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Risk factors associated with recurrence of extremity osteomyelitis treated with the induced membrane technique
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Risk factors associated with recurrence of extremity osteomyelitis treated with the induced membrane technique Xiaohua Wang, Shulin Wang, Jingshu Fu, Dong Sun, Jie Shen, Zhao Xie∗ National & Regional United Engineering Laboratory of Tissue Engineering, Department of Orthopaedics, First Affiliated Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, PR China
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Article history: Accepted 20 November 2019 Available online xxx Keywords: Osteomyelitis Recurrence of infection Masquelet technique Induced membrane technique Pseudomonas aeruginosa
a b s t r a c t Introduction: Our aim was to observe the efficacy of the induced membrane technique in the treatment of extremity osteomyelitis and to analyse the causes of infection recurrence and its risk factors. Methods: We retrospectively analysed 424 cases of extremity osteomyelitis treated with the induced membrane technique in our department between May 2013 and June 2017. Infection recurrence time, recurrence sites and other relevant information were collected, summarized, and analysed. Results: A total of 424 patients were considered as “cured” of osteomyelitis after the first stage and the induced membrane technique was performed to rebuild the bone defects. After a mean follow-up of 31.6 (16–63) months, 52 patients had recurrence of infection, including 42 tibias and 10 femurs. The recurrence rate was 12.26%. Symptoms were relieved in 16 patients after intravenous antibiotic treatment. In the remaining 36 cases (8.49%), the infection was uncontrolled by intravenous antibiotics and surgical debridement was performed. The recurrence rate of infection of the tibia (16.22%) was higher than that of the femur (8.70%). The recurrence rate of post-traumatic osteomyelitis (14.66%) was significantly higher than that of hematogenous osteomyelitis (2.41%). Patients in whom Pseudomonas aeruginosa was isolated at the first stage had a recurrence rate of 28% (7/25), which was higher than that with the other isolated bacteria. Logistic regression analysis showed that repeated operations (≥3), post-traumatic osteomyelitis, and internal fixation at the first stage were risk factors for recurrence of infection, with odds ratios (ORs) of 2.30, 5.53 and 5.28 respectively. Conclusions: The induced membrane technique is an effective method in the treatment of extremity osteomyelitis, although infection recurs in some cases. Repeated operations, post-traumatic osteomyelitis, and internal fixation at the first stage were risk factors for recurrence of infection. P. aeruginosa isolated at the first stage, tibia osteomyelitis, the presence of sinus, or flaps may also be associated with recurrence of infection. © 2019 Elsevier Ltd. All rights reserved.
Introduction Osteomyelitis is a common complication after bone fracture and can be difficult to treat successfully in trauma surgery [1]. It is one of the most challenging musculoskeletal complications in orthopaedic trauma surgery [2]. Factors associated with uncontrollable infection and a high recurrence rate include bacterial virulence and host autoimmunity [3,4]. Previous research found that the overall cure rate of osteomyelitis was 65.5% to 95% [5–7] and there was a high incidence of disability and other complications.
∗ Corresponding author at: Department of Orthopaedics, First Affiliated Hospital, Third Military Medical University (Army Medical University), Gaotanyan No. 30, Chongqing 40 0 038, China. E-mail address: [email protected] (Z. Xie).
In 20 0 0, Masquelet, et al. [8] reported the use of a two-stage surgical method for the treatment of bone defects, which includes debridement and implantation of polymethyl methacrylate (PMMA) cement in the first stage, followed by grafting to rebuild bone defects after formation of the induced membrane. This two stage method is known as the induced membrane technique and has been widely reported in clinical and basic research [9–13]. However, it is mainly performed in cases requiring reconstruction of large bone defects and has not been widely performed in cases of osteomyelitis due to a lack of systematic analysis. Since 2013, our department has used the induced membrane technique for the treatment of extremity osteomyelitis. We proposed the theory of transform bone infection into “bacterial contamination” by expanding debridement [14], and using an antibiotic cement-coated locking plate as a temporary internal fixator [15] to eliminate infection, followed by implantation of PMMA cement to induce the formation
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Please cite this article as: X. Wang, S. Wang and J. Fu et al., Risk factors associated with recurrence of extremity osteomyelitis treated with the induced membrane technique, Injury, https://doi.org/10.1016/j.injury.2019.11.026
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of a membrane, which promotes osteogenesis after bone grafting, an our early research showed good clinical results [13,16]. In this study, by analysing our cases of infection recurrence in extremity osteomyelitis, our aim in this study was to find the risk factors associated with the recurrence of infection. Patients and methods After receiving approval from our Institutional Review Board, we retrospectively analysed the cases of extremity osteomyelitis treated with the induced membrane technique in our department between May 2013 and June 2017. The inclusion criteria were: extremity osteomyelitis; treatment with induced membrane twostage technique; bone defects remaining after debridement; bone grafting completed; and follow-up time > 16 months. The exclusion criteria were: patients who had no surgical treatment; osteomyelitis of the spine, pelvis, skull, and ribs; patients with incomplete follow-up data; and diabetic foot infection. All patients were treated with the induced membrane technique. At the first stage, the sinus, dead bone, and necrotic tissue were removed to identify the bacteria and examine pathology. Bone defects were filled with antibiotic PMMA cement (5 g vancomycin per 40 g gentamicin-loaded bone cement (Heraeus, Hanau, Germany) was added). After debridement, the bone defects were fixed according to the Cierny-Mader classification. There was no need to fix type I and II osteomyelitis. Temporary fixation with a plate was performed for type III and IV osteomyelitis. A locking compression plate was used for external fixation if the incision was difficult to suture, flap transferred in patients with skin defect and incision could not be sutured directly. Antibiotics, based on the bacteria isolated, were intravenously administered for 2 weeks. No oral antibiotics were administered. If no bacteria were isolated, third-generation cephalosporin (Ceftazidime) was administered every 12 h for two weeks. Negative pressure drainage was applied for 10 to 12 days. The second stage was performed 8 weeks after the start of first stage. The effectiveness of the infection treatment was assessed using the following criteria: 1. no pain, redness or pus at the infection site; 2. a normal erythrocyte sedimentation rate (ESR), and Creactive protein (CRP) and white blood cell (WBC) counts; 3. no suppurative inflammation found in the intraoperative pathological examination of the rapid frozen section. If the above three criteria were simultaneously achieved, we concluded that the infection had been successfully eliminated and bone grafting could be performed. If not, debridement was repeated until infection control was achieved. In the second stage, plate, nail, nail attached with plate, no fixation were performed, intravenous antibiotics for 48 h after the operation, X-ray examinations were performed and WBC, ESR, and CRP counts were checked at 1, 3, 6, 9, 12, 18, and 24 months after grafting. Evidence of infection recurrence We considered the following criteria as evidence of infection recurrence: 1. redness, swelling, pain and other symptoms reappearing at the primary site; and an elevated blood indicator (WBC, CRP, or ESR), excluding infection in other parts of the body; 2. continuous sinus or pus at the primary site.
