Periarticular Analgesic Injection Containing A Corticosteroid Reduces D-Dimer Levels After Total Hip Arthroplasty: Retrospective Comparative Cohort Study

Background: Of late, periarticular analgesic injection (PAI) has become a common alternative treatment for pain following total hip arthroplasty (THA). However, the systemic effects of PAI containing corticosteroids in patients subjected to THA have not been investigated. This study evaluated the analgesic ecacy and systemic effects of PAI containing a corticosteroid in patients subjected to THA. Methods: This single-center, retrospective cohort study enrolled patients undergoing unilateral, primary THA. A total of 197 patients (200 hips) were included in the nal analyses, with 87 hips in the PAI group and 113 hips in the control group. Numeric Rating Scale (NRS) and laboratory data were assessed preoperatively and on postoperative days (POD) 1 and 7. Pearson’s correlation coecients were obtained to assess the correlations between the D-dimer level on POD 7 and each outcome measure on POD 1. Results: The postoperative white blood cell count (WBC) was signicantly higher in the PAI group than in the control group. Postoperative NRS, creatine phosphokinase (CK), and C-reactive protein (CRP) levels were signicantly lower in the PAI group. D-dimer levels were signicantly lower in the PAI group on POD 7. Postoperative aspartate transaminase (AST), alanine aminotransferase, blood urea nitrogen, and creatinine levels were within reference ranges. D-dimer levels on POD 7 showed a signicant negative correlation with WBC on POD 1 (r=-0.4652) and a signicant positive correlation with the NRS score and AST, CK, CRP, and D-dimer levels on POD 1 (r=0.1558, 0.2353, 0.2718, 0.3545, and 0.3359, respectively). Conclusions: PAI containing a corticosteroid may be an effective treatment for pain and inammation after THA, and it does not seem to cause drug-induced liver or kidney injury. Moreover, corticosteroid PAI can reduce D-dimer levels, which


Background
Total hip arthroplasty (THA) is a common, standardized, highly cost-effective surgical procedure [1]. However, one report found that the patient dissatisfaction rate following THA was 11% [2]. Postoperative pain is an important factor affecting patients' satisfaction with THA [2,3]. Moreover, poorly managed postoperative pain can cause chronic postoperative pain [4]. Therefore, effective treatment of postoperative pain remains an important challenge for physicians [3]. Conventionally, many strategies have been applied to reduce postoperative pain, including peripheral nerve block, systemic morphine, and continuous epidural analgesia [5]. Recently, periarticular analgesic injection (PAI) has become a common alternative treatment for pain management following THA [6]. However, mixed opinions and con icting results regarding PAI for pain management following THA have been reported [6,7,8]. PAI usually consists of local analgesics that may be combined with corticosteroids, opioids, epinephrine, or nonsteroidal anti-in ammatory drugs (NSAIDs) and then diluted with normal saline [7]. Several reports have been published regarding the analgesic effect of PAI containing corticosteroids and the anti-in ammatory effect of PAI containing NSAIDs in THA [9,10,11].
However, to the best of our knowledge, the systemic effects of PAI containing corticosteroids in patients subjected to THA have not been investigated.
In this study, we aimed to investigate the systemic effects of PAI containing corticosteroids and its e cacy for reducing postoperative pain in patients undergoing primary THA.

