Hyperkalemia

Hyperkalemia is defined as a serum potassium (K+) concentration > 5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia is usually asymptomatic if minor in severity; however, acute elevations or severe hyperkalemia can lead to potentially fatal cardiac arrhythmias. Management is guided by severity and includes measures to stabilize the myocardial membrane potential, transiently shifting K+ intracellularly, removing K+ from the body, and treating the underlying predisposing conditions.

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Overview

General considerations

K+ is the main intracellular cation in all cells and is distributed unevenly between the intracellular fluid (98%) and extracellular fluid (2%). 

  • Disparity is necessary for maintaining the resting membrane potential of cells → K+ balance is tightly regulated
  • Hyperkalemia causes depolarization (i.e., decrease) of the resting membrane potential, leading to the inactivation of Na+ channels → decreased excitability of cardiac cells →  predisposition for arrhythmias 
  • The kidneys are responsible for 90%–95% of the overall K+ regulation.
  • The GI tract secretes 5%–10% of absorbed K+ daily.

Sites of action in the kidney

  • Glomerulus: K+ is freely filtered.
  • Proximal tubule: 65%–70% of filtered K+ is reabsorbed. 
  • Thick ascending limb of the loop of Henle: 10%–25% of filtered K+ is reabsorbed. 
  • Principal cell (cortical collecting duct): K+ is secreted. 
  • 𝛼-Intercalated cell (collecting duct): K+ is reabsorbed (final fine-tuning mechanism).

Normal response to ingested K+

A normal Western diet contains approximately 70–150 mmol of K+ per day. This diet is unlikely to lead to the development of hyperkalemia from increased intake only, owing to the following mechanisms:

  1. Gut absorbs dietary K+ into the bloodstream.
  2. Transcellular shift prevents excessive increase in extracellular fluid (ECF) K+ concentration.
    1. Insulin- and β2-mediated
    2. K+ shifts primarily into muscle and liver cells.
  3. Increased ECF K+ concentration triggers mechanisms for renal K+ excretion.  
  4. Transcellular shifting into muscle/liver cells gradually reverses.
  5. Remainder of ingested K+ load is renally excreted.

Etiology

The etiologies of hyperkalemia can be grouped into 5 categories: transcellular shifts, tissue breakdown, inadequate renal excretion, drug-induced, and pseudohyperkalemia.

Transcellular shifts

  • Certain factors cause K+ to move transiently into or out of cells.
  • The effect of this shift can be significant enough to decrease or increase the measured serum K+.
  • The total body K+ does not change.
  • Factors that cause shifting out of the cell (→ raise of plasma K+):
    • Acidosis: H+/K+ exchange maintains electroneutrality → moves H+ into cell to help balance extracellular pH in exchange for K+ moving out of the cell
    • Hyperosmolality (hyperglycemia, IV contrast, mannitol):
      • High ECF osmolality → shift of water into ECF → decreases ECF K+ concentration → more favorable gradient for diffusion of K+ out of cells
      • Solvent drag on K+ as water leaves the cell may also contribute.
      • Common mechanism in hyperglycemia (i.e., diabetic ketoacidosis (DKA))
    • Exercise: K+ is intentionally released by muscle cells to act as a local vasodilator.
  • Factors that cause shifting into the cell (→ lowers the plasma K+):
    • Insulin: stimulates Na+/K+ ATPase → 3 Na+ move out of cell, 2 K+ move into cell
    • β2-Adrenergic agonist (i.e., albuterol; stimulates Na+/K+ ATPase)
    • Alkalosis: H+/K+ exchanger moves H+ out of cell to help balance extracellular pH in exchange for K+ moving into cell

Tissue breakdown

  • Similar to transcellular shift, but the shift is not reversible
  • Damage to cell results in release of the highly concentrated intracellular K+:
    • Tumor lysis syndrome (high-volume malignant cell death after chemotherapy)
    • Rhabdomyolysis (muscle cells; trauma, crush injuries, prolonged immobilization)
    • RBC transfusion (if multiple units or old blood RBCs lyse over time in storage)
    • GI bleeding (RBC metabolized by GI tract → intracellular K+ released)
    • Large hematoma (RBC reabsorbed and metabolized → intracellular K+ released)
    • Burns (skin cells)

Inadequate renal excretion

Renal failure:

  • Oliguria → ↓ distal flow rate → ↓ K+ secretion 
  • Oliguria plus excess K+ load or aldosterone blocker (ACEi/ARB) will result in hyperkalemia.
  • Oliguria by itself may not cause hyperkalemia.

