key: cord-0813307-sj26x8es
authors: Bentata, Y.; Benabdelhak, M.; Haddiya, I.; Oulali, N.; Housni, B.
title: Severe hypercalcemia requiring acute hemodialysis: A retrospective cohort study with increased incidence during the Covid-19 pandemic
date: 2021-11-12
journal: Am J Emerg Med
DOI: 10.1016/j.ajem.2021.11.013
sha: e55343c2d32509a24dc90a8c6fb70baf56eb8d51
doc_id: 813307
cord_uid: sj26x8es

BACKGROUND: The Covid-19 pandemic has had dramatic consequences on the progression of numerous pathologies, especially neoplastic ones. The orientation of hospital activities toward the care of patients with SARS-Cov2 infection has caused significant delays in the diagnosis and therapy of many other pathologies. What about severe hypercalcemia? The aim of this work was to determine the clinical and biological presentation, etiologies, mortality, and the impact of the Covid-19 pandemic on severe hypercalcemia. MATERIAL AND METHODS: we conducted a retrospective study for 84 months (September 2014 to September 2021) at the Nephrology Unit in University Hospital Mohammed VI, Oujda, Morocco. Included were all adult patients diagnosed with severe hypercalcemia (defined as corrected total serum calcium of >3.5 mmol/l or > 14.0 mg/dl) and who had benefited from one or more hemodialysis sessions. RESULTS: 66 episodes of severe hypercalcemia occurred in 64 patients. The mean age was 57 ± 15 years and 57.6% were female. The mean corrected serum calcium at admission was 16.9 ± 2.1 mg/dl and 33.3% had more than 18.0 mg/dl. Malignancies represented 80.4% of all etiologies. Acute kidney injury was observed in 69.7%. The delta drop in serum calcium 48 h after initiation of medical treatment was 4.64 ± 1.63 mg /dl. Mortality was noted in 14% of all cases. Electrocardiographic abnormalities were observed in 58.3%, 87.5% and 85.7%, respectively, in group 1 (14.0–16.0 mg/dl), group 2 (16.1–18.0 mg/dl), and group 3 (> 18.0 mg/dl) (p = 0.04). The mean serum potassium value was 5.1 ± 1.3, 4.0 ± 1.0, and 3.7 ± 0.7 respectively, in group 1 (14.0–16.0 mg/dl), group 2 (16.1–18.0 mg/dl), and group 3 (> 18.0 mg/dl) (p < 0.001). Newly diagnosed neoplasia, severe hypercalcemia (> 16.0 mg/dl), and mortality have been observed in 15.4% vs. 23.7% (p = 0.31), 25% vs. 50% (p = 0.03), and 35.7% vs. 52.6% (p = 0.13) respectively, in patients before and during the Covid-19 pandemic. CONCLUSIONS: The Covid-19 pandemic caused an increase in both the incidence and severity of hypercalcemia and the hemodialysis practiced in this context remains efficient and safe.

Severe hypercalcemia, also called hypercalcemic crisis or malignant hypercalcemia, a serious electrolyte disturbance and life-threatening condition, is currently mostly encountered in hospital practice, where its incidence remains low and does not exceed 1% of all patients admitted to emergency departments (1). Habitually, we divide hypercalcemia into mild hypercalcemia with serum calcium levels of <12.0 mg/dl, moderate hypercalcemia with serum calcium levels between 12.0 mg/dl and 14.0 mg/dl, and severe hypercalcemia with serum calcium levels above 14.0 mg/dl (2). In adults, malignancies seem to be the main etiologies of severe hypercalcemia, with primary hyperparathyroidism and other types of endocrinopathy as the second cause, followed by less frequent causes, such as iatrogenic etiologies and granulomatous diseases (3) . The most serious complications of severe hypercalcemia that can be life-threatening to patients are cardiovascular, neurological, and kidney complications. Acute kidney injury (AKI) is a frequent complication of severe hypercalcemia and is usually functional, secondary to hypovolemia, itself linked to polyuria caused by hypercalcemia and hypercalciuria, or acute tubular necrosis caused by a nephrotoxic drug, an iodinated contrast agent, associated sepsis or direct tubular toxicity as is the case with light chains in multiple myeloma. The use of renal replacement therapy (RRT)

is often necessary to immediately and effectively correct the hypercalcemia, uremia, and electrolyte disturbances related to AKI. In the current setting of the Covid-19 pandemic, we can assume that the incidence of severe hypercalcemia has increased. Although, since the start of the pandemic, neoplasia from all causes has been a high priority alongside Covid-19 patients, dramatic consequences have occurred.