Methods
This was a single center, retrospective cohort study. The study protocol adhered to the ethical guidelines of the 1975 Declaration of Helsinki, and the study was approved by the institutional review board of our institution. All patients provided opt-out informed consent prior to participation in this study.
A total of 254 patients (288 hips) who had undergone unilateral primary THA at our hospital between May 2019 and January 2020 were initially included. We implemented PAI in our hospital beginning in September 2019 for patients  undergoing THA. Thus, patients who underwent THA from May 2019 to August 2019 were considered the control group, and patients who received THA between September 2019 and January 2020 comprised the PAI group. The study enrolled 140 patients (151 hips) in the control group and 114 patients (137 hips) in the PAI group. In the control group, we excluded 1 hip with hip ankylosis, 7 hips with femoral head necrosis, 5 hips with rapidly destructive coxarthrosis, 4 hips with osteotomy around the hip joints, 3 hips with post-traumatic arthritis of the hip joint, 2 hips with high hip dislocation, 1 hip with an intraoperative fracture, 2 hips with collagen diseases, 3 hips with medical complications, and 10 hips that lacked su cient data. In the PAI group, we excluded 2 hips with hip ankylosis, 6 hips with femoral head necrosis, 2 hips with rapidly destructive coxarthrosis, 3 hips with osteotomy around the hip joint, 4 hips with posttraumatic arthritis of the hip joint, 5 hips with high hip dislocation, 2 hips with collagen diseases, 8 hips of patients with diabetes, and 18 hips that lacked su cient data. Finally, 197 patients (200 hips) with primary hip osteoarthritis or secondary hip osteoarthritis due to developmental dysplasia of the hip joint were enrolled. Thus, the analyses included a total of 113 hips (112 patients) in the control group and 87 hips (85 patients) in the PAI group (Table 1). In the PAI group, injections were performed after total hip prosthesis implantation and prior to closure. The PAI was a 41 ml solution containing 20 mL of 5 mg/mL levobupivacaine, l mL of 40 mg/mL triamcinolone acetonide (Kenacort-A® Intramuscular/Intraarticular Aqueous Suspension Injection; Bristol-Myers Squibb K.K., Tokyo, Japan), and 20 mL normal saline. The surgeon injected 10 mL of the solution into the capsule, 21 mL into the gluteus and external rotators, and 10 mL into the fatty layer. Walking training within the allowable pain range was started without weight-bearing limitations, beginning 1 day after surgery.
The postoperative analgesic protocol was same for both groups. The patients received urbiprofen axetil (Ropion®; Kaken Seiyaku Co., Ltd., Tokyo, Japan) 50 mg as a continuous intravenous infusion within the rst 24 h after surgery (total dose was 200 mg); acetaminophen (Acelio® Intravenous Injection; Terumo Corporation, Tokyo, Japan) at 1,000 mg for patients with body weight ≥ 50 kg (total dose was 4000 mg) or 15 mg/kg for patients with body weight < 50 kg as an intravenous infusion every 6 h during the rst 24 h after surgery; and celecoxib (Celecox®; Astellas Pharma Inc., Tokyo, Japan) 200 mg orally twice daily following an initial dose of 400 mg as the standard analgesic protocol. As rescue drugs, a diclofenac sodium suppository (Voltaren® SUPPO®; Novartis Pharma K.K., Tokyo, Japan) 50 mg or intramuscular pentazocine (Sosegon® Injection; Maruishi Pharmaceutical Co., Ltd., Tokyo, Japan) 15 mg were administered.
Sex, age, body mass index (BMI), operative time, intraoperative blood loss, and postoperative blood loss were assessed. Intraoperative blood loss was calculated based on the contents of the suction bottle and the change in the weight of the used surgical sponges. Postoperative blood loss was calculated based on the contents of the drain.
The primary outcome was the maximum pain level, assessed before surgery, on POD 1, and on POD 7. The patient's pain level was assessed using the Numeric Rating Scale (NRS) [12]. The NRS is a segmented numeric version of the visual analog scale in which a respondent selects a whole number (integers 0-10) that best re ects the intensity of their pain.

Statistical Analyses
All numerical data were expressed as the mean ± standard deviation. All analyses were performed using JMP® Pro software (version 14.2.0, SAS Institute Japan Ltd, Tokyo, Japan). We employed the Wilcoxson signed-rank test to compare BMI, operation time, intra-and postoperative blood loss, pre-and postoperative laboratory data, and pre-and postoperative NRS between the two groups. A chi-squared test was used to compare the male:female proportion between the two groups. Student's t-test was used to compare the mean age between the two groups. The Steel-Dwass test was used to compare the perioperative data (NRS and laboratory data) within each group. Pearson's correlation coe cients were obtained to assess the correlations between the D-dimer level on POD 7 and each outcome on POD 1. The level of signi cance was set at p < 0.05. Post-hoc analysis of the study was performed (effect size = 0.5, two-sided alpha = 0.05, sample size = 113 and 87), and the calculated power was 0.93.

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There were no signi cant differences between the control and PAI groups in age, sex, BMI, intra-or post-operative blood loss, or operation time (Table 1).
Preoperative NRS scores in the PAI group were signi cantly higher than those in the control group, whereas postoperative NRS scores in the PAI group were signi cantly lower than those in the control group (Table 2 and Fig. 1a). Values are expressed as the mean ± standard deviation. PAI: periarticular analgesic injection, NRS: numeric rating scale Table 3 and Fig. 1b-i show the comparisons of laboratory values between the control and PAI groups and the comparison of perioperative laboratory data in each group. The postoperative WBC was signi cantly higher in the PAI group than in the control group, and within the PAI group the WBC was signi cantly higher on POD 7 than before surgery (Table 3 and Fig. 1b). Postoperative CK levels were signi cantly lower in the PAI group than in the control group.
Within the PAI group, CK levels were signi cantly lower on POD 7 than before surgery (Table 3 and Fig. 1c).
Postoperative CRP levels were lower in the PAI group than in the control group (Table 3 and Fig. 1d). Seven days postoperatively, D-dimer levels were signi cantly lower in the PAI group than in the control group (Table 3 and Fig. 1e).
Postoperative AST, ALT, BUN, and Cr levels were within the reference ranges in both groups (Table 3 and Fig. 1f-i).   Table 4).

