Does Dexmedetomidine Decrease the Incidence of Untoward Airway Events After Deep or Awake Extubation in Patients Undergoing Adenotonsillectomy With or Without Myringotomy and Tube Placement?
Phase: PHASE4
Conditions: Adenotonsillar Hypertrophy, Obstructive Sleep Apnea, Tonsillitis, Adenoiditis
Sponsor: Massachusetts Eye and Ear Infirmary

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Does dexmedetomidine decrease the incidence of untoward airway 
events after deep or awake extubation in patients undergoing 
adenotonsillectomy with or without myringotomy and tube placement? 
 
 
 
NCT #: NCT02162433 
 
 
 
1/29/2018 
 
 

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COVER PAGE  
Clinical Protocol Title: Does dexmedetomidine decrease the incidence of 
untoward airway events after deep or awake extubation in patients undergoing 
adenotonsillectomy with or without myringotomy and tube placement? 
HSC #: 14-019H 
 
IRBNet ID: 551737 
Version number and date: 
11, 10/26/2016 
Phase of clinical investigation: N/A 
Name of all sites (if applicable): N/A 
IND/IDE number: 122254                                                                        
Investigational drug(s) or device(s): 
Dexmedetomidine hydrochloride (Precedex) 

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Regulatory Sponsor:     
Department of Anesthesia 
Mass. Eye and Ear, 243 Charles St., Boston, MA 02114 
 
Funding Sponsor:  
Curing Kids Fund 
 
Study Monitor 
Medical Director:  
Sunil Eappen, M.D. 
Department of Anesthesia 
Mass. Eye and Ear, 243 Charles St., Boston, MA 02114 
617-523-7900  
 
Investigator(s): 
Makara Cayer, M.D. 
Department of Anesthesia 
Mass. Eye and Ear, 243 Charles St., Boston, MA 02114 
617-523-7900 
 
Study Coordinator(s): 
Alex Ciaramella  
Department of Anesthesia 
Mass. Eye and Ear, 243 Charles St., Boston, MA 02114 
617-523-4016 
 
 
 

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Statistician: 
Rong Guo 
Mass. Eye and Ear, 325 Cambridge St., Boston, MA 02114 
617-523-5583 
 
Clinical Laboratory(ies), Technical Department(s), and Institution(s) 
Providing Clinical Study Services: 
Department of Anesthesia, Pharmacy, and PACU nursing at Massachusetts Eye 
and Ear Infirmary. 

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STUDY DESIGN SCHEMATIC 
 
 
 

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1. CLINICAL PROTOCOL 
 
1.1 Background 
Adenotonsillectomy (T&A) is the most frequently performed surgical procedure 
in the pediatric population. T&A is associated with a high incidence of 
perioperative respiratory adverse events (11.2%)1 including coughing, breath-
holding, desaturation, partial or complete laryngospasm, bronchospasm, and 
negative pressure pulmonary edema. These respiratory complications in the 
postoperative period frequently lead to prolonged post-anesthesia care unit 
(PACU) and hospital stays in this patient population. Therefore, the 
postoperative period can be highly stressful for both children and their 
parents.2 
 
The incidence of these respiratory adverse events is highest following tracheal 
extubation and in the recovery period.3 Consequently, during emergence from 
anesthesia, tracheal extubation constitutes the most perilous event that may 
determine the incidence of adverse respiratory complications in the 
postoperative period. There remains a controversy as to whether tracheal 
extubation should be performed in a deeply anesthetized patient or in an 
awake patient.3 Given the serious nature of the respiratory complications 
following T&A, the identification of an adjuvant drug therapy that could 
decrease these untoward events would be highly desirable. 
 
Dexmedetomidine hydrochloride is a highly selective α2-adrenoceptor agonist. 
Its properties include sedation, anxiolysis, analgesia with little respiratory 
depression.2,4 In addition, dexmedetomidine has minimal effect on coagulation 
parameters.5 The potential risks of the use of dexmedetomidine, bradycardia 
and hypotension, are very rare.2 
 

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The use of this agent has been increasing in the pediatric population 
undergoing different surgical procedures.6,7,8,9 The drug’s opioid-sparing 
property in patients undergoing T&A is of particular interest. Pain-control in 
patients undergoing T&A can be extremely challenging, as many of these 
children may have an altered central opioid function that could enhance their 
responsiveness to opioid drugs.2,10,11 This 
hypersensitivity to opioids, potentially leading to severe respiratory 
complications, increases the risk of perioperative adverse airway events, thus 
limiting the application of such drugs in this population. 
 
