The Synergistic Effect of Dexmedetomidine on Propofol for Sedation for Pediatric Endoscopy
Phase: PHASE4
Conditions: Anesthesia
Sponsor: Keira Mason

 
 
 
 
 
 
 
 
Title: The Synergistic Effect of Dexmedetomidine on Propofol for Sedation for 
Pediatric Endoscopy 
PI: Keira Mason MD 
NCT#: 02952222 
Version Date: 05/25/2018 

Version 4: May 25th, 2018 
 
 
 
 
  
CHeRP IRB Additional Protocol Information: 
     In addition to the CHeRP SmartForms, all protocols must include the following sections. If a section is not 
applicable for the current protocol please indicate why this is the case. Please note that a complete protocol* 
consists of the CHeRP forms and the information provided in this form. 
TITLE: The Synergistic Effect of Dexmedetomidine on Propofol for Sedation for Pediatric 
Endoscopy 
Propofol is a sedative that is currently being used for sedation of children for upper and lower 
endoscopic studies in Boston Children’s Hospital. Dexmedetomidine is another sedative that is 
currently being used for sedation in BCH in the ICU and in radiology.  Dexmedetomidine is a selective 
alpha-2 agonist, and one advantage in using dexmedetomidine is the lack of respiratory depression that 
is frequently seen in other sedatives.  
 
It has been shown that with concomitant use, dexmedetomidine reduced the need for higher doses of 
anesthetics (Aantaa, 1990; Rao 2014), opioids (Gurbet, 2006; Pestieau, 2011), sedatives (Le Guen, 
2014) and neuromuscular block agents (Memis, 2008). In adults, dexmedetomidine decreased propofol 
requirements for maintenance of optimum depth of anaesthesia during elective spine surgery (Sen, 
2013). 
 
In children, dexmedetomidine reduced the dose of analgesics (Al-Zaben, 2010). Dexmedetomidine 
also reduced propofol requirements during bispectral index-guided closed-loop anesthesia in adults (Le 
Guen, 2014). 
 
This study will compare the propofol requirements of children who receive propofol with that of 
children who receive dexmedetomidine prior to propofol, for sedation for upper and lower endoscopic 
procedures.  
This study will also compare adverse events and other markers of outcomes between the two groups.  
Adverse event capture will begin at the time of the first study-related procedure and continue through 
until the time at which a phone call will be attempted to the patient/parent in the first business day 
following the procedure. Adverse events are consider any untoward medical occurrences associated 
with the use of a drug in humans, whether or not considered drug related. These are summarized in 
section E. 
A. Specific Aims/Objectives  
Primary objective: To compare the propofol requirements (mg/kg) of children who receive 
intravenous propofol with pre-treatment of dexmedetomidine with those of children who do not 
receive dexmedetomidine. 
Secondary objective: To compare the frequency of adverse events and the need for airway 
interventions during the sedation and the recovery period in patients who received dexmedetomidine 
prior to propofol versus patients who received propofol only 

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To compare propofol to dexmedetomidine with respect to:  
-Time required to achieve sedation 
- Need for supplemental sedation during the imaging study 
- Time required to meet discharge criteria from recovery room 
- Adverse events  
- Need for unplanned airway interventions  
 
- Duration of the sedation, need for supplemental doses of medication 
- Emergence Delirium (PAED score) 
- Return of BIS score to baseline (pre-sedation level) in recovery room  
B. Background and Significance  
Both propofol and dexmedetomidine may be used to achieve adequate sedation conditions. Propofol 
has been described to produce successful conditions for completion of the intended study in almost 
99% of the patients. However, in a study that reviewed outcomes when using propofol for almost 
50,000 pediatric procedures, propofol was associated with stridor, laryngospasm, airway 
obstruction, wheezing or central apnea at a rate of 1 in 65 sedations.  The need for airway and 
ventilation interventions which include oral/nasal airway placement, positive pressure mask 
ventilation and tracheal intubation occurred at a rate of 1 in 70 sedations.  Hemodynamic and 
respiratory fluctuations of a minimum of 30% fluctuations in heart rate, blood pressure or 
respiratory rate occurred at a rate of 1 in 165 sedations. Another recent study cited similar 
incidences of hemodynamic variability with propofol as well as inhalational anesthesia in the 
outpatient pediatric setting.  
 
