全膝关节置换术后感染的预防和治疗.

1、Infection Following Total Knee Arthroplasty: Prevention and Management全膝关节置换术后感染的预防和治疗Kevin L. Garvin, MD, and Beau S. Konigsberg, MDAn Instructional Course Lecture, American Academy of Orthopaedic SurgeonsPeriprosthetic joint infection is one of the most formidable challenges for arthroplasty surge

2、ons. Physicians and scientists have worked diligently to lower the incidence of infections around prosthetic joints, but the percentage of patients who develop an infection after primary total knee replacement remains in the range of 0.4% to 2%1-3. Medicare data indicate that the rate of periprosthe

3、tic infection within the first two years after knee arthroplasty is 1.55%. The infection rate in the following two to ten years is an additional 0.46%4,5.关节假体周围感染是关节外科医师所面临的最严峻的挑战之一。尽管医生和科学家们一致努力降低关节假体周围感染的发病率，但初次全膝关节置换术后发生感染的患者的比例仍有0.4%-2%。医疗数据显示，关节假体周围感染在膝关节置换术后前2年的发生率为1.55%，而之后的2-10年的发生率增加0.46%。W

4、hile the percentage of prosthetic knees that are associated with infection is low, the numbers will increase with the growing number of total knee replacements. Kurtz et al. projected that the demand for primary knee arthroplasty will grow by 673%, from 450,000 in 2005 to 3.48 million in 20306. If 2

5、% of the 3.48 million patients develop an infection within the first year after the knee arthroplasty, as many as 69,000 patients may be treated for periprosthetic knee infection each year. This group does not include patients who develop an infection more than one year after the surgery or after a

6、revision total knee arthroplasty. The burden and complexity are also increasing because of the number of resistant pathogens.然而与膝关节假体相关的感染的发生率较低，感染的例数随着全膝关节置换的数量增加而增加。Kurtz等曾经预测需要行初次全膝关节置换的病例数将会从2005年的450，000例增加到2030年的348万例，增加673%。如果348万例患者有2%在膝关节置换术后第1年发生感染，每年大约会有69，000例患者会因膝关节假体周围感染而进行治疗。这些还不包括术后1

7、年以后或者膝关节翻修术后发生感染的患者。因为耐药菌的产生，患者的负担和疾病的复杂性也相应增加了。Staphylococcus aureus accounts for the majority of periprosthetic joint infections. Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are especially difficult to treat7-9. The Staphylococcus infections may be acquired in the hospi

8、tal, but some patients are known carriers of Staphylococcus aureus and infect themselves 10,11. Patients who are carriers can be screened and decolonization can be carried out preoperatively, potentially lowering the risk of periprosthetic joint infection.金黄色葡萄球菌感染占关节假体周围感染的大多数。尤其是耐甲氧酸西林金黄色葡萄球菌（MRSA

9、）感染更难治疗。葡萄球菌感染可能是医学获得性感染，但一些患者是金黄色葡萄球菌携带者，为自身感染。病原菌携带者可以进行筛选，并在术前进行治疗，可以降低关节假体周围感染的风险。Prevention预防A variety of interventions can reduce the incidence of infections. Prior to surgery, surgeons should identify and address host factors associated with an increased risk, carry out decolonization when a

10、patient is a bacterial carrier, and use perioperative antibiotics. Prophylactic antibiotics are effective in preventing surgical site infections. The protocol should be to administer the antibiotics one hour before the surgical incision is made. Rosenberg et al. reported that, in a three-month inter

11、val before the initiation of a protocol to ensure compliance with antibiotic dosing, only twenty-six (65%) of forty patients received prophylactic antibiotics within one hour before the incision12. After the protocol was started, the compliance increased to 180 (97%) of 186 patients (p < 0.0001).

