Abstract
Objectives
This randomized controlled trial aimed to evaluate the short term effects of adding different doses of corticosteroids to periarticular infiltration analgesia (PIA) on pain control and functional recovery after total knee arthroplasty (TKA).
Methods
A total of 234 patients undergoing TKA were randomly assigned to one of three groups: Group H (PIA with 21 mg betamethasone), Group N (PIA with 7 mg betamethasone), and Group C (PIA without corticosteroid). The PIA cocktail (80 mL) consisted of 300 mg of 0.75% ropivacaine, 5 mg morphine, 50 mg flurbiprofen, and 0.4 mL of 1:1000 epinephrine. The primary outcome was the Visual Analog Scale (VAS) score during active knee flexion. Secondary outcomes included resting VAS scores, active range of motion (AROM), 1-min walking distance, knee circumference (measured at three levels: 10 cm above the superior patellar pole, mid-patella, and 10 cm below the inferior patellar pole), total rescue analgesic consumption, serum C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and fasting blood glucose. Tertiary outcomes involved the incidence of postoperative adverse events.
Results
No significant intergroup differences were observed in active flexion VAS scores at any postoperative time point. From postoperative days 1–4, A ROM was significantly greater in Groups H and N than in Group C. Group H also demonstrated significantly reduced mid-patella circumference and lower rescue analgesic consumption compared to the other groups. In addition, CRP and ESR levels were significantly lower in Group H. However, this group exhibited transiently elevated blood glucose at 6 h post-surgery. No significant differences were found among the three groups in other secondary outcomes, including resting VAS, 1-min walking distance, additional knee circumference measurements, and adverse event rates.
Conclusion
The adjunct use of corticosteroids in PIA did not enhance short-term pain control or ambulation capacity after TKA. Although corticosteroid supplementation reduced inflammation, improved early ROM, and decreased rescue analgesic requirements, it induced dose-related hyperglycemia. Therefore, high-dose steroid-containing PIA should be avoided in patients with diabetes or glucose intolerance.
Supplementary Information
The online version contains supplementary material available at 10.1186/s13018-025-06575-5.
Keywords: Corticosteroids, Periarticular infiltration analgesia, Short-term analgesic, Total knee arthroplasty
Introduction
Approximately 60% of patients experience moderate to severe pain after TKA [1, 2]. Inadequate pain control is a major clinical factor hindering rehabilitation and delaying discharge in fast-track arthroplasty protocols [3]. The core principle of Enhanced Recovery After Surgery (ERAS®) focuses on effective pain management, as uncontrolled pain can intensify endocrine, metabolic, and autonomic responses [4, 5]. Periarticular infiltration analgesia (PIA) has become widely accepted as a method for pain control following TKA [6–8]. In orthopedic surgery, PIA typically involves injecting a multimodal drug cocktail—containing agents such as local anesthetics, corticosteroids, epinephrine, and opioids—around the joint cavity to achieve postoperative analgesia. Currently, there is no established standard regarding the specific composition and dosage of drugs used in PIA, although it is known to offer reliable pain relief with a favorable safety profile [9]. Corticosteroids are commonly incorporated due to their local anti-inflammatory effects and their ability to reduce the surgical stress response [10]. Recently, interest has grown in using corticosteroids as part of PIA to enhance short-term pain relief after TKA. However, current evidence remains inconsistent. Several studies have indicated that corticosteroid-containing PIA cocktails can reduce inflammation and provide additional pain relief [11–15], whereas others have shown mild or no benefit [16–18]. Chan et al. [19], demonstrated that the combination of intravenous dexamethasone before spinal anesthesia and PIA with triamcinolone produced enhanced analgesic and anti-inflammatory effects in TKA, suggesting that high-dose corticosteroid administration may significantly improve postoperative pain management and attenuate the stress response.Hence, this randomized controlled trial aimed to (1) evaluate the short-term analgesic effects of corticosteroids as an adjunct to multimodal PIA after TKA, and (2) determine whether high-dose corticosteroids in PIA contribute to better pain control and recovery in the early postoperative period.
