Impact of Nociceptive-Level (NOL) Intraoperative Guided Analgesia During Gynecological Laparoscopic Surgery Under General Anesthesia

Study Overview
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Brief Summary
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The aim of the present study is to show that the use of the NOL device in addition to the Standard of Care (based on mean arterial blood pressure and heart rate values) to guide the administration of opioids compared to the Standard of Care reduces the total fentanyl consumption and the number of intraoperative administration of IV fentanyl during gynecological laparoscopic surgery and improves postoperative outcomes in PACU.

Detailed Description
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Hypothesis: We hypothesize that the group who will be administered intraoperative fentanyl based on NOL + mean arterial blood pressure (MABP) + heart rate (HR) values (SoC+NOL group) versus on MABP and HR (SoC group) will need less intra and postoperative opioid and will report less postoperative pain which will be reflected by a reduced number of adverse effects associated with opioid and/or reduced postoperative pain scores at the PACU arrival resulting in a faster time of readiness to discharge. Background: The NOL index, a nociception monitor using a multiparametric approach, has shown an excellent sensitivity and specificity in detecting noxious stimuli under general anesthesia. This monitor is better than any other classically used clinical parameter in grading nociception under general anesthesia. More recently, a strong correlation between NOL index response to nociceptive stimulus and the level of opioid analgesia during surgery was reported. Studies are now conducted in our center (Maisonneuve-Rosemont Hospital, University of Montreal, Montreal, QC, Canada) to show a better post-operative outcome when using intraoperative NOL monitoring to adapt nociception/anti-nociception balance during general anesthesia (GA) for colorectal surgery. So far, no study has evaluated in gynecological laparoscopic surgery the impact of NOL monitoring to guide the administration of intraoperative IV fentanyl on intra and postoperative opioid consumption and pain scores. Objectives: Primary objective: Reduction in total intraoperative fentanyl consumption (in mcg) and number of intraoperative administrations of IV fentanyl in the SoC+NOL analgesia guided versus SoC analgesia guided group (SoC = Standard of Care). Secondary objectives: Secondary outcome [1] Post-operative opioid consumption (IV hydromorphone in PACU) until patient is ready for discharge from Post-Anesthesia Care Unit. Secondary outcome [2] Post-operative pain scores at rest and at coughing recorded in PACU by using numerical pain rating scales (NRS) in PACU (evaluated Q15min for 1h). Secondary outcome [3] Intraoperative total consumption and frequency of administration of vasoactive drugs. Secondary outcome [4] Post-operative sedation scores with Ramsay Sedation Score recorded every 15 minutes in PACU for at least 1h Secondary outcome [5] Post-operative side-effects within 24 hours post-operatively: Nausea and vomiting: measure of the incidence of any nausea, emetic episodes (retching or vomiting), or both (i.e. postoperative nausea and vomiting) during the first 24 postoperative hours. Upon Discharge from PACU, and at 24 hours post-surgery, patients will verbally rate their worst nausea episode since emergence on an 11-point scale, where 0 represented no nausea and 10 the most severe nausea. Respiratory depression: defined as respiratory rate (RR) below 9 respirations per minutes (RPM). Respiratory rate will be recorded at 5-minute intervals, manually or per PACU monitor. The incidence of RR < 9 RPM during the first 1.5 hours since admission to PACU will be recorded, as well as requirement for naloxone reversal of opioids or additional reversal of muscle relaxants. Itching: score of itching recorded every 10-15 minutes on an 11-point scale, where 0 is no itching and 11 is the most severe itching possible. Secondary outcome [6] Post-operative time to discharge from PACU. This time will be recorded since it may be different from the actual time of discharge which may be prolonged due to non-medical reasons. Patient discharge will be based upon a or b whichever comes first: Time of readiness to discharge from PACU, based on the evaluation of the Aldrete score (out of 9 points) and patient pain level (HMR local score, out of 16 points). Time of discharge from PACU. Secondary outcome [7] Time to first postoperative pain rescue medication administration in PACU or on wards. Methods: Enrollment of 70 randomized adult patients undergoing general anesthesia for gynecological laparoscopic surgery (e.g. hysterectomy, uni- or bilateral Oophorectomy), which will be randomized to 2 groups: SoC guided analgesia (control group) versus SoC+NoL guided analgesia (intervention group). All patients