Intraoperative intravenous versus periarticular injection of glucocorticoids in improving clinical outcomes after total knee arthroplasty: A prospective,randomized and controlled study

Abstract

Background

Glucocorticoids have been widely used in perioperative period for postoperative pain relief after total knee arthroplasty (TKA). However, the optimal administration protocols of glucocorticoids remain controversial. This study aims to compare the efficacy of glucocorticoids between intravenous and periarticular injection on clinical outcomes.

Methods

A total of 114 patients were randomly assigned to intravenous (IV) group (n = 57) and periarticular injection (PI) group (n = 57). The IV group received 10 mg dexamethasone intravenously and the PI group received periarticular injection of 10 mg dexamethasone during the procedure. The clinical outcomes were assessed using visual analogue scale (VAS), knee society score (KSS), range of motion (ROM), knee swelling, inflammation markers and complications after TKA.

Results

The VAS score during walking at 2nd day postoperatively was lower in the PI group compared with the IV group (2.08 ± 1.45 vs 2.73 ± 1.69, p = .039), and there was no significant difference at the other time points of VAS score in two groups. The inflammation markers, knee swelling, knee ROM and KSS score were not statistically different. Vomiting and other complications occurrence were not significantly different between the two groups.

Conclusions

Intraoperative periarticular injection of glucocorticoids has similar analgesic effect compared to intravenous in the postoperative period following TKA and may be even more effective on the second postoperative day. In addition, periarticular injection of glucocorticoids does not impose an excess risk or complication on patients.

Keywords

total knee arthroplasty dexamethasone periarticular injection intravenous postoperative pain

Introduction

Total knee arthroplasty (TKA) has proven to be a reliable and effective method for advanced stages of knee osteoarthritis. However, the moderate to severe postoperative pain associated with TKA is one of the most commonly therapeutic problems, with an incidence rate of 30-60%.^1–3 Despite recent developments in pain control, postoperative pain remains a significant clinical challenge after TKA. Inadequate management of postoperative pain can lead to delayed recovery, prolonged hospital stays, and decreased patient satisfaction.^4,5

Glucocorticoids have been widely used in perioperative period for postoperative pain relief and the prevention of postoperative nausea and vomiting (PONV) due to their powerful anti-inflammatory and antiemetic effects.^6–16 Currently, the administration protocols of glucocorticoids include intravenous administration and periarticular injection. Previous studies have suggested that intraoperative intravenous dexamethasone have the advantages of relieving postoperative pain, reducing the consumption of opiates and decreasing the level of early inflammation markers.^7,14,17–19 An alternative administration is periarticular injection of glucocorticoids which has also been reported in recent years due to the efficacy in reducing postoperative pain.^6,8,11,15 However, the ideal administration protocols of glucocorticoids remain controversial.

At present, there are very few randomized controlled trials of high-level evidence comparing these two administration protocols directly. Therefore, we wondered whether the intraoperative intravenous and periarticular injection of glucocorticoids have different clinical outcomes, including postoperative pain management, prevention of PONV, inflammation, knee swelling, knee function recovery, consumption of opiates and the incidence of complications following primary TKA in this prospective, randomized and controlled study.

Materials and methods

Study design

The study was a prospective, randomized and controlled trial comparing the efficacy of dexamethasone between intravenous and periarticular injection on clinical outcomes following primary TKA. This study was approved by the Human Ethics Committee of *** and was registered with the Chinese Clinical Trial Registry (registration number ChiCTR2000033490). Written informed consent was provided by all patients.

Participants

A total of 163 patients scheduled to undergo unilateral primary TKA were recruited between June 2020 and June 2021 in the Center of Orthopedics Surgery. We excluded patients: (1) < 18 years old; (2) allergy to dexamethasone; (3) daily use of glucocorticoid or strong opioid drugs; (4) with history of serious heart disease (5) with renal insufficiency, active peptic ulcer or rheumatoid arthritis; (6) glycosylated hemoglobin >8; (7) with neurological or psychiatric disorders that may affect pain or cognitive impairment. Ultimately, 114 patients were randomly assigned to two groups (Figure 1).

Figure 1.

Study flow chart.

