β-Agonist Aerosol Distribution in Respiratory Syncytial Virus Bronchiolitis in Infants

MATERIALS AND METHODS

Twelve (5 girls, 7 boys; mean age ± SD, 8 ± 4 mo) (Table 1) spontaneously breathing, wheezy infants, who were hospitalized with a diagnosis of acute bronchiolitis, were enrolled in the study. The diagnosis of bronchiolitis was made in the presence of a history of upper respiratory tract infection followed by the acute onset of respiratory distress with cough, breathlessness, and wheeze and clinical signs of chest hyperinflation, tachypnea, rhonchi, or crepitations occurring during a winter epidemic of bronchiolitis attributed to RSV (12). The clinical status on admission was scored according to the respiratory rate (RR), oxygen saturation (SatO₂), subcostal indrawing, chest auscultation, and general evaluation, with each parameter graded on a scale of 0–2. This score, which was a compilation of other scoring systems used in bronchiolitis (13–15), quantifies the clinical severity of bronchiolitis: A mild clinical stage is characterized by a score of 0–4; 5–7 indicates moderate disease, and 8–10 indicates severe disease.

Inclusion criteria were as follows: (a) first episode of wheezing present for <48 h; (b) proven RSV infection (Testpack radioimmunoassay kit [Abbott Laboratories, Chicago, IL], RSV on material obtained by nasopharyngeal aspiration); (c) age >4 wk and <2 y; (d) admitted to hospital for >12 h; (e) bronchodilator treatments administered at least once every 3 h and on inhaled β-agonist treatment only.

Subjects were excluded if they had a family history of asthma or atopy or if they had cardiopulmonary disease such as BPD, congenital heart disease, immunodeficiency, or CF.

Written informed consent was obtained from the parents or guardians. The study protocol was approved by the Hospital ethics committee and the Ministry of Health.

The dose and distribution of inhaled aerosol were evaluated scintigraphically 12–24 h after admission. No change in treatment schedule or clinical assessment and management occurred except for administration of the prescribed regularly scheduled, study treatments in the nuclear medicine department. These mimicked the treatment provided on the ward.

Image Analysis

Gamma-camera counts in various body areas were measured in the following regions of interest (ROIs): (a) Head: This ROI encompasses the head, including the face and the oropharynx. (b) Trachea, esophagus, and gastric areas: It was difficult to differentiate between the trachea and the underlying esophagus when using planar images. Thus, these regions were drawn as 1 ROI and were combined with the gastric ROI because all 3 regions contribute little to the effect of using bronchodilators. Increased deposition in these areas may contribute to systemic side effects but not to the bronchodilator response. (c) Lung: For regional lung distribution, only the right lung was assessed to avoid corruption of the data by activity in the lower esophagus and stomach behind and adjacent to the left lung (20). The central region at the medial border was 0.5 of the lung height and 0.5 of the lung width; the remaining outer part of the lung was defined as the peripheral region (Fig. 1B) (20). Delineation of lung boundaries was accomplished by superimposing lung dimensions from chest radiographs onto the scintigraphic images or, when these were not available, by transmission scan.

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FIGURE 1.

(A) Anterior image of lungs of patient with bronchiolitis. S = stomach. (B) Diagram of peripheral and central regions of lung used to determine regional aerosol distribution (modified from Phipps et al. (20)).

All ROIs were drawn by 1 author. The coefficient of variation of the counts for this observer was measured with 100 repeated drawings of a single ROI and was found to be 3.5%. Although misalignment of images (for example, posterior vs. anterior) may occur during analysis, we believe no correction for this was necessary, as it should not influence the total lung counts.

The total counts per minute in each ROI were converted to megabecquerels using Equation 1, which was derived from Macey and Marshall (21). Equation 1 incorporated the attenuation factor obtained previously and a camera sensitivity calculation: Eq. 1 where T is the activity in the lungs (MBq), G is the geometric mean of the counts per second corrected for background and decay (cps), E is the efficiency factor for the camera and collimator (cps/MBq), and is the attenuation correction factor.

Deposition in each ROI was expressed as a percentage of the amount of radioactivity delivered from the nebulizer (not as absolute activity) because nebulizer output is variable (22). The amount delivered from the nebulizer (nebulizer output) was equivalent to the difference in radioactivity in the nebulizer before and after nebulization as measured in a dose calibrator (Capintec, Ramsey, NJ).

Secondary outcome measures consisted of the following clinical observations, which were recorded before and 20 min after completion of treatment: (a) SatO₂ by pulse oximetry (on the same FiO₂ as before the treatment); (b) RR (breaths per minute); and (c) heart rate (HR [beats per minute]).

RESULTS

Demographic data and clinical scores of each infant are shown in Table 1. Infants were graded clinically as suffering from bronchiolitis of mild or moderate severity. The average output of the nebulizers at the outport was 40% ± 12% of the initial charge.

