Abstract
A hypercalcemic crisis (HC) is a life-threatening endocrine emergency if not promptly diagnosed and treated. Initial management for HC includes fluid resuscitation, diuresis, bisphosphonates, calcitonin, and glucocorticoids, along with diagnosing the underlying etiology of HC. However, for the refractory HC, continuous renal replacement therapy (CRRT) with regional citrate anticoagulation (RCA) should be considered. We report a case of severe refractory HC successfully managed with CRRT using RCA and surgery. A 56-year-old female patient was admitted to University Medical Center Ho Chi Minh City due to a decrease in consciousness. Laboratory tests and clinical manifestations suggested the diagnosis of primary hyperparathyroidism. The patient was managed with strategies to lower calcium levels, including intravenous normal saline, oral fluid replacement via nasogastric tube, calcitonin, and bisphosphonate; however, the patient did not respond to the initial treatment. Subsequently, the patient underwent CRRT with RCA and calcium-free replacement fluid to reduce the calcium level before parathyroidectomy. The patient was discharged after 10 days of hospitalization. CRRT with RCA appears to be a potential, effective, and safe method for treating refractory hypercalcemic crises. Further research is required to investigate the role of CRRT with RCA in refractory hypercalcemia.
Keywords
Background
Hypercalcemic crisis (HC) is a life-threatening endocrine emergency if not promptly diagnosed and treated. HC can cause acute kidney injury, unconsciousness, respiratory failure due to muscle weakness, and severe arrhythmias leading to cardiac arrest.1,2 Therefore, initial management for HC includes fluid resuscitation, diuresis, bisphosphonates, calcitonin, and glucocorticoids, along with diagnosing the underlying etiology of HC. However, for refractory HC, continuous renal replacement therapy (CRRT) should be considered. 3 There is currently no consensus guideline on using CRRT with regional citrate anticoagulation (RCA) or calcium-free replacement fluid in the treatment of HC. Most of the evidence is limited to case reports demonstrating the effectiveness of CRRT with RCA.4 –6 We report a case of severe refractory HC successfully managed with CRRT using RCA and surgery.
Case presentation
A 56-year-old female patient was admitted to University Medical Center Ho Chi Minh City due to a decrease in consciousness. Ten days before admission, the patient had a fever and dry cough and was treated with amoxicillin/acid clavulanic, prednisone, and acetylcysteine. Six days later, the patient’s condition worsened, presenting with vomiting, dizziness, and somnolence. The brain magnetic resonance imaging results from a lower-level hospital found no abnormalities. The patient was promptly transferred to University Medical Center for further diagnosis and treatment. Her medical history indicated type 2 diabetes mellitus managed with metformin and atorvastatin, with no history of hypercalcemia, fractures, or nephrolithiasis.
At the Emergency Department, the patient had a heart rate of 64 beats/min, blood pressure of 124/70 mmHg, temperature of 36.8°C, and oxygen saturation (SpO2) of 88% in room air. The patient revealed slow responsiveness, a drowsy appearance, and a Glasgow Coma Scale score of 13 (E3M6V4). Neurological examination reported pupils with a diameter of 2.5 mm, positive light reflexes, unrestricted eye movement, negative nystagmus sign, and no other signs of focal neurological deficits. However, there was mild weakness in the extremities, and meningeal signs were negative.
The results of laboratory tests at the time of admission are illustrated in Table 1, indicating suspected acute kidney injury, hypokalemia, hypercalcemia, elevated C-reactive protein, and increased parathyroid hormone (PTH) levels. Electrocardiography and brain computed tomography (CT) did not reveal any abnormalities. The patient underwent a lumbar puncture due to suspected meningitis; however, the cerebrospinal fluid results fell within normal ranges.
The patient’s laboratory test results.
Abnormal values are highlighted in bold.
ALT, alanine aminotransferase; AST, aspartate aminotransferase; fT4, free thyroxine; NH3, ammonia; PTH, parathyroid hormone; TSH, thyroid-stimulating hormone.
HC was identified following the laboratory results in Table 1, with severe hypercalcemia and multi-organ dysfunction. The patient was managed with strategies to lower calcium, including intravenous normal saline, oral fluid replacement via a nasogastric tube, potassium correction, calcitonin, IV zoledronic acid, and IV Furosemide, following the hospital’s guidelines. Ultrasonography revealed a vascularity hypoechoic nodule in the inferior posterior aspect of the left thyroid lobe, measuring 26 mm × 17 mm, with irregular margins. The CT scan of the neck revealed a hypoechoic mass of approximately 25 mm in diameter, located posterior to the left inferior pole of the thyroid gland. We were unable to perform a Tc99m sestamibi scan as the patient was in severe condition, and a Tc99m sestamibi scan is not available at our hospital. Both laboratory tests and clinical manifestations suggested the diagnosis of primary hyperparathyroidism.
