Spacing devices and metered-dose inhalers in childhood asthma

Spacing devices and metered-dose inhalers in childhood asthma

Spacing devices and metered-dose inhalers in childhood asthma H. Levison, M.D., P. A. Reilly, Ph.D., and G. H. Worsley, M.D. T o r o n t o a n d B u r...

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Spacing devices and metered-dose inhalers in childhood asthma H. Levison, M.D., P. A. Reilly, Ph.D., and G. H. Worsley, M.D. T o r o n t o a n d B u r l i n g t o n , Ontario, C a n a d a

THE AOVENT of beta~ selective adrenergic agonists in the treatment of asthma has been accompanied by increased use of aerosols. Recent Canadian prescription statistics show that one fourth of all drugs prescribed for pediatric patients with asthma are in aerosol form. The beta2 ag0nists produce rapid bronchodilation when low doses are administered directly into the bronchial tree. Their success has been followed by the development of aerosol steroids. The usual methods of aerosol formation are either nebulization of an aqueous solution by means of an air compressor or metered delivery from a pressurized freon canister (metered-dose inhaler). The metered-dose inhaler combines portability with a rapid and reliable dose for outpatients. It is reported by many to be difficult to use properly, ~-2 thereby compromising therapeutic response because of decreased or erratic delivery of drug to its site of action in the lungs. To alleviate the perceived coordination problem with the MDI, new devices are being designed and marketed (Fig. 1). These devices can be attached to the MDI, and allow the patient to activate the inhaler and inhale the drug afterward, from the chamber where it is trapped. This eliminates the need for coordination of a slow, deep inspiration with drug release from the MDI. Thus, those individuals who cannot use MDIs may be able to use portable aerosol devices. The new devices have been variously labeled "add-on devices," "extension tubes," and "spacers" (e.g., Aerochamber, Monaghan Medical Corp., Plattsburgh, N.Y.; Inhal-Aid, InspirEase, Key Pharmaceuticals, Miami, Fla.; Cone Spacer, Tube Spacer, A. B. Draco, Lund, Sweden). Their recommendation is rapidly

From the Research Institute, The Hospital for Sick Children, the Division of Chest Diseases, Department of Pediatrics, University of Toronto, and the Department of Pharmacology, University of Toronto; and the Medical Department, Boehringer lngelheim (Canada) Ltd., Burlington. Reprint requests. H. Levison, M.D., The Hospital for Sick Children, 555 University Ave., Toronto, Ont., Canada M5G IX8,

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The Journal of P E D 1A T R I C S Vol. 107. No. 5, November 1985

proliferating among physicians who believe their patients are not using MDIs properly or whose patients complain about difficult instructions. However, a critical analysis of the data supporting the efficacy of the new devices has not yet been carried out. Any evaluation of extension devices necessarily entails a review of the problems and limitations of MDI use, including the impact Of patient techniques, the lung deposition patterns of the aerosol, and the variability in response. Possible improvement after addition of a spacer can then be assessed with the same criteria. Are there particular aspects of the design of Spacers, such as size, shape, or the use of valves, that make one preferable over others? Does the effect of the device interact with the drug? Does a spacer affect dose-response characteristics or duration of drug action? Most important, is there a specific type of patient who can benefit from a spacer? We outline I

FEVj MDI

Forced expiratory volume in 1 second Metered-dose inhaler

]

I

the progress to date in evaluating these issues and suggest areas of future use for spacing devices. LIMITATIONS

OF METERED

DOSE

INHALERS Effective aerosol doses of sympathomimetic drugs are much lower than the corresponding oral doses. For fenoterol hydrobromide, a typical beta2 adrenoceptor agonist, the ratio of equally effective oral and inhaled doses in children is about 25:1.3 However, administration of the aerosol may not be easy for a child. The instructions can be summarized as follows: (1) Shake inhaler; (2) remove cap; (3) tilt head back; (4) perform a slow, deep expiration; (5) place the inhaler in the mouth, with lips sealed; (6) in the middle of a slow deep inspiration, activate the canister; (7) after a full inspiration, hold your breath for at least 5 seconds. Most adults with asthma are unable to perform all of these maneuvers correctly, j When physicians, nurses, and pharmacists were assessed, they also scored poorly on inhaler

