Impact of Nociceptive-Level (NOL) Intraoperative Guided Analgesia During Gynecological Laparoscopic Surgery Under General Anesthesia
Condition: Gynecologic Laparoscopic Surgery; Hysterectomy; Oophorectomy
Study type: Interventional
Phase: Phase 4

Summary: 
      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: 
      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:

        1. 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.

        2. 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.

        3. 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:

        1. 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).

        2. 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.
    

Intervention name(s): Intravenous Fentanyl guided by SoC+NOL; Intravenous Fentanyl guided by SoC
Intervention type(s): Drug; Drug
Intervention description(s): 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.; 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.
Intervention MeSH terms: Fentanyl
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention 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 (Participant, Care Provider, Outcomes Assessor)
Primary purpose: Prevention
Keywords: NOL monitoring; anesthesia; fentanyl consumption; intraoperative