Electrolytes part 2: sodium and calcium

Case scenarios

Abdel, 75, has end-stage chronic kidney disease (eGFR 10 mL/min) secondary to poorly controlled type 2 diabetes. He is currently prescribed calcium 2 tablets twice daily with food, calcitriol 0.25 mcg twice a week, perindopril 5 mg daily, sodium bicarbonate capsule 840 mg daily, furosemide 250 mg daily and insulin aspart + insulin aspart protamine
20 units twice daily. He informs you that he has been told he will likely need dialysis in the coming months. You are reviewing Abdel’s medicines and note that his total calcium levels are low at 1.9 mmol/L.

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Introduction

Electrolytes, including potassium, magnesium, sodium and calcium, are essential to the functioning of the human body. The significance of potassium and magnesium is covered in the first part of this two-part series, Electrolytes part 1: potassium and magnesium – they go hand in hand (page 28). This article focuses on the significance of sodium and calcium disturbances and their management.

As with potassium and magnesium, sodium and calcium are maintained in defined concentrations in the body to allow normal function. Disturbances can have detrimental effects on many body tissues and, when severe, can be life threatening. Concentrations in the blood are influenced by the rate of intake, shifts between intracellular spaces and the blood and excretion, both via the kidneys and gastrointestinal tract. Disturbances of sodium and calcium can occur in several settings, including chronic disease, such as the release of calcium and phosphate from bone in end-stage chronic kidney disease (CKD), and as a medicine adverse effect, such as from diuretics.

Pharmacists can assist in identifying potential causes of sodium and calcium disturbances, and advise on treatment options, particularly with respect to medicines used for management of these conditions.

Risk factors and reference ranges

The risk of sodium and calcium concentration disturbances increases with increasing age, increasing number of comorbidities (such as liver disease, kidney disease and heart failure), dietary changes and acute illness.

Reference ranges usually describe the range of values between which 95% of the healthy population’s test levels are expected to lie.^1,2 This does not automatically mean that patients with results outside the reference ranges are at risk of complications. It also doesn’t mean that all patients with levels within the reference ranges have an optimal concentration. Healthy young patients with electrolytes, such as sodium, slightly outside of the reference ranges rarely suffer problematic consequences, while older patients with cognitive impairments and frequent falls may require tighter sodium control to achieve optimal outcomes. Chronic changes to electrolytes such as sodium and calcium are also less likely to cause acute cardiac or neurological complications than acute changes. As laboratories can have different reference ranges due to different techniques used to collect and analyse specimens, the reference range used by the laboratory that provided the result should be considered when reviewing results.^1,2

Sodium

Reference range (serum)
135–145 mmol/L^2,3

Sodium is an essential electrolyte for all animals and some plants. In contrast to potassium, sodium is largely an extracellular cation with concentrations of around 12 mmol/L inside the cell and around 135–145 mmol/L in the serum (blood).^4–6 Sodium ions are the major cations of extracellular fluid, a fact that can easily be recognised by the larger reference range for serum sodium compared to serum calcium, magnesium or potassium.^2,3 As such, sodium is a major contributor to osmotic pressure that causes fluid shifts between intracellular spaces, extracellular fluids and intravascular spaces, often leading to problematic fluid accumulation (oedema).^4,5

Hyponatraemia

Hyponatraemia is characterised by a concentration of sodium in the blood below the reference range.^4,5 It is a common clinical problem and can be caused by a variety of medical conditions and medicines.

The signs and symptoms of hyponatraemia can be nonspecific and may vary depending on the severity of the condition.^4,5 Mild cases are usually asymptomatic, although elderly patients with mild hyponatraemia with reduced cognitive reserve may have an increased risk of impaired cognition, falls and subsequent fractures.^7,8 Severe cases of hyponatraemia are usually highly clinically relevant, especially when acute.⁵ Symptoms such as nausea, vomiting, headache, confusion, seizures and even coma can occur, especially in acute hyponatraemia.^4,5,7

Organic osmolytes are substances in the brain designed to buffer tonicity changes in the plasma. In response to chronic hyponatraemia, the concentration of organic osmolytes can reduce, resulting in the osmolarity of cerebral tissues matching the reduced osmolarity of the blood, thereby preventing central nervous system (CNS) oedema.^4,5,7–9 Because of this, chronic hyponatraemia is much less likely to be associated with CNS signs and symptoms than acute hyponatraemia.^7,8

