Hyponatremia

4/5/2014 DynaMed
Hyponatremia
Updated 2014 Apr 07 06:14:00 AM: hypotonic IV fluids associated with increased risk of hyponatremia and severe
hyponatremia compared to isotonic IV fluids in hospitalized children (Pediatrics 2014 Jan) view update Show more updates
Related Summaries:
Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
General Information
Description:
plasma sodium < 135 mEq/L (135 mmol/L), reference ranges may vary between laboratories(1)
Types:
hypotonic(1)
hypovolemic
euvolemic
hypervolemic
isotonic(2, 3)
hypertonic(2, 3)
Who is most affected:

common, especially in hospitalized patients and the elderly (1)
Incidence/Prevalence:
hyponatremia is most common electrolyte abnormality in clinical practice (Am J Med 2006 Jul;119(7 Suppl 1):S30)
53% of nursing home residents had ≥ 1 episode of hyponatremia
based on 12-month longitudinal study of 119 nursing home residents aged 60-103 years
Reference - J Am Geriatr Soc 1995 Dec;43(12):1410
Causes and Risk Factors
Causes:
hypotonic hyponatremia (decreased serum osmolarity)
isotonic hyponatremia (normal serum osmolarity)
hypertonic hyponatremia ('translocational', increased serum osmolarity)
Hypotonic hyponatremia:
hypovolemic (decreased extracellular fluid volume)(1, 2, 3)
renal sodium loss
diuretics
osmotic diuresis (glucose, urea, mannitol)
ketonuria
bicarbonaturia
renal tubular acidosis
disequilibrium stage of vomiting
adrenal insufficiency
adrenal insufficiency in adults
adrenal hemorrhage
adrenal tuberculosis (TB)
salt-wasting nephropathy
cerebral salt wasting (CSW)
clinical syndrome characterized by hyponatremia, excessive natriuresis (renal salt loss), volume depletion and
clinical response to volume and salt replacement
condition is distinct from syndrome of inappropriate antidiuretic hormone secretion (SIADH) and occurs in patients
with head trauma, central nervous system (CNS) surgery, tumor or meningitis
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CSW is depletional hyponatremia (polyuria with high urine sodium level) while SIADH is dilutional hyponatremia
Reference - Turk Neurosurg 2010 Jan;20(1):100 PDF, Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub
2009 Sep;153(3):219 PDF
extrarenal sodium loss
dermal losses (for example, sweating or burns)
gastrointestinal (GI) losses (for example, diarrhea or vomiting)
blood loss
fluid sequestration ('third spacing')
bowel obstruction
pancreatitis
peritonitis
rhabdomyolysis
burns
hypervolemic (increased extracellular volume)(1, 2, 3)
heart failure
cirrhosis
nephrotic syndrome
acute renal failure or chronic kidney disease
pregnancy
euvolemic (essentially normal extracellular fluid volume)(1, 2, 3)
syndrome of inappropriate antidiuretic hormone secretion (SIADH)
major causes include malignant, pulmonary, and CNS disease
SIADH is common cause of hyponatremia in elderly patients
based on 2 cohort studies
retrospective review of 405 ambulatory patients in geriatric clinic
46 had hyponatremia, SIADH was apparent cause in 27
Reference - J Am Geriatr Soc 1996 Apr;44(4):404
prospective cohort of 172 patients > 65 years old admitted to geriatric rehabilitation hospital
43 patients had hyponatremia, SIADH was cause in 22
Reference - J Am Geriatr Soc 2001 Jun;49(6):788, correction can be found in J Am Geriatr Soc 2002
Jan;50(1):204
hypothyroidism
water intoxication
excessive parenteral hypotonic fluid administration
primary (psychogenic) polydipsia (Kidney Int 2009 Jul;76(2):233)
freshwater drowning
dilute infant formula
post-transurethral prostatectomy (massive absorption of irrigant solutions that do not contain sodium - maybe isotonic
if 5% mannitol used)
tap water enema as cause of hyponatremia noted in case report (J Am Geriatr Soc 2008 Apr;56[4 suppl]:S25,A22)
acute exercise-associated hyponatremia
hypopituitarism (glucocorticoid deficiency) due to Sheehan syndrome (postpartum panhypopituitarism) in case report
(Kidney Int 2009 Aug;76(3):351)
thiazide-type diuretics
decreased intake of solutes(2)
beer potomania (hyponatremia due to ingestion of large volumes of beer [hypotonic alcohol solutions] with insufficient
food intake for extended periods)
tea-and-toast diet
medications
selective serotonin reuptake inhibitor (SSRIs) (J Am Acad Nurse Pract 2008 Jan;20(1):47, Ann Pharmacother 2006
Sep;40(9):1618)
case report of flecainide-induced hyponatremia can be found in J Cardiovasc Electrophysiol 2009 Oct;20(10):1170
2 case reports of mirtazapine-associated profound hyponatremia can be found in Am J Geriatr Pharmacother 2008
Jun;6(2):91
review of 17 cases of cisplatin-induced renal salt wasting can be found in South Med J 2010 Aug;103(8):793
case report of sodium-wasting nephropathy due to cisplatin can be found in J Support Oncol 2008 Sep-Oct;6(7):305
case reports of severe hyponatremia associated with preeclampsia can be found in J Obstet Gynaecol 2009 Feb;29(2):143
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Isotonic hyponatremia:
isotonic infusion (for example, glucose or mannitol)(3)
pseudohyponatremia(3)
laboratory artifact resulting from severe elevations in serum triglycerides or proteins
should not be seen when newer, ion-specific electrodes are used to measure serum sodium content (replacing older
method of flame photometry)
Hypertonic hyponatremia:
hypertonic infusion (for example, glucose or mannitol)(3)
hyperglycemia - serum sodium decreases by about 1.6 mEq/L (1.6 mmol/L) for each increase in serum glucose of 100 mg/dL
(5.6 mmol/L) (N Engl J Med 1973 Oct 18;289(16):843)
case report of hyponatremia due to hyperglycemia associated with interferon alpha therapy can be found in Acta Oncol
2009;48(1):154
Reviews of causes of hyponatremia:

review of exercise-associated hyponatremia in marathon runners can be found in J Emerg Med 2001 Jul;21(1):47
review of drug-induced hyponatremia can be found in Am J Kidney Dis 2008 Jul;52(1):144
literature review of selective serotonin reuptake inhibitor (SSRI)-associated hyponatremia can be found in J Am Acad Nurse
Pract 2008 Jan;20(1):47
review of SSRI-associated hyponatremia in older adults can be found in Ann Pharmacother 2006 Sep;40(9):1618
review of thiazide-induced hyponatremia can be found in J Clin Hypertens (Greenwich) 2008 Jun;10(6):477
review of diuretic-induced hyponatremia can be found in Am J Nephrol 1999;19(4):447
review of 129 cases of diuretic-induced severe hyponatremia can be found in Chest 1993 Feb;103(2):601
Pathogenesis:
relative excess of water compared to sodium in the extracellular fluid(2)
dilutional (hypotonic) hyponatremia is caused by water retention(3)
most commonly associated with impaired renal excretion of water and caused by excessive water intake in minority of
cases
except for kidney failure, plasma concentrations of arginine vasopressin (antidiuretic hormone [ADH]) are inappropriately
elevated (despite hypotonicity)
translocational (hypertonic) hyponatremia results from shift of fluid from intracellular to the extracellular space driven by solutes
confined to the extracellular compartment (for example, glucose or hypertonic mannitol)(3)
isotonic hyponatremia results from retention of isotonic fluids that do not contain sodium (for example, isotonic mannitol) in the
extracellular fluid (no transcellular fluid shift occurs)(3)
Likely risk factors:
Medications:
Serotonin specific reuptake inhibitors (SSRIs):

