Giovanni Balato 1*, Maria Rizzo 1, Tiziana Ascione 2, Francesco Smeraglia 1 and Massimo Mariconda 1

Transcription

1 Balato et al. BMC Musculoskeletal Disorders (2018) 19:361 RESEARCH ARTICLE Ope Access Re-ifectio rates ad cliical outcomes followig arthrodesis with itramedullary ad exteral fixator for ifected kee prosthesis: a systematic review ad metaaalysis. Giovai Balato 1*, Maria Rizzo 1, Tiziaa Ascioe 2, Fracesco Smeraglia 1 ad Massimo Maricoda 1 Abstract Backgroud: Kee arthrodesis with itramedullary (IM) or exteral fixator (EF) is the most reliable therapeutic optio to achieve defiitive ifectio cotrol i patiets with septic failure of total kee arthroplasty (TKA). The first aim of this study was to compare re-ifectio rates followig kee arthrodesis for periprosthetic joit ifectio (PJI) with IM or EF. The secod aim was to compare rates of radiographic uio, complicatio, ad re-operatio as well as cliical outcomes. Methods: A systematic search was performed i electroic databases for logitudial studies of PJIs (miimum te patiets; miimum follow-up = 1 year) treated by kee arthrodesis with IM or EF. Studies were also required to report the rate of re-ifectio as a outcome measure. Eligible studies were meta-aalyzed usig radom-effect models. Results: The rate (95% cofidece itervals) of re-ifectio was 10.6% (95% CI 7.3 to 14.0) i IM arthrodesis studies. The correspodig re-ifectio rate for EF was 5.4% (95% CI 1.7 to 9.1). This differece was sigificat (p = 0.009). The use of IM resulted i more advatages tha EF for frequecy of major complicatios ad limb shorteig. Other postoperative cliical ad radiographic outcomes were similar for both surgical strategies. Coclusios: The available evidece from the aggregate published data suggests that kee arthrodesis with EF i the specific cotext of PJI has a reduced risk of re-ifectio i compariso with the IM strategy. The use of IM is more effective for the complicatio rate ad shorteig of the affected limb. Keywords: Periprosthetic joit ifectio, Itramedullary, Exteral fixator, Kee arthrodesis, Kee arthroplasty, Reifectio Backgroud Periprosthetic joit ifectio (PJI) is oe of the most serious complicatios of total kee arthroplasty (TKA). Twostage revisio is cosidered as the most effective surgical techique for treatig chroic PJI of the kee [1], but the oe-stage revisio has bee recetly gaiig popularity [2]. These revisio strategies have a re-ifectio rate of * Correspodece: giovaibalato@gmail.com 1 Departmet of Public Health, Sectio of Orthopaedic Surgery, Federico II Uiversity, Via S. Pasii 5, Buildig 12, Naples, Italy Full list of author iformatio is available at the ed of the article 8.8% ad 7.6%, respectively [1]. Risk factors for the developmet of recurret ifectio after revisio surgery iclude isolatio of difficult micro-orgaisms [3, 4], comorbidities [3], ad previous surgeries [4]. Oce ay measures to salvage a fuctioal TKA through multiple revisio procedures have bee exhausted, kee arthrodesis or the above-kee amputatio represet the oly optios to eradicate the ifectio. Amputatio should oly be performed i coditios of severe ad irreversible damage of the boe ad soft-tissues [2, 5] because of its usatisfactory fuctioal results [6, 7]. Coversely, kee arthrodesis The Author(s) Ope Access This article is distributed uder the terms of the Creative Commos Attributio 4.0 Iteratioal Licese ( which permits urestricted use, distributio, ad reproductio i ay medium, provided you give appropriate credit to the origial author(s) ad the source, provide a lik to the Creative Commos licese, ad idicate if chages were made. The Creative Commos Public Domai Dedicatio waiver ( applies to the data made available i this article, uless otherwise stated.

