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Evaluation And Treatment Of Hypernatremia: A Practical Guide To Physicians

Article  in  Postgraduate Medicine · January 2016

DOI: 10.1080/00325481.2016.1147322

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 EVALUATION AND TREATMENT OF HYPERNATREMIA

A PRACTICAL GUIDE TO PHYSICIANS

Liamis G, Filippatos TD, Elisaf MS

Department of Internal Medicine, School of Medicine, University of Ioannina,

Ioannina, Greece

Running head: Evaluation and treatment of hypernatremia

1
ABSTRACT

Hypernatremia (serum sodium concentration >145 mEq/L) is a common

electrolyte disorder with increased morbidity and mortality especially in the

elderly and critically ill patients. The review presents the main pathogenetic

mechanisms of hypernatremia, provides specific directions for the evaluation of

patients with increased sodium levels and describes a detailed algorithm for the

proper correction of hypernatremia. Furthermore, two representative cases of

hypovolemic and hypervolemic hypernatremia are presented along with

practical clues for their proper evaluation and treatment. Accurate diagnosis and

appropriate treatment is crucial since undercorrection or overcorrection of

hypernatremia are both associated with poor patients’ prognosis.

Keywords: sodium, hypernatremia, hypovolemia, correction, water deficit

2
Introduction

Hypernatremia (serum sodium concentration >145 mEq/L) is a common

electrolyte disorder especially in the elderly and critically ill patients.

Hypernatremia is present during admission in some patients but more

frequently is a complication of hospitalization[1-4]. However, hypernatremia is

not restricted only to hospitalized patients but is also common in community

subjects [5]. It should be emphasized that hypernatremia (even if

mild/moderate) is associated with increased morbidity and mortality. Moreover,

delay in the diagnosis and undercorrection or overcorrection of hypernatremia

are both associated with poor patients’ prognosis[1,2,6,7].

Main pathogenetic mechanisms of hypernatremia

The equation of Edelman defines that total exchangeable sodium (Na e+), total

exchangeable potassium (Ke+) and total body water (TBW) are the major

determinants of plasma water sodium concentration[8]. The serum sodium

concentration is given by the equation:

total exchangeable (Na+ + K+)

Serum Na+ =
total body water

Hence, since large variations of potassium homeostasis are not compatible with

life, hypernatremia suggests increased total body sodium and/or decreased total

body water (dehydration)[3,9,10]. The former is usually observed with the

administration of hypertonic sodium solutions. Most cases are due to water loss,

either as a pure water loss (e.g. central or nephrogenic diabetes insipidus) or as

hypotonic fluid loss (e.g. gastrointestinal losses due to osmotic diarrhea, osmotic

diuresis). Some patients develop hypernatremia despite having diminished total

3
body sodium because water loss is in excess of solute (sodium plus potassium)

loss. Additionally, hypernatremia in the hospital setting is usually due to

inadequate or even inappropriate fluid administration combined with decreased

water intake[1-4]. It should also be mentioned that in some cases certain

solutions and less often certain drugs likely contribute to the increased serum

sodium concentration (Table 1)[11].

In any case, the inadequate repletion of water is a prerequisite for the

development of hypernatremia. Thirst is a strong stimulant for water intake and

the most important defensive mechanism against the development of

hypernatremia. Hence, increased serum sodium levels are usually observed in

patients with diminished physical and mental status who cannot drink enough

water to offset insensible or other losses, in patients with hypodipsia or in

infants who are unable to ask for water. Notably, increasing age is associated

with reduced osmotic stimulation of thirst and this is another reason of the

increased incidence of hypernatremia in patients over the age of 60[1,2,9,12-15].