pus appeared, induced membrane technique treatment or debridement was performed. Statistical analysis Multi-factor logistic regression analysis was used for relevant risk factor analyses. We used a t-test or rank sum test to compare measurement data (age, recurrence time, levels of inflammation markers). We used the Pearson’s chi-square test or Fisher-exact test to compare enumeration data (surgical flaps, infection sites, sinus). P < 0.05 was considered significant. Results A total of 424 patients were enrolled in this study. There were 351 males and 73 females with an average age of 37.9 (4–72) years. The mean duration of infection before enrolment was 31.5 months (1 week to 56 years). The infection sites included 259 tibias, 115 femurs, 10 radii and ulnae, 12 humeri, 7 calcanei, 5 fibulas, 3 metatarsal bones, 11 phalanxes and 2 metacarpals. There was recurrence of infection in 52 patients (12.26%), including 43 males and 9 females, and 42 tibias and 10 femurs. The average recurrence time was 46.08 (2–154) weeks after the second stage of the induced membrane technique. Post intravenous antibiotic administration, 16 patients were asymptomatic for > 12 months. Induced membrane technique treatment and debridement was performed in 36 patients (8.49%) due to uncontrolled infection. In the 36 patients who underwent surgical treatment, there were 9 patients treated with induced membrane technique repeated, and 18 patients implanted with antibiotic bone cement was used as a placeholder, during follow up there was no recurrence of infection for at least 20 months in these two groups. Infection continued in 5 patients who required further treatment, 4 of whom underwent amputation due to uncontrolled infection. Clinical manifestations and laboratory tests Among the 52 patients with infection recurrence, 28 showed local redness and swelling, 16 showed relief of symptoms following intravenous antibiotic treatment without surgery, and surgical treatment was performed in 12 patients due to uncontrolled infection. Five patients showed localized pustule initially, followed by suppuration, and 19 patients showed suppuration initially. All patients with exudate underwent surgical treatment. In patients with infection recurrence, 5 (9.62%) had a body temperature > 38.5 °C, 18 (34.6%) had a serum WBC count > 10 thousands/microL, 37 (71.2%) had a serum CRP level > 8 mg/L, and 39 (75%) had an ESR > 20 mm/hr. All three indicators were positive in 12 (23.08%) patients. Bacteria isolated in patients with infection recurrence Among the 36 patients who underwent surgery, 30 (83.3%) had positive bacteria isolated. Of these, 20 (66.7%) were infected with Staphylococcus aureus (including 6 with methicillin-resistant Staphylococcus aureus (MRSA), 3 with P. aeruginosa, 3 with E. coli, and 2 with Streptococcus dysgalactiae. Only 10 patients (27.8%) had the same bacteria as that identified at the first stage. Analysis of related risk factors
Treatment after recurrence When the patients showed signs of infection recurrence at the primary site, intravenous antibiotics (based on the bacteria isolated at the first stage) were administered until relief of symptoms. If there was no significant improvement within 2 weeks, or sinus or
Logistic regression analysis showed that sex, smoking history, age, duration of infection, and different types of bone grafts were not risk factors for recurrence of infection. Repeated operations, post-traumatic osteomyelitis, and internal fixation at the first stage were risk factors for recurrence, and their OR values were 2.30,
Please cite this article as: X. Wang, S. Wang and J. Fu et al., Risk factors associated with recurrence of extremity osteomyelitis treated with the induced membrane technique, Injury, https://doi.org/10.1016/j.injury.2019.11.026
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X. Wang, S. Wang and J. Fu et al. / Injury xxx (xxxx) xxx Table 1 Risk factors of extremity osteomyelitis with/without recurrent of infection. Variables
Odds Ratio (OR)
P Value
Age Smoking history Infection site Bone graft type Diabetics Sinus Repeated operations(≥3 times) Post-traumatic osteomyelitis Internal fixation at the first stage
0.16 1.04 8.75 1.86 1.32 2.30 5.53 5.28 2.41
0.777 0.936 0.119 0.394 0.544 0.05 0.000 0.033 0.019
5.53 and 5.28 respectively. Detailed analyses of the related risk factors are shown in Table 1.
Factors associated with infection recurrence Among the 424 patients, 81 (19.10%) underwent debridement more than once before the second stage and their infection recurrence rate was 32.10% (26/81), which was higher than that of the patients who had debridement only once (7.58%; P ≤ 0.001). In the 108 patients (44.63%) treated with surgical flaps, the infection recurrence rate was 18.52% (20/108). In patients who were not treated with surgical flaps, the infection recurrence rate was 10.13% (32/316) (P = 0.019). The infection recurrence rate in patients with post-traumatic osteomyelitis was 14.66% (50/341), which was higher than that of patients with hematogenous osteomyelitis (2.41%) (P = 0.001). In patients with post-traumatic osteomyelitis there was no significant difference in the recurrence rate between the open fracture and the closed fracture infections (P = 0.151). The infection recurrence rate of the tibia was higher than that of the femur, 16.22% (42/259) and 8.70% (10/115), respectively (P = 0.034). The average infection recurrence time of the tibia was earlier than that of the femur, 40.26 weeks and 70.5 weeks, respectively (P = 0.017). The recurrence rate in patients with sinus was higher than those without sinus, 15.55% (44/283) and 5.67% (8/141), respectively (P = 0.002). The average number of operations in the recurrence group was 3.31, while in the nonrecurrence group, it was 2.23 (P = 0.001). Systemic immune diseases, such as diabetes, had no significant influence on the treatment outcome (P = 0.180), and the number of bacteria species was not significant for recurrence (P = 0.113). The data are shown in Table 2. Laboratory tests: The average serum WBC count at the first stage in patients with infection recurrence was 6.30 × 109 /L, which was lower than that of the non-recurrence group (8.12 × 109 /L) (P < 0.01), while the WBC positive rate in the non-recurrence group was 20.43% (76/372), which was higher than that in the recurrence group, 9.61% (5/52) (P < 0.05). There was no significant difference in the positive rates of the serum levels of ESR and CRP between the two groups. Fixation methods: The infection recurrence rate in patients with internal fixation at the first stage was 15.65% (41/262), which was higher than that of patients with external fixation and no fixation, correspondingly 7.55%(8/106) and (5.36% (3/56), (P = 0.024). There was no statistical difference in the infection recurrence rate between femurs with internal fixation and those with external fixation (P = 0.463). However, there was a significant difference between tibias with internal fixation and those with external fixation, which were 23.9% (33/138) and 6.90% (6/87), respectively (P = 0.002). There was no significant difference in infection recurrence rate between the fixation methods at the second stage (P = 0.119).
