Br. J. Dis.
79, 36 1
FRACTIONAL DEPOSITION FROM A JET NEBULIZER: HOW IT DIFFERS FROM A METERED DOSE INHALER RICHARD Southampton
A. LEWIS Hospital,
4ND JOHN Tremona
S. FLEMING Southampton
Summar_y The fractional deposition from an Inspiron ‘Mini-Neb’ jet nebulizer was assessed in six normal and two asthmatic subjects using technetium-99m-labelled millimicrospheres of human serum albumin suspended in saline. Sixty-six per cent of activity was retained in the apparatus tubing, 20% exhaled, 2% deposited in the mouth and 12% was retained in the lungs. The nebulizer fractional deposition therefore differs from the findings reported for a metered dose inhaler (Newman et al. 1981; Spiro et al. 1984), where 80-85% ofparticles leaving the cannister deposits in the mouth, and only 5-10% in the apparatus. The lung fraction from a nebulizer is, however, similar to the 9-l 1% from an MDI.
Introduction The metered dose inhaler (MDI) and jet nebulizer are the two main methods of delivery of bronchodilators to patients in hospital. Jet nebulizers are also becoming increasingly used at home for both emergency treatment and maintenance therapy for patients with reversible airway obstruction. There is a large difference in maximum recommended dose of beta-agonists for use in the MD1 and nebulizer, the nebulizer dose being up to 50 times higher than the MD1 dose (the maximum recommended single dose in nebulizer and MD1 is ‘10 mg and 0.2 mg respectively for salbutamol, and 10 mg and 0.5 mg respectively for terbutaline). The reason for this high recommended dose of beta-agonist in a nebulizer is unclear. Furthermore, the safety of such high doses in nebulizers, particularly when used unsupervised in the home, is being currently debated (Stableforth 1983). This study was therefore carried out to determine the fate of a radiolabelled solution delivered by a jet nebulizer.
Six normal, non-smoking adults aged 22-39 ( mean 114% (SD 30%) predicted FEV,) and two atopic asthmatics aged 31 and 33 (105Y o and 93% predicted FEV,) took part in this study which was carried Correspondence
Br. J. Dis. Chest:Vol. 79 No. 4
Fig. 1. Nebulizer apparatus: Inspiron Mini-Neb nebulizer (n), driving compressed air (da), auxiliary air (aa), Wright’s respirometer (r), one-way valve (v), side arm (sa), two-way valve (tv), filter in expired line (f), mouthpiece (mp) (see text) out with the consent of both the local ethical committee and the DHSS Administration of Radioactive Substances Advisory Committee. Aerosols were generated from an Inspiron ‘Mini-Neb’ nebulizer driven by compressed air at a flow rate of 8 litres/min under ambient conditions. In addition to the driving gas auxiliary air was drawn in through the side arm of the nebulizer to provide an adequate volume of air for inspiration (Fig. 1). During exhalation, aerosol particles from the nebulizer were able to pass out into the side arm, although a one-way valve placed 150 cm from the nebulizer prevented air passing to atmosphere via this route. The volume of auxiliary air drawn into the side arm during inhalation was measured by a Wright’s respirometer. The subject inhaled the aerosol via a two-way valve, and expired air passed to a filter which collected more than 99.9% of all expired radioactivity. The dead space of the tubing between nebulizer and subject was 50 ml. Aerosol deposition characteristics were studied using technetium-99m-labelled millimicrospheres of human serum albumin suspended in saline. This aerosol did not clear rapidly from the lungs and this avoided the problem of variation between images due to rapid blood clearance of activity which would occur with other non-colloid solutions. We consider that the use of solid microspheres to assess deposition is valid since they were likely to remain suspended in the saline droplets. This assumption is supported by particle size measurement using the Malvern laser particle size analyser of 4.5 p,rn mass median diameter for the millimicrosphere aerosol compared to 4.8 pm for water. After inspiring the radiolabelled aerosol at 30 breaths per minute for 30 seconds each subject was given a glass of water to wash any activity retained in the oesophagus through into the stomach. Image
Immediately after inhaling the aerosol subjects were imaged using a Siemens LFOV Anterior and posterior views were taken of: 1, 2. 3.
the lung fields including the stomach if possible; the stomach and intestines if not included in image 1; head and neck.
