Emergence Agitation and Pain Scores in Pediatric Patients Following Sevoflurane Anesthesia When Comparing Single-modal Versus Multi-modal Analgesia for Routine Ear-nose-throat (ENT) Surgery, a Multi-center Double-blinded Study
Phase: EARLY_PHASE1
Conditions: Emergence Agitation, Pain
Sponsor: Nemours Children's Clinic

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RESEARCH PROTOCOL 
1) Title: 
“Emergence agitation (EA) and pain scores in pediatric patients following sevoflurane 
anesthesia for adenoidectomy and tonsillectomy with or without adenoidectomy 
comparing opioid-only, analgesia with either IV or oral acetaminophen plus opioid 
analgesia, a multi-center double-blinded study” 
 
 
Vesrion 2 July 28, 2017Version 3 January 2018 
 
2) Primary Investigators:  Carlos A. Archilla, MD, Robert B. Bryskin, MD 
 
3) Co-Investigators:  Julie Wei, MD, Anuja Mehta, MD, Jeremy Driscoll, BS, Brian Bender, CRNA, 
Carol Klim, MD, Stefanie Schrum, MD, Joseph Dayan, MD, Timothy M. Maul, PhD 
 
4) Study Coordinators-  Kristin McCrary, MS, CCRP -Orlando 
                                                   Nancy Archer, RN, BSN, CPN- Jacksonville 
 
5) Introduction/Background: Emergence agitation, (EA), is a state of aggressive agitation that 
occurs temporarily during the early stages of emergence from anesthesia. Also referred to as 
emergence delirium, emergence agitation occurs in both adults and children; however, it has 
been known since 1960 that the incidence is higher in pediatric patients (9). Emergence 
agitation is a major source of dissatisfaction for parents, nurses, and others taking care of these 
children. Patients who experience EA may suffer secondary harm due to displacement of 
surgical dressings, removal of catheters, and disruption of surgical closure. These patients 
frequently require additional interventions and may have a prolonged length of stay in the 
post-anesthesia care unit (PACU), even after short surgical procedures. 
 
The etiology of EA after general anesthesia with volatile anesthetics in children remains 
unclear. Numerous studies exist in the literature that have attempted to correlate EA with the 
use of a particular anesthetic agent or technique.  Specifically, the newer, volatile anesthetics, 
sevoflurane and desflurane, have been implicated in a 20-80% increased incidence of adverse 
effects, including inconsolable crying, restlessness, and agitation unrelated to pain (10). 
However, many of these studies did not use a validated scoring system to assess emergence 
agitation appropriately. In 2004, the Pediatric Anesthesia Emergence Delirium (PAED) scale 
was validated as a measure of emergence agitation. In this validation study, the PAED scale 
correlated positively with the former post-operative behavior questionnaire and the scale 
results correlated with clinical observations. This study also showed that patients receiving 
newer volatile anesthetics (sevoflurane) had a higher incidence of EA compared to those 
receiving halothane and this correlated with clinical observations (12). 
 
Sevoflurane is a suitable volatile anesthetic for mask induction because of its pleasant scent 
and lack of irritation. It offers rapid induction of anesthesia, hemodynamic stability, and fast 
emergence.  Although, Anesthesiologists prefer these characteristics for pediatric use, EA 
remains a considerable side effect of this anesthetic that demands increased resources in the 
PACU.  

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Data regarding EA incidence with different analgesic modalities using sevoflurane for 
induction and maintenance of anesthesia in children is scarce, and results are far from 
uniform. The literature is ambiguous on the incidence of EA associated with the use of 
sevoflurane and previous studies concerning EA in children are complicated by a lack of a 
validated EA scale and observed time interval after wake-up from anesthesia. The conflicting 
results may arise from the differences of study design, the background of study patients, and 
study quality. Under the existence of many confounding factors regarding EA, it is hard to draw 
from a single study a definitive answer about whether sevoflurane results in a higher 
probability of EA, as well as what effect and impact the different intra-operative analgesic 
modalities have on EA.   When considering intra-operative analgesic modalities; co-
administration of acetaminophen in addition to the standard opioid analgesic, allows for 
improvement of pain control without change in sensorium, as this non-opioid preparation is 
minimally sedating.  By improving pain control, while holding the type of procedure and 
sedation constant, we hope to demonstrate a decrease in the incidence of EA.  Of additional 
interest is whether the rate at which acetaminophen achieves peak CSF penetration affects EA 
outcomes.  It is known that the primary site of action of acetaminophen is within the CNS and 
that its pharmacodynamic effect is dependent on achieving a sufficient Plasma/CSF level.  The 
rate of CSF penetration has been demonstrated to occur earlier, and at a greater concentration, 
in patients with IV administration compared to PO or PR (16). PR route of administration was 
excluded in this study based on observation by Anderson et al. in pediatric post-tonsillectomy 
patients (17).  The PR plasma acetaminophen Tmax of 3 to 4 hours was not effective in 
achieving the threshold plasma acetaminophen level of 10 mcg/mL in the immediate post-
operative phase. 
 
In this study, we plan to compare the incidence of EA in 3 groups of pediatric patients 
undergoing routine adenoidectomy, or tonsillectomy with or without adenoidectomy, using 
sevoflurane for induction and maintenance of anesthesia.  We will use a validated and 
standardized measurement tool, the PAED scale, to compare EA in those receiving opioid-only 
based analgesia, (IV fentanyl),  to patients receiving multi-modal analgesia consisting of opioid 
plus IV acetaminophen or opioid plus PO acetaminophen.  
 
 The inclusion of adenoidectomy, or tonsillectomy with or without adenoidectomy procedures 
was chosen due to the known observation in clinical experience and previous studies that 
patients undergoing these specific ENT procedures are at higher risk for EA. In a 
comprehensive review of EA published in Anesthesia and Analgesia, ENT surgery was 
identified as a risk factor for increased incidence of EA (15). Some hypothesize that upper 
airway procedures may produce a sense of suffocation when patients emerge from anesthesia. 
It is also hypothesized that the short duration of and fast emergence from the anesthetic are 
contributing factors. The accurate incidence of EA in ENT patients is hard to quantify, as 
studies tend to report more often on patients undergoing ear procedures that are known to be 
of short duration. The incidence of EA reported by this research study team in its previous 
work, showed the incidence of EA for adenoidectomy and adenotonsillectomy surgery to be 
between 34.8% and 43.5% (7). 
 

