Ketorolac Use in Pediatric Patients Undergoing Tonsillectomy

Tonsillectomy/adenoidectomy is an elective operation, mainly in the pediatric population. In
our institution, this procedure is performed by Dr. Jason Mouzakes and the otolaryngology
residents under his supervision. The location of the research is at the Albany Medical Center
Hospital, Main Campus and South Clinical Campus. Duration of this study for each individual
patient will be set at 14 days post procedure, taking into account that bleeding risk with
this procedure is highest within the first 2 weeks post-operatively. Data will be obtained
within 90 days after discharge from the hospital by telephone interview with the parents or
hospital record. We plan to enroll at least 600 patients, 300 in each group, ASA physical
status I to III and age 2 years to 18 years old (inclusive). Parents and children may be
informed about the study at the time when surgery is planned during initial office visit.
Enrollment in the study will be done on the day of the surgery, after the Anesthesiologist or
Otolaryngology/Anesthesiology Resident explains the purpose, benefits and possible risks of
the study and answers all questions of the parents. Before enrollment is finalized, informed
consent and informed assent, if applicable, to take part in a human research study will be
obtained.

Inclusion criteria are: ASA physical status I to III, age of 2 years to 18 years old
(inclusive) scheduled for elective tonsillectomy with or without adenoidectomy. Exclusion
criteria are: allergy to any nonsteroidal anti-inflammatory medications, bleeding disorders,
history of gastrointestinal bleeding, renal impairment, severe asthma, cardiac/hepatic
disease, use of anticoagulation, recent NSAID use (within last 72 hours) or any other medical
problem that in the opinion of investigator would interfere with study participation. After
enrollment, children will be randomized into one of the two groups by a card system. Total of
600 patients will be randomized into 2 groups; 300 patients in each group. The treatment
groups will be as follows: Group 1 (K) = will receive Ketorolac 0.5 mg/kg IV up to a maximum
dose of 30mg, in the form of Ketorolac Tromethamine solution for IV/IM use, 30mg/ml single
dose vial at the completion of the tonsillectomy in the operating room. Group 2 (NS) = will
receive an equivalent weight-based volume of 0.9% NaCl solution at the completion of the
tonsillectomy in the operating room.

At the completion of surgery, patients will be transferred to the post-anesthesia care unit
(PACU). Pain scores upon discharge from PACU will be recorded by PACU nursing staff according
to their standard protocol and displayed on data collection sheet for each patient. The PACU
nurses will use their standard protocol pain scores that are used for all pediatric patients.
Additional pain medication if needed in the PACU will be acetaminophen 15mg/kg oral solution
or opioid medications at discretion of treating anesthesiologist. Acetaminophen will only be
given in PACU if it was not received pre-operatively. Time, dose and effect of supplemental
("rescue") acetaminophen/opioids will be documented and used for statistical analysis.
Children will be united with parents according to standard practice in pediatric PACU.
Presence or absence of nausea and vomiting or any other adverse effects will be recorded.
Patients will be discharged to home from the PACU or 2nd level short-stay recovery unit (at
South Clinical Campus) when standard criteria are met for each patient per protocol.

Randomization Plan:

Patients will be randomized by a card system. There will be 600 cards with 300 labeled (K)
for ketorolac group and 300 labeled (NS) for placebo group along with the assigned subject
number. Preservative free 0.9% normal saline will be used as placebo. Randomization will be
done using www.randomization.com which will generate a randomization sequence with a
concealed blocking schedule. A non-investigator will prepare envelopes numbered sequentially,
each containing a card indicating the subject number (sequentially numbered 1 - 600) and
group as randomized by above plan. Envelopes are opened only upon obtaining consent
maintaining allocation concealment until treatment is initiated. Patients are therefore
assigned a subject number at the initiation of the study. The non-treating anesthesiologist
will open the next sequential envelope (starting from envelope #1) and draw up the specified
drug and give the drug with a patient label to the treating anesthesiologist. The
non-treating anesthesiologist will also tell the treating anesthesiologist the patient's
subject number so it may be recorded on the individual data collection sheet. The
non-treating anesthesiologist will place a patient label on the drug card and store the card
in the anesthesiology office, specifically Dr Afroze's office inside of room D108. Dr
Afroze's office is locked and has minimal access. The patient drug cards will be accessed by
the research team two weeks after the surgery date to record patient data.

