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

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.

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.

Eligibility Criteria:
Inclusion Criteria:

1. Female age 18-75 years
2. ASA I-III
3. adult patients scheduled to undergo elective gynecological laparoscopic surgery (hysterectomy and uni- or bilateral oophorectomy) under general anesthesia
4. patient able to consent in the language of the including center

Exclusion Criteria:

1. use of any type of anesthesia other than general anesthesia (neuraxial, epidural analgesia or local regional anesthesia, e.g. transversus abdominal plane block...)
2. patients with non-regular sinus cardiac rhythm, implanted pacemakers, prescirbed antimuscarinic agents, alpha2-adrenergic agonists, beta1-adrenergic antagonists, and antiarrhythmic agents
3. emergent surgery
4. pregnancy/lactation. Pregnancy test will be performed in all women of child bearing age
5. BMI \> 35 kg/m2
6. preoperative hemodynamic disturbance
7. central nervous system disorder (neurologic/ head trauma/ uncontrolled epileptic seizures)
8. drug or alcohol abuse within the last 6 months (for women, \> 3 drinks on one occasion or \>7 drinks during a week)
9. pre-operative chronic opioid use or chronic pain, equivalent to oxycodone 20mg per oral, per day for more than 6 weeks
10. chronic use of psychoactive drugs within 90 days prior to surgery
11. medical conditions qualifying for ASA III or IV:

    1. untreated or persistent peripheral or central cardiovascular disease
    2. severe pulmonary disease e.g. COPD gold 4, FEV\< 1.0l/s, or (evidence of) elevated paCO2 \> 6.0 kPa
    3. significant hepatic disease with increased bilirubin, INR or low albumin
    4. history of severe cardiac arrhythmia e.g. chronic atrial fibrillation
    5. active pacemaker or defibrillator
12. allergy or intolerance to any of the study drugs
13. intraoperative cardiac arrhythmia