Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)

• Serum sodium <135 mmol/L and serum osmolality <280 mOsm/kg.
• Urine osmolality >100 mOsm/kg, indicating inappropriate water retention.
• Urinary sodium excretion >30–40 mmol/L, despite normal sodium intake.
• Absence of clinical evidence of hypovolemia or edema.
• Correction of hyponatremia with fluid restriction, supporting the inappropriate nature of AVP secretion.
  
  

Central Nervous System (CNS) Disorders

• Vascular events: Stroke, subarachnoid hemorrhage, cavernous sinus thrombosis.
• Infections: Viral, bacterial, tuberculous, or fungal meningitis; encephalitis.
• Neurodegenerative & inflammatory diseases: Multiple sclerosis, CNS lupus, Guillain-Barré syndrome.
• Trauma & structural abnormalities: Head trauma, hydrocephalus, perinatal hypoxia, cerebral atrophy.
• Neuropsychiatric conditions: Acute psychosis, schizophrenia, delirium tremens.
• Tumors & compressive syndromes: Brain tumors, ventriculoatrial shunt obstruction.
• Other conditions: Acute intermittent porphyria, Wernicke encephalopathy, hypoxic-ischemic encephalopathy.
  
  

Neoplastic Disorders

• Pulmonary: Small cell lung carcinoma, mesothelioma.
• Gastrointestinal: Carcinomas of the pancreas, duodenum, and colon.
• Genitourinary: Adrenocortical carcinoma, prostate cancer, ovarian tumors.
• Other malignancies: Brain tumors, nasopharyngeal carcinoma, lymphoma, leukemia, thymoma, Ewing sarcoma.

Pulmonary Disorders

• Infections: Bacterial (e.g., pneumonia, tuberculosis), viral (including COVID-19), fungal (aspergillosis).
• Chronic lung diseases: Chronic obstructive pulmonary disease (COPD), cystic fibrosis, pulmonary fibrosis, emphysema.
• Acute respiratory conditions: Pneumothorax, atelectasis, acute respiratory failure.
• Mechanical ventilation: Positive pressure ventilation may alter intrathoracic pressure, leading to inappropriate ADH release.
  
  

Drug-Induced SIADH

• Antidepressants: Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, paroxetine), tricyclic antidepressants (e.g., amitriptyline).
• Anticonvulsants: Carbamazepine, oxcarbazepine, valproate, phenytoin.
• Antipsychotics: Haloperidol, risperidone, quetiapine.
• Cytotoxic agents: Vincristine, cyclophosphamide, cisplatin.
• Opioids: Morphine, tramadol.
• Other medications: Barbiturates, bromocriptine, nicotine, thiopental, histamine.
  
  

• Nonsteroidal anti-inflammatory drugs (NSAIDs): Indomethacin, aspirin.
• Hypoglycemic agents: Metformin, tolbutamide.
• Oxytocin (large doses): Stimulates renal water reabsorption.
• Vasopressin analogs: Desmopressin (DDAVP), exogenous AVP.
  
  

• Antineoplastics: Melphalan, methotrexate, imatinib.
• Amiodarone: Alters AVP metabolism.
• Ciprofloxacin: May interact with AVP receptors.
• MDMA (Ecstasy): Increases thirst and AVP secretion, exacerbating hyponatremia.
  
  

Postoperative and Hormonal Causes

• Postoperative SIADH: Common after cardiac, neurosurgical, and gastrointestinal surgeries, likely due to stress-related AVP release.
• Pituitary Surgery: Transsphenoidal surgery can cause a delayed form of SIADH peaking at 6–7 days postoperatively.
• Hormone Deficiencies:
  • Hypothyroidism: Impairs renal free water clearance, mimicking SIADH.
  • Hypopituitarism: Indirectly enhances AVP release.
  • Adrenal Insufficiency: Loss of cortisol-mediated AVP suppression.
    
    

Hereditary and Genetic Factors

• Nephrogenic Syndrome of Inappropriate Antidiuresis (NSIAD):
  • X-linked gain-of-function mutation in the vasopressin-2 (V2) receptor leads to unregulated water retention, mimicking SIADH but with low AVP levels.
• Polymorphisms in TRPV4 (hypothalamic osmoreceptor gene):
  • Certain mutations may reset the osmostat, predisposing individuals to chronic mild hyponatremia.
    
    

Other Causes

• Giant Cell Arteritis (Temporal Arteritis): An uncommon but documented inflammatory cause of SIADH.
• HIV/AIDS:
  • Up to 40% of HIV patients develop hyponatremia.
  • SIADH occurs due to opportunistic CNS and pulmonary infections, as well as adrenal insufficiency.