Dexmedetomidine is one of the standard drugs administered for sedation in children who require 
radiologic diagnostic imaging studies (MRI, CT and Nuclear Medicine) in the Department of 
Radiology at BCH. Over 17,000 infants, children and developmentally compromised young adults 
have been sedated with dexmedetomidine at BCH without a cardiac or respiratory arrest, or a need 
to provide positive pressure assisted ventilation. 
 
This study will determine if administration of dexmedetomidine with propofol administration will 
result in lower doses of the latter, which may mean safer outcomes in sedation for upper and lower 
endoscopic procedures. 
C. Preliminary Studies  
      There are currently no preliminary studies available on the synergy of dexmedetomidine with 
propofol administration in comparison to propofol only for pediatric endoscopy.  
D. Design and Methods  
(1) 
Study Design 
This is a prospective, open label, randomized study. 
(2) 
Patient Selection and Inclusion/Exclusion Criteria  
       Inclusion Criteria 

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 
Ages 7-18 years who are scheduled for upper or lower endoscopic procedures at Boston 
Children's Hospital and meets criteria to receive dexmedetomidine or propofol sedation for 
upper and lower endoscopic procedures  
 
Provides written consent to participate in the research study 
 
In females of reproductive age, pregnancy testing (carried out per routine clinical care by the 
anesthesia department) must be negative. 
 
Exclusion Criteria 
 
 
Do not meet established sedation criteria 
 
Refuses administration of study medication prior to sedation  
 
History of allergy, intolerance, or reaction to dexmedetomidine or propofol or hypersensitivity 
 
Current, repaired or risk of Moya-Moya disease 
 
Recent stroke (cerebrovascular accident) within past 6 months 
 
Uncontrolled hypertension 
 
Concomitant use of opioids, beta antagonist, alpha 2 agonist or calcium channel blocker 
 
Egg, soy or lecithin allergy 
 
BMI greater than 30 or weight above 110th percentile 
 
Refuses insertion of intravenous catheter while awake 
 
Currently receiving pharmacologic agents for hypertension or cardiac disease  
 
Currently receiving or has received digoxin within the past 3 months 
 
Active, uncontrolled gastroesophageal reflux – an aspiration risk 
 
Current (or within past 3 months) history of apnea requiring an apnea monitor  
 
Unstable cardiac status (life threatening arrhythmias, abnormal cardiac anatomy, significant 
cardiac dysfunction)  
 
Craniofacial anomaly, which could make it difficult to effectively establish a mask airway for 
positive pressure ventilation if needed 
 
Active, current respiratory issues that are different from the baseline status (pneumonia, 
exacerbation of asthma, bronchiolitis, respiratory syncytial virus)  
 
Methods 
 
Patients in both endoscopy groups will be randomized to two equal treatment groups: those 
who will receive dexmedetomidine with propofol (DP) and those who will receive propofol 
only (P). 
 
All groups will have an intravenous catheter inserted pre-induction, bi-spectral (BIS) monitor, 
standard of care anesthesia monitor  (pulse oximetry, heart rate, ECG, NIBP, capnography via 
nasal cannula) applied and monitored prior to induction (in the GI suite  
No premedication anxiolytics will be administered.   
 
