Fourth Symposium onAerosols and the Lung

April 15-16, 1994Schmallenberg, Germany

Grafschafter Kolloquium: Aerosols and Lung IVApril 15 and 16, 1994

Krankenhaus Kloster GrafschaftZentrum für Pneumologie und Allergologie

Schmallenberg, Germany

Supported by:ISAM

—

International Society for Aerosols in MedicineDPG

—

Deutsche Gesellschaft für Pneumologie

Sponsored by:Boehringer Ingelheim

The Grafschaft Kolloquium "Aerosols and Lung," which began as alocal "aerosol workshop," has expanded internationally. Visitors fromGerman-speaking countries participated.The main topics/aims of the symposium were:

1. the "reality" of CFC-replacement2. recent advances in aerosol therapy3. comparison of different methods for the measurement ofparticle diameter and droplet concentrations

4. free communications

Chairman Prof. Dr. med. Dieter Köhler

Influence of sea-water aerosol on nasal hyperreactivity

J. Fischer; F. Raschke

Institut für Rehabilitationsforschung, Klinik Norderney, D-26548 Norderney

The relative lack of pollution and pollens in combination with the special climatic con-ditions of the North Sea are well known factors in producing beneficial effects on thesymptoms of allergic rhinitis. In order to check the specific therapeutical use of sea-water aerosol, the following investigation was carried out: Inhalation therapy of hy-perosmolaric sea-water (3.6%) was applied for 12 days in 10 patients suffering fromspecific allergic reactions from grass pollens. After 6 days the temperature of the inha-led aerosol was turned from 40 °C into 22 °C. The same procedure using isotonic saltsolution (0.9%) was applied in 10 patients suffering from the same disease. In another10 patients no saline inhalation was applied (control group). Efficacy of therapy wastested by means of the decrease in nasal flow according to a specific pollen provocationtest.Results: Whereas baseline reaction to provocation was a reduction in flow of about70 % in all 3 groups, an increase up to only 38 % decay of nasal flow post provocationwas only found in the sea-water group (p<0.01). Changing temperature of aerosol waswithout additional effect.Conclusion: Even hyperosmolaric sea-water inhalation leads to an improvement of na-sal allergic reactions to grass pollens, showing a protective effect of sea-water aerosolfor specific allergic disease.

279

Analysis of pollen flight in respect of components of a maritime climate

F. Raschke; J. Fischer

Institut für Rehabilitationsforschung, Klinik Norderney, D-26548 Norderney

Pollen flight depends on pollution and climatic conditions as well. North Sea climate isknown for its relative lack of pollen pollution, producing e.g. beneficial effects on aller-gic rhinitis and asthma. In order to investigate the specific therapeutical use of a mari-time climate, continuously collected pollen- and spores-data were analysed and contra-sted to meteorological data. Methods: Pollen and spores were sampled daily from 1986to 1992 from March to September each year using a Burkard spore trap. They werecounted each day according to 11 different classes. Meteorological data (mean diurnaltemperature, rel. humidity, wind direction and velocity, solar radiation, rain activity,and cloud formation) were rendered from a local weather station (DWD) for identicalepochs. Time series analysis (trend, auto- and crosscorrelation) and descriptive statisticswere applied to these data.Results: Pollen flight is present significantly more often on sunny rainless days(especially grass, birch, and nettle pollens), whereas spores flight is independent fromrain and cloud formation. Crosscorrelation reveals grass pollen flight to be dependanton a fair-weather period of at least 4 days. Cladosporia activity on the other hand isindependent of regional weather factors. There is an essential dependency on wind di-rection. Grass pollen flight is active during east, cladosporia during south-east, no flightactivity during wind from north-west. During low and high wind velocity only littleflight activity is present, whereas high flight activity is observed during mean wind ve-locity (8-13 mph).Conclusions: Dependency on wind direction and velocity turned out to represent themost prominent factor for flight activity, thus enabling prognosis and therapeutical useby adaequate behavior.

280

PULMONARY DEPOSITION OF PENTAMIDINE VIA TWO DIFFERENT MECHANICALNEBULIZERS: PARI PROVOCATIONSTEST I® VERSUS RESPIRGARD II®

Glöckle W., Hupert A., Werner P., Ordemann J., Matthys H.

Division of Pneumology, Dept. of Internal Medicine, Universityof Freiburg, D-79106 Freiburg, GermanyIntroduction : Pneumocystis carinii pneumonia (PcP) can occur

particulary in immunocompromised patients with AIDS, cancer andfollowing bone marrow transplantation (BMT). The incidence ofPcP during the first six months following BMT, for example, isas high as 5 - 15%. Therefore, prophylaxis with cotrimoxazol isbeing routinely done. However, allergic reactions andmyelotoxicity are frequent problems with its use. Delivery ofpentamidine to the lungs via aerosol is well tolerated,effective, free of serious side effects and thus appears to bea well suited alternative for PcP-prophylaxis after BMT. Wecompared the Pari Provocationstest I® (1) with the RespirgardII® regarding its efficacy and versatility and whether time,plastic waste and money could be saved.

Methods and patients: Following pre-treatment with fenoterolinhalation 10 patients after BMT, who were free of infections,inhaled 300 mg of pentamidine mixed with 37 MBq 99mTc humanserum albumine (total volume of 6 ml) , an indirect marker ofpentamidine deposition. Nebulization was done in a randomizedcross-over design every 4 weeks using the slow inspiratory vitalcapacity as inhalation maneuver. Total pulmonary and gastric +oropharyngeal deposition was measured with a gamma camera. Apenetration index (PI) was established by comparing theperipheral with the central deposition of pentamidine, correctedfor background radiation.

Results: Total pulmonary deposition of pentamidine (mg ± SEM)was similar for Respirgard II® (9,5 ± 7,2) and PariProvocationstest I® (7,7 ± 2,1). Likewise, the PI was almostidentical (1,4 ± 0,3 and 1,5 ± 0,3). Inhalation time wasshorter with the Pari (14 minutes) and associated with lesssaliva production and dryness of the throat when compared withthe Respirgard II® (20 minutes). Deposition of pentamidineappears to be more predictable using the Pari-System (SEM = 2,1versus 7,2) and is linearly related to the number (6) and volume(60£) of storage bags inhaled.

Conclusions: The new Pari-nebulizer appears to be at least aseffective as the Respirgard II®-system for the delivery ofpentamidine into the lungs. However, patient acceptance due tothe shorter inhalation time and ability to rest up betweeninhalation from the aerosol bags favor the use of the Pari-system. This system is more versatile and can, for example, alsobe used for bronchial provocation tests. The Pari device causesless synthetic waste and is cheaper compared to the RespirgardII®-system with more frequent use (>5 inhalations/week).(1) Matthys H., Koch M.,Eltschka R. , A new aerosol device forbronchial provocation tests. Respiration 60: 343-50, 1993

281

Aerosol Characterization of Medical Nebulizers -A Critical Review of Common Techniques.

J. Gebhart

GSF -Forschungszentrum für Umwelt und Gesundheit, Neuherberg; Institut für BiophysikalischeStrahlenforschung, Paul-Ehrlich-Straße 20, 60596 Frankfürt/M,FRG.

