Clinical trial NCT02451202
Conditions: Laryngoscopic Surgical Procedures
Keywords: "surgical conditions" "deep neuromuscular blockade" "deep neuromuscular paralysis"
Sponsor: Chulalongkorn University
Start date: 2016-06-01; Completion date: 2018-03-01
Enrollment: 102 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
It is unknown the impact of deep neuromuscular paralysis and using a novel agent, sugammadex as an reversal in endolaryngeal surgery.

We will conduct a clinical study aiming to compare two treatment strategies; Deep neuromuscular Blockade and moderate Neuromuscular Blockade. We hypothesize that deep NMB will offer better stillness. We will also descriptively examine if patients would be safely discharged from a recovery room.

Detailed description:

Arms: arm 1: After initial doses of 0.6 mg Rocuronium, a continuous infusion can be initiated to maintain 0 responses to train-of-four (TOF) stimulation or 1-2 responses to Post-Tetanic Count (PTC) (Deep NMB). The pump rate will vary and depends on the PTC value. The initial pump rate will be set at 0.5 mg/kg per hour. In case of a deviation from the required PTC value the pump rate can be increased or decreased. This was left to the discretion of the attending anaesthetist. Deep NMB should be maintained throughout the operation.

The infusion of Rocuronium will be discontinued and Sugammadex will be given 4 mg/kg at the end of surgery, which is from deep NMB (PTC = 1-2). arm 2: After evidence of early spontaneous recovery (\< 10% of control T1) from initial doses of 0.6 mg rocuronium, a continuous infusion can be initiated to maintain 1 to 2 responses to train-of-four stimulation (Moderate NMB). The initial pump rate will be set at 0.5 mg/kg per hour. In case of a deviation from the required TOF value the pump rate can be increased or decreased. This was left to the discretion of the attending anaesthesiologist. Moderate paralysis should be maintained throughout an operation.

At the end of surgery, the infusion of Rocuronium will be discontinued and Sugammadex 2 mg/kg via bolus injections\]will be administered at least reappearance of T2.
Interventions: intervention 1: Deep Neuromuscular Blockade intervention 2: Moderate Neuromuscular Blockade intervention 3: Sugammadex intervention 4: Rocuronium
Intervention descriptions: intervention 1: * During maintenance phase, if recovery after 1 Post-Tetanic-count (PTC) responses, a continuous infusion can be initiated to maintain deep NMB (TOF =0, PTC 1-2).
* At the end of surgery, continuous infusion Rocuronium and Propofol are discontinued and paralysis will be simultaneously reversed by Sugammadex 4mg/kg from PTC 1-2. intervention 2: \- During maintenance phase, if recovery at the presence of \<10% of control T1 of TOF from initial doses of 0.6 mg rocuronium, a continuous infusion can be initiated to maintain TOF = 1 - 2. The initial pump rate will be set at 0.5 mg/kg per hour. intervention 3: None intervention 4: None

Protocol documents:
Prot_SAP_000.pdf: 
Study Title: A Comparison of Surgical Conditions between Deep vs 
Moderate Neuromuscular Blockade with Rocuronium in patients 
undergoing Endolaryngeal Procedures 
NCT Number: NCT02451202 
Document Date: 6 October 2015 


Investigator Initiated Trial 
A full research proposal 
Study Title: 
A Comparison of Surgical Conditions between Deep vs Moderate Neuromuscular 
Blockade with Rocuronium in patients undergoing Endolaryngeal Procedures. 
ชื่อโครงการวิจัย: 
การศึกษาผลการหย่อนกล้ามเนื้อในระดับมาก เปรียบเทียบกับระดับปานกลาง โดยใช้ยารอคคูโรเนียม ในการส่องกล้องผ่าตัดกล่อง
เสียง 
Protocol Approval 
date: 
Date of 
Finalization of 
This Current 
Version of the 
Protocol 
Institution Name 
Department of Anesthesiology, Chulalongkorn Hospital, Chulalongkorn 
University 
Investigator 
Contact 
Information: 
­ Full address
­ Phone No.
­ Fax  No.
­ e-mail address
Assoc.Prof. Oraluxna  Rodanant,M.D. 
Department of Anesthesiology, Chulalongkorn Hospital, Faculty of Medicine, 
Chulalongkorn University 
Sirindhron Building, 1873 Rama 4 Road  ,Pathumwan  , Bangkok  
Thailand   10330 
Phone No. : +662-256 4215, +662-256 4295 
e-mail Address: drtuen@yahoo.com
Co-investigators 
1.
Dr. Jittiya Watcharotayangul, MD.
Department of Anesthesiology, Faculty of Medicine, Ramathibodi Hospital,
Mahidol University. 270 Phyathai, Bangkok 10400, Thailand
Phone No.  +662-2011513 - 23
Fax No.. +662-2-2011569
2.
Dr. Wirat Wasinwong, MD.
Department of Anesthesiology, Faculty of Medicine, Prince Songkla University.
15 Kanrnjanawanit Road, Hatyai Songkhla Thailand  90110
Phone No. +66-7445-1651
3.
Assoc. Prof. Worawut Lapisatepun, MD.
Department of Anesthesiology, Faculty of Medicine, Chiang Mai University.
Second Floor, Somboon-Martin Bld., Chiang Mai Hospital. 110 Indhawaroros,
Aumpur Maung, Chiang Mai 50200
4.
Dr. Phuriphong Songarj, MD. FRCAT.
Department of Anesthesiology, Faculty of Medicine, Siriraj hospital, Mahidol
University.
Sayamintr Building 11th Floor Siriraj Hospital 2 Prannok Road Bangkoknoi
Bangkok Thailand 10700
Telephone : (662) 419-7995, (662) 419-7993, (662) 419-7989 Fax : (662) 411-
3256
5.
Assoc Prof. Mingkwan Wongyingsinn, MD, MSc.  (Statistical analysis
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Plan) 
Department of Anesthesiology, Faculty of Medicine, Siriraj hospital, Mahidol 
University. 
Sayamintr Building 11th Floor Siriraj Hospital 2 Prannok Road Bangkoknoi 
Bangkok Thailand 10700 
Telephone : (662) 419-7995, (662) 419-7993, (662) 419-7989 
Fax : (662) 411-3256 
6.
Dr. Wimonrat Sriraj, MD.
Department of Anesthesiology, Faculty of Medicine, Khonkhan University.
123 Mittraparp Highway, Muang District,
Khon Kaen 40002, Thailand
Telephone: +66 (0) 43 363466, +66 (0) 43 363491, +66 (0) 43 363477, +66 (0)
43 363122
Fax: +66 (0) 43 348375
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Section #2- Protocol Synopsis 
 
TITLE OF STUDY: A Comparison of Surgical Conditions between Deep vs Moderate Neuromuscular Blockade with 
Rocuronium in patients undergoing Endolaryngeal Procedures 
  
 
OBJECTIVES: 
 
Primary Study Objective: To compare the proportion of patients with a score of excellent for surgical conditions of deep 
Neuromuscular Blockade (NMB) (TOF 0, PTC 1–2) versus moderate NMB (TOF 1–2) using Rocuronium in patients 
undergoing Endolaryngeal Procedures 
 
Secondary Study Objective:  
1. 
To describe  the proportion of patients who are Ready to Discharge from operating room, in both the 
sugammadex 4 mg/kg after deep Neuromuscular Blockade (NMB) (TOF 0, PTC 1–2) group and sugammadex 2 
mg/kg after moderate NMB (TOF 1–2) group .  
2. 
To describe  the proportion of patients who are Ready to Discharge from Post Anesthetic Care Unit (PACU), in 
both the sugammadex 4 mg/kg after deep Neuromuscular Blockade (NMB) (TOF 0, PTC 1–2) group and 
sugammadex 2 mg/kg after moderate NMB (TOF 1–2) group .  
3. 
To assess frequency of clinical signs of early recovery during Endolargyngeal Procedures both deep NMB and 
Moderate NMB. 
Clinical signs of early recovery: 
a. 
Airway pressure alarm 
b. 
Movement of Vocal cords on Laryngeal Video monitor  
c. 
Movement of the abdomen 
d. 
Change of End Tidal CO2  
 
 
STUDY DESIGN: Overview: A multi-center, open-label, assessor-blinded, randomized, parallel intervention trial. 
 
