Internal Medicine Deep Pathophysiology
Acid-Base & Electrolyte Disorders: The Complete Pathophysiology
A comprehensive exploration of fluid, electrolyte, and acid-base physiology—understanding the "why" behind every disorder transforms pattern recognition into mechanistic reasoning.
Foundations: The Body's Internal Environment
Before dissecting individual disorders, we must understand the fundamental principles governing body fluid composition, distribution, and regulation. These principles explain why disorders develop and guide rational treatment.
Total Body Water: The Universal Solvent
Water comprises 60% of body weight in men (50% in women, due to higher fat content). This water is distributed across compartments separated by selectively permeable membranes.
Intracellular Fluid (ICF) — 40% Body Weight
The largest compartment. High K⁺ (~140 mEq/L), low Na⁺ (~10 mEq/L), high protein, high phosphate. This composition is maintained by Na⁺/K⁺-ATPase, which pumps 3 Na⁺ out for every 2 K⁺ in, consuming ~25% of basal ATP.
Extracellular Fluid (ECF) — 20% Body Weight
Divided into: Plasma (5% BW, intravascular) and Interstitial fluid (15% BW, between cells). High Na⁺ (~140 mEq/L), low K⁺ (~4 mEq/L), HCO₃⁻ as major buffer. Plasma has proteins; interstitial fluid doesn't.
The Osmolality Principle
Water moves freely between compartments to equalize osmolality. Sodium is the primary ECF osmole; potassium is the primary ICF osmole. A change in sodium concentration reflects a water problem (too much or too little water relative to sodium), NOT a sodium problem. This principle is the foundation of understanding dysnatremias.
Why the Distinction Matters
What is osmolality?
Osmolality = total concentration of all solutes per kg of water. Measured in mOsm/kg. Normal plasma osmolality = 275-295 mOsm/kg. Calculated: 2×Na + Glucose/18 + BUN/2.8.
What is tonicity (effective osmolality)?
Tonicity = concentration of solutes that do NOT freely cross cell membranes and therefore exert osmotic pressure. Effective osmolality = 2×Na + Glucose/18. BUN is excluded because urea crosses membranes freely—it doesn't pull water.
Why does this distinction matter clinically?
A patient with uremia may have high calculated osmolality (from BUN) but normal tonicity—their cells are NOT dehydrated because urea equilibrates across membranes. Tonicity determines water shifts between ICF and ECF. Only effective osmoles cause cellular shrinkage or swelling.
What are the main effective osmoles?
Sodium (and its accompanying anions) in ECF. Glucose (when insulin-deficient, glucose can't enter cells and acts as effective osmole). Mannitol (given therapeutically). Ineffective osmoles include urea, ethanol, methanol, ethylene glycol (they cross membranes and equilibrate).
Osmolality Calculations
Calculated Osm = 2×[Na] + [Glucose]/18 + [BUN]/2.8
Osmol Gap = Measured Osm − Calculated Osm (Normal <10). Elevated gap suggests unmeasured osmoles (toxic alcohols, mannitol)
How the Body Maintains Balance
Stimulus: Hypothalamic osmoreceptors detect ↑osmolality (as little as 1-2% change). Also stimulated by ↓blood volume/pressure (via baroreceptors), nausea, pain, stress.
Response: Posterior pituitary releases ADH (vasopressin). ADH acts on collecting duct V2 receptors → aquaporin-2 insertion → water reabsorption → concentrated urine.
Thirst: Parallel system—osmoreceptors trigger thirst at slightly higher threshold than ADH release. Thirst is the ultimate defense against hypernatremia (if patient can drink).
Result: Water retention, dilution of plasma, normalization of osmolality.
Stimulus: ↓Renal perfusion (sensed by juxtaglomerular cells), ↓Na⁺ delivery to macula densa, sympathetic activation.
Response: Renin release → Angiotensin I → (ACE) → Angiotensin II → (1) Vasoconstriction, (2) Aldosterone release, (3) ADH release, (4) Thirst stimulation.
Aldosterone: Acts on principal cells of collecting duct → ↑ENaC activity → Na⁺ reabsorption, K⁺ secretion.
Result: Sodium retention (with water following), K⁺ excretion, volume expansion.
"Effective" Circulating Volume: The body senses arterial filling, not total body fluid. A patient with heart failure may be volume-overloaded but have low effective circulating volume (poor cardiac output) → RAAS activation despite total body sodium excess.
Pressure Natriuresis: High renal perfusion pressure directly increases sodium excretion—an intrinsic renal mechanism independent of hormones.
ANP/BNP: Released from atria/ventricles in response to stretch. Promote natriuresis and vasodilation. Oppose RAAS. Elevated BNP indicates volume overload/cardiac stress.