Volume 107 Number 5

technique,4 and Newman and Clarke 5 have suggested that they in turn give poor advice to the patients. Noncompliance with instructions thereby is propagated throughout the system. Despite this detailed documentation of patient and physician "error," the relationship of bronchodilator response to many aspects of MDI use does not exist. No correlation between any of the administration maneuvers and response could be demonstrated in a group Of adults with asthma. Furthermore, addition of a small spacer in no way improved the bronchodilation.6 In our laboratory, we purposely desynchronized drug release from the MDI and inhalation of the aerosol by ensuring that the child inhaled only after the MDI was activated. The response to this purposeful hand-lung dyscoordination was similar to the recommended coordinated approach of simultaneous activation and inhalation2 Even a puff from the MDI directed onto the buccal mucosa without regard to phase of respiration produced a therapeutic response in children ages 6 months to 10 years? The impact of hand-lung dyscoordination on therapeutic response seems less than its impact on physician perceptions of inhaler misuse. Nevertheless, an analysis of other components of inhaler technique does reveal that some maneuvers are critical for response. Slow inspiratory flow rates and long (10 seconds) breath holding after inhalation are clearly associated with optimal effects? The coordination of inhaler activation with simultaneous inspiration, although no different from a short delay before inhalation, yields a better response than does a long (>_2 seconds) delay or activation of the MDI followed by exhalation.7' ~0Bronchodilation may also be better with an open rather than closed mouth. H Maximal response to drug has been obtained when inhalation was begun from both nearly empty and nearly full lungs.9, ~: ~2 Simplification of patient instructions to focus on these aspects of technique would improve compliance with the essential maneuvers. Release of medication during a slow inhalation, followed by a long breath h01d, is certainly recommended. Placing the inhaler in front of the open lips may result in aerosol spray directed onto the face rather than into the mouth. Indeed, complicating the instructions may confuse patients and induce improper use of the MDI. Drug inhalation may be further simplified, if necessary, with the sequential technique used in our laboratory5 If the patient first activates the canister, then subsequently (within 1 second of drug release) inhales the drug, the resulting bronchodilation is essentially equivalent to that produced by the coordinated method (Fig. 2). This modification may be particularly suited to the aerosol user who exhales during MDI activation. At least two groups have objectively documented such use) 3 ~4

Spacing devices and metered-dose inhalers in asthma

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663

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\!

\B

L

D

A

Fig. 1. Spacer device. A, Metered-dose inhaler is inserted in one end. B, Adapter for holding inhaler may or may not hold difl'erent drug inhalers, dependingon shape. C, Retention chamber, varying in size from 60 to 1000 ml, holds aerosol cloud after release. D, Exhalation ports, by which patient can exhale without removing mouth from device. E, One-way flap valve, not always present, prevents exhalation into retention chamber. F, lnspiratory flow meter, not always present, ensures slow inspiration. G, Port for inhalation, where patient places mouth.

----

COORDINATED

- -

SEQUENTIAL

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UNCOORDINATED

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.4-

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.2-

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........ I .................

TIME AFTER A D M I N I S T R A T I O N

I

120 IN MINUTES

150

Fig. 2. Change from baseline in FEV1 (_+SE) for three techniques of administration: coordinated, MDI activation and simultaneous inhalation; sequential, MDI activation followed immediately by inhalation; uncoordinated, MDI activation followed by exhalation. There is no significantdifference between coordinated and sequential techniques. (From Rivlin J, Mindorff C, Levison H, Kazim F, Reilly P, Worsley G. J PEDIATR 1983;102:470472. Deposition patterns of aerosols released from an MDI can serve as indicators of what happens to the drug once the patient has released it. More than 80% of the dose is deposited in the oropharynx, as a result of impacti0n of the high-speed aerosol particles. Only 5% to 15% of a dose reaches the conducting airways. Further penetration into

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Levison, Reilly, and Worsley

The Journal o f Pediatrics November 1985

Table. Spacer devices tested in patients with asthma

Aerochamber~,~6.Jg,2o.25 Tube Spacer1~21,22 InhalAid3~ Cone Spacer21,23.29 Reservoir aerosoP4 delivery system (rads)

Response; spacer vs MDI

Volume (m#

Shape

Valve

Better

130 100 700 750 700

Cylindrical 3.2 • 3.2 x 10 cm Barrel shaped Conical Cylindrical

Yes No Yes Yes Yes

X* NA X X

Same or worse

x X* NA

NA, not applicable. *Conflictingstudies.

