Hyperkalaemia

Hyperkalaemia is a serum or plasma potassium concentration over 5.0 mmol/L (clinically relevant over 5.5 mmol/L). It is a life threatening electrolyte emergency because it depolarises the cardiac membrane and can cause conduction block, ventricular fibrillation and asystole.

Clinical relevance. Hyperkalaemia occurs in up to 10% of hospital patients and is most common in chronic kidney disease, acute kidney injury, heart failure, diabetes, and patients taking drugs that raise potassium. Risk of arrhythmia depends on the rate of rise and the associated acidosis, hypocalcaemia and hyponatraemia, rather than the absolute value alone.

Physiology. About 98% of body potassium (3000 to 4000 mmol in adults) is intracellular, kept in by the sodium potassium ATPase pump, insulin and beta 2 adrenergic stimulation. Excretion is mainly renal (90%) through aldosterone dependent secretion in the collecting duct, with the rest in stool.

A rise of serum potassium raises the resting membrane potential toward threshold and inactivates sodium channels, which slows conduction.

Classification by severity.

• Mild: 5.5 to 5.9 mmol/L.
• Moderate: 6.0 to 6.4 mmol/L.
• Severe: 6.5 mmol/L or more (life threatening at any value with electrocardiogram changes).

Classification by mechanism.

• Spurious (pseudohyperkalaemia): haemolysis in vitro, delayed processing, fist clenching, tourniquet time, extreme thrombocytosis (over 1000 x 10^9/L) or leucocytosis (over 100 x 10^9/L), contamination with potassium EDTA, and familial pseudohyperkalaemia.
• Reduced renal excretion: acute kidney injury, chronic kidney disease, hypoaldosteronism, adrenal insufficiency, type 4 renal tubular acidosis, obstruction, and drugs.
• Transcellular shift: acidosis, insulin deficiency with hyperglycaemia, tissue breakdown, beta blockers, digoxin toxicity, suxamethonium, periodic paralysis.
• Increased load: potassium supplements, salt substitutes, blood transfusion, penicillin G potassium, tissue breakdown, haemolysis.

Key distinctions. An isolated, unexpected high potassium in an asymptomatic patient with normal kidney function and a haemolysed sample is likely spurious.

Confirm this with a repeat sample. Do not delay treatment for the repeat if the patient has risk factors or an abnormal electrocardiogram.

History.

• Known kidney disease, diabetes, heart failure, adrenal disease, and transplantation.
• Drugs: ACE inhibitors, angiotensin receptor blockers, aldosterone antagonists (spironolactone, eplerenone), amiloride, triamterene, trimethoprim, NSAIDs, heparin, calcineurin inhibitors (ciclosporin, tacrolimus), beta blockers, digoxin, potassium supplements, penicillin G potassium, pentamidine, drospirenone, and herbal remedies.
• Diet: high potassium foods and salt substitutes. Reduced urine output, dehydration, vomiting, diarrhoea, and recent illness.
• Crush injury, burns, prolonged immobilisation, seizures, intense exercise, haemolysis, tumour lysis (chemotherapy), and blood transfusion.
• Symptoms: weakness, flaccid paralysis, paraesthesia, palpitations, syncope, nausea, and reduced reflexes. Most patients are asymptomatic.

Examination.

• Pulse (bradycardia, irregular), blood pressure, respiratory rate, temperature, volume status, and urine output.
• Muscle power, reflexes, and sensation (ascending weakness can mimic Guillain-Barre syndrome).
• Signs of adrenal insufficiency (pigmentation, postural hypotension), kidney failure (oedema, uraemic signs), urinary retention (palpable bladder), and tissue injury (compartments, swelling, dark urine).
• Continuous electrocardiogram monitoring in suspected moderate or severe hyperkalaemia.

Red flags.

• Electrocardiogram changes: peaked T waves, prolonged PR interval, flattened or absent P waves, broad QRS, sine wave pattern, bradycardia, ventricular tachycardia or fibrillation, or asystole.
• Potassium 6.5 mmol/L or more, or a rapid rise.
• Oliguria or anuria, severe acute kidney injury, or rhabdomyolysis.
• Metabolic acidosis, severe sepsis, tumour lysis, or ongoing tissue breakdown.
• Muscle weakness or paralysis.
• Concurrent digoxin, beta blocker or other conduction slowing drugs.
• Haemodynamic instability.
• Adrenal crisis (hypotension, hyponatraemia, hypoglycaemia).

Special groups. Neonates and children have different reference ranges, and heel prick samples often haemolyse. Older adults on multiple potassium raising drugs are at high risk. Pregnancy: the same doses apply, with foetal monitoring when severe. Patients on dialysis can have a pre-dialysis potassium rise after the long interdialytic interval.

Spurious hyperkalaemia. Haemolysed sample, delayed separation, poor technique, extreme leucocytosis or thrombocytosis, EDTA contamination, familial pseudohyperkalaemia.

Kidney causes. Acute kidney injury (prerenal, intrinsic, obstructive), chronic kidney disease (especially eGFR under 30 mL/min), diabetic nephropathy, interstitial nephritis, obstructive uropathy, sickle cell nephropathy, renal transplant rejection, lupus nephritis.

