Patient handling of a multidose dry powder inhalation device for albuterol

DOI 10.1378/chest.105.4.1077 1994;105;1077-1081Chest

S Kesten, M Elias, A Cartier and K R Chapman inhalation device for albuterol.Patient handling of a multidose dry powder

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*From the Respiratory Division, Toronto Hospital, Toronto,Canada.Supported by Claxo Canada Inc.

Manuscript received June 2, 1993; revision accepted August 19.

CHEST/ 105/4/APRIL 1994 1077

Patient Handling of a Multidose DryPowder Inhalation Device for Albuterol*Steven Kesten, M.D., F.C.C.P.; Martine Elias, M.Sc.;

Andr#{233} Cartier, M.D.; and Kenneth R. Chapman M.D., F.C.C.P.

Background: Studies have suggested that novel in-haling devices may be misused by patients andmedical personnel in the clinical setting soon aftertheir introduction. To assess the adequacy of pa-tient handling of a newer multidose dry powder

albuterol inhaler, we conducted a comprehensivesurvey of use in primary and respiratory practices.Methods: Patients 6 years of age and older and

requiring inhaled fig-agonist for the treatment ofstable obstructive airways disease were recruitedfrom the practices of primary care and specialist

physicians. After instruction from their physician orclinic staff in the use of a multidose dry powderalbuterol inhalation device (Diskhaler), patientsused the device in unblinded fashion for 2 weeksinstead of their usual fl2-agonist. After 2 weeks,

patient use of the device was assessed at a returnclinic visit.Results: A total of 4,529 patients with reversible

airways obstruction participated in a 2-week assess-ment of the device and compared it with their previ-ous az-agonist delivery system. Significantly more

patients preferred the dry powder device (54 per-

cent) over their previous device (29 percent)

(p<O.OOl), with 17 percent expressing no prefer-

ence. After instruction, 98.5 percent of patientscould demonstrate adequate use at the initial visit.Performance difficulties at the initial visit resultingin exclusion from the trial were infrequent but

more common in the elderly (3 percent vs 0.2percent for all other age groups combined, p<O.OOl).

Despite adequate use at the initial visit, at theconclusion of the trial, incorrect use of the devicewas noted in 10.2 percent of the elderly vs 3.2

percent of all other age groups combined (p<O.OOl).Albuterol delivered by Diskhaler was well toler-ated in all patient groups.Conclusions: A majority of patients are able to usea multidose dry powder albuterol inhaler device inthe clinical setting, and prefer the device to previ-

ously used p2-agonist inhalation devices. However,follow-up shows that problems with device handlingmay become apparent in as little as 2 weeks afterinitial instruction, thereby mandating the need forperiodic follow-up and reinstruction.

(Chest 1994; 105:1077-81)

MDlmetered-dose inhaler

I nhaled medication has been the cornerstone of

therapy in obstructive lung diseases for more

than a decade. The initial enthusiasm for pressur-

ized aerosol delivery systems has been tempered by

the realization that not all patients are able to use

such devices adequately. In one of the earliest

reports, Saunders’ found that 11 of 46 patients used

their aerosol inhalers incorrectly, resulting in little

or no response to bronchodilator. Orehek and col-

leagues2 found that the inhalation technique was

suboptimal in 15 of 20 patients. A study by Epstein

and colleagues3 noted that only 98 of 180 patients

could perform as many as 6 of 11 inhaler handling

steps correctly. Subsequent studies have confirmed

the earlier reports as well as noting an increased

frequency of problems in optimal use of aerosol

devices in the elderly.49

To address such problems, alternative delivery

systems for inhaled medication have been devel-

oped. Add-on spacer devices can improve the ability

to use an inhaled device,’0”1 but they are somewhat

cumbersome to carry. Dry powder delivery systems

are also widely available and seem to be as effective

as aerosols when used appropriately.’#{176}�2 One such

device is the multidose dry powder Diskhaler sys-

tem. This device allows the inhalation of medication

when the patient uses it to puncture one of eight

blisters of prepackaged drug on a metal foil disk. A

presumed advantage of the system is the ability to

track accurately the number of doses administered

each day.