12% of elderly treated with paroxetine develop hyponatremia
based on study of 75 men and women aged 63-90 years who were treated with paroxetine for 12 weeks for major
depressive episode
plasma sodium levels checked at 1, 2, 4, 6 and 12 weeks
9 patients (12%) developed hyponatremia (plasma sodium < 135 mEq/L [135 mmol/L]), all within 2 weeks
risk factors for hyponatremia were lower body mass index (BMI) and lower baseline plasma sodium level (< 138 mEq/L
[138 mmol/L])
most patients with hyponatremia remained asymptomatic
Reference - Arch Intern Med 2004 Feb 9;164(3):327
sertraline-induced hyponatremia reported, hyponatremia previously reported with fluoxetine (J Am Geriatr Soc 1998
Dec;46(12):1582), commentary can be found in J Am Geriatr Soc 1999 Oct;47(10):1274
case report of hyponatremia with paroxetine use can be found in J Am Board Fam Pract 2002 Jan-Feb;15(1):63 PDF
case report of severe symptomatic hyponatremia with citalopram can be found in BMC Nephrol 2004 Jan 16;5:2 full-text
reboxetine (a new antidepressant) has been reported to cause hyponatremia, but only 1-3 cases reported (N Engl J Med 2000
Jan 20;342(3):215)
hyponatremia reported with SSRIs and venlafaxine (Effexor) (Prescriber's Letter 2002 Jul;9(7):38)
Other medications:
thiazide use associated with increased risk of hyponatremia
based on population-based cohort study
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13,325 adults ≥ 45 years from Rotterdam Study were evaluated for association between use of thiazide diuretics and risk
of hyponatremia
718 (5.4%) used thiazides at baseline and 2,738 (20.5%) started thiazides during follow-up
522 patients (3.9%) developed hyponatremia (sodium ≤ 135 mmol/L [135 mEq/L])
compared to no thiazide use, thiazide use associated with increased risk of
mild hyponatremia (hazard ratio [HR] 4.66, 95% CI 3.8-5.71)
moderate hyponatremia (HR 7.85, 95% CI 5.3-11.63)
severe hyponatremia (HR 8.28, 95% CI 4.69-14.61)
Reference - Am J Kidney Dis 2013 Jul;62(1):67
hyponatremia has been reported with carbamazepine and oxcarbazepine
risk factors are older age and concurrent use of diuretics
1%-2% rate of hyponatremia reported in children
Reference - J Am Acad Child Adolesc Psychiatry 2006 Jul;45(7):771
case report of severe hyponatremia with theophylline and separate occurrence of severe hyponatremia with trimethoprim 6
months later in the same patient (Arch Intern Med 2001 Jan 22;161(2):291)
intranasal desmopressin (DDAVP, DDVP, Minirin, Stimate Nasal Spray) no longer indicated for treatment of
primary nocturnal enuresis and should not be used in patients with hyponatremia or history of hyponatremia
increased risk of severe hyponatremia (possibly resulting in seizures and death) in certain patients (including children)
treated with intranasal desmopressin for primary nocturnal enuresis
desmopressin tablets should be interrupted during acute illnesses that may lead to fluid and/or electrolyte imbalance
all formulations should be used cautiously in patients at risk for water intoxication with hyponatremia
Reference - FDA MedWatch 2007 Dec 4
Iatrogenic:
Parenteral hypotonic fluid administration:

hypotonic IV fluids associated with increased risk of hyponatremia and severe hyponatremia compared to
isotonic IV fluids in hospitalized children
based on 2 systematic reviews
systematic review of 10 randomized trials evaluating safety of hypotonic vs. isotonic IV maintenance fluids in 855
hospitalized children aged 1 month to 17 years followed for ≥ 8 hours to ≥ 72 hours
hypotonic IV fluids associated with increased risk of
hyponatremia (plasma sodium < 136 mmol/L [136 mEq/L]) in analysis of 7 trials with 554 children
relative risk 2.24 (95% CI 1.52-3.31)
NNH 2-12 with hyponatremia in 15.4% with isotonic IV fluids
severe or symptomatic hyponatremia (plasma sodium < 130 mmol/L [130 mEq/L]) in analysis of 6 trials with 481
children
relative risk 5.29 (95% CI 1.74-16.06)
NNH 4-96 with severe or symptomatic hyponatremia in 1.4% with isotonic IV fluids
no significant difference in risk of hypernatremia
Reference - Pediatrics 2014 Jan;133(1):105
systematic review of 6 studies (2 randomized trials, 1 controlled trial, 3 observational studies)
in meta-analysis of 4 studies, hypotonic IV fluids associated with increased risk of hyponatremia
odds ratio 17.22 (95% CI 8.67-34.2)
Reference - Arch Dis Child 2006 Oct;91(10):828 EBSCOhost Full Text full-text, commentary can be found in
Evid Based Nurs 2007 Apr;10(2):59
administration of hypotonic fluids was most important risk factor for hospital-acquired hyponatremia
based on study of 1,586 children
Reference - Pediatrics 2004 May;113(5):1279, commentary can be found in Pediatrics 2004 Nov;114(5):1368, Pediatrics
2004 Dec;114(6):1741, Pediatrics 2005 Jan;115(1):193 full-text
risk of symptomatic hyponatremia very low with reduced osmolarity oral rehydration solution
based on cohort of 53,280 patients admitted to 1 of 2 hospitals in Bangladesh for uncomplicated watery diarrhea and
treated with reduced osmolarity oral rehydration solution
24 patients (0.045%) developed seizures or altered consciousness associated with hyponatremia
all 24 patients with symptomatic hyponatremia were < 3 years old, representing 0.12% of all diarrhea patients < 3 years
old (NNH 833)
Reference - JAMA 2006 Aug 2;296(5):567, commentary can be found in JAMA 2007 Jan 3;297(1):41
Medical procedures:
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7.5% rate of hyponatremia reported after colonoscopy in series of 40 patients (Lancet 2001 Jan 27;357(9252):282
EBSCOhost Full Text), commentary can be found in Lancet 2001 May 19;357(9268):1621 EBSCOhost Full Text
glycine-induced hypo-osmolar hyponatremia commonly seen following transurethral resection of prostate or endometrial
transcervical resection when operative field irrigated with hypotonic glycine; in case series of 18 patients, 4 had respiratory arrest
and died, while treatment with hypertonic sodium chloride effective in 14 (Arch Intern Med 1997 Jan 27;157(2):223)
fluorescein angiography used in many eye conditions including age-related macular degeneration; patients typically instructed to
consume large fluid amounts; case report of hyponatremia after fluorescein angiography can be found in J Am Geriatr Soc 2006
May;54(5):872
Endurance exercise (marathon running):

