A Randomized Controlled Trial to Compare Hydromorphone vs Fentanyl in Children Undergoing Tonsillectomy Surgery
Phase: EARLY_PHASE1
Conditions: Obstructive Sleep Apnea, Tonsillitis
Sponsor: Washington University School of Medicine

CONFIDENTIAL: This document is the intellectual property of Greg Miller, MD and Michael Montana, MD, PhD. Acceptance 
of this document constitutes the agreement by the recipient that no unpublished information contained herein will be 
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3/26/2020 
 
Page 1 of 15 
RESEARCH PROTOCOL 
 
A RANDOMIZED CONTROLLED TRIAL TO COMPARE HYDROMORPHONE VS 
FENTANYL IN CHILDREN UNDERGOING TONSILLECTOMY SURGERY 
 
 
 
 
Alan Hifko, MD 
Clinical Research Coordinator, Anesthesiology 
ahifko@wustl.edu 
 
Judith Lieu, MD 
Professor, Otolaryngology 
lieujudithe@wustl.edu 
 
Greg Miller, MD 
CA3 Resident, Anesthesiology 
g.c.miller@wustl.edu 
 
Michael C. Montana, MD, PhD 
Assistant Professor, Pediatric Anesthesiology 
montana@wustl.edu 
 
 
 
Original Version: January 22, 2020 
 
Revision: February 12, 2020 
 
Revision: March 26, 2020 
 
 
 
 
 
 
 

CONFIDENTIAL: This document is the intellectual property of Greg Miller, MD and Michael Montana, MD, PhD. Acceptance 
of this document constitutes the agreement by the recipient that no unpublished information contained herein will be 
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3/26/2020 
 
Page 2 of 15 
SYNOPSIS 
 
Objective - To compare hydromorphone versus fentanyl for pain control following 
tonsillectomy or adenotonsillectomy surgery. 
 
Study Period - 2 years 
 
Number of Patients - 300 pediatric patients presenting for tonsillectomy or 
adenotonsillectomy at St. Louis Children’s Hospital (SLCH) 
 
Study Treatment - Hydromorphone vs fentanyl dosed per study design  
 
Study Design - This is a randomized clinical trial with masked assessment, comparing 
recovery indices for patients receiving intermediate acting versus short acting opioid 
analgesia using hydromorphone or fentanyl as intraoperative analgesics. An otherwise 
standardized anesthetic and analgesic regimen will be utilized, consistent with routine 
care at SLCH. Patients will be randomized 1:1 in blocks of 4 within strata. Patients will be 
randomized to receive either hydromorphone or fentanyl throughout the perioperative 
period by opening a sealed protocol envelope.  
 
Inclusion Criteria 
1. Children ages 2 to 15 years old  
2. Presenting for tonsillectomy or adenotonsillectomy surgery 
3. American Society of Anesthesiologists Physical Status (ASAPS) Classification 1, 
2 or 3 
4. Provide Informed Consent / Assent (as appropriate) 
 
Exclusion Criteria 
1. Additional Concurrent surgeries, exclusive of myringotomy tubes, minor oral/nasal 
procedures (e.g. frenulectomy), and endoscopic procedures 
2. Revision tonsillectomy or revision adenotonsillectomy surgery 
3. Known pregnancy 
4. Any condition which would make the participant, in the opinion of the investigator 
or the attending anesthesiologist caring for the patient, unsuitable for the study.  
 
Measurements - We will compare the incidence of administration of analgesic rescue 
medication in the post-operative recovery area. We will also compare post-operative pain 
scores and the amount of opioid pain medications administered to patients 
postoperatively 
expressed 
in 
morphine 
equivalents. 
Optional 
opioid 
plasma 
concentrations will be measured at three time points using mass spectroscopy. 
Additionally, we will compare the rates of post-operative respiratory complications, PONV, 
and length of PACU stay between patients administered fentanyl vs. hydromorphone. 
Finally, we will assess patient and family satisfaction with treatment through a survey sent 
on POD 3 as well as validated NIH PROMIS questionnaires. 
 

CONFIDENTIAL: This document is the intellectual property of Greg Miller, MD and Michael Montana, MD, PhD. Acceptance 
of this document constitutes the agreement by the recipient that no unpublished information contained herein will be 
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3/26/2020 
 
Page 3 of 15 
Outcomes - Perioperative analgesic efficacy and side effect comparisons between 
hydromorphone and fentanyl in children undergoing tonsillectomy surgery. 
 