Regulation of AVP Secretion

• AVP is synthesised in the hypothalamus and stored in the posterior pituitary, where it is released in response to plasma osmolality changes.
• Osmoreceptors in the hypothalamus detect minor changes in plasma sodium concentration:
  • A rise in osmolality (>280 mOsm/kg) triggers AVP release to increase water reabsorption.
  • A decrease in osmolality (<280 mOsm/kg) inhibits AVP, allowing free water excretion.
• In SIADH, AVP secretion occurs independently of osmolality, leading to persistent water retention and hyponatremia.
  
  

• Hypovolemia: Arterial baroreceptors in the left atrium and aorta detect a drop in blood pressure (≥10-20%), triggering AVP secretion.
• Nausea and stress: These are potent AVP stimulants, even in normovolemic individuals.
• Pain and hypoxia: Both activate central AVP secretion, commonly observed in conditions like stroke, trauma, or lung diseases.
• Ectopic AVP production: Some tumors, such as small cell lung cancer, directly secrete AVP regardless of osmotic cues.
  
  

AVP Action and Water Retention

1. Activation of adenylate cyclase, increasing intracellular cAMP.
2. Insertion of aquaporin-2 channels into the apical membrane.
3. Enhanced water reabsorption into the bloodstream, producing highly concentrated urine.
4. Expansion of total body water (TBW), diluting serum sodium and causing hyponatremia.
   
   

Consequences of Water Retention

• Increased total body water (TBW) expands extracellular fluid volume but does not cause overt oedema.
• Increased urine sodium excretion (natriuresis):
  • Volume expansion stimulates natriuretic peptides and suppresses renin-aldosterone activity.
  • This leads to increased sodium excretion, maintaining a euvolemic state.
• Development of hyponatremia:
  • The excess water retention lowers plasma sodium concentration.
  • Persistent urinary sodium loss further exacerbates hypo-osmolality.
    
    

Variants of SIADH and AVP Secretion Patterns

• Excessively high AVP levels, unresponsive to changes in plasma osmolality.
• Urine osmolality remains constantly high.
• Commonly associated with ectopic AVP secretion (e.g., small cell lung cancer).
  
  

• AVP secretion occurs at a lower-than-normal plasma osmolality.
• AVP levels increase linearly as plasma sodium rises.
• Often seen in reset osmostat syndrome, where AVP secretion is regulated at an abnormally low set-point.
  
  

• AVP levels remain within normal physiological range but fail to be suppressed by low plasma osmolality.
• This pattern is seen in some cases of chronic SIADH.
  
  

• Mutation in the vasopressin V2 receptor (gain-of-function) leads to constitutive activation.
• Low or undetectable AVP levels, but persistent antidiuresis.
  
  

• AVP levels increase inappropriately in response to minor decreases in blood pressure.
• Can be seen in patients with neurological conditions affecting baroreceptor function.
  
  

Role of Thirst Mechanisms

• Inappropriate thirst perception in SIADH can lead to excessive water intake, worsening hyponatremia.
• This dysregulation compounds AVP-mediated water retention, contributing to persistent hypo-osmolality.
  
  

Neurological Complications

• Rapid development of hyponatremia (<48 hours) can lead to brain swelling due to water shifting into cells.
• If brain volume increases >5-10%, it may cause:
  • Severe cerebral oedema.
  • Brainstem herniation (potentially fatal).
    
    

• In chronic hyponatremia, brain cells adapt by extruding osmolytes (e.g., glutamate, taurine, myoinositol).
• This adaptation reduces brain swelling and prevents neurological deterioration.
• However, rapid correction of hyponatremia can lead to osmotic demyelination syndrome (ODS).
  
  

• ODS occurs when sodium is corrected too quickly (>0.5 mEq/L/h), leading to:
  • Brain shrinkage due to rapid osmotic water loss.
  • Irreversible demyelination of the pons and other central nervous system structures.
• Risk factors for ODS:
  • Hypokalemia, malnutrition, chronic alcoholism, and liver disease.
  • Severe hyponatremia (<120 mmol/L) with rapid correction.
    
    

Determinants of Urine Output in SIADH

• Urine output depends on solute intake (sodium, potassium, urea).
• Low dietary solute intake (e.g., low-protein diet) worsens SIADH by reducing osmotic diuresis.
  
  

• Some SIADH patients exhibit "partial escape" from AVP-induced water retention:
  • Initially, AVP leads to water retention and hyponatremia.
  • Later, aquaporin-2 expression is downregulated, allowing some degree of free water excretion.
• This escape mechanism limits the severity of hyponatremia in chronic SIADH.
  
  

Prevalence and Incidence

• Hyponatremia (serum Na+ <135 mmol/L) is the most common electrolyte disorder in clinical practice.
• Occurs in 15-28% of hospitalized patients, while clinically significant hyponatremia (serum Na+ <130 mmol/L) occurs in 1-4% of cases.
• The prevalence of community-acquired hyponatremia is approximately 8%, increasing with age (reaching ~12% in individuals ≥75 years).
  
