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Saltbutiken.seEur Respir J 1997; 10: 2465–2473 Copyright ERS Journals Ltd 1997 European Respiratory Journal Printed in UK - all rights reserved The effect of inhaling a dry powder of sodium chloride on
the airways of asthmatic subjects
S.D. Anderson*, J. Spring*, B. Moore**, L.T. Rodwell*, N. Spalding*, I. Gonda+, K. Chan+, A. Walsh+, A.R. Clark+ The effect of inhaling a dry powder of sodium chloride on the airways of asthmatic *Dept of Respiratory Medicine PCP9, subjects. S.D. Anderson, J. Spring, B. Moore, L.T. Rodwell, N. Spalding, I. Gonda, K. Royal Prince Alfred Hospital, Camperdown, Chan, A. Walsh, A.R. Clark. ERS Journals Ltd 1997. NSW, Australia. **St Pauls Hospital, ABSTRACT: Wet aerosols of 4.5% sodium chloride (NaCl) are often used to assess
Vancouver, Canada. +Genentech Inc, SouthSan Francisco CA, USA.
the bronchial responsiveness associated with asthma. We questioned whether dry
NaCl could be used as an alternative.
Correspondence: S.D. Anderson Dry powder NaCl was inhaled from capsules containing either 5, 10, 20 or 40
Dept of Respiratory Medicine mg to a cumulative dose of 635 mg. The powder was delivered via an Inhalator™
PCP9, Royal Prince Alfred HospitalMissenden Road or Halermatic™. The airway sensitivity to the dry and wet NaCl was compared
in 24 patients with asthma aged 19–39 yrs.
All subjects responded to both preparations and the geometric mean (95% con-
fidence intervals) for the provocative dose of NaCl causing forced expiratory vol-
Keywords: Asthma, bronchial provocation, ume in one second (FEV1) to fall 20% from baseline (PD20,NaCl) for dry NaCl was
dry powder, osmotic challenge, sodium 103 mg (68–157) versus 172 mg (102–292), p<0.03 for the wet NaCl. The response
to dry NaCl was reproducible and on repeat challenge the PD20 was 108 mg
Received: February 12 1997 (75–153). The mean maximum fall in FEV1 was approximately 25% on each of
Accepted after revision August 19 1997 the two test days. Spontaneous recovery occurred within 60 min after challenge
with dry NaCl and within 5 min after bronchodilator. There were no serious side-
The major funding for this study came effects requiring medical attention, however some patients coughed on inhalation
from the National Health and Medical Res-earch Council of Australia (JS, LTR) with of the 40 mg dose and three gagged. Arterial oxygen saturation remained within
small grants from the Asthma Foundation of NSW, Boehringer Ingelheim Pty Ltd, We conclude that a suitably prepared dry powder of sodium chloride could
Sydney, NSW, Australia (NS) and Genentech potentially replace wet sodium chloride to assess bronchial responsiveness in patients
Inc, So San Francisco CA, USA.
with asthma, but further studies are required to establish the long-term stability
A patent has been registered internation- of the dry powder preparation.
ally for the use application described in Eur Respir J 1997; 10: 2465–2473. this study, PCT/AU 95/00086.
Bronchial provocation testing, is well established as the output for each challenge test as output differs over a technique for identifying and assessing the severity of time, between nebulizers, and between patients. Another airway hyperresponsiveness in persons suspected of hav- disadvantage, as with other wet aerosols, is that the per- ing asthma . In 1981, SCHOEFFEL et al.  reported son administering the test is also exposed to the aerosol.
that patients with asthma were sensitive to the inhala- For these reasons we investigated the possibility that a tion of wet aerosols of hypotonic and hypertonic saline.
dry powder preparation of sodium chloride (NaCl) could This observation led to the development of a standard- be substituted for the wet aerosol preparation of 4.5% ized bronchial provocation challenge with hypertonic saline both in adults and children [1, 3–8]. Studies com- The aim of this study was to compare the airway sen- paring responses to hypertonic saline and other provoca- sitivity to a suitably prepared dry powder inhalation of tive stimuli commonly used for bronchial provocation NaCl with that of an inhaled wet aerosol preparation of testing have shown good concordance between resp- 4.5% NaCl in patients known to be responsive to chal- onses to hypertonic saline, exercise and hyperventila- lenge with hypertonic saline. The reproducibility of the tion [9–11]. Patients responsive to hypertonic saline have airway responses to the dry powder and the time-course been shown to have bronchial hyperresponsiveness to of spontaneous recovery of the airways after challenge inhaled aerosols of methacholine and histamine with a were also investigated. 20% fall in forced expiratory volume in one second(FEV1) at concentrations <8 mg·mL-1 or a dose <4 µmol.
