Clinical trial NCT02747875
Conditions: Opioid Use, Unspecified
Keywords: pediatric cardiac bypass surgery methadone fentanyl morphine
Sponsor: Andrew Waberski
Start date: 2016-09-01; Completion date: 2019-02-07
Enrollment: 26 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine if methadone improves postoperative pain control in pediatric patient's undergoing cardiac surgery.

Detailed description:
The proposed study will be conducted at Children's National Health System (CNHS). Pediatric subjects undergoing cardiac surgery requiring cardiopulmonary bypass will be recruited. Eligible and consenting participants will be assigned a unique identification number and will be randomly assigned to receive either methadone or fentanyl using a computer-generated randomization scheme. A total of 52 participants will be enrolled to each arm of the study, providing 80% power to detect a 30% difference between groups.

Once informed consent is obtained the inpatient pharmacist at CNHS will randomly assign eligible participants to receive methadone or fentanyl. The pharmacist will prepare 0.3 mcg/kg of methadone and 20 mcg/kg of fentanyl for loading dose administration, diluted to 10 mL.

The IDS pharmacy will store and maintain all medications per Department of Pharmacy standard operating procedures for waste of a controlled substance (C-II) drug.

The treatment phase will begin at the induction of general anesthesia and finish at the end of the surgical procedure. Standard anesthetic practice for monitoring, induction, and maintenance of general anesthesia will be preserved throughout.

Participants will receive either 0.3 mg/kg of methadone or 20 mcg/kg of fentanyl prior to surgical incision, over 20 minutes. The medication will be prepared as described above and all research and staff personnel as well as the study participant will be blinded to treatment group assignment.

As per standard anesthetic practice, the subject will continue to be evaluated for hemodynamic stability, postoperative risk of bleeding, and respiratory effort. Morphine at 0.05 mg/kg per dose will be administered intravenously as needed for pain control. Surgical procedures and times will be recorded in the operative report via the electronic medical record.

Postoperative ICU Phase The postoperative cardiac intensive care unit phase will begin at admission to the Cardiac Intensive Care Unit (CICU) and will end on the third day of hospital admission. Postoperative care including hemodynamic stability, resuscitation, and respiratory support will be at the discretion of the CICU team.

As per CICU protocol, the nurse will monitor and record vital signs and pain scale (FLACC) scores beginning at handoff from the anesthesia team to the intensive care team. The nurse will continue to document vital signs including: blood pressure, heart rate, respiratory rate, oxygen saturation, temperature, minute ventilation when mechanically ventilated, and oxygen supplementation when appropriate, in the electronic medical record every hour. As per nursing protocol, FLACC scores will be recorded in the electronic medical record every 4 hours or when the nursing staff witnesses pain during the entirety of the subject's CICU stay.

All subjects will receive analgesics and sedation medication based on CICU postoperative pain control and agitation protocol

Data Collection The investigator or designee, blinded to group assignment, will collect all of the relevant data from the electronic medical record within six months of the cardiac surgery and enter it into the Medical Center's proprietary web-based data-entry and data-management system, REDcap (Research Electronic Data Capture). The source of information will be medical records at the Children's National Health System "Anesthesiology" and "Bear Tracks" information systems provided by Cerner Corporation.

Data will be obtained specifically for research purposes. Subject identifiers (e.g. name, date of birth, address) will not be entered into the REDcap system. The previously assigned unique identification numbers will be used.

Statistical Considerations Significance will be measured as a 30% reduction in postoperative pain requirement. Statistical analysis will be used to evaluate any differences between the randomization groups in opioid-related adverse events during the first 24-hour postoperative period.

Arms: arm 1: Participants will receive 20 mcg/kg of fentanyl prior to surgical incision, over 20 minutes. The medication will be prepared as described and all research and staff personnel as well as the study participant will be blinded to treatment group assignment. arm 2: Participants will receive 0.3 mg/kg of methadone prior to surgical incision, over 20 minutes. The medication will be prepared as described and all research and staff personnel as well as the study participant will be blinded to treatment group assignment.
Interventions: intervention 1: Methadone intervention 2: Fentanyl
Intervention descriptions: intervention 1: The treatment phase will begin at the induction of general anesthesia and finish at the end of the surgical procedure. Under the direction of the cardiac anesthesiologist subjects will be premedicated and general anesthesia will be induced with standard anesthetic monitoring and management. Participants will receive 0.3 mg/kg of methadone prior to surgical incision, over 20 minutes. General anesthesia will be maintained with inhalational anesthetics and paralytics. The subject will continue to be evaluated for hemodynamic stability, bleeding, and respiratory effort. The postoperative intensive care phase will begin at time of room admission and end at day three of hospital stay. All subjects will receive morphine or oxycodone analgesics and sedation medication based on the hospital's postoperative pain control and agitation protocol. Standard electronic documentation will be maintained throughout and include: medications, vital signs, and events. intervention 2: The treatment phase will begin at the induction of general anesthesia and finish at the end of the surgical procedure. Under the direction of the cardiac anesthesiologist subjects will be premedicated and general anesthesia will be induced with standard anesthetic monitoring and management. Participants will receive 20 mcg/kg of fentanyl prior to surgical incision, over 20 minutes. General anesthesia will be maintained with inhalational anesthetics and paralytics. The subject will continue to be evaluated for hemodynamic stability, bleeding, and respiratory effort. The postoperative intensive care phase will begin at time of room admission and end at day three of hospital stay. All subjects will receive morphine or oxycodone analgesics and sedation medication based on the hospital's postoperative pain control and agitation protocol. Standard electronic documentation will be maintained throughout and include: medications, vital signs, and events.

