Delivery devices

Inhalation devices

Recommendations

1. At each contact, health care professionals should workwith patients and their families on inhaler technique(level I).

2. When prescribing a pressurized metered-dose inhaler(pMDI) for maintenance or acute asthma, physiciansshould recommend use of a valved spacer, with mouth-piece when possible, for all children (level II).

3. Although physicians should allow children choice ofinhaler device, breath-actuated devices such as dry-powder inhalers offer a simpler opdon for maintenancetreatment in children over 5 years of age (level IV).

4. Children tend to "auto-scale" their irihaled medicadondose and the same dose of maintenance medicadon canbe used at all ages for all medicadons (level IV).

5. Physicians, educators and families should be aware thatjet nebulizers are rarely indicated for the treatment ofchronic or acute asthma (level I).

This review, which forms the basis for the consensus,covers the clinical issues that are important for the primarycare pracddoner and asthma educator to understand to op-timize the transfer of knowledge and pracdce to the padentand family. Relevant technical aspects are discussed first,followed by their applicadon to the family. One secdondeals primarily with applicadons in the acute care setdng.

Literature review

A MEDLINE search from 1996 to present was con-ducting using the following keywords: "children,""asthma," "inhaladon technique," "HEA," "aerosols," "pa-tient educadon," "asthma educadon." Appropriate ardcleswere also idendfied from the authors' own knowledge ofthe literature as well as reference lists in ardcles retrieved.

Current evidence review and discussion

Technical aspects

^ Hydrofluoroalkane (HFA) propellants

\ HFA-propellant pressurized metered-dose inhalers: (pMDis) have been shown to be effecdve for the treatment; of asthma in adults and children.'-^ Differences in the me-; tering valve plus actuator mouthpiece of various pMDIsj can result in the delivery of varying quanddes of medica-^ tion of different pardcle sizes. The mass median aerody-

namic diameter of the different formulations ranges fromabout 1 to 4 pm. Eor example, particle delivery to the lungmay be increased 50% of die nominal dose for QVAR, anHEA propellant soludon of beclomethasone dipropionate(BDP),' but remain at 10%-20% for HEA suspension for^muladons such as fludcasone and salbutamol."*'' If a holdingchamber is used with the HEA soludon of BDP, lung de-posidon remains unchanged.'^ However, using a 145-mLvalved holding chamber does not change lung deposidon,but the oropharyngeal dose is reduced 5-fold.

Other ICSs (fiimisolide, triamcinolone) have similar de-posidon characterisdcs in adults when used without opentube spacers with either chlorofluorocarbon (CEC) or HEAformuladons.^'^ Not all HEA-BDP preparadons are thesame. The reladve potency for the HEA soludon of BDP(Qvar, 3M) in adults appears to be about 2.6:1 comparedwith CEC-BDP.' Using an HEA-BDP preparadon deliv-ered via an Easibreathe' (Norton Health Care Ltd., Lon-don, UK), one study in children demonstrated a 1:1 po-tency rado of CEC and HEA preparadons.^ However, inchildren the possibility of inadequate technique couldfavour the use of a holding chamber to deliver an ICS whenusing an MDI. In addition the deposition of the HEAaerosol soludon of BDP is more peripheral because of itslow mass median aerodynamic diameter (1.0 \im) comparedwith CEC-fludcasone (2 }im) or CEC-BDP (3.5 |im).'

To date, the only reported study in children was ran-domized, but open labelled, and compared HEA-BDP de-livered via a spring-loaded breath-actuated device andCEC-BDP delivered via a holding chamber.'' Half the dosewas needed in the HEA group to achieve the same efficacywith no differences in growth, adrenal function or bonemetabolism markers. In addidon, there is litde clinical evi-dence that more peripheral airways should be targeted, aiidbenefit-to-side-effects rados for peripheral versus centraldeposidon must be determined to substandate such an ap-proach. In fact, it has been shown that the opdmum size ofipratropium or salbutamol in adults is 2.8 }im versus 1.5 or5 pm,'" but it is far more difficult to evaluate the benefit-to-side-effect rado for an ICS. HEA-salbutamoI preparadonswith the same aerodynamic size as CEC preparadons havebeen shovim to be equipotent in adults.""''

