Dysnatremia in the ICU - Philippe Le Fevre

Dysnatremia in the ICU
Milap Pokaharela and Clay A. Blocka,b
aSection of Nephrology and Hypertension andbDartmouth Medical School, Dartmouth HitchcockMedical Center, Lebanon, New Hampshire, USA

Correspondence to Clay A. Block, MD, 1 MedicalCenter Dr., Lebanon, NH 03576, USATel: +1 603 653 3830; fax: +1 603 653 3991;e-mail: [email protected]

Current Opinion in Critical Care 2011,17:581–593

Purpose of review

Dysnatremias, disorders of sodium concentration, are exceedingly common in critically

ill patients and confer increased risk for adverse outcomes including mortality. The

physiology that underpins the diagnosis and management of these disorders is complex.

This review seeks to discuss current literature regarding the pathophysiology,

diagnosis, epidemiology, and management of these disorders.

Recent findings

The role of arginine vasopressin in the maintenance of normal and pathologic plasma

osmolality increasingly is refined, improving our ability to diagnose and understand

dysnatremia. Identified recent epidemiologic studies highlight the frequent hospital

acquisition or exacerbation of dysnatremia, confirm the recognized adverse

consequences and explore the potential causality. Despite the complex nature of these

disorders, simple consensus treatment strategies have emerged.

Summary

Dysnatremia remains a common disorder across the spectrum of critically ill patients. It

is frequently hospital acquired. Simplified treatment regimens are proposed and the

potential for prevention or earlier recognition and intervention is emphasized. Future

directions of interest include further exploration of how dysnatremia contributes to

adverse outcomes and new treatment strategies.

Keywords

dysnatremia, hypernatremia, hyponatremia, vasopressin

Curr Opin Crit Care 17:581–593� 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins1070-5295

Introduction

Disorders of sodium concentration, dysnatremias, are

among the most commonly encountered electrolyte

abnormalities in the ICU. They are disorders of relative

water excess or deficiency, resulting in alteration in effec-

tive plasma osmolality (Posm) (tonicity), leading to trans-

cellular shift of water, thereby altering cell volume. This

is in contradistinction to disorders of sodium excess or

deficiency, which produce changes in the extracellular

fluid (ECF) volume, namely edema or hypovolemia, res-

pectively. Hyponatremia is commonly defined as a plasma

sodium concentration (PNa) less than 136 mmol/l; hyper-

natremia, commonly as PNa greater than 145 mmol/l.

Both frequently develop or are exacerbated during

hospitalization and are associated with increased length

of stay (LOS) and mortality. Clinical manifestations may

range from absent to life threatening. Treatment may be

life saving but carries substantial risk of harm. Appropriate

management requires an understanding of underlying

pathophysiology and treatment principles.

PhysiologyUnderstanding dysnatremia starts with an appreciation

that water moves freely between the intacellular fluid

Copyright © Lippincott Williams & Wilkins. Unaut

1070-5295 � 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins

(ICF) compartment and the ECF compartment to main-

tain osmotic equilibrium. As the bulk of the intracellular

solute is accounted for by exchangeable potassium (Ke)

and extracellular solute by exchangeable sodium (Nae)

and their companion anions, the relationship between

these quantities and total body water (TBW) can be

described as [1]:

Posm ¼ Iosm � 2� Nae þ 2� Ke

TBW

Posm will fall as a result of potassium depletion, sodium

depletion, or an increase in TBW. Likewise, Posm will

increase if potassium or sodium is added or if TBW is

reduced. Changes in Posm are usually identified by

changes in PNa. TBW is estimated as a fraction of body

weight: 0.6 in children and healthy, nonelderly men, 0.5

in women and elderly men, and 0.45 in elderly women

[2].

Posm homeostasis, or osmoregulation, requires the integ-

ration of water intake and excretion to be precisely

balanced with salt intake and excretion. Challenges to

osmoregulation occur on a regular basis due to ingestion

of water, salt, exercise, and other routine activities. For

example, an elevation in Posm of approximately

horized reproduction of this article is prohibited.

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582 Renal system

Key points

� Even mild degrees of hyponatremia and hyperna-

tremia confer markedly increased risk for mortality

and increased length of stay.

� Hospital acquired or exacerbated dysnatremia con-

fers a worse prognosis than community acquired

dysnatremia.

� Severe hyponatremia, paradoxically, may have a

better prognosis than moderately severe hypona-

tremia, perhaps because it is more likely to occur

as a primary disorder without multiple comorbid

conditions.

� Acute, symptomatic hyponatremia should be trea-

ted with 3% saline given as 100 ml bolus(es) to

raise the plasma sodium concentration rapidly by

4–6 mmol/l.

� Correction of hyponatremia should be no greater

than 10 mmol/l in the first 24 h and no greater than

18 mmol/l in the first 48 h; correction of hyperna-

tremia should be no greater than 0.5 mmol/l per

hour and bolus therapy with isotonic saline should

be avoided unless there is circulatory collapse.

10 mOsm/kg may occur after 40 min of strenuous exercise

in a hot environment; ingestion of two large glasses of

water (850 ml) can lower Posm by 6 mOsm/kg in 30 min

[3]. Changes in Posm of as little as 1% result in activation

of homeostatic processes that are mediated via neuro-

endocrine pathways orchestrated in the hypothalamus.

Specialized neurons in the organum vasculosum laminae

terminalis (OVLT), supraoptic (SON), and paraventric-

ular nuclei of the hypothalamus sense changes in Posm,

possibly through mechanically sensitive cation channels.

A rise in Posm results in the activation of thirst and the

secretion of antidiuretic hormone [also known as arginine

vasopressin (AVP)]. AVP is synthesized by specialized

neurons in the SON and paraventricular nucleus that give

rise to long axons terminating in the posterior pituitary,

wherein AVP is stored. A fall in the Posm results in

suppression of thirst and suppression of AVP release.

Under normal conditions, AVP is maximally suppressed

at PNa of approximately 135 mmol/l. The hypothalamus

also participates in salt intake (craving) and renal

excretion (via natriuretic peptides). These homeostatic

mechanisms tend to maintain Posm within 1–3% of the

set point, a range compatible with health [4].

AVP exerts its effect by binding to a specific receptor

(V2R) on the basolateral membrane of principal cells of

the collecting tubule of the distal nephron, activating

adenyl cyclase production of cyclic adenosine mono-

phosphate, leading to activation of protein kinase A

(PKA). PKA phosphorylates water channels, aquaporin

2 (AQP2), which undergo exocytotic insertion into

the apical membrane, increasing water permeability.

Ultimately, reabsorbed water is returned to the systemic

circulation via the peritubular capillaries. In the absence

of AVP, AQP2 is internalized and distal nephron water

permeability is greatly reduced. The presence or absence

of AVP can be inferred by measuring the urine osmolality

(Uosm). A Uosm greater than maximally dilute (50–

100 mOsm/l) implies AVP activity. Other actions of

AVP include vasoconstriction, platelet aggregation, and

gluconeogenesis mediated by V1A receptors present on

smooth muscle cells, platelets, and liver. AVP activation

of V1B receptors on the anterior pituitary promotes

release of adrenocorticotropic hormone. AVP secretion

is also stimulated by a reduction in effective arteriolar

blood volume (EABV) mediated by baroreceptors dis-

tributed throughout the circulation. This effect overrides

the expected suppression of AVP and accounts for the

water retention observed in cases of hypovolemia and the

edematous disorders [congestive heart failure (CHF),

cirrhosis, and nephrosis] [1,5��].

