Pathophysiology, Etiologies, and Clinical Presentation of SIADH
Objective
Describe the fundamental mechanisms, common causes, and clinical features of SIADH to enable early recognition and informed diagnostic decisions in the ICU.
1. Introduction to SIADH
SIADH is the leading cause of euvolemic hypotonic hyponatremia in hospitalized patients, driven by inappropriate ADH release. Even mild chronic hyponatremia increases morbidity and mortality.
- Definition: Non-osmotic ADH (AVP) secretion leads to impaired free water excretion, resulting in dilutional hyponatremia in a euvolemic patient.
- Epidemiology: It is the most frequent cause of hypotonic hyponatremia in the ICU and is commonly associated with malignancy, CNS and pulmonary diseases, and polypharmacy.
Key Pearls
- Mild hyponatremia (Na 130–135 mmol/L) can cause subtle cognitive deficits and gait instability.
- Exclude hypovolemia, adrenal insufficiency, and hypothyroidism before diagnosing SIADH.
2. ADH Regulation and Pathophysiology
Under normal conditions, AVP release is tightly controlled by plasma osmolality and volume. In SIADH, non-osmotic stimuli override this regulation, causing persistent V2-receptor activation and water retention.
A. Normal ADH (AVP) Axis
The normal regulation involves hypothalamic osmoreceptors sensing plasma osmolality. When osmolality rises or blood volume drops, the posterior pituitary releases AVP. AVP then acts on V2 receptors in the renal collecting ducts, promoting aquaporin-2 channel insertion, which leads to water reabsorption.
B. Pathophysiology in SIADH
In SIADH, AVP release is uncoupled from osmotic control. Non-osmotic triggers such as baroreceptor activation (due to hypotension or mechanical ventilation), pain, nausea, stress, or cytokines can stimulate AVP release. In some cases, AVP is produced ectopically (e.g., by tumors). This persistent AVP elevation, despite low plasma osmolality, leads to continuous water reabsorption. Consequently, urine osmolality remains inappropriately high (>100 mOsm/kg) and urine sodium concentration is typically elevated (>30 mmol/L, assuming normal salt intake), reflecting a state of free water retention and dilutional hyponatremia.
Normal ADH (AVP) Regulation
(V2 Receptor Activation)
SIADH Pathophysiology
(Pain, Nausea, Drugs, CNS/Pulmonary Dz)
OR Ectopic AVP Production
(Malignancy)
(V2 Receptor Activation)
(despite ↓Osm)
Key Pearls
- Urine osmolality >100 mOsm/kg in the setting of serum hypo-osmolality confirms impaired water excretion.
- Non-osmotic stimuli are ubiquitous in critical illness and must be sought in every case.
3. Etiologies of SIADH in the ICU
SIADH in critically ill patients is often multifactorial. Major categories include paraneoplastic ADH release, CNS insults, pulmonary disease, and certain medications.
| Etiology Category | Examples | Mechanism |
|---|---|---|
| Malignancy | Small cell lung cancer; head/neck tumors, olfactory neuroblastoma | Ectopic ADH production |
| CNS Disorders | Trauma (traumatic brain injury, subdural/epidural hematoma), subarachnoid hemorrhage, stroke, infection (meningitis, encephalitis), hydrocephalus, tumors | Disruption of hypothalamic–pituitary regulation, direct stimulation of ADH release |
| Pulmonary Disease | Pneumonia (bacterial/viral/fungal), tuberculosis, ARDS, asthma exacerbation, positive-pressure ventilation | Hypoxia/inflammation–mediated ADH release, intrathoracic pressure changes |
| Drug-induced | SSRIs (e.g., fluoxetine, sertraline), carbamazepine, oxcarbazepine, NSAIDs, opioids, vincristine, cyclophosphamide, vasopressin analogues (desmopressin, terlipressin), ecstasy (MDMA) | Stimulate ADH release or potentiate its renal action |
| Other | Postoperative state (pain, stress, nausea), HIV infection, severe nausea/vomiting, idiopathic | Various non-osmotic stimuli |
Key Pearls
- Always review new or dose-adjusted medications when hyponatremia develops.
- Paraneoplastic SIADH often precedes cancer diagnosis; consider occult malignancy in unexplained cases, especially with persistent or severe SIADH.
4. Clinical Manifestations
The severity and tempo of hyponatremia determine symptoms. Acute drops cause cerebral edema and neurologic emergencies, while chronic decline results in adaptive cerebral changes and more subtle deficits.
Acute Hyponatremia (≤48 hours)
- Rapid cerebral edema due to osmotic water shift into brain cells
- Headache, nausea, vomiting (often early signs)
- Muscle cramps, weakness
- Lethargy, confusion, disorientation
- Seizures
- Altered consciousness, progressing to stupor or coma
- Respiratory distress or arrest (due to brainstem herniation in severe cases)
Chronic Hyponatremia (>48 hours)
- Cerebral adaptation occurs via extrusion of intracellular osmolytes, reducing brain swelling
- Often asymptomatic or paucisymptomatic
- Mild confusion, attention deficits, memory impairment
- Gait instability, increased risk of falls (especially in elderly)
- Subtle cognitive impairment, reduced concentration
- Fatigue, malaise
- Osteoporosis and increased fracture risk (long-term)
Key Pearls
- Acute, severe hyponatremia (e.g., serum sodium <120 mmol/L) is a neurologic emergency; rapid recognition and appropriate management are critical to prevent irreversible brain injury.