Materials and methods
This three-arm, double-blinded, randomized, placebo-controlled study was approved by the ethics committee of the Second Affiliated Hospital of Guangzhou University of Chinese Medicine (ZF2020-031-01) and registered in the Chinese Clinical Trial Registry (ChiCTR2000038671). Prior to conducting this investigation, the patients provided informed consent.
Patient recruitment
Between October 2020 and September 2021, patients diagnosed with severe knee osteoarthritis and scheduled for unilateral TKA were enrolled from the Department of Orthopedics at the Second Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine. Inclusion criteria comprised patients aged 50–80 years with American Society of Anesthesiologists (ASA) physical status I or II. Exclusion criteria were as follows: 1. significant psychiatric, psychological, or communication disorders; 2. cardiovascular disease, diabetes mellitus, poor perioperative glycemic control (fasting glucose > 8 mmol/L), severe renal or hepatic dysfunction, history of gastric ulcer, or coagulation disorders; 3. central or peripheral neurological conditions impairing completion of postoperative rehabilitation; 4. alcohol or substance abuse; 5. known hypersensitivity to any component of the multimodal cocktail; 6. previous major knee surgery, revision arthroplasty, or knee trauma during the study period.
Of 245 patients assessed for eligibility, 11 were excluded for not meeting the inclusion criteria. The remaining 234 patients were randomly allocated to three groups (n = 78 each): Group H (high-dose betamethasone), Group N (conventional-dose betamethasone), and Group C (no betamethasone) (Fig. 1).
Fig. 1.
CONSORT flow diagram of research
Randomization and blinding
Random assignment was performed by an independent investigator (DL) using a computer-generated blocked random-allocation sequence (Excel, Microsoft Corporation, Redmond, USA). The assignment was done in a 1:1:1 ratio, and the investigator also secured the computer-generated numbers in an envelope. During the surgery, the envelope was opened by an assisting nurse who did not participate in the study. The assisting nurse allocated the patients to groups and prepared the cocktail analgesics in another room based on the assigned envelope. The patients and investigators in charge of collecting and analysing the data were kept unaware of the group they were assigned to. The milky white flurbiprofen axetil injection as an ingredient would make the appearance of three groups of cocktail analgesics show no differences. As a result, the surgeon was blinded during periarticular infiltration.
Interventions
One surgeon performed all surgical procedures under general anesthesia. The process was performed utilizing a standard medial parapatellar approach, during which a tourniquet was used, and Depuy Attune PS prosthesis (Attune ®; DePuy Synthes, Warsaw, IN) was placed. 100 mL cefamandole was administered intravenously 30 min before and after surgery. A dose of 1 g tranexamic acid was administered intravenously 20 min before tourniquet inflation and again 6 h after surgery.Patients were administered low-molecular-weight heparin subcutaneously for thromboprophylaxis 8 h postoperatively and then once daily for two weeks. An oral dose of 400 mg celecoxib was administered from day one before the surgery. Tourniquet was inflated before skin incision and deflated after prosthesis implantation. Carefully hemostasis was applied prior to wound closure.
Before prosthesis implantation, an 80 mL PIA cocktail was prepared and injected into the posterior capsule, medial and lateral collateral ligaments, quadriceps and retinacular tissues, as well as adipose and subcutaneous layers. The base formulation consisted of 300 mg of 0.75% ropivacaine (30 mL), 5 mg morphine (1 mL), 50 mg flurbiprofen axetil (5 mL), 0.4 mL of 1:1000 epinephrine, and normal saline. Group H received 21 mg betamethasone (3 mL), Group N received 7 mg betamethasone (1 mL), and Group C received no corticosteroid. An intra-articular drain was placed through the superolateral aspect of the knee, clamped postoperatively, and released intermittently every 6–8 h. The drain was removed on postoperative day 1 when the 24-h output was less than 200 mL; all patients in this trial met this criterion.
Postoperatively, all patients received intravenous parecoxib sodium (40 mg) twice daily until postoperative day (POD) 3, followed by oral celecoxib (200 mg) every 12 h for 4 weeks. A transdermal buprenorphine patch was applied on POD 1 for one week, after which oral acetaminophen-tramadol (100 mg) was administered every 12 h for 4 weeks. Intramuscular tramadol hydrochloride injection was administered as rescue analgesia if the patient reported intolerable pain or a knee pain VAS score ≥ 4.
