Oral prednisolone administration in postoperative period improves results of TKA in patient with severe range of motion limitation – a paired outcome study

Background. One of the most common problems related to total knee arthroplasty (TKA) is postoperatively limited range of motion, especially in the most dicult cases. The aim of the study was to assess the inuence of oral use of prednisolone in the postoperative period on the nal results in a patient after TKA with severely limited postoperative range of motion. Methods. Thirty-two patients (32 knees) with a mean age of 61.2 years were selected from our prospectively-collected data base with severe knee range of motion limitation (rheumatoid arthritis, psoriasis, ankylosing spondylitis, posttraumatic and postoperative osteoarthritis). Prednisolone was administrated in two doses per day (1 mg per kg of body mass) and then the dose was slowly reduced for no more than three months. Results. The prednisolone group demonstrated signicantly better results one year after the operation than the non-prednisolone group in terms of range of motion (mean extension 0.5˚ and 3.0˚; p=0.02, mean exion 100.1˚ and 88˚; p= 0.01), WOMAC (mean 85.0 and 76.8 points; p=0.02) and KSS clinical score (mean 86.9 and 81.7; p=0.001) and KSS functional score (79.3 and 71.0 points; p=0.01). No signicant differences were observed between the groups in terms of postoperative systemic and surgical site complications; therefore, no complications could be dened as steroid related.


Background
Total knee arthroplasty (TKA) is an effective procedure for the treatment of osteoarthritis. While satisfactory results can be expected in most standard cases 1 , worse absolute outcomes are often observed for cases characterized by more advanced pathology, including primary or secondary osteoarthritis (OA), e.g. posttraumatic or rheumatoid arthritis, or in patients following previous failed orthopedic procedures. 2 Compromised results are most commonly observed for cases of limitation of knee motion. 2 Such limitation of preoperative range of motion (ROM) and severe deformity may cause postoperative recurrence of stiffness, limited postoperative ROM and reduced functional and clinical outcomes after TKA. 3 Jung et al. in their study examined the effect of two postoperative metyloprednisolone treatments on rabbits who had undergone partial synovectomy of the knee (Depo-Medrol, P zer, Brussels, Belgium). The histological examination showed inhibition of the development of in ammatory in ltration, which presented as an absence of cellular reactions (giant cells and mononuclear cells) in the synovium and brous membrane. No changes in the articular cartilage were observed. 4 Another study found general steroid therapy to have a very bene cial in uence on postoperative knee joint mobility in rabbits after partial synovectomy compared to a control group. 5 Those histological studies are in agreement with clinical observations, that a perioperative, intravenous single steroid injection or perioperative, periarticular single-dose injection are effective in improvement of postoperative outcomes without major complications. 6-12 This information, the fact that knee stiffness related to arthro brosis decreases patient satisfaction, and that manipulation under anesthesia not always achieved satisfactory results, led us to investigate the potential of postoperative oral administration of prednisolone. 13 No similar studies were found in the available literature examining the in uence of steroid therapy on the functional results of TKA. Prednisolone treatment looked promising, and appeared to merit introduction in everyday orthopedic practice; hence, we decided to include the procedure for TKA patients demonstrating the most severe degree of knee pathology, resulting in limited range of motion. It was hypothesized that oral administration of prednisolone could improve postoperative range of motion and thus positively in uence the nal result without causing signi cant steroid-related complications.
The aim of the study was to assess the in uence of oral prednisolone use in the postoperative period on the nal results in patients after TKA characterized by severe limitations in preoperative range of motion.