There are, however, disadvantages when using wet aerosols of hypertonic saline. An ultrasonic nebulizer is Twenty four asthmatic subjects (seven males and 17 needed and this requires maintenance and cleaning.
females) aged 19–39 yrs, were recruited from the local Furthermore, a weighing machine is needed to measure community (table 1). All subjects had a baseline FEV1 S.D. ANDERSON ET AL.
Table 1. – Anthropometric details Sal p.r.n. Sal p.r.n. Sal p.r.n. Sal p.r.n. Sal p.r.n. Sal p.r.n. Sal p.r.n. Sal 100 µg 295.2 Sal 600 µg, 508.5 Sal 200 µg 79.65 Sal p.r.n. and p.r.n. Sal p.r.n. Sal p.r.n.
Sal 600 µg, BDP Subj.: subject; FEV1: forced expiratory volume in one second; PD20: provocative dose causing a 20% fall in FEV1; ICS: inhaledcorticosteroid; Fen: fenoterol; Sal: salbutamol; BDP: beclomethasone dipropionate; Bud: budesonide; Theo: theophylline; Terf:terfenadine; 95% CI: 95% confidence intervals; GM: geometric mean. *: values are those of QUANJER et al. .
>60% and a 20% fall in lung function (FEV1) during to commencement of the study. The study was carried challenge with 4.5% saline. They were all nonsmokers out under the Clinical Trial Notification Scheme of the and none had experienced a chest infection in the pre- Therapeutics Goods Administration of Australia (CTN vious 6 weeks. Subjects were asked to refrain from tak- ing short acting bronchodilators for 6 h and long actingbronchodilators for 12 h prior to the study days. No cor-ticosteroids were taken by the subjects on the day of the study and no antihistamines were taken for at least3 days before the study day. All medications (includ- NaCl powder and capsule preparation ing the daily dose of inhaled steroids) are recorded intable 1. The healthy subjects had no personal or fami- The NaCl powder (Mallinckrodt AR; Paris, KY, USA) ly history of asthma, were nonsmokers and did not have was prepared for inhalation at Genentech Inc (So San a positive skin-test to common allergens (dust, grasses, Francisco, CA) by the method of micronization using a animal dander, moulds). The study was approved by the Trost air impact pulverizer (Trost Equipment Corporation, Central Sydney Area Health Service Ethics Committee Newtown, PA, USA). The mill uses compressed nitro- (X93-0061) and all subjects signed a consent form prior gen to break up the NaCl crystals by collision. Prior to DRY POWDER SODIUM CHLORIDE FOR INHALATION IN ASTHMA milling, all parts of the mill were washed with Mili-Q flow rate (50–120 L·min-1 in 10 L·min-1 intervals) and water (Millipore Corporation, Bedford, MA, USA), rinsed the data were graphically correlated to provide an esti- with ethanol, and dried under a stream of compressed mate of flow measurements for each known pressure nitrogen. NaCl was then fed to the micronizer and milled.
change. Pressure tracings were recorded during the chal- The powder was collected and milled once more. The lenge, on a chart recorder (Miniwriter Type WTR771A, powder was then dried in a vacuum oven at 140°C and Watanabe Instruments Corp., Tokyo, Japan) to provide a 5.05 kPa (38 mmHg) vacuum for 1 h, followed by instantaneous readings. The data was analysed more transfer to glass vials and shipment to Sydney. The parti- accurately after testing.