Number of Study Centers: This study will be conducted at 6 centers throughout Thailand. 
  
 
Duration of Participation: Each subject will participate in the study for approximately up to 1 day from the time the subject 
signs the Informed Consent Form (ICF) through the last data collection point. The subjects will be observed for the post-
operative complication for 1 day after study drug cessation.  
    
 
Duration of Study: The total study duration is 16 months (4 months of institutional review board submission/approval, 8 
months of enrollment period, 3 months of study analysis and reporting) 
 
 
Key Inclusion/Exclusion Criteria:  
 
Inclusion criteria:  
1. Male or female aged 18 – 60 years; ASA I-III. 
2. Subjects have been planned for elective endolaryngeal Procedures (Direct Laryngoscopy with laser 
(micro-)surgery in patients with endolaryngeal lesions. 
 
Exclusion criteria: 
1. Any renal impairment (CrCL < 80 ml/ min) 
2. Any hepatic impairment; Child Pugh A, B or C 
3. BMI > 30 kg m2 
4. Known or suspected generalized neuromuscular disorders 
5. Allergies to Rocuronium, Sugammadex, Sevoflurane, Propofol, fentanyl used during general 
anesthesia 
6. Hypersensitivity to the active substance or to any of the excipients 
7. Female patient who are pregnant and breastfeeding. 
8. Patient with poor Glasgow Coma Score and mental derangement who is unable to give informed 
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consent. 
9. Patients with tracheostomy tube. 
 
 
 
INVESTIGATIONAL PRODUCT, DOSE, MODE OF ADMINISTRATION: 
 
Investigational product:  
After initial doses of 0.6 mg Rocuronium, a continuous infusion can be initiated to maintain 0 responses to train-
of-four (TOF) stimulation or 1-2 responses to Post-Tetanic Count (PTC) (Deep NMB). The pump rate will vary and depends 
on the PTC value. The initial pump rate will be set at 0.5 mg/kg per hour. In case of a deviation from the required PTC 
value the pump rate can be increased or decreased. This was left to the discretion of the attending anaesthetist. Deep 
NMB should be maintained throughout the operation. 
The infusion of Rocuronium will be discontinued and Sugammadex will be given 4 mg/kg at the end of surgery, 
which is from deep NMB (PTC = 1-2).  
 
Reference Product:  
After evidence of early spontaneous recovery (< 10% of control T1) from initial doses of 0.4 mg rocuronium, a 
continuous infusion can be initiated to maintain 1 to 2 responses to train-of-four stimulation (Moderate NMB). The initial 
pump rate will be set at 0.5 mg/kg per hour. In case of a deviation from the required TOF value the pump rate can be 
increased or decreased. This was left to the discretion of the attending anaesthesiologist. Moderate paralysis should be 
maintained throughout an operation. 
At the end of surgery, the infusion of Rocuronium will be discontinued and Sugammadex 2 mg/kg via bolus 
injections will be administered at least reappearance of T2. 
 
 
STATISTICAL METHODS: 
 
All subjects entered into paper-based Case Report Forms (CRFs) will be considered as part of the enrollment population, 
and the quality of their data will be assessed for further analyses. The evaluable population will consist of all subjects 
whose data meet the inclusion criteria.  The criteria for exclusion from the evaluable population will be set forth in the Data 
Analysis Plan prior to commencement of any analyses, and will include such criteria as minimum data points required. 
 
 
Data Set to be Analyzed:  
 
Baseline Patients Characteristics: 
We will describe the data distribution of each collected variable. We will characterize subjects in both groups by 
demographics, comorbidities, clinical characteristics i.e. neuromuscular weakness grading, and distribution of ASA 
Classification pattern. Categorical variables will be summarized by frequency and percent while continuous variables will 
be summarized by the mean, median, standard deviation, and range. 
 
Clinical Outcomes: 
The data analysis will be based on the intent-to-treat approach.  Categorical variables will be compared using the Fisher’s 
exact test while continuous variables will be compared using the student’s t-test or Mann-Whitney U test, depending on the 
sample distribution. 
 
The level of statistical significance for all analyses is set at 0.05. All comparisons will be made using an alpha level of 0.05.  
  
 
Sample Size: By using 80% power and 1-sided α=0.05, we performed sample size calculation for the proportional 
outcome.  Based on data from the BLISS study12, the proportion of patients a with a score of Excellent on the Surgical 
Rating Score (SRS) among subjects who receive deep NMB with Rocuronium is approximately 99%, while this proportion 
for patients who received moderate NMB with atacurium followed by mivacurium was lower (82%).  The calculated 
subjects is required 36 subjects per arm.  Since we expect 13% of withdrawal from the study13, we need to inflate the total 
sample size to 80 subjects (40 subjects per arm) 
 
 
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Efficacy Analysis:  
1. Primary Efficacy endpoints:  
The Proportion of patients who have a surgical conditions score of excellent (total score = 8-9) 
will be compared between the Moderate NMB and Deep NMB groups.  
2. Secondary outcome  
1) The proportion of patients who are ready to be discharged from post- operative care, defined 
as Modified Aldrete’s score ≥ 9, at 0, 15, 30,60, 90 minutes after reach of TOF > 0.9 will be 
summarized. 
2) The proportion of patients who are ready to be discharged from the operating room, defined 
as TOF > 0.9 at time of tracheal extubation, at 1, 3, 5, 10  minutes after finish of Procedures 
will be summarized. 
3) The frequency of patients with clinical signs of early recovery during Endolargyngeal 
Procedures will be compared between the deep NMB and Moderate NMB arms. 
 
                                                                                                                                                                
Safety Analysis: This is a post-marketing study of treatment outcomes associated with surgical conditions and readiness 
of discharge from Post-Operating Care Unit(PACU) with Rocuronium and Sugammadex. Responsibility for clinical follow-
up resides with the prescribing physician. Therefore, reporting of AEs and SAEs as they occur in clinical practice should 
follow the established Procedures for approved, marketed drugs in compliance with applicable laws and regulations. This 
applies to AEs and SAEs noted by the prescribing physician through clinical observation, clinical monitoring, diagnostic 
Procedures or other applicable methods. 
 
 
Interim Analysis: N/A  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Section #3- Core Protocol 
 
2.1 Objectives & 
Hypotheses  
 
 
 
 
2.1.1 List the objectives.  
 
 
1.1) Primary Efficacy Objective:   
 
1. To compare the proportion of patients with a score of excellent for surgical 
conditions of deep Neuromuscular Blockade (NMB) (TOF 0, PTC 1–2) 
versus moderate NMB (TOF 1–2) using Rocuronium in patients undergoing 
Endolaryngeal Procedures. 
 