Evidence Base
Rose BD, Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th ed. McGraw-Hill 2001 • Verbalis JG. Disorders of body water homeostasis. Best Pract Res Clin Endocrinol Metab 2003 • Sterns RH. Disorders of Plasma Sodium. NEJM 2015
Acid-Base Physiology: The pH Balance
The body maintains arterial pH between 7.35-7.45 with remarkable precision. Understanding the buffer systems, compensation mechanisms, and systematic approach to analysis enables diagnosis of even complex mixed disorders.
Henderson-Hasselbalch Made Intuitive
The Master Equation
pH = 6.1 + log([HCO₃⁻] / 0.03 × pCO₂)
pH depends on the RATIO of bicarbonate (metabolic) to pCO₂ (respiratory). Normal: HCO₃⁻ = 24 mEq/L, pCO₂ = 40 mmHg
What does this equation tell us clinically?
pH is determined by the ratio of bicarbonate to pCO₂—not absolute values. If both change proportionally in the same direction, pH is preserved. The lungs control pCO₂ (minutes to hours); the kidneys control HCO₃⁻ (hours to days).
Why is the bicarbonate-CO₂ system the most important buffer?
Three reasons: (1) It's present in high concentration (24 mEq/L HCO₃⁻); (2) It's an "open system"—CO₂ can be exhaled, preventing equilibrium and allowing continued buffering; (3) Both components are independently regulated (lungs for CO₂, kidneys for HCO₃⁻). Other buffers (hemoglobin, phosphate, proteins) contribute but can't be regulated.
What happens when acid is added to the body?
H⁺ + HCO₃⁻ → H₂CO₃ → CO₂ + H₂O. Bicarbonate is consumed buffering the acid. The CO₂ produced is exhaled. Acutely, pH falls slightly and HCO₃⁻ drops. Respiratory compensation increases ventilation to lower pCO₂. Renal compensation increases H⁺ excretion and HCO₃⁻ regeneration over days.
Why can't compensation fully restore pH?
Compensation is always incomplete in simple disorders. If the lungs fully compensated for metabolic acidosis, there would be no stimulus to continue hyperventilating. The compensation is limited by the physiological cost (respiratory muscle fatigue) and feedback loops. Normal pH with abnormal HCO₃⁻/pCO₂ indicates a mixed disorder, not "complete compensation."
Classification by Mechanism
Primary: ↓HCO₃⁻
Compensation: ↓pCO₂ (hyperventilation)
pH: Low (<7.35)
Causes: Acid gain OR bicarbonate loss
Primary: ↑HCO₃⁻
Compensation: ↑pCO₂ (hypoventilation)
pH: High (>7.45)
Causes: H⁺ loss OR HCO₃⁻ gain
Primary: ↑pCO₂
Compensation: ↑HCO₃⁻ (renal)
pH: Low (<7.35)
Causes: Hypoventilation
Primary: ↓pCO₂
Compensation: ↓HCO₃⁻ (renal)
pH: High (>7.45)
Causes: Hyperventilation
The Anion Gap: Your Diagnostic Key
Anion Gap Calculation
AG = [Na⁺] − ([Cl⁻] + [HCO₃⁻])
Normal = 8-12 mEq/L (varies by lab). Represents unmeasured anions (albumin, phosphate, sulfate, organic acids)
Mechanism: Acid added that has unmeasured anion
MUDPILES:
• Methanol
• Uremia
• DKA
• Propylene glycol, Paraldehyde
• Iron, Isoniazid, Inborn errors
• Lactic acidosis
• Ethylene glycol
• Salicylates
Mechanism: HCO₃⁻ lost, replaced by Cl⁻
Causes:
• Diarrhea (GI HCO₃⁻ loss)
• RTA (Types 1, 2, 4)
• Early renal failure
• Carbonic anhydrase inhibitors
• Ureteral diversion
• Saline infusion (dilutional)
Use urine anion gap to distinguish renal vs. GI loss
The Delta-Delta (Δ/Δ) Ratio
In pure HAGMA, for every 1 mEq/L rise in AG, HCO₃⁻ falls by ~1 mEq/L. The delta-delta checks this relationship:
Δ/Δ = (AG − 12) / (24 − HCO₃⁻)
Δ/Δ = 1-2: Pure HAGMA (the expected relationship)
Δ/Δ <1: HAGMA + NAGMA (HCO₃⁻ dropped more than AG rose—there's additional non-AG acid or HCO₃⁻ loss)
Δ/Δ >2: HAGMA + Metabolic Alkalosis (HCO₃⁻ didn't drop as much as expected—there's a concurrent process raising HCO₃⁻)
Generation and Maintenance: Two Separate Questions
How is metabolic alkalosis generated?
H⁺ loss (vomiting, NG suction, diuretics) or HCO₃⁻ gain (bicarbonate administration, contraction alkalosis, posthypercapnic state). Normally, the kidney can excrete massive amounts of HCO₃⁻. So why does alkalosis persist?