cle size was measured using a multi-stage liquid impinger For the Inhalator™ the subjects were required to inhale (Astra Draco, Lund, Sweden) and by measuring sodi- the NaCl powder at a flow rate >28 L·min-1. The inspired um and chloride content by flame photometry on each flow rate was checked by having the subject inhale max- stage of the impactor. The Halermatic™ device (Fisons imally from the Inhalator™ while it was attached to an Pharmaceuticals, Loughborough, UK) used was loaded anemometer (Minato AS 800, Minato Medical Science with 120 mg of NaCl (3×40 mg capsules) and, by using Co Ltd, Osaka, Japan) prior to challenge on all of the a pump, a flow rate of 60 L·min-1 was generated through test days. The best of three attempts was recorded. To the device. The particle size analysis was repeated for calibrate the anemometer flows of 25–95 L·min-1 were the Halermatic™ device and performed for the first time generated through a rotameter (Series 2000, GEC-Elliott, with the Inhalator™ (Boehringer Ingelheim Pty Ltd., Ingelheim, Germany) after transport of the NaCl to theSydney laboratory. The same type of multistage liquidimpinger was used as in California, but the sodium and Lung function measurements chloride content was measured at each stage using a vap- Spirometry was performed on an Autospiro AS-300 our pressure osmometer (5500 Vapour Pressure Osmo- spirometer (Minato Medical Science Co Ltd., Osaka, meter; Wescor Inc., UT, USA). The bioburden analysis Japan) and the FEV1 measurement was used as an index was carried out by Northview Pacific Laboratories Inc of change in airway calibre. The predicted FEV1 values (Berkeley, CA, USA). The results for both yeast and used were taken from QUANJER et al. . The spiro- mould showed a value of less than 10 colony-forming meter was calibrated each morning using a 2 L syringe. units (CFU)·g-1 and no coliforms or other pathogenswere detected. The gelatine capsules (No. 2; Gallipot,St Paul, Minnesota, USA) were hand-filled with 5, 10, Oxygen saturation 20 and 40 (±0.2) mg on an analytical balance (BA11OS;Sartorius, Gottingen, Germany) as required under con- Oxygen saturation (Sa,O ) was measured by oximetry trolled conditions (relative humidity 40%, temperature (Ohmeda Biox 3700e, BOC Health Care, Louisville, CO, 20±1°C) in Sydney. The capsules were held in plastic USA) as an index of safety. Sa,O was measured during containers that were stored in a larger glass container the dry NaCl capsule challenges in 22 subjects and for with silica gel and kept in a cool environment. 11 subjects during the wet challenges.
Delivery device Challenge duration and number of capsules Two devices were used to deliver the NaCl powder.
The median (and range) time taken to perform the Subjects No. 1–8 received the NaCl powder via an In- challenge and the number of capsules used was calcu- halator™ (Boehringer Ingelheim Pty Ltd) and subjects lated for the two devices. No. 9–24 received the NaCl powder via a Halermatic™(Fison's Pharmaceuticals Pty Ltd). Both the Halermatic™and the Inhalator™ are single dose devices permitting Study design different doses to be loaded during the challenge. Thesedevices were chosen as they were readily available and Subjects were asked to attend the laboratory on four many of their delivery characteristics are known [12– or five occasions with at least 48 h between visits. The first visit was a control day with a 4.5% NaCl was chal-lenge performed to determine eligibility for the study.
Thereafter the subject performed either two dry powder Flow measurement NaCl capsule challenges (subjects 1–8) or a further wet For the Halermatic™ the subjects were required to aerosol followed by a further dry powder challenge (sub- inhale the NaCl powder at a flow rate between 50–120 L·min-1. As the design of the Halermatic™ precludesthe in-line measurement of flow at each inhalation, a Wet aerosols of 4.5% sodium chloride challenge pressure transducer (DTX Disposable Pressure Trans-ducer; Viggo-Spectromed Oxnard, CA, USA) was used The sensitivity of the subjects to a wet aerosol of to approximate flow changes. To calibrate the pressure 4.5% NaCl was measured on the control day visit. The transducer flows of 50–120 L·min-1 were generated aerosols was generated by a MistO gen EN 143a Ultra- through a rotameter (Series 2000, GEC-Elliott, Croydon, sonic Nebulizer (Timeter, PA, USA). Subjects inhaled UK) in line with the Halermatic™ device which was the aerosols at resting ventilation rates through a two- used to deliver the powder. Pressure changes were mea- way valve (No. 2700; Hans Rudolph, Kansas City, MO, sured through a side port of the Halermatic™ at each USA) connected to the nebulizer by Bennetts smooth S.D. ANDERSON ET AL.
