Conditions: Headache Tumor Seizure Disorder Neurofibromatoses Hydrocephalus Abdominal Neoplasm Spine Deformity
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 40
Healthy volunteers: no

Brief summary:
The purpose of this study is to compare the results of combining two anesthetic medications (dexmedetomidine and propofol) in low doses with a standard dose of a single drug that is commonly used to provide sedation/anesthesia for MRI studies in young children (propofol).

The drugs used for the MRI scan in this study will be chosen randomly. Half the patients will receive small doses of propofol and dexmedetomidine. The other half will receive propofol administered constantly throughout the scan. Other drugs that may be used include sevoflurane and nitrous oxide at the start of the sedation (for placing an intravenous), lidocaine (to reduce the pain of propofol injection) and glycopyrrolate (to prevent the heart rate from decreasing too low. The investigators will record 5 additional blood pressures and heart rates. If additional medications are required to complete the scan, the investigators will administer whatever is necessary. At the end of the study, the investigators will have an observer record the time it takes for participants to spontaneously open eyes , to be able to drink liquids and/or eat and to behave as before the study. Also, it is very important that the investigators find out from participants about changes in behavior, or if eating or sleeping habits were unusual following completion of the study. For that reason, the investigators will call participants in a day or so following the MRI scan.

The investigators expect to recruit 40 children between the ages of 12 and 72 months for the study and hope to have the study completed in December 2018.

Detailed description:
The purpose of this study is to compare the results of combining two anesthetic medications (dexmedetomidine and propofol) in low doses with a standard dose of a single drug that is commonly used to provide sedation/anesthesia for MRI studies in young children (propofol).

Recent studies and the FDA have raised concerns that anesthesia for longer than three hours may have effects on behavior and learning. Although investigators do not know if these effects are caused by drugs or the medical condition a child is being treated for, in December 2016, the FDA published the information below regarding anesthesia for children:

General anesthetic and sedation drugs are used to put people into a deep sleep so they do not feel pain during surgery or procedures.

These drugs are usually injected into a vein or breathed in through a mask. General anesthetic and sedation drugs are widely used to ensure the health, safety, and comfort of children and adults undergoing surgery or other procedures.

Recent studies in children suggest that a single, relatively short exposure to general anesthetic and sedation drugs in infants or toddlers is unlikely to have negative effects on behavior or learning. More research is still needed to fully understand how anesthetics might affect brain development, especially longer or repeated exposures and in more vulnerable children. Anesthetic and sedation drugs are necessary for infants, children, and pregnant women who require surgery or other painful and stressful procedures. https://www.fda.gov/Drugs/DrugSafety/ucm532356.htm Research in neonatal and infant animals has demonstrated that sedative and anesthetic agents, like propofol, produce adverse effects on brain development, including loss of brain cells resulting in long-term, possibly permanent changes in learning and behavior. These adverse effects appear to occur mostly after prolonged periods of sedation or anesthesia (generally greater than 3 hours) and when brain development is occurring at a rapid rate (which roughly occurs in children under 3 years of age). It is not known if similar adverse effects occur in humans. Study participants should be advised that the drugs used to accomplish the procedure may have the potential to increase the loss of nerve cells in the developing brain of young child and that the clinical significance of any such changes is not known. There are some animal studies that suggests dexmedetomidine may be better for a growing infant's brain. However, the effects of dexmedetomidine alone or in combination with propofol on the developing brain have not been thoroughly tested to date." The drugs used for the MRI scan in this study will be chosen randomly. Half the patients will receive small doses of propofol and dexmedetomidine. The other half will receive propofol administered constantly throughout the scan. Other drugs that may be used include sevoflurane and nitrous oxide at the start of the sedation (for placing an intravenous), lidocaine (to reduce the pain of propofol injection) and glycopyrrolate (to prevent the heart rate from decreasing too low. Investigators will record 5 additional blood pressures and heart rates. If additional medications are required to complete the scan, investigators will administer whatever is necessary. At the end of the study, an observer will record the time it takes for spontaneous eye opening, to be able to drink liquids and/or eat and to behave as before the study. Also, it is very important that investigators learn in the following day or two how the participant behaved at home; whether eating, behavior and sleeping were unusual. For that reason, the investigator will call the participant a day or so following the MRI scan.

The investigators expect to recruit 70 children between the ages of 12 and 72 months for the study and hope to have the study completed in 2018.

Arms:
arm 1: Each patient will receive 1 mg/kg lidocaine followed by 2 mg/kg propofol IV once prior to continuous propofol infusion for MRI sedation at 200 mcg/kg/min. Dose will be increased by 50 mcg/kg/min up to 300 mcg/kg/min for movement and decreased to 150 mcg/kg/min if no movement after 30 minutes. Additional 1 mg/kg propofol bolus administered at time of each movement. Study to be terminated if movement persists despite above interventions. arm 2: Each patient will receive: 1 mg/kg lidocaine, 2 mg/kg propofol, 4 mcg/kg glycopyrrolate and single dose dexmedetomidine administered prior to scan. Dexmedetomidine dose is dependent on expected duration of scan and will be equal to 1 mcg/kg/hour x duration of scan in hours. 1 mg/kg propofol will be administered for movement up to 2 times. For continued movement after that, begin propofol infusion at 150 mcg/kg/min. Study to be terminated if movement persists despite above interventions.

