History and exam

Key diagnostic factors

common

presence of risk factors

Be aware that most patients with hyperkalaemia do not have any symptoms, particularly if the hyperkalaemia is mild.[2][12]​ Therefore, risk factors for hyperkalaemia are a key aspect of history and examination.

Key risk factors include: kidney dysfunction (particularly end-stage kidney disease) including those receiving dialysis who are fasting or have missed dialysis; use of renin-angiotensin-aldosterone system inhibitors (RAASi), aldosterone antagonists, or trimethoprim; heart failure; liver disease; tissue breakdown (e.g., rhabdomyolysis, trauma, tumour lysis syndrome, and severe hypothermia); distal renal tubule defects that affect potassium excretion; and diabetes mellitus.

Other diagnostic factors

common

muscle weakness

One of the most common features of hyperkalaemia. In most patients, muscle weakness associated with hyperkalaemia is ascending, beginning at the legs and progressing to the trunk.

generalised fatigue

One of the most common features of hyperkalaemia.[2]​ May progress to flaccid muscle paralysis.[2]

paraesthesia

A common feature of hyperkalaemia.[2]​ May progress to flaccid muscle paralysis.[2]

muscle cramps

A common feature of hyperkalaemia.[2]​ May progress to flaccid muscle paralysis.[2]

uncommon

flaccid muscle paralysis

Fatigue, muscle cramps, and paraesthesia may progress to flaccid muscle paralysis.[2]

bradycardia

Always be alert to the diagnosis of hyperkalaemia if there is severe bradycardia, which results from heart block. Sometimes bradycardia may be the only abnormality.

nausea and vomiting

Can occur with hyperkalaemia.[2]

diarrhoea

Can occur with hyperkalaemia.[2]

shortness of breath

Can occur with hyperkalaemia.[2]

chest pain

Can occur with hyperkalaemia.[2]

palpitations

Can occur with hyperkalaemia.[2]

extrasystoles

May be elicited through cardiac examination.

cardiac pauses

May be elicited through cardiac examination.

tachypnoea

Occurs due to respiratory muscle weakness due to hyperkalaemia.

depressed or absent deep tendon reflexes

Occurs with hyperkalaemia-induced flaccid muscle paralysis.

hypoactive or absent bowel sounds

Occurs if hyperkalaemia-induced ileus is present.

Risk factors

strong

kidney dysfunction

Both acute kidney injury and chronic kidney disease (particularly end-stage renal failure) are significant risk factors for hyperkalaemia.​[1][2][12]​​​​ One study revealed that more than half of all patients in pre-dialysis with chronic kidney disease developed hyperkalaemia.[10] ​The risk of hyperkalaemia increases as glomerular filtration rate (GFR) decreases.[4][52]​​​​​​ Hyperkalaemia is uncommon when estimated GFR (eGFR) is >60 mL/minute/1.73 m².[4]​ In acute kidney injury, hyperkalaemia usually occurs in patients who are oliguric and who also have increased release of potassium from cells. Chronic kidney disease is associated with an increase in fractional potassium excretion that helps to maintain serum potassium, despite a reduction in GFR. Therefore, hyperkalaemia usually occurs in patients with chronic kidney disease if eGFR is <30 mL/minute/1.73 m².[1] However, hyperkalaemia can occur at a higher eGFR if another risk factor is also present.[16][53]

Fasting or missed dialysis sessions lead to hyperkalaemia in patients who are on dialysis, even if these patients do not have diabetes.​​[13][14][15]​ Fasting lowers insulin levels and also causes resistance to beta-adrenergic stimulation of potassium uptake.​​​[14][15]

heart failure

Patients with heart failure have several factors that may put them at a high risk of hyperkalaemia; these include factors that are directly related to the condition (i.e., impaired delivery of sodium and water to the distal renal tubule), associated comorbidities (e.g., diabetes, chronic kidney disease), and use of drugs that cause hyperkalaemia.[23][54]​​

use of renin-angiotensin-aldosterone system inhibitors (RAASi)

RAASi include ACE inhibitors, angiotensin-II receptor antagonists, and direct renin inhibitors. Treatment with a single drug in this class is associated with a low risk of hyperkalaemia if there are no other risk factors present.[17]​ However, if the patient is taking multiple drugs in this class, is receiving potassium supplements, has kidney dysfunction, or is volume depleted, the risk of hyperkalaemia is significantly increased.[18][19][20]​ In one study of 69,426 new users of RAASi, 75% of patients had potassium levels checked within the first year. Potassium levels >5 mmol/L (>5 mEq/L) and >5.5 mmol/L (>5.5 mEq/L) occurred in 5.6% and 1.7%, respectively. Another trial studied the effects of combination therapy with ACE inhibitors and angiotensin-II receptor antagonists in patients with diabetic nephropathy, and found that combination therapy increased the risk of hyperkalaemia (6.3 events per 100 person-years) when compared with monotherapy (2.6 events per 100 person-years) (P<0.001).[19]

The risk of developing hyperkalaemia with certain other drugs may be increased when RAASi are taken concomitantly (see 'use of other drugs that cause hyperkalaemia' below).

use of aldosterone antagonists

Use of aldosterone antagonists (e.g., spironolactone, eplerenone) is a significant risk factor for hyperkalaemia because aldosterone plays an important role in potassium homeostasis.[2][21]​​[23][28][29][30][31]