Outcome measurements
Upon admission, demographic characteristics including age, height, weight, sex, body mass index (BMI), surgical side, and American Society of Anesthesiologists (ASA) physical status were recorded. Baseline characteristics did not show any significant differences, as seen in Table 1.
Table 1.
Baseline characteristics of patients
| Characteristic | Group C (n = 78) | Group N (n = 78) | Group H (n = 78) | p value |
|---|---|---|---|---|
| Gender (M/F) | 10/68 | 15/63 | 11/67 | 0.502a |
| Age (years) | 68.05 ± 6.42 | 69.56 ± 5.55 | 67.88 ± 5.84 | 0.197b |
| Body mass index (kg/m2) | 26.70 ± 3.44 | 25.74 ± 3.28 | 26.00 ± 3.77 | 0.115b |
| Side (L/R) | 32/46 | 28/50 | 36/42 | 0.428a |
| ASA (P1/P2/P3) | 1/63/14 | 0/59/19 | 1/58/19 | 0.717c |
| Comorbidity (Y/N) | 38/40 | 41/37 | 42/36 | 0.801a |
| Pre-op aVAS | 3.13 ± 1.71 | 2.91 ± 1.95 | 3.06 ± 1.42 | 0.769b |
| Per-op VAS | 1.45 ± 1.36 | 1.05 ± 1.28 | 1.38 ± 1.18 | 0.056b |
| Per-op ROM | 105.76 ± 19.85 | 110.64 ± 24.36 | 105.42 ± 24.53 | 0.069b |
| Per-op walkingability | 42.12 ± 10.77 | 41.06 ± 10.50 | 42.12 ± 13.67 | 0.480b |
| Per-op SupraCC | 40.32 ± 3.44 | 39.78 ± 3.23 | 40.21 ± 3.38 | 0.571b |
| Per-op MidCC | 37.90 ± 3.13 | 37.40 ± 3.21 | 37.19 ± 3.04 | 0.109b |
| Per-op SubCC | 33.46 ± 3.28 | 33.27 ± 3.08 | 33.24 ± 3.40 | 0.796b |
Values are mean ± SD or number of cases. a Pearson’s Chi-Squared test. b Kruskal–Wallis H test. c Fisher’s Exact test
The primary outcome was the worst pain during active knee flexion, assessed using a visual analog scale (VAS) at 6 h, 12 h, postoperative days (POD) 1–4, and POD 7. Secondary outcomes comprised resting pain VAS; range of motion (ROM) measured at 6 h, 12 h, POD 1–4, and POD 7; 1-min walking ability and circumference of the knee (10 cm proximal to the superior pole of the patella, mid-portion of the patella and 10 cm distal to the inferior pole of the patella) measured on POD2, 5, 7; The total amount of rescue analgesia. Laboratory outcomes included serum C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) levels measured at 12 h, POD 1, 3, 5, and 7.Additionally, fasting blood glucose levels were measured at 6 h, 12 h, and daily from POD 1–7.
Adverse events including serious adverse events (SAEs) and common adverse events were recorded. The total occurrence rate of common adverse events was analyzed and defined as the presence (yes) or not (no) of any event within the entire study.
Statistical analysis
A 0.8 mean difference in the VAS score between Group H and Group N, and a 0.4 mean difference between Group N and Group C were reported to be scientifically significant [9, 10]. An estimated standard deviation (SD) of 1.5, significance level (α) of 0.05, and power of test (β) of 0.8 were adopted. In time for enabling a drop-out rate of 10 percent, 78 patients in each group, a total of 234 participants for the three groups were required.
Perioperative outcomes will be summarized using the mean ± SD (standard deviation) for continuous variables and the number of cases for categorical variables. All statistical analyses will be conducted using the SPSS 25.0 (IBM, Chicago, USA) and visualized by GraphPad Prism (San Diego, USA). Shapiro–Wilk test is utilized for normality in the distribution of continuous variables and the Kruskal–Wallis H-test is used to compare differences among the three groups. Pearson’s Chi-squared test or Fisher’s Exact test was used for categorical variables to compare within-group differences.