Interventions: intervention 1: propofol intervention 2: Dexmedetomidine intervention 3: Glycopyrrolate intervention 4: Lidocaine 1% Injectable Solution intervention 5: Nitrous Oxide intervention 6: Sevoflurane
Intervention descriptions: intervention 1: propofol 2 mg/kg at start of procedure; 2 mg/kg for movement, 150-300 mcg/kg/minute propofol infusion if movement persists intervention 2: single dose dexmedetomidine administered at start of sedation in the propofol-dexmedetomidine group. Dosing is based upon anticipated duration of scan from 30 - 75 minutes and will range from 0.5 mic/kg to 1.25 mcg/kg intervention 3: 4 mcg/kg glycopyrrolate will be administered at the start of sedation in the propofol-dexmedetomidine group intervention 4: 1 mg/kg intravenous administration prior to propofol administration intervention 5: Inhalation of nitrous oxide may be used for IV placement intervention 6: Inhalation of sevoflurane may be used for IV placement

Protocol document:
Prot_SAP_001.pdf: 
DATE: October 19, 2019 
OFFICIAL TITLE:  
An observer-blinded randomized study of propofol infusion vs bolus dexmedetomidine and 
propofol sedation for pediatric magnetic resonance imaging 
NCT03513757 


TITLE: An observer-blinded randomized study of propofol infusion vs bolus 
dexmedetomidine and propofol sedation for pediatric magnetic resonance imaging 
PRINCIPAL INVESTIGATOR:  Susan P. Taylor, MD, MPH 
PURPOSE OF THE STUDY 
This study is designed to compare the efficacy of low-dose dexmedetomidine and propofol with 
a continuous2infusion of propofol for outpatient magnetic resonance imaging scans performed 
on children ages 12 months to 60 months. The primary outcome to be measured is the 
efficiency of the techniques utilized as measured by time required to establish adequate 
conditions for scanning, time to eye opening, spontaneous movement and readiness for 
discharge from the department to home or clinic. Secondary outcomes include frequency of 
airway obstruction and oxygen desaturation, and hemodynamic changes associated with 
initiation and maintenance of sedation. Any medications required for completion of the study 
will be compared between the groups. In addition, the total drug administered will be 
calculated. Data regarding parental satisfaction and post-procedural behavioral and sleep 
disturbances will be collected. 
HYPOTHESIS / SPECIFIC AIMS 
We hypothesize that low-dose dexmedetomidine and propofol in combination provide 
satisfactory conditions for diagnostic MRI imaging with reduced time to arousal and readiness 
for discharge when compared to continuous infusion of propofol. 
BACKGROUND, SIGNIFICANCE, AND RATIONALE 
Magnetic resonance imaging is utilized with increasing frequency in the diagnosis and 
management of pediatric disease. Unlike other imaging techniques, these studies require a 
significant amount of time for completion, ranging from thirty minutes to several hours. Most 
young children are incapable of remaining immobile for the duration of the scan and require 
sedation and/or anesthesia for a successful study. A number of sedation models have been 
described in the literature and are reviewed here. The use of barbiturates, chloral hydrate, 
propofol, dexmedetomidine, ketamine, benzodiazepines, opioids and inhalational anesthetic 
agents will be reviewed. 
In December 2016, the FDA announced new warnings regarding the use of general anesthetics 
and sedation drugs in young children. (https://www.fda.gov/Drugs/DrugSafety/
ucm532356.htm) which include all of the drugs listed with the exception of dexmedetomidine. 
Published studies in pregnant animals and young animals have shown the use of general 
anesthetic and sedation drugs for more than 3 hours caused widespread loss of nerve cells in the 
brain. Studies in young animals suggest these changes result in long-term effects on the animals’ 
behavior or learning (see Data Summary).1-20 Studies have also been conducted in children,21-43 some 
of which support findings from previous animal studies, particularly after repeated or prolonged 
exposure to these drugs early in life. All the studies in children had limitations, and it is unclear 
whether any negative effects seen in children’s learning or behavior were due to the drugs or to 
other factors, such as the underlying medical condition that led to the need for the surgery or 
procedure. 


