Clinical trial NCT03467750
Conditions: Obstructive Sleep Apnea
Keywords: Adenotonsillectomy Opioids Post-surgical pain Anesthesiology Pediatrics
Sponsor: Emory University
Start date: 2018-07-19; Completion date: 2023-08-22
Enrollment: 63 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized prospective study aims to determine the effect of ketorolac on the total dose of morphine required to achieve postoperative analgesia in children with obstructive sleep apnea (OSA) undergoing adenotonsillectomy. Participants will be randomly assigned to a study group where they will receive ketorolac in addition to the standard of care treatment or will receive only the standard of care pain management. The researchers hypothesize that by administering ketorolac at the end of the procedure once hemostasis has been achieved, it will be possible to decrease the amount of morphine administered in the post-anesthesia care unit (PACU). This study aims to provide a more comprehensive understanding of the efficacy and safety of the current standard post-operative analgesic regimen employed at the study institution, in which opioid analgesia currently plays a prominent role.

Detailed description:
Obstructive sleep apnea (OSA) as an indication for adenotonsillectomy has increased significantly over the past ten years, and now has surpassed recurrent tonsillitis as the most common indication for this procedure. Opioids continue to be the most commonly administered pain medication for these procedures. Studies have shown that patients with OSA have significantly increased sensitivity to opioids that results in post-operative respiratory depression and apnea when administered via standard opioid dosing protocols. Children with OSA were shown to have a nearly fivefold increase in the odds of developing respiratory complications when compared to their counterparts with tonsillitis. Ketorolac possesses similar efficacy to morphine without the problematic complications of respiratory depression, nausea and vomiting, which are commonly seen post-adenotonsillectomy. Importantly, when combined with opioids, ketorolac is opioid-sparing. This synergistic effect means that a similar level of analgesia is achieved using a lower dose of opioid. However, there continues to be concern about using ketorolac due to the potential risk of post-operative bleeding from anti-platelet activity.

This randomized, prospective study aims to determine the effect of ketorolac on the total dose of morphine required to achieve postoperative analgesia in children with OSA undergoing adenotonsillectomy. Participants will be randomly assigned to receive ketorolac or to not receive ketorolac. The post-anesthesia care unit (PACU) nurses, who will be blinded to ketorolac administration, will evaluate the patients using the Face, Legs, Activity, Cry, Consolability (FLACC) scale scores at 10 minutes post-op, 20 minutes post-op and at time of PACU discharge. For patients with a FLACC score of 6-10, morphine (0.05mg/kg) will be administered. For patients with FLACC scores of 3-5, morphine (0.025mg/kg) will be administered. The total amount of opioid required to obtain a FLACC score of less than 3 will be evaluated as the primary outcome. The secondary outcomes to be evaluated will be PACU FLACC scores, time required in PACU, incidence of post-tonsillectomy bleeding and total pain medications administered during hospital admission.

Arms: arm 1: Participants randomized to the ketorolac group will receive 0.5mg/kg IV at the end of the adenotonsillectomy procedure, once hemostasis has been achieved arm 2: Participants randomized to this group will receive the pain management standard of care for the adenotonsillectomy procedure.
Interventions: intervention 1: Ketorolac intervention 2: Standard of Care
Intervention descriptions: intervention 1: Patients in this group will receive 0.5mg/kg of ketorolac, administered intravenously. intervention 2: All patients will undergo inhalational induction with nitrous oxide and sevoflurane. After intravenous (IV) placement, 1-3mg/kg of propofol and 1mcg/kg of fentanyl will be administered. After induction, 0.5mg/kg of dexamethasone and an IV infusion of 15mg/kg of acetaminophen will be administered. During surgery, 0.5mcg/kg of dexmedetomidine and 0.1mg/kg ondansetron will be given.

A rescue dose of 0.5-1mcg/kg of IV Fentanyl will be available for use at the end of the procedure. The decision to administer will be left to the discretion of the attending anesthesiologist. The choice to give this will be made based on variables including patient's condition and a 20% increase in the heart rate and blood pressure.

The PACU nurses, who will be blinded to ketorolac administration, will evaluate the patients using FLACC scores. For patients with a FLACC score of 6-10, morphine 0.05mg/kg will be administered. For patients with FLACC scores of 3-5, morphine 0.025mg/kg will be administered.

