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The n e w e n g l a n d j o u r n a l o f medicine

n engl j med 356;20 www.nejm.org may 17, 20072064

The Syndrome of Inappropriate Antidiuresis

David H. Ellison, M.D., and Tomas Berl, M.D.

From the Division of Nephrology and Hy-pertension and the Department of Physi-ology and Pharmacology, Oregon Healthand Science University and Veterans Af-fairs Medical Center, Portland, OR (D.H.E.);and the Division of Renal Diseases and Hy-pertension, University of Colorado HealthSciences Center, Denver (T.B.). Addressreprint requests to Dr. Ellison at the Divi-sion of Nephrology and Hypertension,Oregon Health and Science University,PP262, 3314 SW U.S. Veterans HospitalRd., Portland, OR 97239, or at [email protected].

N Engl J Med 2007;356:2064-72.Copyright 2007 Massachusetts Medical Society.

A 62-year-old woman noted an unpleasant, sweet taste in her mouth. She otherwisefelt well and was taking no medications. Because dysgeusia is a rare manifestation ofhyponatremia, her serum sodium level was tested and was 122 mmol per liter. Theserum osmolality was 250 mOsm per kilogram of water, the urinary osmolality 635mOsm per kilogram of water, the urinary sodium 85 mmol per liter, and the urinarypotassium 40 mmol per liter. Her thyroid function and adrenal function were normal.

A computed tomographic (CT) scan of the thorax showed a mass in the lower lobe ofthe left lung, which proved to be a small-cell carcinoma. How should her hyponatre-mia be treated?

The Clinical Problem

Hyponatremia, defined as an excess of water in relation to the sodium in the extracel-lular fluid, is the most common electrolyte disorder in hospitalized patients.1Mildhyponatremia (serum sodium,

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n engl j med 356;20 www.nejm.org may 17, 2007 2065

The risk rises with increasing age and is espe-cially high among residents of nursing homes.4Although the causes of SIAD are myriad, they canbe categorized as related to malignant diseases,pulmonary diseases, and disorders of the centralnervous system, among others (Table 1). In addi-tion, a variety of drugs can stimulate the release

of arginine vasopressin or potentiate its action(Table 1); traditionally, some medical authoritiesinclude such drugs among the causes of SIADH,9,10whereas others do not include them in this cat-egory.11

Severe hyponatremia (serum sodium

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Th e n e w e n g l a n d j o u r n a l o f medicine


with hyponatremia suggest SIAD, but are not di-agnostic5; for example, a serum uric acid level ofless than 4 mg per deciliter (238 mol per liter)(in the presence of hyponatremia) has a positivepredictive value for SIAD of 73 to 100%.19-21A uri-nary sodium level of less than 30 mmol per literhas a positive predictive value of 71 to 100% for an

infusion of 0.9% saline to increase the serum so-dium level.18,22

When diagnostic uncertainty remains, volumecontraction of the extracellular fluid can be ruledout by infusing 2 liters of 0.9% saline over a pe-riod of 24 to 48 hours. Even though 0.9% salineis not the preferred treatment for SIAD, it is usu-ally safe when the baseline urinary osmolality isless than 500 mOsm per kilogram of water17,22,23;correction of the hyponatremia suggests underly-ing volume depletion of extracellular fluid. Mea-surement of the serum level of arginine vasopres-

sin is not recommended routinely, because urinaryosmolality above 100 mOsm per kilogram of wateris usually sufficient to indicate excess of circulat-ing arginine vasopressin.

Management

The only definitive treatment of SIAD is elimina-tion of its underlying cause. Most cases caused bymalignant disease resolve with effective antineo-plastic therapy, and most of those due to medica-tion resolve promptly when the offending agent isdiscontinued. When the hyponatremia is chronicand asymptomatic, a diagnosis can be pursued be-fore treatment is initiated.