The brain responds to hypotonic stress in two ways. First,

increased interstitial pressure caused by cerebral edema

results in movement of interstitial fluid into the cere-

brospinal fluid and ultimately into the circulation.

opyright © Lippincott Williams & Wilkins. Unauth

Second, brain cells extrude intracellular solutes, thus

limiting ingress of water and cerebral edema. This pro-

cess begins with extrusion of potassium and sodium

within several hours and continues with the extrusion

of organic osmolytes over several days. It is this adaptive

response that predisposes to osmotic demyelination

during correction of hyponatremia (discussed in detail

below). In the setting of hypernatremia, brain cells will

accumulate potassium and organic osmolytes, thus blunt-

ing cell shrinkage but predisposing the brain to edema if

hypernatremia is rapidly corrected [6–8].

Classification of hyponatremiaThe first step in classification of hyponatremia is to

confirm the presence or absence of a hypoosmolar/

hypotonic condition. Nonhypotonic hyponatremia has a

limited differential diagnosis that is discussed below.

Low Posm usually identifies hypotonic hyponatremia

although hypotonic hyponatremia can also be seen in

the setting of retention of an ineffective osmole (such as

urea or ethanol) that is able to permeate the cell mem-

brane. In these cases, the Posm may be normal or high,

but the plasma tonicity will be low and the clinical

consequences of hypotonic hyponatremia can occur,

including cerebral edema. Hypotonic hyponatremia

due to impaired water excretion can be distinguished

from excess water intake or inadequate solute intake by

determining the Uosm. Low Uosm identifies primary

polydipsia, beer potomania, or tea diet and toast diet.

Uosm greater than 100 mOsm/kg implies AVP activity.

Assessment of the volume status by clinical exam and

orized reproduction of this article is prohibited.

Dysnatremia in the ICU Pokaharel and Block 583

measurement of UNa can then establish if there is

reduction in EABV producing a physiologic AVP stimu-

lation. If euvolemia is identified, AVP activity is most

commonly due to the syndrome of inappropriate anti-

diuretic hormone (SIADH). Diagnostic criteria for

SIADH require hypoosmolality, Uosm greater than

100 mOsm/l, absence of diuretics, absence of edema or

clinical signs of volume depletion, UNa greater than

30 mmol/l, absence of renal impairment, and a clinical

response to water restriction with correction of hypona-

tremia and a reduction in UNa. SIADH has myriad causes

including malignant tumors (especially small cell lung

cancer), pulmonary disorders (infections, airways obstruc-

tion, respiratory failure), central nervous system (CNS)

conditions (masses, hemorrhage, infection, multiple

sclerosis, Guillain–Barre syndrome, etc.), drugs that

stimulate AVP secretion or enhance activity (serotonin

reuptake inhibitors, tricyclics, chlorpropramide, ifosfa-

mide, nonsteroidal anti-inflammatory drugs, cyclophos-

phamide, narcotics, psychotropics, etc.), drugs that have

AVP activity (vasopressin, desmopressin, and oxytocin),

and miscellaneous conditions including postoperative

state, stress, pain, and nausea. Adrenal insufficiency

and hypothyroidism are associated with euvolemic hypo-

natremia and measurement of these hormones is indi-

cated [5��,9��,10].

Algorithms have been developed to facilitate correct

classification (Fig. 1) [9��]. Application of such algorithms

improves the accuracy of classification compared with

clinical judgment by experienced physicians but may still

fail to arrive at the correct diagnosis as determined by

retrospective review by an expert. Confusion can occur

due to overlap in the laboratory findings in conditions of

diuretic use, renal salt wasting, and cerebral salt wasting

(CSW). In these conditions, clinical exam for hypovole-

mia is imprecise; UNa will be relatively high and can

result in misclassification as SIADH. As water excretion

may be subtly impaired in patients with primary poly-

dipsia, Uosm may not be less than 100 mOsm/kg, leading

again to misclassification as SIADH.

Renal salt wasting as a cause of hypovolemia is particu-

larly problematic as these patients have natriuresis by

definition. Renal salt wasting can occur in adrenal insuf-

ficiency that may be congenital or acquired. Renal tubular

injury by cisplatin can cause salt wasting within days to

weeks of exposure. As cisplatin is used to treat solid

tumors that can also cause SIADH, it is crucial to deter-

mine the presence or absence of volume depletion.

Autonomic dysfunction, which can accompany small cell

lung cancer, can further confuse the situation. CSW can

occur in the setting of neurosurgical conditions, such as

subarachnoid hemorrhage (SAH), that are also known to

be associated with SIADH. The diagnosis of CSW relies

on the simultaneous demonstration of unequivocal


volume depletion and elevated UNa in an appropriate

clinical setting. Unfortunately, even direct hemodynamic

assessments sometimes fail to yield unequivocal results.

Such patients should be managed with hypertonic saline

or saline as necessary to ensure maintenance of normo-

natremia and adequate intravascular volume.

Saline infusion has been labeled the ‘gold standard’, as

volume expansion in a sodium-depleted patient should

suppress the hemodynamic stimulus for AVP secretion

and allow excretion of a dilute urine and correction of

hyponatremia. However, in clinical practice, this is not

always practical or effective, as up to 30% of patients

treated with 2 l of isotonic saline failed to elevate PNa by

greater than 5 mmol/l or lower their Uosm. Likewise,

some patients with SIADH will show an improved PNa

with isontonic saline infusion if their Uosm is less than

300 mOsm/l. The fractional excretions of Na, urea, and

uric acid (Table 1) [10,11] have all been utilized to add

diagnostic accuracy. A fractional excretion of sodium

(FENa) greater than 0.15% or a fractional excretion of

urea (FEUrea) favors a diagnosis of SIADH. Plasma uric

acid level of less than 4 mg/dl and FEUric acid greater

than 16% also favor a diagnosis of SIADH [12].

Nonhypotonic hyponatremiaNonhypotonic hyponatremias include those that are

hypertonic due to the retention of a nonpermeable solute

resulting in translocation of water from the intracellular

to the extracellular compartment, thereby lowering the

PNa. The most common cause of this phenomenon is

hyperglycemia due to diabetes mellitus. An analysis

published in 1973 by Katz [13] predicted that the serum

sodium concentration would fall by 1.6 mmol/l for every

100 mg/dl increase in the glucose concentration above

normal. This prediction rule appears to be valid in the

setting of renal failure when there is no osmotic diuresis

to complicate the situation. However, when renal func-

tion is intact, some sodium loss occurs secondary to the

osmotic diuresis provoked by glucosuria leading to a

greater than expected fall in serum sodium concentration.

An average fall in PNa of 2.5 mmol/l was seen in experi-

mentally induced hyperglycemia in healthy patients and

a nonlinear change in PNa was observed (1.6 mmol/l for

glucose levels up to 400 mg/dl then as high as 4 mmol/l for

every 100 mg/dl of glucose concentration for glucose

exceeding 400 mg/dl) [14].

Exogenous solutes such as mannitol can also result in

hypertonic hyponatremia by similar mechanism. Manni-

tol is used therapeutically in a variety of settings to induce

an osmotic diuresis or to induce a hypertonic condition to

treat cerebral edema. If renal function is intact, the

mannitol will be excreted and PNa will recover to normal.