Methods
The patents included in the study were selected from a prospectively-collected database of patients treated for TKA in the years 2008 to 2017 in the department specializing in hip and knee arthroplasties.
Beginning in 2014, it was decided to include oral prednisolone in treating the cases characterized by the most severe limitation of motion. It was believed that this modi cation may improve the range of motion and nal result of arthroplasty. The inclusion criteria for the examined group were as follows: (1) primary or secondary knee osteoarthritis with severe ROM limitation before TKA -no more than 80° of the range of motion and 10° of knee exion contracture, (2) administration of oral prednisolone twice a day after TKA, (3) informed consent for participation in the study. Patients who had experienced previous septic arthritis, revision TKA, allergy to prednisolone, other contraindications to taking prednisolone (severe osteoporosis, uncontrolled diabetes mellitus, active gastrointestinal ulcers, diverticulitis), lost to follow-up and those who did not agree to participate in the study, were excluded.
Thirty eight consecutive patents underwent TKA and were treated with prednisolone postoperatively.
Among them two patients did not agreed to participate in the study, and four were lost to follow-up. After the exclusion process, 32 patients (32 knees) were included in the study (prednisolone group). The mean age was 61.2 years (range from 33 to 82, median 63.8) and the mean BMI was 28.6 kg/m 2 (range from 22.19 to 45.26, median 29.28). The demographic and clinical data are presented in Table 1.
Prednisolone (Encorton, Polfa S.A., Pabianice, Poland) was administrated in two doses per day, with the 12h interval, the rst in the morning at 7 am., and the second in the afternoon at 7 pm. (1 mg per kg of body mass, maximum dose 90mg per day) from the rst postoperative day (total dose from 55mg to 90mg). Sudden steroid withdrawal may cause severe side effects (e.g. joint pain, nausea, vomiting, low blood pressure, muscle pain). To avoid these complications, the dose reduction by 2.5-5mg decrements (once from the morning dose and once from the afternoon dose) every 3-7 days until a dose taken by the patient was reached should be applied. The dose was reduced to zero, or to the dose prescribed to patients before the operation (rheumatoid patients). The duration of treatment took no more than three months.
Patients from the study group were matched with patients who did not receive prednisolone administration and were operated before 2014 (control group, non-prednisolone group). The patients were matched in terms of gender, etiology (primary, postoperative, RA OA), range of motion before operation +/-10˚ (but no more than 80° of the range of motion and 10° of knee exion contracture), type of deformity (varus, valgus or neutral) and age +/-two years.
Pre-operative planning was performed in every case with the use of Orthoview orthopedic digital preoperative planning software. The software allowed an assessment of whether limb axis correction could be performed only by bone cuts. The surgeon assessed the possibility of soft tissue balancing, deformation severity, quality of posterior capsule and collateral ligaments. The age, weight and activity level of the patients were also taken into consideration when choosing the type of implant. Most of the patients in the analyzed cohort required standard condylar implants, with or without a stem. Older, obese and inactive patients were more likely to receive stemmed condylar or semi-constrained knee implants; however, the nal decision was made intraoperatively with regard to knee stability and bone quality. If a full release of the medial collateral ligament was necessary, or severe joint destruction with insu cient collateral ligaments was noted that made joint balancing impossible, a constrained rotating-hinge implant was chosen. Additional reconstruction materials (augments and cones) were used for bone loss management. Information regarding the type of used implant and etiology are presented in Table 2.
All operations were performed by one surgeon, the senior author of the study, with the use of tourniquet through the whole procedure. The mid-line incision and medial para-patellar approach was used for varus and neutral knees, and a lateral approach was used for valgus knees. For severe contractures, extensive exposures including quadriceps snip and/or tibial tubercule osteotomy were performed. No patient underwent metalwork removal during TKA. In all cases, proper patella tracking, full extension and knee exion were checked by the end of surgery.
For patients who underwent multiple procedures on the operated limb, restorable bone graft substitutes with antibiotic beads (Hera ll beads G, Heraeus Medical, Wehrheim, Germany) were inserted to medullary canals as an antibacterial prophylaxis. Allografts were not implanted, but BoneSave (Stryker, USA) bone substitute was needed in one case.
Radiological analysis was used to assess the quality of xation of the components according to the Knee Society Roentgenographic Evaluation and Scoring System. 14

Results
Both groups (prednisolone and none-prednisolone) were matched, so were comparable in terms of age, gender, type of pathology and deformity ( No complications were found that could be de ned as steroid related (including hyperglycemia, and gastrointestinal bleeding). The period of analyzed drug administration was relatively short, so no systemic complications were reported by any of the patients. Radiographs performed at the one-year follow-up showed no signs of loosening. There were no steroid septic complications in either the study or control group (Table 3). One patient from the prednisolone group had PJI, most probably related to steroid injections given in a previous orthopedic center, and he did not agree for another operation. Also, one patient from the non-prednisolone controls developed PJI and required two-stage revision TKA. All patients with wound healing problems demonstrated portable negative pressure wound therapy and all but one were treated successfully. The remaining patient required additional surgical intervention and skin ap transfer.

