Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)

The condition is primarily defined biochemically

• 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 oedema.
• 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.
• Some neoplastic cells exhibit osmoregulatory control of ectopic ADH secretion, responding to plasma osmolality changes in a manner similar to hypothalamic AVP release.

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

Drugs that Stimulate AVP Release

• 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.

Drugs that Potentiate AVP Action

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

Drugs with an Unclear Mechanism

• Antineoplastics: Melphalan, methotrexate, imatinib.
• Amiodarone: Alters AVP metabolism.
• Ciprofloxacin: May interact with AVP receptors.
• MDMA (Ecstasy): Increases thirst and AVP secretion, exacerbating hyponatremia.
• Chemotherapy-induced nausea is also a potent stimulus for AVP secretion, making SIADH a frequent complication of oncology treatments.

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

Osmotic Regulation

• 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.

Non-Osmotic Triggers of AVP Release

• 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

• AVP acts via vasopressin V2 receptors located on the principal cells of the renal collecting duct. This leads to:
  • Activation of adenylate cyclase, increasing intracellular cAMP.
  • Insertion of aquaporin-2 channels into the apical membrane.
  • Enhanced water reabsorption into the bloodstream, producing highly concentrated urine.
• Expansion of total body water (TBW), diluting serum sodium and causing hyponatremia.

Consequences of Water Retention

• Increased 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

Type A (Unregulated AVP Release)

• 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).

Type B (Low Osmotic Threshold)

• 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.

Type C (Persistent AVP Secretion)

• 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.

Type D (Nephrogenic Syndrome of Inappropriate Diuresis – NSIAD)

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

Type E (Altered Baroreceptor Response)

• 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

Acute Brain Swelling and Cerebral Oedema

• 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).

Osmotic Adaptation in Chronic SIADH

• 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).

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

Solute Excretion

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

Escape from AVP Effect

• 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 hospitalised patients.
• 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 anaesthetics, narcotics, or mechanical ventilation
• SIADH accounts for ~30% of hospital-acquired hyponatremia cases.
• In a study of older hospitalised 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 hospitalised 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 hospitalised 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 SIADHNeurological or Pulmonary Disorders

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

Drug and Substance History

• 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.

Fluid Intake Patterns and Thirst Perception

• 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 hospitalised 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, diarrhoea, diuretic use, excessive sweating.

Hypervolemia-related hyponatremia (e.g., CHF, cirrhosis, nephrotic syndrome)

• History of oedema, weight gain, orthopnoea, 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

No signs of hypovolaemia

• No orthostatic hypotension
• No dry mucous membranes
• No reduced skin turgor
• 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 hyponatraemia (e.g., heart failure, liver cirrhosis, nephrotic syndrome) should be considered.

Neurological Findings

Mild to Moderate Hyponatraemia (Na⁺ 125–135 mmol/L)

Cognitive changes

• Confusion
• Disorientation
• Memory impairment

Neuromuscular symptoms

• Generalised muscle weakness
• Mild ataxia
• Postural instability

Severe or Rapid-Onset Hyponatraemia (Na⁺ <120 mmol/L)

Cerebral dysfunction

• Delirium
• Agitation
• Hallucinations
• Drowsiness
• Lethargy

Seizure-related signs

• Myoclonus (spontaneous muscle jerks)
• Generalised 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)
• Tremors
• Ataxia
• Pathologic reflexes (Babinski sign)

Comatose State and Respiratory Failure

• Deep coma in profound hyponatraemia
• Apnoeic episodes
• Respiratory arrest due to brainstem involvement

Additional Systemic Examination

Cardiovascular

• Normal blood pressure
• No peripheral oedema
• No jugular venous distension

Respiratory

• Normal lung auscultation
• Dyspnoea or hypoxia may suggest a pulmonary cause (e.g., pneumonia, lung cancer)

Gastrointestinal

• Normal abdominal examination
• Nausea and vomiting may indicate raised intracranial pressure

Core Laboratory Investigations

Serum Electrolytes and Osmolality

Serum Sodium (Na⁺)

• SIADH presents with hyponatraemia (<135 mmol/L).
• Severe cases (<120 mmol/L) are associated with neurological symptoms.

Serum Osmolality

• Low (<275 mOsm/kg H₂O) confirms hypotonic hyponatraemia.
• In SIADH, serum osmolality remains lower than urine osmolality.

Serum Potassium and Bicarbonate

• Potassium is usually normal, unlike in adrenal insufficiency or diuretic-induced hyponatraemia.
• Normal bicarbonate levels help distinguish SIADH from metabolic disorders.

Urine Electrolytes and Osmolality

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 euvolaemic patients.
• <25 mmol/L suggests hypovolaemic hyponatraemia from extrarenal sodium losses.

Serum Urea and Uric Acid

Serum Urea (<3.6 mmol/L or <10 mg/dL)

• Low due to mild volume expansion, differentiating SIADH from hypovolaemic 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

Endocrine Testing

• 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 euvolaemic hyponatraemia and should be ruled out.

Diagnostic Saline Infusion Test

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

Plasma Copeptin

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

Imaging Studies

Chest Imaging (to Identify Pulmonary Causes)

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

Brain Imaging (to Identify CNS Causes)

• CT or MRI Brain
  • Rule out CNS pathology (tumours, stroke, subarachnoid haemorrhage).
  • Signs of cerebral oedema in severe hyponatraemia.