For repeatedly measured outcomes, a one-way analysis for repeated measures ANOVA test will be performed to compare the difference between the three groups. Dunnett’s test will be applied for post-hoc comparisons. P values < 0.05 will be considered to be statistically significant.
Results
The primary outcomes
When repeated-measures ANOVA with Rescue analgesia, Gender, and Pre-op VAS as covariates were performed, no statistically significant variations in flexion VAS were seen among the three groups at any time points (Table 2).
Table 2.
VAS during flexion
| Outcome | Group C (n = 78) | Group N (n = 78) | Group H (n = 78) | p value |
|---|---|---|---|---|
| VAS during flexion | 0.980a | |||
| Post-op 6 h | 2.87 ± 1.22 | 3.01 ± 1.17 | 2.90 ± 0.98 | 0.810b |
| Post-op 12 h | 2.81 ± 1.41 | 2.78 ± 0.96 | 2.91 ± 1.03 | 0.560b |
| Post-op D1 | 3.32 ± 1.27 | 3.12 ± 1.24 | 2.95 ± 0.97 | 0.215b |
| Post-op D2 | 3.03 ± 1.31 | 2.78 ± 1.42 | 2.67 ± 1.12 | 0.101b |
| Post-op D3 | 2.62 ± 1.33 | 2.64 ± 1.33 | 2.42 ± 1.32 | 0.485b |
| Post-op D4 | 3.92 ± 2.28 | 3.46 ± 2.27 | 4.01 ± 2.47 | 0.309b |
| Post-op D7 | 2.15 ± 0.36 | 2.18 ± 0.39 | 2.29 ± 0.46 | 0.071b |
Values are mean ± SD VAS visual analogue scale. a One-way analysis for repeated measures ANOVA test. b Kruskal–Wallis H test, Rescue analgesia, Gender, Pre-op VAS during flexion were considered as covariates
The secondary outcomes
There were no notable disparities in VAS scores and 1-min walking ability among the three groups at rest (Figs. 2 and 3). In terms of ROM, there was a significant difference between the three groups. Both Group N and Group H exhibited significantly superior ROM compared to Group C in the D1-D4 range. However, there was no substantial disparity observed between Group N and Group H. The information is presented in Table 3. The three groups exhibited notable variations in MidCC, with Group H displaying the most diminutive circumference of the mid-portion of the patella. Patients in Group H had significant lower total rescue analgesia than patients in Group C (Fig. 4). There were no significant differences among the three groups in the SupraCC, SubCC, total analgesic rescue, and adverse event counts (Table 4).
Fig. 2.
VAS at rest. There were no significant differences among three groups in VAS at rest
Fig. 3.
1-mintue walking ability. There were no significant differences among three groups in 1-mintue walking ability
Table 3.
ROM after surgery
| Outcome | Group C (n = 78) | Group N (n = 78) | Group H (n = 78) | p value |
|---|---|---|---|---|
| ROM after surgery | 0.003a | |||
| Post-op 6 h | 55.37 ± 25.09 | 61.37 ± 30.17 | 57.17 ± 25.58 | 0.473b |
| Post-op 12 h | 56.14 ± 24.62 | 63.28 ± 25.96 | 58.19 ± 26.29 | 0.166b |
| Post-op D1 | 68.54 ± 16.77*# | 76.14 ± 20.07* | 76.41 ± 17.09# | 0.003b |
| Post-op D2 | 82.87 ± 13.85*# | 90.88 ± 21.62* | 90.04 ± 15.49# | < 0.001b |
| Post-op D3 | 88.96 ± 14.17*# | 96.58 ± 17.05* | 96.00 ± 13.84# | 0.002b |
| Post-op D4 | 94.27 ± 15.64*# | 100.54 ± 17.07* | 100.22 ± 13.14# | 0.015b |
| Post-op D7 | 101.63 ± 16.03 | 106.10 ± 13.22 | 104.51 ± 13.30 | 0.287b |
Values are mean ± SD VAS visual analogue scale. a One-way analysis for repeated measures ANOVA test. b Kruskal–Wallis H test. *, # Statistically significant for between-group difference
Fig. 4.