If renal function is impaired, dialysis may be used to


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Figure 1 Algorithm for the classification of hyponatremia

Algorithm for the classification of hyponatremia

Hypertonic hyponatremia � Hyperglycemia � Positive osmotic gap (mannitol, sorbitol)

Hypotonic hyponatremiaIsotonic hyponatremia � Hyperproteinemia � Hyperlipidemia

S-Na <130 mmol/l

Serum osmolality

>100 mmol/l<100 mmol/l

<30 mmol/l >30 mmol/l

Frequent causes � Primary polydipsia � Low solute intake � Potomania 1

2 3 2 4

6

65

Hypovolemia[Total body water ↑↑]

[Total body sodium ↓↓]

Extrarenal soluteloss:� Gastrointestinal(diarrhea, vomiting)� ‘Third space’burns� Pancreatitis� Traumatizedmuscle

Edematousdisorders:� Heart failure� Liver cirrhosis� Nephroticsyndrome

Hypervolemia[Total body water ↑↑][Total body sodium ↑]

Hypovolemia[Total body water ↓]


Renal solute loss:� Diuretic excess

Hypovolemia[Total body water ↓]


Urine osmolality

Urine sodium

Extracellular fluid volume

Excessfluid intake

Impaired renalconcentration

� Hypothyroidism� Pain� Nausea� SIAD

� Mineralocorticoiddeficiency

Clinical status Decision making Action required

� Salt losingnephritis� Osmotic diuresis(mannitol, glucose)

� Glucocorticoiddeficiency

Reproduced with permission from [9��].

remove retained mannitol. The presence of mannitol (or

other occult osmolyte) can be inferred by calculating the

osmolar gap:

Osmolar Gap ¼ Posm� ð2� PNaþ ½glucose; mmol=l�

þ ½urea; mmol=l�Þ

The concentrations of glucose and urea in mg/dl can

be converted to mmol/l by dividing by 18 and 2.8,


respectively. An osmolar gap greater than 10 implies

the presence of an unrecognized solute [15].

Various endoscopic procedures, including transurethral

resection of the prostate (TURP) and hysteroscopy, rely

on monopolar electrosurgical instruments that require

optically transparent, nonconductive irrigation solution.

Although a variety of solutions are available, including

those containing mannitol, dextrose, and sorbitol, 1.5%

glycine has been a popular choice. When systemically



absorbed, these solutions can cause hyponatremia and

volume overload. Glycine solutions can cause a constella-

tion of symptoms and signs including nausea, vomiting,

confusion, hypotension, cardiac dysfunction, bradycardia,

visual disturbance, and even coma and death [16]. This

constellation has been referred to as TURP syndrome

and correlates with postoperative glycine concentration.

As ammonia is an intermediate metabolite of glycine,

hyperammonemia can occur. The solution is isotonic

and initially is confined to the ECF compartment. PNa

will fall but tonicity and Posm will remain normal. As

glycine is taken up by muscle cells and metabolized, a

process that requires several hours, PNa will return

toward normal. In a single-center experience, hyponatre-

mia occurred equally frequently in patients randomly

assigned to either glycine or dextrose irrigant solution,

but TURP syndrome developed only in 17 of 120 (14%)

patients randomly assigned to glycine irrigation [17�].

The major risk factor for TURP syndrome appears to

be the volume of irrigant absorbed. Newer technology

incorporating bipolar electrosurgical instruments that are

compatible with use of isotonic saline as an irrigant

should eliminate the occurrence of hyponatremia and

TURP syndrome, but could still result in volume over-

load if systemic absorption is substantial. Glycine absorp-

tion can be recognized by the presence of an osmolal

gap in the appropriate clinical setting. The treatment of

TURP syndrome is supportive. Hypertonic saline

should not be used unless there is concomitant hypotonic

hyponatremia. Dialysis has been utilized in severe cases,

particularly those with hyperammonemia and renal

impairment [18].

Pseudohyponatremia is a relatively uncommon cause

of nonhypotonic hyponatremia that relates to the

measurement of PNa by instruments (chemical auto-

analyzers) that use indirect ion-specific electrodes

(ISEs). These devices dilute the plasma sample prior

to measurement of the sodium concentration and are

calibrated on the basis that normal plasma by volume

contains 93% water and 7% protein and lipid. The

sodium content of plasma is confined to the aqueous

phase. In the setting of hyperproteinemia or hyper-

lipidemia, the water content is actually less than 93%,

leading to an artifactually low PNa determination.

Instruments that use ISEs to measure sodium concen-

tration, such as blood gas analyzers, are not subject to

such artifact. Hyperlipidemia resulting from hypertrigly-

ceridemia causes the specimen to appear turbid;

hypercholesterolemia, on the contrary, does not produce

visibly lactescent serum. Hyperproteinemia can be seen

in cases of endogenous hypergammaglobulinemia, as

in the setting of hepatitis or HIV infection, or in the

setting of exogenous administration of intravenous (i.v.)

gammaglobulin. Although relatively uncommon, it is

important to recognize pseudohyponatremia so that such


patients are not subjected to inappropriate interventions

[5��].

Acute hypotonic hyponatremiaAcute hypotonic hyponatremia, also known as ‘acute

water intoxication’, is seen most frequently in primary

polydipsia, exercise-associated hyponatremia (EAH),

drug ingestions (particularly of 3,4-methylenedioxy-

methamphetamine, ‘ecstasy’), and the administration

or consumption of hypotonic fluids in a medical setting.

Primary polydipsia is a common disorder among patients

with underlying psychiatric disorders, particularly those

with schizophrenia. This condition was found in up to

47% of psychiatry inpatients in series from Cuba, with

almost 7% developing hyponatremia [19]. Hyponatremia

occurs if the volume of water ingestion exceeds the

excretory capacity of the kidneys. The water excretory

capacity of normal kidneys is estimated to be approxi-

mately 10% of the glomerular filtration rate (GFR),

which, in adults, ranges from approximately 108 to

170 l per day depending on age. In the setting of reduced

GFR, hyponatremia may occur with less dramatic fluid

intake. Water intoxication due to excessive consumption

has also been reported in water drinking contests [20].

Endurance exercise is associated with the nonosmotic

release of AVP. EAH occurs when the ingestion of water

is in excess of losses due to sweat, and the excess water is

retained due to the presence of AVP. Sodium loss in

sweat and excessive water intake driven by fear of dehy-

dration appear to contribute to the problem. This

phenomenon has been identified in as many as 7% of

endurance athletes. PNa testing in the finish-line tent at

the Boston Marathon has identified hyponatremia in

4.8% of runners. Two percent had PNa less than 130.

Sixteen were treated with hypertonic oral solution and

10 were treated with i.v. 3% saline raising the PNa by

6–7 mmol/l in approximately 15–30 min and abolishing

symptoms [21,22].

Ecstasy is a popular recreational drug among college age

people, particularly in association with rave parties and

nightclub activities. It has been implicated as a cause of

hyponatremia resulting in seizures and death in numer-

ous case reports. The mechanism appears to be multi-

factorial including induction of AVP release, induction of

thirst, and ready access to water and other hypotonic

fluids. Hyperpyrexia and vigorous activity may contribute

to sodium loss via sweat and lead to volume contraction

that further induces AVP. Women appear to be more

susceptible to ecstasy-related hyponatremia accounting

for approximately 85% of reported cases. Hyponatremia

often corrects spontaneously as a water diuresis ensues as

the effect of the drug dissipates. Asymptomatic to


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Table 1 Differential diagnosis of hyponatremia

Hypotonic antidiuretic hormone present Hypotonic antidiuretic hormone suppressed Isotonic or hypertonic

Reduced ECV (True volume depletion) Increased water intake HypertonicRenal losses Primary polydipsia Hyperglycemia

Diuretics Accidental ingestion MannitolSalt-wasting nephropathy Dilute formulaCerebral salt wasting Swimming IsotonicOsmotic diuresis Tap water enemas PseudohyponatremiaNonreabsorbable anion Absorption of hypotonic irrigant Hyperlipidemia

Gastrointestinal losses Inadequate solute intake HyperproteinemiaExtreme exercise/sweating Tea and toast diet Isotonic irrigant absorptionExtracellular fluid sequestration Beer potomania Glycine

Rhabdomyolysis Renal failure Renal failurePancreatitisBurnsPeritonitisBowel obstruction

Increased ECVCongestive heart failureCirrhosisNephrotic syndromePregnancy

Clinically normal ECVHypothyroidismHypoadrenalismThiazide diureticsSIADH

Malignant diseasesCNS disordersPulmonary disordersDrugs (many)Miscellaneous

Pain, nausea, stressPostoperative stateMutation of vasopressin receptor

ECV, extracellular fluid volume; SIADH, syndrome of inappropriate antidiuretic hormone. Reproduced with permission from [10,11].

moderately symptomatic patients should be observed

until correction occurs. Severe, symptomatic hyponatre-

mia should be managed with hypertonic saline as out-

lined below [23].

