Lumbar epidural analgesia and sciatic and femoral peripheral nerve blocks attenuate the stress-induced response in patients during the early postoperative period following total knee replacement

Invasive surgical procedures cause immune system downregulation by inducing a profound proinflammatory response. Establishing the most effective type of postoperative analgesia is crucial to maintain the equilibrium of the immune system. The purpose of this research was to evaluate the influence of epidural analgesia, peripheral nerve blockade as well as systemic analgesia on stress response in patients during the early postoperative period following total knee replacement. In total, 60 patients undergoing total knee replacement were allocated into three groups (n = 20, per group) in this prospective randomized study. Group 1, Group 2 and Group 3 received epidural analgesia, sciatic and femoral peripheral nerve blocks and systemic analgesia, respectively. Intensity of pain was measured at rest and upon movement. Blood samples were collected at baseline (T0), immediately before (T1) and after (T2) surgery, and 24 (T3) and 72 (T4) h postoperatively. The absolute number of leukocytes, concentrations of catecholamine, cortisol and C-reactive protein were determined. Patients in Group 1 and Group 2 exhibited lower pain scores than Group 3. Concentrations of cortisol and norepinephrine, but not epinephrine, were significantly lower in Group 1 and Group 2 at T2 than in Group 3. Significantly lower interleukin-1β concentrations were observed in Group 1 and Group 2 at T3 and T4 than in Group 3. Interleukin-6 concentrations were minor in Group 1 and Group 2 at T2 than in Group 3. Lumbar epidural analgesia and sciatic and femoral peripheral nerve blocks are effective analgesic techniques that reduce the acute inflammatory stress response in patients during the early postoperative period following total knee replacement.

Analgesia; Cytokines; Hormones; Pain; Stress response; Total knee replacement

[1] Collins JE, Yang YH, Opare-Addo MB, Losina E. Quantifying sustained pain worsening in knee osteoarthritis. Osteoarthritis and Cartilage. 2023; 31: 802–808.

[2] Malafoglia V, Ilari S, Vitiello L, Tenti M, Balzani E, Muscoli C, et al. The interplay between chronic pain, opioids, and the immune system. The Neuroscientist. 2022; 28: 613–627.

[3] Lang-Illievich K, Klivinyi C, Rumpold-Seitlinger G, Dorn C, Bornemann-Cimenti H. The effect of palmitoylethanolamide on pain intensity, central and peripheral sensitization, and pain modulation in healthy volunteers—a randomized, double-blinded, placebo-controlled crossover trial. Nutrients. 2022; 14: 4084.

[4] Plein LM, Rittner HL. Opioids and the immune system—friend or foe. British Journal of Pharmacology. 2018; 175: 2717–2725.

[5] Hafkamp FMJ, Groot Kormelink T, de Jong EC. Targeting DCs for tolerance induction: don’t lose sight of the neutrophils. Frontiers in Immunology. 2021; 12: 732992.

[6] Grosu I, Lavand’homme P. Continuous regional anesthesia and inflammation: a new target. Minerva Anestesiologica. 2015; 81: 1001–1009.

[7] Høgevold HE, Lyberg T, Kähler H, Haug E, Reikerås O. Changes in plasma IL-1beta, TNF-alpha and IL-6 after total hip replacement surgery in general or regional anaesthesia. Cytokine. 2000; 12: 1156–1159.

[8] Gonçalves Dos Santos G, Delay L, Yaksh TL, Corr M. Neuraxial cytokines in pain states. Frontiers in Immunology. 2020; 10: 3061.

[9] Meyer-Frießem CH, Lipke E, Weibel S, Kranke P, Reichl S, Pogatzki-Zahn EM, et al. Perioperative ketamine for postoperative pain management in patients with preoperative opioid intake: a systematic review and meta-analysis. Journal of Clinical Anesthesia. 2022; 78: 110652.

[10] Beiner E, Lucas V, Reichert J, Buhai DV, Jesinghaus M, Vock S, et al. Stress biomarkers in individuals with fibromyalgia syndrome: a systematic review with meta-analysis. Pain. 2023; 164: 1416–1427.

[11] Hou Y, Lu J, Xie J, Zhu R, Wu M, Wang K, et al. Effects of electroacupuncture on perioperative anxiety and stress response in patients undergoing surgery for gastric or colorectal cancer: study protocol for a randomized controlled trial. Frontiers in Psychiatry. 2023; 14: 1095650.

[12] Matsuda M, Huh Y, Ji RR. Roles of inflammation, neurogenic inflammation, and neuroinflammation in pain. Journal of Anesthesia. 2019; 33: 131–139.