2 Balato et al. BMC Musculoskeletal Disorders (2018) 19:361 Page 2 of 10 ca provide acceptable quality of life ad fuctioality of the kee whe there is sufficiet residual boe stock [8]. Curretly, the exteral fixator (EF) ad itramedullary (IM) represet preferred methods to achieve kee arthrodesis i the cotext of septic failure of TKA [9]. Published results of these two surgical strategies have bee variable [9 13]. Ideally, to compare EF ad IM for kee arthrodesis would require evidece from carefully desiged radomized cliical trials that are ulikely to occur give the low PJI evet rates recorded after TKA [1]. The lack of robust evidece from radomized cliical trials results i ucertaity o the effectiveess of these surgical optios. Hece, there is a eed for further work to compare these strategies for arthrodesis. Usig a meta-aalytic approach, our first aim was precisely to evaluate the effectiveess of IM ad EF kee arthrodesis adoptig re-ifectio rate as the primary edpoit. Other relevat outcomes icludig the rate of radiographic uio, complicatio, ad re-operatio as well as the postoperative limb legth discrepacy (LLD), pai, ad fuctioal status were also ivestigated. Moreover, we aimed to compare ad describe the differeces i these outcomes betwee the two surgical optios. Methods Data sources ad search strategy We searched for studies ivestigatig differet outcomes followig kee arthrodesis performed with IM ad/or EF i MEDLINE, Scopus, EMBASE, Web of Sciece, ad Cochrae databases from iceptio up to September The Preferred Reportig Items for Systematic Review ad Meta-Aalyses (PRISMA) [14] methodology guidace was employed. The search strategy used a combiatio of the followig key words: Kee arthroplasty OR Kee replacemet OR Kee prosthesis AND Ifectio OR Septic AND Nail OR Fixator AND Arthrodesis OR Fusio. No laguage restrictios were employed. The referece lists of selected articles were also examied for ay additioal articles ot idetified from the database search. Eligibility criteria We icluded logitudial studies comprisig of cosecutive uselected patiets affected by PJI who were treated by kee arthrodesis usig a IM or EF. We excluded: (i) studies that reported o these surgical methods i selected group of patiets (such as patiets with a specific ifectio or sigle preoperative diagosis); (ii) studies with less tha 1 year of miimum follow-up; (iii) studies with less tha 10 participats; ad (iiii) studies icludig patiets with kee arthrodesis for causes of TKA failure differet from ifectio where the outcome i septic patiets could otbespecificallyassessed. Study assessmet ad data extractio Iitial screeig of titles ad abstracts was performed by two pairs of idepedet reviewers (GB ad MR, FS ad TA). Full text was obtaied for all abstracts that appeared to meet the iclusio criteria or where there was ay ucertaity. Each article was assessed by two idepedet reviewers (GB, FS) usig the iclusio criteria ad ay discrepacies regardig the eligibility of a article were solved with a third author (MM). Thereafter, relevat data were extracted from each icluded study. Two authors (MR, TA) performed quality assessmet of eligible articles usig the Methodological Idex for No-Radomized Studies (MINORS) criteria [15]. MINORS is a valid istrumet desiged to assess the methodological quality of o-radomized surgical studies. It yields a maximum score of 16 ad 24, respectively, for o-comparative ad comparative studies. Statistical aalysis The rate of re-ifectio (i.e. umber of re-ifectios at follow-up/total umber of participats) with 95% cofidece iterval (CI) represeted the primary outcome. Secodary outcomes were the rate of radiographic uio, surgical complicatio, ad re-operatio as well as several cliical fidigs recorded at follow-up icludig the quality of life (SF-36 or SF-12 Questioaire), fuctioality of kee (Oxford Kee score, Kee Society score etc.), severity of pai (Visual aalog scale), ad LLD. Subgroup aalysis was udertake, based o the effect of differet types of IM ad EF o differet outcomes (re-ifectio rate, fusio rate, ad time to fusio). Two broad types of IM (i.e. log ad short) were idetified. For EF arthrodesis, the subgroup aalysis compared the effect of uilateral vs biplaar/circular ad pis vs wires EF. Heterogeeity betwee studies was tested usig the I 2 statistic (0% to 40% = ot relevat; 30% to 60% = moderate; 50% to 90% = substatial; 75% to 100% = cosiderable) [14]. The primary ad secodary outcomes were pooled usig radom effects models to accout for the effect of betwee-study heterogeeity. Due to the usuitability of poolig data for LLD, kee fuctioal scales, the pai severity, ad quality of life questioaires, these outcomes were assessed usig a compariso of meas. A two-sample t test ad chi-square test were used to test the sigificace of cross-sectioal differeces betwee the IM ad EF kee arthrodesis ad betwee differet subgroups of surgical implat. We utilized Ope Meta Aalyst (Ceter for Evidece Sythesis, RI, USA) ad SPSS versio 23 (SPSS, Chicago, IL, USA) for all statistical aalyses. P 0.05 was cosidered sigificat.