  

Hospitalised Patients

• Hospital-acquired hyponatremia is common and may be aggravated by hospitalisation-related factors, including:
  • Administration of hypotonic IV fluids.
  • Surgical stress and pain.
  • Postoperative SIADH due to anesthetics, narcotics, or mechanical ventilation.
• SIADH accounts for ~30% of hospital-acquired hyponatremia cases.
• In a study of older hospitalized patients, ~25% met the diagnostic criteria for SIADH.
  
  

SIADH in Specific Conditions

• Cancer Patients: SIADH is the most common cause of hyponatremia in malignancies, accounting for ~30% of cases.
• Neurosurgical Patients: In one study, SIADH accounted for 62% of hyponatremia cases following neurosurgery.
• Respiratory and CNS Infections:
  • The leading cause of SIADH in hospitalized patients, accounting for 59% of cases.
  • Malignancies (29%) and CNS disorders (10%) are other significant contributors.
    
    

Age and Sex Distribution

• Increasing age (>30 years) is a risk factor for hyponatremia.
• Older adults and children have a higher incidence of SIADH, particularly when hospitalized for pneumonia or meningitis.
• Women are more susceptible to:
  • Drug-induced hyponatremia (e.g., SSRIs, chemotherapy).
  • Exercise-induced hyponatremia (e.g., marathon runners).
• Men appear more likely to develop mild to moderate hyponatremia but not severe hyponatremia.
• Low body weight is an additional risk factor for SIADH.
  
  

Symptoms Based on the Onset and Severity of Hyponatremia

• Acute hyponatremia (rapid onset, <48 hours): More likely to present with neurological symptoms due to brain oedema.
  • Early symptoms: Anorexia, nausea, malaise (often at serum Na+ <125 mEq/L).
  • Severe cases: Headache, confusion, irritability, drowsiness, muscle cramps.
  • Critical symptoms: Seizures, coma, respiratory failure due to increased intracranial pressure.
• Chronic hyponatremia (developing over days to weeks): Symptoms may be subtle or absent due to cerebral adaptation.
  • Cognitive slowing, ataxia, increased fall risk, impaired concentration, decreased reaction times.
  • May be incidentally detected on routine blood tests.
    
    

Key Historical Factors to Identify the Cause of SIADH

• History of CNS disease: Head trauma, brain tumors, stroke, subarachnoid hemorrhage, encephalitis, meningitis, multiple sclerosis.
• Chronic pain syndromes: Conditions requiring opioids or antidepressants.
• Respiratory conditions: Chronic cough, dyspnea, pneumonia, tuberculosis, lung malignancies (e.g., small cell lung cancer).
• Cancer history: Particularly lung, gastrointestinal, genitourinary, and hematologic malignancies.
  
  

• Recent medication use:
  • Drugs known to induce SIADH: SSRIs, tricyclic antidepressants, carbamazepine, valproate, chlorpromazine, opioids, NSAIDs, chemotherapy agents (e.g., cyclophosphamide, vincristine).
  • Recent IV fluid administration: Hypotonic fluids, dextrose solutions, post-surgical IV therapy.
• Substance use:
  • Recreational drugs: Ecstasy (MDMA), heroin (stimulate AVP release and induce water intoxication).
  • Nicotine and alcohol use: May contribute to SIADH or other electrolyte disturbances.
    
    

• Inappropriate thirst or excessive fluid intake:
  • Psychogenic polydipsia (seen in psychiatric conditions).
  • Compulsive water drinking (habitual or due to altered thirst regulation in SIADH).
• Fluid intake in athletes:
  • Endurance athletes (e.g., marathon runners, triathletes) often develop exercise-associated hyponatremia due to excessive water intake and increased AVP secretion.
    
    

Chronicity and Risk Factors for SIADH

• Chronic hyponatremia (>48 hours) vs. acute onset:
  • Determining whether hyponatremia is longstanding can guide management strategies (chronic cases require slower correction to prevent osmotic demyelination syndrome).
• Postoperative history:
  • Surgeries, particularly neurosurgery, abdominal, or thoracic surgery, can trigger postoperative SIADH due to stress-induced AVP secretion.
• Risk factors:
  • Age >50 years: Higher prevalence of SIADH, especially in hospitalized older adults.
  • Nursing home residence: ~18% of elderly residents have hyponatremia, often exacerbated by low-solute diets or diuretic use.
  • History of malignancy or chemotherapy: Common in lung cancer, haematologic cancers.
    
