Perioperative Dexamethasone in Total Knee Arthroplasty: Early Analgesic Benefit Without Major Glycemic Perturbation and Effect Modification by Age, Diabetes, and Regional Analgesia

Perioperative Dexamethasone in Total Knee Arthroplasty: Early Analgesic Benefit Without Major Glycemic Perturbation and Effect Modification by Age, Diabetes, and Regional Analgesia | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Perioperative Dexamethasone in Total Knee Arthroplasty: Early Analgesic Benefit Without Major Glycemic Perturbation and Effect Modification by Age, Diabetes, and Regional Analgesia Serdar Yüksel, Emre Özmen, Muhammed Yusuf Afacan, Alican Barış, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9352754/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 6 You are reading this latest preprint version Abstract Background: Optimal postoperative analgesia after total knee arthroplasty (TKA) remains challenging. Dexamethasone is used as an adjunct to multimodal analgesia, but its subgroup effectiveness and glycemic safety are uncertain. We aimed to determine whether perioperative intravenous dexamethasone improves early postoperative pain (time-weighted mean VAS over 6–48 h) and preserves glycemic safety, and to assess effect modification by age, diabetes status, and peripheral nerve block. Methods: We performed a single-center retrospective observational study of adults undergoing primary, elective TKA grouped by dexamethasone exposure (Dexa+ n=39; Non-Dexa n=65). The primary outcome was time-weighted mean VAS 6–48 h; VAS at 6, 12, 18, 24, 30, 36, 42, and 48 h was also analyzed. Secondary outcomes were preoperative HbA1c and perioperative glucose (Glucose I: evening of surgery; Glucose II: postoperative fasting morning; Glucose III: evening of postoperative day 1). Prespecified subgroups were age (≤65 vs >65 years), diabetes mellitus (DM vs non-DM), and peripheral nerve block (block vs no block). Two-sided tests with α=0.05 were used. Results: Groups were similar in age, sex, and DM prevalence; block use was higher and PCA use lower in Dexa+ (both p 0.05) but was lower with Dexa+ at 12, 24, 30, 36, 42, and 48 h ( p 0.05). In subgroups, Dexa+ improved VAS at all time points in patients >65 years and at 12–48 h in non-DM patients; no benefit was observed in patients ≤65 years or with DM. In patients without block, Dexa+ reduced VAS at all time points; with block, VAS did not differ. Glucose patterns were similar across subgroups, except for a higher first glucose in Dexa+ without block, with later values converging. Conclusions: Perioperative dexamethasone improved early postoperative pain after TKA—particularly in older and non-diabetic patients and when no block was used—without major glycemic perturbations. These findings support selective, risk-adapted use and warrant confirmation in prospective randomized studies. Study type: A level 3 retrospective cohort study Health sciences/Diseases Health sciences/Endocrinology Health sciences/Health care Health sciences/Medical research Figures Figure 1 Figure 2 Figure 3 Figure 4 Highlights Perioperative dexamethasone lowered postoperative pain (VAS) from 12–48 h after TKA, especially in patients >65 years and non-diabetics. No analgesic advantage with dexamethasone was observed in patients ≤65 years, in diabetics, or when a peripheral nerve block was used. Glycemic indices (preoperative HbA1c; perioperative glucose I–III) were broadly comparable between groups, indicating no major glycemic perturbation. What is already known Dexamethasone modestly reduces early postoperative pain and PONV after arthroplasty, with effects concentrated in the first 24–48 hours. Regional anesthesia and local infiltration provide strong early analgesia, potentially limiting the incremental benefit of systemic steroids. Single perioperative doses of dexamethasone can transiently raise glucose but have not been shown to increase PJI risk. What is new In a real-world TKA cohort, dexamethasone improved VAS 12–48 h only in patients >65 years and in non-diabetics. Analgesic benefit disappeared with peripheral nerve block, indicating pathway-dependent effect modification. Preoperative HbA1c and perioperative glucose profiles were similar between groups, aside from a transient early rise that later converged. INTRODUCTION Postoperative pain following total knee arthroplasty (TKA) remains a significant clinical challenge despite advances in surgical technique, anesthesia, and multimodal analgesia protocols ( 1 , 2 ). Moderate to severe pain is common in the immediate postoperative period and is associated with delayed mobilization, increased opioid consumption, prolonged hospital stay, and higher complication rates ( 3 , 4 ). Various pharmacological and regional anesthesia strategies have been employed to optimize pain relief, yet an ideal regimen balancing analgesia, safety, and functional recovery has not been clearly established ( 5 ). In this context, glucocorticoids such as dexamethasone have emerged as promising adjuncts due to their potent anti-inflammatory and antiemetic properties ( 6 , 7 ). Dexamethasone has been widely studied as an adjuvant in regional anesthesia and systemic administration. When given perioperatively, it reduces prostaglandin synthesis, inhibits inflammatory mediators, and prolongs the duration of peripheral nerve blocks ( 7 – 10 ). Several meta-analyses and randomized controlled trials have demonstrated that dexamethasone not only improves postoperative pain control but also decreases opioid consumption, nausea, and vomiting, and hospital stay thereby enhancing patient satisfaction and recovery ( 3 , 7 , 18 – 22 , 8 , 11 – 17 ). However, concerns remain regarding its metabolic effects, particularly postoperative hyperglycemia, which may complicate outcomes in elderly patients and those with diabetes mellitus (DM) ( 23 ). Although some reports indicate that a single low-dose administration is safe, others have suggested potential associations with elevated glucose levels and impaired wound healing, necessitating further investigation ( 23 – 25 ). Clarifying the impact of dexamethasone on postoperative pain and glucose homeostasis is especially important in TKA, where both effective analgesia and metabolic stability are crucial for early rehabilitation and functional recovery. Furthermore, subgroup differences related to age, DM status, and the application of peripheral nerve blocks have not been comprehensively addressed in previous studies. The aim of this study was to evaluate the effects of perioperative dexamethasone on postoperative pain control and glycemic outcomes in patients undergoing TKA, with subgroup analyses stratified by age (≤ 65 vs. >65 years), diabetic status (DM vs. non-DM), and peripheral nerve block application. MATERIALS AND METHODS This retrospective observational study was carried out at our institution following approval by the University of Health Sciences, Istanbul Physical Therapy and Rehabilitation Training and Research Hospital Institutional Ethics Committee. The study was designed and conducted in accordance with the ethical principles of the Declaration of Helsinki. All relevant clinical and laboratory data were extracted from the hospital’s electronic medical record system and charts. Informed consent was obtained from all individual participants included in the study. A total of 104 patients who underwent primary, elective total knee arthroplasty (TKA) in 2025 were included in the analysis. Patients were considered eligible if they were operated for primary gonarthrosis, had complete postoperative pain score documentation covering the first 48 hours, and had at least three postoperative blood glucose measurements available. Patients were excluded if they had undergone revision or bilateral TKA in a single session, required additional major surgery during the same hospitalization, were implanted augments in addition to the primary prosthesis or had incomplete data regarding the study’s primary or secondary outcomes. The study population was divided into two groups according to perioperative administration of intravenous dexamethasone. The Dexa group (n = 39) consisted of patients who received a single intravenous dose of 8mg dexamethasone prior to anesthesia induction, and an additional single intravenous dose of 4mg within the postoperative six hours, while the Non-Dexa group (n = 65) included patients who did not receive dexamethasone. All patients were treated under the institution’s standardized anesthesia and multimodal analgesia protocols. In addition, the administration of peripheral nerve blocks and the use of patient-controlled analgesia (PCA) were systematically recorded. The following variables were collected for analysis: demographic characteristics (age and sex), presence of diabetes mellitus (DM), whether a peripheral nerve block was performed, and whether PCA was utilized postoperatively. Postoperative pain was assessed using the visual analogue scale (VAS; range 0–10) at the 6th, 12th, 18th, 24th, 30th, 36th, 42nd, and 48th postoperative hours. Laboratory data included preoperative glycated hemoglobin (HbA1c) values and three standardized perioperative glucose measurements, referred to as Glucose I, Glucose II, and Glucose III, obtained at predefined time points during the postoperative period. Glucose I was defined as the blood glucose measurement obtained on the evening of the surgery, Glucose II corresponded to the postoperative fasting morning blood glucose level, and Glucose III represented the measurement taken on the evening of the first postoperative day. The primary outcome of the study was the time-weighted mean VAS score over the 6–48-hour postoperative period. Secondary outcomes included preoperatively documented HbA1c levels, perioperative changes in glucose values (Glucose I: evening of surgery, Glucose II: postoperative fasting morning, Glucose III: evening of the first postoperative day), and subgroup analyses stratified by age (≤ 65 vs. >65 years), diabetes status (DM vs. non-DM), and peripheral nerve block application (block vs. no block). All patients scheduled for total knee arthroplasty (TKA) were instructed to remain nil per os for at least 8 hours preoperatively. On the morning of surgery, only patients with hypertension or hypothyroidism continued their routine medications. Immediately before surgery, all patients received intravenous tranexamic acid (100 mg) and cefazolin (2 g, first-generation cephalosporin). A pneumatic tourniquet was applied to every patient and inflated to 300 mmHg. Procedures were performed through a midline skin incision with a medial parapatellar arthrotomy. Bone preparation commenced with the distal femoral cut in all cases. Antibiotic-loaded bone cement was used for every implantation. Depending on patient anatomy and surgeon preference, either posterior-stabilized or cruciate-retaining prostheses were implanted; no patellar components were used. Hemovac drains were not placed, whereas urinary catheterization was performed in all patients. On postoperative day (POD) 0, patients were not mobilized and were managed with anti-embolic stockings. Beginning on POD 1, patients were encouraged to initiate knee flexion exercises, straight-leg raises, and quadriceps stretching, followed by mobilization as tolerated. All patients were discharged on POD 3. During hospitalization, patients received intravenous normal saline (500 mL every 12 hours), an intravenous nonsteroidal anti-inflammatory drug (50 mg/2 mL every 8 hours), an intravenous proton-pump inhibitor (40 mg once each morning), intravenous paracetamol (10 mg/mL every 12 hours), and intravenous tramadol hydrochloride (100 mg/2 mL, up to twice daily as needed). Thromboprophylaxis consisted of subcutaneous enoxaparin sodium (100 mg) once daily in the evening. On POD 0, patients also received three additional doses of intravenous cefazolin (1 g every 8 hours) and three doses of oral tranexamic