 
 Table 1.  Data Elements to be Collected 
Age 
Height 
Weight  
Body Mass Index (BMI) 
Sex 
ASA status 

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NPO status 
Current Medication list 
Primary diagnosis 
Coexisting diagnoses 
Procedure(s) performed 
Sedation start time  
Sedation end time  
Time in which patients meets discharge criteria  
 
 
 
Table 2. Airway Management Interventions 
Endotracheal tube 
Jaw thrust 
Laryngeal mask airway 
Nasotracheal tube 
Oral/Nasal-pharyngeal airway 
O2 mask increase in O2 flow via nasal cannula 
Bag- mask ventilation 
Repositioning of head  
Suction 
Elevation of shoulders with a shoulder roll in order 
to achieve neck extension 
 
 
 
Recruitment Methods 
 
i. HOW, WHERE and WHEN will potential subjects be recruited?  
 
All outpatients who are scheduled for sedation for upper or lower endoscopy will be screened 
for eligibility to participate in the study.   The consent form will be mailed to potential 
families of eligible patients for review up to 2 weeks prior to being contacted by telephone to 
discuss the study in further detail and answer any questions families may have.  All families 
will then be given ample time to decide if they would like to participate in the study and 
verbal consent will be obtained at least 24 hours prior to the scheduled hospital visit. All 
families will also be given ample time to read the consent form on arrival to the department 
prior to giving written consent. The consent form will be signed by the parent, or patient if 
the patient is older than 18 years of age (and assent given by the child where appropriate) on 
the day of the scheduled study after any additional questions are answered. A follow-up 
phone call will also be attempted the first business day after the procedure to identify if any 
adverse events have taken place post discharge and also to answer any additional questions 
parents may have post study participation. If the family is not able to be reached, an 
additional phone call will be made within the first week following the procedure. If possible, 
a voicemail will be left. If not returned, a second call will be attempted within 1 week of the 
procedure. Parents will also be given a direct phone number to the research team in the event 
that they have any questions or concerns. 

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ii. WHAT recruitment methods and materials (e.g. posters, fliers) will be used? - attach all 
materials 
The consent form along with an informational brochure containing a brief description of the 
study will be distributed in advance to all potential study candidates.  
iii. WHO will be responsible for subject recruitment?  
 
  Subject recruitment will be and the responsibility of designated members of the research team 
  working within the Department of Anesthesiology. 
 
(3) 
Description of Study Treatments or Exposures/Predictors  
Intravenous catheters will be initiated as per standard clinical protocol in gastrointestinal 
endoscopy unit. Patients may also choose not to have any adjuvant local anesthesia prior to 
initiation of intravenous access.   All patients will have baseline vital signs (already described) 
documented prior to induction.  Those undergoing upper endoscopy will have 2 sprays of 
Cetacaine to posterior oropharynx prior to induction as part of standard clinical care. All patients 
will receive 4 L of supplemental oxygen by nasal cannula throughout the procedure. 
 
Patients who are randomized into the Dexmedetomidine Group (DP) 
 
Patients in Group DP will receive 0.5 mcg/kg DEX administered over 1 minute followed by an 
infusion of 0.15 mcg/kg/hr.  Following the 0.5 mcg/kg DEX bolus, propofol will be 
administered with the identical protocol (with same endpoint of BIS 40-50) of the P Group. 
Propofol infusion will be started at 200 mcg/kg/min and will be titrated throughout the 
procedure to maintain a BIS 40-50, up to a maximum of 350 mcg/kg/min.  Propofol may be 
administered prn in 10-20 mg increments for any abrupt patient movement which may 
compromise the continuity of the procedure.  Ondansetron (Zofran) 0.1 mg/kg IV will be 
administered after induction. The DEX infusion in the DP group will remain constant throughout 
the procedure, and will be discontinued at the termination of the procedure, simultaneous with 
the discontinuation of the propofol infusion.  For both Group P and DP, the propofol infusion 
will remain until the termination of the procedure.  At termination of procedure, monitors will 
remain and patient will be transported to recovery room for continuation of monitoring as 
indicated below.  
  
No narcotics, no benzodiazepines and no dexamethasone will be administered during the 
anesthetic management for either group.   
 
