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\begin{document}

\title{Homemade valved holding chambers for children with airway
hyperresponsiveness}



\author[1]{Kesanee Chaicoming}%
\author[1]{Aroonwan Preutthipan}%
\author[1]{Anusorn Adelekkittikun}%
\author[1]{Malinee Nugboon}%
\affil[1]{Mahidol University Faculty of Medicine Ramathibodi Hospital}%


\vspace{-1em}



  
  \date{June 17, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Background: During COVID-19 pandemic, a metered-dose inhaler (MDI) with
a valved holding chamber (VHC) is a preferred route of bronchodilator
delivery. We have developed a new homemade VHC, made of a paper coffee
cup and a drinking water bottle. This study was conducted to compare the
bronchodilator response in children with airway hyperresponsiveness
after the use of our homemade VHC and that of a standard commercial one.
Methods: In a randomized, two-period, two-sequence crossover design, we
recruited 20 children, aged 6-15 years, who had greater than 12\%
increase in FEV1 after inhaled salbutamol. They were randomized into
Group A and B. Group A used our VHC on the first day and Aerochamber\selectlanguage{ngerman}® on
the second day. Group B used the same VHCs but in alternate sequence.
Spirometries were performed before and after 400 microgram of salbutamol
MDI was administered via those VHCs. Results: Baseline demographic data
and spirometric values did not have statistically significant
differences between group A and B and between the first and second day
(P \textgreater{} 0.05). After giving salbutamol MDI, both VHCs produced
significant increases in FVC, FEV1 and FEF25-75\% (P \textless{} 0.005).
The improvement in FEV1 did not significantly differ between our
homemade VHC and Aerochamber® (P \textgreater{} 0.05). Conclusion: Our
homemade VHC is effective for an MDI bronchodilator delivery. Since it
is very cheap and easy to make, it may be used as a disposable device to
minimize airborne transmission especially when commercial VHC are not
available.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{KEYWORDS:}

asthma, children, homemade, metered dose inhaler, spacer, valved holding
chamber

\textbf{1. Introduction}

COVID-19 pandemic is the most serious global health crisis in this
century which impacts people around the world, like the World War III.
COVID-19 virus is primarily transmitted between people through
respiratory droplets and contact routes. Recent evidence shows that this
virus can also spread via airborne
transmission.\textsuperscript{1}Therefore nebulization which generates
aerosols should be prohibited because of its potential to generate a
high volume of respiratory aerosols that may be propelled over a longer
distance. It is safest to minimize nebulized treatments in confirmed or
suspected COVID-19 patients. For this reason if a bronchodilator is
required, a metered dose inhaler (MDI) with a spacer or valved holding
chamber (VHC) is preferred.\textsuperscript{2,3}

Spacers and VHCs were developed to eliminate the need for co-ordination
of MDI actuation with inspiration and decreases oropharyngeal
deposition, which also decrease potential side effects of inhaled
corticosteroids such as candidiasis and
dysphonia.\textsuperscript{4}Although the term ``spacer'' and ``VHC''
are frequently used interchangeably but they are not exactly the same.
VHCs are special spacers manufactured with one-way valves, which
regulate inspiratory flow and prevent exhaled gas with moisture into the
spacer. Additional advantages of VHC over spacers include avoidance of
leaking of the aerosol from the spacer, prevention of dilution of the
aerosolized drug in the spacer, and elimination of the cold-Freon
effect.\textsuperscript{5}

In children with severe asthma exacerbations administration of
bronchodilators by MDI with VHCs and face masks was found to be more
effective than by nebulizers.\textsuperscript{6} When a pediatric
hospital implemented the conversion from small volume nebulizers to MDIs
with VHCs to administer beta-agonists in the treatment of acute asthma
exacerbations in children at the emergency room and inpatient wards, the
number of asthma admissions did not change and the number of
re-attendances for unresolved asthma symptoms within 72 hours
decreased.\textsuperscript{7} Although a number of studies showed that
the efficacy of non-valved spacers were comparable to that of
VHCs,\textsuperscript{8} many experts still recommend using VHCs to
deliver bronchodilators from MDIs.\textsuperscript{2,9-11}

Due to high cost, lack of reimbursement and availability of commercial
VHCs, a variety of homemade spacers have been implemented with the use
of plastic cold-drink bottles, plastic mineral water bottles,
polystyrene cups, plastic zip-up bags, cardboard tubes, empty plastic
saline solution bottles and paper spacers.\textsuperscript{12} Their
efficacies have been tested and demonstrated the improvements in
symptoms or lung function of patients with asthma. The degree of
improvement did not differ significantly when comparing those homemade
spacers with nebulizers or commercial
VHCs.\textsuperscript{12}Unfortunately, none of these homemade spacers
have combined with one-way valves.

