Hypo Nat Re Mia

Hyponatremia: epidemiology,
pathophysiology, and therapy.

Verbalis JG.
University of Pittsburgh School of Medicine, Pennsylvania.
Abstract
Despite several decades of research interest and productivity, many aspects of hyponatremia and
hypo-osmolar disorders remain incompletely understood. Among these aspects are questions
relating to the morbidity and mortality actually attributable to hyponatremia, possible hormonal
and gender-associated risk factors underlying susceptibility to neurologic complications from
hyponatremic encephalopathy, the stimuli to arginine vasopressin secretion in some atypical
subsets of patients with the syndrome of inappropriate antidiuretic hormone secretion and other
hyponatremic disorders, the contributions of natriuresis and natriuretic peptides to hyponatremic
states, the pathologic determinants of brain demyelination that sometimes follow rapid correction
of hyponatremia, and appropriate treatment guidelines for patients with acute and chronic
hyponatremia. The recent literature confirms that acceptable answers to these questions and
others are still not available, and a better understanding of basic issues regarding the
pathophysiology of hyponatremia is needed. Several recent advances stand out as being likely to
enhance our future understanding of hyponatremia and hypo-osmolar states. First are studies of
cellular mechanisms of volume regulation in kidney and brain tissue in response to changes in
osmolality. Many, though clearly not all, clinical observations can be better understood by
considering them in the conceptual framework provided by knowledge of cell and body fluid
compartment volume regulation. Second is the elucidation of several important protein structures
via complementary DNA cloning, including the arginine vasopressin V1 and V2 receptors,
several organic osmolyte transporters, and the CHIP28 water channel. Future application of these
new tools to carefully designed and executed physiologic studies will likely add considerable
new knowledge to our understanding of hyponatremia. Third is the development and increasing
application of nuclear magnetic resonance spectroscopy and imaging methods that will allow
more detailed analyses of acute changes in brain metabolism during hyponatremia and following
correction. Finally, the recent development of nonpeptide antagonists to arginine vasopressin V1
and V2 receptors should enable clinical studies to assess more accurately the contribution of
arginine vasopressin-induced antidiuresis to hyponatremia and more importantly holds the
promise of more effective therapies for hyponatremic patients.
PMID: 7859027 [PubMed - indexed for MEDLINE]
Hyponatremia
Sodium: (Normal range: 136 - 145 meq/l)
Sodium plays a vital role in maintaining the concentration and volume of the
extracellular fluid (ECF). It is the main cation of the ECF and a major determinant of
ECF osmolality. Sodium is important in maintaining irritability and conduction of
nerve and muscle tissue and assists with the regulation of acid-base balance. The
average daily intake far exceeds the normal daily requirements. The kidneys are
responsible for excreting the excess and are capable of conserving sodium during
periods of extreme sodium restriction. The kidneys accomplish this primarily
through regulation of water intake/excretion. If the serum sodium falls, the kidneys
respond by excreting water. If the serum sodium increases (increased osmolality)---
thirst center is stimulated--increased ADH release by the posterior pituitary---acts
on kidney to conserve water. Aldosterone also plays a key role by regulating
Na+/ECF volume. Its release causes the kidneys to conserve water and sodium
which results in increased ECF volume. Because changes in serum sodium levels
typically reflect changes in body water balance, gains or losses of total body sodium
are not necessarily reflected by the serum sodium level.
Hyponatremia: (Serum sodium less than 136 meq/L)
Clinical indicators and treatment depend on the cause of hyponatremia and whether
or not it is associated with a normal, decreased or increased ECF volume.
Signs and symptoms: neurologic symptoms usually do not occur until the serum
sodium level has dropped to approximately 120-125 meq/L. Hyponatremia with
decreased ECF volume: irritability, apprehension, dizziness, postural hypotension,
dry mucus membranes, cold and clammy skin, tremors, seizures. Hyponatremia
with normal or increased ECF volume: headache, lassitude, apathy, confusion,
weakness, edema, weight gain, elevated blood pressure, muscle cramps,
convulsions.
History and risk factors: diarrhea, fistulas, vomiting, NG suction, diuretics,
adrenal insufficiency, skin losses (burns, wound drainage), other. Note:
hyperlipidemia, hyperproteinemia, and hyperglycemia may cause a pseudo-
hyponatremia. This must be ruled out before determining therapy. For every 100
mg/dl increase in glucose, the sodium is diluted by 1.6 meq/L.
Diagnostic tests: serum sodium will be less than 136 meq/L. Serum osmolality
will be decreased except in cases of pseudo-hyponatremia, azotemia, or toxins that
increase osmolality (example: ethanol). Urine specific gravity will be decreased
because of the kidneys attempt to excrete excess water. Urine sodium: decreased
(except in SIADH and adrenal insufficiency).
Collaborative management: The goal of therapy is to get the patient out of
immediate danger (eg return the sodium level to greater than 120 meq/L) and then
gradually return the serum sodium to a normal level and restore normal ECF
volume.
Hyponatremia with increased ECF volume and edema
Hypervolemia: low serum serum osmolality (< 280 ), urine sodium < 10 mmol/L,
Usually associated with: CHF, cirrhosis, or acute/chronic renal failure.)
Therapeutic options:
1) For mild cases only (serum sodium > 120 meq/L): Water restriction (limit to 500
to 1500 ml/ 24 hours) and furosemide 40-80 IV/ oral once daily (20-400 mg/day).
2) Patients with CHF, cirrhosis, nephrotic syndrome who usually have excessive ECF
volume have few symptoms referable to hyponatremia. Usually water restriction
combined with treatment of the underlying disorder is successful.
3) If severe symptomatic hyponatremia is present (sodium level < 115 meq/L) in
the volume overloaded patient: Continue water restriction. Also infuse 3%
hypertonic saline.
Calculate sodium deficit: 0.6 x (weight in kg) x (desired sodium - Actual sodium)
Use 0.5 for females. Desired range= 120 - 125 meq/L.
When hyponatremia is symptomatic and acute (< 24 hours in duration), the serum
sodium may be raised safely to 120-125 meq/L in 24 hours or less. In patients with
symptomatic chronic hyponatremia, or hyponatremia of unknown duration, the
serum sodium should be raised slowly (0.5 meq/L/hr) to about 120-125 meq/L in
order to avoid CNS complications (cerebral edema, pontine myelinolysis, seizures)
and/or pulmonary edema. The total increase in these patients should not exceed
10-12 meq/L in 24 hours or <20-25 meq/L over 48 hours. Thereafter, the
hypertonic saline is stopped, and the serum sodium is allowed to rise more slowly
(eg over several days) in response to continued restriction of free water. In all
cases, the serum sodium should be corrected only halfway to normal in the initial 24
hours (120-125 meq/L) to prevent the complications listed above.
Example calculations:
80kg patient; serum sodium=110 meq\L ; male; desired target= 120 meq/L.
1) 0.6 x 80kg x (120-110)= 480 meq (total needed)
2) Amount needed to increase serum level by 0.5 meq/L/hr =
0.6 x 80 x 0.5= 24 meq. (rate should be 24 meq/hr)
3) 3% hypertonic saline contains 513 meq/Liter
[desired rate/hr]/513 x 1000= # ml/hr // Total meq/rate/hr
=infusion time.
Therefore: 24 meq/hr x 1000= 47 ml/hr

513
Length of infusion= 480 meq/ 24 meq= 20 hours
Final order: infuse 3% hypertonic saline at 47 ml/hr for 20 hours.
When infusion is complete, discontinue. Continue with fluid
restriction.
Hyponatremia with isovolemia
Low osmolarity (<280), urine sodium < 10 mmol: water intoxication; urine sodium
> 20: SIADH, hypothyroidism, renal failure, addisons disease, drugs.
Mild: (serum level > 120 meq/L; asymptomatic): furosemide 80mg IV once or twice
daily and Normal saline + 20-40meq KCL/liter infused at 65-150 ml/hr (correct
deficit at 0.5 meq/L/hr or less.)
SIADH: fluid restriction 500-750ml/ day. Demeclocycline 300 to 600mg twice daily.
Use caution in patients with hepatic disease. In emergency situations (sodium <
115) use hypertonic saline (see above) and furosemide.
Symptomatic patients: hypertonic saline and furosemide as above. or hypertonic
saline and water restriction.
Hyponatremia with hypovolemia

Low serum osmolarity (<280). Urine sodium < 10 mmol: vomiting, diarrhea, 3rd
space/respiratory/skin loss. Urine sodium > 20: diuretics, renal injury, RTA, adrenal
insufficiency.
If volume depleted give 500 to 3000 ml of normal saline at 500 ml/hr until no longer
orthostatic, then give normal saline ( + 20-40 meq KCL/ liter) at 65 to 150 ml/hr
until desired level is reached (note: in mild cases, target a level of 130 meq/ Liter).
Each liter of normal saline contains 154 meq. May use the calculations above to
determine approximate length of therapy. If severe hyponatremia is present (<115
meq/L) start hypertonic saline using the dosing guidelines above.
Hyponatremia
Author: Sandy Craig, MD, Adjunct Associate Professor, Department of Emergency Medicine,
University of North Carolina at Chapel Hill, Carolinas Medical Center
Contributor Information and Disclosures
Updated: Apr 13, 2010
Introduction
Background
Serum sodium concentration and serum osmolarity normally are maintained under precise
control by homeostatic mechanisms involving stimulation of thirst, secretion of antidiuretic
hormone (ADH), and renal handling of filtered sodium. Clinically significant hyponatremia is
relatively uncommon and is nonspecific in its presentation; therefore, the physician must
consider the diagnosis in patients presenting with vague constitutional symptoms or with altered
level of consciousness. Irreparable harm can befall the patient when abnormal serum sodium
levels are corrected too quickly or too slowly. The physician must have a thorough
understanding of the pathophysiology of hyponatremia to initiate safe and effective corrective
therapy. The patient's fluid status must be accurately assessed upon presentation, as it guides the
approach to correction.
Hypovolemic hyponatremia
Total body water (TBW) decreases; total body sodium (Na+) decreases to a greater extent. The
extracellular fluid (ECF) volume is decreased.
Euvolemic hyponatremia
TBW increases while total sodium remains normal. The ECF volume is increased minimally to
moderately but without the presence of edema.
Hypervolemic hyponatremia
Total body sodium increases, and TBW increases to a greater extent. The ECF is increased
markedly, with the presence of edema.
Redistributive hyponatremia
Water shifts from the intracellular to the extracellular compartment, with a resultant dilution of
sodium. The TBW and total body sodium are unchanged. This condition occurs with
hyperglycemia or administration of mannitol.
Pseudohyponatremia
The aqueous phase is diluted by excessive proteins or lipids. The TBW and total body sodium
are unchanged. This condition is seen with hypertriglyceridemia and multiple myeloma.
Pathophysiology
Serum sodium concentration is regulated by stimulation of thirst, secretion of ADH, feedback
mechanisms of the renin-angiotensin-aldosterone system, and variations in renal handling of
filtered sodium. Increases in serum osmolarity above the normal range (280-300 mOsm/kg)
stimulate hypothalamic osmoreceptors, which, in turn, cause an increase in thirst and in
circulating levels of ADH. ADH increases free water reabsorption from the urine, yielding urine
of low volume and relatively high osmolarity and, as a result, returning serum osmolarity to
normal. ADH is also secreted in response to hypovolemia, pain, fear, nausea, and hypoxia.
Aldosterone, synthesized by the adrenal cortex, is regulated primarily by serum potassium but
also is released in response to hypovolemia through the renin-angiotensin-aldosterone axis.
Aldosterone causes absorption of sodium at the distal renal tubule. Sodium retention obligates
free water retention, helping to correct the hypovolemic state. The healthy kidney regulates
sodium balance independently of ADH or aldosterone by varying the degree of sodium
absorption at the distal tubule. Hypovolemic states, such as hemorrhage or dehydration, prompt
increases in sodium absorption in the proximal tubule. Increases in vascular volume suppress
tubular sodium reabsorption, resulting in natriuresis and helping to restore normal vascular
volume. Generally, disorders of sodium balance can be traced to a disturbance in thirst or water
acquisition, ADH, aldosterone, or renal sodium transport.
Hyponatremia is physiologically significant when it indicates a state of extracellular
hyposmolarity and a tendency for free water to shift from the vascular space to the intracellular
space. Although cellular edema is well tolerated by most tissues, it is not well tolerated within
the rigid confines of the bony calvarium. Therefore, clinical manifestations of hyponatremia are
related primarily to cerebral edema. The rate of development of hyponatremia plays a critical
role in its pathophysiology and subsequent treatment. When serum sodium concentration falls
slowly, over a period of several days or weeks, the brain is capable of compensating by extrusion
of solutes and fluid to the extracellular space. Compensatory extrusion of solutes reduces the
flow of free water into the intracellular space, and symptoms are much milder for a given degree
of hyponatremia.
When serum sodium concentration falls rapidly, over a period of 24-48 hours, this compensatory
mechanism is overwhelmed and severe cerebral edema may ensue, resulting in brainstem
herniation and death.
Frequency
United States
Hyponatremia is the most common electrolyte disorder, with a marked increase among
hospitalized and nursing home patients. A 1985 prospective study of inpatients in a US acute
care hospital found an overall incidence of approximately 1% and a prevalence of approximately
2.5%. On the surgical ward, approximately 4.4% of postoperative patients developed
hyponatremia within 1 week of surgery. Hyponatremia has also been observed in approximately
30% of patients treated in the intensive care unit.1
International
Though clearly not indicative of the overall prevalence internationally, hyponatremia has been
observed in as high as 42.6% of patients in a large acute care hospital in Singapore and in 30% of
patients hospitalized in an acute care setting in Rotterdam.2,3
Mortality/Morbidity
Pathophysiologic differences between patients with acute and chronic hyponatremia engender
important differences in their morbidity and mortality.
• Patients with acute hyponatremia (developing over 48 h or less) are subject

to more severe degrees of cerebral edema for a given serum sodium level.
The primary cause of morbidity and death is brainstem herniation and
mechanical compression of vital midbrain structures. Rapid identification and
correction of serum sodium level is necessary in patients with severe acute
hyponatremia to avert brainstem herniation and death.
• Patients with chronic hyponatremia (developing over more than 48 h)
experience milder degrees of cerebral edema for a given serum sodium level.
Brainstem herniation has not been observed in patients with chronic
hyponatremia. The principal direct causes of morbidity and death are status
epilepticus (when chronic hyponatremia reaches levels of 110 mEq/L or less)
and cerebral pontine myelinolysis (an unusual demyelination syndrome that
occurs in association with chronic hyponatremia).
• The distinction between acute hyponatremia and chronic hyponatremia has
critical implications in terms of morbidity and mortality and in terms of proper
corrective therapy.
• A 2009 study of 98,411 hospitalized patients found that even mild degrees of
hyponatremia were associated with increased in-hospital, 1-year and 5-year
mortality rates. Mortality was particularly increased in those with
cardiovascular disease, metastatic cancer, and those undergoing orthopedic
procedures.4
• A 2009 study in Copenhagen concluded that hyponatremia in the range of
130-137 mEq/L is also associated with increased mortality rates in the
general population.5
Sex
Overall incidence of hyponatremia is approximately equal in males and females, though
postoperative hyponatremia appears to be more common in menstruant females.
Age
Hyponatremia is most common in the extremes of age; these groups are less able to experience
and express thirst and less able to regulate fluid intake autonomously. Specific settings that have
been known to pose particular risk include the following:
• Infants fed tap water in an effort to treat symptoms of gastroenteritis

• Infants fed dilute formula in attempt to ration
• Elderly patients with diminished sense of thirst, especially when physical
infirmity limits independent access to food and drink
Clinical
History
• The number and severity of symptoms increase with the degree of
hyponatremia and the rapidity with which it develops. When the serum
sodium level falls gradually, over a period of several days or weeks, sodium
levels as low as 110 mEq/L may be reached with minimal symptomatology. In
contrast, an equivalent fall in serum sodium level over 24-48 hours may
overwhelm compensatory mechanisms, leading to severe cerebral edema,
coma, or brainstem herniation.
• Symptoms range from mild anorexia, headache, and muscle cramps, to
significant alteration in mental status including confusion, obtundation, coma,
or status epilepticus.
• Hyponatremia is often seen in association with pulmonary/mediastinal
disease or CNS disorders. Hyponatremia must be considered in patients with
pneumonia, active tuberculosis, pulmonary abscess, neoplasm, or asthma, as
well as in patients with CNS infection, trauma, or neoplasm. Patients with
carcinoma of the nasopharynx, duodenum, stomach, pancreas, ureter,
prostate, or uterus also have an increased risk.
• Hyponatremia is associated with numerous medications. The patient's
medication list should be examined for drugs known to cause hyponatremia.
• Hyponatremia has been noted in patients with poor dietary intake who
consume large amounts of beer (called beer potomania) and after use of the
recreational drug N- methyl-3,4-methylenedioxyamphetamine (ie, MDMA or
ecstasy). MDMA-induced hyponatremia occurs via multiple mechanisms;
these include the induction of syndrome of inappropriate antidiuretic
hormone (SIADH), the encouragement to drink large amounts of water to
prevent unpleasant side effects of the drug, and the tendency among those
intoxicated to be involved in vigorous physical activity that results in heavy
sweating.
• A history of hypothyroidism or adrenal insufficiency should be sought
because each is associated with hyposmolar hyponatremia.
• Patients with clinically significant hyponatremia present with nonspecific
symptoms attributable to cerebral edema. These symptoms, especially when
coupled with a recent history of altered fluid balance, should suggest the
possibility of hyponatremia.
○ Anorexia
○ Nausea and vomiting
○ Difficulty concentrating
○ Confusion
○ Lethargy
○ Agitation
○ Headache
○ Seizures
Physical
Physical findings are highly variable and dependent on the degree and the chronicity of
hyponatremia. Patients with acutely developing hyponatremia are typically symptomatic at a
level of approximately 120 mEq/L. Those patients with chronic hyponatremia tolerate much
lower levels.
• Most abnormal findings on physical examination are characteristically

neurologic in origin.
○ Level of alertness ranging from alert to comatose
○ Variable degrees of cognitive impairment (eg, difficulty with short-term
recall; loss of orientation to person, place, or time; frank confusion or
depression)
○ Focal or generalized seizure activity
○ In those patients with acute severe hyponatremia, signs of brainstem
herniation, including coma; fixed, unilateral, dilated pupil; decorticate
or decerebrate posturing; sudden severe hypertension and respiratory
arrest
• In addition to neurologic findings, patients may exhibit signs of hypovolemia
or hypervolemia. Determining the hydration status of the patient may help
establish the etiology of the hyponatremia and direct subsequent treatment.
○ Dry mucous membranes, tachycardia, diminished skin turgor, and
orthostasis suggest hypovolemic hyponatremia due to excessive loss
of body fluids and replacement with inappropriately dilute fluids.
○ Pulmonary rales, S3 gallop, jugular venous distention, peripheral
edema, or ascites suggest hypervolemic hyponatremia due to excess
retention of sodium and free water (ie, cirrhosis, nephrotic syndrome,
congestive heart failure).
○ Patients who lack findings of hypovolemia or hypervolemia are
considered to have euvolemic hyponatremia, which is consistent with
such etiologies as exogenous free water load, hypothyroidism, cortisol
deficiency, or SIADH.
• Other nonspecific signs include muscle weakness and cramping.
Rhabdomyolysis is an occasional consequence of hyponatremia and should
be considered in patients with muscle pain or tenderness.
Causes
• Hypovolemic hyponatremia develops as sodium and free water are lost and
replaced by inappropriately hypotonic fluids, such as tap water, half-normal
saline, or dextrose in water. Sodium can be lost through renal or nonrenal
routes. Nonrenal routes include GI losses, excessive sweating, third spacing
of fluids (eg, ascites, peritonitis, pancreatitis, burns), and cerebral salt-
wasting syndrome.
○ Excess fluid losses (eg, vomiting, diarrhea, excessive sweating, GI
fistulas or drainage tubes, pancreatitis, burns) that have been replaced
primarily by hypotonic fluids
○ Acute or chronic renal insufficiency, in which the patient may be
unable to excrete adequate amounts of free water
○ Salt-wasting nephropathy
○ Cerebral salt-wasting syndrome seen in patients with traumatic brain
injury, aneurysmal subarachnoid hemorrhage, and intracranial surgery.
Cerebral salt-wasting must be distinguished from SIADH because both
conditions can cause hyponatremia in neurosurgical patients, and yet
the pathophysiology and treatment are different.6
○ Prolonged exercise in a hot environment, especially in patients who
hydrate aggressively with hyposmolar fluids during exertion. Severe
symptomatic hyponatremia has been reported in marathon runners
and in recreational hikers in the Grand Canyon.
• Euvolemic hyponatremia implies normal sodium stores and a total body
excess of free water. This occurs in patients who take in excess hypotonic
fluids.
○ Psychogenic polydipsia, often in psychiatric patients
○ Administration of hypotonic intravenous or irrigation fluids during
procedures or in the immediate postoperative period7,8
○ In one meta-analysis, administration of hypotonic maintenance
intravenous fluids to hospitalized children has been associated with an
increased incidence of acute hyponatremia compared with
administration of isotonic maintenance fluids.9
○ Infants who may have been given inappropriate amounts of free water
○ Ingestion of sodium phosphate or sodium picosulfates and magnesium
citrate combination as a bowel preparation before colonoscopy or
colorectal surgery10
○ SIADH
• Hypervolemic hyponatremia occurs when sodium stores increase
inappropriately.
○ This may result from renal causes such as acute or chronic renal
failure, when dysfunctional kidneys are unable to excrete the ingested
sodium load. It also may occur in response to states of decreased
effective intravascular volume.
○ History of hepatic cirrhosis, congestive heart failure, or nephrotic
syndrome, in which patients are subject to insidious increases in total
body sodium and free water stores
• Uncorrected hypothyroidism or cortisol deficiency (adrenal insufficiency,
hypopituitarism)
• Consumption of large quantities of beer or use of the recreational drug MDMA
(ecstasy)
• Hyponatremia can be caused by many medications. Known offenders include
acetazolamide, amiloride, amphotericin, aripiprazole, atovaquone, thiazide
diuretics, amiodarone, basiliximab, angiotensin II receptor blockers,
angiotensin-converting enzyme inhibitors, bromocriptine, carbamazepine,
carboplatin, carvedilol, celecoxib, cyclophosphamide, clofibrate,
desmopressin, donepezil, duloxetine, eplerenone, gabapentin, haloperidol,
heparin, hydroxyurea, indapamide, indomethacin, ketorolac, levetiracetam,
loop diuretics, lorcainide, mirtazapine, mitoxantrone, nimodipine,
oxcarbazepine, opiates, oxytocin, pimozide, propafenone, proton pump
inhibitors, quetiapine, sirolimus, ticlopidine, tolterodine, vincristine, selective
serotonin reuptake inhibitors, sulfonylureas, trazodone, tolbutamide,
venlafaxine, zalcitabine, and zonisamide.
Hyponatremia
Hyponatremia is decrease in serum Na concentration < 136 mEq/L caused by an excess of water
relative to solute. Common causes include diuretic use, diarrhea, heart failure, and renal disease.
Clinical manifestations are primarily neurologic (due to an osmotic shift of water into brain cells
causing edema), especially in acute hyponatremia, and include headache, confusion, and stupor;
seizures and coma may occur. Diagnosis is by measuring serum Na. Serum and urine electrolytes
and osmolality help determine the cause. Treatment involves restricting water intake and
promoting its loss, replacing any Na deficit, and treating the cause.
Etiology
Hyponatremia reflects an excess of total body water (TBW) relative to total body Na content.
Because total body Na content is reflected by ECF volume status, hyponatremia must be
considered along with status of the ECF volume: hypovolemia, euvolemia, and hypervolemia
(see Table 2: Fluid and Electrolyte Metabolism: Principal Causes of Hyponatremia ). Note that
the ECF volume is not the same as effective plasma volume. For example, decreased effective
plasma volume may occur with decreased ECF volume, but it may also occur with an increased
ECF volume (eg, in heart failure, hypoalbuminemia, capillary leak syndrome).
Table 2
Principal Causes of Hyponatremia

