Biomedical subjects
Publications and source records attributed to S G Devadason.
A novel asthma spacer device, the "Funhaler", incorporates incentive toys which are isolated from the main inspiratory circuit by a valve. Here we show that its use does not compromise drug delivery. Improved adherence combined with satisfactory delivery characteristics suggest that the Funhaler may be useful for management of young asthmatics.
QVAR, an extrafine hydrofluoroalkane/beclomethasone dipropionate formulation, has been shown to double lung deposition in adults. The aim of the present study was to assess the total body deposition and distribution of technetium-99m-labelled (99mTc) QVAR in children after inhalation via an Autohaler. Sixteen male asthmatic children (5-14 yrs) inhaled labelled drug (<4 MBq 99mTc; 100 microg beclomethasone dipropionate) via an Autohaler within 30 min after salbutamol (200 microg) administration. Simultaneous anterior and posterior planar scintigraphic scans (120 s acquisition time) were collected after inhalation of labelled drug. Mean+/-SD lung deposition of labelled drug (attenuation-corrected; percentage of ex-actuator dose) was 36.9+/-9.2, 46.5+/-11.6 and 54.1+/-10.7% in children aged 5-7, 8-10 and 11-14 yrs, respectively. Combined oropharyngeal and gastrointestinal deposition was 59.7+/-8.2, 48.9+/-12.3 and 40.3+/-11.8%. Lung deposition positively correlated with the forced expiratory volume in one second (FEV1) and forced vital capacity (FVC). Gastrointestinal dose negatively correlated with the FEV1, FVC, height and age. In older children (11-14 yrs), lung deposition was almost identical to that reported in adults using QVAR. In children aged 5-10 yrs, lung deposition using QVAR was greater than the levels measured using other commercial aerosol delivery systems. Oropharygeal and gastrointestinal deposition was inversely related to age.
BACKGROUND: Many review articles report the safety and lack of serious side-effects associated with the histamine challenge. Even though methacholine and hypertonic saline are more commonly used to measure airway responsiveness, histamine challenges are used in many countries around the world. Levels of subjects discomfort after a challenge have not been quantified. This study quantified the incidence, severity and duration of subject discomfort after histamine challenge. METHODS: Ninety-nine subjects were recruited in an Australian multi-centre population-based study of the genetic epidemiology of asthma. Subjects completed a histamine challenge with final cumulative dose 3.2 micromol. Immediately, and 10 min, after challenge subjects rated their discomfort for cough, headache, throat irritation, hoarse voice and flushed. Research personnel also reported their perception of subjectdiscomfort. RESULTS: Subjects and research personnel reported a small degree of subject discomfort for all symptoms immediately after the histamine challenge. Overall, median symptom scores were less than 1.5 out of 10. Discomfort scores improved 10 min after challenge and cough, throat irritation and flushed improved significantly CONCLUSIONS: This study confirms the tolerability of the histamine challenge.
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Pressurized metered-dose inhalers attached to spacers are now the most common form of delivery of anti-asthma medication in children. However, no reliable data are available of how much drug reaches the lungs in children of different ages. This information is crucial, as it determines the efficacy of therapy. In this study, we present information on the amount of drug reaching the lungs in children from a pressurized metered-dose inhaler attached to a detergent-coated spacer. We studied 18 asthmatic children inhaling radiolabeled salbutamol through detergent treated spacers to minimize electrostatic charge on the spacer wall. Lung deposition was much higher than expected when using detergent-coated spacers. Mean (SD) lung deposition, expressed as a percentage of the total actuated dose (five actuations), was 16.4% (5.5) in younger children inhaling through a small volume spacer, and 28.2% (6.7) and 41.8% (3. 8) in older children inhaling with different breathing patterns through a large volume spacer. These findings have major implications for dosage regimens for inhaled anti-asthma medication in children. Lower doses may be sufficient for adequate drugs delivered through spacers treated for static to achieve a desired clinical response.