Heart failure, cirrhotic liver disease and syndrome of inappropriate antidiuretic hormone secretion (SIADH) are all potential causes of hyponatraemia.^4,5 Reduced cardiac output in heart failure activates the renin angiotensin aldosterone pathway, which leads to increased aldosterone and release of antidiuretic hormone (ADH).¹⁰ In cirrhotic liver disease, portal hypertension in cirrhosis and the subsequent systemic vasodilation lead to activation of the renin angiotensin aldosterone pathway and increased ADH. Increased ADH leads to increased water retention and thus dilutional hyponatraemia.¹ Hyponatraemia due to SIADH can be a complication of cancers, such as lung cancer, or an adverse effect of a medicine, such as a thiazide diuretic, carbamazepine or antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs) and serotonin and noradrenaline reuptake inhibitors (SNRIs).^2,9,11–13

The harm associated with acute hyponatraemia is not due to a reduction in serum sodium per se, but a reduction in serum osmolarity.^4,5 Importantly, hyponatraemia can be the body’s response to increased serum tonicity (e.g. in cases of hyperglycaemia).¹⁴ In these circumstances, a reduction in serum sodium occurs due to water being pulled into the serum by the raised osmolarity from the hyperglycaemia, thereby diluting the sodium levels.¹⁴ This will result in a picture of hyperosmolar hyponatraemia and requires management of the condition causing the increase in glucose (e.g. poorly controlled diabetes).¹⁴

Pseudohyponatraemia occurs when low plasma sodium concentrations are identified in laboratory analysis, in the presence of significant hyperproteinaemia or hyperlipidaemia, in the absence of true hyponatraemia.^15,16 Lipid or protein levels need to be very significantly raised (e.g. triglyceride levels greater than 17 mmol/L) for pseudohyponatraemia to be likely.^13,15,16 This is a type of isotonic hyponatraemia with management aimed at treating the cause of the hyperproteinaemia or hyperlipidaemia.^15,16

The management of hyponatraemia depends on the underlying cause, fluid status, symptoms and rate of development.^4,5,13 As such, a careful diagnosis is needed, including determining if the patient is hypovolaemic, euvolaemic or hypervolaemic.^4,5,13 Urinary sodium concentrations can help differentiate between these diagnoses.^2,4,5,17 High urine osmolarity and sodium suggest increased ADH is the cause (e.g. SIADH, heart failure, cirrhosis).^13,17 However, loop diuretics such as furosemide can affect urinary sodium, and thus this should be considered when using urinary sodium concentration for diagnostic purposes.^4,9

Hypovolaemic hyponatraemia may occur in cases of dehydration, diarrhoea, vomiting or extreme exercise, and it is treated by administering intravenous (IV) sodium chloride 0.9%.^4,5,13 Euvolaemic hyponatraemia may occur in cases of SIADH due to medicines.^4,5 This is treated by withdrawal of the causative medicine where possible.^4,5,9 In the case of mild hyponatraemia due to antidepressant induced SIADH, clinicians may recommend that the patient trial a different medicine in the same class or a medicine in a different class.¹⁸ Hypervolaemic hyponatraemia may occur in patients with cirrhotic liver disease or heart failure with reduced ejection fraction. Treatment includes loop diuretics and fluid restriction.^4,9,13

In cases of severe acute hyponatraemia, treatment may involve intravenous administration of hypertonic saline (3% sodium chloride) to rapidly increase sodium levels.^4,5,9,13 However, correction of serum sodium levels too rapidly has been associated with osmotic demyelination syndrome (OMS), so the goal of correction should generally be limited to an increase of 4–8 mmol/L/day.^4,5,9,13 Criticisms have been raised around the underuse of hypertonic saline due to fears of OMS.¹⁹ OMS can be prevented by careful consideration of infusion rates of hypertonic saline.^4,9,13,19 Pharmacists should ensure quantities of hypertonic saline dispensed or routinely available in ward areas are limited, and there is a process of ongoing pharmacist review before resupply. Generally hypertonic saline should only be prescribed by a consultant emergency physician or an intensivist (intensive care unit [ICU] doctor) for patients with acute hyponatraemia and serum sodium concentrations less than 120 mmol/L, or having seizures.^4,9,13 See the Therapeutic Guidelines for comprehensive point-of-care advice on management of hyponatraemia with hypertonic saline.¹³

Hypernatraemia

Hypernatraemia is characterised by a concentration of sodium in the blood above the reference range.^4,20 It is a relatively uncommon condition, but it can be a serious medical emergency if left untreated.^4,20 The signs and symptoms of hypernatraemia can be nonspecific and may vary depending on the severity of the condition.^4,20 Mild cases may be asymptomatic, while severe cases can cause a wide range of symptoms, including thirst, dry mouth, restlessness, agitation, confusion, seizures and even coma.^4,20 Hypernatraemia is most commonly caused by excess fluid loss (e.g. profuse diarrhoea). Excess fluid loss is usually compensated for by the body’s strong thirst response, so hypernatraemia generally only occurs when people are unable to access water (e.g. unconscious or bedbound patients). Hypernatraemia is rare outside of ICU. Hypernatraemia is generally treated with replacement of water, either orally or with IV fluids without added sodium, such as glucose 5%.^4,20