Lewis, Fleming: Fractional Deposition from Jet Nebulizer
The images were stored as 128 X 128 matrices on a Medical Data Systems A* computer system. They were accumulated over predefined times which were chosen so that about 200 000 counts were obtained in the lung field and 5000 in the head and neck view. Chest wall thickness of each subject was then assessed by placing cobalt-57 markers anteriorly and posteriorly at the level of the xiphisternum and taking a lateral image. To quantify the distribution of radioactivity in the body, regions of interest were outlined over the lung, the oro- and nasopharynx and the stomach and gut. No activity distinguishable from background activity was observed in any other organ of the body. The actual amount of radioactivity present in each of these regions was assessed by correcting the number of counts on each image for the counting efficiency of the gamma camera collimator system and the attenuation ofthe gamma rays by the body tissue. This method ofcorrecting for attenuation ofbody tissue thickness is fully described elsewhere (Fleming 1979). The amount of radioactive solution lost from the nebulizer was assessed by weighing the nebulizer alone before and after each study. Activity deposited in the apparatus tubing was assessed by subtracting the sum of activity measured in the body and the expired activity measured by scanning the filters from that lost from the nebulizer. Direct measurement of activity leaving the nebulizer by scanning of the apparatus was not carried out because of varying attenuation by the different thicknesses of material within the apparatus. The percentage division of the dose between the apparatus, filter, lung and oropharynx and gut was calculated for each subject. The activity designated as being present in the apparatus included activity which passed into the side arm during exhalation and would normally have passed to atmosphere, but in this study was retained in the side arm tubing.
Results The mean percentage of radioactivity leaving the nebulizer and subsequently depositing in the mouth, lung, nebulizer tubing and expired air is summarized in Fig. 2. In the eight subjects the mean percentage deposited in the body was 14 (SD 5.1)%; 12.4 (SD 4.5)‘/ o was in the lung (range 3.9-18.3%) and 1.5 (SD 0.9)‘/, in the mouth. Eighty-six per cent of the dose was found in either the expired air (19.7 (SD 3.9) O/o), or deposited in the mouthpiece, two-way valve and tubing (66.3 (SD 8.6) O/o). Percentage deposition in the body correlated with the minute ventilation of each subject (Fig. 3, r = 0.7, P
Discussion In this study a mean of 12.4% of activity delivered from an Inspiron ‘Mini-Neb’ jet nebulizer reached and was retained in the lungs. There was considerable individual variation from 3.9 to 18.3%, and this appears to be due partly to differences in the minute ventilation of each subject, since the activity entering the body correlated with minute ventilation (Fig. 3). Subjects breathed at 30 breaths per minute in this study in an attempt to standardize inhalation pattern. Subsequent studies using
Br. J. Dis. Chest: Vol. 79No. 4 m
11% I (a) nebuliser
Fig. 2. Fractional deposition from jet nebulizer (left), with two studies of fractional deposition from an MD1 for comparison on right. (a) Technetium-99m-labelled Teflon particles from Newman et al. (1981) and (b) bromine-77-labelled ipratropium bromide (Spiro et al. 1984)
tidal breathing and five vital capacity breaths have shown similar deposition patterns (unpublished observations). The fraction of aerosol deposited in the lung from a nebulizer will depend on how the apparatus is set up, on the flow rate of the driving gas to the nebulizer (since this
% body deposi
r = 0.70 P < 0.05 ”
minute Fig. 3. The percentage of activity from a jet nebulizer depositing correlation
with the measured
in the body of each subject, showing a during inhalation
Lewis, Fleming: Fractional Deposition
from Jet Nebulizer
determines the particle size; Clay et al. 1983; Lewis 1984), and on the way in which the delivered dose is calculated. Complex and convoluted tubing between nebulizer and subject will reduce the amount ofactivity reaching the lungs. In our study a twoway valve was inserted between the nebulizer and the mouthpiece in order to separate expired from inspired aerosol particles. This may have increased the amount of activity retained within the apparatus compared to simpler nebulizers used in clinical practice. A further modification of our apparatus was the presence of a tube connected to the side arm of the nebulizer. This enabled aerosol particles to pass out into the side arm during the exhalation phase, but they were then prevented from passing to atmosphere by a one-way valve. Some particles could be drawn back into the nebulizer from this tubing during the subsequent inhalation. In clinical use, and in many previous studies (Asmundsson et al. 1973; Shenfield et al. 1974; R&n et al. 1978), the dose has been determined by the amount of drug actually placed in the nebulizer. However, when the nebulizer has been run to ‘dryness’ there may be a variable residual volume of solution left in the nebulizer. We have found this to vary between 0.6 and 1 ml, in an Inspiron ‘Mini-Neb’, depending on how vigorously particles are displaced from the sides of the