Protocol documents:
Prot_000.pdf: 
 
 
1
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TITLE: The Effect of Methadone vs. Fentanyl Administration on Postoperative Pain 
Control in Pediatric Patients Undergoing Cardiac Surgery: A Randomized, Double-
Blinded Controlled Trial 
 
NCT02747875 
 
Original: 06/12/2016 
Updated: 6/12/2018 
Uploaded: 04/06/2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
2
CHILDREN'S NATIONAL HEALTH SYSTEM 
Department of Anesthesiology, Sedation and Perioperative Medicine 
111 Michigan Avenue, NW 
Washington, DC 20010 
(202) 476-2025 
 
RESEARCH PROTOCOL 
Nina Deutsch, M.D. 
Andrew Waberski, M.D. 
 
TITLE: The Effect of Methadone vs. Fentanyl Administration on Postoperative Pain 
Control in Pediatric Patients Undergoing Cardiac Surgery: A Randomized, Double-
Blinded Controlled Trial 
 
ABSTRACT 
The main objective of this study is to determine if administration of methadone in pediatric 
patients undergoing cardiac surgery improves postoperative pain control and potential opioid 
side effects. Large opioid doses are typically administered to patients undergoing congenital 
cardiac surgery to blunt hemodynamic stress response. Previous studies have shown that high 
dose opioid strategies can result in postoperative respiratory depression, ileus, and opioid 
tolerance.1-4 Furthermore, inadequate acute postoperative periods can potentially increase risk for 
long-term pain, decrease patient satisfaction, and potentiate hemodynamic complications.5,6 We 
intend to show through a randomized, double blinded controlled trial that compared to fentanyl, 
methadone administered intraoperative will significantly reduce postoperative opioid 
requirements for pain control by 30% during the first 24 hours. Opioid-related adverse events 
will be monitored closely and a secondary analysis will compare the incidence of side effects 
between the two groups during the first 24-hour postoperative period.  
 
RESEARCH PLAN 
 
A. Specific Aims: 
The main objective of this study is to determine if administration of methadone in pediatric 
patients undergoing cardiac surgery improves postoperative pain control and potential opioid 
side effects.  Large opioid doses are typically administered to patients undergoing congenital 
cardiac surgery to blunt hemodynamic stress response. Previous studies have shown that high 
dose opioid strategies can result in postoperative respiratory depression, ileus, and opioid 
tolerance.1-4 Furthermore, inadequate acute postoperative periods can potentially increase risk for 
long-term pain, decrease patient satisfaction, and potentiate hemodynamic complications.5,6  
 
The Primary Aim of this study is to compare the effect of intraoperative administered 
methadone vs. fentanyl on postoperative opioid requirements during the first 24 hours, in 
pediatric patients undergoing cardiac surgery. 
 


 
 
3
Hypothesis: Compared to fentanyl, methadone administered intraoperative will 
significantly reduce postoperative opioid requirements for pain control during the first 24 
hours.  
 
The Secondary Aim of this study is to complete a secondary analysis of the incidence of opioid-
related adverse events between the two groups during the first 24-hour postoperative period. 
 
B. Background and Significance: 
Pain control and hemodynamic stability are crucial for postoperative pediatric cardiac surgery 
patients. Anesthetic goals during pediatric cardiac surgery aim to blunt neurohormonal stress 
responses to surgical stimulation and cardiopulmonary bypass as well as maintain normal 
hemodynamic parameters. To achieve these goals, a mainstay of care includes administration of 
high dose synthetic opioids and inhalational anesthetics. Recent studies have also shown the 
benefit of multimodal drug therapy and adjuncts including alpha-agonists, such as 
dexmedetomidine.7 
 
Currently, fentanyl is the primary analgesic used during pediatric cardiac surgery for its 
beneficial pharmacokinetic characteristics of rapid onset and high potency.  The mechanism of 
action of fentanyl is through stimulation of the mu-opioid receptor, which provides not only 
analgesia at the mu-1-receptor, but also the undesirable side effects of respiratory depression, 
bradycardia, and physical dependence from stimulation at the mu-2-receptor. Postoperatively, 
morphine is typically administered for postoperative analgesia in the intensive care unit because 
of its pharmacokinetic profile of rapid onset and moderate duration of action.  
 
Methadone is an ideal opioid analgesic for cardiac surgery because it is a strong mu-opioid 
analgesic with a long duration of action, prevents hyperalgesia through NMDA desensitization, 
and prevents morphine-induced tolerance. Furthermore, it meets the analgesic goals in the 
perioperative setting by limiting the neurohormonal stress response, controlling fluctuations in 
pain control, and decreasing unwanted respiratory and cardiovascular side effects. 
 
Both methadone and fentanyl, when administered during major surgery, show hemodynamic and 
pharmacodynamic stability. In one study done by Bowdle et al, no significant differences in 
mean heart rate were found between 20 patients who received fentanyl compared to 33 patients 
who received methadone for induction of anesthesia.8 Additionally, the same study showed that, 
the mean systolic and diastolic blood pressures were significantly lower in patients to whom only 
fentanyl was administered versus those patients who received methadone during the intubation 
period.8 Other studies have demonstrated that methadone does not have decreased clearance for 
immature cytochrome p450 enzymes that would be found in infants less than 1 year old. In a 
study done by Ward et al, no differences were found for methadone clearance when comparing 
methadone between different age groups, including newborns, teenagers, and adults.9 
 
Standard fentanyl doses used in cardiac surgery can potentiate side effects of postoperative 
nausea and vomiting, receptor sensitization, and opioid tolerance.  Studies have shown that high 
dose opioid (fentanyl 30-50 mcg/kg) administration in pediatric cardiac patients is associated 


 
 
