Two-Stage Total Knee Arthroplasty in the Treatment of Advanced Knee Septic Arthritis: Case Series

PURPOSE: Septic arthritis (SA) is dened as the joint inammation secondary to bacterial infection with a potentially fatal condition, but with no established approach treatment currently. Two-stage primary total knee arthroplasty (TKA) with an antibiotic-laden cement spacer has been reported to apply to treat SA of knee effectively in individual cases. We reported our cases aimed to contribute to current information on two-stage TKA in the treatment of advanced SA in knee joint. Methods: We retrospectively screened clinical proles of eleven patients with SA in knee joint who had two-stage TKA with an antibiotic-laden cement spacer. Information of inammatory serological markers were summarized and statistic comparisons were done on Hospital for Special Surgery (HSS) score as well as the degree of the range of motion (ROM) between pre-, interval- and post-operation, with signicant level of p<0.05. Results: Infection in knee joint was eliminated in all eleven patients by two-stage TKA with an antibiotic-laden cement spacer. CRP took 3.4 ± 1.4 weeks (range, 1-6 weeks) to return to normal level, whilst for ESR was 16.3 ± 3.0 weeks (range, 13-23 weeks). Means of HSS score and ROM degree were signicantly increased after both the rst and second-stage surgery (p<0.05). HSS score of three timings were not different in age, gender, micro-organism culture results and comorbidities in our study. Conclusions: Two-stage TKA is an effective treatment in SA in knee joint in controlling infection, relieving clinical severity and improving function of keen joint thereafter. uid by joint puncture. Primary therapy of SA includes the surgical intervention such as arthroscopic or open irrigation and debridement, concerted with effective antibiotics utilization. Arthroscopic surgery has been reported to play effective roles in SA treatment 6 , whilst open irrigation and debridement is usually considered for the patients of chronic infectious arthritis or persistent infection after arthroscopic surgery 4,7,8 . However, there are still cases that could not recover satisfactorily after such primary treatment, and eventually developed into non-salvageable destructive arthritis 3 . Some prospective pilot studies were proposed and suggested that implementing interventional articulate cement spacer in the problematic joint then perform the TKA resulted more effectiveness in control of infection and improvement of functional outcomes 3,9−11 . Previous studies were mostly case reports 3,11−13 , and evidences regarding the therapy aspect was limited. Therefore, this study aims to contribute to existing literature and provide insights into this important topic for future research. pain post-operative complications (including hematoma, seroma, blood transfusion, deep venous thrombosis, and revision surgeries). The repeated measurement of Hospital for Special Surgery Knee (HSS) score among pre-operation (i.e., before the rst-stage TKA surgery), interval period (i.e., after rst-stage and before the second stage TKA surgery), and post-operation (i.e., the latest follow-up) were compared using analysis of variance (ANOVA) and Post-hoc test of multiple group comparison. To determine the effect of a two-stage operation, the degree of pre-, interval- and post- knee range of motion (ROM) were compared using paired t-tests. Two-tailed independent t-test was applied to the comparisons between groups of age (i.e., before or after middle age, following PubMed age ltration of 65 years old), gender, micro-organism culture result (i.e., staphylococcus or negative) and comorbidities (i.e., have or not have). Data were reported in mean ± standard deviation (SD). All statistical analyses were performed using SPSS software version 19.0 (SPSS Inc., Chicago, IL). The level of signicance was set at p < 0.05.


Introduction
Septic arthritis (SA) is an emergency condition of joint infection and 40-50% of the adult patients were affected in the knee [1][2][3] . Patients of SA were always misdiagnosed of rheumatic disease and resulted to inadequate treatment 4 , which leads to irreversible joint destruction and even case-fatality (i.e., 3-29%) 5 .
Therefore, it is indeed important to diagnose this condition early and give effective treatment immediately 1 . The standard diagnosis of SA is based on detection of bacteria in synovial uid by joint puncture. Primary therapy of SA includes the surgical intervention such as arthroscopic or open irrigation and debridement, concerted with effective antibiotics utilization. Arthroscopic surgery has been reported to play effective roles in SA treatment 6 , whilst open irrigation and debridement is usually considered for the patients of chronic infectious arthritis or persistent infection after arthroscopic surgery 4,7,8 . However, there are still cases that could not recover satisfactorily after such primary treatment, and eventually developed into non-salvageable destructive arthritis 3 .
Some prospective pilot studies were proposed and suggested that implementing interventional articulate cement spacer in the problematic joint then perform the TKA resulted more effectiveness in control of infection and improvement of functional outcomes 3,9−11 .
Previous studies were mostly case reports 3,11−13 , and evidences regarding the therapy aspect was limited. Therefore, this study aims to contribute to existing literature and provide insights into this important topic for future research.

