SAFE Nail.

Use of a Interlocking nail with a long acting antibiotic releasing core in patients with high infection risk. Prospective study in 27 cases. Nuno Craveiro Lopes *, Carolina Escalda*, *Senior Orthopedic surgeon, Orthopedic Department, Garcia de Orta Hospital Correspondence to: Nuno Craveiro Lopes Servio de Ortopedia e Traumatologia Hospital Garcia de Orta Av. Prof. Professor Torrado da Silva, Pragal 2801-951 Almada Portugal Fax: 351-212957004 Tel: 351-212727153 E-mail: nuno.lopes@netvisao.pt Conflito of interests: Nothing to declare ABSTRACT Introduction The use of interlocking nails with PMMA cement impregnated with antibiotics is an attractive method for treating or preventing infections of long bones. After conducting a in vitro pilot experimental study to evaluate the stiffness of the nails, the levels of release of antibiotic and clinical efficacy of a modified interlocking nail, with a core of PMMA cement impregnated with vancomycin, the Authors present the experience with the use of a modified nail, filled with polymethylmethacrylate cement impregnated with 2 g of vancomycin (SAFE Nail) to prevent and control infection in 27 cases at high risk. Material and Method We prospectively evaluated 27 cases (8 femurs, 16 tibias and 3 knee arthrodesis), including 8 women and 19 men, average age 42 years (range 15-69 years). 8 cases had open fractures, 11 presented with treatment with external fixators that were converted into SAFE nail, 4 had limb length discrepancy and underwent lengthening over a SAFE nail and 4 had osteomyelitis with fracture or nonunion. In all cases it was used a Grosse nail with two longitudinal series of 5 mm holes, filled with 20 to 40 gr of polymethylmethacrylate cement with 2 grams of vancomycin. The mean follow-up was 14 months (range 8-29 months). It was noted the time until consolidation, the emergence of infection and intercurrences. Results In 23 cases cultures were made prior to the nailing and potentially very aggressive bacteria was found in 17 of these cases (74%). In the overall of cases, there were two problems, five obstacles and no complications. In the group of 8 cases with open fractures, one developed a delayed consolidation, coming to fracture the nail after 3 months. Substitution with SAFE DualCore nail (2nd generation), a reinforced nail, achieved consolidation. Another patient developed a infection with MSSA resistant to vancomycin. Substitution with a SAFE DualCore nail, loaded with cement with flucloxacilin achieved the consolidation and cure of the infection. In the group of 11 cases where conversion of external fixation to SAFE nail was done, consolidation was achieved without the appearance of infection in all cases. Of the 4 cases undergoing lengthening over SAFE nail, regenerated bone took more than three months to consolidate in two cases and a fracture of the nail occurred. We proceeded to the replacement by a SAFE DualCore nail, resulting in the consolidation of the regenerate without the occurrencee of infection.

Finally, 4 cases with osteomyelitis of the tibia treated with a SAFE nail healed their infection. Conclusions The SAFE nail has proved extremely effective in the prevention and treatment of bone infection, when the appropriate antibiotic can be used. Currently in cases where the bacteria is not known, we use two antibiotics, flucloxacillin and vancomycin. In relation to its strength, it was observed that the SAFE nail supports 10% more load than Grosse nail and the same 450,000 load cycles, corresponding to 3 months of use in ambulatory patients, what proved to be insufficient for some patients who present late consolidation. To remedy this fact, changes were introduced in order to reinforce the nail, creating the 2nd generation of SAFE nail called SAFE DualCore nail, which supports about 900.000 load cycles. Keywords: Antibiotic; pin; infection, osteomyelitis, cement, PMMA, open fracture, bone lengthening INTRODUCTION The use of interlocking nails with PMMA cement impregnated with antibiotics is an attractive method for treating or preventing infections of long bones. After conducting a in vitro pilot experimental study to evaluate the stiffness of the nails, the levels of release of antibiotic and clinical efficacy of a modified interlocking nail, with a core of PMMA cement impregnated with vancomycin, the Authors present the experience with the use of a modified nail, filled with polymethylmethacrylate cement impregnated with 2 g of vancomycin (SAFE Nail) to prevent and control infection in 27 cases at high risk.

