Fluid and Electrolyte Disorders

Water-balance disorders (dysnatremias)

• Excess ADH activity: SIADH (small cell lung cancer, CNS injury, pneumonia, SSRIs, carbamazepine), pain/nausea/postoperative state, and "appropriate" ADH release from low effective arterial volume (heart failure, cirrhosis, true hypovolemia)
• Impaired free-water excretion: thiazides poison the cortical diluting segment; advanced CKD limits maximal water clearance; hypothyroidism and glucocorticoid deficiency reduce free-water excretion
• Free-water loss or no access to water: diabetes insipidus (central vs lithium-induced nephrogenic), osmotic diuresis from hyperglycemia or mannitol, fever/tachypnea, and the bedbound or intubated patient who cannot drink
• Renal salt wasting: cerebral salt wasting after subarachnoid hemorrhage or neurosurgery, mineralocorticoid deficiency, and salt-losing tubulopathies (Bartter, Gitelman)

Potassium disorders

• Reduced excretion: CKD, hypoaldosteronism/type 4 RTA, and drugs — ACE inhibitors, ARBs, MRAs, NSAIDs, calcineurin inhibitors, trimethoprim (ENaC blockade), heparin
• Transcellular shift: acidemia, insulin deficiency, beta-blockade, hyperosmolality, succinylcholine; conversely insulin, beta-2 agonists, and alkalemia drive hypokalemia
• Cell lysis: rhabdomyolysis, tumor lysis, massive hemolysis

Metabolic acidosis

• High anion gap: ketoacidosis (diabetic, alcoholic, starvation), lactate from shock or metformin accumulation, uremia, toxic alcohols, salicylate
• Normal gap: diarrhea (GI bicarbonate loss), proximal (type 2) and distal (type 1) RTA, type 4 RTA, large-volume 0.9% saline (hyperchloremic acidosis), acetazolamide

Fundamental Mechanisms of Fluid and Electrolyte Homeostasis

• Osmotic regulation: The hypothalamus responds to changes in serum osmolality (normal 285-295 mOsm/kg) via osmoreceptors, triggering release of antidiuretic hormone (ADH/vasopressin) to maintain water balance; ADH acts on V2 receptors in the collecting duct to increase aquaporin-2 water channel insertion, increasing free water reabsorption
• Volume regulation: The renin-angiotensin-aldosterone system (RAAS) responds to decreased effective arterial blood volume via baroreceptors in the juxtaglomerular apparatus; this pathway activates sodium and water reabsorption in the proximal tubule and collecting duct while suppressing ADH
• Electrolyte transport mechanisms: Na+/K+-ATPase pumps maintain transmembrane ion gradients across all cell membranes; aldosterone upregulates epithelial sodium channels (ENaC) in the collecting duct to increase sodium reabsorption and potassium secretion; loop of Henle creates the countercurrent multiplier system essential for concentration gradients

Specific Pathophysiology by Disorder Type

Hyponatremia (serum Na+ <135 mEq/L)

• Results from excess free water relative to sodium (dilutional hyponatremia most common)
• SIADH (Syndrome of Inappropriate Antidiuretic Hormone): Pathologic ADH secretion occurs from CNS disorders (meningitis, encephalitis, head trauma), malignancy (small cell lung cancer producing ectopic ADH), pulmonary diseases (pneumonia, positive pressure ventilation), and medications (SSRIs, carbamazepine, desmopressin); leads to inappropriate water reabsorption despite low osmolality
• Primary polydipsia: Excessive free water intake overwhelms renal excretory capacity
• Diuretic-induced hyponatremia: Thiazide diuretics block the diluting segment, preventing free water excretion; loop diuretics cause volume depletion activating ADH
• Adrenal insufficiency and hypothyroidism: Both reduce glomerular filtration rate and increase ADH-mediated water reabsorption
• Hepatic cirrhosis and heart failure: Decreased effective arterial blood volume triggers RAAS and ADH release despite low serum osmolality

Hypernatremia (serum Na+ >145 mEq/L)

• Results from net loss of free water relative to sodium or inability to access water
• Insensible losses: Fever and tachypnea increase free water loss from skin and lungs without electrolyte loss
• Central diabetes insipidus: Posterior pituitary damage (trauma, tumors, surgery, infiltrative disease) reduces ADH production, preventing collecting duct water reabsorption
• Nephrogenic diabetes insipidus: Collecting duct unresponsiveness to ADH occurs with chronic lithium therapy (most common cause), amphotericin B, demeclocycline, chronic kidney disease, or genetic mutations (V2 receptor or aquaporin-2 mutations)
• GI losses: Diarrhea causes disproportionate free water loss; vomiting causes hypotonic fluid loss
• Increased sodium intake: Salt poisoning or hypertonic saline administration

