Respiration 5/: 86-90 (1987)
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`© 1987S. Karger AG, Basel
`0025-7931/87/05 12-0086 $ 2.75/0
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`Effect on Spirometry of Distilled Water and Cromoglycate
`Solutions Nebulised by a Small Portable Ultrasonic Nebuliser
` G.B. Rhind, M.F. Sudlow!
`
`DepartmentofRespiratory Medicine, City Hospital, Edinburgh, UK
`
`
` Disodium cromoglycate-
`
`
`
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`Key Words. Asthma- Bronchial hyperreactivity-
` Spirometry - Nebulisation
`- Abstract. The airway response to inhaled ultrasonically nebulised distilled water and
`three disodium cromoglycate solutions (DSCG in distilled water, normalsaline and
`buffered saline) produced by a small portable nebuliser was determined by spirometry
`in,12 stable adult asthmatics in a double-blind trial. The mean percentagefallsin forced
`following distilled water, 5.6% following
`expiratory volumein Is (FEV;) were 13.4%
`DSCGin distilled water, 4.8% following DSCG in normalsaline, 6.9%after DSCGin
`
`buffered saline. The fall in FEV; was significantly greater (p <0.01) after distilled water
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`than after all DSCG solutions with no significant difference between the DSCG solu-
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`tions. Coughing wasalso greater during inhalation ofnebulised distilled waterthan dur-
`
`
`ing inhalation ofnebulised DSCGsolutions (p < 0.01).
`
`other variable which has been suggested as
` Introduction
`a factor in ultrasonic nebulisation bron-
`choconstriction is pH, since normal saline
` Since 1968, when ultrasonically nebu-
`(pH5.6), but not buffered saline (pH6.85),
`lised solutions were first recognised as
`causes bronchoconstriction [9]. Broncho-
`bronchoconstrictors[1], it has been shown
`constriction in response to ultrasonically
`that hypotonic[2, 3] and hypertonic (3, 4]
`nebulised distilled water is specific to pa-
`solutions can cause increased airway ob-
`tients with asthma[4, 6, 8] and can thus be
`struction. Temperature [5] and volume
`used asa test for bronchialreactivity [2, 6,
`nebulised [6], but not particle size [7] are
`8]. With the increasing use of home nebu-
`also of importance although the effect of
`lisers for asthma, this induced broncho-
`temperature has been disputed [6, 8]. An-
`constriction may be important clinically, -
`if solutions other than active bronchodila-
`tors are given by this method. Disodium
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`‘The authors would like to thank Fisons Pharma-
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`ceuticals for financial support.
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`Liquidia's Exhibit 1097
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`Spirometry following Nebulised Cromoglycate
`
`:
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`87
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`Distilled
`water
`
`OSCGin
`water
`
`OSCGin
`normat
`saline
`
`OSCG in
`buffered
`saline
`
`cromoglycate (DSCG)is marketedin a so-
`lution ofdistilled water for such use and
`this is a hypotonic solution which will be
`nebulised at
`room temperature. Since
`DSCGis effective in preventing exercise-
`induced bronchoconstriction when given
`immediately prior to exercise [10], we have
`studied the effect of distilled water and
`DSCGsolutions, ultrasonically nebulised
`by a portable nebuliser unit, on airway
`calibre.
`
`Methods
`
`Maximum
`
`fallinFEW,%
`
`
`
`AG,Bascl
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`ate
`buliser
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`water and.
`
`saline and
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`spirometry
`
`sinforced
`following
`
`DSCGin
`
`
`illed water
`
`SCG solu-
`rf than dur-
`
`
`
`
`ggested as
`
`
` tion bron-
`
`
`al saline
`
`
`(pH6.85),
`
`-Broncho-
`
`
`rasonically
`
`ific to pa-
`
`anthus be
`
` ivity (2, 6,
`
`
`ome nebu-
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`1 broncho-
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`
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`clinically,
`
`
`onchodila-
`
`Disodium
`
`We studied 12 stable asthmatic patients aged
`19-50 years (mean 33 years) whose symptoms were
`controlled on inhaled f,-agonists (12 patients), in-
`haled steroids (6 patients), inhaled DSCG (6 pa-
`tients) and inhaled ipratropium (2 patients). Two pa-
`tients also, took oral theophyllines,
`! took an oral
`p,-agonist and | patient took both oral theophylline
`and an oral B,-agonist. Oral medication was discon-
`tinued 36h before each challenge and inhaled drugs
`were withheld 6h prior to each challenge. Ourlocal
`Ethical Committee approved the study and informed
`consentwas obtained from all patients.
