What is the role of electrolytes in cellular physiology and how do disturbances of electrolyte gradients affect membrane excitability and cellular function?

Electrolyte Pathophysiology of the Cell

Fundamental Principles of Cellular Electrolyte Homeostasis

Electrolytes maintain cellular function through steep concentration gradients across cell membranes, with intracellular potassium (K+) at 140 mEq/L versus extracellular ~4 mEq/L, while sodium (Na+) shows the opposite pattern (10 mEq/L intracellular versus ~140 mEq/L extracellular), and calcium (Ca2+) is maintained at nanomolar levels intracellularly versus millimolar levels extracellularly. 1, 2

The Na+/K+ ATPase Pump: The Master Regulator

• The Na+/K+ ATPase pump is the primary active transport mechanism that establishes and maintains the fundamental electrochemical gradients across all cell membranes 1, 3
• This pump actively extrudes 3 Na+ ions out of the cell while importing 2 K+ ions into the cell, consuming ATP in the process 3, 4
• The magnitude of the potassium gradient across cell membranes directly determines the excitability of nerve and muscle cells, including the myocardium 1
• Under normal conditions, the resting membrane potential remains stable despite minor fluctuations in extracellular electrolyte concentrations 1

Calcium Signaling and Membrane Permeability

• Intracellular Ca2+ concentration is maintained in the low nanomolar range, while extracellular Ca2+ exists in the low millimolar range, creating a steep gradient that drives Ca2+ entry when channels open 1
• The low Ca2+ permeability of resting cell membranes is maintained by Ca2+ ATPase pumps and Na+/Ca2+ exchangers that continuously extrude calcium 1
• Ca2+ entry from the extracellular space serves as a major trigger for cellular responses, including cell death pathways in erythrocytes (eryptosis) and excitation-contraction coupling in muscle cells 1

Pathophysiology of Electrolyte Disturbances

Hyperkalemia: The Most Lethal Electrolyte Disorder

Severe hyperkalemia (>6.5 mmol/L) represents one of the few electrolyte disturbances that can directly cause sudden cardiac arrest by depolarizing cell membranes and abolishing excitability. 1, 5

• Rapid or significant increases in serum potassium result from shifting of potassium from the intracellular to extracellular space, which immediately alters the transmembrane potential 1
• The first clinical indicator is often peaked T waves on ECG, progressing to flattened P waves, prolonged PR interval, widened QRS complex, and ultimately sine-wave pattern leading to asystolic cardiac arrest 1, 5
• Hyperkalemia causes flaccid paralysis, paresthesias, depressed deep tendon reflexes, and respiratory difficulties by preventing normal repolarization of excitable membranes 1, 5
• Renal failure and excessive potassium release from cells (rhabdomyolysis, tumor lysis, hemolysis) are the most common causes 1, 5

Hypokalemia: Membrane Hyperexcitability

• Hypokalemia hyperpolarizes cell membranes, making them less excitable and producing ECG changes including U waves, T-wave flattening, and predisposition to ventricular arrhythmias 1
• For every 1 mEq/L decrease in serum K+ below 3.5 mEq/L, the total body deficit approximates 200-400 mEq 5
• Hypokalemia commonly coexists with hypomagnesemia and may be refractory to correction until magnesium is repleted 1, 5, 6

Calcium and Magnesium: Membrane Stabilizers

• Magnesium is essential for Na+/K+ ATPase pump function and maintaining cellular K+ content; Mg2+ depletion results in concomitant K+ loss from cells 4
• Extracellular Mg2+ concentration controls arterial tone and blood pressure by regulating vascular membrane Mg2+-Ca2+ exchange sites 4
• Reduction in extracellular Mg2+ allows excess Ca2+ entry into cells, producing coronary vasospasm and hypertension 4
• Severe hypomagnesemia (<0.70 mmol/L) prolongs the QT interval and causes ventricular arrhythmias including torsades de pointes 1, 5

Refeeding Syndrome: Catastrophic Electrolyte Shifts

When nutritional support is initiated in severely malnourished patients, sudden insulin-driven shifts of potassium, phosphate, and magnesium into cells can cause precipitous falls in circulating levels, leading to cardiac and respiratory failure, coma, and death. 1, 5

Mechanism of Refeeding Syndrome

• The body adapts to starvation by down-regulating membrane pump activity to conserve energy, causing intracellular electrolytes (K+, Mg2+, Ca2+, phosphate) to leak out while Na+ and water leak into cells 1
• Total body electrolyte depletion exists despite potentially normal plasma levels before feeding 1
• Sudden nutritional support reverses these processes: insulin drives electrolytes back into cells, but total body stores are depleted, causing dangerous plasma level drops 1
• Thiamine deficiency compounds the problem by impairing cardiac function 1

Prevention Protocol

• Start feeding at 10 kcal/kg/day (not the commonly suggested 20 kcal/kg/day which may be too high) with generous electrolyte supplementation from day 1 1, 5
• Administer thiamine 100mg IV before feeding starts and continue for at least 3 days 1, 5
• Monitor potassium, phosphate, magnesium, and calcium every 6-12 hours for the first 3-5 days 5
• Provide generous supplementation of all four electrolytes regardless of initial plasma levels, as intracellular deficits may be massive 1, 5

Critical Clinical Pitfalls

Pseudohyperkalemia

• Always rule out pseudohyperkalemia from hemolysis, repeated fist clenching, or poor phlebotomy technique before initiating aggressive treatment 7
• Repeat measurement with proper technique or obtain arterial sample if K+ >6.0 mmol/L 7

Combined Electrolyte Deficiencies

• Hypokalemia cannot be corrected until hypomagnesemia is addressed, as Mg2+ is required for cellular K+ retention 5, 6, 4
• Hypophosphatemia (<0.32 mmol/L) causes respiratory failure, cardiac arrhythmias, and rhabdomyolysis, particularly in refeeding syndrome 5
• Combined deficiencies significantly amplify cardiac risk and must be corrected simultaneously 7

Medication-Induced Disturbances

• Review all medications that alter electrolyte handling: RAASi drugs, potassium-sparing diuretics, NSAIDs, beta-blockers, trimethoprim-sulfamethoxazole, heparin, and calcineurin inhibitors all cause hyperkalemia 7

Monitoring in High-Risk Populations

• Electrolyte abnormalities occur in up to 65% of critically ill patients with acute-on-chronic renal failure and are associated with increased mortality 5, 7
• Monitor serum potassium every 6-12 hours in critically ill patients and those with acute hyperkalemia 7
• More frequent monitoring (every 4-6 hours) is required during continuous kidney replacement therapy due to significant electrolyte shifts 7
• Target potassium range of 4.0-5.0 mmol/L to prevent adverse cardiac effects 7