Hyponatremia: Physiology, Etiology, and Therapies

Educational Objectives

The goal of this program is to improve management of hyponatremia. After hearing and assimilating this program, the clinician will be better able to:

1. Recognize true hyponatremia.
2. Differentiate among presentations of hypovolemic, euvolemic, and hypervolemic hypo-osmolar hyponatremia.
3. Identify medicines which contribute to syndrome of inappropriate antidiuretic hormone secretion.

Summary

Definition: hyponatremia is characterized by serum sodium 130 to 134 mmol/L (mild), 125 to 129 mmol/L (moderate), or <125 mmol/L (severe) in the setting of low serum osmolality

Epidemiology: the prevalence is ≈10% overall, 12% among individuals >75 yr of age, 18% to 20% among nursing home residents (≤50% of nursing home residents will experience transient hyponatremia in a 12-mo span), and 30% to 35% among hospitalized patients >65 yr of age; hyponatremia occurs secondary to comorbidities which lead to hospitalization; hyponatremia is associated with adverse outcomes (eg, length of hospitalization, readmission, resource use, death), acts a surrogate marker for comorbidity severity, and is associated with worse prognosis for, eg, end-stage renal disease, pulmonary embolism, congestive heart failure (CHF), myocardial infarction, cirrhosis; hyponatremia is associated with gait instability, falls, fracture risk, osteoporosis, and attention deficits

Physiology: intravascular volume — regulated by the renin-aldosterone system, plus urinary sodium release or retention in the distal renal tubule (water is reabsorbed along with sodium); the sympathetic nervous system controls vasoconstriction in the juxtaglomerular apparatus, which releases renin and aldosterone, which impacts total serum amounts, but not concentration, of sodium; osmolality — the number of solutes within serum; normal serum osmolality is 280 to 295 mOsm/kg; increased osmolality induces secretion of antidiuretic hormone (ADH; regulates water retention in the distal renal tubules) from hypothalamic osmoreceptors and triggers thirst; osmolality is independent of volume status; high serum osmolality induces release of ADH and increases urinary osmolality; volume regulation overrides osmolality regulation; nonosmotic release of ADH maintains volume status (during, eg, overdiuresis, hemorrhage, cirrhosis, CHF, nephrotic syndrome) but may cause hyponatremia

Confirmation of true hyponatremia: determine serum osmolality in the setting of hyponatremia; translocational hyponatremia — osmolality >290 mOsm/kg; caused by, eg, hyperglycemia; sodium recalculation is necessary; pseudohyponatremia — serum osmolality is within normal limits; caused by laboratory artifact which occurs secondary to, eg, hypertriglyceridemia, total parenteral nutrition, multiple myeloma, Waldenström macroglobulinemia

Hypo-osmolar hyponatremia: assess the circulating plasma volume; assess spot urine sodium and spot urine osmolality (ensure no diuretic use ≤12 hr; if the patient is on diuretics, hold diuretics for 24 hr and recheck)

Hypovolemia: low urine sodium — indicates functional volume regulatory mechanisms; address the underlying cause; replenish sodium and fluids; high urine sodium — inadequate renal sodium retention leads to compensatory ADH release; conditions include, eg, adrenal insufficiency, ongoing diuretic use, renal tubular acidosis, partial obstruction; morning serum cortisol and adrenocorticotropic hormone (ACTH) stimulation testing may be required; a diuretic screen can rule out diuretic use in a patient with hypokalemia; restrict use of diuretics; address underlying cause; implement volume resuscitation

Hypervolemia: clinical findings include edema, ascites, anasarca, pulmonary edema, and elevated central venous pressure; low urine sodium — causes include low renal perfusion (eg, CHF) and third spacing (eg, cirrhosis, nephrosis); kidneys retain sodium in the absence of diuretics for CHF; ADH levels increase in response to a perceived low-volume state; high urine sodium — renal function and free water excretion are impaired; common with chronic kidney disease (CKD); diagnostic investigations include spot urine protein:creatinine, comprehensive metabolic panel (CMP), echocardiography, abdominal ultrasonography, and brain-type natriuretic peptide; management — implement fluid restriction (1000-1500 mL); escalate loop diuretics (preferable to thiazide diuretics) in patients with decompensated CHF; improvement in hyponatremia decreases mortality in CHF; management of hyponatremia in CKD can be challenging, and avoiding the use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers may be necessary; treatment of hyponatremia in cirrhosis is difficult