Mechanism Category Examples
Decreased TBW and GI losses* Diarrhea
Na, with a relatively Vomiting
greater decrease in
Na
3rd-space Burns
losses* Pancreatitis
Peritonitis
Rhabdomyolysis
Small-bowel obstruction
Renal losses Diuretics
Mineralocorticoid
deficiency
Osmotic diuresis (glucose,
urea, mannitol Some Trade
Names
OSMITROL
RESECTISOL
Click for Drug Monograph
)
Salt-losing nephropathies
(eg, interstitial nephritis,
medullary cystic disease,
partial urinary tract
obstruction, and polycystic
kidney disease)
Euvolemic
hyponatremia
Increased TBW with Drugs Diuretics, barbiturates,
near-normal total carbamazepine Some
body Na Trade Names
TEGRETOL
, chlorpropamide Some
Trade Names
DIABINESE
, clofibrate Some Trade

Names
ATROMID-S
, opioids, tolbutamide
Some Trade Names
ORINASE
, vincristine Some Trade

Names
ONCOVIN
Possibly
cyclophosphamide Some
Trade Names
CYTOXAN
, NSAIDs, oxytocin Some

Trade Names
PITOCIN
SYNTOCINON
Disorders Adrenal insufficiency as in

Addison's disease
Hypothyroidism
Syndrome of inappropriate
ADH secretion
Increased Primary polydipsia
intake of fluids
States that Emotional stress
increase Pain
nonosmotic
release of ADH Postoperative states
Hypervolemic
hyponatremia
Increased total body Extrarenal Cirrhosis
Na with a relatively disorders Heart failure
greater increase in
TBW
Renal disorders Acute kidney dysfunction
Chronic kidney disease
Nephrotic syndrome
TBW = total body water.
*GI and 3rd-space losses cause hyponatremia if replacement
fluids are hypotonic compared to losses.
Hypovolemic hyponatremia: Deficiencies in both TBW and total body Na exist, although
proportionally more Na than water has been lost; the Na deficit produces hypovolemia. In
hypovolemic hyponatremia, both serum osmolality and blood volume decrease. ADH secretion
increases despite a decrease in osmolality to maintain blood volume. The resulting water
retention increases plasma dilution and hyponatremia.
Extrarenal fluid losses, such as those that occur with the losses of Na-containing fluids as in
protracted vomiting, severe diarrhea, or sequestration of fluids in a 3rd space (see Table 3: Fluid
and Electrolyte Metabolism: Composition of Body Fluids ), can cause hyponatremia typically
when losses are replaced by ingesting plain water or liquids low in Na (see Table 4: Fluid and
Electrolyte Metabolism: Approximate Na Content of Common Beverages ) or by hypotonic IV
fluid. Significant ECF fluid losses also cause release of ADH, causing water retention by the
kidneys, which can maintain or worsen hyponatremia. In extrarenal causes of hypovolemia,
because the normal renal response to volume loss is Na conservation, urine Na concentration is
typically < 10 mEq/L.
Table 3
Composition of Body Fluids

Fluid Source NA* K* CL*
Gastric 20–80 5–20 100–
150
Pancreatic 120– 5–15 90–
140 120
Small bowel 100– 5–15 90–
140 130
Bile 120– 5–15 80–
140 120
Ileostomy 45– 3–15 20–
135 115
Diarrheal 10–90 10– 10–
80 110
Sweat 10–30 3–10 10–
35
Burns 140 5 110
*Unit is mEq/L.
Table 4
Approximate Na Content of
Common Beverages
Beverage Na (mEq/L)
Apple juice 1.3
Beer 2.2
Coffee 1
Cola 5–6.5
Diet cola 4.5–6.5
Light beer 1.3
Orange juice 3.7
Sports drink 8–33
Water (including < 1
tap water)
Renal fluid losses resulting in hypovolemic hyponatremia may occur with mineralocorticoid
deficiency, diuretic therapy, osmotic diuresis, or salt-losing nephropathy. Salt-losing
nephropathy encompasses a loosely defined group of intrinsic renal disorders with primarily
renal tubular dysfunction. This group includes interstitial nephritis, medullary cystic disease,
partial urinary tract obstruction, and, occasionally, polycystic kidney disease. Renal causes of
hypovolemic hyponatremia can usually be differentiated from extrarenal causes by the history.
Patients with ongoing renal fluid losses can also be distinguished from patients with extrarenal
fluid losses because the urine Na concentration is inappropriately high (> 20 mEq/L). Urine Na
concentration may not help in differentiation when metabolic alkalosis (as occurs with protracted
vomiting) is present and large amounts of HCO3 are spilled in the urine, obligating the excretion
of Na to maintain electrical neutrality. In metabolic alkalosis, urine Cl concentration frequently
differentiates renal from extrarenal sources of volume depletion (see Acid-Base Regulation and
Disorders: Metabolic Alkalosis).
Diuretics may also produce hypovolemic hyponatremia. Thiazide diuretics, in particular,
decrease the kidneys' diluting capacity and increase Na excretion. Once volume depletion occurs,
the nonosmotic release of ADH causes water retention and worsens hyponatremia. Concomitant
hypokalemia shifts Na intracellularly and enhances ADH release, thereby worsening
hyponatremia. This effect of thiazides may last for up to 2 wk after cessation of therapy;
however, hyponatremia usually responds to replacement of K and volume deficits along with
judicious monitoring of water intake until the drug effect dissipates. Elderly patients may have
increased Na diuresis and are especially susceptible to thiazide-induced hyponatremia,
particularly when they have a preexisting defect in renal capacity to excrete free water. Rarely,
such patients develop severe, life-threatening hyponatremia within a few weeks after the
initiation of a thiazide diuretic. Loop diuretics much less commonly cause hyponatremia.
Euvolemic hyponatremia: In euvolemic (dilutional) hyponatremia, total body Na and thus ECF
volume are normal or near-normal; however, TBW is increased.
Primary polydipsia can cause hyponatremia only when water intake overwhelms the kidneys'
ability to excrete water. Because normal kidneys can excrete up to 25 L urine/day, hyponatremia
due solely to polydipsia results only from the ingestion of large amounts of water or from defects
in renal capacity to excrete free water. Patients affected include those with psychosis or more
modest degrees of polydipsia plus renal insufficiency.
Euvolemic hyponatremia may also result from excessive water intake in the presence of
Addison's disease, hypothyroidism, or nonosmotic ADH release (eg, from stress; postoperative
states; use of drugs such as chlorpropamide Some Trade Names
DIABINESE
or tolbutamide Some Trade Names
ORINASE
, opioids, barbiturates, vincristine Some Trade Names
ONCOVIN
, clofibrate Some Trade Names
ATROMID-S
, carbamazepine Some Trade Names
TEGRETOL
). Postoperative hyponatremia most commonly occurs because of a combination of nonosmotic
ADH release and excessive administration of hypotonic fluids after surgery. Certain drugs (eg,
cyclophosphamide Some Trade Names
CYTOXAN
, NSAIDs, chlorpropamide Some Trade Names
DIABINESE
) potentiate the renal effect of endogenous ADH, whereas others (eg, oxytocin Some Trade
Names
PITOCIN
SYNTOCINON
) have a direct ADH-like effect on the kidneys. A deficiency in water excretion is common in all
these conditions. Diuretics can cause or contribute to euvolemic hyponatremia if another factor
causes water retention or excessive water intake. The syndrome of inappropriate ADH secretion
(SIADH—see Sidebar 1: Fluid and Electrolyte Metabolism: Syndrome of Inappropriate ADH
Secretion ) is another cause of euvolemic hyponatremia.
Sidebar 1
Syndrome of Inappropriate
ADH Secretion
The syndrome of inappropriate
ADH secretion (SIADH) is
attributed to excessive ADH
release. It is defined as less-
than-maximally-dilute urine in
the presence of plasma hypo-
osmolality (hyponatremia)
without volume depletion or
overload, emotional stress, pain,
diuretics, or other drugs that
stimulate ADH secretion in
patients with normal cardiac,
hepatic, renal, adrenal, and
thyroid function. SIADH is
associated with myriad
disorders (see Table 5: Fluid
and Electrolyte Metabolism:
Disorders Associated with
Antidiuretic Hormone Secretion
).
Table 5

Disorder Examples
Cancer CNS
Duodenum
Lung
Lymphoma
Pancreas
CNS disorders Acute
intermittent
porphyria
Acute psychosis
Brain abscess
Encephalitis
Guillain-Barré
syndrome
Head trauma
Meningitis
Stroke
Subdural or
subarachnoid
hemorrhage
Endocrine Addison's
disorders disease
Hypopituitarism
Hypothyroidism
Pulmonary Aspergillosis
disorders and Lung abscess
treatments
Pneumonia
Positive-
pressure
breathing
TB
Miscellaneous Protein-energy
undernutrition
Surgery
Hypervolemic hyponatremia: Hypervolemic hyponatremia is characterized by an increase in both
total body Na (and thus ECF volume) and TBW with a relatively greater increase in TBW.
Various edematous disorders, including heart failure and cirrhosis, cause hypervolemic
hyponatremia. Rarely, hyponatremia occurs in nephrotic syndrome, although
pseudohyponatremia may be due to interference with Na measurement by elevated lipids. In each
of these disorders, a decrease in effective circulating volume results in the release of ADH and
angiotensin II. The following factors contribute to hyponatremia:
• The antidiuretic effect of ADH on the kidneys
• Direct impairment of renal water excretion by angiotensin II
• Decreased GFR
• Stimulation of thirst by angiotensin II
Urine Na excretion is usually < 10 mEq/L, and urine osmolality is high relative to serum
osmolality.
Hyponatremia in AIDS: Hyponatremia has been reported in > 50% of hospitalized patients with
AIDS. Among the many potential contributing factors are
• Administration of hypotonic fluids
• Impaired renal function
• Nonosmotic ADH release due to intravascular volume depletion
• Administration of drugs that impair renal water excretion
In addition, adrenal insufficiency has become increasingly common in AIDS patients as the
result of cytomegalovirus adrenalitis, mycobacterial infection, or interference with adrenal
glucocorticoid and mineralocorticoid synthesis by ketoconazole Some Trade Names
NIZORAL
. SIADH may be present because of coexistent pulmonary or CNS infections.
Symptoms and Signs
Symptoms mainly involve CNS dysfunction. However, when hyponatremia is accompanied by
disturbances in total body Na content, signs of ECF volume depletion or overload also occur (see
Fluid and Electrolyte Metabolism: Volume Overload). In general, older chronically ill patients
with hyponatremia develop more symptoms than younger otherwise healthy patients. Symptoms
are also more severe with faster-onset hyponatremia. Symptoms generally occur when the
effective plasma osmolality falls to < 240 mOsm/kg. Symptoms can be subtle and consist mainly
of changes in mental status, including altered personality, lethargy, and confusion. As the serum
Na falls to < 115 mEq/L, stupor, neuromuscular hyperexcitability, hyperreflexia, seizures, coma,
and death can result.
Severe cerebral edema may occur in premenopausal women with acute hyponatremia, perhaps
because estrogen and progesterone inhibit brain Na+,K+-ATPase and decrease solute extrusion
from brain cells. Sequelae include hypothalamic and posterior pituitary infarction and
occasionally brain stem herniation.
Diagnosis
• Serum and urine electrolytes and osmolality
• Clinical assessment of volume status
Hyponatremia is occasionally suspected in patients who have neurologic abnormalities and are at
risk. However, because findings are nonspecific, hyponatremia is often recognized only after
serum electrolyte measurement.
Serum Na may be low when severe hyperglycemia increases osmolality and water moves out of
cells into the ECF. Serum Na concentration falls about 1.6 mEq/L for every 100-mg/dL (5.55-
mmol/L) rise in the serum glucose concentration above normal. This condition is often called
translocational hyponatremia because it is caused by translocation of Na across cell membranes.
Pseudohyponatremia with normal serum osmolality may occur in hyperlipidemia or extreme
hyperproteinemia, because the lipid or protein occupies space in the volume of serum taken for
analysis; the concentration of Na in serum itself is not affected. Newer methods of measuring
serum electrolytes with ion-selective electrodes circumvent this problem.
Identification of the cause: Identifying the cause can be complex. The history sometimes
suggests a cause (eg, significant fluid loss from vomiting or diarrhea, renal disease, compulsive
fluid ingestion, intake of drugs that stimulate ADH release or enhance ADH action).
The volume status, particularly the presence of obvious volume depletion or overload, suggests
certain causes (see Table 1: Fluid and Electrolyte Metabolism: Common Causes of Volume
Depletion ). Overtly hypovolemic patients usually have an obvious source of fluid loss
(typically treated with hypotonic fluid replacement). Overtly hypervolemic patients usually have
a readily recognizable condition, such as heart failure or hepatic or renal disease. Euvolemic
patients and patients with equivocal volume status require more laboratory testing to identify a
cause.
Laboratory tests should include serum and urine osmolality and electrolytes. Euvolemic patients
should also have thyroid and adrenal function tested. Hypo-osmolality in euvolemic patients
should cause excretion of a large volume of dilute urine (eg, osmolality < 100 mOsm/kg and sp
gr < 1.003). Serum Na concentration and serum osmolality that are low and urine osmolality that
is inappropriately high (120 to 150 mmol/L) with respect to the low serum osmolality suggest
volume overload, volume contraction, or SIADH. Volume overload and volume contraction are
differentiated clinically (see Fluid and Electrolyte Metabolism: Volume depletion; see Fluid and
Electrolyte Metabolism: Volume Overload). When neither volume overload or volume
contraction appears likely, SIADH is considered. Patients with SIADH are usually euvolemic or
slightly hypervolemic. BUN and creatinine values are normal, and serum uric acid is generally
low. Urine Na concentration is usually > 30 mmol/L, and fractional excretion of Na is > 1% (for
calculation, see Approach to the Genitourinary Patient: Other urine tests).
In patients with hypovolemia and normal renal function, Na reabsorption results in a urine Na of
< 20 mmol/L. Urine Na > 20 mmol/L in hypovolemic patients suggests mineralocorticoid
deficiency or salt-losing nephropathy. Hyperkalemia suggests adrenal insufficiency.
Treatment
• When hypovolemic, 0.9% saline
• When hypervolemic, fluid restriction and sometimes a diuretic
• When euvolemic, treatment of cause
• Rarely, cautious correction with hypertonic (3%) saline
Rapid correction of hyponatremia, even mild hyponatremia, risks neurologic complications (see
Fluid and Electrolyte Metabolism: Osmotic demyelination syndrome). Except possibly in the
first few hours of treatment of severe hyponatremia, Na should be corrected no faster than 0.5
mEq/L/h. Even with severe hyponatremia, increase in serum Na concentration should not exceed
10 mEq/L over the first 24 h. Any identified cause of hyponatremia is treated concurrently.
Mild hyponatremia: Mild, asymptomatic hyponatremia (ie, serum Na > 120 mEq/L) requires
restraint because small adjustments are generally sufficient. In diuretic-induced hyponatremia,
elimination of the diuretic may be enough; some patients need some Na or K replacement.
Similarly, when mild hyponatremia results from inappropriate hypotonic parenteral fluid
administration in patients with impaired water excretion, merely altering fluid therapy may
suffice.
With hypovolemia and normal adrenal function, administration of 0.9% saline usually corrects
both hyponatremia and hypovolemia. When the serum Na is < 120 mEq/L, hyponatremia may
not completely correct upon restoration of intravascular volume; restriction of free water
ingestion to ≤ 500 to 1000 mL/24 h may be needed.
In hypervolemic patients, in whom hyponatremia is due to renal Na retention (eg, heart failure,
cirrhosis, nephrotic syndrome) and dilution, water restriction combined with treatment of the
underlying disorder is required. In patients with heart failure, an ACE inhibitor, in conjunction
with a loop diuretic, can correct refractory hyponatremia. In other patients in whom simple fluid
restriction is ineffective, a loop diuretic in escalating doses can be used, sometimes in
conjunction with IV 0.9% normal saline. K and other electrolytes lost in the urine must be
replaced. When hyponatremia is more severe and unresponsive to diuretics, intermittent or
continuous hemofiltration may be needed to control ECF volume while hyponatremia is
corrected with IV 0.9% normal saline.
In euvolemia, treatment is directed at the cause (eg, hypothyroidism, adrenal insufficiency,
diuretic use). When SIADH is present, severe water restriction (eg, 250 to 500 mL/24 h) is
generally required. Additionally, a loop diuretic may be combined with IV 0.9% saline as in
hypervolemic hyponatremia. Lasting correction depends on successful treatment of the
underlying disorder. When the underlying disorder is not correctable, as in metastatic cancer, and
patients find severe water restriction unacceptable, demeclocycline Some Trade Names
DECLOMYCIN
(300 to 600 mg q 12 h) may be helpful by inducing a concentrating defect in the kidneys;
however, demeclocycline Some Trade Names
DECLOMYCIN
may cause acute renal failure. Renal failure is usually reversible when the drug is stopped. IV
conivaptan, an ADH receptor antagonist, causes effective water diuresis without significant loss
of electrolytes in the urine and can be used in hospitalized patients for treatment of resistant
hyponatremia.
Severe hyponatremia: Severe hyponatremia (serum Na < 109 mEq/L; effective osmolality < 238
mOsm/kg) in asymptomatic patients can be treated safely with stringent restriction of water
intake. Treatment is more controversial when neurologic symptoms (eg, confusion, lethargy,
seizures, coma) are present. The debate primarily concerns the pace and degree of hyponatremia
correction. Many experts recommend that serum Na be raised no faster than 1 mEq/L/h, but
replacement rates of up to 2 mEq/L/h for the first 2 to 3 h have been suggested for patients with
seizures. Regardless, the rise should be ≤ 10 mEq/L over the first 24 h. More vigorous correction
risks precipitation of osmotic demyelination syndrome.
Hypertonic (3%) saline (containing 513 mEq Na/L) may be used, but only with frequent (q 2 to 4
h) electrolyte determinations. For patients with seizures or coma, ≤ 100 mL/h may be
administered over 4 to 6 h in amounts sufficient to raise the serum Na 4 to 6 mEq/L. This amount
(in mEq) may be calculated using the Na deficit formula as
(Desired change in Na) × TBW
where TBW is 0.6 × body weight in kg in men and 0.5 × body weight in kg in women.
For example, the amount of Na needed to raise the Na from 106 to 112 in a 70-kg man can be
calculated as follows:
(112 mEq/L − 106 mEq/L) × (0.6 L/kg × 70 kg) = 252 mEq
Because there is 513 mEq Na/L in hypertonic saline, roughly 0.5 L of hypertonic saline is needed
to raise the Na from 106 to 112 mEq/L. Adjustments may be needed based on serum Na
concentrations, which are monitored closely for the first few hours of treatment. Patients with
seizures, coma, or altered mental status need supportive treatment, which may involve
endotracheal intubation, mechanical ventilation, and benzodiazepines (eg, lorazepam Some
Trade Names
ATIVAN
1 to 2 mg IV q 5 to 10 min prn) for seizures.
Osmotic demyelination syndrome: Osmotic demyelination syndrome (previously called central
pontine myelinolysis) may follow too-rapid correction of hyponatremia. Demyelination may
affect the pons and other areas of the brain. Lesions are more common in patients with
alcoholism, undernutrition, or other chronic debilitating illness. Flaccid paralysis, dysarthria, and
dysphagia can evolve over a few days or weeks. The lesion may extend dorsally to involve
sensory tracts and leave patients with a locked-in syndrome (an awake and sentient state in
which patients, because of generalized motor paralysis, cannot communicate, except possibly by
coded eye movements). Damage often is permanent. When Na is replaced too rapidly (eg, > 14
mEq/L/8 h) and neurologic symptoms start to develop, it is critical to prevent further serum Na
increases by stopping hypertonic fluids. In such cases, inducing hyponatremia with hypotonic
fluid may mitigate the development of permanent neurologic damage.
Hyponatremia
Hyponatremia is decrease in serum Na concentration < 136 mEq/L caused by an excess of water
relative to solute. Common causes include diuretic use, diarrhea, heart failure, and renal disease.
Clinical manifestations are primarily neurologic (due to an osmotic shift of water into brain cells
causing edema), especially in acute hyponatremia, and include headache, confusion, and stupor;
seizures and coma may occur. Diagnosis is by measuring serum Na. Serum and urine electrolytes
and osmolality help determine the cause. Treatment involves restricting water intake and
promoting its loss, replacing any Na deficit, and treating the cause.
Etiology
Hyponatremia reflects an excess of total body water (TBW) relative to total body Na content.
Because total body Na content is reflected by ECF volume status, hyponatremia must be
considered along with status of the ECF volume: hypovolemia, euvolemia, and hypervolemia
(see Table 2: Fluid and Electrolyte Metabolism: Principal Causes of Hyponatremia ). Note that
the ECF volume is not the same as effective plasma volume. For example, decreased effective
plasma volume may occur with decreased ECF volume, but it may also occur with an increased
ECF volume (eg, in heart failure, hypoalbuminemia, capillary leak syndrome).
Table 2
Principal Causes of Hyponatremia

