Impact of Continuous Intraoperative Administration of Esmolol on Nociception Level-guided Control of Nociception. The EsmoNOL Randomized Controlled Trial
Phase: PHASE4
Conditions: Opioid Use, Unspecified, Anesthesia, Nociceptive Pain
Sponsor: Ciusss de L'Est de l'Île de Montréal

 
 
1 
 
 
 
STUDY PROTOCOL 
 
 
 
 
 
 
 
Impact of continuous intraoperative administration of esmolol on NOL-
guided control of nociception. The EsmoNOL randomized controlled trial 
 
 
 
 
 
 
 
Version: 3 
February 26, 2024 
 
 
 
 
 
 
ClinicalTrial : NCT06291363 
 
 
 
 
 
 
This trial will be conducted in compliance with the protocol, GCP and the 
applicable regulatory requirements 
 
 

 
 
2 
CONFIDENTIAL 
 
This document is confidential and the property of the University of Montréal. No part of it 
may be transmitted, reproduced, published, or used by other persons without prior 
written authorization from Dr. Pascal Laferrière-Langlois 
 
 
Title 
 
Impact of continuous intraoperative administration of esmolol  on NOL-guided control of 
nociception. The EsmoNOL randomized controlled trial 
 
Version 3, February 26th, 2024 
 
 
Principal investigator: 
Pascal Laferrière-Langlois, MD, MSc, Assistant Professor, Anesthesiologist, 
Department of Anesthesiology and Pain Medicine at University of Montréal 
Maisonneuve-Rosemont Hospital – CIUSSS de l’Est de l'Île de Montréal  
(HMR- CEMTL) 
5415, boulevard de l'Assomption, Montréal, Québec 
H1T 2M4, Canada 
+1-819-432-5847 
pascal.laferriere-langlois@umontreal.ca 
 
 
Co-Investigators: 
Will collaborate and be involved in participants’ inclusion/follow-up at HMR-CEMTL: 
Julien Burey, MD, Anesthesia Fellow, University of Montréal 
Louis Morrison, MD, MSc, Assistant professor, University of Montréal 
Philippe Richebé, MD, PhD Full Professor with tenure, Anesthesiologist, 
Research Chair, Department of Anesthesiology and Pain Medicine at University of Montréal 
Olivier Verdonck, MD, MSc, Chief of the Department of Anesthesiology, Maisonneuve-
Rosemont Hospital, Assistant Professor, Anesthesiologist, University of Montréal 
Nadia Godin, Research Coordinator and RN 
Moulay Idrissi, BEng, MSc, Research Assistant 
 
 
Collaborators and external consultants with specific expertise in the field: 
Will collaborate, but not involved in participants’ inclusion/follow-up at HMR-CEMTL 
 
Hind Idali, Department of medicine, University of Montreal 
Annik Fortier, MSc, Department of Statistics MHICC, Senior Biostatistician, University of 
Montréal 
Marie-Claude Guertin, PhD, Department of Statistics MHICC, Chief Biostatistician, University 
of Montréal 
 

 
 
3 
TABLE OF CONTENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
A. BACKGROUND 
5 
 
B. OBJECTIVES & HYPOTHESIS 
7 
PRIMARY OBJECTIVE 
7 
SECONDARY OBJECTIVES 
7 
      HYPOTHESES 
8 
 
C. METHODS 
8 
STUDY DESIGN 
8 
PATIENT POPULATION 
8 
INCLUSION CRITERIA 
8 
EXCLUSION CRITERIA 
9 
RECRUITMENT 
9 
RANDOMIZATION AND BLINDING 
10 
MONITORING 
10 
 
D.  ENDPOINTS 
13 
PRIMARY ENDPOINT 
13 
SECONDARY ENDPOINTS 
13 
DATA COLLECTION PROCEDURES 
14 
 
E. STATISTICAL PLAN 
15 
SAMPLE SIZE DETERMINATION AND POWER 
15 
STATISTICAL METHODS 
15 
 
F. SAFETY AND ADVERSE EVENTS 
17 
SAFETY AND COMPLIANCE MONITORING 
17 
MEDICAL MONITORING 
17 
DEFINITION OF ADVERSE EVENTS 
17 
ADMINISTRATION OF THE INTERVENTION DRUG : ESMOLOL 
18 
 
 
 
 
 
 
 
G. PROPER HANDLING OF SUBJECTS 
18 
ETHICAL CONSIDERATIONS 
18 

 
 
4 
SUBJECT WITHDRAWAL 
19 
EARLY WITHDRAWAL OF PATIENTS 
19 
WHEN AND HOW TO WITHDRAW PATIENTS 
19 
DATA COLLECTION AND FOLLOW-UP FOR WITHDRAWN PATIENTS 
19 
BREACH OF PROTOCOLE 
19 
RISKS 
20 
 
H. DATA HANDLING AND RECORD KEEPING 
20 
CONFIDENTIALITY AND SECURITY 
20 
ELECTRONIC DATA 
20 
HARD DATA 
20 
CODING DATA 
20 
ACCESSIBILITY 
21 
TRAINING 
21 
LINKED DATA 
21 
 
I. STUDY MONITORING, AUDITING, AND INSPECTING 
21 
STUDY MONITORING PLAN 
21 
AUDITING AND INSPECTING 
21 
 
J. STUDY ADMINISTRATION 
21 
ORGANIZATION AND RECRUITING SITE 
21 
Study Timetable 
22 
 
K. PUBLICATION PLAN 
22 
 
L. BUDGET 
22 
 
M. REFERENCES 
23 
 
N. ANNEXES 
25 
 
O. FIGURE 1 
26 
 
 
 