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A recent study conducted a systematic literature search and showed that the addition of an 
NSAID, acetaminophen or combination of the two, decreased post-operative pain scores and 
opioid requirements in children undergoing surgery including adenotonsillectomy, (14). 
Recent studies have shown improved pain scores when an analgesic adjunct is administered 
(6). Acetaminophen is the safest and most commonly used analgesic in the US and worldwide. 
Acetaminophen is also the standard therapy for post-op discharge pain management in 
patients with routine ENT procedures. Recent studies have evaluated the benefits of adding IV 
acetaminophen or PO acetaminophen to current pain regimens to assess the effects of 
lowering post-operative pain scores and the reduction in use of rescue doses of opioids in the 
recovery room.  It has been reported that the route of administration of acetaminophen may 
have an effect in the duration of analgesia in adenotonsillectomy patients (13). This particular 
work showed the duration of analgesic effect was longer in patients receiving rectal 
acetaminophen. The optimum route of administration of acetaminophen maybe unclear but is 
known that different routes of administration can be associated with different analgesic 
effects. Intravenous acetaminophen has a faster onset and more predictable 
pharmacodynamics than oral or rectal acetaminophen, which may present a theoretical 
benefit. 
 
 
IV acetaminophen is approved for the management of mild to moderate pain in pediatric 
patients and the management of moderate to severe pain as an adjunctive to opioids in 
pediatric patients 2 years of age and older. It has both an onset and peak effect of 15 minutes 
or less, and a duration of analgesic effect between 4 and 6 hours. Dosing depends on patient 
weight and age, as well as the intended frequency of administration. (For all patients 2 to12 
years of age, and any patient weighing less than 50 kg, the dose is 12.5 mg/kg per dose if using 
an every-4-hour schedule, or 15 mg/kg per dose if using an every-6-hour schedule. The 
maximum single dose for these patients is 15 mg/kg. The maximum daily (24-hour) dose for 
these patients is 75 mg/kg (8).)  Acetaminophen is metabolized via glucuronidation and 
sulfation in the liver. In neonates and younger children, studies have shown preferential 
metabolism via sulfation, possibly indicating a decreased risk of hepatotoxicity because 
hepatotoxicity is primarily due to metabolites that arise from the glucuronidation process. 
There are still concerns about hepatotoxicity primarily due to the more bioavailability of the IV 
formulation compared to rectal and oral administrations. In addition, the IV formulation is 
considerably more expensive compared to either the PO or PR routes.   Adverse reactions are 
rare for effects such as malaise, nausea, abdominal pain, rash, hypotension, and increased 
levels of hepatic transaminases.  Studies, met-analyses, and literature reviews show that 
appropriate IV acetaminophen dosing compared to placebo is not associated with 
hepatotoxicity. In general, most cases of hepatotoxicity have been associated with doses 
greater than recommended and with concomitant administration of acetaminophen-
containing products (4, 5). 
 
A recent study using similar numbers of patients per group as proposed in this study, showed 
lower pain scores in groups receiving adjunct administration of IV acetaminophen and rectal 
acetaminophen especially in the first few hours of the post-operative period(1). Another study 

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showed no difference of multi-modal analgesia in decreasing incidence of EA in routine  ear-
nose-throat surgery (2) but did not use standardized PAED scale, used Versed premedication 
in all patients, and studied only short lasting ENT procedures (Bilateral Myringotomies and 
Tube Placement).  Our previous leading research study by this research team, published in the 
European literature, showed no difference between the incidences of EA when comparing the 
two most commonly used volatile anesthetics, sevoflurane and desflurane.  Both groups 
received multi-modal analgesia using opioid plus IV acetaminophen. Clinical observations from 
this study showed upon study termination and thus the decline in use of adjunct IV 
acetaminophen, the incidence of overt EA resulted in a resurgence of needed rescue treatment. 
This led us to suspect the improvement in pain control using adjunct IV acetaminophen may 
have contributed to the diminished incidence of emergence agitation/delirium (EA)(7).  
 
6) Objective: The purpose of the proposed research study is to optimize postoperative outcomes 
in children undergoing adenoidectomy or tonsillectomy with or without adenoidectomy, by 
reducing EA while maintaining adequate pain management. We aim to generate knowledge 
regarding the impact of multi-modal analgesia in pediatric patients undergoing the above-
mentioned surgeries on the incidence of EA and post-operative pain. This information will 
assist anesthesiologists, parents, children and surgeons when determining the most 
appropriate perioperative analgesia to be administered. 
7) Hypothesis:  
The Primary Hypothesis is: The incorporation of acetaminophen in addition to standard opioid 
analgesia in children undergoing adenoidectomy or tonsillectomy with or without 
adenoidectomy will result in a decreased incidence of EA. This will be evaluated using a 
standardized EA measurement tool, the Pediatric Anesthesia Emergence Delirium (PAED) 
scale [Appendix 1].  
The Secondary Hypothesis is: The route of acetaminophen administration (IV vs PO), will not 
have an effect on post-operative EA or pain management. This will be evaluated by comparing 
the pain scores of patients receiving either oral acetaminophen plus opioid or IV 
acetaminophen plus opioid, using the FLACC score for patients 24 months of age to 4 years of 
age and/or sedated patients at time of assessment, Wong-Baker FACES for patients between 4 
and 7 years of age and non-verbal patients, and the Numeric Pain Score for patients 
equal/greater than 7 years of age. 
The findings of this study, which will assess common neurobehavioral and neurocognitive 
disturbances after anesthesia/surgery, and assessment of immediate post-operative pain in 
adenoidectomy or tonsillectomy with or without adenoidectomy, can serve as an investigative 
platform for future studies involving other types of surgery.  
8)  Aims: In order to test our hypotheses, we propose a prospective, randomized, blinded study 
in pediatric patients 24 months through 7 years of age, undergoing adenoidectomy or 
tonsillectomy with or without adenoidectomy,  with two specific aims:  
 