Mechanism Category Examples
Decreased TBW and GI losses* Diarrhea
Na, with a relatively Vomiting
greater decrease in
Na
3rd-space Burns
losses* Pancreatitis
Peritonitis
Rhabdomyolysis
Small-bowel obstruction
Renal losses Diuretics
Mineralocorticoid
deficiency
Osmotic diuresis (glucose,
urea, mannitol Some Trade
Names
OSMITROL
RESECTISOL
)
Salt-losing nephropathies
(eg, interstitial nephritis,
medullary cystic disease,
partial urinary tract
obstruction, and polycystic
kidney disease)
Euvolemic
hyponatremia
Increased TBW with Drugs Diuretics, barbiturates,
near-normal total carbamazepine Some
body Na Trade Names
TEGRETOL
, chlorpropamide Some
Trade Names
DIABINESE
, clofibrate Some Trade

Names
ATROMID-S
, opioids, tolbutamide
Some Trade Names
ORINASE
, vincristine Some Trade

Names
ONCOVIN
Possibly
cyclophosphamide Some
Trade Names
CYTOXAN
, NSAIDs, oxytocin Some

Trade Names
PITOCIN
SYNTOCINON
Disorders Adrenal insufficiency as in

Addison's disease
Hypothyroidism
ADH secretion
Increased Primary polydipsia
intake of fluids
States that Emotional stress
increase Pain
nonosmotic
release of ADH Postoperative states
Hypervolemic
hyponatremia
Increased total body Extrarenal Cirrhosis
Na with a relatively disorders Heart failure
greater increase in
TBW
Renal disorders Acute kidney dysfunction
Chronic kidney disease
Nephrotic syndrome
TBW = total body water.
*GI and 3rd-space losses cause hyponatremia if replacement
fluids are hypotonic compared to losses.
Hypovolemic hyponatremia: Deficiencies in both TBW and total body Na exist, although
proportionally more Na than water has been lost; the Na deficit produces hypovolemia. In
hypovolemic hyponatremia, both serum osmolality and blood volume decrease. ADH secretion
increases despite a decrease in osmolality to maintain blood volume. The resulting water
retention increases plasma dilution and hyponatremia.
Extrarenal fluid losses, such as those that occur with the losses of Na-containing fluids as in
protracted vomiting, severe diarrhea, or sequestration of fluids in a 3rd space (see Table 3: Fluid
and Electrolyte Metabolism: Composition of Body Fluids ), can cause hyponatremia typically
when losses are replaced by ingesting plain water or liquids low in Na (see Table 4: Fluid and
Electrolyte Metabolism: Approximate Na Content of Common Beverages ) or by hypotonic IV
fluid. Significant ECF fluid losses also cause release of ADH, causing water retention by the
kidneys, which can maintain or worsen hyponatremia. In extrarenal causes of hypovolemia,
because the normal renal response to volume loss is Na conservation, urine Na concentration is
typically < 10 mEq/L.
Table 3
Composition of Body Fluids

Fluid Source NA* K* CL*
Gastric 20–80 5–20 100–
150
Pancreatic 120– 5–15 90–
140 120
Small bowel 100– 5–15 90–
140 130
Bile 120– 5–15 80–
140 120
Ileostomy 45– 3–15 20–
135 115
Diarrheal 10–90 10– 10–
80 110
Sweat 10–30 3–10 10–
35
Burns 140 5 110
*Unit is mEq/L.
Table 4
Approximate Na Content of
Common Beverages
Beverage Na (mEq/L)
Apple juice 1.3
Beer 2.2
Coffee 1
Cola 5–6.5
Diet cola 4.5–6.5
Light beer 1.3
Orange juice 3.7
Sports drink 8–33
Water (including < 1
tap water)
Renal fluid losses resulting in hypovolemic hyponatremia may occur with mineralocorticoid
deficiency, diuretic therapy, osmotic diuresis, or salt-losing nephropathy. Salt-losing
nephropathy encompasses a loosely defined group of intrinsic renal disorders with primarily
renal tubular dysfunction. This group includes interstitial nephritis, medullary cystic disease,
partial urinary tract obstruction, and, occasionally, polycystic kidney disease. Renal causes of
hypovolemic hyponatremia can usually be differentiated from extrarenal causes by the history.
Patients with ongoing renal fluid losses can also be distinguished from patients with extrarenal
fluid losses because the urine Na concentration is inappropriately high (> 20 mEq/L). Urine Na
concentration may not help in differentiation when metabolic alkalosis (as occurs with protracted
vomiting) is present and large amounts of HCO3 are spilled in the urine, obligating the excretion
of Na to maintain electrical neutrality. In metabolic alkalosis, urine Cl concentration frequently
differentiates renal from extrarenal sources of volume depletion (see Acid-Base Regulation and
Disorders: Metabolic Alkalosis).
Diuretics may also produce hypovolemic hyponatremia. Thiazide diuretics, in particular,
decrease the kidneys' diluting capacity and increase Na excretion. Once volume depletion occurs,
the nonosmotic release of ADH causes water retention and worsens hyponatremia. Concomitant
hypokalemia shifts Na intracellularly and enhances ADH release, thereby worsening
hyponatremia. This effect of thiazides may last for up to 2 wk after cessation of therapy;
however, hyponatremia usually responds to replacement of K and volume deficits along with
judicious monitoring of water intake until the drug effect dissipates. Elderly patients may have
increased Na diuresis and are especially susceptible to thiazide-induced hyponatremia,
particularly when they have a preexisting defect in renal capacity to excrete free water. Rarely,
such patients develop severe, life-threatening hyponatremia within a few weeks after the
initiation of a thiazide diuretic. Loop diuretics much less commonly cause hyponatremia.
Euvolemic hyponatremia: In euvolemic (dilutional) hyponatremia, total body Na and thus ECF
volume are normal or near-normal; however, TBW is increased.
Primary polydipsia can cause hyponatremia only when water intake overwhelms the kidneys'
ability to excrete water. Because normal kidneys can excrete up to 25 L urine/day, hyponatremia
due solely to polydipsia results only from the ingestion of large amounts of water or from defects
in renal capacity to excrete free water. Patients affected include those with psychosis or more
modest degrees of polydipsia plus renal insufficiency.
Euvolemic hyponatremia may also result from excessive water intake in the presence of
Addison's disease, hypothyroidism, or nonosmotic ADH release (eg, from stress; postoperative
states; use of drugs such as chlorpropamide Some Trade Names
DIABINESE
or tolbutamide Some Trade Names
ORINASE
, opioids, barbiturates, vincristine Some Trade Names
ONCOVIN
, clofibrate Some Trade Names
ATROMID-S
, carbamazepine Some Trade Names
TEGRETOL
). Postoperative hyponatremia most commonly occurs because of a combination of nonosmotic
ADH release and excessive administration of hypotonic fluids after surgery. Certain drugs (eg,
cyclophosphamide Some Trade Names
CYTOXAN
, NSAIDs, chlorpropamide Some Trade Names
DIABINESE
) potentiate the renal effect of endogenous ADH, whereas others (eg, oxytocin Some Trade
Names
PITOCIN
SYNTOCINON
) have a direct ADH-like effect on the kidneys. A deficiency in water excretion is common in all
these conditions. Diuretics can cause or contribute to euvolemic hyponatremia if another factor
causes water retention or excessive water intake. The syndrome of inappropriate ADH secretion
(SIADH—see Sidebar 1: Fluid and Electrolyte Metabolism: Syndrome of Inappropriate ADH
Secretion ) is another cause of euvolemic hyponatremia.
Sidebar 1
ADH Secretion
The syndrome of inappropriate
ADH secretion (SIADH) is
attributed to excessive ADH
release. It is defined as less-
than-maximally-dilute urine in
the presence of plasma hypo-
osmolality (hyponatremia)
without volume depletion or
overload, emotional stress, pain,
diuretics, or other drugs that
stimulate ADH secretion in
patients with normal cardiac,
hepatic, renal, adrenal, and
thyroid function. SIADH is
associated with myriad
disorders (see Table 5: Fluid
and Electrolyte Metabolism:
).
Table 5

Disorder Examples
Cancer CNS
Duodenum
Lung
Lymphoma
Pancreas
CNS disorders Acute
intermittent
porphyria
Acute psychosis
Brain abscess
Encephalitis
Guillain-Barré
syndrome
Head trauma
Meningitis
Stroke
Subdural or
subarachnoid
hemorrhage
Endocrine Addison's
disorders disease
Hypopituitarism
Hypothyroidism
Pulmonary Aspergillosis
disorders and Lung abscess
treatments
Pneumonia
Positive-
pressure
breathing
TB
Miscellaneous Protein-energy
undernutrition
Surgery
Hypervolemic hyponatremia: Hypervolemic hyponatremia is characterized by an increase in both
total body Na (and thus ECF volume) and TBW with a relatively greater increase in TBW.
Various edematous disorders, including heart failure and cirrhosis, cause hypervolemic
hyponatremia. Rarely, hyponatremia occurs in nephrotic syndrome, although
pseudohyponatremia may be due to interference with Na measurement by elevated lipids. In each
of these disorders, a decrease in effective circulating volume results in the release of ADH and
angiotensin II. The following factors contribute to hyponatremia:
• The antidiuretic effect of ADH on the kidneys
• Direct impairment of renal water excretion by angiotensin II
• Decreased GFR
• Stimulation of thirst by angiotensin II
Urine Na excretion is usually < 10 mEq/L, and urine osmolality is high relative to serum
osmolality.
Hyponatremia in AIDS: Hyponatremia has been reported in > 50% of hospitalized patients with
AIDS. Among the many potential contributing factors are
• Administration of hypotonic fluids
• Impaired renal function
• Nonosmotic ADH release due to intravascular volume depletion
• Administration of drugs that impair renal water excretion
In addition, adrenal insufficiency has become increasingly common in AIDS patients as the
result of cytomegalovirus adrenalitis, mycobacterial infection, or interference with adrenal
glucocorticoid and mineralocorticoid synthesis by ketoconazole Some Trade Names
NIZORAL
. SIADH may be present because of coexistent pulmonary or CNS infections.
Symptoms and Signs
Symptoms mainly involve CNS dysfunction. However, when hyponatremia is accompanied by
disturbances in total body Na content, signs of ECF volume depletion or overload also occur (see
Fluid and Electrolyte Metabolism: Volume Overload). In general, older chronically ill patients
with hyponatremia develop more symptoms than younger otherwise healthy patients. Symptoms
are also more severe with faster-onset hyponatremia. Symptoms generally occur when the
effective plasma osmolality falls to < 240 mOsm/kg. Symptoms can be subtle and consist mainly
of changes in mental status, including altered personality, lethargy, and confusion. As the serum
Na falls to < 115 mEq/L, stupor, neuromuscular hyperexcitability, hyperreflexia, seizures, coma,
and death can result.
Severe cerebral edema may occur in premenopausal women with acute hyponatremia, perhaps
because estrogen and progesterone inhibit brain Na+,K+-ATPase and decrease solute extrusion
from brain cells. Sequelae include hypothalamic and posterior pituitary infarction and
occasionally brain stem herniation.
Diagnosis
• Serum and urine electrolytes and osmolality
• Clinical assessment of volume status
Hyponatremia is occasionally suspected in patients who have neurologic abnormalities and are at
risk. However, because findings are nonspecific, hyponatremia is often recognized only after
serum electrolyte measurement.
Serum Na may be low when severe hyperglycemia increases osmolality and water moves out of
cells into the ECF. Serum Na concentration falls about 1.6 mEq/L for every 100-mg/dL (5.55-
mmol/L) rise in the serum glucose concentration above normal. This condition is often called
translocational hyponatremia because it is caused by translocation of Na across cell membranes.
Pseudohyponatremia with normal serum osmolality may occur in hyperlipidemia or extreme
hyperproteinemia, because the lipid or protein occupies space in the volume of serum taken for
analysis; the concentration of Na in serum itself is not affected. Newer methods of measuring
serum electrolytes with ion-selective electrodes circumvent this problem.
Identification of the cause: Identifying the cause can be complex. The history sometimes
suggests a cause (eg, significant fluid loss from vomiting or diarrhea, renal disease, compulsive
fluid ingestion, intake of drugs that stimulate ADH release or enhance ADH action).
The volume status, particularly the presence of obvious volume depletion or overload, suggests
certain causes (see Table 1: Fluid and Electrolyte Metabolism: Common Causes of Volume
Depletion ). Overtly hypovolemic patients usually have an obvious source of fluid loss
(typically treated with hypotonic fluid replacement). Overtly hypervolemic patients usually have
a readily recognizable condition, such as heart failure or hepatic or renal disease. Euvolemic
patients and patients with equivocal volume status require more laboratory testing to identify a
cause.
Laboratory tests should include serum and urine osmolality and electrolytes. Euvolemic patients
should also have thyroid and adrenal function tested. Hypo-osmolality in euvolemic patients
should cause excretion of a large volume of dilute urine (eg, osmolality < 100 mOsm/kg and sp
gr < 1.003). Serum Na concentration and serum osmolality that are low and urine osmolality that
is inappropriately high (120 to 150 mmol/L) with respect to the low serum osmolality suggest
volume overload, volume contraction, or SIADH. Volume overload and volume contraction are
differentiated clinically (see Fluid and Electrolyte Metabolism: Volume depletion; see Fluid and
Electrolyte Metabolism: Volume Overload). When neither volume overload or volume
contraction appears likely, SIADH is considered. Patients with SIADH are usually euvolemic or
slightly hypervolemic. BUN and creatinine values are normal, and serum uric acid is generally
low. Urine Na concentration is usually > 30 mmol/L, and fractional excretion of Na is > 1% (for
calculation, see Approach to the Genitourinary Patient: Other urine tests).
In patients with hypovolemia and normal renal function, Na reabsorption results in a urine Na of
< 20 mmol/L. Urine Na > 20 mmol/L in hypovolemic patients suggests mineralocorticoid
deficiency or salt-losing nephropathy. Hyperkalemia suggests adrenal insufficiency.
Treatment
• When hypovolemic, 0.9% saline
• When hypervolemic, fluid restriction and sometimes a diuretic
• When euvolemic, treatment of cause
• Rarely, cautious correction with hypertonic (3%) saline
Rapid correction of hyponatremia, even mild hyponatremia, risks neurologic complications (see
Fluid and Electrolyte Metabolism: Osmotic demyelination syndrome). Except possibly in the
first few hours of treatment of severe hyponatremia, Na should be corrected no faster than 0.5
mEq/L/h. Even with severe hyponatremia, increase in serum Na concentration should not exceed
10 mEq/L over the first 24 h. Any identified cause of hyponatremia is treated concurrently.
Mild hyponatremia: Mild, asymptomatic hyponatremia (ie, serum Na > 120 mEq/L) requires
restraint because small adjustments are generally sufficient. In diuretic-induced hyponatremia,
elimination of the diuretic may be enough; some patients need some Na or K replacement.
Similarly, when mild hyponatremia results from inappropriate hypotonic parenteral fluid
administration in patients with impaired water excretion, merely altering fluid therapy may
suffice.
With hypovolemia and normal adrenal function, administration of 0.9% saline usually corrects
both hyponatremia and hypovolemia. When the serum Na is < 120 mEq/L, hyponatremia may
not completely correct upon restoration of intravascular volume; restriction of free water
ingestion to ≤ 500 to 1000 mL/24 h may be needed.
In hypervolemic patients, in whom hyponatremia is due to renal Na retention (eg, heart failure,
cirrhosis, nephrotic syndrome) and dilution, water restriction combined with treatment of the
underlying disorder is required. In patients with heart failure, an ACE inhibitor, in conjunction
with a loop diuretic, can correct refractory hyponatremia. In other patients in whom simple fluid
restriction is ineffective, a loop diuretic in escalating doses can be used, sometimes in
conjunction with IV 0.9% normal saline. K and other electrolytes lost in the urine must be
replaced. When hyponatremia is more severe and unresponsive to diuretics, intermittent or
continuous hemofiltration may be needed to control ECF volume while hyponatremia is
corrected with IV 0.9% normal saline.
In euvolemia, treatment is directed at the cause (eg, hypothyroidism, adrenal insufficiency,
diuretic use). When SIADH is present, severe water restriction (eg, 250 to 500 mL/24 h) is
generally required. Additionally, a loop diuretic may be combined with IV 0.9% saline as in
hypervolemic hyponatremia. Lasting correction depends on successful treatment of the
underlying disorder. When the underlying disorder is not correctable, as in metastatic cancer, and
patients find severe water restriction unacceptable, demeclocycline Some Trade Names
DECLOMYCIN
(300 to 600 mg q 12 h) may be helpful by inducing a concentrating defect in the kidneys;
however, demeclocycline Some Trade Names
DECLOMYCIN
may cause acute renal failure. Renal failure is usually reversible when the drug is stopped. IV
conivaptan, an ADH receptor antagonist, causes effective water diuresis without significant loss
of electrolytes in the urine and can be used in hospitalized patients for treatment of resistant
hyponatremia.
Severe hyponatremia: Severe hyponatremia (serum Na < 109 mEq/L; effective osmolality < 238
mOsm/kg) in asymptomatic patients can be treated safely with stringent restriction of water
intake. Treatment is more controversial when neurologic symptoms (eg, confusion, lethargy,
seizures, coma) are present. The debate primarily concerns the pace and degree of hyponatremia
correction. Many experts recommend that serum Na be raised no faster than 1 mEq/L/h, but
replacement rates of up to 2 mEq/L/h for the first 2 to 3 h have been suggested for patients with
seizures. Regardless, the rise should be ≤ 10 mEq/L over the first 24 h. More vigorous correction
risks precipitation of osmotic demyelination syndrome.
Hypertonic (3%) saline (containing 513 mEq Na/L) may be used, but only with frequent (q 2 to 4
h) electrolyte determinations. For patients with seizures or coma, ≤ 100 mL/h may be
administered over 4 to 6 h in amounts sufficient to raise the serum Na 4 to 6 mEq/L. This amount
(in mEq) may be calculated using the Na deficit formula as
(Desired change in Na) × TBW
where TBW is 0.6 × body weight in kg in men and 0.5 × body weight in kg in women.
For example, the amount of Na needed to raise the Na from 106 to 112 in a 70-kg man can be
calculated as follows:
(112 mEq/L − 106 mEq/L) × (0.6 L/kg × 70 kg) = 252 mEq
Because there is 513 mEq Na/L in hypertonic saline, roughly 0.5 L of hypertonic saline is needed
to raise the Na from 106 to 112 mEq/L. Adjustments may be needed based on serum Na
concentrations, which are monitored closely for the first few hours of treatment. Patients with
seizures, coma, or altered mental status need supportive treatment, which may involve
endotracheal intubation, mechanical ventilation, and benzodiazepines (eg, lorazepam Some
Trade Names
ATIVAN
1 to 2 mg IV q 5 to 10 min prn) for seizures.
Osmotic demyelination syndrome: Osmotic demyelination syndrome (previously called central
pontine myelinolysis) may follow too-rapid correction of hyponatremia. Demyelination may
affect the pons and other areas of the brain. Lesions are more common in patients with
alcoholism, undernutrition, or other chronic debilitating illness. Flaccid paralysis, dysarthria, and
dysphagia can evolve over a few days or weeks. The lesion may extend dorsally to involve
sensory tracts and leave patients with a locked-in syndrome (an awake and sentient state in
which patients, because of generalized motor paralysis, cannot communicate, except possibly by
coded eye movements). Damage often is permanent. When Na is replaced too rapidly (eg, > 14
mEq/L/8 h) and neurologic symptoms start to develop, it is critical to prevent further serum Na
increases by stopping hypertonic fluids. In such cases, inducing hyponatremia with hypotonic
fluid may mitigate the development of permanent neurologic damage.
Hyponatremia
Introduction
Background
Hyponatremia is an important and common electrolyte abnormality that can be seen in isolation
or, as most often is the case, as a complication of other medical illnesses.
Sodium is the dominant extracellular cation and cannot freely cross the cell membrane. Its
homeostasis is vital to the normal physiologic function of cells. The normal serum sodium level
is 135-145 mEq/L. Hyponatremia is defined as a serum level of less than 135 mEq/L and is
considered severe when the serum level is below 125 mEq/L.
This article reviews the epidemiology, pathophysiology, differential diagnosis, evaluation, and
treatment of this disorder.
Pathophysiology
Hypoosmolality (serum osmolality <260 mOsm/kg) always indicates excess total body water
relative to body solutes or excess water relative to solute in the extracellular fluid (ECF), as
water moves freely between the intracellular compartment and the extracellular compartment.
This imbalance can be due to solute depletion, solute dilution, or a combination of both.
In the normal condition, renal handling of water is sufficient to excrete as much as 15-20 L of
free water per day. Further, in the normal condition, the body's response to a decreased
osmolality is decreased thirst. Thus, hyponatremia can occur only when some condition impairs
normal free water excretion.1 Generally, hyponatremia is of clinical significance only when it
reflects a drop in the serum osmolality (ie, hypotonic hyponatremia), which is measured directly
via osmometry or is calculated as 2(Na) mEq/L + serum glucose (mg/dL)/18 + BUN
(mg/dL)/2.8.
The recommendations for treatment of hyponatremia rely on the current understanding of CNS
adaptation to an alteration in serum osmolality. In the setting of an acute drop in the serum
osmolality, neuronal cell swelling occurs due to the water shift from the extracellular space to the
intracellular space (ie, Frank Starling forces). Swelling of the brain cells elicits the following 2
osmoregulatory responses:
• It inhibits both arginine vasopressin secretion from neurons in the
hypothalamus and hypothalamic thirst center. This leads to excess water
elimination as dilute urine.
• There is an immediate cellular adaptation with loss of electrolytes, and over
the next few days, there is a more gradual loss of organic intracellular
osmolytes.2
Therefore, correction of hyponatremia must take into account the chronicity of the condition.
Acute hyponatremia (duration <48h) can be safely corrected more quickly than chronic
hyponatremia. Correction of serum sodium that is too rapid can precipitate severe neurologic
complications. Most individuals who present for diagnosis, versus individuals who develop it
while in an inpatient setting, have had hyponatremia for some time, so the condition is chronic,
and correction should proceed accordingly.
Frequency
United States
The incidence of hyponatremia depends largely on the patient population and the criteria used to
establish the diagnosis. A hospital incidence of 15-20% is common (defined as a serum sodium
level of <135 mEq/L), while only 3-5% of patients who are hospitalized have a serum sodium
level of less than 130 mEq/L. Hyponatremia's prevalence is lower in the ambulatory setting.
Mortality/Morbidity
Severe hyponatremia (<125 mEq/L) has a high mortality rate; for instance, when the serum
sodium level is less than 105 mEq/L, the mortality is over 50%, especially in alcoholics.3 In
patients with acute ST-elevation myocardial infarction, the presence of hyponatremia on
admission or early development of hyponatremia is an independent predictor of 30-day
mortality, and the prognosis worsens with the severity of hyponatremia.4 Similarly, cirrhotic
patients with persistent ascites and a low serum sodium level awaiting transplant have a high
mortality risk despite low severity (MELD) scores. The independent predictors ascites and
hyponatremia are findings indicative of hemodynamic decompensation.5,6
Race
Hyponatremia affects all races.
Sex
No sexual predilection exists for hyponatremia. However, symptoms are more likely to occur in
young women than in men.
Age
Hyponatremia is more common in elderly persons, because they have an increased incidence of
comorbid conditions (eg, cardiac, hepatic, or renal failure) that can be complicated by it.
Clinical
History
• Patients may present to medical attention owing to symptoms directly
referable to low serum sodium concentrations. However, many patients
present due to manifestations of other medical comorbidities, with
hyponatremia being recognized only secondarily. For many people, therefore,
the recognition is entirely incidental.
○ Patients may develop clinical symptoms due to the cause of
hyponatremia or the hyponatremia itself.
○ Many medical illnesses, such as congestive heart failure, liver failure,
renal failure, or pneumonia, may be associated with hyponatremia.
These patients frequently present because of primary disease
symptomatology (eg, dyspnea, jaundice, uremia, cough).
○ Symptoms range from nausea and malaise, with mild reduction in the
serum sodium, to lethargy, a decreased level of consciousness,
headache, and (if severe) seizures and coma. Neurologic symptoms
most often are due to very low serum sodium levels (usually <115
mEq/L), resulting in intracerebral osmotic fluid shifts and brain edema.
This neurologic symptom complex can lead to tentorial herniation with
subsequent brain stem compression and respiratory arrest, resulting in
death in the most severe cases.
• The severity of neurologic symptoms correlates well with the rapidity and
severity of the drop in serum sodium. A gradual drop in serum sodium, even
to very low levels, may be tolerated well if it occurs over several days or
weeks, because of neuronal adaptation. The presence of an underlying
neurologic disease, like a seizure disorder, or nonneurologic metabolic
abnormalities, like hypoxia, hypercapnia, or acidosis, also affects the severity
of neurologic symptoms.
• In interviewing the patient, obtaining a detailed medication history, including
information on over-the-counter (OTC) drugs the patient has been using, is
important, because many medications may precipitate hyponatremia (eg,
antipsychotic medications). A dietary history with reference to salt, protein,
and water intake is useful as well. For patients who are hospitalized,
reviewing the records of parenteral fluids administered is crucial.
Physical
• Examination should include orthostatic vital signs and an accurate
assessment of volume status. This determination (ie, hypervolemic,
euvolemic, hypovolemic) often guides treatment decisions.
• A full assessment for medical comorbidity also is essential, with particular
attention paid to cardiopulmonary and neurologic components of the
examination.
Causes
Although the differential diagnosis is quite broad, hyponatremia can be divided into the
following clinically useful groupings:
• Hypertonic hyponatremia: Patients with hypertonic hyponatremia have

