Chapter 26: Acute oncology
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Hypercalcaemia of malignancy
Definition
Hypercalcaemia is a common biochemical abnormality in the blood that can be potentially life‐threatening (Grandjean and McMullen [96]). It is defined as a serum calcium concentration (following adjustment) of 2.65 mmol/L or higher on two occasions and can also be classified according to severity (Clinical Knowledge Summaries [CKS] [39]). Hypercalcaemia can be caused by malignancy, hyperparathyroidism, medications or underlying medical conditions. The initial signs and symptoms can be quite vague but it can also present as dehydration, cardiac arrhythmias or coma. Severe hypercalcaemia is an emergency and requires prompt management to prevent life‐threatening complications to the kidneys, heart and brain (CKS [39]). The nurse's understanding of the pathophysiology, signs and symptoms of hypercalcaemia enables effective diagnosis and holistic management of the patient with complex health needs (Walker [302]).
Anatomy and physiology
Calcium is predominantly found in the bone and calcified cartilage but is also present in the intracellular and extracellular fluids. Calcium is required for muscle and cell contraction, neurotransmission and bone formation (Walker [302]). Calcium levels in the blood (serum calcium) are kept in the normal reference range by parathyroid hormone (PTH), 1,25‐dihydroxy vitamin D3 (calcitriol) and calcitonin (Grandjean and McMullen [96]). PTH and calcitriol physiologically regulate calcium homeostasis, with calcitonin playing a lesser role (Sargent and Smith [263]). These regulators are known to help in the prevention of hypocalcaemia, but are less effective in hypercalcaemia (Sargent and Smith [263]). For hypercalcaemia to develop, normal calcium regulation in which bone is continuously resorbed (removed) by osteoclasts and replaced with new bone created by osteoblasts must be overwhelmed by an excess of PTH, calcitriol or a huge calcium load (Green [97]). Cancer cells release proteins and cytokines that stimulate osteoclasts and enhance bone resorption, causing calcium to be released into the blood and increasing levels of calcium (Sargent and Smith [263]).
Related theory
Eighty per cent of cases of hypercalcaemia are caused by primary hyperparathyroidism and cancer, in particular those of breast, lung and multiple myeloma, with or without bone metastases. In the other 20%, bone metastases cause lysis and release of skeletal calcium. It is important to recognize that drugs such as thiazide diuretics, vitamin D and antacids with calcium co‐prescribed can also be a factor as these drugs are commonly used in cancer care. About 20–30% of all people with cancer develop hypercalcaemia at some point during their illness (Joshi et al. [123]). For most people with malignancy‐associated hypercalcaemia, an underlying cause has already been identified (Bushinsky and Monk [27], Clines [38], Twycross et al. [292]). When hypercalcaemia occurs, it is usually a sign of advanced cancer with a median survival of 3–4 months (Seccareccia [267]).
Symptoms
The symptoms of hypercalcaemia are often non‐specific, and patients who suffer chronically can often be asymptomatic (Minisola et al. [183]). The extent of the symptoms relates to the severity and rate of onset. Symptoms can be grouped together according to the system affected (see Table 26.3).