Fig.1 - Injection of cement with antibiotics inside the nail involved with a Esmach band. MATERIAL AND METHODS

Twenty-seven consecutive cases who presented for treatment at our institution between January 2009 and December 2010 were included in this prospective study. The patients suffered from situations in which the usual methods of treatment had a high risk of infection, for which, at the responsibility of the surgeon nail were modified in order to be adapted to the particular situation of the patient. It was eight women and 19 men with mean age of 42 years, ranging from 15 to 69 years. 8 femurs were treated, 16 tibias and 3 arthrodesis of the knee. All patients were at high risk of infection or with current infection, including 8 cases of open fractures, 11 cases of treatment with external fixators that were converted into nailing, four cases of limb shortening where lengthening with external fixators over nail was and 4 cases of osteomyelitis with fracture or bone loss(Table I). Of the eight open fractures (Fig. 2), 3 were Gustillo grade I, two grade II and 3 grade III [5]. The group of 11 cases treated with external fixation (Fig. 3) had the fixator on average 19 weeks (4-48 weeks). The group of 4 cases underwenting lengthening with external fixator over nail (Fig. 4) maintained the fixator for 12 to 16 weeks for 4 and 5 cm lenghtenings. Of the four cases with osteomyelitis, three were secondary to nailing after open fractures (Fig. 5) and one to a hematogenous osteomyelitis lasting between 2 months and 3 years. In all cases presenting high debit drainage. In three cases a Staphylococcus aureus was isolated, two methicillin-resistant
and on another patient a serracia marescencis.

Fig.2 - H.C., male, 47 years. Open fr GIII comminuted with 3 days of evolution. Nailing with SAFE Nail. Appearance at 10 months. In all cases a Grosse Stryker nail was used, adapted to the bone structure to be treated. The selected nail was prepared in the workshops of the hospital with transfixing perforations of 5mm in diameter in the frontal plane every 4 cm along the nail. At the beginning of the intervention in a sterile environment, the nail was involved in a Esmach band in tension and well reinforced in its proximal part. The cement is prepared in the usual way using 20 to 40gr of PMMA powder according to the internal volume of the nail to be used. 2 g of vancomycin and all of the liquid component was added. Using a cement gun with the application tube cutted short and adapted solidly in the proximal nail hole, the cement was injected slowly inside the nail until it exit through the distal hole (Fig. 1). Then the screw support of the proximal guide is screwed in in order to push the cement in the threaded area. Once the cement gets pasty and before polymerization and heating, the screw is removed and the locking holes are cleaned with a 4-5mm Steinmann pin.

Fig.3 - M.Q., female, 58 years. Reconstruction with the Ilizarov apparatus in a pseudoarthrosis after nail failure. Reconversion to SAFE nail after 5 months of external fixation. Appearance at 15 months. The technique of nailing and locking screws is similar to a normal interlocking nail, except that its introduction into the medullary canal can not be made over the guide wire. All patients received systemic antibiotic therapy, including 2 g of cefazolin and 80 mg of gentamicin every 8 hours for 3 days to prevent postoperative bacteremia. Patients leaved the hospital between the 3rd and 5th postoperative day and was controlled at the outpatient clinic every 15 days and then monthly until consolidation. It was noted the time until the consolidation, the emergence of infection and other intercurrences. RESULTS Exsudate cultures were performed prior to nailing in 25 cases, presenting 18 of these cases, potentially very aggressive bacteria (74%). MSSA was isolates in 10 (40%), two MRSA, 2 Serratia, 2 Shigella (8% each), a Pseudomonas, 1 Enterococcus (4% each), 5 cases had mixed skin flora (20%) and two cultures resulted negative. All patients in the osteomyelitis group had positive cultures with aggressive bacteria, 37.5% of the open fractures, 54% of the conversions group and 75% of the lengthening group.

The mean follow-up was 14 months (range 8-29 months).

Fig.4 - F.H., male, 37 years. Failed TSRH self lengthening nail. Lengthening with external fixator over nail. SAFE nail conversion after 3 months of external fixation. Appearance at 22 months. In the group of 8 cases with open fractures (Fig. 2), we observed the development of delayed union in three cases. In one case SAFE nail brooked at 3 months. A exchange with a SAFE DualCore nail was done (2nd generation, reinforced with metal core and impregnated with 2gr of Vancomycin and 2gr of flucloxacillin), achieving consolidation. The remaining two cases had at the last follow up a delayed union with no signs of infection (at 4 and 6 months). Another patient developed infection with vancomycin-resistant MSSA. Nail substitution was made with a SAFE DualCore nail, achieving the consolidation and cure of the infection. In the group of 11 cases where reconversion of external fixation to SAFE nail was done (Fig.3), there was delayed union in two cases with infection control in all cases.

