hiponatremia 2015

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HyponatremiaHyponatremia is the most common elec-trolyte disorder in hospitalized patients.Hospital-associated hyponatremia in-cludes admission hyponatremia (community-acquired hyponatremia) and hospital-acquiredhyponatremia. The reported incidence ofhospital-associated hyponatremia ranges be-tween 10% and 30%, depending on the defini-tion, patient population, and case mix. It is asso-ciated with increased mortality, hospital lengthof stay, hospital costs, intensive care unit (ICU)days, and chance of readmission (1). Acute on-set or rapid correction of severe chronic casescan cause extensive or fatal brain damage, buteven mild chronic cases can have adverse out-comes, such as decreased cognition, osteopo-rosis, increased risk for falls, and fractures (2).

The CME quiz is available at www.annals.org/intheclinic.aspx. Complete the quiz to earn up to 1.5 CME credits.

Physician WriterDan A. Henry, MD

CMEObjective: To review current evidence for prevention, diagnosis, treatment, and practiceimprovement for hyponatremia.

Funding Source: American College of Physicians.

Disclosures:Dr. Henry, ACP Contributing Author, has disclosed no conflicts of interest.Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-2454.

With the assistance of additional physician writers, Annals of Internal Medicine editorsdevelop In the Clinic using resources of the American College of Physicians, includingACP Smart Medicine andMKSAP (Medical Knowledge and Self-Assessment Program).

In the Clinic does not necessarily represent official ACP clinical policy. For ACP clinicalguidelines, please go to https://www.acponline.org/clinical_information/guidelines/.

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Patients with no underlying dis-ease canmaintain normal plasmasodium levels. Levels are deter-mined by the total exchangeableextracellular sodium and intracel-lular potassium divided by totalbody water. Hyponatremia is adisorder of water balance. Theability to excrete dilute urine al-lows people without any underly-ing disease to drink large amountsof water (nearly a liter an hour)without becoming hyponatremic.Maintenance of water balance re-quires normally functioning kid-neys; sufficient urine urea (theend-product of protein metabo-lism); and suppressed secretion ofthe antidiuretic hormone, arginine

vasopressin (AVP), when plasmasodium levels fall below 135mEq/L. Hyponatremia develops ifmore water is ingested than canbe excreted by the kidneys or ifthe ability to excrete a large vol-ume of dilute urine is compro-mised because of kidney disease,diuretics, low protein intake, or thepresence of AVP. The amount offree water excreted is determinedby urine volume, sodium, and po-tassium. If the sum of urinary so-dium and potassium is less that ofplasma sodium, free water is ex-creted (3). A complete overview ofsodium and water balance can befound elsewhere (4).

PreventionWho is at risk forhyponatremia?Up to 13% of individuals partici-pating in endurance exercise(marathons and triathlons) de-velop hyponatremia, which canbe severe (1 episode of hypona-tremia during a follow-up period of 5.5 years (6).

Diuretics impair the kidney's abilityto excrete dilute urine. Thiazidesare a particularly common cause ofhyponatremia30% of thiazide-treated patients develop hypona-tremia over 10 years (7). In 1 studyof patients who became hypona-tremic after receiving thiazides, theelectrolyte disturbance developedwithin 2 weeks in approximatelytwo thirds of cases and within 5days in half (8). In another study,patients developed hyponatremiaafter a median of 116 days (9). El-derly patients as well as those withlow body weight and hypokalemiahave an increased risk for thiazide-associated hyponatremia (9).Other drugs can interfere with theability to dilute the urine, mostcommonly selective serotonin re-uptake inhibitors (SSRIs), selectivenorepinephrine reuptake inhibi-tors (SNRIs), carbamazepine, andoxcarbazepine. Hyponatremiadevelops in 0.5%30% of pa-tients receiving SSRIs andSNRIs, usually within 2 weeks.Elderly patients, those who hadprevious episodes of hypona-tremia, and patients receivingconcurrent thiazide treatmentare at increased risk (10).

1. Amin A, Deitelzweig S,Christian R, et al. Evalua-tion of incremental health-care resource burden andreadmission rates associ-ated with hospitalizedhyponatremic patients inthe US. J Hosp Med.2012;7:634-9. [PMID:22961813]

2. Renneboog B, Musch W,Vandemergel X, et al.Mild chronic hyponatre-mia is associated withfalls, unsteadiness, andattention deficits. Am JMed. 2006;119:71.e1-8.[PMID: 16431193]

3. Rose BD, Post TW. ClinicalPhysiology of Acid-Baseand Electrolyte Disorders,5th ed. New York:McGraw-Hill: 2001; 699.

4. Eaton DC, Pooler JM.Vander's Renal Physiol-ogy, 8th ed. McGraw-Hill,New York: McGraw-Hill;2013.

5. Almond CS, Shin AY, For-tescue EB, et al. Hypona-tremia among runners inthe Boston Marathon. NEngl J Med. 2005;352:1550-6. [PMID:15829535]

6. Kovesdy CP, Lott EH, JuJL, et al. Hyponatremia,hypernatremia, and mor-tality in patients withchronic kidney diseasewith and without conges-tive heart failure. Circula-tion. 2012;125:677-84.[PMID: 22223429]

7. Leung AA, Wright A, PazoV, et al. Risk of thiazide-induced hyponatremia inpatients with hyperten-sion. Am J Med. 2011;124:1064-72. [PMID:22017784]

8. Chow KM, Kwan BC, SzetoCC. Clinical studies ofthiazide-induced hypona-tremia. J Natl Med Assoc.2004;96:1305-8. [PMID:15540881]

9. Chow KM, Szeto CC,Wong TY, et al. Risk factorsfor thiazide-induced hy-ponatraemia. QJM. 2003;96:911-7. [PMID:14631057]

10. Wilkinson TJ, Begg EJ,Winter AC, et al. Inci-dence and risk factors forhyponatraemia followingtreatment with fluoxetineor paroxetine in elderlypeople. Br J Clin Phar-macol. 1999;47:211-7.[PMID: 10190657]

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The ability to excrete water isalso limited when the posteriorpituitary continues to secreteAVP despite a low plasma so-dium concentration. AVP is se-creted without an osmotic stimu-lus if circulation is inadequate, asin patients with hypovolemia orheart or liver disease. Inappro-priate secretion of AVP occurs inthe absence of both osmotic andhemodynamic stimulus. Affectedpatients have the syndrome ofinappropriate antidiuretic hor-mone secretion (SIADH). Hypo-natremia due to SIADH is com-mon in hospitalized patientsbecause AVP is released in re-sponse to hypoxia, pain, orstress. Patients at particularlyhigh risk include postsurgery pa-tients, elderly persons, personsadmitted to the intensive careunit, and patients with centralnervous system disorders. Finally,hyponatremia is especially com-mon among hospitalized chil-dren receiving hypotonic fluids,and fewer patients develop hy-ponatremia if isotonic salinerather than hypotonic saline isused to treat gastroenteritis (11).