bore tubing (Cat. No. TV 2723) 67.5 cm in length with 30 min or until the FEV1 had returned to within 5% of an internal diameter of 2.2 cm. This unit was weighed the baseline FEV1 value. Subjects 1–8, following the with the tubing, but not the valve (Sartorius, 1216 MP, completion of the second capsule challenge, received 0.5 Gottingen, Germany), before the bronchial challenge mg terbutaline sulphate, actuated into and inhaled from and after the final dose of challenge aerosol had been a Nebuhaler™ and then performed spirometry 5 min later delivered. Thus the output of the nebulizer over time and at 10 min intervals for 30 min, or until the subject was known for each subject on each occasion. The dose had returned to within 5% of the baseline FEV1 value.
of wet aerosol delivered is expressed in milligrams ofNaCl. This value was obtained by multiplying the dose of aerosol delivered in grams by 45 (i.e. 45 mg NaCl·gaerosol delivered-1).
Baseline FEV1, expressed as a percentage of predicted The protocol used to perform the challenge with 4.5% normal, and post-placebo capsule percentage predicted NaCl is described in detail by SMITH and ANDERSON , FEV1 values were expressed as mean±SD and compared although the protocol was modified so that the maxi- using an analysis of variance (ANOVA) and Student's mum dose of aerosol delivered on the control day was greater than the usual dose of 15 g. A further modifi-cation was made by measuring FEV1 in duplicate at Airway sensitivity (PD20,NaCl). Airway sensitivity was only 60 s after each challenge period. This procedure measured as the provoking dose of NaCl that caused a was followed as the maximum response usually occurs 20% fall in FEV1 (PD20,NaCl). These values were cal- within 1 min after each challenge interval.
culated by linear interpolation using the cumulative dose Subjects inhaled the challenge aerosol for 0.5 min and of NaCl causing a 20% fall in FEV1 from the pre-chal- waited 60 s before the FEV1 measurement was perform- lenge value.
ed. If there was a 20% fall in FEV1 from the baseline The geometric mean (GM)±95% confidence interval value, the challenge was stopped and the subject inclu- (95% CI) and range of values were calculated for the ded in the study. If a 20% fall was not recorded, the cha- PD20,NaCl (mg) values and the log PD20,NaCl values and llenge continued for further exposures of l, 2, 4, 8, 8 and compared using Students paired t-test for both inhaler 8 min or part thereof, or ceased when a fall in FEV1 devices and for the wet aerosol challenges. The Pearson ≥20% was recorded. The subjects were eligible for the correlation coefficient (r ) and significance values were study if they had a 20% fall in FEV1 after <22 g of wet calculated for the relationship between the 4.5% saline aerosol containing 990 mg of NaCl had been delivered.
and the first and second NaCl capsule challenge for each Following this challenge, subjects were given 0.5 mg of the two devices. The repeatability of the two NaCl terbutaline sulphate via a pressurized metered dose in- capsule challenges was calculated using the log PD20,NaCl.
haler actuated into a Nebuhaler™ (Astra Pharmaceuticals, The equation previously described  was used to Lund, Sweden).
express repeatability as fold change. The data were alsoexpressed in the manner described by BLAND and ALTMAN.
Dry powder NaCl challenge The ratio of the wet PD20,NaCl challenge:dry PD20,NaCl challenge was calculated to make a relative comparison Subjects performed two challenges with dry powder between the two devices.