Liquid sprays produced by jet nebulizers are polydisperse and consist of spherical particleswith high mass or number concentration (about 106 cm-3). Characteristic features of a spray aerosolare the mass flow of liquid (mg/min) available at the mouth-piece and the droplet size distribution.When applying different sizing techniques to liquid sprays one has to consider that aqueous solutiondroplets can change their diameter due to evaporation within milliseconds.

Conventional techniques apply aerodynamic classification (cascade impactors, centrifuges)for droplet sizing. The droplets of an aqueous solution are usually dried and the remaining residualsare classified. From the aerodynamic diameter of the residuals and the known salt concentration theoriginal droplet size is evaluated. The method immediately yields the droplet spectrum in terms ofmass distribution which is of only interest for drug delivery. One has to take care, however, forcomplete drying and the evaluation of the mass fractions (gravimetry, tracer methods) is somewhattime-consuming.

Laser Particle Counters (LPC) and Aerodynamic Particle Sizers (APS) cannot be used foraqueous droplet sizing since the droplets change their size during their passage through the samplingsystem. The APS, however, may be applicable to dried residuals after dilution of the aerosol by morethan a factor of 103.

Laser Diffraction Techniques (LDT) determine the particle size distribution from a measure-ment of the ensemble diffraction pattern in the near forward direction that results from the illumina-tion of the particle cloud by a collimated laser beam. The technique has been developed into a varietyof commercial systems and meanwhile sizing ranges down to 1 urn or even 0.5 urn are reported.LDT is an 'in situ' method and the droplet cloud in the sensing volume (about 0.5 cm3) is representa-tive of the whole spray. Ensemble diffraction, however, is an indirect sizing method and results in theclassical inversion problem, wherein a continuous size distribution is sought which provides the bestfit to a finite set of experimental data. Measuring results depend on the software-programs used fordata inversion which are handled secret by the manufacturers.

Phase Doppler Anemometry (PDA) belongs to the single particle light interaction techniqueslike the LPC or the APS. It is a Laser Doppler Velocimeter (LDV) which additionally evaluates thesize of single spherical particles. PDA measures the spatial and temporal frequency of the Doppler-shifted light scattered by individual particles passing through a laser-beam-crossing sensing volume.PDA-systems apply multiple photodetectors to collect scattered light originating from slightly dif-ferent angular ranges. The phase shift between the signals of two neighbouring scattering angles canbe directly related to particle diameter (curvature). PDA is an absolute sizing method but requiressphericity of the particles. It also calculates the number (mass) concentration from the number andsize of particles traversing a mathematically defined size-dependent sensing volume. Manufacturersclaim for PDA-systems a diameter range from 1 to 8000 pm with 5 % typical accuracy and a maxi-mum measurable number concentration of about 106 cm-3. Advantages of the PDA-systems are theabsolute measurement of particle size. Weak points are disturbances of the Doppler-signals due tomultiple-scattering in the spray cloud and the need to transfer number concentration into mass con-centration.

Finally, one has to keep in mind for both 'in situ' techniques (LDT and PDA) that aqueousdroplets rapidly change their size due to evaporation, so that experimental results depend on thedistance from the outlet of the nebulizer.

282

Regional Dosages of Drug delivered by Jet Nebulizers.

C. Roth and J. Gebhart

GSF-Forschungszentrum für Umwelt und Gesundheit, Neuherberg; Institut für BiophysikalischeStrahlenforschung Paul-Ehrlich-Straße 20, 60596 Frankfurt/M,FRG.

Nebulizers are used in inhalation therapy for delivery of relatively large doses of drugs andfor patients who are unable to use metered dose inhaler or dry powder inhalers correctly. However,predicting the dose of medication delivered to a patient is difficult and it has been suggested thatunsatisfactory clinical results with therapeutic aerosols may be due partly to the improper selectionand operation of nebulizer equipment. Procedures which allow estimation of delivered dosages areuseful in improving nebulized drug delivery.

In clinical investigations deposition studies with nebulizers are performed with radioaerosols.Usually the nebulizer solution is labelled with 99mTc and an image is taken of the thorax with a

gamma camera immediately after the inhalation of the spray. Regional deposition is estimated for theextrathoracic region, and the central and peripheral regions of the lungs from these gamma camera

images. Quantification of the scan data is usually made by comparing counts obtained from the lungswith those from a lung "phantom" which is a model of the thorax containing a known amount ofradionuclide. But beside of the difficulties in calibration radiolabelling studies are dangerous,expensive, time consuming and mean to expose many people to radioactive aerosols.

Instead of the inhalation of radioaerosols the concentration of the inhaled and exhaled aerosolcan be measured directly by a photometer or can be collected on inhalation and exhalation filters andthe aerosol mass can be determined gravimetrically. These methods provide no information ofregional deposition and ask in the same way for an individual measurement of each patient.

A third alternative is the prediction of the dosages of medication delivered to the differentregions of the repiratory tract. This is accomplished by measuring the output of the nebulizer and thechemical properties of the solution. If a theoretical deposition model tested by many experimentaldata for normals and patients is used to predict regional deposition probabilities the dosage ofmedication delivered to each region of the lungs can be calculated from the mass flow rate and thedroplet size distribution of the spray for the known breathing manoeuver. The regional depositionmodel has to include growing and shrinking of droplets in the lungs which will depend on theconcentration of the nebulized solution.

The distribution of droplet mass over droplet size and the mass flow rate is determined by theresidual technique. The mass flow rate is the mass of spray per unit of time which is alvailable at themouth piece of the nebulizer. It has to be distinguished from the usually used weight loss of thenebulizer solution and can be measured by using a radiotracer and comparing the activity on a filterwith the specific activity of the nebulizer liquid. For the measurement of size distribution the dropletsare passed through a drying path and the remaining residuals are classified by analysing the depositon the different stages of a cascade impactor. From the size distribution of the solid particles theoriginal droplet size distribution is calculated.

283

ATMOSPHERIC AEROSOL POLLUTANTS AND LUNG CANCER:

MEASUREMENTS IN GERMANY

Kvetoslav R. SPURNY

Aerosol Chemist , Eichenweg 6 ,57392 SchmallenbergGermany

KEYWORDS

anthropogenic aerosols,inorganic and organic composition,ambientair concentration,lung cancer

INTRODUCTION

Physico-chemical properties and chemical composition of atmosphe-ric anthropogenic aerosols have been investigated in the countryof Baden-Württenberg,F.R.G.,during a five year's period.Aerosolswere sampled weekly on seven sites,representing two removed andfive urban regions.Special consideration was directed to impor

-tant toxic and carcinogenic aerosol pollutants : asbestos,heavy me-

tals, arsenic, etc ., and to organic carcinogens,as PAH,ChlorinatedPAH, etc.There concentrations have beeen measured during a periodof 3 years.Mean values,as well as concentrations related to yearseasons were correlated to epidemiological data dealing with thelung cancer frequency of the general population.