acid (1 g every 8 hours). Capillary blood glucose was monitored every 8 hours throughout the hospitalization. Statistics Descriptive statistics were presented as mean ± standard deviation, median, minimum, maximum, frequency, and percentage, as appropriate. The normality of data distribution was assessed using the Kolmogorov–Smirnov and Shapiro–Wilk tests. Independent quantitative variables with normal distribution were analyzed using the independent samples t -test, while non-normally distributed independent quantitative variables were evaluated with the Mann–Whitney U test. Categorical variables were compared using the Chi-square test. All statistical analyses were performed using SPSS version 27.0 (IBM Corp., Armonk, NY, USA). A two-tailed p -value < 0.05 was considered statistically significant. The sample size for the two-group comparison was determined using G*Power software (Version 3.1.9.6). For the primary endpoint (time-weighted mean VAS over 6–48 h), the analysis assumed a clinically meaningful difference (Δ) of 1.0 VAS unit, a standard deviation of 1.5–2.0, a two-sided significance level of α = 0.05 (95% reliability), and a statistical power of 80–90%. Under these assumptions, the corresponding effect size (Cohen’s d ) was calculated as 0.50–0.67 (medium to large). The minimum required sample size was therefore 36–63 patients per group for 80% power, or 48–84 patients per group for 90% power. With the available cohorts (Dexa + n = 39; Dexa– n = 65), the study achieved ≥ 80% power to detect differences of approximately 0.85–1.13 VAS units, which is within the range of clinical relevance. RESULTS The study population consisted of 104 patients with a mean age of 68.2 ± 7.9 years of whom 34 were aged ≤65 years, 70 were aged >65 years, 18 were male and 86 female; the prevalence of diabetes mellitus was 35.6%, while peripheral nerve block and patient-controlled analgesia were applied in 20.2% and 15.4% of patients, respectively, with overall median VAS score of 7.0, median HbA1c of 6.0, and median postoperative glucose values of 143.0, 150.0, and 130.0 mg/dL at the first, second, and third measurements, respectively (Table 1). Between the Dexa and non-Dexa groups, no significant differences were found in age, sex distribution, or prevalence of diabetes mellitus (DM) (p>0.05). The rate of peripheral nerve block administration was significantly higher in the Dexa group (p<0.05), whereas patient-controlled analgesia (PCA) use was significantly lower (p0.05), while at the 12th, 24th, 30th, 36th, 42nd, and 48th hours, the Dexa group demonstrated significantly lower values (p0.05) (Table 2). In patients aged ≤65 years, no significant differences were observed in age, sex, or DM distribution (p>0.05). The Dexa group, however, showed a higher rate of peripheral nerve block (p<0.05) and a lower rate of PCA use (p0.05). HbA1c and glucose measurements at all time points were likewise comparable (p>0.05) (Table 3). Among patients aged >65 years, age, sex, and DM distribution were similar between groups (p>0.05). The Dexa group had a significantly higher block rate (p<0.05) and lower PCA use (p<0.05). At all postoperative time points from 6th to 48th hours, VAS scores were significantly lower in the Dexa group (p0.05) (Table 4). In patients without DM, no significant differences were seen in age or sex distribution (p>0.05). Block use was significantly higher in the Dexa group (p<0.05), while PCA use was significantly lower (p0.05) but significantly lower in the Dexa group at the 12th, 18th, 24th, 32nd, 36th, 42nd, and 48th hours (p0.05) (Table 5). Among patients with DM, no significant differences were found in age or sex distribution (p>0.05). The Dexa group had a higher block rate (p0.05). VAS scores from the 6th through 48th hours showed no significant differences (p>0.05). HbA1c values and glucose levels at all measurements were also comparable (p>0.05) (Table 6). In patients without block, age, sex, and DM distribution were similar between groups (p>0.05). PCA use was significantly lower in the Dexa group (p<0.05). At all postoperative time points from 6th to 48th hours, VAS scores were significantly lower in the Dexa group (p0.05). The first glucose measurement was significantly higher in the Dexa group (p0.05) (Table 7). Finally, in patients with block, no significant differences were found in age, sex, or DM distribution (p>0.05). VAS scores at all time points (6th to 48th hours) were similar between groups (p>0.05). HbA1c values and glucose levels at the first, second, and third measurements also showed no significant differences (p>0.05) (Table 8). DISCUSSION Perioperative dexamethasone (Dexa) in our cohort was associated with lower pain scores from 12 to 48 hours after total knee arthroplasty (TKA), with effects concentrated in patients > 65 years, in non-diabetic patients, and in those who did not receive a peripheral nerve block; no analgesic advantage was observed in patients ≤ 65 years, in patients with diabetes, or when a block was used. Glycemic indices (preoperative HbA1c; perioperative glucose I–III) were broadly comparable between groups, suggesting that the analgesic benefits of dexamethasone were achieved without clinically relevant alterations in glycemic control, aside from a transiently higher first glucose among patients without a block who received Dexa, with subsequent convergence. These subgroup and time‐course patterns frame Dexa as a selective adjunct within multimodal pathways. The present study demonstrated earlier and sustained analgesic separation from 12–48 hours after TKA, a pattern concordant with randomized and pooled evidence showing that perioperative Dexa modestly reduces early postoperative pain and opioid use, with the most consistent effects in the first 24–48 hours ( 6 , 8 , 26 – 31 ). Randomized trials in TKA report clinically meaningful early improvements and elements of enhanced recovery when Dexa is incorporated into multimodal pathways ( 13 , 15 , 22 , 32 , 33 ). Longer-term outcomes, however, appear neutral: intravenous Dexa did not reduce persistent postsurgical pain at 12 weeks in a robust placebo-controlled trial ( 21 ), showed no prolonged advantage for pain or sleep on postoperative days 3–7 in DEX-2-TKA follow-up ( 34 ), and did not alter chronic pain or function at 3 years ( 11 ). Meta-analytic signals of improved walking distance, ROM, and global quality of recovery ( 31 ) are consistent with an early window of benefit, mirroring the present cohort’s time-course and subgroup effects in patients > 65 years and in those without diabetes. Dose–schedule selection influences early analgesic magnitude. Higher single doses (e.g., 16–20 mg) have been associated with greater reductions in pain, opioids, and postoperative nausea and vomiting (PONV) on day 1 ( 3 , 14 , 33 , 35 ), and targeted postoperative dosing can extend short-term benefits ( 12 , 15 ). Multiple low-dose regimens frequently outperform a single low dose, reducing pain, inflammatory markers (CRP/IL-6), and PONV without added complications ( 36 , 37 ), a theme echoed by systematic synthesis showing earlier discharge and improved recovery with perioperative corticosteroids, with larger or repeat dosing sometimes yielding greater dynamic pain and PONV reductions ( 38 ). Pragmatic low-dose strategies (e.g., 8 mg IV) are widely used with acceptable safety and only moderate glycemic impact ( 32 ), and two-dose regimens can reduce morphine and pain across 48 hours ( 22 ). Across trials and meta-analyses, timing around induction and/or the first postoperative day captures the interval in which Dexa is most effective ( 3 , 6 – 8 , 26 , 30 ), aligning with the 12–48-hour separation observed here. The observed attenuation of Dexa’s analgesic advantage when a peripheral nerve block was employed is clinically plausible. Comparative evidence ranks local infiltration/intra-articular strategies among the most effective for early TKA pain, potentially diminishing the incremental benefit of systemic agents ( 1 , 2 ). Regarding steroid route as a block adjuvant, systematic reviews indicate broadly similar analgesic gains with perineural and intravenous Dexa, with a perineural edge only when epinephrine is co-administered ( 9 , 10 ). Local steroid via periarticular infiltration can match single-dose IV Dexa for first-24-hour analgesia without excess glycemic or wound risk ( 32 ), and betamethasone may outperform Dexa within cocktail therapy without additional complications ( 39 ). Safety signals are reassuring: adding corticosteroid to periarticular injections does not increase prosthetic joint infection risk ( 40 ). Collectively, these data support a tailored approach—Dexa appears most useful when regional analgesia is absent or limited, which parallels the no-block subgroup effect observed. Across the cohort and subgroups, preoperative HbA1c and perioperative glucose measurements were largely comparable between Dexa and control, aside from a transient first-glucose increase in the no-block Dexa subgroup that subsequently converged. Quantitative synthesis suggests a modest, short-lived rise in glucose within 24 hours after a single perioperative Dexa dose, generally of limited clinical consequence ( 19 ). In type-2 diabetes, randomized and observational studies show transient day-0/1 hyperglycemia yet preserved early analgesic benefit; adequate baseline control and post-operative monitoring can maintain acceptable glycemic profiles ( 16 , 17 , 20 ). Reviews in diabetic populations indicate short-term increases of approximately 30–45 mg/dL after a single dose, albeit with heterogeneous certainty ( 24 ). Importantly, Dexa-associated hyperglycemia has not been linked to greater infectious complications in large diabetic arthroplasty cohorts ( 23 ), and single-dose Dexa has not increased periprosthetic joint infection after THA/TKA ( 41 , 42 ), although higher POD1 glucose has been observed irrespective of diabetic status in some series ( 25 ). Contemporary multidisciplinary guidance recommends individualized dosing and proactive glucose surveillance rather than categorical avoidance in diabetes ( 3 ). Although antiemetic outcomes were not the primary endpoints in this study, robust evidence confirms reductions in PONV and rescue antiemetics with perioperative Dexa ( 4 , 7 ). Trials also suggest improvements in early mobilization and quality-of-recovery ( 31 , 33 ), and multi-study syntheses associate Dexa with shorter length of stay ( 18 , 38 ). Combination strategies, such as tranexamic acid plus Dexa, may further reduce CRP/IL-6, pain, PONV, and fatigue and improve ROM without increasing complications ( 43 ). In parallel, non-pharmacological modalities (education, mind–body techniques, physical therapies) can complement pharmacologic regimens to reduce pain intensity, opioid requirements, and facilitate recovery within multimodal pathways ( 5 ). These broader recovery signals align with the temporal window in which analgesic separation was detected (12–48 hours). Our results reinforce the core messages of contemporary guidelines: perioperative IV Dexa is an effective element of multimodal analgesia after TKA, particularly in the first 48 hours; multiple doses can enhance effect; and use in diabetes warrants caution and monitoring while evidence matures ( 3 ). The age- and block-dependent patterns we observed—benefit in older, non-diabetic, no-block patients—provide pragmatic levers for risk-adapted deployment in everyday practice. The study benefits from an adequate sample size, standardized anesthesia, analgesia, and surgical protocols, and consistent pain assessment at multiple time points using VAS. Inclusion of perioperative glucose monitoring and preoperative HbA1c allowed evaluation of metabolic safety. Subgroup analyses by age, diabetes status, and peripheral nerve block enhanced clinical relevance. The retrospective, single-center design may limit generalizability and introduce