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Bacteria: The infection recurrence rate in patients in whom P. aeruginosa had been isolated at the first stage was 28% (7/25), which was higher than that of S. aureus (including MRSA), which was 10.85% (14/129) (P = 0.031). There was no significant difference in infection recurrence among patients in whom other bacteria had been isolated. Of the 25 patients with P. aeruginosa isolated at the first stage, 19 were sensitive to gentamicin. The recurrence rate of gentamicin-sensitive patients was 15.79% (3/19), while the recurrence rate of gentamicin-resistant patients was 66.67% (4/6) (P = 0.032). Surgical or intravenous antibiotic treatment: Of the 52 patients with infection recurrence, 10 were classified as Cierny-Mader type III, of which 6 (60%) had infection eliminated by intravenous antibiotics. However, of the 42 type IV patients, only 10 (23.81%) had their infection eliminated by intravenous antibiotics, while the remaining 32 needed further surgical debridement (P = 0.026). Of the 52 patients with infection recurrence, 26 required debridement more than once at the first stage, 25 (96.15%) of whom showed no symptom relief after intravenous antibiotics. Of the 26 patients who required only a single debridement, 11 (42.31%) required surgery (P < 0.01). Data are shown in Table 3. Discussion Infection recurrence is one of the most common complications in the treatment of osteomyelitis and the overall cure rate reported in the literature ranges from 65.5% to 95% [5–7,17]. The recurrence of bone infection can be attributed to either relapse or reinfection. Relapse is the reappearance of signs and symptoms of disease plus one or more positive bone cultures for the previously isolated and treated microorganism; Reinfection is the reappearance of the signs and symptoms of the disease plus one or more positive cultures for different microorganisms from those initially isolated and treated [18]. Before bone grafting, we confirmed that the infection had been “cured” according to laboratory tests and intraoperative pathological examination. Of the 424 patients enrolled in the study, 52 had recurrence and the overall cure rate was 87.74%. Among them, 16 were treated with non-surgical treatment and 36 (8.49%) required surgery. The overall cure rate is comparable to previous reports [19], which confirms that the induced membrane technique for the treatment of extremity osteomyelitis is reliable. Our results suggest that repeated operations, post-traumatic osteomyelitis, and internal fixation at the first stage are risk factors for recurrence of infection; thus, more stringent treatments are needed in these cases. It is difficult to achieve minimal inhibitory concentration at the bone infection site with intravenous antibiotics [20–22], therefore thorough debridement is a prerequisite for infection control. As the use of local antibiotics in the treatment of bone infection has become a standard component of osteomyelitis management [23,24], we added vancomycin and gentamicin to the bone cement as they both inhibit gram-positive and gram-negative bacteria. Vancomycin can achieve high antibiotic efficacy without systemic toxicity [25]. Cephalosporins are rarely used because the heat generated by bone cement can destroy the stability the antibiotic, however Yung [26] reported that vancomycin and ceftazidimeloaded bone cement achieved good antibiotic efficacy in cases of infection surrounding a prosthesis. The recurrence of osteomyelitis is due to many factors, such as the host’s state of immunity, the site of infection and the type of bacteria. Our results showed that in patients in whom P. aeruginosa had been isolated at the first stage, the recurrence rate was 28% after bone grafting, which was higher than that of patients infected with other bacteria, including S. aureus and MRSA. The reason why P. aeruginosa infection recurs easily is attributed to three characteristics: First, the P. aeruginosa genome encodes an extensive reper-
Please cite this article as: X. Wang, S. Wang and J. Fu et al., Risk factors associated with recurrence of extremity osteomyelitis treated with the induced membrane technique, Injury, https://doi.org/10.1016/j.injury.2019.11.026
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X. Wang, S. Wang and J. Fu et al. / Injury xxx (xxxx) xxx Table 2 Comparisons between the two cohorts of infection recurrent or not. Events Recurrent No Recurrent Number 52 372 Sex ratio (male/female) 4.78(43/9) 4.78 (308/64) Average age(years) 38.1 (10–65) 37.9 (6–72) Patients with smoking history 36.54%(19/52) 36.56(136/372) Patients with systemic disease 11.54%(6/52) 6.45%(24/372) Average duration of infection(weeks) 194.3(1–2900) 214.5(1–2150) 78.85%(41/52) 59.41%(221/372) Rate of internal fixation at the first stage Patients with sinus 84.62%(44/52) 64.25%(239/372) Infection site (tibia/femur) 42/10 217/105 Types(hematogenous/posttraumatic) 2/50 81/291 Rate of debridement again 50%(26/52) 14.78%(55/372) Average number of operations 3.31±1.62 2.23±1.76 38.46%(20/52) 23.66%(88/372) Patients with flaps Serum levels of preoperative inflammation markers WBC (thousands/microL) 6.30±2.32 8.12±3.49 CRP (mg/L) 12.28±2.30 10.81±1.74 ESR (mm/hr) 21.75±3.12 24.66±1.38 Positive rate of serum levels of preoperative inflammation markers 20.43%(76/372) WBC 9.61% (5/52) CRP 40.38% (21/52) 45.97%(171/372) ESR 36.54%(19/52) 40.32%(150/372)
P Value – >0.05 >0.05 >0.05 >0.05 >0.05 <0.05 <0.01 <0.05 <0.01 <0.01 <0.01 <0.05 <0.01 >0.05 >0.05 <0.05 >0.05 >0.05
WBC: White blood cell; CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate. Table 3 Comparisons of recurrent patients between the two cohorts of surgical or non surgical treatment. Events
Surgical treatment
Number 36 Sex ratio (male/female) 5.0 (30/6) Average age(years) 38.19±2.26 Patients with smoking 41.67%(15/36) Average recurrent time (weeks) 41.47±6.25 Average duration of infection(weeks) 126.39±60.76 Cinery-mader types (III/IV) 4/32 Average number of operations 3.25±0.27 Infection site (tibia/femur) 30/6 Rate of debridement again 69.44%(25/36) Patients with flaps 38.89%(14/36) Serum levels of preoperative inflammation markers WBC (thousands/microL) 6.26±2.39 CRP (mg/L) 10.97±2.23 ESR (mm/hr) 21.6 ± 3.97
No surgical treatment
P Value
16 4.3 (13/3) 37.81±3.12 25%(4/16) 56.44±8.44 114.5 ± 45.33 6/10 3.43±0.42 12/4 6.25%(1/16) 37.5%(6/10)
– >0.05 >0.05 >0.05 <0.05 >0.05 <0.05 >0.05 >0.05 <0.01 >0.05
6.34±2.22 10.44±2.69 21.88±5.88
>0.05 >0.05 >0.05
WBC: White blood cell; CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate.