Surgical Conditions will be rated using a four-point surgical condition scale 
by one dedicated Surgeon from each center. 
 
TOF = Train of Four 
 
PTC = post-tetanic counts 
 
1.2) Secondary Objective:  
1. To describe  the proportion of patients who are Ready to Discharge from 
operating room, in both the sugammadex 4 mg/kg after deep Neuromuscular 
Blockade (NMB) (TOF 0, PTC 1–2) group and sugammadex 2 mg/kg after 
moderate NMB (TOF 1–2) group .  
 
*Readiness to discharge: Readiness to Discharge from operating room, which is 
defined by train of Four ratio > 0.9 at  any time after finish of Procedures.  
 
2. To describe  the proportion of patients who are Ready to Discharge from 
PACU*, in both the sugammadex 4 mg/kg after deep Neuromuscular 
Blockade (NMB) (TOF 0, PTC 1–2) group and sugammadex 2 mg/kg after 
moderate NMB (TOF 1–2) group .  
 
 
*Readiness to discharge from PACU is defined below. 
o 
Modified Aldrete’s scoring system is used for determining 
when patients can be safely discharged from the 
postanesthesia care unit (PACU) to either the postsurgical 
ward or to the second stage (Phase II) recovery area. 
o 
Modified Aldrete’s score: A score ≥ 9 is required for 
discharge. 
 
3. To assess frequency of clinical signs of early recovery during  
Endolargyngeal Procedures both deep NMB and Moderate NMB.. 
 
Clinical signs of early recovery: 
a. Airway pressure alarm 
b. Movement of Vocal cords on Laryngeal Video monitor 
c. Movement of the abdomen 
d. Change of End Tidal CO2 
 
3) Other objectives: - 
- To assess  time from the Post-anesthesia Care Unit (PACU) admission to PACU 
discharge ready 
- To assess time readiness to discharge from operating room, which is time from 
finish of Procedures to train of Four ratio > 0.9.  
- To assess Proportion of patients at risk of Post-Operative Residual Curarization 
(PORC) (definded as TOF < 0.9) at 1,3,5, 10minutes after finish of Procedures and 
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at arrival ,15, 30, 60, and 90 minutes during Post-Operative Care Unit stay. 
- Proportion of patients who have a surgical conditions score in each category 
(Excellent, good, fair and poor). 
• Surgical conditions will be rated using a four-point surgical rating scale 
(SRS) by an anesthesiologist. (not attending physicians) every 15 minutes and every 
change seen or surgeon’s complaint. 
• The SRS will be also rated by an expert anesthesiologist and expert ENT 
surgeon from VDO recorder every change seen at a vocal cord. 
-To assess intubating condition in patients who has endotracheal insertion. This will 
be assessed by anesthesiologists right after finishing intubation..  
2.1.2 List the clinical hypotheses.  
 
1. Sustained deep NMB for the duration of surgery in patients undergoing 
Endolaryngeal Procedures has better surgical conditions compared to those 
receiving moderate NMB when rated using a four-point surgical rating 
condition scale (SRS). 
 
2. The frequency of Clinical Signs of Early recovery during an Endolaryngeal 
Procedures are less frequent in the Deep NMB group compared to the 
Moderate NMB. 
 
 
2.2 Background & 
Rationale, 
Significance of 
Selected Topic & 
Preliminary Data  
 
 
Neuromuscular Blocking (NMB) agents are routinely prescribed in patients who 
undergo an Endolaryngeal Procedures. Ideally, these Procedures require a short 
duration of NMB since they are short and fast operations. Sometimes, they may also  
finish unexpectedly.   In Thailand, a short acting NMB is unavailable.  The use of 
intermediate NMBs has many concerns. During the maintenance phase for patients 
undergoing an Endolaryngeal Procedures under general anesthesia, additional 
boluses of an NMB agent occurs only in response to Surgeon complaints regarding 
muscle tension. The main contributing factor is that further doses of muscle relaxants 
may cause unacceptable delays to extubation.  
 
Secondly, there is a lack of data supporting the use of sustained deep NMB 
throughout Endolaryngeal Procedures. 
 
To maintain the same level of stillness, patients without NMB required more 
anesthetic than patients treated with NMB.1  A study found that 16 of 19 (84%) 
patients had hypopnea or apnea after a manually controlled continuous infusion of 
0.125 mg/kg/min remifentanil for 2 minutes followed by a continuous infusion of 0.05 
mg/kg/min remifentanil.2  Another study examined the combined effect of propofol 
and remifentanil and concluded that their effect on respiration was strikingly 
synergistic, resulting in severe respiratory depression.3  These data has shown that 
NMB is required in Balance Anesthesia. 
 
Given these considerations, we will conduct a randomized, open-label trial aiming to 
compare two treatment strategies; Deep neuromuscular Blockade (TOF 0, PTC 1-2) 
and moderate Neuromuscular Blockade (TOF 1-2) by using Rocuronium 0.6 mg/kg4 
and 0.4 mg/kg5,6 in deep NMB group and moderate NMB group, respectively, as 
intubation doses. Usually, neuromuscular block sufficient for intubation is about 80% 
block or greater. The ED95 is defined as a dose required to produce 95% 
suppression of the first [T1]7.  In this study, after patients are given rocuronium dose 
at 0.4 mg/kg (1.3 x ED95) in moderate group and 0.6 mg/kg (2 x ED95) in deep 
block group, the endotracheal tube will be inserted following the maximal depression 
T16,8. Since the maximal depression T1 function cannot be expressed on TOF watch, 
TOF count can be substituted. Twitches suppression of 90% would equate to a TOF 
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count of 1 or less9 (more detail in exhibit A). We hypothesize that deep NMB will offer 
better surgical conditions. We will also descriptively  examine whether the two dose 
levels of Sugammadex as the reversal agent will provide similar (between the 
moderate and deep block groups) time of readiness to discharge from Operating 
room and PACU, which are defined by train of Four ratio > 0.9  and by Modified 
Aldrete’s score ≥ 9 . Consequently, patients would be safely discharged.  
  
 
2.3 Study Design 
 
 
Protocol overview: 
We will conduct a multi-center, open-label, assessor-blinded, randomized, parallel 
intervention trial at University Hospitals in Thailand. The eligible subjects will be 
randomly allocated to either the deep neuromuscular block group or moderate 
neuromuscular block group. Details of intervention will be explained in the next 
section (treatment protocol). Clinical response will be evaluated. 
 
 
Inclusion criteria:  
1. Male or female aged 18 – 60 years; ASA I-III. 
2. Subjects have been planned for elective  endolaryngeal. Procedures (Direct 
Laryngoscopy with laser (micro-)surgery in patients with endolaryngeal 
lesions 
 
Exclusion criteria: 
1. Any renal impairment (CrCL < 80 ml/ min) 
2. Any hepatic impairment; Child Pugh A, B or C 
3. BMI > 30 kg m2 
4. Known or suspected generalized neuromuscular disorders 
5. Allergies to Rocuronium, Sugammadex, Sevoflurane, Propofol, fentanyl used 
during general anesthesia 
6. Hypersensitivity to the active substance or to any of the excipients 
7. Female patient who are pregnant and breastfeeding. 
8. Patient with poor Glasgow Coma Score and mental derangement who is 
unable to give informed consent. 
9. Patient with Tracheostomy tube. 
 
