Electrolyte & Fluid Replacement

Potassium is predominantly an intracellular cation. The sodium-potassium ATPase pump exchanges intracellular sodium for extracellular potassium in a 3:2 ratio, which keeps intracellular potassium near 140 mEq/L against 4 to 5 mEq/L outside. Because so little potassium is extracellular, the serum level is an unreliable indicator of total body stores.

Potassium also shifts between cells and plasma. Alkalemia, insulin and β-adrenergic stimulation promote its uptake into cells. Metabolic acidosis and cell breakdown push it out, and insulin deficiency in diabetic ketoacidosis can raise serum potassium even while total body potassium is depleted. This is why potassium should not be repleted in dextrose-containing solutions — dextrose stimulates insulin secretion and drives potassium into cells — and why rebound hyperkalemia can follow repletion when a shift was the cause.

Hypokalemia delays repolarization. T-wave flattening comes first, followed by ST depression and the emergence of a U wave; PR and QT intervals may lengthen. Severe hypokalemia can cause torsades de pointes and ventricular tachycardia, and the risk is highest in older patients, in heart disease and with digoxin or antiarrhythmics — low potassium can push digitalis into toxicity.

Hyperkalemia disturbs the resting membrane potential of cardiac myocytes. As potassium climbs, tall peaked T waves appear, then the P waves flatten or vanish, the QRS widens, and finally a sine-wave pattern can progress to asystole. The rate of rise matters more than the number: a patient with chronic hyperkalemia may have a near-normal tracing at a level that, reached acutely, would cause marked changes.

Concentrated potassium chloride must be diluted: direct injection at that concentration may be instantaneously fatal, and fatal arrhythmias and cardiac arrest have followed undiluted administration. Even diluted, it is not infused rapidly, and in renal insufficiency it can cause life-threatening hyperkalemia. Therapy is guided by serial ECGs, especially with digitalis.

When hyperkalemia changes the ECG, treatment follows three steps. Stabilize the membrane: calcium is given first; it does not lower potassium but counters its cardiotoxicity. Calcium gluconate is generally preferred initially; calcium chloride carries 3 times the elemental calcium but is more irritating and more likely to cause tissue necrosis if it extravasates, and calcium should not be given in bicarbonate-containing fluids, to avoid precipitation of calcium carbonate. Shift potassium into cells: insulin, with glucose unless the patient is hyperglycemic, and β2 agonists such as albuterol; sodium bicarbonate may help when there is metabolic acidosis. Remove it: gastrointestinal cation exchangers — sodium polystyrene sulfonate and the newer patiromer and sodium zirconium cyclosilicate (see Potassium Binders) — and, definitively in end-stage kidney disease, hemodialysis.

Two of these drugs have label rules of their own. Sodium bicarbonate raises plasma bicarbonate, buffers excess hydrogen ion and raises blood pH; overly aggressive therapy causes metabolic alkalosis and hypernatremia, and full correction in the first 24 hours is avoided because ventilation lags and an unrecognized alkalosis can follow. A rapid alkalosis also lowers ionized calcium and can cause tetany. Off-label, bicarbonate is used for tricyclic antidepressant overdose with QRS prolongation. Calcium chloride is given slowly into a central or deep vein, never by bolus — rapid injection can cause hypotension, bradycardia, arrhythmias, syncope and cardiac arrest — and its label contraindicates it in ventricular fibrillation and in asystole or electromechanical dissociation.

Magnesium is an essential cofactor for the Na⁺/K⁺-ATPase, and low magnesium inhibits the renal outer medullary potassium (ROMK) channels, increasing urinary potassium loss. That is why potassium replacement alone may fail when hypokalemia and hypomagnesemia coexist — magnesium is repleted first so the potassium can stay. Low magnesium also impairs parathyroid hormone release and causes PTH resistance, so hypocalcemia follows too.

Magnesium regulates the passage of sodium, potassium and calcium through voltage-dependent channels; hypomagnesemia disturbs repolarization, prolonging and dispersing the QT — the substrate of torsades de pointes. Hypokalemia and hypomagnesemia together raise the torsades risk, particularly with QT-prolonging drugs, and intravenous magnesium sulfate has been shown to reverse torsades.

