Wound Leakage With the Use of Calcium Sulphate Beads in Prosthetic Joint Surgeries: A Systematic Review

Since its first use as a bone void filler at the end of the 19th century, calcium sulphate products have been adapted in different ways to aid orthopaedic surgeons. Calcium sulphate local antibiotic delivery systems offer a promising solution in the delivery of high antibiotic concentrations locally for an extended period of time. Over the years, multiple centres have reported side effects such as wound drainage, heterotrophic ossification and hypercalcaemia. This study was carried out to assess the risk of wound drainage in prosthetic joints after implantation of antibiotic-impregnated calcium sulphate beads. Two reviewers searched the literature in three online databases using the Cochrane methodology for systematic reviews. The search of databases yielded 182 articles. The studies without reported post-operative complications, mainly drainage outcomes, were excluded. After screening, seven articles were deemed suitable and selected. Out of the 1,112 cases identified, 43 joints developed wound drainage after calcium sulphate bead placement. This complication was resolved in all these cases by either conservative or operative approaches. The factors implicated in the development of wound drainage include the volume of the product used, procedural placement and host factors. The result of this systematic review shows that calcium sulphate products can be used for treatment and prophylaxis in prosthetic joints with a risk of post-procedural wound drainage. This risk, however, is lesser with the use of synthetic calcium sulphate products as compared with conventional calcium sulphate products.


Introduction And Background
In England and Wales, there are about 160,000 joint replacements performed in a year [1]. This number is up to one million in the United States [2,3] and is expected to increase to four million a year by 2030 [4]. In recent times, calcium sulphate beads have been effectively used in septic and aseptic conditions. The incidence of prosthetic joint infection (PJI) is 1%-2% after primary replacement, with a weighted mean of 0.97% in total hip replacement (THR) and 1.03% in total knee replacement (TKR) from multiple national registries [5]. Prosthetic joint infection (PJI) is a serious limb and life-threatening complication of joint replacement surgery. The current protocol for PJI includes debridement and antibiotic therapy. Surgeons have been increasingly using calcium sulphate beads to deliver antibiotics to the joint space. Calcium sulphate beads are traditionally used as bone filling agents [6]. However, they have been found to be effective in treating PJI as the beads are completely absorbed from the joint space and therefore do not need to be surgically removed. Moreover, because of the beads getting absorbed, 100% of the antibiotic load is released [7].
There is limited literature on the risk associated with using calcium sulphate beads; however, one reported developing wound drainage as a risk of using calcium sulphate beads. The incidence of wound drainage is reported to range from up to 51% [8]. The consequences of wound drainage include a longer hospital stay for the patient, wound care and immobilisation. If wound drainage persists, washout and closure may be indicated. Persistent wound drainage may increase the risk of infection [9]; however, Ferguson et al. found no infections in those treated non-surgically for wound drainage [10]. Wound drainage has been associated with higher volumes of calcium sulphate beads, particularly volumes greater than 20 cc [11]. Wound drainage is also linked to a deeper subcutaneous insertion site and a McPherson systemic host score of C [12].
The aim of this study is to determine the risk of developing wound drainage when using calcium sulphate beads in any prosthetic joint surgery. We aim to determine the factors that increase the risk of developing wound drainage and what measures can be taken to treat wound drainage.

Review Methodology
A literature search of three online databases, namely, MEDLINE (1946 to present), Embase (1974 to present) and Cochrane CENTRAL (1988 to present), using the Cochrane methodology for systematic review was conducted using the keywords 'prosthetic joint', 'total knee replacement' and 'total hip replacement' and cross-searched with 'calcium sulphate beads'. The inclusion criteria selected was any study that has reported complications in any prosthetic joint surgery regardless of the indication and regardless of the language in which the study was published. Studies without reported post-operative drainage outcomes were excluded. All full texts were retrieved and reviewed where open access was not available. Search screening and article shortlisting were performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology ( Figure 1) [13].

PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses
The search yielded a total of 182 articles. All shortlisted studies were reviewed by the junior and senior study members. After review, seven articles were selected in the study as per the inclusion criteria ( Table 1). Data from the selected studies, including the type of calcium sulphate beads and the dose used, and drainage outcomes, are tabulated for a detailed review (Table 1).