hyponatremia common in nonelite marathon runners
based on study of 488 runners in 2002 Boston Marathon who provided blood sample at finish line
13% had hyponatremia (serum sodium < 135 mmol/L [135 mEq/L]), 0.6% had critical hyponatremia (serum sodium <
120 mmol/L [120 mEq/L])
risk factors for hyponatremia on multivariate analysis were weight gain during the race, running time > 4 hours, and
extremes of body mass index (BMI)
Reference - N Engl J Med 2005 Apr 14;352(15):1550, editorial can be found in N Engl J Med 2005 Apr 14;352(15):1516,
commentary can be found in N Engl J Med 2005 Jul 28;353(4):427
case report of acute exertional hyponatremia can be found in Phys Sportsmed 2000 Sep;28(9):61, editorial can be found in
Phys Sportsmed 2000 Sep;28(9);71, considerable commentary can be found in Phys Sportsmed 2001 Jul;29(7):21
Complications and Associated Conditions
Complications:
severe hyponatremia may result in(1)
cerebral edema
seizures
coma
brainstem herniation, respiratory arrest and death
case series of 14 individuals who developed hyponatremic encephalopathy after running the 2003 London Marathon can be
found in (J R Soc Med 2006 Jul;99(7):363 EBSCOhost Full Text full-text)
rapid correction of hyponatremia may result in osmotic demyelination syndrome (central pontine myelinolysis)
neurologic injury typically occurs 2-6 days after correction of serum sodium level and is irreversible(1)
symptoms may include dysarthria, dysphagia, spastic paraparesis, lethargy, seizures and coma, and may progress to
death(1)
volume repletion, cortisol replacement, or discontinuation of thiazides or DDAVP may lead to sudden decrease in central
nervous system secretion of anti-diuretic hormone, resulting in increased water diuresis and rapid rise in serum sodium
('autocorrection')(2)
case presentation of osmotic demyelination syndrome can be found in BMJ 2005 Oct 8;331(7520):825 EBSCOhost
Full Text full-text
case series of 7 individuals with a history of nonsteroidal anti-inflammatory drug use who developed noncardiogenic pulmonary
edema (ARDS) in association with hyponatremic encephalopathy after running marathons can be found in Ann Intern Med 2000
May 2;132(9):711
osmotic diuresis from rapid correction of severe hyponatremia after contrast dye injection in case report (Mayo Clin Proc 2007
Mar;82(3):384 EBSCOhost Full Text)
History and Physical
History:
Chief concern (CC):

mild hyponatremia (plasma sodium 130-135 mEq/L [130-135 mmol/L]) usually asymptomatic(1)
symptoms at plasma sodium 125-130 mEq/L (125-130 mmol/L) may include(1)
nausea
malaise
symptoms at plasma sodium < 115-120 mEq/L (115-120 mmol/L) may include(1)
headache
lethargy
restlessness
weakness
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disorientation
symptoms with severe or rapid onset hyponatremia may include(1)
seizures
coma
respiratory arrest
symptoms more prominent with large or rapid decreases in serum sodium concentration(3)
Medication history:
numerous medications have been associated with hyponatremia (often due to syndrome of inappropriate antidiuretic hormone
secretion [SIADH])
diuretics
antidepressants
antipsychotics
anticonvulsants
chemotherapy
Past medical history (PMH):

history of adrenal insufficiency (adrenal insufficiency in adults, adrenal tuberculosis)
history of head trauma, central nervous system (CNS) surgery, tumor or meningitis (cerebral salt wasting)
history of gastrointestinal illness resulting in severe diarrhea or vomiting
condition predisposing to fluid sequestration/increased extracellular volume including bowel obstruction, pancreatitis,
rhabdomyolysis, heart failure, cirrhosis, kidney disease or pregnancy
malignant, pulmonary, or CNS disease predisposing to syndrome of inappropriate antidiuretic hormone secretion (SIADH)
hypopituitarism or hypothyroidism
Physical:
General physical:
pulse (volume status)(1)
postural blood pressure (volume status)(1)
Skin:
skin turgor (volume status)(1)
Neck:
jugular venous pressure (volume status)(1)
Extremities:
pitting edema (volume status)(1)
Neuro:
altered mental status(1)
lethargy (3)
depressed reflexes(3)
Diagnosis
Making the diagnosis:

plasma sodium < 135 mEq/L (135 mmol/L)(1)
confirm tonicity if etiology unclear (normal serum osmolality 280-295 mOsm/kg H2O)(2)
Differential diagnosis:
laboratory error (variance up to 5 mEq/L [5 mmol/L] considered within normal limits)(1)
pseudohyponatremia(1, 3)
laboratory artifact resulting from severe elevations in serum triglycerides or proteins
should not be seen when newer, ion-specific electrodes are used to measure serum sodium content (replacing older
method of flame photometry)
Testing overview:
initial testing to consider(1)
repeat serum sodium to confirm value (variance up to 5 mEq/L [5 mmol/L] considered within normal limits)
urine "spot sodium" concentration
plasma glucose and lipids
plasma and urine osmolality
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serum creatinine
testing for specific causes(1)
thyroid function
plasma cortisol at baseline and 30-60 minutes after cosyntropin (synthetic adrenocorticotropin hormone) to test for
adrenocortical insufficiency
chest x-ray, especially if euvolemic hyponatremia
computed tomography or magnetic resonance imaging of head and thorax as indicated
Findings of common causes of hypotonic hyponatremia:

psychogenic polydipsia - urine osmolality < 150 mmol/kg
primary renal disease - impaired renal function, urine osmolality > 150 mmol/kg
volume-mediated vasopressin secretion - edema or volume depletion (decreased effective arterial volume), normal renal
function, urine osmolality > 150 mmol/kg
additional considerations if euvolemic, normal renal function, urine osmolality > 150 mmol/kg
adrenal or thyroid insufficiency
rest osmostat if able to dilute in response to water load
syndrome of inappropriate antidiuretic hormone secretion (SIADH) if unable to dilute in response to water load
Blood tests:
Serum sodium:
to estimate total body sodium deficit (see DynaMed calculator for Sodium Deficit in Hyponatremia)(3)
Sodium deficit [in mEq] = (normal serum sodium [in mEq/L] - measured serum sodium [in mEq/L]) × total body water [in L]
total body water (in L) = weight (in kg) x age/gender-specific fraction of body weight
0.6 in children and adult nonelderly men
0.5 in adult nonelderly women and elderly men
0.45 in elderly women
every 100 mg/dL (5.6 mmol/L) increase in serum glucose concentration decreases serum sodium by about 1.6 mEq/L (1.6
mmol/L) (N Engl J Med 1973 Oct 18;289(16):843)
alternative correction factor for serum sodium recommended with severe hyperglycemia (grade C
recommendation [lacking direct evidence])
based on small diagnostic case series
6 healthy volunteers received somatostatin and high-dose glucose infusion to achieve plasma glucose > 600 mg/dL (33.3
mmol/L) followed by insulin infusion to normalize serum glucose (serum sodium and plasma glucose checked every 10
minutes)
measured decrease in serum sodium seen per 100 mg/dL (5.55 mmol/L) glucose elevation
1.6 mEq/L (1.6 mmol/L) for serum glucose < 400 mg/dL (22.2 mmol/L)
4 mEq/L (4 mmol/L) for serum glucose > 440 mg/dL (24.4 mmol/L)
Reference - Am J Med 1999 Apr;106(4):399, commentary can be found in Am J Med 2000 Feb;108(2):180
Serum osmolality:
normal serum osmolality 280-295 mOsm/kg H2O(2)
Urine studies:
Urine sodium:
urinary sodium - useful if volume status difficult to assess(1)
dilutional hyponatremia usually associated with urinary sodium > 30 mEq/L (30 mmol/L)
extracellular fluid depletion associated with urinary sodium < 30 mEq/L (30 mmol/L), unless renal source
interpretation of 'spot' urine sodium concentration by volume status(1)
hypovolemic volume status
urine sodium < 30 mmol/L (30 mEq/L) indicates extrarenal loss (may be higher if IV saline already administered), such
as
dermal losses (sweating, burns)
gastrointestinal losses (vomiting, diarrhea)
pancreatitis
urine sodium > 30 mmol/L (30 mEq/L) indicates renal loss, such as
diuretics
salt wasting nephropathy
cerebral salt wasting
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mineralocorticoid deficiency (adrenal insufficiency in adults)
hypervolemic volume status
urine sodium < 30 mmol/L (30 mEq/L) may indicate
heart failure
cirrhosis with ascites
nephrotic syndrome
urine sodium > 30 mmol/L (30 mEq/L) indicates chronic kidney disease
euvolemic volume status (urine sodium > 30 mmol/L [30 mEq/L] but may be lower if dietary salt restricted) may indicate
hypothyroidism
hypopituitarism (glucocorticoid deficiency)
syndrome of inappropriate antidiuretic hormone secretion (SIADH) - diagnosis based on
plasma osmolality < 270 mOsm/kg
inappropriately high urinary osmolality (> 100 mOsm/kg)
diagnoses of hypothyroidism and glucocorticoid deficiency have been excluded in the euvolemic patient
water intoxication
primary polydipsia
excessive administration of parenteral hypotonic fluids
post-transurethral prostatectomy (may be isotonic)
Urine osmolality:
inappropriately high urine osmolality (> 100 mOsm/kg H2O) typically associated with SIADH and cerebral salt wasting(2)
Treatment
Treatment overview:
acute hyponatremia (< 48 hours)(2)
hypovolemic hyponatremia
stop any diuretics
correct volume depletion with IV isotonic (0.9%) saline
if severe symptoms
IV hypertonic (3%) saline
do not use furosemide until volume status corrected
euvolemic hyponatremia
acute symptomatic patients need prompt correction of sodium
usually symptomatic if sodium < 120 mmol/L (120 mEq/L)
fluid restriction (≤ 1 L/day)
monitor urine output
for acute symptomatic syndrome of inappropriate antidiuretic hormone secretion (SIADH)
IV hypertonic (3%) saline if severe symptoms and onset < 48 hours
furosemide 20-40 mg IV given with hypertonic saline can limit treatment-induced expansion of the extracellular
fluid volume (level 3 [lacking direct] evidence)
monitor sodium levels every 2 hours during acute therapy
stop hypertonic saline for any of
symptoms resolved
sodium ≥ 120 mmol/L (120 mEq/L)
sodium levels have increased by ≥ 18 mmol/L (18 mEq/L)
for acute exercise-associated hyponatremia
if neurologic impairment
start hypertonic saline while awaiting sodium levels
continue until sodium ≥ 125 mmol/L (125 mEq/L) or symptoms resolve
if nonspecific symptoms such as weakness, headache, or dizziness
check serum sodium
hypertonic saline if sodium ≤ 125 mmol/L (125 mEq/L)
chronic hyponatremia (> 48 hours)
correction too rapidly can cause osmotic demyelination syndrome
limit correction rates to < 10 mmol/L (10 mEq/L) in 24 hours and < 18 mmol/L (18 mEq/L) in 48 hours(2)
hypovolemic hyponatremia(2)
stop any diuretics
correct volume depletion with IV isotonic (0.9%) saline
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continue until blood pressure restored and patient has clinical euvolemia
hydrocortisone or fludrocortisone for primary adrenal insufficiency
euvolemic hyponatremia(1)
for SIADH
stop medications known to cause SIADH
fluid restriction (≤ 1 L/day) is initial therapy
salt restriction not needed
if not improving after several days of fluid restrictions
reconsider diagnosis
demeclocycline 600-1,200 mg/day in divided doses if not responding to fluid restriction
for glucocorticoid deficiency
give glucocorticoid supplement
if neurologic symptoms present carefully treat hyponatremia with saline
monitor sodium levels closely to avoid overcorrection
hypervolemic hyponatremia(1)
treat underlying condition
restrict dietary sodium
diuretics
loop diuretics for heart failure
combination potassium sparing diuretic (spironolactone) with loop diuretic for cirrhosis with ascites
arginine vasopressin receptor antagonists (vaptans) appear to correct serum sodium levels in patients with euvolemic or
hypervolemic hyponatremia (level 3 [lacking direct] evidence)
tolvaptan (Samsca) 15 mg/day orally, may be titrated at 24-hour intervals up to 60 mg/day
conivaptan (Vaprisol) 20 mg IV over 30 minutes, then 20 mg/day continuously over 2-4 days
fludrocortisone reported to effectively treat hyponatremia due to cerebral salt wasting based on multiple case reports (level 3
[lacking direct] evidence)
Fluid and electrolytes:

fluid restriction ≤ 1 L/day is standard initial approach for treating chronic asymptomatic hyponatremia < 130 mEq/L (130
mmol/L)(1)
to estimate effect of 1 L of any saline infusion on serum sodium(3)
change in serum sodium = (infusion sodium concentration [mmol/L] - serum sodium concentration [mmol/L]) / (total body
water + 1)
sodium concentrations of various infusates
5% sodium chloride in water = 855 mmol/L
3% sodium chloride in water = 513 mmol/L
0.9% sodium chloride in water = 154 mmol/L
Ringer lactate solution = 130 mmol/L
0.45% sodium chloride in water = 77 mmol/L
0.2% sodium chloride in 5% dextrose in water = 34 mmol/L
5% dextrose in water = 0 mmol/L
total body water (in L) = weight (in kg) x age/gender-specific fraction of body weight
0.6 in children and adult nonelderly men
0.5 in adult nonelderly women and elderly men
0.45 in elderly women
for patients with chronic hyponatremia, serum sodium level should be increased slowly (2)
suggested correction rate
no more than 10-12 mmol/L during the first 24 hours of treatment
< 18 mmol/L over 48 hours
suggested rate of correction based on cohort studies showing that the faster rate of correction was associated with
neurologic complications such as osmotic demyelination syndrome
if serum sodium is rising too quickly, consider
5% dextrose can be administered alone or in combination with desmopressin to treat excessive correction of serum sodium
(Kidney Int 2009 Sep;76(6):587)
desmopressin reported to effectively reverse inadvertent overcorrection of hyponatremia (level 3 [lacking
direct] evidence)
based on case series
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6 patients received desmopressin after serum sodium increased by ≥ 12 mmol/L in 24 hours and 14 patients received
desmopressin prophylactically (patients received 1-5 doses of DDAVP administered in 1-2 mcg IV or subcutaneously)
plasma sodium concentration decreased 2-9 mmol/L in 14 of the 20 patients (including all 6 who had exceeded the
recommended correction rate)
Reference - Clin J Am Soc Nephrol 2008 Mar;3(2):331 full-text
Medications:
Diuretics:
loop diuretic (for example, furosemide) with hypertonic saline infusion suggested to enhance free water clearance, but caution is
necessary because it may cause sodium to rise too rapidly (1)
furosemide diuresis with electrolyte replacement reported to correct hyponatremia over 6-8 hours in syndrome
of inappropriate antidiuretic hormone secretion (SIADH) (level 3 [lacking direct] evidence)
based on case series of 5 hyponatremic (serum sodium < 125 mEq/L [125 mmol/L]) patients with SIADH
patients remained supine for 8-10 hours (except when voiding)
small amounts of water, but no food, ingested
furosemide 1 mg/kg IV given initially and repeated as needed to obtain negative fluid balance
sodium and potassium replaced with 3% saline and appropriate potassium chloride
hyponatremia corrected in all patients in 6-8 hours
Reference - Ann Intern Med 1973 Jun;78(6):870 EBSCOhost Full Text
hypertonic saline plus furosemide reported to be effective in case report (level 3 [lacking direct] evidence)
based on patient with SIADH following head injury
successful treatment reported with 2.5% saline and furosemide 250 mg (dose repeated 2 hours later)
Reference - No Shinkei Geka 1984 Apr;12(5):651
Demeclocycline:
demeclocycline(1)
600-1,200 mg/day in 3 or 4 divided doses
inhibits arginine vasopressin action in kidney collecting duct
indicated for chronic asymptomatic hyponatremia due to SIADH if unresponsive to fluid restriction alone
demeclocycline reported to be superior to lithium for treatment of chronic SIADH (level 3 [lacking direct]
evidence)
based on small case series
10 patients with SIADH despite severe water restriction were treated with demeclocycline 600-1,200 mg/day
serum sodium restored to mean 139 mEq/L (139 mmol/L) in all patients within 5-14 days
lithium carbonate 900 mg/day was ineffective in 3 patients and associated with central nervous system adverse effects in 2
of these patients
Reference - N Engl J Med 1978 Jan 26;298(4):173
demeclocycline has not been shown to be effective for polydipsia-hyponatremia syndrome in patients with psychosis
demeclocycline may not be effective for treatment of polydipsia-hyponatremia in patients with
schizophrenia (level 3 [lacking direct] evidence)
based on small randomized crossover trial
9 patients hospitalized with chronic psychiatric illness (8 with schizophrenia and 1 with schizoaffective disorder) and
documented history of polydipsia resulting in chronic, episodic hyponatremia (serum sodium < 135 mEq/L [135
mmol/L]) were randomized to demeclocycline vs. placebo for 3 weeks and then crossed over to alternate treatment
during active phase patients received 300 mg demeclocycline 2 times daily for 7 days, 3 times daily for 7 days, then 4
times daily for 7 days
comparing demeclocycline vs. placebo, no significant differences found in
number of episodes of severe hyponatremia (serum sodium < 125 mEq/L [125 mmol/L])
overall number of episodes of hyponatremia
no adverse events related to demeclocycline reported
Reference - Biol Psychiatry 1991 Aug 15;30(4):417
demeclocycline associated with small improvements in serum sodium levels in patients with history of
psychosis and polydipsia-hyponatremia syndrome (level 3 [lacking direct] evidence)
based on small case series without clinical outcomes
8 patients with history of psychosis and polydipsia-hyponatremia syndrome received treatment with demeclocycline
trend toward improvement in serum sodium from average baseline 132.6 mEq/L (132.6 mmol/L) to 134.8 mEq/L
(134.8 mmol/L) (p = 0.08)
Reference - Psychiatr Q 1988 Spring;59(1):62
http://web.b.ebscohost.com/dynamed/delivery/printcitation?expand=sec-General-Information,sec-Causes-and-Risk-Factors,sec-Complications-and-Associate… 10/17
4/5/2014 DynaMed
case series of 8 patients with schizophrenia and hyponatremia treated with demeclocycline can be found in Biol Psychiatry
1985 Nov;20(11):1149
case report of irreversible demeclocycline-induced nephrotoxicity during treatment of hyponatremia can be found in Age Ageing
2002 Mar;31(2):151 PDF
reviews of demeclocycline therapy for hyponatremia can be found in
Ann Intern Med 1977 Jan;86(1):113
Lancet 1976 Dec 25;2(8000):1414
Ann Intern Med 1975 Nov;83(5):654
N Engl J Med 1975 Oct 30;293(18):915
Arginine vasopressin receptor antagonists (vaptans):

vaptans inhibit action of antidiuretic hormone (ADH) on kidney resulting in diuresis of solute-free water (aquaresis) (Am J Med
2007 Nov;120(11 Suppl 1):S1)
indicated for euvolemic or hypervolemic hyponatremia (for example syndrome of inappropriate antidiuretic hormone secretion
(SIADH), heart failure, or cirrhosis with ascites) but role in hypovolemic hyponatremia is not yet established (Am J Med 2007
Nov;120(11 Suppl 1):S1)
vaptans appear to correct serum sodium levels in patients with euvolemic or hypervolemic hyponatremia (level
3 [lacking direct] evidence)
based on systematic review of trials without clinical outcomes
systematic review of 15 trials comparing vaptans with or without fluid restriction vs. placebo or no treatment for euvolemic
or hypervolemic hyponatremia
early response defined as normalization of serum sodium level or increase in serum sodium level ≥ 5-6 mmol/L (5-6
mEq/L) 3-7 days after starting therapy
vaptans associated with
increased early response in analysis of 11 trials with 1,125 patients, results limited by heterogeneity (p = 0.01)
relative risk (RR) 3.15 (95% CI 2.27-4.37)
NNT 2-5 assuming early response in 17.4% of controls
more rapid increase in serum sodium levels in analysis of 13 trials with 1,119 patients
weighted mean difference 5.27 mmol/L (5.27 mEq/L) (95% CI 4.27-6.26 mmol/L [4.27-6.26 mEq/L])
results limited by heterogeneity (p < 0.001)
increased risk of rapid sodium correction in analysis of 8 trials with 1,060 patients
RR 2.52 (95% CI 1.26-5.08)
NNH 12-192 assuming rapid sodium correction in 2% of controls
no significant differences in incidence of hypernatremia and adverse events
Reference - Am J Kidney Dis 2010 Aug;56(2):325
commentary suggests role of vaptans in heart failure associated hyponatremia may be limited to patients unresponsive to loop
diuretic (Am J Med 2010 Aug;123(8):e5)
reviews of vaptans for hyponatremia can be found in
Lancet 2008 May 10;371(9624):1624
Heart Fail Rev 2009 Jun;14(2):75 EBSCOhost Full Text, editorial can be found in Heart Fail Rev 2009 Jun;14(2):87
EBSCOhost Full Text
Cell Mol Life Sci 2006 Aug;63(15):1766 EBSCOhost Full Text
Semin Nephrol 2006 May;26(3):234
Kidney Int 2006 Jun;69(12):2124 EBSCOhost Full Text
Tolvaptan (Samsca):
oral V2-receptor antagonist which produces loss of electrolyte-free water (aquaresis) through inhibition of vasopressin in distal
nephron (JAMA 2007 Mar 28;297(12):1332)
tolvaptan FDA approved for in-hospital treatment of hyponatremia (FDA Press Release 2009 May 22)
tolvaptan FDA approved in oral form for clinically significant euvolemic and hypervolemic hyponatremia
clinically significant hyponatremia considered serum sodium < 125 mEq/L (125 mmol/L) or symptomatic and resistant to
correction with fluid restriction
tolvaptan not indicated for patients required urgent treatment or with serious neurologic deficits
tolvaptan should be started and restarted only in hospital where serum sodium can be monitored closely
Reference - Medical News Today 2009 May 22
tolvaptan dosing
initially 15 mg/day orally
may increase to 30 mg/day after 24 hours
4/5/2014 DynaMed
maximum dose 60 mg/day
titrate at intervals ≥ 24 hours
monitor serum sodium and volume status
do not fluid restrict during first 24 hours of therapy in order to avoid too rapid correction of serum sodium
Reference - Samsca prescribing information
tolvaptan appears to normalize and maintain serum sodium levels in significant proportion of patients with
euvolemic or hypervolemic hyponatremia (level 3 [lacking direct] evidence)
based on 2 randomized trials (Study of Ascending Levels of Tolvaptan in Hyponatremia 1 and 2 [SALT-1 and -2]) with high
dropout rates and without clinical outcomes
448 patients ≥ 18 years with euvolemic or hypervolemic hyponatremia (serum sodium < 135 mmol/L [135 mEq/L]) at 42
sites in United States and 50 international sites randomized to tolvaptan 15 mg orally once daily vs. placebo for maximum
30 days
etiology of hyponatremia included heart failure, cirrhosis or SIADH (other causes excluded)
tolvaptan dose titrated to maximum 60 mg/day
61/205 (30%) patients in SALT-1 trial and 62/243 (26%) in SALT-2 trial dropped out
comparing tolvaptan vs. placebo (SALT-1, SALT-2, p < 0.001 for all)
Proportion of patients with normal sodium (> 135 mmol/L [135 mEq/L]):
SALT-1 SALT-2
After 4 days of treatment 40% vs. 13% (NNT 4) 55% vs. 11% (NNT 4)
Abbreviations: SALT-1/SALT-2, Study of Ascending Levels of Tolvaptan in Hyponatremia 1 and 2.
Proportion of patients still with marked hyponatremia (sodium < 130 mmol/L [130
mEq/L]):
SALT-1 SALT-2
Abbreviations: SALT-1/SALT-2, Study of Ascending Levels of Tolvaptan in Hyponatremia 1 and 2.