4
with a higher incidence of postoperative nausea and vomiting. 4 Chia et al. demonstrated an 
increased incidence of emesis postoperatively after administering high doses of fentanyl 
intraoperatively compared to low doses of fentanyl (52% vs. 12%, respectively).4 In contrast, a 
double-blinded, randomized, controlled trial of 55 participants, showed that methadone 
decreased the incidence of nausea and/or vomiting when compared to morphine.10 
 
Sensitization of pain pathways to opioids has potential to cause opioid-induced hyperalgesia.  
The mechanism of opioid-induced hyperalgesia is not well understood, but has been established 
in several common opioids, such as morphine and fentanyl, but not methadone.11 Cardiac surgery 
patients are routinely exposed to opioids during and after congenital repairs in the newborn 
period, intensive care sedation protocols, and subsequent reoperation later in life.  Based on 
exposure rates, this patient population is at risk for opioid-induced hyperalgesia.  The treatment 
of opioid-induced hyperalgesia follows closely the multimodal balanced analgesia pathway: 
supplementing opioids with N-methyl-D-aspartate (NMDA) receptor modulators such as 
ketamine, tapering opioid doses.  Methadone has been shown to be effective in reducing high 
dose opioid-induced hyperalgesia by NMDA antagonism.11,12 
 
Tolerance to opioids leads to escalation in dosing of these medications and increases risk of 
potential side effects. Furthermore, postoperatively and during subsequent cardiac procedures, 
these patients may develop a limited therapeutic window for pain control from the use of similar 
opioids.  In one study high dose fentanyl administered intraoperative was associated with an 18-
50% increase in fentanyl requirements in the immediate postoperative period.4 Methadone 
prevents this buildup of opioid tolerance by antagonizing sensitization of morphine-induced 
receptors.12,13 
 
Potential side effects of drug accumulation exist for fentanyl and morphine due to the 
pharmacokinetic profiles. When administered as boluses, fentanyl has a high risk of drug 
accumulation that increases the risk for respiratory failure, postoperative nausea and vomiting, 
and ileus. Similarly morphine, typically utilized for its longer half-life, can have the same 
trajectory of unanticipated accumulation, variable clearance, or periods of inadequate pain 
control. This occurs because morphine’s pharmacokinetic half-life is 2-4 hours, however its 
desired analgesic effect may not correlate with blood plasma levels. To combat these issues, 
administration of opioids as an infusion has been tried in order to reach a steady state quickly.  
However, this can rapidly cause accumulation, and they are not easily titrated.14 To decrease this 
opioid accumulation from serial boluses and infusions, medications with longer half-lives, such 
as methadone, may be utilized.  It has a short equilibrium half-life and its effect correlates well 
with blood levels.15  
 
Methadone has proven to significantly decrease pain scores and improve quality of pain 
management when compared to other opioids in adult cardiac surgery patients.  A randomized, 
double-blinded, clinical trial in 156 patients following cardiopulmonary bypass surgery 
demonstrated a longer time to postoperative administration of opioid rescue medication in 
patients receiving methadone as compared to fentanyl during anesthesia induction.16 Also, the 
total opioid dose required to alleviate pain within the first postoperative day was significantly 


 
 
5
less in the group receiving methadone when compared to fentanyl. Postextubation levels of pain 
were lower at rest and with coughing, and overall satisfaction scores with pain management were 
better in those patients receiving methadone versus fentanyl. This study also showed no 
increased incidence of opioid-induced side effects including nausea, vomiting, respiratory 
dysfunction, or sedation.16 In a randomized control trial of teenage and adult cardiac patients 
who received methadone, morphine or placebo for induction of anesthesia, the methadone group 
had a lower number of patients requiring additional analgesics within the first 24 hours post 
procedure compared to controls.10 In addition, time to first analgesic dose was longer in those 
patients who received methadone at induction.  Quality measurements of pain control following 
methadone administration were significantly better as compared to morphine and control. 10 The 
prolonged analgesic effect of methadone can potentially improve acute postoperative pain 
control and in turn benefit hemodynamic and respiratory function. 
 
Methadone has been widely used in the intraoperative period to attenuate need for subsequent 
bolus administration of opioids in the postoperative period.  A prospective randomized study by 
Gottschalk et. al, showed a reduction by half in pain scores and a reduction in overall opioid 
requirements at two days when methadone, as compared to a sufentanil infusion, was 
administered prior to incision for patients undergoing complex spine surgery. This study also 
showed lasting analgesia through the third postoperative day and no difference in time to 
extubation, blood product utilization or length of surgery.17 Furthermore, methadone has been 
shown to effectively prolong the postoperative analgesia as compared to morphine, and 
subsequent doses of methadone provide a substantially longer period of pain relief.18,19 A 
randomized, double-blinded, prospective study on analgesic requirements showed that 
methadone decreased the amount of postoperative opioids as compared to morphine in pediatric 
patients undergoing major surgeries. These surgeries include: limb osteotomies, ureteral 
reimplantation, and major general surgical procedures (i.e. pectus excavatum repair).  Mean pain 
scores were lower in the methadone group as compared to the control group.  No opioid related 
complications occurred in either study group.20 Superior postoperative analgesic profiles for 
methadone makes it an ideal choice for controlling pain in the postoperative period for major 
cardiac surgical cases. 
 
Children’s National Health System (CNHS) routinely employs administration of methadone for 
major surgery, including posterior spinal fusion, at doses of 0.3 mg/kg.  This practice is 
supported by work that showed methadone at doses of 0.2-0.25 mg/kg can be used for pain 
control in children undergoing major surgery, including pediatric posterior spinal fusion.20,21 
Additional data shows that methadone at doses of 0.2 mg/kg prior to incision improved 
postoperative pain control in complex spine surgery.17 Furthermore, methadone dosing of 0.2-0.3 
mg/kg showed no changes to postoperative complication rate.16,18,20 The CNHS Cardiac 
Intensive Care Unit (CICU) routinely administers methadone in doses ranging from 0.1-
0.3mg/kg for treatment of withdrawal syndrome and assisting with weaning opioid infusions. 
 
