Electrolyte disorders

Calcium disorders

Serum calcium is often routinely, and unnecessrily, requested with little thought to how an unexpected mildly low or mildly elevated result will be handled. Patients fully investigated previously for fits do not require a repeat calcium and magnesium level each time they come in. However, unexpected hypoparathyroidism can explain a host of mild (and even severe!) symptoms, so the test does have some screening utility in patients with new and somewhat unusual presentations. Correcting the serum calcium probably contributes little. (See here: https://medeval.co.za/wp/aims-and-objectives-of-this-site/knowledge-base/uncategorized/correct-calcium-why-do-it/)

Hypercalcaemia

Hypercalcaemia is usually due to either malignancy or hyperparathyroidism, and the two are relatively easy to differentiate – measure the PTH and look for radiological or clinical evidence of malignancy. (There are many rare associations – e.g. thyrotoxicosis, hypoadrenalism, phaeochromocytoma, sarcoidosis, tuberculosis, and thiazide diuretic use.) Saline may be the initial therapy of choice, but will only drop the serum calcium by about 0.6 mmol/l.¹ Furosemide should NOT be added routinely until you are quite clear that the patient is euvolaemic, and again even then it is not dramatically effective – also about a 0.6 mmol/l drop.² A well-designed comparison of saline versus saline plus furosemide is still to be done, and probably will never happen now that the biphosphonates are available for the treatment of the hypercalcaemia of malignancy.

Biphosphonates lower serum calcium in a dose-dependent way – e.g. pamidronate in doses of 30, 60, and 90 mg led to eucalcaemia at day 7 in 40%, 61% and 100% of patients in one study.³ Oral agents are theoretically tempting because of cost considerations but have very poor systemic availability and there is little evidence that they can be used successfully in this situation. There is some evidence⁴ to suggest that biphosphonates may have a greater effect on hypercalcaemia in some malignancies (e.g. breast) than in others (e.g. myeloma).

Clearly don’t neglect to see if the malignancy itself is treatable – this may be the best way of reducing the calcium level. As a corollary, in patients with terminal malignancy the aggressive treatment of hypercalcaemia simply because it is there, may not be appropriate.

Perspective – diagnostic performance of PTH assays.

This depends to some extent on which assay is performed, with reported sensitivities varying from 40- 86%, and specificity of about 95%. An intact PTH (i.e. not just antibody test to one or other terminal) has been reported as having a sensitivity of 99% in differentiating primary hyperparathyroidism from malignancy (LR+ 14.0, LR- 0.07)⁵

Pre-test probability	0.01	0.05	0.1	0.25	0.5	0.75	0.9	0.95	0.99
Revised probability of hyperparathyroidism.
PTH > 5.3pmol/l	0.12	0.42	0.61	0.82	0.93	0.98	0.99	1.00	1.00
PTH < 5.3pmol/l	0.00	0.00	0.01	0.02	0.07	0.17	0.39	0.57	0.87

Hypocalcaemia

Symptomatic cases are usually secondary to hypoparathyroidism, overly aggressive thyroid surgery, acute rhabdomyolysis or acute pancreatitis. More chronic presentations suggest chronic renal failure or hypoparathyroidism. Osteomalacia is associated with a high alkaline phosphatase level.

The treatment of acute symptomatic hypocalcaemia (tetany) may require intravenous calcium. The chloride salt contains about three times as much elemental calcium per ml as the gluconate (27 vs. 9 mg/ml) but is sclerosant if given through peripheral veins, which thus won’t last long. Rather give 10 ml of 10% calcium gluconate over 10 minutes, (this can be repeated once, depending on response, or lack thereof, and then start a calcium infusion, because the benefits of the bolus will wane after about 6 hours. There is little comparative data on calcium infusion recipes; the data in the image below is an amalgam from various listed regimens⁶ Take care to avoid precipitation (do not mix with bicarbonate or phosphate contiaining solutions, or with amphotericin, ceftriaxone, fluconazole, meropenem, methylprednisone, or phenytoin. If in doubt about compatibility, check both package inserts or consult.