Patients undergoing a lower endoscopy after a bowel prep, will receive a goal of 20 mL/kg 
saline prior to termination of procedure.   
 
Patients who are randomized into the Propofol Group (Group P)  
Patients in Group P will receive intravenous propofol in bolus increments (1.0 to 2.0 mg/kg 
bolus over one minute then 0.5 mg/kg bolus q 1 minute titrated to a BIS of 40-50).  Ondansetron 
(Zofran) 0.1 mg/kg IV will be administered after induction. These patients will be maintained 
with a continuous intravenous infusion of propofol starting at 200 mcg/kg/min and will be 

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titrated to an endpoint of maintaining a BIS level of 40-50, up to a maximum of 350 
mcg/kg/min. Propofol may be administered prn in 10-20 mg increments for any abrupt patient 
movement which may compromise the continuity of the procedure 
 
If any member of the child’s care team, at any time for any reason, believes the patient should be 
taken off the study, participating in the study will end immediately and the child’s care will 
continue at the discretion of the anesthesiologist. Additionally, an inability to perform procedure 
because of inadequate sedation administered following this protocol will result in the child being 
withdrawn from the study. Additionally, if there is a need for pharmacologic intervention for 
respiratory or hemodynamic instability and the patient receives cardiovascular resuscitation with 
the AHA’s Pediatric Advanced Life Support protocol, they will immediately be taken off the 
study and care will continue at the discretion of the anesthesiologist. If the unanticipated need 
for endotracheal intubation or an inhalation-based general anesthetic (which may be related to 
the procedure as well as to the sedation) arises, the child will be taken off the study and care will 
continue at the discretion of the anesthesiologist. 
 
If any one patient experiences a sentinel event, as described in Figure 1, the study will 
immediately be stopped. Appropriate reports will be made to the IRB and FDA. If more than 5 
patients in any one group require a bag mask valve, an oral/nasal airway or CPAP, the study will 
also be stopped and the FDA and IRB will be notified. In addition, if more than 5 patients 
require two or more weight-based IV fluid boluses following hemodynamic changes, the study 
will be stopped and the FDA and IRB will be notified. 
(4) 
Definition of Primary and Secondary Outcomes/Endpoints  
The primary outcomes will be: Dosage/consumption of propofol (mg/kg) in children who 
receive intravenous propofol with pre-treatment of dexmedetomidine to the consumption of 
children who do not receive dexmedetomidine. 
 
 
The Secondary outcomes will be:  
-Time required to achieve sedation 
- Need for supplemental sedation during the imaging study 
- Time required to meet discharge criteria from recovery room 
- Incedence of adverse events (defined in Figure 1) 
- Need for unplanned airway interventions  
- Duration of the sedation, need for supplemental doses of medication 
- Incidence of Emergence Delirium (PAED score) 
- Time of BIS score to return baseline (pre-sedation level) in recovery room  
 
(5) 
Data Collection Methods, Assessments, Interventions and Schedule (what 
assessments performed, how often)  
• 
Data points as outlined in table 1. 
• 
Ramsay Sedation Score (RSS)-at termination of initial dexmedetomidine or propofol bolus, on 
arrival to recovery room, and every fifteen minutes after arrival in recovery room until 
discharged home 

