Incentive device improves spacer technique but not clinical outcome in preschool children with asthma.

AIM: To investigate the influence of an incentive device, the Funhaler, on spacer technique and symptom control in young children with asthma and recurrent wheeze. METHODS: Randomised controlled trial where 132 2-6 year old asthmatic children received regular inhaled fluticasone through Aerochamber Plus, or Funhaler. The setting was a research clinic at Princess Margaret Hospital for Children, Perth, Australia. Subjects were followed up for a year. The main outcome measure was asthma symptoms. Proficiency in spacer technique was measured as salbutamol inhaled from spacer onto filter. Quality of life was measured every three months. Groups were compared in terms of spacer technique, symptoms and quality of life. The relationship between spacer technique and clinical outcome was examined. RESULTS: There was no difference between Funhaler and Aerochamber groups in wheeze free days, cough free days, bronchodilator free days or quality of life (P = 0.90, 0.87, 0.74 and 0.11 respectively). Spacer technique was better in the Funhaler group (P = 0.05), particularly in subjects younger than 4 years of age (P = 0.002). Drug dose on filter (as the mean of five 100 mg doses) ranged from zero to 136 mg. CONCLUSIONS: Use of Funhaler incentive device does not improve clinical outcome, but improves spacer technique in children younger than 4 years. Variability in drug delivery is large in young children using pressurised metered dose inhalers and spacers.

Usage of spacers in respiratory laboratories and the delivered salbutamol dose of spacers available in Australia and New Zealand.

BACKGROUND AND OBJECTIVE: Purchase and disinfection costs together with medication delivery factors may influence the choice of drug delivery options. This study assessed salbutamol delivery habits used in respiratory laboratories and quantified the delivered salbutamol dose of locally available spacers. METHODS: An online survey was used to obtain data on disinfection processes, costs and delivery device choices. The delivered dose of six commercial spacers was assessed. Particle size distribution of salbutamol (Ventolin, GSK, 100µg/actuation) from six spacers of each type was measured by quantifying the amount of drug (µg) deposited on each stage of an Anderson Cascade Impactor (ACI) using UV spectrophotometry. Clinical conditions were simulated using a flow volume simulator (FVS) and delivery of salbutamol via a pressurized metered dose inhaler and spacer to a low-resistance filter was measured. RESULTS: Fifty survey responses were obtained, with 37 (74%) using ≥1 type of spacer of which 92% processed single use spacers. The most commonly used spacers were Volumatic (n=24), Breath-a-tech (n=8) and Space Chamber (n=7). The median disinfection cost was $2.45. Delivered salbutamol dose varied significantly and ranged from 16.98 to 38.28 µg with the ACI and 22.56 to 58.82 µg with the FVS. Using the FVS, small-volume spacers delivered similar doses (22.56 to 28.46 µg), while large-volume spacers delivery was more varied (24.31 to 58.82 µg). CONCLUSIONS: The majority of respiratory laboratories had not updated re-processing policies to comply with new regulations. The delivered salbutamol dose varied significantly and this might effect the choice of preferred spacer type.

In utero smoke exposure and role of maternal and infant glutathione s-transferase genes on airway responsiveness and lung function in infancy.

RATIONALE: Xenobiotics in the maternal circulation are capable of crossing the placental barrier so a reduction in the mother and fetus's detoxification ability due to genetic variation in the glutathione S-transferases (GSTs) could expose the fetus to higher levels of toxins. OBJECTIVES: To investigate the interactive effects of maternal smoking during pregnancy with maternal and infant GST genotypes on airway responsiveness (AR) and lung function in infancy. METHODS: GSTT1, GSTP1 and GSTM1 were genotyped in infants and mothers, in utero smoke exposure was evaluated by questionnaire, AR was assessed by histamine challenge and Vmax(FRC) was measured using the rapid thoracoabdominal compression technique. We investigated the interactive effects of maternal smoking during pregnancy with maternal and infant GST genes on AR and lung function at 1, 6, and 12 months and longitudinally throughout the first year. MEASUREMENTS AND MAIN RESULTS: Infant and/or maternal GSTT1 nonnull was associated with reduced AR at 12 months and throughout the first year and increased Vmax(FRC) at 6 months. Maternal GSTP1 Val/Val or Ile/Val was associated with increased Vmax(FRC) at 6 months. In infants exposed to in utero smoke, infant and/or maternal GSTT1 nonnull was associated with reduced AR at 1 month and throughout the first year and increased Vmax(FRC) throughout the first year. Maternal GSTP1 Val/Val or Ile/Val was associated with increased Vmax(FRC) at 6 months. CONCLUSIONS: GST genes may be especially important during fetal development as they may modify, through proficient detoxification, the effects of in utero maternal smoke exposure on AR and lung function in infants.