OBJECTIVE: To compare lung deposition from a nebulizer and a pressurized metered-dose inhaler (pMDI)/holding chamber to determine their efficiency in aerosol delivery to children. STUDY DESIGN: Children with stable asthma (n = 17) aged 2 to 9 years inhaled in random order radiolabeled salbutamol from a nebulizer and a pMDI through a nonstatic holding chamber. Body and lung deposition of radiolabeled salbutamol was assessed with a gamma camera. RESULTS: Mean (absolute dose) total lung deposition expressed as a percentage of the nebulized dose was 5.4% (108 microg) in younger children (<4 years) and 11.1% (222 microg) in older children (>4 years). Mean (absolute dose) total lung deposition expressed as a percentage of the metered dose was 5.4% (21.6 microg) in younger and 9.6% (38.4 microg) in older children. CONCLUSIONS: For the same age groups we have shown equivalent percentages of total lung deposition of radiolabeled salbutamol aerosolized by either a nebulizer or a pMDI/holding chamber. However, the delivery rate per minute and the total dose of salbutamol deposited were significantly higher for the nebulizer.
Pressurized metered dose inhalers (pMDI) are widely used together with spacers for the treatment of asthma in children. However, the variability of daily medication dose for pMDI/spacer combinations is not known. Electrostatic charge is a potential source of dose variability. Metal spacers have no static charge. This study assessed and compared within-subject variability of aerosol delivery of metal and plastic spacers. This was a randomized, crossover study in children with stable asthma aged 1-4 (group I, n=17) and 5-8 (group II, n=16) yrs. In both groups the amount of drug delivered to the mouth by a metal spacer (Nebuchamber) and one of two plastic (polycarbonate) spacers, i.e. Babyhaler in group I and Volumatic in group II was measured. The metal and plastic spacers were tested at home in a randomized order for 7 days each, using budesonide (200 microg b.i.d.). Aerosol was collected on a filter positioned between spacer and facemask or mouth. Budesonide on the filter was assessed by high performance liquid chromatography. The mean filter dose for each child (mean+/-SD) during the 7 days was expressed as a percentage of the nominal dose. Within-subject variability was expressed as coefficient of variation (CV). Mean filter dose in group I was 41.7+/-10.1% for Nebuchamber and 26.0+/-4.0% for Babyhaler (p<0.001). Mean filter dose in group II was 50.2+/-9.2% for Nebuchamber and 19.4+/-7.2% for Volumatic (p<0.001). Mean CV in group I was 34% for Nebuchamber and 37% for Babyhaler (p=0.44). Mean CV in group II was 23% for Nebuchamber and 34% for Volumatic (p=0.003). There was substantial within-subject dose variability in aerosol delivery in children using a pMDI/spacer at home. This variability was lower for the metal than for the plastic spacer in children 5-8 yrs of age. The dose delivered to the mouth was about two-fold higher for the metal than the plastic spacer independent of age.
Ionic detergents reduce electrostatic charge on plastic spacers, thereby improving in vitro drug delivery. The aim of this study was to gain practical information on the use of detergents and to evaluate the relevance of this information on in vivo drug deposition. Measurement of electrostatic charge and salbutamol particle size distribution was carried out on detergent-coated and noncoated plastic spacers. The efficiency of four household detergents was compared, and the influence of dilution and the duration of the antistatic effect were studied. In addition, the level of radiolabelled salbutamol deposition in the lungs of eight healthy adults was compared after inhalation through a new versus a detergent-coated spacer. In vitro, all tested detergents reduced the electrostatic charge on the spacer surface. This resulted in a mean increase of 37.4% (range 33.5-41.2) in small particle (<6.8 microm) salbutamol output compared with water-rinsed/drip-dried spacers. Dilution had no influence on the results and the effect lasted for at least four weeks. In vivo, the mean lung deposition of radiolabelled salbutamol in healthy subjects was 45.6% (range 43.4-49.5) through a detergent-coated spacer compared to 11.5% (range 7.6-17.9) through a static spacer (p<0.001). In conclusion, household detergents offer a simple and practical solution to the problem of static on plastic spacers and significantly improve both in vitro and in vivo delivery of salbutamol.
