Department of Anesthesia, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
Division of Biostatistics and Epidemiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Brain Behav Immun. 2024 Nov;122:596-603. doi: 10.1016/j.bbi.2024.08.056. Epub 2024 Aug 31.
To determine if baseline cytokines/chemokines and their changes over postoperative days 0-2 (POD0-2) predict acute and chronic postsurgical pain (CPSP) after major surgery.
Prospective, observational, longitudinal nested study.
University-affiliated quaternary children's hospital.
Subjects (≥8 years old) with idiopathic scoliosis undergoing spine fusion or pectus excavatum undergoing Nuss procedure.
Demographics, surgical, psychosocial measures, pain scores, and opioid use over POD0-2 were collected. Cytokine concentrations were analyzed in serial blood samples collected before and up to two weeks after surgery, using Luminex bead arrays. After data preparation, relationships between pre- and post-surgical cytokine concentrations with acute (% time in moderate-severe pain over POD0-2) and chronic (pain score > 3/10 beyond 3 months post-surgery) post-surgical pain were analyzed using univariable and multivariable regression analyses with adjustment for covariates and mixed effects models were used to associate longitudinal cytokine concentrations with pain outcomes.
Analyses included 3,164 repeated measures of 16 cytokines/chemokines from 112 subjects (median age 15.3, IQR 13.5-17.0, 54.5 % female, 59.8 % pectus). Acute postsurgical pain was associated with higher baseline concentrations of GM-CSF (β = 0.95, SE 0.31; p = 0.003), IL-1β (β = 0.84, SE 0.36; p = 0.02), IL-2 (β = 0.78, SE 0.34; p = 0.03), and IL-12 p70 (β = 0.88, SE 0.40; p = 0.03) and longitudinal postoperative elevations in GM-CSF (β = 1.38, SE 0.57; p = 0.03), IFNγ (β = 1.36, SE 0.6; p = 0.03), IL-1β (β = 1.25, SE 0.59; p = 0.03), IL-7 (β = 1.65, SE 0.7; p = 0.02), and IL-12 p70 (β = 1.17, SE 0.58; p = 0.04). In contrast, CPSP was associated with lower baseline concentration of IL-8 (β = -0.39, SE 0.17; p = 0.02), and the risk of developing CPSP was elevated in patients with lower longitudinal postoperative concentrations of IL-6 (β = -0.57, SE 0.26; p = 0.03), IL-8 (β = -0.68, SE 0.24; p = 0.006), and IL-13 (β = -0.48, SE 0.22; p = 0.03). Covariates female (vs. male) sex and surgery type (pectus surgery vs. spine) were associated with higher odds for CPSP in baseline adjusted cytokine-CPSP association models for IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, TNFα, and IL-8, IL-10, respectively.
We identified pro-inflammatory cytokine profiles associated with higher risk of acute postoperative pain. Interestingly, pleiotropic cytokine IL-6, chemokine IL-8 (which promotes neutrophil infiltration and monocyte differentiation), and monocyte-released anti-inflammatory cytokine IL-13, were associated with lower CPSP risk. Our results suggest heterogenous outcomes of cytokine/chemokine signaling that can both promote and protect against post-surgical pain. These may serve as predictive and prognostic biomarkers of pain outcomes following surgery.
确定基线细胞因子/趋化因子及其术后 0-2 天(POD0-2)的变化是否可预测重大手术后的急性和慢性术后疼痛(CPSP)。
前瞻性、观察性、纵向嵌套研究。
附属大学四级儿童医院。
患有特发性脊柱侧凸的患者(接受脊柱融合术)或患有漏斗胸的患者(接受 Nuss 手术)。
收集术前和术后 0-2 天的人口统计学、手术、心理社会测量、疼痛评分和阿片类药物使用情况的数据。使用 Luminex 珠阵列分析术前和术后两周内采集的连续血样中的细胞因子浓度。在数据准备后,使用单变量和多变量回归分析评估急性(POD0-2 中度至重度疼痛时间百分比)和慢性(术后 3 个月以上疼痛评分>3/10)术后疼痛与术前和术后细胞因子浓度之间的关系,并使用混合效应模型将纵向细胞因子浓度与疼痛结果相关联。
分析包括 112 名患者(中位数年龄 15.3,IQR 13.5-17.0,54.5%女性,59.8%漏斗胸)的 16 种细胞因子/趋化因子的 3164 次重复测量。急性术后疼痛与较高的基线 GM-CSF(β=0.95,SE 0.31;p=0.003)、IL-1β(β=0.84,SE 0.36;p=0.02)、IL-2(β=0.78,SE 0.34;p=0.03)和 IL-12 p70(β=0.88,SE 0.40;p=0.03)浓度以及 GM-CSF(β=1.38,SE 0.57;p=0.03)、IFNγ(β=1.36,SE 0.6;p=0.03)、IL-1β(β=1.25,SE 0.59;p=0.03)、IL-7(β=1.65,SE 0.7;p=0.02)和 IL-12 p70(β=1.17,SE 0.58;p=0.04)术后升高相关。相反,CPSP 与较低的 IL-8 基线浓度(β=-0.39,SE 0.17;p=0.02)相关,IL-6(β=-0.57,SE 0.26;p=0.03)、IL-8(β=-0.68,SE 0.24;p=0.006)和 IL-13(β=-0.48,SE 0.22;p=0.03)的纵向术后浓度较低与 CPSP 的发生风险升高相关。协变量女性(与男性相比)性别和手术类型(胸廓手术与脊柱手术)与 IL-2、IL-4、IL-5、IL-6、IL-8、IL-10、TNFα和 IL-8、IL-10、IL-8、IL-10 的基线调整细胞因子-CPSP 关联模型中的 CPSP 发生风险增加相关。
我们确定了与急性术后疼痛风险增加相关的促炎细胞因子谱。有趣的是,多效细胞因子 IL-6、趋化因子 IL-8(促进中性粒细胞浸润和单核细胞分化)和单核细胞释放的抗炎细胞因子 IL-13 与较低的 CPSP 风险相关。我们的结果表明细胞因子/趋化因子信号的异质结果,既可以促进也可以预防手术后疼痛。这些可能是手术相关疼痛结局的预测和预后生物标志物。