will be consented prior to the surgery. Anesthesia will be standardized for all patients, with: IV lidocaine (0.5mg.kg-1), Propofol (2mg.kg-1), IV fentanyl (2mcg.kg-1), IV rocuronium (0.6mg.kg-1). Depth of anesthesia with sevoflurane will be maintained and monitored with the BIS index kept between 40 and 60. In both the groups, rocuronium will be administered to keep the response to the train of four below 2/4 (TOFScan, Draeger). IV fentanyl will be intraoperatively administered based on HR and MABP variations on the SOC group and HR + MABP + NOL index in the NOL group (see attached decision algorithm). At the end of surgery, all patients will be extubated in the OR, then transferred to PACU. In PACU pain scores and recovery scores (PONV, sedation, respiratory depression, itching, delirium…) and hydromorphone requirements to reach a pain < 3/10 will be assessed as well as Aldrete score and time for readiness for PACU discharge. The study will end at PACU discharge. This study will be registered on clinicaltrial.gov website. Power calculation: Statistical analyses will be done using SAS version 9.4 or higher and will be performed at a two-sided 0.05 significance level. The primary objective of the study is reduced in total intraoperative fentanyl consumption (in mcg) and number of intraoperative administration of IV fentanyl in the SoC+NOL analgesia guided versus SoC analgesia guided group. Preliminary results from our center (HMR/CEMTL) showed that patients in SOC group had an IV intraoperative fentanyl consumption of 616 +/- 190 mcg during anesthesia. For an expected decrease of 25% in the SoC+NOL group for this PACU IV hydromorphone consumption, with a type I error α = 0.05 (two-tailed), an 90% power, the total sample size needed is 64. To account for an approximative 10% rate of loss to follow-up or missing data due to technical problems, a total of 70 subjects will be recruited. Because of the large number of secondary objectives and to protect against type I error in a less conservative way than the Bonferroni correction, the Holm step-down procedure will be applied to the sets of secondary hypotheses. Significance/Importance: The main outcomes of this study will be to demonstrate that intraoperative NOL guidance decreases the need of intra- and post-operative opioids and might improve postoperative recovery after this type of gynecological surgery. Study Design: This is a single-center, prospective, randomized, parallel-group, single-blinded. Subject Population: Adult patients scheduled to undergo elective gynecological laparoscopic surgery (hysterectomy and uni- or bilateral oophorectomy) under general anesthesia. Sample Size: 70 patients will be included in this study. Study Duration: 12 months. Study Center: Maisonneuve-Rosemont Hospital, CIUSSS de l'Est de l'Ile de Montreal (CEMTL), University of Montreal, Montreal, Quebec, Canada. Adverse Events: None expected. Subvention: An Independent Investigator Initiated Trial (IIIT) grant application will be sent to the company Medasense Biometrics LTD for the sponsoring of this study. A contract will be made and signed by both the parties: Medasense Biometrics LTD on one hand and the CR-HMR and the CEO of the CEMTL/HMR prior to starting the study.

Official Title
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Impact of Nociceptive-Level (NOL) Intraoperative Guided Analgesia on Pain Scores, Opioid Consumption and Recovery in Postoperative Care Unit in Patients Undergoing Gynecological Laparoscopic Surgery Under General Anesthesia. The NOLGYN Pilot Study

Conditions
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Gynecologic Laparoscopic Surgery, Hysterectomy, Oophorectomy

Intervention / Treatment
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* Drug: Intravenous Fentanyl guided by SoC+NOL
* Drug: Intravenous Fentanyl guided by SoC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female age 18-75 years ASA I-III adult patients scheduled to undergo elective gynecological laparoscopic surgery (hysterectomy and uni- or bilateral oophorectomy) under general anesthesia patient able to consent in the language of the including center Exclusion Criteria: use of any type of anesthesia other than general anesthesia (neuraxial, epidural analgesia or local regional anesthesia, e.g. transversus abdominal plane block...) patients with non-regular sinus cardiac rhythm, implanted pacemakers, prescirbed antimuscarinic agents, alpha2-adrenergic agonists, beta1-adrenergic antagonists, and antiarrhythmic agents emergent surgery pregnancy/lactation. Pregnancy test will be performed in all women of child bearing age BMI > 35 kg/m2 preoperative hemodynamic disturbance central nervous system disorder (neurologic/ head trauma/ uncontrolled epileptic seizures) drug or alcohol abuse within the last 6 months (for women, > 3 drinks on one occasion or >7 drinks during a week) pre-operative chronic opioid use or chronic pain, equivalent to oxycodone 20mg per oral, per day for more than 6 weeks chronic use of psychoactive drugs within 90 days prior to surgery medical conditions qualifying for ASA III or IV: untreated or persistent peripheral or central cardiovascular disease severe pulmonary disease e.g. COPD gold 4, FEV< 1.0l/s, or (evidence of) elevated paCO2 > 6.0 kPa significant hepatic disease with increased bilirubin, INR or low albumin history of severe cardiac arrhythmia e.g. chronic atrial fibrillation active pacemaker or defibrillator allergy or intolerance to any of the study drugs intraoperative cardiac arrhythmia