Suggested infustion rates vary from one or two ampoules of calcium gluconate added to a litre of saline or 5% dextrose water up to infusion rates equivalent to one ampoule per hour:

Oral replacement is with calcium carbonate 1-2 tabs three times per day, usually with additional Vitamin D – e.g. alphacalcidol 0.25- 1 mcg/d, sometimes increasing to 2 or 3 mcg/d. Most forms of Vitamin D are oddly expensive, so see what is available locally.

Perspective – psuedopseudohypoparathyroidism

A sad day when the term was coined… Think of it as a progression:

• Hypoparathyroidism. No or low PTH because of gland failure or removal. Low calcium, and usually a high phosphate.
• Pseudohypoparathyroidism. Low calcium and a high phosphate, but because of end organ resistance to PTH, the serum PTH is high. Phenotype: round face and short hands.
• Pseudopseudohypoparathyroidism. Round face and short hands without the biochemical changes…

Sodium disorders

Hyponatraemia

Hyponatraemia is common in medical patients, but is usually mild and responds to management of the underlying condition. When severe it is usually due to either salt loss from diuretics or relative water retention due to SIADH or cardiac or renal failure. Always consider Addison’s.

SIADH and cerebral salt wasting

Differentiating cerebral salt wasting from SIADH should in theory be very straightforward but sometimes isn’t. In a nutshell, both have high urinary osmolarity (>100 ) and sodium (>40) and SAIDH patients are euvolaemic whereas those with cerebral salt wasting are dehydrated with a raised urea and clinical features of hypovolaemia.⁷ The usual clinical signs of BP, pulse, and postural changes in BP and pulse are not always reliable, and response to a fluid bolus may be helpful in some instances where doubt remains.

Two of the issues faced in clinical practice is that differentiating underhydration and normal hydration may be difficult (overhydrated patients are usually oedematous) but urinary sodium results may be difficult to interpret if patients have been given a diuretic:

Approach:

From the history and context, try to decide whether the hyponatraemia is acute or chronic. In the latter, rapid correction is likely to be harmful.

Check hydration clinically (not very reliable):

• pulse rate, BP, postural drop in BP or rise in pulse
• axillary moisture
• urine specific gravity.

Send a spot urine specimen for measurement of urinary sodium (you do not need to collect a 24 hour specimen).

If the urinary sodium is >40 mM (alternative cut-points of 30 and even 20 have been described – which trade sensitivity for specificity – see the diagram) and the patient is euvolaemic with normal renal, adrenal (cortisol) and thyroid (TSH)) function, the diagnosis is usually SIADH. Alternatively consider the diagnosis likely if the urinary osmolality is greater than 100 mOsm/kg in the presence of reduced serum osmolality (<275 mOsm/kg.)⁸ Thyroid and adrenal function must be normal as well before making the diagnosis, and the patient shouldn’t have been on a diuretic recently.

Manage SIADH by treating the cause, and if the sodium is concerningly low (less than 125 mM) treat by restricting fluid intake to 600 ml per day.

If the potassium is high, or there are clinical concerns about hypoadrenalism, do a morning cortisol. A baseline 9.00 am cortisol of less than 100 nmol/l is strongly suggestive of Addison’s, whereas a value of more than 550 nmol/l effectively excludes the diagnosis.⁹

Although it is tempting to believe that emaciated hyponatraemic HIV positive patients have hypoadrenalism, in practice it is probably no more common than the relative hypocortisolism seen in equivalently ill HIV negative individuals.¹⁰ If the patient is really ill and you are seriously concerned about the possibility of Addison’s it is appropriate to treat as such (hydrocortisone 100 mg 3x/d I.V). while awaiting the result of the random cortisol, which under these circumstances of stress should be high.

Management of hyponatraemia in the setting of dehydration entails giving saline I.V. or oral salt with an adequate supply of water.