normal total body sodium and a dilutional drop in the measured serum
sodium due to the presence of osmotically active molecules in the serum,
which cause a water shift from the intracellular compartment to the
extracellular compartment.
○ Glucose produces a drop in the serum sodium level of 1.6 mEq/L for
each 100 mg/dL of serum glucose greater than 100 mg/dL. This
relationship is nonlinear, with greater reduction in plasma sodium
concentrations with glucose concentrations over 400 mg/dL, making
2.4 mEq/L for each 100 mg/dL increase in glucose over 100 mg/dL a
more accurate correction factor when the glucose is greater than 400
mg/dL.7
○ Other examples of osmotically active molecules include mannitol
(often used to treat brain edema) or maltose (used with intravenous
immunoglobulin administration).
• Normotonic hyponatremia: Severe hyperlipidemia and paraproteinemia can
lead to low measured serum sodium concentrations with normal serum
osmolality. Normally, the plasma water comprises 92-94% of plasma volume.
The plasma water fraction falls with an increase in fats and proteins. The
measured sodium concentration in the total plasma volume is respectively
reduced, although the plasma water sodium concentration and plasma
osmolality are unchanged. This artifactually low sodium (so-called
pseudohyponatremia) is secondary to measurement by flame photometry. It
can be avoided by direct ion-selective electrode measurement.
• Hyponatremia posttransurethral resection of the prostate (TURP) or
hysteroscopy is caused by absorption of irrigants, glycine, sorbitol, or
mannitol, contained in nonconductive flushing solutions used. The degree of
hyponatremia is related to the quantity and the rate of fluid absorbed. The
plasma osmolality is also variable and changes over time.
○ The presence of a relatively large osmolal gap due to the excess
organic solute is diagnostic in the appropriate clinical setting.
Symptomatic patients are treated depending on plasma osmolality and
volume status of patients with either hypertonic saline in hypoosmolar
state or loop diuretic in volume-overloaded patients with normal renal
function.
○ Hemodialysis, which will correct the hyponatremia and remove glycine
and its toxic metabolites, can be used in patients with end-stage renal
disease. Use of isotonic saline as an irrigant instead of glycine with the
new bipolar resectoscope for TURP in high-risk patients (with large
prostates that require lengthy resection) could avoid this complication,
making this disorder a diagnosis of the past.8
• Hypotonic hyponatremia: Hypotonic hyponatremia always reflects the
inability of the kidneys to handle the excretion of free water to match oral
intake. It can be divided pathophysiologically into the following
categories, according to the effective intravascular volume: hypovolemic,
hypervolemic, and euvolemic. These clinically relevant groupings aid in
determination of likely underlying etiology and guiding treatment.
○ Hypovolemic hypotonic hyponatremia: This usually indicates
concomitant solute depletion, with patients presenting with orthostatic
symptoms. The pathophysiology underlying hypovolemic hypotonic
hyponatremia is complex and involves the interplay of carotid
baroreceptors, the sympathetic nervous system, the renin-angiotensin
system, antidiuretic hormone (ADH) secretion (vasopressin), and renal
tubular function. In the setting of decreased intravascular volume (eg,
severe hemorrhage or severe volume depletion secondary to GI or
renal loss, or diuretic use) owing to a decreased stretch on the
baroreceptors in the great veins, aortic arch, and carotid bodies, an
increased sympathetic tone to maintain systemic blood pressure
generally occurs.
○ This increased sympathetic tone, along with decreased renal perfusion
secondary to intravascular volume depletion, results in increased renin
and angiotensin excretion. This, in turn, results in increased sodium
absorption in the proximal tubules of the kidney and consequent
decreased delivery of solutes to distal diluting segments, causing an
impairment of renal free water excretion. There also is a concomitant
increase in serum ADH production that further impairs free water
excretion. Because angiotensin is also a very potent stimulant of thirst,
free water intake is increased, and, at the same time, water excretion
is limited. Together, these changes lead to hyponatremia.
○ Cerebral salt wasting (CSW) is seen with intracranial disorders, such as
subarachnoid hemorrhage, carcinomatous or infectious meningitis, and
metastatic carcinoma, but especially after neurologic procedures.
Disruption of sympathetic neural input into the kidney, which normally
promotes salt and water reabsorption in the proximal nephron
segment through various indirect and direct mechanisms, might cause
renal salt wasting, resulting in reduced plasma volume. Plasma renin
and aldosterone levels fail to rise appropriately in patients with CSW
despite a reduced plasma volume because of disruption of
the sympathetic nervous system. In addition, the release of 1 or more
natriuretic factors could also play a role in the renal salt wasting seen
in CSW. Volume depletion leads to an elevation of plasma vasopressin
levels and impaired free water excretion.
○ Distinguishing between CSW and syndrome of inappropriate ADH
secretion (SIADH) can be challenging, because there is considerable
overlap in the clinical presentation. Vigorous salt replacement is
required in patients with CSW, whereas fluid restriction is the
treatment of choice in patients with SIADH. Infusion of isotonic saline
to correct the volume depletion is usually effective in reversing the
hyponatremia in cerebral salt wasting, since euvolemia will suppress
the release of ADH. The disorder is usually transient, with resolution
occurring within 3-4 weeks of disease onset.9,10
○ Salt-wasting nephropathy causing hypovolemic hyponatremia may
rarely develop in a range of renal disorders (eg, interstitial
nephropathy, medullary cystic disease, polycystic kidney disease,
partial urinary obstruction) with low salt intake.
○ The treatment of choice for hypovolemic hypotonic hyponatremia is
saline infusion.
○ Hypervolemic hypotonic hyponatremia: This is characterized by
clinically detectable edema or ascites that signifies an increase in total
body water and sodium. Paradoxically, however, a decrease in the
effective circulating volume, critical for tissue perfusion, stimulates the
same pathophysiologic mechanism of impaired water excretion by the
kidney that is observed in hypovolemic hypotonic hyponatremia.
○ Commonly encountered examples include liver cirrhosis, congestive
heart failure, nephrotic syndrome, and severe hypoproteinemia
(albumin level <1.5-2 g/dL).
○ The treatment of these patients is usually limited to free water
restriction and diuresis to induce negative water balance.
○ Patients with renal failure and hyponatremia may have normal or high
plasma osmolality because of the urea retention. However, as urea is
not an effective osmole, the patient should be treated as per hypotonic
hyponatremia.
○ Normovolemic (euvolemic) hypotonic hyponatremia: This is a very
common cause of hyponatremia in patients who are hospitalized. It is
associated with nonosmotic and nonvolume related vasopressin (ADH)
secretion (ie, SIADH) secondary to a variety of clinical conditions,
including CNS disturbances, major surgery, trauma, pulmonary tumors,
infection, stress, and certain medications.
○ Common medications associated with SIADH are as follows:
chlorpropamide (potentiating renal action of ADH), carbamazepine
(possesses antidiuretic property), cyclophosphamide (marked water
retention secondary to SIADH and potentially fatal hyponatremia may
ensue in selected cases; use of isotonic saline rather than free water to
maintain a high urine output to prevent hemorrhagic cystitis can
minimize the risk), vincristine, vinblastine, amitriptyline, haloperidol,
selective serotonin reuptake inhibitors (particularly in elderly patients),
and monoamine oxidase (MAO) antidepressants. In these
circumstances, the ability of the kidney to dilute urine in the setting of
serum hypotonicity is reduced.
○ Diuretics may induce hypovolemic hyponatremia. Note that thiazide
diuretics, in contrast to loop diuretics, impair the diluting mechanism
without limiting the concentrating mechanism, thereby impairing the
ability to excrete a free water load. Thus, thiazides are more prone to
causing hyponatremia than are loop diuretics.
○ Hyponatremia is a relatively common adverse effect of desmopressin,
a vasopressin analogue that acts as a pure V2 agonist. Its common use
in the treatment of central diabetes insipidus, von Willebrand disease,
and nocturia in adults and of enuresis in children requires regular
monitoring of serum sodium levels.
○ The diagnostic criteria for SIADH are as follows:
 Normal hepatic, renal, and cardiac function - Clinical euvolemia
(absence of intravascular volume depletion)
 Normal thyroid and adrenal function
 Hypotonic hyponatremia
 Urine osmolality greater than 100 mOsm/kg, generally greater
than 400-500 mOsm/kg with normal renal function
○ Urinary sodium concentrations are also typically greater than 20 mEq/L
on a normal salt diet. Serum uric acid levels are generally reduced; this
is due to reduced tubular uric acid reabsorption, which parallels the
decrease in proximal tubular sodium reabsorption associated with
central volume expansion.
○ Reset osmostat is another important cause of normovolemic hypotonic
hyponatremia. This may occur in elderly patients and during
pregnancy. These patients regulate their serum osmolality around a
reduced set point; however, in contrast to patients with SIADH (who
also have a downward resetting of the osmotic threshold for thirst),11
they are able to dilute their urine in response to a water load to keep
the serum osmolality around the preset low point.
○ Severe hypothyroidism (unknown mechanism, possibly secondary to
low cardiac output and glomerular filtration rate) and adrenal
insufficiency are also associated with nonosmotic vasopressin release
and impaired sodium reabsorption, leading to hypotonic hyponatremia.
Hyponatremia associated with cortisol deficiency, such as primary or
secondary hypoadrenalism, commonly presents subtly and may go
undiagnosed. A random cortisol level check, especially in acute illness,
can be misleading if the level is normal (when it should be high).
Testing for adrenal insufficiency and hypothyroidism should be part of
the hyponatremic workup, as the disorders respond promptly to
hormone replacement. Depending on the etiology, mineralocorticoid
will also need replacement.
○ Severe malnutrition seen in weight-conscious women (low protein, high
water intake diet) is a special condition in which a markedly decreased
intake of solutes occurs, which limits the ability of the kidney to handle
the free water. Because a mandatory solute loss of 50-100 mOsm/kg of
urine exists, free water intake in excess of solute needs can produce
hyponatremia.12 Another example is beer drinker's potomania, because
a diet consisting primarily of beer is rich in free water but solute poor.
○ Compulsive intake of large amounts of free water exceeding the
dilutional capacity of the kidneys (>20 L/d), even with a normal solute
intake of 600-900 mOsm/d, may also result in hyponatremia, but in
contrast to SIADH, the urine is maximally dilute. In addition to a central
defect in thirst regulation, which plays an important role in the
pathogenesis of primary polydipsia, different abnormalities in ADH
regulation have been identified in psychotic patients, all impairing free
water excretion. Transient stimulation of ADH release during acute
psychotic episodes, an increase in the net renal response to ADH,
downward resetting of the osmostat, and antipsychotic medication
may contribute. Limiting water intake will rapidly raise the plasma
sodium concentration as the excess water is readily excreted in dilute
urine.13
○ Hospitalized patients who are infected with human immunodeficiency
virus (HIV) have a high incidence of hyponatremia. In these
individuals, hyponatremia is usually due to at least 1 of the following 3
disorders associated with an increased ADH level:
 Increased release of ADH due to malignancy, to occult or
symptomatic infection of the central nervous system, or to
pneumonia resulting from infection with Pneumocystis carinii or
other organisms.
 Effective volume depletion secondary to fluid loss from the
gastrointestinal tract, due primarily to infectious diarrhea.
 Adrenal insufficiency often due to an adrenalitis, an abnormality
that may be infectious in origin, perhaps being induced by
cytomegalovirus, Mycobacterium avium-intracellulare, or HIV
itself. Affected patients have a high risk of morbidity and
mortality.
○ Treatment generally is that of the underlying cause and free water
restriction.
○ The most common precipitant of hyponatremia in patients after
surgery14 is the iatrogenic infusion of hypotonic fluids. Inappropriate
administration of hypotonic intravenous fluids after surgery increases
the risk of developing hyponatremia in these vulnerable patients, who
retain water due to nonosmotic release of ADH, which is typically
elevated for a few days after most surgical procedures. Hospital-
acquired acute hyponatremia is disturbingly common also among
hospitalized children and adults.
○ Acute hyponatremia is associated with ultra-endurance athletes and
marathon runners. With women making up a higher percentage, the
strongest single predictor is weight gain during the race correlating
with excessive fluid intake. Longer racing time and body mass index
extremes are also associated with hyponatremia, whereas the
composition of fluids consumed (plain water rather than sports drinks
containing electrolytes) is not. Oxidization of glycogen and triglyceride
during a race is associated with the production of "bound" water, which
then becomes an endogenous, electrolyte-free water infusion
contributing to hyponatremia induced by water ingestion in excess of
water losses.
○ Nonsteroidal anti-inflammatory drug (NSAID) use may increase the risk
of development of hyponatremia by strenuous exercise by inhibiting
prostaglandin formation. Prostaglandins have a natriuretic effect.
Prostaglandin depletion increases NaCl reabsorption in the thick
ascending limb of Henle (ultimately increasing medullary tonicity) and
ADH action in the collecting duct, leading to impaired free water
excretion.15
○ Some collapsed runners are normonatremic or even hypernatremic,16
making blanket recommendations difficult. However, fluid intake to the
point of weight gain should be avoided.16,17 Athletes should rely on
thirst as their guide for fluid replacement and avoid fixed, global
recommendations for water intake. Symptomatic hyponatremic
patients should receive 100 mL of 3% sodium chloride over 10 minutes
in the field before transportation to hospital. This maneuver should
raise the plasma sodium concentration an average of 2-3 mEq/L.18
○ Symptomatic and potentially fatal hyponatremia can develop with
rapid onset after ingestion of the designer drug ecstasy
(methylenedioxymethamphetamine, or MDMA), an amphetamine. A
marked increase in water intake via direct thirst stimulation, as well as
inappropriate secretion of ADH, contributes to the hyponatremia seen
with even small amount of drug intake.
○ Nephrogenic syndrome of inappropriate antidiuresis (or NSIAD) is an
SIADH-like clinical and laboratory picture seen in male infants who
present with neurologic symptoms secondary to hyponatremia but who
have undetectable plasma arginine vasopressin (AVP) levels. This
hereditary disorder is secondary to mutations in the V2 vasopressin
receptor, resulting in constitutive activation of the receptor with
elevated cAMP production in the collecting duct principle cells.
Treatment of NSIAD poses a challenge. Water restriction improves
serum sodium levels and osmolality in infants, but it limits calorie
intake in these formula-fed infants. The use of demeclocycline or
lithium is potentially limited because of adverse effects. The current
therapy of choice is fluid restriction and the use of urea to induce an
osmotic diuresis.19
○ Hyponatremic hypertensive syndrome, a rare condition, consists
of severe hypertension associated with renal artery stenosis,
hyponatremia, hypokalemia, severe thirst, and renal dysfunction
characterized by natriuresis, hypercalciuria, renal glycosuria, and
proteinuria. Angiotensin-mediated thirst coupled with nonosmotic
release of vasopressin provoked by angiotensin II and/or hypertensive
encephalopathy are likely mechanisms for this syndrome. Sodium
depletion due to pressure natriuresis and potassium depletion due to
hyperaldosteronism with high plasma renin activity are also likely to
play a role in the pathogenesis of hyponatremia. The abnormalities
resolve with correction of the renal artery stenosis.20
Using a retrospective case note analysis, an Irish study examined the incidence of
hyponatremia in a variety of neurologic conditions.21 The investigators found that
the occurrence of hyponatremia was greater in persons with subarachnoid
hemorrhage (62 out of 316 patients, or 19.6%; p <0.001), intracranial neoplasm (56
out of 355 patients, or 15.8%; p <0.001), traumatic brain injury (44 out of 457
patients, or 9.6%; p <0.001), and pituitary disorders (5 out of 81 patients, or 6.25%;
p = 0.004) than it was in patients with spinal disorders (4 out of 489 patients, or
0.81%).
The investigators also determined that the median hospital stay for patients with
hyponatremia was 19 days, compared with a median stay of 12 days for the study's
other patients.
Revie
w
Synth
èse
The hyponatremic patient: a systematic approach to laboratory
diagnosis
Haralampos J. Milionis, George L. Liamis and Moses S. Elisaf
From the Department of Internal Medicine, University of Ioannina Medical School, Ioannina,
Greece
Correspondence to: Dr. Moses S. Elisaf, Department of Internal Medicine, University of
Ioannina Medical School, GR 451 10 Ioannina, Greece; fax +30 651 097016
Abstract
HYPONATREMIA (SERUM SODIUM LEVEL LESS THAN 134 MMOL/L) is a common
electrolyte disturbance. Its high prevalence and potential neurologic sequelae make a logical and
rigorous differential diagnosis mandatory before any therapeutic intervention. A history of
concurrent illness and medication use as well as the assessment of extracellular volume status on
physical examination may provide useful clues as to the pathogenesis of hyponatremia.
Measurement of the effective serum tonicity (serum osmolality less serum urea level) is the first
step in the laboratory evaluation. In patients with normal or elevated effective serum osmolality
(280 mOsm/kg or greater), pseudohyponatremia should be excluded. In the hypo-osmolar state
(serum osmolality less than 280 mOsm/kg), urine osmolality is used to determine whether water
excretion is normal or impaired. A urine osmolality value of less than 100 mOsm/kg indicates
complete and appropriate suppression of antidiuretic hormone secretion. A urine sodium level
less than 20 mmol/L is indicative of hypovolemia, whereas a level greater than 40 mmol/L is
suggestive of the syndrome of inappropriate antidiuretic hormone secretion. Levels of hormones
(thyroid-stimulating hormone and cortisol) and arterial blood gases should be determined in
difficult cases of hyponatremia.
Hyponatremia (serum sodium level less than 134 mmol/L) is a common electrolyte
disturbance occurring in a broad spectrum of patients, from asymptomatic to
critically ill.1,2 There are serious neurologic sequelae associated with hyponatremia
and its treatment. Therefore, a logical, rigorous differential diagnosis is mandatory
before therapy can be begun.3,4 Since hyponatremia is caused primarily by the
retention of solute-free water, its cause encompasses disorders associated with
limitation in water excretion.5 The principal causes of hyponatremia are summarized
in Table 1.
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As with other electrolyte abnormalities, the history and physical examination can provide
important clues toward the correct diagnosis. In most cases the initial laboratory evaluation
includes measurement of serum osmolality and urine osmolality (by osmometer if available),
urine sodium concentration and serum levels of other electrolytes (potassium, chloride and
bicarbonate) as well as serum concentrations of urea, glucose, uric acid, total proteins and
triglycerides. In addition, determination of serum levels of thyroid-stimulating hormone and
cortisol is important to exclude any associated endocrinopathy (Table 2, Fig. 1). Measurement of
arterial blood gases is also useful in the differential diagnosis of hyponatremia, particularly in
patients with abnormal serum bicarbonate concentrations.
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Fig. 1: Clinical diagnostic algorithm for

View larger hyponatremia. TSH = thyroid-stimulating hormone,
version (16K): EABV = effective arterial blood volume, SIADH =
[in this window] syndrome of inappropriate secretion of antidiuretic
[in a new window] hormone, FE = fractional excretion.
The step-by-step diagnostic evaluation of hyponatremia is shown in Fig. 1.