Hypokalemia (serum K+ <3.5 mEq/L)

• Results from total body potassium depletion (most common), shifts into cells, or both
• Renal potassium wasting: Loop and thiazide diuretics increase distal Na+ delivery and urine flow, promoting K+ secretion via ENaC and ROMK channels; hyperaldosteronism increases ENaC expression and activity; hypomagnesemia impairs ROMK channel closure, worsening K+ secretion
• Intracellular shifts: Alkalemia causes transcellular K+ shift into cells as H+ exits cells; insulin and beta-2 agonists activate Na+/K+-ATPase increasing K+ uptake; catecholamines via beta-2 receptors promote K+ entry
• GI losses: Diarrhea causes direct potassium loss; vomiting causes metabolic alkalosis activating aldosterone and perpetuating renal K+ wasting
• Metabolic alkalosis: Contraction alkalosis from vomiting/diuretics maintains hypokalemia by activating proximal tubule HCO3- reabsorption and distal K+ secretion

Hyperkalemia (serum K+ >5.5 mEq/L)

• Results from decreased renal excretion (most common), cellular release, or increased intake
• Decreased renal excretion: Type 4 renal tubular acidosis (RTA) from hypoaldosteronism (primary adrenal insufficiency, ACE inhibitors, ARBs, NSAIDs reducing renin) or aldosterone resistance (genetic mutations, trimethoprim blocking ENaC, potassium-sparing diuretics)
• Cellular K+ release: Rhabdomyolysis releases massive intracellular K+ and myoglobin; tumor lysis syndrome from chemotherapy causes rapid cell death; hemolysis from transfusion or hemolytic anemia; acidemia drives K+ out of cells
• Medications: ACE inhibitors and ARBs reduce aldosterone; NSAIDs reduce renin production; beta-blockers impair catecholamine-mediated K+ uptake
• Hyperosmolality from hyperglycemia: High glucose creates osmotic gradient causing water and K+ shifts from intracellular to extracellular space

Hypocalcemia (serum Ca2+ <8.5 mg/dL, ionized Ca2+ <4.2 mg/dL)

• Results from decreased PTH secretion, PTH resistance, decreased vitamin D activation, or chelation/sequestration
• Hypoparathyroidism: Parathyroid gland destruction (autoimmune, DiGeorge syndrome from 22q11 deletion), post-thyroid/parathyroid surgery, or magnesium depletion (Mg2+ required for PTH secretion and action)
• Vitamin D deficiency: Reduced sun exposure, malabsorption (celiac disease, Crohn's disease), dietary insufficiency, or chronic kidney disease (loss of 1-alpha hydroxylase needed for active vitamin D production)
• Acute phosphate rise: Tumor lysis syndrome, rhabdomyolysis, or acute kidney injury cause hyperphosphatemia, which precipitates calcium as calcium phosphate deposits

Hypercalcemia (serum Ca2+ >10.5 mg/dL, ionized Ca2+ >5.2 mg/dL)

• Results from PTH-mediated reabsorption (primary hyperparathyroidism), PTHrP production (malignancy), vitamin D excess, or bone resorption
• PTHrP-mediated hypercalcemia: Squamous cell lung cancers, kidney cancers, ovarian cancers, and breast cancers produce PTHrP activating PTH1R on distal tubule cells, increasing calcium reabsorption and phosphate excretion
• Vitamin D-mediated: Granulomatous diseases (sarcoidosis, tuberculosis, histoplasmosis) produce extrarenal 1-alpha hydroxylase, converting 25-hydroxyvitamin D to active 1,25-dihydroxyvitamin D
• Bone resorption: Lymphomas produce 1,25-dihydroxyvitamin D; hyperthyroidism increases osteoclast activity; immobilization in

Hyponatremia — symptoms track rate of fall, not absolute value

• Cerebral edema: water moves down the osmotic gradient into astrocytes, producing headache, nausea, lethargy, confusion, gait unsteadiness; severe/acute drops cause seizures, obtundation, and neurogenic pulmonary edema with respiratory arrest
• Chronic hyponatremia: brain cells extrude organic osmolytes over ~48 hours, so patients may look deceptively well but present with falls, subtle cognitive slowing, and osteoporosis-related fractures
• Volume clues drive the differential: dry mucosa, flat neck veins, and orthostasis in hypovolemia; edema, ascites, and elevated JVP in heart failure/cirrhosis; euvolemic and clinically unremarkable in SIADH

Hypernatremia

• Cell shrinkage: thirst (the earliest and most protective symptom), lethargy, irritability, hyperreflexia, and in extremes osmotic demyelination or bridging-vein tearing with intracranial hemorrhage in infants
• Classic stems: the nursing-home resident with fever and no free-water access, or the postoperative pituitary-surgery patient with polyuria and dilute urine