    

Distinguishing SIADH from Other Causes of Hyponatremia

• Hypovolemia-related hyponatremia (e.g., dehydration, blood loss, renal salt wasting):
  • History of vomiting, diarrhea, diuretic use, excessive sweating.
• Hypervolemia-related hyponatremia (e.g., CHF, cirrhosis, nephrotic syndrome):
  • History of oedema, weight gain, orthopnea, liver or kidney disease.
• Adrenal or thyroid disorders:
  • History of fatigue, weight loss, hypotension (suggesting adrenal insufficiency).
  • Cold intolerance, constipation, dry skin (suggesting hypothyroidism).
    
    

Volume Status Assessment

• SIADH is a euvolemic hyponatremia, meaning:
  • No signs of hypovolemia:
    • No orthostatic hypotension.
    • No dry mucous membranes.
    • No reduced skin turgor.
  • No signs of hypervolemia:
    • No oedema (peripheral or pulmonary).
    • No jugular venous distension.
    • No ascites (seen in cirrhosis).
    • No crackles or S3 gallop (suggesting congestive heart failure).
• If oedema, ascites, or pulmonary congestion is present, other causes of hyponatremia (heart failure, liver cirrhosis, nephrotic syndrome) should be considered.
  
  

Neurological Findings

• Cognitive changes:
  • Confusion, disorientation, memory impairment.
• Neuromuscular symptoms:
  • Generalized muscle weakness.
  • Mild ataxia, postural instability.
    
    

• Cerebral dysfunction:
  • Delirium, agitation, hallucinations.
  • Drowsiness, lethargy.
• Seizure-related signs:
  • Myoclonus (spontaneous muscle jerks).
  • Generalized tonic-clonic seizures.
• Brainstem and respiratory abnormalities:
  • Cheyne-Stokes respiration (periodic breathing pattern).
  • Dysarthria (difficulty articulating speech).
• Severe motor dysfunction:
  • Hyporeflexia (reduced deep tendon reflexes).
  • Asterixis (flapping tremor, seen in metabolic encephalopathy).
  • Tremors and ataxia (unsteady gait, difficulty coordinating movements).
  • Pathologic reflexes (Babinski sign, suggesting central nervous system involvement).
    
    

• Deep coma in profound hyponatremia.
• Brainstem involvement may result in apneic episodes or respiratory arrest.
  
  

Additional Systemic Examination

• Normal blood pressure (no hypotension or hypertension).
• No peripheral signs of volume overload (no dependent edema, jugular venous distension).
  
  

• Normal lung auscultation (absence of crackles or pleural effusions).
• Dyspnea or hypoxia may indicate an underlying pulmonary cause of SIADH (e.g., pneumonia, lung cancer).

• Normal abdominal exam (no ascites, no hepatomegaly).
• Nausea and vomiting may be present due to increased intracranial pressure.
  
  

Core Laboratory Investigations

• Serum Sodium (Na+):
  • SIADH presents with hyponatremia (<135 mmol/L).
  • Severe cases (<120 mmol/L) are associated with neurological symptoms.
• Serum Osmolality:
  • Low (<275 mOsm/kg H₂O) confirms hypotonic hyponatremia.
  • In SIADH, serum osmolality remains lower than urine osmolality.
• Serum Potassium and Bicarbonate:
  • Potassium is usually normal, unlike in adrenal insufficiency or diuretic-induced hyponatremia.
  • Normal bicarbonate levels help distinguish SIADH from metabolic disorders.
    
    

• Urine Osmolality:
  • >100 mOsm/kg H₂O in SIADH, indicating inappropriate AVP activity.
  • <100 mOsm/kg H₂O suggests primary polydipsia or beer potomania.
• Urine Sodium (Na+):
  • >30-40 mmol/L is consistent with SIADH in euvolemic patients.
  • <25 mmol/L suggests hypovolemic hyponatremia from extrarenal sodium losses.
    
    

• Serum Urea (<3.6 mmol/L or <10 mg/dL):
  • Low due to mild volume expansion, differentiating SIADH from hypovolemic states.
• Serum Uric Acid (<4 mg/dL):
  • Low in SIADH due to increased renal clearance.
  • Fractional Excretion of Uric Acid (FEUA) >9% supports SIADH.
    
    

Additional Investigations for Underlying Causes

• Serum Cortisol (Morning, 6-9 AM):
  • >138 nmol/L (>5 µg/dL) rules out adrenal insufficiency.
  • Adrenal insufficiency can mimic SIADH and requires exclusion.
• Serum TSH and Free T4:
  • Normal in SIADH.
  • Hypothyroidism can cause euvolemic hyponatremia and should be ruled out.
    
    

• 1-2 L of Isotonic Saline Infusion:
  • In hypovolemia, serum sodium increases.
  • In SIADH, sodium does not improve or may even decrease.
    
    

• Surrogate marker for AVP levels.
• More stable than AVP and useful in evaluating hyponatremia.