[13] Zhang Y, Lu J, Qin M, Xu M, Luo W, Li B, et al. Effects of different anesthesia methods on postoperative immune function in patients undergoing gastrointestinal tumor resection. Scientific Reports. 2023; 13: 243.

[14] Velcic Brumnjak S, Rakovac I, Papez Kinkela D, Bukal K, Sestan B, Tulic V, et al. Postoperative regional analgesia is effective in preserving perforin-expressing lymphocytes in patients after total knee replacement. Medical Science Monitor. 2018; 24: 5320–5328.

[15] Ilfeld BM, Shuster JJ, Theriaque DW, Mariano ER, Girard PJ, Loland VJ, et al. Long-term pain, stiffness, and functional disability following total knee arthroplasty with and without an extended ambulatory continuous femoral nerve block: a prospective, one-year follow-up of a multicenter, randomized, triple-masked, placebo-controlled trial. Regional Anesthesia and Pain Medicine. 2011; 36: 116–120.

[16] Domecky P, Rejman Patkova A, Mala-Ladova K, Maly J. Inflammatory blood parameters as prognostic factors for implant-associated infection after primary total hip or knee arthroplasty: a systematic review. BMC Musculoskeletal Disorders. 2023; 24: 383.

[17] Martin F, Martinez V, Mazoit JX, Bouhassira D, Cherif K, Gentili ME, et al. Antiinflammatory effect of peripheral nerve blocks after knee surgery: clinical and biologic evaluation. Anesthesiology. 2008; 109: 484–490.

[18] Shanthanna H, Huilgol M, Manivackam VK, Maniar A. Comparative study of ultrasound-guided continuous femoral nerve blockade with continuous epidural analgesia for pain relief following total knee replacement. Indian Journal of Anaesthesia. 2012; 56: 270–275.

[19] Kim JH, Cho MR, Kim SO, Kim JE, Lee DK, Roh WS. A comparison of femoral/sciatic nerve block with lateral femoral cutaneous nerve block and combined spinal epidural anesthesia for total knee replacement arthroplasty. Korean Journal of Anesthesiology. 2012; 62: 448–453.

[20] Chung MY, Kim CJ. The effect of femoral nerve block combined with intravenous patient-controlled analgesia after a unilateral total knee replacement. Korean Journal of Anesthesiology. 2008; 55: 596–601.

[21] Karpetas GZ, Spyraki MK, Giakoumakis SI, Fligou FG, Megas PD, Voyagis GS, et al. Multimodal analgesia protocol for pain management after total knee arthroplasty: comparison of three different regional analgesic techniques. Journal of Musculoskeletal & Neuronal Interactions. 2021; 21: 104–112.

[22] Opree A, Kress M. Involvement of the proinflammatory cytokines tumor necrosis factor-α, IL-1β and IL-6 but not IL-8 in the development of heat hyperalgesia: effects on heat-evoked calcitonin gene-related peptide release from rat skin. The Journal of Neuroscience. 2000; 20: 6289–6293.

[23] Zhao M, Wang F, Shi L, Xue Q. Interleukin-6 serum concentration in the elderly undergoing total knee arthroplasty: a potential predictor of the early postoperative knee joint range of motion. Journal of Back and Musculoskeletal Rehabilitation. 2020; 33: 35–40.

[24] Le V, Kurnutala L, Schiano Di Cola J, Ahmed K, Yarmush J, Eloy JD, et al. Premedication with intravenous ibuprofen improves recovery characteristics and stress response in adults undergoing laparoscopic cholecystectomy: a randomized controlled trial. Pain Medicine. 2016; 17: 1163–1173.

[25] Kuchálik J, Magnuson A, Tina E, Gupta A. Does local infiltration analgesia reduce peri-operative inflammation following total hip arthroplasty? A randomized, double-blind study. BMC Anesthesiology. 2017; 17: 63.

[26] Beloeil H, Ji RR, Berde CB. Effects of bupivacaine and tetrodotoxin on carrageenan-induced hind paw inflammation in rats (part 2): cytokines and p38 mitogen-activated protein kinases in dorsal root ganglia and spinal cord. Anesthesiology. 2006; 105: 139–145.

[27] Bagry H, de la Cuadra Fontaine JC, Asenjo JF, Bracco D, Carli F. Effect of a continuous peripheral nerve block on the inflammatory response in knee arthroplasty. Regional Anesthesia and Pain Medicine. 2008; 33: 17–23.

[28] Kaye AD, Patel N, Bueno FR, Hymel B, Vadivelu N, Kodumudi G, et al. Effect of opiates, anesthetic techniques, and other perioperative factors on surgical cancer patients. The Ochsner Journal. 2014; 14: 216–228.