The causes of SIADH are diverse and are shown in Table 27-1. Four different
patterns of inappropriate ADH release have been identified.
been found between these patterns and the underlying causes of SIADH, however.
Mechanisms for drug-induced SIADH include ADH-like action on the collecting
tubule, central stimulation of ADH release, and potentiation of the ADH effect.
Small-cell lung carcinoma is the most likely cause of C.C.’s SIADH.
CASE 27-7, QUESTION 2: Why was C.C.’s serum sodium concentration lower after the saline infusion?
Isotonic sodium chloride solution (154 mEq/L each of sodium and chloride ions,
or 308 mOsm/L) initially will increase the plasma sodium concentration because its
osmolality is higher than C.C.’s.
58 C.C., however, has a relatively fixed urine
osmolality of 616 mOsm/kg owing to persistent ADH activity; thus, he must excrete
an osmolar load of 616 mOsm in a volume of 1,000 mL of urine at steady state.
Because a total of 1 L of fluid containing 308 mOsm was administered, all the solutes
were excreted in 500 mL of urine output, and 500 mL of free water was retained to
cause a further dilution of sodium and a reduction in serum sodium concentration.
CASE 27-7, QUESTION 3: Why are C.C.’s neurologic manifestations characteristic of hyponatremia?
As the plasma osmolality declines, the osmotic gradient created across the blood–
brain barrier favors the movement of water into the brain and other cells.
movement from the cerebrospinal fluid into the cerebral interstitium results in
cerebral edema. Brain swelling is limited by the meninges and cranium, however,
giving rise to increased intracranial pressure and neurologic symptoms. The degree
of cerebral overhydration and the rapidity of its development appear to correlate
with the severity of symptoms.
When hyponatremia develops in less than 2 to 3 days or the rate of decline in
serum sodium is greater than 0.5 mEq/L/hour, the situation is regarded as acute.
The patient often becomes symptomatic when serum sodium concentration falls to
125 mEq/L; early complaints include nausea, vomiting, and malaise.
symptoms occur more commonly when the serum sodium falls to less than 120 mEq/L
and the rate of decline is greater than 0.5 mEq/L/hour. The patient may present with
headache, tremors, incoordination, delirium, lethargy, and obtundation. As the serum
sodium drops less than 110 to 115 mEq/L, seizure and coma may result.
occasion, severe brain edema leads to transtentorial herniation and eventually death.
Women, especially those who are premenopausal, apparently are more susceptible to
the development of severe neurologic symptoms and irreversible neurologic damage
In contrast to acute hyponatremia, patients who are chronically hyponatremic are
If present, symptoms are usually vague and nonspecific and
tend to occur at lower serum sodium concentrations than those associated with
symptomatic acute hyponatremia.
37,59,61 The patient may experience anorexia, nausea,
vomiting, muscle weakness, and cramps. Irritability, hostility, confusion, and
personality changes may also be seen. At extremely low sodium levels, stupor and,
rarely, seizures have been reported.
Brain Adaptation to Hyponatremia
The difference in symptoms between acute and chronic hyponatremia is related to
cerebral adaptation to hypotonicity. Two adaptive mechanisms are important in
37,40,64,65 First, cerebral overhydration increases the
hydrostatic pressure in the cerebral interstitium, which results in the movement of
fluid from the cerebral interstitial space to the cerebrospinal fluid. Second, the
extrusion of intracellular solutes reduces cellular osmolality, which in turn enhances
water movement out of the cells. Sodium and potassium ions are the initial solutes
extruded, followed over a period of hours to days by osmolytes such as inositol,
glutamine, glutamate, and taurine.
64 Therefore, when the serum sodium concentration
falls faster than the onset of brain osmotic adaptation processes, serious and
permanent neurologic damage can occur.
37,40,64,65 On the other hand, when
hyponatremia develops over the course of 2 to 3 days, symptoms are not usually seen
unless the serum sodium concentration is reduced markedly.
It is often difficult to determine the acuity and chronicity of hyponatremia. Unless
an obvious cause for acute hyponatremia is found, assume that the condition is
37,59,60,65 A rapid decline in serum sodium concentration usually suggests that
hypotonic fluid was administered to a patient with a condition that overwhelms or
impairs renal water excretion. These conditions include psychogenic polydipsia
administration of thiazide diuretics,
41,42 parenteral cyclophosphamide,
and arginine vasopressin or its analogs.
57 C.C.’s symptoms appear to have developed
over the course of 7 days and are consistent with chronic hyponatremia.
Rate of Correction of Hyponatremia
CASE 27-7, QUESTION 4: How should C.C.’s hyponatremia be managed?
C.C.’s water excess should be calculated to estimate the amount of water that
should be removed to achieve the desired sodium concentration.
The treatment of hyponatremia has been controversial. Severe hyponatremia is
associated with high rates of morbidity and mortality, but its treatment can also result
in morbidity. The rate of correction has been implicated as the main cause of
It takes time for the brain to lose osmolytes to reduce cerebral swelling during
hyponatremia; conversely, the rate of reaccumulation of these osmolytes must keep
pace with the rise in serum sodium concentration to avoid brain dehydration and
damage. Indeed, rapid correction of hyponatremia can cause a constellation of
neurologic findings known as osmotic demyelination syndrome (ODS).
manifestations usually are delayed and occur one to several days after the treatment
has been started. Neurologic findings include transient behavioral changes, seizures,
akinetic mutism in mild cases, and features of a pontine disorder in severe cases
(pseudobulbar palsy, quadriparesis, and coma). In some patients, the damage is
irreversible, and central pontine myelinolysis can be documented in fatal cases.