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Specific Aim 1: To compare the incidence of EA in pediatric patients undergoing 
adenoidectomy or tonsillectomy with or without adenoidectomy surgery under sevoflurane 
anesthesia when using opioid-only based intraoperative analgesia, (IV fentanyl),  versus multi-
modal analgesia consisting of IV opioid plus IV acetaminophen or IV opioid plus PO 
acetaminophen regimen. A standardized EA measurement tool, the Pediatric Anesthesia 
Emergence Delirium (PAED) scale [Appendix 1] will be the used. The primary endpoint of this 
aim is the incidence of EA defined as PAED score >12. 
Specific Aim 2:  To assess the effectiveness of acetaminophen plus standard IV opioid versus 
standard IV opioid treatment alone on post-operative pain management using an age-
appropriate validated pain scale. We will accomplish this by comparing the pain scores of 
patients receiving either oral acetaminophen plus IV opioid or IV acetaminophen plus IV 
opioid to IV opioid alone, using the FLACC Score for patients 24 months to 4 years of age and 
sedated patients at time of assessment, Wong-Baker FACES for patients between 4 and 7 years 
of age, and Numeric Pain Scores for patients equal/greater than 7 years of age. The endpoint of 
this aim is the average pain score during the first 60 minutes of recovery. 
 
9) Benefits:  Potential benefits of this research study include understanding patients‘ response to 
their assigned perioperative analgesic modality and the possibility of designing an analgesic 
plan for future surgeries or painful procedures by utilizing the knowledge gained from the 
research.   This study may help us identify which perioperative medication regimen is more 
beneficial to use in children undergoing adenoidectomy or tonsillectomy with or without 
adenoidectomy  in order to decrease agitation, provide better pain control, and decrease 
exposure to multiple opioid doses if an acetaminophen adjunct medication is found beneficial.  
10) Place of Study:  
Nemours Children’s Hospital, Orlando, Florida (Primary Site) 
Wolfson Children’s Hospital, Jacksonville, Florida (Nemours Jacksonville Satellite Site) 
11) Study Design: 
a) Prospective Randomized Study 
b) Study Period: October 2017-March 2018 
c) Potential participants: 375 – 475 based on 20-25% of 4,459 ENT patients in 2016 
d) Study Population: 50 pediatric patients in each group between 24 months through 7 years 
of age undergoing adenoidectomy or tonsillectomy with or without adenoidectomy 
Total Number of Patients: 150  
e)   Based on the preliminary data based on study from Bedirli et al. in other areas of emergence    
delirium, we find that a 3-armed study with equal enrollment in each arm would provide 
sufficient power (90%) to detect an effect size of 0.3 (moderate effect) at alpha=0.05. The 
secondary hypothesis would require over double the effect size (0.7) at the same power (90%) to 
detect any differences in the delivery route. We recognize that this aim will be greatly 
underpowered given the expected effect size of administration route. However, the knowledge 

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gained from this portion of the study will provide valuable information to form the basis of a 
larger multi-centered trial. 
 
12) Methods and Materials:  150 patients between the ages of 24 months  through 7 years, 
scheduled for adenoidectomy or  tonsillectomy with or without adenoidectomy, will be 
randomly divided into three groups of 50 patients. Each group will receive sevoflurane 
induction and maintenance of anesthesia. Sevoflurane, currently the most commonly used 
agent for inhalational induction, will be used for induction of anesthesia, as it is less irritating 
to the tracheobronchial tree than other volatile anesthetic agents and is considered the 
standard for pediatric induction anesthesia. These three groups, (study arms), are identified as 
follows: 
Group A: multi-modal analgesia of IV fentanyl plus IV acetaminophen and oral placebo 
Group B: multi-modal analgesia of IV fentanyl plus PO acetaminophen and IV placebo 
 
Group C: single modal analgesia of IV fentanyl plus oral placebo and IV placebo 
 
Pre-operative procedures:  The Research Pharmacy will have the following standards for 
randomization: prior to patient surgery date; the pharmacy will assemble study kits to contain 
the appropriate drug products based on the 3 randomization scenarios:  A. IV Tylenol and Oral 
Placebo, B. IV Placebo and Oral Tylenol, or C. IV Placebo and Oral Placebo.  The kits will be kept 
in the pharmacy and identified in a blinded fashion from other study team members.  On the 
day of surgery, (patient dosing day), blinded study team member will provide the signed study 
consent to pharmacist, along with the patient’s weight to be used in calculating dosages of 
study drug.  The pharmacist will then assign the patient to 1 of 3 study arms, in a random 
approach. Randomization will be performed by using a method based on the biased coin 
method using a dynamic urn technique (11). Once the study arm has been determined, a study 
number will be assigned and the corresponding kit will be used to prepare the study drugs by 
patient weight. The blinded, randomized study kit information will be kept in a locked Excel 
spreadsheet, with password access, only available to pharmacy team members.  All study 
drugs will be checked and verified by a licensed pharmacist prior to dispensing to a blinded 
study team member. 
 
None of the study patients will receive premedication for sedation. Premedication is not a 
standard treatment at Nemours Children’s Hospital (NCH) as NCH allows parental presence 
during induction of anesthesia to facilitate the transport of the patient to the operating room 
and decrease separation anxiety. Wolfson Children’s Hospital will allow parental presence for 
study patients. Parental presence is an appropriate substitute for sedation premedication.  In 
the pre-operative area, all patients will receive a de-identified PO syrup.  The syrup will be 
prepared by the pharmacy and will contain acetaminophen (15 mg/kg -160mg/5mL 
Manufacturer: Major Pharmaceuticals), for the PO acetaminophen group and placebo flavored 
syrup (Manufacturer: Humco, Ingredients: Sucrose 82.3%, Purified Water, Artificial Flavors, 
0.1% Sodium Benzoate as a preservative, Critic Acid, FDC Red #40, and inert ingredients), for 
the other two groups.  This approach will maintain blindness of the peri-operative staff, and 
patients/parents/guardians. 

