A Randomized Controlled Trial of Intranasal Sub-dissociative Dosing of Ketamine Compared to Intranasal Fentanyl for Treatment of Pain Associated With Acute Extremity Injuries in Children
Phase: PHASE3
Conditions: Pain, Traumatic Limb Injury
Sponsor: Children's Hospital Medical Center, Cincinnati

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STUDY TITLE: 
Pain Reduction with Intranasal Medication for Extremity Injuries (PRIME): A Randomized Clinical 
Noninferiority Trial of Intranasal Ketamine vs. Fentanyl 
 
PROTOCOL TITLE: 
Pain Reduction with Intranasal Medications for Extremity injuries (PRIME) 
 
TRIAL REGISTRATION:  
NCT02778880 
 
DOCUMENT:  
Study Protocol and Statistical Analysis Plan 
 
DOCUMENT DATE:  
November 26, 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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PROTOCOL SYNOPSIS 
STUDY TITLE: 
A Randomized Controlled Trial of Intranasal Sub-dissociative Dosing of Ketamine Compared to Intranasal 
Fentanyl for Treatment of Pain Associated with Acute Extremity Injuries in Children 
 
PROTOCOL TITLE 
Pain Reduction with Intranasal Medications for Extremity injuries (PRIME) 
 
PRINCIPAL INVESTIGATOR: 
Theresa M. Frey, MD 
Assistant Professor Clinical Pediatrics 
Division of Pediatric Emergency Medicine 
Cincinnati Children’s Hospital Medical Center 
Theresa.Frey@cchmc.org 
 
CO-INVESTIGATORS: 
Matthew R. Mittiga, MD 
Todd A. Florin, MD, MSCE 
Michelle C. Caruso, PharmD, BCPS 
Nanhua Zhang, PhD 
 
I.  
ABSTRACT 
 
Introduction: Inadequate pain control in the emergency department, particularly in the pediatric 
population, is a major health concern. The intranasal route of medication administration is gaining 
popularity secondary to its rapid onset of action, minimal discomfort for the patient and relative 
simplicity. When pediatric patients present with moderate to severe pain from traumatic injuries, opioids 
are currently the most frequently used class of analgesia, but they may not always be the best option for 
numerous reasons. Sub-dissociative dosing of ketamine has been shown to be an effective alternative to 
opioids in providing adequate pain relief. 
 
Objectives: The objectives of this study are to 1) determine if intranasal ketamine is non-inferior to 
intranasal fentanyl in reduction of pain in children presenting with extremity injuries and 2) define and 
compare the level of sedation and respiratory side effect profile associated with intranasal ketamine and 
fentanyl.  
 
Methods: The proposed study is a double-blind, randomized clinical non-inferiority trial of intranasal sub-
dissociative ketamine compared to intranasal fentanyl for children ages 8 through 17 years of age 
presenting to the emergency department with moderate or severe pain due to traumatic extremity injury.  
 
Discussion: This study will determine whether intranasal ketamine is an effective alternative to intranasal 
fentanyl for analgesia in children. This would be particularly useful in children who experience adverse 
effects with opioids, have developed opioid tolerance as a result of chronic painful conditions, have poor 
opioid sensitivity due to their genetic predisposition, in pediatric trauma patients with hypotension or in 
patients requiring procedural sedation during their emergency department visit.  
 
 

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II. 
PURPOSE OF STUDY 
The purpose of this study is to compare intranasal sub-dissociative dosing of ketamine with intranasal 
fentanyl for acute pain associated with traumatic limb injuries in children 8-17 years of age presenting to 
the emergency department.  
 
Primary Objective (or Aim) 
The primary objective of this study is to determine if intranasal sub-dissociative ketamine (1.5 mg/kg) is 
non-inferior to intranasal fentanyl (2 mcg/kg) in reduction of moderate and severe pain (VAS score greater 
than 35 mm [1]) associated with extremity injuries in children ages 8 years through 17 years of age.  
 
Hypothesis #1:  Intranasal sub-dissociative ketamine (1.5 mg/kg) and intranasal fentanyl (2 
mcg/kg) will both reduce pain by a mean VAS score of at least 15 mm. There will be no 
significant difference in the means for reduction in pain score between patients receiving 
intranasal ketamine and those receiving intranasal fentanyl.  
 
 
Secondary Objective (or Aim) 
The secondary objective is to define and compare the level of sedation associated with intranasal sub-
dissociative ketamine (1.5 mg/kg) and intranasal fentanyl (2 mcg/kg) as measured by the University of 
Michigan Sedation Scale Score and capnometry values.  
 
 
Hypothesis #2a:  There will be no significant difference in mean sedation scale scores 
 
between the intranasal ketamine group and the intranasal fentanyl group. 
 
 
Hypothesis #2b:  There will be no significant difference in the mean capnometry values 
 
of the two groups.  Patients in both groups will not experience hypopneic  
 
hypoventilation (decrease in capnometry value of ≥ 10 mm Hg). 
 
III. 
BACKGROUND 
 
A recent Institute of Medicine report illustrates that inadequate pain control is a major public 
health concern [2], especially in the emergency department [3]. Despite this increased awareness, pain 
continues to be underdiagnosed and undertreated, particularly in the pediatric population [4, 5]. In one 
study, less than half of 172 children presenting with acute limb fractures received an analgesic during their 
emergency department visit[6]. A more recent study in 2012 looking at 773 children with long bone 
fractures demonstrated that 10% received adequate pain medication, 31% received inadequate pain 
medication and 59% received no pain medication within the first hour of arriving in the emergency 
department [7]. In combined emergency departments where both adults and pediatric patients are 
treated, children are significantly less likely than adults to received pain medications [8, 9], with the 
youngest children being the most vulnerable population [7, 10]. Furthermore, when children do receive 
pain medication, they often encounter long delays in medication administration [11] possibly due to the  
time required to obtain intravenous access. More recently, the intranasal route has been shown to offer 
a more efficient alternative to allow for faster delivery of pain medication [12]. This route is gaining 
popularity secondary to its rapid onset of action, minimal discomfort for the patient and relative 
simplicity.   
 
Opioids are the most commonly used class of analgesic pain medication for children presenting in 
severe pain due to traumatic injuries [7]. Their use during pediatric emergency department visits has 
increased significantly over the past decade [13]. However, multiple studies show the majority of children 
who present in severe pain do not receive opioids, receive doses that are below those recommended [4, 

26Nov2018 
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7-10, 14] or experience long delays in receiving opioids [11, 15]. The reasons for this are unclear, but we 
speculate that this may be due in part to fear of adverse effects of opioids, provider inexperience with 
opioid use in children or fear of contributing to opioid tolerance or abuse. Additionally, due to genetic 
variations that may affect opioid sensitivity, ideal dosing to adequately control severe pain in the majority 
of patients yet avoid adverse medication-related side effects is difficult to ascertain and may lead 
providers to seek out non-opioid alternatives for patients with acute severe pain [16-18].  
 
In the adult population, low dose ketamine is well tolerated and has been used successfully as an 
adjuvant [19-25] and an alternative [26-30] to opioids to provide adequate, rapid pain relief in the 
emergency department.  One study demonstrated that the majority of patients and physicians were 
satisfied with sub-dissociative dosing of ketamine and provided reasons why physicians opted to use 
ketamine, including opioid failure, concern for respiratory depression, concern for opioid allergy and 
concern for hypotension. In this study, 96% of emergency medicine physicians felt that low dose ketamine 
was underused [23].  Though most of these adult studies used the intravenous route, intranasal ketamine 
has also been used successfully in adults with acute pain in the emergency department, inpatient and 
outpatient settings [31-38].   
 
As a dissociative anesthetic, ketamine is the most commonly used agent to facilitate painful 
procedures in the pediatric emergency department [39]. At lower doses, it has been used in children to 
provide analgesia in a variety of acute and chronic pain settings [40].  Low dose ketamine has been used 
effectively in children with terminal diagnoses [41-43], sickle cell disease [44], perioperative pain [45, 46], 
traumatic injuries [47, 48], extensive burns [49] and conditions where opioids are contraindicated [50]. As 
with the adult population, ketamine has been used via the intranasal route to provide adequate analgesia 
and sedation in children, specifically in the pre-hospital setting and in those undergoing various 
procedures [51-59]. 
 
To our knowledge, the PICHFORK trial was the first study to demonstrate the use of intranasal 
sub-dissociative dose ketamine as monotherapy for acute pain in children presenting to the emergency 
department with traumatic injuries [60, 61]. In this study, intranasal fentanyl and ketamine were 
associated with similar pain reduction and satisfaction scores. These study results have yet to be 
replicated. If the results are reproducible, intranasal ketamine would be particularly useful in children who 
experience adverse effects with opioids, have developed opioid tolerance as a result of chronic painful 
conditions, have poor opioid sensitivity due to their genetic predisposition or in pediatric trauma patients 
with hypotension. Additionally, for patients that require procedural sedation for fracture reduction, 
avoiding opioids early in the emergency department visit may help decrease sedation recovery time [62].  
During the PICHFORK trial, adverse events were documented based on patient self-report.  However, 
there have been no studies that document side effects, vital signs, and continuous end tidal CO2 levels 
after administration of intranasal ketamine through direct observation via video monitoring.  The 
objective of this study is to compare intranasal sub-dissociative ketamine with intranasal fentanyl for 
treatment of acute pain associated with traumatic limb injuries in children presenting to the emergency 
department and to document an objective respiratory side effect profile utilizing noninvasive capnometry.  
More specifically, we will compare analgesic effect, sedation level, vital signs, continuous end tidal CO2 
monitoring and adverse events. 
 
 
 
 
 
 
 

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Findings from Clinical Studies 
 
Clinical Studies of Sub-dissociative (Low-Dose) Dose Ketamine in Adults 
 
Intravenous (IV) Administration 
 
When used as monotherapy, subdissociative intravenous ketamine has been shown to provide effective 
analgesia and safety comparable to morphine for acute pain in the emergency department [27, 28]. 
Galinski, et al demonstrated that low doses of IV ketamine significantly lowered consumption of 
morphine by patients presenting to the emergency department with severe acute pain and resulted in 
minimal side effects (6 % with nausea/vomiting and 36% with neuropsychological effects, such as 
dizziness and dysphoria, in the ketamine group vs 6% with nausea/vomiting and 3% with 
neuropsychological effects in the placebo group) [25]. Ketamine combined with either morphine or 
hydromorphone has been shown to provide analgesia superior to that of morphine alone and resulted 
in only few minor side effects [19-22, 24].  In the pre-hospital setting, Tran et al found that ketamine had 
an analgesic effect similar to morphine and carried a lower risk of vomiting and airway problems than 
morphine. They also discovered that ketamine tended to improve blood pressure in hypotensive 
patients to a greater degree [63] (increase of 9.3 mm Hg with ketamine vs 4.8 mm Hg with morphine). In 
adult patients requiring procedural sedation and analgesia, Messenger et al found that patients 
receiving fentanyl and propofol were 5.1 times more likely to have a serious intrasedation event than 
patients receiving ketamine and propofol but the two groups had similar analgesic efficacy [29].  
 
