Fluid and Electrolyte Disturbances¶

Chapter 56 | Harrison's 22e · Part 2 – Cardinal Manifestations & Presentation · Chapter 56

Key Clinical Points¶

Water constitutes ~50% of body weight in women and 60% in men, distributed between intracellular (ICF) and extracellular (ECF) compartments.
Vasopressin (AVP) is the primary hormone regulating water balance; its action begins at a threshold of ~285 mOsm/kg.
AVP response to osmolality is modulated by volume status: hypovolemia lowers the osmotic threshold and increases the slope, while hypervolemia has the opposite effect.
Renal water permeability is regulated via AVP binding to V2 receptors, activating Adenylate Cyclase (AC) and Protein Kinase A (PKA), leading to AQP2 translocation.
Hyponatremia diagnosis relies on volume status and urine sodium (U_{Na}) to differentiate between renal and extrarenal losses.
Hypernatremia management requires calculating free-water deficit and ensuring a correction rate of <10 mEq/L (or mM) per 24 hours.
Hypokalemia diagnosis utilizes U_K and U_{Cl} to distinguish between metabolic alkalosis, renal loss, and extrarenal loss.
Hyperkalemia management prioritizes ECG changes and uses U_{Na} and TTKG to identify underlying causes like renal failure or drug effects.
SIAD is caused by a wide range of factors including malignancies, pulmonary disorders, CNS conditions, and various drugs (e.g., SSRIs, Tricyclics).
Principal cells (PC) manage Na+ reabsorption and K+ secretion; β-intercalated cells (B-IC) are involved in Cl- transport via pendrin.

DEFINITION & CLASSIFICATION¶

• Body Fluid Composition: Water is the most abundant constituent in the body. ◦ Women: ~50% of body weight. ◦ Men: ~60% of body weight. ◦ Distribution: - Intracellular fluid (ICF): 55–75% - Extracellular fluid (ECF): 25–45% - Intravascular (plasma water): 1 part - Extravascular (interstitial): 3 parts • Osmolality: Defined as the solute or particle concentration of a fluid. ◦ Units: milliosmoles per kilogram of water (mOsm/kg). ◦ Water Movement: Diffuses across most membranes to achieve equilibrium (ECF osmolality = ICF osmolality). • Solute Distribution: ◦ ECF: Primarily Na+ and accompanying anions Cl– and HCO–. ◦ ICF: Predominantly K+ and organic phosphate esters (ATP, creatine phosphate, phospholipids). • Tonicity: Determined by solutes restricted to a specific compartment. ◦ Note: Certain solutes (e.g., urea) are "ineffective osmoles" as they do not contribute to water shifts across most membranes.

ETIOLOGY & PATHOPHYSIOLOGY¶

• Water Balance Regulation: Maintained by vasopressin (AVP) secretion, water ingestion, and renal water transport. ◦ Target Range: 280 to 295 mOsm/kg. • Vasopressin (AVP) Dynamics: ◦ Synthesis: Magnocellular neurons in the hypothalamus; released from the posterior pituitary. ◦ Sensing: Osmoreceptor neurons sense osmolality via nonselective, stretch-activated cation channels. ◦ Threshold: Activation occurs at ~285 mOsm/kg. - Above 285 mOsm/kg → Linear relationship between osmolality and AVP. - Above 285 mOsm/kg → Linear increase in perceived intensity of thirst. • Volume Modulation of AVP: ECF volume modifies the relationship between osmolality and AVP release. ◦ Hypovolemia: Reduces osmotic threshold and increases the slope of the response curve. ◦ Hypervolemia: Increases osmotic threshold and reduces the slope of the response curve. • Renal Mechanism (Figure 2 & Figure 3): AVP regulates water permeability in the collecting duct (CD). ◦ Action: AVP binds to V2 receptors → activates Adenylate Cyclase (AC) → increases cAMP → stimulates Protein Kinase A (PKA). ◦ Effect: PKA-dependent phosphorylation of AQP2 → translocation of AQP2 to the apical membrane. ◦ Basolateral Side: AQP3 and AQP4 are expressed on the basolateral membrane to complete transcellular water movement. ◦ Cellular Transport (Figure 3): - Principal Cells (PC): Na+ entry via ENaC; K+ exit via ROMK and BK channels. - β-intercalated cells (B-IC): Cl– transport via SLC26A4 (pendrin) and CLC-Kb.

DIAGNOSTIC APPROACH¶

Hyponatremia (Flowchart 1)¶

Assess Volume Status → Hypovolemic, Euvolemic, or Hypervolemic.
If Hypovolemic:
U_{Na} > 20 → Renal losses (Diuretic excess, Mineralocorticoid deficiency, Salt-losing nephropathy, Bicarbonaturia, Osmotic diuresis, Cerebral salt wasting).
U_{Na} le 20 → Extrarenal losses (Vomiting, Diarrhea, Third spacing, Burns, Pancreatitis, Trauma).
If Euvolemic:
U_{Na} > 20 → Glucocorticoid deficiency, Hyperthyroidism, Stress, Drugs, or SIADH.
If Hypervolemic:
U_{Na} > 20 → Acute or chronic renal failure.
U_{Na} le 20 → Nephrotic syndrome, Cirrhosis, or Cardiac failure.