Euvolemia: low urine sodium — low urine osmolality may indicate primary polydipsia with an obvious psychiatric history; increased fluid intake (≈15 L/day) decreases the concentrating capacity of the loop of Henle; high urine sodium — most common; may be a response to mild hypervolemia; causes include medications and syndrome of inappropriate antidiuretic hormone secretion (SIADH); evaluate for adrenal insufficiency and hypothyroidism (rare); diagnostic investigations include urine osmolality, ACTH stimulation testing, thyroid-stimulating hormone level, drug review, and CMP; vasopressin levels are not helpful

Dietary hyponatremia: causes include nutritional deficiency (eg, tea and toast, beer potomania), severe sodium restriction, and extreme sodium loss (from, eg, high-output ostomy); lack of solutes in urine impairs renal water excretion, resulting in hyponatremia; urine sodium and osmolality are low; serum albumin is often low, as is blood urea nitrogen level (<6 mg/dL); management — includes oral urea (has poor palatability), improved nutrition, salt tablets, and low-dose loop diuretics

Syndrome of inappropriate ADH secretion

Background: excess ADH release in the absence of an osmotic or volume-mediated stimulus; SIADH is a common cause (20-40%) of inpatient hyponatremia in elderly individuals and a frequent cause of hyponatremia with associated comorbidities (eg, CHF, CKD); management of comorbid conditions improves hyponatremia; adrenal insufficiency and hypothyroidism mimic SIADH; urine sodium is typically elevated; urine osmolality is usually >250 mOsm/kg (often >400 mOsm/kg for pure SIADH); serum uric acid may be low

Etiology: common conditions that increase the risk for SIADH include cancer (24%), medications (18-20%), pulmonary disease, central nervous system disorders (eg, microvascular strokes, Parkinson disease), and postoperative state; anxiety, stress, and pain contribute to SIADH; the cause remains unidentified in 50% to 60% of cases; reset osmostat — the normal sodium threshold is reduced to ≈128 mEq/L; confirmed by sodium loading testing; characterized by fluctuations in urine osmolality

Patient evaluation: perform extensive medication review; for classic SIADH, screen for malignancy (eg, computed tomography of the head, chest, and abdomen); assess diet

Causative medications: ecstasy directly stimulates secretion of ADH and induces hyperthermia, which leads to excessive water intake; multiple medications in combination may confuse the picture; evaluate the benefits of medications and reassess the need for prescription; consider dose reduction; potential causative medications include thiazides (4-fold increased risk for hyponatremia in elderly individuals) and antidepressants (risk is greatest in women with small stature); serotonin-norepinephrine reuptake inhibitors (eg, duloxetine, venlafaxine) impart the greatest risk for hyponatremia, followed by selective serotonin reuptake inhibitors (≈5%) and tricyclic antidepressants; drugs least likely to cause hyponatremia include mirtazapine, trazodone, and bupropion; other causative medications include opioids, nonsteroidal anti-inflammatory drugs, psychotropic agents (eg, carbamazepine, haloperidol), chemotherapeutic agents (eg, platinum-based drugs), ciprofloxacin, and desmopressin

Treatment: consider replacing thiazides with other diuretics; consider dose reduction for antidepressants; fluid restriction may be challenging; data indicate poor response to fluid restriction alone when urine osmolality is >500 mOsm/kg; oral urea powder (15 g twice a day dissolved in fruit juice) is effective; sodium chloride tablets increase distal delivery of sodium, which aids diuresis, though avoid in patients with severe hypertension or CHF; loop diuretics in combination with sodium tablets improve serum sodium levels (may not be effective after 30-60 days); tolvaptan is a vasopressin receptor antagonist, though adverse events include severe thirst and hepatic injury

