Evaluation of hyponatremia

Hyponatremia is the most common electrolyte disorder encountered in clinical practice and is estimated to occur in up to 35% of hospital inpatients.[1]Adrogué HJ, Tucker BM, Madias NE. Diagnosis and management of hyponatremia: a review. JAMA. 2022 Jul 19;328(3):280-91. http://www.ncbi.nlm.nih.gov/pubmed/35852524?tool=bestpractice.com ​​​​ It is defined as a serum sodium <135 mEq/L (normal serum sodium concentration is in the range of 135 to 145 mEq/L); severe hyponatremia is defined biochemically as a serum sodium <125 mEq/L. Symptom severity may not correlate with the biochemical level of hyponatremia; management approach should be informed by the presenting clinical symptoms.[2]Ball S, Barth J, Levy M, et al. Society for Endocrinology Endocrine Emergency Guidance: emergency management of severe symptomatic hyponatraemia in adult patients. Endocr Connect. 2016 Sep;5(5):G4-6. https://pmc.ncbi.nlm.nih.gov/articles/PMC5314809 http://www.ncbi.nlm.nih.gov/pubmed/27935814?tool=bestpractice.com Patients with hyponatremia have increased morbidity and mortality compared with patients without hyponatremia.[3]Spasovski G, Vanholder R, Allolio B, et al; Hyponatraemia Guideline Development Group. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Eur J Endocrinol. 2014 Feb 25;170(3):G1-47. https://academic.oup.com/ejendo/article/170/3/G1/6668028 http://www.ncbi.nlm.nih.gov/pubmed/24569125?tool=bestpractice.com ​​[4]Lien YH, Shapiro JI. Hyponatremia: clinical diagnosis and management. Am J Med. 2007 Aug;120(8):653-8. http://www.ncbi.nlm.nih.gov/pubmed/17679119?tool=bestpractice.com ​ Mild hyponatremia is an independent risk factor for adverse outcome and mortality even in the general population.[5]Sajadieh A, Binici Z, Mouridsen MR, et al. Mild hyponatremia carries a poor prognosis in community subjects. Am J Med. 2009 Jul;122(7):679-86. http://www.ncbi.nlm.nih.gov/pubmed/19559171?tool=bestpractice.com

Hyponatremia is primarily a disorder of water balance. A low serum sodium concentration indicates an increase in total body water relative to sodium. The clinical manifestations of hyponatremia depend on the rate of decline of serum sodium. An acute fall in sodium over 24-48 hours produces severe cerebral edema, which can be fatal.[6]Wakil A, Ng JM, Atkin SL. Investigating hyponatraemia. BMJ. 2011 Mar 7;342:d1118. http://www.ncbi.nlm.nih.gov/pubmed/21382929?tool=bestpractice.com A gradual fall in sodium over several days or weeks can be compensated for by the brain, produces relatively modest morbidity and may be asymptomatic.[6]Wakil A, Ng JM, Atkin SL. Investigating hyponatraemia. BMJ. 2011 Mar 7;342:d1118. http://www.ncbi.nlm.nih.gov/pubmed/21382929?tool=bestpractice.com

In most cases, hyponatremia reflects hypotonicity or low effective osmolality. It is often iatrogenic and avoidable. Common causes of hyponatremia include true volume depletion, effective arterial volume depletion (e.g., congestive heart failure, cirrhosis), and drug-induced hyponatremia due to thiazide diuretics or antidepressants.[6]Wakil A, Ng JM, Atkin SL. Investigating hyponatraemia. BMJ. 2011 Mar 7;342:d1118. http://www.ncbi.nlm.nih.gov/pubmed/21382929?tool=bestpractice.com [7]Montanana PA, Modesto i Alapont V, Ocon AP, et al. The use of isotonic fluid as maintenance therapy prevents iatrogenic hyponatremia in pediatrics: a randomized, controlled open study. Pediatr Crit Care Med. 2008 Nov;9(6):589-97. http://www.ncbi.nlm.nih.gov/pubmed/18838929?tool=bestpractice.com [8]Grant P, Ayuk J, Bouloux PM, et al. The diagnosis and management of inpatient hyponatraemia and SIADH. Eur J Clin Invest. 2015 Aug;45(8):888-94. https://onlinelibrary.wiley.com/doi/10.1111/eci.12465 http://www.ncbi.nlm.nih.gov/pubmed/25995119?tool=bestpractice.com

Types of hyponatremia

Hyponatremia can result from a variety of conditions, based on different mechanisms, and can have multiple drivers. It may result from an inappropriate hypotonic fluid intake, inappropriate fluid retention by excessive antidiuretic hormone (ADH) which increases renal water reabsorption, or inadequate renal reabsorption of sodium.

