Impact of Intraoperative Deep Neuromuscular Blockade on NOL-guided Opioid Requirement in LSC Colorectal Surgeries

Study Overview
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Brief Summary
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The aim of the present study is to answer the question whether deep neuromuscular blockade has a clinically significant impact on intra and postoperative pain, opioid requirement and anesthesia related outcomes and side effects for the early phase of recovery (24hs) after colorectal laparoscopic surgery.

Detailed Description
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Background: For the last decade many studies have reported that intraoperative surgical and anesthesia conditions might have an impact of postoperative pain. The most recent surgical literature agrees on the fact the IAP should remain under 15mmhg or even 12mmhg during the whole laparoscopic surgery, and many efforts to do so were developed in the most recent years. On the anesthesia side, deep neuromuscular block was associated with better postoperative recovery when looking at pain parameters such as pain scores and opioid requirements. Nevertheless, all these previous studies, even if recent, did not properly evaluate intraoperative pain and did not well control criteria used to guide the administration of intraoperative opioids, one of the main components of anesthesia. Also, lots of these studies did not properly evaluate or control the depth of hypnosis, another main component of anesthesia. Nowadays, new monitors with extremely better sensitivity and specificity are available for each of the anesthesia component. This might completely revisit the previous findings in the literature and offer much better-quality results. Maisonneuve-Rosemont Hospital in Montreal is a unique center that has invested in new monitors to evaluate each of these anesthesia component: BIS index for depth of hypnosis (BIS device, Covidien, Saint-Laurent, Canada), NOL index (PM-200TM device, Medasense LTD, Ramat Gan, Israel) for nociceptive evaluation (intra-operative pain assessment under general anesthesia), and TOF-scan (NMB monitor, Drager, Mississauga, Canada) for quantitative and 3D evaluation of the depth of muscle relaxation. This study will answer the question whether deep neuromuscular blockade has a clinically significant impact on intra and postoperative pain, opioid requirement and anesthesia related outcomes and side effects for the early phase of recovery (24hs) after colorectal laparoscopic surgery. This study will be conducted in a single center, and will be an open label, single blinded, randomized controlled study. Type of surgery: laparoscopic colorectal surgery with anesthesia time expected to last more than 120min in ASA 1-3 patients, fully consented for primary colorectal laparoscopic surgery. The primary objective of the study: To compare total intra-operative remifentanil consumption during anesthesia for laparoscopic colorectal surgery between two groups: Group D for Deep muscle relaxation and group M for Moderate muscle relaxation. Secondary objectives are listed below. For an expected decrease of 25% in the remifentanil intraoperative consumption per hour of surgery (in mcg) of surgery, with a type I error α = 0.05 (two-tailed), a 90% power, the total sample size needed is 82 (41 per group). To account for an approximative 20% rate of loss to follow-up or missing data due to technical problems, a total of 100 subjects will be recruited. Study Duration: 24 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 has been accepted by the company Merck (see letter attached) for the sponsoring of this study.

Official Title
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A Randomized Parallel Design Study to Compare the Impact of Intraoperative Deep Neuromuscular Blockade on Intraoperative NOL-guided Opioid Requirement and Postoperative Early Outcomes in Laparoscopic Colorectal Surgeries

Conditions
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Laparoscopic Colorectal Surgeries

Intervention / Treatment
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* Drug: Rocuronium IV bolus 0.1 mg/kg guided by TOF that must remain between 1-3 during surgery
* Drug: Rocuronium IV bolus 0.1 mg/kg guided by TOF 0/4 and PTC≤ 2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ASA1-3 patients, fully consented, primary colorectal laparoscopic surgery and no previous laparotomy for the last 5 years BMI < 35, Age > 18yo, no allergy to any of the medications used in this study. Exclusion Criteria: history of coronary artery disease serious cardiac arrhythmia (including atrial fibrillation) history of substance abuse chronic use of psychotropic and/or opioid drugs use of drugs that act on the autonomic nervous system (including β-blockers) history of psychiatric diseases with the need of medication allergy to any drug used in the study protocol refusal of the patient for participation in the study

