Evaluation of Analgesia for Cardiac Elective Surgery in Children

Prospective Randomized Evaluation of Analgesia for Cardiac Elective Surgery in Children (PRECISE Cardiac Trial)

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.

Inclusion Criteria:

• Children aged 3-years - <18 years
• ASA physical status 1, 2, or 3
• Participant or legal guardian can speak and read English or Spanish
• Undergoing the following cardiac surgeries (Categories 1 & 2) that are associated with significant acute surgical pain

STS Category 1:

• ASD, PFO closure
• VSD repairs,
• Aortic stenosis sub-valvular repair
• ASD and Partial anomalous venous return repair
• AV canal transitional
• Conduit replacement
• Valve replacement (AVR, PVR)
• TOF repair without ventriculostomy

STS Category 2:

• Glenn shunt (on Bypass only)
• Fontan surgery (on Bypass only)
• Pulmonary artery plasty (main)
• Left Atrium (LA) to Pulmonary Artery (PA) conduit replacement.

Exclusion Criteria:

• Pregnant patients
• Methadone allergy
• Preoperative prolonged QTc more than 460 msec (-30 days to 0 day)
• Subjects undergoing concomitant treatment with known cytochrome P450 inhibitors included in methadone labeling (i.e. macrolides (e.g. erythromycin), azole-antifungal agents (e.g. ketoconazole, voriconazole), protease inhibitors (e.g. ritonavir), fluconazole, SSRIs (e.g. sertraline, fluvoxamine)
• Preoperative opioid use within 30 days before surgery
• History of severe sleep apnea (have a sleep study with an AHI index score more than 10 or clinical signs of sleep disordered breathing - snoring, daytime drowsiness)
• Significant liver, kidney, neurological disease, developmental delay, or any other co-existing medical condition per discretion of the clinical investigator