Hyponatremia can be classified according to the serum tonicity as being hypertonic, isotonic, or hypotonic:[1]Adrogué HJ, Tucker BM, Madias NE. Diagnosis and management of hyponatremia: a review. JAMA. 2022 Jul 19;328(3):280-91. http://www.ncbi.nlm.nih.gov/pubmed/35852524?tool=bestpractice.com [9]Lippi G, Aloe R. Hyponatremia and pseudohyponatremia: first, do no harm [letter]. Am J Med. 2010 Sep;123(9):e17. http://www.amjmed.com/article/S0002-9343(10)00390-6/fulltext http://www.ncbi.nlm.nih.gov/pubmed/20800135?tool=bestpractice.com [10]Verbalis JG, Goldsmith SR, Greenberg A, et al. Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations. Am J Med. 2013 Oct;126(10 suppl 1):S1-42. https://www.amjmed.com/article/S0002-9343(13)00605-0/fulltext http://www.ncbi.nlm.nih.gov/pubmed/24074529?tool=bestpractice.com

• Hypertonic hyponatremia, also known as redistributive hyponatremia, occurs when the presence of excess levels of an osmolyte such as glucose or mannitol cause water to shift from the intracellular to the extracellular compartment, diluting extracellular sodium.

• Isotonic hyponatremia often indicates pseudohyponatremia, an artifact caused by high lipid or protein levels that results in incorrect laboratory measurement of serum sodium concentration.

• Hypotonic, or true, hyponatremia is the most common and most concerning type of hyponatremia and encompasses all other causes of hyponatremia. It can be further classified according to fluid volume status as hypovolemic, euvolemic, or hypervolemic:

  • Hypovolemic hyponatremia (hypotonic): total body water decreases, but total body sodium decreases to a greater extent. The extracellular fluid volume is also decreased.

  • Euvolemic hyponatremia (hypotonic): total body water increases, but total body sodium remains unchanged. There is a modest increase in extracellular fluid volume, but not enough to cause edema.

  • Hypervolemic hyponatremia (hypotonic): total body water and sodium both increase, but total body water increases to a greater extent. The extracellular fluid volume is markedly increased, causing edema.

Hyponatremia can also be classified according to its rate of onset.[3]Spasovski G, Vanholder R, Allolio B, et al; Hyponatraemia Guideline Development Group. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Eur J Endocrinol. 2014 Feb 25;170(3):G1-47. https://academic.oup.com/ejendo/article/170/3/G1/6668028 http://www.ncbi.nlm.nih.gov/pubmed/24569125?tool=bestpractice.com ​

• Acute hyponatremia is defined as hyponatremia with a duration of <48  hours.

• Chronic hyponatremia is defined as hyponatremia with a duration of at least 48  hours. Chronic hyponatremia is much more common than acute, and cases where the duration of hyponatremia is unclear should be considered to be chronic unless there is clinical evidence suggesting otherwise.

Central nervous system effects of hyponatremia

Hyponatremia is significant when it is associated with a decline in effective extracellular osmolality, or tonicity, as it causes cellular edema. Most tissues can tolerate cellular edema, apart from the bony calvarium due to space limitations. Brain cells have long-term adaptive mechanisms that can compensate for low serum sodium and a decline in effective osmolality/tonicity by giving up ions like potassium and synthesizing organic osmolytes to preserve cell volume. If the sodium concentration falls slowly over several days or weeks, the brain is able to use such mechanisms to adapt. For this reason, patients with chronic hyponatremia have relatively modest cerebral edema and do not develop brainstem herniation. However, if the sodium concentration falls rapidly over 24 to 48 hours, the compensatory mechanisms of the brain are overwhelmed and severe cerebral edema occurs, leading to brainstem herniation, respiratory arrest, and death. This can occur even with a modest fall in serum sodium levels (125-130 mEq/L).

Failure to correct hyponatremia can lead to permanent neurologic damage, as can correcting sodium levels too rapidly.[3]Spasovski G, Vanholder R, Allolio B, et al; Hyponatraemia Guideline Development Group. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Eur J Endocrinol. 2014 Feb 25;170(3):G1-47. https://academic.oup.com/ejendo/article/170/3/G1/6668028 http://www.ncbi.nlm.nih.gov/pubmed/24569125?tool=bestpractice.com ​ When hyponatremia is chronic and the serum sodium concentration increases too rapidly, osmotic demyelination syndrome (ODS; also known as central pontine myelinolysis) may develop. ODS is characterized by altered mental status, reduced motor functioning, and/or abnormalities of balance.[11]Lindner G, Schwarz C, Haidinger M, et al. Hyponatremia in the emergency department. Am J Emerg Med. 2022 Oct;60:1-8. https://www.sciencedirect.com/science/article/pii/S0735675722004600 http://www.ncbi.nlm.nih.gov/pubmed/35870366?tool=bestpractice.com [12]Wang P, Li T. Osmotic demyelination syndrome: clinical and neuroimaging characteristics in a series of 8 cases. Quant Imaging Med Surg. 2023 Jul 1;13(7):4785-91. https://qims.amegroups.org/article/view/113564/html http://www.ncbi.nlm.nih.gov/pubmed/37456327?tool=bestpractice.com