Thorax 1983;38:881-886

Editorial

Therapeutic aerosols 1-Physical and practicalconsiderationsThe inhaled route is a logical means of treatingrespiratory disorders since drugs may be delivereddirectly to the large surface area of the tracheobron-chial tree and alveoli. The value of inhalation treat-ment was recognised by ancient civilisations inIndia, China, and the Middle East, as well as byHippocrates and Galen.' Since those times, and par-ticularly recently, inhalation treatment has increasedgreatly in sophistication, and the advantages of thisroute for the delivery of specific drugs have becomewell recognised. The drugs often begin to act veryrapidly, and as a smaller dose can be used than withoral or intravenous delivery there is generally areduction in the incidence of systemic side effects.

This review is in two parts. This first part willdiscuss the physical nature of therapeutic aerosolsand the importance of ensuring correct use of thevarious inhalation devices if aerosols are to reachtheir required site of action-so far as that is known.The second part will describe the wide range ofdrugs which may be given in aerosol form as topicaltreatment for pulmonary disorders and in someinstances as a form of systemic treatment.

Aerosol kinetics

An aerosol is a suspension of solid particles or liquiddroplets in air. An important but often neglectedaspect of the therapeutic use of aerosols is the factthat they are subject to the laws of aerosol kinetics.These laws govern deposition within the respiratorytract and are concerned principally with inertialimpaction and gravitational sedimentation.2 Othermechanisms, of which Brownian diffusion is the bestknown, are probably of little relevance for therapeu-tic aerosols, and will not be considered further.

Inertial impaction occurs chiefly with larger par-ticles whenever the transporting airstream is fast,changing direction, or turbulent (for example, in theoropharynx or at bifurcations between successiveairway generations). Inertial deposition therefore isconfined mainly to the upper airways-nose, mouth,pharynx, and larynx-and large conducting airwaysof the lung down to 2 mm in diameter. Here thecross sectional area is small and the flow high.Address for reprint requests: Dr SW Clarke, Department of:Thoracic Medicine, Royal Free Hospital, London NW3 2QG.

Gravitational sedimentation, by contrast, is a timedependent process in which small aerosol particlessettle in airways under the effect of gravity, duringeither breath holding or slow tidal breathing. Ittakes place mainly in small airways (<2 mm diam-eter) and alveoli, where the rapid increase in crosssectional area gives low flows and where large par-ticles will rarely penetrate. This combination ofsmall particles in small airways with low flows givestime for the particles to sediment for the shortdistance required.

In general, most aerosol particles greater than 8,am diameter will impact above the level of thelarynx and will not reach the lung.3 Particles of 1-8,um may be deposited by impaction and sedimenta-tion in both large and small airways and alveoli. Par-ticles less than 1 ,um diameter may not be depositedat all, many being respired like an insoluble gas. Ofcourse, the overlap between particle sizes and areaof deposition may be considerable.

Factors affecting deposition

A wide range of other factors influences the deposi-tion of aerosols within the respiratory tract. Thesecan be conveniently divided into three categories:(a) mode of inhalation, (b) aerosol properties, and(c) factors relating to the patient.

MODE OF INHALATIONThe most important features of inhalation are theinhaled volume, the flow rat,, and any breath hold-ing pause maintained at end inspiration. The greaterthe inhaled volume the more peripherally the par-ticles will be distributed in the lungs.4 By contrast, asthe inhaled flow rate is increased particles are morelikely to be deposited in the oropharynx or in thelarge central airways of the lungs by inertial impac-tion.4 A period of breath holding enhances deposi-tion in the more peripheral parts of the lungs bygravitational sedimentation.5

AEROSOL PROPERTIESThe vital physical property of the aerosol itself is theaerodynamic diameter (the product of physicaldiameter and the square root of density). Aerosolparticle size may be measured by several techniques,