Hypernatremia (Flowchart 2)¶

Assess ECF Volume.
If ECF Volume is Increased → Administer hypertonic NaCl or ext{NaHCO}_3.
If ECF Volume is Not Increased → Determine if max concentration of urine ge 100 mOsm/kg?
No → Is urine osmole excretion >750 mOsm/kg?
No → Diuretic / Osmotic diureses.
Yes → Nephrogenic diabetes insipidus.
Yes → Is urine osmole excretion >750 mOsm/kg?
No → Diuretic / Osmotic diureses.
Yes → Central diabetes insipidus.

Hypokalemia (Flowchart 3)¶

Check for Emergency: K^+ < 3.0 mmol/L → Yes → Move to therapy.
Assess Acid-Base Status:
Low ext{HCO}_3^- → Metabolic acidosis (Proximal RTA, Distal RTA, Amphotericin B, Acetazolamide).
High ext{HCO}_3^- and high ext{Cl}^- → Metabolic alkalosis.
Assess Renal Loss (U_K > 15 mmol/day):
If U_K < 15 mmol/day (or < 15 mmol/g) → Extrarenal loss (e.g., sweating, diarrhea).
If U_K > 15 mmol/day → Renal loss.
Evaluate Metabolic Alkalosis (U_{Cl} check):
U_{Cl} < 10 mOsm/L → Vomiting, etc.
U_{Cl} ge 10 mOsm/L → Assess Renin and Cortisol:
High Renin / High Cortisol → Conn's syndrome.
Low Renin / High Cortisol → Cushing's syndrome.
High Renin / Low Cortisol → Lipps-Leigh or SAME.
Low Renin / Low Cortisol → Other mineralocorticoid issues.

Hyperkalemia (Flowchart 4)¶

Initial Assessment:
K^+ ge 5.5 mmol/L with ECG changes → Emergency therapy.
K^+ ge 5.5 mmol/L without ECG changes → Assess for increased K loss or transient hyperkalemia → Treat and re-evaluate.
Determine Etiology via Urine Electrolytes:
U_{Na} < 20 mOsm/L → Decreased distal Na^+ excretion (<40 mEq/L) → Advanced kidney failure (GFR le 90 ml/min) or Drugs (Amiloride, Spironolactone, Triamterine, Trimetazidine, Cyclosporine).
U_{Na} ge 20 mOsm/L → Decreased distal K^+ secretion (No Furosemide) → TTKG assessment:
TTKG < 0 → Low.
TTKG ge 1 → High.

MANAGEMENT & TREATMENT¶

Hypernatremia Management (Table 3):
Step 1: Estimate Total Body Water (TBW) [Women: 50% BW; Men: 60% BW].
Step 2: Calculate free-water deficit → $[(Na^+ - 140)/140] imes TBW$.
Step 3: Administer deficit over 48–72 h, ensuring plasma Na^+ does not decrease by >10 mEq/L (or mM) per 24 h.
Step 4: Calculate free-water clearance (C_{HO}) → $C_{HO} = V imes [(U_{Na} + U_K) / (P_{Na} + P_K)]$.
Step 5: Account for insensible losses (approx 10 mL/kg per day; adjust if ventilated or febrile).
Step 6: Combine deficit and ongoing loss to determine total replacement, avoiding correction of plasma [Na^+] by >10 mEq/L per day.
SIAD Management (Table 1):
Identify underlying cause: Malignant (Lung, GI), Pulmonary (Pneumonia, Asthma), CNS (Encephalitis, Trauma), or Drugs (SSRIs, Tricyclics).
Hypokalemia Treatment:
Emergency cases (K^+ < 3.0 mmol/L) → Move to therapy.
Non-emergency → Treat accordingly and re-evaluate.

COMPLICATIONS & PROGNOSIS¶

• Hyperkalemia Risks: High potassium levels can lead to cardiac complications. ◦ ECG changes are a primary indicator for emergency therapy. ◦ Advanced kidney failure (GFR le 90 ml/min) and drug-induced issues (Amiloride, Spironolactone, Triamterine, Cyclosporine) are key drivers of hyperkalemia.

