The Challenge of Hyponatremia

BRIEF REVIEW www.jasn.org The Challenge of Hyponatremia † ‡ Horacio J. Adrogué* and Nicolaos E. Madias § *Department of Medicine, Baylor College of Medicine, Methodist Hospital, Houston, Texas; †Renal Section, Veterans Affairs Medical Center, Houston, Texas; ‡Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts; and §Division of Nephrology, Department of Medicine, St. Elizabeth’s Medical Center, Boston, Massachusetts ABSTRACT Treatment of hypotonic hyponatremia often challenges clinicians on many counts. pathogenesis and putative cause(s) of Despite similar serum sodium concentrations, clinical manifestations can range from hyponatremia, the case-specificclinical mild to life threatening. Some patients require active management, whereas others and laboratory features, and the associ- recover without intervention. Therapeutic measures frequently yield safe correc- ated clinical risk. Second, a management tion, yet the same measures can result in osmotic demyelination. To address this plan is tailored to the diagnostic findings challenge, we present a practical approach to managing hyponatremia that centers that incorporates quantitative projec- on two elements: a diagnostic evaluation directed at the pathogenesis and putative tions of prescribed fluid therapy and on- causes of hyponatremia, the case-specific clinical and laboratory features, and the going fluid losses on the patient’sserum associated clinical risk; and a management plan tailored to the diagnostic findings sodium, balances potential benefits and that incorporates quantitative projections of fluid therapy and fluid losses on the risks, and emphasizes vigilant monitor- patient’s serum sodium, balances potential benefits and risks, and emphasizes vig- ing. Here we present a practical ap- ilant monitoring. These principles should enable the clinician to formulate a man- proach to managing hyponatremia that agement plan that addresses expeditiously three critical questions: Which of the centers on these principles. determinants of the serum sodium are deranged and what is the underlying culprit? How urgent is the need for intervention? What specific therapy should be instituted and which are the associated pitfalls? DIAGNOSTIC EVALUATION J Am Soc Nephrol 23: 1140–1148, 2012. doi: 10.1681/ASN.2012020128 Estimating the State of the Determinants of the Decreased Serum Sodium Hypotonic hyponatremia, the most com- recognized adverse effects, and the intro- The serum sodium concentration is ap- mon and relevant form of the disorder, duction of vaptans (vasopressin receptor proximated by the sum of the exchange- often challenges clinicians. Little infor- antagonists), have rekindled physician able (osmotically active) portions of the mation might beavailable at presentation interestinthedisorderandcouldimprove body’s sodium and potassium content about the patient and the prevailing hy- its management.1–9 Notwithstanding, divided by total body water (Edelman ponatremia other than its severity. One or current medical care frequently proves equation; Figure 1).23,24 Maintenance of several predisposing conditions might par- suboptimal resulting in adverse conse- serumsodiumoccursasaby-productof ticipate in the generation of hyponatremia. quences of either hyponatremia or its treat- matching the intake of sodium, potassium, Clinical manifestations can vary widely ment both in adults and children.10–17 and water with the corresponding losses. despite similar serum sodium concentra- Relowering the serum sodium has been The Edelman equation establishes that tions. Some patients require active man- introduced to address the not uncom- hypotonic (or dilutional) hyponatremia agement, whereas others recover without mon overcorrection of hyponatremia.18–20 represents an excess of water relative to intervention. Therapeutic measures fre- Even preventive administration of quently yield safe correction, yet the same desmopressin, a hormone that can actu- Published online ahead of print. Publication date measures can result in osmotic demye- ally aggravate hyponatremia, has been available at www.jasn.org. lination. The challenge to the clinician is proposed to counter the risk of over- commonly heightened by major comor- correction.21,22 Correspondence: Dr. Nicolaos E. Madias, Division of Nephrology, Department of Medicine, St. Elizabeth’s bidities such as hepatic encephalopathy We contend that confronting the Medical Center, 736 Cambridge Street, Boston, or potassium depletion. challenge of hyponatremia requires a MA 02135. Email: [email protected] Recentdevelopmentsinhyponatremia, two-pronged approach. First, a diagnos- Copyright © 2012 by the American Society of including epidemiologic insights, newly tic evaluation is aimed at identifying the Nephrology 1140 ISSN : 