What maintains metabolic alkalosis?
The kidney fails to excrete excess HCO₃⁻ because of: (1) Volume depletion (↓GFR, ↑proximal reabsorption); (2) Chloride depletion (HCO₃⁻ must be reabsorbed with Na⁺ when Cl⁻ unavailable); (3) Hypokalemia (stimulates H⁺ secretion, HCO₃⁻ reabsorption); (4) Mineralocorticoid excess (stimulates H⁺ secretion).
How do you classify metabolic alkalosis?
Chloride-responsive (urine Cl⁻ <20): Will correct with saline—vomiting, NG suction, prior diuretics, post-hypercapnia. Volume/chloride depleted.
Chloride-resistant (urine Cl⁻ >20): Won't correct with saline—hyperaldosteronism, Cushing's, severe K⁺ depletion, active diuretic use, Bartter/Gitelman syndromes.
Why Vomiting Causes Alkalosis
Gastric H⁺ loss: Stomach produces HCl. Vomiting loses H⁺ → HCO₃⁻ rises (each H⁺ secreted into stomach generates one HCO₃⁻ in blood; normally the HCO₃⁻ is neutralized when gastric acid reaches duodenum—vomiting prevents this).
Volume depletion: Loss of gastric fluid → RAAS activation → Na⁺ reabsorption with HCO₃⁻ (because Cl⁻ depleted) → alkalosis maintained.
Hypokalemia: K⁺ lost in gastric fluid and urine (aldosterone effect) → worsens alkalosis.
Treatment: Isotonic saline (volume, chloride) + KCl replacement.
Expected Compensation: Is It Appropriate?
Interpreting Compensation
If measured pCO₂ equals expected → Simple disorder with appropriate compensation.
If measured pCO₂ > expected → Additional respiratory acidosis (or less respiratory compensation).
If measured pCO₂ < expected → Additional respiratory alkalosis (or excessive respiratory compensation—rare, suspect mixed disorder).
Evidence Base
Berend K, et al. Physiological approach to assessment of acid-base disturbances. NEJM 2014 • Kraut JA, Madias NE. Metabolic acidosis: pathophysiology, diagnosis and management. Nat Rev Nephrol 2010 • Seifter JL. Integration of acid-base and electrolyte disorders. NEJM 2014
Sodium Disorders: It's About Water
Sodium is the primary extracellular cation and the major determinant of plasma osmolality. Dysnatremias are disorders of water balance, not sodium balance—understanding this principle transforms management.
Serum Sodium Reflects Water, Not Sodium
Why is hyponatremia a water problem, not a sodium problem?
Serum [Na⁺] = Total body Na⁺ / Total body water. Hyponatremia means the ratio is low. This can occur with low, normal, OR high total body sodium—what matters is the relative excess of water. A patient with heart failure may have massive sodium excess but still be hyponatremic because water is retained even more.
Why does water retention occur?
ADH (vasopressin) promotes water retention. ADH is released in response to: (1) High osmolality (appropriate), (2) Low effective circulating volume (appropriate but causes dilutional hyponatremia), (3) SIADH—ADH release despite normal osmolality and volume (inappropriate). Understanding which mechanism is operating guides treatment.
Why does hypernatremia always indicate water deficit?
Unlike sodium (regulated by RAAS), water has an almost perfect defense: thirst. Anyone with access to water and an intact thirst mechanism will drink to prevent hypernatremia. Hypernatremia develops only when: (1) Thirst is impaired (elderly, altered mental status), (2) Access to water is restricted (intubated, immobile), OR (3) Water losses are massive (diabetes insipidus). It ALWAYS means too little water relative to sodium.
The Edelman Equation (Simplified)
[Na⁺] ≈ (Total Body Na⁺ + Total Body K⁺) / Total Body Water
Potassium matters because it can exchange with Na⁺ across cell membranes. Severe hypokalemia can contribute to hyponatremia; K⁺ repletion can raise [Na⁺].
The Diagnostic Algorithm
Check Osmolality: Is It Real?
Hypotonic (<280): True hyponatremia—proceed to next step.
Isotonic (280-295): Pseudohyponatremia (lab artifact from hyperlipidemia/hyperproteinemia—ion-selective electrodes avoid this).
Hypertonic (>295): Translocational—glucose or mannitol pulling water into ECF. Correct Na⁺: add 1.6-2.4 mEq/L for every 100 mg/dL glucose >100.
Assess Volume Status
Hypovolemic: Low BP, tachycardia, dry mucosa, ↑BUN/Cr. Lost Na⁺ and water, but more Na⁺ → ADH release to preserve volume.
Euvolemic: No edema, no volume depletion signs. SIADH, hypothyroidism, adrenal insufficiency, reset osmostat.
Hypervolemic: Edema, JVD. Heart failure, cirrhosis, nephrotic syndrome—low effective circulating volume despite total body excess.