UNLABELLED: The aim of our study was to evaluate the effect of age on lung deposition of radiolabelled budesonide, delivered as a dry powder via Turbuhaler to asthmatic children. A group of 23 asthmatic children, aged 6 to 16 years, with relatively stable asthma inhaled 99mTc-labelled budesonide from a dry powder inhaler (Turbuhaler). Body and lung deposition was assessed using a gamma camera. The mean (range) median peak inspiratory flow during inhalation was 65 1 x min(-1) (45 to 76 1 x min(-1)). Mean (range) total lung deposition of 99mTc-labelled budesonide, expressed as a percentage of the metered dose, was 29.1% (15.6-47.2%) and was positively and significantly correlated with age, height and peak inspiratory flow. CONCLUSION: Total lung deposition of radiolabelled budesonide from a dry powder inhaler (Turbuhaler), is age dependent in children with moderate asthma. However, lung deposition is still satisfactory, even in younger children with lower peak inspiratory flows.
STUDY OBJECTIVES: The aim of our study was to determine the in vitro delivery of salbutamol from a pressurized metered-dose inhaler (pMDI) containing hydrofluoroalkane (HFA) propellant through various delivery devices to four models of a pediatric lung. DESIGN: To determine the effect of electrostatic charge, delivery of salbutamol was initially assessed with a multistage liquid impinger (MSLI) through an inline nonchamber device (Baxter MDI Adapter) and a small (Aerochamber MV) and a large (Nebuhaler) inline chamber device. Following this, the delivery was assessed to four lung models appropriate for a child of 70 kg, 50 kg, 15 kg, and 4 kg, with the same three reduced static devices inserted directly into a pediatric ventilator circuit. MEASUREMENTS AND RESULTS: Reduction of electrostatic charge improved small particle delivery through holding chambers to the MSLI by 12 to 14%. In the ventilator model, the mean delivery was between 1.9% and 5.4% for the nonchamber device, between 14.3% and 27.2% for the small holding chamber, and between 7.2% and 25.7% for the large holding chamber. Delivery was the least efficient in the 4-kg model compared to the 70-kg, 50-kg, and 15-kg models. CONCLUSIONS: Salbutamol from an HFA pMDI is delivered efficiently through inline holding chambers with reduced static in pediatric ventilator settings. A large holding chamber has no advantage over a small holding chamber. In addition, salbutamol delivery is more efficient through a holding chamber than through a nonchamber device.
Inhalation therapy for wheezy infants with either a nebulizer or a pressurized metered-dose inhaler (pMDI) through a spacer is common practice. The aim of our study was to compare aerosol delivery to wheezy infants from a nebulizer and from a pMDI via two small volume spacers. Twenty wheezy infants (aged 4-12 months) were recruited. They inhaled salbutamol from a Pari-Baby nebulizer, from a detergent-coated Babyhaler, and from a Nebuchamber in random order. A filter was placed between the inhalation systems and the patients. The amount of salbutamol deposited on the filter was measured using an ultraviolet spectrophotometer and was expressed as a percentage of the total nebulized or actuated doses. The mean total nebulized dose for the Pari-Baby (1030 micrograms) was higher (P < 0.001) than the mean actuated dose from a pMDI for the Babyhaler (374 micrograms) and for the Nebuchamber (378 micrograms). Mean drug deposition on the filter was 40.2% (150 micrograms) of the total actuated dose for the detergent-coated Babyhaler and 40.7% (154 micrograms) of the total actuated dose for the Nebuchamber. There was no significant difference in drug deposition on the filter between the two spacers. Mean drug deposition on the filter was 25.3% (260 micrograms) of the total nebulized dose for the Pari-Baby nebulizer. There was no weight dependence in drug deposition on the filter for the two spacers, but, drug deposition increased with the subject's weight for the nebulizer. We have shown that aerosol delivery to wheezy infants from a pMDI through small volume spacers is effective and that a higher percentage of the total amount of salbutamol is delivered than from a nebulizer. The weight dependence in drug deposition for the nebulizer can be of clinical relevance.
