Hyperkalemia is defined as a pathological state where the serum potassium concentration exceeds 5.3 mmol/L. In this state, the total body potassium content may be increased (potassium overload), normal, or reduced. Acute hyperkalemia refers to a rapid increase in serum potassium levels over a few days. Chronic hyperkalemia is characterized by recurrent episodes of elevated serum potassium levels over a period of one year, usually in the presence of chronic conditions such as chronic kidney disease, chronic heart failure, diabetes, or long-term use of RAAS inhibitors.
Etiology and Pathogenesis
Potassium Overload Hyperkalemia
The primary feature of this type of hyperkalemia is an increase in the total body potassium content, leading to elevated serum potassium levels.
Reduced Renal Potassium Excretion
Reduced excretion of potassium primarily occurs due to a decline in glomerular filtration rate or impaired tubular potassium secretion. Conditions associated with this mechanism include oliguric acute or chronic renal failure, adrenal insufficiency, hypo-reninemic hypoaldosteronism, renal tubular acidosis, azotemia, and prolonged use of potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), beta-blockers, ACE inhibitors, or nonsteroidal anti-inflammatory drugs (NSAIDs).
Excessive Potassium Intake
Excessive potassium intake in the presence of oliguria may result from a high-potassium diet, intake of potassium-rich medications, overly fast or excessive intravenous potassium supplementation, or transfusion of large amounts of stored or irradiated blood.
Translocation Hyperkalemia
This type of hyperkalemia is usually caused by the release of potassium from inside the cells into the extracellular fluid or an abnormal shift of potassium out of cells. Oliguria or anuria can trigger or exacerbate this condition. The total body potassium content may be increased, normal, or reduced.
Tissue Damage
Potassium from damaged tissues is released into extracellular fluid, as seen in conditions such as severe hemolytic anemia, extensive burns, trauma, chemotherapy for large tumors, dialysis, and rhabdomyolysis.
Impaired Cell Membrane Transport
During metabolic acidosis, potassium shifts to the extracellular space while hydrogen ions (H+) move into cells, leading to a decrease in blood pH and an increase in serum potassium levels.
Severe dehydration and shock cause tissue hypoxia.
Strenuous exercise, status epilepticus, and tetanus are contributing factors.
Hyperkalemic periodic paralysis may occur.
The use of medications such as succinylcholine or arginine is associated with this condition.
Concentrative Hyperkalemia
Severe dehydration, blood loss, or shock can decrease the effective circulating blood volume, leading to blood concentration and a relative increase in potassium concentration. This condition often coexists with prerenal oliguria and reduced potassium excretion. Shock, acidosis, and hypoxia may also promote potassium movement from the intracellular to the extracellular compartment.
Pseudohyperkalemia
Pseudohyperkalemia occurs due to the movement of intracellular potassium into the extracellular compartment caused by factors such as hemolysis in the test tube, poor venipuncture technique, or excessive platelet or white blood cell counts.
Clinical Manifestations
The clinical symptoms of hyperkalemia primarily arise from reduced excitability of the myocardium and neuromuscular tissues. The severity of symptoms depends on the degree and speed of potassium elevation as well as the presence of other electrolyte or water balance disturbances. Mild hyperkalemia is often asymptomatic, whereas acute severe hyperkalemia may result in flaccid paralysis, life-threatening arrhythmias, or even cardiac arrest.
Cardiac Manifestations
Hyperkalemia primarily affects the electrophysiological activity of the myocardium, presenting as changes in the electrocardiogram (ECG), conduction abnormalities, and arrhythmias. The ECG serves as an important reference for assessing the severity of hyperkalemia:
- When serum potassium exceeds 6 mmol/L, tall and peaked T waves with a narrow base are observed.
- When levels are between 7–9 mmol/L, PR interval prolongation, disappearance of P waves, widening of QRS complexes, reduction of R waves, deepening of S waves, and merging of the ST segment with T waves are noted.
- When potassium levels exceed 9–10 mmol/L, sine waves, further QRS widening, and tall, peaked T waves are seen. This may progress to ventricular fibrillation or ventricular flutter.
Blood pressure may rise in the early stages but drop in later stages. Symptoms resembling ischemia, such as pallor, cold and clammy skin, numbness, and muscle or joint pain, may occur due to vascular constriction.
Extracardiac Manifestations
Mild increases in serum potassium reduce the resting membrane potential, leading to increased neuromuscular excitability, which can manifest as paresthesia, tremors, or muscle pain. Severe hyperkalemia significantly reduces the resting membrane potential, bringing it closer to the threshold potential. This inactivates fast sodium channels and decreases muscle cell excitability, resulting in muscle weakness or flaccid paralysis of the limbs.
The central nervous system may show symptoms such as agitation or confusion. Other manifestations of hyperkalemia include gastrointestinal symptoms such as nausea, vomiting, and abdominal pain.
Diagnosis and Differential Diagnosis
A diagnosis of hyperkalemia can be confirmed when the serum potassium concentration exceeds 5.3 mmol/L in the presence of an underlying condition that increases blood potassium levels and/or reduces renal potassium excretion. Hyperkalemia can be classified into mild (5.3–5.5 mmol/L), moderate (5.6–6.0 mmol/L), and severe (>6.0 mmol/L) based on potassium levels. A direct relationship between serum potassium levels and total body potassium content is not always present. In cases of potassium overload, extracellular fluid dilution or alkalosis may result in normal or low serum potassium levels. Conversely, potassium depletion can sometimes occur alongside elevated serum potassium, such as in cases of blood concentration and acidosis. Pseudohyperkalemia, caused by hemolysis from improper blood sampling or processing techniques, must also be excluded during diagnosis. When pseudohyperkalemia is suspected, a repeat test is recommended to confirm the diagnosis and prevent erroneous clinical decisions.