`Four inhalational challenges were carried out at
`_the sametime of day on 4 separate days in a double-
`blindtrial. The solutions studied were distilled water
`(pH 5.5), 10 mg/ml DSCGin distilled water (pH 5.6,
`14% of isotonicity), 10 mg/ml DSCG in normalsa-
`line (pH 5.7) and 10 mg/ml DSCGin buffered saline
`(pH 6.8). A De Vilbiss Pulmosonic nebuliser was
`- used to produce the aerosol and this delivers up to
`0.5 ml/min with a meanparticle size of 2.5 pm. Two
`millilitres of each test solution was nebulised and
`inhaled by normaltidal breathing for 4 min.
`The forced expiratory volume in 1s (FEV,) was
`measured with a water-filled spirometer {I1] before,
`immediately after the challenge, and at 2, 5, 10, 15
`~ and 20 min thereafter. The number of coughs pro-
`duced during inhalation of each nebulised solution
`were counted.
`‘Analysis of variance was determined and where a
`significant effect occurred Duncan’s multiple-range
`test was used to determine which solutions differed
`significantly.
`
`Fig. 1. Change in FEV, following ultrasonically
`nebulised solution of DSCG. 12 patients, mean
`+SEM. * p<0.01.
`
`Results
`
`The mean volume of liquid nebulised
`was 1.3+(SD) 0.2 ml with no difference
`betweenthe test solutions. The nebulisa-
`tion rate was 0.33 ml/min. Baseline FEV,
`for the ‘group was 1.5-3.6 litres (mean 2.5
`litres) andin all patients the baseline FEV
`before each challenge was greater than
`10% of maximum FEV}. Similarly, on the
`4 challenge days the minimum FEV, was
`at least 70% of maximum FEV, (range
`71-93%, mean 86%).
`The mean maximum percentagefall in
`FEV,(from baseline to the minimum post-
`challenge value)
`in the 12 patients is
`shown in figure 1. There was a signifi-
`cantly greater fall in FEV,after inhalation
`of nebulised distilled water'than after all
`DSCGsolutions (p < 0.01) and there were
`no significant differences between the
`DSCG solutions. Three patients had a
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`Rhind/Sudlow
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`BB
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` Table I. Spontaneous variability of FEV, and re-
`
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`sponse to nebulised distilled water in 12 asthmatic
`patientsnn
`Patient Age
`FEV,
`Maximum FEV,
`No.
`fallafter
` variability*
`H,0,%
`%
`er
`
`:
`
`10
`3.6
`28 (97)
`34
`t
`14
`49
`3.4 (81)
`30
`2
`17
`14.7
`1.9 (68)
`39
`3
`72
`33.3
`2.4 (77)
`27
`4
`21
`2.4
`2.1 (81)
`36
`5
`10
`3.5
`2.9 (100)
`25
`6
`10
`8.8
`29: «3.4
`(83)
`7
`35
`27.9
`50
`2.2 (55)
`8
`21
`22.2
`46
`2.5 (69)
`9
`32
`11.7
`19
`3.0(110)
`10
`20
`12.1
`28
`3.6 (84)
`I!
`23
`15.0
`32
`2.2 (50)
`12
`oo
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`.
`
`30
`
`¢A=
`~
`sui
`we
`
`
`
`A
`
`*aeK
`
`Nebulisation
`-—
`
`5
`0
`02 5
`Pre-
`nebuli- Time after nebutisation, min
`sation
`
`20
`
`25
`
`
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`Figures in parentheses are percentof predicted.