Acute Symptomatic Hyponatremia

The most important factors dictating the manage-ment of SIAD are the severity of the hyponatremia,its duration, and the presence or absence of symp-toms (Fig. 2).11,24,25For symptomatic patients withsevere hyponatremia known to have developedwithin 48 hours, clinical experience suggests thatrapid treatment is warranted.26The goal is to raise

the serum sodium level by 1 to 2 mmol per liter perhour by infusing 3% saline; these recommendedrates are guided by data from case series, in theabsence of data from randomized trials, but theyare widely accepted.1Many authorities recommendconcomitant furosemide,1although some recom-mend avoiding it10or reserving it for patients withextracellular-fluid volume expansion.9,27Many ex-perts believe that the magnitude of correction dur-ing the first 24 hours of treatment should be no

Table1.

CausesoftheSyndromeofInappropriateAntidiuresis(SIAD).*

MalignantDiseases

P

ulmonaryDisorders

Disordersofthe

CentralNervousSystem

Drugs

OtherCauses

Carcinoma

LungS

mall-cell

Mesothelioma

Oropharynx

Gastrointestinaltract

Stomach

Duodenum

Pancreas

Genitourinarytract

Ureter

Bladder

Prostate

Endometrium

Endocrinethymoma

Lymphomas

Sarcomas

Ewingssarcoma

Infec

tions

B

acterialpneumonia

V

iralpneumonia

P

ulmonaryabscess

T

uberculosis

A

spergillosis

Asth

ma

Cysticfibrosis

Resp

iratoryfailureassociat-

edwithpositive-pres-

surebreathing

Infection

Encephalitis

Meningitis

Brainabscess

RockyMountainspottedfever

AIDS

Bleedingandmass

es

Subduralhema

toma

Subarachnoidh

emorrhage

Cerebrovascula

raccident

Braintumors

Headtrauma

Hydrocephalus

Cavernoussinu

sthrombosis

Other

Multiplesclerosis

GuillainBarrsyndrome

ShyDragersyn

drome

Delirium

treme

ns

Acuteintermitt

entporphyria

Drugsthatstimulaterelea

seofAVPorenhanceitsaction

Chlorpropramide

SSRIs

Tricyclicantidepressan

ts

Clofibrate(Atromid-S,

WyethAyerst)

Carbamazepine(Epito

l,Lemmon;Tegretol,CibaGeigy)

Vincristine(Oncovin,Lilly;Vincasar,Pharmaciaand

Upjohn)

Nicotine

Narcotics

Antipsychoticdrugs

Ifosfamide(Ifex,Bristo

l-MyersSquibb)

Cyclophosphamide(Cytoxan,

Bristol-MyersSquibb;

Neosar,Pharmacia

andUpjohn)

Nonsteroidalantiinflammatorydrugs

MDMA(ecstasy)

AVPanalogues

Desmopressin(DDAV

P,

RhonePoulencRorer;Stimate,

Centeon)

Oxytocin(Pitocin,

ParkeDavis;Syntocinon,

Novartis)

Vasopressin

Heredit

ary(gain-of-function

mutationsinthevaso-

pressinV

2r

eceptor)

Idiopathic

Transient

End

uranceexercise

Gen

eralanesthesia

Nau

sea

Pain

Stre

ss

*AIDSdenotestheacquiredimm

unodeficiencysyndrome,

AVPargininevasopressin,

SSRIselectiveserotonin-reuptak

einhibitor,andMDMA3,4-methylenedioxymethamphetamine.

The New England Journal of Medicine

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Copyright 2007 Massachusetts Medical Society. All rights reserved.

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more than 8 to 10 mmol per liter, and during thefirst 48 hours no more than 18 to 25 mmol perliter, even when the hyponatremia is acute.1,9,27Oneapproach is to aim for the cessation of neurologicsymptoms, such as seizures, and then reduce thecorrection rate.25An increase in serum sodiumlevels of less than 10 mmol per liter is usually suf-

ficient to reduce the symptoms and prevent com-plications.28(Specific treatment regimens are dis-cussed below.)

