Diagnosis and Treatment of Hyponatremia: Compilation of the Guidelines
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BRIEF REVIEW www.jasn.org Diagnosis and Treatment of Hyponatremia: Compilation of the Guidelines Ewout J. Hoorn and Robert Zietse Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, The Netherlands ABSTRACT Hyponatremia is a common water balance disorder that often poses a diagnostic or approach to hyponatremia, two sets of therapeutic challenge. Therefore, guidelines were developed by professional orga- guidelines have been developed, one by nizations, one from within the United States (2013) and one from within Europe professional organizations from within (2014). This review discusses the diagnosis and treatment of hyponatremia, com- the United States (“United States guide- paring the two guidelines and highlighting recent developments. Diagnostically, the line”) and one from within Europe (“Eu- initial step is to differentiate hypotonic from nonhypotonic hyponatremia. Hypo- ropean guideline,” in which the authors tonic hyponatremia is further differentiated on the basis of urine osmolality, urine of this review participated).6–9 The pro- sodium level, and volume status. Recently identified parameters, including fractional fessional organizations involved in the uric acid excretion and plasma copeptin concentration, may further improve the United States guideline were Tufts Uni- diagnostic approach. The treatment for hyponatremiaischosenonthebasisof versity Office of Continuing Education duration and symptoms. For acute or severely symptomatic hyponatremia, both and In 2 MedEd; the initiative was guidelines adopted the approach of giving a bolus of hypertonic saline. Although also supported by an unrestricted edu- fluid restriction remains the first-line treatment for most forms of chronic hypona- cational grant from Otsuka America tremia, therapy to increase renal free water excretion is often necessary. Vasopres- Pharmaceutical.9 The professional orga- sin receptor antagonists, urea, and loop diuretics serve this purpose, but received nizations involved in the European different recommendations in the two guidelines. Such discrepancies may relate to guideline were the European Renal As- different interpretations of the limited evidence or differences in guideline meth- sociation–European Dialysis and Trans- odology. Nevertheless, the development of guidelines has been important in ad- plantation Association, the European vancing this evolving field. Society of Endocrinology, and the Euro- pean Society of Intensive Care Medi- J Am Soc Nephrol 28: ccc–ccc, 2017. doi: 10.1681/ASN.2016101139 cine.6–8 The United States guideline refrained from using a quality-of-evidence scoring system due to the limited evi- dence. Instead, the guideline was on “ ” Hyponatremia (serum sodium [SNa] studies, because the patient with hypo- the basis of expert panel recommenda- , 136 mmol/L) is a common water bal- natremia does not exist. Instead, the un- tions, which relied on a critical evalua- ance disorder that often poses a diagnos- derlying disease that is complicated by tion of relevant literature by the panel 1 tic or therapeutic challenge. This may hyponatremia usually characterizes pa- members. The European guideline 4,5 explain why management of hyponatre- tients with hyponatremia. The most did perform systematic reviews of the mia is still suboptimal, as also recently common causes of hyponatremia are available evidence using the Grading of illustrated by a hyponatremia registry.2 the syndrome of inappropriate antidiu- Hyponatremia is not a disease but resis (SIAD), diuretic use, polydipsia, rather a pathophysiologic process indi- adrenal insufficiency, hypovolemia, 3 Published online ahead of print. Publication date cating disturbed water homeostasis. heart failure, and liver cirrhosis (the lat- available at www.jasn.org. Therefore, hyponatremia should be fur- ter two are often collectively referred to ther classified in order to provide direc- as “hypervolemic hyponatremia”). Al- Correspondence: Dr. Ewout J. Hoorn, Erasmus Medical Center, Internal Medicine – Nephrology, tions for diagnosis and treatment (Table though recent years have seen several Room D-438, PO Box 2040, 3000 CA, Rotterdam, 1). These classifications illustrate that developments in the diagnosis and treat- The Netherlands. Email: [email protected] hyponatremia is a very heterogeneous ment of hyponatremia, the evidence base Copyright © 2017 by the American Society of disorder. This has complicated clinical is still limited. To capture the current Nephrology J Am Soc Nephrol 28: ccc–ccc, 2017 ISSN : 1046-6673/2805-ccc 1 BRIEF REVIEW www.jasn.org Table 1. Classifications of hyponatremia Limitations of Classification Criteria Clinical Utility Moderate (125–129 mmol/L) Absolute