the terminal airways is limited by sedimentation, airflow, and particle size? Thus a low-velocity aerosol of --<5 ~zm particles inhaled at slow inspiratory rates should result in maximal deposition in the conducting airways. A deep inspiration (to vital capacity), which might allow deep penetration of an aerosol to terminal bronchioles, could be counterbalanced by the high inspiratory flow rates that would naturally accompany such a maneuver. Low inspiratory flow rates, on the other hand, are likely to accompany a more shallow inspiration and improve peripheral deposition. This would explain why only Newman et al., 9 who carefully controlled inspiratory flow rates, show maximum benefit after inhalation from 20% of vital capacity, whereas others, paying less attention to this factor, find maximal effect with almost full lungs? ~.~: Additional variability in deposition is related to the extent of airway obstruction in patients with asthma. The tendency of aerosols to deposit in obstructed large airways occurs with wet nebulization but not with metered-dose aerosols, 5 suggesting that the MDI may be preferable in acute airways obstruction, exactly the opposite of current practice. Because of the therapeutic implication, such observations deserve further investigation. Variations in aerosol response in individual patients and across a population of users are difficult to assess. Decreases in baseline lung function, indicative of worsening asthma, correspond to increased use of inhalers. This suggests either less effectiveness or more urgent requirements for bronchodilation or both. As pulmonary function improves in a child with stable asthma, the measured improvements after bronchodilator may decrease as the response approximates 100% of predicted values, Thus the variable baseline of airflow so characteristic of asthma is an important component of response to aerosols. Variation in inhaler technique, as noted, also contributes to the range of variability in aerosol response. The relative contributions of patient and disease factors remain to be determined.

P O T E N T I A L OF S P A C E R D E V I C E S The instructions for using a spacer device are simple: (1) Insert the inhaler; (2) activate it; (3) inhale from the other end after the drug is released. This is aerosol use made easy. But what has this device done other than simplifying instructions and thereby technique? Is the deposition pattern of the aerosol changed? More important, is therapeutic response improved through consistency in any one patient or on average in the population? The deposition patterns of radiolabeled particles in the lung, as a percentage of total dose, are increased over those with the MDI for at least two spacing devices (Cone Spacer and Tube Spacer) ~5 and are nearly equivalent for another (Aerochamber)? 6 In contrast, the oropharyngeal dose is reduced by a factor of >_10 as a result of the transfer of aerosol impaction from the mouth to the spacing device. Earlier approaches to increasing efficiency of aerosol use focused on the possibility of decreasing cardiac and tremor effects of sympathomimetic drugs by decreasing the oropharyngeal dose. It is now clear that no significant oropharyngeal absorption occurs and that systemic effects are manifestations of the lung dose. ~ Therefore, no particular advantage is gained by using spacers to eliminate oropharyngeal deposition of adrenergic drugs. Steroids, on the other hand, may cause hoarseness, dysphonia, or candidiasis in the throat after deposition. Toogood et al. ~ reduced these effects while increasing therapeutic response by use of the Cone Spacer. An earlier trial in the same laboratory with a prototype Aerochamber led to decreased benefit and adverse effects, probably because the small size decreased the amount available for inhalation?9 Presumably, any device that does not decrease lung dose will be effective in eliminating unwanted local effects of aerosol steroids. A possible alternative to use of a spacer is to gargle after each dose. The lung dose of aerosol particles is only an approximation of the amount of drug at the site of action, because of

Volume 107 Number 5

Spacing devices and metered-dose inhalers in asthma

limitations of radiotracer techniques in discerning small airways from alveoli or large airways. Spacers reduce the size of Freon particles, because a delay between generation of the aerosol and inhalation allows rapid evaporation ("Flash") of the particles before they enter the airways. Smaller particles go farther down the respiratory tree before impacting at bifurcations or sedimenting as a result of gravity. Spacers also increase the proportion of drug reaching the site of action by decreasing the amount lost from impaction. Whether this occurs is dependent on differences between size and shape of spacers and the oropharynx. Different sizes and shapes of spacers may conserve different proportions of aerosol for inhalation. There is a direct relationship between the amount of drug delivered and the size of the spacer. 2~ We have shown a direct relationship between size of spacer and improved bronchodilation in children with asthma. 2' In this context, we can consider the oropharyngeal cavity a holding chamber. Ultimately, the effects of the devices must be measured as improvements in therapeutic response rather than amount of drug delivered. Not all of the devices have been compared with the MDI alone. Of those that have, an equivalent therapeutic response has been cited as justification for use in other, less competent patients. To date, only one study in children with asthma has shown that poor technique is compensated for and bronchodilation increases, whereas in children with good aerosol technique the response is not better when the spacer is added. 2~Most other studies cannot demonstrate improvements in response to MDIs with spacers, except that one device, the Cone Spacer, consistently augments airway response in both children and adults with asthma, regardless o f technique. Thus, the possible target populations who might benefit from the different devices range from a merely theoretical group (Aerochamber) ~6 to a specific subgroup of incoordinated patients (Tube Spacer) z2 to all patients with stable asthma (Cone Spacer). 23 The data in children are summarized in the Table. Some of the sources of differences can be deduced from examination of the characteristics of the devices. CHARACTERISTICS