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Intraoperative Procedures and Administration of intra-op analgesia:  Before induction of 
anesthesia the pre-induction vital signs will be reviewed and ASA standard monitors will be 
applied. Standard ASA monitors include blood pressure, ECG, pulse oxymetry, etCO2 
measurement, respiratory rate and temperature. Induction of anesthesia will be accomplished 
via inhalation of sevoflurane (8 vol%) in nitrous oxide (70%) and oxygen (30%) at a fresh gas 
flow of 10 Lpm. An IV will be established and propofol 2mg/Kg will be administered to 
facilitate endotracheal intubation. After intubation, all children will receive fentanyl (West-
Ward Pharmaceuticals)  2 mcg/kg.   IV Fentanyl is considered standard of care for analgesia 
regimen for these types of surgery. Intra-op anesthesia team will be blinded to the use of non-
opioid IV analgesia and will administer a pharmacy prepared de-identified infusion (pharmacy 
will blind the IV formulation of acetaminophen and all pharmacy formulations will follow 
regulation 797 compounding standards), following intubation that will consist of 0.9% normal 
saline (Baxter Pharmaceuticals), placebo for control groups and IV acetaminophen (15 mg/kg, 
- 1000mg/100 cc Mallinckrodt Pharmaceuticals) for the IV acetaminophen group. The 
maximum single dose will be 750 mg with a 24-hour maximum dose not to exceed 3,750 mg in 
this 24-hour period. The product will infuse for 15 minutes as recommended by the 
manufacturer. For maintenance of anesthesia, children will receive sevoflurane (maximum of 
2.0±0.2 MAC, age adjusted) with a constant fresh gas flow of 2 L/min (maximum FIO2 of 30% 
air mixed with oxygen), using a semi-closed circle breathing system. Ventilation will be 
controlled to maintain normocapnia (ET-CO2 32-38 mmHg). Additional doses of fentanyl can 
be administered, per anesthesiologist’s discretion, in all groups by increments of 0.5 mcg/Kg 
IV per dose for hemodynamic response to surgical stimulation greater than 20% above 
baseline.  Removal of the mouth gag for tonsillectomy/tonsillectomy and 
adenoidectomy/adenoidectomy will be defined as the end of surgery. At this point, inhalation 
anesthetic will be discontinued. Fresh gas flow will be increased to a minimum of 8 Lpm, 100% 
oxygen. Tracheal extubation will be performed when normal ventilation is achieved and cough 
or gag reflex is regained.   
 
13) Inclusion/Exclusion Criteria:  
 
Inclusion Criteria: 
 
a) Patients who are 24 months through 7 years of age 
b) Patients who weigh <50 kg 
c) Patients who are able to take PO medications 
d) Patients who are ASA Classification I and II 
e) Patients who are found to be a candidate after clinical review of detailed History and 
Physical Exam, review of Polysomnogram or Pediatric Sleep Questionnaire 
f) Patients who are scheduled for routine adenoidectomy or tonsillectomy with or without 
adenoidectomy not in conjunction with another invasive or diagnostic procedure         
g) Patients who meet clinical indications for surgery                                                                                 
 
 
 
       Exclusion Criteria: 

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a) Children with a history of developmental delay or psychological disorders that may be at higher 
risk for EA as determined by study physician after review of history and problem list in 
EMR 
b) Patients with previous hypersensitivity to oral or intravenous acetaminophen, fentanyl  or 
any    of its components or ingredients in placebo, 
c) Patients with severe hepatic impairment or severe active hepatic disease 
d) Patients with previous history of Malignant Hyperthermia or susceptibility to volatile 
anesthetics   agents like sevoflurane  
e) Any patient who weighs >50 Kg.  
f) Any patient that requires premedication. Versed may contribute to an increase in EA. 
Premedication is reserved when parental presence is not feasible or for very anxious 
children.  
g) Patients unable to take PO (acetaminophen or placebo) will be excluded from the study.  
h) Children with severe symptomatic sleep apnea that require post-operative hospitalization. 
i) Severe symptomatic sleep apnea is defined as a- patients who has a pre-operative 
polysomnogram and a calculated Apnea-Hypoxia Index greater than 10 b- patients with 
high scoring in Pediatric Sleep Questionnaire (PSQ)  
j) Patients with severe symptoms and findings in physical exam that require post-operative 
hospital admission.  
k) Participant is currently participating or has within the previous 30 days, participated in 
another clinical trial/research study 
 
14) Screening/Consent Process:   Potential participants will be identified and receive basic 
 
Bringing the consent form home to review, allows the family time to discuss study 
participation among themselves, reach out to other family members or physicians for advice. 
Providing this form in advance will help the participants and parents/guardians to distinguish 
the difference between the study consent and surgery-related consent. The research team will 
obtain consent the day of surgery. The potential participants will be brought to the pre-
operative area two hours prior to scheduled procedure to allow ample time to review the 
research study consent once more and have any additional questions answered prior to 
signing the consent. The research team will assure that the child, (as appropriate), and parent 
or guardian has the capacity to understand and make a decision about their child’s 
participation in a research study. The study investigators, (P.I.’s/Co-I.’s), study 
anesthesiologists, will obtain PP consent and Assent for eligible children.  A signed and dated 
copy of all consents forms will be given to the parents. 
 
15)14) 
Intraoperative Standardization and Procedures:  The surgical technique will be 
standardized and a limited group of three surgeons per clinical site that share same 
surgical technique which will be agreed upon at the start of the clinical phase. This technique 
will consist of only Teflon blade cautery and will require no peri-tonsilar local anesthetic 
injection. The number of anesthesia providers involved in the study will be limited to two 
anesthesiologists per clinical site. The anesthesiologists involved on the clinical component of 

