The evaluation of strategies for producing optimal inhalant therapy in preschool children (2-6 years) with chronic asthma
Background: The dose of inhaled medication reaching a patient is dependent on drug formulation, method of delivery, output and correct use of the delivery device and frequency of use. The most commonly used aerosol drug delivery device in preschool children is the pressurised metered-dose inhaler (pMDI) -spacer. This study evaluated strategies for improving the delivery of inhalation therapy in preschool children by focusing on factors affecting the optimal use of pMDI-spacers and on the frequency of their use as determined by adherence to prescribed drug regimes. The study was divided into two parts. Part 1 examined the number and type of breaths needed for efficient drug delivery through a pMDI-spacer in preschool children. Part 2 was a randomised, controlled, prospective clinical trial in which a comparison was made between an incentive spacer device and a small volume spacer with respect to adherence, correct device use (spacer technique) and clinical outcome. Overall aims: • To determine how many tidal breaths are required to effectively inhale medication from different types of spacer/ valved holding chamber devices, and to determine the efficacy of a single maximal inhalation for drug delivery in young children. • To investigate the relationship between factors that determine dose delivery of inhaled asthma maintenance therapy and symptom control in preschool asthmatic children. • To determine the influence of an incentive inhalation delivery device on drug delivery and clinical outcome in preschool asthmatic children. Part One (Chapters Two and Three): Background: The pMDI-spacer combination is currently the most commonly used method of drug delivery to preschool asthmatics. A patient’s competence in using a pMDI-spacer is an important part of drug delivery. Preschool children are instructed to breathe normally (tidally) through spacer devices. There is little evidence on the number of breaths required for optimal drug delivery. Whether the single maximal breath technique has a place in spacer use in preschool children also remains unclear. Due to a lack of data, authors of asthma guidelines have been unable to give evidence-based instruction on how a preschool child should breathe through a spacer. Aims: To determine the optimal method of breathing through a spacer for preschool asthmatic children to ensure effective drug delivery. Hypothesis: Based on technical data on in vitro spacer performance and knowledge of tidal flow patterns in young children the hypothesis is that a limited number of breaths would be sufficient for efficient drug inhalation via spacer in preschool children. Methods: A method for reliably recording and simulating breathing of patients using pMDI-spacer devices was designed, constructed and validated. Breathing flow patterns were recorded in preschool children inhaling placebo from spacers. The breathing patterns were reproduced by a breathing simulator which was connected to spacer devices. Breathing patterns previously recorded using each specific type of spacer, were simulated with the corresponding spacer type. To estimate delivery, the mass of salbutamol was measured on a filter interposed between the spacer and the simulator. Four different spacer devices, the Aerochamber Plus®, Funhaler®, Volumatic® and a modified 500ml plastic soft drink bottle were tested with a salbutamol pMDI. The effect of different numbers of tidal breaths and that of a single maximal breath on drug delivery were compared. Results: Drug delivery via the Funhaler® mean (95CI) was 39% (34-43) and 38% (35-42) of total dose recovered from filter, pMDI and spacer, for two and nine tidal breaths respectively. Drug delivery via the Aerochamber Plus mean (95CI) was 40% (34-46) and 41% (36-47) for two and nine tidal breaths respectively. There was no significant difference in drug delivery after three tidal breaths mean (95CI) 40% (36-44%) and nine tidal breaths nine tidal breaths; mean (95CI) 37% (33-41) for the Volumatic®. With the (unvalved) modified soft drink bottle, there was no significant difference in drug delivery between two, five or nine tidal breaths. Inhalation volumes were almost double the expected tidal volumes. The inhalation volume means (SD) of subjects using the Aerochamber Plus®, the Funhaler®, the Volumatic® and the modified soft drink bottle were respectively 393ml (247), 432ml (225), 384ml (185), 445ml (167) during tidal breathing and 515ml (164), 550ml (239), 503ml (213), 448ml (259) for the single maximal breath manoeuvre. 100% of seven year old children, 84% of six year olds, 76% of five year olds, 38% of four year olds and 20% of three year olds could perform a single maximal breath manoeuvre. Nine tidal breaths resulted in significantly greater drug delivery to filter than single maximal inhalation for both the Funhaler® (p=0.04) and the Volumatic® (p=0.01). There was no significant difference in drug delivery to filter between single maximal inhalation and nine tidal breaths with both the Aerochamber Plus® and the modified soft drink bottle. Conclusion: In preschool children, two tidal breaths were adequate for drug delivery through small volume valved spacers and a 500ml modified soft drink bottle. For a large volume spacer, three tidal breaths were adequate for drug delivery. Part Two (Chapters Four and Five): Background: Drug delivery by pMDI-spacer is determined by many different factors, including spacer technique and adherence to prescribed medication. The effect of both spacer technique and adherence on clinical outcome has been demonstrated in older asthmatics. In this part of the thesis the influence of these factors on clinical outcome in preschool asthmatics was firstly investigated. Thereafter, the additional influence of an incentive spacer device on adherence, spacer technique and clinical outcome was also assessed. Aims: • To investigate the effect of proficiency in spacer technique, as measured by deposition of drug inhaled onto a filter, on clinical outcome in preschool asthmatic children. • To investigate the effect of adherence to prescribed inhaled asthma medication on clinical outcome in preschool asthmatic children. • To investigate the influence of the use of an incentive spacer device on inhaled drug dose, adherence to prescribed treatment and clinical outcome in preschool asthmatic children. Hypothesis: • Proficiency in spacer technique correlates positively with improved clinical outcome. • Good adherence to prescribed medication regimens correlates positively with