Check Urine Studies
Urine Osm <100: ADH is appropriately suppressed—primary polydipsia (water intake exceeds excretion capacity).
Urine Osm >100: ADH is active despite hypoosmolality—appropriate (hypovolemia) or inappropriate (SIADH).
Urine Na⁺ <20: Kidneys avidly retaining Na⁺—hypovolemia or low effective volume (HF, cirrhosis).
Urine Na⁺ >40: Renal Na⁺ wasting or SIADH.
SIADH Criteria
Essential: Hypotonic hyponatremia + Urine Osm >100 + Urine Na⁺ >40 + Euvolemia + Normal thyroid/adrenal function + No diuretics.
Common Causes: CNS disorders (stroke, trauma, infection), pulmonary disease (pneumonia, SCLC), medications (SSRIs, carbamazepine, cyclophosphamide), postoperative state, pain, nausea.
Treatment: Fluid restriction, salt tablets, loop diuretics (block medullary gradient), vasopressin antagonists (vaptans), treat underlying cause.
Osmotic Demyelination Syndrome (ODS)
What is ODS and why does it occur?
ODS (formerly "central pontine myelinolysis") is demyelination—classically in the pons but can be extrapontine—occurring days after rapid hyponatremia correction. Neurons adapt to chronic hypoosmolality by extruding organic osmolytes. Rapid correction causes sudden brain cell shrinkage before osmolytes can be repleted, triggering oligodendrocyte apoptosis and demyelination.
Who is at highest risk?
Chronic hyponatremia (≥48 hours—brain has adapted). Severe hyponatremia (Na⁺ <120). Risk factors: alcoholism, malnutrition, hypokalemia, liver disease. Acute hyponatremia (<48 hours) can be corrected faster because the brain hasn't yet adapted.
What are safe correction rates?
Chronic/unknown duration: ≤8 mEq/L in 24 hours (some recommend ≤6 in high-risk). ≤18 mEq/L in 48 hours.
Acute (<48h) with symptoms: Can correct faster initially (2 mEq/L/hr for first few hours) until symptoms resolve, then slow down.
If overcorrected: D5W infusion ± desmopressin to re-lower sodium.
The 6-8-10 Rule
Safe limits for chronic hyponatremia correction: 6 mEq/L/day if high-risk, 8 mEq/L/day standard, 10 mEq/L/day maximum absolute. Monitor sodium q2-4h during active correction. The most dangerous time is when the underlying cause is reversed (e.g., volume resuscitation in hypovolemic patient)—free water excretion suddenly increases and sodium may rise rapidly.
Always a Water Deficit
Renal: Diabetes insipidus (central or nephrogenic), osmotic diuresis (glucose, mannitol, urea)
Extrarenal: Insensible losses (fever, burns, ventilation), GI losses (diarrhea—especially osmotic)
Urine Osm helps: <300 = DI; >600 = extrarenal loss; 300-600 = partial DI or osmotic diuresis
Iatrogenic: Hypertonic saline, NaHCO₃ administration, sodium-containing medications
Ingestion: Salt poisoning (rare, usually pediatric), seawater ingestion
Mineralocorticoid excess: Primary hyperaldosteronism (mild hypernatremia)
Free Water Deficit
Deficit (L) = TBW × [(Na⁺/140) − 1]
TBW = 0.6 × weight (kg) for men; 0.5 × weight for women. Replace deficit over 48-72 hours (max correction 10-12 mEq/L/day to avoid cerebral edema)
Evidence Base
Sterns RH. Disorders of Plasma Sodium—Causes, Consequences, and Correction. NEJM 2015 • Verbalis JG, et al. Diagnosis, evaluation, and treatment of hyponatremia. Am J Med 2013 • Adrogué HJ, Madias NE. Hypernatremia. NEJM 2000
Potassium Disorders: The Critical Ion
Potassium is the primary intracellular cation (98% inside cells). Its concentration gradient across cell membranes determines resting membrane potential. Small changes in serum K⁺ can be immediately life-threatening—understanding both internal balance (transcellular shifts) and external balance (intake/excretion) is essential.
Two Balances: Internal and External
Minutes to hours
K⁺ INTO cells (↓serum):
• Insulin (Na⁺/K⁺-ATPase stimulation)
• β₂-agonists (catecholamines, albuterol)
• Alkalosis (H⁺/K⁺ exchange)
• Cell uptake (refeeding, blood cell production)
K⁺ OUT OF cells (↑serum):
• Insulin deficiency
• β-blockers
• Acidosis (mineral acids, not organic)
• Cell lysis (rhabdo, hemolysis, tumor lysis)
• Hyperosmolality
Hours to days
K⁺ excretion regulated by:
• Aldosterone (↑secretion)
• Distal Na⁺ delivery (↑flow = ↑secretion)
• Serum K⁺ itself (direct effect on principal cells)
• Urine flow rate
Location: Principal cells of cortical collecting duct
Mechanism: K⁺ secreted through ROMK channels; driven by Na⁺ reabsorption through ENaC creating lumen-negative potential
90% of K⁺ excretion is renal; 10% GI
K⁺ <3.5 mEq/L: Causes and Consequences
What are the major causes of hypokalemia?