The PACU nurses, surgeon, residents, and treating anesthesiologist will all be blinded and
may perform the PACU scoring and data collection. Study drugs will be documented the same
exact way on the anesthesia records for all the study patients. All the study patients'
charts will have both drugs documented as IN study drug dose in mg. The doses of the drugs
are pre-calculated based on the patient's weight and will be drawn by a non-treating
anesthesiologist and administered by the treating anesthesiologist at the time of the
surgery.

Patients for our study will be recruited from the Pediatric ENT clinical practice of Dr.
Mouzakes. Surgery, anesthesia, and postoperative recovery will take place at the Albany
Medical Center Hospital, Main Campus and South Clinical Campus. We plan to enroll 600
children, age of 2 to 18 years old (inclusive) and ASA physical status I to III. We
anticipate completing our study in 12 to 24 months.

Data will be collected and analyzed for: age, gender, weight, ASA status, main diagnosis
(chronic tonsillitis or sleep-disordered breathing), secondary diagnosis (for example,
asthma, GERD, etc.), PACU/step-down time to discharge, PACU/step-down supplemental pain
medication, PACU or step-down nausea/vomiting, and bleeding rates. An
anesthesia/otolaryngology resident blinded to the study group will collect the following
variables (please refer to attached data collection sheets for details on data collection).

Each patient will have an individual data collection sheet with the following information:
subject number, age, gender, weight, ASA status, main diagnosis, secondary diagnosis,
medication administration time, times for surgery start and finish, PACU admission and
discharge time, admission time to step-down unit and discharge from step-down/hospital, time
if/when supplemental pain medications are given, pain scores prior to discharge from PACU,
nausea/vomiting in PACU or step-down unit, and other adverse effect in PACU/step-down unit.
Patient identifiers such as name, MRN, and date of birth will not be recorded on individual
data collection sheet and instead will be stored on a master key which is kept on a locked,
password protected AMC computer inside Dr Afroze's office, which is locked with limited
access.

Data collection sheets will be kept confidential and stored in Dr Afroze's office which is
locked with minimal access. At the conclusion of two weeks post-operatively, patient data
collection sheets and drug cards will be collected from Dr Afroze's office and data will be
entered into Excel data compilation sheet using a locked, password protected Albany Medical
Center computer inside Dr Afroze's office. The patient's subject number, name, MRN, and date
of birth will be recorded on a master key and stored in a locked, password protected Albany
Medical Center computer inside Dr Afroze's office, which is locked with limited access. All
other data will be entered into a separate excel sheet (data compilation sheet) using the
patient's subject number. After at least two weeks post-operatively, the patient's medical
record will be searched for any ER visits, hospital re-admissions, return to the operating
room for post-tonsillectomy bleeding, or possible other adverse effects of significance
documented in the electronic medical record. If all of the above are negative, the parents
will be called to inquire if there were any ER visits, re-admissions, or procedures for
bleeding done at an outside hospital.

Data will be collected and analyzed by the investigators with the help of our experts in
statistics at Main Campus of Albany Medical Center. Only members of the investigation team
and individuals who are helping with data analysis (including medical students and
statisticians) will have access to the data and the data will be contained in Dr Afroze's
office inside D108.

This study will have power of 81% to show that the bleeding rate for new treatment
(ketorolac) is at least as low as the event rate for the control group. This assumes that the
true event rates for the active control and new treatment populations are precisely equal (at
2.0%), that a difference of 3.0% or less is unimportant, that the sample size in the two
groups will be 280 and 280, and that alpha (1 tailed) is set at .05.