OF S P A C E R D E V I C E S

The size, or volume, of the apparatus is a critical factor, as reflected in both deposition and pulmonary function studies. In any comparative study, the detectability of differences between the MDI alone and with a spacer depends largely on the number of subjects, given that the baseline lung function is below 80% of normal and the asthma is stable. The power to detect differences in change in FEV~ <250 ml is quite low (/3 >--0.2) with a dozen or

DIFFERENCE IN 1 2 - % CHANGE OF FEV1 (ADD ON - MDI)

665

30 Minutes 9

8-

4-

10

ss

100

16o

"too 1000

SIZE OF SPACER (ML)

Fig. 3. Improvement of response to aerosol bronchodilator from MDI compared with size of spacer reservoir. From Reilly PA, Levison H, Worsley GH, et al. In: Epstein SW, ed. International Workshop on Metered Dose Inhalers. Mississauga, Ont., Canada: Astra Pharmaceuticals Canada Ltd., 1984:134-142. fewer patients. 6 If the differences in response are plotted against spacer size, however, it is clear that a better response is obtained with volumes of >--750 ml (Fig. 3). This improvement is independent of type of patient, inasmuch as unselected patients were used in most of these trials. Therefore, if a patient is inadequately responding to a bronchodilator, a large spacer device can be added to the MDI. Whether the same effect can be accomplished by increasing the dose is discussed subsequently. The mechanism of the augmented bronchodilation is either increased proportion of drug reaching the lung or increased penetration into the small airways. It does not depend on changes in technique! Toogood et al. ~8have confirmed with steroid aerosol that therapeutic response is increased by a large spacer but not by a small one. Many of the new devices incorporate a one-way valve at the mouthpiece, which, in theory, keeps the aerosol from escaping when the MDI is activated or prevents dispersal if the patient breathes into the apparatus. In tests conducted in our laboratories, a large spacer similar to the Cone Spacer but without the valve was as effective in augmenting response to the MDI as the Cone Spacer itself was. 23 Indeed, a recent report documents a patient unable to use a Cone Spacer because of a sticking valve, z4 Two smaller devices, the Tube Spacer and the Aerochamber, generally do not modify response to an MDI in unselected children with asthma, zL2~ but one (Aerochamber) has a valve and the other does not. It seems clear that the valve is not an important characteristic under these conditions, and may complicate use. The putative role of the valve in uncoordi-

666

Levison, Reilly, and Worsley

The Journal of Pediatrics November 1985

litres 0.5-0.4~ 0.3--

Z/I /Z//

I

0.2--

iiI'~

0.1--

0.0--

I

ll

/

O

--0.1 10

I 100

I 1000

DOSE (micrograms)

Fig. 4. Log dose-vs response curve for nebulized fenoterol. Peak response is achieved by 100 #g. (Adapted from Reilly PA, Yahav J, Mindorff C, Kazim F, Levison H. J PEDIATR1983;103:121126.) nated patients is to prevent dispersal of the aerosol if patient exhales when he or she should inhale but should be regarded as unproved until suitable data are published. Spacing devices tend to be more or less cylindrical, with diameter varying from 4 cm (Tube Spacer, Aerochamber) to about 10 cm (InhalAid, InspirEase). No trends emerge, beyond size, to suggest advantages of one design over another. The only exception may be the Cone Spacer, which forms a cone rather than a cylinder, with the MDI placed at the smaller end. The released aerosol cloud forms a rapidly expanding cone, and impaction may be less likely on the walls of the device compared with a cylinder. This conserves drug for inhalation into the lungs. Certainly the augmented response consistently observed with the Cone Spacer suggests that the shape may be beneficial. No other spacing device has such consistently positive results in clinical trials. Two of the currently available spacers have a flowmetering apparatus that indicates excessively rapid inhalation. This is a practical development arising from decreased response observed with increased inspiratory flow.9 It is a further step in optimizing inhaler technique with a spacer. It is assumed that the observation on inspiratory flow rate made with the MD1 alone are also applicable to drug inhaled from a spacer, but no data have yet been published to verify this. In attempting to choose among the different types of spacers, the primary consideration appears to be size. A volume of >__750 ml consistently improves response. A valve has questionable utility, and inspiratory flow meters could possibly help. All of these observations are based on data from unselected patients with asthma, with no refer-