Sinus and Abdominal Imaging (for Rare Causes)

• CT/MRI Nasal Sinuses
  • Olfactory neuroblastoma (rare ectopic AVP-producing tumour).

Abdominal and Pelvic CT

• Neuroendocrine tumours.
• Adrenal pathology.

Key Diagnostic Approach

 Step 1: Confirm Hyponatraemia

• 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

• Euvolaemia → Likely SIADH
• Hypovolaemia → Consider GI losses, renal losses, adrenal insufficiency
• Hypervolaemia → Consider heart failure, cirrhosis, nephrotic syndrome

Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)

• Euvolaemic hyponatraemia (no oedema, 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

Pseudohyponatraemia

• Occurs in severe hyperlipidaemia, hyperproteinaemia, or hyperglycaemia
• Often asymptomatic (lab artefact rather than true hyponatraemia)
• Laboratory findings:
  • Normal plasma osmolality
  • Corrected serum sodium (adjusted for glucose, lipids, proteins) remains normal

Hypovolaemic Hyponatraemia

• 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 haemorrhage, neurosurgery
  • Persistent dehydration despite natriuresis
• Laboratory findings:
  • Urine sodium >120 mmol/L
  • Fractional excretion of urea <30%
  • Persists despite hypertonic saline administration

Hypervolaemic Hyponatraemia

• Occurs in conditions causing fluid overload:
  • Congestive heart failure (CHF), cirrhosis, nephrotic syndrome
• Signs:
  • Oedema, ascites, jugular venous distension (JVD), dyspnoea, 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)
  • Hyperkalaemia
  • Sodium improves with glucocorticoid therapy

Hypothyroidism

• Signs & Symptoms:
  • Fatigue, cold intolerance, weight gain, dry skin, myxoedema
• Laboratory findings:
  • Elevated TSH, low free T4
  • Hyponatraemia 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

 Acute Hyponatraemia (≤48 Hours) with Severe Symptoms

• 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 hypokalaemia is present
• Avoid overly rapid correction:
  • No more than 8–10 mmol/L in 24 hours to prevent ODS

Chronic Hyponatraemia (>48 Hours) with Severe Symptoms

• 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

Mild to Moderate Symptoms (e.g., Nausea, Lethargy, Headache)

• 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

Asymptomatic or Mild SIADH

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

Pharmacologic Therapies

Vasopressin Receptor Antagonists (Vaptans)

• 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 hospitalisation for initiation
  • Hepatotoxicity: Avoid in liver disease; use ≤30 days
  • High cost limits availability

Hypertonic Saline

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

Urea

• 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

Loop Diuretics (e.g., Furosemide, Torsemide)

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

Demeclocycline

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

Special Considerations

SIADH in Subarachnoid Haemorrhage (SAH)

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

SIADH in Cancer Patients

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

Reset Osmostat SIADH

• Mild, stable hyponatraemia (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, hypokalaemia

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

Cerebral Oedema

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

Noncardiogenic Pulmonary Oedema

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

Osmotic Demyelination Syndrome (ODS)

• Most feared complication of overcorrection of hyponatraemia
• Risk factors:
  • Rapid sodium correction exceeding 8–10 mmol/L per 24 hours
  • Severe hyponatraemia (<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 hyponatraemia 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:
  • Hyponatraemia (Na⁺ <130 mmol/L) increases mortality risk 60-fold
  • Comorbid conditions often contribute to mortality, rather than hyponatraemia itself
  • In-hospital hyponatraemia onset is associated with worse prognosis
• Severe Hyponatraemia (<105 mmol/L):
  • Life-threatening complications become significantly more likely
  • High mortality in multifactorial hyponatraemia

Prognostic Indicators

 Better prognosis

• Identifiable and treatable cause (e.g., drug-induced, infection)
• Mild hyponatraemia with slow onset
• Early and appropriate treatment

Worse prognosis

• Severe hyponatraemia (<105 mmol/L)
• Acute onset (<48 hours)
• Neurological symptoms at presentation
• Overcorrection (>12 mmol/L/day) leading to ODS
• Hyponatraemia acquired during hospitalisation

Neurological Complications

Cerebral Oedema

• Occurs in acute, severe hyponatraemia 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

Osmotic Demyelination Syndrome (ODS) / Central Pontine Myelinolysis (CPM)

• Occurs when sodium is corrected too rapidly (>8–10 mmol/L per 24 hours)
• Mechanism:
  • Brain cells adapt to chronic hyponatraemia by losing organic osmolytes (e.g., myoinositol, taurine)
  • Overcorrection of sodium causes excessive water efflux, leading to cellular shrinkage and demyelination
• Risk factors:
  • Chronic hyponatraemia (<105 mmol/L)
  • Malnutrition, alcoholism, burns, potassium depletion
  • Liver disease, especially cirrhosis
  • Postoperative patients (especially premenopausal women after gynaecologic 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

Noncardiogenic Pulmonary Oedema

• 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:
  • Dyspnoea, hypoxia, crackles on auscultation
  • Normal cardiac function (unlike cardiogenic pulmonary oedema)

Neuromuscular and Cognitive Impairment

Chronic Hyponatraemia-Related Cognitive Decline

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

Gait Instability and Falls

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

Mortality and Long-Term Prognosis

• Severe hyponatraemia (Na⁺ <130 mmol/L) increases mortality risk 60-fold
• Highest risk in hospitalised patients with acute onset hyponatraemia
• Multifactorial hyponatraemia (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 hyponatraemia

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
  
  

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