 
 
 
 
 
 
 
 

 
 
5 
A. 
BACKGROUND  
Opioid analgesic drugs have long been the gold standard treatment for perioperative pain 
relief, playing a crucial role in general anesthesia. Although opioids have a high perioperative 
analgesic efficacy, they typically cause short-term adverse effects and potentially severe long-
term adverse effects as evidenced by the ongoing opioid epidemic in North America 
(Bohringer et al., 2020; Shanthanna et al., 2021). Opioids can also lead to another problematic 
condition known as opioid-induced hyperalgesia (OIH), a paradoxical response characterized 
by increased pain sensitivity in patients using opioids for pain relief (Angst and Clark, 2006; 
Colvin et al., 2019; Richebé et al., 2018). More specifically, it has been proven that high 
intraoperative doses of opioids cause hyperalgesia in patients after surgery (Fletcher and 
Martinez, 2014). Given this, two approaches were explored : opioid-free anesthesia and 
opioid-sparing anesthesia, employing a combination of analgesics and adjuvants via 
continuous infusions (Shanthanna et al., 2021).  
 
Intraoperative beta-blockers as a opioid-sparing strategy 
The use of esmolol as an adjuvant to general anesthesia has been suggested as an opioid-free 
potential alternative. Esmolol is an ultra-short acting cardioselective β1-adrenergic receptor 
antagonist that plays a crucial role in reducing sympathetic overload induced by numerous 
perioperative stimuli such as tracheal intubation, intraoperative events, and extubation 
(Asouhidou and Trikoupi, 2015). Since sympathetic overload generates physiological 
responses that reflect the patient’s pain (Paloheimo et al., 2010), esmolol could serve as a 
viable alternative to opioids in maintaining hemodynamic stability during general anesthesia 
(Asouhidou and Trikoupi, 2015). Although esmolol lacks analgesic or anesthetic properties on 
its own, its combination with propofol or volatile-based anesthesia showed great promise in 
reducing the intraoperative and postoperative analgesic consumption (Celebi et al., 2014).  
 
Previous studies assessing intraoperative esmolol and its administration based on vital signs 
have led to inconsistencies and controversies with some studies supporting its use and others  
disapproving it (Gelineau et al., 2018). However, relying solely on vital signs, such as blood 
pressure (BP) or heart rate (HR), as a guide for esmolol administration may influence the doses 
administered as esmolol can lower BP and HR. Thus, this approach might not be ideal as it 

 
 
6 
could overlook other essential factors and necessitates the adoption of a more comprehensive 
monitoring system that considers a larger range of parameters. 
 
Nociception monitoring as a opioid-sparing strategy 
With the advent of nociception monitoring, new  devices can be used, especially the 
Physiological Monitoring Device PMD-200TM. This device offers the multiparameter 
Nociception Level (NOL) index that integrates five parameters in a dimensionless index : HR, 
heart rate variation (HRV), photoplethysmographic pulse wave amplitude (PPGA), skin 
conductance level (SC), number of SC fluctuations . By continuously analyzing the incoming 
signals with an artificial intelligence algorithm, this monitor provides a real-time index to 
inform the clinician on the level of nociception felt by the anesthetized patient, thus guiding 
the administration of opioids. Even if the core signals reflect the activity of the sympathetic 
nervous system, this monitor has been validated to monitor nociceptive stimuli (Martini et al., 
2015; Renaud-Roy et al., 2019; Shahiri et al., 2022), and has been demonstrated to reduce the 
intraoperative consumption of opioids by 20 to 30% while simultaneously reducing pain and 
opioids consumption in the PACU.  
 
Combining beta-blockers to nociception monitoring 
While it has been demonstrated that chronic usage of beta-blockers does not impair the 
intraoperative validity of the NOL Index (Bergeron et al., 2022), it remains unclear how acute 
administration of short-acting cardioselective β1-adrenergic blocker, such as esmolol, impacts 
the use of sympathetic system-based nociception monitors. Combining the two opioid-sparing 
strategies could either act synergistically, or could antagonize their respective benefits.  
 
Therefore, this study aims to evaluate esmolol’s perfusion impact during induction and 
maintenance of general anesthesia, using NOL-guided control of nociception, in adult patients 
undergoing laparoscopic and lower abdominal surgery, on intraoperative remifentanil  
consumption and postoperative pain in the PACU. 
 
 
 

 
 
7 
B. 
OBJECTIVES & HYPOTHESIS 
Primary Objective 
The main objective of the study is to evaluate the impact of continuous intraoperative infusion 
of esmolol on intraoperative remifentanil administration in patients undergoing general 
anesthesia with NOL-guided nociception management.  
Secondary Objectives 
Secondary objectives cover a wide range of concepts, including the hemodynamic impact of 
esmolol, the pain profile, and the incidence of opioid-related side effects. More specifically, 
we aim to : 
 
1. compare NOL Index variation before and after orotracheal intubation and first surgical 
incision. NOL index will be evaluated 3 minutes after stimulations to record the maximum 
value and calculate the area under the curve ; 
2. compare the mean intraoperative BP and HR; 
3. compare the intraoperative requirements and time weighted average of norepinephrine, 
ephedrine, glycopyrrolate and atropine; 
4. compare the total time and time weighted average with NOL value above > 25. 
5. To compare the total time and time weighted average of hypotension and/or bradycardia 
during surgery; 
6. compare the time to first analgesic requirement in PACU; 
7. compare postoperative morphine equivalent consumption in the post anesthesia care unit 
(PACU); 
8. compare the intensity of pain at rest and under stress, using a verbal rating scale (VRS), 
from arrival to discharge from PACU; 
9. To compare Silvermann Integrated Approach (SIA) Score (combining pain score and opioid 
consumption); 
10. assess postoperative outcomes such as postoperative nausea and vomiting (PONV) and 
amount of antiemetics used in PACU; 
11. compare the time spent in PACU. 

