Hyperkalemia: Comprehensive Overview for Provider Theory Examination
Definition and Classification
Hyperkalemia is a potentially lethal electrolyte disturbance defined as serum potassium concentration exceeding 5.0 mEq/L, with severity classified as mild (5.0-5.5 mEq/L), moderate (5.5-6.0 mEq/L), and severe (>6.0-6.5 mEq/L). 1, 2
- The European Society of Cardiology emphasizes that severe hyperkalemia (>6.5 mEq/L) represents a medical emergency requiring immediate multi-pronged intervention regardless of symptoms 1
- Hyperkalemia was directly responsible for sudden cardiac arrest in 7 of 29,063 hospitalized patients in one retrospective study, with acute kidney injury present in all arrest cases 3
Pathophysiology and Biochemistry
Cellular Potassium Homeostasis
Potassium is maintained predominantly in the intracellular compartment (98% of total body potassium) through the action of the Na+/K+ ATPase pump, which actively transports 3 sodium ions out and 2 potassium ions into cells. 3
- The magnitude of the potassium gradient across cell membranes (normal intracellular K+ ~140 mEq/L vs. extracellular ~4.0 mEq/L) determines excitability of nerve and muscle cells, including the myocardium 3
- The resting membrane potential is calculated by the Nernst equation and is critically dependent on the ratio of intracellular to extracellular potassium concentrations 3
Mechanisms of Hyperkalemia Development
Hyperkalemia develops through three primary mechanisms: transcellular potassium shift from intracellular to extracellular space, decreased renal potassium excretion, or excessive potassium intake in the setting of impaired excretion. 4, 5
Transcellular Shift Mechanisms
- Metabolic acidosis causes hydrogen ions to enter cells in exchange for potassium ions moving out, with approximately 0.6 mEq/L rise in serum potassium for every 0.1 unit decrease in pH 4
- Insulin deficiency impairs Na+/K+ ATPase pump activity, preventing potassium uptake into cells, particularly in skeletal muscle and liver 4
- Beta-adrenergic blockade reduces catecholamine-mediated cellular potassium uptake by blocking beta-2 receptors that normally stimulate the Na+/K+ ATPase pump 5
- Hyperosmolality (from hyperglycemia or mannitol) creates osmotic water movement out of cells, increasing intracellular potassium concentration and driving potassium efflux through solvent drag 5
- Tissue breakdown from rhabdomyolysis, tumor lysis syndrome, or massive hemolysis releases large quantities of intracellular potassium into the circulation 6
Impaired Renal Excretion Mechanisms
The distal nephron, specifically the principal cells of the cortical collecting duct, is the primary site of potassium secretion and the target of most hyperkalemia-inducing medications. 4, 5
- RAAS inhibition (ACE inhibitors, ARBs, direct renin inhibitors, aldosterone antagonists) reduces aldosterone-mediated sodium reabsorption and potassium secretion in the collecting duct, with combination RAAS therapy increasing hyperkalemia risk to 5-10% in heart failure or CKD patients 2, 5
- Potassium-sparing diuretics (amiloride, triamterene) directly block the epithelial sodium channel (ENaC) in principal cells, reducing the electrochemical gradient for potassium secretion 5
- NSAIDs reduce renin release and prostaglandin synthesis, decreasing aldosterone levels and impairing potassium excretion 1, 5
- Calcineurin inhibitors (tacrolimus, cyclosporine) cause hyperkalemia through multiple mechanisms including reduced Na+/K+ ATPase activity and decreased aldosterone responsiveness 5
- Trimethoprim and pentamidine block ENaC channels similar to amiloride, with trimethoprim causing dose-dependent hyperkalemia at doses >320 mg/day 5
- Heparin (both unfractionated and low-molecular-weight) suppresses aldosterone synthesis by inhibiting adrenal aldosterone synthase, with effects appearing within 3-5 days of therapy 2, 5
Chronic Kidney Disease Pathophysiology
- In CKD, reduced nephron mass decreases total potassium excretory capacity, though compensatory mechanisms (increased aldosterone, increased potassium secretion per nephron) maintain potassium balance until GFR falls below 15-20 mL/min 7
- Advanced CKD patients (stage 4-5) develop adaptive increases in colonic potassium secretion, accounting for up to 30% of total potassium excretion 7
Clinical Manifestations
Cardiovascular Effects
The first indicator of hyperkalemia is often peaked T waves (tenting) on ECG rather than clinical symptoms, as hyperkalemia may be asymptomatic until severe. 3, 1