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the protocol are those who are part of the research study team.  Sevoflurane will be used for 
induction and maintenance of anesthesia for all groups. Study participants will receive one of 
the three analgesia regimens per their individual randomized treatment: 
1- IV fentanyl plus oral placebo and IV placebo 
2- IV fentanyl plus IV acetaminophen plus oral placebo 
3- IV fentanyl plus PO acetaminophen and IV placebo 
16)15) 
Post-Operative Standardization and  Measurements:  The post-operative pain 
management approach will be restricted to fentanyl (0.5 mcg/Kg IV/dose titrated to effect) for 
moderate to severe pain.  Ibuprofen (10mg/Kg) PO will be ordered for mild to moderate post-
op pain. Post-op recovery staff will be limited to a maximum of three trained PACU nurses per 
site and will use FLACC Scale for age 24 month to 4 years of age and sedated patients at time of 
assessment, Wong-Baker FACES for patients 4 to 7 years of age and non-verbal patients and 
Numeric Pain Score for patients equal/greater than 7 years of age to assess level of pain. 
Episodes of clinical emergence agitation/delirium (EA), will receive rescue treatment. This 
treatment will consist of 0.5 – 1.0 mcg/Kg IV dexmedetomidine. Our UCF psychiatry faculty 
will review all cases of clinical EA.  This member of our team, who is an expert in EA, will 
assess every case to exclude organic, pharmacologic and situational causes for EA.  This 
analysis will be conducted on a quarterly basis and will assist us in making necessary study 
adjustments. 
Age, gender, height, weight, procedure, duration of surgery, intra-op agents used, exposure and 
time of discontinuation of anesthesia to extubation will be documented for each patient. A 
blinded PACU nurse will monitor the patient. The Post-anesthesia unit monitoring standards 
consist of HR, Blood Pressure, pulse-oxymetry and respiratory rate every 5 minutes times 
3 and every 15 minutes thereafter until discharged from PACU.  Temperature will be obtained 
upon arrival to unit and every hour or as needed. All patients will be evaluated for the Aldrete 
Score which assesses readiness for discharge from post-anesthesia care unit. The PACU nurse 
will record degree of agitation using the PAED scale and measure and record the pain scores 
using either the FLACC for patients 24 months to 4 years of age and patients who are sedated 
at time of assessment, Wonk-Baker FACES for patients 4 to 7 years of age and non-verbal 
patients and Numeric Pain Scores for patients equal/greater than 7 years of age upon 
admission to the PACU and every 15 minutes for approximately 1 hour after admission, or 
until discharge from the PACU, whichever comes first. These nurses will all be experienced in 
the use of PAED scale. There will be three; two-hour study training sessions at each clinical site 
for PACU participating nurses. PACU nurses assigned to this study will be selecting the 
Modified Aldrete scores (respiration, O2saturation, consciousness, circulation, activity) and 
documenting adverse events (nausea, vomiting, shivering, breath-holding, excessive 
secretions, laryngospasm, excessive bleeding) which will be recorded. Children will be 
considered discharge ready with an Aldrete score ≥9, and this will be recorded as previously 
stated. 
 
17)16) 
Adverse Events (AE)/Data Safety Monitoring:  

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      Oversight Responsibilities: Oversight of the trial is provided by the Principal Investigator      
      (PI) and Co-Investigators. 
 
     Monitoring Procedures: 
 The investigative team assures that informed consent is obtained prior to performing any 
research procedures, that all subjects meet eligibility criteria, and that the study is conducted 
according to the IRB-approved research protocol.  Study data are accessible at all times for the 
PI to review. The PI and co-investigators review study conduct accrual, dropouts, protocol 
deviations, interim results and potential protocol modifications on a monthly basis.  The PI and 
co-investigators review AEs individually in real-time and in aggregate on a monthly basis. The 
research team can decide to terminate the study at any time when analyzing reports of adverse 
events. The possibility of adverse events is very low. The PI ensures all protocol deviations, 
AEs, and SAEs are reported to the sponsor (UCF or Baptist Health) IRB and FDA (under IND 
Safety Report 312.32) according to the applicable regulatory requirements. 
 
There will be a mandatory progress report to UCF on July 1st, October 1st and December 15th 
2017, this will be reported to all study sites.  
 
       Collection and Reporting of SAEs and AEs: 
       For this study, the following standard AE definitions are used: 
 
Adverse event:  Any unfavorable and unintended sign, symptom or disease temporally 
associated with the use of a medical treatment or procedure, regardless of whether it is 
considered related to the medical treatment or procedure. 
 
Serious Adverse Event:  Any AE that results in any of the following outcomes: 
 
• 
Life-threatening event 
• 
Event requiring inpatient hospitalization or prolongation of hospitalization 
• 
Death 
• 
Congenital anomaly 
• 
Persistent or significant disability/incapacity 
• 
Required intervention to prevent permanent impairment/damage 
          Criteria for Stopping Study due to Adverse Events: 
 
• 
Any number of deaths   
• 
After 2 non-fatal SAEs 
• 
After any severe neurological event 
• 
After any 3 events where there is a moderate neurologic adverse event which is 
alleviated with simple therapeutic treatments 
AEs are graded according to the following scale: 
 
 Mild:  An experience that is transient, and requires no special treatment or intervention. 
The experience does not generally interfere with usual daily activities.  

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Moderate:  An experience that is alleviated with simple therapeutic treatments.  
 
Severe:  An experience that requires therapeutic intervention. If overnight hospitalization 
is required for treatment, it becomes an SAE.  
 
The study uses the following AE attribution scale:  
 
Not related:  The AE is clearly not related to the study procedures or treatments (i.e., 
another cause of the event is most plausible and/or a clinically plausible temporal 
sequence is inconsistent with the onset of the event).   
 
Possibly related:  An event that follows a reasonable temporal sequence from the 
initiation of study procedures, but that could readily have been produced by a number of 
other factors. 
 
 
Definitely Related:  The AE is clearly related to the study procedures.   
 
AEs identified will be captured in real time as they become known. AEs that result in visits to 
the ED and/or outpatient clinics will be monitored at each site through their readmission-
monitoring program and reported to the department of Anesthesiology by the quality and 
safety officer. In addition, all AEs are reported in Orlando according to the Nemours IRB AE 
reporting guidelines and in Jacksonville, according to the Baptist Health IRB AE guidelines. 
 