Transcellular shift: Insulin, β-agonists, alkalosis, refeeding.
GI loss: Diarrhea (direct K⁺ loss), vomiting (indirect—volume depletion triggers aldosterone → renal K⁺ wasting).
Renal loss: Diuretics (thiazides, loops), hyperaldosteronism, RTA, hypomagnesemia, Bartter/Gitelman syndromes.
Decreased intake: Rare unless severe (anorexia, alcoholism).
How do you determine renal vs. extrarenal loss?
Urine K⁺ <20 mEq/L (or TTKG <3): Appropriate renal conservation—losses are extrarenal (GI) or transcellular shift.
Urine K⁺ >40 mEq/L (or TTKG >7): Renal K⁺ wasting—diuretics, hyperaldosteronism, RTA, hypomagnesemia.
Why does hypomagnesemia cause refractory hypokalemia?
Magnesium normally blocks ROMK channels in the collecting duct. Without intracellular Mg²⁺, ROMK is uninhibited → excessive K⁺ secretion. Additionally, Mg²⁺ depletion impairs Na⁺/K⁺-ATPase. You cannot correct hypokalemia until you correct hypomagnesemia.
What are the clinical manifestations?
Cardiac: U waves, flattened T waves, ST depression, prolonged QT, arrhythmias (PACs, PVCs, VT/VF—especially with digoxin).
Neuromuscular: Weakness (proximal → respiratory), cramps, rhabdomyolysis (severe).
Renal: Nephrogenic DI (impaired concentrating ability), metabolic alkalosis (H⁺ secreted instead of K⁺).
GI: Ileus, constipation.
Hypokalemia Treatment
Oral preferred: KCl 40-80 mEq/day in divided doses. Better tolerated, safer.
IV for severe (<2.5) or symptomatic: Max 10-20 mEq/hr via peripheral line (40 mEq/hr via central line with monitoring). Faster rates cause pain, sclerosis, and cardiac risk.
Rule of thumb: For every 1 mEq/L drop in serum K⁺, total body deficit ≈200-400 mEq. Recheck K⁺ after each 40-60 mEq replaced.
Always check/replace Mg²⁺ if K⁺ refractory to replacement.
K⁺ >5.5 mEq/L: The Emergency
Confirm It's Real (Pseudohyperkalemia)
Hemolyzed sample, prolonged tourniquet, fist clenching, extreme leukocytosis/thrombocytosis can all falsely elevate K⁺. If unexpected, redraw without tourniquet and check immediately. True hyperkalemia with normal renal function is rare—suspect pseudohyperkalemia.
Identify the Cause
Increased intake: Supplements, K⁺-containing salt substitutes, massive transfusion.
Transcellular shift: Acidosis, insulin deficiency, β-blockers, succinylcholine, digoxin toxicity, cell lysis (rhabdo, TLS, hemolysis).
Decreased excretion: AKI, CKD, hypoaldosteronism (Addison's, Type 4 RTA, ACEi/ARBs, NSAIDs, K⁺-sparing diuretics, heparin).
Assess ECG Changes
Progressive ECG changes: Peaked T waves (earliest) → PR prolongation → QRS widening → Loss of P waves → Sine wave pattern → VF/asystole. ECG changes indicate cardiac toxicity requiring emergent treatment. Note: ECG can be normal even with severe hyperkalemia—don't rely on ECG alone.
Hyperkalemia Treatment Protocol
1. STABILIZE MEMBRANE (immediate, if ECG changes): Calcium gluconate 1-2g IV over 2-3 min. Does NOT lower K⁺—protects heart from arrhythmia. Onset seconds, duration 30-60 min. Can repeat.
2. SHIFT K⁺ INTO CELLS (minutes):
• Regular insulin 10 units IV + D50 25-50g (unless glucose >250)—lowers K⁺ 0.5-1.2 mEq/L in 15-30 min
• Albuterol 10-20 mg nebulized—lowers K⁺ 0.5-1.0 mEq/L
• NaHCO₃ (only if acidotic)—less effective than insulin
3. REMOVE K⁺ FROM BODY (hours):
• Loop diuretics (if renal function present)
• Kayexalate (SPS)—GI K⁺ binder, slow and controversial efficacy
• Patiromer or SZC—newer GI K⁺ binders, better evidence
• Hemodialysis—definitive treatment, use if severe/refractory
Evidence Base
Palmer BF, Clegg DJ. Physiology and Pathophysiology of Potassium Homeostasis. Adv Physiol Educ 2016 • Kovesdy CP. Updates in hyperkalemia. Nat Rev Nephrol 2017 • Gennari FJ. Hypokalemia. NEJM 1998
Calcium, Magnesium & Phosphate
These divalent ions are critical for neuromuscular function, bone metabolism, and enzymatic reactions. Their disorders often coexist and interact—correcting one may require addressing another.