Published studies evaluating efficacy, performance,

and adverse effects of inhaled bronchodilators and

their delivery systems have generally been con-

ducted under tightly controlled conditions in small

numbers of carefully selected subjects. Studies un-

der such conditions may fail to reveal potential

problems when the device is used under less than

ideal clinical conditions in large numbers of pa-

tients. For this reason, large surveillance studies are

needed to detect and subsequently correct prob-

lems in usage.

The following report documents the findings of a

community-based surveillance study involving 414



physicians and more than 4,000 patients. The objec- Table 1-Ability to Use the Disk System of the Initial Visit*

1078 Patient Handling of Muttidose Dry Powder Inhalation Device (Kesten eta!)

tives of this study were to evaluate the safety,

acceptance, and ability to use the albuterol multidose

dry powder inhaler under realistic clinical condi-

tions.

Clinical Setting

METHODS

An attempt was made to enlist the participation of physicians

from all geographic regions of Canada. Physicians could be

primary care physicians or specialists, in private or academic

practice, practicing in a group or independently, and working

with or without a nurse or other individual counseling patients

in the correct use of inhaling devices. Physicians were asked to

complete a clinical record form for each of ten asthmatic

patients enrolled into the study over the recruitment period of

20 months.

Patients

Patients were eligible to participate in the study if they were

6 years of age or older, had stable obstructive lung disease as

diagnosed by their physicians, and used an inhaled fl2-agonist

at the time of recruitment. Patients were excluded if they had

previously used the multidose dry powder inhaler system and if

there was a history of significant cardiovascular, endocrine,

hepatic, or renal impairment. Women who were pregnant or of

childbearing potential and not using adequate contraception

were also excluded.

Study Design

The study was an open design of 2 weeks� duration. Dosage

was assigned in a nonrandom manner at the discretion of the

physician. Patients were prescribed an appropriate dosage of

salbutamol that reflected their normal daily dosage regimen of

inhaled fls-agonist. If the patient was using the albuterol dry

powder capsules (Rotacap), the dosage of salbutamol remained

the same. If the patient was using an albuterol metered-dose

inhaler (MDI), twice the microgram dosage was administered

in disk format up to a daily maximum of 1,600 sg in adults

(4 blisters Ventodisk, 400 big, or 8 blisters Ventodisk, 200 �g/d)

and 800 �g in children (4 blisters Ventodisk, 200 �g/d). The

proper use of the device (Tables 1 and 2) was demonstrated to

all patients who in turn were asked to demonstrate their ability

to use it. Patients were requested to take all other regular

medications for asthma or for other conditions as prescribed. At

the end of the 2 weeks, patients were asked to demonstrate their

ability to use the disk device and to evaluate it on the basis of

whether or not they preferred it over the previously used device.

Patients were also asked whether they had experienced any

medical problems since the previous visit. All adverse experi-

ences and intercurrent illnesses occurring during the course of

the trial were recorded as adverse events, regardless of the

apparent relationship to study treatment. Patients were asked if

they had taken the study medication as prescribed. Reasons for

noncompliance were noted in the case record form and, if

appropriate, were documented as adverse events. A major

adverse event was defined as either death, life-threatening

events, disabling or incapacitating events, or events requiring or

prolonging hospitalization.

Data Analysis

The analysis for the correct use of the device at the initial visit

was performed based on all patients enrolled into the study

(n4,572). All the other analyses were based on those patients

Step

Atte mpt, No .(%)

First Second Third Failed Missing

Remove mouthpiece 3,992 505 89 6 30

cover (87) (11) (1) (0) (1)

Load disk into 8,371 1,031 123 15 32

Diskhaler (74) (23) (3) (0) (1)

Puncture blister 8,766

(82)

702

(15)

61

(fl11

(0)

32

(1)

Inhale from device 3,854

(84)

613

(13)

58

(1)

16

(0)

31

(1)

Rotate disk to next 3,599 845 78 16 34

blister (79) (19) (2) (0) (1)

Clean the device 4,158

(91)

839

(7)

29

(1)

5

(0)

41

(1)

*First second, and third refer to the attempt that was successful.