Fig.5 - J.N., male, 27 years. Osteomyelitis after nailing of a open fracture. Nailling with SAFE nail one year after infection. Appearance at 2 and a half years of evolution Of the four cases undergoing lengthening over a SAFE nail (Fig. 4), we detected delayed consolidation of the regenerate with nail failure in 2 cases. A nail exchange with SAFE DualCore nail with bone graft in one patient, lead to consolidation of the regenerate, with no occurrence of infection. Finally, 4 cases with osteomyelitis of the tibia treated with SAFE nail (Fig. 5), achieved consolidation and healed their infection without complications. In the overall of the cases, there were two problems, 5 obstacles and no complications [26]: 3 cases had residual infection of soft tissues appearing between 2 and 4 weeks after nailing, two with superficial lesions were treated with systemic antibiotic therapy with gentamicin and the third with a deep fistula, by surgical debridement and placement of PMMA beads with Meropeneme. All have evolved to progressive closure of the lesions. A patient with open fracture progressed to osteomyelitis by bacterial resistance to Vancomycin. He was treated with exchange of the SAFE nail to a SAFE DualCore nail with flucloxacillin, the antibiotic that the bacteria was sensitive, and evolved to the cure of the infection. Finally, 3 cases (11%) developed delayed consolidation with a failure of the SAFE nail. They have been treated with replacement with a SAFE DualCore nail, one of which with cancellous bone graft taken from the contralateral femur with the RIA system [27].

DISCUSSION
Bone infection requires a sequence of surgical procedures for infection control, to provide stability of the bone structure and to promote the consolidation of the fracture, fragility, or bone loss. Traditional treatment includes serial surgical debridement, various forms of systemic and local antibiotics and bone stabilization with external fixators, which can later be converted into internal fixation once the infection had cleared [8,9,10]

The PMMA cement as spacers or beads impregnated with antibiotics has been used since 1970 [8,15,28,29] in the treatment of bone infection, and has proved an effective method for long term local administration of high doses of antibiotics [ 30], keeping minimal or undetectable systemic levels [6.12]. However, a second surgical procedure is needed to remove the spacers or beads. Other type of carriers of antibiotics have been investigated to prevent the need for a second surgical intervention and in some cases, to facilitate bone healing, including calcium sulfate and various synthetic resorbable polymers [18,19,31,32,33, 34,35,36,37]. The safety of local treatment with PMMA cement loaded with antibiotics is well documented in clinical studies [8,15,18,19,28,29]. It is not available commercially PMMA cement with sufficient concentration of antibiotics for local control of infections, the surgeon has to prepare it using most of the time, several antibiotics in high doses. flucloxacillin and vancomycin proved to be the best combination in our midst because they have a broad spectrum of action adapted to the most common bacterial flora, to be available in the market in powder form, having good heat stability, good release properties and no effect on bone consolidation [18,31,38,39,40,41]. In addition to local treatment, we administer parenteral antibiotics, including cefazolin and gentamicin for 3 to 4 days to prevent postoperative bacteriemia. Most of our patients were treated with procedures that required the use of external fixators for prolonged periods. It is well known in the literature [42,43,44,45], that in these situations there is a high prevalence of infection around threaded pins and wires, muscle contractures and joint stiffness, pain and functional disability, and many patients refuse treatment, they create intolerance to external fixators or are not good candidates because of exaggerated obesity, intolerance or psychological instability. In these cases, the use of the SAFE nail brings an invaluable added value. Several authors reported other methods of combining an intramedullary device with PMMA cement impregnated with antibiotics, including nails with beads [46.47], guide wires [26], Ender [16], Kntscher [48]and interlocking nails[17] covered with PMMA cement with antibiotics. However they all had problems, obstacles and complications in large number, including necessity to remove the beads, to include other mean of stabilization with external immobilization, replacement with a more stable nail in a second timing or because of debonding of the cement outside the nail during insertion or extraction, leading to blockage of the nail and cement inside the medullary canal. The SAFE nail was easy to manufacture and the procedure of filling it with cement impregnated with antibiotics is fast and easy to perform by one of the surgeons, taking about 10 minutes, while the other surgeon prepare the implant site. In this group of patients, the SAFE nail has been very effective in preventing infection and treating open fractures, conversion of external fixation into internal, to do lengthening over nail and to treat osteomyelitis of long bones with bone fragility. All these situations usually require long periods of external fixation and often serial surgeries. It is well documented that the placement of intramedullary PMMA cement impregnated with antibiotics is very effective in the prevention and treatment of osteomyelitis, because it releases locally prolonged and high doses of antibiotics [8,9,18,28,29,31,38,39,40,41]. However the fact that systemic levels of antibiotics are minimal or undetectable [20,21], makes this form of administration by itself insufficient to control the residual soft tissue infection. These infections, which often accompany the process of osteomyelitis, become isolated from the intramedullary environment after 2 weeks of treatment through the bone healing process. So it is necessary to supplement the treatment with appropriate antibiotics, administered systemically or locally in the form of PMMA cement beads with antibiotics.