selection bias. Imbalances in peripheral nerve block and PCA use could have influenced pain results. Glucose was monitored only at three perioperative points limiting metabolic assessment. Functional outcomes such as pre- and postoperative range of motion and clinical scores were not recorded, restricting evaluation of overall recovery. For centers employing standardized regional pathways, Dexa’s incremental analgesic value may be greatest in patients who are older, non-diabetic, or not receiving a block; when blocks are used, Dexa may be reserved for antiemetic prophylaxis and patients at risk of high inflammatory pain. Diabetes should not be an automatic contraindication, but dosing should be conservative with proactive glucose monitoring and attention to baseline HbA1c. Prospective randomized trials should (i) stratify by age and diabetes status; (ii) prespecify interactions with adductor canal/femoral blocks and periarticular injections; (iii) compare single versus multidose schedules across 8–20 mg ranges; (iv) include standardized glycemic trajectories beyond POD1–2; and (v) incorporate functional readouts (ROM, performance-based and patient-reported scores) alongside pain, opioids, PONV, and LOS. Our retrospective, single-center design, imbalance in block/PCA use, three-time-point glucose sampling, and absence of ROM/clinical scores underscore these priorities. In sum, perioperative Dexa meaningfully improves early postoperative pain after TKA in selected patients without major glycemic perturbation, dovetailing with guideline recommendations while highlighting patient- and pathway-specific effect modification that should inform tailored protocols and future trial designs. CONCLUSION Perioperative dexamethasone was associated with clinically meaningful reductions in postoperative pain after total knee arthroplasty, with consistent benefits from 12 to 48 hours and particularly clear effects in patients > 65 years and in non-diabetic patients. No analgesic advantage was detected in patients ≤ 65 years or in those with diabetes. Glycemic indices showed no major perturbations: preoperative HbA1c was comparable between groups and perioperative glucose values were broadly similar across time points and subgroups. These findings support judicious incorporation of dexamethasone into multimodal analgesia protocols for older and non-diabetic patients, while highlighting the need for individualized decision-making in younger or diabetic populations. Given the retrospective, single-center design and lack of functional outcomes, prospective randomized trials with standardized regional techniques, longer glycemic monitoring, and recovery metrics are warranted to confirm efficacy and safety profiles. Declarations Funding: The authors received no financial support for the research, authorship, and/or publication of this article. Data Availabilitiy: The datasets used and/or analysed during the current study available from the corresponding author on reasonable request. References Zhao C, Liao Q, Yang D, Yang M, Xu P. Advances in perioperative pain management for total knee arthroplasty: a review of multimodal analgesic approaches. J Orthop Surg Res [Internet]. 2024 Dec 19;19(1):843. Available from: http://www.ncbi.nlm.nih.gov/pubmed/39696522 Migliorini F, Betsch M, Bardazzi T, Colarossi G, Elezabi HAM, Driessen A, et al. Management of Postoperative Pain Following Primary Total Knee Arthroplasty: A Level I Evidence-Based Bayesian Network Meta-Analysis. Pharmaceuticals [Internet]. 2025 Apr 9;18(4):556. Available from: https://www.mdpi.com/1424-8247/18/4/556 Hannon CP, Fillingham YA, Mason JB, Sterling RS, AAHKS Anesthesia & Analgesia Clinical Practice Guideline Workgroup, Hamilton WG, et al. Corticosteroids in Total Joint Arthroplasty: The Clinical Practice Guidelines of the American Association of Hip and Knee Surgeons, American Society of Regional Anesthesia and Pain Medicine, American Academy of Orthopaedic Surgeons, Hip Society, and Knee. J Arthroplasty [Internet]. 2022 Sep;37(9):1684–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/35970568 Gan TJ, Belani KG, Bergese S, Chung F, Diemunsch P, Habib AS, et al. Fourth Consensus Guidelines for the Management of Postoperative Nausea and Vomiting. Anesth Analg [Internet]. 2020 Aug;131(2):411–48. Available from: http://www.ncbi.nlm.nih.gov/pubmed/32467512 Niyonkuru E, Iqbal MA, Zhang X, Ma P. Complementary Approaches to Postoperative Pain Management: A Review of Non-pharmacological Interventions. Pain Ther [Internet]. 2025 Feb;14(1):121–44. Available from: http://www.ncbi.nlm.nih.gov/pubmed/39681763 Waldron NH, Jones CA, Gan TJ, Allen TK, Habib AS. Impact of perioperative dexamethasone on postoperative analgesia and side-effects: systematic review and meta-analysis. Br J Anaesth [Internet]. 2013 Feb;110(2):191–200. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23220857 De Oliveira GS, Castro-Alves LJS, Ahmad S, Kendall MC, McCarthy RJ. Dexamethasone to prevent postoperative nausea and vomiting: an updated meta-analysis of randomized controlled trials. Anesth Analg [Internet]. 2013 Jan;116(1):58–74. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23223115 De Oliveira GS, Almeida MD, Benzon HT, McCarthy RJ. Perioperative single dose systemic dexamethasone for postoperative pain: a meta-analysis of randomized controlled trials. Anesthesiology [Internet]. 2011 Sep 1;115(3):575–88. Available from: https://journals.lww.com/00000542-201109000-00020 Pehora C, Pearson AM, Kaushal A, Crawford MW, Johnston B. Dexamethasone as an adjuvant to peripheral nerve block. Cochrane Database Syst Rev [Internet]. 2017 Nov 9;2017(11). Available from: http://doi.wiley.com/10.1002/14651858.CD011770.pub2 Zhao WL, Ou XF, Liu J, Zhang WS. Perineural versus intravenous dexamethasone as an adjuvant in regional anesthesia: a systematic review and meta-analysis. J Pain Res [Internet]. 2017;10:1529–43. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28740419 Mølgaard AK, Gasbjerg KS, Skou ST, Mathiesen O, Hägi-Pedersen D. Chronic Pain and Functional Outcome 3 years After Total Knee Arthroplasty and Perioperative Dexamethasone: A Follow-Up of the Randomized, Clinical DEX-2-TKA Trial. J Arthroplasty [Internet]. 2023 Dec;38(12):2592-2598.e2. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0883540323006022 Kim JK, Ro DH, Lee HJ, Park JY, Han HS, Lee MC. Efficacy of Systemic Steroid Use Given One Day After Total Knee Arthroplasty for Pain and Nausea: A Randomized Controlled Study. J Arthroplasty [Internet]. 2020 Jan;35(1):69–75. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0883540319307570 Shaw JH, Wesemann LD, Banka TR, North WT, Charters MA, Davis JJ. The AAHKS Clinical Research Award: Oral Dexamethasone Following Total Knee Arthroplasty: A Double-Blind, Randomized Controlled Trial. J Arthroplasty [Internet]. 2023 Jul;38(7):S15–20. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0883540323004047 Hannon CP, DeBenedetti A, Barrack RL, Kwon YM, Lonner JH, Huddleston JI, et al. The James A. Rand Young Investigator’s Award: What Is the Safest and Most Effective Dose of Intravenous Dexamethasone in Total Knee Arthroplasty? A Multicenter Randomized Controlled Trial. J Arthroplasty [Internet]. 2025 May 30; Available from: http://www.ncbi.nlm.nih.gov/pubmed/40339943 Afshar AM, Sharma SK, Hamidi SH, Marznaki ZH, Mudgal SK, Kamyari N, et al. Comparison of Dexamethasone at Three Doses Administered Postoperatively for Improving Pain Control and Sleep Quality in Patients Who Underwent Total Knee Arthroplasty: A Triple Blind Randomized Controlled Trial. J Arthroplasty [Internet]. 2025 Mar;40(3):658–64. Available from: http://www.ncbi.nlm.nih.gov/pubmed/39284389 Park HJ, Chang MJ, Kim TJ, Kim TW, Choi MH, Moon MK, et al. Intravenous Dexamethasone Transiently Elevates Blood Glucose Levels and Reduces Pain After TKA in Patients with Type-2 Diabetes Mellitus. J Bone Jt Surg [Internet]. 2025 May 21;107(10):1073–81. Available from: https://journals.lww.com/10.2106/JBJS.24.00984 Park HJ, Chang MJ, Kim TW, Kang KS, Chang CB, Kang SB. Effects of Intravenous Dexamethasone on Glycemic Control in Patients With Type 2 Diabetes Mellitus After Total Knee Arthroplasty. J Arthroplasty [Internet]. 2021 Dec;36(12):3909–14. Available from: http://www.ncbi.nlm.nih.gov/pubmed/34446328 Yoshida B, Piple AS, Wang JC, Richardson MK, Christ AB, Heckmann ND. Perioperative Dexamethasone Associated With Decreased Length of Stay After Total Hip and Knee Arthroplasty. J Am Acad Orthop Surg [Internet]. 2023 Oct 1;31(19):e778–87. Available from: http://www.ncbi.nlm.nih.gov/pubmed/37205878 Katerenchuk V, Ribeiro EM, Batista AC. Impact of Intraoperative Dexamethasone on Perioperative Blood Glucose Levels: Systematic Review and Meta-Analysis of Randomized Trials. Anesth Analg [Internet]. 2024 Sep 1;139(3):490–508. Available from: http://www.ncbi.nlm.nih.gov/pubmed/39151135 Chen J, Wang C, Li F, Wang X, Li Y, Feng H, et al. Impact of Dexamethasone on Blood Glucose After Total Knee Arthroplasty in Patients With Type 2 Diabetes. Orthop Surg [Internet]. 2025 Mar;17(3):814–21. Available from: http://www.ncbi.nlm.nih.gov/pubmed/39871680 Kitcharanant N, Leurcharusmee P, Atthakomol P, Jingjit W. Perioperative intravenous dexamethasone did not reduce the severity of persistent postsurgical pain after total knee arthroplasty: a prospective, randomized, double-blind, placebo-controlled trial. J Orthop Surg Res [Internet]. 2024 Dec 19;19(1):854. Available from: https://josr-online.biomedcentral.com/articles/10.1186/s13018-024-05362-y Gasbjerg KS, Hägi-Pedersen D, Lunn TH, Laursen CC, Holmqvist M, Vinstrup LØ, et al. Effect of dexamethasone as an analgesic adjuvant to multimodal pain treatment after total knee arthroplasty: randomised clinical trial. BMJ [Internet]. 2022 Jan 4;e067325. Available from: https://www.bmj.com/lookup/doi/10.1136/bmj-2021-067325 Jones IA, Wier J, Liu KC, Richardson MK, Yoshida B, Palmer R, et al. Dexamethasone-Associated Hyperglycemia is Not Associated With Infectious Complications After Total Joint Arthroplasty in Diabetic Patients. J Arthroplasty [Internet]. 2024 Aug;39(8S1):S43-S52.e5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/38220028 Bonilla JL, Rodriguez-Torres JB, Verar GL, Mason-Nguyen J, Moore CB. Perioperative Dexamethasone for Patients With Diabetes and Its Effect on Blood Glucose After Surgery. J perianesthesia Nurs Off J Am Soc PeriAnesthesia Nurses [Internet]. 2022 Aug;37(4):551–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/35400551 Volkmar AJ, Schultz JD, Rickert MM, Polkowski GG, Engstrom SM, Martin JR. Dexamethasone Is Associated With a Statistically Significant Increase in Postoperative Blood Glucose Levels Following Primary Total Knee Arthroplasty. Arthroplast today [Internet]. 2023 Feb;19:101076. Available from: http://www.ncbi.nlm.nih.gov/pubmed/36624747 Meng J, Li L. The efficiency and safety of dexamethasone for pain control in total joint arthroplasty. Medicine (Baltimore) [Internet]. 2017 Jun;96(24):e7126. Available from: https://journals.lww.com/00005792-201706160-00018 Zhuo Y, Yu R, Wu C, Huang Y, Ye J, Zhang Y. The role of perioperative intravenous low-dose dexamethasone in rapid recovery after total knee arthroplasty: a meta-analysis. J Int Med Res [Internet]. 2021 Mar 8;49(3). Available from: https://journals.sagepub.com/doi/10.1177/0300060521998220 Fan Z, Ma J, Kuang M, Zhang L, Han B, Yang B, et al. The efficacy of dexamethasone reducing postoperative pain and emesis after total knee arthroplasty: A systematic review and meta-analysis. Int J Surg [Internet]. 2018 Apr;52:149–55. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1743919118305739 Li X, Xu G, Xie W, Ma S. The efficacy and safety of dexamethasone for pain management after total knee arthroplasty: A systematic review and meta-analysis. Int J Surg [Internet]. 2018 May;53:65–71. