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J. Pediatr. (Rio J.) vol.81 no.1 Porto Alegre Jan./Feb. 2005
LETTERS TO THE EDITOR
Lung deposition, efficacy and effectiveness of spacer devices
We read with great interest the article written by Rocha Filho et al.1 and now we would like to make some comments and questions about it:
1) In large-volume spacer devices, aerosol particles remain in suspension before being inhaled; thus, for better drug delivery, it is recommendable that the inhalation time should be exactly the same as that one used for smaller devices (often 30 instead of 10 seconds, as mentioned in the article).
2) As three-year-old preschoolers have a different respiratory dynamics from seven-year-old schoolchildren, it seems more appropriate to assess deposition according to age group instead of including these patients in the same analysis; what would the mean age of these groups have been?
3) Since it is a test of hypotheses, the type and extent of the difference to be tested are not indicated when sample size is described; do the differences lie between means or proportions of pulmonary deposition? What were the values? If the difference is between the means, what was the value for the pooled variance on which the sample size calculation was based?
4) In the absence of these assumptions which are essential in analyzing the power of the study we employ the mathematical formula for the differences between the means and we obtain the approximate sample size necessary to ensure a power of 80% indicated in the methodology; thus, in order to detect differences in the means of deposition between Inalair® and Flumax® nearly 20 children and 34 adults2 would be necessary; therefore, we ask: what is the actual power of the study?
5) Besides p value, it is recommendable to include the upper and lower limits of the 95%CI, thus allowing for the better understanding of the statistical significance and its consequent interpretation from a clinical point of view; what were these values? As the analysis of Figure 2 suggests overlapping of pulmonary deposition ranging between the tested spacer devices, shouldn't these results be further developed in the discussion? What are the internal and external validities of the investigation? The results obtained allow the authors to state that "our study clearly demonstrates that small-volume spacer devices are superior to large-volume ones?"
6) In addition, in the randomized clinical trial cited in the references,3 the large-volume spacer device consisted of a 500-ml mineral water bottle that was as efficacious as the nebulizer in the treatment of acute asthma despite the fact that 95.8% of the patients analyzed comprised preschool and school-aged children; are large-volume spacer devices always less efficacious in these age groups?
7) Since inaccuracy cannot be dissociated from any semiquantitative method, would the deposition of technetium phytate per se correspond to the actually inhaled proportion of bronchodilators and/or corticosteroids whose molecules were or were not radiolabeled? What would the actual limitations be in case of in vivo semiquantitative studies? Should these aspects be further developed in the discussion?
8) We understand that the electrostatic charge of plastic spacer devices should be discussed in more detail: do different types of plastic contain the same electrostatic charge? Would Flumax®, which is made of PVC, has the same results as Aerochamber® and other spacers made of polycarbonate? Are there largely accepted methods that could be used to reduce this electrostatic charge? What is the role of household detergents in this case? Do the differences in deposition between metal and plastic spacer devices increase or decrease when plastic devices are coated with these detergents? Would it be methodologically recommendable to coat the tested plastic spacer devices before analyzing pulmonary deposition?
9) As our study was cited (reference 10), it should be stressed that, as an inseparable part of the semiquantitative study we carried out with Flumax,® we included a clinical evaluation, and we obtained favorable results even when the mean age of the analyzed children was 5.5 years; how can this be explained if large-volume spacer devices should be reserved for adolescents and adults? Should this finding be included in the discussion of the commented article?
10) What matters to clinicians is all that occurs in real life and this can be analyzed in effectiveness studies; in two different studies that assessed the asthma program implemented in Belo Horizonte, in which children only used a large-volume spacer device (Flumax®), 2,1414 and approximately 7005 children were evaluated, of which 75% were younger than 5 years, and a reduction of respectively 75.8% and 89% was obtained for the hospitalization rate, and 85 and 91% for emergency room visits, respectively; how can these results be explained in a population that basically consists of preschool children?
11) Finally, according to Anderson,6 "there is no 'best' outcome or 'gold standard' in the assessment of inhaled drug delivery... We need more trials comparing in vitro with in vivo outcomes...; in the final analysis, however, there is no substitute for clinical trials in patients". Should these aspects be further developed in the article?
Paulo A.M. Camargos
Full professor, Department of Pediatrics, School of Medicine, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
José Augusto Rubim de Moura
Assistant professor, Department of Pediatrics, School of Medicine, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
1. Rocha Filho W, Noronha VX, Senna SN, Simal CJ, Mendonça WB. Avaliação da influência da idade e do volume do espaçador na deposição pulmonar de aerossóis. J Pediatr (Rio J). 2004;80:387-90.
2. Hulley SB, Cummings SR, Browner WS, Grady D, Hearst N, Newman TB. Designing clinical research: an epidemiological approach. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2001.
3. Duarte M, Camargos P. Efficacy and safety of a home-made non-valved spacer for bronchodilator therapy in acute asthma. Acta Paediatr. 2002;91:909-13.
4. Fischer GB, Camargos PA. Paediatric asthma management in developing countries. Paediatr Respir Rev. 2002;3:285-91.
5. Fontes MJ. Síndrome sibilante e asma brônquica: proposta de tratamento em crianças e adolescentes através da parceria SUS/UFMG [tese]. Belo Horizonte, MG: Universidade Federal de Minas Gerais; 2002.