1046-6673/2307-1140 JAmSocNephrol23: 1140–1148, 2012 www.jasn.org BRIEF REVIEW Numerous conditions can impose an aquaretic defect and thus predispose to hyponatremia.25,28 Notwithstanding, an effector must be superimposed that would result in a positive electrolyte- free water balance. Typically, the effector is intake of electrolyte-free water in amounts that exceed the composite of renal and extrarenal electrolyte-free water losses. The medical history should provide clues about the predisposing conditions, including an underlying acute or chronic disease, as well as fluid and electrolyte intake and losses, protein intake, changes in body weight, medi- cations (thiazides, selective serotonin reuptake inhibitors), and previous diagnosis of hyponatremia. Physical examination allows assessment of extracellular fluid volume status and identification of signs characteristic of predisposing conditions. Ancillary tests may include serum electrolytes, BUN, cre- atinine, uric acid, serum and urine osmo- Figure 1. Pathogenesis of hypotonic hyponatremia as derived from the Edelman equation. lality, serum cortisol and thyroid panel, Hypotonic hyponatremia represents an excess of water relative to the body’s sodium and and radiologic studies (head computed potassium stores. In that context, patients with hypotonic hyponatremia can feature de- tomography scan or magnetic resonance + + creased, normal, or increased Nae ; decreased or normal Ke ; and decreased, normal, or imaging). + + increased TBW. Nae , exchangeable sodium; Ke , exchangeable potassium; TBW, total Measuring urine electrolytes and com- body water. puting the urine/serum (U/S) electrolyte ratio, which is the sum of the urinary concentrations of sodium and potassium the sodium and potassium stores. Water body water. Loss of potassium depletes dividedbytheserum sodium,canpointto retention usually results from impair- intracellular stores, leading to transfer the effect of the urine output on the level ment of renal excretion of electrolyte- of sodium from the extracellular to the of serum sodium at the time of evaluation free water (aquaresis); less commonly, it intracellular fluid and generating hypo- (Figure 3). If the ratio is approximately 1, is caused by excessive intake of water natremia coupled with hypokalemia. the urine output is not affecting the se- while excretory capacity is normal or Not infrequently, all three determinants rum sodium; if .1, the urine contributes nearly normal.25 might contribute to decreasing serum to lowering the serum sodium; and if In hyponatremia caused by water re- sodium. The clinician must collect the #0.5, it indicates that one-half or more of tention, sodium and potassium stores relevant clinical information and labo- the urine volume amounts to electrolyte- remain essentially unchanged but body ratory data to infer the state of these free water and thus the urine contributes water is increased; these patients exhibit determinants in the individual case of to raising the serum sodium.26,29 The euvolemic hyponatremia, including the hyponatremia. larger the urine output, the greater the syndrome of inappropriate antidiuresis effect of a U/S electrolyte ratio Þ1on (SIAD) and some endocrinopathies.25–27 Unraveling the Predisposing serum sodium. Renal or extrarenal fluid losses deplete Condition and the Effector of sodium,potassium,andwaterstores; Hyponatremia Establishing the Clinical Risk of subsequent water retention results in hy- Generation of hypotonic hyponatremia Hyponatremia ponatremia. These patients exhibit ex- occurs as a by-product of unmatching the The level of serum sodium correlates tracellular fluid volume contraction. electrolyte (sodium and potassium) and inversely with clinical risk, with levels Conversely, retention of sodium and water content of all intake and output ,120 mEq/L being regarded as severe water in edematous disorders can also such that a net gain of electrolyte-free hyponatremia. Clinical manifestations be associated with hyponatremia, which water relative to the body’ssodiumand are dependent on the severity and acute- reflects a disproportionate increase in potassium stores ensues (Figure 2). ness of the hypotonic state.25,30,31 Acute J Am Soc Nephrol 23: 1140–1148, 2012 Managing Hyponatremia 1141 BRIEF REVIEW www.jasn.org hyponatremia results in brain swelling THERAPEUTIC PRINCIPLES encephalopathy, while providing a margin and intracranial hypertension; it can of protection from osmotic demyelin- progress to life-threatening neurologic Treating Actual or Impending Life- ation, a condition that can occasionally de- complications, including seizures, coma, Threatening Complications velop after correcting serum sodium by brain-stem herniation, and respiratory Severely

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