A Prospective, Double-blind, Randomized Study to Investigate the Effect of Sugammadex vs. Neostigmine/Glycopyrrolate on Emergence Delirium During Sevoflurane-rocuronium Anesthesia in Pediatric Patients
Phase: PHASE4
Conditions: Emergence Delirium
Sponsor: Pusan National University Yangsan Hospital

 
Section #1 - Protocol Identification 
Study Title: 
A prospective, double-blind, randomized study to investigate the effect of 
sugammadex vs. neostigmine/glycopyrrolate on emergence delirium during 
sevoflurane-rocuronium anesthesia in pediatric patients 
Institution 
Name 
Pusan National University Yangsan Hospital 
Investigator 
Contact 
Information: 
- Tae-Kyun Kim 
- Department of Anesthesiology and Pain Medicine, 
School of Medicine, Pusan National University, 
Geumo-ro 20, Meulgeumeup, Yangsan, Gyeongnam 626-770, 
South Korea 
- +82 55 3602129 / +82 10 35371971 
- +82 55 3602149 
- anesktk@pusan.ac.kr 
Date of 
document: 
Uploaded: 
- July 11, 2017 
 
- 07/12/2017 03:45 

 
Section #2- Core Protocol 
Objectives & 
Hypotheses 
Objectives. 
The aim of this study is to investigate the effect of sugammadex vs. a 
conventional acetylcholinesterase inhibitor, neostigmine on emergence 
delirium (ED) during sevoflurane-rocuronium anesthesia in pediatric 
patients 
Additionally, the efficacy features of sugammadex compared to neostigmine 
will be examined by measuring the time from start of administration of 
reversal agents to recovery of TOF ratio to 0.7, 0.8, and 0.9. 
Clinical hypotheses. 
Although the etiology of ED remains unclear, a sense of suffocation or 
breathing difficulty during emergence from anesthesia has been suggested 
as a possible cause (1). Thus, reversal of neuromuscular blockade with 
sugammadex in pediatric patients maintained with sevoflurane-rocuronium 
anesthesia may decrease ED due to its faster reversal of neuromuscular 
blockade and decreased possibility of residual blockade. 
Background & 
Rationale, 
Significance of 
Selected Topic 
& Preliminary 
Data 
ED is a postanesthetic phenomenon that develops in the early phase of 
general anesthesia recovery, (usually within the first 30 minutes,) and is 
defined as “a disturbance in a child’s awareness of and attention to his/her 
environment with disorientation and perceptual alterations including 
hypersensitivity to stimuli and hyperactive motor behavior” (2). Children are 
often 
irritable, 
uncompromising, 
uncooperative, 
incoherent, 
and 
inconsolably crying, moaning, kicking, or thrashing (3,4). The incidence of 
ED varies from 2 to 80% (5-7), occurring more frequently in preschool boys 
(8,9). Risk factors also include the following: sevoflurane or desflurane 
anesthesia; ear, nose and throat surgery; preoperative anxiety (10). ED is 
known to increase physical, psychological, and financial burdens in the 
postanesthesia care unit, which emphasizes the importance of its 
prevention. 
Sugammadex has been studied in the pediatric population and has been 

 
shown to be useful when given in similar dosing regimens as that used in 
adults (11). It is licensed in children over 2 years for the routine reversal of 
neuromuscular blockade induced by rocuronium in UK (12). However, the 
Korea Food & Drug Administration (KFDA) has limited its use in the 
pediatric population to date. 
Study Design 
- A single-center, prospective, double-blind, randomized, clinical study 
- 40 children, ASA physical status I or II, preschool children aged 2-7 years, 
scheduled for an elective tonsillectomy with or without adenoidectomy will 
be included in the study. Patients will be excluded in cases of emergency 
surgery, developmental, psychological, cognitive or communication 
disorders, known or suspected neuromuscular disorders that may impair 
neuromuscular blockade,  significant renal or  hepatic dysfunction, 
coagulation disorders, family history of malignant hyperthermia, allergy to 
any of the drugs included in the study protocol, or usage of medication 
known to interact with rocuronium or sugammadex. 
- Patients will be randomly assigned to reversal of neuromuscular blockade 
with either sugammadex group (Group S) or neostigmine/glycopyrrolate 
group (Group N) by a computer-generated random number table. 

 
Study Flowchart 
Study 
Procedures 
Patients are admitted to the hospital the evening before surgery and are 
visited by the research anesthesiologist to conduct preoperative interviews. 
A 24G catheter is inserted into a peripheral vein the night before surgery 
or the morning of surgery. All patients will receive 0.005mg/kg 
glycopyrrolate as anticholinergic premedication ~40 minutes before 
induction of anesthesia. After arrival to the operation room, monitoring of; 
noninvasive arterial blood pressure, peripheral oxygen saturation, 
electrocardiograms 
and 
cutaneous 
temperature 
were 
applied. 
Neuromuscular conduction is assessed by TOF-Watch SX acceleromyograph 
device. The child’s behavior during induction of GA is recorded using the 
Induction Compliance Checklist (ICC) consisting of 11 items (13). 1 mg/kg 
fentanyl and 2 mg/kg propofol is administrated to patients by intravenous 
(iv) route followed by an administration of 0.6 mg/kg rocuronium. Patients 
are intubated at the moment of TOF 0, and maintenance of anesthesia is 
provided by a combination of 50% O2-50% N2O and sevofluran (MAC 1.3- 
1.5). The cessation of electrocautery and removal of the mouth gag defined 
completion of surgery. At this time, sevoflurane and nitrous oxide are 
discontinued. At the end of surgery, inhaled agents are discontinued and 
the oxygen concentration is increased to 100%. No alterations are made to 
the ventilation settings, and no attempt is made to stimulate the patient. 
Time from the start of administration of reversal agents to recovery of the 