Surgery results in the nonosmotic release of AVP lasting

2 days or more. Hypotonic fluid administration during

this interval can result in severe hyponatremia. This

scenario has been implicated in several case reports

describing fatal postoperative hyponatremia. Children

and young women appear to be particularly susceptible

to adverse outcomes in this setting [24�].

Hyponatremia is commonly observed in patients with

SAH, meningitis, and other neurologic and neurosurgical

conditions, and is associated with a poor prognosis. Even

minor degrees of hyponatremia can exacerbate cerebral

edema and worsen the neurologic condition. Guidelines

call for treatment of hyponatremia at a PNa of 131 mmol/l

for all patients with intracranial disorder [25]. A protocol

for a sliding scale approach to hyponatremia in critically

ill patients with neurologic diseases has been effective in

preventing progression of mild acute hyponatremia. The

protocol calls for initiation of enteral salt tablets by

nasogastric tube and i.v. hypertonic saline if the PNa


falls to less than 133 mmol/l or by more than 6 mmol/l over

24–48 h. The protocol starts with NaCl tablets, 3 g per

nasogastric tube every 6 h and 3% saline 20 ml/h. The rate

of 3% saline is then titrated by 10–20 ml/h at 6 h intervals

as needed to achieve a PNa of 136–140 mmol/l (to a

maximum of 80 ml/h). In the event of PNa greater

than140 mmol/l, the 3% saline infusion is held for 6 h.

The regimen resulted in excellent control of PNa in the

normal range. Hypernatremia greater than 145 mmol/l

was exceedingly rare and heart failure was not observed

[26].

Epidemiology and outcomesMany factors have been identified that predispose to

hyponatremia, including extremes of age, surgery, diure-

tic therapy, renal impairment, adrenal impairment, thyr-

oid deficiency, CHF, cirrhosis, CNS disease and

pulmonary disease [27]. Hoorn et al. [28] found a 30%

overall incidence of PNa less than 136 mmol/l and a 38%

incidence in the ICU. Severe hyponatremia, PNa less

than 125, was present in 3% of hospitalized patients and

occurred during hospitalization in fully half of the cases.

Importantly, hospital acquired cases of severe hypona-

tremia were not recognized or treated as promptly as were



cases present on admission. Stelfox et al. [29] reported

ICU acquired hyponatremia (defined as a SNa less than

133 mmol/l) in 11% of patients and that this was associ-

ated with an increase in in-hospital mortality from 16 to

28%. The population studied included medical, surgical,

trauma, and neurologic patients. Higher acute physiology

and chronic health evaluation (APACHE) II scores and

longer ICU LOS were found to be risk factors for hypo-

natremia. Funk et al. [30] defined borderline, mild, and

severe hyponatremia as 130–135 mmol/l, 125–129, and

greater than 125, respectively. They found an overall

incidence of hyponatremia in 17.7% of ICU admissions

with a breakdown of 13.8% classified as borderline, 2.7%

mild, and 1.2% severe. Hyponatremia at all levels was an

independent risk factor for mortality. Adjusted mortality

odds ratios (ORs) were significant at all levels ranging

from 1.3 for borderline to over 1.8 for moderate and

severe cases.

A recent analysis of over 50 000 patients admitted to a

single, large Boston teaching hospital utilizing a liberal

cutoff of PNa less than 138 mmol/l demonstrated a

remarkable 38% incidence of community acquired hypo-

natremia. The analysis was extended to show that hypo-

natremia of even this modest degree was associated with

multiple adverse outcomes including increased mortality

LOS, and discharge to a care facility. Hospital acquired

hyponatremia was equally as frequent, occurring in 38.2%

of patients and was associated with even higher ORs for

adverse outcomes. In this study, hospital aggravated

worsening of community-acquired hyponatremia con-

ferred an even higher mortality risk of hospital mortality

(OR 2.3 vs. 1.66 for hospital acquired vs. 1.5 for com-

munity acquired). In hospital-acquired hyponatremia,

PNa or less 127 mmol/l was associated with a 15-fold

increase in mortality, whereas community-acquired

hyponatremia to the same degree conferred only a

2.5-fold increase risk [31�].

A 2009 study that examined data from approximately

98 000 patients admitted to two large teaching hospitals

found an initial PNa of less than 135 mmol/l in 14.5% and

that an additional 5.2% acquired hyponatremia during

their hospitalization. Approximately half of these patients

underwent multiple determinations of PNa: 20% had

hyponatremia on at least one of the measurements. Of

these, hyponatremia resolved in 7.2%, developed in

3.8%, and persisted in 8.6%. Mild hyponatremia (defined

as 130–134 mmol/l) accounted for the majority of the

cases (83%), moderate (120–130 mmol/l) for 16.8%, and

severe (<120 mmol/l) for 0.2%. When this analysis

was adjusted for the presence of hyperglycemia,

approximately 12–19% of patients initially classified as

hyponatremic were reclassified as normonatremic or

hypernatremic. Compared with normonatremia, hospi-

tal-acquired and persistent hyponatremia each conferred


an approximately three-fold increase in inhospital

mortality, a two-fold increase in 1-year mortality, and

1.3–1.4-fold increase in 5-year mortality. There was no

sex difference in the incidence of hyponatremia, but

women were more likely to have severe hyponatremia.

Patients with the most severe hyponatremia did not have

a statistically increased mortality rate 1.46 (0.73–2.91), a

surprising observation [32].

The relationship between the severity of hyponatremia

and mortality was examined by Chawla et al. [33��] in a

cohort of over 45 000 patients found to have at least one

SNa of less than 135 mmol/l admitted to a large teaching

hospital over an 11-year span ending in 2007. These

authors confirmed a three-fold increase in mortality for

hyponatremic patients vs. normonatremic patients (6.1

vs. 2.3%). They also found that mortality tended to

increase with lower SNa peaking at 11.2% for patients

with SNa of 120–124 mmol/l, but reversing at SNa less

than 120 mmol/l such that mortality fell to approximately

6.8% in the more severely hyponatremic group. The

authors analyzed 53 patients who died and had severe

hyponatremia (SNa <120 mmol/l) and found that 73% of

these patients had moderate or severe hyponatremia on

admission, whereas 27% had normal or mild hyponatre-

mia that worsened. Most patients had recovered to nor-

mal or near normal SNa when death occurred, which was

more than a week after the SNa nadir in most cases. They

found only three cases in which hyponatremia was felt to

play a causal role and only one case in which central

pontine myelinolysis (CPM) might have occurred.

