Effect of Dexmedetomidine on Nol-Index Guided Remifentanil Analgesia

Effect of Dexmedetomidine vs 0.9% Sodium Chloride on Nol-Index Guided Remifentanil Analgesia: a Double-blinded Bicenter Randomized Controlled Trial

Background: Analgesia remains to this day a challenge for anesthesiologists. Dexmedetomidine, a potent central alpha-2 agonist, has been shown to have analgesic and opioid sparing effects. The classic analgesic strategy focuses on opioid administration guided by estimated time of elimination and hemodynamic response (increase in blood pressure and heart rate). This technique is not sensitive and forces the anesthesiologist to be one step behind nociception, the patient's unconscious response to pain. PMD-200 (Medasense, Israel) displays the Nociceptive level (NOL)-Index as marker of nociception. The NOL-Index ranges from 0 (no nociception) to 100 (intense nociception) and the recommended analgesic range during surgery is from 10 to 25 (Medasense recommendations). The goal of this study is to compare two analgesia strategies guided by the NOL Index (range 10-25) using either remifentanil TCI (target controlled infusion) alone or remifentanil TCI associated with a continuous dexmedetomidine infusion. Methods: A total of 100 patients will be included and informed consent will be acquired. This bi-center study will take place at Erasme University Hospital (primary center) and Saint-Pierre University Hospital. Patients will be randomized into either two groups: remifentanil and placebo versus remifentanil and dexmedetomidine. Both groups will be monitored using the PMD-200 that will guide the analgesic therapy strategy. Investigators and patients will be blinded to dexmedetomidine and placebo administration. The primary outcome will be intraoperative remifentanil consumption. Secondary outcomes will include postoperative opioid administration, opioid associated complications, hemodynamics, and hospital length of stay.

Patients in the dexmedetomidine-remifentanil group will receive an infusion of 0.6 mcg/kg in half an hour followed by an infusion of 0.6 mcg/kg/hour.

Patients in the remifentanil group will receive an infusion of 0.9% sodium chloride instead of dexmedetomidine (identical infusion rate)

Remifentanil consumption measured as the amount (µg) of remifentanil administered during the anesthestic

Intraoperative MAP (mean arterial pressure) <65 mmHg* Patients that have chronic hypertension or that are 65 years of age or older will have a MAP threshold of 75mmHg (and not 65mmHg).

MAP<65 mmHg*, HR<45, MAP≥100, HR>90 * Patients that have chronic hypertension or that are 65 years of age or older will have a MAP threshold of 75mmHg for hypotension (and not 65mmHg).

Measurement during key intraoperative periods (before induction, after induction, after intubation, before incision, after incision, every 15 minutes after incision, after end of surgery, and after reversal of anesthesia)

Measurement during key intraoperative periods (before induction, after induction, after intubation, before incision, after incision, every 15 minutes after incision, after end of surgery, and after reversal of anesthesia)

Measurement during key intraoperative periods (before induction, after induction, after intubation, before incision, after incision, every 15 minutes after incision, after end of surgery, and after reversal of anesthesia)

Measurement during key intraoperative periods (before induction, after induction, after intubation, before incision, after incision, every 15 minutes after incision, after end of surgery, and after reversal of anesthesia)

Number of patients with postoperative opioid-related side effect (composite and individual complications)

Post-operative nausea or vomiting within the first 24 h, postoperative hypoxemia (need within 24h postop to have supplemental oxygen (to maintain sat >94%), and pruritus.

Inclusion Criteria: - American Society of Anesthesiologists (ASA) grades 1-2 undergoing scheduled stomatological, cervical, and thyroid surgery anticipated to last at least two hours Exclusion Criteria: ASA score >2 Preoperative organ dysfunction Patients with non-regular cardiac rhythm Implanted pacemakers Emergent surgery Pregnancy or lactation Allergy or intolerance to any of the study drugs Participation in another interventional study Patient refusal

Coeckelenbergh S, Doria S, Patricio D, Perrin L, Engelman E, Rodriguez A, Di Marco L, Van Obbergh L, Estebe JP, Barvais L, Kapessidou P. Effect of dexmedetomidine on Nociception Level Index-guided remifentanil antinociception: A randomised controlled trial. Eur J Anaesthesiol. 2021 May 1;38(5):524-533. doi: 10.1097/EJA.0000000000001402.