Volume depletion:

  • Hypovolemia → ↓ distal Na+ delivery → ↓ K+ secretion 
  • Also occurs in states of total body fluid overload, but with effective arterial blood volume depletion (congestive heart failure, cirrhosis)
  • Volume depletion can also cause AKI → hyperkalemia from oliguria

Functional hypoaldosteronism:

  • Mineralocorticoid deficiency:
    • Primary adrenal insufficiency
    • Hyporeninemic hypoaldosteronism
  • Tubulointerstitial disease: sickle cell disease, urinary tract obstruction
  • Drugs (see table below) 

Drug-induced hyperkalemia

Drugs are a very common cause of hyperkalemia and cause it by a variety of the previously mentioned mechanisms. A key part of the diagnosis of hyperkalemia is to review all the recent drugs and medications that a patient has received.

Table: Drug-induced hyperkalemia
Medication class (examples)Mechanism
ACEi (e.g., lisinopril, captopril)Inhibits angiotensin II formation → decreases aldosterone secretion → decreases renal K+ secretion
ARB (e.g., losartan, valsartan)Blocks angiotensin receptor → ↓ aldosterone secretion → ↓ renal K+ secretion
Direct renin inhibitors (e.g., aliskiren)Blocks renin from converting angiotensinogen to angiotensin l → decreases aldosterone secretion → ↓ renal K+ excretion
K+-sparing diuretics (e.g., amiloride, triamterene, spironolactone)Block epithelial sodium channel (ENaC) (amiloride, triamterene) or the aldosterone receptor (spironolactone, eplerenone) → ↓ renal K+ excretion
Cardiac glycosides (digoxin)Inhibits Na+/K+ ATPase pump → less K+ moved into cells
NSAIDs (e.g., ibuprofen)Decreases renin and aldosterone → ↓ renal K+ secretion
Calcineurin inhibitors (e.g., cyclosporine, tacrolimus)Multifactorial/incompletely understood: ↓ aldosterone release, ↓ aldosterone sensitivity, inhibition of Na+/K+ ATPase pump, blocking of ENaC channel
SuccinylcholineCauses extracellular leakage of K+ through acetylcholine receptor-gated channels
Antimicrobials (e.g., trimethoprim, pentamidine)Block ENaC channel

Pseudohyperkalemia

  • False positive hyperkalemia, due to process of drawing and/or processing of a blood sample
  • Related to blood draw: 
    • Damaged RBCs lyse and release their intracellular K+.
    • Prolonged tourniquet
    • Excessive fist clenching
    • Venipuncture trauma
  • Related to blood sample processing: 
    • Severe thrombocytosis or leukocytosis 
    • More likely if blood sample analysis is delayed
    • Intracellular K+ is released from platelets after clotting in the test tube.
    • WBCs lyse and release intracellular K+

Clinical Presentation

The most severe symptoms of hyperkalemia are impaired electrical conduction in the heart. Cardiac symptoms are more likely to occur with increasing severity and acuity of hyperkalemia; however, even relatively severe hyperkalemia can be asymptomatic. Muscular symptoms may be observed, and these include weakness and paralysis. 

Cardiac symptoms

Cardiac symptoms are the most important symptoms of hyperkalemia, as they can be rapidly fatal.

  • ECG changes follow a characteristic progression with increasing K+:
    • Peaked T waves and short QT interval → PR interval prolongation and QRS widening → loss of P waves → QRS widens to sine wave → asystole
    • This classic progression is often not observed clinically.
    • ECG findings are helpful if present but are not sensitive for hyperkalemia overall.
  • Arrhythmias:
    • Advanced atrioventricular block
    • Sinus bradycardia
    • Sinus arrest
    • Slow idioventricular rhythm
    • Ventricular tachycardia, ventricular fibrillation, and/or asystole if severe
  • Monitoring:
    • Important at all levels of hyperkalemia
    • Can be done with repeat ECGs and/or continuous cardiac monitoring 

Some patients will not have ECG changes or arrhythmias, even with severe hyperkalemia.

ECG changes in hyperkalemia:
In reality, ECG changes in hyperkalemia are more variable and less predictable.