881

copyright. on S

eptember 28, 2020 by guest. P

rotected byhttp://thorax.bm

j.com/

Thorax: first published as 10.1136/thx.38.12.881 on 1 D

ecember 1983. D

ownloaded from

882

the best known of which are cascade impaction6 andlaser light scattering.7 As the aerodynamic diameterincreases from about 2 ,um deposition in theoropharynx and large conducting airways becomesmore likely, although less aerosol is exhaled and lessreaches the most peripheral parts of the lung.89Therapeutic aerosols are usually heterodisperse-that is, they comprise particles of many differentsizes-and their behaviour is probably bestdescribed by the mass median aerodynamic diam-eter (MMAD)'°; half of the aerosol mass is containedin particles smaller and half of the aerosol mass inparticles larger than the MMAD. The ideal size for atherapeutic aerosol is not known precisely but it:may be assumed that the MMAD should be notmore than 5 Am to penetrate into the tracheobron-chial tree and smaller airways if peripheral deposi-tion is required. Most therapeutic aerosols are hy-groscopic, however, and the inhaled particles absorbwater within the humid environment of the respirat-ory tract, subsequently enlarging in size, so that theiraerodynamic behaviour is not fully understood.

FACTORS RELATING TO THE PATIENTThere is a wide intersubject variability of aerosoldeposition apparently related to random anatomicalvariations of airway geometry." Particles of a givensize inhaled during tidal breathing are more readilydeposited in central lung zones in patients with air-way obstruction, and fewer particles reach thelung periphery.4 12 13 Thus the presence of airwaysobstruction is a major determinant of particle depos-ition, with one curious exception. Recent studies ofsingle breath metered dose aerosol deposition haveshown little or no relationship between those depos-ition patterns and the degree of airway obstruc-tion,'4 's suggesting that this type of aerosol canpenetrate equally well to the lung periphery inpatients with both mild and severe airway obstruc-tion.

Types of inhalation device

How do these considerations apply to aerosolsreleased from the various types of inhalation deviceused for treatment? There are three types of devicein common use-the metered dose inhaler (MDI),the dry powder inhaler, and the nebuliser-and eachwill be considered in turn.

METERED DOSE INHALERMetered dose aerosols may be formulated either assuspensions of fine drug crystals or as drug solutionsmixed with chlorofluorocarbon propellants. Ineither case the propellant droplet size, rather thanthe drug particle or droplet size, may influence thesite of deposition.

The propellants have a high vapour pressure ofabout 400 kPa keeping them in the liquid phasewithin the canister. When the aerosol is actuated,the contents of a small metering chamber arereleased with rapid, initial vaporisation of propel-lant, often called "flashing." This breaks up theliquid stream into droplets, which may typically havean MMAD exceeding 35 ,um at the actuatororifice.'6 Particle size reduces to 14 ,um at a distance'of 10 cm and is only marginally less at 25 cm fromthe canister. The propellant droplet velocity may ini-tially exceed 30 m per second (the legal motorwayspeed!).The particle size and velocity of the aerosol

ensure that, although the MDI is compact and port-able, contains several hundred doses, and is appar-ently easy to use, only about 10% of the dosereaches the lungs." Most of the particles impact inthe oropharynx.

Matters are often made worse by failure on thepart of the patients to use the MDI properly. Theincidence of inhaler misuse is high,'8 and this may bedue at least in part to the differing and rather confus-ing instructions issued to patients in manufacturers'leaflets. The most important error is failure to coor-dinate firing the MDI with inhaling (often called a"hand lung" problem), since patients must timetheir inhalation correctly in order to "catch" therapidly moving bolus of aerosol.'9 Many patientsstop inhaling at the moment the aerosol spray isreleased, in reaction to the cold propellant sprayhitting the back of the mouth.19 Other patientsinhale too quickly, or fail to breath hold adequ-ately.'8 Unfortunately, inadequate knowledge aboutgood inhaler technique is not confined topatients-a high proportion of physicians, nurses,and pharmacists may be unable to use an MDI cor-rectly.202' Thus it is likely that many patients usetheir MDIs incorrectly because of poor advice.The optimal mode of inhalation, which maximises

both aerosol delivery to the lungs as assessed byradiotracer techniques22 and bronchodilatorresponse to a metered dose inhaler,23 has recentlybeen explored. This mode involves two vital fea-tures: firstly, firing the MDI during a slow, steadyinhalation and, secondly, following this with a

period of 10 seconds' breath holding (or if less for as

long as possible). Slow inhalation reduces impactionlosses in the upper airways, and breath holdingallows those particles which reach the lungperiphery to settle on to the airways under gravity.Both these features are essential. The bron-chodilator response may not be enhanced by slowinhalation unless the patient holds his breath for 10seconds,24 and bronchodilatation may not beenhanced by breath holding unless the patient