Clinical findings in patients with hypernatremia

Increased serum sodium levels are associated with cellular dehydration and,

consequently, neurological symptoms attributable to dehydration of cerebral

cells predominate in hypernatremic patients. Acute hypernatremia may induce

lethargy, weakness, irritability, seizures and coma. It should be mentioned,

however, that in cases of chronic hypernatremia (>48 hours) an osmotic

adaptation is observed, which limits the degree of cerebral cellular dehydration

and subsequent neurological symptoms. Thus, patients with chronic

4
hypernatremia may be relatively asymptomatic or oligosymptomatic[1,2,9,16-

21].

In addition to the neurologic changes, patients with hypernatremia may exhibit

symptoms and signs of volume expansion (e.g. peripheral and/or pulmonary

edema) or volume depletion (e.g. postural hypotension, tachycardia, decreased

skin turgor, dry mucous membrane, jugular venous pressure <5 cmH2O).

Electrolyte abnormalities are also usually observed in patients with

hypernatremia. In a series of patients with hypernatremia (n = 113, Na+ >148

mEq/L) approximately half of patients also had at least one electrolyte

disturbance (mainly hypermagnesemia and hyperphosphatemia) that was

mainly related to the underlying cause of hypernatremia rather than to

hypernatremia per se[1].

Clinical and laboratory evaluation of patients with increased serum sodium

levels

The delineation of the underlying mechanisms for the development of

hypernatremia is of paramount importance for the appropriate management of

these patients. We therefore provide a detailed algorithm for the clarification of

hypernatremia. With the use of this algorithm patients with increased serum

sodium levels can be divided in 3 main subgroups according to the extracellular

volume status and then using convenient markers, such as urine osmolality

(Uosm) and electrolyte-free water clearance (CeH2O), the clinician can identify the

specific causes of the electrolyte abnormality and appropriately tailor the

therapeutic measures (Table 2)[1,2,4,17,21-24].

5
1. The first step in the approach of a patient with hypernatremia is to

exclude the possibility that the increased serum sodium levels are due to

an artifact. The exclusion of non-appropriate measurement of serum

sodium levels is crucial in order to avoid inappropriate therapeutic

interventions that could potentially have unfavorable outcome[25]. There

are two methods using ion-selective electrodes (ISE) for the

measurement of serum electrolytes, the direct ISE and the indirect ISE.

The latter is prone to spurious dysnatremias in clinical settings

characterized by hypo- or hyperproteinemia and severe

hyperlipidemia[25]. The analysis of electrolyte concentrations with

indirect ISE is preceded by a dilution step of the sample and the

subsequent calculation of concentration results to a falsely low sodium

concentration when water concentration has been changed by

significantly altered protein levels[26]. Indeed, in hypoalbuminemic

states the indirect ISE may overestimate serum sodium concentration up

to 4 mEq/L compared with direct ISE[27,28]. In contrast, “normal” serum

sodium levels in a patient with severe hyperproteinemia or severe

hyperlipidemia should raise the suspicion that true hypernatremia may

be present (pseudonormonatremia). Consequently, the direct ISE, which

does not preclude a dilution step, is proposed in the presence of

conditions that predispose to spurious dysnatremias[25,29]. However,

pseudohypernatremia may be also observed with direct ISE since venous

blood samples are diluted[30]. In patients with suspected

pseudohypernatremia, measurement of serum osmolality with an

osmometer or sodium levels with a direct potentiometer (using one of the

6
 most modern blood gas analyzers), which do not include a dilution step,

can reveal the true serum sodium concentration [31].

2. Another important point is that in patients with hyperglycemia serum

sodium concentration should be corrected by increasing serum Na+ by 1.6

mEq/L for every 100 mg/dl (5.6 mmol/L) increase in the serum glucose

concentration above the upper limit of normal range, while the correction

factor of 4 mEq/L for every 100 mg/dl increment is used for serum

glucose concentration >400 mg/dl (22.2 mmol/l)[25]. It should be

mentioned that the serum sodium concentration abnormalities seen with

hyperglycemia, although resulting from fluid shifts, are real and not

artifactual.

