Hypovolemic Hyponatremia

Hypovolemia from both renal and extrarenal causes is associated with hyponatremia. Renal causes of hypovolemia include primary adrenal insufficiency and hypoaldosteronism, salt-losing nephropathies (e.g., reflux nephropathy, nonoliguric acute tubular necrosis), diuretics, and osmotic diuresis. Random “spot” urine Na⁺ is typically >20 meq/L in these cases but may be <20 meq/L in diuretic-associated hyponatremia if tested long after administration of the drug. Nonrenal causes of hypovolemic hyponatremia include GI loss (e.g., vomiting, diarrhea, tube drainage) and integumentary loss (sweating, burns); urine Na⁺ is typically <20 meq/L in these cases.

Hypovolemia causes profound neurohumoral activation, inducing systems that preserve arterial circulatory integrity, such as the renin-angiotensin-aldosterone (RAA) axis, the sympathetic nervous system, and AVP (Table 1-1 Osmoregulation versus Volume Regulation). The increase in circulating AVP serves to increase the retention of ingested-free H₂O, leading to hyponatremia. The optimal treatment of hypovolemic hyponatremia is volume administration, generally as isotonic crystalloid, i.e., 0.9% NaCl (“normal saline”). If the history suggests that hyponatremia has been “chronic,” i.e., present for 48 h, care should be taken to avoid overcorrection (see below), which can easily occur as AVP levels plummet in response to volume-resuscitation; if necessary, the administration of desmopressin (DDAVP) and free water can reinduce or arrest the correction of hyponatremia (see below). An alternative strategy is to “clamp” AVP bioactivity by administering DDAVP while correcting the serum [Na⁺ ] with hypertonic saline in a more controlled, linear fashion.

Hypervolemic Hyponatremia

The edematous disorders (CHF, hepatic cirrhosis, and nephrotic syndrome) are often associated with mild to moderate degrees of hyponatremia ([Na⁺ ] = 125-135 mmol/L); occasionally, pts with severe CHF or cirrhosis may present with serum [Na⁺ ] <120 mmol/L. The pathophysiology is similar to that in hypovolemic hyponatremia, except that arterial filling and circulatory integrity are decreased due to the specific etiologic factors, i.e., cardiac dysfunction, peripheral vasodilation in cirrhosis, and hypoalbuminemia in nephrotic syndrome. The degree of hyponatremia is an indirect index of the associated neurohumoral activation (Table 1-1 Osmoregulation versus Volume Regulation) and an important prognostic indicator in hypervolemic hyponatremia.

Management consists of treatment of the underlying disorder (e.g., afterload reduction in heart failure, intravenous administration of albumin in cirrhosis, immunomodulatory therapy in some forms of nephrotic syndrome), Na⁺ restriction, diuretic therapy, and, in some pts, H₂O restriction. Vasopressin antagonists (e.g., tolvaptan and conivaptan) are also effective in normalizing hypervolemic hyponatremia associated with CHF; hepatic toxicity of tolvaptan limits its clinical utility in cirrhosis.

Euvolemic Hyponatremia

The syndrome of inappropriate ADH secretion (SIADH) characterizes most cases of euvolemic hyponatremia. Other causes of euvolemic hyponatremia include hypothyroidism and secondary adrenal insufficiency due to pituitary disease; notably, repletion of glucocorticoid levels in the latter may cause a rapid drop in circulating AVP levels and overcorrection of serum [Na⁺ ] (see below).

Common causes of SIADH include pulmonary disease (e.g., pneumonia, tuberculosis, pleural effusion) and central nervous system (CNS) diseases (e.g., tumor, subarachnoid hemorrhage, meningitis); SIADH also occurs with malignancies (primarily small cell carcinoma of the lung) and drugs (e.g., selective serotonin reuptake inhibitors, tricyclic antidepressants, nicotine, vincristine, carbamazepine, narcotic analgesics, antipsychotic drugs, cyclophosphamide, ifosfamide). Optimal treatment of euvolemic hyponatremia includes treatment of the underlying disorder. H₂O restriction to <1 L/d is a cornerstone of therapy, but may be ineffective or poorly tolerated. However, vasopressin antagonists are predictably effective in normalizing serum [Na⁺ ] in SIADH. Alternatives include the administration of loop diuretics to inhibit the countercurrent mechanism and reduce urinary concentration, combined with oral salt tablets to abrogate diuretic-induced salt loss and attendant hypovolemia. More recently, a palatable form of oral urea has become available; oral urea is equivalent to tolvaptan in the management of SIADH, increasing urinary solute (urea) and, thus, urinary H₂O excretion.

Acute Symptomatic Hyponatremia

Acute symptomatic hyponatremia is a medical emergency; a sudden drop in serum [Na⁺ ] can overwhelm the capacity of the brain to regulate cell volume, leading to cerebral edema, seizures, and death. Women, particularly premenopausal women, are particularly prone to such sequelae; neurologic consequences are comparatively rare in male pts. Many of these pts develop hyponatremia from iatrogenic causes, including hypotonic fluids in the postoperative period, prescription of a thiazide diuretic, colonoscopy preparation, or intraoperative use of glycine irrigants. Polydipsia with an associated cause of increased AVP may also cause acute hyponatremia, as can increased H₂O intake in the setting of strenuous exercise, e.g., a marathon. The recreational drug Ecstasy (methylenedioxymethamphetamine [MDMA]) can cause acute hyponatremia, rapidly inducing both AVP release and increased thirst.

Severe symptoms may occur at relatively modest levels of serum [Na⁺ ], e.g., in the mid-120s. Nausea and vomiting are common premonitory symptoms of more severe sequelae. An important concomitant is respiratory failure, which may be hypercapnic due to CNS depression or normocapnic due to neurogenic, noncardiogenic pulmonary edema; the attendant hypoxemia amplifies the impact of hyponatremic encephalopathy.