What potential measures canprevent or limit the severity ofhyponatremia?Clinicians should encourage run-ners to drink fluids only whenthey have increased thirst and tomonitor their body weight toavoid weight gain during exer-cise. Plasma sodium levelsshould be checked 12 weeksafter initiation of thiazide, SNRI,and SSRI therapy, especially inpatients at high risk for hypona-tremia. Thiazides should beavoided in persons with highfluid or low protein intake andduring acute illness.

Plasma sodium levels should bemeasured in all hospitalized pa-tients on admission; low sodiumlevels should be treated basedon the underlying cause. Hypo-tonic fluids and thiazide diuret-ics should be avoided, espe-cially in patients at increasedrisk for hyponatremia. Cliniciansshould monitor daily plasmasodium levels in patients withhyponatremia or in those at in-creased risk.

DiagnosisWhat characteristic symptomsor physical findings shouldalert clinicians to the diagnosisof hyponatremia?

Hyponatremic patients can beasymptomatic or have symptomsthat are moderate (nausea, con-fusion, headache, vomiting) orsevere (delirium; impaired con-

sciousness; seizures; and, rarely,cardiorespiratory arrest). Nota-bly, mild chronic hyponatremia(plasma sodium 125135 mEq/L)may cause subtle neurocognitivedeficits that can only be detectedby careful testing; these deficitsimprove when the plasma so-dium is normalized (12). Becausehyponatremic patients are at risk

11. Neville KA, Verge CF,Rosenberg AR, OMearaMW, et al. Isotonic isbetter than hypotonicsaline for intravenousrehydration of childrenwith gastroenteritis: aprospective randomisedstudy. Arch Dis Child.2006;91:226-32. [PMID:16352625]

12. Bartter FC, Schwartz WB.The syndrome of inap-propriate secretion ofantidiuretic hormone.Am J Med. 1967;42:790-806. [PMID:5337379]

Prevention... Hyponatremia is common in patients participating in en-durance exercise and those receiving thiazides, SSRIs, or SNRIs. Elderlypatients; those with congestive heart failure, cirrhosis, or pneumonia;and persons admitted to the ICU are at increased risk for hospital-acquired hyponatremia. Hypotonic fluids should be avoided inhospitalized patients at increased risk.

CLINICAL BOTTOM LINE

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for osteoporosis, falls, and hipfractures, it should be consideredin the differential diagnosis ofthese conditions (2).

What conditions shouldclinicians consider whenevaluating patients withhyponatremia?Hyponatremia can occur whenrelease of AVP is physiologicallyappropriate, due to decreasedeffective circulating volume, orinappropriate (that is, no physio-logic reason). Urine volume de-creases in response to the releaseof AVP, and hyponatremia will de-velop if water intake exceeds uri-nary and insensible losses of wa-ter. Patients are typically classifiedbased on their total body sodiumas hypovolemic, euvolemic, andhypervolemic (Table 1).

Hypovolemic hyponatremiaPatients with hypovolemic hypo-natremia have a loss (renal or ex-trarenal) of sodium and/or potas-sium and water.

Extrarenal sodium losses can occurwith excessive sweating, pancreati-tis, small bowel obstruction, vomit-ing, and diarrhea. If these lossesare not replaced, they lead to de-creased effective circulating vol-ume and nonosmotic release ofAVP. Hypovolemic hyponatremiacaused by diarrhea or third-spaceloss results in low urine sodiumlevels due to increased renal so-dium reabsorption. Hypovolemiacaused by gastric losses ofhydrochloric acid results in lowurine chloride due to increasedrenal chloride reabsorption, buturine sodiummay not be low be-cause of metabolic alkalosis andresulting bicarbonaturia.

Renal sodium losses occur withglycosuria, cerebral salt wasting(CSW), primary adrenal insuffi-ciency, and diuretics. Loop di-uretics can cause hypovolemichyponatremia, but patients withthiazide-associated hyponatre-

mia are usually clinically euvo-lemic (see next section). CSW isuncommon and can be difficultto differentiate from SIADH. Con-ditions associated with CSW in-clude head injury, subarachnoidhemorrhage, meningitis, enceph-alitis, and central nervous systemtumors or surgery. Patients withCSW have urinary loss of sodiumand water due to a proximal so-dium reabsorption deficit (alsodecreased reabsorption of ureaand uric acid). Because it is oftendifficult to assess volume status inpostneurosurgery patients in theICU, finding a significant negativefluid balance on reviews of thechartIntake/Outputmay indi-cate CSW. In these patients,volume depletion leads to non-osmotic release of AVP and sub-sequent water retention. Similarto patients with SIADH, patientswith CSW have decreased serumlevels of sodium and increasedurinary sodium and osmolality.

A rare but important cause ofhypovolemic hyponatremia isprimary adrenal insufficiency(loss of mineralocorticoids andglucocorticoids, also known asAddison disease). Primary adre-nal insufficiency leads to renalsodium wasting with subsequentvolume depletion, causing non-osmotic release of AVP. Lack ofcortisol also increases AVP re-lease (see isolated glucocorticoiddeficiency in euvolemic hypona-tremia). Patients with Addisondisease typically present with hy-povolemia; hyponatremia; hyper-kalemia; decreased bicarbonate;and increased urine sodium, aninappropriate renal response inthe setting of volume depletion.However, not all patients withprimary adrenal insufficiencyhave this classic presentation.

In a study of 102 patients with Addison dis-ease, 88% were hypotensive (systolic bloodpressure < 110 mm Hg), 12% were ortho-static, and only 66% were hyperkalemic (13).

Table 1. Major Causes of Hypona-tremia Based on Volume Status

HypovolemiaExtrarenal lossesVomitingDiarrheaPancreatitisSweatingSmall bowel obstruction

Renal lossesOsmotic diuresisCerebral salt wastingSalt-losing nephritisDiureticsAddison disease

EuvolemiaPrimary polydipsiaDecreased solute excretionDiureticsHypothyroidismCortisol deficiencySyndrome of inappropriateantidiuretic hormone secretion

HypervolemiaHeart failureLiver disease with cirrhosisNephrotic syndromeChronic kidney disease

13. Nerup J. Addison'sdisease-clinical studies. Areport of 108 cases. ActaEndocrinol. 1974;76:127-41. [PMID:4609691]


Euvolemic hyponatremiaEuvolemic hyponatremia occurswhen total body sodium contentis either normal or slightly de-creased while total body water isincreased. Causes includeSIADH, diuretic use, chronic kid-ney disease, decreased soluteintake, primary polydipsia, gluco-corticoid and thyroid deficiency,and reset osmostat.