3 Balato et al. BMC Musculoskeletal Disorders (2018) 19:361 Page 3 of 10 Results The flow diagram of our search strategy is reported i Fig. 1. The computer search ad maual screeig of referece lists of relevat studies idetified 803 potetially relevat citatios. After iitial screeig based of titles ad abstracts, 74 articles remaied for full text evaluatio. After detailed assessmet, we excluded 48 refereces. The remaiig 26 articles [5, 10, 12, 13, 16 37] were icluded i the meta-aalysis. Two of these [10, 22] wereretrospective studies comparig outcomes of ad EF arthrodesis. Hece, data from 18 ad 10 studies were used for the assessmet of surgical results of kee arthrodesis with IM ad EF, respectively (Table 1). Re-ifectio Studies reportig o re-ifectio outcome after IM arthrodesis icluded 422 participats with 66 re-ifectios at follow-up. The pooled radom-effects re-ifectio rate was 13.3% (95% CI 8.7 to 17.8, p < 0.001). There was moderate heterogeeity betwee the cotributig studies (I 2 = 54%; p = 0.004). O the exclusio of oe sigle outlier study [12], the pooled re-ifectio rate decreased to 10.6% (95% CI 7.3 to 14.0, p < 0.001) ad the heterogeeity was ot sigificat (Fig. 2). There was evidece of publicatio bias (Egger s p = 0.006). Te studies icludig 152 participats reported the re-ifectio rate i patiets who had udergoe EF arthrodesis. There were 15 re-ifectios ad the correspodig pooled re-ifectio rate was 7.2% (95% CI 2.3 to 12.1, p = 0.004). The heterogeeity betwee studies (I 2 = 41%; p = 0.086) was lower i compariso with IM studies. Whe 1 sigle outlier was excluded [21], there was o more heterogeeity betwee studies ad the pooled re-ifectio rate decreased to 5.4% (95% CI 1.7 to 9.1, p = 0.004) (Fig. 3). There was evidece of publicatio bias (Egger s p = 0.001). The differece i re-ifectio rate betwee IM ad EF oce heterogeeity betwee studies was removed was sigificat i favour of EF arthrodesis (p = 0.009).Whe the effect of differet surgical implats was aalyzed usig a subgroup aalysis, the pooled re-ifectio rate of arthrodesis with short ad log IM was 13.1% (95% CI 7.6 to 18.6) ad 14.4% (95% CI 6.7 to 22.2), respectively, with o sigificat differece (Table 2). The heterogeeity of the model was moderate to substatial (I 2 = 54%, P = 0.004). The subgroup aalysis did ot show ay differeces i re-ifectio rate betwee uilateral (7.5%; 95% CI 1.3 to 13.7) ad biplaar/circular (8.5%; 95% CI 0.8 to 16.1) EF arthrodesis. The heterogeeity for this model was ot sigificat (I 2 = 27%, p = 0.179). The re-ifectio rate betwee EF with pis (5.4%; 95 CI 1.3 to 9.5) or wires (5.4%; 95% CI 3.1 to 14.0) was idetical, oce the heterogeeity betwee studies was elimiated (I 2 =0%; p = 0.990) by removig 1 outlier study [21] from the model. Details of the subgroups aalysis for EF arthrodesis are provided i Table 3. Fig. 1 Literature search ad methodology of selectio

4 Balato et al. BMC Musculoskeletal Disorders (2018) 19:361 Page 4 of 10 Table 1 Characteristics of the studies icluded i the systematic review ad meta-aalysis Lead Author, Publicatio Date Locatio Year of study Mea age (years) % male Mea follow up (moths) Participats Twostage/ oe-stage Surgical implat Itramedullary Hugerer et al., 2017 [26] Germay (12 119) 55 NS Short modular Friedrich et al., 2017 [23] Germay NS 31 (12 74) 37 37/0 Short modular Hawi et al., 2015 [5] Germay (24 143) 27 0/27 Short modular cemeted