Table 26.3 Symptoms of acute and chronic hypercalcaemia according to anatomical system
| System | Acute hypercalcaemia | Chronic hypercalcaemia |
|---|---|---|
| General | Flushing, itching, keratitis, conjunctivitis, fatigue, weight loss | Fatigue, corneal calcification |
| Cardiovascular | Hypertension, prolonged PR interval, widened QRS complex, shortened QT interval, bundle branch block, bradycardia, arrhythmias, syncope, cardiac arrest | Prolonged PR interval, widened QRS complex, shortened QT interval, bundle branch block, bradycardia, arrhythmias, hypertension, valvular heart disease, vascular calcification |
| Renal | Thirst, polydipsia; dehydration (due to nephrogenic diabetes insipidus); polyuria; nocturia; frequent urination; renal failure from obstructive uropathy, nephrolithiasis, nephrocalcinosis or pre‐renal causes | Renal impairment (nephrocalcinosis), renal colic (nephrolithiasis), chronic renal failure, renal osteodystrophy |
| Neurological | Tiredness, obtundation, lethargy, confusion, delirium, somnolence, stupor, coma, hypotonia, hyporeflexia, paresis | Impaired concentration and memory loss, dementia, sleep disturbance, decreased concentration |
| Psychiatric | Depression, anxiety, hallucination, psychosis | Irritability, depression, anxiety |
| Gastrointestinal | Anorexia, nausea, vomiting, abdominal pain, dyspepsia, constipation, pancreatitis, peptic ulcer | Anorexia, dyspepsia, weight loss, constipation, pancreatitis, peptic ulcer |
| Skeletal and muscle | Bone pain, muscle weakness | Bone pain, muscle weakness, myalgias, osteoporosis, osteopenia, fragility fractures, osteitis fibrosa cystica, bone cysts, brown tumours of long bones, chondrocalcinosis, joint calcification |
| Haematological | Anaemia | Anaemia |
| Ocular | — | Band keratopathy (cornea) |
Diagnosis
The only way to confirm the diagnosis is a venous blood sample to measure both serum calcium and albumin concentrations (Minisola et al. [183]). Patients who present with symptoms or have severe hypercalcaemia based on blood results should commence treatment immediately and investigation of the underlying cause should be delayed until the life‐threatening situation is under control (Pettifer and Grant [230]). Unless the patient is symptomatic or the classification is severe, the patient can be treated as an outpatient (CKS [39], Legrand [141], Pettifer and Grant [230]).
For people with unexplained, asymptomatic mild (2.65–3.0 mmol/L) or moderate hypercalcaemia (3.01–3.4 mmol/L), there may be more than one cause. Review the medical and family history, clinical features and drug treatments, looking for an underlying cause. Referral to the appropriate specialist, depending on the suspected cause or causes, is recommended (CKS [39], Minisola et al. [183]). The healthcare professional may also organize the following additional investigations to provide further information as to the cause:
- Chest X‐ray (to exclude lung cancer or metastases, sarcoidosis or tuberculosis).
- Renal function and serum electrolytes, including magnesium and phosphate (to assess for chronic kidney disease).
- FBC (to diagnose or exclude anaemia of chronic disease).
- Erythrocyte sedimentation rate (ESR) or C‐reactive protein (CRP) (may be increased in cancer or other inflammatory or granulomatous conditions).
- Serum and urine protein electrophoresis, including testing for urinary Bence Jones protein (to exclude myeloma).
- Liver function tests (LFTs) (to exclude liver metastases or chronic liver failure; also alkaline phosphatase may be increased in primary hyperparathyroidism, Paget's disease with immobilization, myeloma or bone metastases).
- Thyroid function tests (to exclude thyrotoxicosis).
- Serum cortisol (morning sample, at 8–9 am if Addison's disease [a rare cause of hypercalcaemia] is suspected).
- Urinalysis for urine protein (if chronic kidney disease is suspected).
In patients with a known malignancy the main cause is likely to be their cancer but this must not exclude testing for primary hyperparathyroidism. If hypercalcaemia is detected, a blood sample for PTH levels is required as primary hyperparathyroidism may co‐exist with malignancy.
Assessment and management
Nursing management of hypercalcaemia relies on having a high index of suspicion in any patient known to have predisposing pathology, such as breast cancer, or known chronic hypercalcaemia (Walker [302]). Due to the nature of hypercalcaemia, patients present often with vague symptoms, therefore initial nursing assessment is essential to highlight hypercalcaemia as a potential differential diagnosis. If the patient has a known malignancy, then the treatment is the same but be mindful that although this is the likely cause for the hypercalcaemia there may be an additional cause (Twycross et al. [292]). Consider the patient's underlying cancer and whether it is appropriate to treat the hypercalcaemia (Seccareccia [267]). Table 26.4 provides initial nursing actions when hypercalcaemia is suspected.