ANALYTICS AND MEASUREMENTS

Cellulose and polyamide membrane filters,and glass fibers filterswere used for the parallel and simultaneous aerosol sampling.Forthe chemical and physical evaluation of these different filtersamples Electron Microscopy,Ion Chromatography,Gas Chromatography,Mass Spectrometry,Atomic Absorption Spectrometry,as well as theProton Induced X-Ray Fluorescence Spectroscopy were applied.Asbestos and other mineral fibers,acidity,ammonia,alkalines,alka-line earthes,As,Be,Cd,Cr,Co,Ni,Pt,sulfates,nitrates,chlorine, 17PAH,6 PCBs,and 6 PCPhs were regularly analyzed in mixed aerosolsamples.

RESULTS

The measurements have shown,that the industrial cities had the hig-hest concentrations for nearly all investigated pollutants.Duringextreme weather conditions high concentrations of solid aerosols(Total suspended particles TSP) and several organic compounds were

determined.From the other hand,the annual mean concentrations oftoxic and carcinogenic aerosols could be considered as "not to highor "moderate".From the other hand,the extracted aerosols samplestested by in-vitro procedures provided relatively high toxicity andmutagenicity.

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CONCLUSIONS

Toxic aerosols were measured on 7 sites : heavy polluted industrialcities(A,F,G),urban areas(B,D,E) and remote region(E).TSP as wellall inorganic and organic particulate toxic sustances showed simi-lar year's trends(Fig.1,b).Epidemiological data of the publichealth service statistics(Fig.1,a)did not follow exactly similaryear's trends like the TSP and aerosol pollutants.

Fig. 1 : Relative mortalities M per 100.000 inh.by lung cancer

of the general population(a),and the measured annualmean concentrations of TSP(b).

This difference is because the epidemiologic data include lungcancers produced by tobacco smoking.Therefore for a comparisonselectedepidemiological data are needed.Furthermore,it could beshown that the ambient air concentration limits(annual means)forTSP should lay at 50 ug.m-3 or even less(Spurny,1994).

REFERENCE

Spurny, K. R. "Anthropogenic Aerosols and their Toxd.:Wissenschaft und Umwelt 4,(1994) in press.

Components"

285

GENOTOXICITY OF AIRBORNE PARTICULATES ON RODENT TRACHEAL EPITHELIAL CELLSAND HUMAN LYMPHOCYTES IN VITRO

Claudia Hornberg and N.H.SeemayerMedical Institute of Environmental Hygiene at the Heinrich-Heine University, Gurlittstr. 53,D-40223 Düsseldorf, F.R.G.

The respiratory tract is the major target organ for airborne particulates and also the site ofthe most common cancer in man, the bronchogenic carcinoma.The genotoxic activity of airborne particulates leading to mutation and cancer can be studied

using in vitro models of human and rodent cells.In our study samples of airborne particulates were collected in the heavily industrializedRhine-Ruhr region utilizing a high volume sampler HVS 150 (Strohlein Instruments) equippedwith glass fiber filters. Substanes were extracted from filters with dichloromethane ormethanol and were quantitatively transferred to dimethyl sulfoxide or Lutrol E 400(polyethylene glycol, M.W. 400) for cell culture experiments.As a sensitive bioassay for detection of genotoxicity of airborne particulates we used induc-tion of "sister chromatid exchanges" (SCE) in cultures of human lymphocytes and of trachéalepithelial cells of the golden Syrian hamster and the Wistar rat.Human lymphocytes were cultivated as whole blood cultures in medium with phytohem-agglutinine. Epithelial cells from the trachea of the golden Syrian hamster and the rat weredissociated by pronase-treatment and cultivated in a complex medium mixturesupplemented with insulin, hydrocortisone, transferrin, epidermal growth factor andconditioned medium of 3T3 cells.Human lymphocytes and rodent trachéal epithelial cells were incubated with various concen-trations of extracts of airborne particulates in presence of bromdeoxyuridine for 72 or 48hours, the last 3 h presence of demecolcine or nocodazole, respectively.In cultures human lymphocytes and trachéal epithelial cells of the hamster and the ratextracts of airborne particulates led to a dose-related highly significant induction of "sisterchromatid exchanges". In all three test systems very low quantities of substances equivalentto airborne particulates from less than 1 cbm of air revealed strong activity.In comparison, hamster trachéal epithelial cells were the most sensitive followed by rat cellsand thereafter by human lymphocytes.

ReferencesHornberg, C, N.H.Seemayer, W.Hadnagy and K.lvanfy: Trachéal epithelial cells of the

golden Syrian hamster in vitro as a tool for detection of genotoxic activity of airborneparticulates. J.Aerosol. Sei. 24, Suppl. 1, 91-92 (1993)Seemayer, N.H., W.Hadnagy and R.Tomingas: Comparative investigation of genotoxic and

nongenotoxic mechnisms and their relevance in carcinogenesis induced by airborne parti-culates and autmomobile exhaust particulates. In: U.Mohr et al. (Eds.) Advances in ControlledClinical Inhalation Studies. Springer Verlag Berlin

-

Heidelberg 393-

403 (1993).

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INHIBITORY INTERACTION OF SERUM WITH SURFACTANT UPTAKE INTYPE H PNEUMOCYTES. M. Griese. J. Khachani, D. Reinhardt. Kmderpolildinik derUniversität, Pettenkoferstr. 8A, D-80336 München

Exogenous surfactant applied to the alveolar space as an aerosol or as a liposomal suspensionhas to be dispersed in epithelial lining fluid before it is actively taken up, metabolized and

recycled by type-II-pneumocytes. Various lung injuries are associated with movement ofserum or serum components into the alveolar lining fluid. This leakage has been shown toinactivate biophysical properties of surfactant and to deteriorate lung function further. Inaddition serum proteins like a1-protease inhibitor are inhaled for therapeutic intervention.The goal of our experiments was to study the effect of total serum on the uptake of surfactantinto type II cells on the cellular level.Methods: Type-II-pneumocytes were isolated from lungs of adult rats by elastase digestionand panning on IgG coated plates. After a period of 18 h in primary culture the cells werewashed and incubated with a natural bovine surfactant preparation (Alveofact, Thomae,Deutschland), that was previously labelled with [^FfJ-dipalmitoyl-phosphatidylcholine(DPPC). 90 min later uptake was determined as trypsin/EDTA-resistant, cell associatedradioactivity.Results: Uptake of surfactant by type-n-pneumocytes increased in a concentration and timedependent manner over a period of 4 h. Addition of autologous rat serum led to completeinhibition of uptake with increasing dose, achieving half maximal inhibitory concentrations(IC50) at about 0,6% serum. This inhibitory effect of serum was entirely conserved after heatinactivation. Performing the experiments at 4°C leads to blockade of cellular metabolism.Rate of uptake was reduced to about 30% of control values. Addition of serum completelyinhibited uptake. Aggregation and particle size of surfactant liposomes were not

systematically altered by serum as determined by spectrophotoscopy and dynamic laser tightscattering.Conclusion: The data obtained demonstrate inhibitory effects of autologous serum on theuptake of a lipid-extracted natural surfactant preparation by type II cells. These effects ofserum or parts of serum appear in addition to previously well described inhibitory actions onbiophysical surfactant function. The reduced rate of surfactant uptake may interrupt or reducerecycling of alveolar surfactant and thus represent a mechanism that leads to a furtherdeterioration of lung function in lung injury with capillary leakage.

