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. In this study, the pharmacokinetic (PK) characteristics, as well as the pharmacodynamic (PD) characteristics of norepinephrine will be assessed in healthy volunteers during awake conditions and during a steady-state standardized general anesthesia using target-controlled infusions of propofol and remifentanil.

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.

Phase 1:
- norepinephrin: Baseline; before and after Ringerlactate bolus (at 5 min); at the end of infusion of epinephrin bolus (at 15 minutes) and 2 and 5 minutes thereafter; just before start of continuous infusion of norepinephrin (at 30 minutes); just before every incremental step of continuous norepinephrin infusion (at 45, 60, 75, 90 and 105 minutes); 2, 5 and 30 minutes after continuous infusion of epinephrin stopped.
- melatonin: just before start of continuous infusion of norepinephrin (at 30 minutes), just before some incremental steps of continuous norepinephrin infusion (at 60, 90 and 105 minutes); 30 minutes after continuous infusion of epinephrin stopped.

Phase 2:
- norepinephrin: 15 minutes after start of propfol/remifentanil infusion; at the end of infusion of epinephrin bolus (at 15 minutes) and 2 and 5 minutes thereafter; just before start of continuous infusion of norepinephrin (at 30 minutes); just before every incremental step of continuous norepinephrin infusion (at 30, 60, 90, 120, 150 and 180 minutes) and after the noxious stimuli half way during each step (45, 75, 105, 135 and 165 minutes); when continuous infusion of epinephrin and propofol and remifentanil stopped and 2, 5, 10, 20 and 30 minutes thereafter.
- propofol/remifentanil: 15 minutes after start of propfol/remifentanil infusion; just before start of continuous infusion of norepinephrin (at 30 minutes); just before every incremental step of continuous norepinephrin infusion (at 30, 60, 90, 120, 150 and 180 minutes); when continuous infusion of epinephrin and propofol and remifentanil stopped and 2, 5, 10, 20 and 30 minutes thereafter.
- melatonin: just before start of continuous infusion of norepinephrin (at 30 minutes), just before every incremental step of continuous norepinephrin infusion (at 30, 60, 90, 120, 150 and 180 minutes); 30 minutes after continuous infusion of epinephrin stopped.

Phase 1: While the subject is awake, norepinephrine will be administered in a standardized step-up dosing scheme.
Phase 2: 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.