toire of secreted virulence factors [27]; second, P. aeruginosa infection exhibits a particular predilection for soft tissues. As we tend to focus on bone infection it is easy to ignore the debridement of soft tissue where the remaining bacteria are difficult to eliminate by antibiotic treatment and normal immunity [28]. Third, although we added gentamicin to the bone cement, our results showed that the resistance rate of patients with P. aeruginosa to gentamicin was 24%, and the infection recurrence rate in patients with gentamicinresistance was as high as 66.67%. However, the infection recurrence rate in gentamicin-sensitive cases was only 21.05%. Therefore, it is necessary to pay more attention to cases suspected of advanced P. aeruginosa infection. We found an interesting phenomenon in our study. In cases with higher WBC count or higher WBC positive rate at the first stage, the infection recurrence rate after bone grafting was lower, which may be due to these patients’ immune systems being more sensitive to infection, followed the stimulation of their autoimmunity after the initial infection. The rate of infection elimination is closely related to local soft tissue coverage [1,7]. Chadayammuri [17] stated that patients suffering an adverse postoperative outcome tended to have a higher incidence of free-flap procedures compared to those achieving complete healing. In our study, in the 108 patients (44.63%) who were treated with debridement and surgical flaps, the infection re-
currence rate was 18.52%, which was higher than that of patients who not treated with surgical flaps (10.13%). Honda [29] indicated that the excellent blood supply and good soft tissue coverage of the upper extremity contribute to higher success rates than lower extremity bone infections. Our results showed that the infection recurrence rate of tibia osteomyelitis was 16.22%, which was higher than that of the femur, and the average recurrence time was earlier than that of the femur. The poor blood supply and soft tissue coverage of the tibia may be the reason for the higher recurrence rate. The presence of implants promotes both adherence of microbes and biofilm formation [7,30]. It is recognized that internal fixation should not be used in cases of bone infection. Internal fixation after debridement at the first stage was performed in more than 60% (262 cases) of our patients. There are some key points regarding this. First, the internal fixation should be coated by antibiotic bone cement; second, purulent infection of the tissue around the internal fixation should be eliminated before grafting and debridement should be repeated if necessary; third, the internal fixation must be replaced at the second stage, and most importantly, a thorough debridement is a required prior to internal fixation. Our early research showed that the above precautions can ensure a high level of infection-control when internal fixation is performed, and resulted in only one infection recurrence in 13 femurs
Please cite this article as: X. Wang, S. Wang and J. Fu et al., Risk factors associated with recurrence of extremity osteomyelitis treated with the induced membrane technique, Injury, https://doi.org/10.1016/j.injury.2019.11.026
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[15]. In this study, our results showed that the infection recurrence rate in patients with internal fixation was 15.65% (41/262), which was higher than that of external fixation and no fixation. Further analysis showed that there was no significant difference between the femurs with internal fixation and those with external fixation, but there was a significant difference when the tibias with these fixation methods were assessed. The recurrence rate of tibia osteomyelitis with internal fixation was 23.9%, which may be related to the poor soft tissue coverage and blood supply. Thus we recommend the use of internal fixation for femur osteomyelitis at the first stage, because it can reduce complications and inconvenience caused by external fixation. We suggest it should be exchanged at the second stage, however it should be used cautiously with the tibia due to the high rate of infection recurrence. There are many strengths to this study. It had a large number of patients, it used standard techniques, and many different bones were studied. However, there are several drawbacks. First, this was a retrospective review of a very heterogeneous patient population with many different bone locations for the osteomyelitis, which may affect the results. Second, we only used a single technique to treat osteomyelitis. As such it lacked a comparison with other techniques. Third, we failed to identify whether recurrence of infection was due to relapse or reinfection. Conclusion The induced membrane technique is an effective method in the treatment of extremity osteomyelitis, although infection recurs in some cases. Repeated operations, post-traumatic osteomyelitis, and internal fixation at the first stage are risk factors for recurrence of infection. P. aeruginosa isolated at the first stage, tibia osteomyelitis, the presence of sinus, and the use of surgical flaps, may also be associated with recurrence of infection. Ethical review committee statement The Ethics Committee of the first affiliated hospital of Army Medical University, PLA approved all protocols. Declaration of Competing Interest We declare that none of our authors received employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications, and grants from any institution. There is no conflict of interest with any institution Acknowledgements This work was supported by the General Program of National Natural Foundation of China (81672160) and Key Research and Development Program of China (2016YFC1102005). Reference [1] Parsons B, Strauss E. Surgical management of chronic osteomyelitis. Am J Surg 2004;188(1):57–66. [2] Metsemakersa WJ, Kortramb K, Morgensternc M, Moriartyd TF, Meexa I, Kuehle R, et al. Definition of infection after fracture fixation: a systematic review of randomized controlled trials. Injury 2018;49(3):497–504. [3] Schmidmaier G, Lucke M, Wildemann B, Haas NP, Raschke M. Prophylaxis and treatment of implant-related infections by antibiotic-coated implants: a review. Injury 2006;37(Suppl 2):S105–12. [4] Cierny G, Mader JT, Penninck JJ. A clinical staging system for adult osteomyelitis. Clin Orthop Relat Res 2003(414):7–24.