Dexmedetomidine is an attractive drug for managing pediatric patients 
undergoing T&A: it combines mild analgesic effects, opioid-sparing properties, 
and minimal respiratory depression.2,4 Dexmedetomidine also appears to be a 
safe and effective agent in reducing the incidence of early emergence agitation 
in children after tonsillectomy.12 
 
However, the effects of dexmedetomidine on postoperative adverse airway 
events have not been fully studied, and the literature is limited to two studies. 
In one study investigating emergence agitation in sixty children undergoing 
T&A, Guler et al also studied untoward airway events in these patients.6 In this 
investigation, one group received dexmedetomidine 0.5 μg/kg over 5 minutes, 
while the control group received a placebo five minutes before the end of 
surgery. The number of severe coughs per patient in the dexmedetomidine 
group was significantly reduced compared to the control group (p < 0.05). 
Another study by Akin et al compared the effects of dexmedetomidine to 
midazolam administered as premedication on ninety patients undergoing T&A. 
The midazolam group resulted in five cases of laryngospasm, compared to the 
dexmedetomidine group, which exhibited none.13 
 
 

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Given the serious nature of untoward respiratory events in the perioperative 
period associated with T&A, coupled with the paucity of literature on the 
effects of dexmedetomidine on these events, we aim to investigate the effect of 
dexmedetomidine on the perioperative respiratory complications in this patient 
population undergoing both awake and deep tracheal extubation.             
 
References:  
 
1. Ye J, Liu H, Zhang G, et al. Postoperative respiratory complications of 
adenotonsillectomy for obstructive sleep apnea syndrome in older 
children: prevalence, risk factors, and impact on clinical outcome. J 
Otolaryngol Head Neck Surg. 2009; 38(1):49-58. 
 
2. He XY, Cao JP, Shi XY, et al. Dexmedetomidine versus morphine or 
fentanyl in the management of children after tonsillectomy and 
adenoidectomy: A meta-analysis of randomized controlled 
trials. Ann Otol Rhinol Laryngol 2013; 122(2):114-120. 
 
3. Ungern-Sternberg BS, Davies K, Hegarty M, et al. The effect of deep vs. 
awake extubation on respiratory complications in high-risk children 
undergoing adenotonsillectomy: A randomized controlled trial. Eur J 
Anaesthesiol 2013; 30:529–536. 
 
4. Venn RM, Hell J, Grounds RM. Respiratory effects of dexmedetomidine 
in the surgical patient requiring intensive care. Crit Care 2000; 4:302-308. 
 
5. Mizrak A, Karatas E, Saruhan R, Kara F, Oner U, Saricicek V, Baysal E. 
Does dexmedetomidine affect intraoperative blood loss and clotting tests 
in pediatric adenotonsillectomy patients? J Surg Res 2013; 179(1):94-98. 
 
6. Chrysostomou C, Schulman SR, Herrera Castellanos M, et al. A phase 
2/3, Multicenter, Safety, Efficacy, and pharmacokinetic study of 
dexmedetomidine in preterm and term neonates. J Pediatr 2014; 164(2): 
276-282. 
 
7. Guler G, Akin A, Tosun Z, et al. Single-dose dexmedetomidine reduces 
agitation and provides smooth extubation after pediatric 
adenotonsillectomy. Pediatr Anesth 2005; 15:762–766. 
 
8. Su F, Nicolson SC, Zuppa AF. A dose-response study of 
dexmedetomidine administered as the primary sedative in infants 
following open heart surgery. Pediatr Crit Care Med 2013; 14(5): 499-507. 

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9. Cai Y. et al. Efficacy and safety of spontaneous ventilation technique 
using dexmedetomidine for rigid bronchoscopic airway foreign body 
removal in children. Pediatr Anaesth 2013; 23: 1048-1053. 
 
10. Brown KA, Laferrière A, Moss IR. Recurrent hypoxemia in young 
children with obstructive sleep apnea is associated with reduced opioid 
requirement for analgesia. Anesthesiology 2004; 100:806-810.  
 
 
11. Brown KA, Laferrière A, Lakheeram I, et al. Recurrent hypoxemia in 
children is associated with increased analgesic sensitivity to opiates. 
Anesthesiology 2006; 105:665-669.  
 
12. Meng QT, Xia ZY, Luo T, et al. Dexmedetomidine reduces emergence 
agitation after tonsillectomy in children by sevoflurane anesthesia: A 
case-control study. Int J Pediatr Otorhinolaryngol 2012; 76:1036–1041.  
 
13. Akin A, Bayram A, Esmaoglu A, et al. Dexmedetomidine vs midazolam 
for premedication of pediatric patients undergoing anesthesia. Pediatr 
Anaesth 2012; 22:871-876. 
 
Provide a brief description of, and justification for, the proposed route of 
administration, dosage, dosage regimen, and duration of dosing of the 
investigational drug(s) or the investigational device(s) 
0.5 µg/kg of dexmedetomidine diluted in NaCl 0.9% with a maximum 
concentration of 4 µg/ml will be administered through the infusion pump 
over 5 minutes.  
 
Summarize the nature of the individuals (e.g., age range, sex, disease state or 
underlying condition) who will be included in the proposed clinical 
evaluation 
Children 3-16 years of age undergoing adenotonsillectomy.  