SIADH is the most commoncause of euvolemic hyponatre-mia. Patients with this syndromehave a decrease in total bodysodium and an increase in totalbody water resulting in clinicaleuvolemia, but they have labora-tory findings (decreased uric acidand blood urea nitrogen [BUN]creatinine ratio) consistent withslight hypervolemia (12). Table 2presents criteria for diagnosis ofSIADH. SIADH cannot be diag-nosed in patients who are receiv-ing diuretics (particularly thiazidediuretics) or those who have se-vere hypothyroidism or isolatedglucocorticoid insufficiency (sec-ondary adrenal insufficiency). It iscommon in hospitalized patientsand patients treated with SSRIsand SNRIs (10). Table 3 presentscommon causes of SIADH.

Diuretics commonly cause hypo-natremia; thiazides are more of-ten associated with hyponatre-mia than loop diuretics becauseunlike loop diuretics, thiazidesimpair the ability to excrete diluteurine while preserving the abilityto concentrate the urine. Mostpatients with thiazide-inducedhyponatremia are euvolemic(similar to SIADH). They initiallylose sodium but are able to main-tain sodium balance with pro-longed treatment.

In a population-based study, 32.4% of patientswho developed hyponatremia had receivedthiazides; exposure to thiazides was associatedwith a 5-fold greater risk for hyponatremiathan a comparison group with no exposure(hazard ratio, 4.95 [95% CI, 4.125.96]) (14).

Although some studies indicatethat chlorthalidone treatment isassociated with fewer cardio-vascular events than hydrochlo-rothiazide (HCTZ), the former ismore likely to cause hyponatre-mia. A recent study confirmedthat hyponatremia occurs moreoften when chlorthalidone isprescribed in the same dose asHCTZ; however, when the doseof chlorthalidone is half of theHCTZ dose (12.5 mg vs. 25 mg),there is no difference in the in-cidence of hyponatremia (15).

Chronic kidney disease can causeeuvolemic and hypervolemic hy-ponatremia. Patients with chronickidney disease have a decreasedability to dilute and concentrateurine, and urine osmolality is oftenfixed, which limits the ability to in-crease free water excretion (16).Kidney functionmust be normalfor a diagnosis of SIADH.

Primary polydipsia is an unusualcause of hyponatremia; most pa-tients with polydipsia have psychi-atric disease, particularly acute

Table 2. Criteria for the Diagnosis of SIADH

EssentialDecreased effective osmolality of the extracellular fluid (plasma osmolality100 mOsm/kg H2O withnormal renal function) in the presence of decreased effective serum osmolality

Clinical euvolemia, as defined by the absence of signs of hypovolemia(orthostasis, tachycardia, decreased skin turgor, dry mucous membranes) orhypervolemia (subcutaneous edema, ascites)

Absence of urinary sodium conservation (i.e., urine sodium

psychosis with schizophrenia.They can develop hyponatremiathrough rapid ingestion of largeamounts of fluid that exceed thekidney's ability to excrete the vol-ume. Other factors that can con-tribute to hyponatremia in thesepatients include volume depletioncausing increased urine osmolalityand decreased solute excretion;drugs known to cause SIADH; de-creased solute intake; and acutepsychosis, which itself causes anincrease in AVP release (17).

Exercise-associated hyponatre-mia is an acute type of hypona-tremia seen after vigorous endur-ance exercise that occurs withexcessive fluid intake in the pres-ence of increased AVP secretion.

Isolated glucocorticoid deficiencycaused by lack of adrenocortico-trophic hormone (ACTH) results inhyponatremia because cortisol isrequired to inhibit AVP secretion.Aldosterone secretion is notaffected because the reninangiotensinaldosterone systemand levels of potassium control itsrelease. An ACTH stimulation testcan diagnose secondary adrenalinsufficiency, but results can benormal in patients with recent lossof ACTH.

Reset osmostat is a condition inwhich the serum osmolality re-quired to stimulate the release ofAVP is shifted to a lower serumosmolality. This condition hasbeen described in patients withquadriplegia, tuberculosis,chronic malnutrition, and psycho-sis and should be considered in apatient who is diagnosed withSIADH but has stable plasma so-dium levels. The diagnosis is madeby administering a water load tothe patient. In contrast to thosewith SIADH, patients with resetosmostat are able to excrete freewater and reduce urine osmolality.

Hypervolemic hyponatremiaConditions associated with hyper-volemic hyponatremia includeheart failure, cirrhosis with ascites,chronic kidney disease, and thenephrotic syndrome. Patients withthe former two conditions have adecreased effective circulatingvolume. In patients with cirrhosis,decreased effective circulatingvolume is a result of arterial vaso-dilation of the splanchnic circula-tion, which is probably due to in-creased endothelial release of ni-tric oxide. Patients with thenephrotic syndrome have edemausually due to primary sodium re-

Table 3. Common Causes of SIADH

TumorsPulmonary/mediastinal (small cell carcinoma, mesothelioma, thymoma)Nonchest carcinomas (duodenal, stomach, pancreatic, ureteral, prostate,bladder, uterine, nasopharyngeal)

LymphomaEwing sarcoma

Central nervous system disordersMass lesions (tumors, brain abscesses, subdural hematoma)Inflammatory diseases (encephalitis, meningitis, systemic lupus, acuteintermittent porphyria, multiple sclerosis)

Degenerative/demyelinative diseases (Guillain-Barre syndrome, spinal cordlesions)

Miscellaneous (subarachnoid hemorrhage, head trauma, acute and chronicpsychosis, delirium tremens, pituitary stalk section, transsphenoidaladenomectomy, hydrocephalus, cerebrovascular accident, cavernous sinusthrombosis)

Drug-inducedStimulated AVP release (narcotics, nicotine, phenothiazines, tricyclics)Direct renal effects, potentiation of AVP antidiuretic effects (desmopressin,oxytocin, prostaglandin synthesis inhibitors), or both

Mixed or uncertain actions (carbamazepine and oxcarbazepine, chlorpropamide,clofibrate, clozapine, cyclophosphamide, ifosfamide, 3,4-methylenedioxy-methamphetamine [ecstasy], serotonin reuptake inhibitors, vincristine)

Pulmonary diseasesInfections (tuberculosis, acute bacterial and viral pneumonia, pulmonary abscess,aspergillosis, emphysema)

Mechanical/ventilatory (acute respiratory failure, asthma, COPD, positivepressure ventilation)

OtherRocky Mountain spotted feverAIDS and early symptomatic HIV infectionNausea, pain, stressProlonged strenuous exercise (marathon, triathlon, ultramarathon, hot-weatherhiking)

Mutations of the aquaretic vasopressin receptorIdiopathic

AVP = arginine vasopressin; COPD = chronic obstructive pulmonary disease; SIADH =syndrome of inappropriate secretion of antidiuretic hormone.

17. Goldman MB, LuchinsDJ, Robertson GL. Mech-anism of altered watermetabolism in psychoticpatients with polydipsiaand hyponatremia. NEngl J Med. 1988;318:397. [PMID: 3340117]


tention that results in overfilling ofthe intravascular volume.

What is the overall approach tothe diagnosis of hyponatremia?Two papers have highlighted thedifficulties in identifying thecause of hyponatremia.