ence to quality of inhaler technique. Very little published information exists on spacers in uncoordinated users, although this is the target population for whom they were designed! Dyscoordination has almosL~lways been based on subjective criteria. This makes it difficult to interpret results from any studies in such patients, because the population is almost certainly heterogeneous with regard to technique. Each subset of subjects could conceivably respond differently to the addition of a spacer. There may be only a single type of usage error that a spacer can correct, but without objective criteria to document technique, or studies of suitably defined patients, the effectiveness of spacers in correcting dyscoordination remains theoretical. The proportion of uncoordinated users among children with asthma, the important types of errors that can be corrected by spacers, and the magnitude of increased benefit deserve further investigation. It may be that size is not the only important consideration. The type of spacer may prove to be inextricably related to the type of patient, the type of drug, and the dosage of drug. D R U G S A N D D O S A G E AS F A C T O R S I N SPACER USE The beta2 adrenoceptor agonist bronchodilators are amenable to analysis of dose-response characteristics because it is easy to assess pharmacologic effect by spirometry. Isoproterenol, metaproterenol, albuterol (salbutamol), terbutaline, and fenoterol are all delivered by MDI. Early assessments of several of these drugs revealed relatively shallow dose-response curves and suggested that changes in airflow were too far removed, physiologically, from the drug-receptor interaction to generate the classic sigmoid log dose-response curve observed in animal studies. Recently, several of these drugs were retested using much lower dose ranges, and classic dose-response relationships emerged. Isoproterenol metered-dose aerosol, for example, causes maximal bronchodilation at a dose of 20 /.tg. 26 Similarly, albuterol and fenoterol (Fig. 4) can yield maximum effects on airways with doses of <100 /.t.g. 27~28 These values are all well below the metered dose available from an MDI (75, 100, and 200 #g for isoproterenol, albuterol, and fenoterol, respectively). The curves are so steep that the doses from a commercial MDI cause maximal or near maximal bronchodilation in patients with stable asthma. It may be possible to lose a large proportion of drug from commercial inhalers as a result of poor technique, yet obtain maximal airways dilation. Apart from one study 22using terbutaline and the Tube Spacer, no spacer studies in children have demonstrated decreased response to an MDI bronchodilator because of poor technique. The dose-response curve of terbutaline deliv-

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Spacing devices and metered-dose inhalers in asthma

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Number 5

ered by MDI may have a maximal response well above 1000 ~g, compared with the 250 ~,g dose released from the commercial inhaler. 29 Decreases in lung delivery of terbutaline therefore may be reflected by decreases in bronchodilation. The provision of supramaximal doses of bronchodilator in some inhalers may not fully explain the lack of effect of poor technique on patient response. Although we were unable to appreciably modify response to fenoterol with either of two models of Aerochamber or a Tube Spacer, the larger Cone Spacer increased fenoterol response (Fig. 5). 2~ If bronehodilation with the MDI alone is already maximal, further response should not be possible. One explanation may be that the Cone Spacer not only shifts the log dose-response curve to the left by virtue of increased lung dose, but also increases maximal response by reaching more distal airway receptors. 29 The decrease in aerosol particle size that occurs from evaporation of the Freon after release from the canister will allow increased penetration to small airway receptors that cannot be reached by larger aerosols inhaled directly from the MD1, regardless of dose. Such observations also predict that an anticholinergic drug, such as atropine or ipratropium bromide, will not be affected by a Cone Spacer, because there are no cholinergic receptors in the distal airways. Whether the different sympathomimetic bronchodilators are interchangeable is not clear. The Cone Spacer will augment effects of fenoterol and terbutaline, whereas the Tube Spacer does not enhance response to fenoterol and may or may not increase the effects of terbutaline. The InspirEase enhances the response to metaproterenoP 4 but has not been tested with other drugs. Huntley and Weinberger's 3~ device has been compared only with nebulized drug, not the MDI alone. The metered doses of the various sympathomimetics and the shapes of the dose-response curves may be factors in assessing new devices. They have not been well studied with spacers and may be less important than the type of patient and the technique used to deliver drug. Epstein et al. 6 have suggested that patients will find, by trial and error, their own means for effectively administering the drug and that sufficient bronchodilator is available in most aerosols to compensate for wasted medication. CONCLUSIONS

