400 dysarthria, and dysphagia. The diagnosis is usually sus- limited.

The latter occurs in infants, people with physical

pected clinically and can be confirmed by appropriate disabilities, and patients with impaired mental status; in
neuroimaging studies. There is no specific treatment for the postoperative state; and in intubated patients in the
SECTION V

the disorder, which is associated with significant mor- intensive care unit. On rare occasions, impaired thirst
bidity and mortality. Patients with chronic hypona- may be caused by primary hypodipsia.This usually occurs
tremia are most susceptible to the development of ODS as a result of damage to the hypothalamic osmoreceptors
because their brain cell volume has returned to near that control thirst and tends to be associated with abnor-
normal as a result of the osmotic adaptive mechanisms mal osmotic regulation of AVP secretion. Primary
described earlier. Therefore, administration of hyper- hypodipsia may be caused by a variety of pathologic
changes, including granulomatous disease, vascular occlu-
Disorders Complicating Critical Illnesses and Their Management

tonic saline to these individuals can cause sudden

osmotic shrinkage of brain cells. In addition to rapid or sion, and tumors. A subset of patients with hypodipsic
overcorrection of hyponatremia, risk factors for ODS hypernatremia, referred to as essential hypernatremia, do
include prior cerebral anoxic injury; hypokalemia; and not respond to forced water intake. This appears to be
malnutrition, especially secondary to alcoholism. Water because of a specific osmoreceptor defect resulting in
restriction in primary polydipsia and IV saline therapy in nonosmotic regulation of AVP release. Thus, the hemo-
ECF volume–contracted patients may also lead to overly dynamic effects of water loading lead to AVP suppression
rapid correction of hyponatremia as a result of AVP and excretion of dilute urine.
suppression and a brisk water diuresis. This can be pre- The source of free water loss is either renal or
vented by administration of water or use of an AVP ana- extrarenal. Nonrenal loss of water may be caused by
logue to slow down the rate of free-water excretion. evaporation from the skin and respiratory tract (insensi-
ble losses) or loss from the gastrointestinal tract. Insensible
losses are increased with fever, exercise, heat exposure,
and severe burns and in mechanically ventilated patients.
HYPERNATREMIA Furthermore, the Na+ concentration of sweat decreases
with profuse perspiration, thereby increasing solute-free
Etiology
water loss. Diarrhea is the most common gastrointestinal
Hypernatremia is defined as a plasma Na+ concentration cause of hypernatremia. Specifically, osmotic diarrheas
>145 mmol/L. Because Na+ and its accompanying anions (induced by lactulose, sorbitol, or malabsorption of car-
are the major effective ECF osmoles, hypernatremia is a bohydrate) and viral gastroenteritides result in water loss
state of hyperosmolality. As a result of the fixed number exceeding that of Na+ and K+. In contrast, secretory
of ICF particles, maintenance of osmotic equilibrium in diarrheas (e.g., cholera, carcinoid, VIPoma) have a fecal
hypernatremia results in ICF volume contraction. Hyper- osmolality (twice the sum of the concentrations of Na+
natremia may be caused by primary Na+ gain or water and K+) similar to that of plasma and present with ECF
deficit. The two components of an appropriate response volume contraction and a normal plasma Na+ concen-
to hypernatremia are increased water intake stimulated by tration or hyponatremia.
thirst and the excretion of the minimum volume of max- Renal water loss is the most common cause of hyper-
imally concentrated urine reflecting AVP secretion in natremia and is caused by drug-induced or osmotic
response to an osmotic stimulus. diuresis or diabetes insipidus. Loop diuretics interfere
In practice, the majority of cases of hypernatremia with the countercurrent mechanism and produce an
result from the loss of water. Because water is distributed isoosmotic solute diuresis. This results in a decreased
between the ICF and the ECF in a 2:1 ratio, a given medullary interstitial tonicity and impaired renal con-
amount of solute-free water loss will result in a twofold centrating ability. The presence of non-reabsorbed
greater reduction in the ICF compartment than the ECF organic solutes in the tubule lumen impairs the osmotic
compartment. For example, consider three scenarios: the reabsorption of water. This leads to water loss in excess
loss of 1 L of water, isotonic NaCl, or half-isotonic NaCl. of Na+ and K+, known as an osmotic diuresis. The most
If 1 L of water is lost, the ICF volume will decrease by frequent cause of osmotic diuresis is hyperglycemia and
667 mL, but the ECF volume will decrease by only glucosuria in a patient with poorly controlled diabetes
333 mL. Because Na+ is largely restricted to the ECF, this mellitus. IV administration of mannitol and increased
compartment will decrease by 1 L if the fluid lost is isoos- endogenous production of urea (high-protein diet) can
motic. One liter of half-isotonic NaCl is equivalent to also result in an osmotic diuresis.
500 mL of water (one-third ECF, two-thirds ICF) plus Hypernatremia secondary to nonosmotic urinary
500 mL of isotonic saline (all ECF).Therefore, the loss of water loss is usually caused by (1) CDI characterized
1 L of half-isotonic saline decreases the ECF and ICF by impaired AVP secretion or (2) NDI resulting from
volumes by 667 mL and 333 mL, respectively. end-organ (renal) resistance to the actions of AVP.
The degree of hyperosmolality is typically mild unless The most common cause of CDI is destruction of the
the thirst mechanism is abnormal or access to water is neurohypophysis. This may occur as a result of trauma,
neurosurgery, granulomatous disease, neoplasms, vascular CLINICAL APPROACH TO HYPERNATREMIA 401
accidents, or infection. In many cases, CDI is idiopathic ECF Volume
and may occasionally be hereditary.The familial form of