Perspective – clinical guidelines in hyponatraemia

Many clinicians struggle with the management of this condition, and formal guidelines are not always that helpful; careful thought and familiarity with a few variations may be as productive. A group from the Netherlands¹¹ asked 46 physicians to apply a selection of 10 clinical algorithms to three case scenarios (all a little atypical!) The proportion of physicians reaching the correct diagnosis in all three cases using each algorithm ranged from 6 to 12%. This is startlingly weak. Key difficulties identified were:

• The clinical recognition of reduced extracellular fluid volume is not always easy.
• Algorithms didn’t always allow one to differentiate acute from chronic hyponatraemia.
• SIADH should be a diagnosis of exclusion; in particular adrenal insufficiency needs to be formally tested for, as up to a third of patients may not be hyperkalaemic and the ECF volume contraction can be missed.

The authors suggest yet another algorithm which proposes rapid correction of all hyponatraemia present for less than 48 hours, and chronic hyponatraemia associated with fits or coma, but in the latter situation the serum sodium should only be raised until symptoms abate (usually only need a 5 mmol/l increase). In individuals without fits or coma and with chronic hyponatraemia, they suggest a rise of only 4-8 mmol/d, with particular caution in the malnourished or those with associated hypokalaemia. Needless to say, this guideline is as unvalidated as any of the others…

Bolus versus continuous infusion of hypertonic saline to correct symptomatic hyponatraemia

The SALSA trial of 180 patients in Korea found no difference in most outcomes between bolus and infusion, with the over-correction rate (serum sodium rise of >12 mmol/l in 24 hours) being about 20% in both arms.¹²

Perspective – central pontine myelinolysis/osmotic demyelination syndrome

• This very distressing and completely avoidable syndrome is due to rapid correction of chronic hyponatraemia. It has also been described after rapid correction of hypernatraemia. It presents with:
• Deteriorating level of consciousness.
• Flaccid paralysis.
• Facial weakness and difficulty swallowing.
• Abnormal eye movements.

It is associated with Wernicke’s and hepatic encephalopathies, Addison’s, dialysis, and the hyponatraemia of diuretic misuse. There are a number of key principles in its management:

• Patients with chronic hyponatraemia tolerate rapid correction less well than those with acutely developing hyponatraemia.
• Patients who are malnourished are more prone to develop CPM.
• Simply identifying an abnormality does not make it an emergency – in a clinically relatively stable patient there is no need to correct particularly rapidly.

The rate of correction commonly recommended is less than 12 mmol/l in the first 12 hours. This is the safety barrier, not necessarily the ideal rate. An elegant rise of 4-5 mmol/l per day in an otherwise stable chronically hyponatraemic patient is fine. In a volume depleted patient this can even be achieved using half normal saline.¹³

Hypernatraemia

Important causes of severe hypernatraemia are:

Excess water loss – diarrhoea, fever, burns, hyperglycaemia with osmotic diuresis.

Insufficient water intake – strokes, tuberculous meningitis, circumcision rituals

Administration of excess hypertonic saline

The treatment is to administer water. In markedly hypernatraemic individuals who have had time to protect brain osmolarity by the generation of idiogenic osmoles, the sudden infusion of hypotonic solutions can lead to cerebral oedema, so don’t try to correct too rapidly. If there is a need to replace volume (shock) do so with normal saline first – this will still be a hypo-osmolar fluid if the person is markedly hypernatraemic. (Normal saline contains 154 mmol of sodium per litre)

Hypokalaemia

Causes

Gastrointestinal potassium loss – predominantly diarrhoea

Urinary potassium loss – high doses of diuretics, recovery phase of ATN.

Potassium shifts – treatment of DKA, treatment of megaloblastic anaemias, treatment of asthma.

Management

The exact figure at which IV replacement of potassium should commence is a source of some confusion, with little evidence-based help from the literature. In practice, it is often rather academic, as the context is more important than the level. A patient with any degree of hypokalaemia and ongoing diarrhoea warrants intravenous replacement, as the situation is otherwise likely to worsen before it settles. The same applies to the treatment of DKA. A stable patient with a mildly reduced level in whom you are in any case planning to reduce the diuretic dose, having achieved your salt and water balance goals, probably will not need intravenous potassium replacement.