Several in vitro and in vivo studies have emphasized the importance of generating a high inspiratory flow when using a dry powder inhaler. Little attention has been paid to the influence of the inspiratory flow profile on the particle size distribution contained in aerosols generated by these devices. The internal volume of a device such as the Turbuhaler is small compared with a vital capacity breath and it is possible that all the powder has been drawn from the device before peak inspiratory flow has been achieved, particularly if the time to peak inspiratory flow is prolonged. A series of experiments were performed to assess the effect of different flow profiles through the Turbuhaler, each with a peak flow of 60 1 min-1. A 400 microgram budesonide Turbuhaler was enclosed in a chamber allowing air to pass unimpeded through the dosing channels and entrainment ports. A large three-way tap was used to blow powder from the device across a Malvern Mastersizer laser particle sizer which produced a profile of the particle size distribution within the aerosol. The rate of increase in flow through the Turbuhaler was determined by the rate at which the three-way tap was turned, and recorded by means of a pneumotachograph. The rate of increase in flow was found to significantly affect the particle size-distribution within the aerosol. Failure to attain a flow of 30 1 min-1 before 150 ml of air had passed through the device resulted in the aerosol volume median diameter increasing from less than 6.6 microns to greater than 45.3 microns. These results indicate that flow during the initial part of the inspiratory effort may be important in determining the characteristics of the aerosol generated by a dry powder inhaler. With more sophisticated equipment, it might be possible to explore the relationship between flow profile and particle size distribution generated by dry powder devices in more detail.
We tested the hypotheses that in early pregnancy smokers have lower urinary cotinine levels than nonpregnant smokers, and that pregnant nonsmokers exposed to passive smoke have higher cotinine levels than nonsmokers not exposed to passive smoke. This was a prospective, quantitative, comparative study of the urinary cotinine levels and smoking characteristics of pregnant and nonpregnant females. A urine specimen was collected from each subject and the cotinine/creatinine level determined using radio-immunoassay. A questionnaire regarding smoking status, health issues, and demographic variables was administered to each subject. There was no difference in cotinine level between pregnant smokers and control smokers. Pregnant nonsmokers with passive smoke exposure had higher cotinine levels than the same group not passively exposed. Confidence in ability to stop smoking was associated with lower numbers of cigarettes consumed, but was not reflected by lower cotinine levels. These data suggest that if the mother smokes, the fetus is exposed from conception to levels of nicotine which are as high as those in adult female smokers who are not pregnant. The level of fetal exposure to nicotine during early gestation is independent of intention to alter smoking behaviour. Women should be targeted for antismoking public health messages before conception.
Infant lung function can be assessed with the tidal volume "squeeze" technique or, over an extended volume range, with the newer raised volume forced expiration technique (RVFET). We assessed methacholine responsiveness in 11 infants, measuring both maximal expiratory flow at functional residual capacity (V.max,FRC)with the tidal volume technique, and forced expiratory volume/time (FEV(t)) with RVFET. We used a standard methodology for the former. FEV(t) was measured by inflating the infant's lungs to 20 cm H2O and forcing expiration using a jacket setup to transmit a pressure of 20 cm H2O to the airway. Lung function was measured at baseline and after methacholine inhalations, increasing from 0.1 g/L to 10 g/L in half log dosage increments (DI). The provocative concentrations (PC) of methacholine leading to a 40% fall in V.max,FRC and a 15 or 20% fall in FEV(t) were calculated. The mean provocative concentration of methacholine required to produce a 40% fall in V.max,FRC was less than that required to produce a 20% fall in FEV0.5 by 0.39 DI (95% CI, -0.60 to 1.38) and less than that required to produce a 20% fall in FEV0.75 by 0.42 DI (95%, CI, -0.54 to 1.39). Similarly, the provocative concentration of methacholine required to produce a 40% fall in V.max,FRC was less than that required to produce a 15% fall in FEV0.5 by 0.14 DI (95% CI, -0.99 to 1.28) or a 15% fall in FEV0.75 by 0.13 DI (95% CI, -0.80 to 1.08), but the differences were small and not significant. Despite these differences the agreement between the two methods was good, and bronchoconstriction was not attenuated by the forced inspiration delivered by the raised volume maneuver. We conclude that the raised volume forced expiration technique is able to detect methacholine-induced bronchoconstriction.