CHAPTER 39
the disease is inherited in an autosomal dominant fash-
ion and has been attributed to mutations in the propres- Increased Not increased
sophysin (AVP precursor) gene. NDI may be either
inherited or acquired. Congenital NDI is an X-linked Administration of Minimum volume of
hypertonic NaCl maximally concentrated urine
recessive trait caused by mutations in the V2 receptor or NaHCO3
gene. Mutations in the autosomal aquaporin-2 gene may No Yes
also result in NDI. The aquaporin-2 gene encodes the

Fluid and Electrolyte Disturbances

water channel protein whose membrane insertion is Urine osmole Insensible water loss
excretion rate Gastrointestinal water loss
stimulated by AVP. The causes of sporadic NDI are > 750 mosmol/d Remote renal water loss
numerous and include drugs (especially lithium), hyper-
calcemia, hypokalemia, and conditions that impair No Yes

medullary hypertonicity (e.g., papillary necrosis or

Renal response Diuretic
osmotic diuresis). In the second or third trimester, preg- to desmopressin Osmotic diureses
nant women may develop NDI as a result of excessive
elaboration of vasopressinase by the placenta.
Finally, although infrequent, a primary Na+ gain may Urine osmolality increased Urine osmolality unchanged
cause hypernatremia. For example, inadvertent adminis-
tration of hypertonic NaCl or NaHCO3 or replacing Central diabetes insipidus Nephrogenic diabetes insipidus
sugar with salt in infant formula can produce this com-
plication. FIGURE 39-2
Algorithm depicting the clinical approach to hyperna-
tremia. ECF, extracellular fluid.
Clinical Features
As a consequence of hypertonicity, water shifts out of and the physical examination is incomplete without a
cells, leading to a contracted ICF volume. A decreased thorough mental status and neurologic assessment. Mea-
brain cell volume is associated with an increased risk of surement of urine volume and osmolality are essential in
subarachnoid or intracerebral hemorrhage. Hence, the the evaluation of hyperosmolality. The appropriate renal
major symptoms of hypernatremia are neurologic and response to hypernatremia is the excretion of the mini-
include altered mental status, weakness, neuromuscular mum volume (500 mL/d) of maximally concentrated
irritability, focal neurologic deficits, and occasionally urine (urine osmolality >800 mosmol/kg).These findings
coma or seizures. Patients may also complain of polyuria suggest extrarenal or remote renal water loss or adminis-
or thirst. For unknown reasons, patients with polydipsia tration of hypertonic Na+ salt solutions.The presence of a
from CDI tend to prefer ice-cold water. The signs and primary Na+ excess can be confirmed by the presence of
symptoms of volume depletion are often present in ECF volume expansion and natriuresis (urine Na+ con-
patients with a history of excessive sweating, diarrhea, or centration usually >100 mmol/L).
osmotic diuresis. As with hyponatremia, the severity of Many causes of hypernatremia are associated with
the clinical manifestations is related to the acuity and polyuria and a submaximal urine osmolality.The product
magnitude of the increase in plasma Na+ concentration. of the urine volume and osmolality (i.e., the solute excre-
Chronic hypernatremia is generally less symptomatic as tion rate) is helpful in determining the basis of the
a result of adaptive mechanisms designed to defend cell polyuria (see earlier).To maintain a steady state, total solute
volume. Brain cells initially take up Na+ and K+ salts, excretion must equal solute production. As stated above,
later followed by accumulation of organic osmolytes individuals eating a normal diet generate ∼600 mosmol/d.
such as inositol.This serves to restore the brain ICF vol- Therefore, daily solute excretion >750 mosmol defines an
ume toward normal. osmotic diuresis.This can be confirmed by measuring the
urine glucose and urea. In general, patients with both
CDI and NDI present with polyuria and hypotonic urine
Diagnosis
(urine osmolality <250 mosmol/kg). The degree of
(Fig. 39-2) A complete history and physical examination hypernatremia is usually mild unless there is an associated
often provide clues as to the underlying cause of hyperna- thirst abnormality. The clinical history, physical examina-
tremia. Relevant symptoms and signs include the absence tion, and pertinent laboratory data can often rule out
or presence of thirst, diaphoresis, diarrhea, polyuria, and causes of acquired NDI. CDI and NDI can generally be
the features of ECF volume contraction. The history distinguished by administering the AVP analogue desmo-
should include a list of current and recent medications, pressin (10 µg intranasally) after careful water restriction.
 402 The urine osmolality should increase by at least 50% in NSAIDs potentiate AVP action and thereby increase
patients with CDI and will not change in those with urine osmolality and decrease urine volume. Amiloride
NDI. Unfortunately, the diagnosis may sometimes be dif- may be useful in patients with NDI who need to take
SECTION V

ficult because of partial defects in AVP secretion and lithium. The nephrotoxicity of lithium requires the drug
action. to be taken up into collecting duct cells via the
amiloride-sensitive Na+ channel.