CONFIDENTIAL: This document is the intellectual property of Greg Miller, MD and Michael Montana, MD, PhD. Acceptance 
of this document constitutes the agreement by the recipient that no unpublished information contained herein will be 
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3/26/2020 
 
Page 4 of 15 
1. Introduction 
1.1. Study Abstract: Every year hundreds of children undergo tonsillectomy surgery at St. 
Louis Children’s Hospital (SLCH) and many of these children experience significant 
postoperative pain. Severe postoperative pain can delay recovery and hospital discharge 
if it impedes eating and drinking. This pain can also lead to significant patient and parental 
anxiety, and may worsen patient anxiety for future health care related experiences. 
Opioids are commonly used to treat severe pain; however, opioids also have attendant 
side effects such as sedation, postoperative respiratory depression (e.g. apnea), and 
nausea and vomiting. Fentanyl and hydromorphone are the primary opioids used at SLCH 
in the operating theater and the immediate postoperative period. Fentanyl has a shorter 
duration of action than hydromorphone and is often chosen in the belief that using the 
shortest-acting opioid will reduce the risks of sedation and apnea. However, there is 
limited evidence to suggest that this is the case. Interestingly nurses in the SLCH Post 
Anesthesia Care Unit have noted a subjective difference in pain levels in patients 
receiving hydromorphone versus fentanyl with the perception that patients administered 
hydromorphone, on average, require fewer doses of rescue opioid analgesics. In addition, 
a recently completed prospective study of fentanyl vs. hydromorphone for pain control in 
patients undergoing eye muscle surgery suggests that hydromorphone provides both 
lower pain ratings and faster PACU recovery. Our goal is to determine whether there is a 
difference in post-operative outcomes between patients receiving fentanyl or 
hydromorphone post tonsillectomy.  
1.2. Research Questions 
1.2.1. Is there a difference in the rate of administration for rescue opioid analgesic 
medications in children undergoing tonsillectomy who are administered hydromorphone 
as compared to fentanyl perioperatively? 
1.2.2 Is there a difference in the postoperative pain score in children undergoing 
tonsillectomy who are administered hydromorphone as compared to fentanyl 
perioperatively? 
1.2.3. Is there a difference in the cumulative morphine equivalents administered 
postoperatively 
in 
children 
undergoing 
tonsillectomy 
who 
are 
administered 
hydromorphone as compared to fentanyl perioperatively? 
1.2.4. Is there a difference in post anesthesia care unit length of stay in children 
undergoing tonsillectomy who are administered hydromorphone as compared to fentanyl 
perioperatively? 
1.2.5. Is there a difference in nausea or the number of vomiting episodes postoperatively 
and 72 hours after discharge in children undergoing tonsillectomy who are administered 
hydromorphone as compared to fentanyl perioperatively? 

CONFIDENTIAL: This document is the intellectual property of Greg Miller, MD and Michael Montana, MD, PhD. Acceptance 
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3/26/2020 
 