2.4 Study Flowchart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patients who undergo endolaryngeal 
procedure, Age 18-60 years, willing to sign 
inform consent, no exclusion criteria  
Induction and Maintenance with Rocuronuim 
causing Deep Neuromuscular blockade  
(TOF =0, PTC 1-2) throughout surgery 
Induction and Maintenance with Rocuronium 
causing Moderate Neuromuscular blockade 
(TOF = 1-2) throughout surgery 
Randomization
Reversal with Sugammadex 4 mg/kg at the 
end of Surgery. 
Reversal with Sugammadex 2mg/kg at the end 
of surgery and when reappearance of T2. 
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Figure10  
 
Study flow chart (please see last page) 
2.5 Study 
Procedures 
 
All eligible subjects will be identified through hospital admission for Endolaryngeal 
Procedures database on daily basis. The investigator will obtain documented 
consent from each potential subject. Consent must be documented by the subject’s 
dated signature on a consent form along with the dated signature of the person 
conducting the consent discussion. Depending on local law or review committee 
requirements such consent may also need to be signed by an impartial witness. 
 
 
Treatment allocation:  
 
The eligible subjects will be allocated to each study group by randomization.  The 
randomization will be performed by computer-generated block randomization 
algorithm with allocation concealment. The randomization will be stratified into 
“Anesthetic Procedures with endotracheal tube” and Anesthetic Procedures without 
endotracheal tube. 
 
Perioperative protocol: 
All patients received balance anesthesia with Propofol, Fentanyl and Rocuronium 
agents. During the Procedures, routine monitoring is applied [electrocardiography, 
arterial blood pressure, heart rate, electroencephalographic monitoring, pulse 
oxymeter) 
 
Study intervention: 
1. 
Deep Neuromuscular blockade group:  
 
After the enrollment Following induction with Targeting propofol 
concentrations (TCI) of 4 to 4.5 μg/mL, single bolus injection Fentanyl of 1-2 
µg/kg,and single bolus injection rocuronium4 of 0.6mg/kg will be 
administered. When following maximal depression of T1 or TOF count 1 6,9 
endotracheal insertion will be initiated in anesthetic procedures with 
endotracheal tube. Choices of other induction anesthetic agents except NMB 
agent are at the discretion of the attending anesthesiologist. 
 
During maintenance phase, if recovery after 1 Post-Tetanic-count (PTC) 
responses, a continuous infusion can be initiated to maintain deep NMB 
(TOF =0, PTC 1-2). The initial pump rate will be set at 0.5 mg/kg per hour. 
The pump rate could be increased or decreased to keep the target TOF and 
PTC.  
 
During maintenance phase, Fentanyl 0.5 ug/kg may be administered when 
SBP or HR increase by 10%., as well as, Target propofol concentrations of 3 
Intubation 
PTC≥3 add 
rocuronium drip 
TOF count ≥1 add 
rocuronium drip 
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to 6 μg/mL usually maintain satisfactory anaesthesia. 
 
Electroencephalographic monitoring using  either bispectral index (BIS) 
module system or Spectral Entropy is mandatory. BIS value is within the 
range of 40–60. The recommended range of reaction entropy (RE) and and 
state entropy (SE) is 40–60 in appropriate anesthesia depth, which is 
identical to that of BIS. 
 
Deep NMB should be maintained throughout the operation. 
 
At the end of surgery, continuous infusion Rocuronium and Propofol are 
discontinued and paralysis will be simultaneously reversed by Sugammadex 
4mg/kg from PTC 1-2. 
 
TOF will be monitored every 15 seconds. The PTC will be recorded one 
minute after disappearance of single twitch10. PTC will be monitored every 6 
minutes10,11 during surgery.  When it is required TOF during emergence 
phase until patients discharge from PACU., it will be monitored every 15 
seconds during emergence phase, at1,3,5,10 ,15 and subsequently every 5 
minutes after extubation until arrive PACU, and every 15 minutes at PACU 
arrival time until patients discharge from PACU.   
 
2. 
Moderate Neuromuscular blockade group: 
 
After the enrollment, following induction with Targeting propofol 
concentrations (TCI) of 4 to 4.5 μg/mL, single bolus injection Fentanyl of 1-2  
µg/kg ,and single bolus injection rocuronium of 0.4mg/kg5,6 will be 
administered. When following maximal depression of T1 or TOF count 16,9, 
endotracheal tube will be initiated in anesthetic procedures with 
endotracheal tube. Choices of other anesthetic agents except NMB agent 
are at the discretion of the attending anesthesiologist.  
 
During maintenance phase, if recovery at the presence of <10% of control 
T1 of TOF from initial doses of 0.4 mg rocuronium, a continuous infusion can 
be initiated to maintain TOF = 1 – 2. The initial pump rate will be set at 0.5 
mg/kg per hour. 
 
During maintenance phase, Fentanyl 0.5 ug/kg may be administered when 
SBP or HR increase by 10%, as well as, Target propofol concentrations of 3 
to 6 μg/mL usually maintain satisfactory anaesthesia. 
Electroencephalographic monitoring using either bispectral index (BIS) 
module system or Spectral Entropy is mandatory. BIS value is within the 
range of 40–60. The recommended range of reaction entropy (RE) and and 
state entropy (SE) is 40–60 in appropriate anesthesia depth, which is 
identical to that of BIS. 
 
Moderate paralysis should be maintained throughout an operation. 
 
Continuous infusion Rocuronium and Propofol are discontinued at the end of 
surgery. Reversed the paralysis by Sugammadex 2 mg/kg.will be 
administered.at reappearance of T2.   
 
TOF will be monitored every 15 seconds during intraoperative10 and during 
emergence phase.  It will be at 1,3,5,10,15 and subsequently every 5 
minutes after extubation until arrival PACU and every 15 minutes at PACU 
arrival time until patients discharge from PACU. 
    
        
Dosages of anesthetic agents: 
At induction phase: Premedication with midazolam 1-2 mg single intravenously 
bolus could be administered at physician discretion. 
1. Rocuronium4 will be given at an initial dose of 0.6 mg/kg in Deep NMB 
group and 0.4 mg/kg at induction phase; with these doses, patients could 
obtain adequate intubation conditions. Following maximal depression of T1 
or TOF count 16,9, endotracheal tube will be initiated in anesthetic 
procedures with endotracheal tube. 
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2. Propofol will be given administered with the assistance of a Target 
Controlled Infusion (TCI) system.  In adult patients under 55 years of age 
anaesthesia or ASA I-II can usually be induced with target propofol 
concentrations of 3.5 to 4.5 μg/mL. Induction time with these targets is 
generally within the range of 60 to 120 seconds.  
 
A lower initial target concentration should be used in patients over the age of 
about 55 years or in patients of ASA grades III.  
 
3. Fentanyl will be at the discretion of the attending anesthesiologist and is 
administered in single bolus injection of 1 to 2µg/kg.  
 
 
At Maintenance phase: 
1. Rocuronium:  The initial pump rate will be set at 0.5 mg/kg per hour. 
 
Deep NMB: After initial doses of 0.6 mg Rocuronium, a continuous 
infusion can be initiated to maintain 0 responses to train-of-four 
(TOF) stimulation or 1-2 responses to Post-Tetanic Count (PTC) 
(Deep NMB). The pump rate will vary and depends on the PTC 
value. The initial pump rate will be set at 0.5 mg/kg per h. In case of 
a deviation from the required PTC value the pump rate can be 
increased or decreased. This was left to the discretion of the 
attending anaesthetist. 
 