Providing feedback on adherence increases use of preventive medication by asthmatic children.

This study investigates the impact of measuring adherence and providing feedback on medication usage by children with unstable asthma. Adherence was measured using an electronic monitoring device. Subjects were randomized to either being told of their adherence during review consultations or for their adherence to remain undisclosed to their parents and treating physician. Subjects were reviewed monthly for 4 months. Twenty-six children aged between 6 and 14 years were recruited. Adherence was significantly higher in the intervention group (79% versus 58%, p <.01). There were significant improvements in clinical measures of disease control compared with baseline in both groups. The change in forced expiratory volume in 1 s (FEV(1)) (% predicted) was greater in those subjects receiving feedback (13.8% versus 9.8%). However, lung function values were lower in the intervention group at baseline and the relative improvement failed to reach statistical significance. Measuring adherence and providing feedback increases the use of preventive medication. A larger study is required to explore implications for disease control.

The role of GSTP1 polymorphisms and tobacco smoke exposure in children with acute asthma.

BACKGROUND: The glutathione S-transferase enzymes (GSTs) play an important role in the detoxification of environmental tobacco smoke (ETS), which contributes to airway inflammation, a key component of asthma. Genetic variation in GST genes may influence individuals' ability to detoxify environmental pollutants. OBJECTIVE: To examine the role of polymorphisms in GSTP1 (Ile105Val and Ala114Val), alone and in combination with ETS exposure, on atopy and asthma severity. METHODS: GSTP1 Ile105Val and Ala114Val were genotyped and ETS exposure was assessed by parental questionnaire, which was validated by urinary cotinine measurements. Associations between ETS exposure, GSTP1 polymorphisms, and their interaction on atopy and asthma severity were investigated. RESULTS: For the functional GSTP1 105 SNP, those with the Ile/Ile genotype had odds for atopy of 2.77 (p = .054) when assessed by genotype alone, which increased to 9.02 (p = .050) when ETS was included, relative to individuals with other genotypes. Likewise, compared to children with other GSTP1 114 genotypes, those with Ala/Ala genotype had a 5.47-fold (p = .002) increased risk of atopy (p = .020) when assessed by genotype alone, increasing to 9.17-fold when ETS was included. The 105 Ile/Ile individuals all had the AA (105 Ile/Ile and 114 Ala/Ala) haplotype group; therefore, the odds for atopy were the same. Individuals without any *C haplotype (105 Val and 114 Val allele) who were exposed to ETS had a 9.17-fold increased risk of atopy when compared with individuals with at least one *C haplotype and not exposed to ETS (p = .020). CONCLUSION: There were significant interactions between GSTP1 SNPs, atopy, and ETS exposure in this cohort.

Bronchodilator responsiveness in children with asthma is not influenced by spacer device selection.

INTRODUCTION: Spacer devices optimize delivery of aerosol therapies and maximize therapeutic efficacy. We assessed the impact of spacer device on the prevalence and magnitude of bronchodilator response (BDR) in children with asthma. METHODS: Children with physician confirmed asthma and parentally reported symptoms in the last 12 months were recruited for this study. Each participant completed two separate visits (5-10 days apart) with spirometry performed at baseline and following cumulative doses of salbutamol (200, 400, 800, and 200 µg) delivered by either a small volume disposable spacer or a large volume multi-use spacer. Spacer type was alternated for each participant during each visit. The primary outcome was the effect of spacer type on bronchodilator responsiveness. The secondary outcome was to assess the relationships between spacer device, salbutamol dose and the proportion of children with a clinically relevant BDR. RESULTS: Thirty-two children (mean age 11.8 years) completed both visits. Change in lung function following bronchodilators was increased using the large volume spacer, for relative but not absolute increase in FEV1 [mean difference (95% confidence intervals): 1.28% (0.02, 2.54; P = 0.047) and 0.013 L (-0.01, 0.04; P = 0.288)], respectively. There was no observed difference in FVC by spacer type. Overall, 59% (n = 19) of children exhibited a clinically relevant BDR at 400 µg of salbutamol for any spacer and was independent of spacer type. CONCLUSION: Spacer device was not associated with clinically important differences in lung function following bronchodilator inhalation in children with asthma. At a recommended dose of 400 µg, some children with asthma may have their bronchodilator responsiveness misclassified.

