Challenging the dogma that severe hypercalcemia is life threatening

In health, plasma total calcium concentration is maintained within the approximate reference interval: 2.20-2.60 mmol/L (8.8-10.4 mg/dL), so that hypercalcemia (increased blood calcium) is defined as plasma total calcium greater than 2.60 mmol/L (10.4 mg/dL). The two most common causes of hypercalcemia are malignant disease and primary hyperparathyroidism, together accounting for around 80 % of all cases.

Severe hypercalcemia, defined variously in the literature as plasma calcium >3.5 mmol/L (14 mg/dL) or >4.0 mmol/L (16 mg/dL), is rare, but widely considered a potentially fatal condition that requires emergency treatment. The term ”hypercalcemic crisis”, often used for the condition, emphasizes its perceived life-threatening seriousness. The basis for this alarming view is that severe hypercalcemia is supposedly associated with high risk of cardiac arrhythmia and consequent cardiac arrest, as well as CNS effects that result in coma.

The well-established view, reflected in medical textbooks and the wider medical literature, that severe hypercalcemia is an immediate life-threatening condition, is now challenged by the results of this retrospective observational study conducted by a group of emergency care physicians at a French teaching hospital in Nantes. 

Study investigators interrogated their hospital laboratory database to identify all 126,204 adult patients attending the emergency department who had blood calcium concentration measured during a 5-year study period (Jan 2008-Dec 2012). Of the 126,204 patients, 95,933 (76 %) were found to be normocalcemic, 28,263 (22.4 %) were hypocalcemic (calcium <2.20 mmol/L), and 1977 (1.5 %) were hypercalcemic (calcium >2.60 mmol/L). Of the 1977 hypercalcemic patients, just 31 (1.56 % or 0.025 % of the total study population) had severe hypercalcemia (defined for the study as calcium >4.0 mmol/L). This first finding confirms the rarity of severe hypercalcemia; just 31 cases at this hospital emergency department during the 5-year study period. 

In order to assess the clinical significance of severe hypercalcemia, the study authors retrieved and reviewed the full medical record of the 31 identified severely hypercalcemic patients. The primary aim was to determine the prevalence of life-threatening cardiac arrhythmias and/or life-threatening neurological complication (coma) during stay in emergency department among these 31 patients.

A secondary aim was to determine eventual outcome for the patients in terms of mortality. The authors also wanted to determine if in this severely hypercalcemic group there was a correlation between serum calcium concentration and the QTc interval, an electrocardiographic (ECG) parameter. (The literature suggests that shortened QTc interval is a feature of hypercalcemia) 

The 31 patients were predominantly elderly (median age 62 years, interquartile range (IQR), 52-77 years). Most had a significant pre-existing medical condition. For example, 11 (35 %) patients were, at the time of emergency room admission receiving treatment for cancer; four (13 %) had dementia; and 15 (48 %) had hypertension. 

Median calcium concentration of the 31 patients was 4.3 mmol/L (IQR 4.2-4.7 mmol/L); the highest calcium was 5.76 mmol/L. The two most common causes of hypercalcemia were malignancy (either solid tumor or hematological), 20 (65 %) patients, and primary hyperparathyroidism, 5 (16 %) patients. 

Median ED stay was 7 hours 32 minutes (range 5-10 hours). ECG review confirmed that no patient presented with a life-threatening arrhythmia (i.e. no evidence of ventricular tachycardia, ventricular fibrillation, sinus arrest, second degree or third degree atrioventricular blocks). QTc interval was decreased in seven (23 %) patients, normal in 17 (55 %), increased in five (16 %) and not determined in two (6 %) patients. There was no correlation between calcium concentration and QTc interval. 

Review of patients’ Glasgow Coma Scale (GCS) scores recorded during ED admission confirmed that only one of 31 patients presented with coma (defined as GCS score <9/15). The remaining 30 patients had normal level of consciousness (GCS score 15/15) or mild neurological dysfunction (GCS score 14/15). The single comatose patient was an 85-year-old woman with history of dementia, sedative prescription, acute respiratory failure, renal failure and severe hypernatremia (plasma sodium 160 mmol/L).

Given her presenting dire and complex clinical condition, coma could well be due to factors other than severe hypercalcemia. In the event, a decision to withhold life-sustaining therapy (including calcium-lowering medication) was made, and following 2 days of palliative sedation (iv morphine) on a medical ward, this lady died. 

None of the 31 patients died in the emergency department and all were admitted to hospital wards, during which administration of calcium-lowering drugs resulted in normalization of blood calcium in the vast majority (93 %) over the following 4-7 days. 

Three very elderly patients (aged 85, 87 and 94), all in palliative care as a result of pre-existing disease, died during the first week in hospital. These three include the previously mentioned comatose patient. Thus 1-week mortality of the study cohort was 10 %. 

A further six patients died after at least 3 weeks in hospital (calcium level at the time of death was normal in four, but abnormally high in two patients). All six patients were receiving end-of-life palliative care only. The majority (70 %) of these severely hypercalcemic patients survived to hospital discharge. 

This study, which the authors claim is the first to specifically investigate the immediate threat posed by severe hypercalcemia, has revealed no evidence that the condition results in immediate life-threatening cardiac arrhythmia or coma. The cause of death among this study cohort could be justifiably attributed to factors other than severe hypercalcemia. In discussion of their study, the authors critically assess the weak evidence base that underpins the long-held view that severe hypercalcemia is a life-threatening medical emergency.