Emergence Agitation and Pain Scores in Pediatrics When Comparing Single-modal vs Multi-modal Analgesia for ENT Surgery

Place of Study:

Nemours Children's Hospital, Orlando, Florida (Primary Site) Wolfson Children's Hospital,
Jacksonville, Florida (Nemours Jacksonville Satellite Site)

Study Design:

Prospective Randomized Study Total Number of Patients: 150

Methods and Materials: 150 patients will be randomly divided into three groups of 50
patients. Each group will receive sevoflurane induction and maintenance of anesthesia.
Sevoflurane, currently the most commonly used agent for inhalational induction, will be used
for induction of anesthesia, as it is less irritating to the tracheobronchial tree than other
volatile anesthetic agents and is considered the standard for pediatric induction anesthesia.
These three groups, (study arms), are identified as follows:

Group A: multi-modal analgesia of IV fentanyl plus IV acetaminophen and oral placebo Group B:
multi-modal analgesia of IV fentanyl plus PO acetaminophen and IV placebo Group C: single
modal analgesia of IV fentanyl plus oral placebo and IV placebo Pre-operative procedures: The
Research Pharmacy will have the following standards for randomization: prior to patient
surgery date; the pharmacy will assemble study kits to contain the appropriate drug products
based on the 3 randomization scenarios: A. IV Tylenol and Oral Placebo, B. IV Placebo and
Oral Tylenol, or C. IV Placebo and Oral Placebo. The kits will be kept in the pharmacy and
identified in a blinded fashion from other study team members. On the day of surgery,
(patient dosing day), blinded study team member will provide the signed study consent to
pharmacist, along with the patient's weight to be used in calculating dosages of study drug.
The pharmacist will then assign the patient to 1 of 3 study arms, in a random approach.
Randomization will be performed by using a method based on the biased coin method using a
dynamic urn technique. Once the study arm has been determined, the corresponding kit will be
used to prepare the study drugs by patient weight. The blinded, randomized study kit
information will be kept in a locked Excel spreadsheet, with password access, only available
to pharmacy team members. All study drugs will be checked and verified by a licensed
pharmacist prior to dispensing to a blinded study team member.

None of the study patients will receive premedication for sedation. Premedication is not a
standard treatment at Nemours Children's Hospital (NCH) as NCH allows parental presence
during induction of anesthesia to facilitate the transport of the patient to the operating
room and decrease separation anxiety. Wolfson Children's Hospital will allow parental
presence for study patients. Parental presence is an appropriate substitute for sedation
premedication. In the pre-operative area, all patients will receive a de-identified PO syrup.
The syrup will be prepared by the pharmacy and will contain acetaminophen (15 mg/kg
-160mg/5mL Manufacturer: Major Pharmaceuticals), for the PO acetaminophen group and placebo
flavored syrup (Manufacturer: Humco, Ingredients: Sucrose 82.3%, Purified Water, Artificial
Flavors, 0.1% Sodium Benzoate as a preservative, Critic Acid, FDC Red #40, and inert
ingredients), for the other two groups. This approach will maintain blindness of the
peri-operative staff, and patients/parents/guardians.

Intraoperative Procedures and Administration of intra-op analgesia: Before induction of
anesthesia the pre-induction vital signs will be reviewed and ASA standard monitors will be
applied. Standard ASA monitors include blood pressure, ECG, pulse oxymetry, etCO2