Intranasal (IN) Administration 
 
More recently, the intranasal route has been a highly effective method of administering ketamine at 
sub-dissociative doses. One study revealed that intranasal ketamine was an effective analgesic agent in 
56% of patients presenting to the emergency department with severe pain [32] while another 
demonstrated clinically significant reduction in pain scores in 88% of ED patients [31]. In both studies, IN 
ketamine resulted in very mild, transient side effects. Intranasal ketamine has been shown to be a safe, 
well-tolerated alternative to opioids for moderate to severe postoperative pain in adult patients [35, 
38]. Furthermore, intranasal ketamine has provided rapid onset analgesia for breakthrough pain in adult 
patients with chronic pain conditions [33, 34]. One study showed that patients receiving ketamine 
achieved pain relief within 10 minutes of dosing which lasted up to 60 minutes and none of these 
patients required rescue medication to treat the pain episode [34]. (See Appendix A for further details) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLE 1: Sub-dissociative Dose Intranasal Ketamine for Analgesia in Adults 
 
Study 
N 
Ages 
Setting 
Design 
Doses 
Route 
Outcome 
Adverse Effects 
Yeaman, 
2014 
72 
26-52 
years 
(IQR) 
Emergency 
Department, 
Australia 
Prospective 
observational 
study: 
Ketamine, 
second dose if 
no 
improvement in 
15 min 
0.7-1 mg/kg, 
second dose 
(if 
necessary) 
0.5 mg/kg, 
median total 
dose 0.98 
mg/kg 
IN 
56% reported VAS 
reduction ≥20 mm at 
30 minutes 
Dizziness 32% 
Euphoria 24% 
Unpleasant taste 22% 
Drowsiness 19% 
Nausea 12% 
Numbness 8% 
Blurred vision 5% 
Nasal congestion 4% 
Throat irritation 3% 
Headache 3% 
None 21% 
No serious AEs 
Andolfatto, 
2013 
40 
36-57 
years 
(IQR) 
Emergency 
Department, 
Canada 
Prospective 
observational 
study: 
Ketamine  
0.5-0.75 
mg/kg 
IN 
88% reported VAS 
reduction ≥13 mm at 
30 minutes 
(All transient and did 
not require treatment) 
Dizziness 38% 
Unreality feeling 25% 
Fatigue 10% 
Nausea 8% 
Mood change 8% 
Hearing change 3% 
*No headache, general 
discomfort or 
hallucination 
*No serious AEs 
Carr, 2004 
20 
≥18 
years 
Outpatient, 
USA 
Randomized 
double blind 
crossover trial: 
Ketamine vs 
placebo 
Ketamine  
10-50 mg 
IN 
Mean reduction in 
NPIS (10 point scale) 
score was 2.65 for 
ketamine vs 0.81 for 
placebo. IN ketamine 
is safe and effective 
for break through 
pain 
Fatigue 45% 
Dizziness 20% 
Unreality feeling 20% 
Vision changes 10% 
Nausea 10% 
Hearing change 5% 
Mood change 5% 
*No serious AEs 
*No clinically significant 
change in vital signs 
Christensen, 
2007 
40 
≥16 
years 
Postoperative 
USA 
Randomized 
double blind 
single dose 
parallel study: 
Ketamine #1 vs 
#2 vs #3 vs 
placebo 
Ketamine 1 
10 mg 
Ketamine 2 
30 mg 
Ketamine 3 
50 mg 
 
 
IN 
IN Ketamine at 50 mg 
dose demonstrated 
statistically 
significant pain relief 
(VAS score) 
compared to 
placebo. Largest 
difference in mean 
VAS scores relative to 
placebo was 46.5 
mm at 30 minutes. 
In all 4 groups: 
Hypertension 20% 
Poor concentration 8% 
Throat irritation 8% 
Tachycardia 8% 
Emesis 5% 
Placebo vs ketamine: 
Placebo-headache 50% 
Ketamine-dizzy 58%, 
fatigue 55%, nausea 
25%, psychomimetic 
effects 27% 
No serious AEs 

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Afridi, 2013 
18 
18-57 
Inpatient and 
Outpatient, 
London 
Randomized 
double blind 
parallel 
controlled trial: 
Ketamine vs 
Midazolam 
Ketamine 25 
mg 
 
Midazolam 
2 mg 
IN 
Ketamine reduced 
migraine severity but 
not the duration of 
aura, whereas 
midazolam as no 
effect 
Ketamine: 
Euphoria/unreality 55% 
Midazolam: 
Sedation/giddy 44% 
 
 
Clinical Studies of Sub-dissociative Dose Ketamine in Children 
 
Intravenous (IV) Administration 
 
Sub-dissociative intravenous dosing of ketamine has been used safely and effectively in a variety of 
acute and chronic pediatric conditions. One meta-analysis found that administration of ketamine was 
associated with decreased PACU postoperative pain intensity and analgesic requirement [45]. Two 
studies demonstrated that ketamine given prior to tonsillectomy resulted in significantly lower pain 
scores and less rescue analgesic consumption postoperatively with no difference in the incidence of 
vomiting or psychological sequelae [46, 64].  White et al described the use of ketamine as effective 
analgesia in children with toxic megacolon, a painful condition where morphine is contraindicated. None 
of these children reported adverse effects [50].  White et al also described the long-term (37 days), 
successful use of ketamine for a child with extensive burns. This patient tolerated the medication well, 
never developed signs of tolerance and was able to be weaned rapidly without adverse consequences 
[49]. Various hematologic and oncologic painful conditions that are insufficiently controlled with opioids 
have been effectively treated with low dose ketamine infusions. Two studies showed an opioid sparing 
effect of ketamine with no significant increase in adverse effects in children with cancer-related pain 
[41, 42], while another study described sickle cells patients with opioid-refractory pain who achieved 
clinically significant analgesia after the initiation of ketamine infusion [44].  Taylor et al describes the use 
of ketamine for end-of-life neuropathic pain in which all patients noted subjective pain relief and 79% of 
patients had no adverse effects [43].  Ketamine has been used effectively in the pre-hospital setting for 
pediatric trauma patients. None of these patients demonstrated a loss of airway, oxygen desaturation or 
clinically significant emergence reaction after ketamine [48].  One emergency department study 
demonstrated that ketamine combined with midazolam is more effective than fentanyl combined with 
midazolam when used for emergency pediatric orthopedic procedures and that respiratory 
complications occurred less frequently with ketamine than fentanyl [47]. 
 
Intranasal (IN) Administration 
 
The intranasal route of administering ketamine to children has become more popular over the past few 
years.  A study done in 2013 determined that 1 mg/kg intranasal ketamine provided adequate analgesia 
with only mild, transient side effects that did not require any treatment. None of these patients 
experienced dissociation or hallucination [61].  The PICHFORK trial followed in which intranasal 
ketamine and intranasal fentanyl were associated with similar pain reduction (82% and 79% respectively 
had VAS reductions > 20 mm) and satisfaction scores (83% and 72% respectively achieved satisfaction) in 
patients with pain from limb injuries. Again, these patients experienced no serious adverse events [60].  
One case series and one case report describe the effective use of intranasal ketamine in patients where 
intravenous access could not be established. Patients encountered few, non-serious side effects [52, 53]. 
Tsze et al illustrates the use of various doses (3, 6, or 9 mg/kg) of intranasal ketamine for procedural 
sedation in pediatric laceration repair. The only adverse event documented was vomiting in 1 patient 

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[51].  Another study explored the use of ketamine in uncooperative pediatric dental patients. The overall 
sedation success rate was 89% with ketamine only, 84% with ketamine plus midazolam and 69% with 
midazolam only. There were no significant adverse effects in any of the three groups [55]. Intranasal 
ketamine was also found to be a safe and effective premedication in children undergoing MRI with 
nausea and vomiting as the only documented side effect [57].  Multiple studies have demonstrated the 
successful use of intranasal ketamine in combination with either intranasal midazolam or sufentanil as 
an analgesic or sedative for pediatric procedures [54, 56, 58, 59]. These studies demonstrated only few, 
mild adverse effects with intranasal ketamine. (See Appendix B for further details) 
 
 
TABLE 2: Sub-dissociative and Dissociative Dose Intranasal Ketamine for Analgesia in Children 
 
Study 
N 
Ages 
Setting 
Design 
Doses 
Route 
Outcome 
Adverse Effects 
Graudins, 
2015  
 
Ketamine 
for analgesia 
(sub-
dissociative 
low dose) 
73 
3-13 
years 
Emergency 
Department, 
Australia 
Double blind, 
randomized 
controlled trial: 
Fentanyl vs 
Ketamine 
Fentanyl 
1.5 mcg/kg 
 
Ketamine 
1 mg/kg 
IN 
Median reduction 
in VAS score at 30 
minutes for 
ketamine was 45 
mm and for 
fentanyl was 40 
mm (no significant 
difference 
between groups), 
which was 
maintained to 60 
minutes in both 
groups.  
Fentanyl: 
Bad Taste 42% 
Drowsiness 21% 
Dizziness 17% 
Itchy nose 12% 
Nausea 4% 
Dysphoria 4% 
Hallucinations 0% 
Ketamine: 
Bad Taste 25% 
Drowsiness 16% 
Dizziness 30% 
Itchy nose 4% 
Nausea 6% 
Dysphoria 4% 
Hallucinations 6% 
Yeaman, 
2013 
 
Ketamine 
for analgesia 
(sub-
dissociative 
low dose) 
28 
3-13 
years 
Emergency 
Department, 
Australia 
Observational 
study:  
Ketamine 
Ketamine 
0.8-1.48 
mg/kg 
IN 
IN ketamine 
provided adequate 
analgesia by 30 
minutes. Median 
VAS decreased 
from 74.5 mm to 
30 mm. 
Dizziness 36% 
Bad taste 29% 
Dysphoria 14% 
Nausea 11% 
Sore throat 7% 
Diplopia 7% 
Amnesia 4% 
Headache 4% 
Vomiting 4% 
Johansson, 
2013 
 
Ketamine 
for analgesia 
(sub-
dissociative 
low dose) 
9 
7-36 
years 
Prehospital 
trauma,  
Sweden 
Case series: 
(S)-Ketamine 
Ketamine 
0.45 mg/kg-
1.25 mg/kg 
IN 
IN S-ketamine 
provided adequate 
analgesia. Median 
pain score 
decreased from 10 
to 3 (on a 10 point 
scale). 
Vertigo 
Unpleasant taste 
 
Tsze, 2012 
 
Ketamine 
for sedation 
12 
1-7 
years 
Emergency 
Department, 
USA 
Randomized, 
prospective double 
blind trial: 
Ketamine (3 doses) 
Ketamine #1 
3 mg/kg 
Ketamine #2 
6 mg/kg 
Ketamine #3 
IN 
Significantly higher 
proportion of 
successful 
sedations with 9 
mg/kg dose than 
Vomiting 8% 

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(dissociative 
dosing) 
9 mg/kg 
the other two 
doses. 
Gyanesh, 
2013 
 
Ketamine 
for sedation 
(dissociative 
dosing) 
150 
1-10 
years 
Radiology 
(MRI),  
India 
Randomized 
double blind trial: 
Dexmedetomidine 
(DXM) vs 
Ketamine vs 
Normal saline 
DXM 
1 mcg/kg 
 
Ketamine 
5 mg/kg 
 
Normal 
saline 
IN 
DXM and ketamine 
were equally 
effective as pre-
medication. In 
90.4% of DXM 
patients and 82.7% 
of ketamine 
patients, 
satisfaction with  
conditions for IV 
insertion. Total 
dose of propofol 
used was less in 
DXM and ketamine 
groups. 
DXM: 
Bradycardia 4% 
Nausea/Emesis 4% 
Ketamine: 
Nausea/Emesis 10% 
Saline: 
Nausea/Emesis 6% 
Bahetwar, 
2011 
 
Ketamine 
for sedation 
(dissociative 
dosing) 
45 
2-6 
years 
Outpatient 
Dental 
Clinic, India 
Triple blind 
randomized trial:  
Midazolam vs 
Ketamine vs 
Midazolam + 
Ketamine 
Midazolam 
0.3 mg/kg 
 
Ketamine  
6 mg/kg 
 
Midazolam 
0.2 mg/kg 
plus 
Ketamine 
4 mg/kg 
IN 
Ketamine alone 
had the fastest 
onset of sedation. 
Sedation success 
rate with ketamine 
was 89%, 
midazolam was 
69% and 
combination group 
was 84%.  
No significant 
change in vital signs 
between groups. 
 
Ketamine alone: 
Vomiting 24% 
 
Ketamine + 
Midazolam: 
Vomiting 7% 
 
 
 
TABLE 3. Current Unpublished Clinical Trials Involving Intranasal Ketamine 
 
Principal Investigator 
Location 
Indication 
Age 
Dosing 
Study Phase 
FDA application 
IND required 
Zavolkovskaya S 
USA 
Analgesia 
3-17 years 
1 mg/kg 
Enrolling 
NO 
Linakis JG 
USA 
Sedation 
1-7 years 
Unknown 
Completed 
NO 
Poonai N 
Canada 
Sedation 
5-17 years 
5 mg/kg 
Active, not yet 
recruiting 
N/A 
Andolfatto G 
Canada 
Analgesia 
≥ 6 years  
0.5 mg/kg then 
0.25 mg/kg if 
necessary 
Completed 
N/A 
Henneberg SW 
Schmiegelow K 
 
Denmark 
Analgesia 
1-19 years 
0.5 mg/kg 
(plus sufentanil 
0.5 mg/kg) 
Completed 
N/A 
Christophe CM 
France 
Sedation 
Up to 2 
hours 
(newborn) 
2 mg/kg 
Active, not yet 
recruiting 
N/A 
Costa LR 
Brazil 
Sedation 
2-6 years 
4 mg/kg 
Active, not yet 
recruiting 
N/A 

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IV.  
STUDY DESIGN 
 
The proposed study is a double-blind, randomized controlled non-inferiority trial of intranasal sub-
dissociative ketamine compared to intranasal fentanyl for treatment of pain associated with extremity 
injuries.  
 