Patients at greatest risk for osmotic demyelination are those with severe
hyponatremia lasting greater than 2 days and those in whom the rate of correction of
hyponatremia is greater than 12 mEq/L in any 24-hour period.
which was found in about 90% of patients with ODS associated with rapid
hyponatremia correction, has been suspected as a predisposing factor in the
72 Because the etiology of this complication is unclear, it may
be beneficial to correct the hypokalemia before correcting the severe hyponatremia.
Retrospective reviews suggest that acute hyponatremia can be treated safely at a
rate of 1 mEq/L/hour initially, until the serum sodium concentration reaches 120
mEq/L. Thereafter, the rate of correction should be reduced to less than or equal to
0.5 mEq/L/hour, such that an increment in sodium concentration does not exceed 12
59,73 Slow correction is indicated for severe chronic
hyponatremia. No neurologic complications were seen in patients with severe
hyponatremia when the average rate of correction to serum sodium was less than 0.55
mEq/L/hour or when the increase in serum sodium was less than 12 mEq/L in 24
hours or less than 18 mEq/L in 48 hours.
In C.C., the serum sodium concentration should be raised to approximately 120
mEq/L at a correction rate of approximately 0.5 mEq/L/hour, using hypertonic saline
and furosemide. Serum sodium concentrations should be monitored closely because
the equation for calculating water excess does not take into account insensible loss,
which can increase the rate of sodium correction.
The use of normal saline is not useful in C.C. because he excretes salt normally
(urine sodium, 60 mEq/L). C.C.’s sodium deficit is as follows:
Because 1 L of 3% sodium chloride solution contains 513 mEq of sodium,
approximately 700 mL of 3% saline solution, which contains 360 mEq of sodium,
will be required to correct the sodium deficit. The recommended serum sodium
concentration correction rate is 0.5 mEq/L/hour; therefore, a minimum of 20 hours
will be needed to raise the serum sodium concentration by 10 mEq/L (from 110 to
120 mEq/L). The amount of sodium replacement to safely increase the serum sodium
concentration can be determined by the product of the rate of replacement (0.5
mEq/L/hour) and TBW (36 L, Eq. 27-10)—that is, 18 mEq/hour. The maximal rate of
infusion of 3% saline, which contains 0.513 mEq/mL of sodium, is therefore 35
mL/hour (18 mEq/hour)/(0.513 mEq/mL). A rate of 30 mL/hour, therefore, is
appropriate to safely replace C.C.’s sodium deficit.
Because calculations for water excess and sodium deficits are only
approximations, the patient’s serum osmolality, serum sodium, and clinical response
must be monitored closely. Urinary losses can be replaced with 3% sodium chloride
solution and appropriate amounts of potassium.
Chronic Management of the Syndrome of Inappropriate
Antidiuretic Hormone Secretion
CASE 27-7, QUESTION 5: How should C.C.’s SIADH be managed chronically?
SIADH is usually transient if the underlying cause can be removed. Chronic
SIADH can occur, however, as illustrated by C.C. Water restriction sufficient to
create a negative water balance is the primary therapy and should be attempted
In general, all fluids, not just water, should be included in the restriction.
Salt intake, however, should not be reduced or solute depletion can occur. The extent
of fluid restriction depends on urine output, the amount of insensible water loss, and
urine osmolality. For a given amount of solute excretion, patients with a high urine
osmolality require a smaller volume of urine (i.e., more water retained) than those
with a lower urine osmolality (i.e., less water retained). Hence, more stringent water
restriction is required in patients with a high urine osmolality. Commonly, several
days of restriction are needed before a significant increase in plasma osmolality is
When fluid restriction fails to reverse the hypo-osmolar state or when the patient is
unwilling or unable to comply with the severe fluid restriction, drugs that antagonize
the effect of ADH can be used.
37,40 These include loop diuretics,
77 Furosemide (20–40 mg/day) reduces urine
osmolality by blocking the concentrating ability of the kidney.
lithium directly impair the response to ADH at the collecting tubule, inducing
nephrogenic diabetes insipidus.
76,77 Demeclocycline (300–600 mg twice daily) is
usually better tolerated than lithium. Its effect on water excretion is delayed for a few
days, and it dissipates over a similar period of time after the drug is stopped.
Nephrotoxicity has been reported with its use in patients with cirrhosis.
data suggest that phenytoin may inhibit ADH secretion, but its effectiveness is
79 Urea can correct hypo-osmolality by increasing solute-free water
excretion and reducing urinary sodium excretion.
It has been used effectively, at 30
to 60 g/day, both short term and long term, to reduce the need for fluid restriction.
An IV formulation of urea is available commercially; however, for oral
administration, 30 g of urea crystals can be dissolved in 10 mL of aluminum–
magnesium antacid and 100 mL of water. Orange juice or other strongly flavored
liquids can be used to improve palatability.
VASOPRESSIN RECEPTOR ANTAGONISTS
Nonpeptide vasopressin receptor antagonists (VRAs), also known as the “vaptans”
or “aquaretic agents,” constitute a class of agents used for the treatment of
hyponatremia. Arginine vasopressin (AVP), a neuropeptide hormone, plays an
important role in maintaining serum osmolality, as well as circulatory and sodium
82,83 AVP exerts its physiologic effects by acting on V1A, V1B, and V2
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