no significant differences in incidence of serious adverse events
Reference - Study of Ascending Levels of Tolvaptan in Hyponatremia (SALT-1 and -2 trials) N Engl J Med 2006 Nov
16;355(20):2099 full-text, editorial can be found in N Engl J Med 2006 Nov 16;355(20):2146, commentary can be found in
N Engl J Med 2007 Mar 1;356(9):961
long-term use of tolvaptan appears to correct hyponatremia and maintain serum sodium levels in significant
number of patients with euvolemic or hypervolemic hyponatremia (level 3 [lacking direct] evidence)
based on cohort study (open-label extension of SALT trials) without clinical outcomes
study of 111 patients (38 from SALT-1 and 73 from SALT-2) enrolled to receive oral tolvaptan tablet once daily
mean follow-up 1.9 years with total exposure of 77,369 patient-days (212 patient-years)
study population at baseline equally balanced between those with mild (serum sodium 130-135 mmol/L) and marked (<
130 mmol/L) hyponatremia, and those with euvolemia and hypervolemia
maximum dose of tolvaptan was 60 mg once daily, mean dose used 30 mg/day
64 (58%) of patients did not complete the entire 4-year follow-up, with about half discontinuing study because of adverse
events or death
mean serum sodium increased from 130.8 mEq/L (130.8 mmol/L) to > 135 mEq/L (135 mmol/L) throughout the
observation period (p < 0.001 and most observation points)
result similar for patients with heart failure and SIADH, but trend toward lower final serum sodium levels observed for
patients with cirrhosis
> 60% of patients with mild hyponatremia and 45% of patients with marked hyponatremia had normal serum sodium
levels by week 4
Reference - Safety and Sodium Assessment of Long-term Tolvaptan with Hyponatremia (SALTWATER) trial (J Am Soc
Nephrol 2010 Apr;21(4):705 full-text)
tolvaptan may correct serum sodium levels in schizophrenic patients with idiopathic hyponatremia (level 3
4/5/2014 DynaMed
based on small randomized trial without clinical outcomes
19 patients with schizophrenia and idiopathic hyponatremia were randomized to tolvaptan vs. placebo for 30 days
patients with recognized medical causes of hyponatremia excluded from study
tolvaptan titrated to maximum 60 mg/day
tolvaptan associated with increased serum sodium levels at day 4 (p < 0.0055) and day 30 (p < 0.0001)
Reference - Biol Psychiatry 2008 Dec 15;64(12):1097
reviews of tolvaptan for hyponatremia can be found in
Drugs Today (Barc) 2010 Mar;46(3):163
Expert Opin Pharmacother 2010 Mar;11(4):637 (tolvaptan for treatment of hyponatremia associated with psychotic
disorders)
Med Lett Drugs Ther 2009 Nov 30;51(1326):95
J Clin Pharmacol 2007 Dec;47(12):1498
Am J Kidney Dis 2007 Aug;50(2):184
Cardiovasc Drug Rev 2007 Spring;25(1):1 EBSCOhost Full Text
Conivaptan (Vaprisol):
nonselective V1a/V2 receptor antagonist FDA approved in IV form for euvolemic hyponatremia and hypervolemic hyponatremia
initial loading dose 20 mg IV over 30 minutes
follow with continuous infusion of 20 mg IV over 24 hours for 2-4 days
if serum sodium not increasing at desired rate, may increase to 40 mg/day by continuous infusion
administered by adding conivaptan hydrochloride concentrate (20 mg/4 mL) to 5% dextrose solution for injection
monitor vital signs, serum sodium, and neurologic and volume status
contraindicated (due to drug interactions) with potent CYP3A4 inhibitors, azole antifungals, clarithromycin, indinavir and
ritonavir; monitor closely with or avoid use of CYP3A4 substrates, amlodipine, statins and midazolam
common adverse effects include infusion site reactions, hypokalemia, headache and peripheral edema
oral or IV conivaptan increases serum sodium levels in patients with euvolemic or hypervolemic hyponatremia (level 3
see Conivaptan for details
oral or IV conivaptan increases serum sodium levels in patients with euvolemic or hypervolemic hyponatremia
(level 3 [lacking direct] evidence)
based on 4 randomized trials without clinical outcomes
83 patients ≥ 18 years old in 9 European countries with euvolemic or hypervolemic volume status and serum sodium < 130
mEq/L (130 mmol/L) without hyperglycemia were randomized to in-hospital treatment with conivaptan 40 mg/day vs. 80
mg/day vs. placebo orally for 5 days
patients stratified by volume status prior to randomization and all patients placed on fluid restriction (maximum 500 mL
in 3 hours or 2 liters in 24 hours)
comparing conivaptan 40 mg vs. 80 mg vs. placebo
mean change in serum sodium from baseline to end of treatment 6.8 mEq/L vs. 8.8 mEq/L vs. 1.2 mEq/L (6.8
mmol/L vs. 8.8 mmol/L vs. 1.2 mmol/L) (p = 0.0001 for either dose vs. placebo)
serum sodium increased ≥ 4 mEq/L (4 mmol/L) above baseline significantly faster with either dose of conivaptan
(p < 0.001)
serum sodium increased ≥ 6 mEq/L or normalized in 67% vs. 88% vs. 20% (p < 0.001 for either dose vs.
placebo)
Reference - Am J Med Sci 2009 Jan;337(1):28
56 patients ≥ 18 years old who were clinically euvolemic with serum sodium 115-130 mmol/L (115-130 mEq/L) were
randomized to conivaptan 40 mg/day vs. 80 mg/day vs. placebo IV for 4 days
all patients had hypotonic hyponatremia (serum osmolarity < 290 mOsmol/kg H2O without hyperglycemia)
most common etiologies were SIADH and idiopathic
mean serum sodium after 2 and 4 days of treatment higher for both doses of conivaptan than placebo (p < 0.01 for
all)
Reference - Clin Endocrinol (Oxf) 2008 Jul;69(1):159 EBSCOhost Full Text
84 hospitalized patients ≥ 18 years old who were clinically euvolemic or hypervolemic with serum sodium 115-130 mmol/L
(115-130 mEq/L) were all given loading dose of conivaptan 20 mg infused over 30 minutes, then randomized to placebo
vs. conivaptan 40 mg/day vs. conivaptan 80 mg/day IV for 4 days
all patients had hypotonic hyponatremia (serum osmolarity < 290 mOsmol/kg H2O without hyperglycemia)
two-thirds of patients were euvolemic, and proportion of patients with euvolemia and hypervolemia were equivalent
across the 3 groups
both doses of conivaptan associated with significantly higher serum sodium vs. placebo during 4-day treatment period
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(p < 0.0001)
mean increase in serum sodium from baseline to end of treatment
0.8 mEq/L (0.8 mmol/L) with placebo
6.3 mEq/L (6.3 mmol/L) with conivaptan 40 mg/day
9.4 mEq/L (9.4 mmol/L) with conivaptan 80 mg/day
conivaptan significantly improved (p < 0.001 vs. placebo)
time to confirmed increase of serum sodium ≥ 4 mEq/L (4 mmol/L) over baseline
total time with serum sodium ≥ 4 mEq/L (4 mmol/L) over baseline
number of patients with confirmed ≥ 6 mEq/L (6 mmol/L) increase in serum sodium or normal serum sodium (≥
135 mEq/L [135 mmol/L])
infusion-site reactions reported in 1 (3%) patient with conivaptan 40 mg/day and 4 (15%) patients with conivaptan 80
mg/day
Reference - Am J Nephrol 2007;27(5):447 EBSCOhost Full Text
74 patients with euvolemic or hypervolemic hyponatremia (serum sodium < 133 mEq/L [133 mmol/L]) were randomized to
placebo vs. conivaptan 20 mg vs. conivaptan 40 mg orally twice daily for 5 days
all patients received placebo twice daily for 20-28 hours before randomization
Statistical Comparison vs. Placebo:
Outcome Placebo Conivaptan 40 Conivaptan 80