Serum osmolality
The initial approach to the hyponatremic patient is to measure the serum osmolality to determine
whether the hyponatremia represents a true hypo-osmolar state.1,2,5 Although urea contributes to
the absolute value of serum osmolality measured with an osmometer, it does not hold water
within the extracellular space because of its membrane permeability.1 Urea is an ineffective
osmole and does not contribute to the effective serum osmolality (tonicity). Thus, in a patient
with hyponatremia, normal or elevated effective serum osmolality (measured as serum osmolality
less serum urea level in millimoles per litre) suggests the presence of either pseudohyponatremia
(due to hyperparaproteinemia or hypertriglyceridemia) or increased concentrations of other
osmoles, such as glucose and mannitol.1,6,7
In the context of marked hyperlipidemia (hypertriglyceridemia) and lactescent serum, lipids
occupy space in the volume of serum, leading to lower readings in the concentrations of sodium
and free water per litre of serum. However, the physiologically significant serum water and
sodium and serum osmolality remain unaffected. Newer methods using ion-selective electrodes
in the measurement of serum electrolytes may avoid this problem.7,8
In the presence of osmotically active substances (e.g., patients with hyperglycemia or those
receiving mannitol infusions), an increase in serum osmolality is observed, which results in
movement of water out of the cells and subsequently a reduction of the serum sodium level by
dilution. It has been calculated that every increase of 3.4 mmol/L in the serum glucose level will
draw enough water out of the cells to reduce the serum sodium concentration by 1 mmol/L (i.e., a
decrease of 1.6 mmol/L in the serum sodium level per increase of 5.6 mmol/L in the glucose
level).6,9 However, recent evidence suggests that the hyperglycemia-induced decrease in sodium
concentration is considerably higher than the "standard" correction factor of 1.6, especially when
glucose levels are greater than 22.2 mmol/L.10 Hillier and colleagues10 have proposed that a
correction factor of 2.4 mmol/L is a better overall estimate of the association between sodium
levels and glucose levels.
Urine osmolality
If a hypo-osmolar state is confirmed, the next step is to determine whether the ability of the
kidneys to dilute the urine is intact by measuring urine osmolality.11 The normal response of the
kidney is to elaborate maximally dilute urine (urine osmolality less than 100 mOsm/kg, specific
gravity 1.003 or less). If the urine is maximally dilute, it indicates that antidiuretic hormone
(ADH) secretion is completely and appropriately suppressed, a finding seen in patients with
primary polydipsia or reset osmostat syndrome.5,12 Hyponatremia is unlikely to develop in the
setting of an intact urine-diluting mechanism.13,14,15 However, it may occur in the rare case of
patients who ingest large amounts of water (in isolated instances more than 10 to 15 L/d12). In
these cases a tendency to hyponatremia will be unmasked and enhanced by a concurrent (even
mild) impairment in water excretion.13,14,15 This occurs in the setting of central nervous system
dysfunction and in patients receiving antipsychotic agents, or it may be due to nausea or stress-
induced ADH secretion. Another unusual situation, in which modest amounts of fluid intake can
lead to hyponatremia even when the urine-diluting ability is intact, is observed in cases of
extremely reduced solute intake, in which the ability to excrete water is reduced by a poor dietary
intake.14 This phenomenon has been described in patients with chronic alcoholism and is often
referred to as "beer potomania syndrome" but has also been reported in patients with extremely
limited intake of solid foods.13,14,15
Decreased urine osmolality is also observed in some patients with reset osmostat syndrome,
when water intake reduces the serum osmolality below the new threshold for ADH release.16
Reset osmostat syndrome (discussed in a separate section later in this article) is a variant of the
syndrome of inappropriate ADH secretion (SIADH) and is present in about one-third of patients
with SIADH.
Urine sodium concentration

In patients with hyponatremia and inappropriately concentrated urine, it is particularly important
to assess the effective arterial blood volume.11 A decreased volume is by far the most common
cause of hyponatremia in everyday clinical practice.
Hypovolemia can be determined clinically by the presence of postural changes in blood pressure
and pulse rate. Measurement of urine electrolyte levels is also extremely useful in the assessment
of effective arterial blood volume, since patients with volume depletion exhibit low urinary
excretion of sodium and chloride (sodium level less than 20 mmol/L, chloride level less than 20
mmol/L).2,11,17,18 A urine sodium level less than 20 mmol/L in hypovolemia is relevant if renal salt
wasting does not exist.19 On the other hand, an increased urine sodium level is usually observed
in patients with euvolemic hyponatremia (urinary sodium level greater than 40 mmol/L).
However, the urine sodium concentration in euvolemic hyponatremia may be less than 20
mmol/L when dietary sodium intake is low.
An increased urine sodium concentration (greater than 40 mmol/L) is also found in sodium-
wasting conditions, such as recent diuretic therapy, certain renal parenchymal diseases, adrenal
insufficiency and metabolic alkalosis (Table 3).11,17,18 Hyponatremia occurs almost exclusively
with thiazide (and, less commonly, loop) diuretics, which act in the distal tubule, interfering only
with urine dilution.20 Several mechanisms have been postulated, including hypovolemia-
stimulated ADH release, interference with urine dilution in the cortical diluting segment, and an
alteration in osmoreceptor sensitivity and thirst regulation mediated by potassium depletion.20
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The ability of the kidney to both conserve sodium and dilute the urine is impaired in patients with
progressive renal disease owing to the associated osmotic diuresis.11 However, the capacity of
water excretion is relatively maintained in mild to moderate renal disease, and water retention
and hyponatremia are seen only when the glomerular filtration rate falls to very low levels.11 For
instance, when the glomerular filtration rate has fallen to about 5 mL/min, only about 1.5 L/24 h
can be excreted as water. Hence, a patient drinking in excess of that amount will be at risk for
water retention and hyponatremia. In patients with chronic renal failure, salt wasting seems to
occur only after acute reductions in salt intake and is reversible or preventable if salt intake is
gradually reduced over time.21
It is of interest that metabolic alkalosis represents one of the conditions in which volume
depletion may not be associated with decreased urine sodium concentrations.11,22 This condition is
seen primarily in patients presenting with vomiting or even chronic metabolic alkalosis. In this
clinical setting (i.e., active vomiting) a disequilibrium state exists in which the filtered load of
sodium bicarbonate exceeds the reabsorptive capacity of the proximal tubule, which leads to
increased delivery of sodium bicarbonate distally.11,22 Bicarbonate acts as a nonreabsorbable
anion in this situation, resulting in an obligatory sodium bicarbonate loss in the urine. Once
vomiting has ceased and the patient has reached an equilibrium state, the urine sodium level will
be low since the capacity of the proximal tubule for sodium bicarbonate reabsorption now equals
the filtered load.11,22
In the context of metabolic alkalosis related to volume depletion, urinary chloride excretion is
low (less than 10 to 20 mmol/L) owing to increased renal reabsorption of chloride. Therefore,
determination of the urine chloride level may be of help, and this index is sometimes preferred to
the urine sodium level as a measure of extracellular volume.22
In patients with equivocal findings (i.e., urine sodium level 20 to 40 mmol/L), the response of
serum sodium and its fractional excretion (FENa+) to the administration of normal saline (1 to 2
L/d for 1 to 2 days) can be used to establish a correct diagnosis. An increase of less than 5
mmol/L in serum sodium levels and an increase of greater than 0.5% in FENa+ is highly
suggestive of SIADH, whereas the opposite (an increase in serum sodium levels greater than 5
mmol/L and an increase of less than 0.5% in FENa+) is evident in hypovolemia.17,23
Urea and uric acid levels

Serum composition can also be used to assess the effective arterial blood volume. In fact, urea is
particularly sensitive to hypovolemia. Thus, in patients with a normal serum creatinine level, an
increase in serum urea levels (and therefore in the urea:creatinine ratio) suggests hypovolemia,
whereas a decrease in serum urea levels is indicative of an increase in extracellular volume.11,24 In
fact, a low serum urea concentration is frequently reported in patients with SIADH, in whom the
volume is somewhat expanded.25,26,27 Musch and associates23 found that hyponatremic patients
presenting with decreased FENa+ (less than 0.5%) combined with decreased fractional excretion
of urea (less than 55%) responded successfully to the administration of normal saline, signifying
a decrease in effective arterial blood volume (Fig. 1).
Similarly, serum uric acid levels may be used in the differential diagnosis of
hyponatremia.19,25,26,27,28 It has been reported that patients with hypovolemia tend to exhibit
increased serum uric acid levels (greater than 0.3 mmol/L).25 In contrast, in patients with SIADH,
serum uric acid levels are actually depressed (less than 0.24 mmol/L).19,28 This decrease in serum
uric acid levels typically results from an increase in urate excretion (fractional excretion of urate
greater than 10%). Hyperuricuria has been attributed to water retention and the resultant
expansion of serum volume, which, in turn, leads to reduced sodium and urate
reabsorption.19,25,26,27,28 However, it remains questionable whether volume expansion per se is a
major determinant that causes a significant increase in urate excretion rates in humans.29 In fact,
there is evidence that hypouricemia related to high urate clearance may also be encountered in
some hypovolemic patients who exhibit cerebral salt-wasting syndrome30 (this syndrome is
discussed in a separate section later in this article).
Hormonal disorders
It is of interest that the serum sodium concentration may be low (by as much as 130 mmol/L) in
pregnant women owing to human chorionic gonadotropin-induced release of a hormone (relaxin)
that is associated with a downward resetting of serum osmolality.31
Hyponatremia can occur in the setting of adrenal (primary or secondary) insufficiency and
hypothyroidism.32,33 Therefore, serum levels of thyroid-stimulating hormone and random cortisol
should be determined in confusing cases of hyponatremia and before a diagnosis of SIADH is
made. Glucocorticoid deficiency increases water permeability in the collecting tubules. Elevated
ADH levels have also been found in patients with glucocorticoid deficiency.32 In patients with
hypothyroidism, both ADH-mediated and intrarenal mechanisms have been implicated in the
pathogenesis of hyponatremia.33
Acid-base status and potassium homeostasis

Acid-base status and potassium balance should be evaluated in certain cases of hyponatremia
(Table 4).11,34,35 For example, the presence of metabolic acidosis and hyperkalemia is suggestive
of renal function impairment or adrenal insufficiency, whereas a diarrheal syndrome is usually
associated with metabolic acidosis and hypokalemia. Excessive vomiting or the use of diuretics
may result in hyponatremia in association with metabolic alkalosis and hypokalemia. However,
acid-base status and potassium balance are not disturbed in SIADH.34,35
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Special issues
Volume depletion versus syndrome of inappropriate antidiuretic
hormone secretion
Hyponatremia is the most common electrolyte abnormality in the general hospital population
(seen in 2% of patients in hospital).2,5,24 In the everyday clinical setting, hypovolemia and SIADH
are 2 clinical entities of major significance associated with low serum sodium levels.11 It is
therefore useful to be able to differentiate between these conditions by applying simple
diagnostic tests and manoeuvres.11,24 Clinical findings, such as postural changes in blood pressure
and pulse rate, together with laboratory evidence of hemoconcentration (e.g., high hematocrit and
serum total protein values) suggest a hypovolemic state. Furthermore, volume-depleted patients
exhibit more concentrated urine (urine osmolality greater than 450 mOsm/kg) and lower urinary
sodium excretion (urine sodium level less than 20 mmol/L and FENa+ less than 1%) than do
patients with SIADH (urine osmolality greater than 100 mOsm/kg, urine sodium level greater
than 40 mmol/L and FENa+ greater than 1%). In addition, prerenal azotemia (serum
urea:creatinine ratio greater than 0.17) and hyperuricemia (serum uric acid level greater than 0.3
mmol/L) are often present in patients with hypovolemic hyponatremia.19,28 In contrast, patients
with SIADH commonly exhibit low serum uric acid levels (less than 0.24 mmol/L) associated
with increased fractional excretion of urate (greater than 10%).19,28 Finally, the response of serum
sodium and FENa+ to the administration of normal saline (1 to 2 L/d for 2 days) can be used to
establish the correct diagnosis. Patients with hypovolemia respond with an increase of more than
5 mmol/L in serum sodium level together with an increase of less than 0.5% in FENa+; the
opposite is expected in patients with SIADH.23
Reset osmostat syndrome
Reset osmostat syndrome may be identified as a cause of chronic hyponatremia in several
conditions, such as pregnancy, hypovolemic states, quadriplegia, psychosis and other chronic
debilitating illnesses, including tuberculosis, encephalitis, malignant disorders and
malnutrition.16,36,37 The suggested mechanism is a downward resetting of the serum osmolality
level at which the osmoreceptors control ADH secretion.37 Patients with reset osmostat syndrome
commonly exhibit normovolemic hyponatremia, exhibit normal adrenal, renal and thyroid
function and no evidence of cardiac or hepatic disease, exhibit normal excretion of a standard (10
to 15 mL/kg given orally or intravenously) water load (i.e., excretion of more than 80% within 4
hours), exhibit an intact urine-diluting ability, achieving essentially normal maximal urine
dilution (serum osmolality less than 100 mOsm/kg) after an oral water-loading test, and retain the
ability to concentrate urine at a serum osmolality level above the reset level. These features
constitute the diagnostic criteria of the syndrome. Thus, the diagnosis of reset osmostat syndrome
relies on the response to water restriction and the presence of an intact urine-diluting ability,
which result in an increase in urine osmolality, since slight elevation of serum sodium levels will
stimulate ADH release. Patients with reset osmostat syndrome have normal osmoreceptor
responses to changes in serum osmolality, although the threshold for ADH release is reduced.
Consequently, the serum sodium levels are below normal but stable (usually between 125 and
130 mmol/L), since the ability to excrete water is maintained.16,37
Cerebral salt-wasting syndrome versus syndrome of inappropriate
antidiuretic hormone secretion
Cerebral salt-wasting syndrome has been described in patients with intracranial disease (mainly
those with subarachnoid hemorrhage) who manifest hyponatremia and meet some of the
diagnostic criteria of SIADH.38 Cerebral salt-wasting syndrome is not only regarded as a distinct
clinical entity but is also considered by some, particularly neurosurgeons, to be more common
than SIADH.39,40,41 However, in most of these patients there is evidence of extracellular fluid
volume depletion, which stimulates ADH release.38,42,43 In this respect, the high urine sodium
concentration seems to be due to urine sodium wasting and not to volume expansion. Although
the exact mechanism of natriuresis is unknown, it has been suggested that a brain natriuretic
peptide (atrial natriuretic peptide and endogenous ouabain have also been incriminated44) is
released and causes an increase in sodium excretion and in urine volume.11,38 The natriuretic
factor has been identified as a protein and has been partially characterized.44,45 Work is underway
to isolate and identify this natriuretic factor. A natriuretic factor with characteristics similar to
those observed in patients with intracranial disease has been reported in patients with Alzheimer's
disease.45
The changes in uric acid homeostasis are particularly useful in differentiating between SIADH
and cerebral salt-wasting syndrome.28,44 Uric acid levels are depressed in patients with
SIADH,19,25,26,27 whereas in volume-depleted patients with hyponatremia uric acid levels are
normal or slightly increased in the presence of intact renal tubular function.44 However, uric acid
levels are depressed when there is renal salt wasting. In fact, serum uric acid levels in cerebral
salt-wasting syndrome tend to be unexpectedly low owing to a tubular transport abnormality for
uric acid.38,44 Thus, hypouricemia and high urine levels of uric acid may be common features of
intracranial disease in general.44,46 Hypouricemia and increased renal uric acid excretion have
been noted in patients with Alzheimer's disease even in the absence of hyponatremia.38,43,47 There
is also evidence that hypouricemia and hyponatremia coexist in patients with AIDS.44 The course
of hypouricemia after reversal of hyponatremia has been proposed as a useful diagnostic tool in
distinguishing between SIADH and cerebral salt-wasting syndrome.28 Correction of the serum
sodium concentration leads to normalization of uric acid handling by the kidney in SIADH, but
in cerebral salt-wasting syndrome hypouricemia and increased renal uric acid excretion
persist.38,44
The demonstration of a natriuretic factor in the serum of patients with persistent hypouricemia,
hyperuricuria (fractional excretion of urate greater than 10%) and possible renal salt wasting has
raised the possibility that the tubule transport defect for sodium and urate might be due to a
single circulating plasma protein.29,45 It has been postulated that the natriuretic factor is present in
patients with renal salt wasting but not in those with SIADH.44 In clinical practice the
identification of this factor would be valuable in differentiating renal salt wasting from SIADH
before appropriate therapy is started. Since renal salt wasting appears to be more common than
SIADH in patients with intracranial disease, distinguishing between these 2 situations would help
prevent potential complications resulting from inappropriate treatment.45
Footnotes
This article has been peer reviewed.
Contributors: All 3 authors contributed substantially to the manuscript. They were all
involved in drafting and revising the article, and all approved the final version of the
manuscript.
On the pathogenesis of metabolic alkalosis in
hyperaldosteronism
Top of Form
yes platform+medline author author
M.D.
Jerome P. Kassirer1, M.D. Abram M. London1, M.D. David M. Goldman1, M.D. William
B. Schwartz1
Bottom of Form
Received 20 November 1969

Hypersecretion of aldosterone is generally considered to be the proximate cause of metabolic
alkalosis in primary aldosteronism and has also been invoked as an important factor in the
genesis and maintenance of alkalosis in the postoperative patient. Direct evidence supporting
these two concepts is lacking, however. In our study we have examined the role of aldosterone
excess in metabolic alkalosis by administering the hormone in settings closely analogous to those
encountered clinically.
First, to simulate primary aldosteronism we gave 1,000 μg/day of d-aldosterone for three months
to volunteer subjects ingesting a diet containing normal quantities of sodium, potassium and
chloride. This quantity of hormone, although in excess of that usually secreted by patients with
primary aldosteronism, produced a rise of only 1 to 3 mEq/L in plasma bicarbonate
concentration. Since the metabolic fate of endogenous and that of exogenous hormone seem to
be similar, it would appear that aldosterone excess per se is not the proximate cause of metabolic
alkalosis in primary aldosteronism.
Second, we sought to simulate secondary aldosteronism as it is encountered in the postoperative
state by giving 1,000 μg/day of d-aldosterone to subjects with experimental gastric alkalosis and
restricting the dietary intake of either sodium or potassium. Administration of sodium chloride to
a potassium-restricted group and of potassium chloride to a sodium-restricted group in each
instance resulted in prompt restoration of normal acid-base equilibrium. The explanation for the
failure of exogenous aldosterone to induce or sustain significant metabolic alkalosis in situations
which mimic primary and secondary aldosteronism remains uncertain. However, analysis of data
from the published cases of primary aldosteronism raises the possibility that the severity of
potassium depletion occurring in response to a given degree of aldosterone excess may play an
important role in determining whether significant alkalosis will occur.
Acid-Base Physiology
7.5 Metabolic Alkalosis - Compensation
Previous | Index | Next
The compensatory response is hypoventilation
It was believed that the peripheral chemoreceptors alone acted as the initial sensor responding to
the rise in blood pH but further animal studies have indicated that metabolic acid-base disorders
do cause a slow change in brain ISF [H+] and this change allegedly could be sufficient for
account for the change in ventilation that occurs. This view is not accepted by all - see discussion
in Section 2.3)
The hypoventilation causes a compensatory rise in arterial pCO2 but the magnitude of the
response has generally been found to be quite variable. More recent studies have almost
invariably shown that hypoventilation does reliably occur in metabolic alkalosis.
Why is hypoventilation not always found?
This has been attributed to various problems with some of the older studies which did not
account for the presence of conflicting factors, particularly those causing hyperventilation:
• Hyperventilation due to pain - in response to the stress of a painful
arterial puncture. This could lower the measured pCO2 during the procedure.
• Hyperventilation due to pulmonary congestion. Some patients with
metabolic alkalosis due to diuretic use have subclinical pulmonary congestion
sufficient to stimulate intrapulmonary receptors and cause tachypnoea and
give a sensation of dyspnoea. This slight hyperventilation is sufficient to
negate the rise in arterial pCO2.
• Hyperventilation due to hypoxaemia. An associated hypoxaemia will
stimulate the peripheral chemoreceptors and cause hyperventilation if the
arterial pO2 is below 50 to 55mmHg. This may not have been considered in
early studies.
This common association of metabolic alkalosis with factors causing hyperventilation probably
accounts for most of the past findings of variability of the change in arterial pCO2. In effect, this
is saying that many of these patients had a co-existent respiratory alkalosis.
The arterial pCO2 can be quite high in severe cases
It was also widely believed that the maximum value of arterial pCO2 due to compensatory
hypoventilation was 55 to 60mmHg. There is no doubt that this is wrong.
Arterial pCO2 can rise higher than this and values up to 86mmHg have been reported in severe
cases of metabolic alkalosis!
If hypoventilation is sufficient to cause hypoxaemia, this also may stimulate respiration via the
peripheral chemoreceptors. As mentioned above, associated hypoxaemia is probably responsible
for variability in the measured arterial pCO2 in patients who also have a sufficiently low arterial
pO2. Patients who present with hypoxaemia and hypercapnia may be diagnosed with respiratory
failure if the association with metabolic alkalosis is not appreciated. It is usually best in these
patients to administer oxygen and to avoid intubation and ventilation.
A couple of cautions for severe cases:
• For patients that you do not intubate and ventilate: If significant hypoxaemia
was present, its relief can remove the hypoxic respiratory drive with resultant
hypoventilation and a rise in arterial pCO2. This reveals the ‘appropriate’ (in
acid-base terms) physiological response but can cause concern.
• For patients that you you intubate and ventilate: It is easy to render
ventilated patients hypocapnic and this respiratory alkalosis can greatly
worse the alkalemia. Convulsions have occurred in such patients.
The expected pCO2 due to appropriate hypoventilation in simple metabolic alkalosis can be
estimated from the following formula:
Expected pCO2 = 0.7 [HCO3] + 20 mmHg (range: +/- 5)
Note the wide variation allowed (ie a 10 mmHg range) because of the conflicting factors that
affect ventilation (discussed above). This formula is used to determine if a coexistent respiratory
acid-base disorder is present. For example, if pCO2 is much lower than expected, a respiratory
alkalosis is also present.
Perform a stat sodium and glucose level in patients with
refractory seizures: Excerpt from Avoiding Common Pediatric
Errors
Author: Caroline Rassbach, MD
What to Do - Interpret the Data