Indeed, severe hypercalcemia, due to the unavailability of injectable calcitonin in many countries, is increasingly an indication for acute hemodialysis, and its incidence probably (5) . The aim of this study was to determine the clinical and biological presentation, etiologies, organ complications, kidney function, therapeutic methods, mortality, and the impact of the Covid-19 pandemic on the incidence of severe hypercalcemia.

We conducted a retrospective study for 84 months (September 2014 to September 2021) at the Nephrology, Dialysis, and Kidney transplantation Unit in University Hospital Mohammed VI, Oujda, in eastern Morocco, North Africa. Included were all adult patients (> 16 years) diagnosed with severe hypercalcemia that was defined as corrected total serum calcium of ≥ 3.5 mmol/l (≥14.0 mg/dl) and who had benefited from one or more hemodialysis sessions in the acute dialysis unit, whatever the level of kidney function. Acute kidney injury (AKI) was defined using the KDIGO (Kidney Disease Improving Global Outcomes) criteria according to the level of increase in blood creatinine levels and urine output, and all patients were classified stage 3 "Failure" because they all underwent a hemodialysis session regardless of the serum creatinine value (6) . Ethics Committee approval and informed consent were not needed because the study was observational and retrospective and the need for written informed consent was waived due to the retrospective nature of this research. The study was performed with absolute respect for international ethical rules, anonymity, and data protection.

During the study period, 197 patients were admitted to emergency and various medical units for hypercalcemia with corrected total serum calcium greater than 3 mmol/L (12.0 mg/dl) and respectively, in patients before and during the Covid-19 pandemic.

Despite its relative frequency, its severity, the difficulty of its management, the absence of with free calcium dialysate (12) . In this study, the hemodynamic tolerance was not good, with a non-negligible incidence of arterial hypotension and cardiac rhythm disorders, but the observed effect on the lowering of calcemia was interesting. At the same time, the bisphosphonates that have revolutionized the treatment of hypercalcemia were not available during the 1980s and 1990s. Currently, dialysis with free calcium dialysate is not recommended. First-line treatment of a hypercalcemic crisis includes hydration, administration of furosemide after rehydration, intravenous glucosteroids, salmon calcitonin, and intravenous bisphosphonates.

Nevertheless, this arsenal of measures, except salmon calcitonin, which is not available in all countries and medical centers, cannot deeply and rapidly lower the serum calcium; even combined, the time of action of these treatments is approximately 48 hours. Rehydration, J o u r n a l P r e -p r o o f diuretics, and corticosteroids have a less powerful hypocalcemic effect but their association with other treatments results in effective and prolonged action. The onset of action of calcitonin is 2 to 6 hours and should be repeated every 6 to 8 hours without exceeding 48 hours due to the development of tachyphylaxis, itself linked to downregulation of calcitonin receptors. For bisphosphonates, the onset of action is 48 hours and lasts up to 30 days. The use of dialysis with low calcium dialysate (1.25 mmol/l) makes it possible to lower serum calcium, restore kidney function, improve clinical symptoms and reduce morbimortality in a few hours after initiation (13) (14) . In our study, the delta drop in serum calcium 48 hours after initiation of medical treatment, including hemodialysis sessions, was 4.71  1.63 mg /dl and reflects the effectiveness of the treatment initiated. In our series, mortality was not directly related to hypercalcemia and death occurred after correction of hypercalcemia. In this context, mortality remains linked to other complications, particularly infectious, cardiovascular, and neoplastic.

Our study shows a significant increase in cases of severe hypercalcemia as well as in the average corrected total serum calcium level during the Covid-19 pandemic. This is linked to the progression of pre-existing neoplastic disease and the delays in diagnosing new neoplastic diseases resulting from the major impact of the Covid-19 pandemic on the overall organization of hospital activities. Hemodialysis with low calcium dialysate should be performed within hours of the diagnosis, particularly in the presence of neurological symptoms and/or electrocardiographic abnormalities, whatever the kidney function, because cardiac arrhythmia may rapidly progress into complete heart block and cardiac arrest. One to three hemodialysis sessions are usually sufficient to significantly lower the calcium value and correct any associated electrolyte disturbances, thus contributing to an improvement in the overall morbidity and mortality of these patients. Today, hospital activities have resumed their usual rhythms guaranteeing better management of neoplastic disease. 

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disorientation, confusion, coma..) Digestive symptoms (nausea, vomiting, abdominal pain..) metastases and solid cancer

The authors declare that they have no conflicts of interest.Funding: This work has not received any financing or sponsorship.

All the authors of this submitted article declare that they have no conflicts of interest.Funding: This work has not received any financing or sponsoring and all the authors of this submitted article declare that they have no financial conflict.