Treatment of Bronchial Asthma with Terbutaline Inhaled by Conespacer Combined with Positive Expiratory Pressure Mask

Treatment of Bronchial Asthma with Terbutaline Inhaled by Conespacer Combined with Positive Expiratory Pressure Mask* Enka Frischknecht-Christensen, M.D.; Ole N-rregaard, M.D.; and Ronald Dahl, M.D.

The ioftueoce of positive expiratory pressure (PEP) applied during iobalation of a p1-agonist in treatment of bronchial asthma was investigated in a randomized crossover study with two-week treatment periods. In one period, two puffs (0.5 mg) of terbutaline was given from a metered dose inhaJer and inhaled through a device consisting of a conespacer connected to a facemask giving PEP (IO to 15 cm ffsO). In a second period, terbutaline 0.5 mg was inhaJed similarly but without PEP, and in a third period placebo spray was inhaJed with PEP. Treatments were given three times daily. Peak expiratory ftow (PEF) was measured before and after each inhalation and symptom scores for dyspnea, cough, and mucus production were noted in a diary. All treatments increased PEF significantly

Beblt-agonists act as bronchodilators in asthma and

chronic obstructive pulmonary disease (COPD). With an effective inhalation technique, the optimum deposition in the lungs from a metered dose inhaler is less than 10 percent of the dose delivered to the mouth. By delivering the dose through a 750-ml conespacer, the fraction deposited in the lungs can be increased to about 20 percent. 1 Patients with COPD often breathe spontaneously with pursed lips, in this way creating an expiratory resistance and retard. Pursed-lip breathing was shown to decrease expiratory resistance and improve ventilation of slowly ventilated compartments of the lungs, with decreased airway collapse. 2•3 Recently, the application of positive expiratory pressure (PEP) in various forms has gained increasing interest in bronchial asthma and COPD.+7 Continuous positive airway pressure (CPAP) was shown to decrease pulmonary resistance and increase expiratory flow rate in induced bronchial asthma4 and breathing against a column of 10 cm H 20 during and after exercise-induced asthma reduced the postexercise bronchoconstriction.7 These studies indicate that expiratory positive pressure dilates the airways and improves the distribution of ventilation, which might leave the airways available for better deposition of simultaneously inhaled medication. *From the Department of Respiratory Diseases, University Hospital of Aarhus, Aarhus, Denmark. Manuscript received July 13; revision accepted December 14.

(p<0.0001). The mean increase was 32 Umin during treatment with terbutaline and PEP. This was greater than the increase of 25 Umin during terbutaline treatment (p=O.OOS). The increase in PEF during terbutaline treatment was significantly higher than the achieved 18 Umin during PEP (p 0.026). The study showed improved bronchodilation when PEP was combined with inhaJation of P.agonist compared with P.-agonist alone. (Chm 1991; 100:317-21)

=

COPD =chronic obstructive pulmonary disease; CPAP =continuous positive airway pressure; IPPB =intermittent positive pressure breathing; PEF'"' peak expiratory flow; PEP= positive expirlltory pressure

The present study was performed to study whether PEP alone and combined with inhaled terbutaline would influence bronchodilation compared with inhaled terbutaline alone in home treatment of bronchial asthma. To study this, we devised a spacer combined with a facemask giving PEP (Fig 1). PATIENTS AND METHODS

Ten ambulatory patients were included. They were never smokers or nonsmokers, who had not been smoking fur the last five years. They all had a clinical history of bronchial asthma' with paroxysms of wheezing and dyspnea relieved by broncbodilator, hyperresponsive airways, allergy and/or eosinophilia, and they all needed daily bronchodilator treatment. They had all previously shown at least a 15 percent increase in forced expiratory volume in the first second (FEV J or PEF af\er inhalation of 1.25 mg of terbutaline (Bricanyl, Breathair). Patients with persistent air8ow limitation were not excluded when the above symptoms and signs were present. Eight patients completed the study, one patient dropped out because of exacerbation of asthma, and one patient was excluded

F1cuRE 1. Combined Nebuhaler-PEllmask, which is constructed from a 750-ml volume conespacer (Nebuhaler) connected to a facemask with a T-tube fur separation of inspiratory and expiratory air8ow by a valve. Variable resistances can be applied onto the expiratory tube as connections of different diameters. A positive airway pressure will in this way be present only during expiration. CHEST I 100 I 2 I AUGUST, 1991

317

Table 1-Claaractmmca of Eight Bdienta with Bronchial Adhma at the Start of tbs Study• No./Seir/ Age, yr l/F/51