Outpatient management of hyponatremia

Triage: mild symptoms include gait disturbances and fatigue; moderate symptoms include confusion, nausea, headache, and ataxia; severe symptoms include obtundation, confusion, and seizures; symptom severity depends on the rate of change of sodium concentration; patients may tolerate slow changes in concentration; sodium <120 mmol/L requires hospitalization; for sodium 120 to 125 mmol/L, consider hospitalization (more so if acute); advise fluid restriction and thiazide discontinuation in asymptomatic individuals; patients with sodium 125 to 130 mmol/L can usually be managed in the outpatient setting, depending on symptoms; patients with sodium >130 mmol/L may be asymptomatic

Chronic hyponatremia: acute reduction in serum sodium can be quickly corrected; however, unless otherwise documented, assume long-standing hyponatremia; the treatment goal is ≈6 mmol/L per 24 hr; in the presence of severe symptoms, rapid correction (to 118-120 mEq/L) with 3% isotonic saline and intermittent doses of desmopressin may be necessary in the hospital setting

Readings

Adrogué HJ, Madias NE. The syndrome of inappropriate antidiuresis. N Engl J Med. 2023;389(16):1499-1509. doi:10.1056/NEJMcp2210411; Adrogué HJ, Tucker BM, Madias NE. Diagnosis and management of hyponatremia: a review. JAMA. 2022;328(3):280-291. doi:10.1001/jama.2022.11176; Alukal JJ, John S, Thuluvath PJ. Hyponatremia in cirrhosis: an update. Am J Gastroenterol. 2020;115(11):1775-1785. doi:10.14309/ajg.0000000000000786; Aziz F, Sam R, Lew SQ, et al. Pseudohyponatremia: mechanism, diagnosis, clinical associations and management. J Clin Med. 2023;12(12):4076. doi:10.3390/jcm12124076; Clayton JA, Rodgers S, Blakey J, et al. Thiazide diuretic prescription and electrolyte abnormalities in primary care. Br J Clin Pharmacol. 2006;61(1):87-95. doi:10.1111/j.1365-2125.2005.02531.x; Filippatos TD, Makri A, Elisaf MS, et al. Hyponatremia in the elderly: challenges and solutions. Clin Interv Aging. 2017;12:1957-1965. doi:10.2147/CIA.S138535; Gheysens T, Van Den Eede F, de Picker L. The risk of antidepressant-induced hyponatremia: a meta-analysis of antidepressant classes and compounds. Eur Psychiatry. 2024;67(1):e20. doi:10.1192/j.eurpsy.2024.11; Liamis G, Filippatos TD, Elisaf MS. Thiazide-associated hyponatremia in the elderly: what the clinician needs to know. J Geriatr Cardiol. 2016;13(2):175-182. doi:10.11909/j.issn.1671-5411.2016.02.001; Vachharajani TJ, Zaman F, Abreo KD. Hyponatremia in critically ill patients. J Intensive Care Med. 2003;18(1):3-8. doi:10.1177/0885066602239119; Verbrugge FH, Steels P, Grieten L, et al. Hyponatremia in acute decompensated heart failure: depletion versus dilution. J Am Coll Cardiol. 2015;65(5):480-92. doi:10.1016/j.jacc.2014.12.010; Warren A, Grossmann M, Christ-Crain M, et al. Syndrome of inappropriate antidiuresis: from pathophysiology to management. Endocr Rev. 2023;44(5):819-861. doi:10.1210/endrev/bnad010; Workeneh BT, Meena P, Christ-Crain M, et al. Hyponatremia demystified: integrating physiology to shape clinical practice. Adv Kidney Dis Health. 2023;30(2):85-101. doi:10.1053/j.akdh.2022.11.004.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Michels was recorded at the 25th Annual Oregon Geriatrics Society Conference, held October 10-13, 2024, in Sunriver Resort, OR, and presented by Oregon Health and Science University. For more information about upcoming CME activities from this presenter, please visit https://www.ohsu.edu/school-of-medicine/cpd. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

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