Measurement, respiratory rate and temperature. Induction of anesthesia will be accomplished
via inhalation of sevoflurane (8 vol%) in nitrous oxide (70%) and oxygen (30%) at a fresh gas
flow of 10 Lpm. An IV will be established and propofol 2mg/Kg will be administered to
facilitate endotracheal intubation. After intubation, all children will receive fentanyl
(West- Ward Pharmaceuticals) 2 mcg/kg. IV Fentanyl is considered standard of care for
analgesia regimen for these types of surgery. Intra-op anesthesia team will be blinded to the
use of non- opioid IV analgesia and will administer a pharmacy prepared de-identified
infusion (pharmacy will blind the IV formulation of acetaminophen and all pharmacy
formulations will follow regulation 797 compounding standards), following intubation that
will consist of 0.9% normal saline (Baxter Pharmaceuticals), placebo for control groups and
IV acetaminophen (15 mg/kg, - 1000mg/100 cc Mallinckrodt Pharmaceuticals) for the IV
acetaminophen group. The maximum single dose will be 750 mg with a 24-hour maximum dose not
to exceed 3,750 mg in this 24-hour period. The product will infuse for 15 minutes as
recommended by the manufacturer. For maintenance of anesthesia, children will receive
sevoflurane (maximum of 2.0±0.2 MAC, age adjusted) with a constant fresh gas flow of 2 L/min
(maximum FIO2 of 30% air mixed with oxygen), using a semi-closed circle breathing system.
Ventilation will be controlled to maintain normocapnia (ET-CO2 32-38 mmHg). Additional doses
of fentanyl can be administered, per anesthesiologist's discretion, in all groups by
increments of 0.5 mcg/Kg IV per dose for hemodynamic response to surgical stimulation greater
than 20% above baseline. Removal of the mouth gag for tonsillectomy/tonsillectomy and
adenoidectomy/adenoidectomy will be defined as the end of surgery. At this point, inhalation
anesthetic will be discontinued. Fresh gas flow will be increased to 8 Lpm, 100% oxygen.
Tracheal extubation will be performed when normal ventilation is achieved and cough or gag
reflex is regained.

Screening/Consent Process: Potential participants will be identified and receive basic
information about the study and enrollment criteria at ENT clinic by participating ENT
surgeons. A copy of an unsigned consent will be given to the families who are interested in
participating in the study. Anesthesiologists, will obtain PP consent and Assent for eligible
children. A signed and dated copy of all consents forms will be given to the parents.

Intraoperative Standardization and Procedures: The surgical technique will be standardized
and a limited group of two surgeons per clinical site that share same surgical technique
which will be agreed upon at the start of the clinical phase. This technique will consist of
only Teflon blade cautery and will require no peri-tonsilar local anesthetic injection. The
number of anesthesia providers involved in the study will be limited to two anesthesiologists
per clinical site.

The post-operative pain management approach will be restricted to fentanyl (0.5 mcg/Kg
IV/dose titrated to effect) for moderate to severe pain. Ibuprofen (10mg/Kg) PO will be
ordered for mild to moderate post- op pain. Post-op recovery staff will be limited to a
maximum of three trained PACU nurses per site and will use FLACC Scale for age 24 month to 4
years of age and sedated patients at time of assessment, Wong-Baker FACES for patients 4 to 7
years of age and non-verbal patients and Numeric Pain Score for patients equal/greater than 7
years of age to assess level of pain. Episodes of clinical emergence agitation/delirium (EA),
will receive rescue treatment. This treatment will consist of 0.5 - 1.0 mcg/Kg IV
dexmedetomidine.

Age, gender, height, weight, procedure, duration of surgery, intra-op agents used, exposure
and time of discontinuation of anesthesia to extubation will be documented for each patient.
A blinded PACU nurse will monitor the patient. The Post-anesthesia unit monitoring standards
consist of ECG, Blood Pressure, pulse-oxymetry and respiratory rate every 5 minutes times 3
and every 15 minutes thereafter until discharge. Temperature will be obtained upon arrival to
unit and every hour or as needed. All patients will be evaluated for the Aldrete Score which
assesses readiness for discharge from post-anesthesia care unit. The PACU nurse will record
degree of agitation using the PAED scale and measure and record the pain scores using either
the FLACC for patients 24 months to 4 years of age and patients who are sedated at time of
assessment, Wonk-Baker FACES for patients 4 to 7 years of age and non-verbal patients and
Numeric Pain Scores for patients equal/greater than 7 years of age upon admission to the PACU
and every 15 minutes for approximately 1 hour after admission, or until discharge from the
PACU, whichever comes first. These nurses will all be experienced in the use of PAED scale.
There will be three; two-hour study training sessions at each clinical site for PACU
participating nurses. PACU nurses assigned to this study will be selecting the Modified
Aldrete scores (respiration, O2saturation, consciousness, circulation, activity) and
documenting adverse events

Monitoring Procedures:

The investigative team assures that informed consent is obtained prior to performing any
research procedures, that all subjects meet eligibility criteria, and that the study is
conducted according to the IRB-approved research protocol.