In response, Dean Andropoulos observed that “There are no alternatives to these general 
anesthetic drugs for children younger than 3 years of age. . . . The only other drugs in clinical 
use for sedation and anesthesia that do not cause neurodegeneration in animal models are 
dexmedetomidine and opioids, but these agents are not sufficient for general anesthesia and do 
not represent a feasible option by themselves.”1 Sedation failures are common when performed 
by sedation teams or radiologist supervised nurses, necessitating general anesthesia to complete 
the studies at a later date. Prolonged sedation and behavioral issues following the scan maybe 
problematic.  
The safety of propofol administered by intensivists and emergency medicine physicians for MRI 
procedures is well documented for patients as young as one month of age both in-hospital and at 
free-standing imaging centers.2,3 Total propofol doses published in the literature range from 
approximately 7 mg/kg to 12 mg/kg. Mallory et al4 reviewed 7079 sedations comparing propofol 
to pentobarbital and found that although apnea occurred more often in patients receiving 
propofol, the rate of airway complications was not significantly different. Increased sedation 
failure, unplanned admission, prolonged recovery and vomiting were more common among 
patients receiving pentobarbital. 
Kiera Mason et al5 demonstrated the safety of high dose dexmedetomidine administered by non-
anesthesiologists despite the occurrence of hypertension, hypotension and bradycardia. Typical 
dosing strategies were 2-3 mcg/kg load followed by 1-2 mcg/kg/hour maintenance. Siddappa et 
al6 found that despite its excellent safety profile, recovery is prolonged, and additional 
medications, are required to maintain immobility in a significant number of patients. A recent 
article by Boriosi7 suggests that a combination of propofol and dexmedetomidine results in a 
reduced number of adverse events, particularly upper airway obstruction and oxygen 
desaturations when compared to propofol alone. All patients in this cited study received a single 
dose of oral midazolam 0.3-0.5 mg/kg prior to PIV placement. In the prop-dex combination 
group the mean dose of propofol administered was 9 mg/kg compared to 12 mg/kg for propofol 
alone. Furthermore, animal studies suggest that dexmedetomidine may actually have 
neuroprotective effects by reducing cerebral ischemia-induced oxidative stress and apoptosis.8 
With concern for delayed awakening following diagnostic imaging procedures, we began to 
evaluate the effectiveness of low-dose polypharmacy to reduce recovery time and adverse 
behavioral changes. In a QI study conducted in 2014, we observed that for procedures lasting 
less than one hour, 1 mcg/kg/hr dexmedetomidine in combination with 1-2 mg/kg propofol at 
the onset of sedation is effective for successful diagnostic imaging.  In addition to the rapid 
arousal and discharge, the total drug requirement with this strategy is markedly less than that 
published in the literature for propofol alone.  
We aim to conduct a randomized, observer-blinded study to compare the low-dose sedation 
strategy now commonly used by the anesthesia providers at Children’s Hospital of Wisconsin 
with propofol alone for pediatric patients undergoing imaging procedures. Outcome measures in 
addition to the improved efficiency and time to discharge will include total drug dose 
administered, frequency of airway obstruction and oxygen desaturation, and hemodynamic 
changes associated with initiation and maintenance of sedation. Any additional medications 
required for completion of the study will be compared between the groups. 


DESIGN AND METHODS 
Forty outpatients scheduled for elective MRI evaluation will be randomized to receive either 
propofol (Group Prop) as a continuous infusion or a low-dose propofol and dexmedetomidine 
combination (Group PropDex) to establish adequate sedation. All out-patients ages 12 months to 
72 months will be eligible for enrollment. Exclusion criteria are inpatient status, airway 
abnormalities, allergy to any study medications, eggs and soy, and mitochondrial disorders. All 
subjects with any cardiac disease or history of cardiac arrhythmias will be excluded.  
Patients will be randomized to receive either PropDex or Prop by the research pharmacist 
utilizing Research Randomizer an online computer-based random number generator. An 
investigator will be blinded to the drugs selected. He/She will observe the airway manipulations 
and obtain hemodynamic data during the first ten minutes of the procedure. The observer will be 
blinded to the drugs administered. 
ASA guidelines regarding procedural sedation will be followed. All patients will be screened for 
MRI safety, and a focused history and physical examination including neurological, airway, head 
and neck, respiratory and cardiovascular systems will be obtained on the day of the procedure. 
All patients will receive an intravenous infusion of lactated Ringer’s or a dextrose containing 
solution for replacement and maintenance fluids as determined by the anesthesia provider. 
Patients will be anesthetized with sevoflurane and nitrous oxide if necessary for intravenous 
access at the discretion of the anesthesiologist. Otherwise, j-tip lidocaine will be utilized to 
anesthetize the insertion site. Parental presence will be permitted during induction if judged to be 
in the best interest of the patient. Midazolam syrup 0.3 mg/kg may be administered at the 
discretion of the treating anesthesiologist. This is not a part of the study protocol. 
MONITORING 
Monitoring includes videocamera, direct visual observation, electrocardiogram, blood pressure, 
heart rate, respiratory rate and end-tidal CO2
The treating anesthesiologist will monitor the patient during the initiation of sedation. Once a 
stable depth of moderate sedation (Ramsey 3) is established the sedation nurse will monitor and 
record HR, O2 sat, end tidal CO2. Initial blood pressure measurements will be obtained at time 
0, 2, 4, 6 and 10 minutes following initial administration of study drugs.  Blood pressure will 
then be obtained every 5 minutes throughout the procedure for all patients in the propofol 
infusion arm and for any PropDex patients who require infusion of propofol to complete the 
imaging study. Patients in the PropDex group will have blood pressure measurements obtained 
every fifteen minutes after the first 10 minutes except when additional drugs are administered or 
if the blood pressure is not stable and is decreasing at which time the monitoring interval will be 
every five minutes or more frequently until stable blood pressures are recorded. The blood 
pressure monitor interval will be in compliance with the current clinical standard of care at 
Children’s Hospital of Wisconsin and adjusted to comply with standard care at the discretion of 
the anesthesiologist caring for the patient. 