 
 
8 
Hypotheses 
The main hypothesis of this study is to show that patients receiving an intraoperative esmolol 
infusion during a NOL-guided general anesthesia, will consume a lower amount of 
intraoperative remifentanil (mcg.kg-1.h-1) with a reduction of 20 to 30% of intraoperative 
opioid consumption, without impacting hemodynamic parameters. Upon reproducible 
nociceptive stimulation such as orotracheal intubation and initial surgical incision, we expect 
a reduction of the deltaNOL with the administration of esmolol, while still capturing the event 
on the PMD-200. Finally, once the patient reaches the PACU, we expect a longer time to first 
opioid, a lower pain score on arrival, a lower opioid consumption, a reduced incidence of 
PONV, and a shorter PACU stay.  
 
C. 
METHODS 
Study design  
The study design is a prospective randomized controlled double-blinded superiority trial, 
conducted at a single center : Maisonneuve-Rosemont Hospital, part of the Centre intégré 
universitaire de santé et des services sociaux (CIUSSS) de l’est de l’île-de-Montréal (CEMTL), 
located in Montreal, Quebec, Canada. The duration of this study is expected to be 1 year,  from 
February 2024 to February 2025. 
Patient population 
We will screen and aim to recruit consecutive adult patients undergoing laparoscopic  lower 
abdominal surgery expected to last between 60 to 180 minutes.  
Inclusion criteria 
● Fully consented, ASA 1-3 patients from 18yo to 65yo 
● Undergoing laparoscopic surgery associated with sub umbilical mini-laparotomy. 
Eligible surgeries will be hysterectomy (excluding vaginal approach) and left 
hemicolectomy, of duration time expected under 180 minutes, under général 
anesthesia 
● No allergy to one of the medications used in this study 

 
 
9 
Exclusion criteria 
Contraindication to the use of the study drug (esmolol) is an exclusion criterion : 
● Hypotension 
● Sinus bradycardia 
● Sick sinus syndrome 
● Second and third degree A-V block 
● Pulmonary hypertension 
● Right ventricular failure secondary to pulmonary hypertension 
● Decompensated heart failure 
● Cardiogenic shock 
● Nontreated pheochromocytoma 
● Known hypersensitivity to esmolol or any of the inactive ingredients of the product 
● Allergy to esmolol or other beta blockers (cross-sensitivity is possible) 
● Renal dysfunction  
● Airway disease such as asthma or COPD 
● Thyrotoxicosis 
● Myasthenia gravis 
● Raynaud’s disease or oeripheral circulatory disorder 
 
Other situations leading to exclusion : 
● Severe mental impairment 
● Chronic use of opioids, β-adrenergic receptors antagonists  
● High risk of conversion to laparotomy according to the surgical team (>25%) 
Patients will automatically be excluded after recruitment if they withdraw their consent, or if 
laparoscopy is converted to laparotomy. 
 
Recruitment 
The research team will assess the elective surgical list of Maisonneuve-Rosemont Hospital’s 
operating room to identify eligible patients at least one week before their scheduled surgery. 
Potential participants will be contacted by the research team via phone to provide an 

 
 
10 
explanation of the project. The communication form used during these calls will be approved 
by the CIUSSS EMTL Research Ethics Committee.   
 
Patients who express interest will receive the information and consent form via email to 
obtain further details about the study protocol. They will also be informed about the potential 
risks of esmolol before agreeing to participate.   
 
A thorough review of the patients’ medical charts will be conducted to confirm that they meet 
the inclusion criteria and have no exclusion criteria. Subsequently, the research team will meet 
the candidates before the surgery to address any questions they may have. If the patients still 
wish to participate, informed consent will be obtained. Once approved, the patients will sign 
the consent form and undergo randomization.  
 
Randomization and blinding 
Electronic randomization will be performed by a statistician using a computer-generated 
randomized sequence with a variable block size unknown to the investigators, and then 
implemented in a RedCAP™ application. It will be sealed in an opaque envelope and handed 
to the dedicated research staff not involved in patient care and responsible to prepare the 
blinded syringe. The envelope will be opened at the patient's entry into the operating ward, 
after confirming that the surgery will be performed. Once the group is assigned to the patient, 
the research staff will prepare a syringe containing the randomized solution, either esmolol 
or saline.  Each 10ml ampoule contains 100mg of esmolol. Syringe preparation will depend on 
the patient’s adjusted body weight (ABW) and the expected duration of surgery (DOS) in hour 
as indicated on the surgical booking request. The number of ampoules required (NA) will be 
calculated according to the following formula (rounded up to nearest whole number): 
 
𝑁𝐴= 𝐴𝐵𝑊× '0.5 + (1.2 × 𝐷𝑂𝑆)3
100
 
 
 

 
 
11 
 If a syringe recharge is needed during the surgery, a new blinded syringe containing the same 
substance as the previous one, will be prepared by the dedicated research staff and brought 
into the operating room. 
 
The patient, the anesthesiologist, the surgeon, the PACU staff and the research team acting 
as outcome assessors, will all be blinded to the randomization.  
 