The raised-volume forced-expiration technique measures infant lung function over an extended volume range. To improve comparisons between individuals and populations, we investigated the influence of jacket pressure on outcome variables in 21 infants. To quantify pressure transmitted from the jacket to the pleural space at a given lung volume, the jacket was inflated against an occluded airway, and the increase in pressure at the mouth was measured. Flow-volume curves were recorded at transmitted pressure (Ptrans) values ranging from 0 to 41.9 cm H20. The effect of Ptrans on the FEV measures of FEV0.5, FEV0.75, and FVC, and on the forced expiratory flow measures of FEF25%, FEF50% and FEF75% was assessed. At Ptrans values between 0 to 20 cm H20, a significant positive relationship existed between transmitted pressure (Ptrans) and all outcome variables except FVC. At higher Ptrans values, all outcome variables demonstrated pressure independence, with the exception of FEF25% (which remained positive) and FVC (which was negative in a subgroup of wheezy infants). FEF75% values tended to decrease at Ptrans values > 25 cm H20. At Ptrans values between 20 and 25 cm H20, most outcome variables are pressure independent. This range is therefore the most suitable for use with the raised-volume forced expiration technique.
Drug delivery to patients using dry powder inhalers, such as the Turbuhaler, is believed to be influenced by the inspiratory flow used. Clinical studies have indicated that this delivery system can be used effectively by children. However, it is not known how the total and weight-corrected dose delivered to the airways varies with age. A deposition study using technetium-99m (99mTc)-labelled budesonide was performed in order to determine the effect of age on delivery. Twenty one children with cystic fibrosis, aged 4-16 yrs, were recruited. They were clinically stable with normal lung function. Initially, a gamma camera scan was taken in front of a flood source containing 37 MBq of 99mTc. Subsequently, subjects inhaled through a low resistance inspiratory filter connected to a commercially available Turbuhaler. Immediately afterwards they inhaled from a noncommercial Turbuhaler containing budesonide labelled with 99mTc, and then underwent anterior and posterior gamma camera scans. Both Turbuhaler inhalers were attached to a portable spirometer and the peak inspiratory flow through the Turbuhaler was recorded for each inhalation. The total body dose was calculated from the dose deposited on the inspiratory filter connected to the commercial Turbuhaler. Analysis of the gamma camera images provided information on the proportion of the radiolabel delivered to the lungs compared to that deposited in the upper airway and stomach. As expected, a highly significant positive correlation was noted between the peak inspiratory flow generated by the patient through the Turbuhaler and the dose delivered to the lung. Similarly, there was a highly significant positive correlation between age and "total lung dose". However, when total lung dose was corrected for body weight, there was a nonsignificant negative correlation with age. This study suggests that the "weight-corrected lung dose" achieved when children aged > 6 yrs use the Turbuhaler, is largely independent of age. It would appear that the flow-dependent properties of this device are such that the reduced peak inspiratory flow generated by younger children results in a lower dose to the lungs, but that this is off-set by their lower body weight. This is unlikely to be a property of other devices with different flow/drug delivery characteristics.
Attempts to improve drug delivery from conventional jet nebulizers have included the use of storage systems to reduce drug wastage during exhalation. Venturi nebulizers enhance drug delivery during inhalation, reducing treatment times and drug wastage. This study investigated the effect of age on inhaled dose from a conventional jet nebulizer (Acorn) used both with and without a storage chamber (Mizer), compared to two Venturi nebulizers (Ventstream and Pari LC). Filters were attached to the four nebulizer systems, containing salbutamol, and 18 children with cystic fibrosis (3-16 yrs) inhaled through these devices. The quantity of drug collected on the filter was assessed using ultraviolet spectrophotometry. The particle size distribution of the aerosol from each nebulizer system was measured using laser diffraction. Inspiratory filter deposition using the Acorn was lower than the Acorn with Mizer, and both Venturi nebulizers. Filter deposition using the Acorn with Mizer was lower than the Pari LC. No trend with age, height or weight was noted using any nebulizer. Aerosol particle size using the Ventstream was lower than the other nebulizer systems. Drug output from both Venturi nebulizers was more efficient than from the jet nebulizer, used with and without the storage chamber, during inhalation by children with cystic fibrosis. The inhaled dose did not change with the patient's age or size using both types of nebulizer.