Symptomatic Hypercalcaemia Following the Use of Dissolvable Antibiotic Beads in Infected Total Knee Arthroplasty
- 65 Downloads
The gold standard treatment for periprosthetic joint infections is currently a 2-stage revision procedure with the use of antibiotic beads or cement spacer. We report the case of an elderly lady who had an infected total knee replacement and underwent a prosthesis retaining procedure with the use of antibiotic loaded calcium sulphate beads (stimulan in this case). Postoperatively, she became profoundly hypercalcaemic and lethargic. After other causes were excluded, she was taken for surgical washout of the knee joint. This led to prompt normalisation of serum calcium levels and resolution of her symptoms. We recommend the need for routine pre- and postoperative serial calcium measurements when using antibiotic impregnated calcium sulphate beads and that all doctors have an increased awareness of this risk.
KeywordsCalcium impregnated beads Stimulan Hypercalcaemia Infected Knee Arthroplasty
Although only a small amount of patients are affected each year , periprosthetic joint infections can confer significant morbidity, mortality and increased care costs. In 2016, there were 7933 hip revision procedures and 5932 knee revision procedures performed in the UK . To date, there exists no ultimate standard of accepted diagnostic criteria for periprosthetic joint infection, and thus, in 2011, the Musculoskeletal Infection Society (MSIS) convened a workgroup which devised two major criteria and six minor criteria .
Various treatment protocols have been developed  including preservation of the prosthesis with debridement, lavage and antibiotic cover, two-staged revision with antibiotic beads or cement spacer and single-stage revision . Two-stage revision remains gold standard internationally, but there is a role for single-stage revision in elderly patients with a known infecting organism of low virulence. In acute presentations, bacterial biofilm (which encapsulates both the prosthesis and neighbouring bone) may not have formed ; chronically, the presence of a biofilm can necessitate prosthesis removal with radical debridement. Along with any pre-existing comorbidities and whether or not a biofilm has formed, patient outcomes in periprosthetic joint infections depend on various factors such as the state of adjacent soft tissue; if vascularisation is poor, this can greatly inhibit antibiotic penetration . Hence, in addition to limiting systemic absorption (and thus, potentially, toxicity) and achieving concentrations higher than that possible with intravenous delivery, local delivery of antibiotics has a number of advantages . Methods of local delivery that exist include antibiotic impregnated polymethyl methacrylate (PMMA) cement spacer (although much of the antibiotic in cement does not successfully escape), insoluble antibiotic loaded PMMA beads and soluble antibiotic loaded calcium sulphate beads . Research has suggested that calcium sulphate appears to result in higher maintained concentrations of antibiotics for several weeks . Stimulan (Biocomposites Ltd., Keele, UK) is a synthetic hemihydrate, biocompatible, hydrophilic crystal based form of calcium sulphate .
The aim of the case report is to highlight the risk of hypercalcaemia from the use of antibiotic loaded calcium sulphate beads and ensure doctors take suitable precautions to either prevent this from happening, or diagnose and treat promptly. A review of the surrounding literature shows that this complication has been previously reported ; however, no cases published thus far have required surgical intervention to normalise calcium levels.
A 92-year-old lady was admitted via A&E on 9/2/18 with a 3-day history of severe right knee pain with associated fevers and rigours. Her past medical history included chronic obstructive pulmonary disease (COPD), mild heart failure, polymyalgia rheumatic, atrial fibrillation and hypertension. She had a previous total knee replacement (TKR) in 2006 due to symptomatic osteoarthritis. On 10/2/18, the right knee was aspirated using an aseptic technique. Microbiology culture results on 14/2/18 revealed growth of group B haemolytic streptococcus.
After discussion at the multidisciplinary team meeting, she was taken to theatre for a DAIR (debridement, antibiotics and implant retaining) procedure on 16/2/18. Intraoperatively, gross pus was found in the knee joint so following washout, synovectomy and insertion of polyethylene insert, the decision was made to use antibiotic impregnated calcium beads. Twenty cubic centimetre of stimulan containing 2G vancomycin and 240 mg gentamicin were used. Postoperatively, she was well and alert on the ward.
On 21/2/18, it was noted that the patient had clinically deteriorated having become gradually more lethargic and delirious. On reviewing recent biochemistry tests, it was noticed that blood calcium levels were trending up.
Following ortho-geriatric review, a number of tests were performed to investigate the hypercalcaemia, including parathyroid hormone levels, serial renal function tests and a CT chest/abdomen/pelvis to look for metastatic disease. After all these, tests returned as normal; it was hypothesised that the calcium beads could be the causative agent.
