Association of circulating gene expression signatures with stiffness following total knee arthroplasty for osteoarthritis: a pilot study.

A subset of patients undergoing total knee arthroplasty (TKA) for knee osteoarthritis develop debilitating knee stiffness (reduced range of motion) for poorly understood reasons. Dysregulated inflammatory and immune responses to surgery correlate with reduced surgical outcomes, but the dysregulated gene signatures in patients with stiffness after TKA are poorly defined. As a consequence, we are limited in our ability to identify patients at risk of developing poor surgical outcomes and develop preventative approaches. In this pilot study we aimed to identify perioperative blood gene signatures in patients undergoing TKA for knee osteoarthritis and its association with early surgical outcomes, specifically knee range of motion. To do this, we integrated clinical outcomes collected at 6 weeks after surgery with transcriptomics analyses in blood samples collected immediately before surgery and at 24 h after surgery. We found that patients with stiffness at 6 weeks after surgery have a more variable and attenuated circulating gene expression response immediately after surgery. Our results suggest that patients with stiffness following TKA may have distinct gene expression signatures detectable in peripheral blood in the immediate postoperative period.

Intraoperative Acupuncture as Part of a Multimodal Analgesic Regimen to Reduce Opioid Usage After Total Knee Arthroplasty: A Prospective Cohort Trial.

Objective: Given the U.S. opioid crisis, surgeons and anesthesiologists must collaborate to optimize nonopioid analgesics perioperatively. A common surgical procedure, total knee arthroplasty (TKA) is a critical target for opioid reduction and development of enhanced recovery protocols. Auricular therapy can help reduce pain and opioid analgesic use in the perioperative timeperiod, but intraoperative use for TKA has yet to be explored. The aim of the present study was to investigate the effect of integrating intraoperative auricular therapy as part of an opioid-sparing protocol for TKA. Materials and Methods: In this prospective cohort study, 41 patients undergoing primary unilateral TKA under neuraxial anesthesia received a standardized, opioid-free intraoperative protocol including electroauricular acupuncture. The primary outcome was the number of patients able to remain on a low-dose opioid regimen: ≤112.5 oral morphine equivalents. Additional outcomes included patient-reported pain scores, side-effects, and prior experience with acupuncture. Results: Of the 40 patients who completed the study, 26 (65%) maintained a low-dose opioid regimen, with 3 (7%) remaining opioid-free for 30 days. No subjects used opioids beyond 30 days. Mean pain scores were low at rest (Day 0: 3.4, standard deviation [SD] 2.4; Day 1: 2.4, SD 1.8) and moderate with movement (Day 0: 4.8, SD 2.6; Day 1: 5.1, SD 2.1). The most-common side-effects were dry mouth (43.2%), drowsiness (24.3%), and lightheadedness (24.3%). Conclusions: Incorporating intraoperative electroauricular acupuncture into an existing multimodal analgesia regimen is a feasible way to maintain a low-dose opioid regimen after TKA. This research was registered at clinicaltrials.gov as Clinical Trial Number: NCT#04084288.

Identification of biological risk factors for persistent postoperative pain after total knee arthroplasty.

BACKGROUND: There is growing evidence that cytokines and adipokines are associated with osteoarthritis (OA) severity, progression, and severity of associated pain. However, the cytokine response to total knee arthroplasty (TKA) and its association with persistent postoperative pain is not well understood. This study aims to describe the perioperative systemic (plasma) and local (synovial fluid) cytokine profiles of patients who do and do not develop persistent pain after TKA. METHODS: Patients undergoing primary unilateral TKA for end-stage OA were prospectively enrolled. Demographic and clinical data were gathered preoperatively and postoperatively. Synovial fluid was collected pre arthrotomy and plasma was collected at multiple time points before and after surgery. Persistent postoperative pain (PPP) was defined as Numerical Rating Score≥4 at 6 months. Cytokine levels were measured using the V-Plex Human Cytokine 30-Plex Panel (Mesoscale-Rockville, Maryland, USA). Cytokine levels were compared between PPP and minimal pain groups. Given that the study outcomes are exploratory, no adjustment was performed for multiple testing. RESULTS: Incidence of persistent pain at 6 months post TKA was 15/162 (9.3%). Postoperative plasma levels of four cytokines were significantly different in patients who developed persistent postoperative pain: interleukin (IL)-10, IL-1ß, vascular endothelial growth factor, and IL12/IL23p40. Significantly lower IL-10 levels in the prearthrotomy synovial fluid were associated with development of postoperative persistent pain. CONCLUSIONS: This prospective cohort study described a distinct acute perioperative inflammatory response profile in patients who developed persistent post-TKA pain, characterized by significant differences in four cytokines over the first 2 postoperative days. These results support the growing evidence that the patient-specific biologic response to surgery may influence longer-term clinical outcomes after TKA. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT02626533.

Postoperative Serum Cytokine Levels Are Associated With Early Stiffness After Total Knee Arthroplasty: A Prospective Cohort Study.

BACKGROUND: Inflammatory cytokines have been implicated in organ fibrosis; however, their role in the development of arthrofibrosis after total knee arthroplasty (TKA) has not been well explored. The purpose of this study is to assess whether perioperative synovial fluid or blood plasma cytokine levels are associated with reduced early post-TKA range of motion. METHODS: A total of 179 patients with end-stage idiopathic osteoarthritis undergoing TKA were enrolled in this prospective cohort study. Synovial fluid and blood plasma were collected prearthrotomy and plasma was collected longitudinally in the postacute care unit and on postoperative days (PODs) 1 and 2. Stiffness was defined as ≤95° range of motion measured with a goniometer at 6 weeks (±2 weeks). RESULTS: Thirty-two of 162 (19.8%) patients analyzed were stiff at 6 weeks postoperatively. Postoperative plasma levels of 9 cytokines (Eotaxin3, IL-5, IL12_23p40, IP10, VEGF, IL-7, IL-12p70, IL-16, IL-17a) were significantly different between stiff and nonstiff patients on POD1 and/or POD2. An association between preoperative plasma and synovial fluid cytokine levels and the development of postoperative stiffness was not detected. CONCLUSION: The results of this study suggest that there is a distinct acute postoperative cytokine response profile in patients who develop stiffness 6 weeks after TKA. This profile was characterized by significant differences in levels of 9 cytokines over the first 2 postoperative days. These results identify cytokines that are potential biomarkers for risk of early stiffness after TKA and may play a role in the pathophysiology of this outcome.

Intravenous vs Oral Acetaminophen as a Component of Multimodal Analgesia After Total Hip Arthroplasty: A Randomized, Blinded Trial.

BACKGROUND: Multimodal analgesia including acetaminophen is increasingly popular for analgesia after total hip arthroplasty (THA). Intravenous (IV) administration of acetaminophen has pharmacokinetic benefits, but unclear clinical advantages. The authors hypothesized that IV acetaminophen would reduce pain with activity, opioid usage, or opioid-related side effects, compared to oral acetaminophen. METHODS: In this double-blinded, randomized, controlled trial, 154 THA patients received either IV or oral acetaminophen as part of a comprehensive opioid-sparing multimodal analgesia strategy. Primary outcomes were pain with physical therapy on postoperative day (POD) 1, opioid side effects (POD 1), and cumulative opioid use. RESULTS: There was no difference in opioid side effects, pain scores, or opioid use between the groups. CONCLUSION: Patients in both groups had low pain scores, minimal opioid side effects, and limited opioid usage (corresponding to 6 doses of tramadol 100 mg over 3 days). This highlights multimodal analgesia as an effective method of pain control for THA.