Page 5 of 15 
1.2.6. Is there a difference in pain scores reported by the parent 72 hours after discharge 
in children undergoing tonsillectomy who are administered hydromorphone as compared 
to fentanyl perioperatively? 
1.2.7. Is there a difference in the number of desaturation events, defined as SPO2 < 90% 
for 2 minutes or less than 85% for 1 minute, postoperatively in children undergoing 
tonsillectomy who are administered hydromorphone as compared to fentanyl 
perioperatively? 
1.2.8. Is there a difference in the number of witnessed apneic events postoperatively or 
at 72 hours after discharge in children undergoing tonsillectomy who are administered 
hydromorphone as compared to fentanyl perioperatively? 
1.2.9. Is there are difference in patient and family satisfaction with care between children 
undergoing tonsillectomy who are administered hydromorphone as compared to fentanyl 
perioperatively? 
1.3. Purpose of the Study Protocol. The proposed project will test whether there is a 
difference in multiple metrics of pain between patients who receive hydromorphone or 
those who receive fentanyl during tonsillectomy. The results of this study should inform 
the way anesthesiologists approach the treatment of pain following the most common 
pediatric surgical procedure at SLCH, and in the United States. If a difference is found, 
appropriate dissemination of findings could influence the universal approach taken for 
pain control in the most common pediatric surgery. 
2. Background 
2.1. Prior Literature and Studies. Tonsillectomy is the most common pediatric operation 
performed in the United States, with more than 500,000 tonsillectomies performed 
annually1. The primary indication for tonsillectomy is childhood obstructive sleep apnea 
(OSA), defined by periodic, partial or complete obstruction of the upper airway during 
sleep. OSA is a common disorder in pediatric patients, with a prevalence of 1-3%2. It is 
as common as childhood asthma and children with OSA often require tonsillectomy 
surgery to correct their OSA2. As mentioned, the treatment of OSA is the primary 
indication for more than 75% of children undergoing tonsillectomy with or without 
adenoidectomy3. Unfortunately, children at high risk for OSA are three times more likely 
to have post-tonsillectomy respiratory complications and apneic adverse events than 
children at low risk for OSA4,5 and the rate of complications in patients with OSA post-
tonsillectomy (16 –27%) is substantially increased compared to that of the general 
pediatric post-operative population (0 –1.3%) 6-10. These complications include oxygen 
desaturation, hypercapnia, obstructive apneas requiring CPAP or airway instrumentation, 
unexpected ICU admission, and in rare cases, death. Concerns for a heightened risk of 
opioid induced respiratory depression make the peri-operative use of opioids in children 
with OSA particularly challenging and controversial.  

CONFIDENTIAL: This document is the intellectual property of Greg Miller, MD and Michael Montana, MD, PhD. Acceptance 
of this document constitutes the agreement by the recipient that no unpublished information contained herein will be 
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Page 6 of 15 
There is currently not a standard of practice for pain management for tonsillectomy 
surgery at SLCH. Published guidelines recommend decreasing opioid doses in all 
patients with sleep apnea, for fear of respiratory depression, however they do not give 
recommendations regarding the use of short vs. intermediate acting opioids11. The nurses 
in the SLCH PACU have subjectively noted a decreased need for opioid rescue analgesia 
when hydromorphone is administered intraoperatively as compared to fentanyl. 
Additionally, a recently completed prospective study of fentanyl versus hydromorphone 
for pain control in patients undergoing eye muscle surgery at SLCH suggests that 
hydromorphone results in lower pain scores and faster PACU recovery12. There are 
limited data comparing different opioids in pediatric tonsillectomy surgery published in the 
literature. As far as we are aware, this will be the first randomized controlled trial 
comparing the intermediate acting opioid hydromorphone to the shorter acting opioid 
fentanyl for this patient population. 
2.2. Rationale for the Study. Providing safe and effective pain control is important for 
these patients. Subjective observations indicate that hydromorphone may provide 
superior pain control as compared to fentanyl. This hypothesis has not been rigorously 
tested. We aim to ameliorate this deficit.  
3. Study Objectives 
3.1. Primary Aim. The primary aim of our study is to compare the need for rescue opioid 
analgesic medication between patients receiving fentanyl and hydromorphone following 
adenotonsillectomy surgery. We will also compare post-operative pain scores between 
the two groups, and the amount of opioid pain medications administered to patients 
postoperatively expressed in morphine equivalents. Patients will be randomized 1:1 in the 
operating room to receive either fentanyl or hydromorphone during the perioperative 
period. We hypothesize that compared to fentanyl, the use of hydromorphone will result 
in lower need for rescue opioid analgesic in post-surgical recovery.  
3.2. Secondary Aims. The secondary aims of our study are to compare pain scores, the 
rates of post-operative respiratory complications, PONV, and length of PACU stay 
between patients administered fentanyl vs. hydromorphone. We hypothesize that there 
will be no differences between patients who receive fentanyl and those who receive 
hydromorphone. 
 
3.3. Rationale for Selection of Outcome Measures. These are the primary concerns for 
care of patients following tonsillectomy surgery. Nearly all patients will have postoperative 
pain, and many will experience some degree of postoperative nausea and vomiting. 
Respiratory complications are possible after emergence from a general anesthetic, 
especially after the use of opioids in the perioperative setting, and especially after 
tonsillectomy surgery.  
 