STUDY PROTOCOL 
 
Group Prop 
• Peripheral intravenous (IV) placed following j-tip lidocaine local anesthesia or inhalation 
induction with sevoflurane and nitrous oxide 
• Lactated Ringers or other intravenous solution, type and volume infused to be determined 
by anesthesiologist providing care 
• Loading dose propofol 2 mg/kg after administration of 1 mg/kg lidocaine IV 
 
• 0.25 ml/kg/hr normal saline infused over 5 minutes; (see table below) This saline 
administration is the placebo/replacement for the dexmedetomidine administered to 
Group PropDex 
•  
Scan Duration 
30 
45 
60 
75 
Saline dose 
0.125 ml/kg 
0.2 ml/kg 
0.25 ml/kg 
0.3 ml/kg 
Duration of 
saline 
administration 
5 minutes 
5 minutes 
5 minutes 
5 minutes 
Propofol loading 
dose 
2 mg/kg 
2 mg/kg 
2 mg/kg 
2 mg/kg 
Propofol infusion 200mcg/kg/min 200 mcg/kg/min 200mcg/kg/min 200mcg/kg/min 
• 
propofol infusion rate 200 µ/kg/min for 30 minutes, then decreased to 150 mcg/kg/min if no 
movement 
• 
administer 1 mg/kg propofol and increase propofol infusion by 50 mcg/kg/min for movement 
up to 300 /kg/min 
 
Group PropDex 
• Peripheral intravenous (IV) placed following j-tip lidocaine local anesthesia or inhalation 
induction with sevoflurane and nitrous oxide 
• Lactated Ringers volume infused to be determined by anesthesiologist providing care 
• Loading dose propofol 2 mg/kg after administration of 1 mg/kg lidocaine IV 
Scan Duration 
30 
45 
60 
75 
Dexmedetomine dose 
(4 /ml soln) 
0.5 mcg/kg 
 
0.7 mcg/kg 
1 mcg/kg 
1.25 mcg/kg 
Glycopyrrolate dose 
4 mcg/kg 
4 mcg/kg 
4 mcg/kg 
4 mcg/kg 
Duration of 
administration loading 
dose 
5 minutes 
5 minutes 
5 minutes 
5 minutes 
Propofol loading dose 
2 mg/kg 
2 mg/kg 
2 mg/kg 
2 mg/kg 
Propofol infusion 
None 
None 
None 
None 
Dexmedetomidine 
infusion 
None 
None 
None 
None 
• 
propofol 1 mg/kg for patient movement or administration of contrast 
• 
begin propofol infusion at 150 mcg/kg/min if second bolus propofol required to complete 
study 


 
At the completion of the MRI scan patients will be transported to MRI recovery area for 
continued monitoring until awake, are taking appropriate oral or enteral feeds and baseline 
neurological function is observed. 
STATISTICAL ANALYSIS 
Sample size was estimated using previously reported discharge times following propofol 
sedation for MRI procedures and a thirty percent reduction in discharge times when low-dose 
dexmedetomidine and propofol are administered. Wu9 reported a recovery time of 35.7  10.8 
following propofol infusion at 200 µkg-1min-1, resulting in a standardized difference of 0.97. 
Sample size is calculated to be 40 patients when a power of 0.80 and a significance level of 0.05 
is applied.  
Demographic, time, and physiologic measures are summarized by count and percent, mean and 
standard deviation, or median and interquartile range if measures fail skewness or kurtosis tests 
of normality. Baseline group characteristics are compared by standardized differences, and 
measures were compared by Fisher exact, two-sample t, or Kruskal-Wallis equality of rank tests. 
Times to recovery measures are compared by log-rank tests with Kaplan-Meier graphical display 
of decay function. Phases of case are grouped into discrete epochs, during which physiologic 
measures are electronically collected at 2-5 minutes intervals. Repeated physiologic measures are 
analyzed using maximum likelihood cross-sectional panel regression on independent variables of 
treatment group and epoch, with variance adjusted for repeated measures within subject, and 
identity or log-link functions to satisfy normality criteria. Scheffe’s adjustment for multiple 
contrasts are applied to tests of differences between groups across epochs and within groups 
from baseline. Significance for all tests will be  p<0.05. Analysis will be performed with Stata 
(StataCorp. 2017. Stata Statistical Software: Release 15. College Station, TX: StataCorp LLC).\ 
 
DRUGS OR PROCEDURES  
 
Medications to be used in this study: 
 
1. Propofol is approved for use as an anesthetic agent in patients 2 months of age and older. 
2. Glycopyrrolate is recommended by the FDA to be used with propofol when other agents 
or surgical stimulation may increase the risk of bradycardia. (Propofol package insert) 
3. Lidocaine is approved for use in children. The FDA recommends administration of 
lidocaine immediately prior to propofol injection to reduce the pain associated with 
injection of the drug. (Propofol package insert) 
4. Sevoflurane is approved for use in all pediatric patients. 
5. Nitrous oxide is approved for use in all pediatric patients. 
6. Dexmedetomidine is not approved for use in children. However, the drug is used 
routinely for sedation and as an adjunct to general anesthesia at CHW and other 
institutions caring for children. A detailed review of safety data and the justification for 
Off-Label and Investigational Use Of Marketed Drugs, Biologics, and Medical Devices is 
presented in Appendix A 
 


RISK CATEGORY: 
 
(2) 45 CFR 46.405 - Research involving greater than minimal risk but presenting the 
prospect of direct benefit to the individual child subjects involved in the research. 
 