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1743919118306277 Zhou G, Ma L, Jing J, Jiang H. A meta-analysis of dexamethasone for pain management in patients with total knee arthroplasty. Medicine (Baltimore) [Internet]. 2018 Aug;97(35):e11753. Available from: https://journals.lww.com/00005792-201808310-00003 Li P, Qiao Y, Zeng J, Li J, Tan F, Cao Y, et al. A systematic review and meta-analysis on the effects of intravenous dexamethasone on postoperative outcomes in patients undergoing total knee arthroplasty. Langenbeck’s Arch Surg [Internet]. 2025 Jan 24;410(1):49. Available from: https://link.springer.com/10.1007/s00423-025-03618-7 Saini MK, Reddy NR, Reddy PJ, Thakur AS, Reddy CD. The application of low-dose dexamethasone in total knee arthroplasty: finding out the best route and dosage schedule. Arch Orthop Trauma Surg [Internet]. 2022 Jan 24;143(2):1005–12. Available from: https://link.springer.com/10.1007/s00402-022-04356-x Chan TCW, Cheung CW, Wong SSC, Chung AYF, Irwin MG, Chan PK, et al. Preoperative dexamethasone for pain relief after total knee arthroplasty. Eur J Anaesthesiol [Internet]. 2020 Dec;37(12):1157–67. Available from: https://journals.lww.com/10.1097/EJA.0000000000001372 Derby CB, Gasbjerg KS, Hägi‐Pedersen D, Lunn TH, Pedersen NA, Lindholm P, et al. Prolonged effects of dexamethasone following total knee arthroplasty: A pre‐planned sub‐study of the DEX‐2‐TKA trial. Acta Anaesthesiol Scand [Internet]. 2024 Jan 14;68(1):35–42. Available from: https://onlinelibrary.wiley.com/doi/10.1111/aas.14319 Lei Y, Huang Z, Huang Q, Pei F, Huang W. Dose optimization of intravenous dexamethasone for total knee arthroplasty: when two is not better than one. Arch Orthop Trauma Surg [Internet]. 2022 Apr 20;142(4):665–72. Available from: https://link.springer.com/10.1007/s00402-021-03859-3 Xu H, Zhang S, Xie J, Lei Y, Cao G, Pei F. Multiple Doses of Perioperative Dexamethasone Further Improve Clinical Outcomes After Total Knee Arthroplasty: A Prospective, Randomized, Controlled Study. J Arthroplasty [Internet]. 2018 Nov;33(11):3448–54. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0883540318306016 Xu B, Ma J, Huang Q, Huang Z yu, Zhang S yun, Pei F xing. Two doses of low-dose perioperative dexamethasone improve the clinical outcome after total knee arthroplasty: a randomized controlled study. Knee Surgery, Sport Traumatol Arthrosc [Internet]. 2018 May 4;26(5):1549–56. Available from: http://link.springer.com/10.1007/s00167-017-4506-x Lex JR, Edwards TC, Packer TW, Jones GG, Ravi B. Perioperative Systemic Dexamethasone Reduces Length of Stay in Total Joint Arthroplasty: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. J Arthroplasty [Internet]. 2021 Mar;36(3):1168–86. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0883540320310895 Qin K, Sun X, Dou Q, Li B, Bai G, Sun X, et al. Comparison of analgesic effects between betamethasone and dexamethasone in total knee arthroplasty: a prospective randomized controlled trial. Front Med [Internet]. 2025 Jul 9;12. Available from: https://www.frontiersin.org/articles/10.3389/fmed.2025.1575417/full Wong KC, Tay AYW, Liow MHL, Tay DKJ, Pang HN, Yeo SJ. Corticosteroid-Enhanced Multimodal Cocktail Periarticular Injection in Total Knee Arthroplasty Does Not Increase Risks of Prosthetic Joint Infection. J Arthroplasty [Internet]. 2025 Aug 11; Available from: http://www.ncbi.nlm.nih.gov/pubmed/40803559 Richardson AB, Bala A, Wellman SS, Attarian DE, Bolognesi MP, Grant SA. Perioperative Dexamethasone Administration Does Not Increase the Incidence of Postoperative Infection in Total Hip and Knee Arthroplasty: A Retrospective Analysis. J Arthroplasty [Internet]. 2016 Aug;31(8):1784–7. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0883540316000887 Vuorinen MA, Palanne RA, Mäkinen TJ, Leskinen JT, Huhtala H, Huotari KA. Infection safety of dexamethasone in total hip and total knee arthroplasty: a study of eighteen thousand, eight hundred and seventy two operations. Int Orthop [Internet]. 2019 Aug 19;43(8):1787–92. Available from: http://link.springer.com/10.1007/s00264-018-4156-8 Yu Y, Lin H, Wu Z, Xu P, Lei Z. Perioperative combined administration of tranexamic acid and dexamethasone in total knee arthroplasty—benefit versus harm? Medicine (Baltimore) [Internet]. 2019 Aug;98(34):e15852. Available from: https://journals.lww.com/00005792-201908230-00002 Tables Tables 1 to 8 are available in the supplementary files section Additional Declarations No competing interests reported. Supplementary Files Tables.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 01 May, 2026 Reviewers invited by journal 01 May, 2026 Editor assigned by journal 01 May, 2026 Editor invited by journal 24 Apr, 2026 Submission checks completed at journal 20 Apr, 2026 First submitted to journal 20 Apr, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9352754","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":635595889,"identity":"e9ffd862-b969-43dd-b494-38585a51a900","order_by":0,"name":"Serdar Yüksel","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABD0lEQVRIiWNgGAWjYJACCQYGG2YGBjYgs8AGSDA2HiBCSxo7RItBGkhLAzFaDvNDtRwGi+DVIt/e+/DGzz1p0gY30pI/fDA4b7e2/TDQlhqbaFxaDM4cN7bseWZjDNRyTHKGwe3kbWcSgVqOpeU24NIikcYmwXMgLdngRnobMw9Qi9kBoBbGhsM4tcjPf8Ym+efA4foNN9KbP/8xOJdsdv4hfi0MN9jYpHkOHGYGOuyANIPBATuzGwRsMTiTxmwtcyCNWfLMszTJHoPkBLMbQFsS8PhFvv0Y4803B2yY+Y6nGX/4UWFnb3Y+/eGDDzU2uB0GAwoHIHQiWGUCIeVg66CG2hOjeBSMglEwCkYWAAAuhWY6WKh1EAAAAABJRU5ErkJggg==","orcid":"","institution":"Sağlık Bilimleri Üniversitesi","correspondingAuthor":true,"prefix":"","firstName":"Serdar","middleName":"","lastName":"Yüksel","suffix":""},{"id":635595890,"identity":"5fd387f7-607f-49fc-9f87-64d26239a397","order_by":1,"name":"Emre Özmen","email":"","orcid":"","institution":"Sağlık Bilimleri Üniversitesi","correspondingAuthor":false,"prefix":"","firstName":"Emre","middleName":"","lastName":"Özmen","suffix":""},{"id":635595892,"identity":"5eafc233-4c14-401e-b17e-274c2ba11d2f","order_by":2,"name":"Muhammed Yusuf Afacan","email":"","orcid":"","institution":"Sağlık Bilimleri Üniversitesi","correspondingAuthor":false,"prefix":"","firstName":"Muhammed","middleName":"Yusuf","lastName":"Afacan","suffix":""},{"id":635595893,"identity":"c43956ff-ce06-4d8a-a09c-03a764f6714c","order_by":3,"name":"Alican Barış","email":"","orcid":"","institution":"Sağlık Bilimleri Üniversitesi","correspondingAuthor":false,"prefix":"","firstName":"Alican","middleName":"","lastName":"Barış","suffix":""},{"id":635595894,"identity":"f618c794-7783-4c38-b42a-4121b73ad8ce","order_by":4,"name":"Orhan Akıncı","email":"","orcid":"","institution":"Sağlık Bilimleri Üniversitesi","correspondingAuthor":false,"prefix":"","firstName":"Orhan","middleName":"","lastName":"Akıncı","suffix":""},{"id":635595895,"identity":"f6006b25-b188-42e7-a39f-810e200b9c63","order_by":5,"name":"Fahri Erdi Malkoç","email":"","orcid":"","institution":"Sağlık Bilimleri Üniversitesi","correspondingAuthor":false,"prefix":"","firstName":"Fahri","middleName":"Erdi","lastName":"Malkoç","suffix":""},{"id":635595898,"identity":"82d31756-8b7a-4749-890f-6c405999ede1","order_by":6,"name":"Muhammed Yunus Gazaioğlu","email":"","orcid":"","institution":"Sağlık Bilimleri Üniversitesi","correspondingAuthor":false,"prefix":"","firstName":"Muhammed","middleName":"Yunus","lastName":"Gazaioğlu","suffix":""},{"id":635595900,"identity":"82295048-6602-464c-82da-3a574ea873b9","order_by":7,"name":"Okan Can Karadeniz","email":"","orcid":"","institution":"Sağlık Bilimleri Üniversitesi","correspondingAuthor":false,"prefix":"","firstName":"Okan","middleName":"Can","lastName":"Karadeniz","suffix":""}],"badges":[],"createdAt":"2026-04-08 06:54:21","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9352754/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9352754/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":109014499,"identity":"eed2e760-16b6-4ae2-a56f-6199a38ad870","added_by":"auto","created_at":"2026-05-11 17:20:37","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":73039,"visible":true,"origin":"","legend":"\u003cp\u003ePostoperative pain trajectories (VAS 0–10) at 6, 12, 18, 24, 30, 36, 42, and 48 hours comparing patients who received perioperative dexamethasone (Dexa) versus those who did not (Non-Dexa). Asterisks denote time points with between-group differences at \u003cem\u003ep\u003c/em\u003e\u0026lt;0.05; results were not significant at 6 and 18 hours and were significant at 12, 24, 30, 36, 42, and 48 hours.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9352754/v1/223b8d0bea883944797df4c4.png"},{"id":109067864,"identity":"d91bdc4c-2c1c-416a-8d09-a2b0d52c2f58","added_by":"auto","created_at":"2026-05-12 10:02:03","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":67144,"visible":true,"origin":"","legend":"\u003cp\u003ePatients aged \u0026gt;65 years: Dexa versus Non-Dexa VAS trajectories over 6–48 hours; all time points showed significant between-group differences at \u003cem\u003ep\u003c/em\u003e\u0026lt;0.05.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-9352754/v1/c871f436c9530a98119d1ca4.png"},{"id":109014501,"identity":"b59b6583-f625-45bb-adb1-d912924e0790","added_by":"auto","created_at":"2026-05-11 17:20:37","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":73476,"visible":true,"origin":"","legend":"\u003cp\u003ePatients without diabetes mellitus: Dexa versus Non-Dexa VAS trajectories over 6–48 hours; not significant at 6 hours, significant at 12–48 hours (\u003cem\u003ep\u003c/em\u003e\u0026lt;0.05).\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-9352754/v1/6aa8e896fe5d67cbee771e75.png"},{"id":109204440,"identity":"dd05d357-08de-461f-991d-d49111b47bab","added_by":"auto","created_at":"2026-05-13 15:00:03","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":62687,"visible":true,"origin":"","legend":"\u003cp\u003ePatients without peripheral nerve block: Dexa versus Non-Dexa VAS trajectories over 6–48 hours; all time points showed significant between-group differences at \u003cem\u003ep\u003c/em\u003e\u0026lt;0.05.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAbbreviations:\u003c/em\u003e Dexa, dexamethasone; VAS, visual analogue scale; ns, not significant.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-9352754/v1/49856c5b1466cd4c29db0dfe.png"},{"id":109206629,"identity":"c089acd8-410e-4edf-99e3-4c3981df9d02","added_by":"auto","created_at":"2026-05-13 15:14:17","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":414031,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9352754/v1/33738f75-b736-4761-9fb8-88e47e820727.pdf"},{"id":109014498,"identity":"fe008443-68fc-4f40-9fd5-76e0f49a251d","added_by":"auto","created_at":"2026-05-11 17:20:37","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":72729,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-9352754/v1/b8e8dfbc7cd83c0a39c32c2c.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Perioperative Dexamethasone in Total Knee Arthroplasty: Early Analgesic Benefit Without Major Glycemic Perturbation and Effect Modification by Age, Diabetes, and Regional Analgesia","fulltext":[{"header":"Highlights","content":"\u003cul type=\"disc\"\u003e\n \u003cli\u003ePerioperative dexamethasone lowered postoperative pain (VAS) from 12\u0026ndash;48 h after TKA, especially in patients \u0026gt;65 years and non-diabetics.\u003c/li\u003e\n \u003cli\u003eNo analgesic advantage with dexamethasone was observed in patients \u0026le;65 years, in diabetics, or when a peripheral nerve block was used.\u003c/li\u003e\n \u003cli\u003eGlycemic indices (preoperative HbA1c; perioperative glucose I\u0026ndash;III) were broadly comparable between groups, indicating no major glycemic perturbation.\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"What is already known","content":"\u003cul type=\"disc\"\u003e\n \u003cli\u003eDexamethasone modestly reduces early postoperative pain and PONV after arthroplasty, with effects concentrated in the first 24–48 hours.\u003c/li\u003e\n \u003cli\u003eRegional anesthesia and local infiltration provide strong early analgesia, potentially limiting the incremental benefit of systemic steroids.