Imaging Studies

• Chest X-ray or CT Chest:
  • Small cell lung carcinoma (a common ectopic AVP-secreting tumor).
  • Chronic infections (e.g., tuberculosis, pneumonia, bronchiectasis).
    
    

• CT or MRI Brain:
  • Rule out CNS pathology (tumors, stroke, subarachnoid hemorrhage).
  • Signs of cerebral edema in severe hyponatremia.
    
    

• CT/MRI Nasal Sinuses:
  • Olfactory neuroblastoma (rare ectopic AVP-producing tumor).
• Abdominal and Pelvic CT:
  • Neuroendocrine tumors, adrenal pathology

Key Diagnostic Approach

• Step 1: Confirm Hyponatremia
  • Serum Na+ <135 mmol/L
  • Serum osmolality <275 mOsm/kg H₂O
• Step 2: Assess Urine Osmolality
  • Urine osmolality >100 mOsm/kg → Suggests SIADH or other impaired water excretion causes.
  • Urine osmolality <100 mOsm/kg → Suggests primary polydipsia or low-solute intake.
• Step 3: Determine Volume Status
  • Euvolemia → Likely SIADH.
  • Hypovolemia → Consider GI losses, renal losses, adrenal insufficiency.
  • Hypervolemia → Consider heart failure, cirrhosis, nephrotic syndrome.

Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)

• Euvolemic hyponatremia (no edema, normal BP, no dehydration).
• Laboratory findings:
  • Serum osmolality <275 mOsm/kg.
  • Urine osmolality >100 mOsm/kg (inappropriately concentrated).
  • Urine sodium >30–40 mmol/L.
• Requires exclusion of adrenal insufficiency, hypothyroidism, and diuretic use.
  
  

Pseudohyponatremia

• Occurs in severe hyperlipidemia, hyperproteinemia, or hyperglycemia.
• Often asymptomatic (lab artifact rather than true hyponatremia).
• Laboratory findings:
  • Normal plasma osmolality.
  • Corrected serum sodium (adjusted for glucose, lipids, proteins) remains normal.
    
    

Hypovolemic Hyponatremia

• History:
  • Vomiting, diarrhoea, diuretic use.
  • Signs of dehydration (dry mucosa, orthostatic hypotension, skin tenting).
• Laboratory findings:
  • Urine sodium <20 mmol/L (unless renal losses present).
  • Elevated serum urea.
  • Serum sodium improves with normal saline infusion.
    
    

Cerebral Salt-Wasting Syndrome (CSWS)

• History:
  • Recent CNS trauma, subarachnoid hemorrhage, neurosurgery.
  • Persistent dehydration despite natriuresis.
• Laboratory findings:
  • Urine sodium >120 mmol/L.
  • Fractional excretion of urea <30%.
  • Persists despite hypertonic saline administration.
    
    

Hypervolemic Hyponatremia

• Occurs in conditions causing fluid overload:
  • Congestive heart failure (CHF), cirrhosis, nephrotic syndrome.
• Signs:
  • Oedema, ascites, jugular venous distension (JVD), dyspnea, pulmonary congestion.
• Laboratory findings:
  • Urine sodium <40 mmol/L.
  • Elevated central venous pressure (CVP).
  • Evidence of volume overload on clinical exam.
    
    

Psychogenic Polydipsia

• History:
  • Psychiatric disorder (schizophrenia, bipolar disorder).
  • Compulsive water intake (>10 L/day).
• Laboratory findings:
  • Urine osmolality <100 mOsm/kg.
  • 24-hour urine osmoles >600 mOsm.
    
    

Beer Potomania / Low-Solute Intake

• History:
  • Chronic alcohol consumption (beer-heavy diet).
  • Low protein and solute intake.
• Laboratory findings:
  • Urine osmolality <100 mOsm/kg.
  • 24-hour urine osmoles <300 mOsm.
    
    

Renal Failure

• History:
  • Chronic kidney disease (CKD) or acute kidney injury (AKI).
  • Hypertension, fluid retention.
• Laboratory findings:
  • Elevated serum creatinine and blood urea nitrogen (BUN).
  • Reduced glomerular filtration rate (GFR).
    
    

Adrenal Insufficiency (Addison’s Disease)

• Signs & Symptoms:
  • Weakness, weight loss, hypotension, hyperpigmentation.
• Laboratory findings:
  • Low morning cortisol (<138 nmol/L or <5 µg/dL).
  • Hyperkalemia.
  • Sodium improves with glucocorticoid therapy.
    
    

Hypothyroidism

• Signs & Symptoms:
  • Fatigue, cold intolerance, weight gain, dry skin, myxedema.
• Laboratory findings:
  • Elevated TSH, low free T4.
  • Hyponatremia improves with thyroid hormone replacement.