Treatment of AEs: 
In case of a symptomatic event where a severe adverse event or any SAE is noticed, the 
blinding can be broken by accessing a sealed envelope that contains the assigned drugs in the 
randomization process and appropriate treatment will be instituted. These patients will be 
withdrawn from the study but the clinical and research team will continue to collect safety 
information.  This data will be included in the safety database and reported during monthly 
meetings.  Nemours will assure that the participant receives treatment, if needed , for study-
related injuries. Neither Nemours nor the study doctor has a program to pay for medical care 
provided to treat the injury. If the participant has health insurance, it may , or may not, pay for 
the cost of treatment resulting from a study-related injury. If the participant’s insurance does 
not pay, or if the participant does not have insurance, the participant’s parent/legal authorized 
representative may be responsible for paying for the cost of treatment. The 
investigator/institution will ensure that adequate medical care is provided to a research 
participant for any adverse events, including clinically significant laboratory values, related to 
the trial. The investigator/institution will inform the subject when medical care is needed. All 
AE/SAEs will be followed through their resolution or until the investigator attributes the 
AE/SAEs to a cause other than the study drug or assesses them as chronic or stable.  
 
Ameliorating Measures: 
Episodes of clinical emergence agitation/delirium (EA), will receive rescue treatment. This 
treatment will consist of 0.5 – 1.0 mcg/Kg IV dexmedetomidine as previously stated.  
 

12 
Vesrion 2 July28, 2017Version 3 January 4, 2018 
 
All patients will be instructed not to start the next dose of acetaminophen until 6 hours after 
last administered dose. This dose correlates to the time of intra-operative IV infusion 
administration. 
All discharged patients will receive a call within 24 hours of surgery for follow-up. In addition 
to standard questions, they will be asked questions regarding abnormal rashes or 
discoloration of the skin and other potential adverse events like nausea, vomiting, allergic 
reactions, itching, respiratory difficulty, shivering, excessive bleeding, unplanned Emergency 
Room visit, hospitalization or death. 
 
Clinical Research Platform 
Low Risk Pathway 
 
A. Scientific Significance:  This study protocol is designed to address the scientific necessity 
of intra-op and post-op pain management options that are most appropriate in children 
undergoing common surgical procedures. This protocol addresses one of the most common 
risks associated with anesthetics in children less than 7 years of age, emergence agitation (EA).  
Evidence and clinical knowledge have shown that pain and emergence agitation negatively 
affect children’s well-being in the post-operative period. This protocol will likely yield 
generalizable knowledge about subjects’ post-operative pain and agitation that is of vital 
importance for the understanding and amelioration of these two conditions. 
 
B. Risk/Benefit Assessment:  As defined by 21 CFR Subpart D the study team will follow 
principles of additional safeguards in children, which includes parental permission and child 
assent.  The research team offers a study design that includes an appropriate balance of the 
direct benefit of a pain regimen potentially beneficial to a subject’s future surgical or painful 
invasive procedure, while studying the indirect beneficial science of knowing which pain 
regimen is most affective for patients undergoing adenoidectomy or tonsillectomy with or 
without adenoidectomy surgery, while offering adequate pain relief with a lower incidence of 
adverse events including EA. As defined in our introduction, patients of the study age range 
and type of surgery are at highest risk for EA. When balancing the direct and indirect benefits, 
the investigative team feels that these benefits present an acceptably low risk that is at 
minimal or slightly more than minimal risk given adult testing and clinical experience and 
pediatric studies of this FDA-approved drug. The research team feels that the balance between 
anticipated direct and indirect benefits versus expressed risks is favorable.  
Plan for Data Management:  
• Compliance of regulatory documents as well as study data accuracy and completeness, will 
be monitored through an internal study team quality assurance process.  
• Confidentiality throughout the trial is maintained by securing identifiable participant data 
in secured, limited access locations or password protected computer files on the Nemours 
server. Hard copy records will be stored in a protected and limited access location at each 
individual site.   
Withdrawal Considerations: 

13 
Vesrion 2 July28, 2017Version 3 January 4, 2018 
 
 
Our research team follows the ethical principles for participating subjects, participation is 
voluntary.  After full disclosure, the subject can withdraw at any time from participating in the 
research study. 
 
1) Participants are to be withdrawn when a participant/parent/guardian does not consent to 
continued voluntary study participation. 
2) Participants and/or parents/guardians can request withdrawal at any time during the 
research study. Data collected up to point of withdrawal will remain part of the study 
database and subject to confidentiality protections. When voluntary withdrawal is 
requested, the research team will honor this request immediately and completely as 
allowed by law. Understanding the fact that this is a one-time intervention, a withdrawal 
request will result in permanent study withdrawal. 
3) Participants can be withdrawn from protocol if during the course of the protocol: a newly 
discovered clinical aspect increases the participant’s risk; the participant experiences an 
unexpected adverse event that the research physician feels would require study 
withdrawal, the participant experiences any serious adverse events; or the participant no 
longer qualifies for research study participation. 
4) All clinical study data will be maintained, per regulations, including data on participants 
who withdraw voluntarily or participants withdrawn by the clinical research team. All 
withdrawn participants will be notified of their termination. The obtained data will be 
recorded on the CRF and may include demographic information, vital function monitoring, 
drugs administered and recovery room observations including emergence agitation and 
pain assessment scores. 
5) The research team does not plan to replace participants who withdraw. 
6) Participants who withdraw prior to the interventional portion or who will not consent for 
follow up, will have their protected health information maintained as private and not 
assessed by the research team or per Nemours guidelines.  
7) Follow-up: If the participant agrees with follow up after withdrawal, the follow-up may 
include obtaining a 24-hour post-operative call to assess side effects or adverse event 
during the immediate post-operative period. This post-withdrawal assessment will follow 
clinical guidelines and the research team members who are treating physicians must clarify 
their role as a clinician. Information obtained after withdrawal during follow-up 
proceedings will not be used for research considerations unless there is separate consent. 
8) The total number of participants who complete the entire study protocol will be at least 
150. 
 
 
18)17) 
Statistical Analysis/Outcome Measures, Sample Size Rationale:  All statistical 
analysis will be performed in SPSS v23 (IBM Corp.). Data will be assessed for normal 
distribution via Kolmogorov-Smirnov test. For continuous variables, normally distributed data 
will be analyzed using t-test and ANOVA. Non-normal distributions will be analyzed with non-
parametric methods (Mann-Whitney U). For discrete/categorical variables, Chi-squared and 
gamma testing will be performed as appropriate. Time-dependent data will be analyzed via 
ANOVA with repeated measures or Wilcoxon-Ranked Sum testing as appropriate based normal 
distribution testing. All testing will be performed with α=0.05 to determine statistical 
significance.  