Holding chamber properties

Spacer size — The size of the holding chamber may leadto different deposidon efficiencies for different ages.'"* Thevalves may have high resistance,'^ the dead space may be toolarge'^ or the chamber may be too large'* for infants. These

CMAJ • SEPT. 13, 2005; 173 (6) S39

Becker et al

factors need to be taken into account when choosing a hold-ing chamber. In simulated models representing a 7-month-old infant, a 2-year-old toddler and a 4-year-old child, 4holding chambers were assessed using CFC-BDP andCFC-salbutamol.'^ Different holding chambers deliveredsignificantly different amoimts of fine particles and the dosevaried with the medication as well. Depending on the de-vice, variation with age of patient may have been substantialor insignificant. Differences in delivery of HFA products re-quire further study, but it appears that, for HFA-salbuta-mol, spacer volume is not as critical to delivery.'^

Electrostatic properties — Different holding chambershave differing electrostatic properties.'"^ Electrostaticallycharged holding chambers cause significant dose variationscompared with the metal Nebuchamber and deliver a sub-stantially smaller dose to the patient.-" Non-electrostaticdevices have been recommended for young children asthese result in increased deposidon'^'^'; as an alternative,plastic holding chambers may be Ughtly coated with liquiddetergent to eliminate the electrostatic forces.-^ Primingthe holding chamber with repeated puffe has been shown tobe effective' ; however, this practice is not currently recom-mended, mainly because of the waste of the medication andthus cost. Deposition of budesonide in the lungs increasedfrom about 25% using plastic spacers to about 35% whenthe spacer was primed with 20 doses of placebo aerosol, butpriming had no effect in non-electrostadc metal spacerswhere deposidon measured 33%.'° The same effect is seenwhen plasdc spacers are washed and rinsed, and these stepsare detailed and recommended on the package inserts forthese devices. Oropharyngeal dose may be higher usingmetal spacers as more of the larger pardcles in the aerosolare available for inhalation.

Inhaladon delay and muldple actuadons — In adults, a20-s delay in inspiradon after actuadon of an MDI with alarge volume plasdc holding chamber resulted in a 50%drop in the amount of salbutamol reaching the lungs asmeasured by serum levels." Although data are not available

for children, there is no reason to suspect that the same ef-fect will not occur. In an in vitro study under condidons ofconstant flow, a delay of 20 s decreased small-pardcle emis-sion by about two-thirds.^'* There was also a 50% decreaseif muldple puffe were used to load the holding chamber. ^The use of multiple actuations into the spacer beforebreathing decreased pardcle emission by a third for 2 puffeand a half for 5 puffs."^ The tradename, volume and manu-facturer for the various spacers and holding chambers areappended as Table 1.

Relative dosing

Different jet nebulizers are associated with different levelsof deposition and pardcle size. However, many studiesoverwhelmingly demonstrate an approximate 5:1 efficac}'rado for P-adrenergic medicadons delivered via the jet neb-ulizer versus the MDI and holding chamber in children ofvarying ages.^'"-' That is, 500 mg of salbutamol by wet neb-ulizadon would be equivalent to 100 mg by MDI withholding chamber or spacer. Studies using more recent de-signs of nebulizers with inspiratory flow enhancement anda dght-fitdng face mask, may result in a 2:1 rado.-"^" How-ever, in the pracdcal situadon of the child in the emergenc}'department or an infant at home, it is difficult to apply adght-fitdng seal for the duradon of the inhaladon.

In children between the ages of 3 and 5 years, there is noevidence for the superiority of terbutaline sulfate deliveredvia an MDI and holding chamber versus a dry-power in-haler (DPI) in the outpadent setdng.^" Similarly, in olderchildren, the benefits and side-effects of the 2 delivery sys-tems in the emergency setting were similar.^' In adults, de-posidon of budesonide with a DPI appears to be up to dou-ble that using an MDI and holding chamber." Eurthersupport for using the DPI was demonstrated in a dose-reducdon study in children, which showed that budesonidemay be twice as potent in a DPI compared witb an MDIwith a large-voliime plasdc spacer." However, other studies