Intravenous potassium is sclerosant to veins, and needs to be well diluted to avoid potentially lethal cardiac arrhythmias. A reasonable recipe is to put either one (20 mmol) or two (40 mmol) ampules of KCl into a litre of saline or dextrose, mix it thoroughly, and infuse over 6-8 hours (max rate of 20 mmol/hr). Specify the mmol amount and don’t just write a volume. Ideally, like a morphine script, duplicate your message to avoid errors – e.g. state the dose in both mmol, and millilitres, specifying the undiluted concentration. (potassium chloride 15% for intravenous use contains 2 mmol of potassium per millilitre).

e.g. ‘Add 20 mmol (i.e. 10 ml of the 15% solution) KCL to one litre of 5% dextrose water, and mix thoroughly. Infuse each litre over 8 hours to give 3l per 24 hours’.

Oral replacement of KCL (each 600 mg tablet contains 8 mmol KCl), is not very well tolerated, and is seldom needed long-term.

The serum potassium that won’t correct.

Patients with apparently refractory hypokalaemia, where the potassium does not seem to be coming up in spite of your best efforts, should have their serum magnesium measured. If this is low, its correction may allow easier potassium replacement.

Also consider ongoing losses, and simply inadequate replacement, remembering that potassium is predominantly intracellular, and in setting of long standing loss, total body depletion may be considerable.

Perspective – hypomagnesaemia

HIV-associated diarrhoea is probably one of the commonest causes of hypokalaemia, and the associated hypomagnesaemia is sometimes overlooked. Contributing causes besides the GIT losses in these patients may include starvation with reduced intake, refeeding syndrome, acute pancreatitis, drugs (amphotericin, aminoglycosides, diuretics), volume expansion, chronic metabolic acidosis, and the recovery phase of ATN. Apart from refractory hypokalaemia, the clinical manifestations of hypomagnesaemia are similar to those of hypocalcaemia. As magnesium is predominantly an intracellular ion, serum concentrations may remain normal even in the face of quite marked total body deficit, and there is no easy way of ascertaining this. In the face of a high clinical suspicion it may well be reasonable to treat, although it is stated that patients with clinical hypomagnesaemia ‘usually’ have low serum levels. Magnesium infusions raise the serum magnesium abruptly, leading to reduced tubular reabsorption of magnesium and loss of up to 50% of the infused load, so oral replacement with slow release magnesium chloride (about 3 mmol/tab) makes sense if the patient is not vomiting. If parenteral therapy is needed options are either MgSO₄ 1g (4 mmol) IM six hourly or an infusion – e.g. 3g in 200 ml 5% DW over 3-4 hours, and repeated as needed.

Hyperkalaemia

Causes

Renal failure is probably the commonest cause of clinically important hyperkalaemia, but other possibilities are:

• Drug effects – specially the interaction of spironolactone and ACE inhibitors in patients with moderate renal impairment. Also high dose co-trimoxazole, as used to treat pneumocystis, and any patient given inappropriate potassium supplementation.
• Rhabdomyolysis or haemolysis.
• Initial presentation of diabetic ketoacidosis (reverses rapidly with therapy of the DKA).
• Hyporeninaemic hypoaldosteronism – mildly elevated potassium in the face of mild renal impairment in diabetics.
• Addison’s disease.

Management of hyperkalaemia

The key issue is not the absolute level of potassium, but how it got there. A patient on chronic haemodialysis who comes in the with potassium of 6.9 and is due for dialysis in a few hours is probably at far less risk than another patient with an MVA with rhabdomyolysis and a myocardial contusion who has a potassium of 6.4 mmol/l.

If urgent treatment is considered appropriate:

Stop any obvious cause, like a potassium infusion.

Give 10 ml of 10% calcium gluconate slowly IVI as a myocardial stabiliser.

Insulin and glucose:

• Short acting insulin 5-10 units IV stat plus 50 ml of 50% dextrose.
• In renal impairment the insulin hangs around after the glucose is metabolised, so a second dose of glucose, or at least careful monitoring of the fingerprick glucose, is appropriate in the 2-4 hours after first giving insulin and glucose.