Principles of Management

• Treat the underlying cause:
  • Stop causative medications (e.g., SSRIs, opioids, chemotherapy).
  • Manage infections (e.g., pneumonia, meningitis, tuberculosis).
  • Address malignancies (e.g., small cell lung carcinoma).
  • Correct endocrine disorders (e.g., hypothyroidism, adrenal insufficiency).
• Correct serum sodium safely:
  • Avoid rapid correction (>8–10 mmol/L per 24 hours) to prevent osmotic demyelination syndrome (ODS).
  • Monitor sodium closely (every 2–3 hours initially).
• Long-term management for persistent SIADH:
  • Fluid restriction.
  • Pharmacologic interventions (e.g., vaptans, urea, diuretics, demeclocycline).
    
    

Management Based on Symptom Severity

• Neurological symptoms (e.g., seizures, coma, confusion) require urgent intervention.
• Treatment:
  • IV 3% Hypertonic Saline (100 mL boluses every 10 minutes, up to 3 doses).
  • Target sodium correction: 4–6 mmol/L in the first few hours.
  • Furosemide (if volume overload is a concern).
  • Potassium replacement if hypokalemia is present.
• Avoid overly rapid correction:
  • No more than 8–10 mmol/L in 24 hours to prevent ODS.
    
    

• Increased risk of ODS, requiring slower correction.
• Treatment:
  • IV 3% Hypertonic Saline (15–30 mL/hour or small boluses).
  • Monitor sodium every 2–3 hours.
  • Furosemide may be added to increase free water excretion.
  • Stop all hypotonic fluids and address underlying cause.
    
    

• Fluid restriction (800–1000 mL/day) is first-line.
• Oral sodium supplements or urea can be considered.
• Pharmacologic therapy (if fluid restriction fails):
  • Tolvaptan (V2 receptor antagonist) for persistent SIADH.
  • Demeclocycline (off-label) or loop diuretics in resistant cases.
    
    

• Fluid restriction (≤1.5 L/day).
• High dietary solute intake (e.g., increased salt, protein).
• Monitor sodium levels regularly.
  
  

Pharmacologic Therapies

• Tolvaptan (oral) and Conivaptan (IV) block V2 receptors, inhibiting water reabsorption.
• Indications:
  • Moderate to severe SIADH unresponsive to fluid restriction.
• Limitations:
  • Risk of rapid overcorrection → requires hospitalization for initiation.
  • Hepatotoxicity: Avoid in liver disease; use ≤30 days.
  • High cost limits availability.
    
    

• Used only in symptomatic cases.
• 3% saline raises sodium safely if monitored closely.
• Risk of overcorrection → requires frequent sodium checks.
  
  

• Promotes osmotic diuresis by increasing solute load.
• Safe for chronic SIADH and widely used in Europe.
• More effective than fluid restriction alone.
• Side effects: Bitter taste; gastrointestinal discomfort.
  
  

• Reduce urine osmolality, increasing free water excretion.
• Often used with oral salt supplements.
• Risk of hypokalemia → requires potassium monitoring.
  
  

• Reduces renal response to AVP.
• Delayed onset (several days to a week).
• Nephrotoxicity and photosensitivity limit use.
  
  

Special Considerations

• Fluid restriction is avoided due to risk of cerebral vasospasm.
• 3% saline is preferred to prevent hyponatremia-induced cerebral oedema.
  
  

• Treat malignancy if possible (e.g., chemotherapy for small cell lung cancer).
• Vaptans or urea may be needed for chronic cases.
  
  

• Mild, stable hyponatremia (125–135 mmol/L) does not require correction.
• Patients regulate AVP appropriately within a lower sodium range.
  
  

Rate of Sodium Correction

• Patients at risk for ODS:
  • Serum Na+ <120 mmol/L.
  • Chronic alcohol use, malnutrition, liver disease, hypokalemia.
• Safe correction limits:
  • <8 mmol/L in 24 hours.
  • <18 mmol/L in 48 hours.
• "Rescue Strategy" for Overcorrection:
  • IV 5% Dextrose (D5W) + Desmopressin (DDAVP) to reverse excess sodium rise.

Outpatient Management of Chronic SIADH

• Long-term fluid restriction (≤1.5 L/day).
• Urea, salt tablets, or vaptans for refractory cases.
• Regular sodium monitoring (weekly to monthly).
• Avoid overly rapid sodium changes.
  
  

Hospital Discharge Considerations

• Monitor sodium closely before discharge.
• Ensure no risk of further rapid sodium changes.
• Assess need for ongoing outpatient therapy.
• Educate patients on fluid intake and medication adherence.