Moderate NMB: After evidence of early spontaneous recovery  
(< 10% of control T1) from initial doses of 0.4 mg rocuronium, a 
continuous infusion can be initiated to maintain 1 to 2 responses to 
train-of-four stimulation (Moderate NMB). The initial pump rate will 
be set at 0.5 mg/kg per h. In case of a deviation from the required 
TOF value the pump rate can be increased or decreased. This was 
left to the discretion of the attending anaesthesiologist. 
 
2. Opioid :Fentanyl 0.5 µg/kg will be administered when SBP or HR increase 
by 10%.  If there was persistent increase SBP or HR after administration of 
Fentanyl 0.5 µg/kg, the subsequent dose of Fentanyl may be administered at 
the discretion of the attending anesthesiologist. 
 
3. Propofol: Target Propofol concentrations of 3 to 6 μg/mL usually maintain 
satisfactory anesthesia. 
 
 
At emergence phase: 
1. Sugammadex13 will be given 4 mg/kg at the end of surgery,which is from 
deep NMB (PTC = 1-2) or 2 mg/kg if spontaneous recovery has occurred up 
to at least the reappearance of T2 
 
2. Intravenousagents will be stopped at the discretion of attending 
anesthesiologist. 
 
3. Extubation when TOF is ≥ 0.9. 
 
 
 
Withdrawal or Termination from Study:  
Subjects may withdraw at any time or be dropped from the study at the discretion of 
the investigator should any untoward effects occur, such as hypersensitivity.  
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2.6 Study Duration 
The total study duration is 16 months (4 months of institutional review board 
submission/approval, 8 months of recruitment, 3 months of study analysis and 
reporting) 
 
2.7 Statistical 
Analysis and 
Sample Size 
Justification  
The principle investigator will be responsible for analyzing the study data.  
Since the research team is not blinded to the muscle relaxant used and the level of 
NMB, either the attending anesthesiologist or the research assistant is responsible 
for both the administration of the muscle relaxant and the degree of NMB. The 
attending anesthesiologist is also not blinded. He or she will not discuss the NMB 
with the surgeon or the research team. After the surgery has finished, subjects who 
receive rocuronium will be reversed with sugammadex 4 mg/kg or 2 mg/kg. Again, 
this will be known by the attending anesthesiologist only and will be blinded to 
surgeon and Anesthesiologist and Otolaryngologist Experts who will rate the surgical 
conditions..  
 
 
Variables/Time Points of Interest: 
1. Primary outcome:  
 
1) Proportion of patients who have a surgical conditions score of 
excellent, 
 
• 
Surgical conditions will be rated using a four-point surgical rating 
scale (SRS) by the Surgeon right after operation.  
• 
The SRS has been modified from Intubating score10. 
• 
There are three variables, which are ease of laryngoscopy, 
condition of the vocal cords and the Reaction to insertion of the 
endoscopic tube and cuff inflation. These are scored on a four-
point scale (0-3) and the total score is a sum of each 
component to give an overall Surgical Conditions score for each 
patient. 
• 
The assessment is based on the time point right after operation.  
• 
A total score of 8-9 was considered excellent, 6-7 good, 3-5 
poor and 0-2 bad; good and excellent were taken as clinically 
acceptable. 
 
 
2. Secondary outcomes:  
 
 
1) Proportion of patients who are ready to be discharged from post- 
operative care, defined as Modified Aldrete’s score ≥ 9, at 0,15, 30, 
60,90 minutes after reach of TOF > 0.9. 
 
• 
Modified Aldrete’s score: A score ≥ 9 is required for 
discharge. 
. 
2) Proportion of patients who are ready to be discharged from 
operating room, defined as TOF > 0.9 at time of tracheal Extubation, 
1,3,5, 10 minutes after finish of a procedure. 
 
3) Frequency of clinical signs of early recovery during Endolargyngeal 
Procedures. 
 
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Clinical signs of early recovery: 
1) 
Airway pressure alarm 
2) 
Movement of Vocal cords on Laryngeal Video monitor 
3) 
Movement of the abdomen 
4) 
Change of End Tidal CO2 
 
3.   Other outcomes: 
1) Proportion of patient at risk of of Post-Operative Residual 
Curarization (PORC) (TOF ration < 0.9) at 1,3,5,10 minutes after 
finish of a procedure and at 0, 15,30, 60, 90 minutes during Post-
Operative Care Unit stay. 
2) Time to readiness to discharge from Post-operative Care Unit which 
is time from Post-operative Care Unit (PACU) admission to reach 
“acceptable” score of Post-operative discharge score. 
3) Time readiness to discharge from operating room, which is time from 
finish of procedures to train of Four ratio > 0.9 
 
 
4) Proportion of patients who have a surgical conditions score in each 
category (Excellent, good, fair and poor). 
• 
Surgical conditions will be rated using a four-point surgical 
rating scale (SRS) by an anesthesiologist. (not attending 
physicians) every 15 minutes and every change seen or 
surgeon’s complaint. 
• 
The SRS will be also rated by an expert anesthesiologist 
and expert ENT surgeon from VDO recorder every change 
seen at a vocal cord.   
5) Intubating condition in patients who has endotracheal insertion. 
This will be assessed by anesthesiologist right after finishing 
intubation by using the same score of endolaryngeal surgical 
condition  
 
Study Variables during anesthesia 
 
Endolaryngeal surgical condition10: 
During the endolaryngeal Procedures, a surgeon scores the surgical working 
conditions  right after the end of procedures.  We adapted the Intubation Condition 
criteria11,12 included three variables:  
1) 
jaw relaxation and resistance to laryngoscopy blade (laryngoscopy 
component) 
2) 
the position and movement of vocal cords (vocal cord component) 
3) 
coughing (reaction to endolaryngeal and endobroncheal Procedures 
component) 
 
 
 
Evaluation of Endolaryngeal/Endobroncheal surgical conditions12 
 
 
Variable assessed 
Clinically acceptable 
Not clinically acceptable 
Excellent 
= 3 
Good 
= 2 
Poor 
= 1 
Impossible 
= 0 
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Laryngoscopyǂ 
• Jaw relaxation 
 
• Resistance to 
blade 
Easy 
• Relaxed 
 
• None 
Fair 
• Not fully 
relaxed 
• Slight 
Difficult 
• Poor 
relaxation 
• Active 
Impossible 
• No relaxation 
 
Vocal cord  
• Position 
• Movement 
 
• Abducted 
• None 
 
• Intermediated 
• moving 
 
• Closing 
 
• Closed 
Reaction to 
insertion of the 
endoscopic tube 
and cuff inflation 
• Diaphragmatic 
movement 
• coughing 
 
 
 
 
• None 
 
• None 
 
 
 
 
• Slightβ 
movement 
• None 
 
 
 
 
• Vigorous 
movementӪ 
• Sustained 
coughingӪ 
 
 
 
 
• Bucking 
 
• Severe 
coughing  
ǂLaryngoscopy 
Easy: jaw relaxed, no resistance to blade insertion 
Fair: jaw not fully relaxed, slight resistance to blade insertion 
Difficult: poor jaw relaxation, active resistance of the patient to laryngoscopy. 
 
β One to two weak contractions or movement for less than 5 s. 
Ӫ More than two contractions and/or movement for longer than 5 s. 
 