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Female

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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 2 groups of patients. Randomization into group SoC + NOL vs SoC according to randomization list for a total number of 70 patients
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SoC+NOL analgesia guided fentanyl administration<br>A bolus of 2 mcg/kg of IV Fentanyl will be given at the induction of the anesthesia. A bolus of 1 mcg/kg of IV Fentanyl will be given at the time of incision. During surgery, administration of 0.5 mcg/kg of IV Fentanyl will be administered following a pre determinate algorithm based on NOL index + heart rate + mean arterial blood pressure variations. Intervention is NOL monitoring in this group that will help to guide intravenous administration of fentanyl during surgery. | Drug: Intravenous Fentanyl guided by SoC+NOL<br>* Predeterminated bolus of IV Fentanyl will be given at the induction of anesthesia (2 mcg/kg), at the time of incision (1 mcg/kg). During surgery, administration of 0.5 mcg/kg of IV Fentanyl will be administred following a pre determinated algorithm based on NOL index + heart rate + mean arterial blood pressure variations.<br>|
| Active Comparator: SoC analgesia guided group<br>A bolus of IV Fentanyl at the discretion of a physician will be given at the induction of the anesthesia. A bolus of IV Fentanyl at the discretion of a physician will be given at the time of incision. During surgery, administration of IV Fentanyl at the discretion of a physician will be administred following a pre determinated algorithm based on heart rate + mean arterial blood pressure variations. Intervention will be here to use Heart rate and blood pressure to administer intraoperative intravenous fentanyl. | Drug: Intravenous Fentanyl guided by SoC<br>* Bolus of IV Fentanyl at the discretion of a physician will be given at the induction of anesthesia, and at the time of incision. During surgery, administration of IV Fentanyl at the discretion of a physician will be administred following a pre determinated algorithm based on heart rate + mean arterial blood pressure variations.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of intraoperative IV fentanyl consumption in the Soc+NOL guided group compared to the SoC guided group. Total consumption of fentanyl in mcg. | Change of intraoperative IV fentanyl consumption in the SoC+NOL guided group compared to the SoC guided group. | Intra-operative | 
| Change of frequency of intraoperative IV fentanyl administration in the Soc+NOL guided group compared to the SoC guided group. Frequency is in minutes | Change of frequency of intraoperative IV fentanyl administration in the Soc+NOL guided group compared to the SoC guided group. | Intra-operative | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of post-operative IV hydromorphone consumption. Total consumption of hydromorphone in mcg. | Change of postoperative IV hydromorphone consumption in the SoC+NOL guided group compared to the SoC guided group in the post operative care unit (PACU). | PACU stay (1.5 hours) | 
| Assessment of post operative pain at rest at T0 minutes in PACU by using Numerical pain rating scales (NPRS) from 0 to 10 | Assessment of post operative pain at rest at T0 minutes in PACU by using Numerical pain rating scales (NPRS). Score is from 0 to 10. | PACU entrance | 
| Assessment of post operative pain at rest at T15 minutes in PACU by using Numerical pain rating scales (NPRS) from 0 to 10 | Assessment of post operative pain at rest at T15 minutes in PACU by using Numerical pain rating scales (NPRS). Score is from 0 to 10. | 15 min after PACU entrance | 
| Assessment of post operative pain at rest at T30 minutes in PACU by using Numerical pain rating scales (NPRS) from 0 to 10 | Assessment of post operative pain at rest at T30 minutes in PACU by using Numerical pain rating scales (NPRS). Score is from 0 to 10. | 30 min after PACU entrance | 
| Assessment of post operative pain at rest at T45 minutes in PACU by using Numerical pain rating scales (NPRS) from 0 to 10 | Assessment of post operative pain at rest at T45 minutes in PACU by using Numerical pain rating scales (NPRS). Score is from 0 to 10. | 45 min after PACU entrance | 