KEY PEARLS & HIGH-YIELD POINTS¶

• AVP Threshold: approx 285 mOsm/kg is the critical point for AVP and thirst activation. • Hyponatremia Rule of Thumb: U_{Na} > 20 suggests renal loss; U_{Na} le 20 suggests extrarenal loss or failure to excrete sodium. • Hypernatremia Safety: Never correct plasma [Na^+] by >10 mEq/L per day to avoid rapid shifts. • Hypokalemia Differentiation: Use U_{Cl} and Renin/Cortisol levels to distinguish between primary aldosteronism (Conn's) and Cushing's syndrome. • SIAD Causes: Includes a wide range of drugs (SSRIs, Tricyclics) and malignancies (Lung, GI). • Hyperkalemia Drugs: Be alert for Amiloride, Spironolactone, Triamterine, and Cyclosporine as causes of hyperkalemia.

Reference Tables¶

TABLE 56-1 Causes of the Syndrome of Inappropriate Antidiuresis¶

Harrison's 22e, p.349

MALIGNANT DISEASES	PULMONARY DISORDERS	DISORDERS OF THE CENTRAL NERVOUS SYSTEM	DRUGS	OTHER CAUSES
Carcinoma Lung Small cell Mesothelioma Oropharynx Gastrointestinal tract Stomach Duodenum Pancreas Genitourinary tract Ureter Bladder Prostate Endometrium Endocrine thymoma Lymphomas Sarcomas Ewing’s sarcoma	Infections Bacterial pneumonia Viral pneumonia Pulmonary abscess Tuberculosis Aspergillosis Asthma Cystic fibrosis Respiratory failure associated with positive-pressure breathing	Infection Encephalitis Meningitis Brain abscess Rocky Mountain spotted fever AIDS Bleeding and masses Subdural hematoma Subarachnoid hemorrhage Cerebrovascular accident Brain tumors Head trauma Hydrocephalus Cavernous sinus thrombosis Other Multiple sclerosis Guillain-Barré syndrome Shy-Drager syndrome Delirium tremens Acute intermittent porphyria	Drugs that stimulate release of AVP or enhance its action Chlorpropamide SSRIs Tricyclic antidepressants Clofibrate Carbamazepine Vincristine Nicotine Narcotics Antipsychotic drugs Ifosfamide Cyclophosphamide Nonsteroidal anti-inflammatory drugs MDMA (“Ecstasy”, “Molly”) AVP analogues Desmopressin Oxytocin Vasopressin	Hereditary (gain-of-function mutations in the vasopressin V 2 receptor) Idiopathic Transient Endurance exercise General anesthesia Nausea Pain Stress

TABLE 56-2 Causes of Acute Hyponatremia Iatrogenic¶

Harrison's 22e, p.349

Iatrogenic
Postoperative: premenopausal women
Hypotonic fluids with cause of ↑ vasopressin
Glycine irrigation: TURP, uterine surgery
Colonoscopy preparation
Recent institution of thiazides
Polydipsia
MDMA (“Ecstasy,” “Molly”) ingestion
Exercise induced
Multifactorial, e.g., thiazide and polydipsia

TABLE 56-3 Management of Hypernatremia Water Deficit 1. Estimate total-body water (TBW): 50% of body weight in women…¶

Harrison's 22e, p.351

Water Deficit
1. Estimate total-body water (TBW): 50% of body weight in women and 60% in men
  2. Calculate free-water deficit: [(Na+ – 140)/140] × TBW
  3. Administer deficit over 48–72 h, without decrease in plasma Na+
  concentration by >10 mM/24 h
Ongoing Water Losses
1. Calculate free-water clearance, CHO:
  e 2
   U +U 
  CHO=V×1− Na k
  e 2  P Na 
  where V is urinary volume, U is urinary [Na+], U is urinary [K+], and P is
  Na K Na
  plasma [Na+]
Insensible Losses
1. ~10 mL/kg per day: less if ventilated, more if febrile
Total
1. Add components to determine water deficit and ongoing water loss; correct
  the water deficit over 48–72 h and replace daily water loss. Avoid correction
  of plasma [Na+] by >10 mM/d.