Randomization and blinding

A computer-generated randomization list for concealed allocation with a 1:1 ratio was prepared by an independent statistician. Eligible patients were assigned a sequential study number and randomized into two groups. A random allocation was concealed in consecutively numbered, opaque and sealed envelopes by a staff member not involved in the trial. The envelopes were opened on the day of the surgery to determine the treatment grouping and the trial drug was prepared by a nurse not involved in the trial. The patients, surgeons and data collectors were all blinded to patient group assignment.

Procedure

Interventions

Following randomization, the participants are divided into intravenous (IV) group or periarticular injection (PI) group. In the IV group, the cocktail including ropivacaine and flurbiprofen was injected at multiple points around the knee before prosthesis insertion, including synovium, joint capsule, posterior capsule periosteum and fascia, and 10 mg dexamethasone was injected intravenously with 5% glucose and sodium chloride as the solvent. The PI group received periarticular injection of cocktail including 10 mg dexamethasone, ropivacaine and flurbiprofen around the knee before prosthesis fixation at multiple points, and 10 mL of 5% glucose and sodium chloride was injected intravenously.

Preoperative and postoperative medications

All patients followed the same perioperative regimen. Preoperative administration of celecoxib 200 mg per day was given to all patients undergoing knee replacement. On the operative day and the first day after surgery, 40 mg of parecoxib was injected intravenously twice a day. On the third day after the surgery, the patient took celecoxib 200 mg twice a day. If the pain could not be relieved, the tramadol dosage was used and recorded according to the need of the patient. If the nausea and vomiting symptoms could not be relieved, ondansetron was injected intravenously according to the needs of the patients. The dosage of ondansetron was recorded, and the total dosage should not exceed 16 mg.

Surgery and rehabilitation

All patients were anesthetized by adductor nerve block combined with general anesthesia. All TKAs were performed by one of three senior surgeons using a standard medial parapatellar approach with the posterior stable prosthesis (RP, Depuy, Johnson & Johnson, USA). Tourniquets are used only from the fixation of the prosthesis to the closure of the wound. Drainage tube was placed 24 h after operation to reduce postoperative hematoma. All patients in this study were managed by standard clinical pathway. The standard rehabilitation plan is as follows: postoperative day (POD) 1-4: quadriceps femoris setting training, walking with a walker, active range of motion training; POD 5-16: the patient is discharged home or sent to rehabilitation center.

Study assessments

The pain was evaluated at 6h, 24h, 2nd, 3rd and 4th day after operation, and the rest time was at least 30min before the test. Records were made at each time point in the following order: rest (supine) and walking. Using the 100 mm visual analogue scale (VAS; 0, no pain, 100, the most severe pain imaginable) to assess knee pain when rest and walking (5 m) assisted by a walker. The levels of interleukin-6 (IL-6), C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) in blood were measured before operation, POD 1 and POD 3 to reflect the inflammatory reaction. The circumference of 1 cm near the upper edge of patella was measured before operation and POD 3. The range of knee motion (ROM) and knee society score (KSS) were measured by angle measuring instrument before operation, POD 1 and POD 3. The number of patients with nausea and vomiting within 48 h after surgery was recorded. In addition, the cumulative consumption of ondansetron was recorded. The daily cumulative amounts and the total consumption of narcotic drugs were converted into milligram equivalent oxycodone for statistical analysis.

The pain score, functional scale, range of knee motion, wound and complications were evaluated in the outpatient department 2 weeks and 3 months after operation. The definition of wound complications and any wound that is still draining during follow-up or any surgical site that needs to be returned for flushing and debridement. Other complications included deep vein thrombosis, pulmonary embolism, periprosthetic infection, and imaging evidence of avascular necrosis, which we recorded at each follow-up.

Statistical analysis

According to a systematic review study by,²⁰ a sample size of 51 patients per group would be required to detect a clinically relevant differences in pain scores with a mean difference of 1.3 points and a standard deviation of 2.0 points at an α level of 0.025 and a β value of 0.10. Considering the 10% attrition due to cancellation of surgery or expected withdrawal, we selected 114 sample sizes (57 in each group).

All statistical analyses were performed using Statistical Package for Social Sciences version 23.0 (SPSS, Chicago, IL, USA). Quantitative variables were depicted as mean and standard deviation while categorical data were described as number with percentage. The continuous data of demographic characteristics and clinical outcomes were analyzed using independent-samples ttest or Mann-Whitney U test according to the normality of data. And the categorical data were analyzed using chi-square or Fisher exact test. The level of statistical significance was set at p value less than 0.05.

