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Page 6 of 12 Khan et al. J Cancer Metastasis Treat 2019;5:71 I http://dx.doi.org/10.20517/2394-4722.2019.017

Table 2. Criteria for diagnosis syndrome of inappropriate antidiuresis [10,19]
Essential criteria Supplemental criteria
Serum osmolality < 275 mOSm/kg Blood urea nitrogen < 10 mg/dL
Urine osmolality > 100 mOSm/Kg Serum uric acid < 4 mg/dL
‡
Clinical euvolemia: FEurate > 11%
Absence of signs of hypovolemia* and hypervolemia** FENa > 1%
•
Central venous pressure 6-10 cm H 2 O FEurea > 55%
†
Urine sodium > 30 mEq/L Correction of hyponatremia through fluid restriction
No evidence of hypothyroidism, adrenal insufficiency Failure to correct hyponatremia after 0.9% saline infusion
No diuretic use
No renal insufficiency
*Signs of hypovolemia (decreased skin turgor, orthostasis, dry mucus membranes, tachycardia). **Signs of hypervolemia (edema,
•
‡
ascites). FEurate (%) = (urine urate × serum Cr)/(serum urate × urine Cr) × 100. FENa (%) = (urine sodium × serum Cr)/(serum Na ×
†
urine Cr) × 100. FEurea (%) = (urine urea nitrogen × serum Cr)/(blood urea nitrogen × urine Cr) × 100
adrenal, and renal function. After normalization of hyponatremia, FEurate normalizes in patients with
[14]
SIAD (FEurate 4%-11%) but remains persistently elevated in CSW (FEurate > 11%) . Clinical symptoms
and signs of hypovolemia (decreased skin turgor, orthostasis, dry mucus membranes, tachycardia) and
low central venous pressure in the setting of normal kidney function denote CSW. Serum AVP levels
[21]
are elevated as seen in patients with hypovolemia . Identification of CSW from SIAD is of paramount
importance to guide appropriate therapy; aggressive volume and salt repletion in CSW versus fluid
restriction in SIAD.

After correction of hypovolemia, sodium loss is repleted with sodium chloride tablets and fludrocortisone
[29]
with close monitoring of serum electrolytes . Rarely, hypertonic saline is required to correct
[29]
hyponatremia .

APPROACH TO THE DIAGNOSTIC EVALUATION OF HYPONATREMIA
The initial step in the evaluation of hyponatremia is to measure serum osmolality. If hyponatremia is
associated with hypoosmolality, the next step will be to measure urine osmolality and urine sodium. SIAD
is a diagnosis of exclusion after ruling out other causes of euvolemic hyponatremia such as hypothyroidism
(free T4, thyrotropin stimulating hormone) and adrenal insufficiency (total cortisol, adrenocorticotropic
hormone). Other causes that could be excluded in cases of hypotonic hyponatremia are decreased effective
[16]
circulating blood volume and renal insufficiency [Figure 1].

Copeptin is secreted from the posterior pituitary along with AVP. There is a strong correlation between
plasma AVP levels and copeptin levels. Although copeptin levels tend to be highest in small cell lung
cancer, evaluation of copeptin levels between cancer-related versus non cancer-related SIAD show no
significant difference. Multiple other factors (e.g., pain, nausea, stress, medications) contribute to elevated
copeptin levels. Copeptin levels > 84 pmol/L indicate hypovolemic hyponatremia whereas low levels of
[30]
copeptin < 3.9 pmol/L indicate primary polydipsia .

CLINICAL MANAGEMENT/TREATMENT OPTIONS
Definitive treatment for hyponatremia involves treating the underlying cause. Medical therapy [Table 3]
improves the serum sodium level and prevents potential neurologic complications. In patients with severe
[10]
symptomatic hyponatremia, a 5 mEq/L increase of serum sodium is likely to improve clinical symptoms .
The serum sodium should be acutely increased 1-2 mEq/L/h over 3-4 h using hypertonic saline (3%
NaCl). To avoid the risk of over correction, current guidelines recommend i.v. infusion of 150 mL of 3%
hypertonic saline over 20 min, rechecking serum sodium concentration and then, if necessary, repeating
[31]
the 150 mL of 3% hypertonic saline infusion . Frequent monitoring of serum sodium along with 150 mL
of hypertonic saline avoids rapid increase in serum sodium. Hypertonic saline can be administered at an