\u003c/li\u003e\n \u003cli\u003eSingle perioperative doses of dexamethasone can transiently raise glucose but have not been shown to increase PJI risk.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eWhat is new\u003c/strong\u003e\u003c/p\u003e\n\u003cul type=\"disc\"\u003e\n \u003cli\u003eIn a real-world TKA cohort, dexamethasone improved VAS 12–48 h only in patients \u0026gt;65 years and in non-diabetics.\u003c/li\u003e\n \u003cli\u003eAnalgesic benefit disappeared with peripheral nerve block, indicating pathway-dependent effect modification.\u003c/li\u003e\n \u003cli\u003ePreoperative HbA1c and perioperative glucose profiles were similar between groups, aside from a transient early rise that later converged.\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"INTRODUCTION","content":"\u003cp\u003ePostoperative pain following total knee arthroplasty (TKA) remains a significant clinical challenge despite advances in surgical technique, anesthesia, and multimodal analgesia protocols (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Moderate to severe pain is common in the immediate postoperative period and is associated with delayed mobilization, increased opioid consumption, prolonged hospital stay, and higher complication rates (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Various pharmacological and regional anesthesia strategies have been employed to optimize pain relief, yet an ideal regimen balancing analgesia, safety, and functional recovery has not been clearly established (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). In this context, glucocorticoids such as dexamethasone have emerged as promising adjuncts due to their potent anti-inflammatory and antiemetic properties (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDexamethasone has been widely studied as an adjuvant in regional anesthesia and systemic administration. When given perioperatively, it reduces prostaglandin synthesis, inhibits inflammatory mediators, and prolongs the duration of peripheral nerve blocks (\u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Several meta-analyses and randomized controlled trials have demonstrated that dexamethasone not only improves postoperative pain control but also decreases opioid consumption, nausea, and vomiting, and hospital stay thereby enhancing patient satisfaction and recovery (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan additionalcitationids=\"CR19 CR20 CR21\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan additionalcitationids=\"CR12 CR13 CR14 CR15 CR16\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). However, concerns remain regarding its metabolic effects, particularly postoperative hyperglycemia, which may complicate outcomes in elderly patients and those with diabetes mellitus (DM) (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). Although some reports indicate that a single low-dose administration is safe, others have suggested potential associations with elevated glucose levels and impaired wound healing, necessitating further investigation (\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eClarifying the impact of dexamethasone on postoperative pain and glucose homeostasis is especially important in TKA, where both effective analgesia and metabolic stability are crucial for early rehabilitation and functional recovery. Furthermore, subgroup differences related to age, DM status, and the application of peripheral nerve blocks have not been comprehensively addressed in previous studies. The aim of this study was to evaluate the effects of perioperative dexamethasone on postoperative pain control and glycemic outcomes in patients undergoing TKA, with subgroup analyses stratified by age (\u0026le;\u0026thinsp;65 vs. \u0026gt;65 years), diabetic status (DM vs. non-DM), and peripheral nerve block application.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cp\u003e This retrospective observational study was carried out at our institution following approval by the University of Health Sciences, Istanbul Physical Therapy and Rehabilitation Training and Research Hospital Institutional Ethics Committee. The study was designed and conducted in accordance with the ethical principles of the Declaration of Helsinki. All relevant clinical and laboratory data were extracted from the hospital\u0026rsquo;s electronic medical record system and charts. Informed consent was obtained from all individual participants included in the study.\u003c/p\u003e \u003cp\u003eA total of 104 patients who underwent primary, elective total knee arthroplasty (TKA) in 2025 were included in the analysis. Patients were considered eligible if they were operated for primary gonarthrosis, had complete postoperative pain score documentation covering the first 48 hours, and had at least three postoperative blood glucose measurements available. Patients were excluded if they had undergone revision or bilateral TKA in a single session, required additional major surgery during the same hospitalization, were implanted augments in addition to the primary prosthesis or had incomplete data regarding the study\u0026rsquo;s primary or secondary outcomes.\u003c/p\u003e \u003cp\u003eThe study population was divided into two groups according to perioperative administration of intravenous dexamethasone. The Dexa group (n\u0026thinsp;=\u0026thinsp;39) consisted of patients who received a single intravenous dose of 8mg dexamethasone prior to anesthesia induction, and an additional single intravenous dose of 4mg within the postoperative six hours, while the Non-Dexa group (n\u0026thinsp;=\u0026thinsp;65) included patients who did not receive dexamethasone. All patients were treated under the institution\u0026rsquo;s standardized anesthesia and multimodal analgesia protocols. In addition, the administration of peripheral nerve blocks and the use of patient-controlled analgesia (PCA) were systematically recorded.\u003c/p\u003e \u003cp\u003eThe following variables were collected for analysis: demographic characteristics (age and sex), presence of diabetes mellitus (DM), whether a peripheral nerve block was performed, and whether PCA was utilized postoperatively. Postoperative pain was assessed using the visual analogue scale (VAS; range 0\u0026ndash;10) at the 6th, 12th, 18th, 24th, 30th, 36th, 42nd, and 48th postoperative hours. Laboratory data included preoperative glycated hemoglobin (HbA1c) values and three standardized perioperative glucose measurements, referred to as Glucose I, Glucose II, and Glucose III, obtained at predefined time points during the postoperative period. Glucose I was defined as the blood glucose measurement obtained on the evening of the surgery, Glucose II corresponded to the postoperative fasting morning blood glucose level, and Glucose III represented the measurement taken on the evening of the first postoperative day.\u003c/p\u003e \u003cp\u003eThe primary outcome of the study was the time-weighted mean VAS score over the 6\u0026ndash;48-hour postoperative period. Secondary outcomes included preoperatively documented HbA1c levels, perioperative changes in glucose values (Glucose I: evening of surgery, Glucose II: postoperative fasting morning, Glucose III: evening of the first postoperative day), and subgroup analyses stratified by age (\u0026le;\u0026thinsp;65 vs. \u0026gt;65 years), diabetes status (DM vs. non-DM), and peripheral nerve block application (block vs. no block).\u003c/p\u003e \u003cp\u003eAll patients scheduled for total knee arthroplasty (TKA) were instructed to remain nil per os for at least 8 hours preoperatively. On the morning of surgery, only patients with hypertension or hypothyroidism continued their routine medications. Immediately before surgery, all patients received intravenous tranexamic acid (100 mg) and cefazolin (2 g, first-generation cephalosporin). A pneumatic tourniquet was applied to every patient and inflated to 300 mmHg. Procedures were performed through a midline skin incision with a medial parapatellar arthrotomy. Bone preparation commenced with the distal femoral cut in all cases. Antibiotic-loaded bone cement was used for every implantation. Depending on patient anatomy and surgeon preference, either posterior-stabilized or cruciate-retaining prostheses were implanted; no patellar components were used. Hemovac drains were not placed, whereas urinary catheterization was performed in all patients. On postoperative day (POD) 0, patients were not mobilized and were managed with anti-embolic stockings. Beginning on POD 1, patients were encouraged to initiate knee flexion exercises, straight-leg raises, and quadriceps stretching, followed by mobilization as tolerated. All patients were discharged on POD 3. During hospitalization, patients received intravenous normal saline (500 mL every 12 hours), an intravenous nonsteroidal anti-inflammatory drug (50 mg/2 mL every 8 hours), an intravenous proton-pump inhibitor (40 mg once each morning), intravenous paracetamol (10 mg/mL every 12 hours), and intravenous tramadol hydrochloride (100 mg/2 mL, up to twice daily as needed). Thromboprophylaxis consisted of subcutaneous enoxaparin sodium (100 mg) once daily in the evening. On POD 0, patients also received three additional doses of intravenous cefazolin (1 g every 8 hours) and three doses of oral tranexamic acid (1 g every 8 hours). Capillary blood glucose was monitored every 8 hours throughout the hospitalization.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistics\u003c/h2\u003e \u003cp\u003eDescriptive statistics were presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation, median, minimum, maximum, frequency, and percentage, as appropriate. The normality of data distribution was assessed using the Kolmogorov\u0026ndash;Smirnov and Shapiro\u0026ndash;Wilk tests. Independent quantitative variables with normal distribution were analyzed using the independent samples \u003cem\u003et\u003c/em\u003e-test, while non-normally distributed independent quantitative variables were evaluated with the Mann\u0026ndash;Whitney U test. Categorical variables were compared using the Chi-square test. All statistical analyses were performed using SPSS version 27.0 (IBM Corp., Armonk, NY, USA). A two-tailed \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003cp\u003eThe sample size for the two-group comparison was determined using G*Power software (Version 3.1.9.6). For the primary endpoint (time-weighted mean VAS over 6\u0026ndash;48 h), the analysis assumed a clinically meaningful difference (Δ) of 1.0 VAS unit, a standard deviation of 1.5\u0026ndash;2.0, a two-sided significance level of α\u0026thinsp;=\u0026thinsp;0.05 (95% reliability), and a statistical power of 80\u0026ndash;90%. Under these assumptions, the corresponding effect size (Cohen\u0026rsquo;s \u003cem\u003ed\u003c/em\u003e) was calculated as 0.50\u0026ndash;0.67 (medium to large). The minimum required sample size was therefore 36\u0026ndash;63 patients per group for 80% power, or 48\u0026ndash;84 patients per group for 90% power. With the available cohorts (Dexa\u0026thinsp;+\u0026thinsp;n\u0026thinsp;=\u0026thinsp;39; Dexa\u0026ndash; n\u0026thinsp;=\u0026thinsp;65), the study achieved\u0026thinsp;\u0026ge;\u0026thinsp;80% power to detect differences of approximately 0.85\u0026ndash;1.13 VAS units, which is within the range of clinical relevance.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eThe study population consisted of 104 patients with a mean age of 68.2 \u0026plusmn; 7.9 years of whom 34 were aged \u0026le;65 years, 70 were aged \u0026gt;65 years, 18 were male and 86 female; the prevalence of diabetes mellitus was 35.6%, while peripheral nerve block and patient-controlled analgesia were applied in 20.2% and 15.4% of patients, respectively, with overall median VAS score of 7.0, median HbA1c of 6.0, and median postoperative glucose values of 143.0, 150.0, and 130.0 mg/dL at the first, second, and third measurements, respectively (Table 1).