Unavailable data are listed under �Missing.’

who were eligible and demonstrated correct use of the device at

the initial visit (n4,529). Fisher’s exact test was used for

comparisons among the three age groups (<13 years. 13 to 64

years, >64 years) for adverse events, treatment failures, device

preference, and ability to perform the six disk device-handling

steps correctly at the initial visit and after 2 weeks. The analyses

of overall device preference for all age groups and for all

previous device groups were performed using the sign test. Data

are expressed as proportions or means ± SD. Statistical signifi-

cance was considered when p<O.O5.

Patient Population

RESULTS

A total of 4,572 patients were screened. Forty-

three patients were excluded at the initial screening

for a variety of nonmedical and nondevice (0.9

percent) reasons (ie, inability to return in 2 weeks

for follow-up assessment). Of the 4,572 patients, 49

percent were male and 51 percent were female. The

mean age was 39±22 years; 15 were younger than 6

years, 658 were between the ages of 6 and 12 years,

Table 2-Ability to Use the Disk System

After 2 Weeks of Treatment*

Step

Attempt, No. %

Correct Incorrect Missing

Remove mouthpiece cover 4.246

(94)

9

(0)

274

(6)

Load disk into Diskhaler 4,208

(93)

48

(1)

273

(6)

Puncture blister 4.211

(93)

45

(1)

273

(6)

Inhale from device 4,205

(98)

50

(1)

274

(6)

Rotate disk to next blister 4,218

(98)

41

(1)

275

(6)

Clean the device 4,130

(91)

102

(2)

297

(7)

*Unavailable data are listed under “Missing’



Table 3-Patient Preference for Delivery SystemAccording to Previous Device

and by slightly

ously used an

The majority

over half of the patients who previ-

MDI (p<O.OO1 for both) (Table 3).

of pediatric patients preferred the

CHEST/105/4/APRIL, 1994 1079

3,110 were between the ages of 13 and 64 years, and

793 were patients older than 64 years. Age was not

specified in one patient. The mean duration of

obstructive lung disease was 11 years. Fifty-five

percent of the patients were nonsmokers while 45

percent were either exsmokers or present smokers.

Only two patients were considered to have severe

hand problems which could have affected their

handling of the disk device.

At the time of recruitment, 78 percent of patients

were using an MDI alone and 5 percent were using

an MDI with a spacer attachment. Other dry pow-

der inhalers (Rotacap) were used by 11 percent of

the patients. A nebulizer was used by 161 patients.

The remaining patients (n101) used more than one

device prior to the study.

Approximately 56 percent of subjects were as-

signed to use the disk device four times a day, 11

percent three times a day, 9 percent twice a day, 1

percent once daily, and 21 percent stated they used

it as needed. A total of 41 percent of patients were

taking concurrent inhaled corticosteroids.

Patient Performance

Following a demonstration by the investigator, 74

percent of patients were able to perform all maneu-

vers correctly on their first attempt. Approximately

98.5 percent of patients could perform all steps

correctly after three attempts. Thirty patients were

withdrawn because of failure to perform all steps

correctly after three attempts. Performance diffi-

culties at the initial visit resulting in exclusion from

the trial were infrequent but more common in the

elderly (3 percent vs 0.2 percent for all other age

groups combined, p<O.OO1). At the initial visit, the

most common errors occurred when loading the

disk into the inhaler (Table 1). After at least 2 weeks

of treatment, 89.2 percent of patients performed

the different maneuvers correctly with 4.2 percent

of patients unable to do so. Data were unavailable

for 6.6 percent of the patients. At the conclusion of

the trial, incorrect use of the disk device was noted

in 10.2 percent of the elderly and 3.2 percent of all

other age groups combined (p<O.OO1). By contrast

to the initial visit, the most common error at the

conclusion of the trial was in cleaning the device.

This was the most successfully performed maneuver

at the initial visit (Table 2).

At the end of the study, 89 percent of the re-

turned devices were working correctly and 1 per-

cent were not functioning properly; however, data

were unavailable for 10 percent of patients.