Monitoring 
Both groups will undergo routine monitoring according to the CSA guidelines, which will 
encompass non-invasive blood pressure, pulse-oximetry, EKG and a temperature probe.  
Invasive arterial pressure monitoring will be at the discretion of the anesthesiologist in charge 
of the patient. The monitoring will be conducted using the Dräger Infinity C700 (Dräger 
Medical, Lübeck, Germany) monitor. Additionally, all patients will have a unilateral BISTM EEG 
sensor (Medtronic, Canada) placed on their forehead to monitor the depth of anesthesia. A 
Train-of-four scan (TOF scan™; Draeger Medical Canada inc., Mississauga, Ontario, Canada) 
for monitoring neuromuscular function will also be used. It should be noted that this 
monitoring is not specific to research and is provided to all patients undergoing general 
anesthesia at our center. 
 
Throughout the entire anesthesia duration, the NOL index finger probe (PMD-200™ device, 
Medasense Biometrics Ltd, Ramat Gan, Israel) will be applied for monitoring intraoperative 
nociception.  
 
All intraoperative data and events will be recorded on the research computer, as further 
described in the dedicated section of the protocol. 
 
Anesthesia Protocol 
 
Anesthesia induction: All patients will receive 1g PO acetaminophen with 10mL of water prior 
to entering the operating room. Standardized general anesthesia (GA) protocol will be 
administered in both groups following theses procedures: induction with intravenous (IV) slow 

 
 
12 
boluses of  lidocaine to numb the vein, propofol 1.5 to 2 mg.kg-1 (ABW), remifentanil with 
target controlled infusion (TCI) pump and Minto model to reach an effect-site concentration 
of 3ng.ml-1, rocuronium 0.8 mg.kg-1 total body weight (TBW), and dexamethasone 4 mg. 
Videolaryngoscopy (McGrath) and tracheal intubation will be done when TOF < 2/4 and 
remifentanil TCI plasmatic concentration (Cp) and effect-site concentration (Ce) will reach 
their target. Once intubated, remifentanil infusion will be reduced to a Ce of 1ng.ml-1. A no-
touch period of 3 minutes will be observed. Patient’s installation will then resume. This 
induction is part of a standard anesthesia and does not involve any research protocol. It is 
standardized to homogeneize our population. 
 
Intervention:  Patients will be randomized (1:1) in the intervention group and standard care 
(SOC) group. In the intervention group, intravenous esmolol will be given as a bolus (0.5mg.kg-
1) over 5 minutes, and will be started simultaneously to the remifentanil initiation.  
 
Once the bolus of esmolol is over, a perfusion of 20 mcg.kg-1.min-1 will be programmed and 
maintained until the end of the surgery and completion of skin sutures. In the SOC group saline 
will be used in place of esmolol. According to the latest meta analysis evaluating esmolol in an 
opioid-sparing strategy (Gelineau et al., 2018), in all opioids-controlled trials,  it was given as 
a bolus followed by an infusion for the duration of surgery. Initial boluses ranged from 0.5 to 
2 mg.kg-1. The infusion rate varied from 5 mcg.kg-1.min-1 to 300 mcg.kg-1.min-1 (mostly 5 to 
50 mcg.kg-1.min-1). The dosages proposed in this protocol are based on these studies and 
meta-analyses that have used esmolol for morphine-sparing purposes, while maintaining 
minimal hemodynamic impact, hence the use of much lower dosages. 
 
 
Anesthesia maintenance during surgery: 
Nociception management: The remifentanil target controlled infusion will be set at 3 ng.ml-1 
prior to the surgical incision, and will be modified according to the NOL index, as described in 
Figure 1. If the NOL index is > 25 for more than 1 min, we will increase remifentanil TCI by 0.5 
ng.ml-1. This rate will be decreased by steps of 0.25 ng.ml-1 if the NOL index is < 10 for more 
than 3 min. The minimal remifentanil TCI concentration allowed in the protocol will be 1 ng 
ml-1, to ensure a minimal antinociception drug administration in case of inaccuracy of NOL 

 
 
13 
Index in either group. Furthermore, in the event of a TAM > 120% of its basal level, and despite 
a NOL Index between 10 and 25, remifentanil will be increased. 
 
Only the intervention and anesthesia maintenance sections above differ from the usual 
management of patients under general anesthesia. 
 
In both groups, IV hydromorphone 0.006 mg.kg-1 and ondansetron 4 mg will be administered 
once pneumoperitoneum is deflated and skin suture is started. Local anesthetic infiltration of 
the wounds will be performed by the surgical team using a maximum of 30 ml de bupivacaine 
0.5%. Remifentanil infusion will be stopped and removed at the start of wound dressing.  
 
Hemodynamic management: Baseline mean arterial blood pressure (MAP) will be defined as 
the average of three consecutive values taken 1 min apart and determined before the 
induction of general anesthesia. Intravenous (IV) infusion of norepinephrine will be adjusted 
to maintain +/- 20% of the baseline values of the pre-anesthesia MAP. Balanced crystalloids 
will be administered to patients at a rate of 3 ml.kg-1.h-1 (ABW) throughout the surgery. 
Intravenous fluid boluses will be administered at the discretion of the anesthesiologist in 
charge. Perioperative blood management will be done according to guidelines.  
 
Depth of anesthesia management: The maintenance of anesthesia will rely on sevoflurane to 
reach [0.7–1.2] minimal alveolar concentration (MAC; MAC adjusted to the participant’s age) 
and a BIS index of [40-60]. Sevoflurane will be discontinued when the wound dressing is 
completed, and participants will be extubated in the operating room and transferred to the 
post-anesthesia care unit (PACU).  
 