Progressive ECG Changes with Rising Potassium
- 5.5-6.5 mEq/L: Peaked, narrow-based T waves with increased amplitude, particularly in precordial leads V2-V4 3, 8
- 6.5-7.5 mEq/L: Flattened or absent P waves, prolonged PR interval (first-degree AV block), and ST-segment depression 3, 8
- 7.5-8.5 mEq/L: Widened QRS complex (>120 ms), deepened S waves, and merging of S and T waves creating a "sine-wave" pattern 3, 8
- >8.5 mEq/L: Idioventricular rhythms, ventricular fibrillation, or asystolic cardiac arrest 3, 8
Critical caveat: ECG changes are highly variable and less sensitive than laboratory values for predicting hyperkalemia severity or complications, with some patients showing minimal ECG changes despite severe hyperkalemia. 1, 9
Neuromuscular Manifestations
- Muscle weakness progressing from lower to upper extremities, caused by sustained depolarization of muscle cell membranes leading to inactivation of sodium channels 3, 1
- Flaccid paralysis in severe cases (typically K+ >7.0 mEq/L), potentially involving respiratory muscles and causing hypoventilation 3, 1
- Paresthesias (tingling, numbness) in extremities and perioral region 3, 1
- Depressed or absent deep tendon reflexes due to impaired neuromuscular transmission 3, 1
Diagnostic Approach
Laboratory Confirmation
Always verify hyperkalemia is not pseudohyperkalemia from hemolysis, repeated fist clenching during phlebotomy, prolonged tourniquet application, or delayed sample processing before initiating treatment. 2, 9
- Repeat measurement with proper technique (minimal tourniquet time, no fist clenching, prompt processing) or obtain arterial sample if venous sample shows unexpected elevation 2, 9
- Pseudohyperkalemia is particularly common in patients with thrombocytosis (>500,000/μL) or leukocytosis (>100,000/μL) due to potassium release during clotting 9
Immediate ECG Assessment
- Obtain 12-lead ECG immediately in all patients with K+ >5.5 mEq/L to assess for cardiac toxicity 1, 9
- Look specifically for peaked T waves, flattened P waves, prolonged PR interval, and widened QRS complexes, though absence of ECG changes does not exclude significant hyperkalemia 1, 9
Identifying Underlying Etiology
Systematically evaluate for reversible causes including medications (RAAS inhibitors, NSAIDs, potassium-sparing diuretics, trimethoprim, heparin), acute kidney injury, metabolic acidosis, tissue breakdown, and excessive potassium intake. 1, 2
- Check renal function (creatinine, eGFR), acid-base status (venous or arterial blood gas), glucose (to assess for hyperglycemia/hyperosmolality), and creatine kinase (if rhabdomyolysis suspected) 2, 9
- Review all medications including over-the-counter NSAIDs, herbal supplements, and salt substitutes (which contain potassium chloride) 1, 9
Acute Management of Severe Hyperkalemia
Treatment Algorithm by Urgency
For severe hyperkalemia (>6.5 mEq/L) or any hyperkalemia with ECG changes, immediately initiate three-pronged therapy: membrane stabilization, intracellular potassium shift, and potassium removal from the body. 3, 1
Step 1: Cardiac Membrane Stabilization (Immediate - Within 5 Minutes)
Administer IV calcium immediately to antagonize the cardiac effects of hyperkalemia without lowering serum potassium levels. 3, 1
- Calcium gluconate 10%: 15-30 mL (1.5-3 grams) IV over 2-5 minutes, preferred for peripheral IV access due to lower risk of tissue necrosis if extravasation occurs 3, 1, 9
- Calcium chloride 10%: 5-10 mL (500-1000 mg) IV over 2-5 minutes, provides three times more elemental calcium than gluconate but requires central access 3, 1, 9
- Onset of action: 1-3 minutes with duration of 30-60 minutes; repeat dose if no ECG improvement within 5-10 minutes 9
- Pediatric dosing: 20 mg/kg (0.2 mL/kg of 10% solution) over 5-10 minutes 9
- Critical caveat: In malignant hyperthermia with hyperkalemia, use calcium only in extremis as it may worsen calcium overload of myoplasm 9
Step 2: Intracellular Potassium Shift (Within 15-30 Minutes)
Administer multiple agents simultaneously to shift potassium into cells, as effects are additive and temporary (lasting 4-6 hours). 3, 1
Insulin Plus Glucose (Most Reliable Agent)
- Standard dose: 10 units regular insulin IV with 25 grams glucose (50 mL of D50) over 15-30 minutes 3, 1
- Alternative dosing: 0.1 units/kg (approximately 5-7 units in adults) for patients at high risk of hypoglycemia 9
- Onset: 15-30 minutes, peak effect at 60 minutes, duration 4-6 hours 1, 9
- Monitoring: Check glucose at 30,60,90, and 120 minutes post-administration; check potassium every 2-4 hours 9