Resolution and Persistence of SIADH

• Transient SIADH:
  • Drug-induced cases usually resolve once the offending agent is withdrawn.
  • Infectious causes (e.g., pneumonia, meningitis) often resolve with appropriate antimicrobial treatment.
  • Surgical/postoperative SIADH is self-limiting in most cases.
• Chronic or Persistent SIADH:
  • If the underlying condition persists (e.g., malignancies, chronic lung disease, CNS disorders), SIADH may require lifelong management.
  • Fluid restriction compliance is often poor, making pharmacologic therapy necessary.
  • Tolvaptan and other vasopressin antagonists offer hope for long-term management, though safety concerns limit use beyond 30 days.
    
    

Complications of SIADH

• Occurs in acute severe hyponatremia when plasma osmolality drops too rapidly (>10 mOsm/kg/h).
• Can lead to brain herniation and death, especially if untreated.
  
  

• Occurs in conditions of water overload, particularly in endurance athletes (e.g., marathon runners).
• Mechanism involves increased pulmonary capillary permeability due to hyponatremia-induced AVP secretion.
  
  

• Most feared complication of overcorrection of hyponatremia.
• Risk factors:
  • Rapid sodium correction exceeding 8–10 mmol/L per 24 hours.
  • Severe hyponatremia (<105 mmol/L).
  • Liver disease, malnutrition, potassium depletion, burns.
• Neurological consequences:
  • Spastic quadriparesis.
  • Pseudobulbar palsy (dysarthria, dysphagia).
  • Cognitive impairment, coma.
• No effective treatment once ODS occurs → Prevention is key.
  
  

Morbidity and Mortality

• Mild hyponatremia is not benign:
  • Increased risk of falls, fractures, and cognitive impairment.
  • Elderly patients are more susceptible due to greater sensitivity to sodium changes.
  • Association with osteoporosis has been reported.
• Mortality risk:
  • Hyponatremia (Na+ <130 mmol/L) increases mortality risk 60-fold.
  • Comorbid conditions often contribute to mortality, rather than hyponatremia itself.
  • In-hospital hyponatremia onset is associated with worse prognosis.
• Severe Hyponatremia (<105 mmol/L):
  • Life-threatening complications become significantly more likely.
  • High mortality in multifactorial hyponatremia.
    
    

Prognostic Indicators

• Better prognosis:
  • Identifiable and treatable cause (e.g., drug-induced, infection).
  • Mild hyponatremia with slow onset.
  • Early and appropriate treatment.
• Worse prognosis:
  • Severe hyponatremia (<105 mmol/L).
  • Acute onset (<48 hours).
  • Neurological symptoms at presentation.
  • Overcorrection (>12 mmol/L/day) leading to ODS.
  • Hyponatremia acquired during hospitalisation.
    
    

Neurological Complications

• Occurs in acute, severe hyponatremia when plasma osmolality drops too rapidly (>10 mOsm/kg/h).
• Mechanism:
  • Hypo-osmolar plasma leads to osmotic water shift into brain cells, causing intracellular swelling.
  • Brainstem herniation may occur in severe cases.
• Symptoms:
  • Headache, confusion, agitation, seizures, respiratory distress.
  • Severe cases → coma and death.
    
    

• Occurs when sodium is corrected too rapidly (>8-10 mmol/L per 24 hours).
• Mechanism:
  • Brain cells adapt to chronic hyponatremia by losing organic osmolytes (e.g., myoinositol, taurine).
  • Overcorrection of sodium causes excessive water efflux, leading to cellular shrinkage and demyelination.
• Risk factors:
  • Chronic hyponatremia (<105 mmol/L).
  • Malnutrition, alcoholism, burns, potassium depletion.
  • Liver disease, especially cirrhosis.
  • Postoperative patients (especially premenopausal women after gynecologic surgery).
• Clinical Features:
  • Upper motor neuron dysfunction:
    • Spastic quadriparesis, hyperreflexia.
  • Pseudobulbar palsy:
    • Dysarthria, dysphagia, emotional lability.
  • Cognitive impairment:
    • Confusion, seizures, coma.
  • No effective treatment once ODS develops → Prevention is crucial.
    
    

Pulmonary Complications

• Seen in cases of water overload (e.g., endurance athletes, post-surgical patients).
• Mechanism:
  • Excessive water retention increases intravascular volume, leading to pulmonary congestion.
  • Increased capillary permeability worsens fluid accumulation in the lungs.
• Symptoms:
  • Dyspnea, hypoxia, crackles on auscultation.
  • Normal cardiac function (unlike cardiogenic pulmonary oedema).
    
    

Neuromuscular and Cognitive Impairment

• Previously considered asymptomatic, but evidence suggests:
  • Increased risk of cognitive impairment.
  • Memory problems, concentration issues.
  • Depression and mood disturbances.
    
    

• Unsteady gait, tremors, and muscle cramps are common in elderly patients.
• Hyponatremia is a major risk factor for falls and fractures.
• Association with osteoporosis due to increased bone resorption.
  