Calcium

Corrected calcium reference range (serum) 2.1–2.6 mmol/L^2,3

Calcium is an important mineral in the body that plays a crucial role in many physiological processes, including muscle contraction, nerve function and blood clotting.^2,21,22 Calcium is also an important mineral in bones, and sufficient body stores are essential to prevent bone fractures.^21,22 Calcium deposition in other body tissues such as coronary arteries is pathological.^21,22 Parathyroid hormone (PTH) is the major hormone responsible for increasing the levels of calcium in the blood by increasing resorption of bone and decreasing renal secretion of calcium.^21,22 Vitamin D also plays a key role in calcium homeostasis by increasing calcium absorption from the gut.^21,22

Albumin binds approximately half of all the calcium in the blood.^21,22 In patients with low serum albumin, the serum total calcium may be low, despite having a normal amount of serum ionised calcium.^1,21,22 Ionised calcium represents the concentration of calcium unbound to albumin, which is calcium available for physiological actions. However, ionised calcium is not routinely measured, as it is costly to measure and samples require strict handling and storage conditions. Analysis of ionised calcium is usually reserved for patients with significantly abnormal albumin.²³ As such, laboratories will usually report albumin-adjusted total calcium (abbreviated to corrected calcium). Corrected calcium should generally be considered instead of total calcium when reviewing blood test results; it is a surrogate marker for ionised calcium. Where laboratories do not report this, corrected calcium can be calculated using the formula²:
Corrected calcium (mmol/L) = total calcium (mmol/L) + [(40 – serum albumin (g/L))
x 0.02]

For example, a patient with a serum total calcium of 2 mmol/L and an albumin of 30 g/L has a corrected calcium of 2 + (10 x 0.02) = 2.2 mmol/L.

Hypocalcaemia

Hypocalcaemia is a condition characterised by a concentration of calcium in the blood below the reference range.^21,22 The signs and symptoms of hypocalcaemia can be divided into two categories: acute and chronic.^21,22 Acute hypocalcaemia can lead to symptoms such as tingling lips, paraesthesia, muscle cramps, seizures, and even cardiac arrhythmias.^21,22 Chronic hypocalcaemia can increase the risk of fractures due to decreased bone density.^21,22

Causes of hypocalcaemia include^2,21,22:

• Chronic kidney disease; hypocalcaemia is a common clinical problem in the early stages of the disease
• Surgical removal of the parathyroid; severe cases can present immediately after the surgery
• Vitamin D deficiency, an important reversible cause of hypocalcaemia. Vitamin D undergoes a three-step conversion to its most potent form 1,25 dihydroxycholecalciferol, and sunlight exposure is an essential requirement for this process to occur. Groups of patients at risk of vitamin D deficiency in Australia include those with minimal exposure to sunlight, such as bedbound patients and people living in residential aged
  care facilities
• Medicines, including bisphosphonates and loop diuretics.

The management of hypocalcaemia depends on the underlying cause and the severity of the condition.^21–23 In cases of acute severe hypocalcaemia, IV calcium supplementation can be required.^21–23 IV calcium gluconate is first-line therapy and IV calcium chloride second line.^10,21–23 Although generally accepted, IV calcium administration via peripheral lines may cause irritation of veins. Calcium gluconate is often thought to be less irritant to peripheral veins than calcium chloride,²³ but whether this a real difference, or due to lower doses of calcium gluconate being infused compared to calcium chloride in clinical practice, is unclear. A 2013 study of the safety of IV calcium chloride found peripheral administration of IV calcium chloride in 100–250 mL of 5% dextrose was associated with a low incidence of infusion site reactions.²⁴ Nonetheless, patients requiring high doses of IV calcium may require insertion of central lines. Concomitant supplementation with calcitriol can increase serum calcium concentrations more effectively than monotherapy with IV calcium alone.

Individuals with chronic kidney disease should be monitored for hypocalcaemia and treated with calcitriol where needed. However, in this cohort, calcitriol often also increases serum phosphate, which is problematic as these patients already have raised phosphate and this needs to be taken into consideration. Kidney specialists may suggest phosphate control should not be sacrificed to increase serum calcium in patients with CKD.