Results

Baseline characteristics

During the study period, a total of 114 patients were randomized (Figure 1). Fitty-one patients in IV group and fitty-two patients in PI group were included in the analysis. There were no significant differences in demographic characteristics, surgical duration and estimated blood loss between the two groups (Table 1).

Table 1.

Characteristics of the patients at baseline.

	IV group (n = 51)	PI group (n = 52)	p-Value
Age, years	70.51 ± 7.10	69.81 ± 7.56	0.628
Male sex, no. (%)	6 (11.80%)	8 (15.40%)	0.592
Height, cm	156.77 ± 6.70	158.96 ± 6.65	0.099
Weight, kg	65.04 ± 10.05	65.59 ± 10.16	0.784
BMI, kg/m²	26.42 ± 3.44	25.91 ± 3.27	0.441
Pain duration, years	8.50 ± 6.20	7.94 ± 7.56	0.683
Length of hospital stay, days	10.29 ± 2.93	10.13 ± 2.79	0.778
Side of surgery (left), no. (%)	21 (41.2%)	22 (42.3%)	0.907
Surgical duration, min	137.49 ± 19.77	132.10 ± 22.80	0.203
Estimated blood loss, ml	155.88 ± 101.00	146.15 ± 77.59	0.584

Abbreviations: Body mass index (BMI); Intravenous (IV); Periarticular injection (PI).

Visual analog score

In IV group and PI group, patients had similar VAS score at rest at 6 h, 1st, 2nd, 3rd, 4th days, 2 weeks and 3 months postoperatively (Table 2). However, the VAS score during walking at 2nd day postoperatively was lower in the PI group compared with the IV group (2.08 ± 1.45 vs 2.73 ± 1.69, p = .039), and the other time points of VAS score in two groups were no significant difference (Table 2, Figure 2).

Table 2.

Preoperative and postoperative pain evaluation.

	IV group (n = 51)	PI group (n = 52)	p-Value
VAS at rest
Pre-op	0.78 ± 1.12	0.54 ± 0.67	0.178
Post-op 6h	0.35 ± 0.56	0.44 ± 0.61	0.439
Post-op 1d	0.73 ± 1.31	0.69 ± 0.70	0.873
Post-op 2d	0.71 ± 0.81	0.83 ± 0.88	0.469
Post-op 3d	0.67 ± 0.71	0.46 ± 0.78	0.166
Post-op 4d	0.41 ± 0.61	0.38 ± 0.63	0.824
Post-op 2w	2.14 ± 0.63	2.13 ± 0.60	0.983
Post-op 3m	1.39 ± 0.60	1.21 ± 0.41	0.080
VAS during walking
Pre-op	2.90 ± 1.84	2.42 ± 1.88	0.194
Post-op 1d	2.57 ± 1.42	2.67 ± 1.98	0.759
Post-op 2d	2.73 ± 1.69	2.08 ± 1.45	0.039^a
Post-op 3d	2.04 ± 1.20	2.50 ± 1.93	0.148
Post-op 4d	2.08 ± 1.40	1.92 ± 1.25	0.553
Post-op 2w	2.35 ± 0.59	2.31 ± 0.67	0.718
Post-op 3m	1.57 ± 0.54	1.48 ± 0.54	0.411

^a<0.05.

Abbreviations: Visual analog score (VAS ); Preoperative (Pre-op); Post-operative (Post-op); Intravenous (IV0; Periarticular injection (PI).

Figure 2.

Visual analog scale (VAS) pain score at rest (a) and during walking (b) between the intravenous (IV) group and periarticular injection (PI) group during the perioperative period. * indicates a significant difference between the two groups (p < .05).

Knee function and inflammatory indicators

There was not statistically significant difference in the knee swelling at 3rd days postoperatively between the two groups (p > .05) (Table 3). The knee ROM and KSS score also were not statistically different at each postoperative time points (p > .05) (Table 3, Figure 3). Furthermore, the level of IL-6, CRP and ESR at postoperative 1st days and 3rd days were similar in two groups (p > .05) (Table 4, Figure 4).

Table 3.

Preoperative and postoperative knee function.