AND RECOMMENDATIONS

Attachment of a large reservoir spacer to an MDI improves aerosol delivery to the lungs. There is very limited evidence to support such use in specific subgroups of children with asthma, on the basis of improved pulmonary function. On the other hand, the technique is easier and instructions much simpler, although this may be a reflection of unnecessarily complicated guidelines for can-

PERCENT

CHANGE

IN F E V 1

FROM

BASELINE

40-

30-

20-

10-

9 ..... 9 Spacer m--u Canister o----n Nebuliser

a "''.

O-

a ........ a P l a c e b o "'"',...,.... " ' " 4 .............

-10

10

I 60

I 90

I 120

T I M E (rain)

Fig. 5. Effect of Cone Spacer on FEV~ response to 200 ~g fenoterol from MDI. Largest response is with addition of spacer, Both MDI alone and nebulization of 200 #g aqueous fenoterol produce ,,,25% increase in FEVt. (From Rivlin J~ Mindorff C, Reilly P, Levison H. J PED~ATR1984;104:470-4.73. ister use. Young children can learn to use a spacer at an earlier age than they can an MDI. Other than age, characteristics of the candidate for spacer use are poorly defined. Children who exhale on aerosol release or who do not inhale for >--3 seconds could be possible users. Alternatively, parents of young children with asthma could activate the inhalers in the child's open mouth and obtain an adequate response. The type of device selected should have at least a 750 ml reservoir. Smaller devices have yielded equivocal benefits, and their utility remains to be proved. The portability of the larger devices may limit use outside the home. Whether a valve can help in certain kinds of patients remains hypothetical. The selection of bronchodilator to be used in conjunction with a spacer may be a factor if maximal bronchodilation is not being obtained with conventional doses. Most commercial inhalers appear to provide supramaximal doses, so are probably interchangeable in patients with stable asthma. We recommend testing large spacer devices in children obtaining an apparently inadequate response to the current aerosol regimen and who cannot inspire slowly during or immediately after MDI activation. Flow volume curves, with and without the device attached to an MDI, may help determine benefit, especially in children who are not following standard instructions for MDI use. Patient acceptability and ease of use are important, because these factors will ultimately determine whether the child continues to use the device. The full benefits and limitations of spacers will likely await epidemiologic studies of techniques affecting aerosol response, and possibly develop-

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Levison, Reilly, a n d Worsley

ment of simplified instructions for MDIs. Present evidence indicates that large spacers act soleiy by increasing lung dose, even in competent M D I users. The use of sympathomimetic aerosols is expanding rapidly as alternative methods for delivery become available, allowing all types of patients to use them. The determination of suitability o f various devices for different patients will improve response to these drugs and ultimately improve the treatment of asthma. REFERENCES

