Methadone vs. Fentanyl Administration on Postoperative Pain Control in Pediatric Patients Undergoing Cardiac Surgery

Study Overview
=================
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.

Official Title
-----------------
The Effect of Methadone vs. Fentanyl Administration on Postoperative Pain Control in Pediatric Patients Undergoing Cardiac Surgery: A Randomized, Double-Blinded Controlled Trial

Conditions
-----------------
Opioid Use, Unspecified

Intervention / Treatment
-----------------
* Drug: Methadone
* Drug: Fentanyl


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age greater than or equal to 2 years and less than 8 years at the time of randomization. Weight greater than 6 kg. American Society of Anesthesiologists (ASA) physical status of ASA I, II, or III (Appendix I). Informed consent to participate from the parent or legally authorized guardian. Scheduled for congenital cardiac bypass surgery. Exclusion Criteria Subjects will not be eligible to participate in the study if any of the following exclusion criteria apply: History or a family (parent or sibling) history of malignant hyperthermia. 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). Emergency Cardiac Surgery. History of chronic nausea and/or vomiting. Currently receiving inotropic agents or using a pacemaker. 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. History of documented pulmonary hypertension, respiratory dysfunction, or requirement of supplemental oxygen therapy. History of opioid abuse, addiction, or tolerance. Obesity defined as a body weight greater than 130% of the ideal weight. Participation in another clinical trial or any study that may interfere with participation in this trial. History of allergic reaction to methadone or fentanyl.

Ages Eligible for Study
-----------------
Minimum Age: 2 Years
Maximum Age: 7 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control - Fentanyl<br>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. | Drug: Fentanyl<br>* 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.<br>* Other names: Sublimaze;|
| Active Comparator: Treatment - Methadone<br>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. | Drug: Methadone<br>* 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.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Opioid Dose, in Morphine Equivalents, in the First 24 Hours After Pediatric Cardiac Bypass Surgery. | 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. 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. Assuming no difference between the two treatment strategies in the population, a total sample size of 52 in each group will provide 80% power to detect an effect size of 0.1. Significance will be measured as a 30% reduction in postoperative pain requirement. | 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Opioid-related Adverse Events Including: Respiratory Failure, Cardiovascular Instability, and Postoperative Nausea and Vomiting | 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. 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. | 24 hours | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
pediatric, cardiac bypass surgery, methadone, fentanyl, morphine