Val ed holding chambe d ug deli e y
is dependen on b ea hing pa e n and
de ice design
Pé e Csonka
1,2
and Lau i Leh imäki
3,4
A ilia ions:
1
Cen e o Child Heal h Resea ch, Uni e si y o Tampe e and Tampe e Uni e si y Hospi al,
Tampe e, Finland.
2
Te eys alo Heal hca e Oy, Tampe e, Finland.
3
Alle gy Cen e, Tampe e Uni e si y
Hospi al, Tampe e, Finland.
4
Facul y o Medicine and Li e Sciences, Uni e si y o Tampe e, Tampe e, Finland.
Co espondence: Pé e Csonka, Te eys alo Heal hca e, Te eys alo Tampe e, Rau a ienka u 27, 33100
Tampe e, Finland. E-mail: pe e .csonka@ e eys alo.com
ABSTRACT Small child en wi h ai way obs uc ion b ea he wi h e y low idal olumes (VT) and high
espi a o y a es (RRs). These ex eme espi a o y pa e ns a ec d ug deli e y unp edic ably h ough
al ed holding chambe s (VHCs).
We compa ed in an in i o s udy he e ec i eness o wo VHCs, one small (140 mL, Op ichambe
Diamond) and one la ge (350 mL, Babyhale ) wi hou acemasks, o deli e salbu amol o il e s
posi ioned be ween he VHC mou hpieces and a b ea hing simula o . Di e en idal olumes ( om 30 mL
o 200 mL) and RRs (25·min
-1
and 50·min
-1
) we e applied h ough a b ea hing simula o .
The amoun o salbu amol deli e ed inc eased wi h inc easing VTin bo h VHCs o bo h RRs (ρ>0.87
and p<0.001 o bo h de ices a bo h a es). The e ec o RR was no as e iden , bu d ug deli e y ended
o be highe a he highe a e. D ug deli e y was signi ican ly highe h ough he Op ichambe Diamond
as compa ed wi h he Babyhale a e e y combina ion o RR and VTup o a 12- old di e ence.
We ound ma ked di e ences in salbu amol deli e y be ween he Babyhale and Op ichambe Diamond
VHCs. The deli e ed dose o salbu amol inc eased wi h inc easing VTand RR wi h bo h VHCs bu wi h
di e ences ela ed o al e dead spaces. Ins ead o conside ing all VHCs equal in clinical paedia ic
p ac ice, each de ice should be es ed in i o wi h espi a o y pa e ns ele an o small child en wi h
espi a o y di icul ies.
@ERSpublica ions
Child en wi h espi a o y p oblems a e ea ed wi h inhaled d ugs gi en ia al ed holding
chambe s (VHCs). E icacy can a y up o 12- old be ween de ices. The e ec i eness o VHCs
should be es ed in all age g oups wi h di e en espi a o y pa e ns. h p://ow.ly/2Aca30mT2Pa
Ci e his a icle as: Csonka P, Leh imäki L. Val ed holding chambe d ug deli e y is dependen on
b ea hing pa e n and de ice design. ERJ Open Res 2019; 5: 00158-2018 [h ps://doi.o g/10.1183/
23120541.00158-2018].
Copy igh ©ERS 2019. This a icle is open access and dis ibu ed unde he e ms o he C ea i e Commons A ibu ion
Non-Comme cial Licence 4.0.
Recei ed: Sep 11 2018 | Accep ed a e e ision: Oc 28 2018
h ps://doi.o g/10.1183/23120541.00158-2018 ERJ Open Res 2019; 5: 00158-2018
ORIGINAL ARTICLE
PAEDIATRIC PULMONOLOGY
In oduc ion
Recu en wheezing is mos common be o e school age compa ed wi h any o he age g oup [1].
Fu he mo e, acu e exace ba ions o as hma accoun o app oxima ely 10% o he eme gency isi s in
child en esul ing in hospi alisa ion in 20–40% o cases [2]. In young child en, inhaled b onchodila o s
and co icos e oids a e adminis e ed by p essu ised me e ed dose inhale s (pMDIs). The use o al ed
holding chambe s (VHCs) imp o es d ug deli e y and p ecludes he need o coo dina ion o ac ua ion
and inhala ion by holding he ae osol cloud o be eleased only du ing inhala ion [3, 4].
