Question 9

a) List the clinical features of severe symptomatic hypercalcaemia and outline the treatment of this condition.

b) List four common causes of ionised hypocalcaemia and for each give the underlying mechanism.

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College Answer


  • Clinical features:
    • CNS and PNS
    • Confusion
    • Coma
    • Hypotonia
    • Hyporeflexia
    • Paresis
  • Renal findings
    • Renal stones
    • Volume depletion
    • Renal failure
  • GI findings
    • Constipation and fecal impaction
    • Pancreatitis
    • Gastric ulcer
  • Cardiac findings
    • Arrhythmias
    • Hypotension
    • Shortened QT interval

Signs related to underlying malignancy:


Treatment includes reduction of hypercalcaemia and treatment of underlying cause.

Measures for reduction of hypercalcaemia- (listing of agents adequate, doses & mechanism not expected)

Saline/frusemide diuresis- correction of dehydration with about 2L of fluid and 80mg Frusemide 2-4 hourly (only when volume has been adequately replaced) with replacement of urine losses with fluid & monitoring of potassium, calcium, phosphate and magnesium. Caution in cardiac or renal failure.

NB: Although use of frusemide is controversial/may not be beneficial, most current textbooks still include it.

  • Bisphosphonates- Disodium etidronate or pamidronate
  • Corticosteroids- especially if due to sarcoidosis or vit D toxicity
  • Calcitonin
  • Dialysis- Peritoneal or haemodialysis against calcium-free or low calcium concentration dialysate (citrate anticoagulation with CVVHDF)
  • (Gallium nitrate)- nephrotoxic
  • (Mithramycin)- contraindicated in renal or hepatic failure
  • (Octreotide)


Causes of ionised hypocalcaemia – any 4 individual causes:

  • Decreased PTH activity:
    • Hypoparathyroidism
    • Pseudohypoparathyroidism
    • Hypomagnesaemia
  • Vitamin D deficiency:
    • Malabsorption of vitamin D/calcium- steatorrhoea
    • Vitamin D deficient rickets, osteomalacia in adults
  • Excess calcium losses/binding:
    • Rhabdomyolysis
    • Pancreatitis
    • Critical illness (burns, sepsis, toxic shock, etc.)
    • Frusemide and saline diuresis
    • Hyperphosphataemia
    • Citrate toxicity (CVVHDF)
    • Alkalosis / Hyperventilation
    • Fluoride toxicity
    • Oxalate poisoning
    • Tumour Lysis
    • Drugs – biphosphonates, calcitonin, phenytoin
  • Unknown mechanism:
    • Hypermagnesaemia


Features of hypercalcemia are discussed elsewhere.

The table below is a satisfactory short summary:

Clinical Manifestations of Hypercalcemia

Early manifestations (levels < 3.5mmol/L)

  • Constipation

  • Peptic ulcer exacerbation

  • Polyuria

  • Nephrogenic diabetes insipidus

  • Nephrolithiasis

  • Type 1 (distal) renal tubular acidosis

  • Shortened QT interval

  • Bone pain

Late manifestations (levels over 3.5mmol/L)

  • Pancreatitis

  • Renal failure (due to vasoconstriction)

  • Hypertension

  • Delirium, progressing to coma

  • Arrhythmia

  • Muscle weakness

Management of hypercalcemia has indeed moved on since the frusemide diuresis days. All the positive evidence for this practice was published before bisphosphonates became available.

The college graciously allows the candidates to get by without mentioning drug doses.The modern medical approach to hypercalcemia is summarised as the following list, ordered by escalating invasiveness of therapy.

  • Volume restoration
  • Bisphosphonates
  • Calcitonin
  • Renal replacement therapy

Causes of hypocalcemia are discussed elsewhere. They are numerous. Though the college asks specifically about ionised hypocalcemia, they then give a list of all possible causes for this condition. In order to simplify revision, a table of causes is reproduced below:

Causes of Hypocalcemia

Low Parathyroid Hormone

  • Primary hypoparathyroidism (i.e. destruction of the parathyroid glands)
  • Post-operative hypoparathyroidism
  • Hungry bone syndrome
  • HIV infection
  • Haemochromatosis


High or normal Parathyroid hormone

  • Vitamin D deficiency
  • Hypomagnesemia
  • Hyperphosphataemia
  • Renal failure (pseudohypoparathyroidism)
  • Tumour lysis syndrome
  • Acute pancreatitis
  • Alkalosis
  • Depletion in coagulopathy



  • Phenytoin
  • Fluoride toxicity
  • Foscarnet
  • EDTA
  • Citrate
  • Phosphate
  • Bisphosphonates

Ionised hypocalcemia in isolation is rare. It is seen in only one scenario: citrate toxicity. When citrate is used to chelate calcium, the total calcium is normal, but the ionised fraction is low. This is because measurement instruments which detect calcium will also measure citrate-calcium complexes in the serum, but the electrode which measures ionised calcium will only measure the free fraction, which decreases with citrate chelation.


Inzucchi, Silvio E. "Management of hypercalcemia." Postgraduate medicine115.5 (2004).

Ralston, S. H., et al. "Medical management of hypercalcemia." Calcified tissue international 74.1 (2004): 1-11.

Hästbacka, J., and V. Pettilä. "Prevalence and predictive value of ionized hypocalcemia among critically ill patients." Acta anaesthesiologica scandinavica 47.10 (2003): 1264-1269.

LeGrand, Susan B., Dona Leskuski, and Ivan Zama. "Narrative review: furosemide for hypercalcemia: an unproven yet common practice." Annals of internal medicine 149.4 (2008): 259-263.

UpToDate has a nice summary of this topic for the paying customer.

Cooper, Mark S., and Neil JL Gittoes. "Diagnosis and management of hypocalcaemia." BMJ: British Medical Journal 336.7656 (2008): 1298.

Tohme, J. F., and J. P. Bilezikian. "Hypocalcemic emergencies." Endocrinology and metabolism clinics of North America 22.2 (1993): 363-375.

Diercks, Deborah B., et al. "Electrocardiographic manifestations: electrolyte abnormalities." The Journal of emergency medicine 27.2 (2004): 153-160.

LITFL have an excellent point-form summary of citrate toxicity. Much of what we know about it is derived from the sorry experience of patients who were recipients of massive transfusions.

Uhl, L., et al. "Unexpected citrate toxicity and severe hypocalcemia during apheresis." Transfusion 37.10 (1997): 1063-1065.

Bushinsky, David A., and Rebeca D. Monk. "Calcium." The Lancet 352.9124 (1998): 306-311.

Schaer, H., and U. Bachmann. "Ionized calcium in acidosis: differential effect of hypercapnic and lactic acidosis." British journal of anaesthesia 46.11 (1974): 842-848.

Dzik, Walter H., and Scott A. Kirkley. "Citrate toxicity during massive blood transfusion." Transfusion medicine reviews 2.2 (1988): 76-94.