Röher et al., 2015 [12] Germay (12 204) 26 26/0 Short modular cemeted Miralles- Muñoz et al., 2014 [29] Spai (36 60) 29 29/0 Short modular cemeted Scarpoi et al., 2014 [33] Italy (24 105) 38 38/0 Short modular Iacoo et al., 2013 [10] Italy NS 34(13 72) 21 21/0 Short modular Putma et al., 2013 [31] Frace NS 50 (28 90) 31 25/6 Short modular Barto et al., 2008 [17] UK NS NS /1 Short modular Talmo et al., 2007 [34] USA NS (13 114) 29 25/4 Log modular Bargiotas et al., 2006 [16] USA (18 72) 12 12/0 Log locked Crockarell ad Mihalko, 2005 [19] USA (24 96) 10 9/1 Log locked Domigo et al., 2004 [22] Spai Miimum 1year 10 10/0 Short locked Volpi et al., 2004 [35] Frace /0 Short modular Re-ifectios/ persistig ifectios (%) Fusio rate % (time to fusio - moths) Major complicatios Reoperatios Postoperative limb legth discrepacy (mm) Quality score 12 (21.8%) NS /16 5 (13.5%) NS /16 4 (14.8%) NS 0 3 NS 11/16 13 (50%) NS 0 13 NS 10/16 2 (6.9%) NS /16 4 (10.5%) NS /16 3 (14.3%) NS /16 6 (19.4%) 68 (NS) /16 1 (10%) 100 (8) 2 2 NS 8/16 4 (13.8%) 83 (6) /16 2 (16.6%) 83 (5.5) /16 1 (10%) 100 (NS) NS NS 37 9/16 1 (10%) 90 (5) 2 1 NS 8/16 2 (16.6%) 100 (3.6) 1 1 NS 7/16

5 Balato et al. BMC Musculoskeletal Disorders (2018) 19:361 Page 5 of 10 Table 1 Characteristics of the studies icluded i the systematic review ad meta-aalysis (Cotiued) Lead Author, Publicatio Date Gore ad Gasser, 2003 [24] Locatio Year of study USA Mea age (years) % male Mea follow up (moths) (12 288) Participats Twostage/ oe-stage Surgical implat 16 14/2 Log Kutscher or modular Re-ifectios/ persistig ifectios (%) Fusio rate % (time to fusio - moths) Major complicatios Reoperatios Postoperative limb legth discrepacy (mm) Quality score 2 (12.5%)) 87.5 (NS) 3 4 NS 8/16 Waldma et al., 1999 [36] USA NS (24 90) 21 21/0 Short modular 0 (0%) 95 (6.3) 2 2 NS 8/16 Lai et al., 1998 [28] Taiwa (18 94) 28 8/20 Short locked 1 (3.6%) 93 (5.2) /16 Wilde ad Stears, 1989 [37] USA Miimum /0 Log Kutscher 3 (30%) 60 (6.6) /16 Exteral fixator Balci, 2016 [13] Turkey /0 Uilateral EF 1 (6%) 94 (7.6) /16 Coroa et al., 2013 [18] Spai (12 81) 21 0/21 Uilateral EF 3 (14%) 81 (10.3) NS NS 47 9/16 Iacoo et al., 2013 [10] Italy NS 93 (82 110) 10 10/0 Semi circular Hoffma EF 0 (0%) 90 (6.7) /16 Reddy et al., 2011 [32] Idia (12 84) 16 3/16 Ilizarov frame 1 (6%) 94 (6.6) /16 Parratte et al., 2007 [30] Frace (12 162) 14 6/8 2 uilateral EF 0 (0%) 93 (7.3) /16 Kliger et al., 2006 [27] Germay (24 132) 18 11/7 Uilateral EF 1 (6%) 83 (6.3) /16 Domigo et al., 2004 [22] Spai Miimum 1year 11 11/0 Uilateral EF (3) 0 (0%) 100 (6.7) 1 0 NS 8/16 Biplaar EF (8) 100 (6.1) David et al., 2001 [20] Israel (18 60) 10 NS Ilizarov frame 0 (0%) 100 (6.4) /16 Hak et al., 1995 [25] USA (12 186) 20 NS Uilateral EF (7) 1 (5%) 57 (7.1) 13 4 NS 8/16 Biplaar EF (13) 62 (7.1) De Cloedt et al., 1994 [21] Belgium (14 108) 15 NS 2 uilateral EF 8 (53%) 67 (7.3) NS 8 NS 8/16 NS Not stated, EF Exteral fixator

