SIADH (Syndrome of Inappropriate Antidiuretic Hormone Secretion)

Definition

Pathophysiology

• ADH acts on V2 receptors in the renal collecting duct, increasing aquaporin-2 channels and causing excess water reabsorption
• Plasma becomes hypo-osmolar; a subclinical increase in extracellular volume suppresses proximal tubular Na+ reabsorption
• Result: low serum Na+, low plasma osmolality, high urine osmolality, high urine Na+, low serum uric acid
• The normal negative feedback (low plasma osmolality suppressing ADH) is absent because ADH is secreted autonomously - Costanzo Physiology, p. 311

Causes (Mnemonic: PULMONARY CNS DRUG TUMOR)

• Bronchogenic carcinoma (most common) - especially SCLC
• Carcinoma of pancreas, duodenum, ureter
• Non-Hodgkin lymphoma, Hodgkin disease, thymoma

• Tuberculosis, pneumonia, lung abscess, aspergillosis
• Positive pressure mechanical ventilation

• Meningitis, encephalitis, brain abscess, brain tumour
• Head injury, subarachnoid haemorrhage, Guillain-Barre syndrome
• Acute intermittent porphyria

• AVP analogues: desmopressin, oxytocin
• Carbamazepine, valproate (anticonvulsants)
• Antipsychotics, antidepressants (SSRIs, TCAs)
• Nicotine, opiates, MDMA (Ecstasy)
• Chlorpropamide, cyclophosphamide, vincristine

Diagnostic Criteria (Goldman-Cecil / Bartter-Schwartz Criteria)

Clinical Features

• Mild (Na+ 125-135): Nausea, malaise, headache, lethargy
• Moderate: Confusion, muscle cramps, weakness
• Severe/Acute (Na+ < 120 or rapid drop): Seizures, coma, cerebral oedema - can be fatal, especially in women of reproductive age
• Gradual onset allows osmotic adaptation; patients may be surprisingly asymptomatic even with Na+ < 120

Investigations

• Serum Na+ < 136 mmol/L
• Serum osmolality < 275 mOsm/kg
• Urine osmolality > 100 mOsm/kg (inappropriately concentrated)
• Urine Na+ > 20-30 mmol/L
• Serum uric acid - LOW (characteristic and differentiates from other causes of hyponatraemia like CCF, cirrhosis where uric acid is elevated)
• BUN/creatinine - normal
• TFT, cortisol - normal (to exclude hypothyroidism and Addison's)

Treatment

1. Treat the underlying cause

2. Fluid restriction (first-line for mild-moderate)

• Restrict fluid intake to less than urine output + insensible losses (~800-1000 mL/day)
• Gradual correction is essential to avoid osmotic demyelination syndrome (ODS) / Central Pontine Myelinolysis (CPM)

3. Rate of correction

• Target: 0.5-1 mmol/L per hour, maximum 8-10 mmol/L in 24 hours
• Do NOT exceed 12 mmol/L/day to prevent CPM

4. Specific treatments

5. Demeclocycline (150-300 mg 3-4 times daily)

• Inhibits ADH action on renal principal cells
• Used in chronic SIADH; onset of action slow (1-2 weeks)
• Largely replaced by vaptans now

6. Vaptans (V2 receptor antagonists)

• Tolvaptan 15 mg PO daily - selective V2 antagonist
• Conivaptan 20-120 mg PO or 10-40 mg IV - blocks V1A and V2
• Cause aquaresis (free water excretion without Na+ loss)
• Effective in euvolemic and hypervolemic hyponatraemia

Key Differentials

Important Points for Exam

• Most common cause of euvolemic hyponatraemia
• SCLC is the most common malignancy causing SIADH
• Low serum uric acid is the key distinguishing lab finding vs. other causes of hyponatraemia
• Rapid correction of hyponatraemia causes Central Pontine Myelinolysis (osmotic demyelination) - characterised by paraparesis, dysarthria, dysphagia, locked-in state
• 3% NaCl is reserved for severe symptomatic hyponatraemia (seizures/coma only)
• Tolvaptan is FDA-approved for SIADH and hypervolemic hyponatraemia

Hyperkalemia

Definition

• Mild: 5.5-6.0 mEq/L
• Moderate: 6.0-7.0 mEq/L
• Severe: > 7.0 mEq/L (medical emergency)