Intervention drug: 
Ketamine (50 mg/mL) injectable solution is a nonbarbiturate anesthetic chemically designated dl 2-(0-
chlorophenyl)-2-(methylamino) cyclohexanone hydrochloride. It is formulated as a slightly acidic (pH 3.5-
5.5) sterile solution for intravenous or intramuscular injection in concentrations containing the equivalent 
of 50 mg ketamine base per milliliter and contains not more than 0.1 mg/mL Phemerol® (benzethonium 
chloride) added as a preservative. 
 
Comparator drug: 
Fentanyl Citrate Injection, USP, CII (50 mcg/mL) is a sterile, nonpyrogenic solution of fentanyl citrate in 
water for injection. Fentanyl Citrate is a potent opioid agonist. Each milliliter contains fentanyl (as the 
citrate) 50 mcg (0.05 mg). It may contain sodium hydroxide and/or hydrochloric acid for pH adjustment. 
pH 4.7 (4.0 to 7.5). The solution contains no bacteriostat, antimicrobial agent or added buffer and is 
intended only for use as a single-dose injection.  
 
For analgesic dose volumes equal to and less than 0.5 mL, the entire dose will be administered via mucosal 
atomizer in 1 of the nares. Doses greater than 0.5 mL will be divided equally to both nares. Medication 
will be given via the LMA MAD Nasal™ which enables a seal to be formed with the nostril and atomized 
particles of medication to be delivered to the nasal mucosa. 
 
Should the guardian provide consent, the subject will be randomized to receive either the study 
medication of intranasal ketamine (1.5 mg/kg) or the comparator of intranasal fentanyl (2 mcg/kg). 
Patients of guardians who decline will receive standard Cincinnati Children’s Hospital ED therapy for pain 
associated with extremity injuries. Enrolled subjects will be followed for a minimum of 120 minutes after 
receiving the study medication in the emergency department. Study data forms, electronic medical 
records, and continuous video monitoring of patients during the first 15 minutes will provide visual analog 
scale (VAS) pain scores, University of Michigan Sedation Scale scores, capnometry values, vital signs and 
detection of other adverse events. Study data beyond 15 minutes will be obtained from study data forms 
and electronic medical records. 
 
Randomization and Blinding 
 
Randomization will be allocated through permuted block randomization with randomly varied blocks of 6 
and 8 using a 1:1 ratio within blocks. The randomization scheme will be generated by a computer random 
number generator.  Subjects will be randomized to receive either intranasal ketamine (1.5 mg/kg) or 
intranasal fentanyl (2 mcg/kg) upon meeting inclusion criteria. Allocation will be concealed using pre-
numbered syringes of study medication. The color and odor of the two medications in the syringes will be 
identical. The volumes will be slightly different due to the concentrations of the medications, but the 
syringes will be stored in a way that will not allow for comparison between the syringes.  The syringes will 
be stored with sealed envelopes that contain instruction of how much volume of medication to 
administer. The instructions will not contain the name of the medication in the accompanying syringe. 
Investigational drug services (IDS) will prepare the study medication in a sterile fashion and place the pre-
numbered syringes in the pyxis.  Therefore, medications will be prepared prior to patient arrival in the 

26Nov2018 
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emergency department and IDS members will not engage in patient care. The nurses will obtain a pre-
numbered syringe from the pyxis and administer the medication based on weight categories. Due to the 
nearly identical appearance of the syringes and the use of sealed envelopes with administration 
instructions, the nurses, physicians, PCAs, medics, staff, patient and family members will all be blinded to 
whether the subject is receiving ketamine or fentanyl.  
 
The randomization list will be located in the office of investigational drug services. Should the need arise 
to unblind an investigator  due to a subject experiencing a serious adverse event (SAE) or other serious 
circumstance, the investigator will contact investigational drug services for the particular subject in 
question. If there is a perceived immediate need for unblinding, the pharmacy may be contacted regarding 
which drug was given. A report detailing the need to unblind will be generated by the treating physician 
and forwarded to the IRB through the investigator. If unblinding occurs more than 60 minutes after the 
study medication is administered, this will not be considered a protocol violation.  
 
V. 
DURATION 
 
All study measures will occur during the emergency department visit, with the exception of the thirty day 
post treatment phone follow up call. The emergency department phase duration will last 120 minutes 
after study medication is administered while the patient remains in the emergency department. All pain 
scores, sedation scores, capnometry values, vital signs, adverse events, and rescue analgesia will be 
documented within the first 120 minutes of the visit.  
Participants will receive a phone call 30 days after drug treatment to follow up on any adverse events that 
occur beyond 120 minutes after initial medication administration. 
   
The anticipated duration of the enrollment phase of this study is nine months. Data analysis will occur 
over the following two months.  
 
VI. 
SELECTION AND RECRUITMENT OF PARTICIPANTS 
 
Inclusion Criteria: 
 
1) Age 8 years to 17 years (up to the 18th birthday) 
2) Presenting to emergency department with an extremity injury and triaged as an orthopedic 
evaluation. Extremity injuries may be single or multiple 
3) VAS pain score 35 mm or greater 
4) Patient with parent or legal guardian 
5) Parent or legal guardian is willing to provide consent 
 
Exclusion Criteria: 
 
1) Received narcotic pain medication prior to arrival 
2) Evidence of significant head, chest, abdominal, or spine injury 
3) GCS < 15 or unable to self report pain score 
4) Nasal trauma or aberrant nasal/airway anatomy per parent report 
5) Active epistaxis 

26Nov2018 
12 
 
6) Allergy to ketamine, fentanyl or meperidine (Fentanyl and meperidine are both in the same class 
of medications—phenylpiperidines. An allergy to meperidine is an absolute contraindication to 
fentanyl use) 
7) Non-English speaking parent and/or child 
8) History of psychosis 
9) Postmenarchal females without a urine or serum assay documenting the absence of pregnancy  
10) Patient brought in by 20/20 juvenile detention in Cincinnati or in police custody (considered a 
vulnerable population) 
11) Pregnancy 
 
Subjects that do not meet all of the enrollment criteria may not be enrolled.  If there is a question of 
whether a patient qualifies for enrollment, the principal investigators may be contacted. Any violations of 
these criteria must be reported in accordance with IRB Policies and Procedures.  
 
Potential subjects will be identified during triage via the established orthopedic evaluation protocol as 
defined by a patient that has a “suspected acute deformity AND is experiencing pain and/or decreased 
pulses or sensation in the injured extremity.”  When a patient meets the orthopedic evaluation criteria, a 
page will go out to ED staff as is standard procedure. The patient will be brought to the designated location 
as directed by the orthopedic evaluation process. A member of the research study team trained in 
enrollment procedures for this trial will respond to the designated location.  The study staff will screen 
potentially eligible subjects using the protocol inclusion and exclusion criteria.  A urine or serum assay will 
be obtained on all postmenarchal females, if their pain level allows, to document negative pregnancy 
status.  If a urine or serum assay cannot be obtained secondary to pain level, the subject will be excluded 
from the study as per the exclusion criteria. 
 
Sample Size and Power Analysis 
 
The sample size calculation is based on a non-inferiority test of the difference between two means. Group 
sample sizes of 39 and 39 achieve 80% power to detect non-inferiority using a one-sided, two-sample t-
test. The margin of non-inferiority is 10. Literature has shown that the minimum clinically significant 
difference in VAS pain score in children is 10-12 [65, 66] which is why 10 was chosen as our non-inferiority 
margin. The true difference between the means is assumed to be 5 based on the PICHFORK trial, which 
found a median rating reduction of 40 mm (IQR 20 to 45) at 30 minutes for fentanyl and a median rating 
reduction of 45 mm (IQR 20-60) at 30 minutes for ketamine, and therefore, a difference in medians of 5 
(-10 to 20, 95% CI) [60]. Using the IQR information from the PICHFORK trial and assuming normality for 
the pain scores, we estimate the standard deviations to be 29.63 and 22.22 for the rating reduction at 30 
minutes for the fentanyl and ketamine groups, respectively. Therefore, with an α of 0.05 and a β of 0.2 
(80% power), the sample size required to detect this difference was estimated to be 39 subjects in each 
group, for a total of 78 subjects. In order to achieve this number of evaluable subjects, we plan to enroll 
90 subjects, anticipating that not all subjects enrolled will be fully evaluable.  Over the last year, there 
were 634 patients who presented to the CCHMC ED and were triaged as orthopedic evaluations. Of these, 
360 were in the age group specified in the inclusion criteria. Given this data, we expect to be able to 
successfully complete this study as planned. 
 
 
 
 

26Nov2018 
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VII. 
STUDY PROCEDURES 
 
Table 4.  Study Procedures 
 
Visits 
Visit 1 
Visit 2 
Study Procedure 
Screening 
Phase 
Enroll-
ment 
15 
(±5) 
min 
30 
(±5) 
min 
60 
(±5) 
min 
120 
(+30) 
min 
+30 (±5) 
days * 
Informed Consent, Assent 
for subjects ages 12-17 
 
X 
 
 
 
 
 
Review 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
Demographics/Medical 
History 
X 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
Vital signs (HR, RR, BP, O2 
sat) 
 
X 
X 
X 
X 
X 
 
Serum or urine pregnancy 
test for postmenarchal 
females 
X 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
VAS pain score 
 
X 
X 
X 
X 
 
 
UMSS sedation score 
 
X 
X 
X 
X 
 
 
Nasal mucosal exam 
X 
 
 
 
 
X 
 
Smell test 
X 
 
 
 
 
X 
 
Capnometry value 
 
X 
X 
X 
X 
 
 
Randomization 
 
X 
 
 
 
 
 
Dispense study drug 
 
X 
 
 
 
 
 
Adverse 
event/Serious 
adverse event assessment 
 
X 
X 
X 
X 
X 
X 
 
*Visit 2 window +/- 5 days. 
(See Appendix C for study flow diagram, Appendix D for current orthopedic evaluation flow diagram, 
and Appendix E for duration of study procedures) 
 
SCREENING 
 
Potential subjects will be identified during triage via the established orthopedic evaluation protocol as 
defined by a patient that has a suspected acute deformity AND is experiencing pain and/or decreased 
pulses or sensation in the injured extremity. The patient will be brought to the shock trauma suite (STS) 
or designated area as directed via the orthopedic evaluation process where potential subjects will be 
rapidly screened using the protocol inclusion and exclusion criteria. An emergency medicine attending 
physician and/or fellow, resident, nurse, PCA, medic, and child life provider will respond to the STS or 

26Nov2018 
14 
 
designated area as per established protocol. Study staff trained in enrollment procedures for this trial will 
also respond to the STS or designated area. The nurse will obtain patient’s pain score as per the standard 
of care. Physical exam, vital signs, weight and demographics will be collected as part of standard of care 
prior to consent.  
 
VISIT 1 
 
Process of Obtaining Informed Consent 
 
Study staff will carry a pager and present to all orthopedic evaluations that are paged out to the ED staff. 
All patients who are triaged as an orthopedic evaluation will be screened for eligibility. Prior to 
approaching potential subjects, the eligibility criteria will be reviewed with the attending and/or fellow. 
Parents/guardians of subjects who meet eligibility criteria will be approached by trained study staff.  
 
The study staff will briefly introduce the study and gauge the parent/guardian’s interest. Study staff will 
initiate the consent process and review the consent document with parents/guardians who express 
interest. Parents/guardians will be given time to review the consent document independently and ask the 
study staff questions. 
 
After the consent has been thoroughly reviewed and the parent/guardian has had all of their questions 
answered, the study staff will ask the parent/guardian if they would like for their child to participate in 
the research study. If the parent/guardian agrees to have their child participate in the study, then the 
study staff will obtain their signature on the consent document and initiate the start of study procedures. 
Parents/guardians will receive a copy of the signed consent form. Data collected as part of the routine 
standard of care interventions will be used as baseline study data.  
 