 
 

CONFIDENTIAL: This document is the intellectual property of Greg Miller, MD and Michael Montana, MD, PhD. Acceptance 
of this document constitutes the agreement by the recipient that no unpublished information contained herein will be 
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Page 7 of 15 
4. Study Design 
4.1. Overview. This is a randomized clinical trial with masked assessment, comparing 
recovery indices for patients receiving longer acting versus shorter acting opioid 
analgesia using hydromorphone or fentanyl as intraoperative analgesics. An otherwise 
standardized anesthetic and analgesic regimen will be utilized, as consistent with routine 
care at SLCH. 
 
4.2. Inclusion Criteria  
4.2.1. Children ages 2 to 15 years old  
4.2.2. Presenting for tonsillectomy surgery or adenotonsillectomy surgery 
4.2.3. American Society of Anesthesiologists Physical Status (ASAPS) 
Classification 1, 2 or 3 
4.2.3. The caregiver of the child must be able to provide informed consent and the 
child must be able to provide assent (as appropriate) 
 
4.3. Exclusion Criteria 
4.31. Additional Concurrent surgeries, exclusive of myringotomy tubes, minor 
oral/nasal procedures (e.g. frenulectomy), and endoscopic procedures 
4.3.2. Revision tonsillectomy or revision adenotonsillectomy surgery 
4.3.3. Known pregnancy 
4.3.4. Any condition which would make the participant, in the opinion of the 
investigator, unsuitable for the study 
 
4.4. Ethical Considerations. All patients will receive pain medication as well as medication 
to control for postoperative nausea and vomiting as per routine care at SLCH. The 
attending anesthesiologist will accompany the child to the PACU, and rescue drugs will 
be available if additional pain medication is needed or if there is concern for respiratory 
distress. Both medications (hydromorphone and fentanyl) to be compared are standard 
of care analgesics at SLCH and on formulary.  
 
4.5. Risks and Benefits. We do not know if patients will benefit from the intervention. For 
future patients, it is anticipated that investigators may be able to determine whether one 
of the pain medications has a better potential to reduce the need for rescue analgesia 
without a concomitant increase in side effect following tonsillectomy surgery. There is a 
possibility that parents may feel uncomfortable answering some items on the 
questionnaires. 
 
4.6.  Early Withdrawal of Subjects. Patients may be withdrawn from the study if during 
surgery an additional procedure is required or if the lead study physician (MCM) 
determines it is not in the best interest of the patient to continue in the study. Caregivers 
may decide to withdraw their child from the study at any time without penalty. Withdrawn 
children will be replaced with a new subject to maintain a consistent number of enrolled 
patients in each group.  
 
4.7. Study Medications, Administration, and Blood Plasma Concentration Measurements 

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Page 8 of 15 
4.7.1. Hydromorphone. Hydromorphone hydrochloride (4,5α-epoxy-3-hydroxy-17-
methylmorphinan-6-one hydrochloride) is a hydrogenated ketone of morphine. 
Hydromorphone hydrochloride is a pure opioid agonist with the principal therapeutic 
activity of analgesia. A significant feature of the analgesia is that it can occur without loss 
of consciousness. Opioid analgesics also suppress the cough reflex and may cause 
respiratory depression, mood changes, mental clouding, euphoria, dysphoria, nausea, 
vomiting and electroencephalographic changes. Many of the effects described above are 
common to the class of mu-opioid analgesics, which includes morphine, oxycodone, 
hydrocodone, codeine, and fentanyl. Hydromorphone has been most extensively studied 
in adults, however it is commonly used in pediatrics both in the perioperative and inpatient 
settings. At therapeutic plasma levels in adults, hydromorphone is approximately 8-19% 
bound to plasma proteins. Hydromorphone is extensively metabolized via glucuronidation 
in the liver, with greater than 95% of the dose metabolized to hydromorphone-3-
glucuronide along with minor amounts of 6-hydroxy reduction metabolites. Only a small 
amount of the hydromorphone dose is excreted unchanged in the urine. Most of the dose 
is excreted as hydromorphone-3-glucuronide along with minor amounts of 6- hydroxy 
reduction metabolites. The terminal elimination half-life of hydromorphone after an 
intravenous dose is about 2.3 hours in adult FDA studies13. 
 