NaCl. Lung function, as measured by FEV1, was record- The peak inspiratory flow rates (L·min-1) and duration ed on arrival at the laboratory, and 10 min later to estab- of the challenge (min) were calculated for the Inhala- lish its stability. The dose protocol consisted of inhaling tor™ (n=8) and the Halermatic™ (n=16) separately and 0 (empty capsule acting as a placebo) then 5 and/or 10, expressed as median and range of values.
then 20, 40, 80, 160, 160 and 160 mg NaCl. The doses Student's paired t-test, was used to compare the spon- of 40, 80 and 160 was given in multiples of either 20 taneous recovery values (n=15) at 30 and 60 min and or 40 mg capsules. Two FEV1 manoeuvres were per- the recovery values following bronchodilator at 5 and formed 60 s after the completion of each dose and the 60 min. For statistical and graphical reasons all values highest FEV1 measurement was used in calculations.
above the baseline FEV1 were considered to be 0. The FEV1 value taken after the inhalation of the 0 mgcapsule was used to calculate the percentage fall in FEV1in response to the dry NaCl. If the subject had a fall >10% in response to a single dose, then, for safety rea-sons the causative dose was repeated. The challenge was Pre-challenge lung function stopped when a 20% fall in FEV1 was measured or atotal cumulative dose of 635 mg had been given. There was no significant difference for the baseline mean±SD FEV1 values expressed as the percentage ofpredicted FEV1 between any of the test days either with- Time course of recovery of lung function following chal- in or between the two groups (table 2).
Airway sensitivity to NaCl Spontaneous recovery of FEV1 to baseline values (before any capsules were given) following the comple- Individual dose-response curves for the dry powder tion of the first capsule challenge was assessed in all NaCl are illustrated for each device in figure 1 and the subjects by performing spirometry 5 min after comple- individual values for the wet and dry PD20,NaCl chal- tion of the test, and then at 10 min intervals for at least lenge are given in table 1. The GM (95% CI) for the DRY POWDER SODIUM CHLORIDE FOR INHALATION IN ASTHMA Table 2. – Values obtained using the two different devices for inhalation of the dry powder of NaCl Subject Nos. total Peak inspiratory flow L·min-1 Duration of challenge for PD20,NaCl median time min (range) Number of capsules median (range) First dry powder NaCl baseline FEV1 % pred±SD Second dry powder NaCl baseline FEV1 % pred±SD First dry powder NaCl geometric mean PD20 (95% CI) Second dry powder NaCl geometric mean PD20 (95% CI) First wet aerosol 4.5% NaCl baseline FEV1% pred±SD Second wet aerosol 4.5% NaCl baseline FEV1 % pred±SD First wet aerosol 4.5% NaCl geometric mean PD20 (95% CI) Second wet aerosol 4.5% NaCl geometric mean PD20 (95% CI) Pearson's correlation (r ) wet versus dry Repeatability fold change 95% CI PD20: provocative dose causing a 20% fall in forced expiratory volume in one second (FEV1); % pred: percentage of predictedvalue; 95% CI: 95% confidence interval.
Cumulative dose mg Cumulative dose mg Fig. 1. – Individual dose-response curves for a) the eight subjects who inhaled from the Inhalator™ and b) the 16 asthmatics who inhaled fromthe Halermatic™. The provoking dose of dry powder NaCl causing a 20% reduction in FEV1 (PD20) in the 24 asthmatic subjects represented awide range in severity of airway responsiveness. FEV1: forced expiratory volume in one second.
PD20,NaCl for both the 4.5% saline challenge and the Oxygen saturation during challenge dry powder challenges for the two devices is given intable 2. The relationship between the values for PD20,NaCl The initial challenge value and the lowest saturation on the initial wet and dry challenges for the whole group value measured were used to calculate the fall in satu- was r =0.55, p<0.01 (fig. 2) and is given separately for ration during challenge. The Sa,O was measured in 11 the two inhalers in table 2. The relationship between of the 24 subjects during the wet NaCl aerosol chal- the values for PD20,NaCl on the initial dry challenge and lenge. The lowest Sa,O during the wet challenge was the second wet challenge for the 15 subjects who per- 95% and none of the subjects fell more than 2%. During formed two wet challenges was r =0.61, p<0.05. The ratio the first dry capsule two subjects had no Sa,O meas- of wet PD20,NaCl challenge:dry PD20,NaCl challenge was urements. Of the remaining 22 subjects, two fell by 3% 2.55 (0.14–8.87) for the Inhalator™ and 3.12 (0.4– 20.1) during challenge and one fell by 6%. The lowest Sa,O2 for the Halermatic™. These values were not signific- measured during dry NaCl capsule challenge was 92% antly different.