Patients with severe hyponatremia who survived were

more likely have drug-induced hyponatremia (thiazides

and selective serotonin reuptake inhibitors) and were

unlikely to have severe comorbid conditions. The authors

theorize that severe hyponatremia occurs more often

secondary to drug toxicity and is likely to be acute and

treatable (or to resolve), whereas moderate hyponatremia

is more likely to accompany severe comorbid conditions

such as CHF, cirrhosis, and malignancy and therefore

strongly associated with mortality. An editorial that

accompanies this article proposes three clinical scenarios

based on these findings: (scenario 1) hyponatremia causes

mortality directly from cerebral edema or correction

provokes the osmotic demyelination syndrome (ODS);

(scenario 2) hyponatremia occurs secondary to a severe

underlying illness and it is the underlying illness that

causes death; or (scenario 3) hyponatremia exacerbates

organ system dysfunction and contributes to mortality

indirectly [34��]. Little is known about how hyponatre-

mia might affect organ system function but a recent

observation that hyponatremia predicts myocardial

infarction in community patients lends support to the

third scenario [35]. Acutely decompensated heart failure

is another setting in which hyponatremia confers an

independent increased risk for mortality [36�].


C

588 Renal system

Clinical effects of hyponatremia andtreatment

Chronic hyponatremia is often asymptomatic. Most

patients do not have overt clinical symptoms until the

PNa is less than 120 mmol/l. However, even a mild

degree of hyponatremia is associated with falls and

impaired attention and gait in a manner analogous to

an ethanol level of 0.6 g/l [37]. In addition, hyponatremia

has been associated with fractures and osteoporosis

[38�,39,40]. The third national health and nutritional

examination survey found an OR of nearly 3 for devel-

oping osteoporosis at PNa of 133 mmol/l compared with

normonatremic patients. PNa less than 135 mmol/l was

found to be an independent risk factor for hip fracture.

Thiazide diuretics, despite their known effect on

calcium balance, are associated with fractures in elderly

nursing home patients, although this finding has not been

shown to relate to low PNa. Selective serotonin reuptake

inhibitors, a known cause of hyponatremia, are also

associated with falls and fractures in the first 2 weeks

of therapy, a time course that corresponds to the usual

onset of SSRI-related hyponatremia. However, a direct

connection to hyponatremia remains to be established.

Patients with CHF, renal failure, or cirrhosis who also

have hyponatremia have a worse prognosis. Again, it is

not established whether the hyponatremia is simply a

marker of decompensated organ system disease or if

hyponatremia has a direct deleterious effect.

The major clinical concern of hyponatremia is encepha-

lopathy [41]. Initial symptoms are nonspecific and

include headache, lethargy, and nausea. Advanced symp-

toms include lethargy, depressed reflexes, seizures, and

coma followed by death. Although the optimal rate of

correction is often referred to as controversial, guidelines

have been established that recommend an increase in

PNa of less than 10 mmol/l over 24 h and less than

18 mmol/l over 48 h [1]. A rapid rate of correction has

been associated with the development of the ODS, a

potentially devastating neurologic condition. Initial

descriptions identified mainly pontine damage, whereas

subsequent reports have identified more widespread

demyelination, thus central pontine myelinolysis

(CPM) and extrapontine myelinolysis (EPM) can be

grouped as two manifestations of ODS [42]. The most

classic form of this condition presents 2–3 days after

correction of hyponatremia with evidence of neurologic

deterioration after a period of improvement. Symptoms,

depending on the location and severity of the lesions,

may include seizures, parkinsonism, dysarthria, quadri-

paresis, spastic hypertonia, coma, and death. Character-

istic changes may be present on MRI. Early reports

described a uniformly bad prognosis with either death

or persistent severe neurologic impairment. More recent

reports have documented a variable prognosis. The


adaptation by brain cells to hypotonic conditions predis-

poses to injury with rapid correction, which acts like an

acute hypertonic insult. Indeed, ODS has been described

in a patient with acute hypernatremia who never suffered

hyponatremia. Animal studies have confirmed that it is

the correction of hyponatremia, not hyponatremia itself,

that causes ODS. Relowering of PNa has been shown to

ameliorate early signs of ODS in multiple case reports.

The risk for ODS increases with rate of correction greater

than recommended. Although correction rates within

these guidelines are associated with lower risk, there

are case reports of ODS occurring in patients who were

corrected within these limits. More rapid reuptake of

previously extruded organic osmolytes, particularly myoi-

nositol, is also protective. There are regional differences

in the brain with regard to reuptake of osmolytes, perhaps

accounting for the predilection of ODS for the pons and

other structures. Uremia, which is associated with more

rapid reuptake of osmolytes, is protective against ODS.

Patient risk factors appear to include liver disease,

alcoholism, orthotopic liver transplant, female sex, and

postoperative state [5��].

The rate of correction also appears to impact the risk for

rhabdomyolysis. In a retrospective study of 22 patients

with self-induced water intoxication, rhabdomyolysis was

found to be associated with a more rapid rate of correction

of 2 vs. 0.9 mmol/l per hour. The rapid rate of correction

was attributed to spontaneous excretion of large volumes

of dilute urine shortly after presentation [43�].

Acute symptomatic hyponatremia, whether self-induced,

drug-related, or hospital-acquired, is a true medical emer-

gency that demands prompt intervention. In these

patients, hyponatremia has developed faster than brain

adaptation can keep pace resulting in cerebral edema.

Usually the PNa is quite low, often greater than

110 mmol/l, but patients with intracranial disorder, as

noted above, may be symptomatic with more modest

falls in PNa. The presence of symptoms of CNS dysfunc-

tion attributable to cerebral edema should guide the

decision to institute therapy. Even patients with primary

polydipsia or postoperative hyponatremia that is

expected to correct spontaneously should be treated so

as not to delay improvement in cerebral edema. The goal

of therapy for acute symptomatic hyponatremia is to raise

the PNa by 4–6 mmol/l, which according to consensus

has resulted in resolution of hyponatremia-related

seizures, and coma. This is best accomplished by boluses

of 3% saline of 100 ml or 2 ml/kg. This can be repeated

twice if necessary to abort seizures or reverse coma. Note

that the rate of correction in this instance is greater than

the conventional recommendation of 0.5 mmol/l per hour,

but the total correction is limited to approximately

6 mmol/l. Once this correction is achieved and the patient

is neurologically stabilized, further correction should be



delayed or minimized so as not to exceed a net correction

of greater than 10 mmol/l over 24 h or 18 mmol/l over 48 h

[5��]. Chronic hyponatremia, if severely symptomatic,

should initially be treated similarly to those with acute

symptomatic hyponatremia. Some authors have advo-

cated ‘a rule of sixes’ stating that correction should be

‘6 mmol/l in the first 6 h but also limiting correction to

6 mmol in the first day’. Correction should be targeted at

less than the upper desirable to avoid overshooting.

Patients with primary polydipsia, volume depletion, thia-

zide diuretic induced hyponatremia, or cortisol deficiency

related water retention are particularly predisposed to too

rapid correction as they will undergo a water diuresis once

the underlying cause is treated resulting in a rise in PNa

of up to 2 mmol/l per hour. Desmopressin can be used in

such circumstances to terminate or prevent a water diur-

esis, allowing slow, controlled correction of the PNa.

Desmopressin is given every 6 h to maintain consistent

urine concentration. Therapy with 3% saline can then be

titrated to achieve a rate of correction within the guide-

lines. Hypokalemia is another factor that will predispose

to overcorrection as the addition of potassium chloride

(KCl) provides effective osmoles and raises PNa [1,5��].