2/Fnl 31M161 4/M/44 5/F/56 &'F/39 7/F/57

&'MJ24 Mean50.4

Duration

FEV.,

L

FEV/ pred

FEV/ FVC

PEFpred,

of Asthma, yr

1.30 1.10 0.75 3.05 0.70 2.45 1.55 2.10 1.63

0.46 0.60 0.22 0.68 0.29 0.88 0.62 0.48 0.53

0.52 0.61 0.28 0.62 0.52 0.89 0.63 0.66 0.60

400 324 505 604 368 395 376 600 447

12 4 55 3 15 3

11 22 15.6

Umin

*FEV,=forced expired volume in first second; FVC=furced vital capacity; FEV,pred=FEV/predicted FEV,; and PEFpred=predicted peak expiratory flow.

because of noncompliance. Age, duration of asthma, and lung function are shown in 'lllble 1. Predicted values were derived from a 1983 study.• All patients were in daily treatment with inhaled p,agonist, five patients used theophylline, two used oral ~-agonist, and three inhaled corticosteroids. None of the patients used oral corticosteroids. Except for inhaled broncbodilators, their usual treatment was continued and kept constant throughout the study period. The patients were allowed to use additional inhaled p,agonist when needed. All regular and additional treatments were recorded In a diary.

Ethics The patients were given verbal and written Information, and consent to participate was obtained from all. The study was approved by the Ethics Committee of Aarhus and was in accordance with the Helsinki Declaration II. Apparatus

Terbutaline and placebo inhalations were given from a metered

dose inhaler through a Nebuhaler-PEP.mask (Fig 1). It consisted of a 750-ml volume conespacer (Nebuhaler, Draco, Sweden) connected to a PEP.mask (Astra-Meditec, Denmark). The PEP.mask consisted of a facemask with a T-tube for separation of lnsplratory and expiratory airflow by a one-way valve. The valve In the Nebuhaler was removed and connected to the lnsplratory tube of the valve In the PEP.mask. The expiratory resistances could be varied by applying connections of different diameters onto the expiratory tube. A positive airway pressure was in this way present only during expiration. nvatment The study was perfurmed as a crossover study with two-week treatment periods in random order with the following: (1) two puffs (0.5 mg) of terbutaline inhaled through the Nebuhaler-PEP.mask with an expiratory pressure of 10 to 15 cm H,O ('terbutaline-PEP''); (2) similar treatment but without an expiratory resistance connected to the PEP.mask ('"terbutaline"); and (3) two puffs of placebo aerosol inhaled through the Nebuhaler-PEP.mask with an expiratory resistance of 10 to 15 cm H,O \'PEP''). The patients were Instructed to shake the aerosol and actuate twice into the spacer. Afterwards the Nebuhaler-PEP.mask was placed tightly over mouth and nose and the patients inhaled slowly from FRC followed immediately by 10 Inspirations and expirations through the device. When treated with PEP, the patients were taught to adjust their expiratory flow to create a pressure of 10 to 15 cm H.O measured by a manometer. The actual pressure level was individually determined according to the capability ofthe patient to breathe quietly 10 times without use of the auxiliary respiratory muscles. This was clinically assessed by watching the abdomen moving outwards and the thorax elevating

318

during Inspiration without paradoxic movements. The Instructions were given by a specialized physiotherapist. All treatments were given three times daily, in the morning when ~ (around 7 AM), in the afternoon (around 4 PM), and before going to bed (around 10 PM). The study was double-blind concerning the inhaled medication, but open concerning PEP, because the resistance could be felt by the patients. The patients were told that the treatments were terbutaline or placebo with or without PEP.

Diary and Clinical Control

The patients filled in a diary card. Questions regarding dyspnea, cough, and amount of sputum during the day were graded from 0 to 3 (none, mild, moderate, and severe) and answered in the evening. The number of additional puffs of p1-agonist was noted each day. Side elfects should be described In the diary. PEF was measured with a Bowmeter (mini-Wright peak flow meter) before and 15 minutes after each treatment. The highest value of three measurements was recorded. On the day of inclusion, FEV, and furced vital capacity (FVC) were measured with a dry-spirometer (Vitalograph). Before this measurement, the patients withheld inhaled p1-agonist or oral bronchodilators for 12 hours. After each treatment period FEV1 and FVC were measured, but before these measurements the patients were allowed to take the morning dose of the study treatment, because of considerable worsening of the asthma after such delay in medication. Statfatical Methoda The values from the initial three days In each treatment period were excluded from analysis to avoid a carryover effect from the preceding treatment. Results are given In mean and SEM or 95 percent confidence intervals. The level of significance was chosen as0.05. The symptom scores, the additional use of inhaled terhutaline, FEV,, and FVC were analyzed by Friedman test and Wilcoxon rank sum test for paired data. Nonparametric analysis was used because of the small number of data, which did not follow a symmetric