Hyponatremia of Long or Unclear Duration

Most cases of hyponatremia that occur out of thehospital are chronic and minimally symptomatic,except in marathon runners, users of 3,4-methy-lenedioxymethamphetamine (MDMA, also knownas ecstasy), and people who drink water to ex-cess; in these groups, severe symptoms usuallyindicate acute hyponatremia and require rapid cor-

rection.The treatment of hyponatremia with an unclear

duration and nonspecific symptoms or signs (e.g.,headache or lethargy) is particularly challenging.Some reports suggest a high risk if patients arenot treated aggressively29; others suggest that rapidcorrection increases morbidity or mortality.30Un-like patients with acute hyponatremia, those withhyponatremia of longer duration have a docu-mented risk of osmotic demyelination if the serumsodium level is corrected by more than 12 mmolper liter over a period of 24 hours. This disorder,which includes both central pontine and extrapon-tine myelinolysis, begins with lethargy and affec-tive changes (generally after initial improvementof neurologic symptoms with treatment), followedby mutism or dysarthria, spastic quadriparesis,and pseudobulbar palsy.31Case series and experi-mental data indicate that this complication mayresult from rapid correction of hyponatremia thathas been present for more than 48 hours.31

To balance the risks of chronic hyponatremiaagainst the risks of rapid correction, many au-

thorities recommend a modest rate of correction(an increase in serum sodium of 0.5 to 1.0 mmolper liter per hour), using lower rates of saline infu-sion for patients with symptomatic hyponatremiaof unknown duration. Many limit correction to8 mmol per liter over a period of 24 hours and18 mmol per liter over a period of 48 hours; closemonitoring of the rate of correction (every 2 to3 hours)25is recommended to avoid overcorrec-tion. Some authorities recommend brain imaging

(e.g., CT or magnetic resonance imaging) to deter-mine whether cerebral edema is present and togauge the urgency of the need for correction, al-though evidence that imaging improves outcomesis lacking.32

Asymptomatic patients with chronic hyponatre-mia have a low risk of serious neurologic sequelaebut a well-described risk of osmotic demyelinationwith rapid correction.31Therefore, treatment isaimed at correcting the hyponatremia very grad-

ually. Fluid restriction, estimated on the basis oflevels of urinary and plasma electrolytes (Fig. 2),is a cornerstone of therapy.6,33The maximum tol-erated fluid intake is proportional to the oral os-motic load, so adequate intake of dietary proteinand salt should be encouraged. Oral intake of urea(30 g per day) is effective but is poorly tolerated.Demeclocycline (Declomycin, WyethAyerst) (300to 600 mg twice daily) reduces urinary osmolalityand increases serum sodium levels, but its effects

Table 2.Diagnosis of SIAD.*

Essential features

Decreased effective osmolality (100 mOsm/kg of water during hypotonicity

Clinical euvolemia

No clinical signs of volume depletion of extracellular fluidNo orthostasis, tachycardia, decreased skin turgor, or dry mucous

membranes

No clinical signs of excessive volume of extracellular fluid

No edema or ascites

Urinary sodium >40 mmol/liter with normal dietary salt intake

Normal thyroid and adrenal function

No recent use of diuretic agents

Supplemental features

Plasma uric acid 55%

Failure to correct hyponatremia after 0.9% saline infusion

Correction of hyponatremia through fluid restriction

Abnormal result on test of water load (

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can be variable and it can cause nephrotoxicity.Lithium (Eskalith, GlaxoSmithKline; Lithobid, Sol-vay Pharmaceuticals) is no longer recommended.

Vasopressin-Receptor Antagonist Therapy

A more recent option for treating SIAD is conivap-tan (Vaprisol, Astellas Pharma), a vasopressin-receptor antagonist approved by the Food and DrugAdministration in 2005 for intravenous treatmentof euvolemic hyponatremia34and approved in 2007for intravenous treatment of hypervolemic hypo-natremia35(Table 3). In a double-blind, random-ized trial, in patients assigned to conivaptan for

4 days, as compared with those assigned to place-bo, the serum sodium levels increased by 6 mmolper liter. Although hypotension has not been re-

ported in association with conivaptan, it is a risk,because conivaptan is a nonselective vasopressin-receptor antagonist; blocking the vasopressin V

1

receptor induces vasodilation. Currently, conivap-tan use is limited to the treatment of hospitalizedpatients; it might be considered particularly forthose who have moderate-to-severe hyponatremiaand symptoms but not seizures, delirium, or coma,which would warrant the use of hypertonic saline.Infusion-site reactions are common (occurring in

Severe hyponatremia, serum sodiumlevel

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as many as 50% of patients, according to the pack-age insert for the drug), and its metabolism by the3A4 isoform of cytochrome P450 (CYP3A4) can re-sult in drug interactions.

