Multiple Breath Washout to measure lung function in Congenital Diaphragmatic Herniation survivors between 5 and 18 years old

Children with congenital diaphragmatic herniations (CDH) are born with life
threatening pulmonary hypertension and hyperplasia.1 Postnatally, these
children require immediate artificial ventilation and other medical
interventions.1 Unfortunately, even with the current advances in medical
treatment, the mortality of neonates with CDH remains high.1 Of those infants
who survive these crucial interventions, the lung parenchyma and function will
gradually recover to near-normal with age.1 However, pulmonary problems usually
persist even beyond adolescent age. Especially pulmonary obstruction, bronchial
hyperreactivity and pulmonary hypertension are often reported.1-3 For these
reasons are survivors of CDH asked to regularly visit their pediatric
pulmonologist.4

During these visits, pulmonary function is usually measured by spirometry and
body-plethysmography.4 These pulmonary function tests are especially useful in
measuring lung volumes and pulmonary obstruction. However, due to our advances
in postnatal and long-term CDH care, the lung volumes of CDH survivors have
often recovered to near-normal values at pubescent age.1-4 This results in a
mismatch between pulmonary function values and reported symptoms, making these
tests less effective in the pulmonary care of this population.1-4

During recent years an interest has developed for a new pulmonary function test
called Multiple Breath Washout (MBW). During MBW an inert tracer gas, usually
nitrogen, is washed out during tidal breathing of 100% oxygen until 1/40th
(2.5%) of the starting concentration has been reached.5-6 The amount of
functional residual capacity (FRC) turnovers needed to reach this concentration
gives a measure of ventilation inhomogeneity (VI).5-6 VI is mostly affected by
peripheral airway damage, which is in many pulmonary diseases the main location
for mild or early lung disease.5-8 Therefore, the more peripheral airway damage
is present, the longer it will take to wash out an inert tracer gas and the
higher (i.e. worse) the measured VI will be.5-6 In contrast, pulmonary function
tests that focus on lung volumes mainly reflect damage of the larger airways,
which represents more developed lung disease.

Additionally, because a MBW test only requires a tidal breathing pattern, is
non-invasive and requires less cooperation than conventional pulmonary function
tests, it is feasible to perform in all age groups.9-10 For example, spirometry
is challenging for young children to perform, because it involves a forced
expiration maneuver, which requires a certain level of coordination. During a
MBW test children are distracted by watching TV and only have to calmly breathe
through a snorkel-like tube. In short, MBW is more sensitive to mild and early
lung disease than spirometry and body-plethysmography, and is also more
feasible to perform in young children.5-10

MBW has been studied extensively in children with cystic fibrosis, asthma and
primary ciliary dyskinesia.7-8,11 In these studies MBW has found to be more
sensitive in detecting and monitoring children with early or mild lung disease
than other pulmonary function tests.7,8-11 In the field of CDH care where
current pulmonary function tests are becoming less effective in older children,
MBW could be a useful tool in disease monitoring. Unfortunately, few studies
have been carried out in this population.

We intend to perform a cross-sectional pilot study in which we carry out MBW
measurements in 32 children aged 5 to 18. The outcomes will be compared to both
normal values and outcomes of regular spirometry and body-plethysmography
tests. Furthermore will the relation between MBW outcomes and age in our
population be studied in more detail. Prognostic factors of the herniation
present at the birth of our participants, such as liver herniation and
lung-to-head ratio, will be collected and compared to MBW outcomes. Seeing that
one MBW test will be the only additional task for the participants, and that
MBW tests are safe and non-invasive, the burden of participation will be low.

Our research project aims to answer 3 key questions:

1. How do MBW, spirometry and body-plethysmography outcomes compare in
survivors of CDH?

2. What is the relation between MBW outcomes in survivors of CDH and age?

3. Are prognostic factors of the herniation present at birth (e.g. location of
herniation, lung-to-head ratio, liver herniation) associated with increased
(i.e. worse) MBW outcomes in survivors of CDH?