 
 
RISKS AND THE PRECAUTIONS WHICH WILL BE TAKEN TO MINIMIZE RISK 
EXPOSURE 
 
All anesthetic procedures involve risk to the patient. The goal of anesthesia is to produce a 
loss of consciousness and awareness of sensation. Changes in breathing, even apnea, and 
alterations in hemodynamics are expected consequences of anesthesia. The drugs and 
procedures in this study are known to be associated with the following risks: 
 
Anesthetic Risks in this research study 
Peripheral IV 
Pain  
Very likely 
Not serious 
 
Infection 
Very unlikely 
May be serious 
 
Bruising 
Likely, if IV is 
difficult 
Not serious 
 
Injection outside of the 
vein 
unlikely 
Not serious with drugs 
used in this study 
Medications 
 
 
 
   Propofol 
Pain with injection 
Very likely 
Not serious 
 
Low blood pressure 
Very likely 
Not serious; usually still 
normal 
 
Decreased breathing 
Likely 
Not serious if treated 
immediately 
 
Allergic reaction 
Very unlikely 
May be very serious 
 
Unusual movements 
during anesthesia 
Very unlikely 
Not serious; does not 
continue after the drug is 
stopped 
 
Continued sleepiness 
Very likely 
Not serious. Limit 
activity after study 
Dexmedetomidine Low heart rate  
Very likely 
Not serious 
 
High blood pressure 
Likely if given too 
fast 
May be serious 
 
Low blood pressure 
Very likely 
Not serious; usually still 
“normal” 
 
Continued sleepiness 
Very likely at 
higher doses 
Not serious; 
Lidocaine 
Reactions rare when given as a single dose; most side effects are 
overdoses 
 
Ringing in ears 
unlikely 
Not serious 
 
Metallic taste 
unlikely 
Not serious 
 
Seizure 
Very unlikely 
May be serious 
 
Heart rhythm changes 
Extremely unlikely May be very serious 


Glycopyrrolate 
Most side effects are seen with repeated higher doses 
 
Dry mouth 
Likely 
Not serious 
 
Fast heart rate 
Likely 
Not serious 
 
High or low blood 
pressure 
Very unlikely 
May be serious 
Inhalation induction of anesthesia for peripheral IV placement 
Sevoflurane 
Nausea and vomiting 
Unlikely in 
children younger 
than 3 years 
May be serious if severe 
and unable to drink 
liquids 
Nausea and vomiting 
More common in 
older children; 
unlikely following 
short exposure 
May be serious if severe 
and unable to drink 
liquids 
Cough 
Somewhat likely 
May be serious 
Fast heart rate 
Likely 
Not serious 
Slow or difficult 
breathing 
Likely 
May be serious; an 
anesthesia provider will 
help your child breathe to 
prevent serious side 
effects 
Agitation after 
procedure 
Likely 
Not serious, but may be 
unpleasant for caregivers; 
the child is not aware 
when this happens 
Nitrous oxide 
Nausea and vomiting 
Unlikely in young 
children 
May be serious (unlikely) 
when unable to drink 
liquids 
MRI scan 
Allergy to contrast dye 
Very unlikely 
May be very serious 
    
Skin burn 
Very unlikely 
Somewhat serious 
 
Loud noise, hearing 
damage 
Extremely unlikely Not serious 
 
Rescue Maneuvers for Individual Anesthetic Risks 
 
The MRI department consists of 3 magnets with a central work area. Each machine has a 
dedicated anesthesia machine, ventilator, suction equipment, and full non-invasive monitoring 
capabilities. Additional airway equipment, including ambu bag, intubating equipment and 
endotracheal tubes are located in an anesthesia cart stationed in the control room (Zone 3). 
Anesthesia and resuscitation drugs are also located in the cart. Specific interventions for each 
anesthesia drug are listed below. 
Dexmedetomidine 
Adverse reaction 
Definition 
Rescue Maneuvers 
Hypotension 
30% decrease Systolic 
BP from pre-study level 
Lactated Ringers 10cc/kg 
Decrease or stop drug administration 
Phenylephrine 1-2mcg/kg 


Trendelenburg position 
Respiratory depression 
> 30 % decrease 
respiratory rate from pre-
study level 
Stimulation 
Jaw thrust 
Bag and mask ventilation 
Bradycardia/sinus arrest 
Decrease 30% from pre-
study level 
Observation if not symptomatic 
Glycopyrrolate 2 mic/kg IV 
Stop dexmedetomidine infusion 
Stop other medications that affect sinus node 
Glycopyrrolate or atropine 
Pressor agents 
Transient Hypertension 
30 % increase BP from 
pre-study level 
Reduce loading infusion rate 
Nausea 
 
Ondansetron 0.15 mg/kg IV 
Post-marketing adverse events reported in pediatric patients (~250,000 patients 0-11 years)* 
Syncope (3 cases)1 
 
Bedrest until Ramsey 5; up with 
assistance 
Agitation/neuropsych1 
Unable to Console, no eye contact 
Quiet environment 
Tolerance,tachyphylaxis  Not applicable to this study 
Seen after > 24 hour administration 
* IMS Health Inpatient Healthcare Utilization System (IHCarUS). June 2010-May 2015. File: 
Precedex Adhoc Nov 18 2015 
1Reported events occurred following administration of much larger doses of dexmedetomidine 
than will be administered in this study. 
 