Neuromuscular blockade management: The TOF ratio will be maintained at 0/4 with repeated 
boluses of 0.1 mg.kg-1 rocuronium.  The patient’s neuromuscular blockade will be reversed by 
sugammadex 2 mg.kg-1 to and 4 mg.kg-1 (TBW) according to TOF response, to obtain a 
minimum ratio  of 0.9. 
 
 
 

 
 
14 
Patient management in PACU: patients will be transferred to the PACU, and as soon as 
sufficient contact is obtained by the PACU nurses the pain level will be assessed. In the PACU, 
all the postoperative criteria of the study will be assessed until time of readiness for discharge.  
According to standard practice, the attendant nurse will administer IV hydromorphone in 
PACU.  
 
D.  
ENDPOINTS 
Primary endpoint 
The primary endpoint is the intraoperative amount of remifentanil in mcg.kg-1.h-1, 
administered between the first surgical incision and its discontinuation at wound dressing.  
 
Secondary endpoints  
 
o The NOL Index variation before and after orotracheal intubation and first surgical 
incision. NOL index will be evaluated 3 minutes after stimulation to record the 
maximum value and calculate the area under the curve; 
o The mean intraoperative BP and HR; 
o The intraoperative doses and time weighted average of norepinephrine (mg); 
ephedrine (mg), glycopyrrolate (mg) and atropine (mg); 
o Total time and time weighted average with NOL value above > 25; 
o The total time and time weighted average of hypotension (< 20% of the baseline values 
of the pre-anesthesia mean arterial pressure (MAP) and/or bradycardia (HR < 60 
beats/min, or HR < 50 beats/min for a profound bradycardia)) during surgery; 
o The time to first analgesic requirement in PACU;  
o The amount of morphine equivalent consumption for postoperative pain relief in the 
post anesthesia care unit (PACU) in both groups. 
o The intensity of pain at rest and under stress, using a verbal rating scale (VRS), from 
arrival to discharge from PACU. 

 
 
15 
o The Silvermann Integrated Approach (SIA) Score (combining pain score and opioid 
consumption); 
o Postoperative outcomes such as postoperative nausea and vomiting (PONV) and 
amount of antiemetics used in PACU; 
o The time spent in PACU (in minutes); 
 
Data Collection Procedures  
Electronic data from medical monitoring devices, including BIS™ and PMD-200™, will be 
collected. Before collecting any data, all device times will be time-synchronized.  The time of 
anesthesia induction, intubation, surgical incisions, and other intraoperative events will be 
manually recorded. This computer gathers all the data electronically and uses the integrated 
events tag system of the Medasense PMD-200™, or the BetterCare software (provided by 
Dräger, Lübeck, Germany) connected to the Dräger anesthesia workstation. 
 
All anesthesia and surgery-related events, like the type and amount of vasopressor used, will 
be recorded separately on a Case Report Form (CRF). The CRF will be built using RedCap 
software (Vanderbilt University), which will be accessed via electronic tablets by the research 
team in the operating room. Once the anesthesia is complete and the patient extubated, all 
the electronic data will be exported.   
 
The data from various monitor devices (anesthesia workstation, ventilator, BIS Index, NOL 
Index), as well as raw waves form of specific signals (BP, pulse-oximetry, plethysmography, 
EKG), will be electronically extracted under a unique identification number assigned at 
randomisation, to a secured, offline research computer, insuring patient anonymization. 
Patient identity will only be mentioned on the consent form, which will be kept in a locked 
closet in the Department of Anesthesiology at Maisonneuve-Rosemont Hospital for as long as 
required by the law (15 years).   
 
Pain intensity is recorded according to a verbal numerical rating scale (0 = absence of pain, 
and 10 = unbearable pain). 

 
 
16 
 
Opioid requirements, pain scores, and post-operative events such as PONV and critical 
respiratory events will be documented on the PACU record. 
 
E. 
STATISTICAL PLAN 
Sample Size Determination and Power 
Based on a recent unpublished trial (MERK study) recently held at our center focusing on 
colorectal surgeries, we assumed a mean intraoperative remifentanil consumption of 5.59 
mcg.kg-1.h-1 and 7.98, respectively in the intervention and control group, with a combined 
standard deviation of ± 3.24. This data is aligned with recently published international data 
(Sabourdin et al., 2022). With an alpha risk of 5%, a power of 80.0%, a two-tailed test, and an 
estimated dropout ratio of 10.0%, it was calculated that 32 patients would be required in each 
group, to detect a 30% reduction in intraoperative remifentanil administration. 
 
Statistical Methods 
Descriptive statistics will be presented by groups using mean and standard deviation, or 
median and interquartile range if the distribution is skewed or not normal for continuous 
parameters (according to the skewness of the distribution of each parameter). Frequency (%) 
will be used for categorical parameters.  According to the nature of the analyzed endpoints, 
confidence intervals (CIs) between proportions or between means/medians differences will 
be presented. Missing data will be replaced by the maximum value observed (worst-case 
scenario). Risk differences or mean differences with 95% confidence intervals will be reported 
for all outcomes. The alpha value will be set at 0.05 to establish statistical significance.  All 
data will be analyzed by the intention to treat principle. All statistical analysis will be 
performed using SAS, SPSS software or python programmation langage via VS Code or Jupyter 
notebook software.  
 
 
 

 
 
17 
Primary Outcome 
Total dose of remifentanil in mg.kg-1.h-1 will be compared using Wilcoxon Mann-Whitney test 
(assuming data will not necessarily follow a normal distribution).  
 