Table I pre and posoperative patient data

N Name 1 2 JM GW

Age/Sex 57/M 51/M

Date 08/2009 11/2009

Segment Tibia Tibia

Observations Distal GII Segmental GI Medial Cominutive GIII Obese Distal Cominutive GI Medial Cominutive GIII

Initial Treat. SAFE SAFE

Contamination FW 3 weeks 9 days MSSA Flucloxacylin 7 days Pseud. Aerug. Gentamycin 2 days 3 days MSSA Entero.Cloacae Fluclo+Genta 4 days 22 19

Result Consolidation. No Infection Infection Strep B Hem Substitution SAFE DualCore Consolidation Late Consolidation # nail - 3 months No Infection Substitution SAFE DualCore Consolidation. No Infection Consolidation. No Infection

Grup 1 (Open Fractures)

11

3 4 5

MS TS HC

61/F 23/M 47/M

07/2010 07/2010 08/2010

Tibia Tibia Tibia

SAFE SAFE SAFE

11 10

LS

38/M

08/2010

Femur

Diafisal. Gun fire GI

SAFE

10 2

Consolidation. No Infection Infection soft tissues Late Consolidation No Infection ssea Late Consolidation No Infection Consolidation. No Infection

PC

35/M

08/2010

Tibia

Medial GII

SAFE

2 days Mix flora 15 days Negativo 4 months Shigella Spp. MSSA Meropenem 5 months Mix flora 1 Month Mix flora 8 months MSSA Flucloxacylin 4 months Serrat. Maresc Gentamycin 3 months MSSA Flucloxacylin 5 months Negative 2 months Mix flora 5 months Mix flora 4 months MSSA Flucloxacylin 1 ano Shigella Spp Meropeneme 4

CF

17/M

12/2010

Tibia

Distal GIII

SAFE

Grup 2 (Reconversion from External Fixation) 15 9 MS 37/F 03/2010 Femur Pseudartrose Shortening. 3cm Fr. segmentar GIII Fr. segmentar GIII Inf. PTK. Spacer + revision + ExFix AO. Shortening 6 cm Inf. PTK. Spacer + revision + ExFix MonoTube. Shortening 5 cm Knee Instability. Poliomyelitis Pseudartrose distal Shortening. 5cm Fr. Distal GII Cominutive . distal GII Distal Pseudartrosis. Obese Bone loss 10cm Ilizarov

10 11 12

JS AR CF

42/M 49/M 66/M

12/2010 04/2009 11/2010

Tibia Tibia Knee

Fix.Ex.AO ExFixAO Ilizarov

13 26 7

Late Consolidation No Infection Consolidation. No Infection Consolidation. No Infection Infection soft tissues Late consolidation No bone Infection Consolidation. No Infection Consolidation. No Infection Consolidation. No Infection Consolidation. No Infection Consolidation. No Infection Infection soft tissues Consolidation No bone Infection Consolidation. No Infection Late Consolidation # nail - 3 months No Infection Substitution SAFE DualCore Atrophic regenerate # nail - 3 months No Infection Substitution SAFE DualCore and bone graft Consolidation. No Infection

13

JO

69/M

12/2010

Knee

Ilizarov

16

14 15 16 17 18

EJ MQ CG JS SR

48/F 58/F 56/M 42/M 25/F

02/2010 03/2010 10/2009 12/2010 10/2010

Knee Femur Tibia Femur Femur

Ilizarov Ilizarov Ilizarov Ilizarov Ilizarov

15 20 13 8

19

MS

38/F

12/2010

Tibia

Ilizarov

Grup 3 (Bone lenghtening) 20 21 AC VA 18/F 15/M 11/2010 09/2010 Femur Femur Shortening after osteomielytis Shortening 4 cm Resseco de Ewing Shortening 4cm Pseudartrose. proximal Shortening 5cm Aneurismatic bon cyst Shortening 4cm ExFix+ SAFE ExFix+ SAFE 3 months 3 months MSSA Flucloxacylin 4 months MRSA Vancomicina 3 months MSSA Flucloxacylin 4 months MSRA Gentamycin 7 9