| Assessment of post operative pain at rest at T60 minutes in PACU by using Numerical pain rating scales (NPRS) from 0 to 10 | Assessment of post operative pain at rest at T60 minutes in PACU by using Numerical pain rating scales (NPRS). Score is from 0 to 10. | 60 min after PACU entrance | 
| Assessment of post operative pain at rest at T75 minutes in PACU by using Numerical pain rating scales (NPRS) from 0 to 10 | Assessment of post operative pain at rest at T75 minutes in PACU by using Numerical pain rating scales (NPRS). Score is from 0 to 10. | 75 min after PACU entrance | 
| Assessment of post operative pain at rest at T90 minutes in PACU by using Numerical pain rating scales (NPRS) from 0 to 10. | Assessment of post operative pain at rest at T90 minutes in PACU by using Numerical pain rating scales (NPRS). Score is from 0 to 10. | 90 min after PACU entrance | 
| Assessment of post operative pain at coughing at T0 minutes in PACU by using Numerical pain rating scales (NPRS) from 0 to 10. | Assessment of post operative pain at coughing at T0 minutes in PACU by using Numerical pain rating scales (NPRS). Score is from 0 to 10. | at PACU entrance | 
| Assessment of post operative pain at coughing at T15 minutes in PACU by using Numerical pain rating scales (NPRS) from 0 to 10. | Assessment of post operative pain at coughing at T15 minutes in PACU by using Numerical pain rating scales (NPRS). Score is from 0 to 10. | 15 min after PACU entrance | 
| Assessment of post operative pain at coughing at T30 minutes in PACU by using Numerical pain rating scales (NPRS) from 0 to 10. | Assessment of post operative pain at coughing at T30 minutes in PACU by using Numerical pain rating scales (NPRS). Score is from 0 to 10. | 30 min after PACU entrance | 
| Assessment of post operative pain at coughing at T45 minutes in PACU by using Numerical pain rating scales (NPRS) from 0 to 10. | Assessment of post operative pain at coughing at T45 minutes in PACU by using Numerical pain rating scales (NPRS). Score is from 0 to 10. | 45 min after PACU entrance | 
| Assessment of post operative pain at coughing at T60 minutes in PACU by using Numerical pain rating scales (NPRS) from 0 to 10. | Assessment of post operative pain at coughing at T60 minutes in PACU by using Numerical pain rating scales (NPRS). Score is from 0 to 10. | 60 min after PACU entrance | 
| Assessment of post operative pain at coughing at T75 minutes in PACU by using Numerical pain rating scales (NPRS) from 0 to 10. | Assessment of post operative pain at coughing at T75 minutes in PACU by using Numerical pain rating scales (NPRS). Score is from 0 to 10. | 75 min after PACU entrance | 
| Assessment of post operative pain at coughing at T90 minutes in PACU by using Numerical pain rating scales (NPRS) from 0 to 10. | Assessment of post operative pain at coughing at T90 minutes in PACU by using Numerical pain rating scales (NPRS). Score is from 0 to 10. | 90 min after PACU entrance | 
| Evaluation of intraoperative total vasoactive drugs (phenylephrine) consumption in mcg. | Evaluation of intraoperative total phenylephrine consumption (in mcg) | During anesthesia for surgery | 
| Evaluation of intraoperative total vasoactive drugs (ephedrine) consumption in mcg | Evaluation of intraoperative total ephedrine consumption (in mg) | During anesthesia for surgery | 
| Evaluation of intraoperative total vasoactive drugs (diltiazem) consumption in mg | Evaluation of intraoperative total diltiazem consumption (in mg) | During anesthesia for surgery | 
| Evaluation of intraoperative frequency of vasoactive drugs (phenylephrine) administration in number of events | Evaluation of intraoperative frequency of phenylephrine consumption (n) | During anesthesia for surgery | 
| Evaluation of intraoperative frequency of vasoactive drugs (ephedrine) administration in number of events | Evaluation of intraoperative frequency of ephedrine consumption (n) | During anesthesia for surgery | 
| Evaluation of intraoperative frequency of vasoactive drugs (diltiazem) administration in number of events | Evaluation of intraoperative frequency of diltiazem consumption (n) | During anesthesia for surgery | 
| Assessment of post operative sedation at T0 minutes in PACU by using Ramsay Sedation Score from 1 to 6 | Assessment of post operative sedation at T0 minutes in PACU by using Ramsay Sedation Score. Score is from 1 to 6. | at PACU entrance | 
| Assessment of post operative sedation at T15 minutes in PACU by using Ramsay Sedation Score from 1 to 6 | Assessment of post operative sedation at T15 minutes in PACU by using Ramsay Sedation Score. Score is from 1 to 6. | 15 min after PACU entrance | 
| Assessment of post operative sedation at T30 minutes in PACU by using Ramsay Sedation Score from 1 to 6 | Assessment of post operative sedation at T30 minutes in PACU by using Ramsay Sedation Score. Score is from 1 to 6. | 30 min after PACU entrance | 