Formally, the null hypothesis is that the event rate for new treatment is 3.0 percentage
points higher than the event rate for active control, and the study has power of 81.3% to
reject this null. Equivalently, the likelihood is 81.3% that the 95.0% confidence interval
for the difference in event rates will exclude a 3.0 point difference in favor of active
control.

The primary endpoint, bleeding rates, will be compared between the two groups by Chi-square
test (or Fisher's exact test if expected values are 5 or less). Other secondary categorical
data (readmission, PACU nausea/vomitting) will be analyzed similarly. Continuous data (opioid
administrations, PACU pain scores, length of stay in recovery units) will be compared with an
independent sample t-test or Mann-Whitney test if data demonstrates significant
non-normality. Multivariable analysis will be used to determine if bleeding is associated
with the covariates age, gender, weight, ASA status, and primary or secondary diagnoses.

The risks of the study include the risks of possible allergic reactions to ketorolac in
patients with no previously known drugs allergies, and possible decreased pain control for
some patients. However, as is standard of practice, all patients with uncontrolled
post-operative pain will have additional acetaminophen or opioid medications administered as
needed for pain in the post-operative units under the guidance of the treating
anesthesiologist. As previously demonstrated, ketorolac intravenous & intramuscular have been
shown in the anesthesiology literature to be safe with a low incidence of side effects.
Patient's parents will be informed of other possible side effects of ketorolac including
platelet dysfunction with prolonged bleeding at operative site, gastrointestinal bleeding,
and renal dysfunction. There are no described long term side effects from single
intraoperative application of ketorolac. Side-effects that have been noticed in other studies
are minimal and transient. Patient's parents will have access to the investigator and ER
department 24 hours a day, 7 days a week if any concerns appear.

The major benefit from IV ketorolac for patients is potential of adequate pain control for
tonsillectomy with decreased use of opioid analgesia, ameliorating possible negative side
effects of narcotics such as respiratory depression and nausea/vomiting. Achieving adequate
pain control in tonsillectomy patients leads to improved oral intake and decreased risk of
dehydration. Additionally, results of this study will be contributing to improvement in pain
management for future patients undergoing tonsillectomy surgery. Overall, we feel that the
risks involved with this study are minimal and potential benefits are quite large.

The PHI to be collected includes the medical record number and date of birth to identify the
range of age of the participants, possible allergy to medications, and brief past medical
history relevant to the study.

All data will be maintained with strict confidentiality. Data on initial forms will be
handwritten and later entered into a password protected computer file. Patient identifiers
such as name, date of birth, and MRN along with subject number will be recorded on a
password-protected, securely stored Master key on a password-protected AMC computer located
in Dr Afroze's office (D108). Only members of the research group will have access to
patient's individual data collection sheets, data compilation sheet, and master key for
analysis. All personal information of the patients included in the study will be kept for 7
years after the completion of the study.

If consent is not obtained, the patient will not be included in the study and will receive
standard assessment and care, which typically includes single dose 0.5mg/ kg ketorolac at the
completion of the procedure and additional pain medications in recovery areas as needed, such
as acetaminophen or opioids. At any point in the study, the subject may choose to discontinue
participation and opt for standard treatment.

Inclusion Criteria:

-ASA physical status I to III, age of 2 years to 18 years old (inclusive) scheduled for
elective tonsillectomy with or without adenoidectomy.

Exclusion Criteria:

-Exclusion criteria are: allergy to any nonsteroidal anti-inflammatory medications,
bleeding disorders, history of gastrointestinal bleeding, renal impairment, severe asthma,
cardiac/hepatic disease, use of anticoagulation, recent NSAID use (within last 72 hours) or
any other medical problem that in the opinion of investigator would interfere with study
participation.