Individual total right lung and regional right lung ^99mTc-albuterol deposition during acute bronchiolitis is shown in Table 2. Of the total 6-min nebulized dose (i.e., drug aerosol dose leaving the nebulizer [not the nebulizer charge]), 1.5% ± 0.7% reached the right lung with only approximately one third of that penetrating to the peripheral lung zone. There was 7.8% ± 4.9% deposition in the upper respiratory and gastrointestinal tracts and 10%–12% remained on the face. The remainder was found within the tubing and face mask and on the exhalation filter.

The clinical response data are shown in Table 3. Treatment resulted in a statistically significant increase in the mean SatO₂ (92.9% before and 95.5% after treatment; P < 0.01) and the HR (141 beats per minute before and 155 beats per minute after treatment; P < 0.05). There was also a reduction in the RR (56 breaths per minute before and 46 breaths per minute after treatment; P < 0.01). No correlation was found between any of the deposition indices and the clinical response data or any of the demographic parameters (e.g., height, weight, body surface area, or clinical score). Four infants cried much more than the others during aerosol treatments. Surprisingly, in the light of anecdotal evidence that crying greatly diminishes aerosol delivery to the lungs of infants (11) and similar baseline characteristics, the lung deposition of ^99mTc-albuterol and the clinical response did not differ from that of the rest of the group.

DISCUSSION

This study evaluated the fate of therapeutic aerosols in acute bronchiolitis. We found that during the acute stages of the disease, with the nebulizer used, the amount of drug reaching the right lung was only 1.5% ± 0.7% of the delivered dose. Most of the drug mass never reaches the bronchiolar target, and only one third of the total lung dose actually deposits in the more peripheral airways. This finding may explain why nebulized bronchodilator therapy often fails in acute bronchiolitis and may also explain the lack of response to nebulized corticosteroids in most studies (23). Aerosol studies in adults suggest that total lower respiratory tract (LRT) deposition and intrapulmonary aerosol distribution are influenced by patient-related and aerosol generation and delivery system-associated factors. Patient-related factors in this study include altered airway anatomy and physiology, as reflected in a rapid RR, and altered breathing patterns associated with airflow obstruction. The pathophysiologic and clinical features of RSV bronchiolitis are mainly the result of terminal and respiratory bronchiolar and alveolar inflammation characterized by mucosal edema and luminal plugging by inflammatory exudate resulting in airway obstruction. The associated pneumonitis and microatelectasis mainly account for the often-marked hypoxemia due to ventilation-perfusion mismatch (24). These pathophysiologic abnormalities increase airflow resistance and reduce compliance, thus causing rapid and shallow breathing. Therefore, it is not surprising that total lung deposition and particularly peripheral aerosol deposition are very poor in acute bronchiolitis. This presents a problem in infants because of their extremely small airway caliber even when they are well.

The results of our study of acute bronchiolitis in infants are similar to those obtained in infants with other obstructive airway diseases, even though the latter were in clinically stable condition and had a somewhat different pathophysiology. Mallol et al. (10) found that lung deposition in 5 infants with CF was 2.0% ± 0.7% of the nebulized dose, Chua et al. (25) found a lung deposition of 1.3% in 12 infants with CF, and Fok et al. (9) found a lung deposition of 1.74% ± 0.21% in 13 infants with BPD.

The dose of medication reaching the bronchiolar region in infants might be limited primarily by their normally small airway caliber if the aerodynamically large aerosol particles generated by most small-volume nebulizers (commonly used in clinical practice) are used. Further studies using formulations or devices (or both) that produce much smaller aerosol particles are warranted. In this regard, particle-size selective valved holding chambers, such as the AeroChamber (Trudell Medical International, London, Ontario, Canada), selectively remove approximately 90% of a normal saline aerosol over 2.8 μm (26) and provide pressurized metered-dose inhaler (pMDI)-generated ^99mTc-albuterol aerosols of MMAD approximately 1.8 μm. Because this would considerably improve the therapeutic ratio, much larger doses of bronchodilator medication could be safely targeted to the 1- to 2-mm peripheral airways. Furthermore, with the recent introduction of the MMAD of 1.1-μm beclomethasone dipropionate pMDI solution aerosol (QVAR; 3M Pharma, St. Paul, MN), the hypothesis that smaller aerosol particles might provide greater therapeutic benefit in bronchiolitis could be tested (27).

CONCLUSION

In infants with acute RSV bronchiolitis, aerosolized bronchodilators reach the affected terminal airways poorly. The overall LRT deposition fraction provided in 6 min of nebulization is only approximately 1.2% of the nebulizer charge, mainly in the central and intermediate conducting airways. Although this pattern is considerably different from that of older children and adults, it differs little from that described in infants with other, primarily obstructive, pulmonary diseases. In infants, total aerosol deposition and distribution of medication within the LRT, with commonly used relatively large-particle clinical aerosol generators, may be more related to age and upper respiratory tract airway caliber than to the clinical status or underlying disease. There is considerable room for improvement in aerosol delivery in this age group because, in the light of this study, it must be assumed that the poor response to therapy in previous studies may, at least in part, have been associated with failure to target a sufficient dose of the therapeutic aerosols to the affected peripheral airways. A combination of much smaller drug particles and a relatively larger dose of medication targeted specifically to the peripheral airways may improve the therapeutic response and therapeutic ratio.