Endocrine and tubular causes. Primary adrenal insufficiency (Addison disease), congenital adrenal hyperplasia, hyporeninaemic hypoaldosteronism (type 4 renal tubular acidosis), pseudohypoaldosteronism, Gordon syndrome, and aldosterone resistance.

Drug causes. Potassium sparing diuretics, ACE inhibitors, angiotensin receptor blockers, renin inhibitors, NSAIDs, trimethoprim, heparin, calcineurin inhibitors, beta blockers, digoxin toxicity, succinylcholine, potassium supplements, penicillin G, pentamidine, and drospirenone.

Shift and release causes. Metabolic acidosis, diabetic ketoacidosis and hyperosmolar states, rhabdomyolysis, crush injury, burns, tumour lysis syndrome, massive haemolysis, major surgery, intestinal ischaemia, hyperkalaemic periodic paralysis, and exercise.

Load. Excess potassium intake, salt substitutes, massive transfusion, and potassium containing intravenous fluids.

Step 1. Perform a 12 lead electrocardiogram at once and start monitoring in any patient with a potassium of 6.0 mmol/L or more or with symptoms. Do not delay treatment for a repeat sample when electrocardiogram changes are present.

Step 2. Confirm with a repeat sample: a blood gas analyser result on a whole blood sample is quickest. Request a non-haemolysed sample and avoid fist clenching. Treat if the electrocardiogram is abnormal or kidney function is poor.

Step 3. Laboratory tests: urea, creatinine and eGFR, electrolytes, bicarbonate or blood gas (acidosis), glucose, calcium, magnesium, phosphate, creatine kinase, urate, lactate dehydrogenase, full blood count and film, liver tests, and urinalysis.

Step 4. Directed tests for the cause:

• morning cortisol and short synacthen test with renin and aldosterone for suspected adrenal or hypoaldosterone states;
• urinary sodium and potassium (spot urine potassium to creatinine ratio, and urine osmolality);
• drug levels (digoxin, tacrolimus, ciclosporin);
• renal ultrasound for obstruction and size;
• creatine kinase for rhabdomyolysis;
• tumour lysis tests: phosphate, urate, calcium, lactate dehydrogenase.

Interpretation. The electrocardiogram sequence is peaked T waves (potassium 5.5 to 6.5), then loss of P waves and prolonged PR, then widened QRS, sine wave pattern and arrest (over 8 mmol/L).

The electrocardiogram can remain normal in severe hyperkalaemia, so treat the potassium, not only the tracing. A potassium over 6.5 mmol/L in a patient with acute kidney injury needs urgent treatment.

Limitations. Haemolysis can raise potassium by 0.3 to 0.5 mmol/L or more. The electrocardiogram is insensitive. Point of care analysers differ from the laboratory.

Immediate priorities. For potassium 6.5 mmol/L or more, or with electrocardiogram changes: monitor continuously, establish intravenous access, and treat immediately in the order of cardiac protection, shift, and removal. Stop all potassium raising drugs and infusions.

Cardiac protection.

• Calcium gluconate 10% 30 mL (6.8 mmol) IV over 10 minutes with continuous electrocardiogram monitoring. Repeat after 5 to 10 minutes if electrocardiogram changes persist, up to 3 doses. The effect starts in 1 to 3 minutes and lasts 30 to 60 minutes.
• Calcium chloride 10% 10 mL (6.8 mmol) over 10 minutes by a central or large peripheral vein is an alternative. Avoid it peripherally if possible because of tissue injury.
• Cautions: extravasation, digoxin toxicity, and concurrent bicarbonate in the same line (precipitates).
• In digoxin toxicity, give calcium slowly over 20 to 30 minutes, with monitoring, as the risk of harm is low and the arrhythmia risk is high.

Shift potassium into cells (effect in 15 to 30 minutes, lasting 4 to 6 hours).

• Insulin soluble 10 units IV with glucose 50% 50 mL (25 g) over 5 to 15 minutes. Use 5 units in kidney failure (eGFR under 30 mL/minute) or low body weight to reduce the risk of hypoglycaemia.
• Check capillary glucose before and at 30 minutes, then hourly for at least 6 hours. If pre-treatment glucose is under 7 mmol/L, follow with glucose 10% infusion at 50 mL/hour for 5 hours.
• Salbutamol 10 to 20 mg nebulised over 10 minutes (lowers potassium by 0.5 to 1.0 mmol/L; additive to insulin; avoid in unstable angina or tachyarrhythmia; expect tremor and tachycardia; some patients with kidney failure do not respond).
• Sodium bicarbonate: isotonic sodium bicarbonate 1.26% 500 mL IV over 1 hour in patients with metabolic acidosis (pH under 7.2 or bicarbonate under 18 mmol/L) and volume depletion.
• Hypertonic 8.4% bicarbonate 50 mL (50 mmol) over 5 minutes is used in cardiac arrest or severe acidosis with hyperkalaemia (monitor sodium, calcium and volume).