copyright. on S

eptember 28, 2020 by guest. P

rotected byhttp://thorax.bm

j.com/

Thorax: first published as 10.1136/thx.38.12.881 on 1 D

ecember 1983. D

ownloaded from

inhales slowly.'5 Even with this optimal technique(termed the "10 second rule"), no more than about15% of the available dose reaches the lungs. Thismethod is simple and well within the compass ofmost patients. There are some, however, who willnever master the technique, and who should begiven treatment with alternative types of inhalationdevice.

It should be noted that the lung volume at whichaerosol is released and the subsequent inspired vol-ume of air are both relatively unimportant, providedthat inhaled flow rate and breath holding are opti-mal. A delay of about 15 minutes between succes-sive doses of bronchodilator is often advocated, toallow the first dose to act before the next dose isgiven.26 Not all studies, however, have found thisapproach beneficial,2' and since it makes treatmentrather more complicated it may reduce the patient'scompliance. It seems preferable to recommend an

interval of about one minute between successivedoses-long enough to let the actuator nozzle andvalve stem warm up from the sudden temperaturedrop (- 15°C) that occurs each time the inhaler isfired. Theoretically, successive firing may progres-

sively reduce the temperature of the spray, thoughin practice there is no evidence that this matters. Arecent study28 found comparable effects whetherbronchodilator and corticosteroid doses were spaced30 seconds or 7-8 minutes apart, suggesting that thelonger interval between doses did not enhance drugpenetration.An "open mouth" MDI technique has been

advocated-in which the inhaler is held 3-5 cm fromthe open mouth or between the open lips. While thistechnique should reduce oropharyngeal losses ofdrug, and has been shown to enhance therapeuticeffect,29 it cannot be recommended for general use

as the spray may well miss the mouth entirely. Point-ing the inhaler upwards on to the roof of the mouthor downwards on to the tongue are further commonerrors to be avoided. To help patients with coordina-tion problems, breath actuated MDIs have beenintroduced in which the patient's inhalation triggersa spring mechanism which fires the inhaler. Thesedevices tend to release the aerosol rather noisily andviolently, and may need a relatively high inspiratoryflow rate to activate the spring. Perhaps for thesereasons they are not widely used.MDIs place quite high demands on patients' skill,

and good tuition is essential. Physicians mustdemonstrate to patients, preferably using a placeboMDI, how to use their inhalers and must rechecktheir technique from time to time. MDI training aidsmay be useful for patients with poor coordination.30The use of manufacturers' instruction leaflets aloneis not adequate, and there is a need for better and

883

more standardised leaflets giving fewer conflictinginstructions on inhaler technique. It is vital also thatpatients know that a diminished response to theirinhalers means either that the canister is empty, thatthe inhaler is being used wrongly, or that theirasthma is deteriorating; and they should takeappropriate action urgently.

SPACER ATTACHMENTS TO MDISSince particle size and velocity decrease with dis-tance, the provision of a "spacer" between thepatient's lips and the MDI will lead to small, slowlymoving, respirable particles. This principle has ledto the development of various types of spacer deviceor holding chamber, which literally holds the aerosolbefore this is inhaled. A 10 cm long tube spacer(volume approximately 100 cm3) and a 25 cm conespacer shaped like the aerosol spray cloud and witha one way inhalation valve (volume about 750 cm3)are available commercially (the Bricanyl spacerinhaler or Pulmicort inhaler and the Nebuhaler,Astra Pharmaceuticals). In practice these spacershave several beneficial effects: (1) Oropharyngealdeposition is reduced, thereby reducing the inci-dence of oropharyngeal candidiasis and dysphoniawith corticosteroid aerosol therapy.3' (2) Drugdelivery to the lung is improved, depending on thespacer design. The increase in lung deposition is lessthan the reduction in oropharyngeal depositionsince many particles are deposited on the walls ofthe spacer itself. (3) Most importantly, the MDI iseasier for the patient to use. The spray may bereleased into the spacer and inhaled after a briefpause, so that the need to synchronise firing andinhaling is either greatly reduced or entirelyremoved. In fact, firing a bronchodilator spray intothe 10 cm tube spacer and delaying inhalation forthree seconds is as effective as a correctly used MDIwithout a spacer attachment.32 Thus spacers areprobably of most value for patients with poorinhaler technique-particularly those who cannotsynchronise firing the MDI with inhaling-and whomay fail to obtain an adequate lung dose otherwise.There have been many clinical trials with spacer