C. Preliminary Studies: 
Methadone is currently administered during cardiac surgery at the discretion of the cardiac 
anesthesia team.  In a retrospective review of the cases in which methadone has been used at 


 
 
6
Children’s National during the last two years, there has been less opioid requirement in the first 
24 hours. Our proposal would be the first to study methadone in a randomized controlled setting 
in pediatric subjects undergoing cardiac surgery. 
 
D. Research Design and Methods: 
The proposed study will be conducted in a single tertiary medical center (Children’s National 
Health System). Pediatric subjects undergoing cardiac surgery requiring cardiopulmonary bypass 
will be recruited over a period of 24 months. The investigator will identify potential subjects 
from the operative schedule and will make initial contact during the preoperative anesthetic 
evaluation on the day prior to surgery. Eligible and consenting participants will be assigned a 
unique identification number and will be randomly assigned to receive either methadone or 
fentanyl using a computer-generated randomization scheme. A total of 76 participants will be 
enrolled to each arm of the study, providing 80% power to detect a 30% difference between 
groups. The proposed total number of subjects to enroll in the study that includes conservative 
estimates of 10% dropout rate is 168 subjects, with 84 subjects for each arm of the study. 
 
Screening and Randomization Phase 
Once eligibility is confirmed and informed consent is obtained, the investigator or his/her 
designee will conduct a detailed medical history, review of medications taken in the past 24 
hours, and a physical examination including baseline vital signs (heart rate, respiratory rate, 
blood pressure, oxygen saturation, and temperature), physical measurements (height and weight), 
and an initial pain score using the Face, Legs, Activity, Cry, Consolability (FLACC scale) 
(Appendix II). The FLACC scale is a validated behavioral pain scale utilized in young children 
between the ages of 1 and 7 years.22 
 
Eligibility Criteria 
Each of the following criteria must be met for the potential subject to be eligible for study 
participation: 
1. Age greater than or equal to 2 years and less than 8 years at the time of randomization.  
2. American Society of Anesthesiologists (ASA) physical status of ASA II, III, or IV 
(Appendix I). 
3. Informed consent to participate from the parent or legally authorized guardian. 
4. Scheduled for cardiac surgery requiring cardiopulmonary bypass (Appendix V). 
 
Exclusion Criteria 
Subjects will not be eligible to participate in the study if any of the following exclusion criteria 
apply: 
1. History of allergic reaction to methadone or fentanyl. 
2. Emergency Cardiac Surgery. 
3. Currently receiving inotropic agents or using a pacemaker. 
4. Prexisting long QTc interval of greater than 460ms determined by medical history, 
medical record documentation, or electrocardiogram obtained during the routine 
preoperative cardiac surgery evaluation. 
5. History of chronic nausea and/or vomiting. 


 
 
7
6. History of opioid abuse, addiction, or tolerance. 
7. Known significant hepatic disorders determined by medical history, medical record 
documentation, physical examination, or laboratory tests obtained during the routine 
preoperative cardiac surgery evaluation or cardiology visit (International Normalized 
Ratio (INR)>1.5). 
8. Known significant renal disorders determined by medical history, medical record 
documentation, physical examination, or laboratory tests obtained during the routine 
preoperative cardiac surgery evaluation or cardiology visit (Creatinine (Cr) >1.5). 
9. History of documented current pulmonary hypertension on medication. 
10. Obesity defined as a body weight greater than 130% of the ideal weight. 
11. Participation in another clinical trial or any study that may interfere with participation 
in this trial. 
 
The inpatient pharmacist at CNHS will randomly assign eligible participants to receive 
methadone or fentanyl. The randomized groups will be assigned in a 1:1 ratio determined by a 
computer-generated random sequence with an equal number of male and female participants.23 
All investigators, research personnel, staff, and study participants will be blinded to group 
assignment. 
 
The pharmacist will prepare 0.3 mg/kg of methadone and 20 mcg/kg of fentanyl for loading dose 
administration, diluted to 20 mL. 
 
Drug Preparation 
Drug Information: A specific study supply of both methadone and fentanyl will be purchased and 
maintained in the Investigational Drug Service (IDS) pharmacy. Methadone is supplied as a 
single-dose 1 mL vial containing methadone 10 mg/mL; fentanyl is supplied as a single-dose 2 
mL vial containing fentanyl 50 mcg/mL. Orders provided to the IDS pharmacy will reflect the 
weight-based calculated dose for both drugs. The syringes will be prepared with the assigned 
drug and will be diluted to 20 mL, with 0.9% sodium chloride. For example, a 2-year old child 
weighing 12 kg is prescribed 3.6 mg (0.36 mL) of methadone and 240 mcg (4.8 mL) of fentanyl; 
the final syringe will be prepared as 20 mL. A 7-year old child weighing 23 kg is prescribed 6.9 
mg (0.69 mL) of methadone and 460 mcg (9.2 mL) of fentanyl; the final syringe will be prepared 
as 20 mL. 
 
To ensure blinding, final dose preparations will be labeled “Methadone or Fentanyl 20 mLs”; 
dose information will not be provided on the label. Prepared doses will be delivered to the 
operating room (OR) the morning of the scheduled case. Study syringes will have a beyond use 
expiration of 8 hours when stored at room temperature. All transfers of study syringes between 
the IDS and the OR/Anesthesiology will follow institutional requirements for handling of a C-II 
drug. 
 
