Chest
Volume 119, Issue 4, April 2001, Pages 1123-1130
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Clinical Investigations: Antibiotics
Effect of Size and Disease on Estimated Deposition of Drugs Administered Using Jet Nebulization in Children With Cystic Fibrosis

https://doi.org/10.1378/chest.119.4.1123Get rights and content

Study objectives

To develop a model that quantified the nebulizer output that was inhaled by subjects with cystic fibrosis (CF) in order to predict the amount of drug likely to enter the upper airway contained in particles small enough to be deposited in the lower respiratory tract of individual patients.

Design

Forty-three patients (age, 6 to 18 years) with CF, with FEV1 of 26 to 124% of predicted, breathed through a nebulizer circuit with a pneumotachograph in place at the distal end. Algorithms were developed from the measured flows through the pneumotachograph, allowing partitioning of inspiration into undiluted aerosol and fresh gas. In order to validate the algorithms, argon was added to the nebulizing gas flow and then its concentration was analyzed at the mouth by mass spectrometry.

Results

Predictions of the concentration of argon at the mouth were concordant with that measured by mass spectrometry, thus validating the model. Combining data from the model with in vitro nebulizer performance data, predictions for estimates for lung deposition for individuals were possible. Total estimate was independent of patient size or FEV1. The respiratory duty cycle was 0.44 ± 0.05 (mean ± SD) and correlated (r = 0.91, p < 0.001) with estimated deposition and minute ventilation (r = 0.60, p < 0.01). However, when expressed in milligrams per kilogram of body weight, the estimated deposition in smaller children was fourfold higher than in larger children.

Conclusions

If the effect of patient size and pattern of breathing on estimated drug deposition are not considered when prescribing drugs given by nebulization, the result may be overdosing younger children, underdosing older children, or both.

Section snippets

Theory

When the Bain anesthetic circuit was first introduced,16 there was concern that rebreathing expired gas would lead to hypercapnia. To investigate this, in 1983, Meakin and Coates17 developed a model that allowed partitioning of each inspiration into the volume of rebreathed gas, and the volume of fresh anesthetic gas. They justified their model by using the respiratory pattern, measured by a pneumotachograph placed at the distal end of the circuit, to predict the concentration of CO2 that would

Materials and Methods

The subjects had a diagnosis of CF18 and were being followed up in the CF clinic of the Montreal Children's Hospital. They were selected for their willingness and the ability to undergo pulmonary function testing. The Ethics Review Board of the institution had approved the study, and written informed consent was obtained from either the parent or guardian, or the patient, depending upon the age of the patient. Spirometry was performed according to American Thoracic Society guidelines.19 Lung

Results

Forty-three patients from 6 to 18 years of age participated in the study. They ranged in height from 108 to 173 cm, and their FEV1 values ranged from 26 to 124% predicted. Figure 3 shows the Bland and Altman25 plot of limits of agreement for the measured signal from the MS, and the calculated concentration for Ar. The bias ± 2 SDs indicates that the mathematical model successfully defined the pattern of ventilation and the dilution of the aerosol with ambient air. Based on the validity of the

Discussion

In this study, we have developed a model that allows the estimation of the inhaled mass in children with CF, over a wide range of size and disease severity. The inhaled mass when coupled with RF gives an estimate of pulmonary deposition of inhaled tobramycin. There is a striking relationship between estimated deposition normalized for body weight and the height of the child. This suggests that standard doses of medications administered by unvented jet nebulization may result in overdosing small

Appendix

Volume areas 1 to 4 (Fig 2), when summed together, represent the total nebulizer output (aerosol). The equations for each subvolume are as follows: 0t1V.p(t)dt

VDa(apparatusdeadspace)

V.N(t2t1)

tTiV.p(t)dt Also, note that at times t1 and t2, V˙n = V˙p(t1) and V˙p(t2). Now,

% Aerosol =Volumes1to4VT=0t1V.p(t)dt+V.Da+VN(t2+t1)+t2t1V.p(t)dtt2T1V.p(t)dt

Defining V˙pnt(t) as positive for inspiratory flow when V˙pnt(t) > V˙n, then: V.pnt(t)=V.p(t)V.N

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