Our team have developed a new homemade VHC using a clear drinking water
bottle and a paper coffee cup which are common household waste products.
The water bottle acts like a chamber while the paper cup acts as a
facemask. On the cup we made two one-way valves using pieces of plastic
cut from a grocery shopping bag. Since our VHC costs less than one
dollar, it is a perfect substitute for a standard commercial VHC and can
be easily disposed of.

The aim of this study was to compare the bronchodilator response in
children with airway hyperresponsiveness when we used salbutamol MDI
attached to our homemade VHC as against the response obtained when
salbutamol MDI was attached to a standard commercial VHC.



\textbf{2. METHODS}

\textbf{2.1. How to make a homemade valved holding chamber (VHC)}

Prepare the following items: a paper coffee cup (200 mL in volume,
bottom diameter 50 mm, brim diameter 70 mm), a drinking water bottle
(350 mL in volume, bottom diameter 60 mm, orifice diameter 25 mm), a
grocery plastic bag, a ruler, a paper cutter and a sellotape. Draw a
small 1x1 cm square 2-3 cm below the brim of the cup and another one at
the bottom of the cup. Make two holes by cutting along the two squares.
From the grocery plastic bag cut two pieces of flap slightly larger than
the holes. Outside the cup tape one piece over the hole near the edge of
the cup. This will serve as the exhalation valve. Inside the cup tape
the second piece over the bottom hole to create the inhalation valve.
The first flap will open when breathing out while the second one opens
when breathing in. Make a slit of 1 cm down the cup's edge and place it
tightly over the nose. Breathe in and out to test the valves. Soak the
water bottle in detergent (dishwashing liquid) to avoid electrostatic
and leave to dry. Cut the bottom of the water bottle to create a 15 cm
long chamber and place it tightly over the cup. Unscrew the bottle cap
and place the MDI over it and use it as a VHC. The homemade VHC that is
ready to use is shown in Figure 1. Watch the video clip how to make the
VHC at https://youtu.be/V2NmwzmRQvk.

\textbf{2.2. Study populations}

We recruited children, aged 6-15 years, who performed spirometries at
the Pediatric Chest Outpatient Clinic at Ramathibodi Hospital, Bangkok,
Thailand, who showed an increase of 12\% or more in forced expiratory
volume in 1 second (FEV\textsubscript{1}) following administration of
400 microgram of salbutamol MDI. We excluded the children, who did not
pass the acceptable and reproducible criteria of spirometric forced
expiratory maneuvers,\textsuperscript{13} or who has had an acute asthma
exacerbation during the preceding 6 weeks, or whose breathing effort was
not strong enough to see the movement of the exhalation valve. All
parents or guardians of the children provided their informed consent
prior to enrollment in the study. The study was approved by the
Committee on Human Rights Related to Research Involving Human Subjects,
Faculty of Medicine, Ramathibodi Hospital, Mahidol University. No.
MURA2016/260.

\textbf{2.3. Study design}

The study was conducted as a randomized, two-period, two-sequence
crossover design. The two period was separated by 24-hour washout
period. Children were randomized into two groups, A and B. Group A used
the homemade VHC on the first day and Aerochamber Plus
Flow-Vu\selectlanguage{ngerman}\textsuperscript{®} with medium mask for children aged 1-5 years
(Trudell Medical International, London, Ontario, Canada) on the second
day. Group B used Aerochamber\textsuperscript{®} on the first day and
the new VHC on the second day. The diagram of our study design is shown
in Figure 2.

Demographic data of the recruited children were recorded. We informed
all recruited children to stop using salbutamol and other short acting
bronchodilators for at least 6 hours, and to stop using the long acting
bronchodilators for at least 24 hours prior to performing spirometries.
Inhaled corticosteroids and leukotriene antagonists were not stopped.

