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| ID | Type | Description | Link |
|---|---|---|---|
| U01HD116257 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | NIH |
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The purpose of this study is to look at a standardized methadone-based enhanced recovery after surgery protocol following pediatric cardiac surgery. This study will consist of randomly assigning children to receive the methadone-based recovery procedures or to receive current standard of care recovery procedures. Randomly assigning means that there is a 50/50 chance, like a coin flip, of being assigned to either research group.
SPECIFIC AIMS. The multicenter PRECISE Analgesia (Prospective Randomized Evaluation of Analgesia for Cardiac) trials will a) implement and investigate the efficacy and safety of multidose methadone-based standardized enhanced recovery after surgery (ERAS) protocol, and b) develop personalized ERAS protocols including precision methadone and oxycodone dosing, and c) personalized analgesia for the safe and effective opioid-sparing management of surgical pain after cardiac surgery (CS) in children.
The long-term goal is to proactively improve the safety and efficacy of surgical pain control while reducing opioid AEs and the opioid epidemic burden in all children undergoing inpatient surgeries. The central hypothesis is that a standardized, multidose, methadone-based ERAS protocol will reduce acute surgical pain, overall opioid use, RD, PONV, and CPSP compared with standard-of-care short-acting opioid-based analgesia in children undergoing CS (Aim 1). Investigators will use PK and genetic variations along with CPB-related dilution and clinical factors to develop optimal intra- and post-operative methadone dosing in children to enable precision analgesia in the future (Aim 2). Finally, the study team will identify patient profiles with genetic, epigenetic, PK, clinical, and psychological factors to predict benefit from assigned analgesia for optimal clinical outcomes (Aim 3). The expert multidisciplinary and multicenter team will enroll a total of 1000 children to conduct two parallel randomized clinical trials for CS (500 children 1 month-18 yrs from 5 clinical sites). In this study, specifically, Investigators will:
Aim 1. Conduct a randomized trial in CS to compare acute pain relief, opioid-sparing efficacy, and safety of standardized perioperative multidose methadone-based ERAS vs. standard-of-care non-methadone-based analgesia. Acute surgical pain, opioid needs (morphine equivalents), RD, PONV, and CPSP will be lower in methadone-based analgesia compared to short-acting opioid-based analgesia.
Aim 2. Develop precision methadone dosing based on age, CYP2B6 and ORM1 variants, AAG, and CPB. Age, CYP2B6 and ORM1 variants, AAG levels, and CPB-related dilution will explain methadone's PK variability and dose adjustments that correlate with optimal clinical outcomes among 500 children receiving methadone.
Aim 3. Identify patient profiles that predict benefits from the assigned analgesia protocol to optimize clinical outcomes. Personalized risk prediction models will be developed and validated including genetic variants (i.e., CYP2B6, CYP2D6, ABCB1, OPRM1, and FAAH), and psychological and clinical factors to predict benefit with the assigned treatments (methadone or non-methadone) for pre-specified clinical endpoints (i.e., lower acute surgical pain, RD, PONV, OD, and CPSP).
Overall Impact: The study team will develop actionable evidence for the efficacy of standardized, multidose, methadone-based ERAS protocols and will harness genetic, clinical, and psychological factors contributing to variability in methadone and oxycodone PK, acute surgical pain, transition to CPSP, opioid-induced PONV, RD, and dependence to develop personalized analgesia strategy and dosing for children undergoing CS. Implementation of evidence-based standardized methadone-based ERAS pain management and individualized risk prediction will maximize acute surgical pain relief while minimizing opioid use and AEs in millions of children.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Methadone-Based ERAS Group | Experimental | The methadone-based standardized analgesia intervention arm will include standardized perioperative care and analgesia, including intraoperative intravenous methadone (1st dose: 0.1 mg/kg up to a maximum of 5 mg before incision; 2nd dose: 0.1 mg/kg up to a maximum of 5 mg 4 hours after 1st dose) and postoperatively, up to 4 oral or IV doses of methadone (0.1 mg/kg up to a maximum of 5 mg) every 12 hours before discharge as part of standardized multimodal analgesia in the hospital setting. |