 
TOF ratio to 0.7, 0.8, and 0.9 would be recorded in both groups. Times from 
start of administration of rocuronium until reappearance of T2 will also be 
recorded. Return to T2 point (two contractions) on TOF device is replied by 
iv 2 mg/kg sugammadex administration to group S patients and 0.06 mg/kg 
neostigmine + 0.005 mg/kg glycopyrrolate administration to group N 
patients, both contained in a blinded syringe. With the return of the cough 
reflex, patients are allowed to breathe spontaneously. When patients 
demonstrate complete emergence from anesthesia by displaying a regular 
respiratory pattern, facial grimacing, gag reflex, and purposeful movement, 
patients are extubated and transferred to the PACU. Anesthetics and 
perioperative medications, the duration of anesthesia, time to regular 
breathing (i.e., time from administration of reversal agent to time of deep, 
regular breathing), time to awakening (i.e., time from administration of 
reversal agent to time of first cough, facial grimacing and gagging, 
purposeful movement, eye opening), and time to extubation (i.e., time from 
administration of reversal agent to time of tracheal extubation) were 
documented. All perioperative care will be at the discretion of the 
anesthesiologist or other care providers, blinded to the reversal agent, per 
routine practice and will not be influenced or intentionally altered as a 
result of participation in the study. 
One parent or carer meets the child on arrival in the recovery area and the 
child is allowed to regain consciousness undisturbed. During the 
postanesthesia recovery, trained and experienced postanesthesia care unit 
(PACU) nurses, also blinded to the administered agent, will document the 
presence or absence of ED based on Paediatric Anaesthesia Emergence 
Delirium (PAED) scale who are unaware as to which treatment group the 
child is allocated. The measurement time points of PAED scores are: on 
arrival to the PACU; every 5 minutes for the first 15 minutes; and every 15 
minutes for the duration of the recovery room stay. PAED scale consists of 
five items: eye contact, purposeful actions, awareness of the surroundings, 
restlessness, and inconsolability, and a score of 10 or more considered a 
diagnosis of ED and a score ≥ 15 defined as severe ED (2). The first and 
and third item reflect disturbances in the child’s consciousness, and the 
second item addresses changes in the child’s cognition during an ED 
reaction. A delirium-specific score (ED I) is calculated from the first three 
items of the PAED score (eye contact, purposeful actions, awareness of the 

 
surroundings), and defined as a total of nine points or higher. The sum of 
these items have demonstrated to be a superior indicator of ED (sensitivity 
93%) and non-ED cases (specificity 94%), compared to that of other two 
items (ED II: restlessness, inconsolability) (14). The score is recorded at 5 
min, 10 min, 15 min, 20 min, 25 min and 30 min after arrival at PACU. All 
pharmacologic and nonpharmacologic interventions, adverse events, 
clinical signs of residual paralysis, peripheral oxygen saturation, heart rate, 
and minutes of PACU stay will also be recorded. 
Statistical 
Analysis and 
Sample Size 
Justification 
The study data will be analyzed by the medical statistician at Pusan National 
University, Yangsan Hospital. 
Variables/Time Points of Interest 
- PAED scale at 5 min, 10 min, 15 min, 20 min, 25 min and 30 min after 
arrival at PACU (2). The maximum PAED after arrival in the PACU will serve 
as the primary outcome variable. 
Behaviour 
Not 
at 
Just 
a 
Quite   a 
Very 
Extreme 
all 
little 
bit 
much 
ly 
Makes   eye   contact 
4 
3 
2 
1 
0 
with caregiver 
Actions 
are 
4 
3 
2 
1 
0 
purposeful 
Aware 
of 
4 
3 
2 
1 
0 
surroundings 
Restless 
0 
1 
2 
3 
4 
Inconsolable 
0 
1 
2 
3 
4 
Secondary outcome variables are measured as following: 
- Times from start of administration of rocuronium until reappearance of 
T2 
- Time from the start of administration of reversal agents to recovery of the 
TOF ratio to 0.7, 0.8, and 0.9 
- Time to regular breathing: time from administration of reversal agent to 

 
time of deep, regular breathing) 
- Time to awakening: time from administration of reversal agent to time of 
eye opening or child showing purposeful movements) 
- Time to extubation: time from administration of reversal agent to time of 
tracheal extubation) 
Statistical Methods 
Continuous data is reported as mean ± standard deviation and is analyzed 
using an independent sample t-test or analysis of variance for multiple 
comparisons with least signiﬁcant difference test for post hoc analysis. 
Categorical data is reported as percentages and were analyzed using the 
Chi-square test or Fisher exact test as appropriate. Nonparametric data is 
reported as median and inter-quartile range and were analyzed using the 
Mann-Whitney U-test. A P < 0.05 will be considered statistically signiﬁcant. 
Power/Sample Size: 
Based on the reference study, the predicted PAED score of control group is 
17 (11-19) (median (range)). Applying a 40% difference in PAED score as 
the minimum clinically relevant difference and allowing significant level α 
= 0.05 and β (1-power) = 0.2, consequently, 6 children per group should 
be required (15). 
Adverse 
Experience 
Reporting 
All drug-related adverse events will be reported to the IRB committee at 
Pusan National University, Yangsan Hospital. 
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