3. The discrimination between acute (<48 h) and chronic hypernatremia is

also crucial.

4. The assessment of decreased water intake, which is invariably present in

patients with hypernatremia, and the identification of other potential

causes of water losses (renal such as diabetes insipidus or uncontrolled

diabetes mellitus, extra-renal such as gastrointestinal losses or insensible

losses such as in febrile illnesses) is of vital importance. A detailed

medical history with special attention to the determination of a recent use

of drugs that are associated with hypernatremia (Table 1) is also needed.

5. Next step is the assessment of the extracellular volume status, which

should be based on history, physical examination and appropriate

laboratory tests. Hypernatremia accompanied by a decreased volume is

by far the most common type of hypernatremia during admission. In a

series of patients with hypernatremia (n = 113, Na+ >148 mEq/L), those

7
 with hospital-acquired hypernatremia had a clinical and biochemical

profile consistent mainly with normovolemic (51%) or hypovolemic

(41%) hypernatremia, while only 8% of patients had hypervolemic

hypernatremia[1]. However, especially in intensive care units,

hypervolemic hypernatremia is much more common that previously

believed[32]. Patients with volume depletion exhibit low urinary

excretion of sodium (<20 mEq/L)[33]. However, it should be mentioned

that despite the presence of hypovolemia a concentrating defect and an

elevated urine sodium level (>20 mEq/L) might be observed in case of

diuretic administration, osmotic diuresis, postobstructive nephropathy or

the recovery phase from acute tubular necrosis. In such cases, a serum

urea/creatinine ratio >57 is suggested as a reliable index of extracellular

volume depletion[1]. Other signs pointing to presence of hypovolemia

include decreased skin turgor, dry mucous membranes, orthostatic

hypotension, postural tachycardia, prerenal acute renal failure, metabolic

alkalosis and/or hemoconcentration resulting in increased hematocrit or

serum protein levels[33].

The diagnosis of hypervolemic hypernatremia is usually obvious from

physical examination and the history of administration of exogenous

hypertonic sodium-containing solutions. In undefined cases, the

calculation of the sodium (cation) balance is mandatory:

Sodium (cation) balance = [24h oral intake (K++Na+)] + [infused (K+ + Na+)]

− [24h urine (K+ + Na+)]

8
 In cases of hypernatremia, the oral intake of water and solutes is by

definition significantly decreased, so the formula may be simplified to:

Sodium (cation) balance = [infused (K+ + Na+)] − [24h urine (K+ + Na+)]

A positive value indicates that sodium gain contributes to the increase of

serum sodium concentration and is suggestive of the so-called

hypervolemic hypernatremia. Moreover, tonicity balance studies are

confirmatory (see example 2)[1-3,24,34].

6. Next step in the algorithm is the determination of Uosm. A value <300

mosmol/kg suggests diabetes insipidus. In this case the desmopressin test

could differentiate between central and nephrogenic diabetes

insipidus[35]. More specifically, desmopressin administration is

associated with at least 50% increase in Uosm combined with a marked

fall in urine volume in central diabetes insipidus but no changes are

observed in cases of nephrogenous diabetes insipidus[2,16,36]. A Uosm

value between 300-800 mosmol/kg might suggest osmotic diuresis.

However, the diagnosis of a partial diabetes insipidus cannot be ruled out.

In this case the determination of total solute excretion is useful:

Total solute excretion = Uosm × (24h urine volume [L])

The normal value of total solute excretion on a typical western diet is

600-900 mosmol/day; a value >1000 mosmol/day suggests osmotic

diuresis due to glucosuria or increased urea excretion[10]. Finally, a

9
 Uosm value >800 mosmol/kg suggests primary hypodipsia, saline

overload or increased water losses (e.g. insensible or gastrointestinal

water losses)[2,10,36].