Patient Preference

The disk device was preferred by the majority of

patients who previously used dry powder inhalers

Previous

Device, %

Previous No Preference

Device Diskhaler Device or Not Stated

MDI 52 31 17

MDI + spacer 55 30 15

Dry powder 68 18 14

Other 59 20 21

Total 54 29 17

disk delivery system to their previous inhalation

device (p<O.OO1). Approximately half of the adult

and the elderly population preferred the disk deliv-

ery system to their previous inhaler device (p<O.OO1)

(Table 4). In total, 54 percent of patients preferred

the disk device to their previous device (p<O.OOl),

29 percent preferred their previous device, 12 per-

cent expressed no preference, and 5 percent did not

give their opinion. There was no difference in

patient preference by gender; 55 percent of female

and 54 percent of male patients preferred the disk

device over their previous p2-agonist inhaler.

Withdrawals and Adverse Events

A total of 540 patients (12 percent) were with-

drawn from the study; 50 patients in the pediatric

group (8 percent), 363 patients in the adult group

(12 percent), and 127 patients in the elderly popu-

lation (16 percent). Reasons for withdrawal are

listed in Table 5. Failure to return was the most

often reported reason for withdrawal in both pedi-

atric and adult groups (approximately 4 percent in

each), whereas difficulty in use was the most com-

mon reasons for withdrawal in the elderly popula-

tion (5 percent).

A total of 646 adverse events were reported by

491 patients (11 percent); 54 were reported by the

6- to 12-year-old group, 466 events by the 13- to 64-

year-old group, and 126 e�vents by the 65 years of

Table 4-Patient Preference for Delivery SystemAccording to Age Group

Device, %

Previous No Preference

Age, yr Diskhaler Device or Not Stated

<13 78 9 13

13-64 49 33 18

>64 52 33 15

Total 54 29 17



1080 Patient Handling of Multidose Dry Powder Inhalation Device (Kesten eta!)

Table 5-Summary of Reasons for WithdrawalFrom the Study*

Reason for Withdrawal,

No. (%)

Age , yr

,�

<13 13-64 >64

.

Total

Difficult to use 4

(0.6)

8

(0.3)

40

(5.0)

52

(1.1)

Disliked device, drug 1 35 20 56

or study (0.2) (1.1) (2.5) (1.2)

Exacerbation of asthma 3

(0.5)

29

(0.9)

7

(0.9)

39

(0.9)

Failure to return 25

(3.7)

137

(4.4)

12

(1.5)

174

(3.8)

Ineffectiveness of drug 4

(0.6)

63

(2.0)

24

(3.0)

91

(2.0)

Major adverse event 1

(0.2)

6

(0.2)

5

(0.6)

12

(0.3)

Nonmajor adverse 5 66 29 100

event (0.7) (2.1) (3.7) (2.2)

Other 10

(1.5)

45

(1.5)

5

(0.6)

60

(1.3)

*Multiple reasons were given by several patients.

tioned are listed.

All reasons men-

age and over group. The most frequently reported

adverse events were tremor and cough in children

and adults: among children, 5 patients (1 percent)

reported tremor and 7 reported cough (1 percent);

in the adolescent/adult population, 97 patients (3

percent) reported tremor and 54 reported cough (2

percent). Cough and headache were the most fre-

quently reported adverse events among the elderly;

17 patients (2 percent) reported cough, 11 patients

(1 percent) reported headache, and 8 patients (1

percent) reported tremor. A total of 183 patients

(4.0 percent) were classified as treatment failures,

as indicated by worsening of their asthma while

receiving therapy.

A total of 112 patients (2.5 percent) were with-

drawn from the study due to adverse events (100with nonmajor adverse events and 12 with major

adverse events). Of the 112 patients withdrawn, 88

patients experienced adverse events considered by

the investigator to be “drug related.”

Of the 19 major adverse events reported, only 12

resulted in withdrawal. Three of these major ad-

verse events were considered by the investigator to

be “drug related” (ie, assessed as either possibly,

probably, or almost certainly drug related). These

events were exacerbation of asthma within 48 h of

starting therapy, “choking” and elevated blood pres-

sure, and dyspnea and rash.