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Specify whether or not (i.e., to your knowledge) the investigational drug(s) or 
device(s) has been marketed in any other country. Specify if the 
investigational drug(s) or device(s) has been withdrawn from research or 
market in any country for any reason related to its safety or effectiveness. If 
the drug or device has been the subject of controlled clinical trials, detailed 
information of such trials that is relevant to an assessment of the drug’s or 
device’s effectiveness for the proposed investigational use should also be 
provided. 
N/A 
 
 
 
 

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2. STUDY OBJECTIVES 
 
2.1 Primary Objective 
We aim to investigate the effect of dexmedetomidine on the perioperative 
respiratory complications in this patient population undergoing both 
awake and deep tracheal extubation.             
(Note: For Phase 1 clinical research studies, the primary objective should be 
an evaluation of the safety of the investigational drug or device) 
2.2 Secondary Objective(s) 
We also aim to investigate the effect of dexmedetomidine on the 
incidence of nausea and vomiting as well as emergence agitation. In 
addition, we will evaluate the effect of dexmedetomidine on the 
requirement of postoperative pain control medication.   

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3. STUDY DESIGN 
3.1 Study Design Description 
We propose a prospective double-blinded randomized controlled trial. 
336 pediatric patients presenting to Massachusetts Eye and Ear Infirmary 
(MEEI) for adenotonsillectomy with or without myringotomy and tube 
placement who are eligible for the study based on inclusion and 
exclusion criteria will be recruited. A Clinical Pharmacy specialist, will in 
charge of preparing the dexmedetomidine and placebo doses and will 
randomize the patients to four equally numbered groups. The 
anesthesiologist will receive the assignment for the extubation method in 
a sealed envelope from the Clinical Pharmacy specialist. Multiple 
parameters will be recorded in perioperative period to quantify 
perioperative adverse respiratory events. 1- Oxygen saturation will be 
measured at the following intervals: 5 minutes prior to extubation; 
immediately before extubation; every minute for the first 10 minutes 
following extubation; and subsequently, every 5 minutes for the ensuing 
20 minutes. The following parameters will be noted:  
1- desaturation to less than 95% for more than 10 seconds;  
2- breath holding;  
3- complete or partial laryngospasm;  
4- bronchospasm;  
5- croup;  
6- number of episodes of persistent cough (three or more consecutive 
coughs);  
7- negative pressure pulmonary edema; 
8- stridor. 
 

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Add sub studies (if applicable): 
 
We will also investigate the following parameters: 
1) Incidence of emergence agitation;  
2) Incidence of postoperative nausea and vomiting (PONV); 
3) Length of time from end of surgery to leaving the operating 
room;  
4) The length of stay from admission to the PACU to discharge 
home;  
5) 24-hour postoperative pain control requirements assessed by the 
questionnaire given to parents at the time of discharge; 
6) Any unplanned hospital admission due to perioperative 
respiratory adverse events. 
 
3.2 Allocation to Treatment (Incorporate only if the proposed clinical study 
involves multiple treatment arms) 
1. Awake extubation receiving dexmedetomidine;  
2. Awake extubation receiving placebo; 
3. Deep extubation receiving dexmedetomidine; 
4. Deep extubation receiving placebo. 
 
3.2.1 Randomization Procedures:  
The Clinical Pharmacy specialist preparing dexmedetomidine and placebo 
for study will apply randomization and the anesthesiologist will receive 
the assignment for extubation method in a sealed envelope. 
 
 

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3.2.2 Masking Procedures:  
The patient, anesthesiologist and data analyst will be blinded as to which 
group receives which medication. All members of the perioperative care 
will remain blinded to the study drug arm. 
 
3.2.3 Breaking the Mask (only if proposed study is masked) 
The mask will be broken in case of severe bradycardia or hypotension, 
and the patient will be withdrawn from the study. 
Severe bradycardia is define as follows: 
 Children 3-5 years of age: heart rate < 60 beats per minute; 
 Children 6-16 years of age: heart rate <50 beats per minute; 
Severe hypotension is defined as a drop in systolic blood pressure of 
more than 40% drop compared to the baseline systolic blood pressure. 
The treatment of bradycardia in children involves the administration of 
atropine or epinephrine, and in case of isolated hypotension, depending 
on the severity, fluid, phenylephrine or epinephrine will be administered.  

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4. SUBJECT SELECTION 
 
4.1 Subject Inclusion Criteria 
 Patients between 3 to 16 years of age undergoing adenotonsillectomy 
with or without myringotomy and tube placement; 
 ASA class 1 or 2. 
4.2 Subject Exclusion Criteria 
 Known allergy or hypersensitivity reaction to dexmedetomidine; 
 Organ dysfunction (renal/hepatic failure or leukemia); 
 Cardiac disease (congenital or acquired); 
 Airway or thoracic malformation;  
 Cerebral palsy;  
 Hypotonia;  
 Need for premedication with midazolam, ketamine, or dexmedetomidine; 
 Current/recent upper respiratory infection (within four weeks prior to 
the surgery); 
 Asthma; 
 Allergy or intolerance to clonidine; 
 
Non-English speaking parents/patients 

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5. STUDY DRUG(S)/DEVICE(S)  
 
5.1 Study Drug/Device Information 
Dexmedetomidine is an FDA approved drug for use in adults.  
Dexmedetomidine is not an FDA approved drug for use in children. 
0.5 µg/kg of dexmedetomidine diluted into 4 µg/ml concentration and 
drawn up to the appropriate volume with NaCl 0.9% will be administered 
through the infusion pump over a 5-minute period. 
Overweight and obese patients will receive a dose of dexmedetomidine 
based on their estimated lean body mass. 
The volume of normal saline administered to control patients will mimic 
the volume of dexmedetomidine in the treatment group and will be 
administered through an infusion pump over a 5-minute period. The 
volume of NaCl 0.9% for the placebo works out to be 0.125 ml/kg. 
 