Storage and Accountability: The IDS pharmacy is a temperature controlled, limited access area 
restricted to pharmacy personnel only. Both methadone and fentanyl are stored at room 
temperature in the IDS Controlled Substance vault. Drug accountability records will be 


 
 
8
maintained by the IDS pharmacy to reflect drug preparation, including patient initials, subject 
ID, individual dose, lot and expiration of both methadone and fentanyl. Any unused portion of 
both methadone and fentanyl will be disposed per Department of Pharmacy standard operating 
procedures for waste of a controlled substance (C-II) drug. 
 
Treatment Phase 
The treatment phase will begin at the induction of general anesthesia and finish at the end of the 
surgical procedure (Figure 1). Standard anesthetic practice for monitoring, induction, and 
maintenance of general anesthesia will be preserved throughout. 
 
At the discretion of the anesthesiologist, subjects will be premedicated with midazolam 0.5 
mg/kg suspension by mouth (up to 20 mg maximum) or a 0.1 mg/kg intravenous injection.  Oral 
Midazolam has a maximum dose due to the volume of medication administered into the digestive 
tract, high volumes of fluid or volume in the stomach create a higher risk for aspiration during 
anesthetic induction.  The intravenous midazolam maximum dose is 4mg and is subject to 
achieve anxiolytic effect. Standard monitoring procedures will be put in place during the 
induction of general anesthesia, including an electrocardiogram (Lead II and V), heart rate, 
continuous blood pressure, respiratory rate, continuous pulse oximetry, end-tidal CO2, end-tidal 
sevoflourane concentrations, and temperature. 
 
For patients without intravenous access prior to arrival to the operating room, anesthesia will be 
induced via mask inhalation with sevoflurane at 8% or introduced at a low concentration after 
nitrous oxide/oxygen (2:1). Once the participant is anesthetized and intravenous access is 
established, the subject will receive 1 mcg/kg of fentanyl and 1 mg/kg of rocuronium to facilitate 
intubation. 
 
If the subject has intravenous access preoperatively, anesthesia will be induced with intravenous 
anesthetics including: fentanyl 1 mcg/kg and a short acting intravenous anesthetic (ketamine 1-2 
mg/kg bolus, etomidate 0.2-0.3 mg/kg bolus, or propofol 1.5-2.5 mg/kg bolus) at the discretion 
of the anesthesiology team. The subject will also receive 1 mcg/kg of fentanyl and 1 mg/kg of 
rocuronium to facilitate intubation.  
 
After the endotracheal tube is confirmed in situ and secured, the subject will be mechanically 
ventilated. A catheter for measuring arterial blood pressure will be inserted and additional 
intravenous catheters will be placed peripherally or centrally as per practice. 
 
Participants will receive either 0.3 mg/kg of methadone or 20 mcg/kg of fentanyl prior to 
surgical incision, over 60 minutes. The medication will be prepared as described above and all 
research and staff personnel as well as the study participant will be blinded to treatment group 
assignment. 
 
General anesthesia will be maintained with isoflurane. Rocuronium will be titrated to achieve 
surgical paralysis. Subjects will receive the required preoperative antibiotics prior to surgical 
incision. Standard documentation of vital signs will be recorded every 5 minutes in the 


 
 
9
anesthesia record and will include: arterial blood pressures, heart rate, respiratory rate, oxygen 
saturation, end-tidal CO2, end-tidal sevoflurane concentrations, temperature, and mechanical 
ventilator settings. Use of inotropes or vasopressors to maintain hemodynamic stability will be 
recorded. 
 
The subject will be transitioned to cardiopulmonary bypass under the direction of the 
cardiovascular surgeon. On bypass, subjects will receive 0.05 mg/kg of midazolam and 1 mg/kg 
of rocuronium, and Isoflurane. The surgeon will place the usual intracardiac lines and 
electrocardiac pacing. If necessary, inotropes or vasoactive agents will be initiated by the 
cardiovascular surgeon and anesthesiologist. The subject will be transitioned from 
cardiopulmonary bypass to spontaneous circulation by the cardiovascular surgeon and 
anesthesiologist. 
 
Volume resuscitation, inotropes and vasopressors, and electrocardiac pacing will be administered 
as standard care to ensure the subject’s vital signs are stable. Doses of inotropes and 
vasopressors, volume of blood products (i.e. packed red blood cells, platelets, and 
cryoprecipitate), volume of crystalloid, and volume of colloid will be recorded in the anesthesia 
record. 
 
As per standard anesthetic practice, the subject will continue to be evaluated for hemodynamic 
stability, postoperative risk of bleeding, and respiratory effort. Morphine at 0.05 mg/kg per dose 
will be administered intravenously as needed for pain control. All subjects will be started on an 
infusion of dexmedetomidine at 0.25-1 mcg/kg/hr. In the operating room, extubation timing will 
be at the discretion of the anesthesiologist; time of extubation will be recorded in the anesthesia 
record. Subjects who are not prepared for extubation in the operating room will remain intubated, 
mechanically ventilated, and sedated with dexmedetomidine while in the CICU through the 
immediate postoperative period.  The subject will be transported to the cardiac intensive care 
unit (CICU) for monitoring, and care will be transitioned to the cardiac intensive care team. 
 
Surgical procedures and times will be recorded in the operative report via the electronic medical 
record. 
 
Postoperative ICU Phase 
The postoperative CICU phase will begin at admission to the CICU and will end on the third day 
of hospital admission (Figure 1). As mentioned above, subjects who are not prepared for 
extubation in the operating room will remain intubated, mechanically ventilated, and sedated 
with dexmedetomidine in the immediate postoperative period in the CICU. Postoperative care 
including hemodynamic stability, resuscitation, and respiratory support will be at the discretion 
of the CICU team. 
 