The e a e nume ous p oblems ha physicians and ca egi e s encoun e when ea ing small child en wi h
inhaled medica ion deli e ed h ough a pMDI connec ed o a VHC. The only possible inhala ion
echnique in young child en is idal b ea hing. In an s and oddle s ha e highly a iable idal olumes
(VT) and espi a o y a es (RRs). Pa icula ly in he acu e se ing du ing an as hma a ack o b ea hing
di icul y (when b onchodila o s a e mos needed) i is no possible o ins uc e y young child en on he
co ec b ea hing pa e n o op imal d ug deli e y. B ea h holding is no possible in mos child en below
he age o 3 yea s. In addi ion, he d ug deli e y is g ea ly dependen on he pMDI and VHC combina ion
used. As a consequence, he child’s clinical esponse o inhaled medica ions migh be e y di icul
o p edic .
The mos impo an b ea hing pa ame e s a ec ing he deli e ed dose o inhaled medica ions a e RR, VT,
he du y cycle (inspi a o y p opo ion o he b ea hing cycle, I/ o ), and he peak inspi a o y low a e
(PIFR) ha is de e mined by he h ee p e ious a iables. B ea hing pa e n, VT, PIFR, and es ing RR all
change wi h g ow h and de elopmen [5, 6]. VTin he i s yea s o li e, is app oxima ely 7–10 mL·kg
−1
o ideal body weigh [6]. Wi h inc easing age, RR dec eases (median b ea h·min
−1
a <1 yea is 37–44;
1–3 yea s is 25–38; 3–6 yea s is 22–26; and 6–12 yea s is 18–22 b ea h·min
−1
) [7] while VTinc eases.
Du ing b onchocons ic ion, VTdec eases and RR inc eases, compa ed wi h no mal and as hma ic
pa ien s, ha e a highe ange o a ia ion in PIFR compa ed wi h heal hy subjec s [5]. PIFR is linea ly
co ela ed wi h VT[5, 8] and d ug deli e y seems o inc ease wi h a ise in VT. P e ious s udies e alua ing
d ug deli e y by VHCs ha e mainly been done wi h inspi a o y low a es o 20–60 L·min
−1
, and only a
ew ha e used a es <10 L·min
−1
[8–11]. Howe e , low low a es a e clinically impo an , since child en
below school age can ha e inspi a o y low a es as low as 2 L·min
−1
. Also, he op imal numbe o b ea hs
equi ed o emp y he VHC depends on he child’sVT, he olume o he VHC and he al e dead space.
Gene ally, 5–10 b ea hs a e su icien pe ac ua ion [3, 12].
Each VHC has i s own unique ea u es ha a e ela ed o ma e ial, elec os a ic and ae odynamic
cha ac e is ics, olume, dead space, and al e design. The beha iou o an ae osolised d ug depends on he
VHC used [13, 14] and ce ain combina ions o pMDI and VHC may esul in d as ic di e ences in dose
ou pu [3, 10, 12, 15, 16]. In addi ion, d ug deli e y is dependen on he pa ien popula ion unde
in es iga ion [17]. Inhaled d ug deli e y s udies should e alua e each VHC wi h he pa icula a ge
popula ion’s b ea hing pa e n du ing no mal and obs uc i e condi ions.
The e is a ple ho a o VHCs on he ma ke wi h di e en ma e ial, design, olume, and o e all
cha ac e is ics. A signi ican p opo ion o published s udies e alua ing and compa ing he e icacy o
VHCs is unded by hei manu ac u e s, causing a po en ial bias. In addi ion, only a hand ul o s udies
ha e add essed he issue o he b ea hing pa e ns o small child en especially in obs uc i e condi ions. In
many coun ies, he mos widely used VHC is he Babyhale (BH) bo h in heal hca e uni s and a home.
BH also ep esen s a la ge- olume VHC model ha has been used o a numbe o yea s in he acu e ca e
o child en. In con as , he Op ichambe Diamond (OD) ep esen s a new ype o VHC made o
nonconduc ing plas ic wi h a ela i ely small al e dead space and small o e all olume.
We used an in i o se up wi h a il e in e posed be ween he VHC and b ea hing simula o . This allows
mul iple measu emen s o be pe o med ep oducibly minimising con ounding ac o s and ocussing on
hose pa ame e s ha a e ela ed speci ically o he VHCs. Face masks we e excluded om his s udy o
he same eason.
