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Critical review

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For citation purposes: Costa L, Soares D, Aido R, Sousa R. The value of monitoring inflammatory markers after total joint arthroplasty. Hard Tissue 2013 Mar 09;2(2):17

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The value of monitoring inflammatory markers after total joint arthroplasty

L Costa1, D Soares1, R Aido1, R Sousa1*

AbstractIntroductionPeriprosthetic joint infection is a frequent and dreadful complica-tion after total joint arthroplasty. Serological inflammatory markers such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are widely available and easy to use. As such, they are often used as preliminary diagnostic as well as follow-up tools during the course of treatment.

The information they carry is not the same in every clinical scenario, and they should be interpreted ac-cordingly. This review confronts the reader with different doubtful clini-cal situations and then provides the necessary tools to interpret ESR and CRP in each of them: the immediate postoperative period, the chronic painful arthroplasty and between two-staged revision of infected cases. ConclusionSerological inflammatory markers have different diagnostic thresholds in acute and chronic situations. Follow-up measurements during treatment are informative, but complete normaliza-tion is not a mandatory requirement for successful outcome.

IntroductionTotal joint replacement, especially hip and knee, is one of the most suc-cessful surgeries in orthopaedics. The demand for total hip and knee joint arthroplasty is increasing and

is expected to grow even further over the coming decades1. Infection is arguably the most challenging and certainly one of the most frequent complications after joint replace-ment2,3. Despite modern surgical prophylaxis, the incidence of this complication is rising worldwide4,5. It is therefore likely that an increasing number of orthopaedic surgeons and other clinicians will encounter this problem.

Periprosthetic joint infection (PJI) is typically classified according to the timing of symptom development and the mechanism of bacterial con-tamination as acute postoperative, acute delayed (haematogeneous) or chronic. This simple classification scheme greatly influences treatment options. Timely recognition of this grievous complication is crucial as it may make the difference between successful and failed outcome.

Definitive diagnosis is often chal-lenging as a real ‘gold standard’ has yet to be determined6.Currently, it can only be determined after culture results of samples taken during sur-gery. As such, preoperative diagnosis is forced to rely on clinical suspicion as well as on careful scrutiny of labo-ratory and imaging modalities7. In this setting, serological inflamma-tory markers, specifically erythro-cyte sedimentation rate (ESR) and C-reactive protein (CRP), are often used as initial tests even when there is a low suspicion of PJI6. They are also commonly used in monitoring response to therapy since they are inexpensive, non-invasive and widely available tests.

This review confronts the reader with real daily practice doubtful clinical situations and then provides

the necessary tools to interpret ESR and CRP values in three different key periods: the immediate postopera-tive period, diagnosis of a suspect-ed chronic infection and between stages of treatment of an infected total joint arthroplasty. The different thresholds and diagnostic accuracy in each instance will be presented.

DiscussionImmediate postoperative periodClinical caseAn otherwise healthy 73-year-old man underwent right total knee ar-throplasty (TKA) for primary knee osteoarthritis. The first few days after the procedure were uneventful and the patient was discharged on the fifth postoperative day. On discharge, ESR and CRP values were 100 mm/h and 49.2 mg/L respectively. On the 18th postoperative day, the patient presented to the outpatient clinic with scarce serous wound drainage through a small area of macerated-looking skin wound. Blood tests revealed normal leukocytes and el-evated ESR and CRP: 84 mm/h and 6.2 mg/L respectively. The patient was sent home with no antibiot-ics and was seen again a week later. Small and seemingly superficial area of skin necrosis was present, and there was no drainage or obvious in-flammatory signs (Figure 1). ESR was 102 mm/h and CRP was 7.9 mg/L.

Is it normal?ESR is the rate at which red blood cells sediment in 1 h. It is a non-specific haematological test rou-tinely used as an indirect measure of inflammation. CRP is a major acute-phase protein produced by the liver and increases as a response to

* Corresponding author Email: [email protected]

Department of Orthopaedics, Centro Hospitalar do Porto – Hospital de Santo António, Porto, Portugal

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drainage may be normal but, if per-sistent, it is a known risk factor for infection. Maathuis et al.18 proposed a protocol using ESR and CRP as an adjunct to clinical judgement to help dictate the need and timing for debridement in patients with persistent drainage after total joint replacement. Serial measurements of these inflammatory parameters were taken in suspicious circumstances, and only a decrease in ESR and CRP or a decrease in drainage could post-pone or alter the decision to perform open debridement.