	IV group (n = 51)	PI group (n = 52)	p-Value
Knee swelling, cm
Pre-op	43.03 ± 4.73	43.25 ± 4.77	0.811
Post-op 3d	46.10 ± 5.16	46.27 ± 5.75	0.875
Knee ROM, °
Pre-op	106.60 ± 13.25	109.85 ± 18.66	0.312
Post-op 3d	91.21 ± 17.77	92.13 ± 9.78	0.744
Post-op 2w	91.47 ± 11.33	93.87 ± 17.92	0.421
Post-op 3m	110.69 ± 11.49	114.33 ± 13.69	0.147
KSS score
Pre-op	60.39 ± 14.16	64.75 ± 12.01	0.095
Post-op 3d	50.33 ± 11.55	53.38 ± 12.27	0.197
Post-op 2w	53.47 ± 7.82	55.38 ± 9.07	0.254
Post-op 3m	77.14 ± 8.87	79.69 ± 3.44	0.059

Abbreviations: Range of motion (ROM ); Knee society score (KSS ); Preoperative (Pre-op); Post-operative (Post-op); Intravenous (IV ); Periarticular injection (PI).

Figure 3.

Range of motion (ROM) of knee (a) and knee society score (KSS) (b) between the intravenous (IV) group and periarticular injection (PI) group during the perioperative period.

Table 4.

Preoperative and postoperative inflammatory indicators.

	IV group (n = 51)	PI group (n = 52)	p-Value
IL-6 level, pg/ml
Pre-op	6.06 ± 14.65	4.45 ± 4.61	0.451
Post-op 1d	50.29 ± 58.02	45.88 ± 30.27	0.631
Post-op 3d	46.87 ± 63.67	43.46 ± 30.23	0.745
CRP level, mg/L
Pre-op	3.31 ± 4.80	2.39 ± 2.57	0.225
Post-op 1d	25.83 ± 17.56	21.80 ± 10.34	0.170
Post-op 3d	74.25 ± 49.32	66.51 ± 31.83	0.383
ESR level, mm/h
Pre-op	29.45 ± 16.37	25.33 ± 13.73	0.169
Post-op 1d	34.77 ± 16.89	36.97 ± 19.79	0.554
Post-op 3d	53.02 ± 23.25	46.23 ± 23.91	0.181

Abbreviations: C-reactive protein (CRP ); interleukin-6 (IL-6); Erythrocyte sedimentation rate (ESR ); Preoperative (Pre-op); Post-operative (Post-op); Intravenous (IV); periarticular injection (PI).

Figure 4.

The levels of interleukin-6 (IL-6) (a); C-reactive protein (CRP) (b) and erythrocyte sedimentation rate (ESR) (c) between the intravenous (IV) group and periarticular injection (PI) group during the perioperative period.

Postoperative complications

The PONV has occurred in 4 (7.8%) patients in the IV group and 5 (9.6%) patients in the PI group. Additionally, there was no statistical difference in the other complications occurrence, including delayed wound healing, deep vein thrombosis, pulmonary embolism, periprosthetic infection and avascular necrosis between the two groups (p > .05) (Table 5). The amount of ondansetron and opioids consumption were similar in two groups during the postoperative period (p > .05), as shown in Table 5.

Table 5.

Postoperative complications.

	IV group (n = 51)	PI group (n = 52)	p-Value
Nausea and vomiting, no. (%)	4 (7.8%)	5 (9.6%)	1.000
Delayed wound healing, no. (%)	0 (0)	2 (3.8%)	0.484
Deep vein thrombosis, no. (%)	0	0	N/A
Pulmonary embolism, no. (%)	0	0	N/A
Periprosthetic infection, no. (%)	0	0	N/A
Avascular necrosis, no. (%)	0	0	N/A
Ondansetron, mg	0.24 ± 1.24	0.62 ± 2.00	0.249
Opioids, mg	144.61 ± 278.66	123.80 ± 263.70	0.698

Abbreviations: not available (N/A), intravenous (IV ); Periarticular injection (PI).

Discussion

This study was conducted to reveal whether the intraoperative intravenous and periarticular injection of glucocorticoids have different clinical outcomes following primary TKA and which administration route may be more recommended. In the present study, we found that the VAS score during walking at 2nd day postoperatively was lower in the PI group compared with the IV group (p < .05), and the other time points of VAS score in two groups were no significant difference. Additionally, there was no significant difference in knee swelling, knee ROM, KSS score, inflammation markers and complications occurrence between the two groups after TKA.