Table 26.4 Initial actions on suspicion of hypercalcaemia
| Action | Rationale |
|---|---|
| Regular observations: blood pressure (BP), pulse (P), respiratory rate (RR), oxygen saturation (Sats), temperature, National Early Warning Score (NEWS), AVPU (‘alert, voice, pain, unresponsive’ – record of conscious status) | Ensures close monitoring for signs of deterioration, enabling prompt action (Clinical Knowledge Summaries [CKS] [39]) |
| Take bloods (outlined above) if not already done, ensuring that corrected calcium, potassium, magnesium and phosphorus is selected. Avoid prolonged tourniquet application |
Provide diagnostic information
Potassium, magnesium and phosphorus also likely to be deranged (McCurdy and Shanholtz [173])
Prolonged tourniquet application can increase the corrected calcium result (CKS [39]) |
| Ensure electrocardiogram (ECG) is taken and reviewed for possible prolonged or shortened QT interval, widened QRS complex, or bundle branch block | In severe hypercalcaemia the electrical functioning of the heart can be affected (McCurdy and Shanholtz [173]) |
| Cannulate the patient and administer IV fluids (1000 mL sodium chloride 0.9%) in preparation | Promotes renal excretion of calcium and protects kidneys (Dark and Razak [53]) |
| Monitor urine output – risk of acute kidney injury (AKI) or cardiac overload |
Hypercalcaemia can cause renal impairment and calculi (McCurdy and Shanholtz [173])
Speed of administration and amount of fluids can cause cardiac overload in frail patients (Seccareccia [267]) |
| Administer bisphosphonates as prescribed | In severe hypercalcaemia they cause inhibition of osteoclast activity and may have an effect on osteoblasts by allowing them to work more effectively thus reducing levels of circulating calcium (Dark and Razak [53], Seccareccia [267]) |
| Encourage the patient to mobilize if symptomatically able | Helps the body to reabsorb the calcium (CKS [39], Walker [302]) |
| Ensure serum calcium and other electrolytes are monitored regularly (at least 1 week post bisphosphonate) | Hypercalcaemia will usually return within 4–6 weeks of initial treatment if the underlying cause is not treated (Seccareccia [267]) |
| Ensure loop diuretics have been stopped | Loop diuretics are not recommended as they can inhibit calcium reabsorption by the bone (Bower and Cox [23]) |
Hypercalcaemia can cause acute kidney injury (AKI) via the concurrent effects of a hypovolaemic state and vasoconstrictive effects of calcium (Carroll and Schade [30]). It is important that the cancer nurse is aware of this risk as many cases of AKI can be prevented by following the four Ms (Table 26.5). Management of AKI should be based on local policies; an example can be found in NICE [207] clinical guideline 169.
Table 26.5 The four Ms to monitor if a patient is at risk of acute kidney injury (AKI)
| Action | Rationale |
|---|---|
| Monitor the patient: use NEWS, regular blood tests, fluid charts and urine volumes | A change in observations and subsequent increase in NEWS will alert to a potential deterioration in condition and trigger a response (NICE [203]) |
| Maintain circulation: hydration, resuscitation and oxygenation | Ensuring that the patient is adequately perfused and oxygenated and has a patent airway will reduce risk of kidney injury or general deterioration (NICE [207]). Vigorous fluid administration (normal saline) is aimed at reversing renal ischaemia and diluting nephrotoxins (Prowle et al. [236]) |
| Minimize kidney insults: review nephrotoxic medications and the use of contrast media and treat infections | Reduce the stress placed on the kidneys and prevent further damage (Rahman et al. [241]) |
| Manage the acute illness: dehydration, sepsis, heart and liver failure. Untreated, all of these can contribute to AKI | AKI is a medical emergency and is associated with a high incidence of mortality (up to 80%) (Rahman et al. [241]) |
In adults, AKI is diagnosed using any of the following criteria (NICE [207]):
- a rise in serum creatinine of 26 µmol/L or greater within 48 hours
- a 50% or greater rise in serum creatinine known or presumed to have occurred within the past 7 days
- a fall in urine output to less than 0.5 mL/kg/hour for more than 6 hours.