12、 The American Academy of Orthopaedic Surgeons (AAOS) has published guidelines for the most appropriate antibiotics13-15. Cefazolin and cefuroxime are preferred, with clindamycin or vancomycin being recommended for patients with beta-lactam allergies. Vancomycin may also be used for patients who are

13、having surgery in an institution where the prevalence of MRSA or MRSE (methicillin-resistant Staphylococcus epidermidis) in the orthopaedic patients is >25%.有多种干预方法能够降低感染的发生率。术前，医生应当确定并解决增加感染的主要危险因素，当患者为病原菌携带者时应当使用抗生素进行抗菌治疗。预防性使用抗生素对预防手术部位感染是有效的，通常在手术开始前1小时给予。Rosenberg等报道指出，在这种方案实施前3个月间，为确认与抗生素剂量

14、一致，40例患者中，仅有26例（65%）在术前1小时预防性使用了抗生素。该治疗方案开始实施后，执行力得到提高，186例患者中有180例（97%）术前预防性使用了抗生素(p < 0.0001)。美国骨科医师学会（AAOS）已经出版了最适用抗生素使用指南，首选头孢唑啉和头孢呋辛，对-内酰胺类过敏者使用克林霉素或万古霉素。万古霉素也可用于骨科患者MRSA或MRSE发病率25%的机构进行手术的患者。Patients colonized with MRSA or so-called carriers of these resistant pathogens are also candidates

15、for treatment with vancomycin. These patients also should receive additional treatment including chlorhexidine gluconate scrubs and nasal mupirocin. The decolonizing protocols have demonstrated the ability to reduce the rate of staphylococcal infections. Studies have also shown that a decolonizing p

16、rotocol is effective in eradicating MRSA colonization of patients8,16-19感染MRSA的患者或所谓的耐药菌携带者也是使用万古霉素治疗的对象，这些患者还应当接受洗必泰擦洗和鼻部喷莫匹罗星等辅助治疗。清除病原菌的治疗方案已经证明能够降低葡萄球菌感染的发生率。研究还表明，这种治疗方案在根除患者体内MRSA方面效果显著。Host Risk Factors主要危险因素Periprosthetic joint infection has been associated with a number of host risk factors

17、, including malnutrition, smoking, alcoholism, urinary tract infection, and obesity (Table I). In a retrospective review that included 6108 patients who had undergone a total of 8494 hip or knee arthroplasties between 1991 and 2004, Malinzak et al. compared those who had developed a deep infection w

18、ith a non-infected control group20. They found forty-three deep infections (thirty associated with total knee arthroplasty and thirteen, with total hip arthroplasty), for a prevalence of 0.51%. Obesity, younger age, and diabetes mellitus were identified as significant risk factors for infection. Mor

19、bidly obese patients (those with a body-mass index BMI of >50 kg/m2) had an increased odds of developing infection (odds ratio, 21.3). In the group treated with total knee arthroplasty, patients who had a BMI of >40 but <50 kg/m2 had 3.3 times greater odds of developing an infection compare

20、d with those with a BMI of <40 kg/m2. The average age of the patients with an infected knee was 62.8 years, and the average age of those without an infected knee was 69.2 years. Patients with diabetes mellitus were 3.1 times more likely to develop a deep infection than were those without diabetes

21、. Additional studies have shown a clinically relevant benefit to maintaining strict glycemic control in diabetic patients in the perioperative period21. Marchant et al. compared a group of patients with well-controlled diabetes with a group with poorly controlled diabetes when they underwent total k

22、nee arthroplasty and found the odds of developing a wound infection to be increased in the group with poorly controlled diabetes (odds ratio, 2.28)21. Bolognesi et al. reviewed the National Inpatient Sample (NIS) records of 751,340 primary and revision hip and knee replacements, including 64,239 in

23、diabetics, and found no increase in infection in the diabetic population22. However, this finding is likely due to the fact that the NIS was not designed to collect data on complications after the initial hospital stay and is not likely to include the great majority of periprosthetic joint infection

24、s.关节假体周围感染与以下主要因素有关：营养不良、抽烟、酗酒、尿路感染及肥胖（表1）。1991年至2004年，6108例患者共进行了8494例次髋关节或膝关节置换，Malinzak等对其进行了回顾并将深感染者和未感染者进行对照研究。结果发现43例深部感染（30例与全膝关节置换有关，13例与全髋关节置换有关），发病率为0.51%。肥胖、年龄较轻及糖尿病为确定的易发生感染的高危因素。病态肥胖的患者（体重指数【BMI】50kg/m2）发生感染的几率明显增加（概率21.3）。行全膝关节置换小组中，40kg/ m2BMI50kg/m2的患者发生感染的几率较BMI 40kg/ m2的患者高约3.3倍。膝关