The Three Fractions
Calcium Distribution
Ionized (free) Ca²⁺ (45%): The physiologically active fraction. This is what matters clinically.
Protein-bound (40%): Primarily bound to albumin. Not biologically active.
Complexed (15%): Bound to anions (citrate, phosphate, sulfate). Not active.
The Albumin Correction: Corrected Ca = Measured Ca + 0.8 × (4 − Albumin). For every 1 g/dL drop in albumin, measured calcium drops ~0.8 mg/dL—but ionized (active) calcium is unchanged. Better yet: measure ionized calcium directly.
pH Effect: Acidosis increases ionized Ca²⁺ (H⁺ competes for albumin binding sites). Alkalosis decreases ionized Ca²⁺—this is why hyperventilation causes tetany despite normal total calcium.
PTH, Vitamin D, and Calcitonin
Stimulus: Low ionized Ca²⁺ sensed by calcium-sensing receptor (CaSR) on parathyroid cells.
Actions (all raise Ca²⁺):
• Bone: ↑osteoclast activity → Ca²⁺/PO₄³⁻ release
• Kidney: ↑Ca²⁺ reabsorption (DCT), ↓PO₄³⁻ reabsorption (PCT), ↑1,25(OH)₂D production
• Indirectly: ↑intestinal Ca²⁺ absorption via vitamin D
Net effect: ↑Ca²⁺, ↓PO₄³⁻
Activation: Skin (UV) → 25(OH)D (liver) → 1,25(OH)₂D (kidney, stimulated by PTH).
Actions:
• Intestine: ↑Ca²⁺ and PO₄³⁻ absorption (primary effect)
• Bone: Permissive for PTH action, supports mineralization
• Kidney: Minor ↑Ca²⁺ reabsorption
Net effect: ↑Ca²⁺, ↑PO₄³⁻
Causes and Management
• Post-surgical (thyroidectomy)
• Autoimmune
• Infiltrative (hemochromatosis)
• Hypomagnesemia (impairs PTH secretion AND action)
Labs: ↓Ca²⁺, ↑PO₄³⁻, ↓PTH
• Vitamin D deficiency
• CKD (↓1,25D production)
• Malabsorption
• PTH resistance (pseudohypoparathyroidism)
Labs: ↓Ca²⁺, variable PO₄³⁻, ↑PTH
Hypocalcemia Symptoms & Treatment
Symptoms: Perioral numbness, paresthesias, muscle cramps, Chvostek sign (facial twitch), Trousseau sign (carpal spasm), tetany, seizures, prolonged QT, heart failure.
Acute/Symptomatic: Calcium gluconate 1-2g IV over 10-20 min, then continuous infusion 0.5-1.5 mg/kg/hr. Monitor for extravasation (calcium is vesicant).
Chronic: Oral calcium + vitamin D supplementation. Correct hypomagnesemia.
"Bones, Stones, Groans, and Psychiatric Overtones"
What are the two most common causes?
Primary hyperparathyroidism (outpatient): ~90% of outpatient hypercalcemia. Usually adenoma. PTH inappropriately elevated for Ca²⁺ level.
Malignancy (inpatient): ~65% of inpatient hypercalcemia. PTHrP secretion (squamous cell, renal, breast), osteolytic metastases, or 1,25D production (lymphoma).
How do you distinguish them?
PTH elevated: Primary hyperparathyroidism (or familial hypocalciuric hypercalcemia—check urine Ca/Cr ratio).
PTH suppressed (<20): Malignancy, vitamin D toxicity, granulomatous disease, milk-alkali syndrome. Check PTHrP, 25(OH)D, 1,25(OH)₂D.
Why does hypercalcemia cause polyuria?
Calcium activates CaSR in the loop of Henle, inhibiting NKCC2 → impaired concentrating ability (nephrogenic DI). Hypercalcemia also causes volume depletion through decreased intake (nausea, anorexia) and nephrogenic DI, creating a vicious cycle.
Hypercalcemia Treatment
1. Volume resuscitation: NS 200-300 mL/hr initially. Dilutes Ca²⁺ and promotes calciuresis. This is first-line for all hypercalcemia.
2. Loop diuretics: Only AFTER volume repleted. Furosemide inhibits Ca²⁺ reabsorption in loop.
3. Bisphosphonates: Zoledronic acid 4 mg IV or pamidronate 60-90 mg IV. Inhibit osteoclasts. Onset 2-4 days, duration weeks. Best for malignancy.