14 
Vesrion 2 July28, 2017Version 3 January 4, 2018 
 
Outcomes measures from this study are based upon the PAED assessment scale and pain 
scores. The primary hypothesis is that multi-modal analgesia reduces PAED. The secondary 
hypothesis postulates that there is no difference in PAED or pain scores dependent on the 
route of acetaminophen administration. We will assume that the data is normally distributed 
for the purposes of this study, and all comparisons will be made using simple ANOVA testing. 
This requires two separate computations of estimated sample size.  
The sample size estimation is based on data from Bedirli et al.(18) which compared the effects 
of Tramadol (N=39) vs dexmedetomidine (Dex; N=38) in pediatric patients undergoing 
tonsillectomy and adenoidectomy (T&A). They found that Tramadol had an arrival EA score of 
14 (3-17), while the Dex patients had an EA score of 15 (0-17). They also found an 
observational pain score (OPS) of 3 (2-5) for Tramadol, and 5 (3-8) for Dex; and the Ramsay 
sedation scores were 2 (2-2) and 4 (2-5) after 15 minutes in the PACU for Tramadol and Dex, 
respectively. The authors concluded that the EA and OPS were not statistically different 
(p>0.05), but that the Dex group had a higher sedation score after 15 minutes in the PACU 
(p<0.05). 
 
Using the results from their study, the effect size on EA was 0.08; finding a difference in EA 
between these two drugs for a two-tailed analysis with alpha=0.05 and beta=0.2 (Power 80%) 
would require a total sample size of 4192. The effect size on OPS was 0.51, requiring 120 
patients total to determine a difference in a two-tailed test with alpha=0.05 and bet=0.2 
(Power 80%). For Sedation score, the effect size was 1.3, requiring 22 total patients for a two-
tailed test at alpha=0.05 and beta=0.2 (Power 80%).  
Regardless of the outcome measure, it is simple to calculate the necessary population for 
which this study can be done using GPower (v 3.0.10). The first aim of the study is a three-
armed blinded study, which can be estimated using an ANOVA analysis for 3 groups. The plot 
below depicts the required total sample size (assuming equal numbers of patients in each 
group) for a two-tailed analysis at alpha=0.05 vs Power for various effect sizes as found in the 
Bedirli study. Given that our study involves two drugs which are different from each other in 
their analgesic effects, we estimate that an effect size of 0.3 is reasonable for a study such as 
this and would still provide high power (>90%)  (Figure 1).  
 

15 
Vesrion 2 July28, 2017Version 3 January 4, 2018 
 
 
 
For the secondary measure in the study, comparing the administration route of the 
acetaminophen, a standard t-test will be employed. The null hypothesis is that there is no 
difference between the administration routes. As seen in Figure 2, a two-tailed t-test for 
alpha=0.05 with equal numbers of patients in each group, an effect size of 0.7 would be 
required to achieve a study power of 90%, which indicates that a stark difference in route 
of administration would be required for detection at sufficient power levels to consider the 
difference real. A small effect (0.2) would require almost 5,000 patients, which is beyond 
the expectations of a single-center study. 
Overall, based on the preliminary data based on study from Bedirli et al. in other areas 
of emergence delirium, we find that a 3-armed study with equal enrollment in each 
arm would provide sufficient power (90%) to detect an effect size of 0.3 (moderate 
effect) at alpha=0.05. The secondary hypothesis would require over double the effect 
size (0.7) at the same power (90%) to detect any differences in the delivery route. We 
recognize that this aim will be greatly underpowered given the expected effect size of 
administration route. However, the knowledge gained from this portion of the study 
will provide valuable information to form the basis of a larger multi-centered trial. 
 
 
 
Figure 1: Plot of sample size vs study power using ANOVA fixed effects for a 3-
armed study. Each curve is based upon an individual effect size.  

16 
Vesrion 2 July28, 2017Version 3 January 4, 2018 
 
 
 
 
19)18) 
References: 
(1)-Paediatric Anaesthesiology 2010 Nov;20(11):1028-35.  
Two-agent analgesia versus acetaminophen in children having bilateral myringotomies and tubes 
surgery. 
 
Rampersad S1, Jimenez N, Bradford H, Seidel K, Lynn A. 
 
(2)- Duggan ST, Scott LJ. Intravenous paracetamol (acetaminophen). 
Drugs. 2009;69(1):101-113. 
Middle East Journal of Anaesthesiogly, 2016 June; 23(5):543-8. 
Comparison of the effects of preemptive intravenous and rectal acetaminophen on pain 
management after inguinal herniorrhaphy in children: a placebo-controlled study. 
 
Khalili GR, Shafa A, Yousefi R. 
 
(3)- Allegaert K, Anderson BJ, Naulaers G, et al. Intravenous paracetamol 
(propacetamol) pharmacokinetics in term and preterm neonates. European 
Journal of Clinical Pharmacology 2004;60(3):191-197. 
 
(4)- Allegaert K, Rayyan M, De Rijdt T, Van Beek F, Naulaers G. Hepatic 
Figure 2: Plot of sample size vs study power using t-test difference for means with equal 
group size. Each curve is based upon an individual effect size.  

17 
Vesrion 2 July28, 2017Version 3 January 4, 2018 
 
tolerance of repeated intravenous paracetamol administration in neonates. 
Paediatric Anaesthesiology 2008;18(5):388-392. 
 
(5)- Palmer GM, Atkins M, Anderson BJ, et al. I.V. acetaminophen 
pharmacokinetics in neonates after multiple doses. British Journal of Anaesthesiology 
2008;101(4):523-530.  
 
(6)- Tobias JD. Weak analgesics and nonsteroidal anti-inflammatory 
agents in the management of children with acute pain. Pediatric Clinician 
North America. 2000;47(3):527-543. 
 