Following initial therapy regimens consisting of medication to lower serum calcium levels for 36–60 h, the patient’s level of consciousness slightly improved. The levels of ionized and total calcium decreased, but not significantly (total calcium was 3.99 mmol/L and ionized calcium was 1.43 mmol/L; Figure 1). Urine output increased to between 100 and 200 mL/h as renal function improved. The patient was scheduled for a parathyroidectomy. Ongoing efforts to lower the calcium levels are required to achieve a safe threshold before the surgery. Subsequently, the patient underwent CRRT with RCA and calcium-free replacement fluid. The patient used Prism0CAL replacement fluid on CRRT (a solution containing magnesium 0.5 mmol/L, sodium 140 mmol/L, chloride 106 mmol/L, lactate 3.0 mmol/L, bicarbonate 32 mmol/L, and osmolarity 282 mOsm/L) at a filtration rate of 1800 mL/h (25 mL/kg/h). Citrate anticoagulant from the Prismocitrate 18/0 replacement fluid was used during CRRT (a solution containing sodium 180 mmol/L, chloride 86 mmol/L, and citrate 18 mmol/L), with a starting citrate dose of 4 mmol/L. The hospital’s protocol is followed while adjusting the citrate concentration and post-membrane calcium replenishment during the hemofiltration process. The ionized calcium level returned to normal following a 6-h course of CRRT. The patient’s consciousness improved after 12 h of CRRT, and the ionized calcium level dropped to 1.12 mmol/L and the total calcium level to 2.25 mmol/L (Figure 1). The patient underwent a parathyroidectomy after 16 h of CRRT. The surgical procedure reported a yellow, soft, well-defined parathyroid mass with dimensions of 2 cm × 2.5 cm. The histopathology result confirmed parathyroid adenoma. Following the surgery, the PTH level decreased to 1.77 pmol/L. The patient was discharged after 10 days of hospitalization.
Progression of CaTP concentration, iCa, and pCa of the patient during hospitalization.
Discussion
An unusual manifestation of hypercalcemia, known as HC, can be fatal if left undiagnosed and untreated. Currently, there is no consensus definition of HC. Ahmad et al. 1 define HC as a calcium level that exceeds 3.5 mmol/L and is associated with symptoms of multi-organ dysfunction caused by increased calcium levels. However, patients with severe symptoms should be considered for HC, even if the calcium level has not reached the diagnostic cut-off. Most organ systems are impacted by hypercalcemia, with the digestive system being the most commonly affected. Symptoms may include loss of appetite, bloating, constipation, nausea, vomiting, or abdominal pain. Necrotizing pancreatitis can also occur. Acute kidney failure, kidney stones, renal colic, polyuria in the early stages, or oliguria in the later stages are reported. Neurological symptoms, such as agitation, coma, lethargy, confusion, and muscle weakening, can range in severity. In terms of the cardiovascular system, hypercalcemia can lead to QT shortening and arrhythmias.1,2 Severe arrhythmias may occur, especially in patients taking digoxin, leading to mortality. 7
Hypercalcemia results from various etiologies, such as hyperparathyroidism, malignancies, vitamin D toxicity, medications, or genetic disorders. Among these, hyperparathyroidism and malignancies account for nearly 90% of hypercalcemia cases. Hypercalcemia can be asymptomatic or present subtle symptoms. Clinical manifestations become apparent when the calcium level exceeds 3 mmol/L. 1 Hypercalcemia is categorized into three degrees: mild, moderate, and severe. Mild hypercalcemia is defined when the total calcium level ranges from 2.5 to 3 mmol/L, or ionized calcium level is between 1.4 and 2 mmol/L. When the total calcium level is between 3 and 3.5 mmol/L or the ionized calcium level is between 2 and 2.5 mmol/L, moderate hypercalcemia is present. Severe hypercalcemia is considered when the total calcium level exceeds 3.5 mmol/L or ionized calcium concentration exceeds 2.5 mmol/L. 2
The treatment of hypercalcemia depends on its severity and underlying etiology. Initial management includes hydration, diuresis, calcitonin, bisphosphonates, denosumab, and corticosteroids.8,9 In cases of severe hypercalcemia causing a decrease in consciousness, arrhythmia, or progressive acute kidney injury, CRRT with a low-calcium replacement solution may be considered, especially when fluid restriction is mandatory or when there is a poor response to prior treatment. However, the failure rate of CRRT in the treatment of HC remains high. A retrospective study that included 42 cases of HC treated with CRRT showed that 19/42 (45.2%) cases failed to respond to treatments, including medications, surgery, and CRRT with a low-calcium replacement solution (1.25 mmol/L). The mortality rate in the nonresponsive group to all treatment modalities was 58.8%, whereas the mortality rate in the CRRT-responsive group was 10.5%. 3 Currently, there is no international consensus regarding the use of CRRT in the treatment of hypercalcemia. 1 Most of the evidence is limited to case reports demonstrating the effectiveness of CRRT with RCA.4 –6 Therefore, further research is required to investigate the role of CRRT with RCA in refractory hypercalcemia.
