Prospective Randomized Evaluation of Analgesia for Cardiac Elective Surgery in Children (PRECISE Cardiac Trial)
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 500
- 试验地点
- 4
- 主要终点
- Average postoperative pain scores
研究概览
简要总结
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.
详细描述
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Participant)
入排标准
- 年龄范围
- 3 Years 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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
研究组 & 干预措施
Non-Methadone-Based Group
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.
干预措施: Non-methadone based group (Drug)
Methadone-Based ERAS Group
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.
干预措施: Methadone based ERAS (Drug)
结局指标
主要结局
Average postoperative pain scores
时间窗: Postoperative 48 hours
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).
Total postoperative opioid use
时间窗: Postoperative 48 hours
Total Opioid use in Morphine Milligram Equivalents (MME), will be reported as mean (SD).
Average postoperative pain scores
时间窗: Postoperative 48 hours
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).
Total postoperative opioid use
时间窗: Postoperative 48 hours
Total Opioid use in Morphine Milligram Equivalents (MME) (mg), will be reported as mean (SD).
次要结局
- Incidence of Inpatient Respiratory Depression (RD)(Postoperative 120-hours)
- Incidence of Inpatient Postoperative Nausea and Vomiting (PONV)(Postoperative 120-hours)
- Incidence of Inpatient Sedation(Postoperative 120-hours)
- QTc Prolongation(Postoperative 48-hours)
- Length of Hospital Stay (LOS)(Up to 30 days)
- Persistent Opioid Use(1-week, 1-month, and 3-months post-surgery)
- Presence of Chronic Postsurgical Pain (CPSP) at 3-months(3-months post-surgery)
- Presence of Opioid Dependence (OD) at 3-months(3-months post-surgery)
研究者
Senthil Sadhasivam
Professor
University of Pittsburgh