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• 
University of Michigan Sedation Score (UMSS)- at termination of initial dexmedetomidine or 
propofol bolus, on arrival to recovery room, and every fifteen minutes after arrival in recovery 
room until discharged home 
• 
Time to meet baseline BIS (pre-sedation level) in the recovery room.  
• 
Time to meet modified Aldrete discharge criteria (current standard)- measured in minutes from 
the time at which the infusion discontinued to the time at which the patient achieves a 
minimum Aldrete score of 9 
• 
Occurrence of Failed Sedation: Defined as a Failure to sedate with designated protocols.   
• 
The occurrence of any adverse events (Table 2) and the need for supplemental airway 
interventions (Table 3) will be documented  
• 
Heart Rate (HR), Oxygen Saturation (O2 sat), Respiratory Rate (RR), Non Invasive Blood 
Pressure Monitoring (NIBP) (systolic, diastolic and Mean Arterial Blood Pressure/MAP) will 
be measured and documented via computerized record keeping prior to receiving sedation, 
every 5 minutes after the initiation of the dexmedetomidine or propofol bolus and throughout 
the infusion period, then every 5 minutes in recovery room until the patient meets discharge 
criteria (modified Aldrete score of 9 or greater), after which these parameters will be measured 
at 15 minute intervals until the patient leaves the recovery room.  Any deviation in blood 
pressure outside of the 20% accepted norms, will be treated with 20% 0.9 NS fluid boluses (to 
a maximum of two fluid boluses). Deviations in heart rate are not considered by the Hospital or 
Radiology Sedation Committee as adverse events and are not treated unless there is a 
concurrent instability in blood pressure, perfusion, electrocardiogram, pulse oximetry or 
capnography.  The treatment of bradycardia in patients receiving dexmedetomidine with 
anticholinergics is discouraged because such treatment has previously resulted in extreme 
hypertension. 
• 
Electrocardiogram will be monitored. 
• 
An independent observer (designated member of the research team) will document adverse 
events and the need for airway interventions (Table 2 and 3). 
• 
Hemodynamic and respiratory fluctuations will be identified from computerized 
documentation, (thus eliminating bias with respect to identifying fluctuations in blood pressure, 
heart rate and respiratory rate). 
• 
PAED Score on arrival and q15min (or sooner if change of patient behavior) and immediately 
prior to discharge 
• 
If the endoscopist remains blinded to the treatment at the end of the procedure, they will score 
the quality of sedation at the end of the case with the Adapted Dartmouth Operative Conditions 
Scale below (Chandran, 2017). 
 
 

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(6) 
Study Timeline (as applicable) 
We plan to enroll 70 subjects for this study at Boston Children’s Hospital.  We anticipate that this 
study will take up to 2 years to complete. An interim analysis will be performed after 35 patients 
have been enrolled to review data and safety elements of the study and also to determine if patients 
have any obvious improvement in the DP group with a view to terminating the study early.  
E. Adverse Event Criteria and Reporting Procedures  
The World SIVA adverse sedation event reporting tool (Figure 1) will be used to document and 
track adverse events (Mason, 2012).  All adverse events will be reported to the Radiology and 
Hospital Sedation Committee.  These events will be reviewed by an Independent Committee set up 
by the Department of Anesthesia and will be reported to the IRB by this Committee as appropriate. 
According to the recommendations laid out in the Safety Reporting Requirements for INDs and 
BA/BE Studies guide, adverse events that are both serious and unexpected, associated with the use 
of the drug will be reported to the FDA. According to 21 CFR 312.32, an “adverse event or 
suspected adverse reaction is considered "serious" if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes: Death, a life-threatening adverse event, 
inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect.” 
 
Subjects/parents may opt to remove themselves/their child from the study at any point in time. 

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Figure 1. World SIVA adverse sedation event reporting tool 
F. Data Management Methods  
Patient demographic, adverse events and hemodynamic data will be entered into an InFormdatabase 
and then exported into the SAS system for statistical analysis (version 9.2, SAS Institute, Cary, NC).  
 