We are requesting a waiver of assent for young children (defined as patients less than 12 years of age). 
Since we are enrolling patients with moderate to high pain scores, young patients may be limited in their 
capacity to provide assent prior to pain treatment.  We will use parental permission in lieu of assent for 
these patients. However, patients 12-17 years of age will be required to assent to the study. The 
investigators will engage children 12-17 years in a thorough discussion of the study consent and seek their 
input/decision on participation. Their decision to participate will be documented in the informed consent 
process note. It is felt that the child is most served by maximizing focus on the actual discussion with the 
child; documentation of this assent is in the informed consent process note. Study staff will obtain and 
document assent prior to the initiation of study procedures.  
 
Emergency Department Phase 
 
After informed consent is obtained, the subject will be randomized to receive either intranasal ketamine 
(1.5 mg/kg) or intranasal fentanyl (2 mcg/kg). All data will be recorded on a standardized REDCap 
electronic case report form. Investigational drug services will independently prepare the study 
medications in pre-numbered sequential syringes.  The volume, color and odor of the two medications in 
the syringes will be identical. Thus, the ED treatment team, patient and patient’s family, and the research 
team will be blinded to which medication the patient will receive.  The patient’s physician will order plain 
radiographs as per standard of care, and the study drug through an EPIC order set. The study staff and 
nurse will ensure a full set of vital signs (including capnometry value) and urine or serum pregnancy test 
for all post menarchal female patients. A nasal mucosal exam and smell test will be performed prior to 

26Nov2018 
15 
 
drug treatment and at 120 minutes post treatment.  Continuous pulse oximetry, which will be followed 
throughout the 120 minute duration of the study visit, will be applied prior to study drug administration. 
After randomization, the blinded study medication will be obtained from the designated pyxis by the 
nurse, who will prepare and administer a weight based amount of the study treatment under the 
observation of the study staff. Of note, the end tidal capnometry cannula will briefly be removed while 
drug is administered and then immediately replaced. The patient will be observed on monitors for 15 
minutes in the STS or designated area. (Currently, the mean time from arrival in STS for an orthopedic 
evaluation to leaving for radiology is 24 minutes so enrollment in this study should not prolong time in 
the STS or designated area.)  The study staff will document vital signs, capnometry value, a sedation score 
and obtain a pain score from the patient at 15 minutes after drug administration. The nurse will document 
vital signs and a capnometry value at 15 minutes after drug administration. The patient will be taken to 
radiology for plain radiographs of the injured extremity and then to an emergency department room 
where the orthopedic evaluation nurse will give report to the patient’s primary nurse.  The study staff will 
document a sedation score, obtain a pain score, document vital signs and a capnometry value from the 
patient at 30 and 60 minutes from drug administration. At 30 minutes, the study staff will also attempt to 
guess which medication the patient received and document this information in order to assess blinding of 
the study. At 120 minutes, a final set of vitals will be obtained and study staff will review all collected vitals 
and ask a study physician to record if vitals outside of the pre-determined normal ranges (see appendix 
G) are clinically significant or not clinically significant.  
 
Additional data collected during the ED visit will include the need for rescue analgesia within 60 minutes 
of drug administration and adverse events within 120 minutes of drug administration. Enrolled subjects 
will be followed for a minimum of 120 minutes after receiving the study medication in the emergency 
department. Currently, the mean total time orthopedic evaluation patients spend in the emergency 
department is 260 minutes so we do not anticipate that enrollment in this study will prolong ED visits.  
 
Rescue Medication Administration 
 
At any time after receiving the study medication, the patient may request further analgesic medication 
which will be administered at the discretion of the treating PEM physician. Rescue analgesia does not 
require the patient to be withdrawn from the study.  
 
Subjects may be withdrawn from the study for the events listed below. Should this be necessary, the 
subject may be removed from the study and receive further medications and therapies at the discretion 
of the treating PEM physician.  
 
Subject Withdrawal 
 
Subjects may withdraw from the study at any time without prejudice to their care. They may also be 
withdrawn from the study at the discretion of the investigator. The investigator or the sponsor may also 
withdraw subjects who violate the study plan, to protect the subject for reasons of safety or for 
administrative reasons. It will be documented whether or not each subject completes the clinical study.  
 
VISIT 2 
 
Visit 2 will conclude study participation and will consist of a phone follow up to the subject’s parent or 
legal guardian to follow up on any ongoing adverse events from Visit 1 and to determine if any new 

26Nov2018 
16 
 
adverse events occurred. The study team will attempt to reach the subject’s parent by phone at least five 
times within the follow up timeframe (30 +/- 5 days) before considering the subject lost to follow up. 
Adverse events will be followed until resolution or until no further change is expected.  
 
Drugs, Devices, and Biologics:  (see Appendix F for further details) 
The intranasal route of administering medications had been reported for the past 20 years in the 
emergency care of pediatric patients. It has become a popular route of medication administration 
secondary to its rapid onset of action, minimal discomfort for the patient and relative simplicity. The nose 
contains a rich vascular supply with a relatively large surface area. Medications can be absorbed into 
vessels that lead to the superior vena cava bypassing first pass hepatic metabolism that limits 
bioavailability of oral medications. 
 
Intervention drug: 
Ketamine (50 mg/mL) injectable solution is a nonbarbiturate anesthetic chemically designated dl 2-(0-
chlorophenyl)-2-(methylamino) cyclohexanone hydrochloride. It is formulated as a slightly acidic (pH 3.5-
5.5) sterile solution for intravenous or intramuscular injection in concentrations containing the equivalent 
of 50 mg ketamine base per milliliter and contains not more than 0.1 mg/mL Phemerol® (benzethonium 
chloride) added as a preservative. 
 
Human Pharmacokinetics: 
Nielsen, et al in 2014 investigated a pediatric formulation of intranasal sufentanil 0.5 mcg/kg and ketamine 
0.5 mg/kg for procedural pain and determined the bioavailability of ketamine was 35.8%.  Maximum 
plasma concentration (Cmax) of ketamine was 0.102 mg/L (CV 10.8%) and Tmax was 8.5 min (CV 17.3%). 
 
Malinovsky, et al in 1996 determined that after administration of intranasal ketamine in children 10-30 
kg, 2-9 years of age, mean plasma concentrations after 3 mg/kg peaked at 496 ng/mL at 20 minutes and 
after 9 mg/kg peaked at 2104 ng/mL within 21 minutes.  Plasma concentrations of norketamine (the 
predominate active metabolite), peaked at ~120 minutes after nasal ketamine. Calculated bioavailability 
from nasal administration was 50%.  The authors concluded that nasal administration of low doses of 
ketamine produced plasma concentrations associated with analgesia (40-200 mg/mL), but using high 
doses produced high plasma concentrations similar to those that induce anesthesia (1100 to over 2000 
ng/mL. 
 
Packaging:   
The study medication is prepackaged by the distributor in individual sterile vials of 10 mL each.  
 
Labeling: 
The product label reads “Ketamine HCL, Injection USP, Concentrate 500 mg/10 mL (50 mg/mL) for 
intramuscular or slow intravenous use, 10 x 10 mL multi-dose vials.” 
 
Manufacturer: 
 Mylan Institutional LLC, Rockford, IL 
Dosing: 
Ketamine is in individual sterile vials of 10 mL of solution. Investigational drug services will prepackage 
syringes with study medication using aseptic technique, cap the syringes and label each with a specific 
study number.  Using weight based categories, patients who are randomized to receive ketamine will 
receive a dose of 1.5 mg/kg with a max dose of 100 mg. 
 

26Nov2018 
17 
 
Comparator drug: 
Fentanyl Citrate Injection, USP, CII (50 mcg/mL) is a sterile, nonpyrogenic solution of fentanyl citrate in 
water for injection. Fentanyl Citrate is a potent opioid agonist. Each milliliter contains fentanyl (as the 
citrate) 50 mcg (0.05 mg). It may contain sodium hydroxide and/or hydrochloric acid for pH adjustment. 
pH 4.7 (4.0 to 7.5). The solution contains no bacteriostat, antimicrobial agent or added buffer and is 
intended only for use as a single-dose injection.  
 
Intranasal fentanyl is currently the standard of care in the Cincinnati Children’s Hospital Medical Center 
Emergency Department for the treatment of pain associated with acute extremity injuries prior to IV 
placement.  
 
Human Pharmacokinetics 
When fentanyl is administered by the intranasal route, the bioavailability is nearly 70%, with Tmax 
reached in 5–16 minutes.   
 
Borland et al. conducted a study in 2002 looking at use of IN Fentanyl in pediatric patients (3-12 years of 
age) in the emergency department.  With doses of 0.5-3.4 mcg/kg (median 1.5 mcg/kg), the authors found 
the drug achieved therapeutic levels and onset of analgesia within 10 minutes and had a half-life of 1 
hour.  The authors found it unlikely to cause respiratory compromise or hemodynamic instability based 
on no significant differences in HR, RR, BP, or oxygen saturations even with improvement in pain scores. 
 
Packaging: 
The study medication is packaged in 2 mL vials by the manufacturer.  
 
Labeling: 
The product label reads “Fentanyl Citrate, Injection USP, 100 mcg Fentanyl/2 mL (0.05 mg/mL) (50 
mcg/mL) IV or IM use, 2 mL single dose vial.” 
 
Manufacturer: 
West-Ward; Eatontown, NJ 
 
Dosing: 
Fentanyl is in individual sterile vials of 2 mL of solution. Investigational drug services will prepackage 
syringes of study medication using aseptic technique, cap the syringes and label each with a specific study 
number.  Using weight based categories, patients who are randomized to receive Fentanyl will receive a 
dose of 2 mcg/kg with a max dose of 100 mcg. 
 
Syringes with ketamine and fentanyl will look identical to maintain blinding. Syringes will expire after 9 
days. Subjects will receive either intranasal ketamine (1.5 mg/kg) or fentanyl (2 mcg/kg) by blinded syringe 
in a standardized volume.  For analgesic dose volumes equal to and less than 0.5 mL, the entire dose will 
be administered in 1 of the nares. Doses greater than 0.5 mL will be divided equally to both nares.  
 
Medications will be given via a mucosal atomizer device. The LMA MAD Nasal (MAD300) intranasal 
mucosal atomization device (Wolfe-Tory, Medical, Inc, Salt Lake City, UT) will be attached to the Luer-
Lok syringe just before study drug administration to the patient.  0.1 mL of drug solution will be used to 
prime the MAD nasal device.   
 

26Nov2018 
18 
 
These dosages and distribution of medication are similar to previous studies using intranasal ketamine 
and/or intranasal fentanyl in which there were no significant adverse effects observed [53, 60, 61, 67-69]. 
 
Adequate records of study drug administration and disposition will be maintained by the Cincinnati 
Children’s Hospital Investigational Drug Services. The purpose of these records is to ensure regulatory 
authorities and the sponsor that the investigational drug will not be distributed to any person who is not 
a study subject under the terms and conditions set forth in this protocol. The study medication is to be 
prescribed by the members of this investigational team or designee and may not be used for any purpose 
other than that described in this protocol. At study completion, all drug supplies must be returned to the 
sponsor or designee.  
 
VIII. 
DATA ANALYSIS/METHODS 
 
Data Collection and Management 
 
All data will be entered onto standardized electronic data reporting forms after initially being obtained on 
paper forms. The data reporting forms will contain the demographic, physical exam and treatment data 
outlined in this section. The forms will also contain the protected health information of subject name, visit 
date, contact information and medical record number. Data from the forms will be entered into a 
database.  Protected health information will be entered into the database.  The information will be de-
identified after study completion.  
 
Confidentiality will be maintained by using a locked cabinet in the research staff area and by maintaining 
password-protected databases and computers. The password for the database will only be known to the 
research study staff. Study files will be stored in a locked cabinet in the principal investigator’s office which 
has limited public access. Entry to the office is protected by CCHMC ID card entry.  Study files will be de-
identified after publication and retained for 3 years after study closure.  
 
Additionally, data about missed eligible patients will be collected periodically through an EMR report 
and supplemented by chart review to assess screening hours, training needs or other issues that may 
inhibit staff’s ability to enroll. We are requesting a HIPAA waiver to review the patient charts via the 
MRN and day/time of arrival and no information will be used for analysis in the research study. Consent 
would not otherwise be possible for these participants because of the nature of presentation to the ED; 
it is possible that these patients will have arrived when no study staff is available. Data collected on 
missed eligible patients will include MRN, encounter ID, date/time of ED arrival and discharge, means of 
arrival, date of birth, gender, whether or not they met study inclusion/exclusion criteria, disposition, 
discharge diagnosis, and provider name.  
 
