Hypokalaemia

Introduction

Hypokalaemia is defined as a serum potassium below 3.5 mmol/L and is one of the most frequently encountered electrolyte abnormalities in hospital practice, found in up to a fifth of inpatients. It is usually mild, but it becomes clinically important because of its effects on cardiac excitability, skeletal muscle and the kidney.¹

As with hyperkalaemia, it helps to remember that 98% of body potassium is intracellular. A low serum potassium may therefore reflect true total body depletion (from renal or gastrointestinal loss, or poor intake) or simply a shift into cells with normal total body stores. Distinguishing the two matters, because a shift-related hypokalaemia will correct itself and over-replacement risks rebound hyperkalaemia.

Causes

Gastrointestinal losses

• Diarrhoea - the commonest GI cause; loses potassium and bicarbonate, producing a normal anion gap metabolic acidosis with hypokalaemia
• Vomiting and nasogastric aspiration - note the mechanism is largely renal rather than direct loss: volume depletion drives secondary hyperaldosteronism, and the metabolic alkalosis shifts potassium into cells. This produces the classic hypokalaemic, hypochloraemic metabolic alkalosis seen in pyloric stenosis
• Laxative misuse - consider in unexplained hypokalaemia, particularly with eating disorders
• Villous adenoma of the rectum - secretes large volumes of potassium-rich mucus
• Fistulae, ileostomy losses and short bowel syndrome

Renal losses

• Loop and thiazide diuretics - by a clear margin the commonest drug cause; they increase distal sodium delivery and therefore potassium excretion
• Hyperaldosteronism - primary (Conn syndrome) or secondary; causes hypokalaemia with hypertension and metabolic alkalosis
• Cushing syndrome and high-dose corticosteroids - cortisol has mineralocorticoid activity at high concentrations; ectopic ACTH classically causes profound hypokalaemia
• Renal artery stenosis and renin-secreting tumours - secondary hyperaldosteronism
• Liquorice excess and carbenoxolone - inhibit 11-beta-hydroxysteroid dehydrogenase, allowing cortisol to act on mineralocorticoid receptors (apparent mineralocorticoid excess)
• Renal tubular acidosis types 1 and 2 - hypokalaemia with a normal anion gap metabolic acidosis, in contrast to most other renal causes which cause alkalosis
• Bartter and Gitelman syndromes - inherited tubulopathies causing hypokalaemic alkalosis with normal or low blood pressure; Bartter mimics a loop diuretic, Gitelman a thiazide (and Gitelman characteristically also causes hypomagnesaemia and hypocalciuria)
• Hypomagnesaemia - see below; a critically important and often missed cause
• Drugs - amphotericin B, aminoglycosides, cisplatin, high-dose penicillins
• Osmotic diuresis - as in diabetic ketoacidosis and hyperglycaemia
• Recovery phase of AKI and post-obstructive diuresis

Shift into cells

• Insulin - including treatment of DKA, where potassium falls precipitously; and insulin-glucose given for hyperkalaemia
• Beta-2 agonists - salbutamol, especially nebulised and repeated in acute asthma
• Metabolic alkalosis - potassium moves into cells in exchange for hydrogen ions
• Refeeding syndrome - insulin release after starvation drives potassium, phosphate and magnesium intracellularly
• Catecholamines - stress, sepsis, myocardial infarction, and inotropes
• Hypokalaemic periodic paralysis, including the thyrotoxic form

Inadequate intake

Rarely a sole cause in a patient with normal kidneys, since renal conservation is efficient - but it contributes in malnutrition, alcohol dependence, anorexia nervosa and prolonged inadequate parenteral nutrition, and it compounds losses from other sources.

Clinical features

Mild hypokalaemia is usually asymptomatic and detected incidentally. Symptoms generally appear below 3.0 mmol/L and reflect the effect of potassium on excitable membranes - cardiac, skeletal and smooth muscle.

• Generalised muscle weakness, fatigue and myalgia - typically proximal and ascending; severe cases progress to flaccid paralysis and, rarely, respiratory muscle failure
• Muscle cramps and tetany
• Palpitations and arrhythmias - ectopics, atrial fibrillation, ventricular tachycardia and torsades de pointes
• Constipation, ileus and abdominal distension - from smooth muscle involvement
• Polyuria and polydipsia - hypokalaemia causes a nephrogenic diabetes insipidus-like state by impairing renal concentrating ability
• Rhabdomyolysis - severe hypokalaemia impairs muscle blood flow and can cause muscle breakdown, which is worth knowing because it then releases potassium and confuses the picture
• Paraesthesiae and reduced reflexes
• Worsening of glycaemic control - potassium is required for insulin secretion
• Exacerbation of hepatic encephalopathy - hypokalaemia increases renal ammonia production
• Features of the underlying cause - hypertension in Conn's, cushingoid appearance, dental erosion or parotid swelling in bulimia, diarrhoea or vomiting

