膝关节置换术后的膝盖皮肤温度与血清IL-6，C-反应蛋白，红细胞沉积速率的关系的前瞻性研究
Abstract
Knee osteoarthritis is a common cause of severepain and functional limitation. Total knee arthroplasty is aneffective procedure to relieve pain, restore knee function, andimprove quality of life for patients with end stage kneearthritis. The aim of this study was to investigate theinflammatory process in patients with primary knee osteoar-thritis before surgery and in subsequent periods followingtotal knee arthroplasty. A prospective study of 49 patientsundergoing primary total knee replacements was conducted.The patients were evaluated by monitoring serum interleukin-6 (IL-6), C-reactive protein (CRP), erythrocyte sedimentationrate (ESR), knee skin temperature, and clinical status.Measurements were carried out preoperatively and postoper-atively on day one and at two, six, 14, and 26 weeks duringfollow-up review in the knee clinic. The serum IL-6 and CRPwere elevated on the first postoperative day but fell topreoperative values at twoweekspostoperatively. Both returnedto within the normal range by six weeks postoperatively. Inaddition, the postoperative ESRshowed a slow rise with a peaktwoweeks after surgery and returned to the preoperative level at26 weeks postoperatively. The difference in skin temperaturebetween operated and contralateral knees had a mean value of+4.5°C at two weeks. The mean value decreased to +3.5°C atsix weeks, +2.5°C at 14 weeks, and +1.0°C at 26 weeks. Thedifference in skin temperature decreased gradually and eventu-ally there was no statistically significant difference at 26 weeksafter surgery. A sustained elevation in serum IL-6, CRP, ESR,and skin temperature must raise the concern of early compli-cation and may suggest the development of postoperativecomplication such as haematoma and/or infection.
Introduction
Osteoarthritis (OA) is one of the most common degenera-tive joint diseases that progressively results in loss of jointfunction and can lead to substantial morbidity and disabilityin the elderly [1]. Knee osteoarthritis is the leading cause ofsevere pain and functional limitation. Total knee arthro-plasty (TKA) is an effective procedure to relieve pain,restore knee function, and improve quality of life forpatients with end stage knee arthritis.
C-reactive protein (CRP) and erythrocyte sedimentationrate (ESR) are very useful routine laboratory screening tests for diagnosis of potential infection. ESR is a nonspecifichaematological test routinely used as an indirect parameter ofincreased acute phase reactants. CRP is a major acute phasereactant that is produced by the liver in response to inflam-mation, infection, malignancy, and tissue damage [2, 3]. Thesynthesis of CRP is rapidly upregulated, primarily in hepato-cytes, under the control of the proinflammatory cytokines.
Interleukin-6 (IL-6) is produced substantially by mono-cytes and macrophages after antigen activation, eventhough other cells (such as fibroblasts, endothelial cells,and T-lymphocytes) may also synthesise it [4]. Surgery mayinstantly mediate IL-6 release by these cells, or IL-6 releasemay be activated by other locally released cytokines.Synthesis of IL-6 in fibroblasts can be upregulated by bothIL-1 and tumour necrosis factor (TNF)-α[5]. However,levels of TNF-α,IL-1β, and IL-8 are often very low fordetection. TNF-αand IL-1βare most difficult to measurein the systemic circulation even in severely infected patients[6]. Furthermore, IL-6 is principally responsible foractivating the hepatic synthesis of CRP, which has beenconsidered the inflammatory biomarker of choice inorthopaedic surgery [7, 8].
The objective of this study was to investigate theinflammatory process in patients with primary kneeosteoarthritis before surgery and in subsequent periodsfollowing total knee replacement. This study was designedto evaluate the serial changes of serum IL-6, CRP, ESR,knee skin temperature, and clinical status after uncompli-cated TKA. In addition, we investigated whether there weredifferences in temporal values of IL-6, CRP, and ESR andfurther determined the relationships of these parameterswith knee skin temperature post TKA.
Patients and methods
Patients
This study was approved by the Institutional Review Boardon Human Research of the Faculty of Medicine, Chula-longkorn University and was conducted in compliance withthe guidelines of the Declaration of Helsinki. Writteninformed consent was obtained from the patients prior totheir participation in the study.