\textbf{2.4. Spirometry and administration of salbutamol}

Spirometry (Viasys Healthcare Flowscreen Spirometer, California, United
States) was performed with the child in standing position and wearing a
nose clip. All performances fulfilled the criteria for acceptability and
reproducibility of the American Thoracic Society and the European
Respiratory Society.\textsuperscript{13} We used the reference equations
proposed by Polgar \& Promadhat\textsuperscript{14} to calculate percent
predicted FEV\textsubscript{1}. Each child performed spirometry at
baseline prior to receiving 4 puffs of salbutamol MDI
(Ventolin\textsuperscript{®}, 100 microgram/puff, GlaxoSmithKline,
Boronia, Australia).

For the administration of salbutamol, children were told to breathe at
tidal volume for 10 breaths after each puff. The MDI was shaken between
each dose. Repeat doses were delivered 30 seconds after the previous
one. Four puffs were delivered to achieve 400 microgram of salbutamol. A
good seal between the child's face and a paper cup of the homemade VHC
or a face mask of Aerochamber\textsuperscript{®} was ensured by seeing
the movement of exhalation valve or Flow-Vu indicator respectively.
Post-bronchodilator spirometry was carried out in the same manner as
baseline spirometry 15 minutes after salbutamol administration. The
technician who performed spirometry did not know the type of VHC being
used.

\textbf{2.5. Statistical analysis}

Continuous variables are presented as mean \emph{+} SD. Categorical
variables are presented as percentage. The comparisons between the
demographic data of Group A \emph{vs.} B, spirometric parameters
measured before \emph{vs.} after bronchodilator inhalation, spirometric
parameters measured on the first \emph{vs.} the second days, and the
percent increase in FEV\textsubscript{1} above baseline when using the
homemade VHC \emph{vs.} that of Aerochamber\textsuperscript{®} were
conducted using the paired t-test or independent t-test, or chi-square
independence test, as appropriate. All analyses were conducted by using
SPSS for Windows version 18.0. A \emph{P} value of \textless{} 0.05 was
considered statistically significant.



\textbf{3. Results}

Twenty children met the inclusion criteria. None were excluded.
Therefore 20 children were randomized into two groups; 10 in Group A and
10 in Group B. Demographic characteristics and baseline spirometric
parameters is shown in Table 1. The youngest child was 6 years old.

The demographic data and the absolute spirometric values at baseline on
the first day and the second day did not have statistical significance
between Group A and Group B. In addition, there were no significant
differences between baseline spirometric indices (FVC,
FEV\textsubscript{1}, FEF\textsubscript{25-75\%}) of the first day and
the second day suggesting that the one-day washout period was
sufficient. Since the carryover effect was not present, we used the
spirometric data of Group A and B obtained in the two study days to
determine the magnitude of the change in FVC, FEV\textsubscript{1} and
FEF\textsubscript{25-75\%} comparing between the two VHCs as shown in
Table 2.

Both VHCs produced significantly increases in FVC,
FEV\textsubscript{1}and FEF\textsubscript{25-75\%} after giving
bronchodilator (paired t-test, \emph{P} \textless{} 0.005). Percent
increases in all parameters did not show statistically differences
between the two VHCs (independent t-test, \emph{P} \textgreater{} 0.05).
The proportion of children who had a positive post bronchodilator
response (a cutoff point\emph{\textgreater{}} 12\%)\textsuperscript{13}
with the use of the homemade VHC was similar to that of those who used
Aerochamber\textsuperscript{®} (6/20 vs. 6/20, chi-square independence
test, \emph{P} = 1.0). In addition, both VHCs showed significant
increases in FEV\textsubscript{1} percent predicted after bronchodilator
administration (paired t-test, \emph{P} \textless{} 0.005). And the
degree of improvement did not differ between both VHCs (independent
t-test, \emph{P} \textgreater{} 0.05) as shown in Figure 3.

\textbf{4. Discussion}

In the present crossover trial, our homemade VHC yielded a similar
bronchodilator response to a standard commercial VHC
(Aerochamber\textsuperscript{®}) in children with airway
hyperresponsiveness. Both VHCs were effective as shown by significant
increases in FEV\textsubscript{1} after administration of 400 microgram
of salbutamol MDI. Our study showed that the one-way valves on our
homemade VHC were easy to open and close. All of the children
participating in the study were able to breathe and show the movement of
the valves; the youngest being 6 years old.