devices, some of which have shown a greatertherapeutic effect,33 34 (but others no greater35 36) thanthe MDI alone. The discrepancies between the resultsof these trials may be related to the MDI inhalationmanoeuvre used. While spacers may improve drugdelivery to the lungs and therapeutic effect in thosepatients who have a poor inhaler technique, theymay confer little additional clinical benefit for thosewho have a good inhaler technique37; and whilegood technique is most important with an MDI usedalone, it may be less so when the MDI is combinedwith a spacer, though the effect of technique is not

copyright. on S

eptember 28, 2020 by guest. P

rotected byhttp://thorax.bm

j.com/

Thorax: first published as 10.1136/thx.38.12.881 on 1 D

ecember 1983. D

ownloaded from

884

necessarily negligible. Large volume holding cham-bers may be comparable to nebulisers in the deliveryof larger doses of beta agonist aerosol used in thetreatment of severe acute asthma.38 Such chambershave the advantages of portability, simplicity of use,and ease of cleaning. By comparison with theconventional MDI, however, they are still large andbulky.

DRY POWDER INHALERSDry powder inhalers39 are a convenient alternativedelivery system to MDIs. The first dry powderinhaler was introduced for sodium cromoglycate(Spinhaler, Fisons Ltd) and more recently inhalershave become available for dry powder preparationsof salbutamol and beclomethasone dipropionate(Rotahaler, Allen and Hanburys Ltd). With theoriginal cromoglycate preparation inhaled from aspinhaler the MMAD of the drug particles placed inthe capsules was 2.6 ,um and the lactose carrierpowder had 70% of its mass between 30 and 60 ,umin diameter.40 About 5% of the dose reaches thelungs, according to pharmacokinetic studies.4'Recently the capsule has been reformulated and thelactose powder omitted.

Having pierced or fractured the gelatin capsulecontaining the drug, all the patient has to do is toinhale through the device to draw the powder out ofthe capsule. Dry powder inhalers are thus easier touse than MDIs but less convenient because of theneed to load a capsule into the device before use.They are usually reserved for patients who cannotmaster the technique of inhaling from an MDI. Thecorrect inhalation technique for dry powder inhalersis unclear, although rapid inhalation (¢60 1 min-')leads to more efficient emptying of the capsules andbetter dispersion of the powder in the inhaled airstream. At the same time, rapid inhalation is likelyto increase impaction losses in the oropharynx. Theefficacy of various inhalation techniques for drypowder aerosols needs to be tested.

NEBULISERSIn common with other types of inhalation device,the air driven jet nebuliser must be used correctly toachieve optimal drug delivery. Correct use in thiscase, however, depends relatively little on thepatient's inhalation technique (most patients inhaleby tidal breathing) and rather more on the way inwhich the nebuliser is set up and operated. The mostimportant factor governing nebuliser performance isthe flow of compressed air used to generate theaerosol. Aerosol size is inversely proportional to thecompressed gas flow rate and a flow rate of -

6 1 min-' is necessary with most types of jet nebu-liser . This ensures that treatment times are accept-ably short,42 and that the bulk of the aerosol mass is

contained within particles of not more than 5 ,maerodynamic diameter.43 It is insufficiently appreci-ated that the domiciliary oxygen cylinders availablein Britain generally have two flow rate settings only,2 and 4 1 min- ', and that these flows are inadequatefor most of the better known brands of nebuliser. Awide range of electrically driven air compressors isnow available but it is important to select carefullyfrom this range and to ensure that the compressorcan generate a sufficiently rapid air flow rate. Thenebuliser may be powered by a hand held squeezebulb or even a foot pump. These driving systems arerelatively simple and portable, they allow the user tobe independent of cylinders, and they are undoubt-edly useful if nothing else is available. In practice,however, it is difficult to control the compressed airflow rate adequately.There are several facts about nebulisers which are

