Effect of Dexmedetomidine on Nol-Index Guided Remifentanil Analgesia

Study Overview
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Brief Summary
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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.

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

Conditions
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Nociceptive Pain, Anesthesia, Opioid Use, Perioperative/Postoperative Complications

Intervention / Treatment
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* Drug: Dexmedetomidine
* Drug: sodium chloride
* Drug: Remifentanil


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Remifentanil Analgesia<br>Continuous intraoperative analgesia with remifenanil + 0.9% sodium chloride | Drug: sodium chloride<br>* Patients in the remifentanil group will receive an infusion of 0.9% sodium chloride instead of dexmedetomidine (identical infusion rate)<br>* Other names: normal saline 0.9%;Drug: Remifentanil<br>* Both groups will have remifentanil analgesia guided by the Nol-Index<br>* Other names: Ultiva;|
| Active Comparator: Remifentanil and Dexmedetomidine Analgesia<br>Continuous intraoperative analgesia with remifenanil + dexmedetomidine | Drug: Dexmedetomidine<br>* 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.<br>* Other names: Dexdor;Drug: Remifentanil<br>* Both groups will have remifentanil analgesia guided by the Nol-Index<br>* Other names: Ultiva;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Remifentanil consumption measured as the amount (µg) of remifentanil administered during the anesthestic | Intraoperative remifentanil consumption | 6 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Propofol Consumption measured as the amount of propofol (mg) administered during the anesthestic | Intraoperative propofol consumption | 6 hours | 
| Use of vasoactive drugs | Use and amount of vasoactive drugs used (ephedrine/phenylephrine/noradrenaline) | 6 hours | 
| Use of hypotensive drugs | Use and amount of hypotensive drugs used (nicardipine/esmolol) | 6 hours | 
| Net fluid balance | Sum of in (infused fluids) and out (net blood loss, diuresis, other losses) | 6 hours | 
| Time to extubation | Time from end of surgery to extubation of patient | 6 hours | 
| Number of patients with intraoperative hypotension | 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). | 6 hours | 
| Number of patients with intraoperative hypertension | Intraoperative MAP≥100 or surgical need to decrease blood pressure | 6 hours | 
| Number of patients with hemodynamic instability | 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). | 6 hours | 
| Intraoperative heart rate | 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) | 6 hours | 
| Intraoperative blood pressure | 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) | 6 hours | 
| Intraoperative Nol-Index | 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) | 6 hours | 
| Intraoperative remifentanil target cite concentration | 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) | 6 hours | 
| Postoperative morphine consumption | mg of morphine administered postoperatively | 24 hours | 
| 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. | 72 hours | 
| PACU length of stay (LOS) | hours spent at PACU | 48 hours | 
| Hospital LOS | days spents hospitalized | 28 days |