Total rescue analgesia. Patients in Group H had significant lower total rescue analgesia than patients in Group C
Table 4.
circumference of the knee
| Outcome | Group C (n = 78) | Group N (n = 78) | Group H (n = 78) | p value |
|---|---|---|---|---|
| SupraCC | 0.726a | |||
| D2 | 43.45 ± 4.04 | 43.39 ± 3.91 | 42.91 ± 3.64 | 0.656b |
| D5 | 44.76 ± 3.10 | 44.16 ± 2.75 | 44.25 ± 3.05 | 0.663b |
| D7 | 46.74 ± 2.45 | 47.16 ± 2.42 | 47.03 ± 2.97 | 0.729b |
| MidCC | 0.006a | |||
| D2 | 40.82 ± 4.12 | 40.24 ± 3.70 | 39.15 ± 3.10 | 0.018b |
| D5 | 40.82 ± 2.83 | 40.67 ± 2.16 | 39.73 ± 2.33 | 0.054b |
| D7 | 43.55 ± 2.80 | 43.07 ± 2.55 | 43.47 ± 2.90 | 0.487b |
| SubCC | 0.577a | |||
| D2 | 35.09 ± 2.05 | 35.00 ± 2.24 | 34.70 ± 2.61 | 0.739b |
| D5 | 36.08 ± 1.94 | 35.60 ± 2.07 | 35.88 ± 1.66 | 0.462b |
| D7 | 36.11 ± 2.58 | 36.09 ± 2.85 | 36.17 ± 2.57 | 0.976b |
| Total rescue analgesia | 110.88 ± 165.49* | 47.96 ± 86.27 | 58.17 ± 120.67* | 0.024b |
| Adverse event count (Y/N) | 34/44 | 28/50 | 29/49 | 0.573b |
Values are mean ± SD. a One-way analysis for repeated measures ANOVA test. b Kruskal–Wallis H test. * Statistically significant for between-group difference
Laboratory outcomes
The three groups had significant differences in serum CRP, ESR, and fasting blood glucose (Glu). Compared with Groups C and N, CRP levels were significantly lower in Group H at D1, D3, and D5, in addition to the ESR level at D5. Glu levels were significantly higher in group H than in group C at 6 h postoperatively. The Glu levels of group H were the highest in D1 and D2 among the three groups (Table 5).
Table 5.
Laboratory outcomes
| Outcome | Group C (n = 78) | Group N (n = 78) | Group H (n = 78) | p value |
|---|---|---|---|---|
| CRP | < 0.001a | |||
| Post-op 12 h | 10.64 ± 2.94 | 10.88 ± 2.71 | 11.18 ± 2.48 | 0.518b |
| Post-op D1 | 28.68 ± 17.45* | 15.10 ± 13.23# | 15.35 ± 10.93*# | < 0.001b |
| Post-op D3 | 80.86 ± 23.97* | 51.87 ± 12.60# | 49.60 ± 14.67*# | < 0.001b |
| Post-op D5 | 29.00 ± 7.29* | 27.86 ± 5.86# | 26.68 ± 8.51*# | 0.040b |
| Post-op D7 | 23.86 ± 4.15 | 24.03 ± 3.38 | 22.88 ± 3.40 | 0.143b |
| ESR | 0.001a | |||
| Post-op 6 h | 51.03 ± 5.06 | 50.35 ± 5.85 | 50.06 ± 4.71 | 0.374b |
| Post-op D1 | 54.81 ± 9.67 | 52.54 ± 7.38 | 55.03 ± 9.88 | 0.299b |
| Post-op D3 | 69.08 ± 16.28 | 65.54 ± 16.63 | 64.47 ± 16.37 | 0.790b |
| Post-op D5 | 85.18 ± 8.20* | 80.13 ± 7.67# | 82.09 ± 12.39*# | 0.001b |
| Post-op D7 | 80.47 ± 7.33 | 78.63 ± 6.04 | 79.59 ± 6.78 | 0.107b |
| blood glucose | < 0.001a | |||
| Post-op 6 h | 9.18 ± 1.90* | 9.99 ± 2.27 | 10.51 ± 2.28* | 0.003b |
| Post-op 12 h | 9.99 ± 3.02 | 10.51 ± 2.51 | 11.26 ± 3.14 | 0.056b |
| Post-op D1 | 7.29 ± 1.09*# | 8.77 ± 2.34*# | 9.97 ± 2.81*# | < 0.001b |
| Post-op D2 | 6.96 ± 1.54*# | 7.32 ± 1.00* | 7.37 ± 1.06# | < 0.001b |
| Post-op D3 | 6.61 ± 1.42 | 7.05 ± 1.72 | 7.32 ± 2.28 | 0.110b |
| Post-op D4 | 7.04 ± 2.48 | 7.24 ± 1.93 | 7.33 ± 2.05 | 0.385b |
| Post-op D5 | 6.68 ± 0.85 | 6.45 ± 0.88 | 6.65 ± 0.91 | 0.234b |
| Post-op D7 | 5.72 ± 0.82 | 5.68 ± 0.79 | 5.77 ± 0.79 | 0.715b |
Values are mean ± SD VAS visual analogue scale. a One-way analysis for repeated measures ANOVA test. b Kruskal–Wallis H test. *, # Statistically significant for between-group difference