A salbutamol nebuliser (5-10 mg diluted in 4 ml saline) shifts potassium into cells. A metered dose inhaler (12 puffs into a large volume spacer) probably achieves the same effect, although the initial response in the first minute or so is a transient mild (0.15 mmol/l) rise in the serum potassium.¹⁴

Polystyrene resin 15g 6-8 hourly, or 30g as an enema 8 hourly.

Bicarbonate is not efficacious.

The definitive management of hyperkalaemia is with dialysis.

Perspective – treatment of hyperkalaemia.

This is another rather disappointing area from an evidence perspective – the therapies have been around for decades, but RCTs are in short supply.

At what level is hyperkalaemia dangerous?

The widely quoted ‘magic figure’ of 6,5 mmol/l may have some background in animal physiology experiments, but clinical backing is somewhat limited. One observational study¹⁵ found a 28% mortality in those with [K] > 7.0 mmol/l, but 9% if [K] was < 6.5 mmol/l.

How useful is the ECG for detecting hyperkalaemia?

The classic ECG signs of hyperkalaemia are:

• [K] 6-7 mmol/l – tall peaked T waves (>5 mm)
• [K] 7-8 mmol/l – broad or absent P waves, QRS widening.
• [K] 8-9 mmol/l – sinusoidal QRST

In a study looking at the ability of two clinicians to detect any hyperkalaemia from the ECG¹⁶ (sensitivity was <0.43 and specificity <0.86. (LR+ 3.1, LR- 0.7) Sensitivity to detect a potassium of >6.5 mmol/l was <0.62. The bottom line is that the ECG is insufficiently sensitive to exclude clinically important hyperkalaemia. A similar study from 2012 effectively debunked the ability of the ECG to act as either a sensitive marker of hyperkalaemia of a useful follow-up tool, with the classical “laboratory” findings and progression simply not being found as suspected. Bottom line – check the serum level – don’t try and pronounce on it from the ECG.¹⁷

By how much does treatment lower the potassium?

A review looked at effect size of the various interventions:¹⁸

Intervention	Number of trials	Number of pts	Range of [K] drop	Duration (hrs)
Calcium	No significant effect on [K] – ‘membrane stabilisation’
Glucose and insulin	7	74	0.65-1.0	1-6
Salbutamol nebs	9	80	0.53-0.98	1-6
Bicarbonate	4	42	No significant effect
Polystyrene	Published evidence of efficacy unclear.

Out of about 18 studies identified, only one was double-blinded and only two were randomised. In nine studies, the mean initial potassium was already less than 6.0 mmol/l.

It is probably optimistic to expect more than a 0.5-1.0 mmol/l change in [K] with any therapy other than dialysis, although there is some evidence that the effects of different agents may be additive¹⁹, and two studies on the combination of insulin/glucose and nebulised salbutamol reported drops of 1.2 to 1.5 mmol/l, in one study, maximum at one hour, and in one study lasting for more than six hours. A Cochrane review reached a similar conclusion.²⁰

Diabetes insipidus

The commonest scenario is massive polyuria after a head injury. The treatment is desmopressin. Use 10 to 20 mcg nasal solution twice daily. (This works out to about 0.1-0.2 ml twice daily). Sometimes patients are seen after neurosurgery and occasional difficulties arise when transferring from oral treatment where the dose is 0.1 mg three times per day (to a maximum of 0.4 mg 3x/d). The nasal solution dose is one tenth of the oral dose.

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17. Cohen, R. , Ramos, R. , Garcia, C. , Mehmood, S. , Park, Y. , Divittis, A. and Mirrer, B. (2012) Electrocardiogram manifestations in hyperkalemia. World Journal of Cardiovascular Diseases, 2, 57-63. doi: 10.4236/wjcd.2012.22010 ↩

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20. Mahoney BA, Smith WAD, Lo D, Tsoi K, Tonelli M, Clase C. Emergency interventions for hyperkalaemia. Cochrane Database of Systematic Reviews 2005, Issue 2. Art. No.: CD003235 ↩

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