4.7.2. Fentanyl. Fentanyl citrate (N-1-phenethyl-4-piperidyl propionanilide citrate) is a 
potent opioid agonist with principal therapeutic activities of analgesia and sedation. As 
with other potent opioid agonists, the most common serious adverse reactions reported 
to occur with fentanyl are respiratory depression, apnea, rigidity, and bradycardia; if these 
remain untreated, respiratory arrest, circulatory depression, or cardiac arrest could occur. 
Other adverse reactions that have been reported are hypertension, hypotension, 
dizziness, blurred vision, nausea, emesis, diaphoresis, pruritus, urticaria, laryngospasm 
and anaphylaxis. Like hydromorphone, fentanyl has been most extensively studied in 
adults but is commonly used in the pediatric patient population, especially in the 
perioperative period. In adults, the pharmacokinetics of fentanyl can be described as a 
three-compartment model, with a distribution time of 1.7 minutes, redistribution of 13 
minutes and a terminal elimination half-life of 219 minutes. Fentanyl plasma protein 
binding capacity decreases with increasing ionization of the drug. It accumulates in 
skeletal muscle and fat, and is released slowly into the blood. Fentanyl, which is primarily 
metabolized by the liver, demonstrates a high first pass clearance and releases 
approximately 75% of an intravenous dose in urine, mostly as metabolites with less than 
10% representing the unchanged drug. Approximately 9% of the dose is recovered in the 
feces, primarily as metabolites. The onset of action of fentanyl is almost immediate when 
the drug is given intravenously; however, the maximal analgesic and respiratory 
depressant effect may not be noted for several minutes14. 
 
4.7.3. Administration. The study will be conducted in the operating room and in the PACU. 
In the operating room, patients will receive a general anesthetic with an endotracheal tube 
directed by the attending anesthesiologist as per routine care at SLCH. Standard ASA 
monitors, which include pulse oximetry, non-invasive blood pressure monitoring, 
telemetry, heart rate monitoring, and end tidal CO2 and oxygen monitoring will be 

CONFIDENTIAL: This document is the intellectual property of Greg Miller, MD and Michael Montana, MD, PhD. Acceptance 
of this document constitutes the agreement by the recipient that no unpublished information contained herein will be 
published or disclosed without prior written approval.  
 
3/26/2020 
 
Page 9 of 15 
connected to the patient as per standard of care. Patients will be randomized to receive 
either hydromorphone or fentanyl in the operating room determined by opening a sealed 
protocol envelope. Administration and dosing of the randomized opioid to each case will 
be under the direction of the primary anesthesia team under the direction of the pediatric 
anesthesiologist caring for the child. In addition to the randomized opioid, patients will 
receive non-opioid analgesics and PONV prophylaxis as per routine care at SLCH. 
Blinding will be achieved using syringes prepared by SLCH investigational pharmacy. 
 
4.7.4 Optional opioid Plasma Concentration Assessments. Approximately 3 mls of whole 
blood will be collected from patients at three time points: 1) within 10 minutes of 
administration of study drug, 2) within 10 minutes of PACU arrival, and 3) within 10 
minutes of PACU discharge. Blood samples will be collected through an additional IV line 
placed in the surgical suite after anesthesia is given. Opioid (hydromorphone or fentanyl) 
blood levels will be measured using mass spectrometry. This type of analysis does not 
require apriori knowledge of the medication administered and will maintain the masking 
protocol. A Population Pharmacokinetic Analysis will be performed. The patient may 
decline to participate in the blood draw component of the study and remain in the study 
for data collection relating to the primary endpoint. Additionally, failed or missed blood 
draws in individual patients will not adversely affect the population analysis.  
 
4.8. Treatment Regimen. Patients will receive a general anesthetic as per the standard 
of care at SLCH. Analgesia will include opioids and non-opioid adjuvants for pain in 
addition to anti-emetics per routine care at SLCH. Airway maintenance will be via an 
endotracheal tube supervised by the anesthesiologist responsible for the care of the 
patient in the operating room. 
 
4.9. Method for Assigning Subjects to Treatment Groups. Patients will be randomized to 
either hydromorphone or fentanyl in the preoperative area prior to presenting to the 
operating room by investigational pharmacy staff. Randomization will be 1:1 in blocks of 
4 within strata. Stratification will be done by age group (2-7, 8-12, and 13-15), and OSA 
diagnosed using sleep polysomnography within the last year. 
.  
 