Protocol documents:
Prot_SAP_000.pdf: 
Study Protocol 
 
Title: Ketorolac as a Strategy for Reducing Post-operative Opioid 
Requirements in Children with Obstructive Sleep Apnea Undergoing 
Adenotonsillectomy: a Randomized Controlled Trial 
 
NCT Number: NCT03467750 
 
Protocol date: April 20, 2022 


Protocol Title: Ketorolac as a Strategy for Reducing Post-Operative Opioid Requirement in 
Children with OSA undergoing Adenotonsillectomy: A Randomized Contolled Trial
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IRB Form BIO 03152021
PROTOCOL TITLE: Ketorolac as a Strategy for Reducing Post-operative Opioid Requirements in 
Children with Obstructive Sleep Apnea Undergoing Adenotonsillectomy: a Randomized 
Controlled Trial
PRINCIPAL INVESTIGATOR:
Name Laura Gilbertson, MD
Department Anesthesia
Telephone Number 
Email Address 
VERSION: 2:20APR22
FUNDING SOURCE: Anesthesia Department: Atlanta Gas Light Foundation


Protocol Title: Ketorolac as a Strategy for Reducing Post-Operative Opioid Requirement in 
Children with OSA undergoing Adenotonsillectomy: A Randomized Contolled Trial
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REVISION HISTORY
No need to review this section if this is the first version of the protocol you are submitting to the IRB
Revision #
Version 
Date
Summary of Changes
1
20APR22
New protocol template. 
2
20APR22
Statement to include Ketorolac is not indicated for use in 
the pediatric population. (Section 5)


Protocol Title: Ketorolac as a Strategy for Reducing Post-Operative Opioid Requirement in 
Children with OSA undergoing Adenotonsillectomy: A Randomized Contolled Trial
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Table of Contents
1.
Study Summary .......................................................................................................................4
2.
Objectives................................................................................................................................4
3.
Background .............................................................................................................................4
4.
Study Endpoints ......................................................................................................................5
5.
Study Intervention/Investigational Agent...............................................................................5
6.
Procedures Involved................................................................................................................6
7.
Statistical Analysis Plan ..............................................................................................................7
8.
Sharing of Results with Participants........................................................................................7
9.
Study Timelines .......................................................................................................................7
10.   Inclusion and Exclusion Criteria ..............................................................................................8
11.   Vulnerable Populations...........................................................................................................8
12.   Local Number of Participants..................................................................................................8
13.   Recruitment Methods.............................................................................................................8
14.   Withdrawal of Participants .....................................................................................................8
15.   Risk to Participants..................................................................................................................9
16.   Potential Benefits to Participants ...........................................................................................9
17.   Compensation to Participants.................................................................................................9
18.   Data Management and Confidentiality...................................................................................9
19.   Provisions to Monitor the Data to Ensure the Safety of Participants .....................................9
20.   Provisions to Protect the Privacy Interest of Participants.....................................................10
21.   Economic Burden to Participants..........................................................................................10
22.   Informed Consent .................................................................................................................10
23.   Setting...................................................................................................................................10
24.   Resources Available ..............................................................................................................11
26.   References ............................................................................................................................12


Protocol Title: Ketorolac as a Strategy for Reducing Post-Operative Opioid Requirement in 
Children with OSA undergoing Adenotonsillectomy: A Randomized Contolled Trial
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1. Study Summary
Project Title
Ketorolac as a Strategy for Reducing Post-Operative 
Opioid Requirement in Children with OSA undergoing 
Adenotonsillectomy: A Randomized Contolled Trial
Project Design
This study is designed as a randomized controlled trial 
with participants assigned to either Ketorolac or 
Morphine. 
Primary Objective
Determine the effect of Ketorolac administration on 
total postoperative Morphine dosage required to 
achieve analgesia in children
Secondary Objective(s)
Characterize the effect of intra-operative ketorolac 
administration on FLACC pain scores and PACU 
recovery time
Research 
Intervention(s)/Interactions
Ketorolac or Morphine for post-operative 
Study Population
Children’s Healthcare of Atlanta- Egleston
Sample Size
120
Study Duration for 
individual participants
One Day
Study Specific 
Abbreviations/ Definitions 
OSA: Obstructive Sleep Apnea
Funding Source (if any)
Department: Atlanta Gas Light funds
2. Objectives
Our primary aim is to determine the effect of ketorolac administration on total postoperative 
morphine dosage required to achieve analgesia in children with OSA undergoing 
adenotonsillectomy. Our secondary aim will be to characterize the effect of intra-operative 
ketorolac administration on FLACC pain scores and PACU recovery time. The measures we will 
monitoring are PACU morphine requirements, FLACC pain scores, PACU recovery time, 
incidence of post-tonsillectomy bleeding and total amount of pain medications administered 
during hospitalization.
3. Background
Obstructive sleep apnea (OSA) as an indication for adenotonsillectomy has increased 
significantly over the past ten years, and now has surpassed recurrent tonsillitis as the most 