Endolaryngeal surgical site conditions9: 
Excellent ;Score  = 8-9  
Good       ;Score  = 6 -7 
Fair          ;Score  = 3-5 
Poor         ;Score  =0-2 
 
 
Surgical rating 
During the laryngoscopic Procedures, the surgical condition is scored by the surgeon 
using a four-point SRS right after the Procedures. To reduce variability in the surgical 
rating, all surgeries are performed by a single surgeon at each institute.  
 
The surgical rating scores (SRS) condition at 15-minute intervals will be recorded 
and rated by an anesthesiologist during the Procedures. In case of a sudden change 
in surgical conditions, additional scores are obtained. If conditions are poor (score 0 
or 2), muscle relaxation is increased according to protocol. 
 
Before commencing the study, both the surgeon and the anesthesiologists will 
receive training in how to use and implement the specific study Procedures and how 
to rate the surgical condition score.  
 
Moreover, the first five Procedures performed in conformance with this protocol will 
not be used for data analysis; thus, the Procedures will be practiced five times before 
data collection starts. 
 
Intubation score  
At the end of intubation, the intubation condition is scored by anesthesiologist by 
using the same score of endolaryngeal surgical condition  
 
Video images 
The video images will be collected from the camera connected to endoscope placed 
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above vocal cord or field of the surgery.  The images collected will be the images of 
Video monitor used by the surgeon to observe the surgical field throughout the 
Procedures. Variables that could not be captured by VDO recoder i.e. patients’ 
reaction intra-operative, coughing, bucking, diaphragm movement and either 
physician’s complaint of tightness/non-relaxation or request more relaxation agents 
will be recorded by anesthesiologist in the theater. 
 
Thus, the collected video images are identical to the image of the surgeon during the 
Procedures as well as should be included surgical condition related-events occurs 
interoperations.  
 
The videos will be rated by a surgical expert (one Ear-Nose-Throat surgeons with 
expertise in laryngoscopic Procedures) and an anesthesiologist (with expertise 
in giving anesthesia for laryngoscopic Procedures). These experts are blinded to the 
level of NMB and have no knowledge of the study endpoints. The rating score will 
be identical to the surgical rating score. All changes will be recorded.  
 
 
Monitoring10: 
 
Neuromuscular function using an acceleromyograph measured at the wrist (TOF-
watch SX®). The TOF-watch generates an electrical stimulus to the ulnar nerve and 
measures contractions of the adductor pollicis muscle (causing adduction of the 
thumb) through a sensor attached to the tip of the thumb. The thumb is placed in a 
flexible adaptor that applied a constant preload to the thumb. Before administration 
of the NMB agent, the device is calibrated according the specifications of the 
manufacturer. To that end, before administration of the neuromuscular blocking 
agent after induction of general anesthesia, the following Procedures are conducted 
to standardize the neuromuscular monitoring: (i) application of a tetanic ulnar nerve 
stimulation (50 Hz for 5 s); (ii) calibration of the TOF watch; and (iii) performing a 
series of TOF measurements ensuring that the TOF ratio differs by <5% between 
measurements. If the TOF ratio differed by >5% the TOF watch is recalibrated. The 
TOF ratio is normalized to the values obtained during the calibration Procedures. 
After these steps, the neuromuscular blocking agent is administered according to 
protocol.  
The number of thumb twitches upon electrical stimulation of the ulnar nerve is 
measured and recorded.  
 
 
 
• 
At 15 seconds intervals, the TOF was measured and in the case of TOF¼ 0, 
this was followed by the PTC (30 Hz for 5 seconds, 3 seconds later Single 
twitch at 1 Hz) every 6 minutes. In our study, a TOF of 1–2 reflects a 
moderate NMB and a PTC of 1–2 reflects a deep NMB. Finally, when four 
twitches are present in the TOF, the ratio of the fourth to the first twitch was 
determined (the TOF ratio).   
• 
The stimulation of TOF (2 Hz four stimuli) was changed to every 15 seconds 
after end of surgery and then measure at 1, 3, 5 ,10 minutes after finish the 
procedures, and  at 0,15,30,60,90 during in PACU. 
 
Neuromuscular data were collected via an interface to a computer by means of 
the TOF-Watch® SX Monitoring Program.  TOF Watch® SX can also be used 
in GCP clinical studies. The easy-to-read display presents all relevant data. This 
data can be simultaneously uploaded, via a fiber-optic connection, to a computer 
running the TOF-Watch SX Monitor program. 
 
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Additional variables: 
 
Additional variables will include duration of surgery, drug dosages (Propofol, 
fentanyl,  muscle relaxant, reversal agent, other agents used during anesthesia), 
duration from reversal to extubation, ventilatory variables (Tidal volume, respiratory 
rate, breathing pressure), transfer to ward, to ICU or home. 
 
Hemodynamic variables including heart rate (HR), and mean arterial pressure (MAP) 
are recorded pre-induction, 60 seconds after fentanyl injection, after applied of 
Propofol TCI, every minute after tracheal intubation. A HR of <55–60 beat/min 
is determined as bradycardia which is to be treated with atropine 10 µ/kg. The limit 
for hypotension is MAP <60 mmHg which is to be treated with the titration of 
ephedrine intravenously.   The incidence of bradycardia or hypotension will be 
recorded. 
 
 
Post Operative Residual Curarization Evaluation/Follow – Up:  
 
Residual blockade will be evaluated after extubation in the OR and in the PACU, as 
well as at post day 1 ( TOF Ratio < 0.9 [only in OR and PACU] , pulmonary 
complication i.e. desaturation <90%, desaturation < 80%, reintubation, aspirate 
pneumonia, hospital death). 
 
Study measurements in the post-anesthesia care unit In the PACU, the following 
variables will be measured at 15 min, 30 min, 60 min and 90 min: respiratory rate, 
arterial oxygen saturation, numerical pain rating (on a scale from 0, no pain, to 10, 
most severe pain imaginable), bleeding, hoarseness and occurrence of nausea or 
vomiting.  
 
Before discharging from Post-Operative Care Unit, patients will be assessed “time 
readiness to discharge from PACU”  by evaluating Modified Aldrete recovery score.  
The score will be measured at least 15 minutes interval. 
 
MODIFIED Aldrete recovery score14 
 
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• 
Main goals are controlling postoperative pain, controlling nausea and 
vomiting, and reestablishing normothermia prior to discharge 
• 
Majority of patients can meet discharge criteria within 60 minutes in the 
PACU, no demonstrable benefit from a mandatory minimum duration of PACU care 
• 
Outpatients who meet the above discharge criteria may be “fast-tracked” to 
phase 2 recovery, similarly inpatients who meet the same criteria may be transferred 
directly from the OR to their ward. This is required less extensively monitoring. 
 
 
 
Statistical Methods: 
All statistical analysis will be performed by STATA or SPSS, depends on availability. 
 
Baseline Patients Characteristics: 
We will describe the data distribution of each collected variable. We will characterize 
subjects in both groups by demographics, comorbidities, clinical characteristics i.e. 
neuromuscular weakness grading, and distribution of ASA Classification pattern. 
Categorical variables will be summarized by frequency and percent while continuous 
variables will be summarized by the mean, median, standard deviation, and range. 
 