Supported by the Deutsche Forschungsgemeinschaft (Gr 970/3-1)

287

A STUDY OF TUMOR NECROSIS FACTOR a RELEASE BY QUARTZ AND COAL MINE DUSTEXPOSED MACROPHAGES

Ursula Griwatz and N.H. SeemayerMedical Institute of Environmental Hygiene at the Heinrich-Heine University Düsseldorf,AuCrn Hennekamp 50, 40225 Düsseldorf, Germany

In earlier studies we could demonstrate, that quartz dust exposed macrophages release a

cytokin, which stimulates cell proliferation of pneumocyte type II cells (Griwatz et al.,1993).Recent results indicate, that Tumor Necrosis Factor a (TNFa) may have an important role in

pathogenesis of silicosis (Gösset et al., 1991; Piguet et al., 1990). Now we tested, if TNFa is

present in supernatants of quartz and coal mine dust exposed macrophages. After in vitromaturation of monocytes from peripheral blood to cells with characteristics of macrophages,they were incubated with quartz dust DQ12 and coal mine dusts from the Ruhr-valey (H1-D20, 01-05; H1-D21, 01-04; H1-D22, 01-05). The supernatants were collected after an

incubation period of 24 hours. TNFa bioactivity was measured in a cytotoxicity bioassay withL-929 mouse fibroblasts. Cells (80000/well) were cultured in 24-well culture plates andincubated for 24 hours at 37°C with supernatants of dust exposed macrophages and 5ug/mlactinomycin D. Thereafter, the viability of the cells was determined by morphological criteria.Endotoxin is an important stimulant of the TNFa production by human macrophages. Weanalyzed suspensions of coal mine dusts from the Ruhr-valey and quartz dust DQ12 for thepresence of endotoxin by the Limulus amebocyte lysate test (E-Toxate, Sigma). Only thesuspensions of coal mine dusts H1-D20, 01-05 contained endotoxin. The other samples ofcoal mine dusts and quartz dusts gave negative results. Interestingly, only endotoxincontaining coal mine dusts stimulated macrophages to the production of TNFa. In furtherstudies we tested the effect of TNFa as a pure substance on pneumocytes type II (line A-549).While TNFa led to slight stimulation of cell proliferation of pneumocytes type II at lowconcentrations (1ng/ml) a strong inhibition was observed at higher concentrations (50ng/ml).Inhibition of cell proliferation was accompanied by morphological alterations of the epithelialA-549-cells to more spindle shaped cells.ReferencesGösset, P. et al.: Production of Tumor Necrosis Factor alpha and lnterleukin-6 by humanalveolar macrophages exposed in vitro to coal mine dust. Am.J. Resp.Cell. Mol.Biol. 5 (1991),431-436.Griwatz, U. et al.: Effect of cytokines produced by quartz dust treated human macrophages onhuman pneumocyte type II cells (A-549). J. Aerosol of Science, Vol.24, Suppl.1, (1993) 463-464.Piguet, P.F. et al.: Requirement of tumor necrosis factor for development of silica-inducedpulmonary fibrosis. Nature, Vol.344 (1990), pp.245-247.This is part of the Thesis by U.Griwatz at the Westtalische-Wilhelms-University of Münster, Germany.

288

Tolerability and safety of tolafentrine after aerosol inhalation of ascending single doses in healthy men

Koch, H.J.: Bliesath, H.; Hartmann M.; Steinijans V.W.; Wurst W.; Kilian U.

Byk Gulden Pharmaceuticals, Byk-Gulden-Str. 2, D-78467 Konstanz

Tolafentrine (proposed INN), a hexahydro-benzonaphthyridine derivative, is a new phosphodiesterase (PDE) inhibitorwhich preferentially inhibits PDE ¡soenzymes III and IV [1]. It effectively relaxed airway and vascular smooth musclein in-vitro experiments and exhibited a prolonged duration of action compared to zardaverine. In anaesthetized guineapigs tolafentrine, administered by means of an air-jet nebulizer, antagonised histamine-induced bronchospasms [2].

In a single-blind, placebo-controlled study increasing single doses of 0.5 mg, 1 mg and 2.5 mg tolafentrine were

administered to 8 healthy male volunteers (age: 23-

37 years; weight: 64-

99 kg) by means of the Pari

Provocationstest I® (Medanz, Starnberg, FRG) jet nebulizer. Safety, tolerability and preliminary pharmacodynamicswere assessed by heart rate and blood pressure, ECG, clinical laboratory, laryngoscopy, PEF (Mini-Wright Peak FlowMeter®, Clement Clarke, London, UK) and a standardized well-being questionnaire.

No changes of the vital signs measurements, ECG, clinical laboratory or PEF-values compared to placebo were found

during this study in healthy volunteers. One volunteer complained of transient mild cough and mild chest tightnesswith concomitant wheezing after inhalation of tolafentrine which was not dose-dependent and resolved

spontaneously. Another volunteer reported mild irritation of the pharyngeal mucosa after inhalation of 2.5 mgtolafentrine. Laryngoscopy revealed no clinically relevant findings in the laryngo-pharyngeal region. Well-being score

sums and PEF-values did not show significant differences between tolafentrine and placebo as assessed by the one-

sided Page test.

In conclusion, tolafentrine proved to be safe in 8/8 and well tolerated in 7/8 volunteers after aerosol inhalation of

single doses up to 2.5 mg. Unspecific bronchoconstrictive reactions, which are possibly due to osmolality changesduring nebulization [3], cannot be excluded in sensitive persons.

1 Schudt, C. et al.: Amer. Rev. Respi. Dis. 147 (SuppL), A183, 19932 Kilian, U. et al.: Europ. Respi. J. G., Suppl. 17, 320S, 19933 Schoni, M.H. and Kraemer, R.: Europ. Respi. J. 2, 887

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892, 1989

289

Aerosol Derived Airway Morphometry in Healthy SubjectsP. Brand. Ch. Rieger, Th. Beinert, and J.Heyder

GSF-Forschungszentrum für Umwelt und Gesundheit, Projekt Inhalation85758 Oberschleißheim, FRG,

Introduction: Aerosol derived airway morphometry (ADAM) allows the non-invasiveestimation of intrapulmonary airspace dimensions. Since this method has shown

interesting diagnostic capabilities, in this study ADAM was performed in 80 healthysubjects to establish reference values for clinical applications. In each subject airspacedimensions were measured at three different levels of lung inflation and the results were

compared with conventional lung function parameters and anthropométrie data.

Method: Aerosol particles settle in calm air with a constant velocity. If the aerosol is in-haled into airways the decline in particle number concentration during breathholds can beused to calculate the effective airspace dimensions (EAD) as a function of volumetriclung depth. For this purpose the subject inhales a single breath of a monodisperse aerosolwith inert di-2-ethylhexyl sebacate (DEHS) droplets with a diameter of 0.8 urn. Particlenumber concentration as a function of respired volume is monitored by a on-line open-flow system.