In this case, the patient showed typical symptoms of HC, such as nausea, vomiting, muscle weakness, and lethargy, along with a total calcium level of 4.92 mmol/L. Despite following recommended strategies such as fluid resuscitation, diuresis, bisphosphonates, and calcitonin, the total calcium level remained consistently above 3.5 mmol/L. Glucocorticoids were not administered in our case as they are less effective with hyperparathyroidism. 1 We have added successful management of HC cases by using CRRT with citrate anticoagulation to the literature. However, the treatment of each patient should be individualized. We observed the effectiveness of CRRT in rapidly reducing the calcium level, with normalization of ionized calcium levels occurring within 6 h. Therefore, monitoring calcium levels for post-membrane calcium supplementation during CRRT is essential to prevent hypocalcemia.
The effectiveness of lowering calcium levels by CRRT is primarily explained by two mechanisms. First, the replacement solution does not contain calcium or contains only a low level of calcium. 3 However, there are still reports indicating that replacement solutions containing a low concentration of calcium may fail in 55% of HC cases. 3 Second, anticoagulants containing citrate inhibit ionized calcium by binding to form calcium-citrate complexes, which are transported back and excreted in the liver. 10 The anticoagulant mechanism containing citrate is believed to be the primary mechanism for reducing blood calcium levels. Case reports also demonstrate the effectiveness of CRRT with RCA in treating HC. 11 However, it is emphasized that our patient was not supplemented with post-membrane calcium until the blood calcium level returned to normal. Although this may lead to transient episodes of hypocalcemia and could be associated with the emergence of arrhythmia, 12 our patient was closely monitored, and the filtration rate was not relatively high (25 mL/kg) to avoid hypocalcemia.
CRRT with RCA has been a preferred anticoagulation method in critically ill patients, particularly those at high risk for bleeding. It chelates ionized calcium in the extracorporeal circuit, inhibiting the clotting cascade. Low-calcium or calcium-free dialysate enhances this process by maintaining low-calcium levels within the circuit. However, this method has potential safety issues that must be carefully managed, such as hypocalcemia and citrate accumulation. Hypocalcemia is the most common complication associated with RCA. Citrate binds ionized calcium in the blood. Therefore, if calcium supplementation through systemic infusion is inadequate, patients may experience symptoms of hypocalcemia, such as muscle spasms, paresthesia, tetany, and cardiac arrhythmias. Severe hypocalcemia can lead to life-threatening complications, such as asystole. To prevent hypocalcemia, real-time monitoring of both systemic and circuit-ionized calcium levels is essential. The systemic ionized calcium levels should be maintained within the normal range (1.0–1.25 mmol/L), while the circuit calcium concentration should be kept below 0.35 mmol/L to ensure effective anticoagulation. Citrate accumulation can occur when the patient’s ability to metabolize citrate is overwhelmed, leading to an accumulation of citrate in the bloodstream. This is more likely in patients with severe liver dysfunction, where the hepatic metabolism of citrate is impaired, and shock or poor perfusion state. Citrate accumulation manifests as metabolic acidosis, total calcium/ionized calcium ratio >2.5, and persistent hypocalcemia despite adequate calcium infusion. This condition requires immediate intervention, such as reducing citrate infusion rates, increasing dialysate and replacement rates, or discontinuing RCA if necessary. Therefore, clinicians must ensure vigilant monitoring and timely adjustments to calcium infusion and citrate rates, following established protocols and tailoring care to individual patients to mitigate the risks associated with hypocalcemia and citrate toxicity.12,13 Besides, the comparative efficacy and safety of RCA and Low-Molecular-Weight Heparin (LMWH) for CRRT have been studied in patients with severe hypercalcemia. According to Yu et al., 14 RCA offers some advantages over LMWH. RCA had more efficacy in reducing ionized calcium levels than LMWH, with the mean ionized calcium reduction rates after first 4 h was 0.138 ± 0.098 mmol/L/h in the RCA group compared to 0.079 ± 0.033 mmol/L/h in the LMWH group (p = 0.033). RCA showed prolonged filter lifespan (>72 h vs 24 h, interquartile range 15–26, p = 0.012) and minimizing adverse events, such as bleeding. 14
Conclusion
The HC is a life-threatening endocrine emergency if not promptly diagnosed and treated. Hypercalcemia impacts many organ systems, such as the digestive system, urinary system, nervous system, and cardiovascular system. CRRT with citrate anticoagulation appears to be a potential, effective, and safe method for treating refractory hypercalcemic crises.
