The aim of the present study is to show that i.v. ketamine boluses might lead to significant and clinically relevant BIS index increase that might lead to an increase in anesthesia dosing (halogenous gas) when compared to an i.v. continuous infusion of ketamine without any bolus.

Hypothesis: The investigators hypothesize that BIS will not vary when ketamine is given as an i.v. infusion whereas BIS index will significantly vary when ketamine is given as intraoperative repeated bolus on an hourly basis. As a consequence, the bolus group might have a higher consumption of halogenous gases to keep BIS within normal values during anesthesia.

Background: ketamine is a pure NMDA-receptor antagonist widely used in anesthesia for its anesthetic and analgesic properties. However, boluses of intravenous ketamine have been reported to increase BIS values. The present study is the first to compare ketamine effect on BIS values when given as an infusion versus repeated boluses.

Objectives: primary objective: to measure the changes in BIS index values (delta BIS) after each bolus of i.v. ketamine 0.25mg.kg-1 given during anesthesia for surgeries lasting more than 3hs, and to demonstrate a significant increase of this BIS index whereas no significant increase is expected when i.v. ketamine is given as a continuous infusion intraoperatively. Secondary objectives: to measure the changes of BIS index values area under the curve when an infusion of i.v. ketamine 0.25mg.kg-1.h-1 is administered to the patient instead of boluses; to evaluate the time in minutes for the BIS index values to return within +/-10% of the pre-bolus values of this BIS index; to evaluate the time in seconds at which the peak of BIS will occur after ketamine bolus; to evaluate the consumption of halogenous gases during the entire surgery and for each hour of anesthesia (T0 = incision = time for first bolus of ketamine or start of ketamine infusion); to evaluate hemodynamic data (all the data from the ventilator and the monitor are recorded and exported per second) in both groups and see if the infusion group shows less hypotension events needing treatment with i.v. phenylephrine to stay within +/-20% of the mean blood pressure baseline; to evaluate the time for awakening, time for extubation, time spent in post-anesthesia care unit (PACU), delirium and cognitive functions in PACU (CAMshort assessment and MOCA).

Methods: REB from CR-HMR will be obtained. 50 patients undergoing elective general, urological, gynecological surgeries will be explained the study at the pre-anesthesia consultation and then fully consented the day of the surgery. Anesthesia protocol will be fully standardized in both the groups. BIS monitoring will be installed before induction of general anesthesia as well as the standard anesthesia monitoring. Randomization into group infusion versus boluses of ketamine will be done prior to the entrance in the OR, the day of the surgery. Ketamine will be given as follows: in the i.v. ketamine infusion group, an infusion of 0.25 mg.kg-1.h-1 is started with an infusion pump and is kept at the same rate until the surgical team starts closing the deep layers of the abdominal incision. Consumption of the infusion pump is noted at T0 (incision) and at each hour during the surgery and when the infusion is discontinued. In the i.v. ketamine bolus group, 0.25mg.kg-1 of ketamine will be first administered at the time of incision (T0) then every single hour for the rest of the surgery. Study starts at anesthesia induction and incision (T0) for ketamine administration and ends when the patient leaves the PACU. Objectives of the study are cited above.

Data analysis: statistical analyses will be done using SAS version 9.4 or higher and will be performed at a two-sided 0.05 significance level.

Significance/Importance: This is the first study that will compare the impact of the classical intraoperative ketamine administered as repeated i.v. boluses versus as a continuous i.v. infusion during major surgeries lasting more than 3 hours.

Study Design: open label study, with two controlled randomized parallel groups

Subject Population: ASA 1 to 3 adult patients scheduled to undergo elective general, urologic or gynecological surgeries.

Sample Size: 50 patients will be evaluated in this study.

Study Duration: 10 months.

Study Center: Maisonneuve-Rosemont Hospital, CIUSSS de l'Est de l'Ile de Montreal, Montreal, Quebec, Canada.

Adverse Events: None expected.

Inclusion Criteria:

• ASA I to III
• Patients above 18yo
• Gender female or male
• Abdominal general, urological or gynecological surgery with epidural placement

Exclusion Criteria:

• BMI <18 or >35
• Chronic neurological or psychiatric disorder or history of stroke
• Use of psychotropic drugs within 2 weeks prior surgery
• Allergy to ketamine or its excipients or any drug of the anesthesia protocol of this study
• Any contra-indication or patient's refusal for epidural placement

Randomization into group infusion versus boluses of ketamine will be done prior to the entrance in the OR, the day of the surgery