Acute Cytokine Response During Breast Cancer Surgery: Potential Role of Dexamethasone and Lidocaine and Relationship with Postoperative Pain and Complications - Analysis of Three Pooled Pilot Randomized Controlled Trials

Purpose: An imbalance in perioperative cytokine response may cause acute pain and postoperative complications. Anesthetic drugs modulate this cytokine response, but their role in non-major breast cancer surgery is unclear. In an exploratory study, we investigated whether intravenous lidocaine and dexamethasone could modulate the cytokine response into an anti-inflammatory direction. We also evaluated interrelationships between cytokine levels, pain scores and postoperative complications. Our goal is to develop multimodal analgesia regimens optimizing outcome after breast cancer surgery.

Patients and methods: Forty-eight patients undergoing a lumpectomy were randomly assigned to placebo or lidocaine (1.5 mg⋅kg^-1 followed by 2 mg⋅kg^-1⋅hour^-1) supplemented by dexamethasone zero, 4 or 8 mg, yielding six groups of eight patients. Interleukin (IL)-1β, IL-1Ra, IL-6, IL-10 levels and pain scores were measured at baseline and four hours postoperatively. We assessed postoperative complications occurring within 30 days. We noted persistent pain and infections as potential immune-related complications (PIRC). We used multiple regression to disentangle the effects of the individual study drugs (given by their partial regression coefficients (b)). Odds ratios (OR) estimated the link between pain scores and complications.

Results: Dexamethasone 8 mg increased IL-10 (b=12.70 (95% CI=8.06-17.34), P<0.001). Dexamethasone 4 mg and 8 mg decreased the ratio IL-6/IL-10 (b=-2.60 (-3.93 to -1.26), P<0.001 and b=-3.59 (-5.04 to -2.13), P<0.001, respectively). We could not show modulatory effects of lidocaine on cytokines. High pain scores were linked to the occurrence of PIRC's (OR=2.028 (1.134-3.628), P=0.017). Cytokine levels were not related either to acute pain or PIRC.

Conclusion: Dexamethasone modulated the perioperative cytokine response into an anti-inflammatory direction. An overall lidocaine effect was not found. Patients with higher pain scores suffered from more 30-day PIRCs. Cytokine levels were not associated with pain or more postoperative complications, even not with PIRC. Larger studies in breast cancer surgery are needed to confirm these explorative results.

Keywords: acute pain; anesthetic agents; immune response; lumpectomy; perioperative outcomes.