Walking the Isobole of drug Interaction: Comparison of hemodynamic effects, cerebral and tissue oxygenation for 4 equipotent combinations of propofol and remifentanil

In anesthesia, the synergistic interaction between hypnotics and opioids is
used daily to give adequate anesthesia and analgesia at significantly lower
doses than would be needed if only one type of drug was given to reach the same
effect. A lot of research has been done on the interaction of drugs on the
desired effects, but the simultaneous interaction on the unwanted side effects
is less well described. The response surface model of Bouillon et al. predicts
all combinations of propofol and remifentanil effect-site concentrations that
lead to an equipotent desired effect. Due to this model we now are able to
predict which combinations of propofol and remifentanil will lead to, for
instance, a desirable 90% probability of tolerance of laryngoscopy (TOL90) in
the population. However, at this time we don*t know whether some of the
combinations of propofol and remifentanil have a more favorable hemodynamic
stability compared to other combinations on the same isobole, i.e. what the
relationship is between these equipotent combinations and the undesired side
effects such as hemodynamic instability (hypotension, changes in heart rate or
cardiac output), decreases in cerebral or tissue oxygenation (both measured
with near infrared spectroscopy).

To investigate the effects of the different combinations of propofol and
remifentanil on the isobole of TOL90 and to compare hemodynamics, cerebral and
tissue oxygenation for each equipotent combination. To describe the combination
of propofol and remifentanil on the TOL90 isobole with the least hemodynamic
side effects. This study will help the anesthesiologist to increase the safety
of induction and maintenance of anesthesia as we will be able to provide a
priori information on those combinations with the least side effects.
Currently, the post hoc (after the induction) monitoring of side effects is
the only way to guarantee safety.

The goal of this study is to compare the hemodynamic effects (and tissue
oxygenation) of different combinations of remifentanil and propofol that are
known to produce an equipotent anesthetic effect (TOL90). This is a blinded
interventional randomized study. Patients will be randomized to one of four
pre-calculated combinations of propofol and remifentanil effect site
concentration that produce TOL90. The anesthesiologist (staff member) in charge
of airway management will be blinded for the medication administration and will
quantify responsiveness to interventions. This allows maximal prevention of
observation bias while the anesthesiologist or research assistant (medical
doctor) in charge of drug administration and overall management has full
knowledge of any administered medication and can intervene if required for
patient safety. All study parameters will be determined and recorded by
fully-automatic data management system.

Patients will be randomized to receive one of four different combinations of
remifentanil and propofol. All combinations are within the ranges used in
normal clinical practice for induction and maintenance of anesthesia, but
differ in their position on the TOL90 isobole.

All patients will receive a letter with information on this study at least one
week before the planned operation date. Eligible patients will be asked for a
written informed consent prior to the procedure. Patients will then be
randomized to receive one of four predefined combinations of propofol and
remifentanil. These drugs will be administered through commercially available
target controlled infusion pumps. All concentrations and doses fall within the
normal ranges used in clinical practice for induction of anesthesia, and within
the ranges that patients would receive if they weren*t included in this study.
Hemodynamic side effects are expected, (as always when inducing anesthesia) and
if necessary these will be countered using escape medication mentioned in the
protocol, which are also regularly used in clinical practice to counteract the
same side effects. Respiratory side effects are also expected, as in any
general anesthesia, and when these occur, they will be addressed using normal
clinical routines such as airway maneuvers (such as chin lift, jaw thrust etc.)
and manually assisted ventilation, as necessary. After the end of the study
period, additional propofol or remifentanil will be administered if deemed
necessary by the anesthesiologist to achieve the proper depth of anesthesia to
allow tracheal intubation and mechanical ventilation, as in normal clinical
practice.

All additional monitoring devices that are not part of normal clinical practice
(cardiac output, cerebral and tissue oxygenation) are non-invasive and cause no
harm, but provide considerably more detailed information on hemodynamics
compared to blood pressure and heart rate alone. Therefore this study will not
extend the burden or risks for the patients compared to normal clinical
practice.