Hypercalcemia from calcium sulfate antibiotic beads
A patient was admitted with right hip pain from a chronic prosthetic joint infection.
The patient
A 67-year-old woman with a history of essential hypertension, major depressive disorder, and right hip arthroplasty complicated by multiple revisions was admitted with right hip pain from a chronic prosthetic joint infection. She had had her first orthopedic surgery at age 24 years for hip dysplasia, after which she developed limb shortening requiring multiple surgical interventions. A total hip arthroplasty dislocated after a mechanical fall, and surgical revision was complicated by prosthetic joint infection requiring a recent debridement. At admission, her pain was severe, limiting ambulation. On physical exam, skin breakdown with clear discharge was noted at the site of her most recent surgical incision.
CT imaging confirmed dislocation with a large fluid collection concerning for abscess. Broad-spectrum antibiotics were initiated, and she underwent three sequential incision and drainage procedures, starting with removal of hardware and ending with surgical implantation of 20 mL of antibiotic-eluting calcium sulfate beads. Two days after the last of these procedures, hypercalcemia of 12.8 mg/dL (reference range, 8.8 to 10.2 mg/dL) was noted. Her calcium level had been normal, at 9.4 mg/dL, on admission and subsequently increased to 13.4 mg/dL on repeat labs. She did not report any symptoms of hypercalcemia, and mentation was intact. She had no history of malignancy, hypercalcemia during past admissions, or excess intake of calcium or vitamin D.
Workup revealed an elevated ionized calcium level of 7.13 mg/dL (reference range, 4.3 to 5.2 mg/dL). Renal function and levels of phosphorus and 25-hydroxy vitamin D were normal. She had low levels of 1,25-dihydroxy vitamin D (9 pg/mL; reference range, 18 to 72 pg/mL), parathyroid hormone (8.0 pg/mL; reference range, 15.0 to 65.0 pg/mL), and parathyroid hormone-related protein (8 pg/mL; reference range, 11 to 20 pg/mL). No monoclonal spike was seen on serum protein electrophoresis with immunofixation. The surgical team started IV isotonic fluids at 125 mL/h. On repeat testing, her calcium level had increased to 14.3 mg/dL. No EKG changes congruent with hypercalcemia were seen. After an endocrinology consult, she was placed on an aggressive fluid regimen of 1-L bolus followed by an infusion with 200 units of intramuscular calcitonin at 200 mL/h. Her calcium levels trended downward to a normal level of 10 mg/dL over a four-day period. She was discharged home with a prolonged course of antibiotics. Her calcium levels remained normal one year after surgery.
The diagnosis
The diagnosis is parathyroid hormone-independent asymptomatic hypercalcemia related to calcium sulfate beads. Calcium sulfate beads are used to locally deliver high concentration of antibiotics in prosthetic joint infections. In the United States, the most common surgical approach to prosthetic joint infection is a two-stage exchange arthroplasty involving resection of the infected prosthesis followed by placement of a joint spacer for space-filling effect and local antibiotic delivery. The frequency of calcium sulfate bead use is not known, as data remain limited, but this strategy is increasingly favored as the beads do not act as a nidus of infection and are systemically resorbed without needing surgical removal. Hypercalcemia has been reported as a side effect, however, and preoperative hypercalcemia is a contraindication to use. An observational case series of 15 patients reported transient hypercalcemia in three patients, one of whom required treatment. Diagnosis is established by ruling out alternative causes of hypercalcemia in patients who develop acute hypercalcemia after implantation with quick recovery. The differential diagnosis in our case included non-parathyroid hormone-mediated hypercalcemia such as malignancy, sarcoidosis, or excess calcium or vitamin D intake.
The pathophysiology of hypercalcemia from calcium sulfate beads is yet to be elucidated. It may be related to host factors, especially reduced renal function, and may be dose dependent. However, severe hypercalcemia to 16 mg/dL has been reported with as little as 10 mL of calcium sulfate beads, and our patient, like some in case reports, had normal renal function. It is difficult to determine if certain formulations are more likely to produce hypercalcemia, since most of the literature discusses the same formulation. Onset varies from postoperative day one to day four, with peak calcium levels on postoperative days three to five. Treatment depends on severity and the rate of increase. Hypercalcemia up to 14 mg/dL that develops chronically does not always require treatment, but hypercalcemia that exceeds 14 mg/dL, develops acutely, or is asymptomatic should be managed with aggressive fluid resuscitation at the rate of 200 to 250 mL/h, aiming for urine output of 100 to 150 mL/h. Calcitonin rapidly reduces calcium levels but is limited by tachyphylaxis. Antiresorptive agents such as bisphosphonates (or denosumab in reduced renal function) are effective for reducing calcium starting from 48 hours. Occasionally hemodialysis may be required, especially in patients with impaired renal function. Normal calcium levels are achieved in most cases on postoperative days 10 to 14.
Pearls
- Hypercalcemia can result from calcium sulfate bead use in orthopedic procedures; risk factors include impaired renal function and volume of antibiotics.
- The diagnosis of hypercalcemia from calcium sulfate beads is one of exclusion after ruling out alternative causes of parathyroid hormone-independent hypercalcemia.