The contribution of both KCl and NaCl to raising PNa

can be estimated by the following formula from Adrogue

and Madias [10], which describes the anticipated effect of

the infusion of 1 l of a solution:

change in PNa ¼ ðinfusate Naþ infusate KÞ � PNa

TBWþ 1

When actively correcting hyponatremia, it is crucial to

utilize an infusate with an effective osmolality greater

than that of urine. The most common choice of fluid to

correct hyponatremia is 3% saline that has a Na concen-

tration of 513 mmol/l. Furosemide can be added to avoid

expansion of the ECF due to the saline load. As loop

diuretics usually cause a diuresis equivalent to half-

isotonic saline, they may also facilitate correction if the

Uosms are very high. Restriction of free water ingestion

must accompany the active management of hyponatre-

mia unless the stimulus for AVP and water retention has

been alleviated. Demeclocycline, which impairs the

action of AVP, has been used to treat persistent hypo-

natremia due SIADH but renal toxicity and other side

effects limit its acceptance. High salt diet, salt tablets,

high protein intake, and urea supplementation are all

adjunctive measures that can be useful in the manage-

ment of persistent hyponatremia due to SIADH out of

the acute phase [9��,11].

Patients with symptomatic hyponatremia and renal fail-

ure requiring renal replacement therapy are at risk for

rapid correction. Management options include infusion of

hypotonic fluid during dialysis or the use of continuous


renal replacement therapy utilizing replacement fluid

calculated to correct PNa at slow rate [5��].

Vasopressin antagonists, vaptans, are an emerging option

for management of chronic hyponatremia. Vaptans com-

petitively inhibit the binding of AVP to its V2 receptor in

the collecting duct and thereby block the insertion of

aquaporins into the apical membrane. Convivaptan, an

intravenous form that inhibits V1a receptors on smooth

muscle cells, platelets, and liver in addition to V2 recep-

tors, was the first V2R antagonist to be approved by the

US Food and Drug Administration (FDA) for treatment

of euvolemic hyponatremia due to SIADH, hypothyroid-

ism, adrenal insufficiency, or pulmonary conditions. It is

also approved for treatment of hyponatremia associated

with CHF. The metabolism of convivaptan is by the liver

cytochrome system CYP3A4 making it prone to drug

interactions and contraindicated in the setting of potent

CYP3A4 inhibitors [44��]. When given to healthy adults, a

single 20 mg dose resulted in an increase in urine output

and fall in Uosm, peaking in 2 h and persisting for 6 h.

Therapeutically, it is given as a 20 mg bolus followed

by a 20 mg per day continuous infusion maintained for

1–4 days. It has been effective in clinical trials although

data are limited [45,46]. A single-center observational

study of 18 patients found that 67% improved by at least

4 mmol/l but that six patients with initial PNa less than

120 mmol corrected by greater than 10 mmol/l per 24 h, a

rate considered undesirable [47�]. Use of a single bolus of

20 mg in neurointensive care patients hyponatremia

resulted in a 4 mmol/l improvement within 12 h in 59%

of the patients. In this case series, no cases of infusion

vein phlebitis were identified, although this problem was

seen in earlier trials [48]. Finally, although antagonism of

VIa receptors might be problematic for patients with

cirrhosis (VIa agonism has been advocated as a treatment

for hepatorenal syndrome), convivaptan was utilized in

24 patients with end stage liver disease and PNa less than

130 mmol. All patients experienced a modest increase in

PNa (<6 mmol/l) and no complications of the underlying

liver disease were observed [49].

Tolvaptan is the first oral V2R antagonist to be approved

in the United States by the FDA. It has a much greater

affinity for the V2R than for the V1a receptor. The half-

life of tolvaptan is estimated to be 12 h. It is metabolized

in the liver by the CYP3A and, like convivaptan, should

not be used with potent inhibitors of this enzyme. The

onset of action is within 2–4 h [44��]. Multiple studies

have been conducted and now have been summarized

and analyzed including a meta-analysis. It has been

shown to raise PNa by approximately 4 mmol/l on day

4 and by approximately 6 mmol/l on day 30. When used to

treat CHF, it has resulted in weight losses around 2 kg.

Reported adverse effects have been thirst, dry mouth,

and polyuria. Effectiveness has been similar in patients


C

590 Renal system

with euvolemic hyponatremia (principally SIADH) and

CHF and somewhat less effectiveness has been demon-

strated with cirrhosis [50�,51�,52].

HypernatremiaHypernatremia occurs when there is an absolute or

relative deficit of free water. Hypovolemic hypernatremic

patients will display signs of volume depletion, but these

signs may be mild or minimal if there is a small water

deficit and no concomitant lost of solute. Hypervolemic

hypernatremia is caused by the addition of solute in

excess of water. Conditions that impair urinary concen-

tration include central diabetes insipidus, nephrogenic

diabetes insipidus (NDI), hypercalcemia, hypokalemia,

loop diuretics, and osmotic diuresis. Uncontrolled dia-

betes is the most common cause of osmotic diuresis, but a

high protein intake or protein catabolism can also pro-

duce diuresis due to the generation of urea. The latter

may occur in hospitalized patients receiving parenteral or

enteral nutrition with a high protein load. Nonrenal losses

of water are seen in the setting of excessive sweating,

emesis, diarrhea, burns, and tachypnea. Hypertonic

bicarbonate administration or hypertonic saline adminis-

tration is among the iatrogenic causes of hypernatremia.

As a rise in Posm is a potent stimulus of thirst that would

normally prevent or correct hypernatremia, almost all

cases display either impaired thirst (hypodipsia) or

impaired access to water [3,4,53].

The incidence of hypernatremia is approximately 1% in a

general hospital population. An incidence of 10–26% is

identified in ICU populations [54,55�]. In the majority of

cases, hypernatremia is hospital acquired. Community-

acquired hypernatremia is almost always hypovolemic in

nature, but hospital-acquired hypernatremia is frequently

not hypovolemic and some patients may even display

signs of volume overload. Causes of excess fluid loss in

cases of community-acquired hypernatremia include

fever (often from pulmonary infections), uncontrolled

diabetes mellitus, high ambient temperature, osmotic

diarrhea due to lactulose, and furosemide. In almost all

cases, water intake is inadequate due to impaired mental

status. Although emblematic of hypernatremia, diabetes

insipidus is relatively uncommon.

A Netherlands ICU study of 130 hypernatremic ICU

patients identified sepsis, renal impairment, hypokale-

mia, hypoalbuminemia, and the administration of

bicarbonate and mannitol as risk factors. Only 60% of

the patients had negative fluid balance during hyper-

natremia and some had positive fluid balance. Although

no patients received hypertonic saline, the conclusion

was that hypernatremia represented ‘too much salt and

not enough water’ [56]. A retrospective analysis of

approximately 8000 patients admitted to ICUs in France


found 901 individuals with mildly elevated PNa 145–

150 mmol/l and 344 with moderate to severely elevated

PNa greater than 150 mmol/l for an overall prevalence of

15%. The mild group had twice the in-hospital mortality

compared with normonatremic patients, whereas in the

more severe group mortality tripled. Independently

associated risk factors for ICU-acquired hypernatremia

present on ICU entry were male sex, great disease

severity, septic shock, acute respiratory failure, and coma

[55�].

The incidence of hypernatremia in cardiac surgery

patients has also been recently analyzed. A single-center

European experience found a 10% rate of ICU-acquired

hypernatremia that was associated with greater than a

two-fold increased mortality and a nearly six-fold

increased ICU LOS [57�]. A Canadian heart surgery

program found a 4% incidence of hypernatremia that

was also associated with an increased risk of mortality

compared with normonatremia (14 vs. 1.6%). Changes in

PNa greater than 12 mmol/l per day were associated with

an even greater mortality risk of 28%. Interestingly, in

this population the risk for hypernatremia tended to

accrue over time, whereas the risk for hyponatremia

was greatest in the first few days of ICU admission [58�].

Therapeutic hypernatremia has been utilized as an

alternative to mannitol to treat increased intracranial

pressure (ICP) associated with transtentorial herniation.