(recorded for the subject who fell 6%). The remaining There was no significant difference in values for 19 subjects fell less than 3% during challenge. During PD20,NaCl measured between repeated challenges either the second dry capsule challenge three of the 24 sub- for the wet or the dry aerosol (table 2). The repeatabil- jects fell 3% and the remaining 21 subjects fell less than ity expressed as fold-change is given in table 2, and ex- 3% during challenge. The lowest Sa,O recorded during pressed as a Bland and Altman plot as illustrated in the second challenge was 94% which may be consid- ered "normal" or just below. S.D. ANDERSON ET AL.
This initial batch was unsuccessful in provoking an air- way response when delivered by a Halermatic™. The second batch of dry powder had 37% of particles below 7 µm at the time of preparation and 30% at the time of use in Sydney when measured with the Halermatic™ and this was used successfully in subjects 9–24. The third batch received a year later was also a failure going from 38% at source to 13% at the time of use in Sydney.
The fourth batch had 15.8% of the mass below 7 µm and was used successfully when inhaled from the Challenge duration and number of capsules The median duration of the challenge and number of capsules used is given in table 2. Fig. 2. – Individual values obtained for the provoking dose deliv-ered in milligrams of the wet aerosol of 4.5% NaCl to induce a 20% Recovery following dry powder NaCl capsule challenge fall in forced expiratory volume in one second (wet challenge PD20)in relation to the PD20 obtained for the dry powder preparation. ▲ :subjects who inhaled from the Inhalator™; : subjects who inhaled Spontaneous recovery was analysed in 23 subjects fol- from the Halermatic™. : line of identity; : line of cor- lowing the first NaCl challenge. Subject No. 16 was not relation (r =0.55, p<0.01, n=24). The PD 20 for the dry powder was included in the analysis as she did not spontaneously significantly less compared with the wet aerosol although eight of the24 subjects required a greater dose when the dry powder was used. recover and required the administration of bronchodila-tor at 30 min. For n=23 at 30 min post-challenge the mean ±SD percentage reduction from baseline FEV1 wasstill -15±8.8% but at 60 min it was only -7±5.4% belowbaseline. That is, the FEV1 had returned spontaneous- ly to 93% of the baseline value 60 min after challenge.
Recovery after the first capsule challenge following bronchodilator was compared to spontaneous recovery in the eight subjects who used the Inhalator™ (fig. 4).
Five minutes after the bronchodilator had been given the challenge 1 - challenge 2 mean±SD percentage change from baseline FEV1 follow- ing bronchodilator was -5±5.8% compared to -22±6.5% without bronchodilator (n=8, p<0.003). At 60 min the Geometric mean PD Fig. 3. – A Bland and Altman plot relating the geometric mean for the provoking dose of NaCl causing a 20% fall in forced expiratory volume in one second (FEV1) (PD20) for the first and second chal- lenge with dry powder NaCl plotted against the difference between the log10 PD20 values for the 24 subjects who performed repeated challenge. ▲: subjects who inhaled from the Inhalator™; : subjects who inhaled from the Halermatic™; : the point of no differ-ence between the first and second challenge. The repeatability was independent of the dose. The difference in log 10 PD20 values for all but two subjects was ±0.5. Change from baseline FEV -25 Peak inspiratory flow rate (PIFR) The median values for the PIFR measured for both dry powder devices are given in table 2. PIFR exceed- ed 38 L·min-1 in all subjects.
Fig. 4. – The mean±SEM for the forced expiratory volume in onesecond (FEV1) expressed as a percentage reduction from the baselineprechallenge value in the eight subjects who spontaneously recovered Aerosol characteristics of powder preparations and after the first challenge with dry powder sodium chloride ( ) and were given 0.5 mg of terbutaline aerosol immediately after thesecond challenge ( ). The value at time 0 was the maximum For the initial powder preparation the analysis of the reduction in FEV1 recorded and the time after bronchodilator or spon- particle size, using the Halermatic™, revealed that <7% taneous recovery is shown. For seven of the eight subjects the FEV1had returned to within 6% of baseline within 5 min after taking bron- of the NaCl was in the respirable range of ≤7 µm by the chodilator. There was a significant difference in the values for FEV1 time it had reached Sydney, although at the time of pre- 5 min after bronchodilator had been administered (p<0.003). For the paration in California 19% was in the respirable range.
remaining subject recovery took 50 min.