One review that analysed data regarding 16,065 patients from 7 trials showed that hyperkalaemia was more frequently observed in patients on aldosterone antagonists (9.3%) compared with placebo (4.3%) (risk ratio 2.17, 95% CI 1.92 to 2.45; P<0.0001).[21]

The risk of developing hyperkalaemia with certain other drugs may be increased when an aldosterone antagonist is taken concomitantly (see 'use of other drugs that cause hyperkalaemia' below).

use of trimethoprim

Trimethoprim (either on its own or in combination with RAASi) is a strong risk factor for hyperkalaemia. Trimethoprim has amiloride-like properties and behaves as a potassium-sparing diuretic. The change in serum potassium is dose-dependent and greatest in older people, patients with diabetes, and patients with renal insufficiency. Of note, even standard doses of the antibiotic combination trimethoprim/sulfamethoxazole, used commonly for urinary tract infections, can result in significant rises in serum potassium values.[22][35]

liver disease

Patients with liver disease are at significant risk of hyperkalaemia.[1] In one study of 650 patients with acute on chronic liver failure, 12.2% had an episode of hyperkalaemia during hospitalisation.[11]

tissue breakdown

Any cause of tissue breakdown can cause hyperkalaemia if the patient also has kidney dysfunction. This is due to release of intracellular potassium into the extracellular fluid. Clinical examples of tissue breakdown include rhabdomyolysis, trauma, tumour lysis syndrome, and severe hypothermia.[24][25][26]

distal renal tubule defects

Any acquired or inherited defects in the distal renal tubule that affect potassium excretion are important risk factors for hyperkalaemia.[16]​ Type 4 renal tubular acidosis (hyporeninaemic hypoaldosteronism) and pseudohypoaldosteronism type 2 are examples.

diabetes mellitus

Diabetes is a risk factor for hyperkalaemia because it is associated with type 4 renal tubular acidosis (hyporeninaemic hypoaldosteronism). Hyporeninaemic hypoaldosteronism can be caused by a variety of mechanisms in patients with diabetes, including decreased sympathetic drive to renin secretion, decreased renin synthesis due to injury to the juxtaglomerular apparatus, and decreased stimulation of renin release due to hypervolaemia caused by chronic sodium retention.[55]​ Poorly controlled diabetes with significant hyperglycaemia also puts the patient at risk of hyperkalaemia. See 'diabetic ketoacidosis' below.

weak

diabetic ketoacidosis

Hyperkalaemia occurs in diabetic ketoacidosis due to extracellular movement of fluid and potassium in response to extracellular hyperosmolality caused by hyperglycaemia. This can cause a high serum potassium level. However, total body potassium concentration is low due to increased diuresis.

use of other drugs that cause hyperkalaemia

Certain drugs can cause hyperkalaemia, particularly when taken in combination with RAASi or aldosterone antagonists, or if the patient has concurrent kidney dysfunction. These include, but are not limited to:

  • Arginine[56]

  • Azole antifungals (e.g., ketoconazole)[2]

  • Beta-blockers (non-cardioselective[2]

  • Calcineurin inhibitors (e.g., ciclosporin, tacrolimus)[4][40]

  • Digoxin[2]

  • Heparin[2][38]

  • Isoflurane[4]

  • Lithium[2]

  • Mannitol[57]

  • Non-steroidal anti-inflammatory drugs[2]

  • Penicillins[2]

  • Pentamidine[2]

  • Potassium-sparing diuretics (e.g., amiloride, triamterene)[2]

  • Somatostatin[2]

  • Suxamethonium[2]​​​

In particular, certain drugs (e.g., mannitol, arginine, suxamethonium, digoxin) cause hyperkalaemia due to cellular redistribution. This list is not exhaustive and you should consult your local drug formulary for more information.

increased intake of potassium

Increased potassium intake through diet or supplements can cause hyperkalaemia if other risk factors for hyperkalaemia are also present. However, by itself, increased potassium intake does not commonly cause hyperkalaemia due to the efficacy of potassium adaptation.[58]​​ With potassium adaptation, urinary potassium excretion increases, which prevents rise in serum potassium.

metabolic acidosis

Both anion gap and non-anion gap metabolic acidosis can cause hyperkalaemia.[59]​ This is related to movement of potassium from the intracellular to the extracellular compartment. In contrast, only minimal transcellular shifts of potassium occur with respiratory acidosis.

digoxin (digitalis) toxicity

Digitalis toxicity causes hyperkalaemia due to dose-dependent inhibition of the Na-K-ATPase pump.[60]​ It can be caused by overdose of digoxin, or poisoning with structurally-related digitalis glycosides (e.g., digitoxin, digitalis).[61]

primary adrenal insufficiency

Primary adrenal insufficiency (Addison's disease) causes inability to excrete potassium effectively, which leads to hyperkalaemia.[1]

hyperkalaemic periodic paralysis

Hyperkalaemic periodic paralysis is an autosomal dominant disorder in which episodes of weakness or paralysis due to hyperkalaemia are usually precipitated by cold exposure, rest after exercise, fasting, or ingestion of small amounts of potassium. Treatment is not needed because there is spontaneous recovery.[62]

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