Table 1: Dry-powder inhalers*

Dose storage Trade nameNo. doses perstorage unit

1

11

200200

200

2004-8

60

Specificresistance

L

H

H

H

H

MM

LM

Drug

Formoterol

FenoterolTiotropiumbromideBudesonideBudesonide

BudesonideMometasone

Fluticasone

Fluticasone

Single capsule Aerosolizer (Novartis, Surrey, United Kingdom)*Inhalator (Boehringer Ingelheim, Ingelheim, Germany)*Spiriva (Boehringer Ingelheim, Ingelheim, Germany)

Reservoir Turbuhaler (Astra Draco, Lund, Sweden)*

Clickhaler (ML Laboratories, St. Albans, United Kingdom)t

Ultrahaier(Rh6ne-Pouienc Rorer, Loughborough, United Kingdom)t

TwistHaler (Schering Key, Kenilworth, NJ, United States)*

Multi-unit dose Blister Diskhaler (Glaxo Wellcome, Ware, United Kingdom)*Blister/tape Diskus (Glaxo Wellcome, Ware, United Kingdom)*

'Marketed in Europe, Canada or the United States.tUnder development or regulatory review.L 50.05 cm Hp /L per s; M = 0.05-0.01 cm Hp/L per s; H = >0.01 cm Hp/L per s.

S40 JAMC • 13 SEPT. 2005; 173 (6)

Delivery devices

have demonstrated equal bronchodilation with equal dosesfrom these 2 devices.''*'" Only half the dose of fluticasonehas been shown to be delivered by DPI compared with anMDI and holding chamber.^^

Comparisons between fludcasone and budesonide DPIsdemonstrate more consistent delivery of the former overvarying inspiratory flows and ages in children.^' However,the budesonide DPI emitted a much higher dose of fineparticles when used by children ages 4 and 8 years; theavailable dose was twice as high by age 8.' In theory, flneparticles contribute to the efficacy of the inhaled cortico-steroid as they penetrate to the lower airways. Overall, nospecific recommendadons can be made regarding the use ofa DPI or MDI for the treatment of chronic asthma. In theacute care setdng, no specific recommendations can bemade regarding the use of the DPI, MDI or jet nebuHzer.However, a 5:1 rado for drug dose by convendonal jet neb-ulizer compared with MDI and holding chamber is a goodrule in the latter situadon.""^'

Even within holding chambers, different MDI prepara-tions are affected differently.^^-' One cannot necessarilypredict how a holding chamber will affect a pardcular med-ication, and products need to be matched with devices.

Although adding a holding chamber to a DPI has beenshown to decrease the propordon of large pardcles from52% to 30%, it does not alter the number of small ones.'^,The use of a holding chamber would help reduce side ef-fects arising from oral and gastrointesdnal deposidon ofparticles, though these are not very important in childrenusing budesonide. In a review of devices, Bisgaard'" statedthat drug approval processes should clearly specify the de-vice, and discourage the use of other devices, i.e., the deviceshould be an integral part of the prescripdon.

Overall, these data demonstrate that it is important tohave a proper fit of padent and device to obtain opdmalbenefit compared widi risk of adverse effects for the indi-vidual padent.

Inhalation techniques — teaching children to usean inhaler

The padent must demonstrate adequate technique wheninhaled medication is prescribed. To teach the use ofbudesonide DPI, children aged 3, 4 and 5 years and theirparents were shown a video and given written instrucdons;others also received training from a nurse."" The 3-year-olds performed poorly with or without the nurse's training;however, the 4- and 5-year-olds increased peak flowthrough the budesonide DPI significantly with nurse-assisted training. The group receiving assistance from thenurse was given an inhaler modified to provide feedback onPEF at home for 2 weeks. On follow-up, a further im-provement of about 10 L/minute in PEF was noted in the4- and 5-year-old children.

Different techniques can be used with an MDI and hold-ing chamber: ddal breathing with sufficient flow to move

the valve, 5 breaths, or taking 1 deep breath and holding itfor 10 s. These have been demonstrated to be equivalent inschool-age children, ^"*' although, surprisingly, there havebeen no further confirmatory studies. As there may be dififi-culdes with coordinadon during acute episodes that may notbe arise when the young child is well, and breath holdingmay be difficult during acute episodes, the ddal breathingtechnique may be the best method to use. Furthermore,many children can only use the ddal method when firsttaught before the age of 4 or 5. As they akeady know thetechnique of ddal breathing, it might be preferable to con-tinue with this method. As well, for simplicity and consis-tency, it might be best to teach 1 method in general.