Participants
We retrospectively collected and investigated eleven eligible patients attending the Department of Orthopedic of Second Hospital of Lanzhou University in China from January 2014 to December 2020. This protocol was approved by the Medical Ethical Committee of the Second Hospital of Lanzhou University (Supplement), and informed written consent was obtained from participant/guardian. All the patients were diagnosed of SA 14,15 and treated by a two-stage arthroplasty for advanced knee SA consecutively (Fig. 1). All the surgeries were conducted by one surgical team. Deep infection was documented in all eleven cases at the time of initial debridement. We applied no age or gender limitation. All patients had their follow-up at our institution.

Surgical technique and perioperative care
First stage In the rst stage, a conventional medline knee skin incision is performed, followed by exposure of the joint via the parapatellar medial approach and complete removal of the synovial membrane, as well as infected and necrotic tissue. An intra-operative frozen section and bacterial cultivation of synovium and joint uid were taken to con rm the diagnosis and guide the choice of susceptible antibiotic, three biopsies were taken during rst-stage procedure for postoperative pathological examination (Fig. 2). Bone cutting was performed in preparation for primary TKA according to the size of the spacer, and all cuts vancomycin (8 gram). The cement was mixed without vacuum using a "poor mixing technique" to improve antibiotic elution 16 . The antibiotic-loaded bone cement was poured into the spacer block mold at liquid stage, which was shaped as the prosthesis and taken out at the curing period. The antibiotic spacer was then applied to the bone surfaces using a poor bonding technique, which allows some blood to get between the spacer and the bone and for some motion to occur in the knee prior to cement hardening, to facilitate later removal. The femoral spacer block was inserted rst and then an appropriate tibial spacer block adjusted by the extension gap was inserted so that the limb was aligned and tissue tension was slight relax for better postoperative range of motion ( Fig. 4). After numerous irrigations the soft tissues were closed with the use of a suction drain for less than 48 hours.

Second stage
Total knee arthroplasty was performed at least 12 weeks later when laboratory in ammation markers had normalized and there was no further clinical evidence of infection (reddened and hyperthermic joint, drainage from the wound, unreasonable knee pain), intraoperative selection cemented posterior stabilized prosthesis (Smith & Nephew® Primary Total Knee System, GENESIS II) was implanted patella replacement was not performed (Fig. 5).

Antibiotic treatment and perioperative care
After the rst-stage surgery, a two-week intravenous anti-biotherapy was administered according to bacterial culture, and sensitive results whereas vancomycin was used for those without culture and sensitive results. Oral antibiotics (rifampicin + [optimal antibiotics/levo oxacin]) were continued for six weeks until two successive C-reactive protein (CRP) results were normal and erythrocyte sedimentation rate (ESR) results were below twice the value of the high threshold or had a continuous downtrend with no positive signs and symptoms. The CRP and ESR were followed every three days in the rst two weeks and every two weeks thereafter.
During the second stage surgery, we applied vancomycin 1gram prophylaxis in the implantation of primary TKA surgical procedures 17 , and postoperatively vancomycin was continued until wounds were dry. Then treatment was changed to oral rifampicin and levo oxacin for another 24 weeks 18 . Professional rehabilitation and functional training were undertaken by rehabilitation physiatrists in our hospital after stages, and all patients were followed up every three months in the rst year, and once per year after.

Statistical analysis
Patient's les were screened by two authors for residual pain post-operative complications (including hematoma, seroma, blood transfusion, deep venous thrombosis, and revision surgeries). The repeated measurement of Hospital for Special Surgery Knee (HSS) score among pre-operation (i.e., before the rststage TKA surgery), interval period (i.e., after rst-stage and before the second stage TKA surgery), and post-operation (i.e., the latest follow-up) were compared using analysis of variance (ANOVA) and Post-hoc test of multiple group comparison. To determine the effect of a two-stage operation, the degree of pre-, interval-and post-knee range of motion (ROM) were compared using paired t-tests. Two-tailed independent t-test was applied to the comparisons between groups of age (i.e., before or after middle age, following PubMed age ltration of 65 years old), gender, micro-organism culture result (i.e., staphylococcus or negative) and comorbidities (i.e., have or not have). Data were reported in mean ± standard deviation (SD). All statistical analyses were performed using SPSS software version 19.0 (SPSS Inc., Chicago, IL). The level of signi cance was set at p < 0.05.

Results
Eleven patients of six males and ve females were reported in this case-series ( had invasive treatment such as knee injection (KI) (i.e., in 4/11), arthroscopic debridement (AB) (i.e., in 6/11) and open debridement (OB) (i.e., in 7/11) previously. Four patients had comorbidities might compromise immunity: one patient was diabetic, two patients were hypertensive and another had both.