Prevention and Treatment
Early recognition and active treatment of the underlying disease, restriction of potassium intake, and discontinuation of medications that raise blood potassium levels are necessary. The major clinical risk of hyperkalemia is cardiac suppression. Treatment focuses primarily on rapidly lowering blood potassium levels and protecting the heart.
Addressing Cardiac Suppression Due to Potassium
Sodium Lactate or Sodium Bicarbonate Solution
Sodium lactate or bicarbonate can alkalinize the blood, promote the intracellular shift of potassium ions, counteract the cardiac suppressive effects of potassium, increase sodium levels in the distal tubules to enhance Na+-K+ exchange, and promote urinary potassium excretion. Sodium raises plasma osmolarity, leading to volume expansion and dilutional reduction of serum potassium, and has a vagus nerve antagonistic effect to increase heart rate. For severe cases, intravenous infusions of 60–100 ml of 11.2% sodium lactate or 100–200 ml of 4–5% sodium bicarbonate can be administered.
Precautions
Attention should be given to avoid pulmonary edema during administration.
Sodium lactate or sodium acetate is metabolized into sodium bicarbonate in the liver, so caution is needed for patients with liver disease.
Sodium bicarbonate must not be mixed with calcium gluconate to prevent calcium carbonate precipitation.
Calcium Preparations
Calcium salts counteract the cardiotoxic effects of potassium. Commonly used agents include 10% calcium gluconate or 5% calcium chloride, administered as 10–20 ml diluted in an equal amount of 25% glucose solution and injected intravenously at a slow rate. Patients with heart failure should avoid simultaneous use of cardiac glycosides. Calcium does not affect the intracellular and extracellular distribution of potassium but increases the difference between the resting membrane potential and the threshold potential, stabilizing cardiac excitability. Therefore, other methods must be employed to lower serum potassium levels.
Glucose and Insulin
Glucose and insulin promote the intracellular shift of serum potassium. Typically, 25–50% glucose solutions are combined with insulin at a ratio of 1U of regular insulin per 3–4g of glucose, administered through continuous intravenous infusion.
Selective β2-Adrenergic Receptor Agonists
These agents enhance the intracellular shift of potassium. Salbutamol sulfate is used in doses of 10–20 mg, dissolved in 4 ml of 0.9% sodium chloride solution, and inhaled as a nebulizer treatment for over 10 minutes, or 0.5 mg can be administered intravenously over more than 15 minutes.
Hypertonic Saline
Hypertonic saline has a similar mechanism of action to sodium lactate. A rapid effect can be achieved by administering 100–200 ml of 3–5% sodium chloride solution through IV infusion. However, caution should be exercised due to risks of increased circulatory volume, hyperchloremic acidosis, and pulmonary edema. If urine output is normal, isotonic saline may also be an option.
Enhancing Potassium Excretion
Potassium-Excreting Diuretics
Loop diuretics and thiazide diuretics are used to increase potassium excretion, with loop diuretics being more effective than thiazides. Intravenous administration of loop diuretics has greater efficacy than oral administration. Combining these two classes of diuretics improves efficacy, but their effects are limited in cases of renal failure.
Cation Exchange Resins
These resins, which are not absorbed by the gastrointestinal tract, reduce potassium absorption into the bloodstream and promote fecal potassium excretion by exchanging sodium or calcium ions in the resin with potassium ions in the colon. Sodium polystyrene sulfonate is administered orally at 10–20 g two to three times daily or rectally via retention enema by mixing 40 g with 100–200 ml of 25% sorbitol solution. Calcium polystyrene sulfonate can be administered at 15–30 g daily in divided doses, either alone or with 25% sorbitol solution (20 ml orally two to three times daily). Combined use requires caution due to risks of colonic ulcers, necrosis, or electrolyte disturbances.
Novel Potassium Binders
Sodium zirconium cyclosilicate and patiromer are newer potassium-binding agents. Sodium zirconium cyclosilicate is a non-absorbable zirconium-based polymer that selectively captures potassium ions throughout the gastrointestinal tract, reducing intestinal potassium absorption and rapidly lowering serum potassium levels. The initial dose is 10 g, taken orally three times daily. Maintenance therapy should not exceed 10 g/day, with diarrhea being the primary adverse effect. Patiromer, another non-absorbable organic polymer, works mainly in the distal colon where potassium ion concentration is highest.
Dialysis Therapy
Hemodialysis is suitable for patients with persistent serum potassium levels above 6 mmol/L or electrocardiographic abnormalities who do not respond well to pharmacological treatments, especially in cases of concomitant fluid overload and heart failure. Continuous venovenous hemofiltration is recommended for patients with refractory heart failure and hyperkalemia. Peritoneal dialysis can be considered for patients requiring potassium reduction but with limited access to vascular routes for hemodialysis.
Reducing Potassium Sources
High-potassium diets or potassium-containing medications should be discontinued.
High-calorie diets rich in glucose and lipids or parenteral nutrition can reduce the potassium released through catabolic processes by ensuring adequate caloric intake.
Blood clots or necrotic tissues should be cleared.
Stored blood should be avoided.
Infections should be controlled to minimize cellular breakdown.
Prognosis
There is a U-shaped relationship between serum potassium levels and the risk of adverse clinical events. Mortality risk increases significantly when serum potassium exceeds 5.3 mmol/L. Hyperkalemia is associated with elevated mortality rates, ranging from 14% to 41%.