Propofol 
Adverse Event 
Rescue 
 
 
Cardiovascular 
Bradycardia1 
Glycopyrollate if symptomatic 
Arryhthmia 
 
Tachycardia 
 
Hypotension1 
Decrease or stop infusion rate, IV lactated Ringer’s 10 
cc/kg, phenylephrine 
Hypertension1 
Stop administration of drug 
 
 
 
CNS 
Uncontrolled 
athetoid 
movement 
Stop drug administration; administer alternative sedation; 
terminate study 
Injection site 
Burning 
Increase rate of administration; prior administration of 
lidocaine as recommended by FDA attenuates this effect 
Respiratory 
Apnea 
Jaw thrust, baag  
Allergic 
reaction 
Rash 
Anaphylaxis 
Discontinue drug; IV fluids, diphenhydramine, 
epinephrine; airway and cardiovascular support as 
needed 
1Definitions as described in Dexmedetomidine Table above. 


Lidocaine 
Adverse Event 
Definition 
Rescue 
Tinnitus 
Ringing in ears 
Stop administration of drug; 
Symptomatic treatment; reassurance 
Seizure 
Generalized shaking 
Stop drug administration 
Maintain patent airway and assist 
ventilation as needed 
Administer propofol or benzodiazepine 
to stop seizure 
Arrhythmia/cardiac 
arrest 
HR < 60, ventricular 
ectopy; ventricular 
tachycardia or fibrillation; 
asystole 
Stop drug administration 
Cardiopulmonary resuscitation 
Intralipid emulsion 20% 
 
 


 
 
Sevoflurane 
Adverse event 
Definition 
rescue 
Bradycardia 
<30% dec pre-study heart reate 
Decrease concentration of agent; 
glycopyrrolate if needed 
Hypotension 
<30% dec pre-study systolic 
blood pressure 
Decrease sevoflurane, administer 
lactated ringer’s 
Tachycardia 
Transient increase on induction 
up to 50% above baseline 
Decrease sevoflurane 
concentration 
 
Nitrous Oxide 
Hypoxia 
O2 sat < 90% 
Increase O2 concentration of 
delivered gases 
Nausea 
 
Keep NPO; administer IV 
fluids; ondansetron 
 
 
Patients in the propofol group will be receiving routine care and the risk level is minimal as the 
study will only involve data collection. Patients in the prop/dex group will have the additional 
risks of receiving dexmedetomidine and glycopyrrolate. These risks are listed above and include 
hyper- and hypotension, bradycardia and sedation. Glycopyrrolate will be given with 
dexmedetomidine to attenuate the degree of bradycardia known to occur. The FDA recommends 
administration of an anticholinergic agent with the administration of propofol when it is used 
with other agents that may cause bradycardia. Dry mouth is associated with administration of 
glycopyrrolate but at the dose administered the symptoms should be minimal. 
Anesthetic risks will be minimized by following CHW and ASA guidelines for sedation and 
anesthesia. This will include 
• Administration of anesthesia by providers board certified in pediatric anesthesia 
• Appropriate monitoring including videocamera, direct visual observation, 
electrocardiogram, blood pressure, heart rate, respiratory rate and end-tidal CO2 
We will follow standard CHW safety protocols regarding MRI, that include  
• scanning patients for ferromagnetic materials prior to entering the scanner  
• utilization of MRI compatible equipment and monitors 
• Videocamera for continuous observation of patient to readily recognize movement 
• Noise – earplugs and headphones 
• Patients at risk for renal disease will have appropriate laboratory studies performed prior 
to administration of gadolinium whose major route of excretion is renal.  
• For additional information, Please refer to the Children’s Hospital of Wisconsin policy 
and procedure guidelines for procedural sedation. Appendix A 
 
CONFIDENTIALITY PROVISIONS 
 
All paper records are kept in locked cabinets in the anesthesiology department, with restricted 
access. Only de-identified information is stored. Each subject will be assigned a study 


identification  number. The legend associating the study number with the patient medical record 
number will be stored securely by the pharmacy department. Data analysis will be performed on 
a MCW secure server. 
 
ANTICIPATED BENEFITS ASSOCIATED WITH THE PROTOCOL TO HUMAN 
RESEARCH PARTICIPANTS AND SOCIETY  
For patients randomized to the prop/dex group we anticipate that significantly reduced doses of 
anesthetic agents will be administered for MRI studies in small children. These subjects may 
benefit from a more rapid recovery from the procedure. Significantly reduced dosing of both 
propofol and dexmedetomidine may reduce the adverse events and side effects that may be seen 
when either drug is used alone. Because of poorly understood but ongoing concerns for the 
potential adverse outcome on behavior and learning in children exposed to anesthetic agents, 
both the subjects recruited and future patients will benefit from the results of this study.  
Subjects in the propofol group will be treated with a medication that routinely provides 
conditions satisfactory for successful MRI imaging necessary for the diagnosis and treatment of 
their diseases.  There may be no additional benefit to the patients assigned to this group.  
 