Subjects: 79 healthy subjects (38 male, 41 female) aged 20-60 years (20 per decade) withno indication of pulmonary disease underwent ADAM. Spirometry and

Bodyplethysmography were performed before and after the ADAM measurement. Theprotocol was approved by the ethical committee of the Medical School ofMunich.

Results: The measured EAD values are in good agreement with current morphometriclung models and are dependant on lung inflation. With increasing endinspiratory lungvolume airspace dimensions increase. This increase is, at least for more peripheral partsof the lungs, in good agreement with the isotropic lung inflation model. Analysis ofvariance showed that EAD in central airways is dependent on parameters of the flowvolume curve (PEF, FEV\). EAD in peripheral lung regions correlates with the age ofthe subject: EAD increases with increasing age. Subjects of different age groups showstatistically significant group differences. Beyond that, peripheral EAD does not correlatewith any other anthropométrie data or lung function indices.

Conclusions: This results suggest that peripheral EAD delivers diagnostic informationfrom the lung periphery additionally to conventional lung function tests.

290

Sensitivity and Specificity of Aerosol Dispersion and Morphometry as a Diagnostic Tool inEpidemiological Studies

Th. Tuch(1). P. Brand (1), O. Manuwald (3), H. E. Wichmann (2) and J. Heyder (1)

(1) GSF-Forschungszentrum fur Umwelt und Gesundheit, Projekt Inhalation(2) GSF-Forschungszentrum für Umwelt und Gesundheit, Institut für Epidemiologie

85758 Oberschleißheim, FRG(3) Institut für Umweltmedizin im DRK Thüringen e.V.

99096 Erfurt, FRG

Introduction: Aerosol dispersion and morphometry allow the non invasive characterisation of

intrapulmonary gas mixing and airway dimensions. 228 randomly selected citizens from Erfurt, FRGtook part in an epidemiological study on the incidence of lung diseases. The protocol of this studyincluded a questionnaire, conventional spirometry, aerosol dispersion and aerosol morphometry. Thepurpose of this study was to investigate the sensitivity and specificity of aerosol dispersion and

morphometry to detect symptoms ofchronic bronchitis and asthma..

Methods: Aerosol Dispersion: A small aerosol bolus inhaled into the lung is broadened upon exhalation.The broadening of the exhaled bolus is a measure for conective gas mixing in the lungs.Aerosol Morphometry: Aerosol particles settle in calm air with a constant settling velocity. If theaerosol is inhaled into airways the effective airway dimensions (EAD) can be calculated from thedecline in particle number concentration during breathhold. Particle number concentration as a functionof respired volume is monitored by an on-line open-flow system.

Results: Sensitivity and specificity of lung function parameters to detect subjects reporting symptoms ofchronic bronchitis ( frequent cough ) or symptoms of asthma ( wheezing ) was calculated by logisticregression analysis. Sensitivity and specificity to detect symptoms of chronic bronchitis are comparablefor aerosol techniques and conventional spirometry. Combination of both techniques increases

sensitivity and specificity to detect these symptoms distinctively. Symptoms of asthma are betterdetectable using aerosol dispersion and morphometry. The combination of parameters of aerosoldispersion and morphometry with parameters of conventional spirometry yields no further increase in

sensitivity and specificity. These results indicate, that aerosol dispersion and morphometry deliveradditional information from the lungs which can not be accessed by conventional spirometry.

Conclusion: Depending on the nature of lung impairment combination of conventional spirometry andaerosol dispersion and morphometry increases sensitivity and specificity of lung function tests in

epidemiology.

291

Comparison of the in-vitro characterization of JAGO's Dry Powder Inhaler (DPI)Prototype No. 6 compared to Diskhaler® and Turbuhaler®.

Manfred Keller. Eva Trächslin and Andrew Francis,JAGO Pharma AG, Eptingerstr. 51, CH-4132 Muttenz, Switzerland,Tel. +41-(61)-467 55 55, Fax: +41-(61)-467 55 00

The JAGO DPI is constructed as a breath actuated automatically loading and dosingmultidose DPI for the pulmonary administration of both neat drugs and powder blends.The in-vitro performance of the DPI prototype No. 6 fitted with differently shapedmouthpieces was compared to the DPI-devices Diskhaler® and Turbuhaler® by usingeither Glaxos's powder blend of 0.2 mg Beclomethasone-dipropionate (BDP) in 24.8 mgLactose named Becodisk® (CH) or Sanasthmyl Rotadisc 200® (FRG) or Astra's Terbu-taline-sulfate soft pellets (TS) named Berotec® (CH) or Aerodur® (FRG). Since no

pharmacopeial methods are published so far we used the Twin Impinger (TI, App. A, BP93) as test device for both the testing of dose-uniformity and the in-vitro depositionpattern at two "inspiratory flow volumes" of 30 and 60 l/min and sampling times of 5 sec,respectively. The aim of this investigation was to check in comparison to the commerciallyavailable reference products the following parameters: dose-uniformity (DU) per singleand multiple inhalation (measured as weight difference) and the in-vitro (lung)depositionpattern measured by HPLC.The mean values of 24 individual puffs, each fired at 30/60 l/min from DPI-No.6 loadedwith Glaxo's BDP-powderblend were 1.22 mg (RSD = 13%) and 1.31 mg (RSD=16.1%)respectively; min./max. puff weights were within 0.99 mg and 1.68 mg. DPI-no.6 fulfilledfor both substances BDP and TS the dosing-uniformity requirements of USP XXII. Thein-vitro deposition of Glaxo's BDP powder blend to the lower impingement was 23.6%resp. 69.1 ug BDP at 30 l/min and 25.7% resp. 66.8 ug BDP at 60 l/min, indicating a

flow independent drug dosing and atomisation. In contrast hereto dose-uniformity profileof both Diskhaler® and Turbuhaler® was poor and missed by far the USP-requirements.Only 35 of 48 puffs fired from the Diskhaler® (RSD =31%) and 33 of 60 puffs fired fromthe Turbuhaler® (RSD=39,2%) were within the USP-specification of± 25% / 35% of thelabel claim (25 mg and 0.5 mg, respectively). Min./max. puff weights at 30/60 l/min were8 mg and 38.6 mg for Diskhaler® and 0 mg and 0.8 mg for Turbuhaler®; respirablefraction for the first was 22.9% and 23.2% and the latter 23.5% and 40.6%, respectively.From these results can be concluded that none of these tested commercially available DPIswould fulfil the USP-requirements for MDIs.

292

ESTIMATION OF THE REGIONAL LUNG DEPOSITION OFHISTAMINE AEROSOLS PRODUCED WITH A JET NEBULIZER

G. A. FERRON and E. M. APP

GSF-

Forschungszentrum für Umwelt und GesundheitProjekt Inhalation

85764 Oberschleißheim

Aerosols size distributions of jet nebulizers are known from literature or

have to be measured. After nebulization and during transport of the aerosol, partof the water in the droplets evaporate and an equilibrium between the relativehumidity of the air and at the particle surface is approximated. Using thisassumption the mean change in particle sizes can be estimated, if the humidities,airflows and the temperatures of the compressed air and mixing air are known(Ferron and Gebhart, J. Aerosol Sei. 1988, 19, 1083-1086). The deposition ofpolydisperse and hygroscopic aerosols in the human airways can be estimatedwith a method described in literature (Ferron et al., J. Aerosol Sei. 1993, 24, 655).This method needs the size distribution of the aerosol particles and the growthfactor of the particles in the airways.