The increase in ESR and CRP values guided the decision to perform irri-gation and debridement of the knee joint in the presented clinical case. Intraoperative microbiology samples confirmed a polymicrobial infection by methicillin-sensitive Staphylococ-cus aureus and Enterobacter clocae. Appropriate antibiotic therapy was given after surgery, and 2 years after the surgery, the patient remains free of infection.

Painful ArthroplastyClinical CaseA diabetic 63-year-old woman pre-sented complaining with pain in her right knee. TKA had been performed 16 months earlier. The first few post-operative weeks were uneventful, but a relentless pain had been bothering her ever since. There was no knee stiffness and radiographs showed no significant findings (Figure 2). No fe-ver, sinus tract or inflammatory signs were ever present. Blood tests were performed: ESR was 29 mm/h and CRP was 17.3 mg/L. Subsequently, a knee arthrocentesis was performed and synovial fluid leukocyte count was 33,250/µL (98% neutrophil per-centage). An infection diagnosis was made and a two-stage procedure was recommended.

Is it infected?Preoperative identification of PJI in patients presenting with a pain-ful total joint replacement is often

to normal values occurs approxi-mately by the third week after THA, and it may take up to 2 months after TKA8,12,13.

Understanding this normal pattern after uncomplicated arthroplasty is the key to better using these inflam-matory parameters to our advantage in the diagnosis of early acute PJI. Although recent reports have ques-tioned the real value of irrigation and debridement as a means to achieve eradication of infection under spe-cific circumstances16, it is still widely recommended in acute postoperative infections especially in the first 3–4 weeks after surgery17. This simple procedure entails reopening the joint through the original incision, re-moval of unhealthy tissues, thorough lavage and exchange of modular components, while retaining fixed components.

It is therefore crucial to make an accurate and timely diagnosis to in-crease the chances of success17. Clini-cal circumstances, however, are not always clear-cut. A red and swollen joint or even superficial inflamma-tory signs are not always indicative of infection in the early postopera-tive period. Scarce serous wound

inflammation/ infection and other tissue insults such as surgery. To understand the importance of these markers in the postoperative period, it is essential to know their normal kinetic patterns after uncomplicated arthroplasty.

As one would expect, both these markers rise after surgery. The peak is significantly higher after TKA in comparison with THA because the bone and soft tissue trauma is higher in TKA8,9. Due to the very high inter-individual variations of these values, it is not possible to find a thresh-old that predicts the presence of infection10.

Nonetheless, after the initial peak, these values should steadily decrease after uncomplicated arthroplasty. ESR levels usually peak on the fifth postoperative day and drop close to preoperative levels by the end of the third month after THA and the ninth month after TKA8,11. Some stud-ies show that ESR can take up to 1 year to return to normal12,13. CRP, on the other hand, shows a similar but much quicker pattern. It rises more rapidly, usually peaking on the sec-ond or third day and falls swiftly by the fifth to seventh day11,14,15. Return

Figure 1: Clinical aspect on day 18 after surgery (a) and on day 25 (b).

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The major finding common to all these studies is that the negative pre-dictive value when both ESR and CRP are under the threshold value is over 95%19–23. Positive predictive value however, even when both markers are elevated, is not as impressive. In other words, the inflammatory parameters should serve as an initial screening test. If both are negative, the probability of an infection is very low. If at least one of them is positive, a subsequent confirmatory evaluation should be undertaken6.

Although there is no absolute con-sensus as to the exact cut-off points of both ESR and CRP, there is enough evidence that they are useful screen-ing tests. However, caution should be observed when using ESR and CRP to assert infection. Except in clinically obvious scenarios, such as chronic sinus tract communicating with the joint, a confirmatory test should fol-low when studying a painful total joint with positive ESR and/or CRP. Increasing diagnostic thresholds values to increase specificity should be interpreted with caution to avoid significantly lowering the negative predictive value (i.e. missing infected cases).