STOPPING POINTS THAT WOULD NOT ALLOW THE STUDY TO CONTINUE AS 
PROPOSED   
Individual subject stopping criteria include: 
• Sinus or junctional bradycardia below 30% of preoperative heart rate or requiring rescue 
medications or treatments 
• Any cardiac arrhythmia (with the exclusion of sinus tachycardia or sinus bradycardia that 
resolves without intervention) before the initiation of dexmedetomidine infusion 
•  Junctional rhythm sustained for greater than 15 minutes, or requiring rescue medications 
or treatments, or associated with greater than 30% decrease in mean arterial pressure 
(MAP) from preoperative baseline value 
• Onset of second or third degree heart block, regardless of necessitating an intervention 
• Hypotension defined ad 30% decrease in MAP from preoperative baseline value 
• Cardiac arrest or any other life-threatening event 
Events that would serve as criteria for stopping the study include: 
• A single adverse event requiring unanticipated admission to hospital following sedation 
for MRI scan 
• Greater than 20% of subjects experiencing hypotension as defined by 30% decrease from 
baseline 
• Greater than 10% of subjects experiencing severe hypotension as defined by 50% 
decrease from baseline and that requires treatment beyond fluid replacement with IV 
isotonic solution 
• Greater than 20 % of subjects experience bradycardia as defined as heart rate below 30% 
of pre-study heart rate that requires rescue medications. 
Stopping criteria will be assessed continuously starting with the first patient enrolment and 
until study completion. 
We anticipate that the study will be completed after the successful recruitment of 70 patients. 
Because we are studying the procedures currently in place at CHW that have been employed 
safely and successfully for the past three years we do not anticipate safety concerns other than 
those inherent in sedation and anesthetic techniques utilized in the care of children. We are aware 


that randomization to study groups may present potential unanticipated risks to subjects. 
Analysis of the data prior to completion of the study demonstrating significant differences in 
primary outcomes between groups would be grounds for early termination of the study. 
 
DATA SAFETY MONITORING BOARD   
 
The principal investigator will review the data obtained every two weeks to ascertain whether 
unintended adverse outcomes have occurred. All adverse events will be assessed continuously, 
starting with the first patient enrollment and until study completion.  Any serious adverse event 
will be reported to the IRB as required. In addition, if preliminary review of the data suggests 
that differences in the primary outcomes are significant prior to enrolling 70 subjects, the study 
will be terminated at that time. 
 
Severity Grading of Adverse Events 
 
 
Mild  
Moderate 
Severe 
Life-threatening 
Peripheral IV  
      Pain 
Does not interfere 
with activity 
Requires non-
narcotic analgesia 
Requires narcotic 
analgesia 
ER visit 
      Infection 
Resolves with 
topical antibiotic 
therapy 
Requires oral 
antibiotics 
Requires IV 
antibiotics 
Hospital admission 
      Bruising 
Does not interfere 
with activity 
Requires non-
narcotic analgesia 
Requires analgesia 
Interferes with 
activity 
Hospital admission 
     Infiltration 
2.5-5 cm does not 
interfere with 
activity 
5.1-10 cm or 
interferes with 
activity 
>10 cm or prevents 
daily activity 
Necrosis 
Propofol 
 
 
 
 
Pain on injection 
See above  
 
 
 
Hypotension1 
Transient decrease 
to 40% below pre-
study level 
Transient dec to 
50% below pre-
study level; no 
intervention 
Sustained dec to 
less than 30% pre-
study level; requires 
volume 
resuscitation 
Sustained 
hypotension to less 
than 50% pre-study 
level requiring 
inotropic support 
Hypoventilation2 
Transient decrease 
in respiratory rate 
to less than 12; no 
intervention 
Decrease in 
Respiratory rate or 
minute ventilation 
requiring assisted 
bag and mask 
ventilation for > 2 
min 
Sustained decrease 
in respiratory rate 
or minute 
ventilation with 
associated hypoxia 
to O2 sat < 85% for 
> 30 seconds 
Decrease in 
ventilation 
requiring intubation 
and prolonged 
ventilation  
Allergic Reaction 
Hives; symptomatic 
Decrease propofol 
treatment 
Bronchospasm 
requiring 
bronchodilator 
therapy with 
hypotension 
Bronchospasm and 
cardiovascular 
compromise 
requiring 
epinephrine 
Sustained reaction 
requiring ongoing 
inotropic support 
and hospital 
admission 
Athetoid movements 
Involuntary 
movements ; 
resolves with 
discontinuing drug 
N/A 
N/A 
N/A 


Prolonged sedation 
after discontinuing 
drug 
>60 minutes 
unresponsive to 
verbal response 
> 90 min 
unresponsive to 
verbal response  
>90 minutes 
unresponsive to 
physical stimulation 
Requires hospital 
admission 
1Decrease in blood pressure to levels 30% of awake values is an expected outcome of propofol anesthesia 
2Transient hypoventilation and/or apnea are expected results of induction of anesthesia with Propofol 
 