Proper technique includes many steps. Some are essen-dal to receive the medicadon (e.g., removing the protecdvecap), while others may opdmize delivery but have a gradedresponse (e.g., inspiratory flow through the DPP). Othershave been consistendy quoted as important, but may not benecessary at all. Hansen and Pedersen"*^ demonstrated inchildren that breath holding and dldng the head do not im-prove response to bronchodilator. In addidon, the responsewas idendcal whether they inhaled from fimcdonal residualcapacity or residual volume.

Studies have not been able to demonstrate that giving apadent a preference increases adherence in Iong-term ther-

' apy. In general, the simpler the device, the smaller thechance it will be damaged or lost. Cost is an effecdve bar-rier to use of medicadons. The holding chamber generallyrepresents an addidonal cost; the cost of the medicadon isabout the same for DPIs and MDIs. In adults, although theMDI was the most vinidely prescribed device in the UnitedKingdom, padents preferred DPIs and performed betterwith them."* The most common technique-related problemcited was too-slow an inspiradon. In this study, the breath-actuated MDI, an inspiratory flow driven device, washighly preferred as well as easy to use. Another audit of. 22padents of all ages in private pracdce showed that 63%were using an MDI.''^ However, once again, correct usagewas higher with DPIs than MDIs.

Chen and colleagues'*** surveyed 132 children aged 8-13years and found that children who inhaled medicadon un-aided had a better knowledge of asthma and their tech-nique was superior to those who were helped by their par-ents. Increased skill was associated with the family's degreeof sadsfacdon with the physician's educadonal program,reading of related publicadons, older age and number ofasthma attacks in the previous year."* ' Kamps and cowork-ers ° evaluated padent characterisdcs in 47 children referredto a terdary asthma clinic. Good technique was associatedwith previous repeated instrucdon sessions that includeddemonstrating the skill to a health care professional. After 1session, only 57% demonstrated correct technique, but af-ter 3 sessions this value rose to 98%. Giraud and Roche"evaluated 3955 quesdonnaires from adults regarding in-haladon technique and concluded that asthma instabilitywas related to misuse of MDIs, pardcularly poor coordina-

CMAJ • SEPT. 13, 2005; 173 (6) S41

Becker et al

tion. Comprehensive instructions combined with repeated olds.*^ One study showed that 43% of 4 year olds, 67% of 5checks of proper technique in the pharmacy or clinical trial year olds and 80% of 6 year olds could effectively use thesetting dramatically increased good performance, from device. ^ Concerns have been raised that although young39% (general practitioner demonstration only) to 79% and children may use the DPI successfully when well, they may93%, respectively." have problems during acute exacerbations. However, bene-

Vodoff and associates" found that in children under 4 fit fi-om using the device was demonstrated in children agedyears of age, the most common errors in using an MDI 6-17 years, with FEVi as low as 25% of predicted value. 'were not shaking the device before use (48%) and taking 2 Onhoj and associates'^ recently demonstrated thatconsecutive puffs (28%). budesonide delivered fi-om an MDI and holding chamber

Although 1 study'** clearly demonstrated the superiority to children aged 2-6 years resulted in the same plasma con-of using one type of device versus multiple ones in adults, centration of budesonide as in adults. They also showedthere have been no similar studies in children. There is a that the total patient dose was independent of age, but thattendency to prescribe p-adrenergic medications using an lung dose increases with age, while oropharyngeal dose de-MDI or an ICS using a DPI. The DPI requires a rapid deep creases. Deposition using the MDI and holding chamber ininspiration, whereas the MDI requires a slow one. This can infants may be in the range of 2% of the nominal dose,'"be confusing. In addition, the most common problem asso- whereas in adults it is 10%-20%; thus, it appears that chil-ciated with the use of a DPI is poor quality ofthe rapid deep dren auto-scale dose delivery to the lungs as opposed to de-inspiration." '**' Provided the drugs are available, we recom- livery at the mouth.^^mend 1 type of device to optimize technique for all chil- For jet nebulized medications, including cromoglycatedren, especially when an ICS is being delivered via a DPI. and salbutamol in infants, <1% ofthe wet nebulized dose