`Fig. 2, Change in FEV,with time after nebulisa-
`tion. Meanin 12 patients with asthma. @ = Distilled
`highest FEV, - towest FEV,
`
`water, A = DSCG in distilled water; = DSCG
`
`for 6 monthsprior to study
`oe
`
`
`x 100.
`in normal saline; O = DSCG in buffered saline.
`. Variability = highestFEV,
`
`
`* p<0.05, ** p< 0.01, *** p< 0,002.
`SS—_—ee
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`greater than 20% fall in FEV, after dis-
`tilled water nebulisation. One patient (pa-
`tient 5) had a fall in FEV, of 21% after
`nebulised DSCG in buffered saline. The
`baseline priorto this challenge was accept-
`able at 90% of maximum.Theindividual
`maximumfalls in FEV, are shownin table
`I with each patient’s spontaneousvariabil-
`ity in FEV, at clinic visits during the
`6-month period priorto this study.
`The mean absolute fall in FEV; at each
`time interval after the challenge was calcu-
`lated. There was, no difference immedi-
`ately after the challenge, but there was a
`significantly greaterfall after distilled wa-
`ter (comparedto all DSCGsolutions)at 2
`
`min (p <0.002), 5 minutes (p<0.05) and
`10 min (p<0.01). After 10 min there was
`no significant difference betweenthe solu-
`tions (fig. 2). However, patients 4 and 8
`had audible wheeze persisting to 30 min
`after nebulisation of distilled water and
`the FEV, remained 25 and 24% below the
`starting value, respectively. Both patients
`required treatment with inhaled bron-
`chodilator.
`The mean number of coughs per pa-
`tient during nebulisation was 2.4 for dis-
`tilled water, 0.9 for DSCG and distilled
`water, 0.3 for DSCGin normalsaline and
`0.8 for DSCG in buffered saline. The
`mean numberof coughs during water neb-
`
`
`
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`
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`89
`Spirometry following Nebulised Cromoglycate
`
`
`
`
`
`
`
`
`We conclude that nebulised DSCG in
`distilled water is safe when given via this
`portable ultrasonic nebuliser to stable
`asthmatics.
`Theoretically,
`nebulised
`DSCGideally would be given in a nor-
`motonic buffered solution, but this pro-
`duced the same response as the other
`DSCGsolutionsandin fact | patient had
`Although the output of the nebuliser
`a greater than 20% fall in FEV, after such
`was small (0.33 ml/min) we have shown
`a solution. To prevent anyfall in FEV, we
`that under conditions prevailing at home
`suggest prior therapy with a bronchodila-
`this unit can provoke bronchoconstriction
`
`tor may be a worthwhile precautionasthis
`if a hypotonic solution such as distilled
`
`has been shown to block mist broncho-
`water is used. This can produceasignifi-
`constriction [2]. Also it may be worthwhile
`
`cantfall in FEV, of up to 33% with a mean
`heating the solution to 37°C if this method
`percentagefall of 13.4%. The effect on the
`of delivery is considered in asthmatics
`—oT
`airways is reduced in the presence of
`who have marked bronchial hyperreactiv-
`6
`20
`25
`DSCGin the solution being nebulised.
`tion, min
`ity. It should also be pointed out that, as
`This could be explained by the slight in-
`the volume of liquid nebulised and in-
`crease in tonicity of DSCGin distilled wa-
`haled has been shownto be of importance
`ter comparedto distilled water alone, but
`in producing bronchoconstriction [6], we
`there is also the possibility that DSCG
`cannot comment on the use of DSCGin
`given with the waterexertsits effect phar-
`distilled water in a nebuliser with a greater
`macologically in the same waythat it pro-
`tects against exercise-induced asthma, and
`output.
`it has been suggested that a changein os-
`molarity may be importantin exercise-in-
`duced asthma [12]. DSCG has already
`been shown to protect against broncho-
`constriction produced byultrasonic nebu-
`lisation of a hypotonic solution when
`given prior to the challenge (2, 6], but has
`not been studied whengivenas part of that
`challenge. It was interesting to note that1
`patient had a 21% fall in FEV, after nebu-
`lised DSCG in buffered saline, especially
`as the baseline was within 10% maximum.