Intravenous and periarticular injection of glucocorticoids have been proven to be effective way to relieve pain after artificial joint replacement, but the best way to use glucocorticoids to relieve pain in TKA has not been determined. According to our outcomes, intraoperative periarticular injection of dexamethasone resulted in more significant pain relief in the early postoperative period after TKA. ²¹ argued that the pain scores at rest and during walking were significantly lower in patients who received periarticular injection of glucocorticoids than those who received intravenous administration of glucocorticoids in the early post-TKA period, which is consistent with our speculation. However, in the Hatayama’s study, the intravenous administration group received 10 mg dexamethasone but the periarticular injection group received a 40 mg triamcinolone acetonide, which might have contributed to the difference in results.²¹

IL-6 is widely associated with inflammation, which has a vital role in the process of neutrophils and macrophage activation during surgery and trauma, and IL-6 can induce the production of CRP in hepatocytes.^22,23 Previous studies revealed that the serum inflammatory cytokines including interleukins (ILs), C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) might be related to postoperative pain^24–28. ²⁸ suggested that serum inflammatory cytokines are positively correlated with acute postoperative pain following primary TKA. In the present study, there were no significant differences in the mean IL-6, CRP and ESR at 1st days and 3rd days postoperatively between the two groups, showing the similar anti-inflammatory effect of dexamethasone in IV group and PI group in the early postoperative period.²¹ suggested that the mechanism of pain relief may be a direct inhibitory effect of glucocorticoids on signal transduction in pain C-fibers rather than the reduction in inflammation.²⁹ showed that IL-6 and CRP in the early postoperative period after TKA were significantly higher in topical dexamethasone group, but the postoperative pain scores were significantly lower in topical group comparing with intravenous group, which was not consistent with our results.

In addition, the inflammatory responses after surgical injury contribute to the knee swelling and impaired function of knee.^30,31 Anti-inflammatory treatment can reduce knee swelling effectively, especially at the early postoperative stage.³¹ reported that preoperative intravenous methylprednisolone was able to effectively reduce knee swelling within 24 h after TKA. However,³² showed that a reduction in knee swelling after TKA was reported in 65.4% of patients who received periarticular injection of glucocorticoids. In this study, we found the similar outcomes between the two groups on reducing the knee swelling, the ROM of knee and the KSS score evaluated at 3rd days postoperatively. These results illustrate that the intravenous and periarticular injection of dexamethasone play the same role in improving knee swelling and knee function recovery after TKA.

Although glucocorticoids have obvious benefits in the perioperative period of artificial joint replacement, its application in the perioperative period of total joint replacement has not become a routine due to the concern of related side effects. However, these side effects are only related to the long-term use of glucocorticoids. Numerous studies have revealed that there was no significant increase of adverse reactions for patients who used glucocorticoids in perioperative period.^33–35 The complications including PONV, delayed wound healing, deep vein thrombosis, pulmonary embolism, periprosthetic infection, avascular necrosis and the consumption of ondansetron and opioids were similar between IV group and PI group. The incidence and severity of side effects are related to the dosage, time, dosage form and injection site. Periarticular injection can reduce the total dosage of glucocorticoids and reduce systemic adverse reactions, such as transient facial flushing, excitement, sleep disorders, elevated blood pressure or blood sugar.³⁶

This study had several limitations. First, patients in this study were from a single center with a short period. Second, no placebo group was set in the study, and blank control was lacking. Third, all patients underwent adductor block, and the pain scale may be masked in the early postoperative period. However, we had to implement adductor nerve block to minimize pain and nausea after TKA due to ethical considerations.

Conclusions

In conclusion, this study supports that intraoperative periarticular injection of glucocorticoids has similar analgesic effect compared to intravenous in the postoperative period following TKA and and may be even more effective on the second postoperative day. In addition, periarticular injection of glucocorticoids does not impose an excess risk or complication on patients.

Footnotes

Acknowledgements

We thank our study participants and their family.