Secondary Outcome 
Intraoperative and postoperative data collected in the groups will be compared using 
parametric (Student t-test) or nonparametric tests (Mann-Withney U test) depending on the 
type of variables and their distribution, and a chi-square test will be used for proportion. Data 
collected over time on categorical variables or on those which are not normally distributed 
will be analyzed with non-parametric tests. 
 
Drug Perfusion trajectories 
We will calculate Z scores for remifentanil and norepinephrine rates of perfusion with the 
mean and standard deviation (SD) of all participants calculated at the same time point  - in the 
following approach: 
 
 
where χ corresponds to the individual rate of perfusion registered, μ and σ correspond to the 
mean and SD of all participants at the same time. 
 
We will use nociception Z scores to define the level of the importance of intraoperative opioid 
and norepinephrine administration needed to maintain adequate NOL index. Intraoperative 
administration will be classified as mild or major: 
-    None : a decrease in Z score < 1 SD, 
-    Minor: a decrease in Z score ≥ 1 SD, 
-    Major: a decrease in Z score ≥ 1.96 SD. 
 
 
 

 
 
18 
F. 
SAFETY AND ADVERSE EVENTS 
Safety And Compliance Monitoring 
Ensuring participant safety is a top priority for the research team and hospital staff. In the 
unlikely chance of an unexpected adverse event, the principal investigator, Dr. Pascal 
Laferrière-Langlois, will be immediately notified. Prompt actions will be taken to provide 
appropriate care.  
 
The devices used in this study include standard anesthetic monitoring, with the addition of a 
non-invasive finger probe for NOL analysis. Classical monitoring will always be recorded and 
serve as the reference for anesthesia guidance.   
 
Patients experiencing adverse reactions will be closely monitored by the appropriate doctor 
until discharged from the PACU. If necessary, they will be hospitalized for further observation. 
 
Medical Monitoring 
The study has a low level of risk. The Principal Investigator (PI) or designated personnel will 
regularly review all data, such as study completeness, enrollment, protocol deviations, 
dropouts, and adverse events, on a weekly or bi-weekly basis.  
 
Definition Of Adverse Events 
An adverse event is any unfavorable and unintended sign, symptom or disease temporarily 
associated with the use of a medical treatment or procedure, regardless of whether it is 
considered related to the medical treatment or procedure. Adverse events will be graded as 
Mild, Moderate or Severe, and as Related / Possibly Related / Not Related to study 
procedures. 
 
Follow-up of subjects after adverse events 

 
 
19 
In the event of beta-blocker overdose or intoxication, the first line of treatment is to 
administer treatments to accelerate heart rate: atropine, glycopyrrolate or isoprenaline. If 
these treatments are not effective in treating cardiovascular symptoms, glucagon can be used. 
Glucagon activates myocardial adenylcyclase, stimulates cyclic AMP synthesis and increases 
contractility and heart rate, even in the presence of high concentrations of beta-blockers. 
Patients included in the research project will be continuously monitored and standardized for 
general anesthesia. Emergency drugs for rapid treatment of bradycardia or hypotension will 
be ready and available throughout the patient's stay in the institution. Anesthetists, 
respiratory therapists and nurses will also be on standby at all times should any of these side 
effects occur and require urgent treatment. Dealing with these side effects is an integral part 
of our day-to-day work in the operating theatre and recovery room. 
Patients experiencing adverse reactions will be closely monitored by the appropriate doctor. 
Since esmolol has a 30-minute clearance time, they will benefit from prolonged monitoring 
for at least 2 hours until discharged from the PACU. Observations during this time wil be add 
to the patient’s medical record. 
If necessary, they will be hospitalized for further observation. In collaboration with the surgical 
team, a member of the anesthesia department will visit the patient before he or she is 
discharged home. 
 
 
Procedures for eliciting reports of and for recording and reporting adverse event and 
intercurrent illnesses 
In the event of an adverse event, all clinical information and developments concerning the 
patient will be recorded on the anesthetic and/or postoperative monitoring sheet. These will 
be integrated into the patient's medical record, along with any subsequent potential clinical 
assessments. 
We'll notify Health Canada within 15 days or 7 days if the reaction is life-threatening or results 
in death. A detailed report and assessment within the next 8 days, in accordance with Food 
and Drug Regulations, subsection C.05.014. 
An adverse event report will be also be made to CIUSSS EMTL Research Ethics Committee. 
 
 

 
 
20 
Administration of the intervention drug : esmolol 
The onset of action of esmolol is short, around 30 seconds,  as is its duration of action which 
revolves between 10 and 30 minutes maximum. Patients will be closely monitored throughout 
this period, and the risk of adverse effects beyond this point is extremely low. 
 
Standard Canadian Anesthesiologists' Society (CAS) monitoring will be installed before the 
start of esmolol perfusion and will be maintained until transfer to the recovery room where 
the patient will also be closely monitored. Emergency medication will be available at the 
patient's bedside if an adverse reaction occurs.  
 
The use of Esmolol (Brevibloc) has been associated with the following adverse reactions : 
o Hypotension : symptomatic hypotension (hyperhidrosis, dizziness) and asymptomatic 
hypotension  
o Bradycardia 
o Pulmonary edema 
o Bronchospasm 
o Administration site reactions some serious in nature. They include signs and symptoms 
of infusion site irritation and inflammation but also severe reactions ( 
thrombophlebitis , necrosis and blistering) , in particular when associated with 
extravasation. 
 
Although esmolol has been used in several studies aiming to reduce intraoperative opioid 
administration, this indication is not included in the product monograph. Therefore, we 
sought and received approval (no objection letter) from Health Canada on 2024/02/23. 
 