Table 2-Mean Daily Symptom Scorn during Two Weeb of '.lreatrnent with Posiliw Espiratory Pteuunr (PEP), 'Ierbutaline Inhalation ('Ierb), and PEP Combined with 'Arbataline Inhalationa (Terb-PEP).* Treatment

Dyspnea

Cough

Sputum

PEP Terb Terb-PEP

1.5 (1.3-1.7) 1.3 (1.1-1.5) 1.6 (1.4-1.9) p<0.01

1.1 (0.9-1.4) 1.0 (0.8-1.2) 0.9 (0.7-1.2) p<0.05

1.3 (1.0-1.5) 1.1 (1.0-1.4) 1.0 (0.8-1.3) p<0.01

*Mean and 95 percent confidence intervals

PEF L/MIN 380

PEP

TERBUTALINE AND PEP

TERBUTALINE

350 340 330

...

•••

•••

320 310 300 290 280 270 260 250 468 o

10

12

14

BEFORE NfALATION

468 e

10. 12

14

AFTER NfALATION

468

10

12

14

DAY

I

FIGURE 2. PEF before and after inhalation during the treatment periods (mean and SEM).

PEF L/Mtt.I

400

400 MORNlllG

AFTERNOON

EVEMllG

350

350

... ····

... ·······

300

300

250

250

PEP

BEFORE INHALATION

"

AFTER NiALATION

•

TERBUTALINE TERBUTALINE AND PEP

FIGURE 3. PEF before and after inhalation during the day (mean and 9.5'1> confidence intervals).

CHEST I 100 I 2 I AUGUST, 1991

319

~sian

distribution, 10 and the symptom score belonged to an

ordinal scale. The daily PEF measurements were numerous and were analyzed

by paired t test and analysis of multivariance (ANOVA) in order to evaluate both the in8uence of time and the in8uence of treatment. RESULTS

Asthma Symptom Sc~s

The symptom scores were significantly different during the three treatment periods (Table 2). Dyspnea score was lowest during "terbutaline" whereas sputum score was significantly lowest during "terbutalinePEP" and cough score was lower during "terbutalinePEP" compared with "PEP,'' but not significantly different from "terbutaline". No side effects were reported. ~ak Expiratory Flow (PEF) PEF before and after aerosol inhalations are shown in Figures 2 and 3. PEF after inhalation was significantly (p<0.0001 for all) higher than before inhalation during all treatment periods (Fig 2). PEF showed similar diurnal variation during all treatments with lower values in the morning (Fig 3). The increase in PEF was significantly different between the treatments (p=0.008, ANOVA). The mean increase in PEF with "terbutaline-PEP" was 32 Umin (CI, 29 to 36 Umin) which was significantly higher (p=0.005, t test) than during "terbutaline:' Mean increase in PEF during "terbutaline" was 25 Umin (CI, 21 to 28 Umin) and significantly higher than the increase in PEF of 18 Umin (CI, 14 to 22 Umin) during "PEP" (p = 0.03, t test). The percentage increase in PEF during the day was minimum and maximum 4 and 6 for "PEP,'' 6 and 14 for "terbutaline," and 9 and 12 for "terbutaline-PEP." Lung Function Measurements at the Clinic T~ FEV1 and FVC after all treatments were significantly higher than the values measured at the start of the study (Table 3), but there was no significant difference between the treatments. The measurements were done 2 to 8 hours after the morning dose, but were performed at the same time of the day for each patient. Additional Use of A-Agonist

There was no significant difference between the treatments in the use of additional puffs of ~ 2 -agonists; mean number of additional puffs per day were 4.3, 4.6, and 4.4 during "PEP," "terbutaline;' and "terbutaline-PEP,'' respectively. DISCUSSION

This study compared the effect on daily peak expiratory flow and symptoms of PEP, inhaled terbutaline, and combined terbutaline-PEP inhalation in home treatment of bronchial asthma. The bronchodilation after inhaled terbutaline was enhanced by the 320

