The Risk of Iatrogenic Hypercalcemia in Patients Undergoing Calcium Sulphate Beads Implantation in Prosthetic Joint Surgery: A Systematic Review

Calcium sulphate beads are increasingly being used in the management of prosthetic joint infections (PJI). Traditionally their use was limited to a void or dead space-filling combined with other additives such as Hydroxyapatite. Over the last decade, they have been developed to act more frequently as an antibiotics delivery system. Stimulan, a bio-absorbable form of Calcium sulfate, theoretically has an increased risk of hypercalcemia. Over the last few years, there have been published case reports which report it as an isolated cause of iatrogenic hypercalcemia. The sparsity of literature on this topic makes it difficult for surgeons to decide on the use of Calcium sulphate beads in patients with hypercalcemia predisposition in conditions like autoimmune disorders, sarcoidosis, malignancy, granulomatous diseases, heterotopic ossification, and hyperparathyroidism. The study was performed to assess the risk of hypercalcemia in patients after Calcium sulphate beads implantation in PJI. Two reviewers searched relevant literature in 3 online databases using cochrane methodology for systematic reviews. Studies reporting complications with the use of calcium sulphate beads in prosthetic joints were included. Studies reporting on less than five patients and studies reporting use in any other surgeries were excluded. The search of databases resulted in a total of 96 articles. After screening, a total of four articles were deemed suitable to be included in the analysis. A total of 1049 patients underwent calcium sulfate beads implantation, out of which 44 (4.2%) reported hypercalcemia with 41 (3.91%) transient in nature and 3 (0.28%) required management, including one with ICU admission. The result of this systematic review shows that calcium sulphate beads are safe and effective against PJI. There is a significant risk of transient hypercalcemia in susceptible patients and a low risk of symptomatic hypercalcemia.


Introduction And Background
The use of calcium sulfate as a bone void filler is over a century old. However, its use remained limited until 1959 when Peltier et al. found that this substance (a component of plaster of Paris) acts as a potent agent for bone filling, allowing bone formation without any foreign body reaction [1]. Traditionally PMMA (Polymethyl methacrylate) was used as an antibiotics carrier system in infections, but the need for removal after surgery has remained a significant downside [2]. The calcium sulfate beads are increasingly used these days as a bone filler and antibiotic delivery system in infections and fractures [3,4]. Several drug combinations, including antifungals, have been used with Calcium sulphate beads for prosthetic joint infections, including vancomycin, gentamycin, tobramycin, amikacin, and caspofungin [5][6][7][8]. Over the last decade, several case reports and case series have highlighted the incidence of hypercalcemia with Calcium sulphate beads use [5][6][7][8][9]. There is a lack of evidence of its safety profile in patients with a risk of high serum calcium such as hyperparathyroidism, malignancy, autoimmune disorders, and granulomatous diseases. Hypercalcemia can lead to cardiac arrhythmia, confusion, renal stones, and increased hospital stays [10].
This study aims to assess the risk of hypercalcemia using Calcium sulphate beads in prosthetic joint infections. It proposes the consideration of additional monitoring in high-risk patients. Furthermore, if Calcium sulphate beads increase the serum calcium levels, are there any specific needs to monitor serum calcium levels in high-risk patient groups considering serum calcium are not routinely monitored postoperatively. Two reviewers searched relevant literature in 3 online databases using cochrane methodology for systematic   1  2  1  1  3 reviews. The words "Calcium sulphate beads", "calcium sulfate beads", and "Stimulan" were cross searched with the words "Arthroplasty", "joints", "complication", and "hypercalcemia" in Pubmed, Cochrane, and Embase. A total of 96 articles were found; after the removal of duplications, 58 articles were attained. Two reviewers reviewed the shortlisted articles' titles and abstracts against inclusion criteria. Fifteen full articles were reviewed, and four were selected for the study. Eligibility criteria were any study that reported the use of Calcium sulfate beads in prosthetic joints with mentioning of complications. Disagreements for inclusion were discussed between the reviewers and, if not resolved, discussed with one of the senior authors. The Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) methodology was used [ Figure 1] [11]. The design methodology of each study was determined using the guidelines described by Mathes and Pieper [12]. FIGURE 1: PRISMA study methodology used for the systematic review. [11]