Discussion
Page 6/12 The use of steroids in patients undergoing total knee and hip arthroplasties has been extensively described in the literature. A perioperative, systemic single steroid injection has been shown to be effective in the reduction of postoperative pain, postoperative opioid consumption, hospital stay, reduction of postoperative vomiting and nausea. 10−12 Some authors report that a perioperative, periarticular single-dose injection can improve short-term functional recovery and clinical parameters, resulting in better outcomes without any increase in perioperative complications. 13−16 However, these studies examine short-term administration of steroids and the short-term effects observed during a hospital stay. In contrast, our present study examines the results of postoperative oral prednisolone administration in patients, one year after TKA. Oral application was prescribed depending on the patient weight and continued for up to three months in all cases, regardless of the range of motion limitation. In this case, the main aim of prednisolone administration was not to reduce the postoperative side effects of anesthesia, but gain better functional results and motion: secondary to persistent pain and loss of function, knee stiffness related to joint arthro brosis following primary TKA can lead to unsatisfactory patient outcomes. This may require intensive rehabilitation, manipulation under anesthesia (MUA) or even revision knee arthroplasty. 6 No similar studies were found by us in the present literature.
Our results indicate that patients who received prednisolone as postoperative therapy gained better outcomes than the controls, as indicated by WOMAC, clinical and functional KSS and ROM scores. This improvement may be associated with the analgesic effect known to be provided by glucocorticoids, which acts by inhibiting peripheral phospholipase; this effect will reduce anxiety and allow better rehabilitation. In addition, steroids have also been found to have anti-in ammatory effects. 4,5,10−12 In properly performed TKA postoperative joint contracture is related to the development of intra-articular adhesions, created on the basis of a hematoma, and related to an excessive brosis within the articular capsule. 4 Glucocorticoids prevent broblast migration, as well as their growth and development; they are also known to inhibit the synthesis of collagen. It is possible that glucocorticoids such as prednisolone may act through in uencing broblast activity, as well as collagen production or degradation, judging from periarticular and intra-articular adhesions, excessive broplasia of the cicatrix. 4 Interest has recently grown in the perioperative systemic use of steroids in patients undergoing total knee and hip replacement, with a number of well-designed studies, systematic reviews and metanalyses being published. 6,11,17 However it is di cult to make comparisons between studies due to the variation in the doses and types of steroids used, as well as the timing of administration. A meta-analysis of randomized trials by Yue et al. con rmed that steroid injections offer positive bene ts in terms of lower incidence of postoperative nausea and vomiting, as well as reduction of acute postoperative pain, hospital stay, without signi cant complications or adverse events. They also note an improvement in early functional rehabilitation and in ammation control. The examined studies focused on perioperative systemic administration of steroids with the aim of shortening recovery time in total knee and hip arthroplasty; medications were given before the operation with one or two doses possibly being given every eight hours following the operation. 11,12,17 Lower levels of IL-6 have been found within 24 hours following the operation 18 , and lower CRP concentrations have been recorded in steroid groups in the 24 hours following THA. 12 In addition, lower IL-6 levels have were also observed 12 hours after operation. 19 Perioperative systemic steroid administration is associated with reduction of pain shortly after operation, with the effects being well de ned within the rst 24 hours, following which, the differences disappear. 12,19 Another metanalysis of three studies con rmed lower opioid consumption within 48 hours of the operation following steroid administration. 11 Metanalyses comparing steroid and non-steroid groups clearly show a low risk of complications such as super cial or deep infection, delayed wound healing, ONFH, venous thromboembolic events and pruritus, and that this risk is similar in both groups. 11,17 It would be interesting to investigate whether steroid administration could improve the rehabilitation process. Some studies have shown that, similar to pain reduction, administration also has a positive effect on very early functional outcomes: the effects are seen mostly within the rst postoperative days, before discharge from the hospital 10,12 , however, no signi cant difference can be seen between steroid and non-steroid groups at six weeks and one year following the procedure. 20 Hence it appears to be logical to prolong steroid administration to gain better rehabilitation results, as con rmed by our research.
Steroids can also be administered through periarticular steroid injections; these can be supplemented with local anesthetics and epinephrine to reduce post-operative pain and in ammation. This route of administration also improves short-term functional recovery and clinical parameters, resulting in better outcomes for patients without being associated with steroid-related complications. 16 The short term, local pain-relieving effect of this kind of multimodal cocktail has been con rmed by other authors 13,15 , for example, a metanalysis by Cui et al. con rms that steroid injection in TKA/THA provides short-term advantages in pain relief and antiemetic effects. 14 There are some limitations of the study. The rst is that it uses a relatively small group of patients; however, the study is focused on very speci c rare cases characterized by severe, advanced osteoarthritis which is primary, secondary or related to autoimmunological diseases. Also, as the material was collected in a center specializing in hip and knee surgery, it would be di cult to collect a larger sample. The second limitation is related to heterogeneity of the prednisolone group: knee pathology comprises a broad spectrum etiologies and deformities that require the use of implants with an adequate level of constraints. The effect of this heterogeneity was reduced as much as possible by matching individual patients from the study group with similar ones from the control group with regard to gender, etiology, range of motion before operation and type of deformity. The third limitation of the study is variety of implant used, what was dependent on bone defects and ligamentous stability. Finally, the fourth limitation is related to the fact that patients from both groups were operated in different time periods: prednisolone treatments began in 2014, and the patients from control group were treated before this period; hence, this can be regarded as a historical group.