Hypokalaemia

Hypokalaemia is a serum potassium concentration under 3.5 mmol/L. It is common in hospital patients, usually from gastrointestinal loss, diuretics or poor intake, and its importance lies in cardiac arrhythmia, muscle weakness and the underlying disease.

Clinical relevance. Hypokalaemia occurs in about 20% of hospital patients and up to half of those on thiazide or loop diuretics. Risk is highest with heart disease, digoxin, QT prolonging drugs, hypomagnesaemia, and acute myocardial infarction.

Physiology. Most potassium is intracellular (98%), and the serum level is regulated by renal excretion, insulin, catecholamines, acid base balance and aldosterone. A serum potassium of 3.0 mmol/L usually reflects a total deficit of 200 to 400 mmol, and each further fall of 1 mmol/L under 3.0 mmol/L adds about 200 to 400 mmol.

Classification by severity.

• Mild: 3.0 to 3.4 mmol/L.
• Moderate: 2.5 to 2.9 mmol/L.
• Severe: under 2.5 mmol/L (high risk of arrhythmia, paralysis and rhabdomyolysis).

Classification by mechanism.

• Redistribution into cells: insulin, beta 2 agonists, alkalosis, thyrotoxic and familial periodic paralysis, refeeding, rapid cell production (treatment of megaloblastic anaemia, granulocyte colony stimulating factor), hypothermia, theophylline or caffeine toxicity, barium poisoning.
• Renal loss: diuretics, mineralocorticoid excess, magnesium deficiency, renal tubular disorders, and drugs.
• Gastrointestinal loss: vomiting (mainly through renal loss from alkalosis), diarrhoea, laxative abuse, fistulae and villous adenoma.
• Reduced intake and other losses: starvation, alcohol, dialysis, and sweating.
• Spurious: delayed analysis of a sample with marked leucocytosis.

Key distinctions. A urinary potassium under 20 mmol/day (or spot potassium to creatinine ratio under 1.5 mmol/mmol) suggests non-renal loss or redistribution, and over 30 mmol/day with hypokalaemia indicates inappropriate renal loss. Hypokalaemia with hypertension and alkalosis points to mineralocorticoid excess.

History.

• Vomiting, diarrhoea, laxatives, poor intake, anorexia, alcohol use, and weight change.
• Drugs: loop and thiazide diuretics, insulin, salbutamol and other beta agonists, theophylline, corticosteroids, amphotericin B, aminoglycosides, cisplatin, penicillins in high dose, laxatives, liquorice, fludrocortisone, and lithium.
• Weakness, cramps, myalgia, palpitations, constipation, polyuria and polydipsia, and episodes of paralysis (periodic paralysis, with onset at night or after exercise or a carbohydrate meal).
• Hypertension, headaches, family history of hypokalaemia or hypertension, thyroid symptoms, and recent insulin or feeding.
• Cardiac disease and use of digoxin or QT prolonging drugs.

Examination.

• Pulse (irregular), blood pressure (high in mineralocorticoid excess, low or postural in diuretic and gastrointestinal loss), volume status, and respiratory effort.
• Muscle power (proximal weakness), reflexes (reduced), and abdominal examination (distension, reduced bowel sounds from ileus).
• Signs of Cushing syndrome, hyperthyroidism (tremor, goitre), and eating disorder.
• Continuous electrocardiogram for potassium under 3.0 mmol/L, symptoms or cardiac disease.

Red flags.

• Electrocardiogram changes: ST segment depression, flattened or inverted T waves, prominent U waves, prolonged QT interval, frequent ectopics, ventricular tachycardia (including torsades de pointes), or ventricular fibrillation.
• Potassium under 2.5 mmol/L, or a rapid fall.
• Ascending paralysis or respiratory muscle weakness.
• Rhabdomyolysis (muscle pain, dark urine).
• Concurrent digoxin, QT prolonging drug, heart disease or acute coronary syndrome.
• Ileus or severe constipation.
• Severe hypertension with hypokalaemia (primary aldosteronism, Cushing syndrome, renal artery stenosis).
• Severe hypomagnesaemia.
• Hypokalaemia in a patient with an eating disorder, alcohol dependence or on refeeding.

Special groups. Children need weight based dosing. Older adults are at high risk with diuretics. Pregnancy: hyperemesis causes loss, and potassium is replaced with the same doses used in other adults, with monitoring. Patients with kidney disease are replaced cautiously because of risk of rebound hyperkalaemia.

Gastrointestinal loss. Vomiting (with metabolic alkalosis), diarrhoea (with metabolic acidosis), laxative or enema abuse, ileostomy or fistula loss, villous adenoma, bowel obstruction, nasogastric suction, and intestinal infection.

Renal loss with normal or low blood pressure.

• Drugs: loop and thiazide diuretics, osmotic diuretics, acetazolamide, amphotericin B, aminoglycosides, cisplatin, ifosfamide, high dose penicillins, and corticosteroids.
• Tubular disorders: Bartter syndrome, Gitelman syndrome, renal tubular acidosis (types 1 and 2, Fanconi syndrome), and magnesium depletion.
• Osmotic diuresis in hyperglycaemia, diabetic ketoacidosis, post obstructive diuresis, and the recovery phase of acute tubular necrosis.