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Muscular symptoms

  • Muscle weakness
  • Ascending flaccid paralysis (can resemble Guillain–Barré syndrome)
  • Unlikely to have respiratory failure due to respiratory muscle weakness

Management and Diagnosis

The management of hyperkalemia often takes precedence over the diagnosis because of the possibility of life-threatening arrhythmias and is guided by determining the level of urgency needed for treatment. Usually, the etiology of hyperkalemia is not difficult to determine and is not impeded by treating it first.

Management

  1. Hyperkalemic emergency?  
    • ECG changes, arrhythmia, or severe muscle weakness/paralysis
    • Serum K+ usually > 6.5 mEq/L 
    • Options for emergency treatment:
      • IV calcium to stabilize myocardium
      • Insulin/glucose +/– sodium bicarbonate +/– β2 agonist, to shift K+ into cells
      • Cation exchange resin +/– loop diuretic to remove K+
      • Hemodialysis
    • Monitor serum K+ frequently
    • Continuous cardiac monitoring and/or repeat ECG while treating
    • Consult nephrology early
  2. Lab result accurate?
    • Hemolyzed specimen?
      • Very common type of pseudohyperkalemia
      • Most labs will routinely indicate if specimen is hemolyzed.  
      • Redraw lab prior to making treatment decisions.
    • Less common causes of pseudohyperkalemia?
      • Severe thrombocytosis (i.e., > 1000 × 109/L)
      • Severe leukocytosis (i.e., > 50,000 × 109/L)
      • Measure plasma K+ (rather than routine serum K+) to obtain accurate level.
  3. Moderate hyperkalemia with high risk?
    • Generally asymptomatic and without ECG changes
    • Serum K+ 5.5–6.5 mEq/L with high-risk factor:
      • Sudden increase (e.g., 3.7 mEq/L to 6 mEq/L overnight) 
      • Ongoing K+ release (e.g., tumor lysis, rhabdomyolysis)
      • Ongoing K+ absorption (e.g., GI bleeding) 
      • Kidney dysfunction
      • Metabolic acidosis
    • Treat similarly to hyperkalemic emergency, but no need for IV calcium.
  4. Moderate hyperkalemia without high risk?
    • Generally asymptomatic and without ECG changes
    • Serum K+ 5.5–6.5 mEq/L without any of the above risk factors
    • Treat urgently:
      • Cation exchange resin +/– loop diuretic +/– hemodialysis to remove K+
      • Differences with emergent treatment:
        • Do not need IV calcium 
        • Do not necessarily need shifting measures
    • Monitor serum K+ frequently
    • Continuous cardiac monitoring and/or repeat ECG while treating
  5. Mild hyperkalemia?
    • Generally asymptomatic and without ECG changes
    • Serum K+ < 5.5 mEq/L 
    • Does not require urgent treatment
    • Management is primarily risk-factor modification:
      • Dietary K+ restriction if renal dysfunction
      • Stop/adjust offending medications (e.g., ACEi/ARB, NSAIDs, etc.).
      • Start/adjust loop or thiazide diuretics.
      • Start/adjust oral sodium bicarbonate.
      • Start/adjust cation exchange resin.
  6. Identify and treat any contributing underlying diseases.
Table: Acute therapeutic options for hyperkalemia
GoalInterventionProperties/indication
Stabilize the myocardiumIV calcium
  • Antagonizes effect on membrane potential
  • Indicated in hyperkalemic emergency
  • Onset within minutes, lasts 30–60 minutes
  • May require repeat doses if emergent symptoms remain
  • Worsens digoxin toxicity (use cautiously)
Shift K+ into cellsInsulin
  • ↓ ECF K+ via transcellular shift
  • Most effective transcellular shifting option
  • Onset 10–20 min, lasts 4–6 hours
  • Repeat every 2–4 hours, if needed.
  • Usually given with dextrose (D50W), to avoid hypoglycemia
  • Monitor fingerstick blood glucose closely.
Sodium bicarbonate (NaHCO3)
  • ↓ ECF K+ via transcellular shift
  • Onset 15–30 minutes
  • Lasts as long as serum bicarbonate remains improved
  • More effective if metabolic acidosis is initially present
β2 agonist
  • ↓ ECF K+ via transcellular shift
  • Onset 30 minutes, lasts for 2 hours
  • Can cause tachycardia (caution in heart disease)
Remove K+ from the bodyVia urine
  • Furosemide +/– normal saline (NS)
  • NS avoids hypovolemia from diuretic → maintains distal tubular flow rate needed for K+ secretion
Via GI tractCation exchange resins: bind K+ in exchange for Na+ or Ca2+
Dialysis
  • Primary option if patient is on long-term dialysis
  • Indicated for any patient with life-threatening hyperkalemia unresponsive to other measures
  • Hemodialysis is preferred (removes K+ faster than peritoneal dialysis)

