Hypercalcaemia in the oncology patient
Hypercalcaemia in paediatric oncology may be real or spurious (blood sampling problems especially with fragile peripheral leukaemic blasts).
Causes
Hypercalcaemia is encountered infrequently in paediatric oncology compared with adult practice. However, it is seen in about 0.4% of cases and most often with:
Acute lymphoblastic leukaemia
Rhabdomyosarcoma
Malignant rhabdoid tumour of the kidney
Non-Hodgkin's lymphoma
Hodgkin's disease
Ewing sarcoma
Neuroblastoma (due to bone mets or as a complication of cis-retinoic acid therapy)
Hepatoblastoma.
Hypercalcaemia is more common in palliative care patients who are more likely to have bone metastases.
As well as being associated with tumour burden or bone and bone marrow invasion it may also be associated with:
Immobility
Cis-retinoic acid and ATRA
Paraneoplastic syndromes (very rare in children)
Adrenal insufficiency.
Clinical features
Usually quite non-specific so a high index of suspicion is required:
weakness and lethargy
hyporeflexia
nausea and vomiting
abdominal pain and constipation
polyuria
progression to stupor and coma (seen with levels in children > 3.74 mmol/l).
Diagnosis
A serum calcium level is part of the work up of all patients presenting with a suspected diagnosis of cancer. In many hospitals it is done routinely as part of the pre-determined oncology biochemistry panel. Similarly, the serum calcium level should be determined in paediatric oncology patients when:
they relapse or progress
during palliative care, when symptoms may suggest hypercalcaemia and it is thought that the patient may benefit from correction of the hypercalcaemia.
in patients receiving cis-retinoic acid or ATRA.
If hypercalcaemia is found, also perform ECG looking for shortened QT interval and arrythmias.
ECG features of hypercalcaemia include:
T wave flattening or inversion
Mild prolongation of the QRS and PR intervals
ST-elevation
Presence of J wave at the end of the QRS complex
Other tests
25OH Vit D, Consider cortisol if not on steroids
PTH, Mg, P, renal function, urine Ca Cr ratio
Consider checking PTHRP
Treatment
Calcium levels may be factitiously raised by problems with blood sampling, especially in leukaemia with a high white cell count where the fragile cells may leak calcium in the tube. Repeat the sample before initiating aggressive therapy.
The goals of treating hypercalcaemia include increased elimination from the extracellular fluid, reducing gastrointestinal (GI) absorption and decreasing bone resorption.
Immediate therapy is directed at restoring intravascular volume and promoting calcium excretion in the urine with an infusion of 0.9% saline at twice the maintenance rate until any fluid deficit is replaced and diuresis occurs (urine output ≥ 200 mL/h to 300 mL/h). Remember with severe hypercalcaemia the UO will be >4ml/kg per from the hypercalciuria (acquired nephrogenic DI).
Note the variability of reference intervals by age (see section below).
Hemodialysis is the treatment of choice to rapidly decrease serum calcium in patients with heart failure or renal insufficiency. Loop diuretics should be used with caution as even though they may enhance renal excretion, paradoxical hypercalcaemia can occur due to bone resorption.
| Mild | |
|---|---|
| Total calcium Ionised calcium | < 3 mmol/L < 2 mmol/L |
| If asymptomatic, ensure adequate oral hydration and avoid calcium exacerbating substances. Monitor calcium until normalised. | |
| Moderate | |
|---|---|
| Total calcium Ionised calcium | 3 – 3.5mmol/L 2 – 2.5mmol/L |
| Check renal function ASAP. Start cardiac monitoring if Ca > 2.9mmol/L If asymptomatic or mildly symptomatic with chronic hypercalcaemia, treat as per mild. If acute rise in calcium or significantly symptomatic, treat as per severe. | |
| Severe | |
|---|---|
| Total calcium Ionised calcium | > 3.5mmol/L > 2.5mmol/L |
| Consult with paediatric endocrinology and/or renal if renal impairment. Start cardiac monitoring if Ca > 2.9mmol/L Start hyperhydration (3L/m2/24 hours total fluid intake) using 0.9% NaCl. Frusemide may be considered but is controversial, as there is no evidence that it helps. It is usually used in cases of renal failure or symptomatic volume overload. | |
| Salmon Calcitonin Discuss with endocrinology 4 iu/kg Q12hourly IM or SC Can increase to 8iu/kg q6hourly if needed. This is useful in short term and will decrease calcium within 4-6 hours by 0.3 – 0.5mmol/L. Patients develop tachyphylaxis and it has limited benefit beyond 24 – 48 hours but is very useful in situations where the cause of the hypercalcaemia is able to be resolved rapidly. | |
| Bisphosphonates These continue to have effect for up to 4 weeks therefore patient may become significantly hypocalcaemic and hypophosphataemic if the driver of the hypercalcaemia is removed. The maximum effect is in 2 – 4 days. Check serum calcium and phosphate at least twice weekly as there may be a period of hypocalcaemia (and ↓ serum phosphate) requiring supplementation. Side-effects include: 'flu'-like symptoms – fever, myalgia, CRP, bony aches; eye inflammation, lymphopenia and GIT symptoms. It has also been rarely associated with osteonecrosis of the jaw. | |
Dosing
See Intravenous Bisphosphonate Therapy guideline (Starship Endocrinology)
Reference Intervals
Total plasma calcium
Units: mmol/L
| Age | Total plasma calcium |
|---|---|
| Day 1 - 3 | 1.80 - 2.80 |
| Day 4 to 1 yr | 2.10 - 2.80 |
| > 1 yr | 2.10 - 2.55 |
This test measures total plasma calcium (includes ionised, protein-bound, and complexed fractions). Reference ranges above apply to total calcium when serum albumin is normal, and to corrected calcium (adjusted for albumin concentration).
Serum albumin should always be measured in conjunction with total calcium, to enable calculation of corrected calcium.
Prolonged stasis during venepuncture and haemolysis will give falsely high values.
Conversion factors:
mg/100 mL x 0.25 = mmol/L
mmol/L x 4 = mg/100mL
Uncertainty of measurement: 6%
Ionised calcium
Units: mmol/L
| Age | Ionised calcium |
|---|---|
| Day 1 to 1 yr | 1.15 - 1.45 |
| > 1 yr | 1.15 - 1.30 |
Conversion factors:
mg/100 mL x 0.25 = mmol/L
mmol/L x 4 = mg/100 mL
Uncertainty of measurement: 0.05 mmol/L
Calcium/creatinine ratio
| Age | Calcium/creatinine ratio (mmol/mmol) |
|---|---|
| 6m - 1 yr | 0.09 - 2.2 |
| 1 - 2 yr | 0.07 - 1.5 |
| 2 - 3 yr | 0.06 - 1.4 |
| 3 - 5 yr | 0.05 - 1.1 |
| 5 - 7 yr | 0.04 - 0.7 |
| 7 - 17 yr | 0.04 - 0.7 |
| Adult | < 0.6 |
Conversion factors:
mg/100 mL x 0.25 = mmol/L
mmol/L x 4 = mg/100 mL
Uncertainty of measurement: 10%