6. Anderson PJ. Assessment end points for inhaled drug delivery. Respir Care. 2000;45:737-55.
We appreciate the interest of Professors Camargos and Rubim in our study1 as well as their comments. It should be recalled that the aim of our study was to assess the pulmonary deposition of radioisotope-labeled aerosol. Therefore, the data presented do not allow making any conclusions about the clinical efficiency of the spacer devices analyzed. We agree that pulmonary deposition varies with the type of medication used. However, we did not find any evidence in the literature for the hypothesis that aerosol particles remain in suspension for a longer time in large-volume spacer devices, requiring a longer inhalation time. Why 30 seconds instead of 20, 25 or 15 seconds?
Our opinion is that the major factors related to the pulmonary deposition of a certain aerosol are the size of the particles, more specifically, the median mass diameter of these particles, and the inspiratory flow. When, besides the variables mentioned above, spacer devices are used, the electrostatic charge and the patient's tidal volume (8 to 10 ml/kg) are of paramount importance. Therefore, a child weighing 15 kg has a tidal volume around 120 to 150 ml. Two breaths with the small-volume spacer and five breaths with the large-volume spacer should be enough for the entire content of the spacer to be inhaled. In fact, one co-author (Simal CJR) observed that, regardless of age, almost all the radioisotope-labeled aerosol within the spacer was inhaled during the first two breaths with the spacer (personal communication). It is the same co-author of the study conducted by Rubim et al.,2 in which a similar technique was used to assess pulmonary deposition. Therefore, we do not believe that 30 seconds of inhalation with large-volume spacers would bring any additional benefits.
The electrostatic charge also has a remarkable effect on pulmonary deposition. We agree that the electrostatic charge may vary with the type of material used. A spacer made of PVC such as Flumax? is likely to have a different electrostatic charge from spacers made of polycarbonate such as Aerochamber?. Moreover, the electrostatic charge is influenced by the climate and by the volume in the spacer device. It is inversely proportional to air humidity and to the size of the spacer. Therefore, the electrostatic charge is higher in drier conditions and in small-volume spacers, reducing the amount of aerosol particles. Anyway, no matter which material which the spacer is made of, the electrostatic charge will always be smaller in metal spacers, since this type of material has no electrostatic charge. This important difference can be overcome when spacers are rinsed with a neutral detergent, thus eliminating the electrostatic charge from PVC or polycarbonate spacer devices. The aim of our study was to assess the effect of this electrostatic charge on different spacer devices, so we were not supposed to eliminate it by rinsing the spacer with detergent. We also believe that metal spacers are more practical in emergency care because they do not have to be rinsed with neutral detergent after being used by the patient.
The power of the sample was based on the fact that the size of the three comparison groups is equal to 9, considering a significance level of 0.05, a common standard deviation of 8.7 and a mean variance of 68.756. These data are necessary to calculate the power of the study when we have three or more comparison groups. In our opinion, the comment about the p value is unfounded since confidence intervals were not calculated. Figure 2 shows the boxplots for pulmonary deposition in three spacer devices according to age and not to confidence intervals. The crux of the matter is not whether the difference between the three groups is significant. A small difference can be statistically significant and have no clinical relevance. The extent of the difference is what really matters.
We should highlight that large-volume spacers have been used on a smaller scale, even in Brazil. While numerous small-volume spacers are available, Flumax? is the only large-volume spacer available in the Brazilian market. Large-volume spacers are cumbersome and unwieldy, not easily mounted, and contain electrostatic charge. At no moment was it documented that large-volume spacers are better than small-volume ones. Our study is in line with several other literature studies that indicate the superiority of small-volume spacers which, contrary to their sizable counterparts, can be used at any age. At the last Brazilian Congress on Pediatric Pulmonology held in Rio de Janeiro in April 2004, Dr. Hawm Tildden analyzed pulmonary deposition, using a more sophisticated method than the one employed by us, and confirmed a low pulmonary deposition when he tested Flumax? at his laboratory in the Netherlands (personal communication).
Finally, we totally agree with professors Camargos and Rubim when they say that many of the statements made by us and them have to be corroborated by well-designed clinical studies. The clinical experience of Belo Horizonte in the treatment of asthmatic children at the public health level is an example of how these patients can benefit from a well-designed and properly conducted program. Despite the decrease in asthma hospitalization rates, we question whether the use of small-volume spacers could bring additional benefits. This seems to be the concern of the team in charge of the study, given that small-volume spacers are already available for the public in Belo Horizonte. Likewise, the aim of the study carried out by Rubim et al. was not to compare the clinical efficiency of different spacers. We did not infer that large-volume spacers are inefficient; instead, we meant that small-volume spacers are superior to the large-volume ones in terms of pulmonary deposition. Hypotheses are indeed the driving force behind the growth of knowledge. If not supported by well-designed clinical trials, these hypotheses are merely speculative. Because of that, we are carrying out a double-blind comparative study in our setting in order to assess the use of different spacer devices in approximately 200 patients. With this study, we hope to answer some of the questions raised here, since half-truths can be downright lies. Clinical impression and personal experience are certainly useful in formulating a hypothesis, but they cannot replace objective data obtained through well-designed clinical trials. A hypothesis should be tested, but until it is not, it should not be regarded as fact.
Wilson Rocha Filho
Coordinator of the Division of Pediatric Allergy and Pulmonology, Hospital Felício Rocho and Centro Geral de Pediatria, Belo Horizonte, MG, Brazil
1. Rocha Filho W. Noronha VX, Senna SN, Simal CJ, Mendonça WB. Avaliação da idade e do volume do espaçador na deposição pulmonar de aerossóis. J Pediatr (Rio J). 2004;80:387-90.
2. Rubim JA, Simal CJ, Lasmar LM, Camargos PA. Deposição pulmonar de radioaerossol e desempenho clínico verificado com espaçador desenvolvido no Brasil. J Pediatr (Rio J). 2000;76:434-42.
José Augusto Rubim de Moura