Potassium disorders

• Hyperkalemia: partial depolarization inactivates sodium channels — ascending weakness, paresthesias, and above all cardiac conduction disease; patients are often asymptomatic until the ECG changes, so hyperkalemia is a lab-and-ECG diagnosis
• Hypokalemia: hyperpolarization causes weakness, cramps, ileus, polyuria (nephrogenic DI from ROMK downregulation), rhabdomyolysis at severe levels, and palpitations from ectopy

Calcium and acid–base

• Hypocalcemia: increased neuromuscular excitability — perioral numbness, carpopedal spasm, Chvostek and Trousseau signs, laryngospasm, seizures
• Hypercalcemia: "stones, bones, groans, thrones, and psychiatric overtones" — nephrolithiasis, bone pain, constipation, polyuria from nephrogenic DI, confusion
• Metabolic acidosis: Kussmaul respirations (deep, sighing hyperventilation) as respiratory compensation, with fruity breath in ketoacidosis and hypotension from catecholamine resistance at low pH

Hyponatremia — a three-step algorithm (US expert panel, Verbalis et al.)

• Step 1, serum osmolality: confirms true hypotonic hyponatremia (<275 mOsm/kg). Normal osmolality suggests pseudohyponatremia from severe hypertriglyceridemia or paraproteinemia; high osmolality means translocational hyponatremia from hyperglycemia or mannitol
• Step 2, urine osmolality: <100 mOsm/kg means ADH is appropriately suppressed — primary polydipsia, beer potomania, low solute intake. >100 mOsm/kg means ADH activity persists
• Step 3, urine sodium plus volume exam: urine Na <25–30 mEq/L with clinical hypovolemia or edematous states (heart failure, cirrhosis) indicates avid renal Na retention; urine Na >30–40 mEq/L in a euvolemic patient with concentrated urine, low uric acid, and low BUN supports SIADH, which remains a diagnosis of exclusion requiring normal thyroid and adrenal function (check TSH and morning cortisol)
• Cerebral salt wasting shares the SIADH lab profile but the patient is volume-*depleted* with high urine output and a negative salt balance, typically after subarachnoid hemorrhage

Potassium

• Obtain an ECG immediately in any hyperkalemia — peaked T waves, then PR prolongation and P-wave loss, then QRS widening to a sine wave. Repeat a hemolyzed specimen only if the patient is stable and the ECG is normal (pseudohyperkalemia)
• Hypokalemia: check magnesium (repletion fails until Mg is corrected), and use urine K (or K/creatinine ratio) plus acid–base status to separate GI loss from renal wasting

Acid–base sequence

• Arterial or venous blood gas with electrolytes; compute the anion gap (Na − [Cl + HCO3]) and correct it for albumin
• Winter's formula (expected PaCO2 = 1.5 × HCO3 + 8 ± 2) detects a superimposed respiratory disorder; the delta-delta identifies mixed gap/non-gap pictures
• Urine anion gap in normal-gap acidosis: negative ("neGUTive") with diarrhea, positive with renal tubular acidosis; urine pH >5.5 despite acidemia points to distal (type 1) RTA, and hyperkalemia with mild acidosis points to type 4

Immediate stabilization

• Severe symptomatic hyponatremia (seizure, coma, respiratory arrest): the US expert panel (Verbalis et al.) endorses a bolus of 3% hypertonic saline — 100 mL IV over ~10 minutes, repeated up to three times as needed — targeting a prompt rise of about 4–6 mEq/L, which is enough to reverse herniation physiology
• Hyperkalemia with ECG changes: per AHA ACLS, give IV calcium (calcium gluconate 1 g) first to restore the membrane threshold potential — it does not lower potassium; then shift with insulin plus dextrose (regular insulin 10 units IV with glucose) and nebulized albuterol; sodium bicarbonate only helps in concomitant metabolic acidosis

Definitive/first-line therapy by disorder

• Hypovolemic hyponatremia: isotonic crystalloid; ADH shuts off once volume is restored, so watch for an abrupt autocorrection overshoot
• SIADH: fluid restriction is first-line, with oral salt tablets or urea plus a loop diuretic as escalation; vasopressin V2 antagonists (tolvaptan, IV conivaptan) are reserved options — the FDA warns against use beyond 30 days and in liver disease
• Hypervolemic hyponatremia: sodium and water restriction with a loop diuretic (furosemide); treat the underlying heart failure or cirrhosis
• Hypernatremia: restore volume first, then replace the calculated free-water deficit enterally or with hypotonic fluid; desmopressin for central DI, and a thiazide plus amiloride for lithium-induced nephrogenic DI
• Chronic hyperkalemia: dietary potassium restriction, loop or thiazide diuretic, and potassium binders (patiromer, sodium zirconium cyclosilicate); KDIGO favors binder use to preserve RAAS blockade rather than abandoning it
• Metabolic acidosis: treat the cause — insulin and fluids per ADA for DKA (bicarbonate only at pH <6.9), and oral sodium bicarbonate for CKD acidosis per KDIGO