Assessing adherence and factors associated with adherence in young children with asthma.

BACKGROUND AND OBJECTIVE: Adherence with preventive asthma medication by young children is an important factor when evaluating a suboptimal response to treatment. However, few data exist regarding the accuracy of subjective measures of adherence and factors associated with adherence in young children. METHODS: Fifty-one asthmatic children aged 18 months to 7 years had their use of preventive asthma medication monitored using an electronic monitoring device (Smartinhaler) for 1 month. At a follow-up visit the child's parent was asked how often medication had been given and they also completed a confidential questionnaire that included questions about medication usage, barriers to optimal adherence and parenting. The treating physician made an estimate of the child's likely use of medication. RESULTS: The median use of medication as determined by the Smartinhaler was 70.5% (range 21.4-100%). The parents' verbal reports (85.1%) and questionnaire responses (84.2%) overestimated medication usage. The physician was not able to determine which parents correctly estimated their child's use of medication (P = 0.28). The child's age, level of parental education and annual family income did not influence adherence. Parents reported simply 'forgetting' or their child's 'reaction to being given medication' as the principal barriers to adherence. There was a significant association between how stressful the parent found parenting and adherence (P = 0.05). CONCLUSION: Adherence with preventive medication, even within the context of a research study, was generally low and highly variable. Subjective measures of adherence were found to overestimate adherence in young asthmatics.

Facemasks and aerosol delivery in vivo.

It has been shown in vitro that even a small air leak in the facemask can drastically reduce the efficiency of drug delivery. In addition, it has been shown that drug deposition on the face does significantly add to overall drug loss and has the potential of local side effects. The aim of this study is therefore to verify these findings in vivo. Eight asymptomatic recurrently wheezy children, aged 18-36 months, inhaled a radiolabeled salbutamol formulation either from a pressurized metered-dose inhaler through a spacer with attached facemask or from a nebulizer with attached facemask. Drug deposition of radiolabeled salbutamol was assessed with a gamma camera and expressed as a percentage of the total dose. Lung deposition expressed as a percentage of the total dose (metered dose and nebulizer fill, respectively) was 0.2% and 0.3% in children who inhaled with a non-tightly fitted facemask. Lung deposition was 0.6% and 1.4% in screaming children with a tightly fitted facemask and between 4.8% and 8.2% in patients breathing normally. Overall mask deposition was between 0.8% and 5.2%. Overall face deposition was between 2.6% and 8.4%. The results from this pilot study support the results found in in vitro studies, where a facemask leak greatly reduces drug delivery to the patient.

In vitro evaluation of an asthma dosing device: the smart-inhaler.

Monitoring devices attached to pressurised metered dose inhalers provide an important objective measurement of patient adherence with asthma medications in clinical and research settings. The Smart-inhaler is a relatively new device that has not been previously validated. This study examines the accuracy of the Smart-inhaler in a bench-top experiment and compares it with a previously validated device, the Doser. Ten Smart-inhalers and five Dosers were actuated twice on two occasions per day for 30 days (120 doses). Six Smart-inhalers were also actuated 30 times in rapid succession to examine the ability of the Smart-inhaler to detect "dumping". Five Smart-inhalers failed to detect the first one or two doses. However, when the aerosol canister was placed more firmly in the device, actuating the device in the process, the following two doses were recorded accurately in all ten devices. Otherwise all ten Smart-inhalers and five Dosers recorded all actuations faithfully and there were no spurious recordings. The six Smart-inhalers recorded all 30 doses delivered in rapid succession. The Smart-inhaler and Doser are both highly accurate at measuring actuated doses and no spurious doses were recorded in an in vitro setting.

Recent advances in aerosol therapy for children with asthma.