Question 1
We will include children aged 5-18 years with a history of CDH who have a
regular follow-up visit scheduled during our study period. During these
follow-up visits, spirometry and body-plethysmography measurements are standard
of care. Children will be asked to perform a supplemental MBW test when they
choose to participate. The MBW outcomes will be compared to the spirometry and
plethysmography outcomes. Thus far, no studies have been performed on the use
of MBW in children with CDH aged 5-18 years old.
Question 2
Our study population will consist of four age groups of 5, 8, 12 and 17 years
old respectively, as routine follow-up takes place at these ages. We will try
to include 8 children in each age group to reach a total study population of 32
children. Using these age groups, we will try to find an association between
age and MBW outcomes. It is our hypothesis that younger participants will have
higher (i.e. worse) MBW outcomes. Even though it may be unlikely that a
significant relation can be found with the amount of children we aim to include
in this pilot study, finding a trend would still be valuable for future
research.
Question 3
Some characteristics of diaphragmatic herniations of neonates are related to
prognosis. These factors include the side of the defect in the diaphragm, the
lung-to-head ratio, the presence of liver herniation, the requirement of
extracorporeal membrane oxygenation (ECMO) and whether the child was born
prematurely. It is our hypothesis that presence of these prognostic factors at
birth will be associated with (impairment of) lung development and therefore
with a worse pulmonary function at later age and therefore worse MBW outcomes.
Information about these prognostic factors has already been saved in the
electronic patient files as part of standard care. Patients and their parents
will be asked for their permission to extract these data and use them for this
study. *

Patients with a history of CDH regularly visit the hospital for follow-up with,
amongst others, their pediatric pulmonologist and surgeon. Patients with a
history of Bochdalek-type CDH and/or their parents will receive a call from
either their treating pediatric pulmonologist or surgeon. During this call,
they will be asked whether they are interested in receiving the patient
information file (PIF) of this study by mail. When patients and/or their
parents agree to participate in this study, the participation forms will be
signed at the next follow-up visit together with their treating pediatric
pulmonologist or surgeon. Patients with a hernia-type other than Bochdalek, or
patients who had any pulmonary surgery other than sequestration removal will
not be asked to participate. Furthermore, children with a pulmonary infection
requiring antibiotics within 4 weeks from the follow-up visit, or with a
pulmonary infection not requiring antibiotics within 2 weeks from the follow-up
visit are excluded from this study.
Only a MBW test will be scheduled in addition to the spirometry and
body-plethysmography tests which are part of routine care. During the MBW test
patients will be accompanied by a post-graduate medical student who has been
trained and certified in performing MBW tests with children of the target age
group. Before starting the test, the researcher will introduce and explain the
procedure to the patient and parents. The researcher will also ask the patient
to choose a program to watch on TV. Watching TV during the test helps to
distract the children which stimulates a tidal breathing pattern. Maintaining a
stable tidal breathing pattern is important for achieving a test result of good
quality.
When the test starts the patient will breathe through a snorkel-like mouthpiece
and wear a nose-clip. Therefore, a closed breathing circuit is created in which
only 100% oxygen is delivered to the patient. By inhaling only oxygen, the
subject will washout the resident nitrogen present in the lungs breath by
breath until the target concentration of 1/40th (2.5%) of the starting nitrogen
concentration has been reached. It is expected that in this population reaching
the target concentration will take approximately 2-3 minutes. However,
depending on the extent of peripheral airway damage this estimation could be
increased. After reaching the target concentration, the researcher will stop
the test which thereby completes one MBW trial. The patient can now remove his
mouth from the mouthpiece and breathe normal room air. After every trial there
is a waiting period of 1.5 times the trial time in order to wash the nitrogen
present in room air back into the lungs. After this waiting period, another
trial is started.
In order to successfully complete the MBW test occasion, at least two trials
will have to be of good quality. Factors which can decrease the quality of
trials are the opening of the closed circuit by a leak or unstable breathing
patterns of the child. the researcher will try to prevent problems in
acceptability by coaching and comforting the child to breathe calmly and to
stimulate the patient to focus on watching TV. One test occasion typically
includes several MBW-trials to obtain at least two trials that are technically
valid. The researcher will try to collect three successful trials, minimizing
the chance of losing the test occasion when one of the trials still turns out
to be unacceptable after post-test quality control. Dependent on the amount of
trials needed to achieve three or more acceptable trials and the amount of
peripheral airway damage present, total testing time will usually take 30 to 45
minutes including the introduction and explanation of the test to patient and
parents. A maximum of two subjects per age-group will be replaced when subjects
do not succeed in achieving two technically valid MBW-trials. MBW-test success
rates will be reported in our study and will be compared to spirometry and
body-box success rates.
In this study we will furthermore ask the patients and parents for permission
to use the spirometry and body-plethysmography outcomes from the same follow-up
visit for our study. These outcomes will be needed to answer our research
questions. Furthermore, we will ask permission to use demographic data of the
patients, and prognostic factors of the herniation present at birth. The
prognostic factors will include the side of the herniation in the diaphragm,
the lung-to-head ratio, the presence of liver herniation, the requirement of
extracorporeal membrane oxygenation (ECMO) and whether the child was born
prematurely including the gestational age at birth. These data will all be
collected either during a regular follow-up visit, or retrospectively from the
electronic patient file by a member of the research team. Collection of these
data will therefore not pose any extra burden on the patient and his/her
parents.

negligible burden, no risks