- Hypoglycemia risk factors: Low baseline glucose, no diabetes history, female sex, altered renal function 9
- Can repeat every 4-6 hours if hyperkalemia persists, with careful glucose and potassium monitoring 9
Nebulized Beta-2 Agonist
- Albuterol: 10-20 mg nebulized over 15 minutes (4-8 times the standard bronchodilator dose) 3, 1, 9
- Onset: 30 minutes, duration 2-4 hours 1, 9
- Lowers potassium by 0.5-1.0 mEq/L through beta-2 receptor stimulation of Na+/K+ ATPase pump 9
- Use as adjunctive therapy with insulin/glucose for additive effect 1, 9
Sodium Bicarbonate (Only if Metabolic Acidosis Present)
- Dose: 50 mEq (50 mL of 8.4% solution) IV over 5 minutes 3
- Indication: Use ONLY in patients with concurrent metabolic acidosis (pH <7.35, bicarbonate <22 mEq/L) 1, 9
- Mechanism: Corrects acidosis-induced transcellular potassium shift and increases distal sodium delivery to enhance renal potassium excretion 2, 9
- Onset: 30-60 minutes, less reliable than insulin or albuterol 1, 9
- Critical pitfall: Do not use in patients without metabolic acidosis, as efficacy is minimal and may cause volume overload 9
Step 3: Potassium Removal from Body (Within 1-6 Hours)
Implement definitive potassium removal strategies, as membrane stabilization and intracellular shift are temporary measures that do not reduce total body potassium. 3, 1
Loop Diuretics (If Adequate Renal Function)
- Furosemide: 40-80 mg IV, titrate to achieve urine output >200 mL/hour 3, 1, 9
- Mechanism: Increases distal sodium delivery and flow rate to collecting duct, enhancing potassium secretion 9
- Effective only if eGFR >30 mL/min; higher doses (up to 160-200 mg) may be needed in CKD 9
Hemodialysis (Most Effective Method)
- Indications: Severe hyperkalemia unresponsive to medical management, oliguria/anuria, end-stage renal disease, or K+ >7.0 mEq/L with ECG changes 3, 1, 9
- Efficacy: Removes 25-50 mEq potassium per hour, lowering serum potassium by 1.0-1.5 mEq/L per session 9
- Most reliable method for definitive potassium removal, particularly in renal failure 3, 6
Potassium Binders (Slower Onset)
Sodium polystyrene sulfonate (Kayexalate): 15-50 grams PO or per rectum with sorbitol 3
Sodium zirconium cyclosilicate (Lokelma): 10 grams PO three times daily for 48 hours 9, 10
Patiromer (Veltassa): 8.4 grams PO once daily, titrate up to 25.2 grams daily 9
ACLS Modifications for Cardiac Arrest Due to Hyperkalemia
When cardiac arrest occurs secondary to hyperkalemia, administer adjuvant IV therapy (calcium, insulin/glucose, bicarbonate if acidotic) in addition to standard ACLS protocols. 3
- Continue high-quality CPR and standard ACLS algorithms while simultaneously treating hyperkalemia 3
- Consider emergency hemodialysis during resuscitation if available 3
Chronic Hyperkalemia Management
Medication Optimization Strategy
Do not permanently discontinue RAAS inhibitors (ACE inhibitors, ARBs, mineralocorticoid antagonists) after a single elevated potassium measurement, as this eliminates proven mortality benefits in heart failure and CKD. 1, 2, 7
Algorithm for RAAS Inhibitor Management
K+ 5.0-5.5 mEq/L: Continue RAAS inhibitor at current dose, eliminate contributing factors (NSAIDs, potassium supplements, salt substitutes), optimize diuretic therapy, and recheck potassium in 1 week 2, 9
K+ 5.5-6.0 mEq/L: Reduce RAAS inhibitor dose by 50%, initiate potassium binder (patiromer or sodium zirconium cyclosilicate), eliminate contributing medications, and recheck potassium in 3-5 days 2, 9
K+ 6.0-6.5 mEq/L: Temporarily hold RAAS inhibitor, initiate potassium binder, optimize diuretic therapy, and recheck potassium in 24-48 hours; restart RAAS inhibitor at reduced dose once K+ <5.5 mEq/L 2, 9
K+ >6.5 mEq/L: Discontinue RAAS inhibitor temporarily, treat as acute severe hyperkalemia (see above), initiate potassium binder, and restart RAAS inhibitor at lowest dose once K+ <5.0 mEq/L with close monitoring 2, 9
Newer Potassium Binders for Chronic Management
Patiromer and sodium zirconium cyclosilicate are preferred over sodium polystyrene sulfonate for long-term management, allowing continuation of life-saving RAAS inhibitor therapy. 1, 9, 7
Patiromer: Start 8.4 grams once daily, titrate by 8.4 grams weekly to maximum 25.2 grams daily based on potassium levels 9
Sodium zirconium cyclosilicate: 10 grams three times daily for 48 hours, then 5-15 grams once daily for maintenance 9
Diuretic Optimization
- Loop diuretics (furosemide 40-80 mg daily) increase urinary potassium excretion by enhancing distal sodium delivery 1, 9