SNa concentration Symptoms do not always a versus severe/profound correlate with degree of hyponatremia (,125 mmol/L) Acute versus chronic Time of development (cutoff 48 h) Time of development not always known Symptomatic versus asymptomatic Presence of symptoms Many symptoms aspecific; chronic hyponatremia may be symptomatic Hypotonic, isotonic, or hypertonic Measured serum osmolality Ineffective osmoles (e.g., urea, ethanol) are also measured Hypovolemic, euvolemic, hypervolemic Clinical assessment of Clinical assessment of volume status volume status has low sensitivity and specificity a 7,9 SNa,125 mmol/L is defined as “severe hyponatremia” by the United States guideline, and as “profound hyponatremia” by the European guideline. Recommendations Assessment Develop- or protein.16 The United States guide- less able to reabsorb sodium.7,22 In ad- ment and Evaluation scoring system. line subsequently divided hypotonic dition, advanced CKD usually impairs Both guideline committees were interdis- hyponatremia into hypovolemic, euvo- water excretion, complicating the eval- ciplinary, and the European guideline was lemic, and hypervolemic hyponatre- uation of the role of vasopressin in water endorsed by the European societies of ne- mia.9 Although this represents the balance.23 These considerations prompted phrology, endocrinology, and intensive most traditional and commonly used the European guideline committee care.6–8 This brief review will compare approach to hypotonic hyponatremia, to propose an algorithm that prioritizes the two guidelines to discuss the diagnosis it deserves scrutiny. Hypovolemic and UOsm and UNa over volume status (Fig- and treatment of hyponatremia, while euvolemic hyponatremia are notori- ure 1). It also incorporates the limita- also highlighting recent developments. ously difficult to differentiate on the ba- tions of UNa. In addition, it recommends Because of the breadth of both guidelines, sis of physical examination,17 whereas early identification of acute or symp- this review will focus on the salient fea- hypervolemic hyponatremia is usually tomatic hyponatremia to identify pa- tures. Toplace both guidelines in perspec- clinically obvious (presence of edema tients in whom immediate treatment is tive we will integrate in our discussion the or ascites). Two studies that analyzed indicated. Two additional diagnostic pertinent comments published after their the diagnostic performance of the clin- tests for hyponatremia merit discussion, release.10–13 ical assessment of volume status in pa- including a trial of volume expansion tients with hyponatremia reported low and the fractional uric acid excretion sensitivity (50%–80%) and specificity (FEUA). A trial of volume expansion DIFFERENTIAL DIAGNOSIS OF (30%–50%).18,19 Previously, we showed with isotonic saline can be used to diag- HYPONATREMIA that clinicians often misclassify hypona- nose hypovolemic hyponatremia.18 tremia when using algorithms that start Although a rise in SNa in response to iso- Although the United States guideline did with clinical assessment of volume sta- tonic saline would be consistent with not present a diagnostic algorithm, the tus.20 Similarly, physicians in training hypovolemic hyponatremia, another classifications of hyponatremia on the had a better diagnostic performance possibility would be that the stimulus basis of tonicity and volume status than senior physicians when using an for vasopressin release in a patient with were discussed.9 The initial differentia- algorithm in which urine osmolality SIAD abated. Such stimuli are often tion in hypotonic and nonhypotonic (UOsm) and urine sodium (UNa)con- nonspecific and transient, including 14,24 hyponatremia is important, because centration are prioritized over assess- pain or nausea. In addition, SNa management is different.14 Nonhypo- ment of volume status.21 Because the has been shown to improve upon saline tonic hyponatremia is usually caused by kidneys will respond to hypovolemia infusion in patients with SIAD with 25 hyperglycemia, but may also be caused or a low effective arterial blood volume UOsm,500 mOsm/kg. Conversely, by the administration of mannitol or with sodium retention, UNa,30 mmol/L isotonic saline may sometimes worsen hypertonic radiocontrast.7 In these set- can be used to identify both hypovole- hyponatremia, a phenomenon called tings, management is usually conserva- mic and hypervolemic hyponatremia. “desalination.”26 In response to the tive, although a decrease in extracellular Three caveats, however, should be em- United States guideline, Gross raised 15 tonicity may occur during treatment. phasized: (1)UNa will also be low in pa- the issue of how to deal with mixed Nonhypotonic hyponatremia can also be tients consuming a low sodium diet forms of hyponatremia, for example