The aim of the absorbable beads is to provide higher local levels of an antibiotic than possible with intravenous administration. The advantage of calcium sulphate beads over use of PMMA cement spacer/beads, which result in a rapid reduction in antibiotic levels within 24 h of implantation, is that they release high sustained concentrations for several weeks . After discussion with other consultants in the department who regularly use stimulan, none of them had knowledge or experience of this complication. On review of the surrounding literature, it appears that this complication has been previously reported, but only once in the UK. Kallala et al describes a case report of 15 patients whom received absorbable calcium beads following infected prosthetic joint revision surgery of the hip and knee. They found that 3 patients developed hypercalcaemia with 1 patient requiring treatment in the form of intravenous rehydration and bisphosphonates . The paper concluded that they recommend routine serum calcium measurements postoperatively in patients who have had absorbable calcium beads inserted. This is also particularly important given that clinical features of acute hypercalcaemia may well include non-specific features not unusual in postoperative elderly patients such as drowsiness, fatigue, nausea and constipation. We suggest that a further avenue of investigation would include gaining predictive insight into the likelihood of hypercalcaemia following the use of absorbable calcium beads. For example, as well as pre-operative calcium levels, pre-operative documentation could include highlighting other theoretical hypercalcaemia risks such as high stage chronic kidney disease, thiazide use or malignancy. This information, if coupled with postoperative calcium levels and amount of stimulan used, could not only help establish what factors lead to certain patients developing iatrogenic hypercalcaemia but may also assist in a more informed approach in the selection of bead volumes used for a given patient.
McPherson et al  conducted a large case series of 250 patients in the USA following treatment of prosthetic joint infection with absorbable calcium beads (stimulan). They reported no cases of hypercalcaemia and low rates of wound drainage and heterotrophic ossification, which was only associated with the use of > 20 cc of beads. It is logical that an increased quantity of beads used would increase the risk of hypercalcaemia, with Kallala et al reporting 1 patient with hypercalcaemia in their case series who had 40 cc of beads administered, which is double the quantity used for the patient in this case report. It is important to note the US food and drug administration have an active adverse reaction report regarding transient hypercalcaemia following use of stimulan in infected prosthetic joint revision surgery. This presented 3 weeks after implantation and was attributed to renal failure secondary to vancomycin toxicity, which was not suspected in our case report .
Finally, another hypothesis could be that the addition of both vancomycin and gentamicin into the calcium sulphate beads may cause a structural instability, and therefore lead to early disintegration or uncontrolled release. This would be the only major confounding factor between this case and previous case reports listed above as they only used vancomycin loaded beads. On review of surrounding literature this does not appear to have been looked into before and may warrant further research to evaluate.
It is clear from this case report that hypercalcaemia following the implantation of absorbable calcium beads can confer a significant risk to patients. We recommend that all surgeons using any of the antibiotic impregnated calcium sulphate beads (not just stimulan) have an awareness of this risk and consider the quantity of beads used in elderly, frail patients. If suspected, we have shown that prompt surgical debridement can be an effective treatment; however, other medical management options can be considered if the patient is not in extremist. As stated by Kallala et al, we would repeatedly highlight the need for routine pre and postoperative serial calcium measurements in these patients.
I can confirm that all authors were fully involved in the study and preparation of the manuscript and that the material within has not been and will not be submitted for publication elsewhere.
Compliance with Ethical Standards
I can confirm that all authors have followed the guidelines stated on the Declaration of Helsinki 1964.
Conflict of Interest
- 2.2017 National Joint Registry 14th Annual ReportGoogle Scholar
- 4.McPherson EJ, Peters CL. Musculoskeletal infection. In: Flynn JM, editor. Orthopaedic Knowledge Update. 10th ed. Rosemont: American Academy of Orthopaedic Surgeons; 2011. p. 239–58.Google Scholar
- 7.McPherson EJ, Dipane MV, Sherif SM. Dissolvable antibiotic beads in treatment of periprosthetic joint infection - the use of synthetic pure calcium sulfate (Stimulan®) impregnated with vancomycin and tobramycin. Reconstructive Review, Joint Implant Surgery & Research Foundation; 2013:32–43.Google Scholar
- 9.McKee MD et al. A prospective, randomised clinical trial comparing an antiobiotic-impregnated bioabsorbable bone substitute with standard antibiotic-impregnanted cement beads in the treatment of chronic osteomyelitis and infected nonunion. Journal of Orthopaedic Trauma, Aug 2010- Volume 24, Issue 8, P483-490CrossRefGoogle Scholar
- 10.Kallala R, et al. Hypercalcaemia following the use of antibiotic-eluting absorbable calcium sulphate beads in revision arthroplasty for injection. Joint infections use antibiotic impregnated beads. Bone Joint J. 2015;97B(9):12371–41.Google Scholar