\u003c/p\u003e\n\u003cp\u003eBetween the Dexa and non-Dexa groups, no significant differences were found in age, sex distribution, or prevalence of diabetes mellitus (DM) (p\u0026gt;0.05). The rate of peripheral nerve block administration was significantly higher in the Dexa group (p\u0026lt;0.05), whereas patient-controlled analgesia (PCA) use was significantly lower (p\u0026lt;0.05). VAS scores at the 6th and 18th postoperative hours were similar between groups (p\u0026gt;0.05), while at the 12th, 24th, 30th, 36th, 42nd, and 48th hours, the Dexa group demonstrated significantly lower values (p\u0026lt;0.05). HbA1c levels and glucose measurements at the first, second, and third time points were comparable between groups (p\u0026gt;0.05) (Table 2).\u003c/p\u003e\n\u003cp\u003eIn patients aged \u0026le;65 years, no significant differences were observed in age, sex, or DM distribution (p\u0026gt;0.05). The Dexa group, however, showed a higher rate of peripheral nerve block (p\u0026lt;0.05) and a lower rate of PCA use (p\u0026lt;0.05). VAS scores at the 6th, 12th, 18th, 24th, 32nd, 36th, 42nd, and 48th hours did not differ significantly between groups (p\u0026gt;0.05). HbA1c and glucose measurements at all time points were likewise comparable (p\u0026gt;0.05) (Table 3).\u003c/p\u003e\n\u003cp\u003eAmong patients aged \u0026gt;65 years, age, sex, and DM distribution were similar between groups (p\u0026gt;0.05). The Dexa group had a significantly higher block rate (p\u0026lt;0.05) and lower PCA use (p\u0026lt;0.05). At all postoperative time points from 6th to 48th hours, VAS scores were significantly lower in the Dexa group (p\u0026lt;0.05). HbA1c and glucose levels at all three measurements showed no significant differences (p\u0026gt;0.05) (Table 4).\u003c/p\u003e\n\u003cp\u003eIn patients without DM, no significant differences were seen in age or sex distribution (p\u0026gt;0.05). Block use was significantly higher in the Dexa group (p\u0026lt;0.05), while PCA use was significantly lower (p\u0026lt;0.05). VAS scores were comparable at the 6th hour (p\u0026gt;0.05) but significantly lower in the Dexa group at the 12th, 18th, 24th, 32nd, 36th, 42nd, and 48th hours (p\u0026lt;0.05). HbA1c and glucose measurements at all time points were not significantly different (p\u0026gt;0.05) (Table 5).\u003c/p\u003e\n\u003cp\u003eAmong patients with DM, no significant differences were found in age or sex distribution (p\u0026gt;0.05). The Dexa group had a higher block rate (p\u0026lt;0.05), but PCA use was similar between groups (p\u0026gt;0.05). VAS scores from the 6th through 48th hours showed no significant differences (p\u0026gt;0.05). HbA1c values and glucose levels at all measurements were also comparable (p\u0026gt;0.05) (Table 6).\u003c/p\u003e\n\u003cp\u003eIn patients without block, age, sex, and DM distribution were similar between groups (p\u0026gt;0.05). PCA use was significantly lower in the Dexa group (p\u0026lt;0.05). At all postoperative time points from 6th to 48th hours, VAS scores were significantly lower in the Dexa group (p\u0026lt;0.05). HbA1c values showed no significant differences (p\u0026gt;0.05). The first glucose measurement was significantly higher in the Dexa group (p\u0026lt;0.05), whereas the second and third measurements were comparable (p\u0026gt;0.05) (Table 7).\u003c/p\u003e\n\u003cp\u003eFinally, in patients with block, no significant differences were found in age, sex, or DM distribution (p\u0026gt;0.05). VAS scores at all time points (6th to 48th hours) were similar between groups (p\u0026gt;0.05). HbA1c values and glucose levels at the first, second, and third measurements also showed no significant differences (p\u0026gt;0.05) (Table 8).\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003ePerioperative dexamethasone (Dexa) in our cohort was associated with lower pain scores from 12 to 48 hours after total knee arthroplasty (TKA), with effects concentrated in patients\u0026thinsp;\u0026gt;\u0026thinsp;65 years, in non-diabetic patients, and in those who did not receive a peripheral nerve block; no analgesic advantage was observed in patients\u0026thinsp;\u0026le;\u0026thinsp;65 years, in patients with diabetes, or when a block was used. Glycemic indices (preoperative HbA1c; perioperative glucose I\u0026ndash;III) were broadly comparable between groups, suggesting that the analgesic benefits of dexamethasone were achieved without clinically relevant alterations in glycemic control, aside from a transiently higher first glucose among patients without a block who received Dexa, with subsequent convergence. These subgroup and time‐course patterns frame Dexa as a selective adjunct within multimodal pathways.\u003c/p\u003e \u003cp\u003eThe present study demonstrated earlier and sustained analgesic separation from 12\u0026ndash;48 hours after TKA, a pattern concordant with randomized and pooled evidence showing that perioperative Dexa modestly reduces early postoperative pain and opioid use, with the most consistent effects in the first 24\u0026ndash;48 hours (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan additionalcitationids=\"CR27 CR28 CR29 CR30\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). Randomized trials in TKA report clinically meaningful early improvements and elements of enhanced recovery when Dexa is incorporated into multimodal pathways (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). Longer-term outcomes, however, appear neutral: intravenous Dexa did not reduce persistent postsurgical pain at 12 weeks in a robust placebo-controlled trial (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e), showed no prolonged advantage for pain or sleep on postoperative days 3\u0026ndash;7 in DEX-2-TKA follow-up (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e), and did not alter chronic pain or function at 3 years (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Meta-analytic signals of improved walking distance, ROM, and global quality of recovery (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e) are consistent with an early window of benefit, mirroring the present cohort\u0026rsquo;s time-course and subgroup effects in patients\u0026thinsp;\u0026gt;\u0026thinsp;65 years and in those without diabetes.\u003c/p\u003e \u003cp\u003eDose\u0026ndash;schedule selection influences early analgesic magnitude. Higher single doses (e.g., 16\u0026ndash;20 mg) have been associated with greater reductions in pain, opioids, and postoperative nausea and vomiting (PONV) on day 1 (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e), and targeted postoperative dosing can extend short-term benefits (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Multiple low-dose regimens frequently outperform a single low dose, reducing pain, inflammatory markers (CRP/IL-6), and PONV without added complications (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e), a theme echoed by systematic synthesis showing earlier discharge and improved recovery with perioperative corticosteroids, with larger or repeat dosing sometimes yielding greater dynamic pain and PONV reductions (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e). Pragmatic low-dose strategies (e.g., 8 mg IV) are widely used with acceptable safety and only moderate glycemic impact (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e), and two-dose regimens can reduce morphine and pain across 48 hours (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Across trials and meta-analyses, timing around induction and/or the first postoperative day captures the interval in which Dexa is most effective (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e), aligning with the 12\u0026ndash;48-hour separation observed here.\u003c/p\u003e \u003cp\u003eThe observed attenuation of Dexa\u0026rsquo;s analgesic advantage when a peripheral nerve block was employed is clinically plausible. Comparative evidence ranks local infiltration/intra-articular strategies among the most effective for early TKA pain, potentially diminishing the incremental benefit of systemic agents (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Regarding steroid route as a block adjuvant, systematic reviews indicate broadly similar analgesic gains with perineural and intravenous Dexa, with a perineural edge only when epinephrine is co-administered (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Local steroid via periarticular infiltration can match single-dose IV Dexa for first-24-hour analgesia without excess glycemic or wound risk (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e), and betamethasone may outperform Dexa within cocktail therapy without additional complications (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e). Safety signals are reassuring: adding corticosteroid to periarticular injections does not increase prosthetic joint infection risk (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e). Collectively, these data support a tailored approach\u0026mdash;Dexa appears most useful when regional analgesia is absent or limited, which parallels the no-block subgroup effect observed.\u003c/p\u003e \u003cp\u003eAcross the cohort and subgroups, preoperative HbA1c and perioperative glucose measurements were largely comparable between Dexa and control, aside from a transient first-glucose increase in the no-block Dexa subgroup that subsequently converged. Quantitative synthesis suggests a modest, short-lived rise in glucose within 24 hours after a single perioperative Dexa dose, generally of limited clinical consequence (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). In type-2 diabetes, randomized and observational studies show transient day-0/1 hyperglycemia yet preserved early analgesic benefit; adequate baseline control and post-operative monitoring can maintain acceptable glycemic profiles (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Reviews in diabetic populations indicate short-term increases of approximately 30\u0026ndash;45 mg/dL after a single dose, albeit with heterogeneous certainty (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Importantly, Dexa-associated hyperglycemia has not been linked to greater infectious complications in large diabetic arthroplasty cohorts (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e), and single-dose Dexa has not increased periprosthetic joint infection after THA/TKA (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e), although higher POD1 glucose has been observed irrespective of diabetic status in some series (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Contemporary multidisciplinary guidance recommends individualized dosing and proactive glucose surveillance rather than categorical avoidance in diabetes (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAlthough antiemetic outcomes were not the primary endpoints in this study, robust evidence confirms reductions in PONV and rescue antiemetics with perioperative Dexa (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Trials also suggest improvements in early mobilization and quality-of-recovery (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e), and multi-study syntheses associate Dexa with shorter length of stay (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e). Combination strategies, such as tranexamic acid plus Dexa, may further reduce CRP/IL-6, pain, PONV, and fatigue and improve ROM without increasing complications (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e). In parallel, non-pharmacological modalities (education, mind\u0026ndash;body techniques, physical therapies) can complement pharmacologic regimens to reduce pain intensity, opioid requirements, and facilitate recovery within multimodal pathways (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). These broader recovery signals align with the temporal window in which analgesic separation was detected (12\u0026ndash;48 hours).