Remove potassium from the body.

• Sodium zirconium cyclosilicate 10 g orally three times daily for up to 48 hours (effect starts within 1 hour), then 5 to 10 g once daily for maintenance.
• Adjust maintenance by response, from 5 g every second day to 15 g daily (maximum 15 g daily). Each 5 g contains about 400 mg sodium: monitor oedema and blood pressure, and hypokalaemia. Take other oral drugs with pH dependent absorption at least 2 hours apart.
• Patiromer 8.4 g orally once daily with food (titrate by 8.4 g weekly to a maximum of 25.2 g daily; onset 7 hours; separate from other drugs by 3 hours; monitor magnesium). Used for chronic hyperkalaemia rather than emergencies.
• Calcium polystyrene sulphonate 15 g orally three to four times daily (maximum 60 g daily; or 30 g rectally once daily) is slow and carries a risk of bowel necrosis, with limited evidence. Avoid it in patients with ileus, obstruction or after bowel surgery.
• Furosemide 40 to 80 mg IV (up to 160 to 200 mg in kidney failure; given as repeated doses or an infusion of 10 to 20 mg/hour), in patients who are euvolaemic or fluid overloaded and still produce urine. Monitor urine output, sodium and volume status.
• In hypovolaemic patients, give isotonic saline 0.9% 500 mL to 1 L IV over 30 to 60 minutes first.
• Haemodialysis for severe or refractory hyperkalaemia, acute kidney injury with oliguria, rhabdomyolysis, tumour lysis, severe acidosis or fluid overload. It is the most effective means and lowers potassium by 1 mmol/L in the first hour. Haemofiltration in the unstable patient.

Treat the cause.

• Stop or reduce ACE inhibitors, angiotensin receptor blockers, aldosterone antagonists, potassium sparing diuretics, NSAIDs, trimethoprim and potassium supplements.
• Reintroduce them after resolution where there is a compelling indication, with a binder as support.
• Adrenal crisis: hydrocortisone 100 mg IV then 50 mg IV every 6 hours (or an infusion of 200 mg over 24 hours), with isotonic saline and glucose. Fludrocortisone 50 to 100 micrograms orally once daily for hypoaldosteronism with monitoring of blood pressure and potassium.
• Rhabdomyolysis, tumour lysis and obstruction: isotonic saline to maintain urine output of 200 to 300 mL/hour in rhabdomyolysis (adjust for cardiac and kidney function).
• Give rasburicase 0.2 mg/kg IV once daily for 3 to 7 days for tumour lysis with high urate (avoid in G6PD deficiency). Relieve urinary obstruction with a catheter. Use renal replacement therapy.
• Diabetic ketoacidosis: insulin infusion with potassium replacement once potassium is under 5.5 mmol/L, since total body potassium is low.

Mild to moderate hyperkalaemia without electrocardiogram changes (5.5 to 6.4 mmol/L).

• Repeat the sample within 24 hours (or at once when the patient is unwell). Review drugs and diet (potassium restriction to about 50 to 60 mmol/day). Correct volume depletion and acidosis. Give a loop or thiazide diuretic when the patient is not hypovolaemic.
• Use a binder when the potassium is persistent, to allow continued use of ACE inhibitors and aldosterone antagonists. Options are sodium zirconium cyclosilicate 10 g orally three times daily for up to 48 hours then 5 to 10 g once daily, or patiromer 8.4 g once daily.
• Chronic metabolic acidosis in kidney disease: sodium bicarbonate 500 mg to 1 g orally two to three times daily, titrated to a serum bicarbonate of 22 mmol/L or more (monitor sodium load, oedema and blood pressure).

Monitoring. Continuous electrocardiogram until potassium is under 6.0 mmol/L and the electrocardiogram has normalised. Check potassium at 1, 2, 4, 6, 12 and 24 hours after treatment (rebound occurs as insulin and salbutamol effects wear off after 4 to 6 hours).

Check capillary glucose hourly for 6 hours after insulin, urine output hourly, creatinine, bicarbonate and calcium daily, and magnesium.

Referral and escalation. Critical care or high dependency for potassium of 6.5 mmol/L or more with electrocardiogram changes, refractory hyperkalaemia, or arrhythmia. Nephrology for dialysis, kidney failure, and refractory or recurrent hyperkalaemia. Endocrinology for adrenal disease. Pharmacy review for drug causes. Dietitian for dietary advice.

Admission criteria. Potassium 6.5 mmol/L or more, any electrocardiogram change, potassium 6.0 mmol/L or more with acute kidney injury, rapid rise, symptoms, rhabdomyolysis, oliguria, sepsis, adrenal crisis, tumour lysis, or failure of outpatient measures.

Discharge and safety netting. Discharge when potassium is under 5.5 mmol/L on repeat testing, the cause is addressed, and drugs are reviewed. Repeat potassium and creatinine in 1 to 7 days (depending on cause and severity) and again after restarting or changing a potassium raising drug. Patients return for palpitations, syncope, muscle weakness, reduced urine output or vomiting.