Treatment:
HYPERNATREMIA
POTASSIUM
Disorders Complicating Critical Illnesses and Their Management

The therapeutic goals are to stop ongoing water loss by

treating the underlying cause and to correct the water Potassium Balance
deficit. The ECF volume should be restored in hypov-
Potassium is the major intracellular cation. The normal
olemic patients. The quantity of water required to cor-
plasma K+ concentration is 3.5–5.0 mmol/L; the con-
rect the deficit can be calculated from the following
centration inside cells is about 150 mmol/L. Therefore,
equation:
the amount of K+ in the ECF (30–70 mmol) constitutes
Plasma Na+ concentration − 140
Water deficit =
140
× Total body water <2% of the total body K+ content (2500–4500 mmol).
The ratio of ICF to ECF K+ concentration (normally
In hypernatremia caused by water loss, total body 38:1) is the principal result of the resting membrane
water is approximately 50% and 40% of lean body potential and is crucial for normal neuromuscular func-
weight in men and women, respectively. For example, tion. The basolateral Na+, K+-ATPase pump actively
a 50-kg woman with a plasma Na+ concentration of transports K+ in and Na+ out of the cell in a 2:3 ratio,
160 mmol/L has an estimated free-water deficit of 2.9 L and the passive outward diffusion of K+ is quantitatively
{[(160 − 140) ÷ 140] × (0.4 × 50)}. As in hyponatremia, the most important factor that generates the resting
rapid correction of hypernatremia is potentially danger- membrane potential. The activity of the electrogenic
ous. In this case, a sudden decrease in osmolality could Na+, K+-ATPase pump may be stimulated as a result of
potentially cause a rapid shift of water into cells that an increased intracellular Na+ concentration and inhib-
have undergone osmotic adaptation. This would result ited in the setting of digoxin toxicity or chronic illness
in swollen brain cells and increase the risk of seizures or such as heart failure or renal failure.
permanent neurologic damage. Therefore, the water The K+ intake of individuals on an average Western
deficit should be corrected slowly over at least 48–72 h. diet is 40–120 mmol/d, or approximately 1 mmol/kg per
When calculating the rate of water replacement, ongo- day, 90% of which is absorbed by the gastrointestinal tract.
ing losses should be taken into account, and the plasma Maintenance of the steady state necessitates matching K+
Na+ concentration should be lowered by 0.5 mmol/L per h ingestion with excretion. Initially, extrarenal adaptive
and by no more than 12 mmol/L over the first 24 h. mechanisms, followed later by urinary excretion, prevent
The safest route of administration of water is by a doubling of the plasma K+ concentration that would
mouth or via a nasogastric tube (or other feeding tube). occur if the dietary K+ load remained in the ECF com-
Alternatively, 5% dextrose in water or half-isotonic partment. Immediately after a meal, most of the absorbed
saline can be given IV. The appropriate treatment of CDI K+ enters cells as a result of the initial elevation in the
consists of administering desmopressin intranasally. plasma K+ concentration and facilitated by insulin release
Other options for decreasing urine output include a and basal catecholamine levels. Eventually, however, the
low-salt diet in combination with low-dose thiazide excess K+ is excreted in the urine (see below).The regula-
diuretic therapy. In some patients with partial CDI, drugs tion of gastrointestinal K+ handling is not well under-
that either stimulate AVP secretion or enhance its action stood. The amount of K+ lost in the stool can increase
on the kidney have been useful. These include chlor- from 10 to 50 or 60% (of dietary intake) in people with
propamide, clofibrate, carbamazepine, and nonsteroidal chronic renal insufficiency. In addition, colonic secretion
antiinflammatory drugs (NSAIDs). The concentrating of K+ is stimulated in patients with large volumes of diar-
defect in NDI may be reversible by treating the underly- rhea, resulting in potentially severe K+ depletion.
ing disorder or eliminating the offending drug. Sympto-
matic polyuria caused by NDI can be treated with a low-
Potassium Excretion
Na + diet and thiazide diuretics, as described above.
This induces mild volume depletion, which leads to Renal excretion is the major route of elimination of
enhanced proximal reabsorption of salt and water and dietary and other sources of excess K+.The filtered load
decreased delivery to the site of action of AVP, the col- of K+ (GFR × plasma K+ concentration = 180 L/d ×
lecting duct. By impairing renal prostaglandin synthesis, 4 mmol/L = 720 mmol/d) is 10- to 20-fold greater than the
ECF K+ content. About 90% of filtered K+ is reabsorbed