.

12.

13.

14.

15.

effects of isoprenaline, orciprenaline, and salbutamol aerosols in asthma, Arch. Dis. Child. 46:502, 1971. Biiodeau, M., and Roy, J. C.: Ventilation studies for the evaluation of bronchodilator aerosols: Comparative study of isoproterenol and metaproterenol sulfate, Can. Med. Assoc. J. 99~585, 1968. Spitzbath, H., and Albers, P.: Observations on the effect on cardiovascular function of I -(3,5-dihydroxyphenyl)- l- hydroxy-2-isopropyl aminoethane in human beings, Drugs Made in Germany 4~136, 1961. McEvoy, J. D., Vall-Spinosa, A., and Patterson, J. W.: As- sessment of orciprenaline and isoproterenol infusions in asth- matic patients, Am. Rev. Respir. Dis. 108:490, 1973. Stamm, S. J.: Reliability of capillary blood for measurement of pOZ and O2 saturation, Dis. Chest 52:1919, 1957. Dickman, M. L., Schmidt, C. S., and Gardner, R. H. Spirometric standards for normal children and adolesents, Am. Rev. Respir. Dis. 104~680, 1971.

APPENDIX Management protocol used in the study

I. Initial clinical evaluation A. History and physical examination B. Laboratory tests

1.

2.

3.

4.

5.

Hct, white blood cell count with differential Blood gases (from arterialized capillary sam- ples)14 Urinalysis Pulmonary function tests: Forced vital capacity (FVC), forced expiratory volume in one second (FEV1) and forced expiratory flow from 25% to 75% of vital capacity (FEFZSQ-& using a wedge (Vitalor) spirometer operated by trained pulmonary therapists Bacterial and viral throat cultures if infection

was suspected II. Therapy

A.

B.

C.

D.

E.

I&avenous fluids: 20 ml/kg the first hour; then 50 to 55 ml/kg/24 hr Electrolyte replacement: K + 2 meg/kg/24 hr; Na + 3 megikgi24 hr Aminophylline: 7 mglkg intravenously the first 10 min; then 15 mg/kg/24 hr Intravenous steroids: Dexamethasone, 0.3 mg/kg stat followed by 0.3 mg/kg/24 hr Oxygen: 6 L/min by mask initially; then adjusted according to patient’s need and bIood gas results

III. Follow-up therapy after 24 hr A. Bronchodilator mist pm B. Switch to oral bronchodilator and steroids as pa-

tient’s condition improves C. Daily spirograms throughout hospital stay