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[24] Cierny G. Surgical treatment of osteomyelitis. Plast Reconstr Surg 2011;127(Suppl 1):190S–204S. [25] Zalavras CG, Patzakis MJ, Holtom P. Local antibiotic therapy in the treatment of open fractures and osteomyelitis. Clin Orthop Relat Res 2004;427:86–93. [26] Hsu Y-H, C-c H, Hsieh P-H, Shih H-N, Ueng SWN, Chang Y. Vancomycin and ceftazidime in bone cement as a potentially effective treatment for knee periprosthetic joint infection. J Bone Joint Surg 2017;99(3):223–31. [27] Stover CK, Pham XQ, Erwin AL, Mizoguchi SD, Warrener P, Hickey MJ, et al. Complete genome sequence of Pseudomonas aeruginosa PAO1, an opportunistic pathogen. Nature 20 0 0;406(6799):959–64. [28] Crousilles A, Maunders E, Bartlett S, Fan C, Ukor EF, Abdelhamid Y, et al. Which microbial factors really are important in Pseudomonas aeruginosa infections? Future Microbiol 2015;10(11):1825–36. [29] Honda H, McDonald JR. Current recommendations in the management of osteomyelitis of the hand and wrist. 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Risk factors associated with recurrence of extremity osteomyelitis treated with the induced membrane technique Xiaohua Wang, Shulin Wang, Jingshu Fu, Dong Sun, Jie Shen, Zhao Xie∗ National & Regional United Engineering Laboratory of Tissue Engineering, Department of Orthopaedics, First Affiliated Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, PR China
a r t i c l e
i n f o
Article history: Accepted 20 November 2019 Available online xxx Keywords: Osteomyelitis Recurrence of infection Masquelet technique Induced membrane technique Pseudomonas aeruginosa
a b s t r a c t Introduction: Our aim was to observe the efficacy of the induced membrane technique in the treatment of extremity osteomyelitis and to analyse the causes of infection recurrence and its risk factors. Methods: We retrospectively analysed 424 cases of extremity osteomyelitis treated with the induced membrane technique in our department between May 2013 and June 2017. Infection recurrence time, recurrence sites and other relevant information were collected, summarized, and analysed. Results: A total of 424 patients were considered as “cured” of osteomyelitis after the first stage and the induced membrane technique was performed to rebuild the bone defects. After a mean follow-up of 31.6 (16–63) months, 52 patients had recurrence of infection, including 42 tibias and 10 femurs. The recurrence rate was 12.26%. Symptoms were relieved in 16 patients after intravenous antibiotic treatment. In the remaining 36 cases (8.49%), the infection was uncontrolled by intravenous antibiotics and surgical debridement was performed. The recurrence rate of infection of the tibia (16.22%) was higher than that of the femur (8.70%). The recurrence rate of post-traumatic osteomyelitis (14.66%) was significantly higher than that of hematogenous osteomyelitis (2.41%). Patients in whom Pseudomonas aeruginosa was isolated at the first stage had a recurrence rate of 28% (7/25), which was higher than that with the other isolated bacteria. Logistic regression analysis showed that repeated operations (≥3), post-traumatic osteomyelitis, and internal fixation at the first stage were risk factors for recurrence of infection, with odds ratios (ORs) of 2.30, 5.53 and 5.28 respectively. Conclusions: The induced membrane technique is an effective method in the treatment of extremity osteomyelitis, although infection recurs in some cases. Repeated operations, post-traumatic osteomyelitis, and internal fixation at the first stage were risk factors for recurrence of infection. P. aeruginosa isolated at the first stage, tibia osteomyelitis, the presence of sinus, or flaps may also be associated with recurrence of infection. © 2019 Elsevier Ltd. All rights reserved.
Introduction Osteomyelitis is a common complication after bone fracture and can be difficult to treat successfully in trauma surgery [1]. It is one of the most challenging musculoskeletal complications in orthopaedic trauma surgery [2]. Factors associated with uncontrollable infection and a high recurrence rate include bacterial virulence and host autoimmunity [3,4]. Previous research found that the overall cure rate of osteomyelitis was 65.5% to 95% [5–7] and there was a high incidence of disability and other complications.
∗ Corresponding author at: Department of Orthopaedics, First Affiliated Hospital, Third Military Medical University (Army Medical University), Gaotanyan No. 30, Chongqing 40 0 038, China. E-mail address: [email protected] (Z. Xie).
In 20 0 0, Masquelet, et al. [8] reported the use of a two-stage surgical method for the treatment of bone defects, which includes debridement and implantation of polymethyl methacrylate (PMMA) cement in the first stage, followed by grafting to rebuild bone defects after formation of the induced membrane. This two stage method is known as the induced membrane technique and has been widely reported in clinical and basic research [9–13]. However, it is mainly performed in cases requiring reconstruction of large bone defects and has not been widely performed in cases of osteomyelitis due to a lack of systematic analysis. Since 2013, our department has used the induced membrane technique for the treatment of extremity osteomyelitis. We proposed the theory of transform bone infection into “bacterial contamination” by expanding debridement [14], and using an antibiotic cement-coated locking plate as a temporary internal fixator [15] to eliminate infection, followed by implantation of PMMA cement to induce the formation
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of a membrane, which promotes osteogenesis after bone grafting, an our early research showed good clinical results [13,16]. In this study, by analysing our cases of infection recurrence in extremity osteomyelitis, our aim in this study was to find the risk factors associated with the recurrence of infection. Patients and methods After receiving approval from our Institutional Review Board, we retrospectively analysed the cases of extremity osteomyelitis treated with the induced membrane technique in our department between May 2013 and June 2017. The inclusion criteria were: extremity osteomyelitis; treatment with induced membrane twostage technique; bone defects remaining after debridement; bone grafting completed; and follow-up time > 16 months. The exclusion criteria were: patients who had no surgical treatment; osteomyelitis of the spine, pelvis, skull, and ribs; patients with incomplete follow-up data; and diabetic foot infection. All patients were treated with the induced membrane technique. At the first stage, the sinus, dead bone, and necrotic tissue were removed to identify the bacteria and examine pathology. Bone defects were filled with antibiotic PMMA cement (5 g vancomycin per 40 g gentamicin-loaded bone cement (Heraeus, Hanau, Germany) was added). After debridement, the bone defects were fixed according to the Cierny-Mader classification. There was no need to fix type I and II osteomyelitis. Temporary fixation with a plate was performed for type III and IV osteomyelitis. A locking compression plate was used for external fixation if the incision was difficult to suture, flap transferred in patients with skin defect and incision could not be sutured directly. Antibiotics, based on the bacteria isolated, were intravenously administered for 2 weeks. No oral antibiotics were administered. If no bacteria were isolated, third-generation cephalosporin (Ceftazidime) was administered every 12 h for two weeks. Negative pressure drainage was applied for 10 to 12 days. The second stage was performed 8 weeks after the start of first stage. The effectiveness of the infection treatment was assessed using the following criteria: 1. no pain, redness or pus at the infection site; 2. a normal erythrocyte sedimentation rate (ESR), and Creactive protein (CRP) and white blood cell (WBC) counts; 3. no suppurative inflammation found in the intraoperative pathological examination of the rapid frozen section. If the above three criteria were simultaneously achieved, we concluded that the infection had been successfully eliminated and bone grafting could be performed. If not, debridement was repeated until infection control was achieved. In the second stage, plate, nail, nail attached with plate, no fixation were performed, intravenous antibiotics for 48 h after the operation, X-ray examinations were performed and WBC, ESR, and CRP counts were checked at 1, 3, 6, 9, 12, 18, and 24 months after grafting. Evidence of infection recurrence We considered the following criteria as evidence of infection recurrence: 1. redness, swelling, pain and other symptoms reappearing at the primary site; and an elevated blood indicator (WBC, CRP, or ESR), excluding infection in other parts of the body; 2. continuous sinus or pus at the primary site.