Primary Endpoint 
 
The primary endpoint is the difference between the mean reduction in pain scores between the ketamine 
group and the fentanyl group as measured by the visual analog scale (VAS) at 30 minutes after study 
intervention.  
 
The pain VAS is a unidimensional measure of pain intensity which has been widely used in diverse 
populations [66, 72, 73]. It is a continuous scale comprised of a horizontal or vertical line that is 10 cm 
(100 mm) in length anchored by two verbal descriptors representing pain extremes. The scale is most 

26Nov2018 
19 
 
commonly anchored by “no pain” (score of 0) and “pain as bad as it could be” or “worst imaginable pain” 
(score of 100). To avoid clustering of scores around a preferred numeric value, numbers or verbal 
descriptors at intermediate points are not present. The patient is asked to place a line perpendicular to 
the VAS line at the point that represents their current pain intensity. Using a ruler, the score is determined 
by measuring the distance (mm) on the 10-cm line between the “no pain” anchor and the patient's mark, 
providing a range of scores from 0–100.  The visual analog scale has been shown to be valid and reliable 
in children 8 to 17 years of age suffering from acute pain and that a minimum clinically significant 
difference in VAS score ranges from 10 to 12 mm in children and adolescents [65, 66]. The optimal cut 
points for mild, moderate and severe pain on the VAS for children and adolescents have been determined 
to be 35 and 60 mm [1].  
 
Secondary Endpoints 
 
The secondary endpoints are to: 
 
▪ 
Define and compare the level of sedation associated with intranasal sub-dissociative 
ketamine (1.5 mg/kg) and intranasal fentanyl (2 mcg/kg) as measured by the University 
of Michigan Sedation Scale Score and capnometry values.  
▪ 
Compare adverse effects associated with intranasal sub-dissociative ketamine and 
intranasal fentanyl 
▪ 
Compare vital sign changes associated with intranasal sub-dissociative ketamine and 
intranasal fentanyl 
 
An additional secondary endpoint will be the difference between the ketamine group and the fentanyl 
group in pain score as measured by the visual analog scale at 15 and 60 minutes after study intervention. 
 
Screening and Baseline Evaluation 
 
Physical Examination 
 
Baseline evaluation will include a physical examination and demographics as are routinely performed 
during the orthopedic evaluation process. Items recorded from physical examination will be weight and 
extremity injured. An exam of the nasal mucosa will be performed, and a nasal smell test will be 
administered prior to drug treatment and at 120 minutes post treatment. Demographic data recorded 
will include age, gender, ethnicity and race.  
If there is a discrepancy between the information provided by the parent and information provided in the 
chart, the information provided by the parent will be used.  
100 mm 

26Nov2018 
20 
 
Vital signs 
 
Vital sign data will be recorded at baseline, 15 minutes, 30 minutes, 60 minutes, and 120 minutes. It will 
include heart rate, respiratory rate, blood pressure, oxygen saturation and end tidal capnometry value. 
However, an end tidal capnometry value will not be obtained at the 120 minute assessment. Oxygen 
saturation levels and capnometry values will be obtained from the cardio-respiratory monitor once an 
appropriate waveform is obtained. Cardio-respiratory monitoring with pulse oximetry will be continuous 
for 120 minutes after the study medication is administered. 
 
Table 5. Covariates 
Age 
Gender 
Race 
Insurance status 
Weight 
Time to medication from injury 
Time to medication from arrival to ED 
Injury Type 
Extremity injured 
Mechanism of injury 
 
Other Evaluations/Measures 
A urine or serum pregnancy test will be collected from all post menarchal females, and results must be 
negative before drug treatment may be initiated. 
 
Visual analog scale pain scores will be obtained by study staff as described above.  
 
University of Michigan Sedation Scale (UMSS) scores will also be obtained at baseline, 15, 30 and 60 
minutes after study intervention. The University of Michigan Sedation Scale is a valid and reliable tool that 
allows for rapid assessment of the depth of sedation in children. It is a simple observational tool that 
assesses the level of alertness on a five-point scale [74]. It has been validated in children and has shown 
to have significant inter-rater reliability.  
 
 
 

26Nov2018 
21 
 
Efficacy Evaluations 
 
Diagnostic Tests, Scales, Measures 
 
A VAS score, UMSS sedation score and vital signs will be obtained at study entry and at 15 minutes, 30 
minutes and 60 minutes after administration of study medication. Changes between these time points 
will be evaluated. The time from initial physician evaluation to study medication and to ED disposition will 
be recorded. Adjunct measures including additional analgesia or anti-emetics will be recorded.  
 
Of note, pain scores, sedation scores, vital signs, capnometry values, and adverse effects will be obtained 
at specific windows of time such that the “15 minute” value will be obtained between 10 and 20 minutes 
after medication is given, “30 minute” value will be obtained between 25 and 35 minutes after medication 
is given, “60 minute” value will be obtained between 55 and 65 minutes after medication is given and 
“120 minute” value will be obtained between 120 and 150 minutes after medication is given.  
 
Statistical Methods 
 
Baseline Data 
 
Baseline and demographic characteristics will be summarized by standard descriptive summary statistics. 
This will include means and standard deviations for continuous variables expected to be normally 
distributed, such as age, vital signs, capnometry values, weight and VAS pain scores; proportions for 
categorical variables such as gender, race and injury location; and medians with ranges for variables 
expected to not be normally distributed, such as UMSS sedation scores.  All continuous variables will be 
assessed for normality; parametric statistics will be used for normally distributed variables and non-
parametric statistics will be used for non-normally distributed variables.  
 
Efficacy Analysis 
 
The primary analysis will include all subjects randomized based on the principle of intention to treat. If 
necessary, a per-protocol analysis will also be performed to assess efficacy of the treatments actually 
received.  The primary efficacy endpoint will be the difference in mean pain scores between the ketamine 
group and the fentanyl group at 30 minutes after study intervention. This difference will be evaluated 
using the t-test.  
 
Demographic and historical baseline information of the 2 study groups will be compared using t-tests 
(means), Mann-Whitney U (medians), and chi-square (proportions) tests. If there are any significant 
differences, linear regression will be performed to adjust for significantly different covariates.   
 
For secondary outcomes, t-tests, or Mann-Whitney U where appropriate, will be used to evaluate 
differences in continuous outcomes (e.g. heart rate, blood pressure). Chi-square tests will be used to 
evaluate proportions in dichotomous outcomes (e.g. proportion with presence of specific adverse effects). 
Risk differences with 95% confidence intervals will be used to compare dichotomous outcomes such as 
the use of rescue analgesia and adverse events.  
 
 
 

26Nov2018 
22 
 
Safety Analysis 
 
All subjects entered into the study will be included in the safety analysis. The frequencies of adverse 
events, including type, body system, severity and relationship to the study drug, will be summarized. We 
do not anticipate any serious adverse events. However, if one were to occur, it would be described in 
detail.  
 
Adverse event incidence will be summarized along with the corresponding exact binomial 95% two-sided 
confidence intervals. 
 
Test of Non-Inferiority 
 
A one-sided two-sample t-test will be used to test whether the pain reduction using ketamine is non-
inferior to that of fentanyl. When the variances of the two groups are unequal, Welch’s t-test will be used; 
if the data are not normally distributed, the Mann-Whitney (Wilcoxon signed rank) U test will be used [75, 
76].  
 
Interim Analysis 
 
Due to the expected short duration of the study, no interim analysis will be performed. However, ongoing 
safety analysis of adverse events, serious adverse events and toxicities will be done.  
 
IX. 
FACILITIES AND PERFORMANCE SITES 
 
The study will be conducted at one investigative site in the United States. Cincinnati Children’s Hospital 
Medical Center is an academic, freestanding, 523 bed children’s hospital with 32,981 admissions and 
125,130 Emergency Department visits annually.  The population is diverse and includes 51% Caucasian, 
40% African American, 2% Hispanic, and 7% other.  Study enrollment will only be performed at the base 
campus. 
 
X.  
POTENTIAL BENEFITS 
 
Intranasal sub-dissociative dosing of ketamine has been shown in multiple studies to provide adequate 
analgesia to pediatric patients experiencing moderate to severe pain. Therefore, patients receiving the 
study medication may receive adequate analgesia and avoid the side effects associated with opioids and 
potentially the increased chance of adverse effects as a result of opioids in combination with ketamine 
procedural sedation later during their ED visit. Furthermore, patients who are genetically predisposed to 
have poor opioid sensitivity or those who have developed opioid tolerance due to other chronic painful 
conditions may find more benefit with the study medication.  
 
XI. 
POTENTIAL RISKS, DISCOMFORTS, INCONVENIENCES and PRECAUTIONS 
 
There are minimal risks associated with the administration of sub-dissociative ketamine via the intranasal 
route. All studies performed using intranasal ketamine at sub-dissociative dosing in children showed only 
minimal adverse events and no serious adverse events associated with the study medication.  Examples 
of mild adverse events which could be expected to occur with both medications include drowsiness, 

26Nov2018 
23 
 
dizziness, pruritus, nausea, vomiting, dysphoria, unpleasant taste, vision changes, throat irritation, 
headache, and mild increase in heart rate and blood pressure.  
 
Based on pharmacokinetic studies on intranasal ketamine use in children, the mean plasma 
concentrations peaked at about 20 minutes and the plasma concentrations of norketamine (the 
predominate active metabolite), peaked at about 120 minutes after administration of intranasal 
ketamine. Subjects will be observed in the emergency department for a minimum of 2 hours after study 
medication administration, thus providing resources and personnel for immediate, emergency care 
should the need arise. Those patients who are admitted and remain in the ED less than 2 hours will be 
monitored for the entirety of their ED stay. The admitting team will then be notified that they received a 
study medication. This length of observation is consistent with the amount of time that patients who are 
triaged as an orthopedic evaluation spend in the ED for standard therapy as most of these patients tend 
to remain in the ED for longer than two hours. This observation time does not pose any increased risk to 
the patient.  Those patients discharged from the ED will be provided appropriate follow up instructions as 
per standard of care.  
 
For these reasons, we expect enrollment in this trial to be of minimal risk to patients.  
 
XII. 
RISK/BENEFIT ANALYSIS 
 
Due to the prospect of direct benefit to patients and minimal risk to patients, the risk-benefit ratio seems 
favorable to patients, parents and providers. 
 
XIII. 
DATA AND SAFETY MONITORING 
 
Clinical Adverse Events 
 
Clinical adverse events (AEs) will be monitored throughout the study. All adverse events will be followed 
until resolution. 
 
Adverse Event Reporting 
 
All on-site serious adverse events will be reported to the IRB in accordance with CCHMC IRB policies. 
Adverse Events will be reported to the IRB per CCHMC Research Policy R-18. 
 
Definition of an Adverse Event 
 
An adverse event is any untoward medical occurrence in a subject who has received an intervention (drug, 
biologic, or other intervention).  The occurrence does not necessarily have to have a causal relationship 
with the treatment.  An AE can therefore be any unfavorable or unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. Adverse event monitoring for the 
emergency department phase would start at the time of randomization and end at two hours after initial 
medication administration. Any additional adverse events that occur beyond 120 minutes after initial 
medication administration will be obtained during the 30 day follow up phone call. 
 

26Nov2018 
24 
 
All AEs (including serious AEs) will be noted in the study records and on the case report form with a full 
description including the nature, date and time of onset, determination of non-serious versus serious, 
intensity (mild, moderate, severe), duration, causality, and outcome of the event. SAEs will be reported 
within 24 hours. 
 
Definition of a Serious Adverse Event (SAE) 
 
An SAE is any adverse drug experience occurring at any dose that results in any of the following outcomes:  
▪ 
death 
▪ 
a life-threatening event (at risk of death at the time of the event)  
▪ 
requires inpatient hospitalization or prolongation of existing hospitalization 
▪ 
a persistent or significant disability/incapacity 
▪ 
results in a congenital anomaly or birth defect 
Important medical events that may not result in death, be life-threatening, or require hospitalization may 
be considered a serious adverse drug event when, based upon appropriate medical judgment, they may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition.  The one exception to these criteria is hospitalization for repair and/or pain 
management associated with the injury. Since this can be expected as part of the standard treatment 
course for orthopedic injuries, admissions for this reason will not be reported as a serious adverse event. 
However, all admissions will be tracked and those related to adverse events or for reasons other than 
injury repair or pain management will be reported as an SAE.  
 