(7)- Jeremy N. DRISCOLL, Brian M. BENDER, Carlos A. ARCHILLA, Carol M. KLIM, J. HOSSAIN, 
George MYCHASKIW II, Julie L. WEI  
Comparing incidence of emergence delirium between sevoflurane and desflurane in children 
following routine otolaryngology procedures, Minerva Anestesiologica , 2016; NOV 30 
 
(8) Ofirmev Production Information, Mallinckrodt Pharmaceuticals, 2017 OFV 1683 02/17 
 
(9) Smessaert A, Schehr CA, Artusio JF Jr. Observations in the immediate postanaesthesia period. 
II. Mode of recovery. British Journal of Anaesthesiology 1960;32:181–5.  
(10) Welborn LG, Hannallah RS, Norden JM, Ruttimann UE, Callan CM. Comparison of emergence 
and recovery characteristics of sevoflurane, desflurane, and halothane in pediatric ambulatory 
patients. Anesthesia and Analgesia 1996;83:917–20.  
(11) Schulz KF, Grimes DA. Generation of allocation sequences in randomised trials: chance, not 
choice. The Lancet 2002;359:515-519. 
 
(12) Development and Psychometric Evaluation of the Pediatric Anesthesia Emergence Delirium 
Scale 
Nancy Sikich, M.Sc., R.N.; Jerrold Lerman, B.A.Sc., M.D., F.R.C.P.C., F.A.N.Z.C.A. 
Anesthesiology 5 2004, Vol.100, 1138-1145.  
 
(13) Capici F, Ingelmo PM, Davidson A, et al. Randomized controlled trial of duration of analgesia 
following intravenous or rectal acetaminophen after adenotonsillectomy in children. British 
Journal of Anaesthesiology 2008;100:251–255. 
(14) Opioid-sparing effects of perioperative paracetamol and nonsteroidal anti-inflammatory 
drugs (NSAIDs) in children 
Ivan Wong,1,2 Celia St John-Green,2 and Suellen M Walker1,3 
Paediatric Anaesthesiology: 2013 Jun; 23(6): 475–495. 
Published online 2013 Apr 9. doi:  10.1111/pan.12163 
 

18 
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(15) Emergence delirium in children: many questions, few answers: Vlaikovic, GP, Sindielic, RP, 
Anesthesia and Analgesia 2007 Jan; 104(1):84-91 
(16) Plasma and cerebrospinal fluid pharmacokinetic parameters after single-dose administration 
of intravenous, oral, or rectal acetaminophen. 
Singla NK1, Parulan C, Samson R, Hutchinson J, Bushnell R, Beja EG, Ang RRoyal MA 
Pain Practice. 2012 Sep;12(7):523-32. doi: 10.1111/j.1533-2500.2012.00556.x. Epub 2012 Apr 
24. 
(17) Analgesic efficacy of paracetamol in children using tonsillectomy as a pain model. 
Anderson B1, Kanagasundarum S, Woollard G.   
 
Anaesthesia Intensive Care. 1996 Dec;24(6):669-73. 
 
(18) Tramadol vs dexmedetomidine for emergence agitation control in pediatric 
patients undergoing adenotonsillectomy with sevoflurane anesthesia: prospective 
randomized controlled clinical study 
Nurdan Bedirli* , Mehmet Akçabay and Ulku Emik 
BMC Anesthesiology (2017) 17:41 
DOI 10.1186/s12871-017-0332-4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

19 
Vesrion 2 July28, 2017Version 3 January 4, 2018 
 
APPENDIX 1: Pediatric Anesthesia Delirium (PAED) Scale 
SCORE 
1. The child makes eye contact with the caregiver. 
 
2. The child’s actions are purposeful. 
 
3. The child is aware of his or her surroundings. 
4. 
 
4 = Not at all 
3 = Just a little 
2 = Quite a bit 
1 = Very much 
0 = Extremely 
5.4. 
The child is restless. 
 
6.5. 
The child is inconsolable. 
0 = Not at all 
1 = Just a little 
2 = Quite a bit 
3 = Very much 
4 = Extremely 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Formatted: Indent: Left:  0.5",  No bullets or numbering

20 
Vesrion 2 July28, 2017Version 3 January 4, 2018 
 
 
CRF 
 
Name: 
Sex: 
Height: 
Patient #: 
Date: 
History: 
Diagnosis: 
Operation: 
Surgeon : 
 
Age: 
MRN: 
Weight: 
BMI: 
Group: (circle below) 
Opioid only - 
Opioid plus IV acetaminophen- 
Opioid plus PO acetaminophen- 
Anesthesiologist: 
 
 

 
21 
 
Anesthesia Induction: 
Time:  
 
MAP:  
 
HR: 
 
 
SpO2: 
Hypnotic: Sevo          % 
Analgesia:  Fentanyl          µg,     
IV acetaminophen             mg,      
PO acetaminophen            mg 
Postoperative analgesia: 
Intubation Time :  
Surgical Start Time: 
 
 
Anesthesia Maintenance: 
Sevo:                   MAC 
Time:  
 
MAP:  
 
HR: 
 
 
SpO2: 
Time End of Surgery: 
 
 
Time End of Sevo: 
Time End of Extubation:  
FGF:  
L/min 
 
Time:  
 
MAP:  
 
HR: 
 
 
SpO2: 
 
 
 
 
 
 
 

 
22 
 
PACU Record (Time:                  to                     ) 
 
Admissi
on to 
PACU 
15 min 30 min 45 min 60 min 
 
 
Discharg
e from 
PACU 
PAED 
Scale 
 
 
 
 
 
 
 
 
Modified 
Aldrete 
Scores 
 
 
 
 
 
 
 
 
FLACC  
 
 
 
 
 
 
 
 
Wong-
Baker 
FACES 
 
 
 
 
 
 
 
 
Numeric 
Pain 
Score 
 
 
 
 
 
 
 
 
Pain 
Meds 
Used  
(Fentany
l Dose; 
Ibuprofe
n) 
 
 
 
 
 
 
 
 
 
Adverse events to be documented:  
Nausea 
Vomiting 
Shivering  

 
23 
 
Breath-holding 
Respiratory depression 
Pruritus  
Excessive secretions 
Laryngospasm  
Excessive bleeding 
Anaphylaxis 
Skin reaction – rash 
Skin reaction – discoloration including jaundice 
Abdominal Pain 
Hypotension 
Death 
Unplanned hospitalization 
Other