Subject safety will be guaranteed by research and hospital staff at all times during the 
completion of the study procedures. All adverse effects will be recorded and patients at risk 
of serious side effects will be screened and excluded from the present study. 
 
G. 
PROPER HANDLING OF SUBJECTS 

 
 
21 
Ethical Considerations 
 
 
 
 
 
 
 
 
 
No undiagnosed conditions should be identified in the context of this study. In the inadvertent 
diagnosis of a new condition, the participant might be excluded, per our exclusion criterias, or 
remain enrolled based on the manifestation and disease severity. We will file a consultation 
request to the appropriate physician, for example a vascular surgeon. We will ensure that the 
required clinical care is appropriately provided to the participant. 
 
Subject Withdrawal  
 
 
 
 
 
 
 
 
Early Withdrawal of Patients 
We will track the number of withdrawn subjects. Possible reasons a subject may withdraw is 
a desire to discontinue their participation. 
  
When and How to Withdraw Patients 
A withdrawal occurs when a participant voluntarily chooses to leave or is no longer able to 
participate in the research study  (impossibility to obtain stable NOL Index signal, conversion 
to laparotomy). We will remove a participant if they mention to the research personnel that 
they no longer wish to continue with the study. Withdrawal of consent can occur either before 
the anesthesia, or after once the patient reaches the post-anesthesia care unit (PACU). The 
research personnel will keep all personal health information secured in the database. 
 
Data Collection and Follow-up for Withdrawn Patients 
We will not store data after participant withdrawal. 
Breach of protocol 
Three distinct events can lead to a forced breach of protocol during anesthesia : impossibility 
to obtain stable NOL index signal despite optimization attempts for at least 20 minutes, 
conversion to laparotomy, or hemodynamic instability. In the improbable event of a major 
hemodynamic instability potentially attributable to or worsened by the administration of one 
of the study drugs, the anesthesiologist can decide to stop the protocol.  
 

 
 
22 
In all three scenarios, the blinding will be lifted and the perfusion of the research medication 
will be stopped. These events will be collected and analyzed subsequently. 
 
 
 
Risks  
There is very little risk involved with participation in this study. Both groups will benefit from 
all best practices concerning their anesthetic management, as well as the strategies usually 
used to optimize perioperative opioid sparing. Side effects that may be associated with the 
use of esmolol are described in the section "Safety and adverse events”.  
 
H. 
DATA HANDLING AND RECORD KEEPING 
Confidentiality and Security  
Protected health information will not be re-used or disclosed to a third party except as 
required by law, for authorized oversight of the research, or as permitted by an authorization 
signed by the research subject. 
 
Electronic Data 
Data will be stored on a password-protected laptop which has been assigned to Dr Pascal 
Laferrière-Langlois. He will maintain primary responsibility for this computer and the data it 
contains.  
 
Hard Data 
Paper copies (consent form) of patient information will be stored in a locked file cabinet in a 
locked office in the Department of Anesthesiology. 
 

 
 
23 
Coding Data 
Data are confidential. Data will be assigned a unique study code (P1, P2, and so on up until 
PX) and the codes will be linked to the subject’s identities. The link will be kept separately 
from the data so that no patient can be identified in the event of loss or theft. 
 
Accessibility 
Only the PI and the co-investigators will have access to all the data during the study and study 
analysis. All records relating to this clinical trial will be retained for a period of 15 years. 
 
Training 
Every person involved in this study will receive appropriate training and abide by 
confidentiality guidelines to protect the subject’s privacy. 
All Health Information Protection Act rules and regulations will be strictly followed. 
 
Linked Data 
There will be no linked data. 
 
I. 
STUDY MONITORING, AUDITING, AND INSPECTING 
Study Monitoring Plan 
 
 
 
 
 
 
 
 
 
Every week the PI will check the recruitment and data collection. 
 
Auditing and Inspecting 
 
There will be no formal plan for auditing or inspecting. 
 
J. 
STUDY ADMINISTRATION 

 
 
24 
Organization and Recruiting Site 
 
 
 
 
 
 
 
The operating schedule will be reviewed in advance. Eligible patients will be contacted by 
phone to discuss their possible inclusion in the study. The investigator team will meet with 
them the day prior to or on the day of surgery. If they give their consent to participate, it will 
be collected, and time will be allocated to answer any questions they may have. They will be 
given a copy of the information and consent form . 
Study Timetable 
 
 
 
 
 
 
 
 
 
Depending on validation by the ethical authorities, inclusions should begin in February or 
March 2024. Given the study population, we estimate that we will be able to include a target 
number of subjects by September or October 2024. Data consolidation will be completed one 
month following the last enrollment.  
Analysis and publication should follow shortly thereafter.  
K. 
PUBLICATION PLAN 
We plan to publish the results of this trial in a high-impact factor journal in the field of 
anesthesia, for example Anesthesiology or the Canadian journal of anesthesia. 
 
L. 
BUDGET 
This study will be supported by funds from Dr Pascal Laferrière-Langlois at the CR-HMR and 
the Department of Anesthesiology and Pain Medicine. The usual resources of the anesthesia 
research department will be solicited. 
 