1. Epstein SW, Manning CPR, Ashley M J, Corey PN. Survey of the clinical use of pressurized aerosol inhalers. Can Med Assoc J 1979;120:813-816. 2. Crompton GK. Problems patients have using pressurized aerosol inhalers. Eur J Respir Dis 1982;63 (suppl 119):101104. 3. Gurwitz D, Mindorff C, Levison H, Reilly PA. Long-term evaluation of fcnotcrol by two different methods of administration (oral versus metered aerosol). J Asthma 1983;20:3134. 4. Kelling JS, Strohl KP, Smith RL, Altose MD. Physician knowledge in the use of canister nebulizers. Chest 1983;83:612-614. 5. Newman SP, Clarke SW. Therapeutic aerosols, l. Physical and practical considerations. Thorax 1983;38:881-887. 6. Epstein SW, Parsons JE, Corey PN, et al. A comparison of three means of pressurized aerosol inhaler use. Am Rev Respir Dis 1983;I28:253-255. 7. Rivlin J, Mirldorff C, gevison H, et al. Effect of administration technique on bronchodilator response to fenoterol in a metered-dose inhaler. J PEmawa 1983;102:470-472. 8. Shore SC, Wcinberg EG. Administration of bronchodilator to young children. Br Med J 1973;2:350. 9. Newman SP, Pavia D, Clarke SW. How should a pressurized beta-adrenergic bronchodilator be inhaIed? Eur J Respir Dis 1981;62:3-21. 10. Bloomfield P, Crompton GK, Winsey NJP. A tube spacer to improve inhalation of drugs from pressurized aerosols. Br Med J 1979;2:1479. 11. Williams T, Reilly PA, Thomas P, Bradley D. Modifying delivery technique of fenoterol from a metered dose inhaler. Ann Allergy 1984;52:279-281. 12. Riley DJ, Weitz BW, Edelman N H. The response of asthmatic subjects to isoproterenol inhaled at different lung volumes. Am Rev Respir Dis 1976;1 I4:509-515. 13. Shim C, Williams MH Jr. The adequacy of inhalation of aerosol from canister nebulizers. Am J Med 1980;69:891894. 14. Tobin MJ, Jenouri G, Danta l, ct al. Response to bronchodilator drug administration by a new reservoir aerosol delivery system and a review of other auxiliary delivery systems, Am Rev Respir Dis 1982;126:670-675.

The Journal o f Pediatrics November 1985

15. Newman SP, Mor6n F, Pavia D, et al. Deposition of pressurized suspension aerosols inhaled through extension devices. Am Rev Respir Dis 1981;124:317-320. 16. Dolovich M, Ruffin R, Corr D, Newhouse MT. Clinical evaluation of a simple demand inhal~ttion MDI aerosol delivery device. Chest 1983;84:36-41. 17. Ruffin RE, Montgomery JM, Newhouse MT. Site of betaadrenergic receptors in the respiratory tract: use of fenoterol administerd by two methods. Chest 1978;74:256-260. 18. Toogood JH, Baskerville J, Jennings B, Lefcoe NM, Johansson SA. Use of spacers to facilitate inhaled corticosteroid treatment of asthma. Am Rev Respir Dis 1984;129:723729. 19. Toogood J, Jennings B, Baskerville J, Newhouse M. Assessment of a device for reducing oropharyngeal complications of beclomethasone aerosol therapy. Am Rev Respir Dis 1981;123:113. 20. Corr D, Dolovich M, McCormack D, et al: Design and characteristics of a portable, breath actuated, particle size selective medical aerosol inhaler. J Aerosol Sci 1982;13:1-7. 21. Reilly PA, Levison H, Worsley GH, et al. Add-on devices for delivery of aerosol drugs to children. In: Epstein SW, ed. International Workshop on Metered Dose Inhalers. Mississauga, Ont., Canada: Astra Pharmaceuticals Canada Ltd., 1984;134-142. 22. Pedersen S. Aerosol treatment of bronchoconstriction in children with or without a tube spacer. N Engl J Med 1983 ;308:1328-1330. 23. Rivlin J, Mindorff C, Reilly PA, Levison H. Pulmonary response to a bronchodilator delivered from three inhalation devices. J PEDIATR 1984;104:470-473. 24. Cox ID, Wallis PJW, Apps MCP. Potential limitations of conical spacer device in severe asthma. Br Med J 1984;288:1044. 25. Gurwitz D, Levison H, Mindorff C, et al. Assessment of a new device (Aerochamber) for use with aerosol drugs in asthmatic children. Ann Allergy 1983;50:166-170. 26. Williams MH Jr, Kane C. Dose response of patients with asthma to inhaled isoproterenol. Am Rev Respir Dis 1975; I 11:321-324. 27. Reilly PA, Yahav J, Mindorff C, et ah Dose-response characteristics of nebulized fcnoterol in asthmatic children. J PEDIATR 1983;103:121-126. 28. Harvey JE, Tattersfield AE. Airway response to satbutamol: effect of regular salbutamol inhalations in normal atopic and asthmatic subjects. Thorax 1982;37:280-287. 29, Cushley M J, Lewis RA, Tattersfield AE. Comparison of three techniques of inhalation on the airway response to terbutaline, Thorax 1983;38:908-913. 30. Huntley W, Weinberger M. Evaluation of bronchodilation from aerosol beta-2 agonists delivered by the InhalAid device to young children. J Asthma 1984;21:265-270.