A 30–60 ml bolus of 23.4% saline (equivalent sodium

dose to 240–480 ml of 3% saline) successfully reversed

signs of herniation in 57 of 76 events (75%), 22 of

whom subsequently survived to discharge including five

who were reported to have only mild residual deficits.

ICP, when measured, fell significantly by 1 h. Clinical

improvement and fall in ICP correlated with a rise in PNa

by at least 5 mmol/l and PNa greater than 145 mmol/l

[59]. A 23.4% saline has also been used to treat cerebral

hypoperfusion to prevent elevation of ICP after SAH

[60]. Reviewers of the therapeutic use of 23.4% saline

point out that it can cause severe tissue injury in the

event of extravasation and that central venous access is

necessary. They also postulate that 3% saline given in

equivalent doses may be as effective, but that this com-

parison has not been done [61].

The clinical consequences of hypernatremia include

insulin resistance, impaired gluconeogenesis, and cardiac

dysfunction in addition to the neurologic consequences.

The brain injury that occurs with hypernatremia has been

postulated to result in part from shrinkage of the brain

away from the skull causing mechanical stress on vessels

that could lead to hemorrhage and or ischemia. As evi-

denced by multiple case reports, rapid, severe elevations

of PNa can result in ODS even in the absence of previous

hyponatremia [62�]. Hypernatremic patients may display



irritation, agitation, lethargy, depressed mental status,

seizures, and coma. Burn patients who develop hyper-

natremia have a higher mortality and there is evidence

that the hypernatremia may worsen the burn itself [63].

Treatment of hypernatremia in the ICU should start with

prevention. Predisposing conditions are recognizable;

for example, polyuria, diarrhea, fever, respiratory failure,

inability to take in water spontaneously, osmotic diarrhea,

and uncontrolled diabetes. Electrolytes are frequently

measured. Therefore, it is reasonable to identify a rising

PNa before severe derangement occurs. Indeed, the

occurrence of hypernatremia in the ICU has been

proposed as an indicator of quality of care [64]. Once

recognized, fluid therapy can be modified to prevent

progression and correct any adverse changes that have

already occurred. The optimal rate of correction of hyper-

natremia has not been extensively studied. A comparison

of patients treated for hypernatremia who developed

cerebral edema with similar patients who did not found

that initial isotonic saline bolus, a faster rate of fluid

administration, more severe hypernatremia at initiation

of treatment (PNa 167 mmol/l vs. 161 mmol/l), and a

faster rate of correction of PNa (1 mmol/l per hour vs.

0.5 mmol/l per hour) were all associated with the early

development of cerebral edema [65�]. The choice of

rehydration fluid did not appear to influence the


Table 2 Differential diagnosis of hypernatremia

Pure water loss Hypotonic

Insensible losses Renal lossNo access to water Loop diu

OsmoticATN (poPostobsRenal im

GastrointeEmesisDiarrheaOsmotic

ExcessiveBurns

HypodipsiaInadequate replacement

Central (neurogenic) DITraumaSurgeryInfiltrative/infectious disorders

Sarcoid, tuberculosis, histiocytosisTumors, cystsEthanol

Nephrogenic DICongenitalAcquired

Renal damageCystic diseases, sickle cellHypokalemia, hypercalcemia

DrugsLithium, demeclocyclineAVP receptor antagonistsAmphotericin B, foscarnet

ATN, acute tubular necrosis; AVP, arginine vasopressin; DI, diabetes insipi

occurrence of neurologic complications. The authors

proposed that isotonic saline volume expansion be

avoided in the absence of severe circulatory impairment.

The overall rehydration should be limited to no more

than 6.8 ml/kg per hour and the rate of correction should

not be greater than 0.5 mmol/l per hour. Higher initial

PNa should be treated even more conservatively. The

Adrogue–Madias [53] formula described above can

be used to estimate the degree of correction that may

be achieved with administration of 1 l of a particular fluid

therapy. Alternatively, water deficit can be estimated as

follows:

Water deficit¼TBW (PNa/140�1).

Water can then be administered to correct the total

deficit gradually with a target rate greater than

0.5 mmol/l per hour. It is common for differences

between expected and achieved results to be substantial.

Ongoing losses must be considered in therapeutic

planning so that not only is the deficit addressed but

also further deficit will not occur. It is important to

measure PNa frequently and adjust therapy to maintain

the target rate of correction.

In the event of central or gestational diabetes insipidus,

desmopressin can be given to restore renal concentration


loss Hypertonic gain

es Hypertonic intravenous infusionsretics Sodium bicarbonatediuresis Hyperalimentation

lyuric phase) Salinetructive Hypertonic ingestionspairment Enteral feeding formulasstinal losses Sea water

Hypertonic saline enemasHypertonic intrauterine infusion

laxatives Hypertonic dialysatesweating Cushing’s syndrome

Primary hyperaldosteronism

dus. Reproduced with permission from [53].

C

592 Renal system

and abort polyuria. Renal failure that accompanies hyper-

natremia is often due to renal hypoperfusion and may

reverse with restoration of euvolemia. Renal failure

requiring renal replacement therapy is challenging, as

conventional dialysis will tend to rapidly correct hyper-

natremia, an effect that is undesirable unless it is known

that the hypernatremia is of very acute onset. Continuous

renal replacement therapy may be advantageous in this

setting as the replacement fluid composition and admin-

istration rate can be modified to achieve the desired rate

of correction.

ConclusionHyponatremia and hypernatremia are commonly encoun-

tered in ICU patients and are associated with adverse

outcomes including mortality and prolonged LOS. In the

minority of cases, dysnatremia results directly in death or

severe neurologic impairment. It remains uncertain

whether dysnatremia is a marker of poor prognosis or

an active contributor to adverse outcomes in the remain-

ing cases, but evidence of direct adverse effects on

multiple organ systems is emerging. Both hyponatremia

and hypernatremia frequently arise or worsen in the

hospital, representing an opportunity to identify and

address these disorders before derangement is severe.

A broad range of causes can be considered and attention

to underlying physiologic principles will aid in establish-

ing the correct diagnosis. Acute, severe hyponatremia

should be treated promptly with 3% saline to raise the

PNa by 4–6 mmol. Otherwise, both hyponatremia and

hypernatremia should be treated conservatively such that

PNa does not rise or fall by more than 8–10 mmol/l per

day. Many experts recommend targeting only a 6 mmol/l

change. Formulas can be used to estimate water excess or

deficit and to estimate the effect that intravenous

solutions will have on PNa, but there can be substantial

discrepancy between predicted and achieved results.

Therefore, the clinician must measure the PNa fre-

quently and adjust therapy accordingly to optimize the

chance for recovery (Table 2).

AcknowledgementsThe authors would like to thank Dr Howard Corwin for the opportunity tocontribute to this article.

Conflicts of interestThere are no conflicts of interest.

References and recommended readingPapers of particular interest, published within the annual period of review, havebeen highlighted as:� of special interest�� of outstanding interestAdditional references related to this topic can also be found in the CurrentWorld Literature section in this issue (p. 668).

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31

�Wald R, Jaber BL, Price LL, et al. Impact of hospital associated hyponatremiaon selected outcomes. Arch Intern Med 2010; 170:294–302.

An impressively large analysis of a US teaching hospital population that empha-sizes the important role of nosocomial hyponatremia and also points out that long-term outcomes, as well as short-term mortality, are influenced by hyponatremia.

32 Waikar SS, Mount DB, Curhan GC. Mortality after hospitalization with mild,moderate, and severe hyponatremia. Am J Med 2009; 122:857–865.