Causes

1. Pseudohyperkalemia (Factitious - Rule out first!)

• Fist clenching during venipuncture
• Haemolysis of sample (most common)
• Thrombocytosis, leukocytosis, erythrocytosis (in vitro K+ release)
• Cooling of blood sample after venipuncture

2. Transcellular Shift (K+ moves from ICF → ECF)

• Acidosis (non-anion gap metabolic / respiratory) - H+/K+ exchange
  • Note: NOT in lactic acidosis or ketoacidosis
• Insulin deficiency / resistance (diabetes)
• β-blockers (non-selective) - block Na+/K+-ATPase
• Digoxin toxicity - inhibits Na+/K+-ATPase
• Succinylcholine - depolarising muscle relaxant (dangerous in burns, crush injury, denervation)
• Hyperosmolality - mannitol, hypertonic saline, hypertonic glucose (solvent drag)
• Tumour lysis syndrome, rhabdomyolysis - massive cell death
• Hyperkalemic periodic paralysis

3. Decreased Renal Excretion (Most common overall cause)

• Acute kidney injury / CKD / ESRD
• Adrenal insufficiency (Addison's disease) - low aldosterone
• Hyporeninemic hypoaldosteronism (Type 4 RTA) - diabetic nephropathy, tubulointerstitial disease
• Drugs blocking the RAAS:
  • ACE inhibitors, ARBs, direct renin inhibitors (aliskiren)
  • Spironolactone, eplerenone (mineralocorticoid receptor blockers)
  • Amiloride, triamterene (ENaC blockers)
  • NSAIDs, cyclosporine, tacrolimus
  • Heparin (suppresses aldosterone synthesis)
• Decreased distal delivery: CCF, volume depletion

4. Excessive Intake

• Rarely the sole cause unless renal excretion is also impaired
• High K+ foods: salt substitutes, dried fruits, bananas, oranges, potatoes, tomatoes, spinach, nuts

Clinical Features

Cardiac (Most serious - can cause sudden death)

• Palpitations, syncope, sudden cardiac death
• Ventricular arrhythmias, VF, asystole

Neuromuscular

• Muscle weakness, fatigue
• Ascending flaccid paralysis
• Hypoventilation (if respiratory muscles involved)
• Paraesthesias

ECG Changes (Progressive - KEY for exam)

Peaked T waves in precordial leads (especially V2-V4) are the hallmark early finding.

Management

Step 1 - Membrane Stabilisation (Immediate - prevents arrhythmia)

• Acts within minutes; lasts 30-60 min
• Does NOT lower K+ - only antagonises cardiac membrane effect
• Repeat in 5-10 min if no ECG improvement
• Use calcium chloride if central access available (3x more elemental calcium)

Step 2 - Shift K+ into cells (Temporising - within 15-60 min)

Insulin + glucose is the most reliable and rapid K+-lowering measure.

Step 3 - Remove K+ from body (Definitive)

Step 4 - Treat underlying cause + Chronic management

• Dietary K+ restriction (avoid bananas, dried fruits, salt substitutes)
• Stop offending drugs (ACE inhibitors, K+-sparing diuretics, NSAIDs)
• Correct acidosis with oral alkali (NaHCO3 tablets)
• Fludrocortisone in hypoaldosteronism
• Loop diuretics to promote kaliuresis if renal function adequate

Key Exam Points

1. Pseudohyperkalemia must always be excluded first - repeat the sample without fist clenching
2. Calcium gluconate is the first drug given - it does NOT lower K+; it only protects the heart
3. Insulin + glucose is the fastest and most effective K+-shifting agent
4. Succinylcholine is contraindicated in burns, crush injury, rhabdomyolysis, prolonged immobilisation (can raise K+ by 0.5-1 mEq/L acutely; more in susceptible patients → fatal arrhythmia)
5. Acidosis causes hyperkalemia ONLY in non-anion gap metabolic acidosis - NOT in lactic acidosis or DKA
6. Type 4 RTA (hyporeninemic hypoaldosteronism) = most common cause of hyperkalemia in diabetics with mild-moderate CKD
7. Sine wave pattern on ECG = imminent VF - dialyse urgently