As per CICU protocol, the nurse will monitor and record vital signs and FLACC scores 
beginning at handoff from the anesthesia team to the intensive care team. The nurse will continue 
to document vital signs including: blood pressure, heart rate, respiratory rate, oxygen saturation, 
temperature, minute ventilation when mechanically ventilated, and oxygen supplementation 


 
 
10
when appropriate, in the electronic medical record every hour. As per nursing protocol, FLACC 
scores will be recorded in the electronic medical record every 4 hours or when the nursing staff 
witnesses pain during the entirety of the subject’s CICU stay. 
 
All subjects will receive analgesics and sedation medication based on CICU postoperative pain 
control and agitation protocol as follows: 
• The nurse will document all medications administered in the electronic medical record. 
• Non-pharmacologic pain treatment plans such as music therapy and parental presence 
will be initiated. 
• Infusion of 0.25-1 mcg/kg/hr of dexmedetomidine for acute postoperative agitation or 
anxiety with the goal being zero to one on the Modified Motor Activity Assessment Scale 
(Appendix III).  This will be discontinued by the intensive care team as the patient 
transitions from the immediate postoperative period to a lower acuity of care or in the 
case where anxiolysis is no longer clinically required. 
• Non-opioids including acetaminophen 15 mg/kg/dose around the clock every 4 hours for 
48 hours then as needed, with maximum doses of 500 mg or 2 grams/24 hours, and 
ketorolac 0.25-0.5 mg/kg/dose every 6 hours for 48 hours once the chest tube output is 
less than 5 ml/kg/hour and non-sanguineous (maximum dose 15-30 mg).   
• Opioids for postoperative pain control will include oxycodone at 0.1 mg/kg enterally 
every 6 hours as needed for pain greater than or equal to a FLACC score of 4 (once 
taking enteral medication), maximum of 5-10 mg/dose. Morphine, 0.05-0.1 mg/kg will 
also be administered intravenously as needed for pain greater than or equal to a FLACC 
score of 4. The nursing staff will document opioid doses and time of administration in the 
electronic medical record. 
Nausea and Vomiting: 
• As per standard postoperative protocol, subjects will receive antiemetics (0.1 mg/kg of 
ondansetron IV or 0.25 mg/kg of promethazine IV) for recorded episodes of moderate or 
severe nausea and emesis. Adverse events including nausea, vomiting, arrhythmias, and 
hypoventilation as well as the total number of antiemetic doses and total doses given per 
kilogram will be recorded in the electronic medical record. 
 
Figure 1. Timeline of treatment and postoperative ICU phase.  


 
 
11
 
 
 
 
Data Collection 
The investigator or designee, blinded to group assignment, will collect all of the relevant data 
(Appendix IV) from the electronic medical record within six months of the cardiac surgery and 
enter it into the Medical Center’s proprietary web-based data-entry and data-management 
system, REDcap (Research Electronic Data Capture). The source of information will be medical 
records at the Children’s National Health System “Anesthesiology” and “Bear Tracks” 
information systems provided by Cerner Corporation.  
 
Data will be obtained specifically for research purposes. Subject identifiers (e.g. name, date of 
birth, address) will not be entered into the REDcap system. The previously assigned unique 
identification numbers will be used. 
 
Statistical Considerations 
All analyses will be conducted under the intent-to-treat principle using the assigned 
randomization groups. The distribution of all variables will be assessed and transformations or 
nonparametric methods will be employed accordingly. The primary study outcome is the total 
postoperative opioid dose in morphine equivalents in the first 24 hours and will be analyzed 
quantitatively. 
 
The distribution of the total opioid dose in the first 24 hours will be evaluated by randomization 
group (methadone vs. fentanyl) and differences between groups will be tested using the 
parametric t-test or Wilcoxon rank-sum test, if appropriate. 
 


 
 
12
Power: For the Primary Aim, it is hypothesized that compared to fentanyl, methadone 
administered intraoperative will result in a significantly lower total opioid dose (morphine or 
oxycodone) during the first 24 hour postoperative period. An internal case review was performed 
on 76 cardiac surgery patients (mean age 4.3±1.7, mean weight 17.1±7.45 kg) who received 10-
30mcg/kg of fentanyl prior to the cessation of cardiopulmonary bypass, did not receive a patient 
controlled analgesic device or infusion in the postoperative period, and who met the criteria of 
age from 2 to 8 years old.  This analysis demonstrates the mean total dose of morphine in the 
first 24 hour postoperative period to be 0.363 mg/kg, with a standard deviation of 0.239. 
Assuming no difference between the two treatment strategies in the population, a total sample 
size required is 76 in each group.  This will provide 80% power to detect an effect size of 0.109, 
using a two-sample t-test at the 0.05 significance level. Significance will be measured as a 30% 
reduction in postoperative pain requirement. 
 
We will consider a dropout rate of 10% and plan to enroll a total of 168 patients, 84 in each arm, 
in this randomized control study. 
 
Secondary Analyses: For the Secondary Aim the Pearson’s contingency chi-square test will be 
used to evaluate any differences between the randomization groups in opioid-related adverse 
events during the first 24-hour postoperative period. 
 
E. Study Population 
The population for this study will be both male and female pediatric subjects from all ethnic 
backgrounds, with an ASA physical classification of II, III, or IV who will undergo congenital 
cardiac bypass surgery. 
 
F. Human Subjects 
The research material obtained from human subjects will be in the form of data collection as 
previously described.  Data will be obtained specifically for research purposes. 
 