Discussion
To our knowledge, this study is the rst to investigate the effect of PAI containing a corticosteroid on laboratory data following THA. Our ndings indicate that corticosteroid PAI is an effective treatment for pain and in ammation after THA. Corticosteroid PAI may lead to early ambulation, reduced D-dimer levels, and, consequently, a reduced risk of deep venous thrombosis (DVT).
Levobupivacaine, which is the S-enantiomer of bupivacaine, is a long-acting local anesthetic drug [13]. Compared to ropivacaine, levobupivacaine has a longer duration of action and the half-life is approximately 4 hours [13,14,15]. Levobupivacaine has a wider margin of safety, in terms of cardiovascular and central nervous system adverse effects, compared with bupivacaine [16]. Therefore, levobupivacaine has been used in PAI [17,18]. However, some previous studies have found that PAI (levobupivacaine and/or epinephrine) in THA did not reduce postoperative pain [17,18].
Conversely, our study demonstrated lower NRS in the PAI group on POD 1 and 7, which indicates that the corticosteroid may have had an effect on postoperative pain.
Previous studies reported that trauma and surgery, including THA, cause the release of interleukin (IL)-6, causing local in ammation at the site of injury [19,20,21]. CRP is an acute-phase protein that increases after in ammation and a marker that re ects the severity of in ammation [19,22]. The release of IL-6 during in ammation leads to the production of CRP [19]. CK is an energy production enzyme in the mitochondria and is primarily found in muscle tissues [23]. CK elevation is a feature of muscle in ammation or damage [24]. Corticosteroids have an anti-in ammatory effect, via the inhibition of the synthesis of phospholipase A2, thereby reducing the production of the pro-in ammatory derivatives of arachidonic acid, e.g. IL-1, IL-2, IL-6, and tumor necrosis factor (TNF-α) [25,26]. An anti-in ammatory effect of glucocorticoids (e.g., reduction of IL-6 in the drain uid and CRP) in total knee arthroplasty has been reported [27]. Postoperative CRP and CK levels were lower in the PAI group than in the control group, owing to the antiin ammatory effect of the corticosteroid in this study.
Triamcinolone acetonide was the corticosteroid used in this study. It is an intermediate-acting glucocorticoid with a halflife between 18 and 36 hours [25,28]. Intramuscular administration of triamcinolone acetonide provides a slow absorption and prolonged duration [28,29]. In this study, CRP levels and CK levels on POD 7 were lower in the PAI group than in the control group. Surprisingly, in the PAI group, CK levels were signi cantly lower on POD 7 than before surgery. Therefore, PAI containing triamcinolone acetonide may have a prolonged anti-in ammatory effect after THA, for at least 7 days postoperatively.
Postoperative pain is considered a form of acute pain owing to surgical trauma with an in ammatory reaction and initiation of an afferent neuronal barrage [30]. Therefore, reducing in ammation is important for reducing postoperative pain. Additionally, postoperative in ammation affects the immediate functional recovery after THA [31], and pain management following THA is important for early postoperative rehabilitation [32]. This study demonstrated the analgesic effect of PAI containing a corticosteroid on POD 7 owing to the anti-in ammatory effect of a corticosteroid that has a long duration of activity [28,29]. Therefore, the analgesic effect of PAI containing a corticosteroid may accelerate early postoperative rehabilitation.
DVT and pulmonary embolus are potential life-threating complications after THA, and their prevention is a universal quality improvement initiative [33,34]. D-dimer is a degradation product of a cross-linked brin blood clot [35], and the elevation of D-dimer levels is caused by acute venous thromboembolism, recent major surgery, hemorrhage, trauma, pregnancy, and cancer [35]. A D-dimer test is a simple and useful method for diagnosing DVT, because the incorporation of a D-dimer test into a clinical diagnostic strategy can identify DVT without ultrasonography [36,37]. Antithrombotic drugs, an intermittent compression device, pneumatic foot pumps, graduated compression stockings, and early ambulation are methods for preventing DVT in patients after surgery [38,39]. Additionally, early ambulation prevents the development of high postoperative D-dimer levels [40]. In our study, there was no signi cant difference between the Ddimer levels of the two groups on POD 1. However, the D-dimer levels were signi cantly lower in the PAI group than in the control group on POD 7.
Glucocorticoids can stimulate the bone marrow to produce more granulocytes, inhibit neutrophil apoptosis, and impair the migration of granulocytes to sites of in ammation or infection through the vasculature [41,42,43]. This results in increased numbers of circulating neutrophils [41,42,43]. In this study, the postoperative WBC was signi cantly higher in the PAI group than in the control group, and the WBC in the PAI group was signi cantly higher on POD 7 than before surgery. The postoperative WBC elevation in the PAI group may be due to the prolonged effect of the corticosteroid on granulocytes.
AST is found in the liver, heart, muscle, kidneys, brain, and blood cells [44]. ALT is found in the plasma and other organs; however, most ALT is found in the liver [44].
In our study, postoperative AST levels were lower in the PAI group than in the control group. There were no signi cant differences between pre and postoperative AST levels within the PAI group. Postoperative ALT levels were not signi cantly different between the two groups. Levobupivacaine and corticosteroids are mainly metabolized by the liver [45,46]; normal postoperative ALT levels in both groups indicate that there was no drug hepatopathy following THA with or without corticosteroid PAI. Thus, the anti-in ammatory effects of the corticosteroid may have prevented muscle damage and in uenced AST levels in the PAI group, as observed with CK.
BUN and Cr are biomarkers of kidney function [47]. The differences in BUN and Cr levels on POD 7 were inconsistent between the groups. Both BUN and Cr levels were within their reference ranges on POD 7. The metabolization of levobupivacaine and corticosteroids occurs primarily in the liver [45,45]; therefore, it was assumed that PAI containing a corticosteroid did not directly produce any drug-induced kidney injury.
In the PAI group, the NRS score and CPK, and CRP levels on POD 1 were lower than those in the control group. In all hips in both groups, the NRS score and CPK, and CRP levels on POD 1 showed signi cant positive correlations with D-dimer levels on POD 7. The analgesic and anti-in ammatory effect of PAI containing a corticosteroid may lead to early ambulation, resulting in lower postoperative D-dimer levels and a lower risk of DVT.
There are several limitations in our study. First, CRP was the only in ammatory marker investigated. Other indices to evaluate in ammation, such as IL-6, were lacking. However, evaluating CRP may be su cient for investigating the grade of in ammation because CRP is highly correlated with IL-6 [48]. Second, postoperative functional performance was not investigated. Therefore, we could not investigate an association between postoperative functional performance and Ddimer levels. In the future, assessments of postoperative functional performance are needed. Third, there was no assessment of the incidence of DVT, which is associated with elevated D-dimer levels, using computed tomographic scanning or ultrasonography [49]. Although imaging tests are not always necessary for the diagnosis of DVT [37], imaging tests may be needed to determine whether PAI containing a corticosteroid accurately reduces DVT in future studies. Finally, the contents of the PAI in this study were a corticosteroid and levobupivacaine. A group that receives a PAI containing only a corticosteroid, without levobupivacaine, may be necessary to de nitively investigate the antiin ammatory effect of corticosteroids.

