The role of cytokines in acute and chronic postsurgical pain after major musculoskeletal surgeries in a quaternary pediatric center

Study Objective

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.

Design

Prospective, observational, longitudinal nested study.

Setting

University-affiliated quaternary children’s hospital.

Patients

Subjects (≥8 years old) with idiopathic scoliosis undergoing spine fusion or pectus excavatum undergoing Nuss procedure.

Measurements

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.

Main Results

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.

Conclusion

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.