pus appeared, induced membrane technique treatment or debridement was performed. Statistical analysis Multi-factor logistic regression analysis was used for relevant risk factor analyses. We used a t-test or rank sum test to compare measurement data (age, recurrence time, levels of inflammation markers). We used the Pearson’s chi-square test or Fisher-exact test to compare enumeration data (surgical flaps, infection sites, sinus). P < 0.05 was considered significant. Results A total of 424 patients were enrolled in this study. There were 351 males and 73 females with an average age of 37.9 (4–72) years. The mean duration of infection before enrolment was 31.5 months (1 week to 56 years). The infection sites included 259 tibias, 115 femurs, 10 radii and ulnae, 12 humeri, 7 calcanei, 5 fibulas, 3 metatarsal bones, 11 phalanxes and 2 metacarpals. There was recurrence of infection in 52 patients (12.26%), including 43 males and 9 females, and 42 tibias and 10 femurs. The average recurrence time was 46.08 (2–154) weeks after the second stage of the induced membrane technique. Post intravenous antibiotic administration, 16 patients were asymptomatic for > 12 months. Induced membrane technique treatment and debridement was performed in 36 patients (8.49%) due to uncontrolled infection. In the 36 patients who underwent surgical treatment, there were 9 patients treated with induced membrane technique repeated, and 18 patients implanted with antibiotic bone cement was used as a placeholder, during follow up there was no recurrence of infection for at least 20 months in these two groups. Infection continued in 5 patients who required further treatment, 4 of whom underwent amputation due to uncontrolled infection. Clinical manifestations and laboratory tests Among the 52 patients with infection recurrence, 28 showed local redness and swelling, 16 showed relief of symptoms following intravenous antibiotic treatment without surgery, and surgical treatment was performed in 12 patients due to uncontrolled infection. Five patients showed localized pustule initially, followed by suppuration, and 19 patients showed suppuration initially. All patients with exudate underwent surgical treatment. In patients with infection recurrence, 5 (9.62%) had a body temperature > 38.5 °C, 18 (34.6%) had a serum WBC count > 10 thousands/microL, 37 (71.2%) had a serum CRP level > 8 mg/L, and 39 (75%) had an ESR > 20 mm/hr. All three indicators were positive in 12 (23.08%) patients. Bacteria isolated in patients with infection recurrence Among the 36 patients who underwent surgery, 30 (83.3%) had positive bacteria isolated. Of these, 20 (66.7%) were infected with Staphylococcus aureus (including 6 with methicillin-resistant Staphylococcus aureus (MRSA), 3 with P. aeruginosa, 3 with E. coli, and 2 with Streptococcus dysgalactiae. Only 10 patients (27.8%) had the same bacteria as that identified at the first stage. Analysis of related risk factors
Treatment after recurrence When the patients showed signs of infection recurrence at the primary site, intravenous antibiotics (based on the bacteria isolated at the first stage) were administered until relief of symptoms. If there was no significant improvement within 2 weeks, or sinus or
Logistic regression analysis showed that sex, smoking history, age, duration of infection, and different types of bone grafts were not risk factors for recurrence of infection. Repeated operations, post-traumatic osteomyelitis, and internal fixation at the first stage were risk factors for recurrence, and their OR values were 2.30,
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X. Wang, S. Wang and J. Fu et al. / Injury xxx (xxxx) xxx Table 1 Risk factors of extremity osteomyelitis with/without recurrent of infection. Variables
Odds Ratio (OR)
P Value
Age Smoking history Infection site Bone graft type Diabetics Sinus Repeated operations(≥3 times) Post-traumatic osteomyelitis Internal fixation at the first stage
0.16 1.04 8.75 1.86 1.32 2.30 5.53 5.28 2.41
0.777 0.936 0.119 0.394 0.544 0.05 0.000 0.033 0.019
5.53 and 5.28 respectively. Detailed analyses of the related risk factors are shown in Table 1.
Factors associated with infection recurrence Among the 424 patients, 81 (19.10%) underwent debridement more than once before the second stage and their infection recurrence rate was 32.10% (26/81), which was higher than that of the patients who had debridement only once (7.58%; P ≤ 0.001). In the 108 patients (44.63%) treated with surgical flaps, the infection recurrence rate was 18.52% (20/108). In patients who were not treated with surgical flaps, the infection recurrence rate was 10.13% (32/316) (P = 0.019). The infection recurrence rate in patients with post-traumatic osteomyelitis was 14.66% (50/341), which was higher than that of patients with hematogenous osteomyelitis (2.41%) (P = 0.001). In patients with post-traumatic osteomyelitis there was no significant difference in the recurrence rate between the open fracture and the closed fracture infections (P = 0.151). The infection recurrence rate of the tibia was higher than that of the femur, 16.22% (42/259) and 8.70% (10/115), respectively (P = 0.034). The average infection recurrence time of the tibia was earlier than that of the femur, 40.26 weeks and 70.5 weeks, respectively (P = 0.017). The recurrence rate in patients with sinus was higher than those without sinus, 15.55% (44/283) and 5.67% (8/141), respectively (P = 0.002). The average number of operations in the recurrence group was 3.31, while in the nonrecurrence group, it was 2.23 (P = 0.001). Systemic immune diseases, such as diabetes, had no significant influence on the treatment outcome (P = 0.180), and the number of bacteria species was not significant for recurrence (P = 0.113). The data are shown in Table 2. Laboratory tests: The average serum WBC count at the first stage in patients with infection recurrence was 6.30 × 109 /L, which was lower than that of the non-recurrence group (8.12 × 109 /L) (P < 0.01), while the WBC positive rate in the non-recurrence group was 20.43% (76/372), which was higher than that in the recurrence group, 9.61% (5/52) (P < 0.05). There was no significant difference in the positive rates of the serum levels of ESR and CRP between the two groups. Fixation methods: The infection recurrence rate in patients with internal fixation at the first stage was 15.65% (41/262), which was higher than that of patients with external fixation and no fixation, correspondingly 7.55%(8/106) and (5.36% (3/56), (P = 0.024). There was no statistical difference in the infection recurrence rate between femurs with internal fixation and those with external fixation (P = 0.463). However, there was a significant difference between tibias with internal fixation and those with external fixation, which were 23.9% (33/138) and 6.90% (6/87), respectively (P = 0.002). There was no significant difference in infection recurrence rate between the fixation methods at the second stage (P = 0.119).