mg/day mg/day
Median time to confirmed increase in serum sodium ≥ 4 71.7 hours 27.5 hours (p = 12.1 hours (p =
mEq/L (4 mmol/L) over baseline 0.044) 0.002)
Mean total time serum sodium ≥ 4 mEq/L (4 mmol/L) 46.5 hours 69.8 hours (not 88.8 hours (p =
above baseline significant) 0.001)
Mean increase in serum sodium at end of treatment 3.4 mEq/L 6.4 mEq/L (6.4 8.2 mEq/L (8.2
(3.4 mmol/L) mmol/L) (p = mmol/L) (p =
0.081) 0.001)
Confirmed normal serum sodium (≥ 135 mEq/L [135 48% 71% (not significant) 82% (p = 0.014,
mmol/L]) or increase ≥ 6 mEq/L (6 mmol/L) NNT 3)
Reference - J Clin Endocrinol Metab 2006 Jun;91(6):2145 full-text
conivaptan therapy reportedly not associated with clinically significant electrocardiogram (ECG) changes (Adv Ther 2007 Mar-
Apr;24(2):310 EBSCOhost Full Text)
reviews of conivaptan can be found in
Am J Health Syst Pharm 2007 Jul 1;64(13):1385 EBSCOhost Full Text
Drugs Today (Barc) 2006 Jun;42(6):379
Clin Ther 2009 Jul;31(7):1542
Fludrocortisone:
fludrocortisone reported to effectively treat hyponatremia due to cerebral salt wasting (CSW) (level 3 [lacking
direct] evidence)
based on multiple case reports
report of a 34-month-old boy with lissencephaly and CSW successfully treated with fludrocortisone can be found in Turk
Neurosurg 2010 Jan;20(1):100 PDF
report of successful treatment of CSW in a 75-year-old man with a history of head trauma using fludrocortisone can be
found in Arch Intern Med 2008 Feb 11;168(3):325 full-text, correction can be found in Arch Intern Med 2008 Apr
14;168(7):748
case report of treatment for CSW with saline hydration and fludrocortisone in a 17-year-old adolescent boy with head
trauma can be found in Saudi J Kidney Dis Transpl 2007 Mar;18(1):95 full-text
case series of 4 children with CSW managed with fludrocortisone can be found in Pediatrics 2006 Dec;118(6):e1904 full-text
series of 3 cases of CSW complicating tuberculosis meningitis managed with fludrocortisone can be found in Ann Trop
Paediatr 2005 Dec;25(4):297
case report of 11-year-old boy diagnosed with CSW after development of seizures following intracranial tumor section
successfully treated with fludrocortisone can be found in Pediatr Neurosurg 2001 Oct;35(4):216
case report and a 29-month-old boy with tuberculous meningitis who developed CSW treated with fludrocortisone can be
found in Pediatr Nephrol 1998 Nov;12(9):769
4/5/2014 DynaMed
case series of 3 elderly patients with recent history of head trauma who developed CSW treated with fludrocortisone can be
found in Ann Intern Med 1987 Feb;106(2):187
Urea:
urea is quickly absorbed and renally excreted after oral administration resulting in efficient osmotic diuresis (J Clin
Psychopharmacol 2009 Oct;29(5):499)
not well tolerated(1)
urea 30-60 g/day reported to be effective (level 3 [lacking direct] evidence)
based on uncontrolled case series with 7 patients
control defined as serum sodium > 128 mEq/L (128 mmol/L)
5 patients controlled with urea 30 g/day drank 1-2 L/day
2 patients controlled with urea 60 g/day drank up to 3.1 L/day
Reference - Br Med J (Clin Res Ed) 1981 Oct 24;283(6299):1081 EBSCOhost Full Text full-text
oral urea solution reported to be effective in SIADH in children (level 3 [lacking direct] evidence)
based on case series without clinical outcomes
4 children with chronic SIADH were previously unsuccessfully treated with fluid restriction
children given 30%-50% oral urea solution, titrated until serum sodium normal
all children normalized serum sodium
no toxicities or side effects noted
Reference - J Pediatr 2006 Jan;148(1):128
oral urea treatment may improve serum sodium levels in patients with schizophrenia and polydipsia-
hyponatremia syndrome (level 3 [lacking direct] evidence)
based on small, uncontrolled trial without clinical outcomes
7 patients with schizophrenia and known history of polydipsia, serum sodium < 135 mEq/L during routine blood analysis in
previous 6 months and ≥ 1 documented episode of water intoxication received oral urea therapy 2-3 times daily
initial urea dose 30 g/day, titrated to 67.5 g/day (after minimal effect noted at 30 g and 45 g)
serum sodium increase during 7-month observation period
average 4 PM serum sodium increased from baseline 127.6 mEq/L to 133.5 mEq/L (127.6 mmol/L to 133.5 mmol/L)
(p < 0.001)
average 6 AM serum sodium increased from 131.1 mEq/L to 136.3 mEq/L (131.1 mmol/L to 136.3 mmol/L) (p <
0.01)
Reference - J Clin Psychopharmacol 2009 Oct;29(5):499
urea 30 g/day allowed normal water intake despite SIADH for 11 weeks in case report (Am J Med 1980 Jul;69(1):99)
Other medications:
lithium(1)
inhibits arginine vasopressin action in kidney collecting duct (similar to demeclocycline and vaptans)
effects inconsistent and associated with renal impairment, central nervous system effects and thyroid disorders
case report of correction of hyponatremia with levothyroxine in a 72-year-old woman with idiopathic hypopituitarism can be
found in Arch Intern Med 1978 May;138(5):820
Follow-up:
monitor serum sodium frequently (every 1-2 hours) during correction(1)
Prognosis
preoperative hyponatremia associated with increased risk of 30-day morbidity and mortality
based on cohort study
964,263 patients having major surgery evaluated for 30-day perioperative outcomes
7.8% had preoperative hyponatremia
comparing preoperative hyponatremia vs. normal sodium levels (p < 0.001 for all)
30-day all-cause mortality in 5.2% vs. 1.3%
perioperative major coronary events in 1.8% vs. 0.7%
wound infections in 7.4% vs. 4.6%
pneumonia in 3.7% vs. 1.5%
Reference - Arch Intern Med 2012 Oct 22;172(19):1474, editorial can be found in Arch Intern Med 2012 Oct
22;172(19):1482
hyponatremia on admission or during hospitalization associated with increased risk of in-hospital mortality
based on cohort of 53,236 adult patients admitted to hospital for whom data on admission serum sodium concentrations
were available
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37.9% had hyponatremia on admission and 38.2% developed hyponatremia during hospitalization