A systematic review by Brocklebank and colleagues" appears to reach the lungs. ^ Chua and colleagues' ^ showedconcluded that the evidence in both children and adults that saline delivered via a nebulizer results in about 3 timesdoes not reveal any preference for other devices over the the deposition in 6-18 year olds versus infants. If the childMDI and holding chamber for both ICSs (3 pediatric stud- uses a mask, lung deposition will decrease as well." Anotheries) and P-adrenergics (11 pediatric studies). They state that radiolabelling stud/^ showed that children under the age ofas the MDI is the cheapest device, its use is to be recom- 4 years had approximately 5% deposition whether a jetmended in preference to other types of inhalers. However, nebulizer or an MDI and holding chamber was used, buta recent review of the literature'^ showed that each type of this increased in children over the age of 4 years to aboutinhaler system can deliver effective therapy to patients 10%. One study" measured the deposition on a filterwhen they use the inhaler properly, suggesting that selec- placed at the mouth in infants 4-30 months of age using ation of an inhaler system for patients should be based on jet nebuHzer and holding chamber and found an increaseseveral considerations such as availability of the drug pre- with age in budesonide deposited at the mouth. Wildhaherscribed in the preferred device, the patient's age and ability and associates'^ demonstrated increasing deposition ofto use the device, the clinical setting and cost. salbutamol on a filter at the mouth of infants weighing

From a practical point of view, instructions should be 6-11 kg. These children are at weights where inspirator)'kept simple. Using one type of device is important. As flows would be just starting to match the flow of the airmentioned, MDIs with a holding chamber are strongly nebuiization." The results confirmed the hypothesis that ifpreferred to MDIs alone in all children. Many children feel the driving airflow of the nebuHzer exceeds the maximumthey can inhale using the MDI alone, although they have inspiratory flow of the infant, tben medication will be lostbeen told to always use the holding chamber. This device is to the atmosphere during inhalation. Information about thefar more cumbersome to transport than a DPI. As well, various dry powder inhalers is provided in Table 2.older children are self-conscious of bulky devices they may The general body of evidence now suggests that there isneed to take to sporting events. Once a child can use the a good degree of auto-scaling with age for any type of de-DPI, this is the preferred device. vice, but how accurate this is in terms of meaning that 1

dose can be used for all ages is uncertain.Age and devices

Cognitive state — crying, awake, asleepIn children, the budesonide DPI has been shown to be

used at inspiratory flows as low as 30 L/minute.^ However, Following an anecdote in a study demonstrating thetwice the effect is produced at flows of 60 L/minute. In a marked decrease in deposition in infants who cried, " a weO-study using radiolabelling, 6-16 year old children using a done controlled trial clearly demonstrated that drug deliv-budesonide DPI were found to increase lung deposition ery decreased by two-thirds in infants who were distressedwith age and height." Children aged 3 or 4 years can effec- compared with infants who were calm during inhalationtively use this device,^" but those under 5 years of age End it when using a holding chamber and face mask.^ It is, there-difficult to learn consistent technique.^' Proper education fore, suggested that these devices not be used to deliverand home training can improve technique in 4 and 5 year ICSs in infants who are crying. However, in 1 study, 38% of

S42 JAMC • 13 SEPT. 2005; 173 (6)

Delivery devices

infants repeatedly cried while receiving therapy/' Treat-ment may be tried when the infant is sleeping.^^ Alterna-tively, behaviour modification approaches may help to ha-bituate the child to the mask. Although wet nebulizadon isgenerally not preferred, the mask used with this technique,which is not tight fitting, may be more acceptable to the in-fant and may be preferred in this setting. On the otherhand, in the emergency department, the shorter timeneeded to use an MDI and holding chamber may make itpreferable to the wet nebulizer. A study*** using jet nebuliza-don to administer radiolabelled aerosol to infants with cysticfibrosis while sedated or awake found no difference in depo-sition. If difficulties arise because the infant is agitated whileawake, a trial while the infant is asleep may be beneficial.