DISCUSSION

The objectives of this study were to assess the

efficacy of albuterol delivered by a multidose dry

powder disk system in a large population of patients

with reversible airways obstruction being treated in

a realistic clinical venue. The medication and device

were well tolerated with 11 percent of patients

reporting adverse effects; these were generally mi-

nor and only infrequently resulted in withdrawal

from the study. There were no differences in the

incidence of adverse effects in the elderly compared

with the other age groups. Patient acceptance of the

device was high with a majority of patients prefer-

ring the disk system over their previous system

regardless of age or gender. The proper use of the

inhaler device could be taught easily to the majority

of patients. However, a small number of patients

demonstrated inadequate handling after 2 weeks of

use suggesting the need for repeated verification of

and teaching of inhaler technique.

Perhaps the most important barrier to effective

delivery of inhaled medication is the ability of the

patient to use the delivery systems adequately.

Studies have demonstrated that a significant pro-

portion of patients cannot properly coordinate the

use of the oldest delivery system, the aerosol

MDI.’8 While this difficulty is evident in all age

groups, elderly patients may represent a group at

higher risk of inadequate technique.9 Therefore, the

disk system described herein may have a particu-

larly useful role in such patients, although we note

that the elderly group in this study was more likely

to have had difficulties in using the device.

Newer inhaled medication delivery systems and

add-on spacer devices have been developed in the

hope of creating a more “user friendly” system that

can deliver an accurate amount of medication. Add-

on spacer devices have the additional advantage of

decreasing local deposition of drug.13 Both add-on

spacers and a multiple-dose dry powder delivery

system (Turbuhaler) have been favorably evalu-

ated as replacement devices for those with difficul-

ties using MDIs.’#{176}”2 The disk system has also been

proposed as another alternative to the MDI.

Studies under well-controlled conditions with

oarefully screened patients with relatively small

numbers have demonstrated the effectiveness of

the disk system compared with the MDI and the

Turbuhaler system.’4”5 It appears that all presently

available delivery systems are capable of delivering

effective doses of �2-agonists. However, the artifi-

cial conditions of these studies and the relatively

small numbers of subjects evaluated may not be

representative of important clinical findings in the

community once a device is available. Infrequent

significant adverse events may be uncovered only in

large studies.

In the present study, the most common, albeit

infrequent, side effects were cough, tremor, and

headache. An age-related increase in any of the

common adverse events was not found. There were



CHEST/105/4/APRIL,1994 1081

only 3 of 4,572 patients who experienced major

adverse events that were considered to be drug

related (allergic reaction in 1, increase in asthma

symptoms in 1, and increase in blood pressure in

1). The rate of withdrawal due to deteriorating

asthma was not inordinately high compared with

other studies.’4

We recognize the limitations of this relatively

simple open and unblinded trial. However, the

latitude of such a design allows for the recruitment

of large numbers of subjects and important evalua-

tions of infrequent events and general acceptance

or lack of acceptance of a new device and/or drug

under realistic conditions. In addition, the large

number of subjects recruited in this study forms an

appropriate baseline for the expected incidence of

adverse effects associated with inhaled j32-agonists,

a feature that may be important when comparing

presently available agents with newer, longer-acting

preparations.

In summary, the Diskhaler system represents a

reasonable alternative to other available inhaled

airway medication delivery systems; it is easy to

learn, well accepted, effective, and has a low inci-

dence of adverse events. These conclusions apply to

all age groups, although the elderly may require

additional monitoring to ensure they are able to use

the device properly.

ACKNOWLEDCMENTS: We wish to gratefully acknowledgethe invaluable assistance of Wendy Cirling, Raymond Lam, andElizabeth Pellegrini in the preparation ot this manuscript.

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DOI 10.1378/chest.105.4.1077 1994;105; 1077-1081Chest

S Kesten, M Elias, A Cartier and K R ChapmanPatient handling of a multidose dry powder inhalation device for albuterol.

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