Discussion
Prosthetic joint infection (PJI) is a severe complication with an incidence of 1-2% of primary arthroplasties and is associated with a high morbidity rate [13]. The Musculoskeletal Infection Society (MSIS) proposed diagnostic criteria for Periprosthetic Joint infection, which includes the presence of sinus tract communicating with the prosthesis, isolating a bug, and six laboratory parameters as listed in [ Table 1] [14]. The European Bone and Joint Infection Society's (EBJIS) definition of Periprosthetic infection is becoming more popular and is considered more sensitive by various authors [15][16][17]. Periprosthetic infection is challenging to manage; it impacts patients' lives and has significant economic implications on the healthcare system. A study published in 2020 has shown that following a primary Total Hip Replacement, patients who develop PJI and undergo revision surgery cost over five times (33,000 pounds) more than the patients not undergone revision surgery in inpatient and daycare admissions [18]. Staging of the patient has great influence over the possible risk of PJI [ Table 2, 3] [19]. Pre-operative optimization of modifiable risks of those factors is associated with improved overall outcomes. There are several pre-operative bundle protocols; however, several variables are consistently present across the varying protocols: such as BMI (<35 kg/m2), Haemoglobin (>11 -12 g/dl), Glucose control (e.g. HbA1C < 7.0 -7.5 %), no tobacco use for > 30 days, MRSA (Methicillin-resistant Staphylococcus aureus colonization status) and nutritional status as indicated by albumin (>3.0 -3.5 g/dl) [20].   A principle of treatment option for all PJI is thorough debridement and adequate delivery of antibiotics to the affected joint space. Surgical treatment options for PJI include single-stage revision (2 in 1), two-stage revision, and DAIR procedure (Debridement and Implant retention, which involved exchanging the modular components of the affected prosthesis). The latter procedure included the implantation of calcium sulfate beads and intravenous antibiotics [17]. Although the best surgical approach for all cases of PJI cannot be identified, it is universally accepted that antibiotics play an essential role in the management of PJI. Generally, long-term antibiotics are effective; however, in cases of PJI, local devascularization of infected tissues can prevent local antibiotic delivery.

Infection
Moreover, in chronic scenarios, biofilm formation protects the pathogen(s) from the bactericidal action of antibiotics [21]. In this case, local delivery systems offer a solution. A study has shown that antibioticimpregnated Calcium sulphate hemihydrate is a useful tool for local delivery of therapeutic concentrations. Calcium sulphate acts as a mineral phase of bone, and they are absorbed at a rate similar to bone formation; thus, they provide structural support and prevent fibrous tissue ingrowth [23]. They act as a vehicle for local high-dose antibiotic delivery. In each of their five postoperative days, they are evaluated with Tobramycin and Vancomycin, and mean local concentrations exceeded the minimum amount of antibiotic needed to inhibit common pathogens [22].
The use of calcium sulphate inside the body is not a new phenomenon [23]. The first internal use was reported by Dressmann et al. in 1892 when they used gypsum(calcium sulphate dihydrate) to fill body defects in 8 patients [24]. Peltier first documented the concern of hypercalcemia by implantation of absorbable calcium compounds in 1969. He observed an initial rise in calcium levels in dogs in the postoperative period, a finding that was not later demonstrated on patients [1]. It has been hypothesized that hypercalcemia following placement of calcium sulphate compounds is due to a rapid uptake of calcium ions from dilated capillary beds, so-called 'dumping' of calcium into the systemic circulation. This occurrence is poorly understood and is thought to be brought on by a combination of host factors [7].
In our review, we identified 1049 patients undergoing revision arthroplasty. The predominant indication was PJI. Transient hypercalcemia was identified in 44 (4.2%) of these patients collectively. 3 (0.28%) of these cases developed symptomatic hypercalcemia, requiring one ICU admission therapy. Forty-one cases did not need any calcium-specific therapy.
Evidence of iatrogenic hypercalcemia from the use of Stimulan is also found in multiple case reports [25][26][27].
In one of these cases reported by Jung et al. [9], the serum calcium rose to 5.41mmol/l. While three of these four cases were treated with fluid resuscitation and calcitonin, one patient developed renal failure and anuria [27]. This patient had to undergo multiple sessions of hemodialysis for 22 days, followed by recovery. In 2013, McPherson et al. [5] conducted an extensive analysis of 250 patients undergoing revision arthroplasty. They aimed to review complications arising from using calcium sulphate beads as a therapeutic and preventive modality. They found these devices were associated with a complication rate of 11.6%, including wound drainage (3.2%) and heterogenous ossification (1.2%). However, no cases of hypercalcemia or hypercalcemia-associated symptoms were reported in this study [ Table 5].  The first study to report hypercalcemia in a cohort was conducted by Kallala et al. in 2015 [6]. They prospectively analyzed 15 patients undergoing revision arthroplasty for PJI. They found transient hypercalcemia in 3 (20%) of their cases, with one of these going on to develop symptomatic hypercalcemia.

