Opioid Use, Unspecified
Conditions
Keywords
pediatric, cardiac bypass surgery, methadone, fentanyl, morphine
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.
Interventions
DRUGMethadone
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.
DRUGFentanyl
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.
Sponsors
Andrew Waberski
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
2 Years to 7 Years
Healthy volunteers
Yes
Inclusion criteria
1. Age greater than or equal to 2 years and less than 8 years at the time of randomization. 2. Weight greater than 6 kg. 3. American Society of Anesthesiologists (ASA) physical status of ASA I, II, or III (Appendix I). 4. Informed consent to participate from the parent or legally authorized guardian. 5. Scheduled for congenital cardiac bypass surgery.
Exclusion criteria
Subjects will not be eligible to participate in the study if any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Opioid Dose, in Morphine Equivalents, in the First 24 Hours After Pediatric Cardiac Bypass Surgery. | 24 hours | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Opioid-related Adverse Events Including: Respiratory Failure, Cardiovascular Instability, and Postoperative Nausea and Vomiting | 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. 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. |
Countries
United States
Participant flow
Recruitment details
The trial was terminated because enrollment in the clinical trial did not reach the target number of subjects needed to achieve target power and was insufficient to produce statistically reliable results. Additionally, without notice formulations of the study drug methadone became unavailable and remain unavailable due to production shortages.
Participants by arm
| Arm | Count |
|---|---|
| Control - Fentanyl 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.
Fentanyl: 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. | 12 |
| Treatment - Methadone 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.
Methadone: 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. | 14 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Physician Decision | 1 | 0 |
Baseline characteristics
| Characteristic | Treatment - Methadone | Total | Control - Fentanyl |
|---|---|---|---|
| Age, Categorical <=18 years | 14 Participants | 26 Participants | 12 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 4.4 years | 4.2 years | 4.1 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 6 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 9 Participants | 17 Participants | 8 Participants |
| Region of Enrollment United States | 14 participants | 26 participants | 12 participants |
| Sex: Female, Male Female | 7 Participants | 10 Participants | 3 Participants |
| Sex: Female, Male Male | 7 Participants | 16 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 1 / 14 |
| other Total, other adverse events | 0 / 12 | 0 / 14 |
| serious Total, serious adverse events | 0 / 12 | 1 / 14 |
Outcome results
Primary
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.
Time frame: 24 hours
Population: The trail was terminated because enrollment in the clinical trial did not reach the target number of subjects needed to achieve target power and was insufficient to produce statistically reliable results. Additionally, without notice formulations of the study drug methadone became unavailable and remain unavailable due to production shortages. Therefore, no analysis was performed on the data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Control - Fentanyl | Total Opioid Dose, in Morphine Equivalents, in the First 24 Hours After Pediatric Cardiac Bypass Surgery. | 0.55 mg postop morphine equivelant 24hr | Standard Deviation 0.21 |
| Treatment - Methadone | Total Opioid Dose, in Morphine Equivalents, in the First 24 Hours After Pediatric Cardiac Bypass Surgery. | 0.48 mg postop morphine equivelant 24hr | Standard Deviation 0.24 |
Secondary
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.
Time frame: 24 hours
Population: The trail was terminated because enrollment in the clinical trial did not reach the target number of subjects needed to achieve target power and was insufficient to produce statistically reliable results. Additionally, without notice formulations of the study drug methadone became unavailable and remain unavailable due to production shortages. Therefore, no analysis was performed on the data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Control - Fentanyl | Opioid-related Adverse Events Including: Respiratory Failure, Cardiovascular Instability, and Postoperative Nausea and Vomiting | Ondansetron Doses | 3.81 events | Standard Deviation 1.7 |
| Control - Fentanyl | Opioid-related Adverse Events Including: Respiratory Failure, Cardiovascular Instability, and Postoperative Nausea and Vomiting | Emesis Episodes | 2.72 events | Standard Deviation 2.45 |
| Control - Fentanyl | Opioid-related Adverse Events Including: Respiratory Failure, Cardiovascular Instability, and Postoperative Nausea and Vomiting | Hypoventilation Episodes | 0 events | Standard Deviation 0 |
| Control - Fentanyl | Opioid-related Adverse Events Including: Respiratory Failure, Cardiovascular Instability, and Postoperative Nausea and Vomiting | Arrhythmias | 0 events | Standard Deviation 0 |
| Treatment - Methadone | Opioid-related Adverse Events Including: Respiratory Failure, Cardiovascular Instability, and Postoperative Nausea and Vomiting | Arrhythmias | 0 events | Standard Deviation 0 |
| Treatment - Methadone | Opioid-related Adverse Events Including: Respiratory Failure, Cardiovascular Instability, and Postoperative Nausea and Vomiting | Ondansetron Doses | 3.43 events | Standard Deviation 2.47 |
| Treatment - Methadone | Opioid-related Adverse Events Including: Respiratory Failure, Cardiovascular Instability, and Postoperative Nausea and Vomiting | Hypoventilation Episodes | 0 events | Standard Deviation 0 |
| Treatment - Methadone | Opioid-related Adverse Events Including: Respiratory Failure, Cardiovascular Instability, and Postoperative Nausea and Vomiting | Emesis Episodes | 2.08 events | Standard Deviation 1.9 |