5.2 Study Drug/Device Compliance/Adherence  
N/A 
 
5.3 Study Drug Supplies 
Formulation and Packaging 
Precedex (dexmedetomidine hydrochloride) injection is a sterile, non-
pyrogenic solution suitable for intravenous infusion following dilution. 
Dexmedetomidine hydrochloride is the S-enantiomer of medetomidine 
and is chemically described as (+)-4-(S)-[1-(2,3-dimethylphenyl)ethyl]-1H-
imidazole monohydrochloride. Precedex has a molecular weight of 236.7 
with the empirical formula of C13H16N2 • HCl.  

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The structural formula is: 
 
 
 
 
 
 
Dexmedetomidine hydrochloride is a white or almost white powder that 
is freely soluble in water and has a pKa of 7.1. Its partition coefficient in-
octanol: water at pH 7.4 is 2.89. Precedex is supplied as a clear, colorless, 
isotonic solution with a pH of 4.5 to 7.0. Each mL of Precedex Injection, 
Concentrate contains 118 mcg of dexmedetomidine hydrochloride 
equivalent to 100 mcg of dexmedetomidine and 9 mg of sodium chloride 
in water. Each mL of Precedex Injection contains 4.72 mcg of 
dexmedetomidine hydrochloride equivalent to 4 mcg dexmedetomidine 
and 9 mg of sodium chloride in water. The solution is preservative-free 
and contains no additives or chemical stabilizers. Dexmedetomidine is 
not FDA approved for use children undergoing adenotonsillectomy. 
 
Preparing and Dispensing 
The dexmedetomidine and placebo syringes will be prepared by an 
independent investigator (Clinical Pharmacy specialist) not involved in 
the perioperative care of the study patients.  
 
 
 

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Administration 
Dexmedetomidine will be diluted in NaCl 0.9% to a concentration of 4 
µg/ml. 0.5 µg/kg dexmedetomidine will be administered to the patients 
through an infusion pump over 5 minutes.  
Normal Saline (Placebo) 0.125 ml/kg will be administered to the patients 
through an infusion pump over 5 minutes. 
The procedure will be investigator-directed for the study drugs. We will 
inform the research subjects before the surgery that they will receive 
either dexmedetomidine or a placebo during the anesthesia process. 
 
5.4 Study Drug/Device Storage and Accountability 
Precedex Injection, Concentrate 
Precedex (dexmedetomidine hydrochloride) injection, Concentrate 200 
mcg/2 mL (100 mcg/mL) is available in 2 mL clear glass vial. Vials are 
intended for single use only. 
 
NDC No. Container Size 
0409-1638-02 Vial 2 mL 
 
Precedex Injection 
Precedex (dexmedetomidine hydrochloride) injection is available as 
200 mcg/50 mL (4 mcg/mL) and 400 mcg/100 mL (4 mcg/mL) in 50 mL 
and 
100 mL clear glass bottles, respectively.  
 
NDC No. Container Size 
0409-1660-50 Bottle 50 mL 
0409-1660-10 Bottle 100 mL 
 

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Dexmedetomidine vials and placebo (sodium chloride 0.9%) vials will be 
stored in the Pharmacy at controlled room temperature (15-25 degrees 
Celsius). The Pharmacist will maintain drug accountability records for 
both dexmedetomidine and sodium chloride. All activities related to drug 
receipt, drug dispensation to subjects, and drug waste will be 
documented on the drug accountability log for each 
medication. Additionally, a perpetual inventory is maintained for each 
medication. 
 
5.5 Other Medications 
The following drugs are part of the anesthesia process and will be 
administered to all patients undergoing surgery regardless of the  
proposed research study protocol:  
 Administration 
- 
Acetaminophen 15 mg/kg orally to the maximum of 650 mg at 
least 30 minutes prior to surgery; 
- 
Patients 10 years or older will receive LMX-4 cream (Lidocaine 4%; 
Ferndale Pharmaceuticals; Deed; UK) on the dorsum of both hands 
30 minutes prior to surgery, unless contraindicated; 
- 
Propofol 1-3mg/kg IV in patients undergoing IV induction and 1-
2mg/kg IV in patients undergoing inhalational induction; 
- 
Remifentanil 1-2 μg/kg IV; 
- 
Dexamethasone (0.5 mg/kg to a maximum of 10 mg) IV; 
- 
Ondansetron (0.1 mg/kg to a maximum of 4 mg) IV; 
- 
Morphine 0.05- 0.1 mg/kg IV. 

