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

Abstract

Sandra AS van den Heuvel,1 Selina EI van der Wal,1 Ewald M Bronkhorst,2 Michiel C Warlé,3 May Ronday,4 Judith Plat,4 Nens van Alfen,5 Leo AB Joosten,6 Jos GC Lerou,1 Kris CP Vissers,1 Monique AH Steegers7 1Department of Anesthesiology, Pain and Palliative Medicine, Radboud University Medical Centre, Nijmegen, the Netherlands; 2Department of Health Evidence, Radboud University Medical Centre, Nijmegen, the Netherlands; 3Division of Vascular and Transplant Surgery, Department of Surgery, Radboud University Medical Centre, Nijmegen, the Netherlands; 4Department of Anesthesiology, Alexander Monro Breast Cancer Hospital, Bilthoven, the Netherlands; 5Donders Institute for Brain Cognition and Behavior, Department of Neurology, Radboud University Medical Centre, Nijmegen, the Netherlands; 6Department of Internal Medicine and Radboud Centre for Infectious Diseases, Radboud University Medical Centre, Nijmegen, the Netherlands; 7Department of Anesthesiology, Pain and Palliative Medicine, Amsterdam University Medical Centre, Amsterdam, the NetherlandsCorrespondence: Sandra AS van den HeuvelDepartment of Anesthesiology, Pain and Palliative Medicine, Radboud University Nijmegen Medical Center, Internal mail 630, P.O. Box 9101, Nijmegen 6525 GA, the NetherlandsTel [phone]Email [email protected]: 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

Keywords

• acute pain
• anesthetic agents
• immune response
• lumpectomy
• perioperative outcomes