Author’s note

The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was funded by the Major Science and Technology Project of Guangdong Province, grant number 2015B020225007; Natural Science Foundation of Guangdong Province, grant number 2018A0303130206 and 2021A1515011008; Guangdong Medical Science and Technology Research Fund, grant number A2019150; Scientific Research Project of Guangdong Traditional Chinese Medicine Bureau, grant number 20221008 and Starting fund of National Natural Science Foundation of Guangdong Provincial People’s Hospital, grant number 8207050645 and 8217051081.

Institutional review board statement

The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the human ethics committee of Guangdong Provincial People’s Hospital (reference number No. GDREC2018522H (R1)).

Informed Consent

Informed consent was obtained from all subjects involved in the study.

ORCID iDs

Qingtian Li

Guibin Fang

Data Availability Statement

The datasets used and/or analyzed during the current study can be available from the corresponding author upon reasonable request.*

References

Yang

Zhao

Zhang

X-H

, et al. Comparison of sevoflurane and propofol on the incidence of postoperative pain and quality of life in patients undergoing total knee arthroplasty with chronic pain before surgery. Pain Pract: The Official Journal of World Institute of Pain 2021; 21(1): 37–44.

J-W

Y-S

Xiao

L-K

. Postoperative pain management in total knee arthroplasty. Orthop Surg 2019; 11(5): 755–761.

Seo

Kim

Seo

, et al. Comparison of the effect of continuous femoral nerve block and adductor canal block after primary total knee arthroplasty. Clin Orthop Surg 2017; 9(3): 303–309.

Wainwright

Gill

McDonald

, et al. Consensus statement for perioperative care in total hip replacement and total knee replacement surgery: enhanced Recovery after Surgery (ERAS) Society recommendations. Acta Orthop 2020; 91(1).

Berend

Lombardi

. Advances in pain management: game changers in knee arthroplasty. The bone & Joint Journal 2014; 96-B(11 Supple A): 7–9.

Tsukada

Wakui

Hoshino

. The impact of including corticosteroid in a periarticular injection for pain control after total knee arthroplasty: a double-blind randomised controlled trial. The bone & joint journal 2016; 98-B(2): 194–200.

Zhuo

, et al. The role of perioperative intravenous low-dose dexamethasone in rapid recovery after total knee arthroplasty: a meta-analysis. J Int Med Res 2021; 49(3): 300060521998220.

Liu

, et al. Efficacy of additional corticosteroids to multimodal cocktail periarticular injection in total knee arthroplasty: a meta-analysis of randomized controlled trials. J Orthop Surg Res 2021; 16(1): 77.

, et al. The optimal dosage, route and timing of glucocorticoids administration for improving knee function, pain and inflammation in primary total knee arthroplasty: a systematic review and network meta-analysis of 34 randomized trials. Int J Surg 2020; 82: 182–191.

10.

Kim

Lee

, et al. Efficacy of systemic steroid use given one day after total knee arthroplasty for pain and nausea: a randomized controlled study. J Arthroplasty 2020; 35(1): 69–75.

11.

Kurosaka

Tsukada

Ogawa

, et al. Comparison of early-stage and late-stage periarticular injection for pain relief after total hip arthroplasty: a double-blind randomized controlled trial. J Arthroplasty 2020; 35(5): 1275–1280.

12.

Chan

VWK

Chan

, et al. Combination effect of high-dose preoperative and periarticular steroid injection in total knee arthroplasty. A randomized controlled study. J Arthroplasty 2021; 36(1): 130–134.e2.

13.

Cheng

BLY

EHK

Hui

GKM

, et al. Pre-operative intravenous steroid improves pain and joint mobility after total knee arthroplasty in Chinese population: a double-blind randomized controlled trial. Eur J Orthop Surg Traumatol 2019; 29(7): 1473–1479.

14.

Tammachote

Kanitnate

. Intravenous dexamethasone injection reduces pain from 12 to 21 hours after total knee arthroplasty: a double-blind, randomized, placebo-controlled trial. J Arthroplasty 2020; 35(2): 394–400.

15.

Tsukada

Kurosaka

Maeda

, et al. Early stage periarticular injection during total knee arthroplasty may provide a better postoperative pain relief than late-stage periarticular injection: a randomized-controlled trial. Knee Surg Sports Traumatol Arthrosc 2019; 27(4): 1124–1131.

16.

, et al. Perioperative multiple low-dose Dexamethasones improves postoperative clinical outcomes after Total knee arthroplasty. BMC Muscoskel Disord 2018; 19(1): 428.