hyponatremia associated with increased in-hospital mortality
for hyponatremia present on admission, adjusted odds ratio (adjusted OR) 1.52 (95% CI 1.36-1.69)
for hospital-acquired hyponatremia, adjusted OR 1.66 (95% CI 1.39-1.98)
Reference - Arch Intern Med 2010 Feb 8;170(3):294
hyponatremia (on admission or during hospitalization) associated with longer length of stay in hospitalized
elderly patients
based on cohort of 103 patients (mean age 82 years) admitted to geriatric wards
19 (18%) had hyponatremia on admission, 24 (23%) developed hyponatremia during admission
66 (65%) returned to previous residence, less likely in patients with larger decrease in serum sodium (p < 0.001)
Reference - Arch Gerontol Geriatr 2007 Nov-Dec;45(3):253
major morbidity and mortality common in patients with chronic, symptomatic hyponatremia (sodium < 130
mEq/L [130 mmol/L])
based on small prospective cohort study
53 postmenopausal women with chronic, symptomatic hyponatremia (chronic plasma sodium < 130 mEq/L [130 mmol/L]
with central nervous system manifestations) followed up for 1 year
death or major morbidity occurred in 44 (83%) patients
outcomes did not correlate with initial plasma sodium level or rate of correction
Reference - JAMA 1999 Jun 23-30;281(24):2299 full-text, commentary can be found in JAMA 1999 Dec 22-
29;282(24):2298
in patients with postoperative hyponatremic encephalopathy, risk of death or brain damage appears higher in
women than in men and higher in menstruant women than postmenopausal women
based on case-control study
65 adults with postoperative hyponatremic encephalopathy were compared with 674 adults with postoperative
hyponatremia without encephalopathy
increased risk of death or permanent brain damage from hyponatremic encephalopathy associated with
female sex compared to male sex (relative risk 28, 95% Cl 5-141)
menstruant status compared to postmenopausal status in women (relative risk 26, 95% CI 11-62)
Reference - Ann Intern Med 1992 Dec 1;117(11):891 EBSCOhost Full Text, commentary can be found in Ann Intern
Med 1993 Jun 15;118(12):984 EBSCOhost Full Text
hypoxia appears to be underlying cause of brain damage in hyponatremia, patients with brain damage all had hypoxia (editorial
in JAMA 1999 Jun 23-30;281(24):2342)
Prevention and Screening
Prevention:
use hypotonic fluids cautiously in hospitalized patients; hyponatremia will develop if electrolyte-free water intake exceeds capacity
for water excretion plus insensible losses(3)
maintenance fluids in hospitalized children
IV maintenance with hypotonic solution for ≥ 24 hours associated with increased risk of hyponatremia in
children (level 3 [lacking direct] evidence)
based on 2 randomized trials without clinical outcomes
258 children aged 6 months to 16 years randomized to 48 hours of postoperative IV maintenance with isotonic (0.9%
saline) vs. hypotonic (0.45% saline) solution
hyponatremia in 22.7% with isotonic solution vs. 40.8% with hypotonic solution (p = 0.004, NNT 6)
no significant difference in hypernatremia, adverse events associated with acute plasma sodium level changes, or
antidiuretic hormone levels
Reference - Pediatrics 2011 Nov;128(5):857 full-text, editorial can be found in Pediatrics 2011 Nov;128(5):980 full-
text
167 children hospitalized and requiring IV maintenance for ≥ 24 hours randomized to 1 of 3 treatment options
0.9% saline in 5% dextrose at the standard maintenance rate
0.18% saline in 5% dextrose at the standard maintenance rate
0.18% saline in 5% dextrose at two-thirds of the standard maintenance rate
hyponatremia (plasma sodium < 130 mEq/L) in
14.3% with 0.18% saline in 5% dextrose at the standard maintenance rate (p = 0.014 vs. 0.9% saline at
standard maintenance rate, NNH 8)
3.8% with 0.18% saline in 5% dextrose at two-thirds of the standard maintenance rate (p = 0.056 vs.
0.18% saline at standard maintenance rate)
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1.72% with 0.9% saline in 5% dextrose
Reference - Pediatr Nephrol 2010 Nov;25(11):2303 EBSCOhost Full Text
0.9% saline and 0.45% saline associated with similar serum sodium levels during the first 12 hours of
fluid therapy in children without severe baseline hyponatremia (level 3 [lacking direct] evidence)
based small on randomized trial without clinical outcomes
37 children aged 3 months to 18 years hospitalized for medical and postoperative care randomized to 0.9% saline IV
vs. 0.45% saline IV for 12 hours
duration and rate of study fluid infusion and volume of additional isotonic fluids given were similar for the two groups
no significant differences in serum sodium
1 child in each group developed hyponatremia (serum sodium < 136 mmol/L)
Reference - BMC Pediatr 2011 Sep 23;11:82 EBSCOhost Full Text full-text
hydration during sports should be based on individual needs (such as, thirst) and not as much as tolerated; overhydration can
lead to hyponatremia (Phys Sportsmed 2003 Jul;31(7):15)
American College of Sports Medicine position stand on exercise and fluid replacement can be found in Med Sci Sports Exerc
2007 Feb;39(2):377
Guidelines and Resources
Patient Information
ICD-9/ICD-10 Codes
References
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Hyponatremia

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Hyponatremia

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4/5/2014 DynaMed

Who is most affected:

Reviews of causes of hyponatremia:

Likely risk factors:

Serotonin specific reuptake inhibitors (SSRIs):

Parenteral hypotonic fluid administration:

Endurance exercise (marathon running):

Chief concern (CC):

Past medical history (PMH):

Making the diagnosis:

Findings of common causes of hypotonic hyponatremia:

Fluid and electrolytes:

Arginine vasopressin receptor antagonists (vaptans):

Abbreviations: SALT-1/SALT-2, Study of Ascending Levels of Tolvaptan in Hyponatremia 1 and 2.

Abbreviations: SALT-1/SALT-2, Study of Ascending Levels of Tolvaptan in Hyponatremia 1 and 2.

Statistical Comparison vs. Placebo:

Outcome Placebo Conivaptan 40 Conivaptan 80

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