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 Rescue Medication or Therapy 
- 
Atropine 0.02 mg/kg for bradycardia; 
- 
Phenylephrine 1 mcg/kg for hypotension; 
- 
Epinephrine 1 mcg/kg in case of severe bradycardia or 
hypotension. 

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6. BIOSPECIMEN COLLECTION (IF APPLICABLE) 
 
 
6.1 Specimen preparation, handling, and shipping 
 
N/A 
6.2 Instruction for specimen preparation, handling and storage 
 
N/A 
6.3 Specimen shipment 
 
N/A 
6.4 Future use of stored specimens 
 
N/A 

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7. STUDY PROCEDURES 
 
7.1 Recruitment Procedures 
A letter with detailed summary of the study will be sent to referring 
physicians to provide the letter to study eligible patients and their family 
members at the time of pre-operation. The referring physician will also 
explain to them that the study coordinator will be approaching them on 
the day of the surgery to discuss. 
7.2 Screening Procedures 
Pregnancy test for children of more than 12 years of age will be 
performed. Patients will also be screened for any conditions that increase 
the risk of complications, allergies or intolerance, current medications, 
and ASA classification. 
 
7.3 Enrollment/Baseline Procedures 
All patients meeting inclusion criteria and not excluded by exclusion 
criteria. 
 
7.4 Study Drug or Device Procedures 
Dexmedetomidine and normal saline will be infused through an infusion 
pump. 
 
7.5 Standard of Care Procedures 
Deep or awake extubation of patients. 
 

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7.6 Follow-up Procedures (Incorporate only if follow-up procedures will be 
performed) 
We will contact all study subjects by phone 24 hours after discharge in 
order to assess their pain level and pain control requirement. This follow-
up will be performed only in study participants. 
 
7.7 Unscheduled Visits 
N/A 
7.8 Early Termination 
In case of severe bradycardia or hypotension requiring CPR following 
dexmedetomidine administration, the patient’s participation in the study 
will be terminated. The data from patients withdrawn from the study will 
not be used. 
 
7.9 Schedule of Activities (Study Table) 
Provide a table that summarizes the clinical protocol procedures; to 
include the procedures that will be performed at screening, during the 
study drug administration, and at follow-up (if applicable) to the study 
drug or device administration. Please contact HSC@meei.harvard.edu if 
you would like to see an example. 
 

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Preoperative 
Evaluation 
 
 
 
 
 
 
 
 
 
 
 
 
 Children ≥ 12 years old will be screened by pregnancy 
testing. 
 Research only: We will discuss the research study with 
the patient and family in the pre-operative area; the risks 
and benefits will be explained to the patient and family 
by the anesthesiologist two hours before the surgery. 
 Research only: Patients’ parents will be asked to sign a 
consent form, and the patient, if eligible, will sign a child 
assent.  
 Patient demographics and characteristics, including ASA 
classification and comorbid conditions, will be recorded.  
 Patients will receive acetaminophen 15 mg/kg to the 
maximum of 650 mg orally at least 30 minutes prior to 
surgery in the preoperative holding area on the pediatric 
floor.  
 Research only: Patients will be assigned to four groups 
according to the pharmacy randomization: 1-awake 
extubation receiving dexmedetomidine; 2-awake 
extubation receiving placebo; 3-deep extubation 
receiving dexmedetomidine; 4-deep extubation receiving 
placebo.   
 An IV catheter will be placed in all children 10 years or 
older in the preoperative holding area on the surgical 
floor. 
 Standard ASA monitors, including pulse-oximetry, ECG, 
non-invasive blood pressure, and capnography, will be 
used in all patients. 

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 Research only: The anesthesiologist will be informed as 
to whether the patient belongs to the deep or awake 
extubation group in a sealed envelope. 
 Research only: All members of the perioperative team 
will be blinded to the drug arm of the study. 
 Patients will be transferred to the operation room.  
Intraoperative 
Phase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Induction: The anesthesia process will start with 
intravenous (IV) induction with propofol (1-3mg/kg) (for 
children ≥ 10 years old) or inhalation induction with 70% 
nitrous oxide and 8% sevoflurane (for children <10 years 
old). After inhalational induction, an IV will be placed in 
children < 10 years old, and propofol 1-2mg/kg. Next, all 
children will be administered remifentanil 1-2 µg/kg and 
then intubated with a cuffed endotracheal tube. 
 Research only: Study intervention: Following tracheal 
intubation, patients will receive either dexmedetomidine 
(dexmedetomidine 0.5 µg/kg diluted in NaCl 0.9% to 
achieve concentration of 4µg/ml) or a placebo (same 
volume of NaCl 0.9%), both over a 5-minute time period. 
 Maintenance: The maintenance of anesthesia will be 
achieved with sevoflurane. All children will receive 
dexamethasone (0.5 mg/kg to a maximum of 10 mg), 
ondansetron (0.1 mg/kg to a maximum of 4 mg) for 
antiemetic prophylaxis, and morphine 0.05-0.1 mg/kg 
for pain control. The dose of morphine will be adjusted 
for patients with OSA to receive 0.05 mg/kg. 