Magnesium controls convulsions by blocking neuromuscular transmission: it decreases the acetylcholine released at the end plate by the motor nerve impulse. That is the pharmacology of toxicity too. As plasma magnesium rises above about 4 mEq/L the deep tendon reflexes decrease, and they disappear as the level approaches 10 mEq/L, where respiratory paralysis may occur; heart block may occur at this or lower levels, and levels above 12 mEq/L may be fatal. Magnesium also dilates vessels, so larger doses lower blood pressure.

Because magnesium is removed solely by the kidneys, renal impairment invites accumulation. The knee jerk is tested before each repeated dose, and intravenous calcium antagonizes magnesium’s central and peripheral effects; until it can be given, ventilation is supported. Magnesium also potentiates neuromuscular blocking agents. Its label indications are magnesium deficiency and the prevention and control of seizures in pre-eclampsia and eclampsia.

About 40% of serum calcium is free and ionized — the biologically active part; most of the rest is bound to albumin. Total calcium therefore falls with hypoalbuminemia (about 0.8 mg/dL for each 1 g/dL drop in albumin below 4 g/dL) while ionized calcium may be normal. pH shifts the balance: acidosis reduces albumin binding and raises ionized calcium, and alkalosis lowers it. Citrate in transfused blood binds calcium, so massive transfusion can drop ionized calcium acutely.

Low ionized calcium raises neuromuscular excitability — Chvostek and Trousseau signs, perioral numbness, tetany — and prolongs the QTc, which can lead to torsades. Intravenous calcium gluconate dissociates into ionized calcium in plasma and is labeled for acute symptomatic hypocalcemia.

Intravenous potassium phosphates is a source of phosphorus for hypophosphatemia when oral or enteral replacement is not possible, and for parenteral nutrition. Phosphate and calcium travel together: excess phosphate forms insoluble calcium phosphate, causing hypocalcemia with tetany and nephrocalcinosis with acute kidney injury, and calcium phosphate precipitates have caused fatal pulmonary emboli. So calcium is checked and normalized first, the infusion never runs with calcium-containing fluids, and hyperphosphatemia, hypercalcemia or significant hypocalcemia contraindicates it.

The product is also a potassium load. Undiluted or rapid “IV push” administration has caused cardiac arrest and death, so it is given only after dilution and only when serum potassium is below the label’s threshold, and never in hyperkalemia or severe renal impairment. Phosphate infusion can also lower magnesium (and calcium) in hypercalcemia or diabetic ketoacidosis.

Hypophosphatemia (adult serum phosphate below 2.5 mg/dL) is far more prevalent in alcoholism, diabetic ketoacidosis and sepsis. Several drugs cause it by shifting phosphate into cells — insulin therapy, intravenous glucose and catecholamines such as albuterol — and diuretics and corticosteroids increase its renal loss. Refeeding syndrome is the same shift on a large scale: when a starved, phosphate-depleted patient is fed, insulin and glucose drive phosphate into cells, causing profound hypophosphatemia. The most common symptom is weakness; severe deficiency can cause rhabdomyolysis and weaken the heart and respiratory muscles.

Isotonic fluids — 0.9% saline and lactated Ringer solution — do not cross into cells; they distribute through the whole extracellular compartment, so of 1 L only about 250 mL stays in the vessels. Hypotonic fluids (0.45% saline; dextrose 5%, which acts as free water once the dextrose is metabolized) let water move into cells — overuse of 0.45% saline can cause hyponatremia and cerebral edema. Hypertonic 3% saline draws water out of cells and is used for severe symptomatic hyponatremia, with strict limits on the rate of correction because rapid correction of chronic hyponatremia causes osmotic demyelination (see Vasopressin Antagonists).

Normal saline carries an equal load of chloride. Given in large volumes it can cause a non-anion-gap hyperchloremic metabolic acidosis; the acidosis can in turn shift potassium out of cells. Lactated Ringer solution, a balanced crystalloid whose lactate is metabolized to bicarbonate, is less likely to do this.

That same lactate makes lactated Ringer solution an alkalinizing agent: it can cause or worsen a metabolic alkalosis, and in severe hepatic impairment, where lactate metabolism falls, it can worsen an anion-gap metabolic acidosis. It contains potassium and calcium, so it is avoided when hyperkalemia or hypercalcemia is a risk, and its potassium is too low to correct severe hypokalemia. 3% saline is strongly hypertonic (about 1027 mOsmol/L) and is given through a large vein, because hypertonic solutions can damage veins.