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A calcium level of 3.17 mmol/l was recorded on the second postoperative day and was managed with 4 litres of normal saline and 4mg IV Zolendronate over 24 hours. The calcium levels peaked at 3.54 mmol/l on the fifth postoperative day despite ongoing treatment, after which the patient was moved to intensive care and made a full recovery subsequently [ Table 5].
Another large study published by Kallala et al. in 2018 examined complications associated with a calcium sulphate antibiotic delivery system [7]. This study enrolled 755 patients undergoing revision arthroplasty and found hypercalcemia in 41 (5.4%) patients. Two of these patients also developed symptoms and were treated with normal saline and intravenous bisphosphonates, followed by the return of calcium to baseline. The mean calcium postoperatively for the hypercalcemic patients was 2.97 mmol/l which returned to baseline on the fifth postoperative day [ Table 5].
The latest addition to the literature regarding iatrogenic hypercalcemia was made by Sandiford et al. in 2020 [8]. They prospectively evaluated 29 patients undergoing revision hip arthroplasty for evidence of hypercalcemia. They measured serum calcium levels serially and found that the mean calcium of their cohort increased from 2.5 mmol/l preoperatively to 2.7 mmol/l on the first postoperative day (p=0.09). This increase was sustained in the first two weeks, after which the mean calcium levels returned to 2.4mmol/l six weeks postoperatively. No patients in this cohort developed symptomatic or transient hypercalcemia, and none needed treatment. Note that the reference range of calcium for this study was <3 mmol/l [ Table 5].   Table 5] [5].
The procedural spaces used for the implantation of calcium sulphate beads can also potentially be related to calcium absorption. This can be related to variable vascular patterns in and around a joint. In hip surgery, Kallala et al. used the space inferior to the acetabulum and proximal femur for implantation [6,7], while Sandiford chose intracapsular implantation [8]. In knee surgery, medial and lateral gutters were used by both McPherson and Kallala et al. [ Table 5] [5][6][7].
In our literature review regarding iatrogenic hypercalcemia due to calcium sulphate beads, we did not find any attributed mortality. However, significant side effects have been reported, including serious morbidities such as renal failure and symptoms requiring ICU admission. These studies and the theoretical risk of absorption of rapid calcium absorption via capillary beds around the implantation site warrant caution and vigilance on the orthopaedic surgeon and management team.

Conclusions
Hypercalcemia is a potential complication in patients undergoing calcium sulphate bead implantation in prosthetic joint surgery. This complication is rare in occurrence but can result in morbidity for the patient. Further studies are needed to evaluate this relationship.

Conflicts of interest:
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