Changes in VC, DLCO, DLNO and exhaled breath after an one-hour oxygen dive with a PO2 of 190 kPa as an indication for pulmonary oxygen toxicity.

Breathing of oxygen during a longer time with a partial pressure (PO2) of more
than 50 kPa can lead to pulmonary oxygen intoxication (POT). The most mentioned
changes which can be found are atelectasis, interstitial oedema, inflammation
and finally fibrosis. Although this kind of lung damage in principle is
reversible, the continuation of breathing oxygen will eventually lead to
irreversible lung damage as can be seen in Acute Respiratory Distress Syndrome
(ARDS). Nowadays, changes in lung function are used as an indicator for the
development of POT. Most mentioned indicators arethe decrease in vital capacity
(VC) and diffusing capacity for carbon monoxide (DLco).

Based on the changes in VC Clark & Lambertsen (1970) introduced the Unit of
Pulmonary Toxicity Dose (UPTD) in the early seventies. By using the UPTD one
could predict the median decrease of the VC after being exposed to oxygen with
a given PO2 during a specific time. For example a 450 UPTD exposure could lead
to a median VC decrease of 2%. A derived application of this UPTD format is
being used in the anaesthesia and intensive care setting where it is a rule
of the thumb that breathing 100% oxygen (PO2 of about 100 kPA) may not last
longer than 24 hours. Although this median decrease of VC is most often used,
it is suggested that not VC but DLco detects POT earlier and better than VC
(Clark 1970, Lowry 2002, Thorsen 1993, van Ooij 2011). The preference for this
VC indicator was mainly motivated by its easy handling by laymen which stood in
contrast with the difficult measurement of DLco.

In contrast to the seventies Dlco can nowadays easier and faster be measured.
With the development of new techniques it is possible to determine also the
diffusing capacity for nitric oxide (DLno). An advantage of this new method is
that it is capable to measure the specific alterations in the alveolo-capillary
membrane. By using DLno one could detect where POT generates; in the alveolar
membrane (Dm) or in the capillary of the lung vascular bed (VC). A disadvantage
of both techniques are that they can only be used in cooperative persons. Using
it in an IC setting is not possible.
With the introduction of the electric nose (also called e-nose) this could be
used for IC-patients, in contrast to DLco and DLno. The e-nose is able to
measure volatile organic components (VOC) in the exhaled air. In the apparatus
there are nano sensors which can bind specific VOC's. By analyzing these VOC's
one can determine different VOC-patterns (EB) which can be used in recognizing
a specific disease like f.e. asthma and emphysema. In the earlier phase of POT
inflammation is one of the key features. Due to this inflammation changes in EB
could develop which can be detected by e-nose. This would offer us an ideal
method for IC-patients to see whether POT is developing or not. Unfortunately,
no studies have been published regarding this theory.

Our hypothesis is that breathing oxygen with a PO2 of 190 kPa during 60 minutes
will lead to changes in DLno earlier than in DLno. In contrast VC will show no
significant changes after this exposition. Furthermore this kind of oxygen will
specific changes in EB as measured with the e-nose.

Primary Objective:
1. Will an exposure to oxygen with a PO2 = 190 kPa lead to changes primarily
in DLno compared to DLco?

Secondary Objectives:
1. After an exposure to oxygen with a PO2 = 190 kPa for one hour, are the
changes primarily located in the Dm or in the Vc?
2. Is there a specific EB measurable after an exposure to oxygen with a PO2 =
190 kPa for one hour?

This study is a randomized cross-over trial in which the subjects are measured
during three days.

Study day 1: baseline measurement will be done in which we measure VC, DLco,
DLno and EB for 6 times within a period of 24 hours. The subject will not be
exposed to either oxygen or pressure. With these measurements we will study any
diurnal rhythm effect which could confound our measurements. We call this study
day "Baseline day".

Study day 2: during this day the subject will make a wet dive to 9 meters
during 60 minutes. He will either breath 100% oxygen (active exposure) or air
(control, PO2 max 40 kPa) in random order. Before the dive and 5 times after
the dive VC, DLco, DLno and EB will be measured at the same time points as
during the baseline measurements. Besides, in 15 subjects venous blood sample
(two times ) will be taken to determine the oxidative stress (OS) status before
and after the oxygen exposure. In this way we can see what the personal
oxidative burden is due to this kind of oxygen exposure.

Study day 3: this one is congruous as day 2 but now the subjects will breath
the other type of breathing gas. In other words: if on day 2 oxygen was
breathed he will now breath air during the dive. The time points for measuring
VC, DLco, DLno and EB will be the same as on day 1 and day 2. This also
concerns the venous blood samples.

Every subject will perform one dive with air and one with 100% oxygen. These
dives will be done in random order.

Benefits:
For military oxygen diving as well as intensive care medicine it is of
importance to know at which level and duration of breathing oxygen will lead to
POT. By using the proper indicators it will help oxygen divers to plan their
oxygen dives better or an intensivist to administer oxygen for each patient to
the right duration.

Risks assessment, group relatedness and burden:
Within the scope of this study the subjects will be imposed to some life-style
restrictions concerning eating, drinking and sporting. To our opinion this
regime will not disproportionate infringe their private life.

The measurements of VC, DLco, DLno and EB are not invasive, simple and
complications are not known. As DLco has to be corrected for Hb a fingertip
blood sample will be necessary to measure Hb. The burden of the fingertip blood
sampling is in our opinion minimal and complication is not to be expected. To
measure the oxidative stress status venous blood must be taken (vena mediana
cubiti). This venous puncture is concerned simple and the possible complication
is hematoma due to leakage of venous blood out of the puncture vessel.

Any well performed in-water dive has some risk of DCS. The risk of DCS
associated with this dive simulation can be considered as very small (0.1%).
Besides, this diving profile lays well within the maximal diving time of the
used diving tables (300 minutes).
During an oxygen dive to 9 meter, there is a risk of the occurrence of an
epileptic insult due to cerebral oxygen toxicity. Using the articles of Arieli
(2002) and Butler (2004) this riks can be determined at below 5%. This
estimations are based on oxygen divers who are subjected to exertion. As our
subjects will not perform any exercise we expect the risk of an insult due to
cerebral oxygen toxicity to be substantially less than 5%. If nevertheless an
insult does occurs the proper action will be taken according to "Noodplan
Neurologische Zuurstof Vergiftiging" (NZV) (see section K6).

All in all, we think the burden of these simulations can be considered low, and
less than with a real, wet oxygen dive.