Inhalational drug delivery is the primary mode of asthma therapy in children and is the main focus of this article. Pressurized metered dose inhalers (pMDIs) are now the method of choice in infants and children under 5 years old, when used in combination with an appropriate valved holding chamber or spacer. Spacers are particularly important for steroid inhalation to maximize lung deposition and minimize unwanted oropharyngeal deposition. Optimal inhalation technique with a pMDI-spacer in infants is to inhale the drug by breathing tidally through the spacer. Drug delivery to the lungs using pMDIs can vary greatly, depending on the formulation used and the age of the child. Dry powder inhalers (DPIs) are driven by the peak inspiratory flow of the patient and are usually not appropriate for children under 5 or 6 years of age. Nebulizers continue to play a role in the treatment of acute asthma where high doses of bronchodilator are required, though multiple doses via pMDI spacer may suffice. Important drug delivery issues specific to children include compliance, use of mask versus mouthpiece, lower tidal volumes and inspiratory flows, determination of appropriate dosages, and minimization of adverse local and systemic effects.

In vitro validation of 99mTc-HFA-FP delivered via pMDI-spacer.

The purpose of the study was to label Flixotide (fluticasone propionate [FP] with HFA propellant), with technetium-99m and validate that (99m)Tc acts as a suitable marker for FP when delivered via pMDI-spacer. Sodium pertechnetate was mixed with 5 mL of butanone. (99m)Tc was extracted into butanone and transferred into an empty canister. The (99m)Tc lined canister was heated, and the butanone evaporated to dryness. A supercooled commercial Flixotide canister was decrimped, and the contents transferred to the (99m)Tc lined canister and recrimped. The particle size distribution of FP and (99m)Tc from 10 radiolabeled canisters was measured using an Anderson cascade impactor calibrated to 28.3 L/min, and compared to commercial FP. The drug (FP) content of each particle size fraction was measured using ultraviolet spectrophotometry and the (99m)Tc level in each fraction was measured using an ionization chamber. The percentage of particles in the fine particle fraction (<;4.7 microm) and the percentage of (99m)Tc from commercial and radiolabeled canisters were compared. The mean (SD) % FP in the fine particle fraction, before and after label was 43.2 (1.8) % and 43.9 (2.6) %, respectively. The mean (SD) % (99m)Tc in the fine particle fraction was 42.1 (5.1) %. The mean %FP exiting spacer at (<4.7 microm) before labeling was not significantly different from the mean % FP exiting spacer at (<4.7 microm) after labeling (p > 0.05). The mean % (99m)Tc attached to particles at (<4.7 microm) after radiolabeling was not significantly different from the mean % FP levels (p > 0.05). The validation in this study indicates that (99m)Tc can act as a suitable marker for HFAFP, delivered via pMDI-spacer.

Lung deposition of 99mTc-radiolabeled albuterol delivered through a pressurized metered dose inhaler and spacer with facemask or mouthpiece in children with asthma.

BACKGROUND: Research on the use of a pressurized metered dose inhaler (pMDI) with spacer (pMDI/spacer) in children has indicated oral inhalation via the spacer mouthpiece is more efficient than the combination of oral and nasal inhalation that occurs when a pMDI/spacer is used with a facemask. Changes in pMDI formulations and developments in spacer and facemask designs have highlighted the need for new comparative studies of spacer use, particularly focusing on the age at which children can be taught to transition from use of a pMDI/spacer with facemask to use of the spacer mouthpiece. METHODS: Twelve children aged 3-5 years (7 males) with stable asthma were recruited. Of these, 10 children (6 males) completed both arms of the study. A transmission scan of each compliant subject was taken using a 37 MBq (99m)Tc flood source. Actuations (2-3) of a (99m)Tc-radiolabeled albuterol pMDI were administered through an antistatic spacer (OptiChamber Diamond) via either a facemask (medium LiteTouch facemask), or the spacer mouthpiece. The subject's inhalation pattern was simultaneously recorded using a pMDI Datalogger, and narrative data relating to tolerance and compliance were documented. Anterior and posterior planar scintigraphic scans were taken immediately after aerosol administration. RESULTS: Mean (SD) lung deposition (% total dose) was 18.1 (9.1)% with the facemask and 22.5 (7.9)% with the spacer mouthpiece (p>0.05). Peripheral lung deposition (expressed as peripheral:central (P:C) ratio) was higher in 7 out of 10 children with the facemask compared with the spacer mouthpiece: 1.3 (0.26) vs. 1.2 (0.35); (p=0.11). Head and neck deposition was higher with use of the facemask compared with the spacer mouthpiece: 19.7 (10.6)% vs. 10.8 (5.3)% (p=0.011). CONCLUSIONS: Lung deposition achieved using the spacer with facemask was higher than previously reported, with a difference of only 4.4% of total dose measured compared to the deposition with mouthpiece. This may be due to a combination of factors including pMDI formulation, and use of an antistatic spacer with a flexible, well-fitting facemask.