DRY POWDER SODIUM CHLORIDE FOR INHALATION IN ASTHMA subjects who had received bronchodilator had all returned qualitative differences between the devices, as evident to baseline whereas those who recovered spontaneously from the individual dose-response curves. While there had an FEV1 compared with baseline of -6±6.8% (n=8, were some differences between the PD20,NaCl for the two devices this was more likely to have been relatedto the severity of their asthma, as their responses to thewet aerosol were similarly smaller. Furthermore, the ratio Healthy control subjects of the wet PD20,NaCl:dry PD20,NaCl was similar for bothdevices. The values observed for repeatability on the Five healthy control subjects (aged 19–22 yrs) per- Halermatic™ were somewhat better than the Inhalator™ formed an inhalational challenge using the dry powder but this may have been due to the small numbers of sub- NaCl administered from the Halermatic™ device. Four jects studied on the Inhalator™. Both devices were ade- received a dose of 620 mg and one a dose of 540 mg.
quate for the delivery of the salt although the Inhalator None of these healthy volunteers, who acted as control was easier to use because it pierced the capsules more subjects, recorded a PD20,NaCl and the maximum fall in easily. We also found that the Inhalator™ caused less FEV1 was 6.5% with the range being 0–6.5%. cough compared with the Halermatic™. This may bebecause of the higher inspiratory resistance of theInhalator™, resulting in less deposition of the powder on the back of the throat.
We do not know where in the respiratory tract the In this study we have shown that a dry powder prepa- NaCl was deposited or what percentage of the inhaled ration of NaCl, delivered from a capsule via either a dose was deposited in the lower respiratory tract. The Halermatic™ or an Inhalator™ device, can provoke air- relatively small changes in Sa,O , in most subjects, sug- way narrowing in the same asthmatic subjects who are gest that the site of deposition of the NaCl was more sensitive to the wet aerosol preparation of 4.5% NaCl.
likely to be the larger airways. Further studies with lab- Furthermore, the airway response to the dry powder had elled NaCl are required to determine the ratio of peri- good repeatability and spontaneous recovery from the pheral to central deposition of the powder in the airways challenge occurred over 60 min. With the aid of a bron- chodilator FEV1 recovered to 95% of the baseline value We have measured the size of the wet aerosol parti- in less than 10 min.
cles of the NaCl after passing through the tubing and The wet aerosol was always performed first on the valve to 3.6 µm with a geometric SD less than 1.1 .
control day because the entry criteria required that. How- We have also measured the amount of wet aerosol reach- ever, the difference in PD20,NaCl values for the first dry ing the mouth as 47% of that reaching the inspiratory challenge and either the first or the second wet chal- port of the two-way valve . On the basis of these lenge was similar, suggesting that there was no order measurements we have estimated the volume of wet aerosol reaching the lower respiratory tract to be approx- In order to evaluate the dry powder we used subjects imately 10% of the volume generated by the nebulizer who had a wide variation in their wet PD20,NaCl and . This is a value similar to that which has been mea- two different devices. Thus, the subject who was most sured for jet nebulizers . The percentage of parti- sensitive to the 4.5% NaCl wet aerosol required less cles of dry powder of NaCl less than 7 µm measured than 30 s exposure with a PD20,NaCl of 7 mg while the at the site of testing was 15.8% for the Inhalator™ and least sensitive subject required 22 min exposure and had 30% for the Halermatic™. It is possible that a higher a PD20,NaCl of 955 mg. A PD20,NaCl of less than 90 mg proportion of the dry powder aerosol entered the lower is regarded as consistent with severe bronchial respon- respiratory tract with the Inhalator™ compared with the siveness, 90–270 mg as moderate and greater than 270 Halermatic™  but we have no in vivo data on depo- mg as mild responsiveness to wet NaCl challenge .