Seizures are one of the most common neurologic conditions affecting children. The majority are
short, self-limited seizures that occur secondary to disorders originating outside the brain.
Examples include high fever, infection, head trauma, hypoxia, and toxins. Less than one third of
seizures in children occur as a result of epilepsy. When a child presents with a first-time seizure,
or when a child with a known seizure disorder presents with prolonged seizure, metabolic causes
should be considered. Obtaining stat serum glucose and sodium levels are essential in these
children.
Initialassessmentofanychildwithaseizureshouldincludeevaluationof the airway, breathing, and
circulation (ABCs). The provider should perform vital signs and place the patient on a cardiac
monitor and on supplemental oxygen. The provider should then obtain a detailed history and
perform a quick physical examination, including a neurologic examination, searching for clues to
the etiology of the seizure. Life-threatening conditions, such as meningitis, sepsis, head trauma,
and toxin ingestion, should be considered in the differential diagnosis.
When a seizure lasts >5 minutes, intravenous access should be attained and stat serum glucose
and sodium levels drawn. Serum calcium, phosphorus, magnesium, blood urea nitrogen, and a
complete blood count may also be indicated. Urine for toxicology and serum anticonvulsant
levels may be helpful. A benzodiazepine such as lorazepam or a barbiturate should be
administered as a first-line drug to stop the seizure. Lorazepam administration can be repeated
every 10 to 15 minutes if needed.
If the seizure continues for >10 minutes, a second anticonvulsant, such as phenobarbital or
phenytoin, should be administered. Metabolic derangements, such as hypoglycemia and
hyponatremia, should be treated as soon as they are diagnosed.
When the seizure activity persists >30 minutes, it is referred to as status epilepticus.
Administration of a second long-acting anticonvulsant is indicated for status epilepticus. In
addition, the practitioner should prepare for intubation and general anesthesia as the seizure
approaches 45 minutes.
Complications of status epilepticus include hypoxia, lactic acidosis, hyperkalemia,
hypoglycemia, shock, hyperpyrexia, renal and respiratory failure, and death.
Hypoglycemia and hyponatremia are the most frequent metabolic derangements that cause
seizure. Hypoglycemia occurs most commonly in neonates in the setting of hypoxia, toxemia,
gestational diabetes, or a normal delivery. In older children, it occurs because of prolonged
fasting, malabsorption and malnutrition, systemic disease, and hyperinsulinemia. Hypoglycemia
in infants presents as cyanosis, apnea, hypothermia, hypotonia, poor feeding, lethargy, or
seizures. In older children, signs of hypoglycemia
includeanxiety,tachycardia,sweating,tremulousness,weakness,hunger,and seizures. At any age,
hypoglycemia should be considered as a cause of a
seizure.Seizuressecondarytohypoglycemiashouldbetreatedwith2mL/kg of 50% glucose
intravenously.
Hyponatremia, another metabolic cause for seizure, is one of the most common electrolyte
disturbances occurring in hospitals. It usually results from excess free water intake in the
presence of impaired free water excretion. Examples include syndrome of inappropriate secretion
of antidiuretic hormone (SIADH), postoperative hyponatremia, water intoxication, overdilution
of infant formula, and diuretic use. When hyponatremia occurs, water shifts into the intracellular
space, resulting in cellular swelling. This may present clinically as cerebral edema and
encephalopathy with headache, nausea, vomiting, emesis, and weakness. It may progress to
altered mental status, seizures, respiratory arrest, and cerebral herniation.
Symptomatic hyponatremia is a medical emergency and should be treated with hypertonic 3%
saline intravenously. For seizing patients or for those with increased intracranial pressure, the
hypertonic saline should be infused rapidly enough to raise the serum sodium level by 4 to 8
mEq/L during the first hour or until seizure activity ceases. For less severe symptoms, hypertonic
saline should be infused with a goal of raising the serum sodium by 1 mEq/L/hr. In general, 1
mL/kg of hypertonic saline will raise the serum sodium level by 1 mEq/L. Practitioners should
be aware that overly fast correction of hyponatremia can result in devastating cerebral
demyelination.
Practitioners should remember to consider metabolic derangements in patients with seizures. Stat
serum glucose and sodium levels should be checked for all patients with prolonged or refractory
seizures.
Suggested Readings
Johnston MV. Seizures in childhood. In: Behrman RE, Kliegman RM, Jenson HB, eds. Nelson
Textbookof Pediatrics. 17thed.Philadelphia: Saunders;2004: chapter586,pages1993–2009.
Moritz ML, Ayus JC. Disorders of water metabolism in children: hyponatremia and
hypernatremia. Pediatr Rev. 2002;23(11):371–380.
Sabo-Graham T, Seay AR. Management of status epilepticus in children. Pediatr Rev.
1998;19(9)306–310.
SperlingMA.Hypoglycemia.In:BehrmanRE,KliegmanRM,JensonHB,eds.NelsonTextbook of
Pediatrics. 17th ed. Philadelphia: Saunders; 2004: - .
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• Book Title: Avoiding Common Pediatric Errors
• Author(s): Anthony D Slonim MD, DrPH; Lisa Marcucci MD
• Year of Publication: 2008
• Copyright Details: Avoiding Common Pediatric Errors, Copyright © 2008
Lippincott Williams & Wilkins.
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Syndrome of inappropriate antidiuretic
hormone hypersecretion
From Wikipedia, the free encyclopedia
Jump to: navigation, search
antidiuretic hormone
Classification and external resources
ICD-10 E22.2
ICD-9 253.6
DiseasesDB 12050
MedlinePlus 003702
eMedicine emerg/784 med/3541 ped/2190
MeSH D007177
The syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH) is a condition

mostly found in patients diagnosed with small cell carcinoma of the lung, pneumonia, brain
tumors, head trauma, strokes, meningitis, encephalitis, more. This is a syndrome characterized by
excessive release of antidiuretic hormone (ADH or vasopressin) from the posterior pituitary
gland or another source. The result is hyponatremia, and sometimes fluid overload. Vasopressin
has other important functions, addressed in the appropriate articles.
Contents
[hide]
• 1 Pathophysiology
• 2 Clinical Findings
• 3 Diagnosis
• 4 Causes
• 5 Management
• 6 Differential
diagnosis
• 7 History
• 8 References
[edit] Pathophysiology
The normal function of ADH on the kidneys is to control the amount of water reabsorbed by
kidney nephrons. ADH acts in the distal portion of the renal tubule (Distal Convoluted Tubule)
as well as on the collecting duct and causes the retention of water, but not solute. Hence, ADH
activity effectively dilutes the blood (decreasing the concentrations of solutes such as sodium).
ADH is secreted to prevent water loss in the kidneys. When water is ingested, it is taken up into
the circulation and results in a dilution of the plasma. This dilution, otherwise described as a
reduction in plasma osmolality, is detected by osmoreceptors in the hypothalamus of the brain
and these then switch off the release of ADH. The decreasing concentration of ADH effectively
inhibits the aquaporins in the collecting ducts and distal convoluted tubules in the nephrons of
the kidney. Hence, less water is reabsorbed, thereby increasing urine output, decreasing urine
osmolality, and normalizing blood osmolality. In SIADH the release of ADH is not inhibited by
a reduction in plasma osmolality when the individual ingests water and the osmolality of the
plasma drops. As the main solute of plasma is sodium, this hypoosmolar state is usually detected
as a low sodium level on laboratory testing. SIADH is therefore primarily a condition that results
in the abnormal handling of water loading and not a problem with excessive solute loss. This is
why it is usually treated with fluid (in particular water) restriction. Diuretics may also be given to
decrease reabsorption of water, but care must be taken not to correct water imbalances too
rapidly.
This causes dilutional hyponatremia and all the consequences associated with that condition:
headache, nausea, vomiting, and confusion may ensue. Severe hyponatremia may cause
convulsions or coma.
The abnormalities underlying type D syndrome of inappropriate antidiuretic hormone
hypersecretion concern individuals where vasopressin release and response are normal but where
abnormal renal expression and translocation of aquaporin 2, or both are found.[1] It has been
suggested that this is due to abnormalities in the secretion of secretin in the brain and that
"Secretin as a neurosecretory hormone from the posterior pituitary, therefore, could be the long-
sought vasopressin independent mechanism to solve the riddle that has puzzled clinicians and
physiologists for decades."[1]
[edit] Clinical Findings

In general, increased ADH causes water retention and extracellular fluid volume expansion
without edema or hypertension, owing to natriuresis (retention of water and passing of sodium in
urine). The water retention and sodium loss both cause hyponatremia, which is a key feature in
SIADH. Hyponatremia and concentrated urine (UOsm >300 mOsm) are seen, as well as no signs
of edema or dehydration. When hyponatremia is severe (sodium <120 mOsm), or acute in onset,
symptoms of cerebral edema become prominent (irritability, confusion, seizures, and coma).
[edit] Diagnosis
Laboratory findings in diagnosis of SIADH include-
• Hyponatremia <135 mEq/L, and POsm <270 mOsm/kg. Hyponatremia is often
treated pharmaceutically through the use of vasopressin receptor
antagonists, which include the approved drug Vasopril and phase III drug
lixivaptan.
Other findings include-
• Urine sodium concentration >20 mEq/L (inappropriate natriuresis). Urine
sodium concentration may be normal reflecting dietary intake.
• Maintained hypervolemia
• Suppression of renin-angiotensin system
• No equal concentration of atrial natriuretic peptide
• Low blood urea nitrogen (BUN)
• Low creatinine
• Low uric acid
• Low albumin
[edit] Causes
Some common causes of SIADH include:
• meningitis (treated with fluid restriction and diuretics)
• Head injury
○ Subarachnoid hemorrhage
• Cancers
○ Lung cancer (especially small cell lung cancer, as well as other small-
cell malignancies of other organs)
• Infections
○ Brain abscess
○ Pneumonia
○ Lung abscess
• Drugs
○ Chlorpropamide
○ Clofibrate
○ Phenothiazine
○ Cyclophosphamide
○ Carbamazepine
○ Selective serotonin reuptake inhibitors (SSRIs, a class of
antidepressants)
○ Methylenedioxymethamphetamine (MDMA, commonly called Ecstasy.
SIADH due to taking ecstasy was cited as a factor in the death of Leah
Betts)
○ oxytocin
○ vincristine
• Hypothyroidism
[edit] Management
Management of SIADH includes:
• Treating underlying causes when possible.
• Fluid restriction to 800-1,000 ml/d should be obtained to increase serum
sodium.
• Intravenous saline - For very symptomatic patients (severe confusion,
convulsions, or coma) hypertonic saline (5%) 200-300 ml IV in 3-4 h should
be given.
• Drugs
○ Demeclocycline can be used in chronic situations when fluid
restrictions are difficult to maintain; demeclocycline is the most potent
inhibitor of AVP action.
○ Conivaptan - an antagonist of both V1A and V2 vasopressin receptors. Its
indications are "treatment of euvolemic hyponatremia (e.g. the
syndrome of inappropriate secretion of antidiuretic hormone, or in the
setting of hypothyroidism, adrenal insufficiency, pulmonary disorders,
etc.) in hospitalized patients."[2]
○ Tolvaptan - an antagonist of the V2 vasopressin receptor. A randomized
controlled trial showed tolvaptan is able to raise serum sodium in
patients with euvolemic or hypervolemic hyponatremia[3]
Care must be taken when correcting hyponatremia. A rapid rise in the sodium level may cause
central pontine myelinolysis.[4]
Avoid correction by more than 12 mEq/L/day
[edit] Differential diagnosis

Cerebral salt wasting syndrome also presents with hyponatremia.
[edit] History
The condition was first described by researchers from Boston, Massachusetts and Bethesda,
Maryland (including Dr Frederic Bartter) in two patients with lung cancer.[5] Criteria were
developed by Schwartz and Bartter in 1967,[6] and have remained essentially unchanged since
then.[7] The condition is occasionally referred to by the names of the authors of the first report -
Schwartz-Bartter syndrome.[8]
Toxicity, Digitalis
Introduction
Background
Digitalis is a cardiac glycoside with many important therapeutic considerations. Although these
concerns are predominant in the adult population, acute digitalis poisoning in the pediatric
population is well described in the literature. Despite improved pharmacologic knowledge,
digitalis poisoning continues to be a serious problem in infants and children because of its wide
availability and narrow therapeutic index. The availability of digoxin-specific fragment antigen
binding (Fab) antibody fragments has considerably improved the outlook of patients with severe
forms of digitalis poisoning.
Digoxin is the most widely used cardiac glycoside and the only digitalis preparation in common
therapeutic use in the United States. In 1980, digoxin was the eighth most widely prescribed drug
in the United States; many recent surveys list it among the top 10 drugs prescribed in office
practice. Digitalislike compounds are also found in certain plants such as the common oleander,
foxglove, yew berry, dogbane, lily of the valley, and red squill, as well as in certain toad species.
Herbal exposure usually occurs through the ingestion of plants or the inhalation of smoke from
burning plants. Cardiac glycoside toxicity accounts for 2.6% of reported cases of toxicity due to
plant ingestion.
Pathophysiology
Digitalis inhibits the active transport of sodium and potassium across cell membranes by binding
to a specific site on the extracytoplasmic surface of the alpha subunit of the sodium-activated and
potassium-activated adenosine triphosphatase (NaK ATPase) pump; this binding is a reversible
process. The net result is an increase in the intracellular sodium and calcium concentrations and a
decrease in the intracellular potassium concentration. Digitalis increases phase 4 of the action
potential in most myocardial tissue, leading to a reduction of conduction velocity with increased
automaticity and ectopic activity. Improved inotropy is due to an increased concentration of
cytosolic calcium ions during systole. Digitalis also has a negative chronotropic action, which is
partly a vagal effect and partly a direct effect on the sinoatrial (SA) node.
The therapeutic daily dose of digoxin ranges from about 0.005 mg/kg in premature infants to as
much as 0.75 mg in adults. The absorption of digoxin tablets is 70-80%; its bioavailability is
95%. The kidney excretes 60-80% of the digoxin dose unchanged. The onset of action by oral
(PO) administration occurs in 30-120 minutes; the onset of action with intravenous (IV)
administration occurs in 5-30 minutes. The peak effect with PO dosing is 2-6 hours, and that
with IV dosing is 5-30 hours. Only 1% of the total amount of digoxin in the body is in the serum;
of that amount, approximately 25% is protein bound.
The volume of distribution is 6-10 L/kg in adults, 10 L/kg in neonates, and as much as 16 L/kg in
infants and toddlers. At therapeutic levels, the elimination half-life is 36 hours with renal
excretion. In acute digoxin intoxication in toddlers and children, the average plasma half-life is
11 hours. With acute intoxication, plasma concentrations extrapolated to time zero is lower in
toddlers than in infants and older children because of their increased volume of distribution and
clearance.
The lethal dose of digoxin is considered to be 20-50 times the maintenance dose taken at once. In
healthy adults, a does of less than 5 mg seldom causes severe toxicity, but a does of more than 10
mg is almost always fatal. In the pediatric population, the ingestion of more than 4 mg or 0.3
mg/kg portends serious toxicity.
Frequency
United States
The prevalence of digitalis toxicity in the pediatric population are difficult to establish. As many
as 15% of hospitalized adults are receiving digoxin therapy, and the prevalence of digoxin
toxicity is as high as 30%. In 1985, the American Association of Poison Control Centers
(AAPCC) National Data Collection System (Toxic Exposure Surveillance System) reported 1015
cases of cardiac glycoside overdose, of which 584 involved children younger than 6 years, and
56 involved children aged 6-17 years.1 Of all adult and pediatric patients, 842 cases (83%) were
nonintentional.
Mortality/Morbidity
Overall mortality rates vary among different pediatric studies; rates of 10-24% were reported
before the introduction of digoxin-specific Fab antibody fragments. The overall mortality rate
and rate of response to Fab therapy in children are similar to those in adults. The mortality rate as
a direct result of cardiac toxicity is 3-21%.
Sex
The incidence of digitalis poisoning is higher in males than in females; males also have a higher
mortality rate.
Age
Manifestations of digitalis toxicity vary depending on age; populations at the extremes of age are
most susceptible. For instance, ventricular ectopy is most prevalent in older patients; conduction
defects and supraventricular ectopic rhythms are most prevalent in younger patients.
Most cases of cardiac glycoside toxicity related to plant ingestion occur in children younger than
6 years. Of the 1015 cases of cardiac glycoside overdose reported by the AAPCC in 1985, 584
involved children younger than 6 years, and 56 involved children aged 6-17 years.1 In 80% of
reported cases of digitalis toxicity in toddlers, children had found and ingested their
grandparents' medications.
Clinical
History
Most cases of pediatric digitalis poisoning are unintentional ingestions; thus, a good social
history with emphasis on available medications and the extent of home childproofing is
necessary.
• CNS
○ Lethargy or drowsiness
○ Confusion or giddiness
○ Headaches
○ Hallucinations
○ Visual changes, including aberrations in color vision (chromatopsia)
and yellow halos around lights (xanthopsia), transient amblyopia or
scotomata, and decreased visual acuity
○ Seizures (rare)
○ Syncope
• GI system
○ Nausea and vomiting
○ Diarrhea
○ Anorexia, weight loss, or failure to thrive
○ Abdominal pain
• Cardiovascular system (see Procedures)
Physical
Patients can have an asymptomatic period of several minutes to several hours after the oral
administration of a single toxic dose. Clinical signs may be subtle or obvious, depending on the
severity of toxicity. Acute toxicity is rarely subtle, and chronic toxicity may be difficult to
diagnose. CNS changes, most notably nausea, vomiting, and drowsiness are the most common
extracardiac manifestations. Visual changes usually affect patients with chronic toxicity.
Emphasis should be placed on the vital signs and the neurologic and cardiovascular findings.
Causes
• Therapeutic administration can cause toxicity.
○ Usual therapeutic doses
○ Doses with errors in prescription, dispensing, or administration
• Acute nontherapeutic overdose can cause toxicity.
○ Unintentional
○ Suicidal
○ Homicidal
• The main causes of digitalis toxicity in the pediatric population include the
following:
○ Erroneous dosing in infants, which is usually parenteral and frequently
fatal
○ Unintentional ingestion in younger children, which is rarely fatal
○ Intentional ingestion in older children and young adults, which results
in variable mortality rates. In addition, many suicide attempts with
digitalis ingestion have been reported in the pediatric population.
• Electrolytic abnormalities can worsen digitalis toxicity.
○ Hypokalemia can worsen toxicity. Hypokalemia is usually observed
with chronic toxicity or in patients taking diuretics. Hypokalemia
reduces the rate of sodium-activated and potassium-activated
adenosine triphosphatase (NaK ATPase) pump turnover and
exacerbates pump inhibition due to digitalis.
○ Hyperkalemia can also worsen toxicity. In pediatric patients,
hyperkalemia is usually a complication of acute toxicity rather than a
cause; however, preexisting hyperkalemia increases the risk of
morbidity and mortality.
○ Hypomagnesemia and hypercalcemia aggravate toxicity.
• Concomitant use of the following drugs can exacerbate digitalis toxicity:
○ Quinidine, procainamide, amiodarone, calcium channel blockers, beta-
blockers
○ Diuretics, including spironolactone
○ Erythromycin and tetracycline: These agents can increase serum
digoxin levels by inactivating an enteric bacterium (Eubacterium
species) that is present in 10% of the population. This bacterium
inactivates digoxin in the GI tract.
• Other risk factors include the following:
○ Renal dysfunction
○ Hypothyroidism
○ Hypoxemia
○ Alkalosis
○ Myocardial disease
○ Extremes of age
Cardiac Glycosides (Digitalis Compounds)
General Pharmacology
Cardiac glycosides represent a family of compounds that are derived from the foxglove plant
(Digitalis purpurea). The therapeutic benefits of digitalis were first described by William
Withering in 1785. Initially, digitalis was used to treat dropsy, which is an old term for edema.
Subsequent investigations found that digitalis was most useful for edema that was caused by a
weakened heart (i.e., heart failure).
Mechanisms of action
Digitalis compounds are potent inhibitors of cellular Na+/K+-ATPase. This ion transport system
moves sodium ions out of the cell and brings potassium ions into the cell. This transport function
is necessary for cell survival because sodium diffusion into the cell and potassium diffusion out
of the cell down their concentration gradients would reduce their concentration differences
(gradients) across the cell membrane over time. Loss of these ion gradients would lead to cellular
depolarization and loss of the negative membrane potential that is required for normal cell
function. The Na+/K+-ATPase also plays an active role in the membrane potential. this pump is
electrogenic because it transports 3 sodium ions out of the cell for every 2 potassium ions that
enter the cell. This can add several negative millivolts to the membrane potential depending on
the activity of the pump.
Cardiac myocytes, as well as many other cells, have a Na+-Ca++ exchanger (not an active energy-
requiring pump) that is essential for maintaining sodium and calcium homeostasis. The exact
mechanism by which this exchanger works is unclear. It is known that calcium and sodium can
move in either direction across the sarcolemma. Furthermore, three sodium ions are exchanged
for each calcium, therefore an electrogenic potential is generated by this exchanger. The
direction of movement of these ions (either inward or outward) depends upon the membrane
potential and the chemical gradient for the ions. We also know that an increase in intracellular
sodium concentration competes for calcium through this exchange mechanism leading to an
increase in intracellular calcium concentration. As intracellular sodium increases, the
concentration gradient driving sodium into the cell across the exchanger is reduced, thereby
reducing the activity of the exchanger, which decreases the movement of calcium out of the cell.
Therefore, mechanisms that lead to an accumulation of intracellular sodium cause a subsequent
accumulation of intracellular calcium because of decreased exchange pump activity.
By inhibiting the Na+/K+-ATPase, cardiac glycosides cause intracellular sodium concentration to
increase. This then leads to an accumulation of intracellular calcium via the Na+-Ca++ exchange
system. In the heart, increased intracellular calcium causes more calcium to be released by the
sarcoplasmic reticulum, thereby making more calcium available to bind to troponin-C, which
increases contractility (inotropy). Inhibition of the Na+/K+-ATPase in vascular smooth muscle
causes depolarization, which causes smooth muscle contraction and vasoconstriction.
By mechanisms that are not fully understood, digitalis compounds also increase vagal efferent
activity to the heart. This parasympathomimetic action of digitalis reduces sinoatrial firing rate
(decreases heart rate; negative chronotropy) and reduces conduction velocity of electrical
impulses through the atrioventricular node (negative dromotropy).
Pharmacokinetics and toxicity
The long half-life of digitalis compounds necessitates special considerations when dosing. With
a half-life of 40 hours, digoxin would require several days of constant dosing to reach steady-
state, therapeutic plasma levels (digitoxin with a half-life of 160 hours, would require almost a
month!). Therefore, when initiating treatment, a special dosing regimen involving "loading
doses" is used to rapidly increase digoxin plasma levels. This process is termed "digitalization."
For digoxin, the therapeutic plasma concentration range is 0.5 - 1.5 ng/ml. It is very important
that therapeutic plasma levels are not exceeded because digitalis compounds have a relatively
narrow therapeutic safety window. Plasma concentrations above 2.0 ng/ml can lead to digitalis
toxicity, which is manifested as arrhythmias, some of which may be life-threatening. If toxicity
occurs with digoxin, it may take several days for the plasma concentrations to fall to safe levels
because of the long half-life. There is available for digoxin toxicity an immune Fab (Digibind)
that can be used to rapidly reduce plasma digoxin levels. Potassium supplementation can also
reverse the toxic effects of digoxin if the toxicity is related to hypokalemia (see below).
Drug Interactions
Many commonly used drugs interact with digitalis compounds. The Class IA antiarrhythmic,
quinidine, competes with digoxin for binding sites and depresses renal clearance of digoxin.
These effects increase digoxin levels and can produce toxicity. Similar interactions occur with
calcium-channel blockers and nonsteroidal anti-inflammatory drugs. Other drugs that
interact with digitalis compounds are amiodarone (Class III antiarrhythmic) and beta-blockers.
Diuretics can indirectly interact with digoxin because of their potential for decreasing plasma
potassium levels (i.e., producing hypokalemia). Because potassium competes with digoxin for
binding sites on the Na+/K+-ATPase, hypokalemia results in increased digoxin binding and
thereby enhances its therapeutic and toxic effects. Hypercalcemia enhances digitalis-induced
increases in intracellular calcium, which can lead to calcium overload and increased
susceptibility to digitalis-induced arrhythmias. Hypomagnesemia also sensitizes the heart to
digitalis-induced arrhythmias.
Therapeutic Uses
Therapeutic Uses of
Digitalis Compounds
Heart Failure
• ↑ inotropy
• ↑ ejection fraction
• ↓ preload
• ↓ pulmonary congestion/edema
Arrhythmias
• ↓ AV nodal conduction
(parasympathomimetic effect)
• ↓ ventricular rate in atrial flutter
and fibrillation
Heart failure
Digitalis compounds have historically been used in the treatment of chronic heart failure owing
to their cardiotonic effect. Although newer and more efficacious treatments for heart failure are
available, digitalis compounds are still widely used. Clinical studies in heart failure patients have
shown that digoxin, when used in conjunction with diuretics and vasodilators, improves cardiac
output and ejection fraction, and reduces filling pressures and pulmonary capillary wedge
pressure (this reduces pulmonary congestion and edema); heart rate changes very little. These
effects are to be expected for a drug that increases inotropy. Although the direct effect of digoxin
on blood vessels is vasoconstriction, when given to patients in heart failure, the systemic
vascular resistance falls. This most likely results from the improvement in cardiac output, which
leads to withdrawal of compensatory vasoconstrictor mechanisms (e.g., sympathetic adrenergic
activity and angiotensin II influences). Digitalis compounds have a small direct diuretic effect on
the kidneys, which is beneficial in heart failure patients.
Atrial fibrillation and flutter
Atrial fibrillation and flutter lead to a rapid ventricular rate that can impair ventricular filling
(due to decreased filling time) and reduce cardiac output. Furthermore, chronic ventricular
tachycardia can lead to heart failure. Digitalis compounds, such as digoxin, are useful for
reducing ventricular rate when it is being driven by a high atrial rate. The mechanism of this
beneficial effect of digoxin is its ability to activate vagal efferent nerves to the heart
(parasympathomimetic effect). Vagal activation can reduce the conduction of electrical impulses
within the atrioventricular node to the point where some of the impulses will be blocked. When
this occurs, fewer impulses reach the ventricles and ventricular rate falls. Digoxin also increases
the effective refractory period within the atrioventricular node.
Specific Drugs
Three different digitalis compounds (cardiac glycosides) are listed in the table below. The
compound most commonly used in the U.S. is digoxin. Ouabain is used primarily as a research
tool. (See www.rxlist.com for more details on digoxin).
Drug Oral Availability* Half-life (hours) Elimination
Digoxin 75% 40 kidneys
Digitoxin >90% 160 liver
Ouabain 0% 20 kidneys
* percent absorption
Side Effects and Contraindications