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  Extubation: At the end of the procedure, all patients will 
be placed on 100% oxygen: at this point, they will 
undergo either deep or awake tracheal extubation based 
on the prior randomization. However, the 
anesthesiologist will be able to overrule this decision 
based on his/her clinical judgment should the alternate 
method of extubation be indicated at the end of the case. 
Awake extubation will be performed when the patient 
demonstrates stable vital signs and adequate tidal 
volume, combined with one or more of the following 
responses: following commands, eye opening, 
purposeful movement, or coughing. Deep extubation will 
be performed when the patient’s end-tidal sevoflurane 
level is greater than one minimum alveolar concentration 
(MAC), and he/she is in the surgical plane of anesthesia. 
Postoperative 
Phase 
 
 
 
 
 
 
 
 
 
 
 
 
 All patients will be transported to PACU in lateral 
decubitus position on a facemask receiving oxygen or 
blow by oxygen ( 6L/min). Oxygen will be administered 
for 30 minutes continuously once in the PACU.   
 The anesthesiologist will remain with the patient until 
he/she is stable enough to be handed off to the PACU 
nurse.  
 After 30 minutes, supplemental oxygen can be 
discontinued if patient is able to maintain an oxygen 
saturation of greater than 95% on room air. 
 Research only: Oxygen saturation will be measured at the 
following intervals: 5 minutes prior to extubation; 
immediately prior to extubation; every minute for the 

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Postoperative 
Phase 
Continued 
first 10 minutes following extubation; and subsequently, 
every 5 minutes for the ensuing 20 minutes. 
 Research only: Heart rate and blood pressure will be 
measured at the following intervals: upon arrival at the 
PACU; every subsequent 5 minutes for the first 30 
minutes. 
 Research only: Multiple parameters will be recorded in 
perioperative period to quantify perioperative adverse 
respiratory events: 1- desaturation to less than 95% for 
more than 10 seconds will be noted; 2- breath holding; 3- 
complete or partial laryngospasm; 4- bronchospasm; 5- 
croup; 6- number of episodes of persistent cough (more 
than three consecutive coughs); 7- negative pressure 
pulmonary edema; and 8-stridor. 
 Research only: In addition to the above measures, the 
patient’s pain level in the PACU will be assessed using 
the FLACC Scale or Wong Baker faces charts, depending 
on the age of the patient.  
 Research only: Finally, the following parameters will also 
be recorded by the Study coordinator or 
anesthesiologist: 1- occurrence of emergence agitation 
using the PAED Scale; 2- episodes of vomiting; 3- length 
of time from the end of surgery to leaving the operating 
room; 4- length of stay in minutes from admission to the 
PACU to discharge home; 5- any unplanned hospital 
admission due to perioperative respiratory adverse 
events. 
 

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Discharge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Patients meeting the discharge criteria will be discharged 
home. 
 Patients with planned or unplanned hospital overnight 
admission will be discharged to the pediatric floor or 
PICU depending on the patient’s disposition. 
 Research only: During discharge home, the patient’s 
parents will be given a sheet to record breathing issues, 
including hoarseness, snoring (longer than 10 seconds), 
breath holding, and severe coughing. Parents will also be 
asked to record the amount of pain medication 
administered postoperatively to their children during the 
first 24 hours. They will also be asked to record any 
incidence of nausea and vomiting. Patients will be 
followed up to ascertain how they fared postoperatively. 
All data from the parents’ sheet will be recorded. 
 In patients admitted overnight, breathing issues, 
including hoarseness, snoring (longer than 10 seconds), 
breath holding, and severe coughing will be recorded. 
The amount of pain medication administered during the 
first 24-hours postoperatively will be noted, as will be 
any incidence of nausea and vomiting.  
Data Analysis 
 Research only: Data will be analyzed using chi-square or 
Fisher’s exact test for all four groups and pairwise 

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comparison between any 2 groups.  
 

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8. SAFETY AND EFFECTIVENESS ASSESSMENTS 
 
8.1 Safety Assessments 
The vital signs of the patient will be continuously monitored during the 
procedure. Heart rate and blood pressure will be monitored during the 
entire surgery for bradycardia and hypotension. Vital signs will be 
monitored in the PACU in order to detect any respiratory complications 
or adverse effects due to medications.  
 
8.2 Effectiveness Assessments 
Oxygen saturation will be monitored continuously intraoperatively, as 
well as postoperatively in the recovery room. For the purpose of this 
study, oxygen saturation will be recorded at the following intervals: 5 
minutes prior to extubation; immediately before extubation; every minute 
for the first 10 minutes following extubation; and subsequently, every 5 
minutes for the ensuing 20 minutes. Blood pressure and heart rate will be 
monitored intraoperatively every 5 minutes, on arrival in the PACU, then 
every 5 minutes in the recovery room for the first 30 minutes.  
 