7. The determination of CeH2O:

Urine (Na+ + K+)

CeH20=Vurine × (1 – )
Serum Na+

can differentiate between renal or extrarenal water losses. Thus, a

significantly increased positive value suggests increased renal water

losses due to osmotic diuresis, furosemide administration, renal failure or

diabetes insipidus, while a value close to zero or even (rarely) negative

points toward to gastrointestinal or insensible water losses[22,37-39].

7. Taking into account the high incidence of concomitant electrolyte

disorders on patients with hypernatremia other electrolytes like

potassium, magnesium, calcium and phosphorus should also be carefully

monitored[1]. Moreover, an impairment of kidney concentrating ability,

through decreased expression and enhanced autophagic degradation of

aquaporin-2 channels, is observed in hypokalemic (serum potassium

levels <3 mEq/L) and/or hypercalcemic states [serum calcium

concentration >11 mg/dL (2.75 mmol/L)] and may contribute to the

development of hypernatremia[10,40,41]. Of note, the co-existence of

electrolyte abnormalities with hypernatremia may provide important

clues toward the correct diagnosis. For example, the constellation of mild

10
 hypernatremia, history of hypertension and hypokalemia is characteristic

of primary hyperaldosteronism[42].

TREATMENT OF HYPERNATREMIA

The basic principles of treatment of hypernatremia according to the volume

status are provided in Table 3. Special emphasis should be given to the

appropriate choice and rate of administration of intravenous solution during the

management of hypernatremia.

The first step is the determination of the water deficit by the equation:

Serum Na+
Water deficit = Total body water [L] × ( − 1)
140

This equation estimates the amount of water required to decrease serum

concentration to 140 mEq/L[8,17,23,36]. The total body water is estimated as

60% or 50% of lean body weight in men and women, respectively, while in the

water-depleted hypernatremic patients lower values are usually used (50% of

lean body weight in men and 40% in women).

Importantly, the rate of serum sodium lowering should be estimated based on

the severity of neurologic symptoms, the absolute level of the serum sodium

concentration and mainly the time of development of hypernatremia and the

resultant hypertonicity (acute or chronic). A reduction of <8–10 mEq/L/day in

11
serum sodium concentration is appropriate in the majority of cases since a more

rapid correction may be followed by cerebral edema. However, a more

aggressive reduction of serum sodium by 1 mEq/L/hour for the first 6-8 hour is

recommended in patients with acute symptomatic hypernatremia to prevent the

devastating consequences of cellular dehydration including intracerebral or

subarachnoid hemorrhages or even the demyelination syndrome[2,36,43-45].

The second step is the determination of the amount and rate of water

administration required to decrease serum sodium by 8–10 mEq/L/day (see

first example). For this determination clinicians should also take into account

and replace the renal and extra-renal water losses and the insensible losses.

Thus, the infused amount of water should be:

Total infused amount of water⁄day = calculated water deficit needed

to decrease serum sodium levels by 8–10 mEq/L/day + insensible

losses + renal/extra-renal (e.g. gastrointestinal) water losses

The estimated insensible water losses are usually 30-50 ml/hour or 10

ml/kg/day; in febrile patients an additional 3.5 ml/kg/day per 1oC should be

added[46,47]. The renal water losses can be estimated by the electrolyte free

water clearance (CeH2O) as previously mentioned.

Next step is the selection of the proper solution for the decrease of serum sodium

levels. Notably, if a hypotonic saline solution is to be given, the free water

content of the solution should be estimated. Thus, hypotonic (N/2) saline

solution (sodium chloride 0.45%) is a combination of 500 ml of free water and

500 ml of isotonic saline (sodium chloride 0.9%). Hence, the calculated amount

12
of water needed to decrease serum sodium levels should be doubled if hypotonic

(N/2) solution is used[10].