22

SD

51/M

11/2010

Femur

ExFix+ SAFE

22

23

FH

37/M

08/2009

Femur

TSRH nail

Grup 4 (Osteomyelitis with bone fragility) 29 24 FR 36/F 01/2009 Tibia Open fracture nailing. Medial Grosse nail Consolidation. No Infection

N Name 25 CR

Age/Sex 16/F

Date 09/2009

Segment Tibia

Observations Hematogenic Proximal

Initial Treat. SAFE nail

Contamination FW 3 years MSSA Flucloxacylin 1 year Serracia Mares Gentamycin 3,5 months MSSA Flucloxacylin 21

Result Consolidation. No Infection Infection soft tissues Consolidation No Infection ssea Consolidation. No Infection

29

26

JN

27/M

01/2009

Tibia

Open fracture nailing. Medial

Ilizarov

17

27

GT

51/M

01/2010

Tibia

Open fracture nailing. Medial

Grosse nail

In three cases we observed the reappearance of active soft tissue fistula after 2 weeks of treatment, which progressed to healing with systemic antibiotic therapy in two cases and the other case with use of PMMA cement beads impregnated with antibiotic. The levels of the bending forces that are exerted on the femur and tibia of an adult in their normal activities represents up to 0.6 times the body weight when walking (40 kg) and 1.3 times when climbing stairs (100 kg) [24]. These bending forces never are reached in a patient with lower limb pathology underwent a nailling of the femur or tibia and using cruches. On the other hand, it is described that intramedullary nails have a lifespan of about 450 to 500,000 load cycles, which corresponds to about 3 to 4 months of use, leading to its failure in the meantime if there is no bone consolidation [25 ]. The rate of delayed consolidation and pseudarthrosis after internal fixation of the closed fractures of the tibia, varies from 5 to 13%. It is known that this rate increases exponentially when it comes to an open fracture, reaching up to 47% in Gustillo grade I and II and 74% in grade III [49]. In the group of 27 cases we treated, there was need for a second surgery procedure in 5 cases (18.5%), including 3 nail failures (11%) after 3 months in patients with delayed consolidation . This number is acceptable and low comparatively to the data of other authors and given the severity and high risk of complications and additional surgeries associated with alternative treatment with prolonged external fixation. [45].

Fig.6 Method for extraction of broken nail, using: a) a retrograde 3mm Kirschner wire to push, or b) an anterograde 5mm threaded pin to pull In three cases it was necessary to remove broken SAFE nails, the procedure was easy to perform using a 3mm Kirschner wire inserted retrograde, through the intercondylar notch of the femur or the calcaneus, to push proximally the distal fragment of the broken nail, or a threaded pin, anterograde, to pull the distal fragment (Fig.6). In the overall of the 27 cases, there were two problems, 5 obstacles and no complications. To avoid the obstacles that arose, modifications were introduced to the nail to reinforce it and give more resistance to fatigue and simultaneously to increase the spectrum of action and dose of antibiotics, leading to the 2nd generation of SAFE nails, called SAFE DualCore nail.

CONCLUSIONS The authors conclude that this device, an example of a new class of implants - implants biologically active, can represent an added value compared to current methods of treatment of open fractures, conversions of external fixation in internal fixation and treatment of bone infections with weakening or bone loss. The procedure is simpler and faster, the nail is more resistant than the normal nails, allowing the choice of appropriate antibiotic with local release of high doses and prolonged treatment, able to establish a suppressive antibiotic therapy, thus avoiding the recurrence of infection, with less intercurrences than similar methods. In the treated patients, the SAFE nail has proved extremely effective in the prevention and treatment of bone infection, when the appropriate antibiotic can be used. Currently in cases where the bacteria are not known, we use two antibiotics, flucloxacillin and vancomycin. In relation to its strength, it was observed that with a bending load of 40 to 80 kg, it is 10% stronger than the correspondent standard Grosse nail. Its resistance to fatigue showed, however, to be insufficient for some patients who have delayed consolidation. To remedy this fact, modifications were introduced to the nail so as to reinforce it and give more resistance to fatigue, giving rise to the 2nd generation of SAFE nails, called SAFE DualCore nail.
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