The following parameters will also be monitored and recorded in the 
perioperative period to quantify adverse respiratory events:  
1- desaturation to less than 95% for more than 10 seconds;  
2- breath holding;  
3- complete or partial laryngospasm;  
4- bronchospasm;  
5- number of episodes of persistent cough (three or more 

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consecutive coughs);  
6- croup;  
7- negative pressure pulmonary edema; 
8- stridor. 
The occurrence of one or more of these postoperative respiratory complications 
constitutes the primary outcome measure for analysis in this study. 

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9. ADVERSE EVENT RECORDING AND REPORTING 
 
9.1 Recording Requirements 
Research subjects will be monitored for adverse events during and after 
the procedure. All observed adverse events regardless of study group or 
suspected causal relationship to the study drug will be recorded in the 
subjects’ case histories (source data) and electronic anesthesia records. 
For all adverse events, any pertinent information will be collected to 
permit: 1- adequate determination of the outcome of the event (whether 
the event should be classified as a serious adverse event); and, 2- 
assessment of the casual relationship between the adverse event and the 
study drug.  
Adverse events associated with the study drug will be followed until the 
event resolves and the patient stabilizes to a level acceptable to the 
Sponsor-Investigator. 
 
 
9.2 REPORTING PROCEDURES 
 REPORTING OF ADVERSE EVENTS TO FDA 
Adverse events will be reported to the FDA. 
  Reporting Adverse Events to Other External Entities 
Adverse events will be reported to the manufacturer of Precedex.  
 
 Reporting Adverse Events to the Human Studies Committee  
Any adverse effects including hypotension and bradycardia will be 
reported.  

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9.3 Withdrawal of Subjects due to Adverse Events? 
In case of severe hypotension and bradycardia, we will withdraw the 
subjects from the study. In case of severe hypertension, the subjects will 
also be withdrawn from the study  
 

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10. STATISTICAL METHODS/DATA ANALYSIS 
 
10.1 Primary endpoint(s) or outcome measure(s) 
The occurrence of one or more of these postoperative respiratory 
complications constitute the primary outcome measure for analysis in 
this study:  
1- Desaturation to less than 95% for more than 10 seconds; 
2- Breath holding; 
3- Complete or partial laryngospasm; 
4- Bronchospasm; 
5- Croup; 
6- Number of episodes of persistent cough (three or more 
consecutive coughs); 
7- Negative pressure pulmonary edema; 
8- Stridor. 
 
10.2 Secondary endpoints or outcome measure(s) 
We will also investigate the following parameters: 
1. Incidence of emergence agitation;  
2. Incidence of postoperative nausea and vomiting (PONV); 
3. Length of time from the end of surgery to leaving the operating 
room;  
4. The length of stay from admission to the PACU to discharge home;  
5. 24-hour postoperative pain control requirements; 
6. Any unplanned hospital admission due to perioperative respiratory 
adverse events. 

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10.3 Sample Size Determination 
Based on the study by Patel et al comparing the untoward outcomes in 
children undergoing awake versus deep extubation after 
adenotonsillectomy, a difference in complication rate has been shown 
between the two groups, with 11% (2 out of 18) versus 30% (6 out of 20), 
respectively, exhibiting airway complications during extubation.1 Based 
on these results, a two-group χ 2 test with a 0.05 two-sided significance 
level would have an 80% power to detect the difference between the 
‘awake’ group and ‘deep’ group given a sample size of 71 in each group. 
Guler et al compared untoward events after awake extubation in patients 
undergoing tonsillectomy who received dexmedetomidine 0.5 mcg/kg 
during the procedure to a placebo group who did not: they observed that 
the rate incidence of severe cough was significantly lower in the 
dexmedetomidine group (0%) compared to the placebo group (30%).2 
Based on these results, a two-group χ 2 test with a 0.05 two-sided 
significance level would have an 80% power to detect the difference 
between the ‘dexmedetomidine’ group  and ‘placebo’ group given a 
sample size of 22 in each group. 
Since we will be comparing the results of the ‘deep’ versus ‘awake’ as well 
as those of the ‘dexmedetomidine’ versus ‘placebo’ outcomes, each group 
will require a sample size of 71. 
We anticipate that, at most, 15% of randomized patients will not provide 
complete data on their assigned drug/extubation combination 
randomized arm because the anesthesiologist overrules the assigned 
extubation method due to the clinical needs of the patient during the 
case. Therefore, in order to assure that there will be at least 71 subjects 
on each study arm with complete data, we will enroll and randomize a 

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total of 336 patients with equal probability to the four arms (84 patients 
in each group) using a block randomization scheme. 
References: 
1. 1- Patel RI, Hannallah RS, Norden J, et al. Emergence airway 
complications in children: a comparison of tracheal extubation in 
awake and deeply anesthetized patients. Anesth Analg 1991; 73:266–
270. 
 
2. Guler G, Akin A, Tosun Z et al. Single-dose dexmedetomidine reduces 
agitation and provides smooth extubation after pediatric 
adenotonsillectomy. Pediatr Anaesth 2005; 15:762–766. 
 