Frequent determination of serum sodium, urea and creatinine levels as well as

urine sodium and potassium is crucial. Other electrolytes like potassium,

magnesium, calcium and phosphorus should also be carefully monitored[1]. The

correction of electrolyte abnormalities may improve the outcome. Especially the

correction of hypokalemia and hypercalcemia, which may contribute to

hypernatremia by impairing kidney concentrating ability, should be included in

the therapeutic interventions[48].

Generally, proper adjustment of the treatment schedule is mandatory for the safe

and effective management of patients with hypernatremia[1-3,17].

It is worth mentioning that the formula proposed by Adrogue - Madias and

verified by Liamis et al[20,49] can be reliably used in hypernatremic patients to

estimate the effect of 1 liter of any infusate on the patient’s serum sodium:

[(Na+ + K+) of the infusate] − (serum Na+)

ΔNa+ =
Total body water +1

The Adrogue–Madias formula considers the patient as a closed system, does not

take into account the ongoing renal or extra-renal water losses and hence

frequent adjustments of therapy may be needed. It should also be mentioned

that the formula did not predict correctly the alterations of serum sodium

concentration in a subgroup of patients with hypernatremia and severe

extracellular volume depletion along with marked reduction of renal function;

thus in this subgroup of patients caution is needed when using this formula[20].

13
As it is obvious from the Adrogue-Madias formula the amount of potassium

added to the infusate should be taken into account when estimating the change

of serum sodium levels during treatment. Potassium is as osmotically active as

sodium. Thus, the potassium concentration should be taken into account in the

previous equations as well as when estimating the tonicity of infusates. For

example, 1 liter of 0.9% sodium chloride plus two ampules of potassium chloride

(containing 13.5 mEq/L of potassium each) is a hypertonic solution

[(Na++K+)=181 mEq/L) with an osmolality of 362 mosmol/L. Similarly, quarter-

isotonic saline (sodium concentration of 38.5 mEq/L) after adding 40 mEq of

potassium is osmotically equivalent to half-isotonic saline (sodium concentration

of 77 mEq/L)[50].

CASE STUDIES

We present here the appropriate treatment of two representative cases of

hypernatremia. As a prerequisite in all cases of hypernatremia, both patients

experienced inability of adequate water intake. The first case exemplifies a

patient with hypernatremia related with volume depletion (hypovolemic

hypernatremia) and the second case describes a patient with hypernatremia due

to sodium overload (hypervolemic hypernatremia). In the latter case, which

represents the case of “too much salt and too little water”, tonicity balance

studies could help both to better understand and successfully manage this not

well known entity[3,34]. Hypervolemic hypernatremia was considered a rather

infrequent cause of hypernatremia due to excessive sodium administration

(accidentally use of a hypertonic sodium chloride or sodium bicarbonate solution

14
during treatment of hyponatremia or metabolic acidosis, respectively). However,

this entity is also described in patients with decreased water intake and

increased renal water losses associated with abnormalities in urinary

concentrating ability or even extra-renal losses, in whom isotonic sodium

chloride solution (±potassium chloride) is administered. Thus, the replacement

of hypotonic losses with isotonic saline solution could lead to increased total

sodium content in relation to total body water and subsequently to

hypernatremia. Recently published studies have described case series with

hypervolemic hypernatremia developed during treatment of hypovolemic shock,

diabetes-associated hypovolemia, or recovering from acute renal failure[3,24,51-

53].

Example 1: A patient with hypovolemic hypernatremia

A 78-year-old male patient (body weight 60 kg) with an acute respiratory illness

of three-days duration developed somnolence and was admitted to the hospital

with increased serum sodium levels (serum Na+ 158 mEq/L). Laboratory

investigation showed: urea 90 mg/dl, creatinine 1.6 mg/dl, potassium 3.8

mEq/L, Uosm 810 mosmol/kg. In a random urine specimen sodium

concentration was 19 mEq/L and potassium 80 mEq/L. The urine volume during

the first 6 hours was 200 ml.