Ages Eligible for Study
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Minimum Age: 18 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
Interventional Model Description: Tow groups of patients. Randomization into group D for Deep muscle relaxation vs group M for Moderate muscle relaxation according to a randomization list for a total number of 100 patients
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group M for Moderate muscle relaxation, low doses rocuronium<br>A bolus of 0.4 mg/kg of IV rocuronium will be given at the induction of the anesthesia. Rocuronium IV bolus guided by TOF that must remain between 1-3 / 4 during surgery. | Drug: Rocuronium IV bolus 0.1 mg/kg guided by TOF that must remain between 1-3 during surgery<br>* Bolus of rocuronium 0.1 mg/kg at the discretion of anesthetist to keep the TOF between 1-3 out of 4 during surgery<br>|
| Experimental: Group D for Deep muscle relaxation, high doses rocuronium<br>A bolus of 0.4 mg/kg of IV rocuronium will be given at the induction of the anesthesia. Bolus of rocuronium 0.1 mg/kg IV will be given during surgery to keep the TOF 0/4 and a PTC ≤ 2 (parameters measured every 10 minutes). | Drug: Rocuronium IV bolus 0.1 mg/kg guided by TOF 0/4 and PTC≤ 2<br>* Bolus of rocuronium 0.1 mg/kg IV will be given during surgery for a TOF 0/4 and a PTC ≤ 2 (parameters measured every 10 minutes).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total intra-operative remifentanil consumption during surgery in mcg/kg/h | To compare total intra-operative remifentanil consumption (in mcg per hour from T0 incision until Tend = start dressing) during anesthesia for laparoscopic colorectal surgery between two groups: Group D for Deep muscle relaxation and group M for Moderate muscle relaxation | Intra-operative (from T0 incision until Tend = start dressing) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of IV boluses and increases of remifentanil infusion, number, no unit | To compare the number of IV boluses and increases of remifentanil infusion needed in group D versus M | Intra-operative (from T0 incision until Tend = start dressing) | 
| Number of times NOL index passes over the threshold of 25, number, no unit | To compare the number of times NOL index passes over the threshold of 25 (considered as painful threshold in an anesthetized patient) during anesthesia in group D versus M | Intra-operative (from T0 incision until Tend = start dressing) | 
| Area Under the Curve (AUCs) whenever the NOL is above 25, no unit | To compare the Area Under the Curve (AUCs) of all the intraoperative periods for which the NOL index will be above the pain threshold of 25 from T0 until Tend | Intra-operative (from T0 incision until Tend = start dressing) | 
| Total intraoperative time from T0 until Tend with NOL above 25 in minutes | To compare the total intraoperative time in minutes from T0 until Tend with NOL index above 25, with NOL index between 10 and 25, and with NOL index below 10 in group D versus M | Intra-operative (from T0 incision until Tend = start dressing) | 
| Intraoperative level of intra-abdominal pressure (IAP) in mmHg | To compare between group D versus M the intraoperative level of intra-abdominal pressure (IAP) to keep a surgeons' satisfaction score (Leiden Surgical Rating Scale L-SRS) | Intra-operative (from T0 incision until Tend = start dressing) | 
| Abdominal insufflation duration in minutes | To compare the time in minutes spent with abdominal insufflation and laparoscopic surgery between group D and M | Intra-operative (from T0 incision until Tend = start dressing) | 
| Time for awakening and extubation in seconds | To compare the time for awakening and extubation (performed for all patients in the Operating Room, OR) between group D and M | Intra-operative (from T0 incision until Tend = start dressing) | 
| Pain score at rest on a scale from 0 to 10 | To compare maximal postoperative pain scores (Numeric Rating Scale, NRS) at: arrival in postanesthesia care unit (PACU), and every 15 min until PACU discharge at rest and coughing/mobilization | every 15 minutes until discharge from PACU, up to 3 hours | 
| Pain score at coughing/mobilization on a scale from 0 to 10 | To compare maximal postoperative pain scores (Numeric Rating Scale, NRS) at: arrival in postanesthesia care unit (PACU), and every 15 min until PACU discharge at rest and coughing/mobilization | every 15 minutes until discharge from PACU, up to 3 hours | 
| Pain score at the shoulder on a scale from 0 to 10 | To compare the incidence of shoulder pain and intensity (maximal NRS score at the shoulder) in PACU at arrival then every 15 minutes, between group D versus M | every 15 minutes until discharge from PACU, up to 3 hours | 
| Postoperative Hydromorphone consumption in mg in Postoperative Care Unit (PACU) | To compare the total amount of hydromorphone (in mg) given IV in PACU as a pain killer titration following a strict PACU protocol to reach a NRS pain score < 4/10 between group D and M | every 15 minutes until discharge from PACU, up to 3 hours | 
| Pain score at rest at 8hs on a scale from 0 to 10 | To compare maximal postoperative pain scores at rest at 8 hours after surgery between group D and M | 8 hours after surgery in hospital | 
| Pain score at coughing/mobilization at 8hs on a scale from 0 to 10 | To compare maximal postoperative pain scores at coughing/movement at 8 hours after surgery between group D and M | 8 hours after surgery in hospital | 
| Pain score at rest at 16hs on a scale from 0 to 10 | To compare maximal postoperative pain scores at rest at 16 hours after surgery between group D and M | 16 hours after surgery in hospital | 
| Pain score at coughing/mobilization at 16hs on a scale from 0 to 10 | To compare maximal postoperative pain scores at coughing/movement at 16 hours after surgery between group D and M | 16 hours after surgery in hospital | 
| Pain score at rest at 24hs on a scale from 0 to 10 | To compare maximal postoperative pain scores at rest at 24 hours after surgery between group D and M | 24 hours after surgery in hospital | 
| Pain score at coughing/mobilization at 24hs on a scale from 0 to 10 | To compare maximal postoperative pain scores at coughing/movement every 24 hours after surgery between group D and M | 24 hours after surgery in hospital | 
| Amount of opioids received in 24h as Patient Controlled Analgesia in mg | To compare analgesic requirements for 24 hours given as patient controlled analgesia (PCA) in mg over 24hs | 24 hours after surgery in hospital | 
| Recovery score QOR15 questionnaire (150 points maximum for this questionnaire) | To compare recovery scores (QOR15) from 0 to 150 points at 24 hours after surgery | 24 hours after surgery in hospital | 
| POSS postoperative Sedation score in PACU on a scale from 1 to 4 | Sedation score in PACU | every 30 minutes from T0 = arrival in PACU until discharge from PACU, up to 3 hours | 
| postoperative nausea and vomiting score in PACU on a scale from 0 to 3 | nausea and vomiting score in PACU from 0 to 3 | every 30 minutes from T0 = arrival in PACU until discharge from PACU, up to 3 hours | 
| postoperative Aldrete score in PACU on a scale from 5 to 15 | Recovery score in PACU to decide on the possibility of discharge of the patient from PACU | every 30 minutes from T0 = arrival in PACU until discharge from PACU, up to 3 hours | 

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