Modeling the respiratory effects of subanesthetic doses of propofol under closed-loop or non-steady-state conditions without and with a remifentanil background infusion in healthy volunteers.

(page 2 protocol)
Apart from being an additive to intravenous anesthesia, propofol is used
frequently as sedative both by anesthesia specialists (i.e. anesthesiologists)
and by non-specialists sucht as nurses and physicians outside the
anesthesiology specialty (for example, during performance of diagnostic
procedures). Propofol, just as most anesthetics, sedatives and analgesics,
produces respiratory depression with the possiblity of life-threatening events
related to irregular breathing, apnea, and hypoxia. Despite the possiblity for
serious adverse events (note that these only occur when propofol is used by
non-specialists; anesthesiologist consider propofol a safe and easy to use
drug) little research is done on the dose-effect relationship of propofol with
respect to respiratory depression. Our current study is aimed to do so.
Furthermore, since in clinical practice propofol is often used in combination
with an opioid we will perform additional studies in which we will assess the
propofol dose-effect relationship during the intravenous infusion of the opioid
remifentanil. Remifentanil will be infused at a low-dose causing limited effect
on breathing. In combination with propofol significantly measurable effects are
to be expected though.
In the current study, we aim to measure breathing under so-called closed-loop
conditions. This means that the feedback loop between the chemical stimuli in
the blood and breathing remains intact. This is very different from so-called
steady-state experiments using end-tidal (or arterial) forcing of oxygen and
carbon dioxide. In these kinds of studies the true drug effect is observed
without the confounding effects of increasing levels of CO2. We developed a
data analysis technique that does take the CO2 kinetics and dynamics into
account and consequently the correct values for potency and onset/offset are
estimated without the need for clamping the CO2. We aim to study propofol under
closed-loop conditions to better mimic reality (on the experimental side of the
study).

Study aims (see page 2 of the protocol)
a. To assess the dose-response relationship of propofol on breathing.
b. To assess the interaction of propofol and remifentanil on breathing.
c. To qunatify the data under closed-loop conditions using an emprical model of
the drug induced respiratory depression that incorporates drug effect on
respiratory neurons and the kinetics and dynamics of CO2

We will study 24 healthy volunteers of either sex. The design is a non placebo
controlled . The experiment consists of two separate experimental parts. In
part 1, a propofol infusion is started, during 30 minutes in total, divided in
three sessions of different target concentrations, eacht during 10 minutes (700
ng/ml, 1400 ng/ml or 2100 ng/ml) in randomized order. Breathing measurements
are performed continuously during the propofol infusion up till 30 minutes
after ending the infusion. During the breathing measurments, all volunteers
breath an inspiratory gas of 100% oxygen. After experimental run 1 there is a
two hour wash-out period. After this the second experimental run takes place.
During this run a background infusion of remifentanil is started (of either 0.8
ng/ml or 1.6 ng/ml). Volunteers will be randomized for one of these target
concentrations. After the start of the background infusion, the propofol
infusion of the first experimental run is repeated. Again, breathing
measurements are performed. During the experiments blood samples will be taken
from the arterial line (15 in totaal) in order to assess drug concentrations in
the blood.

The experiment consists of two separate experimental parts. In part 1, a
propofol infusion is started, during 30 minutes in total, divided in three
sessions of different target concentrations, eacht during 10 minutes (700
ng/ml, 1400 ng/ml or 2100 ng/ml) in randomized order. Breathing measurements
are performed continuously during the propofol infusion up till 30 minutes
after ending the infusion. During the breathing measurments, all volunteers
breath an inspiratory gas of 100% oxygen. After experimental run 1 there is a
two hour wash-out period. After this the second experimental run takes place.
During this run a background infusion of remifentanil is started (of either 0.8
ng/ml or 1.6 ng/ml). Volunteers will be randomized for one of these target
concentrations. After the start of the background infusion, the propofol
infusion of the first experimental run is repeated. Again, breathing
measurements are performed. During the experiments blood samples will be taken
from the arterial line (15 in totaal) in order to assess drug concentrations in
the blood.

See page 8 and 9 of the protocol.
Volunteers will be subjected to a physical examination and a medical history.
This will be done at the ambulatory anesthesia service.
Volunteers will be asked to refrain from food and drinks for at least 8 hrs
prior to the study. Furthermore no alcohol/coffee/tea/chocolate is allowed for
the 24 h prior to the study and no grapefruite juice for the seven days prior
to the study.
The experiment takes with preparations about 6 h. The effects after the
experiment will be minimal, as the study medications have a very short half
life.
During the experiments the following invasive procedures will be performed;
An arterial line will be inserted. At the department of anesthesiology there is
a lot of experience with the use arterial lines during experiments in
volunteers. The arterial line is used for frequent blood sampling (15 times, 75
ml in total) and invasive monitoring of blood pressure.
Removal of the arterial line can cause some bruising. After removal a pressure
bandage is applied up till 6-8 hrs after the end of the study.
A venous line will be inserted, that is used for the administation of propofol,
remifentanil and fluids. Removal of this line can cause some bruising.
During the experiment (2 runs of 60 minutes) ventilation will be monitored by
spontaneous mask ventilation connected to the measurement apparatus. However,
the volunteer will be able to breath freely.
Side effect can be nausea, that is treated with ondansetron (Zofran), a potent
anti-emetic.
Furthermore, a headache can occur because of mild hypercapnia, caused by the
experiment. This headache usually resolves with paracetamol 500 mg or 1000 mg
orally.
Respiratory depression, however not to be expected, will, if significant
(saturation < 90 % or end tidal CO2 > 10 kPa), be treated by the administration
of naloxon, a opioid antagonist. Also the experiment will end and the infusion
will be stopped.
Sedation as a consequence of propofol administration, althought at the used
dosages not to be clinically relevant, will be continuously monitored by the
EEG/BIS. Also, because of the very short half life of remifentanil (elimination
is rapid by plasma esterases) and the short half life of propofol, any
threatening side effects will disappear soon after the end of the infusion.