In the first study, 121 consecutive patients pre-senting with plasma sodium levels

If plasma osmolality is low (< 275mOsm/kg H2O) after increasedurea and glucose are correctedfor, the patient has hypotonichyponatremia, the most commonform of hyponatremia.

What is the role of volumestatus, urine osmolality, andurinary sodium in theevaluation of patients withhyponatremia?If the patient has hypotonic hy-ponatremia, the next step is tomeasure urine osmolality (Fig-ure). If urine osmolality is < 100mOsm/kg H2O, then polydipsiaor decreased solute excretion isusually the cause. Urine osmola-lity 200mOsm/kg H2O, the patient is not receiv-ing diuretics, and kidney functionis normal, then AVP is playing anetiologic role. To determine thecause of AVP secretion, the nextstep is to classify the patient'svolume status on the basis ofthe history and physical exami-nation. Volume status is typi-cally classified into 3 categories:hypovolemia, clinical euvol-emia, or hypervolemia.

Patients with hypovolemic hypo-natremia are further subdividedinto whether they are experienc-ing extrarenal or renal sodiumlosses. If extrarenal losses arelikely (due to vomiting, diarrhea,pancreatitis, and small bowel ob-struction), urinary studies shouldshow low sodium (< 30 mEq/L)and increased osmolality. Oneexception is vomiting patients; inthese cases, urinary sodiumcould be > 30 mEq/L but urinarychloride will be < 30 mEq/L. Re-

Figure. Approach to the diagnosis of hyponatremia.

Measure plasmaosmolality, urea,

and glucose

Normotonicity275295 mOsm/kg Hyperlipidemia Hyperproteinemia Glycine

Hypertonicity withosmotically activesolutes present> 295 mOsm/kg Glucose Mannitol Glycine

High probabiityof hypovolemia

Clinicaleuvolemia

Appendix Figure 1 Appendix Figure 2 Appendix Figure 3

HypervolemiaPolydipsiaDecreased solute excertion Beer potomania Tea and toast diet

Consider Polydipsia Decreased solute excretion Beer potomania Tea and toast diet

Measure U ,osmU ,Na Ucl

Uosm < 100mOsm/kg

Uosm 100200mOsm/kg

Uosm > 200mOsm/kg

PNa < 136 mEq/L

Hypotonicity* 100 or

nal sodium losses occur with di-uretic use, primary adrenal insuf-ficiency, salt-losing nephritis, andCSW. In these patients, urinarysodium will be > 30 mEq/L.

Clinical euvolemia can be difficultto differentiate from mild hypo-volemia. Even with a history sug-gestive of sodium loss (e.g., diar-rhea), water retention may makethe patient seem euvolemic. Inthese cases, measurement of uri-nary sodium can be very useful indifferentiating between hypovo-lemia and euvolemia. Urinary so-dium level < 30 mEq/L has 63%80% sensitivity and 72%100%specificity for hypovolemia,whereas urinary sodium >30mEq/L has 87%100% sensitivityand 52%83% specificity for euv-olemia (2122). Administration ofnormal saline as a diagnostic testmay be necessary in patients withurinary sodium < 20 and > 20mEq/L or < 40 mEq/L to distin-guish between hypovolemic hy-ponatremia and SIADH, with co-existent salt depletion. Patientswith salt-depleted SIADH do notnormalize plasma sodium afteradministration of normal saline;urine osmolality remains high,and the administered sodium isexcreted in the urine. By contrast,hypovolemic hyponatremia im-proves after administration ofnormal saline; the urine osmolal-ity decreases, and urinary sodiumdoes not increase until the pa-tient becomes euvolemic.

In patients with hypervolemia dueto heart failure, cirrhosis, or thenephrotic syndrome, the diagnosisis usually based on history andphysical examination. The urinarysodium should be < 30mEq/L inthese patients unless they are re-ceiving diuretics.

What is the role of imagingstudies in the diagnosis ofhyponatremia?Patients with unexplainedSIADH should have imagingstudies to identify the potentialunderlying cause. All patientsshould have chest radiography,and clinicians should considerordering chest computed to-mography in smokers. Magneticresonance imaging of the brainis indicated if neurologicabnormalities are found onphysical examination afterplasma sodium has beennormalized.

When should clinicians consulta nephrologist or anendocrinologist?Clinicians should consult with anephrologist or endocrinologistif the cause of hyponatremia isunknown and if guidance isneeded for the appropriate evalu-ation of SIADH. These specialistscan also give advice on the use ofnormal saline in patients with pos-sible SIADH and plasma sodiumlevels < 120mEq/L.

Diagnosis... Identifying the cause of hyponatremia can be challengingbecause it is often difficult to distinguish whether the patient is slightlyvolume depleted or euvolemic. In patients for whom volume status isuncertain, saline infusion may be useful. Before SIADH is diagnosed, thethiazide treatment must be stopped to determine the effect on plasmasodium and to rule out secondary adrenal insufficiency andhypothyroidism.


21. Chung HM, Kluge R,Schrier RW, et al. Clinicalassessment of extracellu-lar fluid volume in hypo-natremia. Am J Med.1987;83:905-8. [PMID:3 674097]

22. Musch W, Thimpont J,Vandervelde D, et al.Combined fractionalexcretion of sodium andurea better predicts re-sponse to salaine inhyponatremia than dousual clinical and bio-chemical parameters. AmJ Med. 1995;99:348-55.[PMID: 7573088]


TreatmentWhat is the overall approach totreatment of hyponatremia?The overall approach to hypona-tremia treatment depends on acu-ity, severity, and cause. Hyponatre-mia is acute if the duration isknown to be < 48 hours andchronic if the duration is un-known or > 48 hours. Enduranceexercise with water intoxication,psychogenic polydipsia, use ofsuch drugs as 3, 4-methyle-dioxymethamfetamine (ecstasy),colonoscopy preparation, andpostoperative states are associ-ated with acute hyponatremia.Acute hyponatremia can be char-acterized by swelling of brain cellsand can lead to cerebral edemawith risk for brain herniation. Thus,patients with acute hyponatremiarequire urgent normalization ofsodium levels. Over 2448 hours,the brain can adapt to hyponatre-mia by losing organic solutes,which allows intracellular osmolal-ity to equal plasma osmolality with-out a large increase in brain cellwater. After 48 hours, this loss ofsolutes predisposes patients withchronic hyponatremia to braindamage if hyponatremia is cor-rected too rapidly.

The severity of hyponatremia istypically classified as mild, moder-ate, or severe. Guidelines releasedby professional societies havesomeminor differences in the so-dium levels associated with thesecategories. In 2013, a recommen-dations from a U.S.-based expertpanel classifiedmild hyponatremiaas 130135mEq/L, moderate as120129mEq/L, and severe as< 120mEq/L (23). In 2014, a clini-cal practice guideline on diagnosisand treatment of hyponatremiafrom the European Society of En-docrinology, the European Societyof Intensive CareMedicine, andthe European Renal AssociationEuropean Dialysis and TransplantAssociation classifiedmild hypona-

tremia as 130135mEq/L, moder-ate as 125129mEq/L, and severeas < 125mEq/L (24).