\u003c/p\u003e \u003cp\u003eOur results reinforce the core messages of contemporary guidelines: perioperative IV Dexa is an effective element of multimodal analgesia after TKA, particularly in the first 48 hours; multiple doses can enhance effect; and use in diabetes warrants caution and monitoring while evidence matures (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). The age- and block-dependent patterns we observed\u0026mdash;benefit in older, non-diabetic, no-block patients\u0026mdash;provide pragmatic levers for risk-adapted deployment in everyday practice.\u003c/p\u003e \u003cp\u003eThe study benefits from an adequate sample size, standardized anesthesia, analgesia, and surgical protocols, and consistent pain assessment at multiple time points using VAS. Inclusion of perioperative glucose monitoring and preoperative HbA1c allowed evaluation of metabolic safety. Subgroup analyses by age, diabetes status, and peripheral nerve block enhanced clinical relevance. The retrospective, single-center design may limit generalizability and introduce selection bias. Imbalances in peripheral nerve block and PCA use could have influenced pain results. Glucose was monitored only at three perioperative points limiting metabolic assessment. Functional outcomes such as pre- and postoperative range of motion and clinical scores were not recorded, restricting evaluation of overall recovery. For centers employing standardized regional pathways, Dexa\u0026rsquo;s incremental analgesic value may be greatest in patients who are older, non-diabetic, or not receiving a block; when blocks are used, Dexa may be reserved for antiemetic prophylaxis and patients at risk of high inflammatory pain. Diabetes should not be an automatic contraindication, but dosing should be conservative with proactive glucose monitoring and attention to baseline HbA1c. Prospective randomized trials should (i) stratify by age and diabetes status; (ii) prespecify interactions with adductor canal/femoral blocks and periarticular injections; (iii) compare single versus multidose schedules across 8\u0026ndash;20 mg ranges; (iv) include standardized glycemic trajectories beyond POD1\u0026ndash;2; and (v) incorporate functional readouts (ROM, performance-based and patient-reported scores) alongside pain, opioids, PONV, and LOS. Our retrospective, single-center design, imbalance in block/PCA use, three-time-point glucose sampling, and absence of ROM/clinical scores underscore these priorities.\u003c/p\u003e \u003cp\u003e In sum, perioperative Dexa meaningfully improves early postoperative pain after TKA in selected patients without major glycemic perturbation, dovetailing with guideline recommendations while highlighting patient- and pathway-specific effect modification that should inform tailored protocols and future trial designs.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003ePerioperative dexamethasone was associated with clinically meaningful reductions in postoperative pain after total knee arthroplasty, with consistent benefits from 12 to 48 hours and particularly clear effects in patients\u0026thinsp;\u0026gt;\u0026thinsp;65 years and in non-diabetic patients. No analgesic advantage was detected in patients\u0026thinsp;\u0026le;\u0026thinsp;65 years or in those with diabetes. Glycemic indices showed no major perturbations: preoperative HbA1c was comparable between groups and perioperative glucose values were broadly similar across time points and subgroups. These findings support judicious incorporation of dexamethasone into multimodal analgesia protocols for older and non-diabetic patients, while highlighting the need for individualized decision-making in younger or diabetic populations. Given the retrospective, single-center design and lack of functional outcomes, prospective randomized trials with standardized regional techniques, longer glycemic monitoring, and recovery metrics are warranted to confirm efficacy and safety profiles.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding: The authors received no financial support for the research, authorship, and/or publication of this article.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availabilitiy: The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eZhao C, Liao Q, Yang D, Yang M, Xu P. Advances in perioperative pain management for total knee arthroplasty: a review of multimodal analgesic approaches. J Orthop Surg Res [Internet]. 2024 Dec 19;19(1):843. Available from: http://www.ncbi.nlm.nih.gov/pubmed/39696522\u003c/li\u003e\n \u003cli\u003eMigliorini F, Betsch M, Bardazzi T, Colarossi G, Elezabi HAM, Driessen A, et al. Management of Postoperative Pain Following Primary Total Knee Arthroplasty: A Level I Evidence-Based Bayesian Network Meta-Analysis. Pharmaceuticals [Internet]. 2025 Apr 9;18(4):556. Available from: https://www.mdpi.com/1424-8247/18/4/556\u003c/li\u003e\n \u003cli\u003eHannon CP, Fillingham YA, Mason JB, Sterling RS, AAHKS Anesthesia \u0026amp; Analgesia Clinical Practice Guideline Workgroup, Hamilton WG, et al. Corticosteroids in Total Joint Arthroplasty: The Clinical Practice Guidelines of the American Association of Hip and Knee Surgeons, American Society of Regional Anesthesia and Pain Medicine, American Academy of Orthopaedic Surgeons, Hip Society, and Knee. J Arthroplasty [Internet]. 2022 Sep;37(9):1684\u0026ndash;7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/35970568\u003c/li\u003e\n \u003cli\u003eGan TJ, Belani KG, Bergese S, Chung F, Diemunsch P, Habib AS, et al. Fourth Consensus Guidelines for the Management of Postoperative Nausea and Vomiting. Anesth Analg [Internet]. 2020 Aug;131(2):411\u0026ndash;48. Available from: http://www.ncbi.nlm.nih.gov/pubmed/32467512\u003c/li\u003e\n \u003cli\u003eNiyonkuru E, Iqbal MA, Zhang X, Ma P. Complementary Approaches to Postoperative Pain Management: A Review of Non-pharmacological Interventions. Pain Ther [Internet]. 2025 Feb;14(1):121\u0026ndash;44. Available from: http://www.ncbi.nlm.nih.gov/pubmed/39681763\u003c/li\u003e\n \u003cli\u003eWaldron NH, Jones CA, Gan TJ, Allen TK, Habib AS. Impact of perioperative dexamethasone on postoperative analgesia and side-effects: systematic review and meta-analysis. Br J Anaesth [Internet]. 2013 Feb;110(2):191\u0026ndash;200. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23220857\u003c/li\u003e\n \u003cli\u003eDe Oliveira GS, Castro-Alves LJS, Ahmad S, Kendall MC, McCarthy RJ. Dexamethasone to prevent postoperative nausea and vomiting: an updated meta-analysis of randomized controlled trials. Anesth Analg [Internet]. 2013 Jan;116(1):58\u0026ndash;74. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23223115\u003c/li\u003e\n \u003cli\u003eDe Oliveira GS, Almeida MD, Benzon HT, McCarthy RJ. Perioperative single dose systemic dexamethasone for postoperative pain: a meta-analysis of randomized controlled trials. Anesthesiology [Internet]. 2011 Sep 1;115(3):575\u0026ndash;88. Available from: https://journals.lww.com/00000542-201109000-00020\u003c/li\u003e\n \u003cli\u003ePehora C, Pearson AM, Kaushal A, Crawford MW, Johnston B. Dexamethasone as an adjuvant to peripheral nerve block. Cochrane Database Syst Rev [Internet]. 2017 Nov 9;2017(11). Available from: http://doi.wiley.com/10.1002/14651858.CD011770.pub2\u003c/li\u003e\n \u003cli\u003eZhao WL, Ou XF, Liu J, Zhang WS. Perineural versus intravenous dexamethasone as an adjuvant in regional anesthesia: a systematic review and meta-analysis. J Pain Res [Internet]. 2017;10:1529\u0026ndash;43. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28740419\u003c/li\u003e\n \u003cli\u003eM\u0026oslash;lgaard AK, Gasbjerg KS, Skou ST, Mathiesen O, H\u0026auml;gi-Pedersen D. Chronic Pain and Functional Outcome 3 years After Total Knee Arthroplasty and Perioperative Dexamethasone: A Follow-Up of the Randomized, Clinical DEX-2-TKA Trial. J Arthroplasty [Internet]. 2023 Dec;38(12):2592-2598.e2. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0883540323006022\u003c/li\u003e\n \u003cli\u003eKim JK, Ro DH, Lee HJ, Park JY, Han HS, Lee MC. Efficacy of Systemic Steroid Use Given One Day After Total Knee Arthroplasty for Pain and Nausea: A Randomized Controlled Study. J Arthroplasty [Internet]. 2020 Jan;35(1):69\u0026ndash;75. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0883540319307570\u003c/li\u003e\n \u003cli\u003eShaw JH, Wesemann LD, Banka TR, North WT, Charters MA, Davis JJ. The AAHKS Clinical Research Award: Oral Dexamethasone Following Total Knee Arthroplasty: A Double-Blind, Randomized Controlled Trial. J Arthroplasty [Internet]. 2023 Jul;38(7):S15\u0026ndash;20. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0883540323004047\u003c/li\u003e\n \u003cli\u003eHannon CP, DeBenedetti A, Barrack RL, Kwon YM, Lonner JH, Huddleston JI, et al. The James A. Rand Young Investigator\u0026rsquo;s Award: What Is the Safest and Most Effective Dose of Intravenous Dexamethasone in Total Knee Arthroplasty? A Multicenter Randomized Controlled Trial. J Arthroplasty [Internet]. 2025 May 30; Available from: http://www.ncbi.nlm.nih.gov/pubmed/40339943\u003c/li\u003e\n \u003cli\u003eAfshar AM, Sharma SK, Hamidi SH, Marznaki ZH, Mudgal SK, Kamyari N, et al. Comparison of Dexamethasone at Three Doses Administered Postoperatively for Improving Pain Control and Sleep Quality in Patients Who Underwent Total Knee Arthroplasty: A Triple Blind Randomized Controlled Trial. J Arthroplasty [Internet]. 2025 Mar;40(3):658\u0026ndash;64. Available from: http://www.ncbi.nlm.nih.gov/pubmed/39284389\u003c/li\u003e\n \u003cli\u003ePark HJ, Chang MJ, Kim TJ, Kim TW, Choi MH, Moon MK, et al. Intravenous Dexamethasone Transiently Elevates Blood Glucose Levels and Reduces Pain After TKA in Patients with Type-2 Diabetes Mellitus. J Bone Jt Surg [Internet]. 2025 May 21;107(10):1073\u0026ndash;81. Available from: https://journals.lww.com/10.2106/JBJS.24.00984\u003c/li\u003e\n \u003cli\u003ePark HJ, Chang MJ, Kim TW, Kang KS, Chang CB, Kang SB. Effects of Intravenous Dexamethasone on Glycemic Control in Patients With Type 2 Diabetes Mellitus After Total Knee Arthroplasty. J Arthroplasty [Internet]. 2021 Dec;36(12):3909\u0026ndash;14. Available from: http://www.ncbi.nlm.nih.gov/pubmed/34446328\u003c/li\u003e\n \u003cli\u003eYoshida B, Piple AS, Wang JC, Richardson MK, Christ AB, Heckmann ND. Perioperative Dexamethasone Associated With Decreased Length of Stay After Total Hip and Knee Arthroplasty. J Am Acad Orthop Surg [Internet]. 2023 Oct 1;31(19):e778\u0026ndash;87. Available from: http://www.ncbi.nlm.nih.gov/pubmed/37205878\u003c/li\u003e\n \u003cli\u003eKaterenchuk V, Ribeiro EM, Batista AC. Impact of Intraoperative Dexamethasone on Perioperative Blood Glucose Levels: Systematic Review and Meta-Analysis of Randomized Trials. Anesth Analg [Internet]. 2024 Sep 1;139(3):490\u0026ndash;508. Available from: http://www.ncbi.nlm.nih.gov/pubmed/39151135\u003c/li\u003e\n \u003cli\u003eChen J, Wang C, Li F, Wang X, Li Y, Feng H, et al. Impact of Dexamethasone on Blood Glucose After Total Knee Arthroplasty in Patients With Type 2 Diabetes. Orthop Surg [Internet]. 2025 Mar;17(3):814\u0026ndash;21. Available from: http://www.ncbi.nlm.nih.gov/pubmed/39871680\u003c/li\u003e\n \u003cli\u003eKitcharanant N, Leurcharusmee P, Atthakomol P, Jingjit W. Perioperative intravenous dexamethasone did not reduce the severity of persistent postsurgical pain after total knee arthroplasty: a prospective, randomized, double-blind, placebo-controlled trial. J Orthop Surg Res [Internet]. 2024 Dec 19;19(1):854. Available from: https://josr-online.biomedcentral.com/articles/10.1186/s13018-024-05362-y\u003c/li\u003e\n \u003cli\u003eGasbjerg KS, H\u0026auml;gi-Pedersen D, Lunn TH, Laursen CC, Holmqvist M, Vinstrup L\u0026Oslash;, et al. Effect of dexamethasone as an analgesic adjuvant to multimodal pain treatment after total knee arthroplasty: randomised clinical trial. BMJ [Internet]. 