Markers of Oxidative Stress from Supplemental Oxygen in critically-ill children

Severe viral lower respiratory tract infection (VLRTI) is the most common
reason for pediatric intensive care unit admission and forms a major healthcare
burden worldwide. Children with severe VLRTI are commonly treated with both
non-invasive and invasive (mechanical ventilation) oxygen therapy due to
hypoxia. However, optimal oxygen saturation targets in critically-ill children
are currently unknown. In comparison, in adults there is also an ongoing debate
regarding saturation targets and whether supplemental oxygen (hyperoxia) should
be kept to a minimum (conservative oxygenation) or can be given more liberal.
The basis for this discussion is that hyperoxia may increase the production of
reactive oxygen species, which could induce oxidative stress and lung
epithelial injury. At present, there is no evidence on whether or not
conservative oxygenation can reduce oxidative stress compared to liberal
oxygenation in children, in particular not in the setting of a pro-inflammatory
pulmonary micro-environment (e.g. due to VLRTI). Measurement of volatile
organic compounds in exhaled breath can be used as a non-invasive, easy
obtainable marker for oxidative stress in vivo in patients receiving oxygen
therapy. In addition, in vitro epithelial cell based systems can assess the
effects of oxygen therapy on the lung micro-environment level.

In this study, short term conservative oxygenation is hypothesized to reduce
markers of oxidative stress in exhaled breath in comparison with short term
liberal oxygenation. Secondly, as compared to hyperoxia, normoxic conditions is
hypothesized to reduce oxidative stress and injury of lung epithelial cells in
a pro-inflammatory micro-environment in vitro.

This study has two parts. The main objective of part 1 (in vivo) is todetermine
changes in markers of oxidative stress in exhaled breath as a result of
different short term oxygenation strategies (liberal versus conservative) . The
main objective of part 2 (in vitro) is to assess differences in makers of
oxidative stress and lung epithelial cell injury after prolonged hyperoxic
versus normoxic conditions in the setting of a pro-inflammatory
micro-environment in vitro.

This will be a randomized cross-over study of two different short term
oxygenation protocols (liberal and conservative) during ongoing mechanical
ventilation as part of usual clinical care.

No investigational product is administered. Two short term oxygenation
protocols will be used during ongoing mechanical ventilation as part of usual
clinical care.

Patients with VLRTI who will participate in this study will undergo two short
term oxygenation protocols (3 hours) as an adaption of usual clinical care on
two separate days. On both days, non-invasive exhaled breath samples will be
collected five times, and on the third day one blind non-bronchoscopic lavage
(mini-BAL) will be performed. Patients without VLRTI who will participate in
this study will undergo one short term oxygenation protocol (3 hours) as an
adaption of usual clinical care on a single day, upon which non-invasive
exhaled breath samples will be collected five times.
The expected physical discomfort associated with participation in this study is
minimal as patients will be sedated for the entire duration of the study
protocol as part of usual clinical care. Therefore patients will be unaware of
the study procedures. The risks with participation in this study are expected
to be minimal, as the brief adaption of usual clinical care is not expected to
have any detrimental or lasting effects on the patients. The study
(non-invasive and single invasive) procedures used to obtain data are also
expected to impose minimal risks. No direct benefit for the patient comes from
participation in this study, however, it is expected that the results from this
study will benefit the specific patient population and future patients. As
mechanical ventilation is not part of clinical care for non-critically ill
children and data regarding critically-ill adults cannot be properly translated
to children, it is imperative that this study is performed in this specific
population. The risk and burden of participation in this study is expected to
be minimal as compared to the risks and burden of usual clinical care for these
patients.