nebulizer back into the bottom of the reservoir. So, in this study, to avoid such variation we have calculated the delivered dose of aerosol as that amount of solution which was found by repeat weighing to have left the nebulizer. Thus, when comparing distribution from a nebulizer with a metered dose inhaler we have considered the fate ofdrug leaving the drug container in both cases. The 12% lung deposition in our study is in agreement with the study of Shenfield et al. (1974), where l&20% of the dose placed in a variety of nebulizers both with and without intermittent positive pressure breathing (IPPB) deposited in the body. In her indirect study she measured tritiated salbutamol in plasma and urine, and found 80% of early plasma levels were in the ‘free’ form indicating lung deposition. Ruffin et al. (1978) found up to 10% deposition in two nebulizers with IPPB, by direct lung scanning. In more complex apparatus where the dead space between the nebulizer and mouthpiece is increased, the lung deposition may fall to l-2% (Asmundsson et al. 1973). In the jet nebulizer the majority of aerosol is retained in the apparatus and the tubing, or passes out of the side arm during exhalation. Only a very small percentage (2%) deposits in the oropharynx (Fig. 2). This contrasts with the findings of the MD1 (Fig. 2) w h ere, despite similar lung fraction (9-l l%), there is much greater oropharyngeal deposition ([email protected]
%) with a very small percentage remaining in the apparatus (O-l %). The most striking difference in the fractional deposition of an MD1 and nebulizer is the oropharyngeal deposition of [email protected]
% with the MD1 compared to 2% with the nebulizer. This is probably due to two main factors: 1. 2.
Particle velocity is very high from the MDI, but is no greater than inspiratory flow rate with the nebulizer. The majority ofparticles from a nebulizer are only drawn into the mouth during inspiration, but may enter the mouth at any part of the respiratory cycle when using the MDI.
Br. J. Dis. Chest:Vol. 79No. 4
The large fraction of activity which was either retained in the nebulizer or passed out into the side arm is due to the greater length of apparatus compared to an MDI, the presence of the two-way valve, and the fact that aerosol may pass out of the apparatus during exhalation. The increase in exhaled fraction from the nebulizer may be due to exhalation of undeposited particles from the dead space of both the apparatus and oropharynx. The high velocity of particles from the MD1 would reduce the numbers remaining undeposited. The similarity of lung deposition between jet nebulizer and MD1 indicates that both apparatuses are, under the conditions of the studies, of similar efficiency at delivery of drug to the lungs. This supports the findings of recent dose-response studies (Anderson et al. 1982; Cushley et al. 1983; Stainforth et al. 1983a), where the airway response was similar when the same dose of bronchodilator was given by MD1 and nebulizer. If both the MD1 and nebulizer deliver the same proportion of administered drug to the lung, then the lung dose when nebulizing 10 mg salbutamol is equivalent to 100 standard 0.1 mg inhalations from an MDI. This implies that either the maximum recommended dose of bronchodilator from a nebulizer is too great, or the cautious use of small doses of bronchodilator from the MD1 is unnecessary. Recently both these points have been raised. The widespread use of high doses of salbutamol from a nebulizer may not be necessary for all patients and may carry some increased risk of side effects (Neville et al. 1982). It has been suggested that there may be a relationship between an increase in asthma deaths in New Zealand, and the widespread use ofdomiciliary nebulization (Grant 1983). On the other hand it has also been suggested that the use of the relatively small doses of bronchodilator from the MD1 may lead to dangerous undertreatment of an acute asthmatic attack (Crompton 1984). Direct comparisons of the comparable lung fractions from nebulizer and MD1 should be made with caution, however, since this does not take into account that the total percentage body dose is about 90% with the MD1 compared to 13% from the nebulizer. Potential side effects from the swallowed fraction should not be ignored. although beta,-sympathomimetics have been shown to cause tachycardia from the inhaled rather than the swallowed fraction (Stainforth et al. 1983b). Also the drug from the MD1 is administered over a much shorter time than a nebulizer so peak blood levels ofbronchodilators may be higher. In one study (Stainforth et al. 1983b), when up to 5 mg of salbutamol was delivered by both ultrasonic and jet nebulizer and MDI, whereas heart rate was unchanged with the nebulized drug, there was a marked rise following delivery from an MD1 despite a similar degree of bronchodilatation. While the introduction of a prepacked single 2.5 mg dose of salbutamol may have reduced the widespread prescribing ofvery high doses from a nebulizer, the effects of the anticipated introduction of high dose salbutamol from a metered dose inhaler is awaited with some concern. /
We are grateful to Professor A. E. Tattersfield and Dr G. M. Sterling for their helpful comments. The work of R.A.L. was supported by the Chest, Heart and Stroke Association.