Hypercalcaemia

Hypercalcaemia is a condition characterised by a concentration of calcium in the blood above the reference range.²⁵ The signs and symptoms of hypercalcaemia can be nonspecific and may vary depending on the severity of the condition.^25,26 Mild cases can be asymptomatic, while severe cases can cause a wide range of symptoms, including nausea, vomiting, constipation, abdominal pain, bone pain, confusion and muscle weakness.^2,25–27 Patients with hypercalcaemia can also have an increased risk of kidney stones, osteoporosis and cardiovascular disease.^25–27

Hypercalcaemia is a common complication of cancer, primary hyperparathyroidism and secondary hyperparathyroidism in the later stages of CKD and can be caused by some medicines, such as thiazide diuretics and lithium.^2,25,26,28

Treatment of hypercalcaemia can involve IV hydration with normal saline to promote calcium excretion through the kidneys, and IV bisphosphonates which lower calcium levels by decreasing bone resorption mediated by osteoclasts.^25,26,29 Zoledronic acid is preferred as first line treatment for hypercalcaemia, but pamidronate can also be used.^25,26,29 Patients should be warned of possible flu-like reactions that can occur with initial infusions.^9,29 Calcitonin salmon (salcatonin) is sometimes used in the short term for severe acute hypercalcaemia; however, tachyphylaxis (progressive decrease in response to the treatment) usually develops after around 48 hours, so it is only useful as an adjunct to other therapies.^9,25,26,29 When hypercalcaemia is caused by a granulomatous process (e.g. sarcoidosis or lymphoma), prednisone is often used to lower calcium levels.²⁹ When hypercalcaemia is associated with CKD, cinacalcet can be used to lower calcium levels.⁹ It increases the sensitivity of the parathyroid tissue to calcium, thereby supressing PTH.⁹ Disappointingly the EVOLVE study failed to show a reduction in death or cardiovascular events with cinacalcet treatment in hypercalcaemia associated with CKD.³⁰

Knowledge to practice

Early recognition and appropriate management of electrolyte and mineral disturbances is important to optimise patient outcomes. Pharmacists can contribute by assisting in the identification of disturbances by routinely reviewing patients’ sodium and calcium levels, if available, when undertaking a medicines review. Pharmacists can also contribute to the management of electrolyte disturbances by providing clinical advice on potential causes (particularly medicine causes), the chronicity of the disturbance, when treatment is required, management strategies (particularly advice on electrolyte and medicine dosing and administration) and ensuring appropriate availability of electrolyte supplements and medicines.

Conclusion

Sodium and calcium both play crucial roles in the body, and while small deviations from reference ranges often don’t warrant treatment (either with supplementation or other medicines), more severe deviations can be life threatening and require urgent treatment. Understanding common causes and standard treatment recommendations for severe disturbances can enable pharmacists to play a role in the identification and management of these.

Key points

• Hyponatraemia is a relatively common occurrence in patients with heart failure or chronic liver disease. In these cohorts, it is often mild and chronic and does not warrant treatment.
• Treatment for hyponatraemia is heavily guided by the underlying cause, and careful use of hypertonic saline by clinicians experienced with its use is warranted in severe acute cases.
• Chronic kidney disease is a common cause of hypocalcaemia. Calcitriol supplementation has a role in these patients but may come with the
  burden of increasing already raised serum phosphate.
• Hypercalcaemia is common in malignancy and fluids and IV bisphosphonates are important treatments for these patients.   

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References

1. Connor TH, MacKenzie BA, DeBord DG, et al. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings. Cincinnati, OH. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health. 2016.
2. Sansom LN, ed. Australian pharmaceutical formulary and handbook. 2024. Compounding; [updated 2024 Feb 16]. At: https://apf.psa.org.au/compounding/good-compounding-practice-0
3. USP <800>: Hazardous drugs–handling in healthcare settings. Rockville, MD. United States Pharmacopeial Convention. 2016.
4. International Society of Oncology Pharmacy Practitioners. ISOPP Standards for the Safe Handling of Cytotoxics. J Oncol Pharm Practice 2022;28(3 (supplement)):1–126.
5. Victorian Therapeutic Advisory Group. Handling of Hazardous Medicines Victorian Framework. 2021. At: victag.org.au/VicTAG_Handling_of_Hazardous_Medicine_Framework_Nov_2021_Final.pdf
6. Easty AC, Coakley N, Cheng R et al. Safe handling of cytotoxics: guideline recommendations. Current oncology (Toronto, Ont.) 2015;22(1):e27–e37.

Our authors

Karl Winckel (he/him) BPharm, Grad Cert Clin Pharm (UK), Dip Pharm Prac (UK), Grad Cert Higher Ed (UQ), Cert Psych Therap (UK), AdvPracPharm is an Advanced Practice credentialed pharmacist and a conjoint pharmacist working between the School of Pharmacy, University of Queensland, and the Princess Alexandra Hospital in Brisbane.

DR Carlos Santini (he/him) MBBS is a clinical pharmacology advanced trainee at the Princess Alexandra Hospital.

Our reviewer

DR Natalie Soulsby (she/her) PhD, MSc Clin Pharm, BSc (Hons) Pharm, AACPA, FPS, FSHP, Adv Pract Pharm