| Assessment of post operative sedation at T45 minutes in PACU by using Ramsay Sedation Score from 1 to 6 | Assessment of post operative sedation at T45 minutes in PACU by using Ramsay Sedation Score. Score is from 1 to 6. | 45 min after PACU entrance | 
| Assessment of post operative sedation at T60 minutes in PACU by using Ramsay Sedation Score from 1 to 6 | Assessment of post operative sedation at T60 minutes in PACU by using Ramsay Sedation Score. Score is from 1 to 6. | 60 min after PACU entrance | 
| Assessment of post operative sedation at T75 minutes in PACU by using Ramsay Sedation Score from 1 to 6 | Assessment of post operative sedation at T75 minutes in PACU by using Ramsay Sedation Score. Score is from 1 to 6. | 75 min after PACU entrance | 
| Assessment of post operative sedation at T90 minutes in PACU by using Ramsay Sedation Score from 1 to 6 | Assessment of post operative sedation at T90 minutes in PACU by using Ramsay Sedation Score. Score is from 1 to 6. | 90 min after PACU entrance | 
| Number of nausea episodes in the 24 hours upon discharge from PACU | To record the number of nausea episodes in the he 24 hours upon discharge from PACU (n) | The 24 hours upon discharge from PACU | 
| Number of emetic episodes in the 24 hours upon discharge from PACU | To record the number of emetic episodes (retching or vomiting) in the he 24 hours upon discharge from PACU (n) | The 24 hours upon discharge from PACU | 
| Number of nausea AND vomiting episodes in the 24 hours upon discharge from PACU | To record the number of nausea AND vomiting episodes in the he 24 hours upon discharge from PACU (n) | The 24 hours upon discharge from PACU | 
| Patient self evaluation of nausea intensity | Patient verbal rate of their worst nausea episode since emergence using a 11 points scale (0: no nausea to 10: most severe nausea) | The 24 hours upon emergence | 
| Incidence of respiratory depression episodes | Incidence of respiratory rate < 9 respirations per minute episodes the first 1.5 hour since the admission to PACU (n) | 1.5 hour since the admission to PACU | 
| Incidence of requirement for naloxone reversal of opioids | Incidence of requirement for naloxone reversal of opioids the first 1.5 hour since the admission to PACU (n) | 1.5 hour since the admission to PACU | 
| Incidence of requirement for additional reversal of muscle relaxants | Incidence of requirement for additional reversal of muscle relaxants the first 1.5 hour since the admission to PACU (n) | 1.5 hour since the admission to PACU | 
| Assessment of post operative itching at T0 minutes in PACU from 0 to 10 | Assessment of post operative itching at T0 minutes in PACU by using a 11 points scale (0: no itching, to 10: the most severe itching possible) | At PACU entrance | 
| Assessment of post operative itching at T15 minutes in PACU from 0 to 10 | Assessment of post operative itching at T15 minutes in PACU by using a 11 points scale (0: no itching, to 10: the most severe itching possible) | 15 min after PACU entrance | 
| Assessment of post operative itching at T30 minutes in PACU from 0 to 10 | Assessment of post operative itching at T30 minutes in PACU by using a 11 points scale (0: no itching, to 10: the most severe itching possible) | 30 min after PACU entrance | 
| Assessment of post operative itching at T45 minutes in PACU from 0 to 10 | Assessment of post operative itching at T45 minutes in PACU by using a 11 points scale (0: no itching, to 10: the most severe itching possible) | 45 min after PACU entrance | 
| Assessment of post operative itching at T60 minutes in PACU from 0 to 10 | Assessment of post operative itching at T60 minutes in PACU by using a 11 points scale (0: no itching, to 10: the most severe itching possible) | 60 min after PACU entrance | 
| Assessment of post operative itching at T75 minutes in PACU from 0 to 10 | Assessment of post operative itching at T75 minutes in PACU by using a 11 points scale (0: no itching, to 10: the most severe itching possible) | 75 min after PACU entrance | 
| Assessment of post operative itching at T90 minutes in PACU from 0 to 10 | Assessment of post operative itching at T90 minutes in PACU by using a 11 points scale (0: no itching, to 10: the most severe itching possible) | 90 min after PACU entrance | 
| Post operative time to discharge from PACU in min | To record the time since the admission to the discharge from PACU (min) | PACU stay (1.5 hours) | 
| Time to the first postoperative pain rescue medication administration in PACU in min | To record the time since the admission in the PACU to the first postoperative pain rescue medication administration in PACU (min) | PACU stay (1.5 hours) | 
| Time to the first postoperative pain rescue medication administration after the PACU discharge | To record the time since the discharge of PACU to the first postoperative pain rescue medication administration in PACU (min) | The 24 hours upon discharge from PACU | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NOL monitoring, anesthesia, fentanyl consumption, intraoperative