insufficiently appreciated. As with the MDI, onlyabout 10% of the dose from a nebuliser reaches thelungs, most of it being retained as large droplets onthe internal walls of the nebuliser itself." Althoughmuch larger doses are customarily placed in nebuli-sers than are given from MDIs, the dose responsecurves may be similar for both.45 The outputdepends on the volume fill and gas flow rate. Manypharmaceutical data compendia sheets recommenda 2 ml volume fill, although a higher percentage ofthe drug solution is released as aerosol if this volumeis diluted to 4 or 6 mI.42 Thus the dose from 2 mlmay be inadequate. A combination of 4 ml volumefill and 6 1 min-' gas flow rate is recommended toensure a high aerosol output, small particle size, andshort treatment time. A recent hospital question-naire46 showed that patients may be treated withnebulisers operated at flow rates varying from 1 to10 1 min-' and a diluent volume fill ranging from 0 5to 10 ml. With many of these combinations the dosewould be predictably inadequate.

Nebulisers may be used with either a facemask ora mouthpiece, according to the patient's prefer-ence.47 Aerosol wastage on the face and in thenasopharynx will be greater with the facemask. Theuse of intermittent positive pressure breathing(IPPB) is often advocated with nebulised bron-chodilators on the grounds that this "forces" moreaerosol into peripheral lung regions. In fact, thistechnique appears to have no definite advantagesover the inhalation of aerosol by tidal breathing48 orthe delivery of comparable doses of bronchodilatorfrom an MDI.49

Nebulisers may be either"disposable" (to be dis-carded after each use) or "sterilisable." Most socalled disposable nebulisers have a lifespan of two tothree months if used carefully, but like the "sterilis-able" nebulisers they must be thoroughly cleaned to

copyright. on S

eptember 28, 2020 by guest. P

rotected byhttp://thorax.bm

j.com/

Thorax: first published as 10.1136/thx.38.12.881 on 1 D

ecember 1983. D

ownloaded from

885

avoid bacterial contamination. Some types of nebul-iser are difficult to clean since they cannot be takenapart, and furthermore the cleaning procedure mayultimately impair their performance. The filters andair intake grill on the air compressor should also becleaned regularly. Aspergillus species have been cul-tured from fluff accumulating at these locations.5"Also Pseudomonas aeruginosa is known to colonisewater traps. When inhaled both may have poten-tially lethal consequences.

Ultrasonic nebulisers, in which high frequencysound waves are passed through liquid in a reservoirto create an aerosol, ar.e widely used abroad but lessso in Britain. Particle size and output may varywidely and have not been categorised satisfactorily.Also most require a mains electricity supply.Recently a portable, battery powered nebuliserbased on a small, vertical rotating disc has beendeveloped.5' It has a lower aerosol output rate,however, than most jet nebulisers.

In recent years nebulisers have become popularfor use both in hospital and in the home, particularlyin the treatment of severe asthma. It is thought thata larger dose of bronchodilator might be deliveredto the lungs more readily than with an MDI. Cer-tainly this means of administration is tolerated wellin adults and distressed children. Whether it fulfilsall expectations remains debatable and there may bea partial placebo effect. Nevertheless, the nebuliseris a versatile device by which an increasingly widerange of drugs may be administered for topical andsystemic treatment. There are some exciting pros-pects, which the second part of this review will dis-cuss further.

STEPHEN P NEWMANSTEWART W CLARKE

Department of Thoracic MedicineRoyal Free Hospital

London

References

'Ziment I. Respiratory pharmacology and therapeutics.Philadelphia: WB Saunders, 1978:1-7.

2 Stuart BO. Deposition of inhaled aerosols. Arch InternMed 1973;131:60-73.

3Swift DL. Generation and respiratory deposition oftherapeutic aerosols. Am Rev Respir Dis 1980;122:71-7.

Pavia D, Thomson ML, Clarke SW, Shannon HS. Effectof lung function and mode of inhalation on penetra-tion of aerosol into the human lung. Thorax 1977;32:194-7.

Palmes ED. Measurement of pulmonary air spaces usingaerosols. Arch Intern Med 1973;131:76-9.