Contraindicated/avoid

• Correcting chronic hyponatremia faster than roughly 8 mEq/L per 24 hours in high-risk patients
• Isotonic saline in SIADH — the desalination effect can lower sodium further
• Calcium in a digoxin-toxic patient, and reliance on binders alone for acute hyperkalemia

Of the disorder

• Cerebral edema and herniation (emergency): acute hyponatremia gives astrocytes no time to extrude osmolytes; heralded by vomiting, headache, seizure, and a widened pulse pressure with bradycardia
• Malignant arrhythmia from hyperkalemia (emergency): progressive conduction slowing culminates in a sine-wave QRS, then asystole or ventricular fibrillation/pulseless VT
• Torsades de pointes from hypokalemia and hypomagnesemia (emergency): delayed repolarization with U waves and QT prolongation; treat with IV magnesium
• Laryngospasm and seizure in acute hypocalcemia (emergency), classically after total thyroidectomy or in tumor lysis syndrome
• Falls, fractures, and gait ataxia in chronic hyponatremia, even when the patient appears asymptomatic
• Nephrogenic DI and nephrocalcinosis from prolonged hypokalemia or hypercalcemia

Of the treatment

• Osmotic demyelination syndrome (emergency): overrapid correction of chronic hyponatremia dehydrates oligodendrocytes in the pons; symptoms are biphasic — the patient improves, then 2–6 days later develops dysarthria, dysphagia, spastic quadriparesis, and locked-in syndrome; MRI changes lag behind the clinical picture. Highest risk with serum Na <120 mEq/L, alcohol use disorder, malnutrition, liver disease, and hypokalemia. If overcorrection occurs, relower with hypotonic fluid (D5W) plus desmopressin
• Cerebral edema from overrapid hypernatremia correction: brain cells that accumulated idiogenic osmoles swell when tonicity falls too fast — seizures in a previously improving patient
• Hypoglycemia after insulin given for hyperkalemia: check glucose serially; hypoglycemia is the most common iatrogenic complication of this maneuver
• Volume overload and pulmonary edema from hypertonic or isotonic saline in heart failure or cirrhosis
• Rebound hyperkalemia several hours after shifting therapy, because insulin and albuterol redistribute rather than remove potassium — definitive removal requires diuresis, binders, or dialysis
• Intestinal necrosis reported with sodium polystyrene sulfonate, particularly with sorbitol and in postoperative patients

• Measure serum osmolality before anything else in hyponatremia: normal osmolality means pseudohyponatremia (hypertriglyceridemia, myeloma); high osmolality means hyperglycemia. Only hypotonic hyponatremia gets treated as "real."
• Urine osmolality <100 mOsm/kg = primary polydipsia or beer potomania; the kidney is doing its job and the answer is not fluid restriction plus a vaptan
• SIADH is euvolemic with concentrated urine, urine Na >30–40 mEq/L, and low serum uric acid and BUN; cerebral salt wasting looks identical on labs but the patient is hypovolemic after subarachnoid hemorrhage — the distinguishing feature is volume status, and the treatment diverges (fluid restriction vs saline repletion)
• The single best next step in any hyperkalemia stem is an ECG, and if it is abnormal, IV calcium before insulin — calcium stabilizes the myocyte membrane but does not lower the potassium
• Trimethoprim blocks ENaC like amiloride: a CKD patient on an ACE inhibitor who gets trimethoprim–sulfamethoxazole for a UTI is the classic hyperkalemia setup, alongside type 4 RTA
• Osmotic demyelination is the buzzword payoff for overcorrection: locked-in syndrome days after a "successful" sodium correction. Limit correction to about 8 mEq/L per 24 hours in high-risk patients (alcohol use disorder, malnutrition, hypokalemia, liver disease) per the US hyponatremia expert panel
• Refractory hypokalemia means check magnesium: hypomagnesemia releases ROMK inhibition and drives ongoing renal potassium loss, so potassium repletion fails until magnesium is replaced
• Common distractor: giving 0.9% saline for SIADH. The kidney excretes the salt and retains the water (desalination), and the sodium falls further. Another distractor is treating a number rather than symptoms — chronic asymptomatic hyponatremia never warrants hypertonic saline