Discussion
The key findings of the present study are as follows: (1) Both normal dose nor high doses of corticosteroids, when added to multimodal cocktail PIA, did not provide any benefits in terms of short-term pain control and 1-min walking capacity after TKA, even when considering factors such as rescue analgesia, gender, pre-op VAS as covariates; (2) The groups receiving corticosteroid had lower levels of CRP and ESR, a s well as better ROM compared to the group not receiving corticosteroids. The high-dose corticosteroid group had the smallest MidCC; (3) The corticosteroid-containing cocktail regimens caused an alarming ascendance of fasting blood glucose on early POD, particularly in the high-dose group.
Previous studies that investigated the analgesic effect of steroids in PIA had inconsistent results. Several previous studies had demonstrated negative additional pain-relieving similar to the study. Christensen et al. [17] conducted the initial study to specifically examine corticosteroids in TKA using 40 mg of methylprednisolone and discovered that there was no difference in pain scores, ROM, or Knee Society Scores at any time point. El-Boghdadly et al. [20] applied PIA containing ropivacaine, ketorolac, and epinephrine with or without 8 mg dexamethasone and found that the corticosteroid group was not associated with clinically important analgesic benefits in patients undergoing TKA. Chia et al. [16] administered both low and high dosages of triamcinolone acetate but failed to observe any significant difference in any clinical outcome. It is important to note that the primary outcomes were the cumulative total of the average weekly RVAS and AVAS instead of pain at any time point within a week post-operatively. The current study focused on whether high dose or low dose of corticosteroid in multimodal cocktail PIA attributed to superior pain management in the early stage after TKA. The study observed no statistically significant changes in VAS during flexion or at rest among the three groups. The phenomenon can be attributed to the synergistic analgesic effect of the multimodal cocktail PIA, in which each drug would provide a meaningful analgesic effect, via its mechanism. Local anesthetics block peripheral nociceptors [21], while opioids stimulate the activity of peripheral opioid receptors of inflamed tissue [22, 23]. NSAIDs suppress the activity of cyclooxygenase in the arachidonic acid cascade, while corticosteroids hinder the synthesis of phospholipase A2 in the arachidonic acid cascade [24, 25]. It can be assumed that corticosteroids and NSAIDs might encounter a ceiling effect in pain release due to their same target pathway (arachidonic acid cascade) in their analgesic mechanisms. The result of the present study was consistent with the research conducted by Kim et al. [26], in which methylprednisolone did not show a significant additional analgesic effect when added to a combination of ropivacaine, morphine, and ketorolac. The combination of ropivacaine, morphine, and ketorolac is suggested as a favourable option for PIA following TKA in terms of synergistic analgesic effect and efficiency of the drug combination.