Between stages of treatmentClinical caseA 66-year-old man with a history of right total hip arthroplasty for primary osteoarthritis 3 years ago presented with a painful hip and a chronic draining sinus tract commu-nicating with the prosthesis. ESR was 17 mm/h and CRP was 14.8 mg/L. A diagnosis of PJI was made and the two-stage exchange was selected.

First-stage surgery was performed and coagulase-negative Staphylo-cocci grew on several intraoperative samples (Figure 3). After 2 weeks of IV antibiotics, the patient was dis-charged and sent home with oral antibiotics for another 4 weeks. Con-secutive ESR and CRP measurements showed persistent elevation of ESR (Table 1).

classic threshold values, thus provid-ing higher sensitivity and specificity for the diagnosis of PJI. Greidanus et al.20, in a prospective study that evaluated 151 infected total knee arthroplasties, found that optimal thresholds would be ESR > 22.5 mm/h and CRP > 13.5 mg/L. Similar cut-off points for TKA were later found by Piper et al.21 that reached ESR > 19 mm/h and CRP > 14.5 mg/L as optimal values for the diagnosis of infection studying 297 cases.

In the same study21, the authors found that in 221 total hip replace-ments, the optimized cut-off value of CRP was similar to the com-monly used 10 mg/L but found that ESR should be lowered to about 13 mm/h. On the other hand, Ghanem et al.22 studying 479 hip cases found the optimal values to be 31mm/h for ESR and 20.5 mg/L for CRP. Another recent study23 focusing on 77 infect-ed hips found 32.5 mm/h for ESR and 9.76 mg/L for CRP as the best possible thresholds.

difficult. Given their wide availability, ESR and CRP are often used as initial tests even when there is a low suspi-cion of PJI6. It is vital to know how to correctly interpret them.

The cut-off values most common-ly used in the literature as predic-tive of prosthetic joint infection is ESR > 30 mm/h and CRP > 10mg/L. A meta-analysis by Berbari et al.19 shows that ESR sensitivity and speci-ficity is 75% and 70% respectively and CRP has a slightly higher accu-racy, reaching 88% sensitivity and 74% specificity. They also found that the diagnostic odds ratio was higher for TKA than for total hip arthroplas-ty for all markers. The major limita-tion of this analysis is that diagnostic thresholds of each marker were dif-ferent among the studies included (although the vast majority adopted ESR > 30 mm/h and CRP > 10mg/L).

Recently, several studies were un-dertaken using modern statistical tools known as receiver operator curves. The goal is to optimize these

Figure 2: Normal radiographs of a painful right total knee replacement.

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easier and more trustworthy clinical assessment. Favourable ESR and CRP kinetics, especially after antibiotic discontinuation, serve as an adjunct to decision, but complete normaliza-tion is neither essential nor enough to ensure a successful outcome.

The authors believe there is lit-tle role for deferring reimplantation until all serologic markers have nor-malized. In the case presented, good local soft tissue conditions guided the decision to go ahead with second-stage surgery despite persistent el-evation of inflammatory parameters. Two years after surgery, the patient remains painless and infection free.

Other alternativesSeveral other serological markers have been studied in the context of prosthetic joint infection. Procalci-tonin has been studied especially in the diagnosis of infection in the chronic setting. Although it has been shown to have a good specificity (al-beit not higher than CRP), it has a low sensitivity and a negative predic-tive value32. Interleukin-6 is another studied alternative. It has been stud-ied in the diagnosis of chronic infec-tion and showed excellent sensitivity and specificity when a >10 pg/mL cut-off was used33. In the early un-complicated postoperative period, it also shows an increase/decrease pattern much like CRP. The much faster peak and return to normal can hypothetically be advantageous and allow an earlier diagnosis34. As the expected return to normal after uncomplicated arthroplasty is faster, an infection can be hypothetically de-tected by an earlier increase in IL-6 levels than in CRP levels.