- Chronic hyponatremia, even if mild, may present solely with falls, subtle mental status changes, or an increased fracture risk, particularly in older adults.
5. Risk Factors and Predisposing Conditions
The risk of developing SIADH is amplified by a combination of preexisting diseases, acute stressors common in the ICU setting, and iatrogenic factors. A multifactorial assessment is essential for identifying patients at risk.
- Underlying Chronic Conditions:
- Known malignancies, especially small cell lung cancer
- History of CNS tumors, trauma, or surgery
- Chronic pulmonary diseases (e.g., COPD, tuberculosis)
- Previous episodes of SIADH
- ICU Triggers:
- Mechanical ventilation (especially with positive end-expiratory pressure – PEEP)
- Postoperative state (pain, stress, nausea, non-osmotic ADH release)
- Sepsis and severe inflammatory states
- Significant pain or nausea from any cause
- Major surgery or trauma
- Iatrogenic Contributors:
- Administration of hypotonic fluids (e.g., D5W, 0.45% NaCl) in susceptible individuals
- Use of ADH‐stimulating drugs or drugs that potentiate ADH effect (see Etiologies table)
- High doses of opioids
Key Pearls
- A multifactorial assessment often uncovers combined triggers in most ICU patients who develop SIADH. It’s rarely a single cause.
- Preventive strategies are crucial, including judicious fluid selection (preferring isotonic fluids when maintenance fluids are needed) and thorough medication reconciliation to identify and potentially modify or discontinue offending agents.
6. Summary and Clinical Pearls
SIADH is characterized by euvolemic, hypotonic hyponatremia resulting from inappropriately high antidiuretic hormone (AVP) activity, leading to impaired water excretion.
Diagnostic Criteria (Bartter & Schwartz, adapted)
The diagnosis of SIADH generally requires the following criteria to be met:
- Serum osmolality <275 mOsm/kg H₂O.
- Urine osmolality >100 mOsm/kg H₂O (in the presence of serum hypo-osmolality).
- Urine sodium concentration >30 mmol/L (with normal dietary salt and water intake).
- Clinical euvolemia (absence of signs of hypovolemia like orthostasis or tachycardia, and absence of signs of hypervolemia like edema or ascites).
- Exclusion of other potential causes of hyponatremia, particularly hypothyroidism, adrenal insufficiency (secondary hypocortisolism), and significant renal dysfunction or diuretic use.
Key Management Implications
Effective management hinges on accurate volume status assessment, a comprehensive review of medications to identify potential culprits, and targeted therapy aimed at correcting hyponatremia safely and addressing the underlying cause of SIADH.
Key Clinical Pearls
- Always correct serum sodium for hyperglycemia. For every 100 mg/dL (5.5 mmol/L) increase in glucose above normal (approx. 100 mg/dL), the measured serum sodium decreases by approximately 1.6 to 2.4 mmol/L. Using a correction factor of 2.4 mmol/L is common.
- When in doubt about the chronicity of hyponatremia (i.e., whether it developed acutely or chronically), it is safest to assume it is chronic to avoid overly rapid correction, which can lead to osmotic demyelination syndrome (ODS).
References
- Verbalis JG, Goldsmith SR, Greenberg A, et al. Diagnosis, evaluation, and treatment of hyponatremia: Expert panel recommendations. Am J Med. 2013;126(10 Suppl 1):S1–S42.
- Spasovski G, Vanholder R, Allolio B, et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Eur J Endocrinol. 2014;170(3):G1–G47.
- Bartter FC, Schwartz WB. The syndrome of inappropriate secretion of antidiuretic hormone. Am J Med. 1967;42(5):790-806.
- Schrier RW. Water and sodium retention in edematous disorders: role of vasopressin and aldosterone. Am J Med. 2006;119(7 Suppl 1):S47-S53.
- Janicic N, Verbalis JG. Evaluation and management of hypo-osmolality in hospitalized patients. Endocrinol Metab Clin North Am. 2003;32(2):459–481.
- Liamis G, Milionis H, Elisaf M. A review of drug-induced hyponatraemia. Am J Kidney Dis. 2008;52(1):144–153.
- Fenske W, Störk S, Koschker AC, et al. Utility and limitations of the traditional diagnostic approach to hyponatremia: a diagnostic study. Am J Med. 2010;123(7):652–657.
- Hillier TA, Abbott RD, Barrett EJ. Hyponatremia: evaluating the correction factor for hyperglycemia. Am J Med. 1999;106(4):399–403.
- Sterns RH, Nigwekar SU, Hix JK. Treatment of hyponatremia. Curr Opin Nephrol Hypertens. 2010;19(5):493–498.
- Sterns RH, Hix JK, Silver S. Treatment of hyponatremia. Semin Nephrol. 2009;29(3):282–299.