To our knowledge, this is the first study showing the effectiveness of a
homemade VHC incorporated with two one-way valves. The material used to
make the VHC are readily available in every home. A paper coffee cup is
selected because it is relatively nonelectrostatic and easier to cut and
make holes than a plastic cup. Zar et al conducted a study using a
500-mL plastic bottle to make a spacer. They had to use a heated mould
of steel wire to melt a hole at the base of the bottle. The hole must
have the same size and shape as the mouthpiece of the
MDI.\textsuperscript{15} So Zar's spacer is a lot more complicated to
make than ours. Another advantage is its quality to fit tightly and
safely over the nose and mouth of the child by only making a short slit
down the edge of the paper cup and place this slit over the nose bridge.
The paper cup simulates a face mask of a commercial VHC. If the face
mask fits well, it will minimize aerosol leakage into the environment
and increase therapeutic aerosolized drug to the
lungs.\textsuperscript{16} Vilarinho et al conducted a study using a
saline bottle to make a spacer. They had to cover the cutting edge of
the bottle with Band-Aid to soften the contact and prevent abrasions or
other injuries to the child's face.\textsuperscript{17} Contrary to
Vilarinho's spacer, we do not need any other covering because the open
round rim of the paper cup is soft and smooth.

The other essential part of our VHC is the drinking water bottle. We
chose a drinking water bottle since it is clear and cylindrical like
commercial VHC. When its base is cut out horizontally, the body of the
bottle perfectly encases the coffee cup. After removing the cap from the
bottle, the MDI actuator or mouthpiece is inserted into the orifice of
the bottle. Typically the diameter of the actuator fits well with the
orifice of the bottle, leaving a little gap which allows air to flow
into the bottle when the patient inhales. Without this gap, the bottle
would collapse during forceful inhalation. Since electrostatic charge
from a plastic bottle can reduce drug delivery, we therefore eliminated
the electrostatic charge by washing an empty bottle with detergent and
water and air-dried which could reduce electrostatic charge on the side
walls and increase aerosol deposition to the
lungs.\textsuperscript{18}Another way to reduce the electrostatic charge
inside the dry water bottle is to prime the bottle initially with 15
puffs of MDI medication.\textsuperscript{19} This later method is faster
but more expensive than washing the bottle with soap and let it dry. In
addition to electrostatic charge, performance of each VHC may vary
according to their size and volume. Theoretically, the VHC should
ideally be 100-700 mL in volume and should provide a distance of
\emph{\textgreater{}} 10 cm between the MDI and the patient's
mouth.\textsuperscript{9,20} So in this study we decided to use a
drinking water bottle 350 mL in volume and cut it into 15 cm in length.

Rodriguez-Martinez et al conducted a systematic review in 2008 comparing
the bronchodilator response delivered through MDI using homemade
spacers, to the use of commercial VHCs in children with acute
exacerbations of wheezing or asthma. In 6 trials with 658 participants
included in their study, no significant differences in terms of clinical
responses were demonstrated between the homemade spacers and commercial
VHCs.\textsuperscript{12}. Aerochamber\textsuperscript{®} was used as a
reference of commercial VHCs in 4 out of the 6 trials. In this current
study we also used Aerochamber\textsuperscript{®} as a reference not
only because it is available in our country but it also has considerably
scientific data especially in young
children.\textsuperscript{4,21,22}The findings of our study are
consistent with those previously reported. But we did not measure the
clinical outcomes. Only the spirometric parameters before and after
bronchodilators were used for comparison. FEV\textsubscript{1} were
increased significantly after bronchodilators delivered through either
our VHC or Aerochamber\textsuperscript{®} with the similar level of
improvement. Since our study design aimed to compare our VHC with a
commercial VHC, we could not address whether or not our VHC has more
efficacy over the other homemade spacers without one-way valves. The
long-term performance, clinical efficacy, aerosol delivery and
deposition of our VHC needs further studies.