While reimplanting a new pros-thesis in a persistently infected site is a concern, overreliance on normalization of these serological markers may lead to an exaggerated and unnecessary time interval be-tween stages, thus increasing patient morbidity. Ghanem et al.30 were the first to address this issue specifically. In their study including 109 infected total knee replacements treated ac-cording to the two-stage protocol, 23 patients (21%) required revi-sion surgery for recurrence of pros-thetic joint infection. There were no significant differences in mean ESR or CRP values (at the time of reim-plantation) or significantly different variations of these parameters (be-tween resection and reimplantation) when comparing both groups. These findings were later confirmed by an independent study group that stud-ied serum ESR and CRP as well as synovial fluid white blood cell count and differential before the second stage31. The authors were unable to identify any single, or combination of, commonly used testing modalities to reliably identify persistent infection following resection TKA for a deep periprosthetic infection. The ESR and CRP were particularly unreliable and frequently abnormal even when the infection had been controlled.

The decision regarding the exact timing for reimplantation remains difficult as it relies for the most part on the subjective clinical judgement of the treating physician. Favour-able local soft tissues, such as correct wound healing and absence of local warmth, are a major factor. In this regard, the knee being a more su-perficial joint than the hip, allows an

When is it safe to do a new prosthesis?Although numerous studies report favourable outcomes after one-stage revision surgery, two-stage surgery has traditionally been considered as the gold standard for management of chronic infections24,25.Two-stage exchange consists of debridement, resection of infected implants with or without placement of a tempo-rary antibiotic-impregnated cement spacer and delayed reimplantation of a new prosthesis after infection is deemed to be eradicated.

Determining the appropriate tim-ing and criteria for reimplantation that result in minimal reinfection rates remains controversial. Most surgeons prefer that ESR and CRP return to normal before proceeding with reim-plantation, but there really is no solid scientific evidence to back it up26,27.Some investigators have proceeded with reimplantation only when knee aspirate cultures were negative for bacterial growth, but the high false-negative rates of culture possibly re-sulting from the prolonged antibiotic treatment raise concerns28,29.

Figure 3: Radiograph of a right hip antibiotic loaded cement spacer.

Table 1 Inflammatory parameter measurements between two-stage revision surgeries

Preoperative Day 2 Day 5 2 weeks 6 weeks* 2 monthsESR (mm/h) 17 - 77 58 32 24CRP (mg/L) 14.8 127.9 73.9 49.7 13.4 11.8*Antibiotic therapy discontinuation at this point.

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17. Osmon DR, Berbari EF, Berendt AR, Lew D, Zimmerli W, Steckelberg JM, et al. Diagnosis and management of pros-thetic joint infection: clinical practice guidelines by the infectious diseases so-ciety of america. Clin Infect Dis. 2013 Jan; 56(1):e1–e25.18. PGM Maathuis BdHSB. Timing of open debridement for suspected infection of joint prosthesis: a report on 551 patients. Curr Orthop Pract. 2009 Sep;20(5): 541–5.19. Berbari E, Mabry T, Tsaras G,Spangehl M, Erwin PJ, Murad MH, et al. Inflammatory blood laboratory levels as markers of prosthetic joint infec-tion: a systematic review and meta-analysis. J Bone Joint Surg Am. 2010 Sep;92(11):2102–9.20. Greidanus NV, Masri BA, Garbuz DS, Wilson SD, McAlinden MG, Xu M, et al. Use of erythrocyte sedimentation rate and C-reactive protein level to diagnose infection before revision total knee ar-throplasty. A prospective evaluation. J Bone Joint Surg Am. 2007 Jul;89(7): 1409–16.21. Piper KE, Fernandez-Sampedro M,Steckelberg KE, Mandrekar JN, Karau MJ, Steckelberg JM, et al. C-reactive protein, erythrocyte sedimentation rate and or-thopedic implant infection. PLoS One. 2010 Feb;5(2):e9358.22. Ghanem E, Antoci V, Jr, Pulido L,Joshi A, Hozack W, Parvizi J. The use of receiver operating characteristics analysis in determining erythrocyte sedimentation rate and C-reactive protein levels in diagnosing peripros-thetic infection prior to revision total hip arthroplasty. Int J Infect Dis. 2009 Nov;13(6):e444–9.23. Costa CR, Johnson AJ, Naziri Q, Maralunda GA, Delanois RE, Mont MA. Efficacy of erythrocyte sedimentation rate and C-reactive protein level in de-termining periprosthetic hip infections. Am J Orthop (Belle Mead NJ). 2012 Apr; 41(4):160–5.24. Beswick AD, Elvers KT, Smith AJ, Goo-berman-Hill R, Lovering A, Blom AW. What is the evidence base to guide surgical treatment of infected hip prostheses? Sys-tematic review of longitudinal studies in unselected patients. BMC Med. 2012 Feb; 10:18.25. Zimmerli W, Trampuz A, Ochsner PE. Prosthetic-joint infections. N Engl J Med. 2004 Oct;351(16):1645–54.