Renal loss with hypertension. Primary aldosteronism (adenoma, bilateral hyperplasia), Cushing syndrome, ectopic ACTH, renovascular hypertension, renin secreting tumour, liquorice ingestion, congenital adrenal hyperplasia, Liddle syndrome, and apparent mineralocorticoid excess.

Redistribution. Insulin therapy and refeeding, beta agonist use, alkalosis, familial hypokalaemic periodic paralysis, thyrotoxic periodic paralysis, rapid cell proliferation (leukaemia, treatment of anaemia), and toxins (barium, theophylline, caffeine, chloroquine).

Reduced intake and other losses. Starvation, anorexia nervosa, alcohol use disorder, excessive sweating, burns, and dialysis.

Spurious. Marked leucocytosis with delayed sample analysis, or contamination.

Step 1. Perform an electrocardiogram and check whether the patient has symptoms. Confirm the result and identify immediate hazards.

Step 2. Laboratory tests: urea, creatinine, electrolytes, bicarbonate or blood gas, glucose, calcium, magnesium (always, because hypomagnesaemia causes refractory hypokalaemia), phosphate, creatine kinase, thyroid function, full blood count, and urinalysis.

Step 3. Establish the cause from history and drugs. If unexplained: spot urine potassium, creatinine, sodium, chloride and osmolality, or a 24 hour urine potassium.

• Urine potassium under 20 mmol/day (or potassium to creatinine ratio under 1.5 mmol/mmol): extrarenal loss (diarrhoea, laxatives, poor intake), redistribution, or past diuretic use.
• Urine potassium over 30 mmol/day: renal loss (diuretics, tubular disorder, mineralocorticoid excess, magnesium depletion).
• Blood pressure and acid base then separate causes:
  • normal or low blood pressure with metabolic alkalosis and low urinary chloride (under 20 mmol/L) indicates vomiting or remote diuretic use
  • with high urinary chloride (over 20 mmol/L): current diuretics, Bartter or Gitelman syndrome
  • normal or low blood pressure with metabolic acidosis indicates diarrhoea, laxative abuse, or renal tubular acidosis (check urine pH and anion gap)
  • hypertension with alkalosis needs plasma renin and aldosterone (ratio, ideally taken after correcting potassium and with interfering drugs stopped), cortisol, and imaging

Step 4. Further tests when indicated:

• aldosterone to renin ratio with adrenal CT and adrenal vein sampling
• 24 hour urinary free cortisol or overnight dexamethasone suppression
• thyroid function in periodic paralysis (low TSH and raised free thyroxine)
• genetic testing for Gitelman and Bartter syndromes
• urine diuretic and laxative screen, and renal ultrasound

Interpretation. Electrocardiogram changes correlate poorly with potassium level. Persistent hypokalaemia despite replacement suggests magnesium depletion, ongoing losses, or mineralocorticoid excess. A low TSH with hypokalaemic paralysis in a young man (often of Asian or Latin American descent) suggests thyrotoxic periodic paralysis.

Limitations. A single value does not reflect total body deficit. Urine potassium varies with intake and timing. Aldosterone to renin ratio is affected by potassium, drugs and sodium intake.

Immediate priorities. Continuous electrocardiogram monitoring for potassium under 3.0 mmol/L, with symptoms, or with cardiac disease. Treat life threatening arrhythmia or paralysis with intravenous potassium, correct magnesium, treat the cause, and stop drugs that lower potassium or prolong the QT interval.

Oral replacement (mild to moderate, 2.5 to 3.4 mmol/L, no electrocardiogram changes, functioning gut).

• Potassium chloride modified release tablets 600 mg (8 mmol) or effervescent potassium chloride 12 mmol tablets, giving 40 to 80 mmol daily orally in 2 to 4 divided doses with food and a full glass of water, for 3 to 5 days, adjusted to the repeat potassium measured every 24 to 48 hours.
• Maximum 100 to 120 mmol daily (with monitoring).
• Cautions:
  • gastrointestinal irritation and ulceration (do not use in oesophageal obstruction, strictures, or delayed gastric emptying)
  • kidney impairment (start at 20 mmol daily with eGFR under 30 mL/minute and recheck in 24 hours)
  • potassium sparing drugs, ACE inhibitors, angiotensin receptor blockers, and adrenal insufficiency, because of risk of hyperkalaemia

Intravenous replacement (severe, under 2.5 mmol/L, any electrocardiogram change or arrhythmia, paralysis, rhabdomyolysis, digoxin toxicity, or when oral intake is not possible).