The investigator will identify subjects who are eligible for this study after review of the surgical 
schedule. Subjects and their parents will be approached about participation in the study after the 
preoperative anesthetic evaluation has been completed. The investigator or his designee will 
describe the study protocol and procedures and answer any questions pertaining to the study. 
Written informed consent will be obtained from the subject’s parent or legal guardian in 
accordance with all applicable regulatory requirements. Informed consent will be obtained prior 
to conducting any study related tests or procedures. Subjects will be approached during the 
preoperative anesthetic evaluation in a private closed-door forum in the preoperative surgical 
waiting area. The subject's parent or legal guardian will be given time to deliberate and a copy of 
the signed consent can be taken home. No other opportunity will be allowed for consenting. 
 
Interpreters will be present for the informed consent for non-English speaking subject. A short 
form of the consent in Spanish or Arabic will be made available. 
 


 
 
13
The participant’s involvement in the study will begin at the time informed consent is obtained 
and end after three days of follow-up in the CICU. 
 
G. Risks and Side Effects 
The potential risks realted to the use of methadone include respiratory depression and 
arrhythmias associated with prolongation of the QTc interval on ECG. 
 
The risk of respiratory depression exists with all administered opioid medications including 
methadone and fentanyl. As per the standard of care, subjects will remain mechanically 
ventilated throughout the duration of the surgical procedure, from induction to emergence.  
Adequacy of ventilation and oxygenation will be required for discontinuation of mechanical 
ventilation and emergence from anesthesia during the treatment phase. Subjects who do not meet 
extubation criteria will remain intubated, mechanically ventilated, and sedated with 
dexmedetomidine while in the intensive care unit until the subject has adequate ventilation and 
oxygenation. The intensive care team will manage postoperative respiratory support as standard 
of care. If prolonged intubation and mechanical ventilation is secondary to intraoperative opioid 
administration at three days this will be grounds for disclosure of opioid medication administered 
in the intraoperative period. These adverse events will be reported to the regulatory committee 
for review. 
Normal QTc values adjusted for age and gender for diagnosing QT prolongation for children 
between the ages of 1 and 15 years old is less than 440ms, borderline QT prolongation is 
considered 440ms-460ms, and prolonged is greater than 460ms.24 Furthermore, in data pooled 
from 4 studies the QTc for newborns receiving methadone remained in the normal range of 
400ms with a standard deviation of 20ms.9 Prolongation of the QT interval and cardiac 
conduction abnormality is more closely related to chronic adult dosing of methadone, large 
multiple daily doses, or treatment of addiction.25 Subjects will not be eligible if their preoperative 
QTc interval is greater than 460ms or documentation of acquired or congenital long QT-
syndrome.  Advanced age and methadone doses greater than 100 mg/day were independently 
associated with having a cardiac event.26 In this pediatric study no subject will receive doses of 
100 mg/day. Licensed physicians and nurses will monitor patients in the perioperative setting. As 
per standard of care licenses physicians and nurses will take electrocardiograms in the 
postoperative period for abnormal telemetry tracings. Arrhythmias interpreted by the intensive 
care staff during the first 24-hour period to be medication induced will require standard practice 
intervention and care. Within the first 24 hour period recurrent arrhythmias arising from the 
prolongation of the correct QT interval that cause hemodynamic instability refractory to therapy 
will be grounds for disclosure of opioid medication administered in the intraoperative period. 
These adverse events will be reported to the regulatory committee for review. 
No other risks related to study participation are anticipated. 
 
H. Benefits 
 


 
 
14
The information generated by this study will provide clinically useful information regarding the 
effectiveness of methadone. Subjects may benefit from the direct analgesic effects of 
intraoperative administration of opioids. Although participation in this study may not benefit all 
subjects, the information obtained can be directly applied to children for future use. 
 
I. Outside Consultants/Collaborators 
No outside consultants will be used. 
 
J. Contractual Agreements 
There are no contractual agreements. There are no additional costs to subjects for participation. 
 
L. Conflicts Of Interest 
There are no conflicts of interest. 
 
M. Confidentiality 
Subject confidentiality will be maintained at all times. To protect the privacy of subjects and 
maintain confidentiality of medical record, each subject will be assigned a unique study 
identification number and all participant data will be labeled only with the study identification 
code. The study necessitates that a master subject enrollment log containing the subject’s name 
and medical record number be kept in the study files, but limited access to this log (consisting of 
site study personnel and Federal Regulatory personnel in the event of an audit) will be 
implemented.  All study case report forms will be stored in a locked cabinet in the Investigators 
office/office suite.  Data entered via the web-based electronic data collection system will be 
securely stored on the Medical Center’s server. The results of this study may be published in 
scientific journals or presented at medical meetings, but the subject’s identity will not be 
disclosed. HIPAA compliance will be adhered to at all times per IRB and Institutional standards. 
 
N. Subject Compensation 
There is no subject compensation for participation in this study. 
 
O. Facilities and Equipment 
This study will be conducted in the operating rooms and CICU of Children’s National Health 
System. All materials for this study are a part of routine care. 
 
P. Appendix 
 
APPENDIX I 
American Society of Anesthesiologists (ASA) classification of physical status: 
 
Class I. There is no organic, physiologic, biochemical or psychiatric disturbance.  The pathologic 
process for which operation is to be performed is localized and is not a systemic disturbance. 
 
Class II. Mild to moderate systemic disturbance caused either by the condition to be treated 
surgically or by other pathophysiologic processes. 


 
 
15
 
Class III. Severe systemic disturbances or disease from whatever cause, even though it may not 
be possible to definite the degree of disability with finality. 
 
Class IV. Indicative of the subject with severe systemic disorder already life threatening, not 
always correctable by the operative procedure. 
 