These methods are applied to the inhalation of histamine aerosols withdifferent concentrations produced with a Pari Inhalerboy (Pari, Starnberg). It isassumed that the mass median diameter of the aerosol is 2.6 um and has a

geometric standard deviation of 2.15 (Sterk et al, Bull Physiopathol. Respir. 1984,20, 65), the relative humidity of the air is 20% and no mixing air is used. Theisotonic concentration of histamine dihydrochloride is 22.4 g/1 (Merck Index). Forthe concentrations of 0.06 and 22.4 g/1 histamine the depositions in theextrathoracic, bronchial and pulmonary region are 5.3% and 5.3%, 11 and 14%,and 33 and 41%, respectively. The corresponding values for the total depositionare 49 and 60%. If the histamine solution is adjusted to an isotonic solution, forexample with NaCl, no change in deposition would occur, and the latter of thelisted values are valid.

Conclusion: Different concentrations of histamine influence the regional andtotal deposition in the lungs by about 20%. No differences are found if thenebulizer solution is adjusted to an isotonic saline solution.

293

Application of Computational Fluid Dynamicsto Characterize Cutoff Diameters in the Twin Impinger

R. Jäger-Waldau and H. Mehring,Ing. E. Pfeiffer GmbH&Co.KG, Postfach 1460, 78304 Radolfzell, GermanyThe Twin Impinger is widely used to characterize respirable aerosol fractions. However,even though the TI is recommended by the British Pharmacopeia [1], the obtainedquantitative results depend on different intrinsic factors of the TI which are not knownquantitatively.A theoretical flow model [2] was employed to gain insight of droplet trajectories andimpaction conditions under different flow conditions. Discrete particle trajectories werecalculated by solving equation 1 :

EQUATIONl PpUp^ = -|-^-PaCDCV-U)|V-U|+Up(pp-pa)g+PaUp-^-where p is the density, u the volume, V and U the particle and air velocities, respectively, gthe gravitational constant. The subscripts p and a stand for particle and air, respectively.Equation 1, Newtonian equation of motion, consists of a drag term, a term due togravitational forces and a term which gives a force due to pressure gradient. Generally,other terms are included in equation 1 but omitted here since in our case they do notcontribute substantially to the particle dynamics. For complete description see reference[2]. Cj) is the drag coefficient which is expressed by equation 2.

equation z CD =—(1+0.15 ReDQ687) if ReD < 200 where ReD =^'^D Repv pip p n

In order to calculate the particle trajectories it is required to determine the fluid velocity atthe droplet's instantaneous locatioa Simplified flow fields for the 90° bend and a potentialflow model (Axially symmetrical stagnation point flow) for the first stage of the TI wereemployed. In all cases the flux was kept constant and the time steps during calculation werekept at 210"5s wich is shorter than the relaxation time (ca. lO'VlO'V) of the dropletstraced.The flow field through the throat was modeled by applying a constant gradient radially.Trajectories for 5 um, 20 um, and 30 um droplets which are injected at a velocity of25 m/s and an angle of +25°were calculated. Droplets bigger than 25 urn will impactwhich is in accordance with Hallworth's [3] calculations. Lowering the flow rate or theinjection angle will result in an increase of the cut off diameter. A lower injection velocityof5 m/s is used which is in the same order ofmagnitude like the flow rate going through thethroat. A 40 um dropletwill deposit in the throat when there is a flow rate of60 l/min while

294

it does not with 101/min. The cut off diameter is approximately 35 urn at 601/min.To model the impaction of droplets in the first stage of the TI an axially symmetricalstagnation point flow was used. The potential of the velocity can then be described as

follows: equation 3 (I>(x,y,z) = -(x2 + y2-

2z2) where x2 + y2 = r2The flow is axially symmetrical to the z-axis and the components of the velocity are thefollowing:0 EQUATION 4 u = 2ar, w = -4az

The equation of the streamline is: ,dz w zEQUATION 5 — =— = -2-dr u rIntegration of the streamlines results in:

EQUATION 6 r2 -Z = const

Impaction curves were calculated for particle diameters varying from 3-50 um dependingon injection point. An overall collection efficency curve for the impingement instrumentwas then evaluated. The result showed good agreement with the work of Fuchs [2],Mercer [4] and Hesketh [5] in the range of Vstk =0.4...0.6 . To conpare our data with thedata found in literature it is important to know about the different mathematicalapproaches. Our analytical approach describes the trajectories of each single particle. Noinformation is lost due to the knowledge of the particle trajectories at any time as well as thecondition of the flow field simultaneously. However, all models presented in e.g. [2,4,5]do give a collection efficency integrally via stop distances.The results of TI measurments from Hallworth did not fit to our calculations due to thesetup of the impingement instrument. Impaction behavior in the first stage is effected byparticle deposition in the 90° bend whereas in our model a constant particle deviation onthe cross section is presupposed. A uniform distribution per area (cross section) does notgive the same results Hallworth reported. Different injection points and angles wereinvestigated to find a local particle distribution that gives a D0^ = 6.4um. For MDI's rubberadaptors are often used to ensure central injection of spray. Particles in the range of l-8umrelax within a distance of 5mm (at an injection velocity of 25m/s) and follow the centralstream. This is why the cut off diameter D0 5 of the first stage in the TI is 6.4um incomparison to 16.2um if particles would uniformly distributed over the cross section.ReferencesIII British Pharmacopeia Appendix XVIIC (1988). Pressurized Inhalations: Depositionof the Emitted Dose, Apparatus A. A204-A207121 Fuchs, N.A., The Mechanics of Aerosols, Pergamon Press, 1964ßl Hallworth G.W., and Westmoreland D.G. (1987). The twin impinger: a simple devicefor assessing the delivery of drugs from metered dose pressurized aerosol inhalers. Journalof Pharmacy and Pharmacology CASSI (London) 39, 966-972IAI Mercer, T.T., Aerosol Technology in Hazard Evaluation, Academic Press, 1973, NewYork151 Hesketh, H.E., Fine particles in gaseous media, Ann Arbor Science, 1977, Ann Arbor

295

Monodisperse Solid Particle-Aerosol Generation Using theCondensation Aerosol Generator of the Series SLGC. Peters and A. Rudolph, Topas GmbH, Hofmannstrasse 37, D-01277 Dresden, Germany

The Condensation aerosol generator series SLG is based on the principle of controlledheterogeneous condensation and is detailed described elsewhere (Peters and Altmann, 1993).Using DEHS as aerosol substance monodisperse aerosols with high number concentrations(106#/cc) and mean diameter from 0.1 up to 8pm can easily be generated. For many applicationsin different fields it is of interest to produce solid aerosol particles (e.g. calibration of CascadeImpactors or investigation of particle deposition in the respiratory system). Main problems raisingfrom producing solid aerosol particles are the requirement of a reheater temperature high enoughto revaporize the nuclei vapor mixture, instrument cleaning and handling of the material to be used(melting, etc.). Experiments with two aerosol substances Stearic Acid and Carnauba Wax werecarried out. The generated aerosol were analyzed by means of a Sedicell, Palas and themeasured count mean geometric diameter (CMGD) are plotted in Figure 1 and 2. The geometricstandard deviation has always been obtained less than 1.10.