6 Mercer TT, Goddard RF, Flores RL. Output charac-teristics of several commercial nebulisers. Ann Allergy1965 ;23:214-20.

Swithenbank J, Beer JM, Taylor DS, Abbott D,McCreath GC. A laser diagnostic technique for themeasurement of droplet and particle size distribution.Progress in Astronautics and Aeronautics 1976;53:421-47.

Lippmann M, Albert RE. The effect of particle size onthe regional deposition of inhaled aerosols in thehuman respiratory tract. Am Ind Hyg Assoc J1969;30:257-75.

Foord N, Black A, Walsh M. Regional deposition of2-5-7-5 ,um diameter particles in healthy male non-smokers. J Aerosol Sci 1978;9:343-57.

0 Morrow PE. An evaluation of the physical properties ofmonodisperse and heterodisperse aerosols used in theassessment of bronchial function. Chest 1981 ;80,suppl:809-13.

lYu CP, Nicolaides P, Soong TT. Effect of random airwaysizes on aerosol deposition. Am Ind Hyg Assoc J1979;40:999-1005.

12 Dolovich MB, Sanchis J, Rossman C, Newhouse MT.Aerosol penetrance: a sensitive index of peripheralairway obstruction. J Appl Physiol 1976;40:468-71.

3 Goldberg IS, Lourenco RV. Deposition of aerosols inpulmonary disease. Arch Intern Med 1973; 131:88-91.

4 Newman SP, Killip M, Pavia D, Moren F, Clarke SW.Do particle size and airway obstruction affect thedeposition of pressurised inhalation aerosols? Thorax1983;38:233.

'5 Dolovich M, Ruffin R, Corr D, Newhouse MT. Clinicalevaluation of a simple demand-inhalation MDIaerosol delivery device. Chest 1983;84:36-41.

16 Clarke SW, Newman SP. Differences between pressur-ized aerosol and stable dust particles. Chest 1981;80,suppl:907-8.

" Newman SP, Moren F, Pavia D, Sheahan NF, ClarkeSW. Deposition of pressurised aerosols in the humanrespiratory tract. Thorax 1981 ;36:52-5.

1 Epstein SW, Manning CPR, Ashley MJ, Corey PN. Sur-vey of the clinical use of pressurised aerosol inhalers.Can Med Assoc J 1979;120:813-6.

'9 Crompton GK. Problems patients have using pressurisedaerosol inhalers. Eur J Respir Dis 1982;63,suppl119: 101-4.

20 Frew AJ, Macfarlane JTM. Are medical staff any betterat using inhalers than patients? Thorax 1982;37:780.

21 Kelling JS, Strohl KP, Smith RL, Altose MD. Physicianknowledge in the use of canister nebulisers. Chest1983;83:612-4.

22 Newman SP, Pavia D, Garland N, Clarke SW. Effects ofvarious inhalation modes on the deposition of radioac-tive pressurised aerosols. Eur J Respir Dis 1982; 63,suppl 119:57-65.

23 Newman SP, Pavia D, Clarke SW. How should a pressur-ised 3-adrenergic bronchodilator be inhaled? Eur JRespir Dis 1981;62:3-20.

24 Williams TJ. The importance of aerosol technique: doesspeed of inhalation matter? Br J Dis Chest 1982:76:223-8.

23 Lawford P, McKenzie D. Pressurised aerosol technique:influence of breath-holding time and relationship ofinhaler to mouth. Br J Dis Chest 1982;76:229-33.

26 Heimer D, Shim C, Williams MH. The effects of sequen-tial inhalations of metaproterenol aerosol in asthma. JAllergy Clin Immunol 1980;66:75-7.

27 Lawford P, McKenzie D. Pressurised aerosol inhalertechnique: How important are inhalation from

copyright. on S

eptember 28, 2020 by guest. P

rotected byhttp://thorax.bm

j.com/

Thorax: first published as 10.1136/thx.38.12.881 on 1 D

ecember 1983. D

ownloaded from

886

residual volume, inspiratory flow rate and the timeinterval between puffs? Br J Dis Chest 1983;77:276-81.

28 Muers M, Dawkins K. Effect of a timed interval betweeninhalation of beta agonist and corticosteroid aerosolson the control of chronic asthma. Thorax1983;38:378-82.