The main aims o his s udy we e o 1) assess whe he he e a e clinically signi ican ad an ages o a newe
and smalle ype o VHC compa ed wi h an olde and la ge VHC and 2) o e alua e he e ec s o VTand
RR on d ug deli e y om a pMDI using VTand RRs ha a e ele an o small child en wi h espi a o y
di icul ies.
Ma e ials and me hods
De ice se up
Deli e y o salbu amol sul a e gene a ed by a pMDI (Ven oline E ohale 1 mg·mL
−1
, Glaxo Wellcome
P oduc ion, E eux, F ance) was measu ed h ough a small olume (140 mL OD, Philips Respi onics, UK)
h ps://doi.o g/10.1183/23120541.00158-2018 2
PAEDIATRIC PULMONOLOGY | P. CSONKA AND L. LEHTIMÄKI
and a la ge- olume (350 mL BH, GlaxoSmi hKline, USA) plas ic VHC. Th ee sepa a e de ices om
di e en manu ac u ing lo s we e used o bo h VHCs.
P io o measu emen s all he VHC componen s we e imme sed in lukewa m wa e wi h de e gen (Fai y
Liquid; P oc o & Gamble, Ha oga e, UK), insed unde unning ap wa e , and le o ai d y e ically.
A il e (PARI Respi a o y Equipmen , Inc., USA) was placed in a low-dead-space (10 mL) il e holde
and connec ed be ween he VHC mou h piece and he b ea hing simula o (Sinus B ea hing Simula o ;
PARI, S a nbe g, Ge many) ( igu e 1). The simula o p oduced al e na ing inspi a ions and expi a ions
wi h sinusoidal wa e and a du y cycle (inspi a o y p opo ion o he b ea hing cycle) o 0.5. The accu acy
o he b ea hing simula o was alida ed by a Fluke VT305 Gas Flow Analyze (Fluke Biomedical, USA).
Measu emen p o ocols
We used wo di e en RRs (25 min
−1
and 50 min
−1
) and i e di e en VT(30 mL, 50 mL, 100 mL,
150 mL and 200 mL). The co esponding minu e en ila ions wi h mean and peak inspi a o y lows a
each VTand RR a e p esen ed in able 1. A each combina ion o RR and VT, Ven olin was ac ua ed and
salbu amol ou pu was measu ed on h ee eplica ions using each o h ee sepa a e de ices o bo h BH
and OD. Thus, nine measu emen s o salbu amol ou pu a each combina ion o RR and VTa e used in
he esul s.
Be o e each measu emen sequence, pMDIs we e p imed by ac ua ing hose i e imes o was e. Be o e
e e y ac ua ion he pMDI was shaken igo ously i e imes. The pMDI was hen inse ed in o he VHC
and ac ua ed once immedia ely a he s a o inhala ion. Salbu amol was le o accumula e in o he il e
o eigh b ea hing cycles. The il e s we e sealed un il analysis wi h Pa a ilm M (Bemis Company, Inc.,
Oshkosh, WI, USA).
Fil e analysis
D ug pa icles deposi ed on he il e s a each measu emen p o ocol we e eco e ed and analysed by
high-pe o mance liquid ch oma og aphy (HPLC) ca ied ou by Emmace Consul ing AB (Lund, Sweden).
The HPLC me hod was based on an in e nal s anda d me hodology and he limi o quan i a ion (LOQ)
was de e mined as he peak heigh co esponding o 10 imes he noise le el. The LOQ was 2 µg.
FIGURE 1 Tes ig. The il e was
placed in a il e holde and
connec ed be ween he al ed
holding chambe mou h piece and
he b ea hing simula o .
TABLE 1 Measu emen p o ocols used and co esponding mean and peak inspi a o y lows
VTmL RR min
−1
Minu e en ila ion
L·min
−1
Mean inspi a o y
low L·min
−1
Peak inspi a o y
low L·min
−1
30 25 0.75 1.5 2.4
50 1.5 3.0 4.7
50 25 1.25 2.5 3.9
50 2.5 5.0 7.9
100 25 2.5 5.0 7.9
50 5.0 10.0 15.7
150 25 3.75 7.5 11.8
50 7.5 15.0 23.6
200 25 5.0 10.0 15.7
50 10.0 20.0 31.4
VT: idal olume; RR: espi a o y a e.
h ps://doi.o g/10.1183/23120541.00158-2018 3
PAEDIATRIC PULMONOLOGY | P. CSONKA AND L. LEHTIMÄKI
The HPLC sys em (Agilen 1100) was i ed wi h he app op ia e column (Symme y (Wa e s), C18, 5 µm,
50×3.9 mm
2
). B acke ing s anda ds we e made up and un, and he accu acy o he s anda ds was checked.