25、节感染患者的平均年龄为62.8岁，膝关节未感染患者的平均年龄为69.2岁。糖尿病患者发生深部感染的可能性要比非糖尿病患者高出3.1倍。其他的研究证明，对糖尿病患者在围手术期进行严格的血糖控制有益于临床康复。Marchant等对血糖控制较好和较差的患者进行了对比，发现全膝关节置换术后，后者发生伤口感染的几率较前者增加（概率2.28）。Bolognesi等对全国住院患者进行抽样并对其中751,340例初次手术和翻修患者的住院记录进行回顾，其中64,239例为糖尿病患者，结果发现糖尿病患者的感染率并未增加。但是，这一结果可能与NIS没有设计收集初次住院的并发症的数据有关，可能不包括大多数关节假体周围

26、感染。Obesity is also a host risk factor for infection associated with wound-healing complications. Winiarsky et al. compared a group of morbidly obese patients who had had a total of fifty total knee arthroplasties with a control group of non-morbidly obese patients who had had a total of 1768 total k

27、nee arthroplasties23. In the morbidly obese group, there was a 22% rate of wound complications (eleven patients) and five deep infections. In contrast, the control group had a 2% rate of wound complications and a 0.6% rate of deep infections. The nutritional status of obese patients should be evalua

28、ted by obtaining serum albumin and transferrin levels as well as a total lymphocyte count. If their nutritional status is poor (a transferrin level of <200 mg/dL, an albumin level of <3.5 g/dL, or a total lymphocyte count of <1500 cells/mm3), obese patients should be referred to a primary c

29、are provider or nutritionist prior to total knee arthroplasty.肥胖也是感染的主要危险因素，与伤口愈合并发症相关。Winiarsky等对病态性肥胖、共50例全膝关节置换的患者和非病态性肥胖、共1768例全膝关节置换的患者进行了比较，病态肥胖组伤口感染发生率约为22%（11/50），5例发生深部感染。对照组中伤口感染的发生率为2%，深部感染的发生率为0.6%。通过检测血清蛋白、转铁蛋白水平及总淋巴细胞计数对肥胖患者的营养状态进行评估，如果营养状态较差（转铁蛋白200mg/dL，血清蛋白<3.5g/dL或淋巴细胞计数<1500

30、个/mm3)，全膝关节置换术前应当先行基础营养支持治疗。Patients at increased risk for infection because of obesity should be informed of that risk and counseled about ways to reduce it. If a morbidly obese patient has an adequate nutritional status, bariatric surgery may be recommended prior to arthroplasty.对于因肥胖而感染风险增加的患者，应当

31、告知其风险并推荐降低风险的一些方法。如果病态肥胖患者营养状态较好，建议在行全膝关节置换术前行减肥手术。Postoperative wound drainage and wound-healing complications are associated with an increased prevalence of infections. A study comparing seventy-eight patients who had a periprosthetic joint infection with a control population without an infection

32、showed that hematoma formation, wound drainage, and a mean international normalized ratio (INR) of >1.5 had been more prevalent in the group with a periprosthetic joint infection24. Galat et al. reviewed the cases of forty-two patients (forty-two knees) who had had surgical evacuation of a postop

33、erative hematoma within thirty days after a primary total knee arthroplasty25. An additional group of forty-two patients was matched to the group in an attempt to identify risk factors for the development of the hematoma. The two-year probabilities of additional major surgery (component resection, m

34、uscle flap coverage, or amputation) and of developing a deep infection were 12.3% and 10.5%, respectively, in the patients who had surgical evacuation of the hematoma. In the control group, the probabilities for the same complications were 0.6% and 0.8%. A history of a bleeding disorder had a signif

35、icant association with the development of a hematoma requiring surgical evacuation (p = 0.046). Matar et al. reported several additional preoperative, intraoperative, and postoperative factors that are associated with periprosthetic joint infection. These authors provide recommendations for addressi

36、ng factors that may contribute to or increase the risk of infection26.术后伤口引流及伤口愈合过程中的并发症与感染的发生率增加有关。一项对78例发生关节假体周围感染的患者和没有感染的对照组患者的对比研究显示，血肿形成、伤口引流、平均INR1.5在关节假体周围感染组中较为常见。Galat等对初次全膝关节置换术后30天内发生血肿并行血肿清除术的42例患者进行了回顾，另外42例患者为对照组，目的是确定发生血肿的解除因素。血肿清除患者中术后2年需要再行手术和发生深部感染的概率分别是12.3%、10.5%，对照组中，同样的并发症的概率分