knee arthroplasty in the United States. J Arthroplasty. 2008 Oct;23(7):984–91.6. Della VC, Parvizi J, Bauer TW, Dicesare PE, Evans RP, Segreti J, et al. Diagnosis of periprosthetic joint infections of the hip and knee. J Am Acad Orthop Surg. 2010 Dec; 18(12):760–70.7. Parvizi J, Zmistowski B, Berbari EF,Bauer TW, Springer BD, Della Valle CJ, et al. New definition for periprosthetic joint infection: from the Workgroup of the Musculoskeletal Infection Society. Clin Orthop Relat Res. 2011 Nov;469(11): 2992–4.8. Bilgen O, Atici T, Durak K, Karaemi-nogullari, Bilgen MS. C-reactive protein values and erythrocyte sedimentation rates after total hip and total knee ar-throplasty. J Int Med Res. 2001 Jan; 29(1):7–12.9. Moreschini O, Greggi G, Giordano MC, Nocente M, Margheritini F. Postoperative physiopathological analysis of inflam-matory parameters in patients undergo-ing hip or knee arthroplasty. Int J Tissue React. 2001;23(4):151–4.10. Dupont C, Rodenbach J, FlachaireE. The value of C-reactive protein for postoperative monitoring of lower limb arthroplasty. Ann Readapt Med Phys. 2008 Jun;51(5):348–57.11. Larsson S, Thelander U, Friberg S.C-reactive protein (CRP) levels after elec-tive orthopedic surgery. Clin Orthop Relat Res. 1992 Feb;275:237–42.12. Aalto K, Osterman K, Peltola H, Rasanen J. Changes in erythrocyte sedi-mentation rate and C-reactive protein after total hip arthroplasty. Clin Orthop Relat Res. 1984 Apr;184:118–20.13. Shih LY, Wu JJ, Yang DJ. Erythrocytesedimentation rate and C-reactive protein values in patients with total hip arthro-plasty. Clin Orthop Relat Res. 1987 Dec; 225:238–46.14. Choudhry RR, Rice RP, Triffitt PD, Harper WM, Gregg PJ. Plasma viscosity and C-reactive protein after total hip and knee arthroplasty. J Bone Joint Surg Br. 1992 Jul;74(4):523–4.15. White J, Kelly M, Dunsmuir R. C-reac-tive protein level after total hip and total knee replacement. J Bone Joint Surg Br. 1998 Sep;80(5):909–11.16. Koyonos L, Zmistowski B, Della Valle CJ, Parvizi J. Infection control rate of ir-rigation and debridement for peripros-thetic joint infection. Clin Orthop Relat Res. 2011 Nov;469(11):3043–8.

These alternatives are neither as extensively studied nor as widely available as ESR and CRP. The lat-ter are simple routine laboratory tests performed worldwide that can give precious and due time informa-tion in a variety of clinical scenarios regarding prosthetic joint infections.

ConclusionESR and CRP tests are very useful in the management of musculoskel-etal infections. Nevertheless, the information they provide is not the same in every clinical scenario and they should thus be interpreted ac-cordingly. Diagnostic thresholds are different in the acute and chronic infected prosthetic joints and pos-sibly also different between hip and knee replacements. Follow-up measurements during treatment are somewhat informative, but com-plete normalization is not a man-datory requirement for successful outcome.

Abbreviations listCRP, C-reactive protein; ESR, eryth-rocyte sedimentation rate; PJI, periprosthetic joint infection; TKA, total knee arthroplasty

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