Forty-nine patients, aged 50–78 years, diagnosed withprimary knee osteoarthritis (40 females and nine males;mean age 67.8±1.1 years) were recruited in this prospectivestudy over a 26-week period. We excluded any patients withinflammatory arthritis, a systemic inflammatory or autoim-mune disorder, or a history of any type of cancer or chronicillness. All patients underwent total knee arthroplasty at ourinstitute from September 2007 to August 2008 and wereoperated upon by one surgeon (AT) using the standardsurgical technique. The routine anaesthesiamethodwas spinalblock and when spinal anaesthesia was ineffective, generalanaesthesia was administered. In each case the standardparapatellar approach was used with a tourniquet. Femoral,tibial and patellar components were NexGen (Zimmer,Warsaw, Indiana, USA) using polymethylmethacrylate ce-ment Palacos R containing gentamycin (Heraeus MedicalGmbH, Germany). Awound drain with vacuum suction wasused and was removed on the first day after surgery. Allpatients were mobilised on the second operative day.
The skin temperature of both knees was evaluatedpostoperatively at two, six, 14, and 26 weeks duringfollow-up review in the knee clinic. The temperature wasdetermined using digital pocket surface thermometers atfour different locations on the anterior aspect of the knee(superomedial, superolateral, inferomedial, and inferolateralborder of the patella). The mean of the two readings wastaken as the final temperature. A similar measurement wasalso carried out on the contralateral knee, which served asthe control. Assessment taken at midday was selected as thetime for taking readings for the rest of the study. For eachpatient, the same thermometer was used throughout thecourse of the study.
Laboratory methods
Venous blood samples were obtained before surgery, and onthe first postoperative day and at two, six, 14, and 26-weeksfollow-up. The blood samples were centrifuged to removecells and debris, and stored at?80°C until analysis. C-reactive protein was measured using the latex particleenhanced nephelometric immune assay on the BN ProSpecanalyser (Dade Behring, Germany) and was expressed inmilligrams per decilitre (mg/dl). Erythrocyte sedimenta-tion rate was determined using the Westergren method.The concentrations of IL-6 in serum were performed bycommercially available human IL-6 enzyme-linked im-munosorbent assay (ELISA) MAX sets (Biolegend, SanDiego, CA) according to the manufacturer’s instructions.Concisely, 96-well microtiter plates were precoated withmonoclonal antibody supplied in the kit, and a blockingsolution was added to eliminate nonspecific antigenbinding. After washing, the wells were incubated witheither serum or known concentration standards ofrecombinant human IL-6 at room temperature. Afterplate washing, a biotin-labelled detection antibody wasadded. Following incubation and washing, an avidin-horseradish peroxidase enzyme and color substrate wasapplied for the detection of binding. Lastly, the reactionwas stopped with the stop solution, and then absorbancewas measured at 450 nm using an automated microplatereader. Recombinant human IL-6 was used to develop astandard curve.
Statistical analysis
Statistical analysis was performed using the StatisticalPackage for Social Sciences software, version 16.0 forWindows (SPSS Inc., Chicago, IL, USA). All values wereexpressed as mean± standard deviation (SD). Comparisonsbetween groups were employed using Student’s t-test andMann-WhitneyU-test. A P-value<0.05 was considered toindicate statistical significance.
Results
There were no complications within the study period or onfurther follow-up. Patients who developed complicationsfollowing knee replacement were excluded from the study.The values of serum IL-6, CRP, and ESR are shown inTable1. Serum IL-6 concentration elevated rapidly andpeaked 24 hours postoperatively at maximum levels (184.5±53.5 pg/ml). In addition, the CRP levels increased andreached maximum levels (85.0±21.7 mg/dl) within the firstpostoperative day in all patients. Both serum IL-6 and CRPfell to preoperative values at two weeks and returned towithin the normal range by six weeks postoperatively.Comparison of these two inflammatory markers demon-strates a statistically significant difference during the first 24postoperative hours (P<0.0001).
In comparison, the postoperative ESR showed a slowrise with a peak two weeks after surgery (58.0 ±28.3 mm/hr) and returned to the preoperative level at 26 weekspostoperatively. The temporal patterns of mean levels of IL-6, CRP, and ESR before and after surgery were demon-stratedinFig. 1. The difference in skin temperaturebetween operated and contralateral knees had a mean valueof +4.5°C at two weeks (Fig.2). The mean value decreasedto +3.5°C at six weeks, +2.5°C at 14 weeks, and +1.0°C at26 weeks. The difference in skin temperature decreasedgradually and eventually there was no statistically signifi-cant difference at 26 weeks after surgery (P>0.05) (Fig.2).