Interface — face mask v. mouthpiece

It has been clearly demonstrated in children that breath-ing through a mask via the nose decreases lung depositionby up to 67% compared with breathing through a mouth-piece using a jet nebulizer," There are no similar in vivostudies using an MDI with a spacer attached. However, arecent study using a model of the upper airways and face tosimulate aerosol dehvery in an infant or young child froman MDI and spacer showed the importance of maintaininga good seal between the face and the mask.™ Face masks

Table 2 :

pMDIspacerdesign

Holdingchamber

Reverseflow

Spacers and valved

Trade name

Aerochamber Pius

AeroChamberMAXVortex

NebuchamberBabyhaler

Nebuhaier

VolumaticOpti-ChamberAdvantagePocketChamber

FunHaier

Space Chamber

Lite A ireDisposable

Inspirease

E-Z Spacer

holding chambers

Volume, mL Manufacturer

145

198

194

280350

700

750218

110

225

235

150

. 750

700

Trudell Medical,Canada

Trudell Medicai,CanadaPari, Germany

AstraZeneca, Sweden

GiaxoSmithKleine,United Kingdom

Astra, Sweden

Glaxo, United StatesResplronics Inc.,United StatesFerraris RespiratoryIncInfaMed Ltd

AirFlow Products,New ZealandThayer Medical,United States/Methapharm,Brantford, CanadaSchering Corp.,United States

WE Pharmaceuticals,Ramona, CA, UnitedStates

with leaks of various sizes were created, and delivery ofbudesonide MDI aerosol via metal valved holding chamberwas measured in the model. The data showed that the lungdose was substantially reduced when the leak occurred nearthe nose compared with the chin area. Although we cannotbe sure that patients using a mask will, in fact, breathethrough the nose, it would seem prudent to use a mouth-piece at as young an age as feasible to maximize the chanceof increased deposition.

Differences in mask design have been shown to affectthe amount of aerosol deposited on the face and in theeyes. ' In addition, if the dead space of the mask is compa-rable to the tidal volume of the infant, httle aerosol willreach the lung.

Wet nebulizers in acute care

Numerous studies compare MDIs and holding chamberwith wet nebulizers in the acute care setting in childrenover the age of 2 years' as well as 4 in infants."'" Threestudies in the infants used a 4:1 or 5:1 rado of medicationin the MDI and holding chamber versus jet nebulizer. Infact, 1 study demonstrated a lower admission rate to hospi-tal using the MDI system versus the jet nebulizer." Catesand coworkers'*^ performed a systematic review of 21 trials

/comparing the MDI and holding chamber to jet nebuliza-don in the acute care setdng in adults and children. Therewere no differences between devices in either age group interms of admission rates, length of stay in the emergencydepartment (except for 1 study in children showing ashorter stay with MDI) or pulmonary funcdon. There werefewer side-effects in children using the MDI, pardcularly alower pulse."'^^ All generally demonstrate the 5:1 rado ofthe MDI dose to the wet nebuHzer dose, but clearly therewill be variadon depending on the quality of the devicesand the cooperadon of the child.

Recently a study demonstrated the equivalence of thebudesonide DPI and the MDI with holding chamber forschool-aged children as young as 6 years old in the emer-gency setting with FEV, as low as 25% of predicted.^'These children were all able to generate PEFs through theDPI greater than 30 L/minute.

The barriers to implementadon ofthese devices have of-ten been habit or issues of sterilizadon. These can be over-come. Cost of medicadon and dme to administer can begready reduced. However, 1 adult study has demonstratedthat, if dme needs to be spent at the bedside observing cor-rect use of the MDI versus leaving the padent with the jetnebulizer alone, then the savings might not be significant.^''The MDI and holding chamber method is preferred overthe wet nebulizer at all ages. After age 6, the budesonideDPI may be used. However, there are no data concerningother DPIs in the acute care setting. As the budesonideDPI can be used in the acute care setdng," there is no fearof using it for the complete inhaladon therapy treatment inthe child 6 years of age and older.

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Wet (jet) nehulizers in the chronic setting

There is also debate about the value of wet nebulizersfor treatment of chronic asthma.""" The compressor de-vices and medications are more costly and cumbersome,which may decrease adherence to therapy. As well, particlesize from wet nebulizers varies greatly depending on thedevice and compressor.**"- ' Overall, there is no rationale forconsidering the use of a wet nebulizer for the vast majorityof patients with asthma.

^2-adrenergic medications do not enhancedeposition of ICSs

It has been common practice to inhale a p2-adrenergicmedication "to dilate the airways" before administering theinhaled corticosteroid. No studies have validated this. Inaddition, in young children, any delay will decrease deposi-tion. It is recommended that the most important medica-tion be used first, not after premedication with a bron-chodilator.

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