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Bacteria: The infection recurrence rate in patients in whom P. aeruginosa had been isolated at the first stage was 28% (7/25), which was higher than that of S. aureus (including MRSA), which was 10.85% (14/129) (P = 0.031). There was no significant difference in infection recurrence among patients in whom other bacteria had been isolated. Of the 25 patients with P. aeruginosa isolated at the first stage, 19 were sensitive to gentamicin. The recurrence rate of gentamicin-sensitive patients was 15.79% (3/19), while the recurrence rate of gentamicin-resistant patients was 66.67% (4/6) (P = 0.032). Surgical or intravenous antibiotic treatment: Of the 52 patients with infection recurrence, 10 were classified as Cierny-Mader type III, of which 6 (60%) had infection eliminated by intravenous antibiotics. However, of the 42 type IV patients, only 10 (23.81%) had their infection eliminated by intravenous antibiotics, while the remaining 32 needed further surgical debridement (P = 0.026). Of the 52 patients with infection recurrence, 26 required debridement more than once at the first stage, 25 (96.15%) of whom showed no symptom relief after intravenous antibiotics. Of the 26 patients who required only a single debridement, 11 (42.31%) required surgery (P < 0.01). Data are shown in Table 3. Discussion Infection recurrence is one of the most common complications in the treatment of osteomyelitis and the overall cure rate reported in the literature ranges from 65.5% to 95% [5–7,17]. The recurrence of bone infection can be attributed to either relapse or reinfection. Relapse is the reappearance of signs and symptoms of disease plus one or more positive bone cultures for the previously isolated and treated microorganism; Reinfection is the reappearance of the signs and symptoms of the disease plus one or more positive cultures for different microorganisms from those initially isolated and treated [18]. Before bone grafting, we confirmed that the infection had been “cured” according to laboratory tests and intraoperative pathological examination. Of the 424 patients enrolled in the study, 52 had recurrence and the overall cure rate was 87.74%. Among them, 16 were treated with non-surgical treatment and 36 (8.49%) required surgery. The overall cure rate is comparable to previous reports [19], which confirms that the induced membrane technique for the treatment of extremity osteomyelitis is reliable. Our results suggest that repeated operations, post-traumatic osteomyelitis, and internal fixation at the first stage are risk factors for recurrence of infection; thus, more stringent treatments are needed in these cases. It is difficult to achieve minimal inhibitory concentration at the bone infection site with intravenous antibiotics [20–22], therefore thorough debridement is a prerequisite for infection control. As the use of local antibiotics in the treatment of bone infection has become a standard component of osteomyelitis management [23,24], we added vancomycin and gentamicin to the bone cement as they both inhibit gram-positive and gram-negative bacteria. Vancomycin can achieve high antibiotic efficacy without systemic toxicity [25]. Cephalosporins are rarely used because the heat generated by bone cement can destroy the stability the antibiotic, however Yung [26] reported that vancomycin and ceftazidimeloaded bone cement achieved good antibiotic efficacy in cases of infection surrounding a prosthesis. The recurrence of osteomyelitis is due to many factors, such as the host’s state of immunity, the site of infection and the type of bacteria. Our results showed that in patients in whom P. aeruginosa had been isolated at the first stage, the recurrence rate was 28% after bone grafting, which was higher than that of patients infected with other bacteria, including S. aureus and MRSA. The reason why P. aeruginosa infection recurs easily is attributed to three characteristics: First, the P. aeruginosa genome encodes an extensive reper-
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X. Wang, S. Wang and J. Fu et al. / Injury xxx (xxxx) xxx Table 2 Comparisons between the two cohorts of infection recurrent or not. Events Recurrent No Recurrent Number 52 372 Sex ratio (male/female) 4.78(43/9) 4.78 (308/64) Average age(years) 38.1 (10–65) 37.9 (6–72) Patients with smoking history 36.54%(19/52) 36.56(136/372) Patients with systemic disease 11.54%(6/52) 6.45%(24/372) Average duration of infection(weeks) 194.3(1–2900) 214.5(1–2150) 78.85%(41/52) 59.41%(221/372) Rate of internal fixation at the first stage Patients with sinus 84.62%(44/52) 64.25%(239/372) Infection site (tibia/femur) 42/10 217/105 Types(hematogenous/posttraumatic) 2/50 81/291 Rate of debridement again 50%(26/52) 14.78%(55/372) Average number of operations 3.31±1.62 2.23±1.76 38.46%(20/52) 23.66%(88/372) Patients with flaps Serum levels of preoperative inflammation markers WBC (thousands/microL) 6.30±2.32 8.12±3.49 CRP (mg/L) 12.28±2.30 10.81±1.74 ESR (mm/hr) 21.75±3.12 24.66±1.38 Positive rate of serum levels of preoperative inflammation markers 20.43%(76/372) WBC 9.61% (5/52) CRP 40.38% (21/52) 45.97%(171/372) ESR 36.54%(19/52) 40.32%(150/372)
P Value – >0.05 >0.05 >0.05 >0.05 >0.05 <0.05 <0.01 <0.05 <0.01 <0.01 <0.01 <0.05 <0.01 >0.05 >0.05 <0.05 >0.05 >0.05
WBC: White blood cell; CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate. Table 3 Comparisons of recurrent patients between the two cohorts of surgical or non surgical treatment. Events
Surgical treatment
Number 36 Sex ratio (male/female) 5.0 (30/6) Average age(years) 38.19±2.26 Patients with smoking 41.67%(15/36) Average recurrent time (weeks) 41.47±6.25 Average duration of infection(weeks) 126.39±60.76 Cinery-mader types (III/IV) 4/32 Average number of operations 3.25±0.27 Infection site (tibia/femur) 30/6 Rate of debridement again 69.44%(25/36) Patients with flaps 38.89%(14/36) Serum levels of preoperative inflammation markers WBC (thousands/microL) 6.26±2.39 CRP (mg/L) 10.97±2.23 ESR (mm/hr) 21.6 ± 3.97
No surgical treatment
P Value
16 4.3 (13/3) 37.81±3.12 25%(4/16) 56.44±8.44 114.5 ± 45.33 6/10 3.43±0.42 12/4 6.25%(1/16) 37.5%(6/10)
– >0.05 >0.05 >0.05 <0.05 >0.05 <0.05 >0.05 >0.05 <0.01 >0.05
6.34±2.22 10.44±2.69 21.88±5.88
>0.05 >0.05 >0.05
WBC: White blood cell; CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate.