4. Calcitonin: 4 IU/kg q12h. Rapid onset (hours) but tachyphylaxis in 48h. Use as bridge to bisphosphonates.
5. Dialysis: For severe, refractory, or renal failure.
6. Steroids: For granulomatous disease (↓1,25D production), myeloma, vitamin D toxicity.
The Often-Forgotten Electrolytes
Magnesium (Normal 1.7-2.2 mg/dL)
Hypomagnesemia causes: Diuretics, alcoholism, diarrhea, PPI use, diabetic ketoacidosis, refeeding.
Clinical: Similar to hypocalcemia (tetany, arrhythmias), refractory hypokalemia, refractory hypocalcemia.
Treatment: IV magnesium sulfate 1-2g for severe; oral Mg oxide/citrate for mild. Check and replace in all critically ill patients.
Phosphate (Normal 2.5-4.5 mg/dL)
Hypophosphatemia causes: Refeeding syndrome, respiratory alkalosis, DKA treatment, alcoholism, malabsorption.
Clinical (severe <1.0): Respiratory failure (diaphragm weakness), cardiac dysfunction, rhabdomyolysis, hemolysis, encephalopathy.
Hyperphosphatemia causes: CKD (most common), rhabdomyolysis, tumor lysis, hypoparathyroidism.
Treatment: Phosphate binders (calcium-based, sevelamer), dialysis for severe. High PO₄³⁻ with high Ca²⁺ = calciphylaxis risk.
Evidence Base
Goltzman D. Approach to Hypercalcemia. In: Endotext. 2019 • Cooper MS, Gittoes NJL. Diagnosis and management of hypocalcemia. BMJ 2008 • Cheungpasitporn W, et al. Hypomagnesemia. Am J Med 2015
Fluid Therapy: Mechanism-Based Prescribing
IV fluid therapy is one of the most common interventions in medicine. Knowing the composition and distribution of fluids transforms prescribing from habit to precision.
Where Does the Fluid Go?
D5W: Distributes as free water—⅔ ICF, ⅓ ECF. Only ~8% remains intravascular. Use for free water replacement (hypernatremia).
NS (0.9%): Stays in ECF—¼ intravascular, ¾ interstitial. ~250 mL of 1L stays in vessels. Use for volume resuscitation.
Balanced crystalloids (LR, Plasmalyte): Similar to NS but physiologic chloride. SMART trial showed benefit in critically ill. Preferred for most resuscitation.
NS vs Balanced Crystalloids
For most patients needing resuscitation, balanced crystalloids are preferred. NS remains appropriate for: severe hyperkalemia (no K⁺ in fluid), metabolic alkalosis (Cl⁻ helps), and as carrier fluid with blood products.
Matching Fluid to Pathophysiology
Goal: Restore intravascular volume and tissue perfusion.
Fluid: Balanced crystalloid (LR or Plasmalyte) for initial resuscitation. Blood products for hemorrhage.
How much: Bolus 500-1000 mL, reassess. Target MAP >65, urine output >0.5 mL/kg/hr, lactate clearance. Avoid excessive crystalloid (edema, coagulopathy).
Goal: Replace free water deficit; correct Na⁺ slowly (≤10-12 mEq/L/day).
Fluid: D5W (free water) or hypotonic saline (½NS, ¼NS). Enteral water if possible.
Calculate deficit: TBW × [(Na⁺/140) − 1]. Replace over 48-72 hours plus ongoing losses.
Goal: Restore volume; Na⁺ will correct as volume normalizes and ADH suppresses.
Fluid: Normal saline (isotonic). Avoid hypotonic fluids (would worsen hyponatremia).
Caution: Once volume restored, ADH will shut off → water diuresis → rapid Na⁺ rise. Monitor Na⁺ q2-4h. May need D5W to slow correction.
Initial: NS 1-1.5 L in first hour (volume resuscitation).
Maintenance: NS 250-500 mL/hr. Switch to ½NS when corrected Na⁺ is normal/high.
Add dextrose: D5 ½NS when glucose reaches 200-250 (DKA) or 250-300 (HHS)—allows continued insulin for ketosis without hypoglycemia.
K⁺: Add 20-40 mEq KCl per liter once K⁺ <5.2 and urine output present.
Classic "4-2-1" Rule: 4 mL/kg/hr for first 10 kg + 2 mL/kg/hr for next 10 kg + 1 mL/kg/hr thereafter.
70 kg adult: 40 + 20 + 50 = 110 mL/hr = ~2.5 L/day.
Fluid: Traditionally D5 ½NS + 20 mEq KCl/L. Provides water, some Na⁺, dextrose for minimal calories, and K⁺ replacement.
Caution: Many hospitalized patients develop hyponatremia from maintenance fluids (ADH elevation from pain, nausea, surgery). Consider isotonic maintenance (D5NS) in at-risk patients.