Diagnosis

  1. AKI or CKD present?
  2. Recent process that could cause transcellular shift? 
    • New or worsening metabolic acidosis (including DKA)
    • Recent intense exercise
    • Recent surgery
  3. Other predisposing disease process present?
    • Hypovolemia or other states of decreased effective arterial blood volume (congestive heart failure, cirrhosis)
    • High cell turnover (tumor lysis syndrome, rhabdomyolysis, burns)
    • RBC absorption (RBC transfusion, GI bleeding, large hematoma reabsorption) 
  4. Review medication list carefully.
  5. Check plasma renin activity and aldosterone if etiology is still not identified.

Differential Diagnosis

  • Rhabdomyolysis: large-scale muscle cell death, which can result from many possible etiologies (trauma, drugs, toxins, infections): Serum K+ can increase suddenly if rhabdomyolysis is unrecognized or inadequately treated or if AKI develops (common complication). Rhabdomyolysis is diagnosed by a serum CK level > 5 times the upper limit of normal and treated with IV fluids.
  • Tumor lysis syndrome: large-scale malignant cell death, often sudden and brought on by the initiation of chemotherapy: Large amounts of intracellular K+, phosphate, and uric acid are released when malignant cells die. Treated with rasburicase (for hyperuricemia), calcium supplementation, and dialysis, if necessary.
  • Digoxin toxicity: Digoxin is the only commonly used cardiac glycoside. Toxicity is common, as the therapeutic window is narrow and excretion is renal. Clinical presentation includes arrhythmias, hyperkalemia, and characteristic vision changes, including increased yellow colors in vision (xanthopsia). Treated with digoxin-specific antibody (Fab) fragments, which bind to and thereby inactivate the circulating drug. 
  • Malignant hyperthermia: a life-threatening syndrome characterized by hyperthermia, muscle rigidity, and hyperkalemia (via rhabdomyolysis): Malignant hyperthermia is triggered by perioperative volatile anesthetic use in genetically predisposed patients. Treatment includes dantrolene (skeletal muscle reluctant) and supportive care.
  • Primary adrenal insufficiency (Addison’s disease): a rare, autoimmune type of destruction of the adrenal glands: Addison’s disease is diagnosed by measuring aldosterone (low), renin (high), serum cortisol (low), and ACTH (low) and ACTH stimulation test. Addison’s disease leads to hyperkalemia primarily through hypoaldosteronism. The disease manifests acutely as adrenal crisis, which is an emergency because of circulatory shock. Acute treatment is high-dose glucocorticoids and supportive care. Long-term treatment is by substituting glucocorticoids (hydrocortisone) and mineralocorticoids (fludrocortisone).  
  • Diabetic ketoacidosis (DKA): severe acidosis caused by insulin deficiency, usually in the setting of type 1 diabetes: Presents with total body K+ deficit (urinary losses from osmotic diuresis/polyuria); however, serum K+ will be normal or high. Treatment is by insulin replacement followed by K+ supplementation once the plasma level falls. If there is even mild hypokalemia on presentation, this represents severe total body K+ deficit, and the plasma K+ will decrease even further once an insulin drip is started. In this situation, K+ must be replaced until the plasma level is at least 3.3 mEq/L prior to starting insulin. 
  • Hyperkalemic periodic paralysis: a rare genetic disease with autosomal dominant inheritance: Hyperkalemic periodic paralysis is characterized by acute attacks of muscle weakness and/or paralysis due to hyperkalemia from severe transcellular shifting of K+. Attacks are precipitated by cold temperatures, rest after exercise, and/or K+ ingestion. If recovery is not spontaneous, treatment is with inhaled β2 agonists and K+-removing therapies (e.g., furosemide, cation exchange resins, dialysis).
  • Type IV renal tubular acidosis (RTA): a syndrome of decreased urinary secretion of K+ and H+ at the principal cell, resulting in a non–anion gap metabolic acidosis and hyperkalemia: Common causes include diabetes, NSAIDs, calcineurin inhibitors, heparin, and Addison’s disease. Diagnosed by history and measuring serum cortisol, renin, and aldosterone. Treatment is by mineralocorticoid replacement (e.g., fludrocortisone). Hyperkalemia is usually not severe unless concurrent predisposing factors are present.

References

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