How rapidly should sodiumlevels be corrected in acute andseverely symptomatichyponatremia, and how shouldthey be monitored?In patients with acute hyponatre-mia or severely symptomaticchronic hyponatremia (alteredmental status, seizures, and fre-quent vomiting), it is important torapidly reverse cerebral edema byincreasing plasma sodium by 5mEq/L. On the other hand, in pa-tients with chronic hyponatremia,the plasma sodium level shouldnot be raised > 10mEq/L within24 hours and/or > 18mEq/L within48 hours. These are limits thatshould not be exceeded ratherthan goals of therapy. Because it iseasy to overshoot themark (seebelow), the goal of therapy shouldbe set well below the therapeuticlimit. Recommended rates of cor-rection in patients with chronichyponatremia at high risk forosmotic demyelination are 46mEq/L per day.

Guidance for the treatment of hos-pitalized patients with acute andchronic symptomatic hyponatre-mia, includingmonitoring ofplasma sodium, is presented inTable 4. It is primarily based onthe European recommendations(24) as well as U.S. expert panelrecommendations whenever thereare significant differences (23).

Data on outcomes of 56 patients with plasma so-dium levels 105 mmol/L were obtained frommembers of the American Society of Nephrology.Increasedchronicityofhyponatremiaandahigh rateof correction in the first 48 hours of treatment weresignificantly associated with complications. No neu-rologic complications were observed among pa-tients corrected by < 12 mmol/L per 24 hours, orby < 18mmol/L per 48 hours. In this cohort of pa-tients with severe chronic hyponatremia, neurologiccomplicationswhich were probably secondary to

23. Verbalis JG, GoldsmithSR, Greenberg A, et al.Diagnosis, evaluation,and treatment of hy-ponatremia:expert panelrecommendations. Am JMed. 2013;126:S1-42.[PMID: 24074529]

24. Spasovski G, VanholderR, Allolio B, et al. Hypo-natremia Guideline De-velopment Group. Clini-cal practice guideline ondiagnosis and treatmentof hyponatremia. Eur JEndocrinol. 2014;170:G1-G47. [PMID:24074529]


pontine and extrapontine myelinolysiswere lessfrequent in patients whose electrolyte imbalancewas corrected more slowly (25).

It is extremely difficult to predictthe rate of correction of plasmasodium levels. Initially, when pa-tients are given hypertonic saline,the formula that is often used topredict the initial increase inplasma takes into account the ad-ministered amount of volume, so-dium, and potassium and totalbody water (based on age andsex). It should be noted that thisformula is based on a closed sys-

tem that does not take into con-sideration urinary loss of electro-lytes or water, which substantiallyaffects the actual change in plasmasodium.

In a retrospective study of 62 hyponatremic pa-tients treated with a low rate of hypertonic saline,several patients were unintentionally overcor-rected (11% by > 12mEq/L in 24 h and 9.7% by>18 mEq/L in 48 h), despite frequent adjust-ments in the infusion rate and/or administrationof 5% dextrose in water. Using a predictive for-mula in patients with plasma sodium < 120mEq/L, the observed increase in plasma sodiumexceeded the formula's estimated increase in

Table 4. Treatment of Hospitalized Patients With Hyponatremia, According to Symptoms

Severe (cardiorespiratory arrest,seizures, deep somnolence,and coma)

Administer 150 mL 3% saline over 20 min, then check plasma sodium levels whilerepeating the infusion of hypertonic saline over 20 min; continue 3% saline with target of5-mEq/L increase in plasma sodium, then stop hypertonic saline

Expert panel: 100 mL of 3% saline infused over 10 min x 3 as needed with urgentcorrection 46 mEq/L

Do not increase plasma sodium more than 10 mEq/L in 24 h and in the next 24 h greaterthan 8 mEq/L

For the first 24 h, monitor plasma sodium levels every 6 h depending on changes; whenstable, measure levels every 24 h

No improvement Continue 3% saline aiming for an additional 1-mEq/L/h increase in plasma sodiumStop 3% saline infusion when symptoms improve, plasma sodium levels increases10 mEq/L, or it reaches 130 mEq/L, whichever occurs first

Monitor plasma sodium every 4 h for the duration of hypertonic saline infusion, then every6 h for the first 24 h; when stable, measure plasma sodium every 24 h

Acute hyponatremia withoutsevere or moderately severesymptoms

If acute, decrease in plasma sodium >10 mEq/L infuse 150 mL 3% saline over 20 minExpert panel: Mild to moderate symptoms with a low risk of herniation, 3% hypertonicsaline infused at 0.52 mL/kg/h

Monitor plasma sodium after 4, 12, and 24 h; when stable measure plasma sodium every24 h

Moderately severe (nauseaconfusion, headache,vomiting)

Immediate treatment with 150 mL 3% hypertonic saline over 20 min; aim for a 5- mEq/L/24 h increase but limit plasma sodium to a 10-mEq/L increase in the first 24 h and 8mEq/L during every 24 h thereafter until plasma sodium reaches 130 mEq/L

Check plasma sodium levels after 1, 6, and 12 hExpert panel: No indication for hypertonic saline; minimum correction of plasma sodiumby 48 mEq/L per day with a lower goal of 46 mEq/L per day if risk for ODS is high;limits should not exceed 8 mEq/L in any 24-h period if risk for ODS is high

Chronic hyponatremia withoutsevere or moderately severesymptoms

Stop nonessential fluids, medications, and other factors that can contribute to or provokehyponatremia

Do not treat with the sole aim of increasing the plasma sodiumAvoid an increase in plasma sodium >10 mEq/L during the first 24 h and >8 mEq/L duringeach 24 h thereafter

Monitor plasma sodium every 6 h until the plasma sodium stabilizesOverrapid correction Overcorrection of hyponatremia is a medical emergency. In most cases, excessive

correction results from the emergence of a water diuresis after resolution of the cause ofhyponatremia

If plasma sodium has increased by > 10 mEq/L in 24 h or 18 mEq/L in 48 h, discontinueongoing active treatment

Consult an expert as to administer 5% dextrose in water in individual doses anddesmopressin to reduce urine volume until the plasma sodium is less than the limits ofovercorrection

Monitor plasma sodium every 2 h until it corrects, then every 4-6 h for the first 48 h

ODS = osmotic demyelination syndrome.