Evidence Base
Semler MW, et al. Balanced Crystalloids versus Saline in Critically Ill Adults (SMART). NEJM 2018 • Self WH, et al. Balanced Crystalloids versus Saline in Noncritically Ill Adults (SALT-ED). NEJM 2018 • Myburgh JA, Mythen MG. Resuscitation Fluids. NEJM 2013
Clinical Integration: The Systematic Approach
Complex acid-base and electrolyte disorders require systematic analysis. This section integrates the pathophysiology into practical diagnostic and treatment algorithms.
The Five-Step Approach
Look at pH: Acidemia or Alkalemia?
pH <7.35 = acidemia (net acid process dominates). pH >7.45 = alkalemia (net alkaline process dominates). pH 7.35-7.45 = normal (or mixed disorder where opposing processes balance).
Identify Primary Disorder
Compare HCO₃⁻ and pCO₂ to pH direction. Acidemia + low HCO₃⁻ = metabolic acidosis. Acidemia + high pCO₂ = respiratory acidosis. Alkalemia + high HCO₃⁻ = metabolic alkalosis. Alkalemia + low pCO₂ = respiratory alkalosis.
Calculate Expected Compensation
Use Winter's formula (metabolic acidosis), or compensation rules. If measured pCO₂/HCO₃⁻ matches expected → simple disorder. If different → mixed disorder present.
Calculate Anion Gap (if Metabolic Acidosis)
AG = Na − (Cl + HCO₃). Correct for albumin: for every 1 g/dL albumin below 4, add 2.5 to AG. Elevated AG = HAGMA. Normal AG = NAGMA (calculate urine AG to distinguish renal vs. GI loss).
Calculate Delta-Delta (if HAGMA)
Δ/Δ = (AG − 12) / (24 − HCO₃). Ratio 1-2 = pure HAGMA. Ratio <1 = HAGMA + NAGMA. Ratio >2 = HAGMA + metabolic alkalosis.
Putting It All Together
Case 1: DKA
Labs: pH 7.22, pCO₂ 24, HCO₃⁻ 10, Na⁺ 132, K⁺ 5.4, Cl⁻ 98, glucose 450
Analysis:
• Step 1: pH 7.22 = acidemia
• Step 2: Low HCO₃⁻ = metabolic acidosis
• Step 3: Expected pCO₂ = 1.5(10) + 8 = 23. Measured 24 ≈ expected → appropriate compensation, simple disorder
• Step 4: AG = 132 − (98 + 10) = 24 → HAGMA
• Step 5: Δ/Δ = (24−12)/(24−10) = 12/14 = 0.86 → HAGMA + NAGMA (makes sense—DKA often has component of hyperchloremic acidosis from saline resuscitation or ketone excretion)
Diagnosis: HAGMA (DKA) + possible mild NAGMA component
Case 2: Vomiting + COPD
Labs: pH 7.42, pCO₂ 55, HCO₃⁻ 35, Na⁺ 138, K⁺ 2.8, Cl⁻ 88
Analysis:
• Step 1: pH 7.42 = normal (but look at components!)
• Step 2: High HCO₃⁻ AND high pCO₂ → opposing processes
• For metabolic alkalosis: Expected pCO₂ = 0.7(35) + 21 = 45.5. Measured is 55 (higher than expected)
• For chronic respiratory acidosis: Expected HCO₃⁻ = 24 + 3.5×(55−40)/10 = 24 + 5.25 = 29.25. Measured is 35 (higher than expected)
Diagnosis: Mixed metabolic alkalosis (vomiting) + chronic respiratory acidosis (COPD). The pH is normal because they oppose each other.
Case 3: Altered Mental Status
Labs: Na⁺ 118, K⁺ 4.2, Serum Osm 248, Urine Osm 520, Urine Na⁺ 65
Analysis:
• Hypotonic (serum osm 248) hyponatremia
• Urine Osm 520 > 100 → ADH is active
• Urine Na⁺ 65 > 40 → not avid Na⁺ retention
• Clinical: no edema, no orthostasis → euvolemic
Diagnosis: SIADH (euvolemic hypotonic hyponatremia with concentrated urine and high urine Na⁺)
Management: Fluid restriction. If severe symptoms (seizures, obtundation), 3% saline 100-150 mL boluses to raise Na⁺ 4-6 mEq/L, then slow correction ≤8 mEq/L/24h.
— The Principle of Fluid & Electrolyte Medicine
Key References
Seifter JL. Integration of acid-base and electrolyte disorders. NEJM 2014 • Berend K, et al. Physiological approach to assessment of acid-base disturbances. NEJM 2014 • Sterns RH. Disorders of Plasma Sodium. NEJM 2015 • Palmer BF. Regulation of Potassium Homeostasis. Clin J Am Soc Nephrol 2015