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ID
Source
Brief title
Health condition
Anesthesia
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint of this study will be the association between ABP and plasma concentrations of norepinephrine (awake state), and the association of ABP and plasma concentrations of norepinephrine during steady-state general anesthesia with propofol and remifentanil.
Secondary outcome
- 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.
Background summary
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.
Study 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.
Study design
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.
Intervention
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.
Inclusion criteria
American Society of Anesthesiologists (ASA) Physical Status I or II
No exclusion criterion is present
Informed, and willing to give written informed consent.
Exclusion criteria
Refusal of the volunteer to participate
Pregnancy
Diseases involving the cardiovascular system (hypertension, coronary artery disease, prior acute myocardial infarction, any valvular and/or myocardial disease involving decrease in ejection fraction, arrhythmias, which are either symptomatic or require continuous medication/pacemaker/automatic internal cardioverter defibrillator)
A difference > 15 mmHg in measured systolic or diastolic blood pressure value (SBP, DBP) between the left and right upper arm, as determined by non-invasive cuff oscillometry during the screening visit.
An increased risk of difficult mask ventilation or tracheal intubation, as judged by the anesthesiologist-researcher.
Pulmonary disease
Gastric or endocrinologic diseases
End-stage liver or kidney failure
Use of tricyclic antidepressive medication or MAO inhibitors.
Design
Recruitment
IPD sharing statement
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| NTR-new | NL9312 |
| Other | METc Brabant : to be anounced after submission |