4.10. Preparation of the Study Drugs. Equi-analgesic dose tables poorly accommodate 
differences in rapid redistribution between drugs. Establishing a definitive therapeutic 
equivalence between hydromorphone and fentanyl for the patient population, type of 
stimulus, and duration of procedure is challenging a priori. Previous data gather at SLCH 
and clinical expertise guide our dosing choices. Hydromorphone, when utilized as the 
sole opiate intraoperatively is dosed with median 10 ± 4 mcg/kg with16 mcg/kg as the 
80th percentile, and fentanyl is dosed with median 0.9±0.5 mcg/kg, with 1.5 mcg/kg at the 
80th percentile. We will use these current medians to guide our dosing. We will initiate 
medication dosing of patients with hydromorphone 10 mcg/kg, and fentanyl 1 mcg/kg. 
Conveniently, formulary preparation of hydromorphone is at 500 mcg / ml and fentanyl at 
50 mcg/ml. Thus, blinding should be achievable as the same volume of medication (ml/kg) 
can be safely administered for each drug.  

CONFIDENTIAL: This document is the intellectual property of Greg Miller, MD and Michael Montana, MD, PhD. Acceptance 
of this document constitutes the agreement by the recipient that no unpublished information contained herein will be 
published or disclosed without prior written approval.  
 
3/26/2020 
 
Page 10 of 15 
Regarding feasibility, we conducted an informal survey of attending 
anesthesiologists at SLCH. We had an approximately 50% response rate and all were 
willing to give these two drugs at the proposed doses in a blinded fashion.  
 
 
 
5. Study Procedures 
5.1. Screening for Eligibility. The patient’s medical record will be screened for: age of 
child, type of surgical procedure planned, history of previous surgery, classification score 
for anesthesia, whether child is in custody of a legal caregiver, and ability to 
consent/assent to the study. 
 
5.2. Enrollment. The surgery schedule at SLCH is posted in advance therefore it is 
straightforward to determine daily if there are eligible subjects to approach for inclusion. 
The patient’s medical history is available to screen for eligibility criteria prior to asking if 
they would be interested in participating. The day prior to the surgery, a nurse may contact 
the family to deliver preoperative instructions. At this time, the family may be told a study 
is being conducted and given details on possible participation. Additionally, the research 
team will identify potential patients on the day of surgery that may qualify for the study. A 
member of the research team will then approach the family in the private room in the 
surgical preoperative area to discuss the study and review the consent form. The study 
group will consist of 300 patients who are presenting for tonsillectomy surgery or 
tonsillectomy and adenoidectomy surgery. Enrollment completion will be achieved once 
consent for up to 360 patients is obtained, assuming a 20% drop-out rate from the study, 
with an end goal of 300 patients.  
 
5.3. Schedule of Measurements. Consenting families will be evaluated with the YPAS-m 
scale prior to surgery. At the time consent is obtained, parents will also be asked to 
complete a brief demographic data form. Any preoperative sleep studies (also known as 
polysomnograms) that subjects had previously received will be reviewed. After surgery, 
the post-operative recovery nurse will evaluate the patient’s pain using rFLACC scale on 
arrival to the Post Anesthesia Care Unit (PACU), and then every five minutes during the 
patient’s stay. This is standard of care.  
After transferring from Phase I recovery, a member of the research team will 
continue to evaluate patient’s pain using the same scale on arrival and before discharge. 
The patient’s level of pain (rFLACC) and need for any additional analgesic medications 
will also be evaluated. rFLACC is standard of care at SLCH and all personnel are well 
versed in its application. After discharge, the patient will receive a telephone call or text 
at 24 hours after surgery to evaluate post-operative nausea and vomiting and the level of 
pain at home. The need for additional pain medication will also be assessed. This is 
standard of care at SLCH and performed for all patients who are discharged the day of 
surgery, regardless of type of surgery. Respiratory events will be assessed initially using 
SpO2 monitoring immediately after arrival to the PACU, followed by clinical assessment 
after PACU discharge. Postoperative nausea and vomiting is assessed using observation 
and patient verbalization. 

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of this document constitutes the agreement by the recipient that no unpublished information contained herein will be 
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3/26/2020 
 
Page 11 of 15 
Patient and family satisfaction with care will be assessed using a survey on 
postoperative day 3, as well as the validated NIH PROMIS questionnaires for Pediatric 
Self-Report (ages 8-17) and Parent Proxy Report (ages 5-17). We will use the following 
NIH PROMIS questionnaires: Pain Behavior, Pain Interference, and Pain Quality.  
PROMIS questionnaires will be sent to patients via e-mail through the REDCap server 
on postoperative day 7 (+ 1 day).  
 