33

��Chawla A, Sterns RH, Nigwekar SU, Cappucio JD. Mortality and serumsodium: do patients die from or with hyponatremia? Clin J Am Soc Nephrol2011; 6:960–965.

An intriguing and novel investigation of why and how hyponatremia contributes toexcess mortality.

34

��Hoorn EJ, Zietse R. Hyponatremia and mortality: how innocent is the by-stander? Clin J Am Soc Nephrol 2011; 6:951–953.

The companion editorial to [32] offers conjecture and a framework in which toconsider the mortality impact of hyponatremia.

35 Sajadieh A, Binici Z, Mouridsen MR, et al. Mild hyponatremia carries a poorprognosis in community subjects. Am J Med 2009; 122:679–686.

36

�Mohammed AA, van Kimmenade RR, Richards M, et al. Hyponatremia,natriuretic peptides, and outcomes in acutely decompensated heart failure:results from the international collaborative of NT-proBNP study. Circ HeartFail 2010; 3:354–361.

This study enhances and confirms our understanding that hyponatremia is a graveprognostic marker in CHF.

37 Renneboog B, Musch W, Vandemergel X, et al. Mild chronic hyponatremia isassociated with falls, unsteadiness, and attention deficits. Am J Med 2006;119:71.e1–71.e8.

38

�Ayus JC, Moritz ML. Bone disease as a new complication of hyponatremia:moving beyond brain injury. Clin J Am Soc Nephrol 2010; 5:167–168.

A consciousness raising discussion on the potential of hyponatremia to do harmoutside of the CNS.

39 Kinsella S, Moran S, Sullivan MO, et al. Hyponatremia independent ofosteoporosis is associated with fracture occurrence. Clin J Am Soc Nephrol2010; 5:275–280.

40 Verbalis JG, Barsony J, Sugimura Y, et al. Hyponatremia-induced osteoporo-sis. J Bone Miner Res 2010; 25:554–563.

41 Adroque HJ. Consequences of inadequate management of hyponatremia. AmJ Nephrol 2005; 25:240–249.

42 Brown W. Osmotic demyellination disorders: central pontine and extrapontinemyelinolyis. Curr Opin Neurol 2000; 13:691–697.

43

�Morita S, Inokuchi S, Yamamoto R, et al. Risk factors for rhabdomyolysis inself-induced water intoxication (SIWI) patients. J Emerg Med 2010; 38:293–296.

A brief report on a potentially underappreciated complication of the correction ofhyponatremia.

44

��Ferguson-Myrthil N. Novel agents for the treatment of hyponatremia. CardiolRev 2010; 18:313–321.

A comprehensive review of the physiology and literature regarding the use ofvasopressin receptor antagonists in the treatment of hyponatremia.

45 Li-Ng M, Verbalis JG. Convivaptan: evidence supporting its therapeutic use inhyponatremia. Core Evid 2010; 4:83–92.

46 Wright WL, Asbury WH, Gilmore JL, Samuels OB. Convivaptan for hypona-tremia in the neurocritical care unit. Neurocrit Care 2009; 11:14–19.

47

�Velez JC, Dopson SJ, Sanders DS, et al. Intravenous convivaptan for thetreatment of hyponatremia caused by the syndrome of inappropriate secretionof antidiuretic hormone in hospitalized patients: a single center experience.Nephrol Dial Transplant 2010; 25:1524–1531.

A report of the practical experience of the effectiveness of convivaptan in ‘real-world’ use.


48 Murphy T, Dhar R, Diringer M. Convivaptan bolus dosing for the correctionof hyponatremia in the neurointensive care unit. Neurocrit Care 2009; 11:14–19.

49 O’leary JG, Davis GL. Convivaptan increases serum sodium in hyponatremicpatients with end-stage liver disease. Liver Transplant 2009; 15:1325–1329.

50

�Rozen-Zvi B, Yahav D, Gheorghiade M, et al. Vasopressin receptor antago-nists for the treatment of hyponatremia: systematic review and meta-analysis.Am J Kid Dis 2010; 56:325–337.

A current summary of the literature describing the use of vaptans for hyponatremicdisorders.

51

�Berl T, Quittnat-Pellitier F, Verbalis JG, et al. SALTWATER investigators: oraltolvapatn is safe and effective in chronic hyponatremia. J Am Soc Nephrol2010; 21:705–712.

An extension of the initial clinical trials of tolvaptan reporting on a larger number ofpatients.

52 Nemerovski C, Hutchinson DJ. Treatment of hypervolemic or euvolemichyponatremia associated with heart failure, cirrhosis, or the syndrome ofinappropriate antidiuretic hormone with tolvaptan: a clinical review. Clin Ther2010; 32:1012–1032.

53 Adrogue HJ, Madias NE. Hypernatremia. N Eng J Med 2000; 342:1493–1499.

54 Pavlevsky PM, Bhargrath R, Greenberg A. Hypernatremia in hospitalizedpatients. Ann Int Med 1996; 124:197–203.

55

�Darmon M, Timsit JF, Francais A, et al. Association between hypernatremiaacquired in the ICU and mortality: a cohort study. Nephrol Dial Transplant2010; 25:2510–2515.

A mirror of similar studies of hyponatremia annotated above that emphasizes thenosocomial nature of hypernatremia and its adverse impact.

56 Hoorn EJ, Betjes MG, Weigel J, Zietse R. Hypernatremia in critically illpatients: too little water and too much salt. Nephrol Dial Transplant 2008;23:1562–1568.

57

�Lindner G, Funk GC, Lassnigg A, et al. Intensive care-acquired hypernatremiaafter major cardiothoracic surgery is associated with increased mortality.Intensive Care Med 2010; 36:1718–1723.

A previously little reported segment of intensive care patients are shown to havesignificant risk for hypernatremia and adverse outcomes.

58

�Stelfox HT, Ahmed SB, Zygun D, et al. Characterization of intensive care unitacquired hyponatremia and hypernatremia following cardiac surgery. Can JAnaesth 2010; 57:650–658.

This report also identifies cardiac surgery patients as an at-risk population forhypernatremia.

59 Koenig MA, Bryan M, Lewin JL 3rd, et al. Reversal of transtentorial herniationwith hypertonic saline. Neurology 2008; 70:1023–1029.

60 Tseng MY, Kirkpatrick PJ. Enhancement of cerebral blood flow usinghypertonic saline therapy improves outcome in patients with poor-gradespontaneous subarachnoid hemorrhage. J Neurosurg 2007; 107:274–282.

61 Palmer BF, Sterns RH. Fluid, electrolytes and acid-base disturbances.NephSAP 2009; 8:146–147.

62

�Naik KR, Saroja AO. Seasonal postpartum hypernatremic encephalopathywith osmotic extrapontine myelinolysis and rhabdomyolysis. J Neurol Sci2010; 291:5–11.

A fascinating report of osmotic demyelination injury in a group of patients withhypernatremia of uncertain cause.

63 Namdar T, Siemers F, Stollwerck PL, et al. Increased mortality in hyperna-tremic burned patients. Ger Med Sci 2010; 8:Doc11.

64 Polderman KH, Schreudeer WO, van Schnijnedel RJM, Thijs LG. Hypern-tremia in the intensive care unit: an indicator of quality of care? Crit Care Med1999; 27:1105–1108.

65

�Fang C, Mao J, Dai Y, et al. Fluid management of hypernatremic dehydration toprevent cerebral oedema: a retrospective case control study of 97 children inChina. J Paediatr Child Health 2010; 46:301–303.

Although a retrospective analysis of a pediatric population, it offers firm sugges-tions on the fluid management of hypernatremia and points out the surprisingpotential risk of isotonic saline boluses in these patients.


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