Protocol Title: Ketorolac as a Strategy for Reducing Post-Operative Opioid Requirement in 
Children with OSA undergoing Adenotonsillectomy: A Randomized Contolled Trial
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common indication for this procedure1.  Opioids continue to be the most commonly 
administered pain medication for these procedures. Studies have shown that patients with OSA 
have significantly increased sensitivity to opioids that results in post-operative respiratory 
depression and apnea when administered via standard opioid dosing protocols1-3.  Children 
with OSA were shown to have a nearly fivefold increase in the odds of developing respiratory 
complications when compared to their counterparts with tonsillitis4. As such, it is imperative 
that current anesthetic management of children undergoing this procedure remains as safe and 
effective as possible for this growing population. Ketorolac possesses similar efficacy to 
morphine without the same incidence of respiratory depression, nausea and vomiting, which 
are commonly seen post-adenotonsillectomy5. Importantly, when combined with opioids, 
ketorolac is opioid-sparing. This synergistic effect means that a similar level of analgesia is 
achieved using a lower dose of opioid. However, there continues to be concern about using 
ketorolac due to the potential risk of post-operative bleeding from anti-platelet activity.  
To our knowledge, the use of ketorolac as part of an analgesic regimen has not yet been 
studied in the specific population of children with OSA undergoing adenotonsillectomy, though 
they stand to benefit from it the most. In this randomized prospective study, we will determine 
the effect of ketorolac on the total dose of morphine required to achieve postoperative 
analgesia in children with OSA undergoing adenotonsillectomy. 
4. Study Endpoints
We hypothesize that by administering ketorolac at the end of the procedure once hemostasis 
has been achieved, we can decrease the amount of morphine administered in the PACU. By 
decreasing FLACC pain scores and opioid administration, we aim to decrease the PACU length 
of stay. Additional costs are incurred due to utilization of additional resources, increased length 
of stay, and unanticipated intensive care.  This study will provide a more comprehensive 
understanding of the efficacy and safety of the current standard postoperative analgesic 
regimen employed at our institution, in which opioid analgesia currently plays a prominent role. 
5. Study Intervention/Investigational Agent 
Although not indicated for use in the pediatric population, Ketorolac possesses similar efficacy 
to morphine and other major opioid analgesics, but does not cause respiratory depression and 
is not associated with nausea and vomiting, both commonly described complications post-
adenotonsillectomy5. Importantly, when combined with opioids, it is opioid-sparing. This 
synergistic effect means that a similar level of analgesia is achieved using a lower dose of 
opioid. Improved quality of analgesia, in addition to reduction of opioid-related adverse effects, 
makes ketorolac an ideal adjuvant to study in an OSA population. While data remain mixed as 
to whether ketorolac contributes to increased hemorrhage post-adenotonsillectomy through 