The major side effect of digitalis compounds is cardiac arrhythmia, especially atrial tachycardias
and atrioventricular block. Digitalis compounds are contraindicated in patients who are
hypokalemic, or who have atrioventricular block or Wolff-Parkinson-White (WPW) syndrome.
Impaired renal function leads to enhanced plasma levels of digoxin because digoxin is eliminated
by the kidneys. Lean, elderly patients are more susceptible to digitalis toxicity because they often
have reduced renal function, and their reduced muscle mass increases plasma digoxin levels at a
given dose because muscle Na+/K+-ATPase acts as a large binding reservoir for digitalis.
Revised 01/30/10
Understanding hypokalemia
IN HYPOKALEMIA, the serum potassium level drops below 3.5 mEq/liter. Because the normal
range for a serum potassium level is a narrow one (3.5 to 5 mEq/liter), a slight decrease has
profound consequences.
How it happens
Remember that the body can't conserve potassium; inadequate intake and excessive output of
potassium upsets the balance and causes a deficiency of total body potassium. Let's take a closer
look at these and other causes of potassium loss.
* Not enough intake. Very simply, a lack of potassium intake decreases the body's potassium
level. That happens if a person isn't eating enough food containing potassium or is getting
potassium-deficient I.V. fluids.
* Too much output. Intestinal fluids contain a lot of potassium. Thus, severe gastrointestinal
fluid losses from suction, lavage, prolonged vomiting, diarrhea, or laxative abuse can deplete the
body's potassium supply. Fistulas and severe diaphoresis also contribute to potassium loss.
In addition, potassium can be depleted through the kidneys. High glucose concentration in the
urine causes osmotic diuresis, and potassium is lost through the urine. Potassium losses are also
seen in renal tubular acidosis, magnesium depletion, Cushing's syndrome, and periods of high
stress. Diuresis that occurs with a newly functioning transplanted kidney can lead to
hypokalemia.
* Drugs upsetting the balance. Certain drugs also trigger potassium loss: diuretics (such as
thiazide and loop diuretics), certain antibiotics (such as gentamicin, carbenicillin, and
amphotericin B), laxatives (when abused), corticosteroids, insulin, cisplatin, and adrenergic
agents (such as albuterol and epinephrine).
Excessive secretion of insulin, whether endogenous or exogenous, may shift circulating
potassium into the cells. Potassium levels also drop when adrenergic agents, such as epinephrine
or albuterol, are used to treat asthma.
* Diseases wreak havoc too. Any condition that leads to the loss of gastric acids can cause
alkalosis and hypokalemia. With alkalosis, potassium ions move into the cells as hydrogen ions
move out, leaving less potassium in the blood. Disorders associated with hypokalemia include
hepatic disease, hyperaldosteronism, acute alcoholism, heart failure, malabsorption syndrome,
nephritis, and Bartter's syndrome.
What to look for
The signs and symptoms of a low potassium level reflect how important this electrolyte is to
normal body functions.
* Neuromuscular alerts. Skeletal muscle weakness, especially in the legs, is a sign of a moderate
potassium loss. Weakness progresses and paresthesia develops. Leg cramps occur. Deep tendon
reflexes may be decreased or absent, and the respiratory muscles could be paralyzed or
weakened.
Because of potassium's effects on cell function, hypokalemia can lead to rhabdomyolysis, a
breakdown of muscle fibers leading to myoglobin in the urine. As smooth muscle is affected by
hypokalemia, the patient may develop anorexia, nausea, and vomiting.
* ECG alerts. The patient's pulse may be weak and irregular, and he may have orthostatic
hypotension. The ECG may show a flattened T wave, a depressed ST segment, and a
characteristic U wave.
Ventricular arrhythmias and cardiac arrest can result from hypokalemia. Closely watch a
hypokalemic patient who's taking digitalis glycosides and a diuretic; hypokalemia can potentiate
digitalis toxicity.
* Other problems. In addition, the pabent may experience intestinal problems such as decreased
bowel sounds, constipation, and paralytic ileus. When hypokalemia is prolonged, the kidneys
can't concentrate urine and diuresis occurs.
What tests show
The following test results help confirm the diagnosis of hypokalemia:
* serum potassium level less than 3.5 mEq/liter
* elevated pH and bicarbonate levels
* slightly elevated serum glucose level characteristic ECG changes.
How hypokalemia is treated
Treatment of hypokalemia focuses on restoring a normal potassium balance, preventing serious
complications, and removing or treating the underlying causes. Treatment varies depending on
the severity of the imbalance.
* Provide a high-potassium diet.
* If increased dietary potassium isn't sufficient to treat less-acute hypokalemia, provide oral
potassium supplements using potassium salts, preferably potassium chloride, as ordered.
* If hypokalemia is severe or the patient can't take oral supplements, administer IN. potassium
replacement therapy.
Once the serum potassium level is back to normal, the patient may get a sustained-release oral
potassium supplement as well as increased dietary potassium. Patients taking diuretics may be
switched to a potassium-- sparing diuretic to prevent excessive urinary potassium loss.
How you intervene
Careful monitoring and skilled interventions can help prevent hypokalemia and spare your
patient complications. For patients at risk for developing hypokalemia and those who have
hypokalemia already, you'll want to perform these actions:
Assess and monitor
* Monitor vital signs, especially pulse and blood pressure. Hypokalemia can cause orthostatic
hypotension.
How is digoxin associated with hypokalemia?
Usually, hyperkalemia is associated with usage of digoxin. This is due to the blocking action
of digoxin on the Na/K ase which results in accumulation of extracellular K+.
Most of the times, patients presenting with heart problems are already on diuretics before they
are prescribed with digoxin. Diuretics cause hypokalemia as they result in excessive excretion of
K+ from the body. Hypokalemia in turn causes digoxin toxicity. Digoxin toxicity does not cause
hypokalemia, but hypokalemia can worsen digoxin toxicity.
Toxicity, Digitalis
Introduction
Background
The therapeutic properties of cardiac glycosides (eg, digoxin, a product of the foxglove plant)
have been known since the days of the Roman Empire. The ancient Romans used red squill, a
cardiac glycoside derived from the sea onion, as a diuretic and heart medicine. Cardiac
glycosides are found in certain flowering plants such as oleander and lily-of-the-valley. Certain
herbal dietary supplements also contain cardiac glycosides.
Physicians first studied digoxin in the 18th century. William Withering published his classic
account of foxglove and some of its medical uses in 1785, remarking upon his experience with
digitalis. Indians in South America had used cardiac glycosides in their dart poisons. Digitalis
toxicity was well known in previous centuries, and some have suggested that the toxic visual
symptoms of digitalis may have played a role in Van Gogh's use of swirling greens and yellows.
During the early 20th century, the drug was introduced as treatment of atrial fibrillation. Only
subsequently was the value of digitalis for the treatment of congestive heart failure (CHF)
established.
The syndrome of digoxin toxicity was originally described in 1785 by Withering.

Pathophysiology
Digoxin's inotropic effect results from the inhibition of the sodium-potassium adenosine
triphosphatase (NA+/K+ ATPase) pump. The subsequent rise in intracellular calcium (Ca++) and
sodium (NA+) coupled with the loss of intracellular potassium (K+) increases the force of
myocardial muscle contraction (contractility), resulting in a net positive inotropic effect.
Digoxin also increases the automaticity of Purkinje fibers but slows conduction through the
atrioventricular (AV) node. Cardiac dysrhythmias associated with an increase in automaticity
and a decrease in conduction may result.
The relationship between digoxin toxicity and the serum digoxin level is complex; clinical
toxicity results from the interactions between digitalis, various electrolyte abnormalities, and
their combined effect on the Na+/K+ ATPase pump.
Cardiac glycoside toxicity from plants, such as oleander, foxglove, and lily-of-the-valley, is
uncommon but potentially lethal. Case reports of toxicity from these sources implicate the
preparation of extracts and teas as the usual culprit.
Frequency
United States
Approximately 0.4% of all hospital admissions, 1.1% of outpatients on digoxin, and 10-18% of
nursing home patients develop toxicity.
In 2006, the American Association of Poison Control Centers reported an incidence of 2610
toxic digitalis exposures. The overall incidence of digoxin toxicity has decreased because of a
number of factors including increased awareness of drug interactions, decreased use of digoxin
to treat heart failure and arrhythmias, and the availability of accurate rapid radioimmunoassays to
monitor drug levels. Although the number of digitalis exposures is far less than the incidence of
calcium channel blocker toxicity (10,031 cases) or beta-blocker toxicity (18,253 cases), the
mortality rate from digitalis toxicity is far higher with 22 deaths reported versus 13 deaths from
calcium channel antagonists and only 4 deaths attributed to beta-blocker toxicity.1
Cardiovascular drug poisoning including digitalis toxicity ranks as the third leading cause of
death from all poisonings in 2006.
Data from the 2007 Annual Report of the American Association of Poison Control Centers is
similar to previous data, with 2565 digitalis exposures reported. However, fatalities were lower,
with 10 deaths reported.2
International
Approximately 2.1% of inpatients on digoxin and 0.3% of all admissions develop toxicity.
Mortality/Morbidity
• Morbidity is usually 4.6-10%; however, morbidity is 50% if the digoxin level is
greater than 6 ng/mL.
• Mortality due to digoxin exposure varies with the population studied. Adult
mortality depends on underlying comorbidity. In general, older people have a
worse outcome than adults who, in turn, have a worse outcome than
children.
Age
Advanced age (>80 y) is an independent risk factor and is associated with increased morbidity
and mortality.
Clinical
History
• Constitutional symptoms (eg, weakness, fatigue)
• Cardiovascular
○ Palpitations
○ Syncope
○ Dyspnea
• Central nervous system
○ Confusion and somnolence
○ Dizziness without vertigo
○ Agitation, delirium, and hallucinations
○ Headache
○ Paresthesias and neuropathic pain
○ Seizures (extremely rare)
• Ocular
○ Disturbances of color vision with a tendency to yellow-green coloring
○ Blurred vision and diplopia
○ Halos and scotomas
○ Photophobia
• Gastrointestinal
○ Nausea, vomiting, anorexia, and diarrhea
○ Abdominal pain (uncommon)
Physical
Hemodynamic instability is related directly to the presence of a dysrhythmia or acute congestive
heart failure (CHF).
• Cardiovascular findings on physical examination relate to the severity of CHF,

dysrhythmias, or hemodynamic instability.
○ Digoxin toxicity may cause any dysrhythmia. Classically, dysrhythmias
that are associated with increased automaticity and decreased AV
conduction occur (ie, paroxysmal atrial tachycardia with 2:1 block,
accelerated junctional rhythm, or bidirectional ventricular tachycardia
[torsade de pointes], depicted in the images below).
○
Bidirectional tachycardia in a patient with digitalis toxicity.

[ CLOSE WINDOW ]
eMedicine Specialties > Emergency Medicine > Toxicology
Toxicity, Digitalis
Introduction
Background
The therapeutic properties of cardiac glycosides (eg, digoxin, a product of the foxglove plant)
have been known since the days of the Roman Empire. The ancient Romans used red squill, a
cardiac glycoside derived from the sea onion, as a diuretic and heart medicine. Cardiac
glycosides are found in certain flowering plants such as oleander and lily-of-the-valley. Certain
herbal dietary supplements also contain cardiac glycosides.
Physicians first studied digoxin in the 18th century. William Withering published his classic
account of foxglove and some of its medical uses in 1785, remarking upon his experience with
digitalis. Indians in South America had used cardiac glycosides in their dart poisons. Digitalis
toxicity was well known in previous centuries, and some have suggested that the toxic visual
symptoms of digitalis may have played a role in Van Gogh's use of swirling greens and yellows.
During the early 20th century, the drug was introduced as treatment of atrial fibrillation. Only
subsequently was the value of digitalis for the treatment of congestive heart failure (CHF)
established.
The syndrome of digoxin toxicity was originally described in 1785 by Withering.

Pathophysiology
Digoxin's inotropic effect results from the inhibition of the sodium-potassium adenosine
triphosphatase (NA+/K+ ATPase) pump. The subsequent rise in intracellular calcium (Ca++) and
sodium (NA+) coupled with the loss of intracellular potassium (K+) increases the force of
myocardial muscle contraction (contractility), resulting in a net positive inotropic effect.
Digoxin also increases the automaticity of Purkinje fibers but slows conduction through the
atrioventricular (AV) node. Cardiac dysrhythmias associated with an increase in automaticity
and a decrease in conduction may result.
The relationship between digoxin toxicity and the serum digoxin level is complex; clinical
toxicity results from the interactions between digitalis, various electrolyte abnormalities, and
their combined effect on the Na+/K+ ATPase pump.
Cardiac glycoside toxicity from plants, such as oleander, foxglove, and lily-of-the-valley, is
uncommon but potentially lethal. Case reports of toxicity from these sources implicate the
preparation of extracts and teas as the usual culprit.
Frequency
United States
Approximately 0.4% of all hospital admissions, 1.1% of outpatients on digoxin, and 10-18% of
nursing home patients develop toxicity.
In 2006, the American Association of Poison Control Centers reported an incidence of 2610
toxic digitalis exposures. The overall incidence of digoxin toxicity has decreased because of a
number of factors including increased awareness of drug interactions, decreased use of digoxin
to treat heart failure and arrhythmias, and the availability of accurate rapid radioimmunoassays to
monitor drug levels. Although the number of digitalis exposures is far less than the incidence of
calcium channel blocker toxicity (10,031 cases) or beta-blocker toxicity (18,253 cases), the
mortality rate from digitalis toxicity is far higher with 22 deaths reported versus 13 deaths from
calcium channel antagonists and only 4 deaths attributed to beta-blocker toxicity.1
Cardiovascular drug poisoning including digitalis toxicity ranks as the third leading cause of
death from all poisonings in 2006.
Data from the 2007 Annual Report of the American Association of Poison Control Centers is
similar to previous data, with 2565 digitalis exposures reported. However, fatalities were lower,
with 10 deaths reported.2
International
Approximately 2.1% of inpatients on digoxin and 0.3% of all admissions develop toxicity.
Mortality/Morbidity
• Morbidity is usually 4.6-10%; however, morbidity is 50% if the digoxin level is
greater than 6 ng/mL.
• Mortality due to digoxin exposure varies with the population studied. Adult
mortality depends on underlying comorbidity. In general, older people have a
worse outcome than adults who, in turn, have a worse outcome than
children.
Age
Advanced age (>80 y) is an independent risk factor and is associated with increased morbidity
and mortality.
Clinical
History
• Constitutional symptoms (eg, weakness, fatigue)
• Cardiovascular
○ Palpitations
○ Syncope
○ Dyspnea
• Central nervous system
○ Confusion and somnolence
○ Dizziness without vertigo
○ Agitation, delirium, and hallucinations
○ Headache
○ Paresthesias and neuropathic pain
○ Seizures (extremely rare)
• Ocular
○ Disturbances of color vision with a tendency to yellow-green coloring
○ Blurred vision and diplopia
○ Halos and scotomas
○ Photophobia
• Gastrointestinal
○ Nausea, vomiting, anorexia, and diarrhea
○ Abdominal pain (uncommon)
Physical
Hemodynamic instability is related directly to the presence of a dysrhythmia or acute congestive
heart failure (CHF).
• Cardiovascular findings on physical examination relate to the severity of CHF,

dysrhythmias, or hemodynamic instability.
○ Digoxin toxicity may cause any dysrhythmia. Classically, dysrhythmias
that are associated with increased automaticity and decreased AV
conduction occur (ie, paroxysmal atrial tachycardia with 2:1 block,
accelerated junctional rhythm, or bidirectional ventricular tachycardia
[torsade de pointes], depicted in the images below).
○