  

Mortality and Long-Term Prognosis

• Severe hyponatremia (Na+ < 130 mmol/L) increases mortality risk 60-fold.
• Highest risk in hospitalized patients with acute onset hyponatremia.
• Multifactorial hyponatremia (e.g., in critically ill patients) is associated with poor outcomes.
• Patients who develop SIADH during hospitalisation have worse survival rates than those admitted with pre-existing hyponatremia.
  
  

Prevention Strategies

• Slow correction of sodium (<8 mmol/L per 24 hours) to prevent ODS.
• Frequent monitoring of sodium levels in at-risk patients.
• Careful management of fluid therapy in postoperative and critically ill patients.
  
  

1. Adrogue HJ, Madias NE. Hyponatremia. New England Journal of Medicine. 2000;342(21):1581-1589
2. Bartter FC, Schwartz WB. The syndrome of inappropriate secretion of antidiuretic hormone. American Journal of Medicine. 1967;42(5):790-806.
3. Berl T, Quittnat-Pelletier F, Verbalis JG, et al. Oral tolvaptan is safe and effective in chronic hyponatremia. Journal of the American Society of Nephrology. 2010;21(4):705-712.Clayton JA, Le Jeune IR, Hall IP. Severe hyponatremia in medical inpatients: etiology, assessment, and outcome. QJM. 2006;99(8):505-511.
4. Corona G, Giuliani C, Parenti G, et al. Hyponatremia in cancer patients. Critical Reviews in Oncology/Hematology. 2016;105:107-123.
5. Decaux G, Musch W. Clinical laboratory evaluation of the syndrome of inappropriate secretion of antidiuretic hormone. Clinical Journal of the American Society of Nephrology. 2008;3(5):1175-1184.
6. Ellison DH, Berl T. The syndrome of inappropriate antidiuresis. New England Journal of Medicine. 2007;356(20):2064-2072.
7. Fenske W, Störk S, Blechschmidt A, et al. Copeptin in the differential diagnosis of hyponatremia. Journal of Clinical Endocrinology & Metabolism. 2009;94(1):123-129.
8. Gill G, Huda B, Boyd A, et al. Characteristics and mortality of severe hyponatremia—a hospital-based study. Clinical Endocrinology (Oxford). 2006;65(2):246-249.
9. Hawkins RC. Age and gender as risk factors for hyponatremia and hypernatremia. Clinica Chimica Acta. 2003;337(1-2):169-172.
10. Liamis G, Filippatos TD, Elisaf MS. Thiazide-associated hyponatremia in the elderly: What the clinician needs to know. Journal of Geriatric Cardiology. 2016;13(2):175-182.
11. Laureno R, Karp BI. Myelinolysis after correction of hyponatremia. Annals of Internal Medicine. 1997;126(1):57-62.
12. Maesaka JK, Imbriano LJ, Miyawaki N. SIADH is a misnomer: Role of osmotic and non-osmotic stimuli of vasopressin. American Journal of the Medical Sciences. 2016;352(5):429-435.
13. O’Neill PA, McLean KA, Haywood S, et al. Age and gender associations in impaired water handling in elderly hospitalized patients. American Journal of Medicine. 1994;97(4):225-230.
14. Robertson GL. Regulation of arginine vasopressin in the syndrome of inappropriate antidiuresis. American Journal of Medicine. 2006;119(7 Suppl 1):S36-42.
15. Rose BD, Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders. 5th ed. McGraw-Hill; 2001.
16. Schrier RW. Body water homeostasis: Clinical disorders of urinary dilution and concentration. Journal of the American Society of Nephrology. 2006;17(7):1820-1832.
17. Sterns RH, Hix JK, Silver SM. Management of hyponatremia in the ICU. Chest. 2013;144(2):672-679.
18. Sterns RH, Silver SM. Brain volume regulation in response to hypo-osmolality and its correction. American Journal of Medicine. 2006;119(7 Suppl 1):S12-S16.
19. Sterns RH. Disorders of plasma sodium—Causes, consequences, and correction. New England Journal of Medicine. 2015;372(1):55-65.
20. Spasovski G, Vanholder R, Allolio B, et al. Clinical practice guideline on diagnosis and treatment of hyponatremia. European Journal of Endocrinology. 2014;170(3):G1-G47.
21. Upadhyay A, Jaber BL, Madias NE. Incidence and prevalence of hyponatremia. American Journal of Medicine. 2006;119(7 Suppl 1):S30-S35.
22. Verbalis JG, Goldsmith SR, Greenberg A, et al. Diagnosis, evaluation, and treatment of hyponatremia: Expert panel recommendations. American Journal of Medicine. 2013;126(10 Suppl 1):S1-S42.