Discussion
In our review, across seven studies, we identified 1,112 patients who underwent prosthetic joint surgeries for various aseptic and septic indications ( and Lum et al. [22]) have not specified drainage complications in the PJI patient group ( Table 3). The diagnosis of PJI is commonly made using the criteria proposed by the Musculoskeletal Infection Society ( Table 4) [14]. A combination of conservative and operative strategies was reported by the authors, which eventually resulted in resolution in all cases.     [14].
While the efficacy of local antibiotic delivery by calcium sulphate beads is well documented, potential side effects have also been recognised, which include excessive wound drainage requiring intervention, heterotrophic calcification, reactive synovitis and transient hypercalcaemia. Chronic infections in prostheses are characterised by biofilms that are not easily eradicated by conventional antibiotic therapy [15]. Any residual biofilm after implant removal can serve as a focus for persistent infection and morbidity. Conventional methods including parenteral antibiotics fail to achieve the desired concentration in local tissue for reliable and effective eradication of infection. Local antibiotic delivery systems offer a promising solution to this problem. Kanellakopoulou et al. showed that an antibiotic-soaked calcium sulphate delivery system (Stimulan) can provide concentrations more than 300 times the minimum inhibitory concentration of causative organisms in studies on rabbits [16]. This method of delivery not only promises effective antimicrobial activity but also avoids the systemic toxicity of systemic antibiotics.
The pathophysiology of wound drainage due to calcium sulphate is well established but poorly understood. This adverse effect is thought to occur due to accelerated absorption of calcium sulphate beads, which then lead to the development of a calcium-rich fluid. This calcium-rich fluid is suspected to cause increased wound drainage via two possible mechanisms. Firstly, the calcium-rich hyperosmolar fluid exerts an osmotic effect and promotes fluid sequestration in the surgical planes where the beads have been planted. Secondly, it is thought to trigger a direct inflammatory response that leads to fluid collection [24,25]. Both these mechanisms may contribute to the wound drainage seen in patients after the use of calcium sulphate products. However, the exact mechanism is still unknown.
McPherson et al. proposed that this inflammatory process was due to the derivation of prior calcium sulphate products from gypsum, a naturally derived compound [20]. Stimulan, a commercially pure, synthetic calcium sulphate compound, offered a less harsh atmosphere to the synovial joint environment and was a promising answer to this problem [20]. This was reinforced by their study that showed that only 3.2% of the cases developed significant wound leakage that required intervention. Furthermore, they attributed these cases to excessive use of the product, quality of local tissue and health of the subjects. They recommended the use of Stimulan to be restricted to less than 30 cc to avoid this complication (Table 1) [20].
In cases where wound drainage was significant enough to warrant intervention, a variety of methods were employed. McPherson et al. used lavage with debridement wound VAC placement or application of compressive dressing, which resulted in eventual resolution [20]. Kallala et al. stopped anticoagulants if the drainage was found within five days with redressing or if it occurred after five days and thorough washout was done under general anaesthesia [19]. The single case of wound drainage in Sandiford's series was treated by re-exploration upon which a defect was found in the insertion of abductors, closure of which resulted in resolution [17]. Other studies reported resolution of drainage with conservative management such as redressing and observation [22,23].
Wound drainage is also thought to be related to the procedural placement of calcium sulphate beads. Subcutaneous placement is thought to lead to increased wound drainage and is avoided by watertight closure of deeper spaces [21]. McPherson et al. [20] and Kallala et al. [18,19] planted Stimulan beads in the medial and lateral gutters in knee arthroplasty. The deep hip space inferior to the acetabulum was used in the hip cases. Agarwal et al. used the bigger beads within the joint space with smaller bead insertion into the medullary cavity (Table 1) [23]. Subcutaneous positing of beads was actively avoided in all studies, which is also recommended by the manufacturers.  [20]. However, a statistical correlation between the volume of beads and drainage is yet to be established.
As explained previously, physical phenomena are thought to promote fluid sequestration and trigger inflammation, which is responsible for excessive wound drainage [20,24,25]. This mechanism is thought to be exaggerated in patients with existing medical conditions. McPherson et al. reported that most of their cases with wound drainage were MSIS class B and C cases [20]. Kallala et al. also reported that the rate of complications was greater in patients with medical conditions [19]. More studies are needed to establish and elaborate on this correlation. The rate of wound drainage varies with different calcium sulphate derivatives used and can also be affected by the type of surgery and the indication for intervention. This ranges from 3.6% in a study conducted by Kelly, who used OsteoSet (Wright Medical Technology Inc., Arlington, USA) [26], to 51% as reported by Ziran et al. using calcium sulphate combined with demineralised bone matrix [8].
The use of synthetic calcium sulphate products has offered a potentially promising solution to a problem faced by orthopaedic surgeons worldwide. Over the years, the use of this calcium sulphate antibiotic delivery system has increased. However, clarity regarding the efficacy of this product and its potential side effects is lacking. Side effects such as wound drainage, heterotrophic ossification and hypercalcaemia are well documented [17][18][19][20][21][22][23].

Conclusions
Our study has shown that a small number of patients developed wound leakage after calcium sulphate bead implantation in prosthetic joint surgeries. However, the correlation of these complications with host factors, product volume and placement in surgery is not well understood. More studies are needed to understand this causality and the factors that play a role in complications arising from the use of calcium sulphate beads.

Conflicts of interest:
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