There are some limitations to our VHC. The presence of the one-way
valves may limit their use in small infants who have shallow breathing.
Their breathing effort may be too weak to open the valves. Reginato et
al showed that approximately 20\% of infants under 2 years of age were
unable to open the one-way valve of various VHCs during their
inspiratory cycles.\textsuperscript{23} Herbes et al found that more
than half of the newborns were unable to generate an inspiratory flow
capable of opening the one-way valve of a VHC, even when using an
appropriate VHC and face mask.\textsuperscript{24} Therefore we would
suggest to observe the movement of the valves first. If the valves do
not move with respirations even though the cup fits well without
leakage, it is not suitable to use this homemade VHC in that patient.
Second limitation of our VHC is that it is not as durable as commercial
VHCs. The paper cup is easily damaged and needs to be replaced. The part
of water bottle is more durable and lasts much longer than the coffee
cup. Although the water bottle can be washed with detergent, the paper
cup cannot endure the same use. The valves made of tiny thin plastic cut
from a disposable grocery shopping bag can be damaged when the cup is
washed or wiped. So we recommend the cup to be air dried after use.
Since the coffee cup with one-way valves is very cheap and easy to make,
frequent replacement is recommended. Our VHC may be considered as an
alternative disposable device that parents can make easily and cheaply
at home.

During the COVID-19 pandemic, nebulized bronchodilators for presumptive
or confirmed COVID-19 patients may not be safe due to the generation of
aerosols, which increases the risk that respiratory droplets will remain
in the air and spread the virus. Bronchodilator delivery via MDI with
VHC instead of nebulization is strongly
recommended.\textsuperscript{2,3,10} In addition, the VHC should not be
shared in order to prevent the spreading of virus. Therefore the VHCs
are considered an essential accessory device in all hospitals in the
face of COVID-19. Our homemade VHC should be an ideal solutions to this
problem. It is a lot cheaper than any other commercial VHCs. It is
effective to deliver the bronchodilators and very easy to make. Since it
is not durable, we would suggest to use it as a disposable medical
device for an individual patient. For adult patients, our VHC can be
enlarged by using larger sizes of coffee cup and water bottle.
Additional research may be needed to determine its efficacy in adults
with asthma in the future.

In conclusion, a homemade VHC is a promising alternative option of
medical device for use with an MDI medication. It is made from a paper
coffee cup and a drinking water bottle which costs less than one dollar.
To make this VHC is easy and fast. The coffee cup seals over the nose
and mouth simulating a face mask. The movement of valves with
respiration reassures medication delivery to the lungs. It is effective
as shown by significant bronchodilator response. This VHC would be most
helpful in COVID-19 crisis when nebulization is prohibited due to
concerns that nebulizers may help disseminate COVID-19 to other patients
and to physicians, nurses and other personal. Due to its low-cost, this
homemade VHC can be used as a disposable medical device for any
patients, with or without COVID-19 infection, who suffer from
bronchospasm, especially in developing countries where commercial VHCs
are not reachable.

\textbf{Acknowledgments}

The authors would like to pay respect to Professor Allan Coates for his
kind advice and encouragement towards our work on this homemade VHC.
Likewise we thank to M.L. Sirina Jittalan for her editorial assistance,
Harutai Kamalaporn, M.D., Teeradej Kuptanon, M.D. and Thitida
Chaisupamongkollarp for valuable suggestions.

\textbf{Conflict of interests}

The authors declare that there are no conflict of interests.



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21. Dissanayake S, Suggett J. A review of the in vitro and in vivo
valved holding chamber (VHC) literature with a focus on the AeroChamber
Plus Flow-Vu Anti-static VHC. \emph{Ther Adv Respir
Dis.}2018;12:1753465817751346. http://doi.org/10.1177/1753465817751346

22. McIvor RA, Devlin HM, Kaplan A. Optimizing the Delivery of Inhaled
Medication for Respiratory Patients: The Role of Valved Holding
Chambers. \emph{Can Respir J.} 2018;2018:5076259.
http://doi.org/10.1155/2018/5076259

23. Reginato R, Amantea SL, Krumenauer R. Pressure gradient and
inspiratory times required for valve opening of various holding
chambers. \emph{Allergy Asthma Proc.} 2011;32(2):137-141.
http://doi.org/10.2500/aap.2011.32.3421

24. Herbes C, Goncalves AM, Motta GC, Ventura D, Colvero M, Amantea SL.
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this system correctly? \emph{Pediatr Pulmonol.} 2019;54(9):1417-1421.
http://doi.org/10.1002/ppul.24436

\textbf{Hosted file}

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\textbf{Hosted file}

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