• Premixed potassium chloride 40 mmol in 1 litre of isotonic saline over 4 hours (10 mmol/hour) by a peripheral vein. The maximum peripheral concentration is 40 mmol/litre (more concentrated solutions can cause phlebitis), and the maximum rate is 10 mmol/hour peripherally. Use isotonic saline, not glucose, because glucose induces insulin release that lowers potassium further.
• Life threatening arrhythmia or severe paralysis: potassium chloride 20 mmol/hour (up to 40 mmol/hour in cardiac arrest from specialist advice) through a central vein, with continuous electrocardiogram monitoring and potassium checks every 1 to 2 hours. Premixed bags of 20 mmol in 50 mL or 100 mL are used for central infusions.
• Maximum 200 mmol in 24 hours (total), with adjustment for kidney impairment (reduce rate by half, and check potassium every 2 to 4 hours) and for heart failure (use concentrated solutions through a central line to avoid fluid load).
• Recheck potassium after each 20 to 40 mmol, then every 4 to 6 hours until it is 3.5 mmol/L or more and stable, then daily. Each 10 mmol given raises serum potassium by about 0.1 mmol/L, but the response varies with ongoing losses and kidney function.

Magnesium. Check magnesium in every patient. Correct a level under 0.7 mmol/L:

• magnesium sulphate 2 g (8 mmol) IV over 20 minutes to 1 hour for arrhythmia
• or 20 mmol (5 g) IV over 4 to 12 hours, repeated daily for 2 to 3 days until the level is over 0.7 mmol/L
• monitor reflexes, respiratory rate, blood pressure and creatinine, and reduce by 50% in kidney impairment; stop for loss of reflexes

Oral magnesium (magnesium glycerophosphate 4 mmol two to three times daily) can cause diarrhoea.

Cause specific treatment.

• Diuretic induced: reduce or stop the diuretic where possible.
• Add an ACE inhibitor or an angiotensin receptor blocker, or amiloride 5 to 10 mg orally once daily (maximum 20 mg daily), or spironolactone 25 to 100 mg orally once daily.
• For spironolactone: maximum 400 mg daily in primary aldosteronism; check potassium and creatinine at 1 week and 1 month; avoid when eGFR is under 30 mL/minute or with potassium over 5.0 mmol/L; monitor for gynaecomastia.
• Gastrointestinal loss: treat vomiting with ondansetron 4 to 8 mg IV or orally every 8 hours (maximum 16 mg for each IV dose, 24 mg daily; monitor QTc).
• Treat diarrhoea, stop laxatives, give isotonic saline for volume depletion, and add potassium to replacement fluids.
• Primary aldosteronism: spironolactone 25 mg once daily increased every 4 weeks to 100 mg (up to 400 mg), with surgery (adrenalectomy) for a unilateral adenoma.
• Gitelman and Bartter syndromes: large oral doses of potassium chloride (up to 100 to 200 mmol daily in divided doses), magnesium, a high salt diet, potassium sparing diuretics, and sometimes indomethacin, under specialist care.
• Refeeding syndrome: replace potassium (40 to 80 mmol daily), phosphate and magnesium, and give thiamine 100 to 300 mg IV or orally once daily, starting nutrition at 10 to 20 kcal/kg/day with monitoring.
• Diabetic ketoacidosis: add potassium 20 to 40 mmol/L to fluids when potassium is under 5.5 mmol/L and urine output is present; delay insulin if potassium is under 3.3 mmol/L until replacement has begun.
• Hypokalaemic periodic paralysis: oral potassium chloride 0.5 to 1 mmol/kg (maximum 100 mmol) in divided doses and recheck potassium every 1 to 2 hours, because of rebound hyperkalaemia.
• Thyrotoxic periodic paralysis needs a non-selective beta blocker (propranolol 1 to 3 mg/kg orally, with monitoring of heart rate and blood pressure; avoid in asthma) with low dose potassium (maximum 10 mmol/hour), and treatment of thyrotoxicosis.
• Digoxin toxicity: keep potassium at 4.0 mmol/L or more.
• Alcohol and eating disorders: replace potassium, magnesium, phosphate and thiamine, and manage nutrition with specialist support.

Monitoring.

• Continuous electrocardiogram for infusion rates over 10 mmol/hour or severe hypokalaemia.
• Potassium every 1 to 2 hours with central infusions, and every 4 to 6 hours with peripheral infusions.
• Magnesium, creatinine, bicarbonate and glucose daily; fluid balance and urine output.
• Repeat potassium after 1 week in outpatients on supplements.

Referral and escalation. Critical care or high dependency for arrhythmia or paralysis and rates over 10 mmol/hour. Endocrinology for suspected mineralocorticoid excess, Cushing syndrome or periodic paralysis. Nephrology for tubular disorders. Gastroenterology for chronic diarrhoea. Psychiatry and dietetics for eating disorders.

Admission criteria. Potassium under 2.5 mmol/L, or under 3.0 mmol/L with electrocardiogram changes, arrhythmia, cardiac disease, digoxin, paralysis, rhabdomyolysis, ileus, inability to take oral replacement, or an unexplained cause that needs urgent evaluation.

Discharge and safety netting. Discharge when potassium is 3.0 mmol/L or more with a normal electrocardiogram, the cause is treated, and oral replacement is established, with repeat potassium and magnesium within 3 to 7 days. Patients return for palpitations, syncope, weakness, cramps, persistent vomiting or diarrhoea, or reduced urine output. Review diuretics and diet (potassium rich foods such as bananas, potatoes, spinach and beans).