TABLE 56-4 Causes of Hypokalemia I. Decreased intake¶

Harrison's 22e, p.354

I. Decreased intake
A. Starvation
B. Clay ingestion
II. Redistribution into cells
A. Acid-base
1. Metabolic alkalosis
B. Hormonal
1. Insulin
2. Increased β-adrenergic sympathetic activity: post–myocardial
2
infarction, head injury
3. β-Adrenergic agonists—bronchodilators, tocolytics
2
4. α-Adrenergic antagonists
5. Thyrotoxic periodic paralysis
6. Downstream stimulation of Na+/K+-ATPase: theophylline, caffeine
C. Anabolic state
1. Vitamin B or folic acid administration (red blood cell production)
12
2. Granulocyte-macrophage colony-stimulating factor (white blood cell
production)
3. Total parenteral nutrition
D. Other
1. Pseudohypokalemia
2. Hypothermia
3. Familial hypokalemic periodic paralysis
4. Barium toxicity: systemic inhibition of “leak” K+ channels
III. Increased loss
A. Nonrenal
1. Gastrointestinal loss (diarrhea)
2. Integumentary loss (sweat)
B. Renal
1. Increased distal flow and distal Na+ delivery: diuretics, osmotic
diuresis, salt-wasting nephropathies
2. Increased secretion of potassium
a. Mineralocorticoid excess: primary hyperaldosteronism (aldosterone-
producing adenomas, primary or unilateral adrenal hyperplasia,
idiopathic hyperaldosteronism due to bilateral adrenal hyperplasia,
and adrenal carcinoma), genetic hyperaldosteronism (familial
hyperaldosteronism types I/II/III, congenital adrenal hyperplasias),
secondary hyperaldosteronism (malignant hypertension, renin-
secreting tumors, renal artery stenosis, hypovolemia), Cushing’s
syndrome, Bartter’s syndrome, Gitelman’s syndrome
b. Apparent mineralocorticoid excess: genetic deficiency of
11β-dehydrogenase-2 (syndrome of apparent mineralocorticoid
excess), inhibition of 11β-dehydrogenase-2 (glycyrrhetinic/
glycyrrhizinic acid and/or carbenoxolone; itraconazole and
posaconazole; licorice, food products, drugs), Liddle’s syndrome
(genetic activation of epithelial Na+ channels)
c. Distal delivery of nonreabsorbed anions: vomiting, nasogastric
suction, proximal renal tubular acidosis, diabetic ketoacidosis, glue-
sniffing (toluene abuse), penicillin derivatives (penicillin, nafcillin,
dicloxacillin, ticarcillin, oxacillin, and carbenicillin)
3. Magnesium deficiency

TABLE 56-5 Causes of Hyperkalemia I. Pseudohyperkalemia¶

Harrison's 22e, p.358

I. Pseudohyperkalemia
A. Cellular efflux; thrombocytosis, erythrocytosis, leukocytosis, in vitro
hemolysis
B. Hereditary defects in red cell membrane transport
II. Intra- to extracellular shift
A. Acidosis
B. Hyperosmolality; radiocontrast, hypertonic dextrose, mannitol
C. β-Adrenergic antagonists (noncardioselective agents)
2
D. Digoxin and related glycosides (yellow oleander, foxglove, bufadienolide)
E. Hyperkalemic periodic paralysis
F. Lysine, arginine, and ε-aminocaproic acid (structurally similar, positively
charged)
G. Succinylcholine; thermal trauma, neuromuscular injury, disuse atrophy,
mucositis, or prolonged immobilization
H. Rapid tumor lysis
III. Inadequate excretion
A. Inhibition of the renin-angiotensin-aldosterone axis; ↑ risk of
hyperkalemia when used in combination
1. Angiotensin-converting enzyme (ACE) inhibitors
2. Renin inhibitors; aliskiren (in combination with ACE inhibitors or
angiotensin receptor blockers [ARBs])
3. ARBs
4. Blockade of the mineralocorticoid receptor: spironolactone,
eplerenone, drospirenone
5. Blockade of the epithelial sodium channel (ENaC): amiloride,
triamterene, trimethoprim, pentamidine, nafamostat
B. Decreased distal delivery
1. Congestive heart failure
2. Volume depletion
C. Hyporeninemic hypoaldosteronism
1. Tubulointerstitial diseases: systemic lupus erythematosus (SLE), sickle
cell anemia, obstructive uropathy
2. Diabetes, diabetic nephropathy
3. Drugs: nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase
2 (COX2) inhibitors, β blockers, cyclosporine, tacrolimus
4. Chronic kidney disease, advanced age
5. Pseudohypoaldosteronism type II: defects in WNK1 or WNK4 kinases,
Kelch-like 3 (KLHL3), or Cullin 3 (CUL3)
D. Renal resistance to mineralocorticoid
1. Tubulointerstitial diseases: SLE, amyloidosis, sickle cell anemia,
obstructive uropathy, post–acute tubular necrosis
2. Hereditary: pseudohypoaldosteronism type I; defects in the
mineralocorticoid receptor or the epithelial sodium channel (ENaC)
E. Advanced renal insufficiency
1. Chronic kidney disease
2. End-stage renal disease
3. Acute oliguric kidney injury
F. Primary adrenal insufficiency
1. Autoimmune: Addison’s disease, polyglandular endocrinopathy
2. Infectious: HIV, cytomegalovirus, tuberculosis, disseminated fungal
infection
3. Infiltrative: amyloidosis, malignancy, metastatic cancer
4. Drug-associated: heparin, low-molecular-weight heparin
5. Hereditary: adrenal hypoplasia congenita, congenital lipoid adrenal
hyperplasia, aldosterone synthase deficiency
6. Adrenal hemorrhage or infarction, including in antiphospholipid
syndrome