6 Balato et al. BMC Musculoskeletal Disorders (2018) 19:361 Page 6 of 10 Fig. 2 Rates of re-ifectio i patiets treated by kee arthrodesis with itramedullary (1 outlier removed [12]). The summary estimates preseted were calculated usig radom-effects models; CI, cofidece iterval (bars) Major complicatios ad re-operatios Data for major complicatios (excludig re-ifectio) were pooled across 17 ad 8 studies, respectively, for IM ad EF arthrodesis. The most frequet major complicatio for IM ad EF were implat failure ad o-uio, respectively. Pi track ifectio was reported with high frequecy i all series of EFs but was ot regarded as a major complicatio. The pooled radom effects complicatio rate was 11.0% (95% CI 6.5 to 15.5, p < 0.001) for IM ad 22.3% (95% CI 9.6 to 34.9, p < 0.001) for EF. Aalysis of data revealed sigificat differece for treatmet effect i favour of IM (p < 0.001). Heterogeeity betwee studies was substatial for both treatmet strategies (IM I 2 = 66%; EF I 2 = 72%). Sevetee ad 9 studies reported data regardig re-operatios for arthrodesis with IM ad EF, with a pooled radom effects rate of 17.2% (95% CI 11.4 to 23.1, p < 0.001; I 2 = 66%) ad 19.3% (95% CI 9.4 to 29.3; p < 0.001; I 2 = 66%), respectively. This differece was ot sigificat (p = 0.447). Radiographic uio Overall, the rate of radiographic uio was ot sigificatly differet betwee IM ad EF arthrodesis but the mea time to fusio was shorter with IM (5.78 rage moths vs rage moths; p = 0.031). I detail, data o the radiographic uio rate followig arthrodesis with IM were obtaied from 11 of 18 studies. No such data were available i more recet articles (i.e. after 2013). The pooled radom effects uio rate for IM arthrodesis was 89.4% (95% CI 84.1 to 94.8, p < 0.001), with o-relevat heterogeeity betwee studies (I 2 =40%;P = 0.082). The subgroup aalysis did ot show sigificat differeces i rate of boe uio followig kee arthrodesis with short periarticular (91.2%; 95% CI 84.4 to 98.1) or log IM (86.1%; 95% CI 77.4 to 94.7) (Table 2). All 10 studies o EF ivestigated radiographic uio as a outcome. The pooled radom effects uio rate for this surgical optio was 87.9% (95% CI 81.0 to 94.9, p < 0.001), with moderate Fig. 3 Rates of re-ifectio i patiets treated by kee arthrodesis with exteral fixator (1 outlier removed [21]). The summary estimates preseted were calculated usig radom-effects models; CI, cofidece iterval (bars)

7 Balato et al. BMC Musculoskeletal Disorders (2018) 19:361 Page 7 of 10 Table 2 Subgroup aalysis of itramedullary arthrodesis studies Outcome Publicatios () Cases Log Short Re-ifectio 18 Total No Yes Boe fusio 11 Total No Yes Time to fusio (moths ± SD) SD Stadard deviatio ± ± 0.6 heterogeeity betwee studies (I 2 =57%; p =0.013). O the exclusio of the two oldest studies, 21,25 the pooled uio rate for EF icreased to 92.0% (95% CI 87.5 to 96.4, p < 0.001) ad o heterogeeity was preset (I 2 =0%; p = 0.484). Uiplaar ad biplaar/circular EF had similar rate of boe fusio (Uilateral = 86.1%; 95% CI 77.1 to 95.1; biplaar/circular = 89.1%; 95% CI 81.4 to 96.8), but a early sigificat differece i this outcome was detected whe EF with pis (85.8%; 95% CI 77.9 to 93.7) was compared to EF with wires ( % CI 86.0 to 103.1). The mea time to boe fusio also was shorter for the wire EF tha for pi EF. Details of the subgroup aalysis for EF arthrodesis are give i Table 3. Cliical outcomes The compariso of cliical outcomes followig IM ad EF kee arthrodesis is reported i Table 4. With the umbers available, the oly sigificat differece betwee these two surgical optios was a bigger LLD i patiets who had udergoe arthrodesis with EF i compariso with those treated with IM. The extreme variability i assessmet tools preveted us to perform ay comparative aalyses of kee fuctioality. Discussio Kee arthrodesis with IM or EF is the most reliable therapeutic optio to