37、别是0.6%和0.8%。有出血性疾病病史与术后发生血肿且需要手术清除明显相关(p = 0.046)。Matar等报道了术前、术中、术后与关节假体周围感染相关的一些其它因素，这些学者建议要对可能导致或增加感染的危险因素进行处理。Diagnosis诊断The evaluation of patients suspected of having a periprosthetic joint infection should follow a logical sequence. The AAOS developed a Clinical Practice Guideline to help stand

38、ardize this process (Figs. 1, 2, and 3). The patients history and physical examination should initially raise suspicion that there is an infection. Typically, patients with a periprosthetic joint infection describe almost continuous pain and usually have stiffness or limited knee motion. Fever or ma

39、laise is strongly suggestive of infection, but they are not typical findings. If a draining sinus is present, the joint is considered to be infected until proven otherwise.对可疑关节假体周围感染的患者的评估应遵循逻辑，AAOS提出了“临床实践指南”以使评估程序更标准化（图1,2,3）。根据患者的病史及体格检查，应当首先对是否感染提出疑问。尤其是关节假体周围感染的患者多数表现为膝关节持续性的疼痛，通常伴有关节僵硬或活动受限。发

40、热或全身不适强烈提示感染，但并不典型。如果出现静脉塌陷，只有在其他方面得到确认，才能考虑为关节感染。The next step in the evaluation of patients for whom there is a clinical suspicion of infection is the use of laboratory tests27. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level should be measured whenever a patient is sus

41、pected of having an infection at the site of a total joint arthroplasty. The cutoff for normal and abnormal values for these inflammatory markers was evaluated prospectively in a study of 151 knees in 145 patients who had presented for revision knee surgery27. This study suggest that an ESR of >2

42、2.5 mm/hr (normal, 30 mm/hr) and a CRP level of >13.5 mg/L (normal, 10 mg/L) were reliably suggestive of a periprosthetic joint infection.评估可疑感染的另外一个方法是实验室检查，对可疑全膝关节置换手术部位有感染的患者，均应当检测血沉（ESR）及C-反应蛋白（CRP）水平。在一项对145例曾行膝关节翻修术的患者共151例次膝关节的术前研究中，对炎性标志正常和异常价值标准进行评估。该研究指出对于ESR >22.5 mm/hr，CRP >13.5

43、 mg/L者，则明确提示关节假体周围存在感染。The diagnostic accuracy of the interleukin-6 (IL-6) serum level was evaluated in a prospective study of fifty-eight patients with a periprosthetic joint infection28. IL-6 is produced by stimulated macrophages, but the level returns to normal forty-eight to seventy-two hours af

44、ter a procedure. The authors found that the IL-6 level was a more accurate marker than either the ESR or the CRP level for the detection of periprosthetic infection. A meta-analysis of publications related to the diagnosis of infections around prosthetic joints included thirty eligible studies with

45、data on a total of 3909 hip and knee arthroplasties29. The prevalence of periprosthetic joint infection was 32.5%. The best diagnostic accuracy was provided by the IL-6 level, followed by the CRP level, ESR, and white blood-cell (WBC) count. One of the weaknesses of that meta-analysis was that it in

46、cluded only one large study and two smaller studies measuring the usefulness of the IL-6 level but twenty-five studies evaluating the usefulness of the ESR, twenty-three evaluating the usefulness of the CRP level, and fifteen evaluating the usefulness of the WBC count. The cost of each of these test

47、s was not evaluated.在一项58例关节假体周围感染患者的前瞻性研究中，作者对血清IL-6水平的诊断准确性进行了评估。IL-6由受刺激的巨噬细胞产生，但是术后48-72小时的水平值是正常的。作者认为，在发现假体周围感染方面，IL-6水平值是一个比ESR或CRP更为精确的指标。对诊断为关节假体周围感染有关的文献进行荟萃分析，其中包括30项符合条件的研究，共有3909例次的髋关节和膝关节进行了置换。关节假体周围感染的发生率为32.5%，最准确的诊断条件是IL-6水平，接下来依次是CRP水平、ESR和WBC。荟萃分析的缺点之一是仅有一项大样本和两项小样本研究是针对IL-6水平的作用，