combination with PEP, shown by the immediate increases in PEF. The symptom scores showed only small differences; however, the scales to differentiate symptom severity were not detailed. No side effects were reported. It was not possible to make a double-blind design, because the expiratory pressure can be felt, and treatment with placebo without PEP was not included due to the severity of the disease; but with the three treatments, we endeavored to make the nearest possible approach to a double-blind design. The increases in PEF were modest and apparently not of long duration, since there were no differences between the treatments concerning baseline lung function. This was probably due to the severity of the disease and the need for daily oral bronchodilators and inhaled steroids, but even brief relief could be valuable in a disabling condition such as chronic bronchial asthma. The patients had different degrees of airway obstruction, but all patients showed a similar pattern with a significant increase in PEF when PEP was applied, a greater increase after terbutaline treatment, and the greatest increase with combined terbutaline and PEP treatment. Although the magnitude of increases in PEF was small, it was comparable to the findings of other studies of bronchodilator aerosols in home treatment. In a Danish home treatment study of 140 patients (122 with bronchial asthma, 47 with chronic bronchitis, and 19 with emphysema) with reversible airway obstruction (defined as at least 15 percent increase in FEV1 after inhalation of 1.25 mg of terbutaline), inhalation with equal doses of terbutaline with metered dose inhaler or with a powder device increased PEF by 11 and 12 percent. 11 We find it interesting that PEP alone showed a uniform pattern of significant increases in PEF, though to a minor extent than after terbutaline treatment, indicating that PEP alone dilates airways. This is in accordance with findings from studies concerning pursed-lip breathing in COPD, 2 as well as CPAP in induced asthma, 4 expiration in a 10-cm H 20 column in exercise-induced asthma, 7 and PEP.mask giving Table 3-Forced b:piratory Volume in First Second and Forced b:piratory Vital Capacity (FVC) Meaaured at the Clinic 'before and after Two weeb of ~with Poei&e &piratory ~n1 (PEP). 'lerbutaline Inhalation ('Ierb). and PEP Combined with 'Ierbutaline Inhalatioru (Terb-PEP). * (FEV1)

Treatment

FEV.,L

FVCV, L

Baseline PEP Terb Terb-PEP

1.63 (1.09-2.52)

2. 70 (2.02-3.58)

1.82 (1.19-2.62) 1.99 (1.o.5-2.59) 2.00 (1.28-2.72)

2.88 (2.10-3.65) 2.96 (1.81-3.47) 3.10 (2.32-3.88)

p
reduced volume of trapped gas in cystic fibrosis. 12 The increased pressure in the airways created by the different forms of expiratory positive pressure seems to distend bronchi and bronchioles. In patients with expiratory air8ow limitation, collapse ofairways during expiration occurs to a greater extent than in healthy subjects, and during PEP the pressure gradients are moved from the airways to the PE~resistance, leaving the airways more open. In this way the distribution of the ventilation and thereby the deposition of inhaled medication might be improved, giving further bronchodilation. The retarded expiration might allow more time for retaining the medication in the distal airways. The various forms of PEP, including pursed-lip breathing, may have similar effects provided that inhalation of medication is simultaneous with the application of expiratory pressure. Opening of the airways might enhance mobilization of airway secretion, which could contribute to the increase in PEF after PEP alone. The effect on airway secretion was supported by a previous study showing a marked decrease in the number of acute exacerbations in chronic bronchitis with daily use of chest physiotherapy with PE~mask compared with physiotherapy alone. 13 Similarly, PEP increased the amount of expectorated mucus in patients with cystic fibrosis, but whether PEP or chest physiotherapy alone is superior in treatment of cystic fibrosis remains a controversy. 1u 5 In addition to the expiratory retard, PEP might induce changes in breathing pattern similar to the pursed-lip breathing with increased tidal volume and decreased frequency. 3 The significance of this with respect to the technique of inhalation of medication probably is of minor importance. It was shown that exhalation to residual volume before inhalation, tilting the neck, breath-holding after inhalation, and pause between the puffs did not improve the response compared with slow inhalation from functional residual capacity when using an aerosol with tube-spacer. 16 With this background, we gave the patients in our study the simple instructions as described, and we optimized the inhalation technique by using the big conespacer with a one-way valve, which so far has been shown to give the greatest aerosol delivery to the lungs. The terminology of positive airway pressure can be confusing, and we find it important to stress that the various forms of PEP mentioned herein has nothing to do with the previously widely used intermittent positive pressure breathing (IPPB). With IPPB, an inspiratory tidal volume was delivered by a simple ventilator; thus, IPPB refers solely to an inspiratory positive pressure and IPPB was shown not to improve the effect of nebulized bronchodilator. 17 In conclusion, our study showed enhanced broncho-

dilation after terbutaline inhaled with PEP, and indicated a bronchodilator effect of PEP alone, and the combination of the spacer with PEP seems to improve inhalation therapy in obstructive pulmonary diseases.

ACKNOWLEDGMENT: Thank you to physiotherapist Tonny Nedel'J!lllll'd for proper and careful instruction. ThanlC you to AstraMeClitec, Denmark, for the Nebuhaler-PEP.mask, and to Draco, Sweden, for providing the terbutaline and placebo metered dose inhalers.

REFERENCES

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