Hypertonic Saline Test

The hypertonic saline test (HST) assesses osmotically stimulated ADH release by raising plasma sodium to at least 150 mmol/L with a controlled infusion of 3% saline, while measuring copeptin or ADH. It is the most accurate test for separating central diabetes insipidus from primary polydipsia and nephrogenic diabetes insipidus, and is increasingly used in place of the water deprivation test.

Copeptin is a stable surrogate of ADH, measured by an automated immunoassay in 1 to 2 hours. A copeptin value of 4.9 pmol/L or more when sodium is 150 mmol/L or more excludes central diabetes insipidus, with sensitivity and specificity about 96 to 97%.

The test is used in hospital under supervision because hypertonic saline can cause rapid sodium changes. It replaced prolonged water deprivation in centres with copeptin assays because it is faster (about 3 hours against 8 to 17 hours), has higher diagnostic accuracy (96% versus 70%), and is safer in monitored settings. Arginine stimulation of copeptin is an alternative that is better tolerated, with a cut off of 3.8 pmol/L at 60 minutes and accuracy near 93%.

Indications. Polyuria and polydipsia with unexplained dilute urine in whom diabetes insipidus is suspected, especially when the water deprivation test is equivocal. Distinguishing partial central diabetes insipidus from primary polydipsia. Evaluation of suspected disorders of osmoregulation (adipsic diabetes insipidus, reset osmostat). Suspected diabetes insipidus after pituitary surgery with mild features.

Contraindications and cautions. Hypernatraemia at baseline (over 145 mmol/L) because the diagnosis is already clear. Heart failure, severe renal impairment, hypertension that is uncontrolled, and seizures. Untreated adrenal insufficiency. Pregnancy. Close monitoring is needed in children.

Preparation. Baseline fasting is not necessary but fluid intake is restricted during the test. Antidiuretics are reviewed. Patients are in a day case ward with intravenous access and continuous observation. Baseline tests include electrolytes, plasma osmolality and copeptin.

Procedure.

• Baseline sample for sodium, osmolality and copeptin. Pre-test plasma sodium is recorded.
• Infuse 3% sodium chloride at 0.15 mL/kg/min over 1 hour, then reduce to 0.05 mL/kg/min (or a fixed bolus of 250 mL over 15 minutes in some adult procedures).
• Measure plasma sodium every 30 minutes until it reaches 150 mmol/L or more.
• Take a sample for copeptin (and ADH if available) when sodium is 150 mmol/L or more, then stop the infusion.
• Give oral water to drink after the end and monitor sodium until it falls under 145 mmol/L.
• The patient is observed for headache, nausea, thirst and neurological signs.

Copeptin at sodium 150 mmol/L or more.

• Copeptin over 4.9 pmol/L: excludes central diabetes insipidus. Primary polydipsia or a normal response is likely, and nephrogenic diabetes insipidus is considered if the urine remains dilute with high copeptin.
• Copeptin under 4.9 pmol/L: central diabetes insipidus (complete or partial).
• The sensitivity and specificity for central diabetes insipidus is about 96% and 97%, and the test also detects partial deficiency.
• Baseline unstimulated copeptin over 21.4 pmol/L without prior water restriction diagnoses nephrogenic diabetes insipidus directly, and under 2.6 pmol/L with high osmolality suggests central disease.

Interpretation patterns.

Associated findings. Plasma osmolality over 295 mOsm/kg with inappropriately dilute urine confirms diabetes insipidus. Adipsic forms present with hypernatraemia and no thirst. Reset osmostat shows a shifted threshold and a normal response at lower sodium.

Critical values and findings needing immediate action.

• Plasma sodium rise over 10 mmol/L in an hour, or sodium over 155 mmol/L: stop the infusion, and give water.
• Neurological symptoms (severe headache, confusion, seizure): stop the test and correct the sodium cautiously.
• Pulmonary oedema or heart failure: stop the infusion and give diuretic.
• Confirmed central diabetes insipidus: desmopressin treatment, pituitary MRI and anterior pituitary function testing.
• Confirmed primary polydipsia: behavioural therapy and psychiatric review, without desmopressin.

Interferences and pitfalls.

• Copeptin results depend on the assay, and the cut off of 4.9 pmol/L is for the BRAHMS assay. Local validation is needed.
• Copeptin is stable but can be raised by nausea, stress, hypoglycaemia, pain, surgery and acute illness, so the test is done in a calm, stable patient.
• Hypertonic saline is hazardous in cardiac and renal impairment, and too rapid infusion risks osmotic injury.
• Antidiuretic and diuretic drugs (carbamazepine, SSRIs, vincristine, lithium, thiazides) alter ADH.
• Cortisol deficiency alters results, and replacement is adequate before testing.
• Copeptin cannot replace the clinical assessment of drug history, imaging and genetic testing.
• Sodium targets differ slightly between centres, and the local written procedure is followed.
• The test is not a replacement for a desmopressin therapeutic response in practice, where an observed fall in urine output with desmopressin remains a clinical confirmation.

Special groups.

• Children: hypertonic saline is used with lower infusion rates and strict monitoring, in paediatric endocrine units.
• Pregnancy: avoided.
• Post-neurosurgery patients: copeptin may be low shortly after surgery because of oedema, and testing is repeated after several weeks.
• Older adults: more susceptible to sodium shifts and fluid overload, so closer monitoring is needed.
• Regions: availability of copeptin assay is limited, and the arginine test is an alternative.

Follow up tests. Pituitary MRI with posterior pituitary bright spot assessment, anterior pituitary function (cortisol, TSH, free T4, prolactin, IGF-1, gonadotrophins), serum and urine osmolality, 24-hour urine volume, serum calcium, potassium and glucose, observed desmopressin response, genetic testing in familial disease, and autoimmune and infiltrative workup (angiotensin converting enzyme, IgG4, chest imaging).