The concentration of iron in real-world geogenic PM10 is associated with increased inflammation and deficits in lung function in mice.

BACKGROUND: There are many communities around the world that are exposed to high levels of particulate matter <10 µm (PM10) of geogenic (earth derived) origin. Mineral dusts in the occupational setting are associated with poor lung health, however very little is known about the impact of heterogeneous community derived particles. We have preliminary evidence to suggest that the concentration of iron (Fe) may be associated with the lung inflammatory response to geogenic PM10. We aimed to determine which physico-chemical characteristics of community sampled geogenic PM10 are associated with adverse lung responses. METHODS: We collected geogenic PM10 from four towns in the arid regions of Western Australia. Adult female BALB/c mice were exposed to 100 µg of particles and assessed for inflammatory and lung function responses 6 hours, 24 hours and 7 days post-exposure. We assessed the physico-chemical characteristics of the particles and correlated these with lung outcomes in the mice using principal components analysis and multivariate linear regression. RESULTS: Geogenic particles induced an acute inflammatory response that peaked 6 hours post-exposure and a deficit in lung mechanics 7 days post-exposure. This deficit in lung mechanics was positively associated with the concentration of Fe and particle size variability and inversely associated with the concentration of Si. CONCLUSIONS: The lung response to geogenic PM10 is complex and highly dependent on the physico-chemical characteristics of the particles. In particular, the concentration of Fe in the particles may be a key indicator of the potential population health consequences for inhaling geogenic PM10.

Vibrating membrane devices deliver aerosols more efficient than standard devices: a study in a neonatal upper airway model.

BACKGROUND: Aerosol therapy in preterm infants is challenging, as a very small proportion of the drug deposits in the lungs. AIM: Our aim was to compare efficiency of standard devices with newer, more efficient aerosol delivery devices. METHODS: Using salbutamol as a drug marker, we studied two prototypes of the investigational eFlow(®) nebulizer for babies (PARI Pharma GmbH), a jet nebulizer (Intersurgical(®) Cirrus(®)), and a pressurized metered dose inhaler (pMDI; GSK) with a detergent-coated holding chamber (AeroChamber(®) MV) in the premature infant nose throat-model (PrINT-model) of a 32-week preterm infant (1,750 g). A filter or an impactor was placed below the infant model's "trachea" to capture the drug dose or particle size, respectively, that would have been deposited in the lung. RESULTS: Lung dose (percentage of nominal dose) was 1.5%, 6.8%, and 18.0-20.6% for the jet nebulizer, pMDI-holding chamber, and investigational eFlow nebulizers, respectively (p<0.001). Jet nebulizer residue was 69.4% and 10.7-13.9% for the investigational eFlow nebulizers (p<0.001). Adding an elbow extension between the eFlow and the model significantly lowered lung dose (p<0.001). A breathing pattern with lower tidal volume decreased deposition in the PrINT-model and device residue (p<0.05), but did not decrease lung dose. CONCLUSIONS: In a model for infant aerosol inhalation, we confirmed low lung dose using jet nebulizers and pMDI-holding chambers, whereas newer, more specialized vibrating membrane devices, designed specifically for use in preterm infants, deliver up to 20 times more drug to the infant's lung.

Introduction: Aerosol delivery of orally inhaled agents.