10.4 Analysis Population (if applicable) 
Children between 3 months and 16 years old undergoing 
adenotonsillectomy constitute the population of analysis. 
10.5 Effectiveness Analysis (if applicable) 
N/A 
 
10.6 Safety Analysis 
A Data Safety Monitoring Board will conduct a safety analysis after the 
following numbers for patient recruitment in each arm have been 
reached:  
 40 total patients recruited with approximately 10 patients in each 
group 
 84 total patients recruited with approximately 21 patients in each 
group 
 168 total patients recruited with approximately 42 patients in each 
group 
 252 total patients recruited with approximately 63 patients in each 
group  

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This data reflects approximately 12%, 25%, 50%, and 75% of the total 
estimated subject recruitment population, respectively. The Data Safety 
Monitoring Board will specifically monitor for any adverse events in each 
group. In case of serious concerns regarding adverse events in either 
group, the study will be terminated. 
 
10.7 Interim Analysis  
A statistician will perform an interim analysis when half of the sample 
size for each group has been recruited 

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11. DATA AND SAFETY MONITORING  
 
11.1 Data and Safety Monitoring Plan  
The research coordinator will be responsible for data gathering. The 
study coordinator will be responsible for filling out the data collection 
sheet in the OR with input from the anesthesiologist assigned to the 
patient. The research coordinator or principal investigator will record the 
data collection sheet in the PACU. The anesthesiologist assigned to the 
patient will monitor for any adverse events. In case of severe bradycardia 
or hypotension following dexmedetomidine administration, the mask will 
be broken and the patient will be withdrawn from the study. All 
anesthesiologists involved in the study have access to the protocol and 
their feedback and concerns have been already added to the protocol. 
Progress notes of the study will be sent to the IRB annually. A statistician 
will perform an interim analysis when half of the sample size for each 
group has been recruited. A Data Safety Monitoring Board will be 
responsible for safety monitoring. 
 

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12. DATA HANDLING, RECORD-KEEPING AND MONITORING 
 
12.1 Data Recording, Record-Keeping and Monitoring  
The Source Data are the clinical findings and observations, laboratory 
and test data, and other information contained in the Source Documents 
and electronic anesthesia records. The Source Documents are the original 
records (and certified copies of original records) including, but not 
limited to, hospital medical records, physician or office charts, physician 
or nursing notes, subject diaries or evaluation checklists, pharmacy 
dispensing records, and recorded data from automated instruments, x-
rays, etc. All Source data and documents will be stored in patients’ paper 
and LMR charts. The electronic anesthesia records will be searched for 
any deviation from the study protocol, including drug administrations 
and vital signs. 
 
All research data collected, including monitoring data, will be recorded as 
research records on an MEEI password protected computer. The signed 
parental consent forms and child assents will be locked in the drawers 
located in anesthesia office on the 7th floor of MEEI main building. Only 
the study coordinator and the principal investigator have access to these 
drawers. 
 
 

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13. STUDY DISCONTINUATION CRITERIA 
 
13.1 Discontinuation of Individual Research Subjects 
In case of any major drug side effects (bradycardia and hypotension) or 
at the patient or parents’ request, patient participation will be 
terminated. 
 
13.2 Sponsor-Investigator Discontinuation of the Clinical Research Study 
In case of significant advantages or disadvantages, the principal 
investigator or sponsor will discontinue the clinical research study.  

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14. APPENDICES 
 
14.1 Schedule of Events  
1. Parents will be informed about the research at the time of the surgery 
scheduling and will receive the consent form from the surgeon’s office; 
2. Patients will present to MEEI two hours prior to surgery on the day of the 
surgery and will be assessed by the anesthesiologist; 
3. Parents of patients who meet the inclusion and exclusion criteria will be 
informed about the study; 
4. Written consent will be obtained from the parents and eligible children 
will be asked to sign an assent form;  
5. Patients will be randomized to one of the four study groups by the 
pharmacy 
6. All patients will receive oral acetaminophen in the preoperative area; 
7. An IV will be placed preoperatively on the surgical floor in all patients ≥ 
10 years; 
8. Prior to induction, the anesthesiologist will be informed about which 
method of extubation the patient will undergo; 
9. All patients will undergo parent-present induction; 
10. Patients will receive all the intraoperative induction medication 
according to the study protocol; 
11. Patients < 10 years will undergo inhalational induction; 
12. Patients ≥ 10 years will undergo IV induction; 
13. Patients will receive dexmedetomidine or placebo infusion after 
induction; 
14. At the end of the procedure, the patients will undergo either deep or 
awake extubation according to the prior randomization; 

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15. The anesthesiologist will record all the study data in the OR until the 
patient has been handed off to the PACU nurse; 
16. After extubation, the patient will be transferred to the PACU and handed 
off to the PACU nurse; 
17. A data recorder will record all the study data during patient’s PACU stay; 
18. During discharge, parents will be asked to fill out a data sheet during the 
first 24-hours after discharge; 
19. A follow-up phone call will be made 24 hours after discharge to obtain 
parent-documented data. 
 
14.2 Case Report Form(s) 
14.3 DSMB Charter