Discussion
Infection following joint arthroplasty is a major concern forsurgeons and other medical practitioners. Nonspecificclinical presentation makes it difficult to distinguish from those indicating infection. Objective data are needed toexclude the possibility of infection despite suspiciousclinical symptoms and signs. CRP and ESR have beenextensively used to examine the presence of infectionfollowing surgery. IL-6 appears to be a major endogenousprotein mediator of fever and the acute phase response aftersurgery [5]. IL-6 also plays a crucial role in the inductionand regulation of the acute phase protein response,particularly that of CRP synthesis by hepatocytes [9].Elevated CRP, ESR, and skin temperature can raise concernthat infection may be present following TKA [10]. It isimperative therefore to investigate the temporal patterns ofIL-6, CRP, ESR, and knee skin temperature after uncom-plicated TKA.
Our results have demonstrated that there is a significantrise in IL-6 and CRP. In comparison, ESR differs in thetemporal pattern of postoperative level after TKA. ESR hadslower temporal changes and lower amplitude changes.These findings are in accordance with those of previousstudies reporting the postoperative levels of IL-6, CRP, andESR after total joint replacement [11, 12]. Serum IL-6 andCRP correlate with a high degree of inflammatory activitywith a more rapid increase and a faster return to normalvalues than ESR, suggesting that IL-6 and/or CRP measure-ments could be more favourable than ESR measurements indetermining the presence of infection during the earlypostoperative period. Moreover, previous studies haveindicated that IL-6 may be a better indicator of postoper-ative inflammatory response [13–15]. IL-6 levels reach themaximum level in the first six to 12 hours followingsurgery and fall back to their baseline range by 48 to 72hours postoperatively [13, 16, 17]. CRP levels peak two tothree days after surgery and return to normal valuesapproximately three weeks postoperatively [18–20].
This study has also shown that the skin temperature ofthe operated knee is significantly raised following surgeryand gradually decreased by 26 weeks postoperatively. Thistemperature difference is presumably attributed to thepostoperative inflammatory response in the operated knee.In agreement with our findings, Mehra et al. havedemonstrated that skin temperature of the operated kneeincreases in the early postoperative period but returns tonormal at 18 weeks postoperatively [21]. Haidar et al. havealso shown a decrease in the mean difference between theoperated and contralateral knee over time [22].
Significant postoperative elevations in IL-6, CRP, ESR,and knee skin temperature should be a normal response tosurgical trauma and not an indication of complications.Measurements of these parameters, including at least onepreoperative measurement, are required when the clinicalsignificance of the postoperative values of these parametersis indicated. If postoperative values of these parameterscontinue to be elevated for several days with respect to thepreoperative value, or even show a tendency to rise, furtherinvestigation for this must be carefully evaluated.
It should be noted, however, that we are aware of someinherent limitations. Firstly, we did not collect blood speci-mens during the early postoperative period when CRP andESR are elevated. This made it difficult to determine preciselywhen peak CRP and ESR was achieved. No blood samplingwas collected between the first and 14th postoperative days,whichmade it impossible to tell the exact timewhenCRP and/or ESR reach the maximum level. Secondly, our study wasbased on a relatively small number of enrolled patients. Afurther investigation with a larger number of subjects wouldbe needed to make a strong conclusion. Finally, the resultsderived from our study cannot necessarily be extrapolated inmen because of female predominance of subjects with kneeOA.
In conclusion, this study demonstrates the temporalpatterns of serum IL-6, CRP, ESR, and knee skintemperature in osteoarthritis patients undergoing TKA.The use of serum IL-6 in conjunction with CRP and ESRwas suggested to verify infection following surgery. Asustained elevation in serum IL-6, CRP, ESR, and skintemperature must raise the concern of early complicationand may suggest the development of postoperative compli-cation such as haematoma and/or infection.
Acknowledgements This investigation was supported by the Ratch-adapiseksompotch Fund, Faculty of Medicine, Chulalongkorn Uni-versity, Thailand Research Fund, and the National Research Councilof Thailand. We are grateful to Chulalongkorn Medical ResearchCenter (ChulaMRC) for kindly providing facilities.
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