25. Sterns RH, Cappuccio JD,Silver SM, et al. Neuro-logic sequelae after treat-ment of severe hypona-tremia:a multicenterperspective. J Am SocNephrolol. 1994;4:1522-30. [PMID: 8025225]


74.2%. Inadvertent overcorrection was due todocumented water diuresis in 40% of cases (26)

How are patients with chronicasymptomatic hyponatremiatreated?Table 5 presents guidance forthe treatment of patients withchronic asymptomatic hyponatre-mia. Recommendations arebased on expert consensus. It isimportant not to administer iso-tonic saline to symptomatic orasymptomatic clinically euv-olemic patients with plasma so-dium 120 mEq/L because lev-els may decrease if urine ishypertonic (i.e., the sum of uri-nary concentrations of sodiumplus potassium exceeds plasmasodium concentration) (3). Theinitial treatment of patients witheuvolemic hypovolemia includesfluid restriction and stopping anymedications that could causeSIADH. Salt should not be re-stricted in patients with SIADHbecause they have decreasedtotal body sodium. Fluid restric-

tion alone is usually unsuccessfulif the sum of urinary sodium con-centration plus potassium ismore than half the plasma so-dium concentration (27).

What are manifestations of theosmotic demyelinationsyndrome and who is at risk?When chronic hyponatremia iscorrected too rapidly, the inabil-ity of the brain to rapidly recoverorganic solutes lost in the adap-tation to hyponatremia may leadto the osmotic demyelinationsyndrome (ODS). The neurologicsymptoms of this syndrome (dys-arthria, dysphagia, paraparesis orquadriparesis, confusion, obtun-dation, and coma) typically occur26 days after correction. Factorsthat increase risk for ODS includeinitial plasma sodium level < 105mEq/L; hypokalemia; and a his-tory of alcoholism, malnutrition,and advanced liver disease. ODSis more likely to occur if the in-crease in plasma sodium exceeds10 mEq/L within 24 hours and 18

Table 5. Treatment of Patients with Asymptomatic Chronic Hyponatremia

Condition Treatment

Hypovolemia due to gastrointestinallosses and sweating*

Isotonic saline; consider concomitant desmopressin

Diuretics* Discontinue diuretics and if no improvement administer isotonic salineAddison disease* Isotonic saline; glucocorticoid and mineralocorticoid replacementGlucocorticoid insufficiency* Glucocorticoid replacementPrimary polydipsia* Restrict water; discontinue diuretics and any drug known to cause SIADH; if

volume-depleted or decreased solute excretion, cautiously administer isotonicsaline and consider desmopressin (if no access to fluids) initially or if there is arapid increase in urine output and/or plasma sodium

Decreased solute intake* Restrict water; discontinue diuretics and any drug known to cause SIADH; ifvolume-depleted or decreased solute excretion, cautiously administer isotonicsaline and consider desmopressin (if no access to fluids) initially or if there is arapid increase in urine output and/or plasma sodium; increase electrolytes andprotein in their diet

Heart failure Restrict water and salt; loop diuretics in cases of fluid overloadCirrhosis with ascites Restrict water and salt; administer diuretics; possible albumin infusion with diureticsNephrotic syndrome Restrict water and salt; diuretics; if clinically decreased effective circulating volume,

administer albumin with diureticsChronic kidney disease Restrict water and salt; loop diuretics if fluid overload is presentSIADH Discontinue diuretics and any drug known to cause SIADH; restrict water but not salt;

consider oral urea, salt tablets, furosemide with salt tablets, and demeclocycline ifwater restriction is not effective; do not use vaptans unless benefit is greater thanrisk and only for 1 month if following FDA guidelines

FDA = U.S. Food and Drug Administration; SIADH = syndrome of inappropriate antidiuretic hormone secretion.* All patients are at risk for rapid correction. Loop diuretics should increase free water clearance.

26. Mohmand HK, Issa D,Ahmad Z, et al. Hyper-tonic saline for hypona-tremia: risk of inadver-tent overcorrection. ClinJ Am Soc Nephrol. 2007;2:1110-7. [PMID:17913972]

27. Furst H, Hallows KR, PostJ, et al. The urine/plasmaelectrolyte ratio: a predic-tive guide to water re-striction. Am J Med Sci.2000;319:240. [PMID:10768609]


mEq/L within 48 hours. Further-more, plasma sodium may in-crease more than intended if thecause of hyponatremia is revers-ible. When the reason for hypo-natremia is removed (by volumeresuscitation, discontinuation of amedication, cortisol replacement,correction of hypoxia, or recov-ery from stress), AVP secretion issuppressed, and excretion of di-lute urine (water diuresis) resultsin a rapid increase in the plasmasodium concentration.

Overcorrection of hyponatremia isa medical emergency and shouldbe avoided. If plasma sodium in-creases too rapidly, desmopressin(synthetic AVP) can be given toprevent further urinary waterlosses. Someauthors have sug-gested that desmopressin begivenas soon as the targeteddaily in-crease in plasma sodium levels (68mEq/L) has been achievedorwaterdiuresis begins.Others suggest giv-ingdesmopressin immediately topatientswith reversible causes ofhyponatremia, in anticipationof,rather than in response to, an unwel-comewater diuresis. Plasma sodiumis then increasedwith a slow infusionof hypertonic saline, adjusted tocorrect hyponatremiaby 6mEq/Lper day (28), while repeateddosesof desmopressin are given topre-vent urinarywater losses. In a recentreview (29), the authors suggestedstartingdesmopressin alongwithisotonic saline in hypovolemic pa-tients, psychiatric patientswith hypo-natremiadue topolydipsia (not cur-rently drinking), andpatientswithlow solute intakewhohave a rapidincrease in urine output. The role ofdesmopressin inmanaginghypona-tremia requires further research (29).

When should patients behospitalized for managementof hyponatremia?Hyponatremic patients who aresymptomatic (e.g., confusion,headache, vomiting, and sei-zures) and those with acute hypo-natremia, plasma sodium level

< 125 mEq/L, or risk factors forODS should be hospitalized.

How should clinicians counselpatients about salt and fluidintake and when to seekclinical care?Treatment of patients with hyper-volemic hyponatremia due toheart failure includes restriction ofdietary salt to 1.5 to 3.0 g/day andfluid restriction. Some studies haveshown poorer clinical outcomeswith lower salt intake. In general,patients should be counseled tolimit fluid intake to 1.52 L/day un-less hyponatremia worsens (30).Patients with SIADH should be ad-vised to limit fluid intake to around800mL/day and not to restrict saltintake. Patients should seek care ifthey experience alteredmentalstatus, falls, or persistent nauseabecause thesemay be symptomsof hyponatremia.