Serious adverse event monitoring starts at the time of consent and ends at the time of discharge or 
admission.  All SAEs will be followed until resolution, the event is considered to be medically stable, or for 
30 days after the subject completes the study, whichever occurs first.  
 
A distinction should be drawn between serious and severe AEs.  A severe AE is a major event of its type.  
A severe AE does not necessarily need to be considered serious.  For example, nausea which persists for 
several hours may be considered severe nausea, but would not be an SAE.  On the other hand, a stroke 
that results in only a limited degree of disability may be considered a mild stroke, but would be an SAE.  
 
Serious Adverse Events (SAEs) Specific to this Study 
 
There has been documentation of a few significant adverse effects associated with the medications 
included in this study. These effects are exceedingly rare and are anticipated to be even rarer through an 
intranasal route of drug administration compared with an intravenous route and with sub-dissociative 
dosing of ketamine as compared with dissociative dosing.  
 
Ketamine:  cardiac arrhythmia, hypertensive emergency, prolonged emergence reaction, anaphylaxis, 
laryngospasm, apnea 
 
Fentanyl:  cardiac arrhythmia, cardiopulmonary arrest, chest wall rigidity, hypertensive emergency, 
hypotension, pulmonary embolism, anaphylaxis, apnea, bronchospasm, laryngospasm 
 

26Nov2018 
25 
 
In the  exceedingly rare instance that one of these serious adverse effects was to occur, the patient would 
be treated for that particular emergency in a manner that is standard of care at CCHMC were the 
emergency to occur in any other setting.  
 
Relationship of SAE to study drug or other intervention 
 
The relationship of each SAE to the study intervention should be characterized using one of the following 
terms in accordance with CCHMC IRB Guidelines: definitely, probably, possibly, or unrelated. 
 
Monitoring Plan 
 
The medical monitor is the person responsible for the safety monitoring in this protocol and he will 
monitor all clinically significant adverse events (AEs) and provide consultation for any AEs that the 
investigators question the classification, severity or relatedness originally documented at the time of the 
ED visit.  The medical monitor will be Scott Reeves, MD. He is a member of the Division of Emergency 
Medicine, who will not be involved with enrollment. 
 
A risk-based monitoring plan will be developed for the conduct of study monitoring.  On-site monitoring 
will occur throughout the duration of the study.  A study initiation visit will be conducted by the study 
monitoring staff to ensure that the study staff have been completely trained in protocol procedures and 
Good Clinical Practices (GCP) and that facilities and personnel are adequate.   Scheduled monitoring will 
occur at least once per year during the conduct of the trial, with the option of making a second visit if 
needed to address over-enrollment, under-enrollment, or protocol deviation issues.  The Monitoring Plan 
will detail the frequency and level of intensity of on-site monitoring visits.  In general, the study will be 
monitored for all subjects at a level of 100% of study data gathered for inclusion and exclusion criteria, 
informed consent procedures, and adverse events.  At a minimum, at least 20% of the study subject’s data 
will be monitored against the study’s database. 
 
During scheduled interim monitoring visits, the monitors will verify that the protocol is being followed 
and that data are being collected according to protocol requirements.  The monitors will review the Study 
Regulatory File to determine that all required documentation is being collected and that the IRB approval 
for the study is current.  They will then verify that each subject has signed the correct version of the 
informed consent document, and that this document is filed in the subject’s file.  Adverse event 
documentation is checked for completeness and accuracy.  Drug and supplies accountability will also be 
monitored.  At the study closeout, the monitors confirm that all data have been reviewed, all source 
documents have been verified, and all required documents are present in the Study Regulatory File.  The 
table below describes the variables to be reviewed during monitoring visits. 
 
Variable 
% of Records Reviewed 
Informed consents 
100% 
Eligibility criteria for all screened subjects 
100% 
Adverse events 
100% 
Drug accountability 
20% of active subjects 
Protocol adherence 
20% of active subjects 
Verification of eCRFs with source documents 
20% of active subjects 

26Nov2018 
26 
 
Central study files-inclusion of all applicable documents 
100% 
Protocol deviations/violations 
100% 
 
AEs will be reported to the IRB as detailed below. Adverse events will be recorded on the study data form 
by the study team. Any serious adverse events (SAEs) will be reported to the investigator or designee 
immediately. Study forms and charts will be reviewed by the study coordinator and principal investigator 
for AEs after the ED visit. All identified AEs will be recorded. The investigator will determine the grade and 
attribution.  If unblinding is required, the investigator will notify the IRB. The protocol and consent will be 
reviewed by the investigator to determine if any changes are required. SAE’s that are related to the study 
and unexpected will be reported to the IRB and FDA. Any serious adverse events and/or adverse events 
that occur during the study will be followed to resolution. 
 
For the purpose of this study, toxicity is defined using the Common Terminology Criteria for Adverse 
Events (CTCAE) v4.0 as defined by the National Cancer Institute 
(http://ctep.cancer.gov/reporting/ctc.html).  
 
Grade level 4 or greater toxicity which are unexpected and related to the study will be reported to the 
IRB within 48 hours. Examples pertinent to this protocol include: life threatening respiratory 
compromise resulting in intubation, anaphylaxis, hypotension, hypertensive crisis, life-threatening 
cardiac arrhythmias requiring urgent intervention, nausea and emesis with life-threatening 
consequences, and change in mental status including states harmful to the subject.  
 
Subjects will be withdrawn from study drug exposure if any of the following events occur during the 
patient’s stay in the ED: 
▪ 
The subject has a SAE possibly or definitely related to the study drug 
▪ 
The subject experiences a level 4 toxicity as defined by CTCAE 
▪ 
The subject experiences one or more level 3 toxicities as defined by CTCAE  
▪ 
The subject has an adverse event experience that would, in the investigator’s judgment, make 
continued participation in the study not in the subject’s best medical interest. 
 
The trial will stop enrollment for the following events: 
▪ 
A SAE rate related to the study intervention of greater than or equal to 2 in 10 subjects is detected 
▪ 
Subjects experiencing grade 3 toxicities occur more frequently than 3 in 10 subjects. 
 
If the trial is stopped for the above events, a complete report of the events, AEs and SAEs will be provided 
to the IRB and FDA for review. The protocol and consent will be reviewed and any recommendations for 
revisions will be approved by the IRB before enrollment is reopened.  
 
XIV. 
PRIVACY AND CONFIDENTIALITY 
 
All data and records generated during this study will be kept confidential in accordance with institutional 
policies and HIPAA on subject privacy and that the investigator and other site personnel will not use such 
data and records for any purpose other than conducting the study. Safeguards to maintain confidentiality 
are discussed in Section VIII. 
 
 

26Nov2018 
27 
 
XV. 
COST OF PARTICIPATION 
 
Third party payers and participants will not be billed for research procedures described.  
 
XVI. 
PAYMENT FOR PARTICIPATION 
 
Participants who complete the ED study procedures will be compensated with a $10 gift card for their 
time and effort towards the study. 
 
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APPENDICES 
 
APPENDIX A:  Clinical Studies of Sub-dissociative (Intranasal and Intravenous) Dose Ketamine in Adults 
 
Study 
N 
Ages 
Setting 
Design 
Doses 
Route 
Outcome 
Yeaman, 2014 
72 
26-52 years 
(IQR) 
Emergency 
Department, 
Australia 
Prospective 
observational study: 
Ketamine, second 
dose if no 
improvement in 15 
min 
0.7-1 mg/kg, 
second dose (if 
necessary) 0.5 
mg/kg, median 
total dose 0.98 
mg/kg 
IN 
56% reported VAS 
reduction ≥20 mm at 
30 minutes 
Andolfatto, 2013 
40 
36-57 years 
(IQR) 
Emergency 
Department, 
Canada 
Prospective 
observational study: 
Ketamine  
0.5-0.75 mg/kg 
IN 
88% reported VAS 
reduction ≥13 mm at 
30 minutes 
Huge, 2010 
16 
54.5 ± 21.4 
years 
Outpatient, 
Germany  
Double blind 
randomized trial:   
(S)-Ketamine at 2 
different doses 
Group 1:  
0.2 mg/kg  
 
Group 2:  
0.4 mg/kg 
IN 
Group 1: pain reduction 
to 70±10% of initial 
pain at 60 minutes 
Group 2: pain reduction 
to 61±13% of initial 
pain at 60 minutes 
Carr, 2004 
20 
≥18 years 
Outpatient, 
USA 
Randomized double 
blind crossover trial: 
Ketamine vs placebo 
Ketamine  
10-50 mg 
IN 
Mean reduction in NPIS 
(10 point scale) score 
was 2.65 for ketamine 
vs 0.81 for placebo. IN 
ketamine is safe and 
effective for break 
through pain 
Christensen, 
2007 
40 
≥16 years 
Postoperative
USA 
Randomized double 
blind single dose 
parallel study: 
Ketamine #1 vs #2 vs 
#3 vs placebo 
Ketamine 1 
10 mg 
Ketamine 2 
30 mg 
Ketamine 3 
50 mg 
 
 
IN 
IN Ketamine at 50 mg 
dose demonstrated 
statistically significant 
pain relief (VAS score) 
compared to placebo. 
Largest difference in 
mean VAS scores 
relative to placebo was 
46.5 mm at 30 minutes. 
Abdel-Ghaffar, 
2012 
60 
18-65 years 
Pre-operative  
Egypt 
Randomized double 
blind placebo 
controlled trial: 
Ketamine vs Fentanyl 
vs Saline 
Ketamine 
1.5 mg/kg 
 
Fentanyl 
1.5 mcg/kg 
IN 
Ketamine and fentanyl 
significantly prolonged 
time to first analgesic 
request. VAS scores 
were significantly lower 
with ketamine and 
fentanyl compared to 
saline in first 4h postop 
Afridi, 2013 
18 
18-57 
Inpatient and 
Outpatient, 
London 
Randomized double 
blind parallel 
controlled trial: 
Ketamine vs 
Midazolam 
Ketamine 25 mg 
 
Midazolam 2 mg 
IN 
Ketamine reduced the 
severity but not the 
duration of aura, 
whereas midazolam as 
no effect 

26Nov2018 
32 
 
Riediger, 2015 
22 
≥18 years 
Postoperative 
Switzerland 
Randomized double 
blind noninferiority 
trial: 
S-
Ketamine+Midazolam 
Vs 
Morphine  
S-ketamine 6 mg 
alternating with 
Midazolam 0.75 
mg (lockout 
interval of 20 min 
between meds) 
 
Morphine 2 mg 
(lockout interval 
of 12 min) 
IN 
Similar NRS scores in 
morphine and S-
ketamine groups as 1, 
2, 4, 24, 48 and 72 
hours after surgery. No 
difference in bolus 
demands and deliveries 
of medications. 
Messenger, 2008 
63 
14-65 years 
Emergency 
Department, 
Canada 
Randomized double 
blind controlled triai: 
ketamine vs fentanyl  
(followed by propofol) 
Ketamine 0.3 
mg/kg 
 
Fentanyl 1.5 
mcg/kg 
IV 
Ketamine and fentanyl 
have similar efficacy. 
Sub-dissociative 
ketamine is safer than 
fentanyl for ED 
procedural sedation 
and analgesia with 
propofol. 
Galinski, 2007 
65 
18-70 years 
Emergency 
Department, 
France 
Multicenter, 
randomized double 
blind trial:  
Ketamine + morphine  
vs 
Normal saline + 
morphine 
Ketamine  
0.2 mg/kg 
 
Morphine  
0.1 mg/kg 
IV 
Morphine consumption 
significantly lower in 
ketamine group than 
placebo (0.149 mg/kg 
vs 0.202 mg/kg). No 
significant difference in 
VAS score at 30 
minutes 
Gurnani, 1996 
40 
Adult 
Emergency 
Department, 
India 
Randomized double 
blind pilot trial: 
Ketamine dose 
followed by infusion 
vs 
Morphine dose 
followed by q4 hour 
dosing 
Ketamine 
0.25 mg/kg initial 
dose, infusion at  
0.1 mg/kg/hr 
 
Morphine  
0.1 mg/kg initial 
dose,  
0.1 mg/kg q4 
 
IV 
VAS scores significantly 
lower in ketamine 
group. 
Patients in ketamine 
group significantly less 
drowsy.  
No ketamine patients 
required supplemental 
analgesia vs 90% of 
morphine patients 
required supplemental 
analgesia 
Motov, 2015 
90 
18-55 years 
Emergency 
Department, 
USA 
Randomized double 
blind trial: Ketamine 
vs Morphine 
Ketamine 
0.3 mg/kg 
 