Several previous studies reported that the addition of corticosteroid to the PIA significantly improved analgesic effect following primary unilateral TKA [8, 19, 27]. It should be noted that the majority of those studies demonstrated transient (within 24 h) or mild analgesic effect, or solely employed local anesthetics as the control. The authors of the present study reached a consensus that it is of utmost importance to distinguish between a meaningful improvement in a clinical context and a significant difference in a statistical context. This distinction was made when evaluating the effectiveness of pain management strategies in TKA, using the minimal clinically important difference (MCID) as the standard method [28, 29]. A meta-analysis conducted by Huang et al. [30] revealed that the reduction in resting pain scores occurring from 6 to 72 h did not reach the MCID—defined as a reduction of 2.26 points by Danoff et al. [29] or 0.9 points by Machado et al. [28]. Moreover, they found that neither the results of the simultaneous bilateral knee trials nor those of the cross-over bilateral knee trial provided substantial evidence that corticosteroid addition can significantly improve analgesia based on the MCID.
Serum CRP and ESR levels are commonly employed as biochemical markers of inflammatory response following TKA [31–33].Most previous studies have demonstrated that the addition of corticosteroids to PIA significantly decreases CRP and ESR levels and improves ROM during the first few days after TKA. Consistent with these findings, the present study also found the smallest MidCC in the high-dose corticosteroid group. These effects can be explained by the anti-inflammatory mechanism of glucocorticoids. Tissue injury causes activation of cytosolic phospholipase A2 (cPLA2), which releases arachidonic acid and subsequently generates eicosanoids including prostaglandins, thromboxanes, prostacyclins, and leukotrienes [34]. Glucocorticoids exert anti-inflammatory effects by inhibiting cPLA2 expression in injured tissues [35]. Thus, periarticular steroid infiltration may reduce local inflammatory response and minimize soft tissue edema during the early stage after TKA. This mechanism can lead to decreased CRP and ESR levels, improved ROM, and reduced knee circumference.
Corticosteroids are known to cause hyperglycemia which defined as greater than 7.6 mmol/L [36, 37] in postoperative period as suggested by some studies and meta-analyses [38, 39]. There are concerns regarding the administration of high dose of glucocorticoids (i.e. 20–40 mg for dexamethasone and 100–200 mg of methylprednisolone) particularly in patients undergoing total knee arthroplasty. These issues arise from the fact that these medications might elevate blood sugar levels and potentially lead to surgical wound-healing-related problems [17, 40].
Only a limited number of studies have undertaken detailed studies on the impact of corticosteroid containing cocktail PIA on postoperative blood glucose during TKA surgery. Chan VWK found that a high percentage of patients (67–83%) experienced transient hyperglycemia from the night of surgery to postoperative D1 [19]. However, due to the fact that the author used bilateral TKA surgery on the same patient as the experimental group and control group, postoperative blood glucose monitoring was unable to complete the control study. The study conducted by Saini et al. provides a more comprehensive explanation of the impact of different administration methods on postoperative blood glucose [27]. Although all doses were 8 mg of dexamethasone, the postoperative 24-h blood glucose levels in the SDIV group (single dose IV) were significantly higher than those in the PAID group (peripheral injection) and LID group (low interval dose). There was no statistical difference between preoperative and the 48-h blood glucose levels, indicating that intravenous one-time administration had the most significant impact on postoperative blood glucose. The blood glucose changes of D3-D7 were not monitored, which is a supplementary research content of this article. In the present study, the blood glucose levels of the three groups of patients peaked at 12 h after surgery and gradually decreased. The group treated with corticosteroid containing PIA exhibited a substantial increase in comparison to the non-corticosteroid group on D1 and D2. From D3 to D7, there was no statistical difference among the three groups. These results indicate that corticosteroids shortly amplified the effect of blood sugar ascendance caused by surgical stress. This concern has clinical significance because postoperative hyperglycemia is considered as an independent risk factor for wound complications and periprosthetic joint infection [41, 42]. The physicians are required to be definite about the effect of transient hyperglycemia and insulin resistance on perioperative complications in the setting of fast-track arthroplasty. Therefore, the risks and benefits of using high-dose corticosteroids in PIA should be carefully weighed. Based on the present study, the inclusion of corticosteroids in PIA did not increase the incidence of wound complications or periprosthetic joint infection during the three-month follow-up period.