2022 Jan 4;e067325. Available from: https://www.bmj.com/lookup/doi/10.1136/bmj-2021-067325\u003c/li\u003e\n \u003cli\u003eJones IA, Wier J, Liu KC, Richardson MK, Yoshida B, Palmer R, et al. Dexamethasone-Associated Hyperglycemia is Not Associated With Infectious Complications After Total Joint Arthroplasty in Diabetic Patients. J Arthroplasty [Internet]. 2024 Aug;39(8S1):S43-S52.e5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/38220028\u003c/li\u003e\n \u003cli\u003eBonilla JL, Rodriguez-Torres JB, Verar GL, Mason-Nguyen J, Moore CB. Perioperative Dexamethasone for Patients With Diabetes and Its Effect on Blood Glucose After Surgery. J perianesthesia Nurs Off J Am Soc PeriAnesthesia Nurses [Internet]. 2022 Aug;37(4):551\u0026ndash;6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/35400551\u003c/li\u003e\n \u003cli\u003eVolkmar AJ, Schultz JD, Rickert MM, Polkowski GG, Engstrom SM, Martin JR. Dexamethasone Is Associated With a Statistically Significant Increase in Postoperative Blood Glucose Levels Following Primary Total Knee Arthroplasty. Arthroplast today [Internet]. 2023 Feb;19:101076. Available from: http://www.ncbi.nlm.nih.gov/pubmed/36624747\u003c/li\u003e\n \u003cli\u003eMeng J, Li L. The efficiency and safety of dexamethasone for pain control in total joint arthroplasty. Medicine (Baltimore) [Internet]. 2017 Jun;96(24):e7126. Available from: https://journals.lww.com/00005792-201706160-00018\u003c/li\u003e\n \u003cli\u003eZhuo Y, Yu R, Wu C, Huang Y, Ye J, Zhang Y. The role of perioperative intravenous low-dose dexamethasone in rapid recovery after total knee arthroplasty: a meta-analysis. J Int Med Res [Internet]. 2021 Mar 8;49(3). Available from: https://journals.sagepub.com/doi/10.1177/0300060521998220\u003c/li\u003e\n \u003cli\u003eFan Z, Ma J, Kuang M, Zhang L, Han B, Yang B, et al. The efficacy of dexamethasone reducing postoperative pain and emesis after total knee arthroplasty: A systematic review and meta-analysis. Int J Surg [Internet]. 2018 Apr;52:149\u0026ndash;55. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1743919118305739\u003c/li\u003e\n \u003cli\u003eLi X, Xu G, Xie W, Ma S. The efficacy and safety of dexamethasone for pain management after total knee arthroplasty: A systematic review and meta-analysis. Int J Surg [Internet]. 2018 May;53:65\u0026ndash;71. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1743919118306277\u003c/li\u003e\n \u003cli\u003eZhou G, Ma L, Jing J, Jiang H. A meta-analysis of dexamethasone for pain management in patients with total knee arthroplasty. Medicine (Baltimore) [Internet]. 2018 Aug;97(35):e11753. Available from: https://journals.lww.com/00005792-201808310-00003\u003c/li\u003e\n \u003cli\u003eLi P, Qiao Y, Zeng J, Li J, Tan F, Cao Y, et al. A systematic review and meta-analysis on the effects of intravenous dexamethasone on postoperative outcomes in patients undergoing total knee arthroplasty. Langenbeck\u0026rsquo;s Arch Surg [Internet]. 2025 Jan 24;410(1):49. Available from: https://link.springer.com/10.1007/s00423-025-03618-7\u003c/li\u003e\n \u003cli\u003eSaini MK, Reddy NR, Reddy PJ, Thakur AS, Reddy CD. The application of low-dose dexamethasone in total knee arthroplasty: finding out the best route and dosage schedule. Arch Orthop Trauma Surg [Internet]. 2022 Jan 24;143(2):1005\u0026ndash;12. Available from: https://link.springer.com/10.1007/s00402-022-04356-x\u003c/li\u003e\n \u003cli\u003eChan TCW, Cheung CW, Wong SSC, Chung AYF, Irwin MG, Chan PK, et al. Preoperative dexamethasone for pain relief after total knee arthroplasty. Eur J Anaesthesiol [Internet]. 2020 Dec;37(12):1157\u0026ndash;67. Available from: https://journals.lww.com/10.1097/EJA.0000000000001372\u003c/li\u003e\n \u003cli\u003eDerby CB, Gasbjerg KS, H\u0026auml;gi‐Pedersen D, Lunn TH, Pedersen NA, Lindholm P, et al. Prolonged effects of dexamethasone following total knee arthroplasty: A pre‐planned sub‐study of the \u0026lt;scp\u0026gt;DEX‐2‐TKA\u0026lt;/scp\u0026gt; trial. Acta Anaesthesiol Scand [Internet]. 2024 Jan 14;68(1):35\u0026ndash;42. Available from: https://onlinelibrary.wiley.com/doi/10.1111/aas.14319\u003c/li\u003e\n \u003cli\u003eLei Y, Huang Z, Huang Q, Pei F, Huang W. Dose optimization of intravenous dexamethasone for total knee arthroplasty: when two is not better than one. Arch Orthop Trauma Surg [Internet]. 2022 Apr 20;142(4):665\u0026ndash;72. Available from: https://link.springer.com/10.1007/s00402-021-03859-3\u003c/li\u003e\n \u003cli\u003eXu H, Zhang S, Xie J, Lei Y, Cao G, Pei F. Multiple Doses of Perioperative Dexamethasone Further Improve Clinical Outcomes After Total Knee Arthroplasty: A Prospective, Randomized, Controlled Study. J Arthroplasty [Internet]. 2018 Nov;33(11):3448\u0026ndash;54. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0883540318306016\u003c/li\u003e\n \u003cli\u003eXu B, Ma J, Huang Q, Huang Z yu, Zhang S yun, Pei F xing. Two doses of low-dose perioperative dexamethasone improve the clinical outcome after total knee arthroplasty: a randomized controlled study. Knee Surgery, Sport Traumatol Arthrosc [Internet]. 2018 May 4;26(5):1549\u0026ndash;56. Available from: http://link.springer.com/10.1007/s00167-017-4506-x\u003c/li\u003e\n \u003cli\u003eLex JR, Edwards TC, Packer TW, Jones GG, Ravi B. Perioperative Systemic Dexamethasone Reduces Length of Stay in Total Joint Arthroplasty: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. J Arthroplasty [Internet]. 2021 Mar;36(3):1168\u0026ndash;86. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0883540320310895\u003c/li\u003e\n \u003cli\u003eQin K, Sun X, Dou Q, Li B, Bai G, Sun X, et al. Comparison of analgesic effects between betamethasone and dexamethasone in total knee arthroplasty: a prospective randomized controlled trial. Front Med [Internet]. 2025 Jul 9;12. Available from: https://www.frontiersin.org/articles/10.3389/fmed.2025.1575417/full\u003c/li\u003e\n \u003cli\u003eWong KC, Tay AYW, Liow MHL, Tay DKJ, Pang HN, Yeo SJ. Corticosteroid-Enhanced Multimodal Cocktail Periarticular Injection in Total Knee Arthroplasty Does Not Increase Risks of Prosthetic Joint Infection. J Arthroplasty [Internet]. 2025 Aug 11; Available from: http://www.ncbi.nlm.nih.gov/pubmed/40803559\u003c/li\u003e\n \u003cli\u003eRichardson AB, Bala A, Wellman SS, Attarian DE, Bolognesi MP, Grant SA. Perioperative Dexamethasone Administration Does Not Increase the Incidence of Postoperative Infection in Total Hip and Knee Arthroplasty: A Retrospective Analysis. J Arthroplasty [Internet]. 2016 Aug;31(8):1784\u0026ndash;7. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0883540316000887\u003c/li\u003e\n \u003cli\u003eVuorinen MA, Palanne RA, M\u0026auml;kinen TJ, Leskinen JT, Huhtala H, Huotari KA. Infection safety of dexamethasone in total hip and total knee arthroplasty: a study of eighteen thousand, eight hundred and seventy two operations. Int Orthop [Internet]. 2019 Aug 19;43(8):1787\u0026ndash;92. Available from: http://link.springer.com/10.1007/s00264-018-4156-8\u003c/li\u003e\n \u003cli\u003eYu Y, Lin H, Wu Z, Xu P, Lei Z. Perioperative combined administration of tranexamic acid and dexamethasone in total knee arthroplasty\u0026mdash;benefit versus harm? Medicine (Baltimore) [Internet]. 2019 Aug;98(34):e15852. Available from: https://journals.lww.com/00005792-201908230-00002\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 8 are available in the supplementary files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-9352754/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9352754/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Optimal postoperative analgesia after total knee arthroplasty (TKA) remains challenging. Dexamethasone is used as an adjunct to multimodal analgesia, but its subgroup effectiveness and glycemic safety are uncertain. We aimed to determine whether perioperative intravenous dexamethasone improves early postoperative pain (time-weighted mean VAS over 6–48 h) and preserves glycemic safety, and to assess effect modification by age, diabetes status, and peripheral nerve block.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e We performed a single-center retrospective observational study of adults undergoing primary, elective TKA grouped by dexamethasone exposure (Dexa+ n=39; Non-Dexa n=65). The primary outcome was time-weighted mean VAS 6–48 h; VAS at 6, 12, 18, 24, 30, 36, 42, and 48 h was also analyzed. Secondary outcomes were preoperative HbA1c and perioperative glucose (Glucose I: evening of surgery; Glucose II: postoperative fasting morning; Glucose III: evening of postoperative day 1). Prespecified subgroups were age (≤65 vs \u0026gt;65 years), diabetes mellitus (DM vs non-DM), and peripheral nerve block (block vs no block). Two-sided tests with α=0.05 were used.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Groups were similar in age, sex, and DM prevalence; block use was higher and PCA use lower in Dexa+ (both \u003cem\u003ep\u003c/em\u003e\u0026lt;0.05). Overall, VAS did not differ at 6 and 18 h (\u003cem\u003ep\u003c/em\u003e\u0026gt;0.05) but was lower with Dexa+ at 12, 24, 30, 36, 42, and 48 h (\u003cem\u003ep\u003c/em\u003e\u0026lt;0.05). HbA1c and all glucose measures were comparable (\u003cem\u003ep\u003c/em\u003e\u0026gt;0.05). In subgroups, Dexa+ improved VAS at all time points in patients \u0026gt;65 years and at 12–48 h in non-DM patients; no benefit was observed in patients ≤65 years or with DM. In patients without block, Dexa+ reduced VAS at all time points; with block, VAS did not differ. Glucose patterns were similar across subgroups, except for a higher first glucose in Dexa+ without block, with later values converging.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e Perioperative dexamethasone improved early postoperative pain after TKA—particularly in older and non-diabetic patients and when no block was used—without major glycemic perturbations. These findings support selective, risk-adapted use and warrant confirmation in prospective randomized studies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy type: \u003c/strong\u003eA level 3 retrospective cohort study\u003c/p\u003e","manuscriptTitle":"Perioperative Dexamethasone in Total Knee Arthroplasty: Early Analgesic Benefit Without Major Glycemic Perturbation and Effect Modification by Age, Diabetes, and Regional Analgesia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-11 17:20:32","doi":"10.21203/rs.3.rs-9352754/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"194164330933235929749403338408055059530","date":"2026-05-01T20:49:54+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-05-01T12:00:43+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-05-01T11:58:54+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-04-24T05:06:24+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-20T14:20:31+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2026-04-20T13:25:32+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e25128f3-da58-43e1-a1c0-8904dc6662c4","owner":[],"postedDate":"May 11th, 2026","published":true,"recentEditorialEvents":[{"type":"reviewerAgreed","content":"194164330933235929749403338408055059530","date":"2026-05-01T20:49:54+00:00","index":67,"fulltext":""},{"type":"reviewersInvited","content":"13","date":"2026-05-01T12:00:43+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-05-01T11:58:54+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":67647823,"name":"Health sciences/Diseases"},{"id":67647824,"name":"Health sciences/Endocrinology"},{"id":67647825,"name":"Health sciences/Health care"},{"id":67647826,"name":"Health sciences/Medical research"}],"tags":[],"updatedAt":"2026-05-11T17:20:32+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-11 17:20:32","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9352754","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9352754","identity":"rs-9352754","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}