Dexmedetomidine 
Bradycardia1 
HR <35% below 
pre-drug level; 
normal BP, ET 
CO2 
HR < 40% below 
pre-drug level, 
normal BP, ETCO2 
HR < 50% below 
pre-drug level; 
requires 
anticholinergic 
Sustained 
bradycardia < 50% 
pre-drug requiring 
hospital admission 
Hypertension2 
BP > 40% above 
pre-drug level; no 
therapy 
BP>60% above 
pre-drug level; 
resolves within 5 
minutes without 
therapy 
BP> 70% above 
pre-drug level; 
resolves within 5 
minutes; may 
require intervention 
Sustained BP > 
50% above pre-
drug level requires 
ongoing therapy 
and hospital 
admission 
Hypotension3 
Transient dec to 
30% below pre-
study level (<5 
min) 
Transient dec to 
40% below pre-
study level; no 
intervention 
(<5min) 
Sustained dec to 
less than 40% pre-
study level; 
requires volume 
(>5 min) 
resuscitation  
Sustained 
hypotension to less 
than 50% > 10 min 
pre-study level 
requiring inotropic 
support 
Prolonged sedation 
after discontinuing 
drug 
>45 minutes 
unresponsive to 
verbal response 
> 60 unresponsive 
to verbal response 
>60 minutes 
unresponsive to 
physical stimulation 
Requires hospital 
admission 
Lidocaine4 
Tinnitus, metallic 
taste; no 
intervention 
Seizure; resolves 
spontaneously or 
with 
benzodiazepine 
Cardiac arrhythmia 
and seizure 
Cardiac arrest 
requiring CPR; 
intraipid therapy 
Glycopyrrolate 
Dry mouth 
Tachycardia, 
agitation 
Central 
anticholinergic 
syndrome (2 case 
reports since 1991) 
Resolves with 
physostigmine 
Central 
Anticholinergic 
syndrome (2 case 
reports since 1991) 
Sustained, requires 
hospitalization 
     hypotension 
Reported to be 
associated with 
benzoyl alcohol in 
neonates. Not seen 
in older patients 
 
 
 
1Bradycardia in adult clinical trials defined as < 40 beats/min or < 30% pre-study drug level. Pediatric HRs 
vary by age and frequently “baseline” values are obtained in agitated crying patients. 
2Hypertension is generally self-limited and attenuated by slow administration of bolus. 
3Hypotension defined in adult clinical trials as <30% pre-study infusion value, systolic pressure <80, diastolic 
<50 
4These side effects are observed at higher lidocaine doses, generally > 5 mg/kg unless intra-arterial injection 
results in high brain concentrations of the drug. Even tinnitus would not be expected at the drug doses for this 
study. 
 
Sevoflurane 
Nausea and vomiting 
Nausea, resolves 
spontaneously, able 
to take oral liquids 
Nausea; unable to 
take liquids; 
Nausea and 
vomiting; requires 
Nausea and 
vomiting sustained 


resolves with 
antiemetic therapy 
IV hydration and 
antiemetic therapy 
requiring hospital 
admission 
Airway irritability 
Transient cough 
Mild laryngospasm 
resolves with 
positive pressure 
ventilation 
Laryngospasm 
requiring 
succinylcholine to 
resolve 
Sustained airway 
irritability 
requiring hospital 
admission 
Hypoventilation 
 
 
 
 
Emergence delirium 
Post-procedure 
delirium lasting < 
10 minutes; 
resolves 
spontaneously 
Post-procedure 
delirium lasting > 
20 minutes; 
resolves 
spontaneously 
Post procedure 
delirium resulting 
in physical harm to 
patient 
Post procedure 
delirium requiring 
hospital admission 
 
Nitrous Oxide 
Nausea, resolves 
spontaneously, able 
to take oral liquids 
Nausea; unable to 
take liquids; 
resolves with 
antiemetic therapy 
Nausea and 
vomiting; requires 
IV hydration and 
antiemetic therapy 
Nausea and 
vomiting sustained 
requiring hospital 
admission 
 
 


M 2. Causality Definitions 
 
Causality term 
Assessment criteria 
Certain 
• Event with plausible time relationship to drug intake 
• Cannot be explained by disease or other drugs 
• Response to withdrawal plausible 
• Event definitive pharmacologically or phenomenologically (i.e. an 
objective and specific medical disorder or a recognised 
pharmacological phenomenon) 
• Rechallenge satisfactory, if necessary 
Probable/Likely 
• Event, with reasonable time relationship to drug intake  
• Unlikely to be attributed to disease or other drugs  
• Response to withdrawal clinically reasonable 
• Rechallenge not required 
Possible 
• Event with reasonable time relationship to drug intake  
• Could also be explained by disease or other drugs  
• Information on drug withdrawal may be lacking or unclear 
Unlikely 
• Event with a time to drug intake that makes a relationship 
improbable (but not impossible)   
• Disease or other drugs provide plausible explanations 
Conditional/ 
Unclassified 
• Adverse reaction 
• More data for proper assessment needed, or  
•  Additional data under examination 
Unassessable/ 
Unclassifiable 
• Report suggesting an adverse reaction  
• Cannot be judged because information is insufficient or 
contradictory  
• Data cannot be supplemented or verified 
 
 
 


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