Although not yet clinically available, oral vaso-

pressin-receptor antagonists that are selective forthe vasopressin V

2receptor have been developed

(Table 3). In two randomized, controlled trials oftolvaptan, serum sodium levels rose from a meanbaseline level of 129 mmol per liter within 24hours after the administration of the first doseof active drug and remained significantly higher(by 4 mmol per liter) than the levels in the placebogroup (P

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be confusing. Other formulas incorporate amountsof salt and water infused and excreted39,40; theseadd precision, but at the price of complexity.A simpler strategy that results in similar infusionrates is to infuse 3% saline (513 mmol per liter) ata rate of 1 to 2 ml per kilogram of body weightper hour9to increase the serum sodium level by1 to 2 mmol per liter per hour; twice this infusionrate (2 to 4 ml per kilogram per hour) may be usedfor a limited period in patients with coma or sei-zures; half the rate (0.5 ml per kilogram per hour)should be used if symptoms are mild.9Many au-thorities recommend using furosemide (20 to 40mg intravenously) with saline because it promotes

free-water excretion and prevents extracellular-fluid volume expansion. Loop diuretics also in-crease the rate of increase in the serum sodiumlevel. The rate of change in serum sodium levelsmust be monitored every 2 to 3 hours, and theinfusion adjusted as needed.

Osmotic Demyelination

When symptoms of osmotic demyelination developduring the treatment of hyponatremia, case reportssuggest that it may be possible to reverse the neu-

rologic deficits by again lowering the serum so-dium level. In two patients who had neurologicsymptoms after rapid correction of serum sodiumlevels,41,42symptoms diminished when serum so-dium levels were modestly reduced by adminis-tering the vasopressin analogue desmopressin(DDAVP, RhonePoulenc Rorer; Stimate, Centeon)and 5% dextrose.

Cerebral Salt Wasting

SIAD may be difficult to distinguish from cerebralsalt wasting, a syndrome of hyponatremia and ex-tracellular-fluid volume depletion in patients withinsults to the central nervous system.43,44The pri-

mary feature that differentiates cerebral salt wast-ing from SIAD is extracellular-fluid volume deple-tion, but clinical assessment of volume status isimprecise.18,45In a study that used central venouspressure (

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tion for patients who have hyponatremia with sub-arachnoid hemorrhage, because of the risks as-sociated with volume depletion in these patients.

Prevention of Postoperative Hyponatremia

Surgical procedures typically increase circulatinglevels of arginine vasopressin; nevertheless, hypo-

tonic intravenous fluids are frequently adminis-tered perioperatively.47Most authorities recom-mend 0.9% sodium chloride in adults during theperioperative period, as long as hypernatremia isnot present.48,49

Guidelines from Professional

Societies

There are no professional guidelines for evaluat-ing and treating SIAD.

Summary and Recommendations

The patient described in the vignette apparently haschronic hyponatremia attributable to SIAD; she has

no neurologic symptoms. Treating the underlyingcause (in this case, small-cell lung cancer) is thedefinitive means of correcting the hyponatremia.In the absence of symptoms, gradual correction ofthe hyponatremia is appropriate and should involveadequate solute intake (including salt and protein)and fluid restriction, starting at 500 ml per day of

water (on the basis of the formula shown in Fig. 2).If the patient were disoriented, we would recom-mend increasing her serum sodium level by 0.5 to1 mmol per liter per hour for a total of 8 mmol perliter during the first day. This increase can be ac-complished by promoting free-water excretion withthe use of furosemide and replacing sodium andpotassium losses with 0.9% saline. Alternatively,conivaptan might be used to increase the serum so-dium level, although clinical experience with vaso-pressin-receptor antagonists remains very limited.

Dr. Ellison reports receiving research grants from Chemica

Technologies, and Dr. Berl reports receiving consulting feesfrom Astellas and Sanofi-Aventis, lecture fees from Astellas, andresearch support from Otsuka. No other potential conflict ofinterest relevant to this article was reported.

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