250 C

0,0 0,5Normalized saturator flowrate

0,0 0,5 1,0Normalized saturator flowrate

Figure 2: CMGD of a Carnauba Wax Aerosol vs.Ratio between Total and Saturator Flowrate forDifferent Saturator Temperatures

Figure 1 : CMGD of Stearic Acid Aerosol vs. Ratiobetween Total and Saturator Flowrate for DifferentSaturator TemperaturesIt has been found that the SLG can also be used to produce monodisperse aerosols of solidparticles. It can be seen that different thermodynamic properties lead to a specific particle size at agiven operation condition. The reduction of nuclei concentration (special feature of the SLG 270)can be used to extend the particle size range (Figure 2, dashed line). The free adjustable reheatertemperature Is very suitable, if various aerosol substances are used. Depending on the substancethe location inside the condensation chimney where the heterogenous condensation starts can bedefined and by this way the length of condensation. For melted aerosol substances, the controlbehavior of the saturator temperature and rapid reaching a new adjusted particle size arecomparable to using a low-volatile liquid (DEHS) as aerosol substance.Ref.: Peters, C. and Altmann, J. (1993) J. Aerosol Medicine 6, 307-315.

296

ESTIMATION OF PHAGOCYTOSIS OF MAGNETIC MICRO-PARTICLES IN THE HUMAN LUNG

W. BARTH1. W. MÖLLER2, W. POHLIT1, W. STAHLHOFEN2, J. WIEGAND2

11nstitut für Biophysik, Johann-Wolfgang-Goethe-Universität Frankfurt and2GSF

-

Forschungszentrum fur Umwelt und Gesundheit, Institut für BiophysikalischeStrahlenforschung, Paul-Ehrlich-Straße 20, D-60596 Frankfurt am Main, Germany

In this paper Magnetopneumography (MPG)-methods are used to determine the fraction ofmagnetic material outside and inside of the macrophages. After inhalation the alveolar macro-phages begin to phagocytize the magnetite particles (Fe^O^. In hamster lungs 87% of theparticles are phagocytized during 24 hours after inhalation (Geiser et al., 1990). In vivoMPG-measurements of the time dependent course ofphagocytosis continously during the whole time

after inhalation are presented.There are two different ways to magnetize the lungs by the particles (Stahlhofen, 1993): i) Pri-mary magnetization is performed in a strong magnetic field (lOOmT); all magnetic domains arealigned parallel to the external field, ii) Applying a weak external magnetic field B^, a magnetictorque Nmag arises on a rémanent dipole m, rotating the magnetized particles in direction to theexternal magnetic field. The rotation is retarded by a hydrodynamic torque mainly determined bythe viscosity n of the surrounding medium, the angular velocity d9/dt and the rémanent

magnetization of the particles.The following analysis bases on the hypothesis, that particles inside of macrophages are rotatedduring secondary magnetization, while the free particles resist the rotational shear. After primarymagnetization the flux density Bmax produced by the rmf of the inhaled particles is measured;Bmax consists out of a rotatable (Br) and a non-rotatable (Bnr) fraction: Bmax = Br + Bnr. Afterinhalation all particles are outside of the macrophages (Bmax = Bnr). In the following time pha-gocytosis takes place, the fraction Bnr is reduced and Br increases (0 < Bnr < Bmax; Br +Bnr =Bmax) The fraction of phagocytized particles was measured by a two step-secondary magneti-zation, where the field direction was reversed, yielding to different absolute rmf s. The non-

rotatable fraction is determined by the crossover with the horizontal axis. First experimentsshows the time course of phagocytized particles (phagocytosis quota), increasing to a value of

nearly 95%. The half life is approx. 2h, when an exponential function is considered. It can be

concluded, that MPG-methods are usefull to determine the time course and the efficiency ofphagocytosis in vivo.Acknowledgement:This work was partially supported by the „Deutsche Forschungsgemeinschaft" under contract Po 108/7-1 and bythe CEC under contract F13PCT 930064A.

References:Geiser M., Cruz-Orive L.M., Im Hof V., Gehr P.(1990), Journal ofMicroscopy, Vol. 160, Pt 1, pp. 75-80Stahlhofen W., Möller W. (1993), Radiation and Environmental Biophysics, Vol. 32, 221-238

297

Experience with the Reservoir-

and Bolus Method in the4-

step Carbacholtest.

M. Mohorn, R. Schäfer, B. Bartuschka, A. ReißigPneumologische Abteilung der Klinik für Innere Medizin,Klinik IV, Friedrich-Schiller-üniversität Jena.

Aim our investigations were the comparison between the reser-

voir-method ( Provokations-Test I ,Co. Pari, mist capacity0,081 ml/min) and the bolus-method ( Provojet, Co. Ganshornmist capacity 4,7 mg/s ) in the unspecific provocation test.

We performed the 4-step carbachol test in 640 outdoor

patients, with suspect of bronchial hyperreactivity, with one

of both methods. Basis of the dosage was the mist capacty of

the Provocations Test 1 equipment. It was step 1=6%,step 2 = 12%, step 3 = 41% and step 4 = 100% of the completedosis of carbachol.The measeruments of resistance were made by the Siemens body-plethysmograph modernized by Co. Gut. The carbachol test was

positive if resistance increases > 3hPa/l/s and final value> 5 hPa/l/s.Results: Group 1 (reservoir method,n=420) were 169 ( = 40,2% )

negative, in group 2 (bolus method, n=220) were 87 ( = 39,5% )

negative.There was no statistical difference between both methods.Both methods were useful for the unspecific provokations test.

