Evaluation of pharmacokinetic and *dynamic characteristics of norepinephrine for the augmentation of arterial blood pressure in healthy volunteers prior to and during general anesthesia

Intraoperative hypotension is an important risk-factor for the development of
renal, myocardial and cerebral complications following surgery. Therefore,
vasopressors such as norepinephrine, are commonly used for maintaining or
restoring arterial blood pressure (ABP) during general anesthesia. There is
however surprisingly little information on the dose-response of norepinephrine,
both in awake patients, and in patients under general anesthesia. Also, the
administration of norepinephrine is reactive, i.e. follows when hypotension has
already occurred, and should ideally be proactive, i.e. to prevent hypotension
from developing, ultimately minimizing the risk of postoperative organ injury.

Primary Objective:
To assess the effect of the administration of norepinephrine on ABP while
subjects are awake and subsequently, to study the effects of the interactions
of norepinephrine and anesthetics (propofol and remifentanil) on ABP under
steady-state conditions during general anesthesia.

Secondary Objective(s):
- Evaluation of the effect of the interaction between propofol, remifentanil
and norepinephrine on hemodynamics during general anesthesia.
- Evaluation of the effect(s) of endogenous norepinephrine plasma concentration
on the relationship between administered dose (and plasma concentration) of
norepinephrine and induced hemodynamic alteration(s).
- Evaluation of the Beloeil norepinephrine PKPKD model.
- Assessment of changes in mean systemic filling pressure prior to and after
induction of general anesthesia, as assessed by arm stop-flow measurements by
application of a rapidly inflated tourniquet.
- Evaluation of the dose-dependent effect of administered norepinephrine on
plasma melatonin concentrations prior to and after induction of general
anaesthesia.
- Evaluation of the dose-dependent effect of administered norepinephrine on EEG
indices both during awake states and during general anesthesia.

This study is a prospective, single center, single period, crossover healthy
volunteer study.

After application of standard non-invasive cardiopulmonary monitoring, a
peripheral intravenous line will be inserted. Subsequently, a radial artery
catheter will be placed under local anesthesia for continuous monitoring of ABP
and stroke volume/cardiac output. While the subject is awake, norepinephrine
will be administered in a standardized step-up dosing scheme. After a wash-out
phase, general anesthesia will be induced using a standardized propofol *
remifentanil dosage administration. Once steady-state has been achieved,
norepinephrine will be administered, again in a standardized step-up dosing
scheme and surgical incision will be mimicked using noxious electrical tetanic
stimulation.
During interventions, arterial blood samples will be drawn for the
determination of drug concentrations. Hemodynamic effects (including ABP) will
be continuously monitored.

In this study, we will provide standard anesthesia which we use normally in
daily standard clinical practice. Subjects will be paid volunteers. An
intravenous line (drug and fluid infusion) and an arterial line for blood
sampling and blood pressure/cardiac output monitoring, will be inserted on the
non-dominant hand under local anesthesia, by a certified anesthesiologist using
state-of the art techniques used daily during routine perioperative anesthetic
care. Possible risks include hematoma, infiltration, embolism and phlebitis,
but these risks are considered rare, especially in healthy volunteers. The
total volume of blood sampling has no clinical impact. All other monitoring
will be non-invasive and will not harm the subject. The application of noxious
tetanic stimulation will have no negative impact since it will be applied
solely under general anesthesia only, and will be used within the limitations
as set by the manufacturer. Theoretically, tetanic stimulation may result in
skin burns at the location of the electrodes. Norepinephrine, as well as
propofol and remifentanil, are routinely used drugs in daily clinical practice.
The use of these drugs in a controlled environment in healthy volunteers is
safe. The administration of norepinephrine will remain within the dosing
guidelines provided by the manufacturer. Well defined cessation criteria will
prevent individuals from reaching a dangerously high ABP. The anesthesiologist
remains in control of drug dosing.
During recovery, the subject may experience a sore throat secondary to airway
manipulation while being under general anesthesia. Subjects may experience
mild side-effects after recovery from general anesthesia that are directly
related to the administration of anesthetic drugs. In general, current medical
conditions may *worsen* temporarily in the period of the administration of
general anesthesia. Nausea may occur directly after recovery. Also, the subject
may experience a subtle drowsiness in the days following the administration of
general anesthesia. Finally, it may appear that subjects experience a temporary
sleeping disorder and/or a diminished ability to concentrate