S anda ds we e injec ed h ough he un a leas six imes. The pe cen age ela i e s anda d de ia ion o
b acke ing s anda ds was <2% h oughou he un wi h excellen linea i y (y=0.0021x, R
2
=0.9998).
S a is ics
No o mal sample size calcula ion was pe o med. On he basis o p e ious s udies, i was an icipa ed ha
nine measu emen s o each se ing (al oge he 20 di e en combina ions) would allow he de ec ion o
possible signi ican di e ences. The da a we e no assumed o be no mally dis ibu ed. In i o il e dose
alues a e epo ed as means, medians and minimum and maximum alues. To es o he di e ence in
in i o il e dose be ween he VHCs o be ween di e en RRs, we used he Mann–Whi ney U- es .
To assess he co ela ion be ween VTand in i o il e dose we used he Spea man ank co ela ion.
The so wa e IBM SPSS S a is ics o Windows, e sion 24 (IBM Co p, A monk, NY, USA) was used o
he da a analysis.
Resul s
The e ec o idal olume on d ug deli e y
The e was a s ong and s a is ically signi ican co ela ion be ween VTand in i o il e dose o salbu amol
wi h bo h VHCs a bo h RRs ( igu es 2 and 3). The amoun o salbu amol a ailable o inhala ion
inc eased almos linea ly wi h VT. Fo BH (VHC olume 350 mL) he Spea man ank co ela ion
coe icien s we e 0.944 (p<0.001) and 0.965 (p<0.001) a RRs o 25·min
−1
and 50·min
−1
espec i ely. Fo
OD (VHC olume 140 mL) he Spea man ank co ela ion coe icien s we e 0.893 (p<0.001) a bo h RRs
(25 min
−1
and 50 min
−1
).
The e ec o RR on d ug deli e y
The median dose o salbu amol eco e ed was signi ican ly lowe a a RR o 25 min
−1
compa ed wi h a RR
o 50 min
−1
excep o OD a a VTo 30 mL and 200 mL and o BH a a VTo 50 mL. The lowes
median amoun o d ug a ailable o inhala ion was 1.5 µg o BH wi h he b ea hing pa e n o RR a
25 min
−1
and VTo 30 mL. The highes median amoun o d ug a ailable o inhala ion was 57.7 µg o
OD wi h a RR o 50 min
−1
and VTo 200 mL. Bo h VHCs showed a 2–3- old ange di e ence be ween
he minimum and maximum dose ou pu ( able 2).
Dose ou pu di e ence be ween VHCs
Wi h a RR o 25 min
−1
and he lowes VTo 30 mL he e was an app oxima ely 12- old di e ence in
median salbu amol doses be ween BH and OD (1.5 µg e sus 18.5 µg; p=0.002). Wi h a highe VT he
di e ence be ween VHCs was smalle bu emained signi ican a all VT alues and bo h RRs ( able 2).
Discussion
In his s udy we ha e demons a ed in a simula ion model ha b ea hing pa e n has a signi ican e ec on
β
2
-agonis d ug deli e y om VHCs. Al hough he amoun o salbu amol eco e ed om he il e
FIGURE 2 In i o il e dose o
salbu amol wi h la ge al ed holding
chambe , Babyhale ( olume 350 mL).
Respi a o y a e o 25 min
−1
and
50 min
−1
and idal olume om 30
o 200 mL. Rho: Spea man’s ank
co ela ion coe icien .
80
25; ho 0.944, p<0.001
Respi a o y a e b ea hs pe min
100
60
40
20
0
In i o fil e dose o salbu amol µg
Tidal olume mL
30 50 100 150 200
50; ho 0.965, p<0.001
h ps://doi.o g/10.1183/23120541.00158-2018 4
PAEDIATRIC PULMONOLOGY | P. CSONKA AND L. LEHTIMÄKI
inc eased wi h RRs and VT alues in bo h VHCs, he e was a ma ked di e ence be ween he wo de ices
in es iga ed. Compa ed wi h OD, he salbu amol ou pu o BH was signi ican ly lowe wi h all b ea hing
pa e ns. When BH was used a a VTo 30 mL and a RR o 25·min
−1
he salbu amol amoun in he il e
was p ac ically ze o. The e was a 2 o 12- old di e ence o deli e ed dose be ween BH and OD, a ou ing
OD wi h e e y b ea hing a angemen .