- Thiazide diuretics can be added to loop diuretics for synergistic effect in patients with eGFR >30 mL/min 1
- Fludrocortisone (0.1-0.2 mg daily) increases potassium excretion in aldosterone deficiency but carries risk of fluid retention and hypertension 1
Dietary Modifications
Restrict dietary potassium to <3 grams/day (approximately 50-70 mmol/day) in patients with recurrent hyperkalemia, though evidence linking dietary intake to serum levels is limited. 2, 9
- High-potassium foods to avoid: Bananas, oranges, melons, potatoes, tomato products, legumes, lentils, chocolate, yogurt, salt substitutes (contain potassium chloride) 2, 9
- Caveat: Potassium-rich diets provide cardiovascular benefits including blood pressure reduction; dietary restriction should be balanced against these benefits in otherwise healthy individuals 9
Monitoring Protocol
Check potassium within 1 week of starting or escalating RAAS inhibitors, with reassessment 7-10 days after any dose change or initiation of potassium binder therapy. 1, 9
- High-risk patients (advanced CKD, heart failure, diabetes, elderly, history of hyperkalemia) require more frequent monitoring: weekly for first month, then monthly for 3 months, then every 3-6 months 1, 9
- After potassium binder initiation: Check potassium at 1 week, 2 weeks, 1 month, then monthly to assess efficacy and prevent hypokalemia 9
Special Populations
Chronic Kidney Disease
- CKD Stage 4-5 patients tolerate higher potassium levels (optimal range 3.3-5.5 mEq/L vs. 3.5-5.0 mEq/L in earlier stages) due to compensatory mechanisms 9
- Maintain RAAS inhibitors aggressively in proteinuric CKD using potassium binders, as these drugs slow CKD progression 9
- Up to 73% risk of hyperkalemia in advanced CKD, particularly with RAAS inhibitor use 1
Heart Failure
- Up to 40% risk of hyperkalemia in chronic heart failure patients, especially those on spironolactone or eplerenone 1
- One-third of heart failure patients requiring mineralocorticoid receptor antagonists develop K+ >5.0 mEq/L 2
- Discontinuing RAAS inhibitors offsets survival benefits; use potassium binders to maintain therapy 1, 2
Diabetes Mellitus
- Hyporeninemic hypoaldosteronism (Type 4 RTA) is common in diabetic nephropathy, causing impaired potassium excretion even with preserved GFR 2
- Higher risk with concurrent use of RAAS inhibitors and NSAIDs 2
Critical Pitfalls to Avoid
Diagnostic Pitfalls
- Failing to rule out pseudohyperkalemia before initiating aggressive treatment, particularly in patients with thrombocytosis or leukocytosis 2, 9
- Relying solely on ECG findings, which are highly variable and less sensitive than laboratory values for predicting severity 1, 9
- Overlooking ECG changes in patients with documented hyperkalemia, as absence of symptoms does not exclude cardiac toxicity 2
Treatment Pitfalls
- Delaying treatment while waiting for repeat laboratory confirmation when clinical suspicion is high and ECG changes are present 2
- Using sodium bicarbonate in patients without metabolic acidosis, where efficacy is minimal 1, 9
- Forgetting to administer glucose with insulin, leading to potentially severe hypoglycemia 9
- Assuming temporary measures remove potassium: Calcium, insulin, and beta-agonists only temporize; definitive removal requires diuretics, binders, or dialysis 9
- Using sodium polystyrene sulfonate for acute management, given delayed onset and risk of intestinal necrosis 2
Chronic Management Pitfalls
- Permanently discontinuing RAAS inhibitors due to moderate hyperkalemia, eliminating mortality and morbidity benefits 1, 2, 9
- Inadequate use of loop diuretics in patients with preserved renal function who could benefit from enhanced urinary potassium excretion 2
- Failing to discontinue or reduce RAAS inhibitors when potassium exceeds 6.0 mmol/L, leading to refractory hyperkalemia 2
- Not monitoring for hypokalemia after initiating potassium binders, which may be more dangerous than mild hyperkalemia 9
Rebound Hyperkalemia
- Rebound occurs 2-4 hours after temporary measures (insulin, albuterol, bicarbonate) wear off, requiring repeat dosing or definitive removal strategies 2
- Stored blood products can release significant potassium during transfusion, causing acute hyperkalemia in susceptible patients 2
Hospital Admission Criteria
Admit all patients with severe hyperkalemia (>6.0 mEq/L), any hyperkalemia with ECG changes, symptomatic hyperkalemia, or high-risk comorbidities (advanced CKD, heart failure, diabetes). 2