Deposition scintigraphy methods have been used extensively to provide qualitative and quantitative data on aerosol drug deposition in the lungs. However, differences in methodology among the different centers performing these studies have limited the application of these techniques, especially in regulatory roles. As an introduction to the standardized techniques developed by the International Society for Aerosols in Medicine (ISAM) Regulatory Affairs Networking Group, we present potential advantages of the use of standard techniques for deposition scintigraphy. Specifically, we propose that standardized techniques would allow for better comparisons between labs and would facilitate multicenter studies. They would allow for improved methods of establishing equivalence and could be better utilized to establish dosing for new medications. They would allow for the performance of more accurate dose ranging or multidose studies and complement pharmacokinetic studies of new inhaled medications. Standardized techniques could help to establish the relationship between the deposition of drug in the lungs and clinical effect, and may also facilitate clinical measurements of deposited dose for medications with narrow therapeutic indices. In the sections that follow, we discuss the best techniques used to perform deposition scintigraphy through planar, single-photon emission computed tomography, and positron emission tomography modalities and propose a detailed set of standardized methods for each. These include methods for radiolabel validation, radiolabel accountability and mass balance, and imaging acquisition and analysis.

Validation of radiolabeling of drug formulations for aerosol deposition assessment of orally inhaled products.

Radiolabeling of inhaler formulations for imaging studies is an indirect method of determining lung deposition and regional distribution of drug in human subjects. Hence, ensuring that the radiotracer and drug exhibit similar aerodynamic characteristics when aerosolized, and that addition of the radiotracer has not significantly altered the characteristics of the formulation, are critical steps in the development of a radiolabeling method. The validation phase should occur during development of the radiolabeling method, prior to commencement of in vivo studies. The validation process involves characterization of the aerodynamic particle size distribution (APSD) of drug in the reference formulation, and of both drug and radiotracer in the radiolabeled formulation, using multistage cascade impaction. We propose the adoption of acceptance criteria similar to those recommended by the EMA and ISAM/IPAC-RS for determination of therapeutic equivalence of orally inhaled products: (a) if only total lung deposition is being quantified, the fine particle fraction ratio of both radiolabeled drug and radiotracer to that of the reference drug should fall between 0.85 and 1.18, and (b) if regional lung deposition (e.g., outer and inner lung regions) is to be quantified, the ratio of both radiolabeled drug and radiotracer to reference drug on each impactor stage or group of stages should fall between 0.85 and 1.18. If impactor stages are grouped together, at least four separate groups should be provided. In addition, while conducting in vivo studies, measurement of the APSD of the inhaler used on each study day is recommended to check its suitability for use in man.

Usefulness of parental response to questions about adherence to prescribed inhaled corticosteroids in young children.

BACKGROUND: Adherence to prescribed inhaled medication is often low in young children. Poor adherence to medication may contribute to lack of symptom control. Doctors are not good at predicting the adherence rates of their patients, and parental report of adherence does not correlate with objective measures of adherence. The objective of this study was to investigate whether parental admission of non-adherence and reasons given for non-adherence correlated with objectively measured adherence. METHODS: Adherence to prescribed inhaled corticosteroid treatment was monitored electronically in 132 children aged 2-6 years who were participating in a randomised controlled trial comparing different inhaler devices. Follow-up was carried out every 3 months for a year. Parental answers to simple questions about adherence were compared to electronically measured adherence. RESULTS: Mean adherence ranged from zero to 100%. Intra-participant adherence varied throughout the year-long study period (mean variance for individual children between quarterly periods was 28.5%). Parents who reported missed doses, generally missed at least half of the prescribed doses. Parents who reported that not a single prescribed dose was missed, still missed 20% of doses on average. Adherence was particularly low when parents cited initiating their own trial off medication as a reason for missing doses. CONCLUSIONS: By examining parental response to questions enquiring whether any doses were missed, healthcare providers can gain a modest degree of insight into their patients' true adherence to prescribed medication. Adherence to prescribed asthma medication is extremely variable in young children. TRIAL REGISTRATION NUMBER: Data from this study were derived from a randomised controlled trial (ACTRN12608000294358).

Standardization of techniques for using planar (2D) imaging for aerosol deposition assessment of orally inhaled products.