achieve defiitive ifectio cotrol i patiets with septic failure of TKA [8, 9]. Deficiet P boe stock, impaired quality of boy surfaces, ad shorteed limbs may compromise the success of the procedure ad lead to poor fuctioal results [38]. To the best of our kowledge, this is the first review that compares IM ad EF to achieve kee arthrodesis i the specific cotext of PJI. Ideed, two previous systematic reviews [11, 38] were ot limited to studies of septic patiets oly. The most recet meta-aalysis o the same topic [11] is differet from our study for eligibility criteria ad the primary edpoit. Ideed, White et al. [11] evaluated comparative studies that icluded also patiets who had udergoe kee arthrodesis for aseptic failure of TKA. The rate of radiographic uio was assessed as a primary outcome. The iclusio criteria led these authors to select 12 comparative studies for the aalysis, oe of which was a radomized trial. Oly two of these studies [10, 22] were used i our meta-aalysis i that remaiig studies did ot fulfilled our striget exclusio criteria because of methodological issues (e.g. mixed diagosis ad surgical strategy, small sample size, short follow-up period etc.). Coversely, we performed the meta-aalysis by selectig studies that reported results of kee arthrodesis with EF or IM oly i the specific cotext of septic failure of TKA. This approach has already be used i oe previous meta-aalysis that specifically dealt with the surgical revisio of ifected TKA [1]. Followig previous studies [1], our primary outcome was the re-ifectio rate. Actually, ifectio cotrol is the mai goal of treatmet whe salvage surgery is performed for septic failure of TKA. Differetly from the meta-aalysis of White et al. [11], we assessed boe fusio as a secodary outcome. Ideed, achievig boe fusio may ot be ecessary i kee arthrodesis with the use of modular lockig IM s [33]. The eligibility criteria ad selectio of outcomes i the curret aalysis also eabled us to iclude studies o kee arthrodesis performed with the most recet modular IM s that were completely excluded from the study of White et al. [11]. The preset aalysis showed that IM or EF arthrodesis have similar re-ifectio rates. However, most studies i the curret meta-aalysis oly provided data o oe of these two treatmet strategies, which made Table 3 Subgroup aalysis of exteral fixator arthrodesis studies Outcome Publicatios () Uilateral =66 Bipl/Circ =86 p Pis = 126 Wires =26 Re-ifectio 10 No a Yes a 1 Boe fusio 10 No Yes Time to fusio (moths ± SD) ± ± ± ± Bipl/Circ Biplaar/Circular, SD Stadard deviatio a 1 outlier study removed P

8 Balato et al. BMC Musculoskeletal Disorders (2018) 19:361 Page 8 of 10 Table 4 Cliical Outcomes Itramedullary Exteral Fixator P Studies () Patiets () Mea SD Studies () Patiets () Mea SD value SF-36 or SF-12 questioaire PCS MCS PF BP RP GH SF RE VT MH VAS pai LLD (mm) SD Stadard deviatio, SF-36 Short form-36, SF-12 Short form-12, PCS Physical compoet summary, MCS Metal compoet summary, PF Physical fuctioig, BP Bodily pai, RP Role-physical, GH Geeral health, SF Social fuctioig, RE Role-emotioal, VT Vitality, MH Metal health, VAS Visual aalogue scale, LLD Limb legth discrepacy iteral matchig of studied samples missig. This makes more importat to remove outliers ad reduce heterogeeity, so that fair comparisos betwee the two groups could be made. Actually, a excess rate of re-ifectio after