298

RESPONSES OF THE CANINE LUNGS DURING LONG-TERMEXPOSURE TO A NEUTRAL SULFITE AND AN ACIDIC SULFATE

AEROSOL AT LOW CONCENTRATIONS

J.Heyder, I.Beck-Speier, P.Dirscherl, G.A.Ferron, E.Karg,W.G.Kreyling, A.-G.Lenz, K.Maler, H.Schulz, S.Takenaka,

A.Ziesenis

GSF-Forschungszentrum für Umwelt und GesundheitProjekt Inhalation

D-85758 Oberschleißheim, Germany

In a recent study, 8 beagle-dogs housed in whole body chamberswere daily exposed for 22.5 h over a period of 290 days to aneutral sulfite aerosol at a level well below that at which acutetoxicity would be expected (Heyder et al.Inh.Toxicol.4,1992,159-174). Respirable sulfite particles with amass median aerodynamic diameter of 0.6 /t/m were used as asurrogate for particle-bound inorganic S(IV) compounds at aconcentration equivalent to a sulfur dioxide concentration of 0.6mg m . After about 200 days of exposure the protein andalbumin content of the lavage fluid increased indicating analtered integrity of the alveolar-capillary barrier for serumproteins. At the same time also an increased release of thelysosomal enzyme ß-N-acetylglucosaminidase from phagocyteswas observed. Alveolar macrophages showed a reducedphagocytic capacity and production of oxygen-derived freeradicals, and macrophage-mediated particle clearance wasaltered. The diffusion capacity of the lungs was reduced as aresult of a reduction in surface area available for gas exchange.There is increasing evidence that the acidity of environmentalparticles may have to be considered a health risk. Therefore, in afollow-up study over a period of 400 days, 8 beagle-dogs weredally exposed for 16.5 h to the neutral sulfite aerosol and for 6 hto an acidic sulfate aerosol of comparable particle size. Thehydrogen ion concentration delivered to the lungs was 13 //molm"3. The daily sulfite burden of the animals was the same as inthe previous study.Although synergistic effects were anticipated, the functionalresponses of the lungs to sulfur (IV) under acidic conditions areless distinct or even reversed (i.e.macrophage-mediated particleclearance and oxidative burst) when compared with thoseobserved under neutral conditions.

In conclusion, investigation of respiratory responses to single airpollutants may not provide insight into respiratory responsesassociated with exposure to multiple air pollutants.

299

A New Nebulizer System for GentleWarming of AerosolMartin Knoch

PARI GmbH, Starnberg, Germany

Compressed-air nebulizers produce medication aerosols via a high-speed air jet which sucks theliquid medication from a reservoir and, due to the high shear stresses on the surface, tears it intodroplets. The primary aerosol which is thereby produced contains a wide range of droplet sizes.Impaction surfaces are located in the nebulizer in such a manner that only the finest droplets reach thepatient whereas the larger ones fall back into the reservoir.

The droplets evaporate very quickly when mixed with the air flow due to the extremely enlargedsurface area. The evaporation of the returning droplets produces water vapor which does not contributeto the transport of the medication. This results in a continuous increase of the medication concentrationin the reservoir as well as a decrease in the aerosol temperature (Phipps and Gonda 1990). Simulta-neously however, the sizes of the droplet spectrum are reduced due to evaporation so that a higheraerosol output is delivered through the mouthpiece. This effect is taken advantage of in nebulizers witha ventilation tube to increase the inspiration-controlled output. The entrained air is thereby fed throughthe nebulizer during inspiration and favors the evaporation of the primary aerosol and therefore also thereduction of the droplet sizes.

Evaporation effects are intensified even more by adding warm or dry entrained air for increasingthe output (with the same droplet spectrum) or for reducing the droplet sizes (at the same output)(Everard et al., 1993). This can be effected by integrating a heating unit into the nebulizer's ventilationtube. Since the medication solution itself is not heated directly and does not come into direct contactwith the heating surfaces, a gentle warming of the aerosol is insured for the first time. The evaporationof the droplets which occurs when the pre-heated air is added, simultaneously prevents the medicationfrom overheating. In case of very sensitive medications one should make sure beforehand that thesubstance will not be damaged.

The PARI THERM aerosol heating unit warms the aerosol to about body temperature. Thus, theirritation due to the cold air, which is known for the compressor-driven nebulizers, is eliminated. Also, itis beneficial to the airways since moist air is delivered at a comfortable temperature. Now, inhalationtherapy is no longer a problem for patients who are particularly sensitive to cold air.

The droplet spectrum at the mouthpiece was adapted to that of the nebulizer without a heatingunit (PARI LL nebulizer, MMD 3 pm). The aerosol output is 25-30% higher which shortens therapy timeaccordingly. In combination with the integrated interrupter button, the medication used and the addedwarmth are exploited optimally.

Everard M L, Peckham D, Knox A and Perkins AC (1993). Can aerosols from nebulisers be Improved by the addition of adrying chamber? Proc. British Thoracic Soc, Thorax 48,427

Phipps, P R and Gonda I (1990). Droplets produced by medical nebulizers. Some factors affecting their size and solute con-centration. Chest 97 (6), 1327-1332

300

Jet Nebulizers: Improvement and Expansion of ApplicationsMartin Knoch

PARI GmbH, Starnberg, Germany

Jet nebulizers are well accepted especially for home Inhalation therapy mainly due to their simplehandling and reliable application. Their use, in contrast to metered dose inhalers requires little coordi-nation and can be learned without much training. The integration of an interrupter button has contribu-ted considerably to the recognized high efficiency of jet nebulizers in their intra-bronchial deposition oftherapeutic aerosols. This interrupter button enables the patient to actively initiate the nebulization.Thus, aerosol losses during expiration are, for the most part, avoided and a larger portion of themedication is available for inhalation (Clay and Clarke 1987). The pauses in the interval nebulization canbe compensated for by the inspiration-controlled increase in output which nebulizers with a ventilationtube offer.

The fact that more aerosol is produced with increasing inspiratory flow can be used for a consi-derably simplified application which, despite continuous nebulization, insures a high aerosol utilization.For just this reason the PARI LC PLUS nebulizer has a valve system instead of the interrupter button.During inhalation surrounding air flows through the inspiratory valve on the ventilation tube to thenebulization chamber. There it increases the output of respirable droplets due to additional evaporation.An expiratory valve Is located on the mouthpiece of the nebulizer which is closed during inhalation.During exhalation, the inspiratory valve closes thereby preventing air entrainment into the nebulizer sothat only a minimal amount of aerosol is produced. This excess aerosol, together with the exhaled air,exits through the expiratory valve in the mouthpiece. Since the output ratio is 1:3 for an inspiratory flowfrom 5 l/min to 20 l/min, then about 70% of the aerosol is delivered and only about 30% is lost duringspontaneous breathing. This is about the same loss as is expected with patients not experienced Inusing the interrupter button. The aerosol utilization depends on the maximum inspiratory flow duringspontaneous breathing aswell as the ratio of length of Inspiration to that of expiration.

The PARI LC PLUS nebulizer is especially beneficial for children and the elderly who have troublewith the correct inhalation technique and the coordination of the interrupter button. Also, despite thehigh efficiency, the therapy time is up to 30% shorter than with intermittent nebulization. This has a

positive effect on the compliance.The system was developed further keeping the aerosol application for babies and infants in mind.

The effect of the inspiratory flow on the aerosol output is of less importance for this application. Moreimportant is the continuous delivery of fresh aerosol. The dead space volume ventilated duringexhalation must be minimized. In the PARI BABY nebulizer this is achieved through a tight-fitting, softsilicon mask in the appropriate size. The nebulizer can be held vertically even in a prone or semi-proneposition due to the rotatable angular fitting. Ventilation slits, offering the shortest route through whichthe exhaled and excess aerosol can flow out, are located right behind the mask. This special design ofthe PARI BABY nebulizer therefore makes a direct and reliable aerosol application possible even withlowest tidal volumes.

Clay MM and Clarke SW (1987). Wastage of drug from nebulisers: a review. J. Royal Soc. Med. 80,38-39

301