Morphine  
0.1 mg/kg 
IV 
Ketamine is as effective 
as morphine for 
analgesia at 15 and 30 
minutes (8.6 vs 8.5 at 
baseline, 3.2 vs 4.2 at 
30 minutes) 
Miller, 2015 
45 
18-59 years 
Emergency 
Department, 
USA 
Randomized 
controlled double 
blind superiority trial: 
Ketamine vs Morphine 
Ketamine 
0.3 mg/kg 
 
Morphine 
0.1 mg/kg 
IV 
Ketamine did not 
produce a greater 
reduction in NRS scores 
compared with 
morphine. Time to 
achieve maximum 
reduction in NRS was 5 

26Nov2018 
33 
 
min for ketamine and 
100 min for morphine 
Tran, 2014 
308 
>30 
months 
Prehospital 
trauma, 
Vietnam 
Prospective, cluster 
randomized study: 
Ketamine vs Morphine 
Ketamine 
0.2-0.3 mg/kg 
 
Morphine 
10 mg (adults) 
5 mg (children) 
IV 
 
 
IM 
Ketamine provided an 
analgesic effect equal 
to that of morphine, no 
significant differences 
between the two 
groups. 
Beaudoin, 2014 
60 
18-65 years 
Emergency 
Department, 
USA 
Randomized 
controlled double 
blind trial:  
Morphine/NS 
Vs 
Morphine/Ketamine 1 
Vs 
Morphine/Ketamine 2 
Morphine 
0.5 mg/kg 
 
Ketamine 1 
0.15 mg/kg 
 
Ketamine 2 
0.3 mg/kg 
IV 
SPIDs (summed pain 
intensity difference) 
were higher for the 
ketamine groups. 
Patients in morphine 
group required rescue 
analgesia sooner than 
the ketamine groups. 
Patients with the 
higher ketamine dose 
sustained analgesic 
effect longer. 
Lester, 2010 
35 
21-57 years 
Emergency 
Department, 
USA 
Retrospective chart 
review: low dose 
ketamine as adjunct 
to opioids 
0.1-0.6 mg/kg 
(5-35 mg) 
IV (30) 
IM (5) 
Improvement in pain in 
54% of cases 
Johansson, 2009 
27 
Adults 
Prehospital 
trauma, 
Sweden 
Prospective cohort 
study: Morphine  
vs 
Morphine+Ketamine 
Morphine  
0.2 mg/kg 
 
Morphine 
(0.1 mg/kg) + 
Ketamine 
(0.2 mg/kg) 
IV 
Ketamine/morphine 
group had significant 
lower NRS scores than 
morphine alone 
(5.4±1.9 vs 3.1±1.4) 
Ahern, 2013 
30 
23-62 years 
Emergency 
Department, 
USA 
Prospective 
observational study: 
Hydromorphone + 
Ketamine 
Hydromorphone 
(0.5 mg) 
 
Ketamine (15 mg) 
IV 
Mean reduction in NRS 
score at 5 min was 6 
and at 15 min was 5. 
SPID at 30 min was 25 
and at 60 min was 41. 
(This protocol provided 
profound, rapid pain 
relief) 
Jennings, 2012 
135 
≥18 years 
Prehospital 
trauma, 
Australia 
Prospective, 
randomized controlled 
multicenter study: 
Morphine alone vs 
Morphine+Ketamine 
Morphine 5 mg 
every 5 min until 
pain free 
 
Morphine 5 mg + 
Ketamine 10 or 20 
mg then 10 mg 
every 3 min until 
pain free 
IV 
Morphine plus 
ketamine provides 
analgesia superior to 
that of morphine alone. 
(mean NRS reduction of 
5.6 vs 3.2). Ketamine 
had a quicker reduction 
of pain intensity. 
 
 
 
 

26Nov2018 
34 
 
 
 
APPENDIX B:  Clinical Studies of Sub-dissociative (Intranasal and Intravenous) and Dissociative 
(Intranasal) Dose Ketamine in Children 
 
Study 
N 
Ages 
Setting 
Design 
Doses 
Route 
Outcome 
Graudins, 2015 
 
Ketamine for 
analgesia (sub-
dissociative low 
dose) 
73 
3-13 years 
Emergency 
Department, 
Australia 
Double blind, 
randomized 
controlled trial: 
Fentanyl vs Ketamine 
Fentanyl 
1.5 mcg/kg 
 
Ketamine 
1 mg/kg 
IN 
Median reduction in 
VAS score at 30 
minutes for ketamine 
was 45 mm and for 
fentanyl was 40 mm 
(no significant 
difference between 
groups), which was 
maintained to 60 
minutes in both groups.  
Yeaman, 2013 
 
Ketamine for 
analgesia (sub-
dissociative low 
dose) 
28 
3-13 years 
Emergency 
Department, 
Australia 
Observational study:  
Ketamine 
Ketamine 
0.8-1.48 mg/kg 
IN 
IN ketamine provided 
adequate analgesia by 
30 minutes. Median 
VAS decreased from 
74.5 mm to 30 mm. 
Johansson, 
2013 
 
Ketamine for 
analgesia (sub-
dissociative low 
dose) 
9 
7-36 years 
Prehospital 
trauma, 
Sweden 
Case series: 
(S)-Ketamine 
Ketamine 
0.45 mg/kg-1.25 
mg/kg 
IN 
IN S-ketamine provided 
adequate analgesia. 
Median pain score 
decreased from 10 to 3 
(on a 10 point scale). 
Nielsen, 2013 
 
Ketamine for 
analgesia (sub-
dissociative low 
dose) 
50 
0.8-17 years 
Inpatient, 
Denmark 
Prospective 
nonrandomized trial:  
Sufentanil + Ketamine 
Sufentanil 
0.5 mcg.kg  
PLUS 
Ketamine 
0.5 mg/kg 
IN 
Provided rapid 
analgesia in 78% of 
patients (decreased 
pain score to ≤5 on 10 
pt scale). 
Tsze, 2012 
 
Ketamine for 
sedation 
(dissociative 
dosing) 
12 
1-7 years 
Emergency 
Department, 
USA 
Randomized, 
prospective double 
blind trial: 
Ketamine (3 doses) 
Ketamine #1 
3 mg/kg 
Ketamine #2 
6 mg/kg 
Ketamine #3 
9 mg/kg 
IN 
Significantly higher 
proportion of 
successful sedations 
with 9 mg/kg dose than 
the other two doses. 
Reid, 2011 
 
Ketamine for 
analgesia (sub-
dissociative low 
dose) 
1 
9 years 
Prehospital, 
Australia 
Case Report: 
Ketamine 
Ketamine 
0.5 mg/kg 
IN 
Provided rapid 
resolution of pain and 
effective anxiolysis 
Roelofse, 2004 
 
Ketamine for 
sedation 
50 
5-7 years 
Operating 
room (Dental), 
New Zealand 
Randomized double 
blind trial: 
Sufentanil/Midazolam 
Vs 
Ketamine/Midazolam 
Sufentanil  
20 mcg + 
Midazolam 
 0.3 mg/kg 
 
IN 
No significant 
difference in sedation 
and anxiety levels pre-
operatively or in 

26Nov2018 
35 
 
(dissociative 
dosing) 
Ketamine 
5 mg/kg + 
Midazolam  
0.3 mg/kg 
postoperative recovery 
between the 2 groups. 
Sufentanil group 
experienced less pain 
but not statistically 
significant (P > 0.05). 
Bahetwar, 2011 
 
Ketamine for 
sedation 
(dissociative 
dosing) 
45 
2-6 years 
Outpatient 
Dental Clinic, 
India 
Triple blind 
randomized trial:  
Midazolam vs 
Ketamine vs 
Midazolam+Ketamine 
Midazolam 
0.3 mg/kg 
 
Ketamine  
6 mg/kg 
 
Midazolam 
0.2 mg/kg plus 
Ketamine 
4 mg/kg 
IN 
Ketamine alone had the 
fastest onset of 
sedation. Sedation 
success rate with 
ketamine was 89%, 
midazolam was 69% 
and combination group 
was 84%.  
Khatavkar, 
2014 
 
Ketamine for 
sedation 
(dissociative 
dosing) 
60 
1-12 years 
Pre-operative, 
India 
Randomized single 
blind trial: 
Midazolam vs 
Midazolam+Ketamine 
Midazolam 
0.2 mg/kg 
 
Midazolam 
0.15 mg/kg + 
Ketamine 
1 mg/kg 
IN 
Sedation score, 
anxiolysis, reaction to 
IV insertion, face mask 
acceptance and 
emotional reaction 
were significantly 
better in 
Midazolam+Ketamine 
group 
Gyanesh, 2013 
 
Ketamine for 
sedation 
(dissociative 
dosing) 
150 
1-10 years 
Radiology 
(MRI),  
India 
Randomized double 
blind trial: 
Dexmedetomidine vs 
Ketamine vs 
Normal saline 
Dexmedetomidine 
1 mcg/kg 
 
Ketamine 
5 mg/kg 
 
Normal saline 
IN 
Dexmedetomidine and 
ketamine were equally 
effective as 
premedication. In 
90.4% of DXM patients 
and 82.7% of ketamine 
patients, 
anesthesiologists were 
satisfied with 
conditions for IV 
insertion. Total dose of 
propofol used was less 
in DXM and ketamine 
groups. 
Buonsenso, 
2014 
 
Ketamine for 
sedation 
(dissociative 
dosing) 
36 
< 14 years 
Inpatient,  
Italy 
Randomized double 
blind placebo 
controlled trial: 
Midazolam+Ketamine 
Vs 
Normal saline 
Midazolam 
0.5 mg/kg + 
Ketamine 2 mg/kg 
 
IN 
Significantly better 
MOPS (Modified 
Objective Pain Score) 
reduction in treatment 
group. Mean MOPS in 
treatment group was 
3.5 vs mean MOPS in 
placebo group was 7.2 
Kennedy, 1998 
 
Ketamine for 
sedation 
260 
5-15 years 
Emergency 
Department, 
USA 
Randomized 
nonblinded trial: 
Fentanyl+midazolam 
vs 
Ketamine+midazolam  
Midazolam  
0.5 mg/kg 
Fentanyl 
0.5 mcg/kg 
Ketamine 
IV 
Patients receiving 
ketamine had 
significant reduction in 
mean OSBD-R scores 
compared to those 

26Nov2018 
36 
 
(dissociative 
dosing) 
0.5 mg/kg 
receiving fentanyl 
during fracture 
reduction 
Elhakim, 2003 
 
Ketamine for 
analgesia (sub-
dissociative low 
dose) 
 
 
50 
5-12 years 
Preoperative, 
Egypt 
Randomized double 
blind placebo 
controlled trial: 
Ketamine + diclofenac 
+ fentanyl 
Vs 
Placebo + diclofenac + 
fentanyl 
 
Ketamine 
0.1 mg/kg 
 
Normal saline 
(same volume) 
 
Diclofenac 
2 mg/kg 
 
Fentanyl 
1 mcg/kg 
IM 
Ketamine group had 
significantly lower pain 
scores at rest and on 
swallowing 
postoperatively.  
Ketamine group 
required less 
postoperative 
analgesia. 
Finkel, 2007 
 
Ketamine for 
analgesia (sub-
dissociative low 
dose) 
11 
3-17 years 
Inpatient,  
USA 
Retrospective review: 
Ketamine infusion in 
addition to opioid 
analgesia 
Ketamine 
0.1-1 mg/kg/hr 
IV 
73% of patients 
experienced significant 
decrease in opioid 
requirements after 
ketamine initiated 
White, 2011 
 
Ketamine for 
analgesia (sub-
dissociative low 
dose) 
100 
3-14 years 
Inpatient, 
United 
Kingdom 
Retrospective review: 
Morphine PCA  
Vs 
Morphine+Ketamine 
PCA 
Morphine PCA  
1 mg/kg made up 
to 50 mL with 
saline 
 
Morphine 1 
mg/kg PLUS 
Ketamine 1 mg/kg 
PCA made up to 
50 mL with saline 
 
(bolus 20-40 
mcg/kg, infusion 
0-40 mcg/kg/hr, 
max 4h dose of 
400 mcg/kg) 
IV 
Addition of ketamine to 
the morphine PCA is 
associated with 
reduced morphine 
consumption and 
improved pain scores. 
Taylor, 2014 
 