TABLE 2 In i o il e dose o salbu amol eco e ed om he il e wi h espi a o y a e (RR) o
25·min
−1
and 50·min
−1
and di e en idal olume (VT)
BH
OD
BH
OD
0.0+
13.7
2.4
14.5
3.1
13.4
5.7
21.1
25
50
BH
OD
BH
OD
25
50
BH
OD
BH
OD
25
50
BH
OD
BH
OD
25
50
BH
OD
BH
OD
25
50
30
VHCRR min–1
VT mL
50
100
150
200
8.8
24.3
11.6
29.4
15.4
23.2
19.8
41.1
15.7
33.7
27.7
32.1
2.5
32.3
5.5
28.3
10.2
24.1
9.5
34.9
16.2
34.2
18.4
40.9
21.9
38.2
32.1
52.3
25.7
49.2
38.5
94.2
1.3§
19.7
3.8
19.3
5.5
19.6
7.6
29.7
11.2
28.7
15.2
35.2
17.9
32.1
27.5
46.0
21.6
42.8
34.2
46.9
1.5§
18.5
In i o il e dose o salbu amol µg
Minimum Maximum Mean Median
3.5
17.8
4.4
19.5
7.6
29.8
9.6
27.9
15.4
35.0
17.6
33.7
29.2
46.3
23.3
41.6
33.7
57.7
0.004*
p- alue¶
0.818
0.088
0.002*
0.041*
0.041*
0.004*
0.002*
<0.001*
0.113
0.002*
p- alue#
0.002*
<0.001*
0.002*
0.002*
0.002*
0.002*
0.002*
<0.001*
0.004*
Compa ing wo al ed holding chambe (VHCs): Babyhale (BH) and Op ichambe Diamond (OD).
#
: be ween BH and OD. Mann–Whi ney U- es ;
¶
: RR 25 min
−1
and 50 min
−1
o he same VHC wi h he
same VT, Mann–Whi ney U- es ;
+
: esul is below limi o quan i ica ion (LOQ) and de ec ion (LOD);
§
: esul
is below LOQ bu abo e LOD. *: p<0.05.
FIGURE 3 In i o il e dose o
salbu amol wi h small al ed holding
chambe , Op ichambe Diamond
( olume 140 mL). Respi a o y a e o
25 min
−1
and 50 min
−1
and idal
olume om 30 o 200 mL. Rho:
Spea man’s ank co ela ion coe icien .
80
25; ho 0.873, p<0.001
Respi a o y a e b ea hs pe min
100
60
40
*
20
0
In i o fil e dose o salbu amol µg
Tidal olume mL
30 50 100 150 200
50; ho 0.873, p<0.001
h ps://doi.o g/10.1183/23120541.00158-2018 5
PAEDIATRIC PULMONOLOGY | P. CSONKA AND L. LEHTIMÄKI

Since each age g oup has i s own b ea hing pa e n (and he b ea hing pa e n is also di e en i he child
has b onchial obs uc ion) i is essen ial o e alua e d ug deli e y o each a ge g oup. Ou s udy gi es
impo an in o ma ion wi h clinical implica ions abou a pa ien g oup ha is challenging o ea .
Child en below school age ha e e y low espi a o y low a es compa ed wi h olde child en and adul s,
al hough in some speci ic condi ions child en migh ha e highe VT alues han p e iously hough [18].
We used espi a o y pa e ns ha ep esen child en younge han 7 yea s [5–7]. Fo example, wi h a RR
o 25 min
−1
and a VTo 100 mL, minu e en ila ion is as low as 2.5 L·min
−1
and sinusoidal app oxima ion
o he b ea hing p o ile gi es es ima es o he mean inspi a o y low a e o 5.0 L·min
−1
and PIFR o
7.9 L·min
−1
. P e ious publica ions ha e mainly ocussed on VT alues >150 mL and low a es o
20–60 L·min
−1
. Inspi a o y low a es <10 L·min
−1
we e only used in some s udies [8, 10, 11].