Two-dimensional (2D or planar) imaging with (99m)Tc radiolabels enables quantification of whole-lung and regional lung depositions for orally inhaled drug products. This article recommends standardized methodology for 2D imaging studies. Simultaneous anterior and posterior imaging with a dual-headed gamma camera is preferred, but imaging with a single-headed gamma camera is also acceptable. Correction of raw data for the effects of gamma ray attenuation is considered essential for accurate quantification, for instance, using transmission scanning with a flood-field source of (99m)Tc or (57)Co. Evidence should be provided of the accuracy of the quantification method, for instance, by determining "mass balance." Lung deposition may be expressed as a percentage of ex-valve or ex-device dose, but should also be given as mass of drug when possible. Assessment of regional lung deposition requires delineation of the lung borders, using X-ray computed tomography, radioactive gas scans ((133)Xe or (81m)Kr), or transmission scans. When quantifying regional lung deposition, the lung should be divided into outer (O) and inner (I) zones. A penetration index should be calculated, as the O/I ratio for aerosol, normalized to that for a radioactive gas or transmission scan. A variety of methods can be used to assess lung deposition and distribution. Methodology and results should be documented in detail, so that data from different centers may be compared. The use of appropriate methodology will provide greater confidence in the results of 2D imaging studies, and should allay concerns that such studies are qualitative or semiquantitative in nature.

Aerosol inhalation from spacers and valved holding chambers requires few tidal breaths for children.

OBJECTIVE: The goal was to determine the number of breaths required to inhale salbutamol from different spacers/valved holding chambers (VHCs). METHODS: Breathing patterns were recorded for 2- to 7-year-old children inhaling placebo from 4 different spacers/VHCs and were simulated by a flow generator. Drug delivery with different numbers of tidal breaths and with a single maximal breath was compared. RESULTS: With tidal breathing, mean inhalation volumes were large, ranging from 384 mL to 445 mL. Mean values for drug delivery with an Aerochamber Plus (Trudell, London, Canada) were 40% (95% confidence interval [CI]: 34%-46%) and 41% (95% CI: 36%-47%) of the total dose with 2 and 9 tidal breaths, respectively. Mean drug delivery values with these breath numbers with a Funhaler (Visiomed, Perth, Australia) were 39% (95% CI: 34%-43%) and 38% (95% CI: 35%-42%), respectively. With a Volumatic (GlaxoSmithKline, Melbourne, Australia), mean drug delivery values with 2 and 9 tidal breaths were 37% (95% CI: 33%-41%) and 43% (95% CI: 40%-46%), respectively (P = .02); there was no significant difference in drug delivery with 3 versus 9 tidal breaths. With the modified soft drink bottle, drug delivery. Drug delivery was not improved with a single maximal breath with any device. CONCLUSION: For young children, tidal breaths through a spacer/VHC were much larger than expected. Two tidal breaths were adequate for small-volume VHCs and a 500-mL modified soft drink bottle, and 3 tidal breaths were adequate for the larger Volumatic VHC.

Validation of methodology for recording breathing and simulating drug delivery through spacers and valved holding chambers.

BACKGROUND: Output from spacers (or valved holding chambers) is sensitive to changes in breathing pattern. Different spacers have unique characteristics that may influence breathing. A method used for breathing simulation, where the simulated breathing can be recorded on subjects while they are using spacers, may allow for more accurate in vitro estimation of drug delivery in specific populations, using specific spacers. METHODS: A flow chamber was used to record breathing while salbutamol was administered to two adult subjects through different spacers. Each subject performed a series of breathing patterns over a range of different inhalation volumes and flows. Salbutamol "inhaled" by subjects was captured on inspiratory filters and quantified by ultraviolet spectrophotometry. Recorded breathing patterns were simulated and ex vivo drug delivery was compared to in vitro drug delivery. Three equipment configurations were used to validate different aspects of the methodology. Configuration 1: breathing recorded by pneumotachometer placed directly between a human subject and the spacer. Breathing simulation performed with an identical setup. Configuration 2: spacer enclosed within a flow-chamber while breathing was recorded. Breathing simulation performed with an identical setup. Configuration 3: spacer enclosed in flow chamber to record breathing, but not when simulating breathing. In each configuration, the ex vivo and in vitro (simulated) filter doses were compared. RESULTS: Configuration 1: the median difference between ex vivo and in vitro filter doses was 0.4% (range: -12.2 to 6.9%). Configuration 2: the median difference was -2.3% (range: -9.0 to 5.0%). Configuration 3: the median difference was 1.7% (range: -11.5 to 3.9%). CONCLUSION: Our results indicate that in vitro simulated drug delivery using this method of recording using a flow chamber, closely approximates ex vivo total drug delivery. This technique allows for recording of breathing on patients while they are using spacers, with minimum increase in dead space or resistance, and no physical alteration in the patient-device interface.