Class V. The moribund subject who has little chance of survival but is submitted to operation in 
desperation. 
 
APPENDIX II 
Face, Legs, Activity, Cry, Consolability Scale (FLACC)22 
Categories 
0 
1 
2 
Face 
No particular 
expression or smile 
Occasional grimace 
or frown, withdrawn, 
disinterested 
Frequent to constant 
quivering chin, 
clenched jaw 
Legs 
Normal position or 
relaxed 
Uneasy, restless, 
tense 
Kicking, or legs 
drawn up 
Activity 
Lying quietly, normal 
position, moves 
easily 
Squirming, shifting 
back and forth, tense 
Arched, rigid or 
jerking 
Cry 
No cry (awake or 
asleep) 
Moans or whimpers; 
occasional complaint 
Crying steadily, 
screams or sobs, 
frequent complaints 
Consolability 
Content, relaxed 
Reassured by 
occasional touching, 
hugging or being 
talked to, distractible 
Difficult to console 
or comfort 
Scores range from zero to ten.  
0= Relaxed and comfortable 
1-3=Mild discomfort 
4-6= Moderate pain 
7-10= Severe pain/ discomfort 
 
APPENDIX III 
Modified Motor Activity Assessment Scale (MMAAS) 
The MMAAS will be scores as the subject’s response to voice, then touch, and then noxious 
stimulation (i.e. planned ETT suctioning or <5 seconds of nailbed pressure). 
 
(-3) Unresponsive=  No spontaneous respiratory effort.  Minimal or no response to noxious* 
stimulus.  Does not communicate or follow commands.  
  


 
 
16
(-2) Responsive only to noxious* stimuli:  Spontaneous but ineffective respiratory effort.  
Opens eyes or raises eyebrows or turns head toward stimulus or moves limbs with noxious* 
stimulus.  Some spontaneous movement.  Does not communicate. 
  
(-1) Responsive to gentle touch or name:  Opens eyes or raises eyebrows or turns head toward 
stimulus or moves limbs with gentle touch or when name is spoken.  Follows simple commands.  
Drifts off after stimulation 
  
(0) Calm and cooperative:  Spontaneous and effective tidal volume.  No external stimulus is 
required to elicit movement.  Calm, awakens easily, and follows commands 
  
(+1) Restless but cooperative:  No external stimulus is required to elicit movement.  Increased 
limb movement.   Picking at tubes but consolable. 
  
(+2) Agitated:  Having difficulty synchronizing with ventilator.  No external stimulus is 
required to elicit movement.  Attempting to sit or moves limbs to get up.  Difficult to console 
despite frequent attempts.  Requires physical restrain 
  
(+3) Dangerously agitated:  Unsynchronized with mechanical ventilation - desaturating.  No 
external stimulus is required to elicit movement.  Subject unsafe- attempting to pull at 
ETT/catheters.  Biting ETT.  Thrashing side to side; climbing over the rail; striking at staff. 
 
Appendix IV 
Data Collection Form 
 
Medical Record Number 
Age 
Weight 
Date and times of surgery 
Surgery performed 
Cardiopulmonary bypass times 
Drugs, doses, times administered intraoperative 
Time of intubation and extubation 
Vasoactive and inotropic dose and time administered 
Total volume of blood products administered (FFP, PLTs, Cryo) 
Drugs, doses, and times administered postoperative 
 
Appendix V - Pediatric Cardiac Surgery Requiring Cardiopulmonary Bypass 
• Absent Pulmonary Valve Repair 
• Anomalous Left Coronary Artery 
Reimplantation 
• Aortic Stenosis Repair 
• Aortic Regurgitation Repair 
• Aortopulmonary Window Repair 
• Atrial Septal Defect Repair 
• Atrioventricular Septal Defect, Complete 
Repair 
• Atrioventricular Septal Defect, Partial 
Repair 
• Bicuspid Aortic Valve Repair 


 
 
17
• Coarctation of the Aorta Repair 
• Coronary Artery Fistula Repair 
• Damus-Kaye-Stansel Procedure 
• Dilated Cardiomyopathy Repair 
• Double Aortic Arch Repair 
• Double-Inlet Left Ventricle Repair 
• Double-Outlet Right Ventricle Repair 
• Ebstein's Anomaly Repair 
• Eisenmenger Complex Repair 
• Endocardial Cushion Defect Repair 
• Fontan Operation 
• Bidirectional Glenn Procedure 
• Hypertension, Pulmonary Treatment 
• Hypertension, Systemic Treatment 
• Hypertrophic Cardiomyopathy Repair 
• Hypoplastic Left Heart Syndrome Repair 
• Interrupted Aortic Arch Repair 
• Kawasaki Disease Treatment 
• Marfan Syndrome Repair 
• Mitral Stenosis Repair 
• Mitral Valve Prolapse Repair  
• Partial Anomalous Pulmonary Venous 
Repair 
• Patent Ductus Arteriosus Ligation & 
Division 
• Pulmonary Atresia Repair 
• Pulmonary Stenosis Repair 
• Ross Procedure 
• Septal Myectomy 
• Single Ventricle Repair - Tricuspid 
Atresia 
• Single Ventricle Repair - Double Inlet 
Left Ventricle 
• Single Ventricle Repair - Hypoplastic Left 
Heart Syndrome 
• Tetralogy of Fallot Repair 
• Total Anomalous Pulmonary Venous 
Repair 
• Transposition of the Great Arteries, D-
Type Repair 
• Tricuspid Atresia Repair 
• Tricuspid Valve Repair 
• Truncus Arteriosus Repair 
• Vascular Ring Repair 
• Ventricular Septal Defect Repair     
 
 
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