A 67-year-old male patient who has depression and is on sertraline presents with increasing confusion over the past week. Initial plasma sodium is 109 mEq/L. On exam, he weighs 70 kg and is euvolemic. His urine osmolarity (Uosm) is 800 mosm/L with a urine sodium (UNa) of 40 mEq/L. He is somnolent but awakens to sternal rub. How should this patient’s hyponatremia be evaluated and managed?
Hyponatremia, a disorder of excess total body water in relation to sodium, occurs in up to 42% of hospitalized patients.1,2 Regardless of the cause, hyponatremia is usually associated with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) or with the appropriate elevation of antidiuretic hormone (ADH), known as hypovolemia. ADH is produced in the hypothalamus and released in the posterior pituitary in response to increasing plasma osmolarity (pOSM) or effective circulating volume depletion. ADH acts in the cortical collecting duct to increase the number of luminal aquaporin channels, increasing water reabsorption and decreasing plasma osmolarity. When hyponatremia is severe, the movement of water into cells causes cellular brain swelling, and clinical symptoms progress from malaise, headache, and nausea to obtundation, seizures, or respiratory arrest (see Figure 1). Even mild, chronic hyponatremia (120-131 mEq/L) is associated with an increased risk of falls due to mild gait and attention impairment.3
Step 1: Plasma osmolarity
The first step in diagnosing the cause of hyponatremia and treating it is to measure pOSM. The majority of patients with hyponatremia have hypoosmolar hyponatremia and therefore have a low pOSM; however, patients may have normal or high osmolarity. Hyponatremia with normal osmolarity can be caused by pseudohyponatremia (i.e., hyperglycemia, paraproteinemia, hyperlipidemia), severe renal failure, ingestion of excess alcohol, or post-transurethral resection of prostate or bladder.
Hyponatremia with high pOSM occurs as a result of elevated levels of an extra solute in the plasma that does not readily enter cells. This draws water into the extracellular fluid and lowers the sodium concentration. This will most commonly result from hyperglycemia or infusion of mannitol.
Step 2: Assess volume status with physical exam, urine sodium (UNa)
The majority of patients with hyponatremia will have low pOSM. These patients should be categorized by volume status: hypovolemic, euvolemic, or hypervolemic (see Figure 2). On exam, hypervolemia is usually evident, and the cause of hypervolemic hyponatremia is usually elicited from a patient’s history; however, differentiating between hypovolemic and euvolemic hyponatremia by history and physical exam can be difficult, because examination findings are neither sensitive nor specific.4 UNa should always be evaluated, especially when differentiating between hypovolemic and euvolemic. This was illustrated in a study of 58 non-edematous patients with hyponatremia. Investigators determined which patients had hypovolemic hyponatremia based on their response to saline infusion. Of the patients identified as hypovolemic using physical exam, only 47% responded to saline. In contrast, a spot UNa of less than 30 mEq/L was 80% sensitive and 100% specific for saline responsiveness.5 Although the majority of hypovolemic hyponatremia patients will have a low UNa, the following causes of hypovolemic hyponatremia can result in high UNa: diuretics, adrenal insufficiency, salt-wasting nephropathy, and cerebral salt-wasting.