All our asthmatic subjects displayed the expected air- For 50% of the subjects, the dose required to record way response and none of the healthy subjects respond- a PD20,NaCl was less than 100 mg when the dry pow- ed. Healthy nonasthmatic subjects do not demonstrate der was used. For one subject with very mild asthma, bronchial responsiveness to 4.5% saline and the mean±SD receiving 1,200 µg·day-1 of the aerosol corticosteroid percentage reduction from baseline FEV1 for a group budesonide, a cumulative dose of 493 mg was required, of 75 people has been previously reported as 4.6±3.1% but this was reproducible with 503 mg being required . The limited number of healthy control subjects inves- on the second challenge. This was substantially less than tigated in this study related to the limited availability the dose required by wet aerosol in the same subject.
of dry powder.
However there were three subjects who required sub- The two inhalers used were selected because they stantially more dry powder than wet aerosol. Some sub- were both commercially available. However, their char- jects showed much greater variation in their PD20,NaCl acteristics were different in the way in which the cap- on the two test days. However, the repeatability for the sules were pierced and the powder dispersed and they dry powder compared well with the repeatability for wet had differing inspiratory resistances (low for the Haler- aerosol challenge performed in the same subjects. Fur- matic™ and high for the Inhalator™). The airway res- thermore, the repeatability compares well with other ponses to dry NaCl were not compared in the same challenge tests such as histamine or methacholine [22, subjects using both devices, because only a small amount of dry NaCl was available and 12 months separated the There were no adverse experiences requiring medical two studies. However there did not appear to be any intervention with the dry powder. The Sa,O as measured S.D. ANDERSON ET AL.
by ear oximetry remained above 94% in all but one sub- of the test aerosol to the investigator. Another is the ject. Three subjects did gag with the 40 mg dose but safe disposable nature of the device and the substance.
even with this there was no significant fall in their Sa,O .
There would be considerable time saved in using dry We were not required to give bronchodilator immedi- powders compared with wet aerosol preparations in that ately at the end of challenge in any subject. One sub- the equipment used for nebulization and to determine ject was given a bronchodilator 30 min after challenge output is expensive and requires cleaning and regular on the day spontaneous recovery was being document- ed. The dry NaCl powder was well tolerated at the lower This is the first report of the airway narrowing effects doses but with the 40 mg capsule some subjects found of dry particles of sodium chloride in known asthmat- difficulty with inhaling quickly and coughed. The cough- ic subjects. The challenge with sodium chloride would ing could have reduced deposition and be the reason appear as safe as any other challenge with which we that some subjects required a much higher dose of dry have had experience, i.e. methacholine, histamine, exer- NaCl compared with the wet NaCl aerosol. Furthermore, cise and hyperventilation. Further studies are required it is possible that the dry powder provided a potent pha- to establish safety and efficacy and acceptability in larg- ryngeal stimulus contributing to the airway narrowing er groups of subjects and to compare responses with by causing reflex bronchoconstriction.
other stimuli commonly used for bronchial provocation From our studies using the liquid impinger we had testing. From a technical standpoint, long-term stabili- 40–70% recovered on the "throat" and Stage 1 (parti- ty of the dry powder of sodium chloride and achieving cles above 13 µm) This is probably the reason that many a greater proportion of substance in the respirable range patients coughed while inspiring the 40 mg capsules.
(to reduce coughing) are important issues that need to Ideally a greater percentage of the dose would have a be addressed before commercial development is con- particle size in the respirable range. Indeed the most important issue relating to this study was the reliabilityand stability of the dry powder preparations. We received Acknowledgements: The authors would like to thank
four batches of NaCl from California and only two of G. King and I. Young for their medical assistance these were used successfully in Sydney. Further stud- and J. Brannan for analysis of the results. ies are required to establish the long-term stability ofthe powder preparation before studies are performed onsensitivity and specificity of the challenge in large num- bers of subjects.
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International Environmental Modelling and Software Society (iEMSs) 2012 International Congress on Environmental Modelling and Software Managing Resources of a Limited Planet, Sixth Biennial Meeting, Leipzig, Germany R. Seppelt, A.A. Voinov, S. Lange, D. Bankamp (Eds.) Enhancing Stocks and Flows modelling to support sustainable resource management