[ CLOSE WINDOW ]
○
Torsades de pointes.
[ CLOSE WINDOW ]
○ Premature ventricular contractions (PVCs) are the most common
dysrhythmia. Bigeminy or trigeminy occurs frequently.
○ Sinus bradycardia and other bradyarrhythmias are very common. Slow
atrial fibrillation with very little variation in the ventricular rate
(regularization of the R-R interval) may occur.
○ First-degree heart block, second-degree AV block, complete AV
dissociation, and third-degree heart block are also very common.
○ Rapid atrial fibrillation or atrial flutter is rare.
○ Ventricular tachycardia is an especially serious finding.
○ Cardiac arrest from asystole or ventricular fibrillation is usually fatal.
• Gastrointestinal symptoms are common, but the abdominal examination is
usually nonspecific.
• Neurological findings are related to changes in sensorium or mental status.
Lateralizing findings usually indicate another disease process.
• Visual changes occur, but the pupils are spared, and objective findings are
few.
• Drug-induced fever does not occur.
Causes
• Deteriorating renal function, dehydration, electrolyte disturbances, or drug
interactions usually precipitates chronic toxicity.
• Acute overdose or accidental exposure to plants containing cardiac
glycosides may cause acute toxicity.
• Hypokalemia, hypernatremia, or hypomagnesemia increases the toxic
cardiovascular effects of digoxin because of their depressive effects on the
NA+/K+ ATPase pump.
○ Digoxin toxicity does not cause hypokalemia, but hypokalemia can
worsen digoxin toxicity.
○ Hyperkalemia is the usual electrolyte abnormality precipitated by
digoxin toxicity, primarily in the acute setting. Hyperkalemia may be
associated with acute renal failure that subsequently precipitates
digoxin toxicity. Chronic digoxin toxicity does not usually cause
hyperkalemia.
• Acidosis depresses the Na+/K+ ATPase pump and may cause digoxin toxicity.
• Myocardial ischemia suppresses the Na+/K+ ATPase pump and independently
alters myocardial automaticity. Digoxin toxicity is more likely in this setting.
• Erroneous dosing, especially in infants receiving parenteral digoxin,
unfortunately, is a frequent cause of digoxin toxicity and is usually associated
with high mortality.
• Hypothyroid patients are prone to digoxin toxicity secondary to decreased
renal excretion and a smaller volume of distribution.
• Bioavailability varies depending on the drug formulation.
○ Lanoxin has 25% less bioavailability than Lanoxicaps.
○ Toxicity may occur by increasing bioavailability.
○ Certain antibiotics that suppress intestinal flora may increase
absorption of digoxin.
• Drug interactions are one of the most common causes of digoxin toxicity.
○ Some medications directly increase digoxin plasma levels; other
medications alter renal excretion or induce electrolyte abnormalities.
○ Drugs that have been reported to cause digoxin toxicity include the
following:
 Amiloride - May reduce the inotropic response to digoxin
 Amiodarone - Reduces renal and nonrenal clearance of digoxin
and may have additive effects on the heart rate
 Benzodiazepines (alprazolam, diazepam) - Have been associated
with isolated reports of digoxin toxicity
 Beta-blockers (propranolol, metoprolol, atenolol) - May have
additive effects on the heart rate; carvedilol may increase
digoxin blood levels in addition to potentiating its effects on the
heart rate
 Calcium channel blockers - Diltiazem and verapamil increase
serum digoxin levels; not all calcium channel blockers share this
effect.
 Cyclosporine - May increase digoxin levels, possibly due to
reduced renal excretion
 Erythromycin, clarithromycin, and tetracyclines - May increase
digoxin levels
 Propafenone - Increases digoxin level; effects are variable.
 Quinidine - Increases digoxin level substantially but clinical
effect is variable; related drugs such as hydroxychloroquine or
quinine may also affect levels.
 Propylthiouracil - May increase digoxin levels by reducing
thyroid hormone levels
 Indomethacin
 Spironolactone - May interfere with digoxin assays; may directly
increase digoxin levels; may alter renal excretion.
 Hydrochlorothiazide
 Furosemide and other loop diuretics
 Triamterene
 Amphotericin B - May precipitate hypokalemia and subsequent
digoxin toxicity
 Succinylcholine - Increased risk of dysrhythmias has been
reported.
○ Herb/nutraceutical - Avoid ephedra (risk of cardiac stimulation); avoid
natural licorice (causes sodium and water retention and increases
potassium loss).
• Clinical digoxin toxicity represents a complex interaction between digoxin
and various electrolyte and renal abnormalities. A patient with normal digoxin
levels (0.5-2 ng/mL) but renal insufficiency or severe hypokalemia may have
more serious cardiotoxicity than a patient with high digoxin levels and no
renal or electrolyte disturbances.
○
[ CLOSE WINDOW ]
○ Premature ventricular contractions (PVCs) are the most common
dysrhythmia. Bigeminy or trigeminy occurs frequently.
○ Sinus bradycardia and other bradyarrhythmias are very common. Slow
atrial fibrillation with very little variation in the ventricular rate
(regularization of the R-R interval) may occur.
○ First-degree heart block, second-degree AV block, complete AV
dissociation, and third-degree heart block are also very common.
○ Rapid atrial fibrillation or atrial flutter is rare.
○ Ventricular tachycardia is an especially serious finding.
○ Cardiac arrest from asystole or ventricular fibrillation is usually fatal.
• Gastrointestinal symptoms are common, but the abdominal examination is
usually nonspecific.
• Neurological findings are related to changes in sensorium or mental status.
Lateralizing findings usually indicate another disease process.
• Visual changes occur, but the pupils are spared, and objective findings are
few.
• Drug-induced fever does not occur.
Causes
• Deteriorating renal function, dehydration, electrolyte disturbances, or drug
interactions usually precipitates chronic toxicity.
• Acute overdose or accidental exposure to plants containing cardiac
glycosides may cause acute toxicity.
• Hypokalemia, hypernatremia, or hypomagnesemia increases the toxic
cardiovascular effects of digoxin because of their depressive effects on the
NA+/K+ ATPase pump.
○ Digoxin toxicity does not cause hypokalemia, but hypokalemia can
worsen digoxin toxicity.
○ Hyperkalemia is the usual electrolyte abnormality precipitated by
digoxin toxicity, primarily in the acute setting. Hyperkalemia may be
associated with acute renal failure that subsequently precipitates
digoxin toxicity. Chronic digoxin toxicity does not usually cause
hyperkalemia.
• Acidosis depresses the Na+/K+ ATPase pump and may cause digoxin toxicity.
• Myocardial ischemia suppresses the Na+/K+ ATPase pump and independently
alters myocardial automaticity. Digoxin toxicity is more likely in this setting.
• Erroneous dosing, especially in infants receiving parenteral digoxin,
unfortunately, is a frequent cause of digoxin toxicity and is usually associated
with high mortality.
• Hypothyroid patients are prone to digoxin toxicity secondary to decreased
renal excretion and a smaller volume of distribution.
• Bioavailability varies depending on the drug formulation.
○ Lanoxin has 25% less bioavailability than Lanoxicaps.
○ Toxicity may occur by increasing bioavailability.
○ Certain antibiotics that suppress intestinal flora may increase
absorption of digoxin.
• Drug interactions are one of the most common causes of digoxin toxicity.
○ Some medications directly increase digoxin plasma levels; other
medications alter renal excretion or induce electrolyte abnormalities.
○ Drugs that have been reported to cause digoxin toxicity include the
following:
 Amiloride - May reduce the inotropic response to digoxin
 Amiodarone - Reduces renal and nonrenal clearance of digoxin
and may have additive effects on the heart rate
 Benzodiazepines (alprazolam, diazepam) - Have been associated
with isolated reports of digoxin toxicity
 Beta-blockers (propranolol, metoprolol, atenolol) - May have
additive effects on the heart rate; carvedilol may increase
digoxin blood levels in addition to potentiating its effects on the
heart rate
 Calcium channel blockers - Diltiazem and verapamil increase
serum digoxin levels; not all calcium channel blockers share this
effect.
 Cyclosporine - May increase digoxin levels, possibly due to
reduced renal excretion
 Erythromycin, clarithromycin, and tetracyclines - May increase
digoxin levels
 Propafenone - Increases digoxin level; effects are variable.
 Quinidine - Increases digoxin level substantially but clinical
effect is variable; related drugs such as hydroxychloroquine or
quinine may also affect levels.
 Propylthiouracil - May increase digoxin levels by reducing
thyroid hormone levels
 Indomethacin
 Spironolactone - May interfere with digoxin assays; may directly
increase digoxin levels; may alter renal excretion.
 Hydrochlorothiazide
 Furosemide and other loop diuretics
 Triamterene
 Amphotericin B - May precipitate hypokalemia and subsequent
digoxin toxicity
 Succinylcholine - Increased risk of dysrhythmias has been
reported.
○ Herb/nutraceutical - Avoid ephedra (risk of cardiac stimulation); avoid
natural licorice (causes sodium and water retention and increases
potassium loss).
• Clinical digoxin toxicity represents a complex interaction between digoxin
and various electrolyte and renal abnormalities. A patient with normal digoxin
levels (0.5-2 ng/mL) but renal insufficiency or severe hypokalemia may have
more serious cardiotoxicity than a patient with high digoxin levels and no
renal or electrolyte disturbances.
MED3 Digitalis toxicity, hyperkalemia, and
acute renal failure. (Medicine).
MED3 DIGITALIS TOXICITY, HYPERKALEMIA Hyperkalemia Definition
The normal concentration of potassium in the serum is in the range of 3.5 to 5.0 mM.
Hyperkalemia refers to serum or plasma levels of potassium ions above 5.0 mM. , AND ACUTE
RENAL FAILURE acute renal failure Acute kidney failure Nephrology An abrupt decline in
renal function, triggered by various processes–eg, sepsis, shock, trauma, kidney stones, drug
toxicity-aspirin, lithium, substances of abuse, toxins, iodinated radiocontrast.
..... Click the link for more information.. S. Hinan Ahmed, MD, James Smith, MD, and Richard
Paul, MD. Medical University of South Carolina “MUSC” redirects here. For Abel Santa María
airport in Santa Clara, Cuba (ICAO code MUSC), see Abel Santa María Airport.
The Medical University of South Carolina

..... Click the link for more information., Charleston.
We present a case of digitalis toxicity with associated hyperkalemia and acute renal failure. A
76-year-old white woman with PMH PMH
abbr.
past medical history significant for A-fib (1997), CHF CHF
In currencies, this is the abbreviation for the Swiss Franc.
Notes:
The currency market, also known as the Foreign Exchange market, is the largest financial market
in the world, with a daily average volume of over US $1 trillion.
..... Click the link for more information., HTN, DM who was brought to the ER by family with
C/O intermittent chest pain, worsening SOB, markedly decreased appetite, weakness, and
confusion about 2 or 3 days. Also C/O visual hallucinations, nausea, and decreased urine output.
Her medications included digoxin digoxin: see digitalis.
..... Click the link for more information. 0.375 mg QD, coumadin 5 mg QD, synthroid 0.1 mg
QD, glipizide 10 mg QD, tiazac 120 mg QD, darvocet N-100/PRN, lasix 20 mg/PRN. On
physical examination VS: T-98, P 53, RR 18, BP 101/64 mm Hg. Patient was in NAD, A & O X
3; Lungs: bibasilar crackles; CVS: irregularly irregular, bradycardia bradycardia: see arrhythmia.
, grade II/VI SBM; ABD: Soft, NT, ND, + BS; BXTRE: 3+ LB edema R>L. Labs on admission
included WBC: 8.5, Hgb: 9.7, Hct: 28.2; Na: 135, K: 6.5; Cl: 101; HCO3: 20; BUN: 67; Cr: 5.5;
Glu: 91; Ca: 8.8, Mg: 2.8, PO4: 5.7 PT: 30.9, INR: 4.27, PTT: 56.8; TSH: 1.63. An ECG in the
revealed bradycardia (HR-40) with junctional rhythm. UA: bacteria-many, WBC-46, RBC-23,
leuk-small, protein-30; Digoxin level: 7.7. Patient has a baseline Sr. Cr. of 0.9. Patient received 5
vials of digibind in the ER, with digoxin level decreasing to <0.3 within 2 hours. Repeat ECG:
Sinus rhythm with first degree AV block, ST segment slanting especially in lateral leads,
shortened Q-T interval. Received IVF, kayexalate, and lasix. INR, K + and Sr. Cr. continued to
decrease. Patient's acute renal failure may have been the cause of digitalis toxicity or vice versa.
Although digitalis toxicity has been shown to cause hyperkalemia, it is not usually known to
cause acute renal failure. The acute renal failure was prerenal as a calculated FeNa was 0.13, but
with patient's history of lasix use it is not as reliable.
COPYRIGHT 2001 Southern Medical Association
No portion of this article can be reproduced without the express written permission from the
copyright holder.
Copyright 2001, Gale Group. All rights reserved. Gale Group is a Thomson Corporation
Company.
Syndrome of inappropriate antidiuretic
hormone hypersecretion
From Wikipedia, the free encyclopedia
Jump to: navigation, search
antidiuretic hormone
Classification and external resources
ICD-10 E22.2
ICD-9 253.6
DiseasesDB 12050
MedlinePlus 003702
eMedicine emerg/784 med/3541 ped/2190
MeSH D007177
The syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH) is a condition

mostly found in patients diagnosed with small cell carcinoma of the lung, pneumonia, brain
tumors, head trauma, strokes, meningitis, encephalitis, more. This is a syndrome characterized by
excessive release of antidiuretic hormone (ADH or vasopressin) from the posterior pituitary
gland or another source. The result is hyponatremia, and sometimes fluid overload. Vasopressin
has other important functions, addressed in the appropriate articles.
Contents
[hide]
• 1 Pathophysiology
• 2 Clinical Findings
• 3 Diagnosis
• 4 Causes
• 5 Management
• 6 Differential
diagnosis
• 7 History
• 8 References
[edit] Pathophysiology
The normal function of ADH on the kidneys is to control the amount of water reabsorbed by
kidney nephrons. ADH acts in the distal portion of the renal tubule (Distal Convoluted Tubule)
as well as on the collecting duct and causes the retention of water, but not solute. Hence, ADH
activity effectively dilutes the blood (decreasing the concentrations of solutes such as sodium).
ADH is secreted to prevent water loss in the kidneys. When water is ingested, it is taken up into
the circulation and results in a dilution of the plasma. This dilution, otherwise described as a
reduction in plasma osmolality, is detected by osmoreceptors in the hypothalamus of the brain
and these then switch off the release of ADH. The decreasing concentration of ADH effectively
inhibits the aquaporins in the collecting ducts and distal convoluted tubules in the nephrons of
the kidney. Hence, less water is reabsorbed, thereby increasing urine output, decreasing urine
osmolality, and normalizing blood osmolality. In SIADH the release of ADH is not inhibited by
a reduction in plasma osmolality when the individual ingests water and the osmolality of the
plasma drops. As the main solute of plasma is sodium, this hypoosmolar state is usually detected
as a low sodium level on laboratory testing. SIADH is therefore primarily a condition that results
in the abnormal handling of water loading and not a problem with excessive solute loss. This is
why it is usually treated with fluid (in particular water) restriction. Diuretics may also be given to
decrease reabsorption of water, but care must be taken not to correct water imbalances too
rapidly.
This causes dilutional hyponatremia and all the consequences associated with that condition:
headache, nausea, vomiting, and confusion may ensue. Severe hyponatremia may cause
convulsions or coma.
The abnormalities underlying type D syndrome of inappropriate antidiuretic hormone
hypersecretion concern individuals where vasopressin release and response are normal but where
abnormal renal expression and translocation of aquaporin 2, or both are found.[1] It has been
suggested that this is due to abnormalities in the secretion of secretin in the brain and that
"Secretin as a neurosecretory hormone from the posterior pituitary, therefore, could be the long-
sought vasopressin independent mechanism to solve the riddle that has puzzled clinicians and
physiologists for decades."[1]
[edit] Clinical Findings

In general, increased ADH causes water retention and extracellular fluid volume expansion
without edema or hypertension, owing to natriuresis (retention of water and passing of sodium in
urine). The water retention and sodium loss both cause hyponatremia, which is a key feature in
SIADH. Hyponatremia and concentrated urine (UOsm >300 mOsm) are seen, as well as no signs
of edema or dehydration. When hyponatremia is severe (sodium <120 mOsm), or acute in onset,
symptoms of cerebral edema become prominent (irritability, confusion, seizures, and coma).
[edit] Diagnosis
Laboratory findings in diagnosis of SIADH include-
• Hyponatremia <135 mEq/L, and POsm <270 mOsm/kg. Hyponatremia is often
treated pharmaceutically through the use of vasopressin receptor
antagonists, which include the approved drug Vasopril and phase III drug
lixivaptan.
Other findings include-
• Urine sodium concentration >20 mEq/L (inappropriate natriuresis). Urine
sodium concentration may be normal reflecting dietary intake.
• Maintained hypervolemia
• Suppression of renin-angiotensin system
• No equal concentration of atrial natriuretic peptide
• Low blood urea nitrogen (BUN)
• Low creatinine
• Low uric acid
• Low albumin
[edit] Causes
Some common causes of SIADH include:
• meningitis (treated with fluid restriction and diuretics)
• Head injury
○ Subarachnoid hemorrhage
• Cancers
○ Lung cancer (especially small cell lung cancer, as well as other small-
cell malignancies of other organs)
• Infections
○ Brain abscess
○ Pneumonia
○ Lung abscess
• Drugs
○ Chlorpropamide
○ Clofibrate
○ Phenothiazine
○ Cyclophosphamide
○ Carbamazepine
○ Selective serotonin reuptake inhibitors (SSRIs, a class of
antidepressants)
○ Methylenedioxymethamphetamine (MDMA, commonly called Ecstasy.
SIADH due to taking ecstasy was cited as a factor in the death of Leah
Betts)
○ oxytocin
○ vincristine
• Hypothyroidism
[edit] Management
Management of SIADH includes:
• Treating underlying causes when possible.
• Fluid restriction to 800-1,000 ml/d should be obtained to increase serum
sodium.
• Intravenous saline - For very symptomatic patients (severe confusion,
convulsions, or coma) hypertonic saline (5%) 200-300 ml IV in 3-4 h should
be given.
• Drugs
○ Demeclocycline can be used in chronic situations when fluid
restrictions are difficult to maintain; demeclocycline is the most potent
inhibitor of AVP action.
○ Conivaptan - an antagonist of both V1A and V2 vasopressin receptors. Its
indications are "treatment of euvolemic hyponatremia (e.g. the
syndrome of inappropriate secretion of antidiuretic hormone, or in the
setting of hypothyroidism, adrenal insufficiency, pulmonary disorders,
etc.) in hospitalized patients."[2]
○ Tolvaptan - an antagonist of the V2 vasopressin receptor. A randomized
controlled trial showed tolvaptan is able to raise serum sodium in
patients with euvolemic or hypervolemic hyponatremia[3]
Care must be taken when correcting hyponatremia. A rapid rise in the sodium level may cause
central pontine myelinolysis.[4]
Avoid correction by more than 12 mEq/L/day
[edit] Differential diagnosis

Cerebral salt wasting syndrome also presents with hyponatremia.
[edit] History
The condition was first described by researchers from Boston, Massachusetts and Bethesda,
Maryland (including Dr Frederic Bartter) in two patients with lung cancer.[5] Criteria were
developed by Schwartz and Bartter in 1967,[6] and have remained essentially unchanged since
then.[7] The condition is occasionally referred to by the names of the authors of the first report -
Schwartz-Bartter syndrome.[8]

Hypo Nat Re Mia

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Hypo Nat Re Mia

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Hyponatremia: epidemiology,

pathophysiology, and therapy.

Therefore: 24 meq/hr x 1000= 47 ml/hr

Hyponatremia with hypovolemia

• Patients with acute hyponatremia (developing over 48 h or less) are subject

• Infants fed tap water in an effort to treat symptoms of gastroenteritis

• Most abnormal findings on physical examination are characteristically

Principal Causes of Hyponatremia

, clofibrate Some Trade

, vincristine Some Trade

, NSAIDs, oxytocin Some

Disorders Adrenal insufficiency as in

Composition of Body Fluids

Disorders Associated with

Principal Causes of Hyponatremia

, clofibrate Some Trade

, vincristine Some Trade

, NSAIDs, oxytocin Some

Disorders Adrenal insufficiency as in

Composition of Body Fluids

Disorders Associated with

• Hypertonic hyponatremia: Patients with hypertonic hyponatremia have

View this Table

Fig. 1: Clinical diagnostic algorithm for

The step-by-step diagnostic evaluation of hyponatremia is shown in Fig. 1.

Urine sodium concentration

View this Table

Urea and uric acid levels

Acid-base status and potassium homeostasis

View this Table

Received 20 November 1969

What to Do - Interpret the Data

Book Source Details

More About Hypoglycemia

More Medical Textbooks Online about Hypoglycemia

Classification and external resources

eMedicine emerg/784 med/3541 ped/2190

The syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH) is a condition

[edit] Clinical Findings

[edit] Differential diagnosis

Digoxin 75% 40 kidneys

Digitoxin >90% 160 liver

Side Effects and Contraindications

The syndrome of digoxin toxicity was originally described in 1785 by Withering.

• Cardiovascular findings on physical examination relate to the severity of CHF,

Bidirectional tachycardia in a patient with digitalis toxicity.

The syndrome of digoxin toxicity was originally described in 1785 by Withering.

• Cardiovascular findings on physical examination relate to the severity of CHF,

Bidirectional tachycardia in a patient with digitalis toxicity.

The Medical University of South Carolina

In currencies, this is the abbreviation for the Swiss Franc.

Classification and external resources

eMedicine emerg/784 med/3541 ped/2190

The syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH) is a condition

[edit] Clinical Findings

[edit] Differential diagnosis

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