The Role of Cytokines in Acute and Chronic Postsurgical Pain in Pediatric Patients after Major Musculoskeletal Surgeries

Study ObjectiveTo determine if baseline cytokines and their changes over postoperative days 0-2 (POD0-2) predict acute and chronic postsurgical pain (CPSP) after major surgery. DesignProspective, observational, longitudinal nested study. SettingUniversity-affiliated quaternary childrens hospital. PatientsSubjects ([≥]8 years old) with idiopathic scoliosis undergoing spine fusion or pectus excavatum undergoing Nuss procedure. MeasurementsDemographics, surgical, psychosocial measures, pain scores, and opioid use over POD0-2 were collected. Cytokine concentrations were analyzed in serial blood samples collected before and after (up to two weeks) 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) pain were analyzed. After adjusting for covariates, univariate/multivariate regression analyses were conducted to associate baseline cytokine concentrations with postoperative pain, and mixed effects models were used to associate longitudinal cytokine concentrations with pain outcomes. Main ResultsAnalyses included 3,164 measures of 16 cytokines 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 ({beta}=0.95, SE 0.31; p=.003), IL-1{beta} ({beta}=0.84, SE 0.36; p=.02), IL-2 ({beta}=0.78, SE 0.34; p=.03), and IL-12 p70 ({beta}=0.88, SE 0.40; p=.03) and longitudinal postoperative elevations in GM-CSF ({beta}=1.38, SE 0.57; p=.03), IFN{gamma} ({beta}=1.36, SE 0.6; p=.03), IL-1{beta} ({beta}=1.25, SE 0.59; p=.03), IL-7 ({beta}=1.65, SE 0.7, p=.02), and IL-12 p70 ({beta}=1.17, SE 0.58; p=.04). In contrast, CPSP was associated with lower baseline concentration of IL-8 ({beta}= -0.39, SE 0.17; p=.02), and the risk of developing CPSP was elevated in patients with lower longitudinal postoperative concentrations of IL-6 ({beta}= -0.57, SE 0.26; p=.03), IL-8 ({beta}= - 0.68, SE 0.24; p=.006), and IL-13 ({beta}= -0.48, SE 0.22; p=.03). Furthermore, higher odds for CPSP were found for females (vs. males) for IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, and TNF, and for pectus (vs. spine) surgery for IL-8 and IL-10. ConclusionWe identified pro-inflammatory cytokines associated with increased acute postoperative pain and anti-inflammatory cytokines associated with lower CPSP risk, with potential to serve as predictive and prognostic biomarkers.