Protocol Title: Ketorolac as a Strategy for Reducing Post-Operative Opioid Requirement in 
Children with OSA undergoing Adenotonsillectomy: A Randomized Contolled Trial
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inhibition of platelet aggregation and prolonged bleeding time, several studies have recently 
emerged that are either reassuring or equivocal. 
A systematic review and meta-analysis showed that while ketorolac is associated with a five-
fold bleeding risk in adults after any surgical procedure, children under 18 were not at a 
significantly increased risk for bleeding post-tonsillectomy5. Another quantitative systematic 
review showed that while NSAIDs were equianalgesic when compared with opioids, and the risk 
of emesis was significantly decreased, the evidence for NSAIDs to increase bleeding risk post-
tonsillectomy was equivocal9.  A recently updated Cochrane study reviewed 15 trials assessing 
the effect of NSAIDs on bleeding in children undergoing elective tonsillectomy or 
adenotonsillectomy8, which found no significant increased risk of bleeding when NSAIDs are 
used in pediatric tonsillectomy. 
6. Procedures Involved
After consent has been obtained, patients will be randomly assigned to ketorolac group or non-
ketorolac group. All patients will receive a similar anesthetic with inhalational induction with 
the exception of the ketorolac group receiving 0.5mg/kg IV ketorolac at the end of the 
procedure once hemostasis has been achieved. The PACU nurses, who will be blinded to 
ketorolac administration, will evaluate the patients using FLACC scores at 10 minutes post-op, 
20 minutes post-op and at time of PACU discharge. For patients with a FLACC score of 6-10, 
morphine 0.05mg/kg will be administered. For patients with FLACC scores of 3-5, morphine 
0.025mg/kg will be administered. The total amount of opioid required to obtain a FLACC score 
of less than 3 will be evaluated as the primary outcome. The secondary outcomes to be 
evaluated will be PACU FLACC scores, time required in PACU, incidence of post-tonsillectomy 
bleeding and total pain medications administered during hospital admission. 
All patients will undergo inhalational induction with Nitrous Oxide and Sevoflurane. After IV 
placement, propofol 1-3mg/kg and fentanyl 1mcg/kg will be administered prior to intubation.  
Immediately after induction, dexamethasone 0.5mg/kg and an IV infusion of acetaminophen 
15mg/kg will be administered. During the intra-op course, dexmedetomidine 0.5mcg/kg and 
odansetron 0.1mg/kg will be given. Patients in the ketorolac group will receive 0.5mg/kg IV, 
while those in the non-ketorolac group will not receive any.
A rescue dose of Fentanyl 0.5-1mcg/kg IV will be available for administration at the end of the 
procedure. The decision to administer this will be left to the discretion of the attending 
anesthesiologist for the case. The choice to give this will be made based on variables including 
patient’s condition and a 20% increase in the heart rate and blood pressure.In PACU, nurses will 
be blinded to ketorolac administration, but will be informed of all other medications given. 


Protocol Title: Ketorolac as a Strategy for Reducing Post-Operative Opioid Requirement in 
Children with OSA undergoing Adenotonsillectomy: A Randomized Contolled Trial
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The PACU nurses will evaluate the patients using FLACC scores at 10 minutes post-op, 20 
minutes post-op and at time of PACU discharge. For patients with a FLACC score of 6-10, 
morphine 0.05mg/kg will be administered. For patients with FLACC scores of 3-5, morphine 
0.025mg/kg will be administered. For patients with FLACC scores of 0-2, no morphine will be 
administered. The total amount of morphine required to obtain a FLACC score of less than 3 will 
be recorded.
The PACU length of stay will be monitored as a secondary outcome, as decreasing the PACU 
length of stay may also be a benefit of ketorolac administration. In addition, we will monitor for 
post-tonsillectomy bleeding and categorize as either post-tonsillectomy bleeding requiring 
surgical intervention or post-tonsillectomy bleeding not requiring surgical intervention. In 
addition, the total amount of pain medication required during hospitalization will be evaluated.
Once the patient is discharged, there will be no further collection of data or follow-up with the 
participant. 
7. Statistical Analysis Plan
 Descriptive statistics will be calculated for all variables of interest and will include means and 
standard deviations, medians and ranges, or counts and percentages, as appropriate. 
Characteristics of subjects who received ketorolac will be compared to those who did not 
receive ketorolac using Chi-square tests for comparisons of categorical variables (i.e. gender, 
race, etc.) and two-sample tests or Mann-Whitney tests for continuous variables (i.e. age, 
apnea hypopnea index, etc.). For binary outcomes, such as post-tonsillectomy bleeding, cohorts 
will be compared using Chi-square tests. Generalized linear models will be used to compare 
differences in amount of narcotic among the two tonsillectomy cohorts, adjusting for any 
differences in patient and surgical characteristics that may exist between the two groups. 
Statistical significant will be performed using Stata v. 13.1 (College Station, TX). 
8. Sharing of Results with Participants
 Study results will not be shared with participants.
9. Study Timelines

The duration of an individual participant’s participation in the study.

The duration anticipated enrolling all study participants.

The estimated date for the investigators to complete this study (complete primary 
analyses)
The subject will participate for one day. 


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10. Inclusion and Exclusion Criteria
             Inclusion Criteria:

Patients 2 years old through 18 years of age

Diagnosis of sleep disordered breathing or obstructive sleep apnea

Children undergoing elective tonsillectomy or adneotonsillectomy at Children’s 
Healthcare of Atlanta Egleston location 

Parent or legal guardian willing to participate, and able to understand and sign the 
provided informed consent  

No known coagulation defect
             Exclusion Criteria:

Parent or legal guardian unwilling to participate or understand 
and sign the provided informed consent

Known coagulation defect

Patients on longstanding NSAID therapy

Known renal impairment
11. Vulnerable Populations
Females that are pregnant or believe to be pregnant, will not be considered for participation in 
the study, due to medical contraindications. 
Cognitively Impaired children will not be considered for participation in the study.
12. Local Number of Participants
We will enroll a total of 120 participants for this study. 
13. Recruitment Methods

Both the Principal Investigator and study staff will take initiative to search for potential 
study candidates on Epic. 