Investigations

• 12-lead ECG - essential in moderate or severe hypokalaemia, and in anyone on digoxin or with cardiac disease
• Serum magnesium - check in every case; hypomagnesaemia is a common cause of refractory hypokalaemia
• U&Es, creatinine and eGFR - renal function and associated abnormalities
• Venous blood gas or bicarbonate - to establish whether there is a metabolic alkalosis or acidosis, which discriminates between causes
• Glucose - DKA and refeeding risk
• Calcium and phosphate - often disturbed together, especially in refeeding syndrome
• Urinary potassium and creatinine (spot sample or 24-hour) - low suggests GI or dietary cause, high indicates renal wasting
• Urinary chloride - helps separate vomiting (low urinary chloride) from diuretic use (high)
• Aldosterone and renin (aldosterone-to-renin ratio) - if hypokalaemia is associated with hypertension, to screen for primary hyperaldosteronism
• Cortisol testing - overnight dexamethasone suppression or 24-hour urinary free cortisol if Cushing syndrome is suspected
• Thyroid function - thyrotoxic periodic paralysis
• Digoxin level - if the patient takes digoxin, since hypokalaemia potentiates toxicity
• Creatine kinase - if there is significant weakness, to detect rhabdomyolysis
• A careful drug and laxative history - including over-the-counter laxatives, salbutamol use and liquorice consumption

ECG changes

• Small, flattened or inverted T waves
• Prominent U waves - an additional deflection after the T wave, best seen in the precordial leads; the classic finding
• ST segment depression
• Prolonged PR interval and increased P wave amplitude
• Apparent QT prolongation - in reality often a fused QU interval, but functionally it carries the same risk of torsades de pointes
• Ventricular and atrial ectopics, progressing to VT, VF and torsades

Management

Management has three components: replace potassium safely, correct magnesium, and treat the underlying cause. The second of these is the one most often forgotten.

Oral replacement

• Preferred where the patient is stable, able to swallow, and potassium is above about 2.5 mmol/L without ECG changes
• Potassium chloride preparations - e.g. Sando-K (12 mmol K⁺ per tablet), typically 2 tablets three times daily, adjusted to response
• Take with food - the main adverse effects are nausea, gastric irritation and, rarely, ulceration
• Dietary advice - bananas, oranges and orange juice, tomatoes, potatoes, avocado, dried fruit, nuts and beans
• Recheck potassium within a few days, and continue until the cause is corrected

Intravenous replacement

Treating the underlying cause

• Review and adjust diuretics - consider switching to or adding a potassium-sparing diuretic (spironolactone, amiloride) where ongoing diuresis is needed
• Treat diarrhoea and vomiting, and replace ongoing GI losses
• Address laxative misuse and eating disorders with appropriate specialist input
• Investigate and treat hyperaldosteronism - spironolactone or adrenalectomy in Conn syndrome
• Stop liquorice, and review corticosteroid dosing
• In DKA, anticipate the fall in potassium: withhold insulin if potassium is below 3.5 mmol/L until replacement has begun, and add potassium to fluids once it is below 5.5
• In refeeding syndrome, replace potassium, phosphate and magnesium, give thiamine, and reintroduce feeding slowly
• Review salbutamol use in asthma, where repeated nebulisers commonly cause transient hypokalaemia
• Check and manage digoxin - hypokalaemia potentiates toxicity

Complications

• Ventricular arrhythmias - ventricular tachycardia, ventricular fibrillation and torsades de pointes; the principal danger
• Digoxin toxicity - precipitated at otherwise therapeutic levels because potassium and digoxin compete at the Na⁺/K⁺-ATPase
• Atrial fibrillation and other supraventricular arrhythmias
• Cardiac arrest
• Flaccid paralysis and respiratory muscle weakness in severe depletion
• Rhabdomyolysis - from impaired muscle perfusion
• Ileus and constipation
• Nephrogenic diabetes insipidus with polyuria and polydipsia; chronic hypokalaemia can cause hypokalaemic nephropathy with interstitial fibrosis
• Impaired glucose tolerance, since potassium is needed for insulin release
• Precipitation or worsening of hepatic encephalopathy
• Complications of treatment - rebound hyperkalaemia from over-rapid replacement, phlebitis and pain from peripheral infusion, and the catastrophic consequences of a potassium bolus

Red flags

Prognosis

Mild hypokalaemia is generally benign and corrects readily once the underlying cause is addressed. Most cases in practice arise from diuretics or a self-limiting episode of vomiting or diarrhoea, respond to oral replacement, and cause no lasting harm. The important qualification is that even mild hypokalaemia is not harmless in the wrong context - in patients with ischaemic heart disease, heart failure, left ventricular hypertrophy or digoxin therapy, potassium levels in the 3.0-3.5 range are independently associated with increased arrhythmic risk and mortality. Many cardiologists therefore aim to keep potassium above 4.0 mmol/L in such patients rather than merely within the reference range.

Severe hypokalaemia is potentially fatal but fully reversible with prompt treatment. Arrhythmias and muscle weakness resolve as potassium is restored, and there is usually no residual deficit. The risks in this group come as much from treatment as from the abnormality itself - over-rapid replacement causing rebound hyperkalaemia, and the well-documented catastrophe of concentrated potassium given as a bolus.

Long-term outcome depends on the underlying cause. Diuretic-induced hypokalaemia is easily managed with dose adjustment, potassium-sparing agents or supplementation. Primary hyperaldosteronism is potentially curable by adrenalectomy, and identifying it converts a lifetime of refractory hypertension and potassium supplements into a treatable diagnosis - which is why hypokalaemia with hypertension should always be investigated rather than simply corrected. Conversely, chronic untreated hypokalaemia can cause hypokalaemic nephropathy, with tubulointerstitial fibrosis and progressive renal impairment, and hypokalaemia arising from eating disorders or laxative misuse carries the prognosis of the underlying psychiatric condition, which is considerably more serious than the electrolyte result alone suggests.