Collection and Reporting of SAEs and AEs:

For this study, the following standard AE definitions are used:

Adverse event: Any unfavorable and unintended sign, symptom or disease temporally associated
with the use of a medical treatment or procedure, regardless of whether it is considered
related to the medical treatment or procedure.

Serious Adverse Event: Any AE that results in any of the following outcomes:

- Life-threatening event

- Event requiring inpatient hospitalization or prolongation of hospitalization

- Death

- Congenital anomaly

- Persistent or significant disability/incapacity

- Required intervention to prevent permanent impairment/damage

AEs identified will be captured in real time as they become known. AEs that result in visits
to the ED and/or outpatient clinics will be monitored at each site through their readmission-
monitoring program and reported to the department of Anesthesiology by the quality and safety
officer. In addition, all AEs are reported in Orlando according to the Nemours IRB AE
reporting guidelines and in Jacksonville, according to the Baptist Health IRB AE guidelines.

Treatment of AEs:

In case of a symptomatic event where a severe adverse event or any SAE is noticed, the
blinding can be broken by accessing a sealed envelope that contains the assigned drugs in the
randomization process and appropriate treatment will be instituted. These patients will be
withdrawn from the study but the clinical and research team will continue to collect safety
information. This data will be included in the safety database and reported during monthly
meetings. Nemours will assure that the participant receives treatment, if needed , for study-
related injuries.

Ameliorating Measures:

Episodes of clinical emergence agitation/delirium (EA), will receive rescue treatment. This
treatment will consist of 0.5 - 1.0 mcg/Kg IV dexmedetomidine as previously stated.

All patients will be instructed not to start the next dose of acetaminophen until 6 hours
after last administered dose. This dose correlates to the time of intra-operative IV infusion
administration.

All discharged patients will receive a call within 24 hours of surgery for follow-up.

- Compliance of regulatory documents as well as study data accuracy and completeness, will
be monitored through an internal study team quality assurance process.

- Confidentiality throughout the trial is maintained by securing identifiable participant
data in secured,

Inclusion Criteria:

1. Patients who are 24 months through 7 years of age

2. Patients who weigh <50 kg

3. Patients who are able to take PO medications

4. Patients who are ASA Classification I and II

5. Patients who are found to be a candidate after clinical review of detailed History and
Physical Exam, review of Polysomnogram or Pediatric Sleep Questionnaire

6. Patients who are scheduled for routine adenoidectomy or tonsillectomy with or without
adenoidectomy not in conjunction with another invasive or diagnostic procedure

7. Patients who meet clinical indications for surgery

8. Family and patient must be proficient in English to understand consent, post-operative
instructions, and facilitate the assessment after emergence of anesthesia

Exclusion Criteria:

1. Children with a history of developmental delay or psychological disorders that may be
at higher risk for EA as determined by study physician after review of history and
problem list in EMR

2. Patients with previous hypersensitivity to oral or intravenous acetaminophen, fentanyl
or any of its components or ingredients in placebo,

3. Patients with severe hepatic impairment or severe active hepatic disease

4. Patients with previous history of Malignant Hyperthermia or susceptibility to volatile
anesthetics agents like sevoflurane

5. Any patient who weighs >50 Kg.

6. Any patient that requires premedication. Versed may contribute to an increase in EA.
Premedication is reserved when parental presence is not feasible or for very anxious
children.

7. Patients unable to take PO (acetaminophen or placebo) will be excluded from the study.

8. Children with severe symptomatic sleep apnea that require post-operative
hospitalization.

9. Severe symptomatic sleep apnea is defined as a- patients who has a pre-operative
polysomnogram and a calculated Apnea-Hypoxia Index greater than 10 b- patients with
high scoring in Pediatric Sleep Questionnaire (PSQ)

10. Patients with severe symptoms and findings in physical exam that require
post-operative hospital admission.

11. Patients and/or families not proficient in English

12. Participant is currently participating or has within the previous 30 days,
participated in another clinical trial/research study