IM arthrodesis became evidet oce outlier studies were dropped off from the meta-aalysis. Icreased risk of recurret ifectio with IM ig as compared to EF arthrodesis has bee previously reported [9, 10], eve though this fidig is ot supported by oe recet meta-aalysis [11]. Overall, these results suggest cautio if the use of IM ig is plaed i difficult-to-treat PJIs (i.e. isolatio of multi-resistat micro-orgaisms, multiple comorbidities etc). The preset meta-aalysis has show that patiets who had udergoe arthrodesis with IM have lower rate of major complicatios i compariso with those treated with EF, but the pooled rate of re-operatio is similar. Besides major complicatios, the eed for daily pi site care to prevet local complicatios represets a drawback whe usig the EF [9]. The rate of radiographic uio i the studies icluded i this review was similar betwee IM ad EF, differetly from oe recet meta-aalysis [11] that foud better results with IM ig. With the umbers available, o differeces i fusio rate emerged betwee log ad short periarticular s. Several recet studies reportig results of modular IM implats disregarded boy uio as a edpoit sice it was ot cosidered essetial to obtai successful outcome [5, 10, 12, 23, 26, 29, 33]. Coversely, boy uio is of outmost importace for EF arthrodesis. Ideed, Coroa et al. [18] showed that 82% of patiets treated with EF who achieve fusio is satisfied with the result. Amog those who do ot achieve fusio, 75% is dissatisfied. No sigificat differece i the rate ad time of boe fusio was detected whe uilateral or biplaar/circular EF was used to obtai kee arthrodesis. However, there was a tedecy toward better results usig circular fixators ad wires. Despite umerous disadvatages (frame maiteace, cosmetic discomfort, risk of eurovascular damage durig wire isertio), circular exteral fixatio offers possible progressive adjustmet to stimulate the boy fusio while keepig maximum triplaar stability at the arthrodesis site [32]. The severe boe defect represets a specific problem followig multiple revisios for PJI ad direct boy uio i these circumstaces will result i marked LLD. The shorteig of limb has detrimetal effect o fuctioal outcome [8], with a breakpoit of 2 to 3 cm [39]. Friedrich et al. [23] set a mius two cetimeters to allow walkig without circumductio of the leg after IM ig. The mea LLD followig IM ig i the preset aalysis was about 2 cm ad was sigificatly smaller tha that recorded after EF arthrodesis, cofirmig previous positive results of modular without boe fusio [5]. No sigificat differeces i the quality of life ad severity of pai betwee the two surgical strategies were detected i this study, but these fidigs should be iterpreted with cautio i the cotext of the limited available data. Moreover, the paucity of literature data preveted us to perform a subgroup aalysis that related the boe uio to cliical outcomes. Previous studies reported moderate physical disability ad mild metal disability after kee arthrodesis idepedet of the surgical strategy [17, 19]. Literature data for postoperative pai are icoclusive. Sigificat postoperative improvemet i pai has bee reported followig IM