What other therapies,including medications, areused in the management ofhyponatremia?The Appendix Table (availableat www.annals.org) presents anoverview of medications used totreat patients with asymptomatichyponatremia. When fluid re-striction is unsuccessful, treat-ment options include use of salttablets alone or with loop diuret-ics (particularly if the urine os-molality is > 500 mOsm/kg). Al-though urea (usually 30 g/d) hasbeen shown to be as effective astolvaptan (31), it is not readilyavailable in the United Statesand not very palatable. Deme-clocycline acts on the collectingduct to decrease its response toAVP and has been used to treathyponatremia. The Europeanguidelines (24) recommendagainst demeclocycline becauseof its delayed onset of actionand increased chance of acutekidney injury. The U.S. expertpanel recommends demeclocy-cline as an alternative treatment

28. Sood L, Sterns RH, HixJK, et al. Hypertonicsaline and desmopres-sin: a simple strategy forsafe correction of severehyponatremia. Am JKidney Dis. 2013;61:571-8. [PMID:23266328]

29. Tzamaloukas AH, ShapiroJI, Raj DS, et al. Manage-ment of severe hypona-tremia: infusion of hyper-tonic saline anddesmopressin or infusionof vasopressin inhibitors?Am J Med Sci 2014;0(0]:1-8. [PMID: 25247759]

30. Yancy CW, Jessup M,Bozkurt B, et al. 2013ACCF/AHA Guidelines forthe management ofheart failure: executivesummary. Circulation.2013;128:1810-52.[PMID: 23741057]

31. Soupart A, Coffernils M,Couturier B, et al. Efficacyand tolerance of ureacompared with vaptansfor long-term treatmentof patients with SIADH.Clin J Am Soc Nephrol.2012;7:742-7. [PMID:22403276]


if fluid restriction is unsuc-cessful. Loop diuretics can beuseful in managing hyponatre-mia in patients with heart failureby increasing free water excre-tion. In severely symptomatichyponatremic patients with con-gestive heart failure (CHF)and/or liver disease with ascites,administration of loop diureticswith hypertonic saline can de-crease the chance of fluid over-load.

When should cliniciansconsider use of vasopressin-receptor antagonists?Vasopressin-receptor antago-nists (vaptans) block the effectof AVP, leading to increasedfree water excretion. Conivap-tan is an intravenous formula-tion and is approved for treat-ment of SIADH. Tolvaptan is anoral formulation approved formanaging hyponatremia in CHFand SIADH. The 2014 Europeanguidelines (24) recommendagainst vaptans for treatment ofhyponatremia in patients withSIADH and expanded extracel-lular fluid. Although theseguidelines acknowledge thatvaptans increase plasma so-dium in these patients, they alsoexpress concerns about the in-creased risk for rapid correctionof plasma sodium and lack ofmortality benefit. There are re-ports of neurologic sequelae inpatients who were treated withtolvaptan whose plasma sodiumcorrection exceeded the sug-gested rate and possibly in-creased the risk for death.During the past year, severalnational recommendations andguidelines (from the UnitedKingdom, Sweden, and Spain)have been published on man-agement of hyponatremia. Eachrecommended use of tolvaptanif fluid restriction was unsuc-cessful in managing plasmasodium levels in patients withhyponatremia.

The U.S. Food and Drug Admin-istration (FDA) has limitedtolvaptan use to 1 month, basedon reports of hepatotoxicity as-sociated with high doses in pa-tients with autosomal dominantpolycystic kidney disease. TheFDA also limits use to patientswith plasma sodium < 125mEq/L, unless they are symp-tomatic and have not re-sponded to fluid restriction.The expert panel (23) acknowl-edged the concern about vap-tans and hepatotoxicity. Toavoid overcorrection, the panelrecommended that vaptans beused alone rather than in con-junction with other treatmentsfor hyponatremia. The panel rec-ommended checking plasma so-dium levels every 68 hours dur-ing initiation of vaptan treatmentand not initially restricting fluidintake. Although the panel statedthat these drugs could be used aslong-term therapy, it noted thatsuch use would probably be lim-ited by high cost and FDA restric-tions. Even with these significantconcerns, clinicians should con-sider treatment with vaptans inpatients who have not respondedto other measures (i.e., plasmasodium < 125mEq/L and/or per-sistent symptoms believed to bedue to hyponatremia) if the antici-pated benefit exceeds the risk.

When should cliniciansconsult a nephrologist orendocrinologist for treatmentof hyponatremia?Clinicians should consult a neph-rologist or endocrinologist forguidance when administration ofhypertonic saline and/or vaptans isconsidered. Consultations are alsoindicated for acute, severe, orsymptomatic hyponatremia(plasma sodium < 120mEq/L) andfor help in managing patients withrisk factors for ODS, patients whohave had overly rapid correction,or those who require long-termtherapy for hyponatremia.


Practice ImprovementWhat do professionalorganizations recommendregarding the diagnosis andtreatment of hyponatremia?The 2013 US Expert Panel Rec-ommendations (23) and 2014European Clinical PracticeGuidelines (24) are recent guide-lines addressing the diagnosisand treatment of hyponatremia.

Guidelines from the AmericanCollege of Cardiology/AmericanHeart Association address the

management of all aspects ofheart failure, including sodiumand water restriction (30) (http://circ.ahajournals.org/content/128/16/1810.full?sid=6716f9b4-016f-4ed6-8a58-d74807c7eeb9).

Guidelines from the EuropeanSociety of Cardiology addressthe diagnosis and treatment ofheart failure (http://eurheartj.oxfordjournals.org/content/33/14/1787.long).

In the Clinic

Tool KitHyponatremia

NIH MedLine Pluswww.nlm.nih.gov/medlineplus/ency/article/000394.htm

Clinical Guidelineswww.ese-hormones.org/guidelines/joint.aspxwww.eje-online.org/content/170/3/G1.full

Description and Informationwww.mayoclinic.org/diseases-conditions/hyponatremia/basics/definition/CON-20031445?p=1

Patient Resourceswww.mayoclinic.org/diseases-conditions/hyponatremia/basics/definition/con-20031445

http://umm.edu/health/medical/ency/articles/hyponatremia

Patient Resources in Spanishhttp://nkdep.nih.gov/inicio.shtml In

theClinic

Treatment... Patients with severe hyponatremia, acute hyponatremia, ormoderate to severe symptoms should be hospitalized for diagnosis andtreatment. It is important to administer hypertonic saline to rapidly cor-rect plasma sodium levels in patients with acute hyponatremia, even ifthey are asymptomatic (e.g., exercise-associated hyponatremia), andpatients with moderate to severe symptoms (chronic or acute). It is alsoimportant to monitor patients closely and not to increase levels > 10mEq/L within 24 hours or 18 mEq/L within 48 hours. The recommendedrates of sodium correction are lower in patients at risk for ODS. Factorsthat increase risk for this syndrome include an initial plasma sodiumlevel < 105 mEq/L, hypokalemia, alcoholism, malnutrition, and ad-vanced liver disease. Clinicians considering tolvaptan should take intoaccount the FDA recommendation not to exceed 1 month of use.



WHAT YOU SHOULDKNOW ABOUTHYPONATREMIA

What Is Hyponatremia?Hyponatremia is a condition that occurs when so-dium levels in the body are too low. Sodium, orsalt, is a mineral in the blood. Sodium helps tocontrol the amount of water in your body. Whensodium levels are low, your body holds onto toomuch water. Too much water in the body can bedangerous and cause serious health problems.Low sodium levels can be caused by:

Certain medications, like water pills (diuretics)or some antidepressants

Some health conditions, like heart failure,kidney disease, or liver problems

Drinking too much water after intenseexercise, such as running a marathon

What Are the Warning Signs ofHyponatremia?