G. Quality Control Method  

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To ensure that data will be of the highest quality and accuracy, research team personnel will routinely 
check and monitor data entry, missing data, and any inconsistencies. 
H. Data Analysis Plan  
Baseline characteristics will be compared between the dexmedetomidine and propofol (DP) treatment 
group and the propofol (P) treatment group to determine any baseline imbalances which may occur 
despite randomization. Student t-test will be used to compare continuous (normally-distributed data) 
and Fisher’s exact test for comparing binary proportions. Airway obstruction and other adverse event 
rates will be assessed and 95% confidence intervals will be constructed using Wilson’s method 
(Newcombe 1998). Multivariate logistic regression will be applied to identify any variables (age, 
gender, ASA status, treatment) that are correlated with adverse events and with hemodynamic outcome 
exceeding the 20% boundary above the upper normal age-based reference range.  Time to sedation, 
procedure time, and time to meet discharge criteria will be compared between Dexmedetomidine and 
Propofol groups using two-sample t-tests with analysis of variance (ANOVA) used to adjust for 
covariates such as age, gender and ASA classification which could influence the results. Two-tailed 
values of P<0.05 will be considered statistically significant. Statistical analysis will be performed using 
SAS statistical software (version 9.2, SAS Institute, Cary, NC). 
I. Statistical Power and Sample Considerations  
Power analysis indicated that a sample size of 32 patients randomly assigned to dexmedetomidine and 
propofol will provide 80% power (2-tailed α = 0.05, β = 0.20) to detect a 50% difference (25% vs. 
75%) in the propofol dose using a chi-square test of binomial proportions between two independent 
groups. To account for 10% possible dropout, we will increase this sample size to 35 patients per 
group. This means that a total of 70 patients will be randomized equally to the DP and P treatment 
groups.  
J. Study Organization  
The principal investigator for this study is Dr. Keira Mason from the Department of Anesthesia, 
Perioperative and Pain Medicine at Boston Children’s Hospital.  
K. Data and Safety Monitoring Plan 
Dr. Mason and approved members of the research team will be responsible for all data and safety 
monitoring. An independent data monitor will also be part of this group. Data and safety monitoring 
will be reviewed every 10 subjects recruited or earlier if a specific problem is identified. Data and 
safety monitoring will be performed after every patient if a serious side effect has been noted and no 
more patients will be recruited, enrolled or studied until the cause been thoroughly investigated. If, 
after careful review by the data and safety monitoring committee, there is a probability that the study 
might have caused or contributed to the serious reaction, then this will be reported to the IRB and the 
study halted until a risk/benefit assessment can be made. An interim analysis will be performed after 
35 patients have been enrolled to review data and safety elements of the study and also to determine if 
patients have any obvious improvement in the DP group with a view to terminating the study early. 
L. Risks and Discomforts 
Patients enrolled in the study and randomized to the P treatment group would receive what had been 
normal standard of care for sedation in the GI Suite for upper and lower endoscopic procedures in 

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BCH. For the patients randomized to the DP treatment group, there is a slight increase in risk over the 
P group. However, these medications are commonly used together at Boston Children’s Hospital and 
for sedation practices. There are limited studies for administering both drugs in pediatric patients; 
however, these studies have shown dexmedetomidine to be a safe and effective agent with beneficial 
effects. 
M. Potential Benefits 
The patients in the P group will not receive an immediate, direct benefit from participation in the 
study, aside from the sedation received.  In the future, following completion of this study, we 
anticipate that the results obtained from this study will guide us in optimizing patient care by 
determining any advantage in administering dexmedetomidine with propofol. The patients in the DP 
group have the potential for an increased chance of emergence delirium, decreased need for analgesics 
and decreased propofol requirements. Decreasing the dose of propofol may decrease the risk of airway 
complications associated with propofol 
N. Privacy Provisions 
Access to the electronic database will be restricted to IRB approved study staff and will be password 
protected.   
O. Confidentiality Provisions 
The privacy of the study subjects will be maintained. Only the investigators and IRB approved 
members of the study team will know the identity of the subject whose data is being analyzed. Prior to 
analysis, all HIPAA identifiers will be removed. Data will be stored securely in a locked cabinet in a 
locked office. Research subject identifiers will be removed, linked or destroyed as soon as possible. 
The only document that contains a link to the identity of subjects will be kept securely in a locked 
cabinet in a locked office. 

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* If you are an investigator submitting an IND or IDE, this document alone does not constitute and complete 
protocol. You must submit your full IND/IDE application as an attachment for this section.