Discussion
The treatment principle of knee SA to date includes surgical treatment and appropriate antibiotics 19 . However, the effect of the above treatments on advanced infectious arthritis is very poor, yet there is no established guidelines for such conditions, especially in the demanding adults. Though limited therapeutic options, there were several researches put effects on applying two-stage approach to primary TKA and tried to improve the e ciency 2,3,11,20 . In our study, demands in eliminating infection, relieving symptoms and returning function were ful lled, Also, we reported similar experience and endings as previous studies, though with small sample size. Therefore, two-stage TKA could be treated as a potential option in sever knee SA management.
Patients enrolled to this study were all diagnosed of knee SA, which ful lled the criteria of badly damaged knee joint, exfoliated cartilage and failure in controlling infection by arthroscopy and open debridement. We referred the operation mode from B Hochreiter et al. 11 . Regarding the femoral cutting, we applied the simple extramedullary guiding method in rst stage, which achieved the therapeutic outcomes of decreasing risk of surgery-related infection spreading and better function recovery. Previous study reported 21 that valgus angles in 30-51% of patients who received TKA were ranged beyond the Valgus Cut Angle (i.e., 5 to 7 degrees), which un tted to intramedullary guide tools, and such un ttness resulted the malalignment of knee after TKA. Thus, in the rststage, we applied the simple extramedullary guiding method in cutting distal femur to all eleven patients, which was equivalent to individualized valgus, and the alignment of all eleven patients were approprate. In addition, extramedullary guiding method could reduce the spread of infection and decrease the risk of bleeding and fat embolism. Further more, this extramedullary guiding method does not need C-arm uoroscopy for femoral head during operation which could reduce radiation injury of patient.
CRP of all eleven patients were returned to normal level within six weeks after the rst stage, though ESR decreasing slower. Previous studies suggested that spacer surface bio lm formation due to long interval period would casue infection recurrence. Our patients were suggested to receive the second-stage surgery within three months, whereas ful ll the criteria that ≥ 2 times CRP test results in normal range, ESR hal y decreased and no infected symptoms such as joint redness, fever, wound drainage and unreasonable knee pain.
Infection were eliminated in all eleven patients, and their knee joint function also returned to the level for supporting daily activities. However, patient 3 and 6 did not fully follow our advice on functional exercise after the rst stage, which resulted rigid knee joint surrounded by scar tissues. Thus, we had to perform the tibial tubercle osteotomy to expose the joint clearly and help to nish the operation in the second-stage surgery. Nevertheless, they had smaller ROM than other patients after surgery. We emphasized and strengthened functional exercise to them, including knee exion and extension, lower limb muscle strength exercise and partial-weight bearing exercise, which accelerated their recovery in post-operation. In corresponding to our results, the knee joint function (i.e., HSS score) would signi cantly increase after both two stages. Therefore the function exercise should be insisted across the whole process especially within one month after each operation, which do affects the effect of this surgery.
Previous studies on age and gender mainly focused on patients with osteoarthritis undergoing primary TKA, which reported that patients received primary TKA of female were averagely postponeed three years later than male and had lower Knee Function scores than men preoperatively and postoperatively 22 . Such ngings demonstrated that earlier initiation of treatment may enhance postoperative outcomes in women. Another study 23 revealed that female gender, younger age and worse preoperative pain predict greater risk of moderate-severe pain postoperatively in patients with primary and revision TKA. However, the information on such factors in ucing the functional outcomes of two-stage TKA of knee SA is indeed scant. We did the comparisons on age, gender, microorganism culture result and comorbidities but failed to identify difference. Otherwise, previous studies had only focused on elderly patients and we performed two-stage TKA in two young patient (i.e., 22,31 years old) whose knee joint were with serious damaging, cartilage denudation and exion deformity.
Arthroscopic and open debridement failed to control his advanced infection. Eventually we had to perform two-stage TKA to save him from joint arthrodesis. However, further studies of randomized controlled trial and appreciate sample size are expected.
However, just like many previous studies 2,11,20,24 , our study has some limitations. First of all, our study was a retrospective study with a limited number of patients, the reason is that advanced knee arthritis combined with severe knee joint disability is not common but is di cult to treat. Second, we had no control group.Though small sample size, our study provided valuable information to this rare clinical challenge. We could conclude that the two-stage TKA with antibiotic-laden cement spacer should be considered as a potential option in the treatment of non-salvageable knee SA, as well as the application of extramedullary guiding method.
Conclusion: Two-stage TKA with extramedullary guiding method is an effective treatment in SA in knee joint in controlling infection, relieving clinical severity and improving function of keen joint thereafter. The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate
The protocol for this study was approved by the Scienti c Ethics Committee