 
 

 
 
25 
M. 
REFERENCES 
 
Angst, M.S., Clark, J.D., 2006. Opioid-induced hyperalgesia: a qualitative systematic review. 
Anesthesiology 104, 570–587. https://doi.org/10.1097/00000542-200603000-00025 
 
Asouhidou, I., Trikoupi, A., 2015. Esmolol reduces anesthetic requirements thereby facilitating 
early extubation; a prospective controlled study in patients undergoing intracranial 
surgery. BMC Anesthesiol. 15, 172. https://doi.org/10.1186/s12871-015-0154-1 
 
Bergeron, C., Brulotte, V., Pelen, F., Clairoux, A., Bélanger, M.-E., Issa, R., Urbanowicz, R., 
Tanoubi, I., Drolet, P., Fortier, L.-P., Verdonck, O., Fortier, A., Espitalier, F., Richebé, P., 
2022. Impact of chronic treatment by β1-adrenergic antagonists on Nociceptive-Level 
(NOL) index variation after a standardized noxious stimulus under general anesthesia: 
a cohort study. J. Clin. Monit. Comput. 36, 109–120. https://doi.org/10.1007/s10877-
020-00626-4 
 
Bohringer, C., Astorga, C., Liu, H., 2020. The Benefits of Opioid Free Anesthesia and the 
Precautions Necessary When Employing It. Transl. Perioper. Pain Med. 7, 152–157. 
 
Celebi, N., Cizmeci, E.A., Canbay, O., 2014. [Intraoperative esmolol infusion reduces 
postoperative analgesic consumption and anaesthetic use during septorhinoplasty: a 
randomized 
trial]. 
Rev. 
Bras. 
Anestesiol. 
64, 
343–349. 
https://doi.org/10.1016/j.bjan.2013.10.013 
 
Colvin, L.A., Bull, F., Hales, T.G., 2019. Perioperative opioid analgesia-when is enough too 
much? A review of opioid-induced tolerance and hyperalgesia. Lancet Lond. Engl. 393, 
1558–1568. https://doi.org/10.1016/S0140-6736(19)30430-1 
 
Fletcher, D., Martinez, V., 2014. Opioid-induced hyperalgesia in patients after surgery: a 
systematic review and a meta-analysis. Br. J. Anaesth. 112, 991–1004. 
https://doi.org/10.1093/bja/aeu137 
 
Gelineau, A.M., King, M.R., Ladha, K.S., Burns, S.M., Houle, T., Anderson, T.A., 2018. 
Intraoperative Esmolol as an Adjunct for Perioperative Opioid and Postoperative Pain 
Reduction: A Systematic Review, Meta-analysis, and Meta-regression. Anesth. Analg. 
126, 1035–1049. https://doi.org/10.1213/ANE.0000000000002469 
 
Martini, C.H., Boon, M., Broens, S.J.L., Hekkelman, E.F., Oudhoff, L.A., Buddeke, A.W., Dahan, 
A., 2015. Ability of the nociception level, a multiparameter composite of autonomic 
signals, to detect noxious stimuli during propofol-remifentanil anesthesia. 

 
 
26 
Anesthesiology 123, 524–534. https://doi.org/10.1097/ALN.0000000000000757 
 
Paloheimo, M.P.J., Sahanne, S., Uutela, K.H., 2010. Autonomic nervous system state: the 
effect of general anaesthesia and bilateral tonsillectomy after unilateral infiltration of 
lidocaine. Br. J. Anaesth. 104, 587–595. https://doi.org/10.1093/bja/aeq065 
 
Renaud-Roy, E., Stöckle, P.-A., Maximos, S., Brulotte, V., Sideris, L., Dubé, P., Drolet, P., 
Tanoubi, I., Issa, R., Verdonck, O., Fortier, L.-P., Richebé, P., 2019. Correlation between 
incremental remifentanil doses and the Nociception Level (NOL) index response after 
intraoperative noxious stimuli. Can. J. Anaesth. J. Can. Anesth. 66, 1049–1061. 
https://doi.org/10.1007/s12630-019-01372-1 
 
Richebé, P., Capdevila, X., Rivat, C., 2018. Persistent Postsurgical Pain: Pathophysiology and 
Preventative 
Pharmacologic 
Considerations. 
Anesthesiology 
129, 
590–607. 
https://doi.org/10.1097/ALN.0000000000002238 
 
Sabourdin, N., Burey, J., Tuffet, S., Thomin, A., Rousseau, A., Al-Hawari, M., Taconet, C., 
Louvet, N., Constant, I., 2022. Analgesia Nociception Index-Guided Remifentanil versus 
Standard Care during Propofol Anesthesia: A Randomized Controlled Trial. J. Clin. Med. 
11, 333. https://doi.org/10.3390/jcm11020333 
 
Shahiri, T.S., Richebé, P., Richard-Lalonde, M., Gélinas, C., 2022. Description of the validity of 
the Analgesia Nociception Index (ANI) and Nociception Level Index (NOL) for 
nociception assessment in anesthetized patients undergoing surgery: a systematized 
review. J. Clin. Monit. Comput. 36, 623–635. https://doi.org/10.1007/s10877-021-
00772-3 
 
Shanthanna, H., Ladha, K.S., Kehlet, H., Joshi, G.P., 2021. Perioperative Opioid Administration. 
Anesthesiology 134, 645–659. https://doi.org/10.1097/ALN.0000000000003572 
 
 
 

 
 
27 
N. 
ANNEXES 
 
Drug preparation: 
 
Groupe Esmolol : 4 amp. BREVIBLOC of 10ml (10mg.ml-1) in a 50ml syringe. 
Groupe SOC : 40 ml of saline in a 50ml syringe. 
- 
Initial bolus : 0.5mg.kg-1 
- 
Infusion : 1.2mg.kg-1.h-1 (= 20mcg.kg-1.min-1) 
 
PMD-200 homologation 
PMD-200 medical device homologation number used for research: 99488. It is to be used in 
accordance with its approved indications for use. 
 
 
 
 
 

 
 
28 
O. 
FIGURE 1