17.

Huang

, et al. Two doses of low-dose perioperative dexamethasone improve the clinical outcome after total knee arthroplasty: a randomized controlled study. Knee Surg Sports Traumatol Arthrosc 2018; 26(5): 1549–1556.

18.

Dissanayake

Robertson

, et al. Does dexamethasone reduce hospital readiness for discharge, pain, nausea, and early patient satisfaction in hip and knee arthroplasty? A randomized, controlled trial. J Arthroplasty 2018; 33(11): 3429–3436.

19.

Chan

TCW

Cheung

Wong

SSC

, et al. Preoperative dexamethasone for pain relief after total knee arthroplasty: a randomised controlled trial. Eur J Anaesthesiol 2020; 37(12): 1157–1167.

20.

Mohammad

Hamilton

Strickland

, et al. Perioperative adjuvant corticosteroids for postoperative analgesia in knee arthroplasty. Acta Orthop 2018; 89(1): 71–76.

21.

Hatayama

Terauchi

Oshima

, et al. Comparison of intravenous and periarticular administration of corticosteroids in total knee arthroplasty: a prospective, randomized controlled study. J Bone Joint Surg Am 2021; 103(4): 319–325.

22.

Kishimoto

. The biology of interleukin-6. Blood 1989; 74(1).

23.

Scheller

Chalaris

Schmidt-Arras

, et al. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta 2011; 1813(5): 878–888.

24.

Honsawek

Deepaisarnsakul

Tanavalee

, et al. Relationship of serum IL-6, C-reactive protein, erythrocyte sedimentation rate, and knee skin temperature after total knee arthroplasty: a prospective study. Int Orthop 2011; 35(1): 31–35.

25.

Chen

Bai

Xie

, et al. Inflammatory response to orthopedic biomaterials after total hip replacement. J Orthop Sci : Official Journal of the Japanese Orthopaedic Association 2012; 17(4): 407–412.

26.

Takeshita

Nakamura

Ohtori

, et al. Sensory innervation and inflammatory cytokines in hypertrophic synovia associated with pain transmission in osteoarthritis of the hip: a case-control study. Rheumatology 2012; 51(10): 1790–1795.

27.

Watkins

Maier

Goehler

. Immune activation: the role of pro-inflammatory cytokines in inflammation, illness responses and pathological pain states. Pain 1995; 63(3): 289–302.

28.

H-B

Yang

T-M

Zeng

, et al. Correlations between inflammatory cytokines, muscle damage markers and acute postoperative pain following primary total knee arthroplasty. BMC Muscoskel Disord 2017; 18(1): 265.

29.

Wang

Zhao

, et al. Comparison of intravenous and topical dexamethasone for total knee arthroplasty: a randomized double-blinded controlled study of effects on dexamethasone administration route and enhanced recovery. J Arthroplasty 2021; 36(5): 1599–1606.

30.

Smith

Erasmus

Myburgh

. Endocrine and immune effects of dexamethasone in unilateral total knee replacement. J Int Med Res 2006; 34(6): 603–611.

31.

Rytter

Stilling

Munk

, et al. Methylprednisolone reduces pain and decreases knee swelling in the first 24 h after fast-track unicompartmental knee arthroplasty. Knee Surg Sports Traumatol Arthrosc : Official Journal of the ESSKA 2017; 25(1): 284–290.

32.

Klement

Luzzi

Siddiqi

, et al.

Intra-articular corticosteroid injection following total knee arthroplasty: is it effective?

J Arthroplasty 2019; 34(2): 303–308.

33.

Sauerland

Nagelschmidt

Mallmann

, et al. Risks and benefits of preoperative high dose methylprednisolone in surgical patients: a systematic review. Drug Saf 2000; 23(5): 449–461.

34.

Jørgensen

Pitter

Kehlet

. Safety aspects of preoperative high-dose glucocorticoid in primary total knee replacement. Br J Anaesth 2017; 119(2): 267–275.

35.

Salerno

Hermann

. Efficacy and safety of steroid use for postoperative pain relief. Update and review of the medical literature. J Bone Joint Surg Am 2006; 88(6): 1361–1372.

36.

Stout

Friedly

Standaert

. Systemic absorption and side effects of locally injected glucocorticoids. PM R 2019; 11(4): 409–419.