48、25项研究是评估ESR的作用，23项研究是评估CRP的作用，15项研究是评估WBC的作用。这些检测的成本均未进行评估。The next step when suspicion of infection persists is aspiration at the site of the prosthetic joint and analysis of the periprosthetic fluid. The analysis of the aspirated fluid should include a cell count to determine the absolute number o

49、f leukocytes and the percentage of cells that are neutrophils. Somewhere between 1100 and 3000 leukocytes/mL indicates an infection30,31. The percentage of leukocytes that are neutrophils should be at least 60% for the joint to be considered infected32-34. Finally, specimens of the fluid should be c

50、ultured to identify bacteria and their sensitivity to available antibiotics. Gram staining of fluid specimens has a poor sensitivity and a poor predictive value, and the results do not generally alter the patients treatment35.当怀疑存在感染时，另一个方法是对关节假体周围进行穿刺抽液并对假体周围的液体进行分析。对穿刺液进行分析应当包括细胞计数，以确定白细胞的绝对数和中性粒细

51、胞所占百分比。如果某一部位的白细胞计数在1100-3000个/mL之间，则表示有感染。中性粒细胞所占白细胞的百分比至少为60%，则考虑关节感染。最后，应当对穿刺液样本进行培养，以确定细菌类型及对抗生素的敏感性。对穿刺液样本进行革兰氏染色敏感性较差，预测价值不高，结果通常不会改变患者的治疗方案。In the early postoperative period, levels of inflammatory markers and the synovial WBC count may be elevated despite the joint not being infected. Bedair

52、 et al. evaluated the results of knee aspirations performed within six weeks after primary total knee arthroplasties and compared the ESR, CRP level, and WBC count and differential between patients with and those without a postoperative infection36. The CRP level, synovial WBC count, and percentage

53、of polymorphonuclear cells in the differential WBC count were found to be higher in the infected group, but the optimal cutoff for the synovial WBC count as a reliable marker of infection was much higher than the numbers given above. This study showed a synovial WBC count of 27,800 cells/mL in the a

54、spirate from the site of a total knee arthroplasty in the acute postoperative period to be the best predictor of infection. With the use of this cutoff, there was a 94% positive predictive value and a 98% negative predictive value.在术后早期，尽管关节没有感染，但炎性标志水平及滑液中的WBC计数也可能会升高。Bedair等在初次全膝关节置换术后6周对膝关节进行穿刺结果

55、进行分析评估，并对术后感染和未感染患者的ESR、CRP及WBC计数及其差异进行了比较。CRP水平、滑液中WBC计数及多形核细胞在不同白细胞计数中所占百分比在感染组中较高，但是滑液中WBC计数最佳值作为感染的可靠指标比上述所给数值的可靠性均较高。本研究表明，全膝关节置换部位穿刺滑液中WBC计数27,800个/mL，则是术后急性感染的最佳预测指标。利用这一数值，其阳性预测率为94%，阴性预测率为98%。Aerobic, anaerobic, and fungal cultures are performed routinely, whereas molecular testing has the

56、potential for routine use but currently is developmental. The challenges facing orthopaedic surgeons include both false-positive and false-negative cultures. False-positive fluid and tissue cultures are unfortunately common37. If the history, physical findings, levels of inflammatory markers, and ce

57、ll count in the fluid are normal, then it is highly probable that a positive culture is false-positive. The corollary to this dilemma is when the history, physical findings, levels of inflammatory markers, and cell count in the fluid are elevated but the culture is negative. This problem of false-ne

58、gative cultures is also common; it may occur 5% to 10% of the time38. Berbari et al. studied 897 cases of periprosthetic joint infection seen over a ten-year interval. Sixty (7%) of the infections were associated with negative cultures, and in thirty-two (53%) of these sixty cases the patient had re

59、ceived prior antibiotics. Of the sixty infections, thirty-four (57%) were treated with a two-stage implant exchange; twelve (20%), with debridement and component retention; eight (13%), with resection arthroplasty; five (8%), with one-stage exchange; and one (2%), with amputation. Patients were treated with parenteral antibiotics for an average of twenty-eight days, with forty-nine (82%) of them receiving a cephalosporin. The five-year estimate of implant survival without infection was 94% for the patients with a two-stage exchange and 71%