Potential patients will be identified on Epic via surgery status board. Patients who are 
undergoing adenotonsillectomy will be approached by study staff prior to their 
procedure.

No flyers, advertisements or social media/online recruitment mechanisms will be used 
to recruit patients. 
14. Withdrawal of Participants
Parents or Legal Authorized Representative may withdrawal participant from study without 
penalty at any given time.  
A participant may be withdrawn from study if their surgery is scheduled after hours, or if they 
do not receive paralytic. 
Principal Investigator may withdrawal subject at her discretion as deemed fit for patient safety.


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Children with OSA undergoing Adenotonsillectomy: A Randomized Contolled Trial
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15. Risk to Participants
The drug that is being tested may not work any better than regular care. 1-10% of patients that 
take Ketorolac may have: 

Nausea

Abdominal Pain

Headaches
Serious, less common risks include:

Post-procedure bleeding, after tonsil removal (3%), in children with OSA (2%)

Less than (1%): chance of allergic or anaphylactic reaction.
16. Potential Benefits to Participants
The study drug may not work any better than regular care; however, we anticipate less 
morphine will be administered post-operatively. 
17. Compensation to Participants
There will be no compensation provided to participants.
18. Data Management and Confidentiality
Confidentiality will be maintained throughout the entire process from obtaining consent to data 
analysis. Confidentiality will be maintained by only recording information absolutely necessary 
to fulfill the study’s objectives. Information directly identifying patients (names, addresses, 
telephone numbers, social security numbers, email addresses, and account numbers) will be 
excluded from any publication or presentation. In the research database, patients will be 
identified by their assigned study number. The database, along with the code linking a subject’s 
identity to an assigned number, will be locked in the office of the principal investigator or 
designee.
If a participant declines to participate in the study, the participant will not be assigned a study 
ID number and the study coordinators will not collect any data on the participant. If the 
participant agrees to participate in the study, the participant will be assigned a study ID number 
and the study coordinators will collect data points pertinent to the study. These procedures will 
help prevent unauthorized inclusion of the patient’s data in the RedCap database.
19.  Provisions to Monitor the Data to Ensure the Safety of Participants
Monitoring of Adverse Events (AEs) and Serious Adverse Events (SAEs) is an important aspect of 
data collection. After enrollment, the principal investigator or designee will collect the adverse 
experiences from the medical record. The study subjects will be reviewed on a case-by-case 
basis. The principal investigator will determine the seriousness of each adverse event and 


Protocol Title: Ketorolac as a Strategy for Reducing Post-Operative Opioid Requirement in 
Children with OSA undergoing Adenotonsillectomy: A Randomized Contolled Trial
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whether or not the event was related to the study. Serious adverse events (life-threatening, 
requiring intervention) will be reported to the IRB within the guidelines set by the IRB.
After 50% of patients enrolled have undergone surgery, evaluation of the rates of post-
tonsillectomy bleeding will be carefully evaluated. If any significant increase is noted, the study 
will be evaluated by the principal investigator for possible discontinuation.
20. Provisions to Protect the Privacy Interest of Participants
Potential participants will be approached for consent in a private area/room to discuss study 
procedures. Participants will have ample time to ask any questions during consent process; they 
will be reminded that their participation in the study is voluntary, and they will not be penalized 
if they choose not to participate in the study. Participant discussion and data will be limited to 
study personnel only.
21. Economic Burden to Participants
 Participants will not incur any charges related to the study.
22. Informed Consent 
 Only those patients who meet the Inclusion criteria will be considered as possible study 
candidates. A thorough discussion between the parents or legal guardian and the principal 
investigator, or the study coordinator will occur during the study consent process.  No study 
related procedure will occur prior to obtaining appropriate informed consent. Patients will be 
enrolled consecutively as they present to Children’s Healthcare of Atlanta. The parents or legal 
guardian of the patient will be approached in clinic prior to surgery by the principal investigator, 
or the study coordinator to discuss the goals, benefits and risks of the project.  Written 
informed consent will be obtained following this discussion.  For the occasions when parents do 
not arrive at the hospital until the day of surgery, they will be approached only if there is 
sufficient time to allow for their full consideration. One parent even if the other parent is alive, 
known, competent, reasonably available, and shares legal responsibility for the care and 
custody of the child.
Patients undergoing emergent/urgent procedures or when there is insufficient time for the 
parents to thoroughly consider the goals, benefits and risks of this project will not be 
approached for enrollment.  
Non-English-Speaking Participants  
Due to budget restrictions, we will not approach Non-English speaking candidates.
Cognitively Impaired Adults  
Adults who are cognitively impaired will not be approached for study enrollment. 
23. Setting

The research team will identify patients at Children’s Healthcare of Atlanta-Egleston, 
that meet the inclusion criteria via Epic by viewing surgery status board. 