The results of the present study should be interpreted with caution in light of several limitations. First, the related small sample size, which was hypothesized based on a 0.8 mean difference in the VAS score between Group H and Group N and a 0.4 mean difference between Group N and Group C, was probably underpowered for the current outcomes. It is possible that the actual efficacy of corticosteroid-containing PIA in postoperative analgesia after TKA may not be fully reflected. Second, the relatively short observation time may not fully reflect the long-term adverse effects of corticosteroid-containing PIA. The current study aimed to assess the short-term efficiency of corticosteroid-containing PIA on pain control after TKA. Third, due to the impact of the COVID-19 pandemic in China, the outpatient follow-ups for suburban patients have been affected and restricted, and the 14-day follow-up data are partially missing. After analyzed the data, we believed that the 7-day data were sufficient to reflect the core objective of this trial, and the 14-day follow-up data did not affect the conclusive results of this trial. It was assumed that a three-month follow-up on adverse events including wound complications and periprosthetic joint infection was sufficient. Ultimately, due to the study design, we were unable to include other measures to evaluate pain and knee function, such as gait and other functional performances, as well as the length of hospital stay. This study did not adjust for confounding factors such as TKA alignment and mechanical causes [8].
Conclusion
Neither the average dose nor high dose of corticosteroids added to the multimodal cocktail PIA showed benefits for short-term pain control and 1-min walking capacity after TKA. The corticosteroid groups exhibited lower levels of CRP and ESR, better ROM than non-corticosteroid group. Additionally, the high corticosteroid dose group had the smallest MidCC. The corticosteroid-containing cocktail regimens caused an alarming ascendance of fasting blood glucose on early POD, particularly in the high-dose group. Cocktails that include corticosteroids may provide certain functional benefits and may not offer any pain-relieving advantages. There is, however, a risk of increasing blood glucose in the short term after surgery. Therefore, clinicians should exercise caution when using these cocktails in patients with diabetes or impaired glucose tolerance.
Supplementary Information
Below is the link to the electronic supplementary material.
Author contributions
Yang Li and Chunjian Zi: contributed to the study conception and design and drafted the manuscript. Dingkun Lin and Da Guo: performed the implementation and feasibility analysis of the study. Yang Li: collated the data. Weiming Yang and Hongliang Liu: conducted statistical analysis and proofread the manuscript. Yihui Yu: analyzed and interpreted the results. Xing Li and Yang Lyu: revised the manuscript. Peng Yang and Da Guo: were responsible for quality control and review of the manuscript, as well as the overall supervision and management of the project.
Funding
This study was supported by the Guangdong Basic and Applied Basic Research Foundation (No. 2021A1515011596), Guangdong Provincial Hospital of Chinese Medicine Scientific and Technological Research Special Project (YN2020MS05, YN2024MS048), Special Research Project for Top Talents of Guangdong Provincial Hospital of Chinese Medicine (BY2022LC06), and Science and Technology Program of Guangzhou, China (No. 2024A03J0118).
Data availability
All data generated or analysed during this study are included within the article and related files.
Declarations
Ethics approval and consent to participate
The study protocol was reviewed and approved by the Ethics Committee of Guangdong Provincial Hospital of Traditional Chinese Medicine (ethics number: ZF2020-031-01), and conformed to the ethical standards for medical research involving human subjects, as laid out in the1964 Declaration of Helsinki and its later amendments.Participants provided written informed consent prior to taking part in the study.
Consent for publication
Consent for publication was obtained from the participants.
Competing interests
The authors declare no competing interests. Full ICMJE author disclosure forms are available for this article online, as supplementary material.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Yang Li and Chunjian Zi: Co-first authors.
Contributor Information
Xing Li, Email: liqixi723@126.com.
Yihui Yu, Email: y489518073@163.com.
Dingkun Lin, Email: lindingkun@126.com.
Da Guo, Email: guo_da2023@163.com.
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Associated Data
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Supplementary Materials
Data Availability Statement
All data generated or analysed during this study are included within the article and related files.