To support management, the nurse should ensure that the patient's volume status (including pulse, blood pressure, peripheral perfusion and jugular venous pressure), renal function and serum potassium level (to exclude hyperkalaemia) have been assessed (CKS [40], NICE [207]). Management of AKI in hypercalcaemia is linked directly to reducing the serum calcium level through rehydration and bisphosphonates (Moyses‐Neto et al. [190]). Bisphosphonates (pamidronate or zoledronic acid) are classified as first‐line therapy for malignant hypercalcaemia (CKS [39], Mallik et al. [160], McCurdy and Shanholtz [173]). Bisphosphonates bind to hydroxyapatite and inhibit osteoclastic reabsorption and bone crystal dissolution (Higdon and Higdon [108], McCurdy and Shanholtz [173]). The effects of these are expected to be seen 2–4 days after administration, supporting the use of this treatment in the palliative setting (Mallik et al. [160]).
The key to management is avoiding hypovolaemia by maintaining haemodynamic stability to ensure adequate renal perfusion (Rahman et al. [241]). If fluid resuscitation is required, isotonic solutions (e.g. 250 mL 0.9% sodium chloride in increments) are preferred over hyperoncotic solutions (e.g. dextrans, hydroxyethyl starch, albumin) (NICE [207]). If the patient has persistent hypotension they may require vasopressors; the critical care outreach team should be involved at this point (Prowle et al. [236]). Attention to electrolyte imbalances (e.g. hyperkalaemia, hyperphosphataemia, hypermagnesaemia, hyponatraemia, hypernatraemia, metabolic acidosis) is important. This is particularly important in AKI due to hypercalcaemia as these parameters may already be altered (CKS [40]).
The use of diuretics is not recommended in hypercalcaemia and should only be used in AKI in the management of volume overload (NICE [207], Rahman et al. [241]). It should also be noted that diuretics do not improve morbidity, mortality or renal outcomes, and should not be used to prevent or treat AKI in the absence of volume overload (Lewington and Kanagasundaram [145]).
Medications that potentially affect renal function by direct toxicity or by haemodynamic mechanisms should be discontinued; for example, metformin (Glucophage) should not be given to patients with diabetes mellitus who develop AKI (Lewington and Kanagasundaram [145]). The dosages of essential medications should be adjusted for the lower level of kidney function. This includes supportive therapies (e.g. antibiotics, maintenance of adequate nutrition, mechanical ventilation, glycaemic control, anaemia management) which should be pursued based on standard management practices.
If the person is asymptomatic with mild or moderate hypercalcaemia (adjusted serum calcium 3.40 mmol/L or less), repeat the blood test a week later to exclude rapidly increasing hypercalcaemia suggestive of cancer (CKS [39]). Ensure that the patient is given clear information regarding signs and symptoms along with advice to drink six to eight glasses of water a day to prevent nephrolithiasis, provided there are no contraindications such as renal impairment or heart failure, and to maintain a normal diet (Clines [38], Walker [302]). The literature suggests that restriction of dietary calcium and vitamin D can lead to malnutrition (CKS [40]).
For all patients ensure that they avoid any drugs or vitamin supplements containing calcium and encourage mobilization as this aids the reabsorption of calcium (CKS [39]). Calcium levels should be checked within 2 weeks after initial treatment as it is noted that calcium levels can begin rising within 4 weeks of treatment (Seccareccia [267]). It is known that cancer‐associated hypercalcaemia is more likely to become symptomatic at lower serum calcium levels and that the serum calcium increases more rapidly (Clines [38], Ralston et al. [242]).