`The cause of this observation is not
`known,but the solution was nebulised at
`room temperature and it has been sug-
`gested that
`isotonic saline nebulised at
`room temperature may produce bron-
`choconstriction[13].
`
`
`heapeAReenRaatBeeranSeSeek:
`
`
`
`
`
`
`ime after nebulisa-
`hma. @ = Distilled
`‘water; = DSCG
`n buffered saline.
`2
`
`
`
`
`
`(p<0.05) and
`
`- min there was
`
`tween the solu-
`
`tients 4 and 8
`
`ting to 30 min
`
`led water and
`
`24% below the
`Both patients
`
`inhaled bron-
`
`
`
`
`
`
`
`
`
`oughs per pa-
`as 2.4 for dis-
`i anddistilled
`nal saline and
`d saline. The
`ing water neb-
`
`ulisation was significantly higher than for
`each DSCG solution (p<0.01) with no
`difference between DSCGsolutions.
`
`Discussion
`
`Nn
`
`too
`
`>
`
`wa
`
`References
`
`Cheney, F.W.; Butler,J.: The effects of ultrasoni-
`cally produced aerosols on airway resistance in
`man.Anaesthesiology 29: 1099 (1968).
`Allegra, L.; Bianco,S.: Nonspecific broncho-reac-
`tivity obtained with an ultrasonic aeroso! of dis-
`tilled water. Eur. J. resp. Dis. 61: suppl. 106, pp.
`41-49 (1980).
`Schoeffel, R.E.; Anderson, S.D.; Altounyan,
`R.E.: Bronchial hyperreactivity in response to in-
`halation of ultrasonically nebulised solutions of
`distilled water and saline. Br. med.
`J. 283:
`1285-1287 (1981).
`Malik, S.K.; Jenkins, D.E.: Alterationsin airway
`dynamics following inhalation ofultrasonic mist.
`Chest 62: 660-64 (1972).
`Lewis, R.A.; Tattersfield, A.E.: Cold-induced
`bronchoconstriction: interation with prostaglan-
`
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`

`
`
`(Abstract).
`11 McKerrow,C.B.; McDermott, M.; Gilson, J.C.:
`A spirometer for measuring the forced expiratory
`bronchoconstriction
`din-induced
`6 Anderson, S.D.; Schoeffel, R.E.; Finney, M.:
`volume with a simple calibrating device. Lancet
`
`
`Clin.Sci. 59: 12 (1980).
`Evaluation of ultrasonically nebulised solutions
`iz 149-151 (1960).
`for provocation testing in patients with asthma.
`12 Elwood, R.K.; Hogg,J.C.; Pare,
`Thorax38: 284-291 (1983).
`sponsetoosmolarchallengeinasthma(Abstract).
`7 Ruffin, R.E.; Dolovich, M.B.; Wolff, R.K.; New-
`Am.Rev.resp. Dis. 125: 61 (1982).
`house, M.T.: The effects of preferential deposi-
`13 Lewis, R.A.;Tattersfield, A.E.: Letter. Br. med.J.
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`
`
`
`
`
`_ tion ofhistamine in the humanairway. Am. Rev.
`284: 47 (1982).
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`resp. Dis. 117: 485-492 (1978).
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`
`8 Higgenbottam, Ts Stokes, T.C.; Jamieson, S.;
`Hill, L.: Bronchial reactivity in asthmatic adults
`Received: April9, 1985
`
`
`with normal spirometric values. Br. med.J, 286:
`Acceptedafterrevision:June26, 1986
`
`
`
`
`9 Lilker,E.S.:Letter.Br.med.J,284: 417(1982).
`Dr.G.B.Rhind,"
`b
`
`
`10 Davies,S.E.:Effectofdisodiumcromoglycateon
`RayneLaboratory,CityHospital,
`Pe
`Be
`exercise-induced asthma. Br. med.J. iii: 593-594
`Greenbank Drive,
`Edinburgh EH10 5SB (UK)
`
`
` (1968).
`
`
`
`
`
`
`
`1012-1014 (1983).
`
`:4
`
`¢ 5é
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`P.D.: Airway re-
`
`
`
`
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