Ketamine for 
analgesia (sub-
dissociative low 
dose) 
14 
1 month-23 
years 
Inpatient and 
Outpatient, 
USA 
Retrospective case 
review: 
Ketamine PCA in 
addition to prolonged 
opioid use 
Ketamine 
0.014-0.308 
mg/kg/hr with 
demand dose of 
0.03/0.5 mg/kg 
every 10-60 min 
IV 
All patients with opioid 
refractory neuropathic 
pain had improved pain 
with the addition of 
ketamine to pain 
regimen 
White, 2006 
 
Ketamine for 
analgesia (sub-
dissociative low 
dose) 
3 
12 years 
Inpatient, 
United 
Kingdom 
Case series of patients 
with toxic megacolon: 
Ketamine PCA 
Ketamine PCA 
2 mg/kg made up 
to 50 mL with 5% 
dextrose (infusion 
0-40 mcg/kg/hr, 
bolus 20-40 
mcg/kg, lockout 
period 10-30 min 
IV 
Improved pain scores in 
all patients.  
Safe and effective use 
of ketamine infusion  
White, 2007 
 
1 
9 years 
Inpatient, 
Canada 
Case report: 
Morphine 
40 mcg/kg/hr 
IV 
Long term ketamine 
infusion (37 days) 

26Nov2018 
37 
 
Ketamine for 
analgesia (sub-
dissociative low 
dose) 
Ketamine infusion in 
addition to Morphine 
infusion 
 
Ketamine 
80-200 mcg/kg/hr  
provided safe and 
effective analgesia 
Dal, 2007 
 
Ketamine for 
analgesia (sub-
dissociative low 
dose) 
90 
2-12 years 
Perioperative, 
Turkey 
Randomized placebo 
controlled trial: 
Saline 
 vs  
IV Ketamine bolus  
vs 
Peritonsillar ketamine 
infiltration 
Saline 2 mL 
 
Ketamine bolus 
0.5 mg/kg 
 
Ketamine 
infiltration 
0.5 mg/kg 
IV  
 
 
Ketamine groups had 
significant lower 
observational pain 
scores in hospital and 
at home than saline 
group. No significant 
difference in pain score 
between ketamine 
groups. Saline group 
had significantly shorter 
time to first rescue 
analgesia. 
Bredmose, 
2009 
 
Ketamine for 
analgesia and 
sedation 
164 
< 16 years 
Prehospital 
trauma, 
United 
Kingdom 
Retrospective 
database review: 
Ketamine use 
(68% of these patients 
also received 
Midazolam) 
Ketamine  
0.1-5.8 mg/kg 
(mean=1.0 mg/kg) 
 
Midazolam 
0.1-0.5 mg/kg 
(mean=0.1 mg/kg) 
IV/IM 
Ketamine provided 
adequate analgesia and 
appropriate sedation 
without major side 
effects 
Zempsky, 2010 
 
Ketamine for 
analgesia (sub-
dissociative low 
dose) 
5 
12-18 years 
Inpatient,  
USA 
Case series of sickle 
cell disease patients: 
Ketamine infusion 
Ketamine 
0.1-0.2 mg/kg/hr 
IV 
2 of 5 patients achieved 
adequate pain control. 
1 patient used 
significantly less 
opioids.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

26Nov2018 
38 
 
APPENDIX C:  Study Flow Diagram 
Triage RN completes 
assessment, hx, and VS
Suspected acute deformity 
AND pt in pain and/or 
decrease pulses or 
sensation in injured ext?
RN continues normal 
triage process
Triage RN tells Statline to 
page Ortho Eval
Pt taken to STS or 
designated area
Attending and/or fellow, 
resident, RN, PCA, medic, 
childlife respond
· MD does exam
· PCA or medic puts on 
monitors
· RN obtains pain score
MD determines pt needs 
xray and pain medication
Study staff responds to 
STS or designated area
Study staff informs parent 
of study & obtains 
consent “if qualify”
Study staff checks with 
MD if pt meets criteria
Pt gets standard ortho 
eval care
Study staff tells MD and 
RN pt enrolled
RN rechecks if allergy to 
fentanyl or ketamine
MD puts in order for xrays 
and study drug
 (EPIC order set)
Study staff observes as RN 
gets numbered syringe 
from designated pyxis and 
documents syringe 
number
RN and study staff ensure 
full set VS including 
baseline EtCO2
RN gives study drug, study 
staff marks time zero
Pt observed in STS or 
designated area on 
monitors for 15 mins
Study staff does 
pain and sedation 
score at T15
RN does VS at T15
Pt taken to radiology for 
xrays
Ortho eval RN report to 
pt’s RN and pt taken to 
room
Study staff does 
pain and sedation 
score at T30
Pt’s 1° RN does VS 
at T30
Study staff does 
pain and sedation 
score at T60
Pt’s 1° RN does VS 
at T60
Yes
No
No
Yes
 

26Nov2018 
39 
 
APPENDIX D:  Current Orthopedic Evaluation Flow Diagram 
 
 
 
 
Triage RN completes assessment, 
history, and vital signs 
Is triage 5 or 6 open?   
RN continues normal triage 
process and offers pain 
medications if indicated 
YES 
Does the patient have a suspected 
acute deformity AND is the patient 
experiencing pain and/or decreased 
pulses or sensation in the injured 
extremity?   
NO 
Triage RN notifies STATLINE to 
page an Ortho Eval   
NO 
Patient is taken to STS or 
an exam room and an 
Ortho eval is called  
RN moves patient 
to triage 5 or 6 
YES 
Patient taken to x-ray and 
trauma RN gives hand-off to 
the primary care nurse in the 
team 
Medication administered 
and vital signs obtained at 
least 10 minutes after the 
dose given  
SRU or other available  
RN performs an independent 
double check of the medication 
Attending, fellow (if 
present), resident, trauma 
core RN, PCA, medic, SRU 
trauma RN, and child life 
respond to the page 
MD performs a quick exam 
and places orders for x-ray 
and pain medication if 
indicated.  ED charting 
occurs in EPIC.  Resus 
Narrator is not used   
Patient taken to exam room 
after x-ray   
Refer to P&T policy: 
Pain management 
and analgesia   

26Nov2018 
40 
 
 
APPENDIX E:  Study Procedures 
 
Study Procedure 
Who? 
How much time? 
Screening for eligibility 
Research Study Staff 
5 minutes 
Obtain baseline 
measurements (vital signs, 
EtCO2, weight, VAS, UMSS) 
Nursing/Research study staff 
3 minutes 
Order, dispense and 
administer study medication 
Patient’s physician/Nursing 
5 minutes 
Obtain measurements at 15 
minutes after medication 
Nursing/Research study staff 
1 minute 
Obtain measurements at 30 
minutes after medication 
Nursing/Research study staff 
1 minute 
Obtain measurements at 60 
minutes after medication 
Nursing/Research study staff 
1 minute 
Document adverse events 
Research study staff 
Throughout ED visit 
Phone Follow up call 
Research study staff 
10 minutes 
 
 
 
APPENDIX F: Drug Information and Package Inserts 
 
Ketamine Human Pharmacokinetics 
▪ 
Nielsen, et al in 2014 investigated a pediatric formulation of intranasal sufentanil 0.5 mcg/kg 
and ketamine 0.5 mg/kg for procedural pain and determined the bioavailability of ketamine was 
35.8%.  Maximum plasma concentration (Cmax) of ketamine was 0.102 mg/L (CV 10.8%) and 
Tmax was 8.5 min (CV 17.3%). 
 
▪ 
Malinovsky, et al in 1996 determined that after intranasal ketamine in children 10-30 kg, 2-9 
years of age, mean plasma concentrations after 3 mg/kg peaked at 496 ng/mL at 20 minutes and 
after 9 mg/kg peaked at 2104 ng/mL within 21 minutes.  Plasma concentrations of norketamine 
(the predominate metabolite), peaked at ~120 minutes after nasal ketamine. Calculated 
bioavailability from nasal administration was 0.5.  The authors concluded that nasal 
administration of low doses of ketamine produced plasma concentrations associated with 
analgesia, but using high doses produced high plasma concentrations similar to those that 
induce anesthesia. 
Dosing: 
Children:  
IM: 3 to 7 mg/kg  
IV: Range: 0.5 to 2 mg/kg, use smaller doses (0.5 to 1 mg/kg) for sedation for minor procedures; 
usual induction dosage: 1 to 2 mg/kg  
Adults:  
IM: 3 to 8 mg/kg  
IV: Range: 1 to 4.5 mg/kg; usual induction dosage: 1 to 2 mg/kg  

26Nov2018 
41 
 
 
 
Fentanyl Human Pharmacokinetics 
▪ 
Onset of action: Analgesia: Intranasal: Children 3-12 years: 5-10 minutes (Borland, 2002) 
▪ 
Half-life:  Nasal spray: 15-25 hours (based on a multiple-dose pharmacokinetic study when doses 
are administered in the same nostril and separated by a 1-, 2-, or 4-hour time lapse) 
▪ 
Time to peak serum concentration: Nasal spray: Median: 15-21 minutes 
Dosing: 
Infants and Children: 
Acute pain: IV: Opioid-naive:  
Infants: Limited data available: Initial: 1-2 mcg/kg/dose; may repeat at 2-4 hour intervals; 
in opioid-tolerant or younger infants, titration to higher doses may be required (up to 4 
mcg/kg/dose) (Hegenbarth, 2008; Nelson, 1996; WHO, 2012) 
Children: Limited data available in children <2 years: Initial: 1-2 mcg/kg/dose; may repeat 
at 30- to 60-minute intervals; in opioid-tolerant children, titration to higher doses may be 
required (Hegenbarth, 2008; Nelson, 1996; WHO, 2012) 
Analgesia for minor procedures/sedation: Limited data available in children <2 years: 
IM, IV: 1-2 mcg/kg/dose; administer 3 minutes before the procedure; maximum dose: 50 
mcg; may repeat 1/2 original dose every 3-5 minutes if necessary; titrate to effect 
(Cramton, 2012; Krauss, 2006; Zeltzer, 1990) 
Intranasal (using parenteral preparation): Limited data available: Infants and Children ≥10 
kg: 1.5 mcg/kg once (maximum: 100 mcg/dose); reported range: 1-2 mcg/kg; some 
studies that used an initial dose of 1.5 mcg/kg allowed for additional incremental doses 
of 0.3-0.5 mcg/kg to be administered every 5 minutes, not to exceed a total dose of 3 
mcg/kg depending on pain type and severity (Borland, 2002; Borland, 2005; Borland, 
2007; Chung, 2010; Cole, 2009; Crellin, 2010; Herd, 2009; Manjushree, 2002; Saunders, 
2010) 
Adolescents and Adults: 
Analgesia for minor procedures/sedation:  
IV: 0.5-1 mcg/kg/dose; may repeat after 30-60 minutes; or 25-50 mcg, repeat full dose in 
5 minutes if needed, may repeat 4-5 times with 25 mcg at 5-minute intervals if needed. 
 
 
Manufacturer Information 
 
Ketamine Hydrochloride Injection, USP, CII (50 mg/mL):   Mylan Institutional LLC, Rockford, IL 
 
Fentanyl Citrate Injection, USP, CII (50 mcg/mL):  West-Ward Pharmaceuticals, Eatontown, New Jersey 
 
LMA MAD Nasal Intranasal Mucosal Atomization Device:  Wolfe-Tory Medical, Inc. Salt Lake City, Utah 
84107 
 
Note: Please see Ketamine and Fentanyl package inserts for further information. 
 
 
 
 

26Nov2018 
42 
 
 
APPENDIX G: Normal Ranges for Study Vital Signs 
 
NORMAL VALUES (notify MD if outside range) 
HEART RATE (per minute) 
Age 
Awake Rate 
8-10 years 
60 to 150 
> 10 years 
45 to 140 
 
RESPIRATORY RATE (breaths/minute) 
Age 
Rate 
8-10 years 
10 to 30 
> 10 years 
10 to 30 
 
BLOOD PRESSURE 
Age 
Systolic Pressure 
(top) 
Diastolic Pressure 
(bottom) 
8-9 years 
80-160 
40-80 
10-11 years 
80-160 
50-80 
> 11 years 
90-160 
50-80 
 
OXYGEN SATURATION should always be greater than 90 % 
END TIDAL should not decrease by more than 10 from baseline  
VAS should not increase by more than 15 from previous assessment 
UMSS should be 2 or less