5.4. Safety and Compliance Monitoring. All patients will be monitored by an 
anesthesiologist for the first 5 minutes in the PACU and then every 5 minutes by a 
registered nurse until discharged from the PACU to the Same Day Surgery unit. 
Monitoring is continuous until the patient recovers from anesthesia and then every 5 
minutes x3, then every 15 minutes until PACU discharge. The same tool, the rFLACC, is 
used throughout the hospitalization to assess pain. Postoperative nausea and vomiting 
is assessed using observation and patient verbalization. 
 
5.5. Medical Monitoring. The PI will be monitoring all unblinded data as it is collected 
throughout the study and share the information with the anesthesiologists and the 
surgeons. In general, the Department of Anesthesiology has developed a specific set of 
Standard Operating Procedures (SOPs) for clinical research. All individuals working on 
study are required to read and be familiar with and compliant with the SOPs. The SOPs 
are in part developed from and are compliant with the Institutional Guidelines, including 
those for a) Interactions with the Washington University Human Subjects Review 
Committee, b) Informed Consent Development and Implementation, c) Subject 
Recruitment and Screening, d) Subject Management While on Study, e) Adverse Event 
Reporting. The potential risks of this study are attributable to the use of opioids in the 
perioperative period.  
As already per routine care at SLCH, there will always be a non-study team 
attending anesthesiologist available both in the operating room and in the PACU to care 
for the patient in the event of any potential adverse event. This includes the availability of 
any resuscitation medications and/or equipment including but not limited to naloxone and 
emergent airway equipment. 
 
5.6. Data Collection Procedures for Adverse Events. An adverse event would be evident 
as the study data on pain control, respiratory events, and PONV are collected as per 
routine standard of care. 
 
5.7. Reporting of Adverse Events. Any adverse event will be reported to the IRB within 7 
days as required. Any occurrences of serious adverse events or death will be reported 
within 24 hours. 
 
6. Statistical Plan 
6.1. Sample Size Determination and Sample Size Estimation. Sample size estimations 
were performed to determine the number of patients required to see a 50% reduction in 
the patients requiring rescue analgesia between the group receiving fentanyl and the 

CONFIDENTIAL: This document is the intellectual property of Greg Miller, MD and Michael Montana, MD, PhD. Acceptance 
of this document constitutes the agreement by the recipient that no unpublished information contained herein will be 
published or disclosed without prior written approval.  
 
3/26/2020 
 
Page 12 of 15 
group receiving hydromorphone. Each estimation assumed achieving 80% Power, Alpha 
of 5%, 2 study groups at 1:1 ratio, and 20% attrition (equivalent by study group).  
Multiple power curves were calculated. As examples, assuming the proportion 
using rescue analgesics among patients in the fentanyl study group was 36% compared 
to a 50% reduction down to 18% for the hydromorphone group, a power analysis 
comparing independent proportions would require a total sample size of 228 participants. 
If 50% of the Fentanyl study group utilized rescue analgesics, detecting a 50% reduction 
down to 25% for the Hydromorphone group, a power analysis comparing independent 
proportions would require a total sample size of 139 participants (Fig. 1). We selected 
300 patients based on an assumed proportion of 0.35 in the fentanyl group requiring 
rescue opioid analgesia and a goal of 50% reduction in patients requiring analgesia.  
 

CONFIDENTIAL: This document is the intellectual property of Greg Miller, MD and Michael Montana, MD, PhD. Acceptance 
of this document constitutes the agreement by the recipient that no unpublished information contained herein will be 
published or disclosed without prior written approval.  
 
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Page 13 of 15 
Figure 1: Sample size estimation curves. P2 = Fentanyl. 
 
 
 
6.2. Analysis Plan. De-identified data will be entered into an excel spreadsheet and then 
SPSS will be used for data analysis. Demographic data will be summarized using 
descriptive statistics and the two groups will be examined for baseline differences. 
Descriptive statistics will include proportions, means, and standard deviation to determine 
statistically significant differences (p<0.05). If the differences at baseline are significant, 
confounders will be addressed using multivariate adjustment techniques. Alpha level 0.05 
will be used. 
 