29 Connolly CK. Methods of using pressurised aerosols. BrMed J 1975;iii:21.

30 Woolcock A. A training aid for pressurised inhalers. Br JDis Chest 1980;74:395-7.

31 Toogood JH, Jennings B, Baskerville J, Johansson SA.Clinical use of spacer systems for corticosteroid inha-lation therapy: a preliminary analysis. Eur J RespirDis 1982;63,suppl 122:100-7.

32 Bloomfield P, Crompton GK, Winsey NJP. A tubespacer to improve inhalation of drugs from pressurisedaerosols. Br Med J 1979;ii: 1479.

33 Lindgren SB, Formgren H, Moren F. Improved aerosoltherapy of asthma: effect of actuator tube size on drugavailability. Eur J Respir Dis 1980;61:56-61.

34 Ellul-Micallef R, Mor6n F, Wetterlin K, Hidinger KC.Use of a special inhaler attachment in asthmatic chil-dren. Thorax 1980;35:620-3.

35 Gomm SA, Keaney NP, Winsey NJP, Stretton TB.Effect of an extension tube on the bronchodilatorefficacy of terbutaline delivery from a metered doseinhaler. Thorax 1980;35:552-6.

36 Poppius H. Inhalation of terbutaline spray through anextended mouthpiece: effect on central and peripheralairways. Respiration 1980;40:278-83.

37 Lindgren SB, Larsson S. Inhalation of terbutaline sul-phate through a conventional actuator or a pearshaped tube: effects and side effects. Eur J Respir Dis1982;63:504-9.

38 Morgan MDL, Singh BV, Frame MF, Williams SJ. Ter-butaline aerosol given through a pear spacer in acutesevere asthma. Br Med J 1982;285:849-50.

39 Crompton GK. Clinical use of dry powder systems. EurJ

Respir Dis 1982;63,suppl 122:96-8.40 Bell JH, Hartley PS, Cox JSG. Dry powder aerosols I: A.

new powder inhalation device. J Pharm Sci1971 ;60:1559-65.

41 Walker SR, Evans ME, Richards AJ, Paterson JW. Thefate of (14C) sodium cromoglycate in man. J PharmPharmacol 1972;24:525-31.

42 Clay MM, Pavia D, Newman SP, Lennard-Jones T,Clarke SW. Assessment of jet nebulisers for lungaerosol therapy. Lancet 1983;ii:592-4.

43 Clay MM, Pavia D, Newman SP, Clarke SW. Factorsinfluencing the size distribution of aerosols from jetnebulisers. Thorax 1983;38:754-8.

4Lewis RA, Fleming JS, Balachandran W, Tattersfield A.Particle size distribution and deposition from a jetnebuliser: influence of humidity and temperature. ClinSci- 1981;62:5P (abstract).

4 Cushley MJ, Lewis RA, Tattersfield AE. Comparison ofthree techniques of inhalation on the airway responseto terbutaline. Thorax 1983;38:908-13.

46 Stainforth JN, Lewis RA, Tattersfield AE. Dosage anddelivery of nebulised beta agonists in hospital. Thorax1983;38:750-3.

47 Stevenson RD, Wilson RSE. Facemask or mouthpiecefor delivery of nebulised bronchodilator aerosols. Br JDis Chest 1981;75:88-90.

48 Fergusson RJ, Carmichael J, Rafferty P, Willey RF,Crompton GK, Grant IWB. Nebulised salbutamol inlife threatening asthma: Is IPPB necessary? Br J DisChest 1983;77:255-61.

49 Anderson PB, Goude A, Peake MD. Comparison of sal-butamol given by intermittent positive-pressure brea-thing and pressure packed aerosol in chronic asthma.Thorax 1982;37:612-6.

50 George RH, Gillet AP. Allergic bronchopulmonaryaspergillosis. Arch Dis Childhood 1980;55:910.

s, Malem H, Ward M, Henry D, Smith WHR, Gonda I.Early experience with a vertical spinning disc-nebuliser. Lancet 1981 ;ii:664-6.

copyright. on S

eptember 28, 2020 by guest. P

rotected byhttp://thorax.bm

j.com/

Thorax: first published as 10.1136/thx.38.12.881 on 1 D

ecember 1983. D

ownloaded from