9 Balato et al. BMC Musculoskeletal Disorders (2018) 19:361 Page 9 of 10 arthrodesis [10, 16, 40], but other authors [12] obtaied much worse results. Ramazzii-Castro et al. [41] foud better result for pai i patiets who had udergoe arthrodesis with EF whe compared to other surgical strategies. The limitatios of this study deserve attetio. First, this meta-aalysis was performed o cohort studies, because of the lack of radomized cotrolled trials o the outcome of kee arthrodesis with EF ad IM. Hece, there was low quality of evidece for each outcome. Moreover, variable desig ad the differet way to assess results may have cotributed to the heterogeeity betwee studies that emerged for some outcomes assessed i the preset metaaalysis. Nevertheless, oce few outliers were excluded the heterogeeity disappeared. We also ackowledge the limited umber of studies o EF arthrodesis. This limitatio preveted us to perform a robust compariso betwee the two procedures, especially for secodary cliical edpoits, ad to carry out a subgroup aalysis to assess the ifluece of differet factors (i.e. umber of surgical stages, umber of previous surgeries, boe fusio etc.) o the outcomes. Lastly, sigificat publicatio bias was idetified i both treatmet groups, which might udermie the coclusio of the study. This study also shows differet stregths. First, we adopted striget eligibility criteria that led to the exclusio of studies that assessed results of kee arthrodesis for causes differet from the septic failure of TKA. Actually, kee arthrodesis for PJI compels the surgeo to deal with specific cliical ad microbiologic problems. Furthermore, ulike oe recet meta-aalysis [11], we icluded oly studies with adequate sample size ad follow-up iterval. Ideed, studies with less tha 10 participats are more likely to be case series which do ot iclude cosecutive patiets [1]. Similarly, a follow-up time of less tha 1 year is ot suitable to compare decisio-makig outcomes i a meta-aalysis [14]. Aother stregth of this study is the use of a validated istrumet for o-radomized surgical studies to assess the methodological quality of studies icluded. Fially, we compared post-operative cliical outcomes that have ot bee cosidered i previous reviews [11, 38]. Coclusios The available evidece suggests that kee arthrodesis with EF i the specific cotext of PJI has a reduced risk of re-ifectio i compariso with the IM strategy. Hece, cautio should be exercised particularly whe the use of IM is plaed i difficult-to-treat PJIs. The use of IM is more advatageous tha EF with respect to importat cliical outcomes such as the frequecy of major complicatios ad postoperative LLD. Abbreviatios CI: Cofidece iterval; EF: Exteral fixator; IM: Itramedullary; LLD: Limb legth discrepacy; MINORS: Methodological Idex for No-Radomized Studies; PJI: Periprosthetic joit ifectio; PRISMA: Preferred Reportig Items for Systematic Review ad Meta-Aalyses; SF-12: 12-item short form health survey; SF-36: 36-item short form health survey; TKA: Total kee arthroplasty Authors cotributios GB, MR, TA, FS ad MM were ivolved i the coceptual discussio ad desig of the review, i the critical appraisal of the cotet ad have give fial approval to the versio to be published. Ethics approval ad coset to participate Not applicable. Coset for publicatio All data geerated or aalyzed durig this study are icluded i this published article. Competig iterests The authors declare that they have o competig iterests. Publisher s Note Spriger Nature remais eutral with regard to jurisdictioal claims i published maps ad istitutioal affiliatios. 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