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Children with OSA undergoing Adenotonsillectomy: A Randomized Contolled Trial
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
Potential candidates will be approached 

The CHOA pharmacy will dispense the study drug after the patient is ramdomized.

The study drug will be administered in the operating room, the patient will be followed 
in the PACU for collection of study data points.

Once the patient has been discharged from the hospital, there will be no follow-up by 
the study team and no additional data will be collected.
24. Resources Available
All study staff have completed the required CITI training and understand their duties and 
role in the study. Knowledge of the protocol and study procedures will be reviewed with study 
members prior to patient recruitment; this will ensure patients are screened, consented, and 
monitored appropriately.


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Children with OSA undergoing Adenotonsillectomy: A Randomized Contolled Trial
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25. References
1. 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;100:806–10.
2. Waters KA, McBrien F, Stewart P, Hinder M, Wharton S. Effects of OSA, inhalational 
anesthesia, and fentanyl on the airway and ventilation of children. J Appl Physiol 
2002;92:1987–94.
3. Raghavendran S, Bagry H, Detheux G, Zhang X, Brouillette RT, Brown KA. An anesthetic 
management protocol to decrease respiratory complications after adenotonsillectomy in 
children with severe sleep apnea. Anesth Analg 2010;110:1093–101.
4. Graziela DLC, Pacheco-Periera  C, Aydinoz S, Bhattacharjee R, Tan HL, Kheirandish-Gozal 
L, Flores-Mir C, Gozal D. Adenotonsillectomy complications: a meta-analysis. Pediatrics 
2015;136(4):702-18.
5. Forrest JB1, Heitlinger EL, Revell S. Ketorolac for postoperative pain management in 
children. Drug Saf 1997 May;16(5):309-29.
6. Graziela DLC, Pacheco-Periera  C, Aydinoz S, Bhattacharjee R, Tan HL, Kheirandish-Gozal 
L, Flores-Mir C, Gozal D. Adenotonsillectomy complications: a meta-analysis. Pediatrics 
2015;136(4):702-18.
7. Maslin B, Lipana L, Roth B, Kodumudi G, Vadivelu N. Safety Considerations in the Use of 
Ketorolac for Postoperative Pain. Curr Drug Saf 2016.
8. Chan DK1, Parikh SR.  Perioperative ketorolac increases post-tonsillectomy hemorrhage 
in adults but not children. Laryngoscope 2014 Aug;124(8):1789-93.
9. Cardwell M,Siviter G,Smith A.  Non-steroidal anti-inflammatory drugs and perioperative 
bleeding in paediatric tonsillectomy. Cochrane Database Syst Rev 2005 Apr 18 (2).
10. Møiniche S1, Rømsing J, Dahl JB, Tramèr MR. Nonsteroidal anti-inflammatory drugs and 
the risk of operative site bleeding after tonsillectomy: a quantitative systematic review. 
Anesth Analg 2003 Jan;96(1):68-77.
11. Brown KA, Laferriere A, Lakheeram I, Moss IR. Recurrent hypoxemia in children is 
associated with increased analgesic sensitivity to opiates. Anesthesiology 2006;105:665-
9.
12. Riggin L, Ramakrishna J, Sommer DD, Koren G. A 2013 updates systematic review & meta-
analysis of 36 randomized controlled trials; no apparent effects of nonsteroidal anti-
inflammatory agents on the risk of bleeding after tonsillectomy. Clin Otolaryng 
2013;38:115-29.
13. Perkins JN, Liang C, Gao D, Schultz L, Friedman NR. Risk of post-tonsillectomy hemorrhage 
by clinical diagnosis. Laryngoscope 2012;122(10):2311-5.
14. Coté C, Posner K, Domino K. Death or Neurologic Injury after Tonsillectomy in Children 
with a Focus on Obstructive Sleep Apnea: Houston, We Have a Problem! Anesth Analg 
2014;118: 1276–1283.