By age, minu e en ila ion is inc easing due o o e all g ow h and de elopmen (inc eased heigh , lung
olume, and al eola su ace a ea). Howe e , he inc ease in V
is no ully e oked by simul aneous
dec eases in RR. The e o e, i is likely ha in olde child en, he es ing idal b ea hing leads o be e
deposi ion h ough a VHC compa ed wi h in an s and oddle s. As he VTand RR ises, he ae osol
speed inc eases and he e is less ime o he pa icles o p ecipi a e inside he VHC. P e ious s udies
also desc ibed inhala ion olume and low dependence o d ug deli e y h ough VHCs [8, 19, 20–22].
CHAVEZ e al. [11] ound ha g adually inc easing he VT om 36 o 290 mL, he il e dose o albu e ol
inc eased in a loga i hmic ashion wi h bo h RRs o 12 and 24 L·min
−1
.MITCHELL e al. [10] obse ed
ma ked di e ences on he e ec o b ea hing pa e ns be ween h ee VHC designs (Space Chambe ,
Ven -170 and Child Ae oChambe ). Fo example, wi h a VTo 50 mL and a RR o 30 min
−1
,oneo he
VHCs yielded unde ec able le els o salbu amol compa ed wi h a 37-µg il e dose om ano he de ice.
In ou measu emen s, o collec he d ug deposi ed on he il e , we used eigh b ea hing cycles. In some
s udies i was shown ha e en wo cycles was su icien o eliable collec ion. Howe e , we wan ed o
make su e ha he VHC was emp ied e en using b ea hing pa e ns o child en unde 2 yea s o age wi h
alowVT. We used a I/ o o 0.5. The I/ o is independen o age and a ies be ween 0.3 and 0.5 [5].
Since all measu emen s we e done wi h he same du y cycle, his pa ame e does no a ec he obse ed
di e ence be ween de ices.
To minimise he e ec o s a ic cha ge all VHCs we e p ewashed wi h de e gen and ai d ied be o e use
[3, 19, 23, 24]. Despi e s anda dised and well-con olled condi ions, we ound a ma ked di e ence in he
pe o mance o he wo de ices used. VHCs on he ma ke di e in olume, shape, ma e ial, al e
mechanism and o e all design, all o which can in luence he ae osol dis ibu ion, p ecipi a ion pa e n,
and d ug deli e y in an unp edic able ashion [22, 25]. Fo example, i has been specula ed ha in a la ge
olume VHC, ae osol concen a ion and pa icle impac ion is less han in smalle olume VHCs, which
esul s in lowe inhaled doses a a small VTbu highe doses when he VHC can be emp ied as e wi h a
la ge VT. The ela i ely la ge dead space in he BH (40 mL) and subop imal al e unc ion can pa ly
explain he low VHC ou pu a a small VT[12, 21, 22]. I is no en i ely clea why BH pe o med poo ly
compa ed wi h OD.
A ecen me a-analysis concluded ha VHCs a e as e ec i e as nebulise s in elie ing acu e
b onchocons ic ion wi h b onchodila o s [26]. Howe e , his e iew did no include child en unde he
age o 2 yea s wi h a low VT. In addi ion, wo o he h ee s udies using BH a ou ed nebulise s in con as
wi h he o e all conclusion o he e iew. The esul s o such me a-analyses canno be gene alised o
conside all VHCs as equal o small child en in he need o acu e inhaled as hma medica ion. Hence,
di e en VHCs should no be conside ed o be in e changeable [27].
The dose esponse o β
2
-agonis s is ela i ely shallow [28, 29]. In s able as hma, ha ing a lowe espi able
salbu amol dose a ailable may ha e li le consequences. Howe e , in acu e se ings he obse ed deg ee o
d ug deli e y di e ences may ha e se ious consequences. This magni ude o pe o mance a iabili y
implies he po en ial o clinically ele an di e ences when salbu amol and o he inhaled medica ion a e
adminis e ed ia VHCs. One migh a gue ha by inc easing he adminis e ed doses one could ob ain he
desi ed he apeu ic e ec . Howe e , inc easing he dose will no necessa ily inc ease he deli e ed dose
linea ly. In addi ion, his app oach is no cos -e ec i e and may inc ease he isk o side e ec s. Fo his
eason, i is a high p io i y o es each VHC in he in ended a ge popula ion wi h each ype o pMDI.