Clinical Outcomes: 
The data analysis will be based on the intent-to-treat approach.  All 
comparisons will be made using an alpha level of 0.05 
1. Primary Efficacy endpoints:  
 
The Proportion of patients who have a surgical conditions score of 
excellent will be compared between the Moderate NMB and Deep 
NMB groups using Fisher’s Exact test 
 
 
 
 
2. Secondary outcome  
 
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1) The proportion of patients who are ready to be discharged from 
post- operative care, defined as Modified Aldrete’s score ≥ 9, at 
arrival, 15,30,60, 90 minutes after reach of TOF > 0.9 will be 
summarized. 
 
2) The proportion of patients who are ready to be discharged from the 
operating room, defined as TOF > 0.9 at time of tracheal extubation, 
at 1,3,5, 10 minutes after finish of Procedures will be summarized. 
 
3) The frequency of patients with clinical signs of early recovery during 
Endolargyngeal Procedures will be compared between the deep 
NMB and Moderate NMB arms using Fisher’s Exact test. 
 
Clinical signs of early recovery: 
1) 
Airway pressure alarm 
2) 
Movement of Vocal cords on Laryngeal Video monitor 
3) 
Movement of the abdomen 
4) 
Change of End Tidal CO2 
 
Other outcomes: 
- 
1) 
Proportion of patient at risk of Post-Operative Residual Curarization (PORC) 
(PORC) (TOF ratio < 0.9) at 1,3,5,10, minutes after finish of Procedures and 
at arrival ,15,30, 60,90minutes during Post-Operative Care Unit stay. 
2) 
Time to ready-to-discharge from Post-operative Care Unit which is time from 
Post-operative Care Unit (PACU) admission to reach “acceptable” score of 
Post-operative discharge score. 
3) 
Time to ready-to-discharge from operating room, which is time from finish of 
Procedures to train of Four ratio > 0.9 
4)       Intubating condition in patients who has endotracheal insertion. This will be 
assessed by anesthesiologist right after finishing intubation by using the 
same score of endolaryngeal surgical condition  
 
 
Categorical variables will be compared using the Fisher’s exact test while 
continuous variables will be compared using the student’s t-test or Mann-Whitney U 
test, depending on the sample distribution. 
 
Descriptive will be utilized to describe surgical conditions rating by Anesthesiologists 
during the Procedures, and VDO Surgical condition scoring by an ENT surgeon and 
Anesthesiologist. Categorical variables will be summarized by frequency and 
percent while continuous variables will be summarized by the mean, median, 
standard deviation, and range. 
 
Descriptive and univariate statistics may be utilized to describe demographics and 
baseline characteristics of subjects. Multivariate logistic regression analysis may be 
employed to examine the predictive value of various baseline factors on efficacy 
endpoints. 
 
Sample size calculation:  
The primary outcome’s sample size calculation: 
 
Based on data from the BLISS study15, the proportion of patients a with a score of 
Excellent on the Surgical Rating Score (SRS) among subjects who receive deep 
NMB with Rocuronium is approximately 99%, while this proportion for patients who 
received moderate NMB with atacurium followed by mivacurium was lower (82%).. 
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          By using 80% power and 1-sided α=0.05, we performed sample size 
calculation by using the following formula. 
 
 
For the proportion outcomes  
 
 
 
 
All expected primary outcome, secondary outcomes and calculated sample sizes are 
shown in the following table 
 
 
Deep 
NMB 
Mode
rate 
NMB 
Sample 
size 
Primary outcome 
 
 
80% 
Power  
- Proportion of Excellent 
99% 
82% 
36/arm 
 
 
 
Since we expect 13% of withdrawal from the study16, we need to inflate the total 
sample size to 80 subjects (40 subjects per arm). 
 
As mentioned in the earlier session, the first five Procedures performed in 
conformance with this protocol will not be used for data analysis; thus, the 
Procedures will be practiced five times each center before data collection starts. 
 
Therefore, the total enrolled patients are 110 patients. 
 
 
2.8 Specific Drug 
Supply 
Requirements  
 
It is required  300  vials of  open label-Esmeron® (Rocuconium), ,150  vials of open label-
Sugammadex.   . Rocuronium and Sugammadex supplies should be sent from Zeulig to the 
study site in a bulk container, on a quarterly basis. Study drugs will be sourced locally and in 
original packaging according to the sponsor  suggestion. Our research nurse will be 
responsible for storing, distributing the supplies as well as dispositions the unused supplies. 
 
 
Calculations: 
Base on surgical duration of 1- 2 hours, 1 vial of 0.6 mg/kg rocuronium (10mg/ml in 5 
ml) will be required at induction and starting continuous infusion of 0.5 mg/kg/hour 
rocuronium will be used for maintainence. 
Patient’s distribution according to weight from 50-85 kg were estimated and used for 
calculation for all studied medications. 
• 
50 kg = 50% of sample population 
• 
65 kg = 20% of sample population 
• 
75 kg = 20% of sample population 
• 
85 kg = 10% of sample population 
 
Moderate NMB: 1Vials/case for maintenance with continuous infusion of 0.5 mg/kg/h 
rocuronium during the case. 
Deep NMB: 1 vial/case for maintenance with continuous infusion of 0.5 mg/kg/h 
Rocuronium during the case 
2
2
1
2
)
(p
)
Z
)(
1
)(
(
2
p
Z
p
p
n
−
+
−
=
α
β
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(Total number  of rocuronium for Deep and Moderate is required = 300 vials)) 
 
Sugammadex 4mg/kg or 2 mg/kg (200 mg /vials) will be given in Deep or Moderate 
rocuronium block arm, respectively. 2 vials are required for patients whose weight 
above 50 kgs in each arm. [Total number of Sugammadex required = 150 vials]   
 
The actual cost of some anesthetic agents/equipment i.e. Propofol, TCI pump, 
infusion pump, End Tidal CO2 and BIS monitoing are able to be reimbursed as these 
may not be used as the routine practice. The maximum reimbursement of these is 
319,000 THB for entire study. 
2.9 Adverse 
Experience 
Reporting 
All serious adverse experiences, regardless of relatedness to study medications will 
be collected throughout the course of study therapy and at least 7 days after the end 
of study therapy. 
 
1. Recording Adverse Experiences 
 
An adverse experience is defined as any unfavorable and unintended change in the 
structure, function, or chemistry of the body temporally associated with the use of the 
study's products, whether or not considered related to the use of the product. Any 
worsening (i.e., any clinically significant adverse change in frequency and/or 
intensity) of a preexisting condition which is temporally associated with the use of the 
product, is also an adverse experience. 
          Changes resulting from normal growth and development which do not vary 
significantly in frequency or severity from expected levels are not to be considered 
adverse experiences. Examples of this may include, but are not limited to, teething, 
typical crying in infants and children, and onset of menses or menopause occurring 
at a physiologically appropriate time. 
          Adverse experiences may occur in the course of the use of a product in clinical 
studies or within the follow-up period specified by the protocol, or prescribed in 
clinical practice, from overdose (whether accidental or intentional), from abuse, and 
from withdrawal. 
          Such events will be recorded at each examination on the Adverse Experience 
Case Report Forms/Worksheets. 
 
2. Immediate Reporting of Adverse Experiences to the SPONSOR 
Serious Adverse Experiences 
 
Any serious adverse experience, including death due to any cause, which occurs to 
any subject/subject entered into this study or within 14 days following cessation of 
treatment or within the established off therapy follow-up period for safety described 
in the protocol, whether or not related to the study product, must be reported within 
24 hours to one of the individual(s) listed on the contact information page. 
          Additionally, any serious adverse experience considered by an investigator 
who is a qualified physician to be possibly, probably, or definitely related to the 
investigational product that is brought to the attention of the investigator at any time 
outside of the time period specified in the previous paragraph also must be reported 
immediately to one of the individuals listed on the sponsor contact information page 
found in the administrative binder. All subjects/subjects with serious adverse 
experiences must be followed up for outcome. 
 