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| Non-Methadone-Based Group | Active Comparator | Children randomized to the standard-of-care arm will receive standard opioid analgesia protocol without intra- and post-operative methadone per the current site standards. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Methadone based ERAS | Drug | Children randomized to the methadone arm will include standardized perioperative care and analgesia, including intraoperative intravenous methadone (1st dose: 0.1 mg/kg up to a maximum of 5 mg before incision; 2nd dose: 0.1 mg/kg up to a maximum of 5 mg 4 hours after 1st dose) and postoperatively, up to 4 oral or IV doses of methadone (0.1 mg/kg up to a maximum of 5 mg) every 12 hours before discharge as part of standardized multimodal analgesia in the hospital setting. |
| Measure | Description | Time Frame |
|---|---|---|
| Average postoperative pain scores | Average postoperative pain scores within 48 hours of surgery (Numerical Rating Scale [NRS], or Facial expression, Leg movement, Activity, Cry, and Consolability [FLACC], both 0-10). Outcome will be reported based on area under the curve (AUC) as mean(SD). | Postoperative 48 hours |
| Total postoperative opioid use | Total Opioid use in Morphine Milligram Equivalents (MME), will be reported as mean (SD). | Postoperative 48 hours |
| Measure | Description | Time Frame |
|---|---|---|
| Incidence of Inpatient Respiratory Depression (RD) | RD is defined as respiratory rate <8 breaths per minute requiring oxygen in the absence of airway obstruction. | Postoperative 120-hours |
| Incidence of Inpatient Postoperative Nausea and Vomiting (PONV) |
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Inclusion Criteria:
STS Category 1:
STS Category 2:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Senthilkumar Sadhasivam, MD,MPH, MBA, FASA | Contact | 4126474484 | sadhasivams@upmc.edu | |
| Dayana Alsamsam, BSPS, MSc | Contact | alsamsamd@upmc.edu |
| Name | Affiliation | Role |
|---|---|---|
| Senthilkumar Sadhasivam, MD | University of Pittsburgh | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| UPMC Children's Hospital | Recruiting | Pittsburgh | Pennsylvania | 15213 | United States |
Identifiable data and specimens will be shared with the sponsor of the study. The investigators and the study team will comply with all the NIH's Public Access and Data Sharing requirements including Release of Publications and Sharing of Underlying Primary Data. Release of Publications: The investigators will publish their results in open access journals for broad and free availability immediately without any embargo period. Electronic copies of publications will be deposited within four weeks of acceptance by a journal in PubMed Central with proper metadata to be made discoverable and accessible upon publication.
Time frame is within 5-years of study completion.
Online collaborative tools to facilitate data sharing such as SharePoint or Xythos
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| ID | Term |
|---|---|
| D059039 | Standard of Care |
| ID | Term |
|---|---|
| D019984 | Quality Indicators, Health Care |
| D011787 | Quality of Health Care |
| D006298 | Health Services Administration |
| D017530 | Health Care Quality, Access, and Evaluation |
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Randomized Clinical Trial
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| Non-methadone based group | Drug | Children randomized to the standard-of-care arm will receive standard opioid analgesia protocol without intra- and post-operative methadone per the current site standards. |
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PONV will be assessed by self-report, EMR, and medication use. Outcome measure will be reported as n(%). |
| Postoperative 120-hours |
| Incidence of Inpatient Sedation | Sedation will be assessed using the Ramsay Sedation Scale (RSS) and validated sedation scales extracted from the EMR. Outcome measure will be reported as n(%) | Postoperative 120-hours |
| QTc Prolongation | QTc prolongation is defined as more than 460 msec. Outcome measure will be reported as n(%). | Postoperative 48-hours |
| Length of Hospital Stay (LOS) | LOS will be recorded in days. Outcome measure will be reported as mean(SD). | Up to 30 days |
| Persistent Opioid Use | Based on Prescription Drug Monitoring Program (PDMP) and self-report data. Outcome measure will be reported as n(%) | 1-week, 1-month, and 3-months post-surgery |
| Presence of Chronic Postsurgical Pain (CPSP) at 3-months | CPSP incidence will be defined using NRS pain >3/10 and functional limitations based on Functional Disability Inventory (FDI). NRS pain scores are on a scale of 0=no pain at all and 10=worst pain imaginable. Outcome measure will be reported as n(%) | 3-months post-surgery |
| Presence of Opioid Dependence (OD) at 3-months | OD will be assessed using PROMIS and Prescription Pain Medication Misuse (PPMM). Outcome measure will be reported as n(%). | 3-months post-surgery |