improved clinical outcome. • Use of an incentive spacer device, the Funhaler® , improves both competency in spacer technique and adherence to prescribed medication and thereby improves clinical outcome in preschool children with asthma. Methods: A prospective randomised, controlled clinical trial was performed. Subjects were two to six year old children who had doctor-diagnosed asthma and were on daily maintenance therapy with inhaled corticosteroids. Maintenance therapy was delivered by Funhaler® in the study group and Aerochamber Plus® in the control group. Subjects were assessed for the following outcomes at three-monthly intervals for one year: (1) Proficiency in spacer technique was measured at each study visit by measuring the drug dose deposited on a filter interposed between the subject and the spacer. (2) Adherence was monitored using an electronic monitoring device (Smartinhaler) (3) Asthma symptoms were monitored using diary cards. (4) Quality of life (QoL) was measured using the PedsQL questionnaires. (5) Lung function was monitored using the forced oscillation technique. The Funhaler group was then compared with the Aerochamber Plus group in terms of determinants of drug delivery and markers of clinical outcome. Results: One hundred and thirty two subjects were included in the study. One hundred and eleven patients (84%) completed the study. By the six month follow-up, significantly more subjects in the Funhaler group had dropped out of the study (p=0.04). Throughout the clinical trial, there was large intra-subject variation in proficiency in spacer technique, as measured by drug dose deposited on filter. Individual patient drug doses recovered from the filters ranged from zero to 136μg (calculated as the mean of five 100μg pMDI actuations). There was no significant correlation between proficiency in using the delivery device and any measure of asthma control (p > 0.05). Correcting for age, gender, and adherence to prescribed medication did not influence the results. Inter subject variability in adherence to prescribed medication was extremely high throughout the study. Adherence to prescribed medication ranged from 1% to 99%. There was a significant correlation between adherence to prescribed medication and nights without wheeze, throughout the study period (r = 0.01; p = 0.01). The correlation between adherence to prescribed medication and nights without wheeze remained after correcting for age, gender, proficiency in spacer technique, and the number of nights without wheeze at the baseline visit (r = 0.01; p = <.01). There was also a significant correlation between adherence to prescribed treatment and (daytime) days without wheeze (r = 0.01; p = 0.01). The correlation ceased to be significant after correcting for age, gender, proficiency in spacer technique, and (daytime) days without wheeze at the time of the baseline visit. There was a significant correlation between adherence to prescribed medication and bronchodilator free days (r = 0.01; p = 0.02) throughout the study. After correcting for age, gender, proficiency in spacer technique, and bronchodilator free days at baseline, the correlation between adherence to prescribed medication and bronchodilator free days remained significant (r = 0.01; p = 0.01). There was no significant correlation between adherence and other markers of clinical outcome. After correcting for age and gender, the Funhaler group demonstrated significantly higher proficiency in spacer technique as determined by filter dose (p = 0.05). The improved proficiency in spacer technique in the Funhaler group was limited to subjects who were younger than 4 years of age at the baseline visit (p < 0.01). There was no significant difference in adherence to prescribed medication between the Funhaler group and the Aerochamber Plus group (p = 0.93). Correcting for age and gender did not influence the results. At the start of the clinical trial (baseline visit), the Funhaler group reported significantly less days without wheeze (p = 0.03), and significantly less bronchodilator free days (p = 0.02) than the Aerochamber Plus group in the seven days before the baseline visit. The Funhaler group also scored lower than the Aerochamber group in terms of QoL scores at the time of randomisation (p = 0.05). Where needed, various measures were used to correct for the significant differences at baseline, between the Funhaler group and the Aerochamber Plus group. There was no significant difference between the Funhaler group and the Aerochamber Plus group in terms any of clinical outcome measures used. Correcting for age, gender did not influence the results. Discussion: Use of the Funhaler® therefore appeared to specifically improve drug delivery in those subjects who, with a conventional spacer, would have inhaled very low doses of medication. The Funhaler® was therefore partially successful as an incentive device, as its use positively influenced drug delivery in a specific sub-group of preschool children. Proficiency in spacer technique did not translate to improved clinical outcomes. Various reasons for the lack of association between proficiency in spacer technique and clinical outcome, including the inevitable inherent limitations in design in a clinical study, are discussed. Results suggest that adherence to prescribed medication regimens correlates positively with improved clinical outcome in preschool children with asthma. Use of the Funhaler® did not improve adherence to prescribed medication, or clinical outcome, in preschool children with asthma. Funhaler® therefore failed as an incentive device to improve long term adherence, and clinical outcome, in preschool asthmatic children. Future design for an incentive device will need to consider providing feedback that is of more ongoing interest to the child. As the large variation, as observed in this study, in proficiency in spacer technique, and adherence to prescribed medication, is likely to influence results of clinical trials, an awareness of the variation in spacer technique and drug delivery may contribute towards the accurate interpretation of results in future studies. Finally, the wide variation in both proficiency in spacer technique, and adherence to prescribed medication, both factors that determine drug delivery to patients, highlight the importance of pursuing ways to improve inhalation drug delivery to preschool children in order to eliminate the variability in prescribed medication that eventually reaches patients. The delivery to the lungs of a constant, reliably repeatable inhaled drug dose should be a continuing aim for aerosol scientists and physicians.