We used RRs and VT alues ep esen ing small child en in need o acu e inhaled medica ions as he a ge
popula ion. The pa ame e s we e o mimic a eal-li e se ing bu in a well-con olled manne . Ideally, d ug
deli e y should be quan i ied h ough he VHC as he pa ien would ac ually b ea he. In i o s udies a e
indispensable; ne e heless in i o measu emen s p o ide ep oducibili y when e alua ing he e ec o
idal b ea hing, low, and when compa ing di e en de ices.
Ou me hodology was limi ed o measu ing in i o o al dose deli e y. Co ela ion be ween in i o and
in i o da a and clinically ele an he apeu ic e ec s is di icul o p edic . VHC ou pu gene ally
h ps://doi.o g/10.1183/23120541.00158-2018 6
PAEDIATRIC PULMONOLOGY | P. CSONKA AND L. LEHTIMÄKI
inc eases wi h an inc ease in inhala ion olume and low [8] and eaches a pla eau a a ound 30 L·min
−1
,
depending on VHC dimensions [9]. While lung dose also inc eases wi h VT, a some poin he accele a ed
inspi a o y low can e en ually ha e a nega i e e ec on lung dose [21]. We did no e alua e he amoun
o d ug ha po en ially would ha e impac ed on he o al ca i y, pha ynx and uppe ai ways. None heless,
i could be specula ed ha wi h he lows we used he pla eau o VHC ou pu and in i o lung deposi ion
was no an issue. The he apeu ic amoun o d ug eaching he lowe ai ways is p obably e en smalle
han de ec ed on he il e s. Fo his eason, he di e ences in de ices and hei capaci y o d ug deli e y
may be e en mo e signi ican .
We used a espi a o y simula o ha p oduced a sinusoidal o m o espi a o y cycle. Al hough VT alues
and RRs in ou s udy we e compa able wi h eal-li e se ings, peak inspi a o y low p obably di e s om
eal b ea hing cycles whe e inspi a o y p opo ion and cu e shape di e om an expe imen al sinusoidal
pa e n. Howe e , he e is conside able a ia ion in espi a o y pa e ns be ween indi iduals especially
du ing an acu e espi a o y dis ess and e en a ia ion be ween espi a o y cycles in he same indi idual.
The e o e, simula ed models can ne e mimic eal-li e b ea hing pa e ns o he smalles de ail.
Pa o he a ia ion in ou esul s may be due o he unc ion o he pMDI i sel (Ven olin E ohale ) and
HPLC analysis me hod o he d ug deli e y. Howe e , hese ac o s a ec each espi a o y pa e n and
bo h VHCs es ed simila ly and canno explain he de ec ed di e ences in d ug deli e y be ween di e en
b ea hing pa e ns and de ices.
Conclusions
In ou inancially independen in i o s udy, we ound a ma ked di e ence in salbu amol deli e y
be ween he wo VHCs s udied (BH and OD). The deli e ed il e dose o bo h VHCs inc eased wi h
inc easing VTand RR. BH pe o med especially poo ly wi h a VT<150 mL. In small child en wi h as hma
exace ba ion ha ing a e y low VT, he e migh be close o ze o amoun o he d ug a ailable o
inhala ion. When aining physicians and ca egi e s, he e should be mo e emphasis on how b ea hing
pa e ns a ec d ug deli e y and e en ually he success o ea men when using VHCs in small child en.
Ins ead o conside ing all VHCs as equal, all combina ions o pMDI+VHC should be sys ema ically es ed
in o de o es ablish he mos e ec i e and eliable combina ions o be licensed o clinical p ac ice.
Acknowledgemen s: We would like o hank Jan S edmy (Paedia ic Alle gology, Child en’s Hospi al Falun, Dala na,
Sweden) o his aluable collabo a ion and Mikael Csonka (Uni e si y o Tampe e, Finland) o his p ac ical help.
Con lic o in e es : P. Csonka epo s pe sonal ees om The moFishe , ALK-Abello and O ionPha ma, ou side he
submi ed wo k. L. Leh imäki epo s pe sonal ees om As aZeneca, Boeh inge Ingelheim, Chiesi, GSK,
Mundipha ma, No a is, O ionPha ma, Te a and ALK, ou side he submi ed wo k.
Suppo s a emen : This s udy was suppo ed by he Founda ion o he Finnish An i-Tube culosis Associa ion, Resea ch
Founda ion o he Pulmona y Disease, Tampe e Tube culosis Founda ion, and Väinö and Laina Ki i Founda ion.
Funding in o ma ion o his a icle has been deposi ed wi h he C oss e Funde Regis y.
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