Oxidative Stress and Surgical Recovery
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Phosphorylation of STAT-3 in MDSC (Myeloid-derived Suppressor Cells)
研究概览
简要总结
Chronic pain, functional impairment and slow rates of recovery are key issues for patients after surgery and trauma. No preventative strategy in current use unequivocally modifies these rates, and few novel approaches have been tested. Furthermore, persistent postsurgical pain is a major route to chronic opioid use, opioid use disorder and, regrettably, opioid overdose. Most strategies designed to limit chronic pain or enhance functional recovery after surgery are directed at modulating peripheral and central nervous system activity and do not strongly modify the underlying tissue pathophysiology or fundamental systemic responses. Strategies limiting oxidative stress in the perioperative period, on the other hand, might limit tissue damage, organ dysfunction and immune system activation.
N-acetyl cysteine (NAC) is an antioxidant well-studied in the perioperative period; it is very safe, relatively inexpensive and widely available. The central hypothesis is, therefore, that perioperative administration of NAC will reduce perioperative oxidative stress, limit immune system activation and improve key indices of surgical recovery. Although the planned work will not comprehensively address this hypothesis, it will identify the most useful tools and help the researchers estimate the required sample sizes for more definitive externally funded efforts.
详细描述
This is a randomized, double-blind, placebo controlled interventional pilot study in 20 patients undergoing first-time total hip arthroplasty (THA) for chronic osteoarthritis at Stanford Medicine. The researchers will screen, enroll and collect biologic and behavioral data from 20 participants as outlined in previous observational and interventional clinical studies undertaken in close collaboration with the Department of Orthopedic Surgery. In particular, standard operating procedures for screening, recruiting, laboratory assessments, and clinical data collection are in place including eligibility screening via EPIC (EHR) ahead of patients' preoperative visit, coordinated recruitment and consenting during the pre-surgery visit including study- related laboratory work, further preoperative assessments after the visit (e.g. remote completion of questionnaires and direct import of results into REDCap), and real-time tracking of the data collection and storage process (e.g. including phone/email reminders if data are missing).
Repeated assessments of pain, physical function, and analgesic medication will be made before surgery, daily on postoperative days 1-3, and then twice a week in post-op weeks 1 - 6. Delirium will be measured days 1-3 while in-hospital. Additional data will include demographics (age, BMI, sex, race, and ethnicity), surgical/anesthesia data (e.g. duration), and medical/medication history.
Peripheral blood samples will be collected before surgery and 1hr and 24hr after surgery based on our prior study showing that monocyte activation (including STAT3, CREB and NFkB signaling responses in CD14+CD16- monocytes) early after surgery strongly correlates with delayed pain resolution and functional impairment. Exhaled breath samples will be collected intraoperatively prior to incision and at wound closure as well as at 1 and 24 hours after surgery.
N-Acetylcysteine infusion: A loading dose of 50 mg/kg will be started as a 1-hour infusion before surgical incision, and will be followed by a maintenance dose of 50 mg/kg administered over 4 hours. This is a standard dosing paradigm that is safe when used intraoperatively and rarely causes significant adverse effects (mainly allergic reactions).
Surgery and anesthesia: Participants will undergo unilateral hip arthroplasty performed by three surgeons using the same approach. The anesthetic and perioperative management of patients is standardized and follows ERAS-based recommendations.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male of female
- •Planning to undergo primary total hip arthroplasty
- •Fluent in English
- •Willing and able to sign an informed consent form and HIPAA authorization and to comply with study procedures
排除标准
- •Infectious disease within the last month
- •Immune-suppressant therapy within the last 2 months (e.g., azathioprine or cyclosporine)
- •Chronic medication with potential immune-modulatory effects (e.g., daily oral morphine-equivalent intake > 30 mg)
- •Major surgery within the last 3 months or minor surgery within the last month.
- •History of substance abuse (e.g., alcoholism, drug dependency)
- •Autoimmune disease interfering with data interpretation (e.g. lupus)
- •Renal, hepatic, cardiovascular, or respiratory diseases resulting in clinically relevant impaired function
- •Active malignancy
- •Participation in another clinical trial of an investigational drug or device within the last month that, in the investigator's opinion, would create an increased risk to the participant or compromise the integrity of the study
- •Other conditions compromising a participant's safety or the integrity of the study
研究组 & 干预措施
N-acetyl cysteine
N-acetyl cysteine will be administered as follows: A loading dose of 50 mg/kg will be started as a 1-hour infusion before surgical incision, and will be followed by a maintenance dose of 50 mg/kg administered over 4 hours.
干预措施: N-acetyl cysteine (Drug)
Normal Saline
Normal will be administered as follows: A normal saline infusion will administered at a rate and duration to mimic the N-acetyl cysteine administration.
干预措施: Normal Saline (Other)
结局指标
主要结局
Phosphorylation of STAT-3 in MDSC (Myeloid-derived Suppressor Cells)
时间窗: Measurements will be made in samples collected before and 24 hours after surgery.
STAT3 phosphorylation in MDSC cells is measured in all MDSC cells before (T0) and one day after surgery (T1) using mass cytometry. The median phosphorylation in this cell population is then determined for each time point. The change in phosphorylation is expressed as the arc sinh ratio of these two medians (ratio = arc sinh \[median pSTAT3-T1/median pSTAT3-T0\]).
Brief Pain Inventory Pain Score
时间窗: post-operative week 6
The Brief Pain Inventory was used to measure pain and pain interference following surgery. BPI Pain Composite Score was derived from worst pain, least pain, average pain, and pain right now subscale scores. BPI Pain Interference Composite Score (representing how pain interferes with daily life) was derived from general activity, mood, walking ability, normal work, relationships with others, sleep, and enjoyment of life subscale scores. Each composite score is the median value of the combined median values for each participant of the respective subscale scores (range for subscale and overall scores: 0 to 10, higher scores indicate more severe pain/pain interference).
次要结局
- Pain Score(Baseline through post-op day 1 (composite scores over 24 hours following surgery))
研究者
Martin Angst
Professor of Anesthesia
Stanford University