Conclusions
PAI containing a corticosteroid was found to be an effective treatment for pain and in ammation following THA.
Considering the lower postoperative D-dimer levels observed in the PAI group, the analgesic and anti-in ammatory effects of corticosteroid PAI may have the potential to accelerate early ambulation and reduce the risk of DVT. The study was approved by our institutional review board. All patients provided informed consent based on an opt-out policy prior to participation in this study (reference number: 2020-06-R-06).

Consent for publication
Not applicable.

Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests.

Funding
None.
Authors' contributions AH initiated the study, analyzed the data, wrote the rst draft of the manuscript, and contributed signi cantly to the nal draft of the manuscript. MS initiated and designed the study, collected data, helped with the rst draft of the manuscript, and contributed signi cantly to the nal draft of the manuscript. HH, SK, SE, and ME initiated and designed the study and collected data. MM collected data, helped with the rst draft of the manuscript, contributed signi cantly to the nal draft of the manuscript, and supervised the study. All authors read and approved the nal manuscript.

Figure 1
Comparison of perioperative data within each group and between the two groups The gray zone shows the reference range for each laboratory value. Signi cant differences in perioperative data in the control group are marked as *P<0.05, **P<0.01, and ***P<0.001. Signi cant differences in perioperative data in the PAI group are marked as †P<0.05, † †P<0.01, and † † †P<0.001. Signi cant differences between the two groups are marked as §P<0.05, § §P<0.01, and § § §P<0.001. PAI: periarticular analgesic injection, WBC: white blood cell count, AST: aspartate transaminase, ALT: alanine aminotransferase, CK: creatine phosphokinase, BUN: blood urea nitrogen, Cr: creatinine, CRP: C-reactive protein, NRS: numeric rating scale