7. Data Handling and Record Keeping 
7.1. Confidentiality and Security. The consent forms and all questionnaires will be 
collected and stored in a locked file drawer in a locked office. Responses to 
questionnaires will be entered into a password protected computer. All study data will be 
entered into a database on a password protected computer. Only study team members 
will have access to the data. All reporting of data will be in the aggregate. 
 
8. Risks, Study Monitoring and Administration 
8.1. Monitoring. Studies conducted in the Department of Anesthesiology follow the 
Washington University Institutional Review Board Policies and Procedures (last revision 
January 21, 2019). All individuals working on the study are required to read and be familiar 
with and compliant with the IRB Policies and Procedures. The specific monitoring plan for 
this investigation is commensurate with the risks and the size and complexity of the 
investigations planned. The potential risks are attributable to the use of opioids in the 
perioperative period. Both drugs of interest are standard of care medications and on 
formulary at SLCH. Thus, the risk of study participation is nearly identical to that incurred 
with having a tonsillectomy at SLCH, regardless of study participation. Based on the small 
size and relatively low risk nature of the protocol, the investigating physicians are involved 
in the monitoring plan. Additionally, a board-certified anesthesiologist practicing in 
pediatric anesthesia at SCLH who is not a member of the research team will be included 
in the monitoring of all adverse events. These individuals will review the annual summary 
60
80
100
120
140
160
180
200
220
240
260
280
300
320
340
360
0
0.2
0.4
0.6
0.8
1
Power (1-β err prob)
 = 0.2
 = 0.25
 = 0.3
 = 0.35
 = 0.4
Proportion p2
z tests - Proportions: Difference between two independent proportions
Tail(s) = Two. Proportion p1 = 0.2. α err prob = 0.05. Allocation ratio N2/N1 = 1
Total sample size

CONFIDENTIAL: This document is the intellectual property of Greg Miller, MD and Michael Montana, MD, PhD. Acceptance 
of this document constitutes the agreement by the recipient that no unpublished information contained herein will be 
published or disclosed without prior written approval.  
 
3/26/2020 
 
Page 14 of 15 
of adverse events. All reports of a Serious Adverse Event, or an Unexpected Adverse 
Event will be reviewed and reported to the IRB. The investigators will follow the 
requirements for principle investigator reporting requirements as outlined in Section X of 
the IRB Policies and Procedures.   
 
8.2. Funding and Conflicts of Interest. Departmental funding; an intramural ICTS grant is 
pending. No conflicts of interest for any of the study team members. 
 
8.3. Study Timetable. The study is expected to start immediately after receiving IRB 
approval. Data collection will take 24-36 months; analysis another 3-6 months. 
 
9. Publication Plan 
Publication in a peer-reviewed medical journal is expected following completion of the 
data collection and analysis of the results. Presentation at regional and/or national 
meetings is also anticipated. Establishing best practices for the use of opioids in children 
is a high priority in pediatric anesthesia, and we anticipate national interest in this 
research. 
 
10. Management of Intercurrent Events 
10.1. Adverse Experiences: The investigator will closely monitor subjects for evidence of 
adverse events. All adverse events will be reported and followed until satisfactory 
resolution. The description of the adverse experience will include the time of onset, 
duration, intensity, etiology, relationship to the study drug (none, unlikely, possible, 
probable, highly probable), and any treatment required. 
 
10.2. Premature Discontinuation: If a subject withdraws from the study, the subject will be 
replaced to provide the required number of subjects. Subjects will be withdrawn without 
penalty if the investigator decides that discontinuation is in the best interest of the subject, 
or the subject requests withdrawal from the study.  
 

CONFIDENTIAL: This document is the intellectual property of Greg Miller, MD and Michael Montana, MD, PhD. Acceptance 
of this document constitutes the agreement by the recipient that no unpublished information contained herein will be 
published or disclosed without prior written approval.  
 
3/26/2020 
 
Page 15 of 15 
10. References  
 
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sleep-disordered breathing in children. Laryngoscope 2013; 123: 1055-8 
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Brown KA: Outcome, risk, and error and the child with obstructive sleep apnea. 
Paediatr Anaesth 2011; 21: 771-80 
3. 
Bhattacharyya N, Lin HW: Changes and consistencies in the epidemiology of 
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De Luca Canto G, Pacheco-Pereira C, Aydinoz S, Bhattacharjee R, Tan HL, 
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