toire of secreted virulence factors [27]; second, P. aeruginosa infection exhibits a particular predilection for soft tissues. As we tend to focus on bone infection it is easy to ignore the debridement of soft tissue where the remaining bacteria are difficult to eliminate by antibiotic treatment and normal immunity [28]. Third, although we added gentamicin to the bone cement, our results showed that the resistance rate of patients with P. aeruginosa to gentamicin was 24%, and the infection recurrence rate in patients with gentamicinresistance was as high as 66.67%. However, the infection recurrence rate in gentamicin-sensitive cases was only 21.05%. Therefore, it is necessary to pay more attention to cases suspected of advanced P. aeruginosa infection. We found an interesting phenomenon in our study. In cases with higher WBC count or higher WBC positive rate at the first stage, the infection recurrence rate after bone grafting was lower, which may be due to these patients’ immune systems being more sensitive to infection, followed the stimulation of their autoimmunity after the initial infection. The rate of infection elimination is closely related to local soft tissue coverage [1,7]. Chadayammuri [17] stated that patients suffering an adverse postoperative outcome tended to have a higher incidence of free-flap procedures compared to those achieving complete healing. In our study, in the 108 patients (44.63%) who were treated with debridement and surgical flaps, the infection re-
currence rate was 18.52%, which was higher than that of patients who not treated with surgical flaps (10.13%). Honda [29] indicated that the excellent blood supply and good soft tissue coverage of the upper extremity contribute to higher success rates than lower extremity bone infections. Our results showed that the infection recurrence rate of tibia osteomyelitis was 16.22%, which was higher than that of the femur, and the average recurrence time was earlier than that of the femur. The poor blood supply and soft tissue coverage of the tibia may be the reason for the higher recurrence rate. The presence of implants promotes both adherence of microbes and biofilm formation [7,30]. It is recognized that internal fixation should not be used in cases of bone infection. Internal fixation after debridement at the first stage was performed in more than 60% (262 cases) of our patients. There are some key points regarding this. First, the internal fixation should be coated by antibiotic bone cement; second, purulent infection of the tissue around the internal fixation should be eliminated before grafting and debridement should be repeated if necessary; third, the internal fixation must be replaced at the second stage, and most importantly, a thorough debridement is a required prior to internal fixation. Our early research showed that the above precautions can ensure a high level of infection-control when internal fixation is performed, and resulted in only one infection recurrence in 13 femurs
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[15]. In this study, our results showed that the infection recurrence rate in patients with internal fixation was 15.65% (41/262), which was higher than that of external fixation and no fixation. Further analysis showed that there was no significant difference between the femurs with internal fixation and those with external fixation, but there was a significant difference when the tibias with these fixation methods were assessed. The recurrence rate of tibia osteomyelitis with internal fixation was 23.9%, which may be related to the poor soft tissue coverage and blood supply. Thus we recommend the use of internal fixation for femur osteomyelitis at the first stage, because it can reduce complications and inconvenience caused by external fixation. We suggest it should be exchanged at the second stage, however it should be used cautiously with the tibia due to the high rate of infection recurrence. There are many strengths to this study. It had a large number of patients, it used standard techniques, and many different bones were studied. However, there are several drawbacks. First, this was a retrospective review of a very heterogeneous patient population with many different bone locations for the osteomyelitis, which may affect the results. Second, we only used a single technique to treat osteomyelitis. As such it lacked a comparison with other techniques. Third, we failed to identify whether recurrence of infection was due to relapse or reinfection. Conclusion The induced membrane technique is an effective method in the treatment of extremity osteomyelitis, although infection recurs in some cases. Repeated operations, post-traumatic osteomyelitis, and internal fixation at the first stage are risk factors for recurrence of infection. P. aeruginosa isolated at the first stage, tibia osteomyelitis, the presence of sinus, and the use of surgical flaps, may also be associated with recurrence of infection. Ethical review committee statement The Ethics Committee of the first affiliated hospital of Army Medical University, PLA approved all protocols. Declaration of Competing Interest We declare that none of our authors received employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications, and grants from any institution. There is no conflict of interest with any institution Acknowledgements This work was supported by the General Program of National Natural Foundation of China (81672160) and Key Research and Development Program of China (2016YFC1102005). Reference [1] Parsons B, Strauss E. Surgical management of chronic osteomyelitis. Am J Surg 2004;188(1):57–66. [2] Metsemakersa WJ, Kortramb K, Morgensternc M, Moriartyd TF, Meexa I, Kuehle R, et al. Definition of infection after fracture fixation: a systematic review of randomized controlled trials. Injury 2018;49(3):497–504. [3] Schmidmaier G, Lucke M, Wildemann B, Haas NP, Raschke M. Prophylaxis and treatment of implant-related infections by antibiotic-coated implants: a review. Injury 2006;37(Suppl 2):S105–12. [4] Cierny G, Mader JT, Penninck JJ. A clinical staging system for adult osteomyelitis. Clin Orthop Relat Res 2003(414):7–24.
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Please cite this article as: X. Wang, S. Wang and J. Fu et al., Risk factors associated with recurrence of extremity osteomyelitis treated with the induced membrane technique, Injury, https://doi.org/10.1016/j.injury.2019.11.026