Lewis, Fleming: Fractional Deposition from Jet Nebulizer
References Anderson, P. B., Goude, A. & Peake, M. D. (1982) C om p arison of salbutamol given by intermittent positive-pressure breathing and pressure-packed aerosol in chronic asthma. Thorax 37,612-616. Asmundsson, T., Johnson, R. F., Kilburn, K. H. & Goodrich, J. K. (1973) Effrcieney ofnebulizers for depositing saline in human lung. Am. Rev. resp. Dis. 108, 506-512. Clay, M. M., Pavia, D., Newman, S. P. & Clarke, S. W. (1983) Factors influencing the size distribution of aerosols from jet nebulisers. Thorax 38, 755-759. Crompton, G. K. (1984) Illogical warnings on Ventolin inhalers. Br. med. J. 288, 1231-1232. Cushley, M. J., Lewis, R. A. & Tattersfield, A. E. (1983) C om p arison of three techniques of inhalation on the airway response to terbutaline. Thorax 38, 908-913. Fleming, J. S. (1979) A technique for the absolute measurement ofactivity using a gamma camera and computer. Phys. Med. Biol. 4, 176-180. Grant, I. W. B. (1983) Asthma in New Zealand. Br. med.J. 286, 374-377. Lewis, R. A. (1984) Inhalation drugs in asthma management: state of the art, factors affecting delivery and clinical response to inhaled drugs. New Engl. Reg. Alleru Proc. 5, 23-33. Neville, E., Corris, P. A., Vivian, J., Nariman, S. & Gibson, G. J. (1982) Nebulised salbutamol and angina. Br. med. J. 285, 795-797. Newman, S. P., Pavia, D., Moren, F., Sheahan, N. F. & Clarke, S. W. (1981) Deposition ofpressurised aerosols in the human respiratory tract. Thorax 36, 52-55. R&in, R. E., Obminski, G. & Newhouse, M. T. (1978) Aerosol salbutamol administration by IPPB: lowest effective dose. Thorax 33, 689-693. Shenlield, G. M., Evans, M. E. & Paterson, J. W. (1974) The effect of different nebulizers with and without intermittent positive pressure breathing on the absorption ofmetabolism of salbutamol. Br. J. din. Pharmac. 1, 295-300. Spiro, S. G., Singh, C. A., Tolfree, S. E. J., Partridge, M. & Short, M. D. (1984) Direct labelling of ipratropium bromide aerosol and its deposition pattern in normal subjects and patients with chronic bronchitis. Thorax 39, 432-435. Stableforth, D. E. (1983) Death from asthma (Editorial). Thorax 38, 801-805. Stainforth, J. N., Lewis, R. A. & Tattersfield, A. E. (1983a) Dosage and delivery of nebulised beta agonists in hospital. Thorax 38, 751-754. Stainforth, J. N., Sturgiss, P. J. & Tattersfield, A:E. (198313) Effect ofsalbutamol delivered by metereddose inhaler and jet and ultrasonic nebuliser on FEV, and heart rate in patients with chronic asthma. Thorax 38, 707-708.