Sometimes hyponatremia has no symptoms. Other times, symptoms include nausea,confusion, headache, or vomiting.

On rare occasions, symptoms are moresevere. Severe symptoms can includeseizures, temporary loss of mental abilities,and trouble breathing.

How Is Hyponatremia Diagnosed? Your doctor will collect a blood and urinesample to test sodium levels.

Imaging tests may be ordered to check forsigns of hyponatremia. These tests mayinclude an x-ray to check for normal fluidlevels in your lungs or an MRI of the brain tolook for things that might cause hyponatremia(for example, brain tumors).

How Is Hyponatremia Treated? In mild cases, your doctor may simply adviseyou to drink less fluid or change yourmedications.

Sometimes your doctor will give you amedicine that helps reduce the amount ofwater in your body.

In more severe cases, you may need to go tothe hospital for diagnosis and treatment. An IVfilled with a salt-based fluid may be used toincrease your sodium levels.

Questions for My Doctor Do I need to drink less water? Should I eat more salt? Do I need to change my diet? When can I expect my symptoms to go away? Could this cause any long-term problems? Should I change the medicines I take? How can I prevent this from happening in thefuture?

When should I contact my doctor?

Bottom Line Hyponatremia is a condition that occurs whensodium levels in the body are too low. Thesodium in your blood helps to control theamount of water in your body. When sodium istoo low, there is too much water in your body.This can be dangerous and cause healthproblems.

Symptoms of hyponatremia can range fromheadache or nausea to serious confusion andseizures.

To check for hyponatremia, your doctor willcollect a blood and urine sample. He or shemay also order further testing, like x-ray or anMRI.

Treatment will depend on how severe yoursymptoms are. Treatment could include usingan IV to increase your sodium levels, taking amedicine to lessen the water in your body, orsimply drinking less water.

For More InformationMedline Pluswww.nlm.nih.gov/medlineplus/ency/article/000394.htm

National Kidney Foundationhttps://www.kidney.org/atoz/content/Hyponatremia

In the ClinicAnnals of Internal Medicine

Patie

ntInform

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Appendix Figure 1. Approach to the diagnosis of hypovolemic hyponatremia.

High Probability of Hypovolemia Based on clinical historyand physical examination

VariableUNa

UNa 30mEq/L

Diuretics Extrarenal lossesVomiting*DiarrheaPancreatitisSweatingSmall bowel obstruction

Renallosses

Osmotic diuresis (glucose, urea bicarbonaturia)

Sait-Iosing nephritisAddison diseaseCSW

D/C diuretics

Failure tonormalize PNa

ACTH-stimulation

test

Consistent withAddison disease

Treatment:Glucocorticoids and mineralocorticoids

Administer0.9% saline

Failure tonormalize PNa

Normalize PNa

Hypovolemia

Hypovolemia

Decreasing Uosm No change in Uosm UNa increases

Salt-depleted SIADH

ACTH = adrenocorticotrophic hormone; CSW = cerebral salt wasting; D/C = discontinue; SIADH = syndrome of inappropriate antidiuretichormone secretion.* If patient is vomiting, UCl should be low. Volume-depleted elderly patients can have urinary sodium > 30 mEq/L but FENa

Appendix Figure 2. Approach to the diagnosis of euvolemic hyponatremia.

Clinical Euvolemia

Probablehypovolemia

Probableeuvolemia

UNa 20 UNa 40mEq/L

D/C diuretics

Not SIADH

Hypovolemiaor euvolemia

PNanormalizes

PNa decreases or no change

PNa increases

Failure of PNa to normalize

SIADH Cortisol deficiencyHypothyroidism*

Unclear diagnosis afterruling out cortisol deficiency,

hypothyroidism

Administer 12 L 0.9% saline

SIADH

SIADH

Decreased UNa No change in Uosm UNa increases

Administer additional saline

No change in Uosm UNa increases

Decreasing Uosm

Hypovolemia Salt-depleted SIADH

D/C = discontinue; SIADH = syndrome of inappropriate antidiuretic hormone secretion.* Severe hypothyroidism = urinary sodium < 20 mEq/L. If plasma sodium < 120 mEq/L, consult endocrinologist or nephrologist for guidance.

Appendix Figure 3. Approach tothe diagnosis of hypervolemichyponatremia.

Hypervolemia

UNa 30mEq/L

Heart failureLiver diseaseNephrotic syndrome

Chronic kidney diseaseDiuretic use in: Heart failure Liver disease Nephrotic syndrome

*

* If patient is receiving diuretics, urinary so-dium can be >30 mEq/L. Patients with chronic kidney disease canalso be euvolemic.

! 2015 American College of Physicians In the Clinic Annals of Internal Medicine 4 August 2015Downloaded From: http://annals.org/ by a University of Pittsburgh User on 08/11/2015

Appendix Table. Drug and Nondrug Treatment for Hyponatremia

Drug or Drug Class Dosing Side Effects Precautions Clinical Use

Sodium chloridetablets

515 g daily Hypernatremia, fluid overload SIADH common whencombined withfurosemide

Furosemide (Lasix) 2080 mg daily Orthostatic hypotension,hyperuricemia, azotemia,ototoxicity, impairedglucose tolerance,pancreatitis

Water and electrolytedepletion; cautionwith sulfonamidehypersensitivity,CKD, hepaticimpairment*

Combined with sodiumsupplementation inSIADH, CHF, andliver disease withascites

Urea 1530 g daily Too rapid an increase inserum sodium, poorpalatability, azotemia athigher doses

Monitor serumsodium levels

SIADH

Demeclocycline(Declomycin)

6001200 mg totaldaily dose,dosed 3 to 4times daily

CNS side effects, nausea,vomiting, diarrhea,photosensitivity, azotemia,acute renal failure,hematologic effects withlong-term therapy

Avoid withpregnancy; cautionwith hepaticdisease, CKD; donot administerwithin 4 hours ofdrugs containingdivalent or trivalentcations; administer1 h before or 2 hafter meals

SIADH

Tolvaptan (Samsca) 15 mg daily, then30 mg daily;maximum 60mg daily

Xerostomia, asthenia,hyperglycemia, anorexia,hepatic disease,constipation, thirst,pollakiuria, polyuria,dehydration, orthostatichypotension, neurologicsequelae when correctionof serum sodium exceedsthe suggested rate

Initiate and reinitiatein a hospital andmonitor serumsodium levels;avoid if CrCl*

Can be useful in SIADHand CHF if benefitexceeds risk

CHF = congestive heart failure; CKD = chronic kidney disease; CNS = central nervous system; CrCl = creatinine clearance; CYP =cytochrome P450 isoenzyme; P-gp = P-glycoprotein; SCr = serum creatinine; SIADH = syndrome of inappropriate antidiuretichormone secretion.* Black box warning.

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