3. Responsibility for Reporting Adverse Experiences 
 
All adverse experiences will be reported to regulatory agencies, IRB/IECs, in 
accordance with all applicable global laws and regulations. 
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2.10 Itemized Study 
Budget 
See attached excel in separate sheet 
2.11 References 
1.
Li et al. The Effects of Neuromuscular Blockade on Operating Conditions
During General Anesthesia for Spinal Surgery. J Neurosurg Anesthesiol
2014;26:45–49.
2.
Moerman AT, Herregods LL, De Vos MM, et al. Manual versus target-
controlled infusion remifentanil administration in spontaneously breathing
patients. Anesth Analg. 2009;108:828–834.
3.
Nieuwenhuijs DJ, Olofsen E, Romberg RR, et al. Response surface
modeling of remifentanil–propofol interaction on cardiorespiratory control and
bispectral index. Anesthesiology. 2003;98:312–322.
4.
Rocuronium, Local Package Insert: RA 8730 TH S1 (Ref 2.1) Latest updated
July 2002
5.
Lapisatepun W et al. Rapid sequence induction with rocuronium at 0.45
mg/kg: comparison of intubating conditions between ketamine and propofol
induction. Chiang Mai Med J 2010; 49(1): 11-17
6.
Siddik-Sayyid SM et al. Excellent intubating conditions with remifentanil-
propofol and either low-dose rocuronium or succinylcholine. Can J Anaesth.
2009 Jul;56(7):483-8.
7.
Rocuronium, Zemuron® Product Monograph Last Revised: August 7, 2012
Merck Canada Inc
8.
Fuchs-Buder T et al. Rocuronium for anesthesia induction in elective
procedures. Time course of muscular blockade and intubation after
administration of 2-compartment ED95 (0.6 mg/kg) and dose reduction (0.4
mg/kg). Anaesthesist. 1999 Mar;48(3):164-8.
9.
McGrath DC, Hunter MJ. Monitoring of neuromuscular block. Contin Educ
Anaesth Crit Care Pain (February 2006) 6 (1): 7-12.
10. Fuchs-Buder T. et al. Good clinical research practice in pharmacodynamics
studies of neuromuscular blocking agents II: the Stockholm revision. Acta
Anaesthesiol Scand 2007; 51: 789–808
11. Howardy-Hansen P. et al.  Tactile evaluation of posttetanic count (PTC).
Anesthesiology 1984;60:372-374.
12. Cooper R. et al. Comparison of intubating conditions after administration of
Org 9246 (Rocuronium) and Suxamethonium. British Journal of Anaesthesia
1992; 69: 269-273.
13. Sugammadex, Local Package Insert: RA 8700001 OS S2 (ref 1.0) Latest
Updated 22 Jan 2017.
14. Vasanawala M, Macario A, Canales M. Some common problems in the
postanesthetic care unit. Contemp Surg. 2000;56:691-700.
15. Martini CH et al. Evaluation of surgical conditions during laparoscopic
surgery in patients with moderate vs. deep neuromuscular block. British
Journal of Anaesthesia August 2013: doi:10.1093/bja/aet377.
16. Flockton E.A. et al. Reversal of rocuronium-induced neuromuscular block
with sugammadex is faster than reversal of cisatracurium-induced block with
neostigmine. Br. J. Anaesth. (2008) 100 (5): 622-630.
doi: 10.1093/bja/aen037.
17. Jian-dong G et al. Evaluation of entropy for monitoring the depth of
anesthesia compared with bispectral index: a multicenter clinical trial.
Chinese Medical Journal 2012;125(8):1389-1392.
2.12 Publication 
Plan 
Within 3 months after the study completion, we plan to submit an abstract of study to 
an international scientific meeting. 
Within 6 months after the study completion, we plan to submit one manuscript to the 
International Journal related to Anesthesiology field. 
      Protocol No 51815 
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Study Flow Chart 
Study Procedures 
Day 0 
Day 1 
Day2 
Inclusion/Exclusion Evaluation 
x 
Informed Consent 
x 
Medical History Review 
x 
OR* Surgeon Assessment 
Q15 min 
OR Anesthesiologist Assessment 
Q15 min 
OR TOF Watch® monitoring 
Q15 sec 
OR PTC monitoring 
Q 6 min 
OR Anesthetic routine monitoring 
Q15 min 
OR residual blockade 
At Extubation, 
1,3,5,10minutes 
Study Procedures 
Minutes 
15 
30 
60 
90 
PACU** routine monitoring 
x 
x 
x 
x 
PACU TOF Watch® monitoring 
x 
x 
x 
x 
PACU residual blockade 
assessment 
x 
x 
x 
x 
PACU readniness time to 
discharge 
x 
x 
x 
x 
Study Procedures 
At arrival 
(24 hours 
post 
PACU) 
Ward residual blockade 
assessment 
x 
x 
*OR =Operating Room, ** PACU = Post Anesthetic Recovery Room
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Patient characteristics 
Gr M 
(N =48) 
Gr D 
(N=49) 
Gender              
Female 
Male 
ASA physical status 
1 
2 
Airway type 
Tracheal tube 
Tubeless 
Combination  
AGE (years) 
BMI (kg/m2) 
Operation time (minutes) 
Anesthetics 
Fentanyl (µg) 
Propofol (mg) 
Rocuronium (mg) 
Sugammadex (mg) 
20 (41.7%) 
28 (58.3%) 
18 (37.5%) 
30 (62.5%) 
27 (56.3%) 
17 (35.4%) 
4 (8.3%) 
43.5 (11.78) 
23.75(3.66) 
53.73(73.99) 
75.96 (54.0) 
465.6 (257.26) 
38.36 (16.51) 
132.99 (35.7) 
23 (46.9%) 
26 (53.1%) 
19 (38.8%) 
30 (61.2%) 
25 (51.0%) 
21 (42.9%) 
3 (6.1%) 
42.31(13.28) 
22.07(5.15) 
78.84 (186.97) 
82.4(52.13) 
481.88 (206.56) 
53.65 (16.38) 
237.53 (37.66) 
Data were presented in number (%) or mean(SD) 


 
 
Intraoperative outcomes 
Gr M 
Gr D 
p-value 
Surgical Grading  
   Clinically acceptable 
   Not acceptable 
Surgeon’s compliant 
Cough 
Total additional doses of Rocuronium 
 
43 (89.6%) 
5(10.4%) 
9(18.7%) 
34(70.8%) 
23 (47.9%) 
 
49(100%) 
0 
5 (10.2%) 
16(32.7%) 
10 (20.4%) 
 
 
0.027* 
0.231 
<0.001* 
0.005* 
 
 


 
 
Recovery parameters 
Gr M 
Gr D 
p-value 
Time to T4 (seconds)† 
60(60-120) 
60(60-120) 
0.497 
Time to TOF0.9 (seconds)‡ 
180(120-240) 
120(109-180) 
0.034* 
PORC at PACU (number of patients)§ 
0 
0 
- 
Time to ALD≥9 (minutes)¶ 
33(18-48) 
27[14-42] 
0.253 
Nausea/Vomiting (number of patients) 
0(0%) 
4(8.2%) 
0.117