Hypernatremia was clearly ascribed to decreased water intake associated with

increased insensible water losses due to the coexistent respiratory infection.

Laboratory investigation points toward a moderate degree of volume depletion

15
(low urine sodium and increased serum urea/creatinine ratio but no orthostatic

changes or oliguria). An increased Uosm also confirms that extrarenal water

losses contribute to the development of hypernatremia. The low C eH2O (74

ml/6h) implies that increased renal water losses do not play a major role in the

pathogenesis of hypernatremia.

The calculated water deficit [since total body water is estimated in 30 L (body

weight/2) is approximately 3.9 L. Since the patient was oligosymptomatic and it

is anticipated that hypernatremia was chronic (>48h), a value of 8 mEq/L/day

decrease of serum sodium was considered appropriate. Hence, approximately

21/2 days [(total decrease by 18 mEq/L)/(8 mEq/L/day correction)] and

approximately 1560 ml/day (3.9 L/2,5 days) of water are needed to

appropriately correct serum Na+ from 158 mEq/L to 140 mEq/L with a rate of 8

mEq/L/day. Thus, approximately 65 ml/hour (1560 ml/24 hours) of water

should be administrated. However, estimated insensible water losses (30-50

ml/h), should also be taken into account in the calculation of the volume of water

necessary to effectively decrease serum sodium. Thus, approximately 95

ml/hour of water should be initially administered.

Since a moderate degree of extracellular volume depletion was evident, half-

isotonic (N/2, 77 mEq Na+) sodium chloride solution was preferred. Thus, two

times of the calculated amount of free water should be given: 200 ml/hour of

hypotonic (N/2) sodium chloride (0.45%) solution should be administered.

Frequent (even few hours) determination of serum and urine electrolytes but

also parameters of renal function is of paramount importance for the effective

16
and safe decrease of serum sodium. This careful monitoring could allow the

physicians to modify the rate of infusion as necessary.

Furthermore, during treatment the renal water losses should be calculated to

properly adjust the intervention. For example, if the subsequent 6 hours of

therapy the urine volume is 400 ml and urine (Na++K+) is 120 mEq/L, the CeH2O

(thus the renal water losses calculated as the electrolyte free water clearance) is

16 ml/hour (96 ml in 6 hours). Thus, the infusion rate of free water should be

increased to 111 ml/hour.

Alternatively, the infusate formula proposed by Adrogue-Madias could also be

used to calculate the amount of the infusate solution to approximately decrease

serum sodium. In our case, if a hypotonic saline solution (sodium chloride 0.45%,

N/2) is selected, the decrease of serum sodium levels can be easily predicted for

each L of this fluid: ΔΝα+ = -2.6 mEq/L. Thus, approximately 3 L [(8 mEq/L/day

reduction)/(ΔΝα+ 2.6 mEq/L)] of this solution are needed to achieve a decrease

of serum sodium by 8 mEq/L/d. The calculated rate of infusion, 125 ml/h

(3L/24h), is not significantly different than the rate previously calculated. It

should be mentioned that the equation of Adrogue and Madias does not take into

account the ongoing renal and extrarenal water losses. Furthermore, as the

Adrogue and Madias equation points out, the amount of potassium administered

in the infusate solution, should be taken into account, since the tonicity of the

infusates depends on their (Na++K+) content.

Note: a) In cases of severe extracellular volume depletion associated with

hemodynamic abnormalities with oliguria and orthostatic changes, normal saline

(isotonic NaCl solution 0.9%, 154 mEq/L Na+) should be initially given to restore

17
intravascular volume. Simultaneously, a small decrease of serum sodium is

anticipated given that the osmolality of normal saline (154 mEq Na+ + 154 mEq

Cl- are equal to 308 mOsm/L) is often lower than the hypernatremic patients’

serum osmolality. However, the administration of normal saline might be

accompanied by a small increase in serum sodium levels in some cases of

ongoing hypotonic fluid losses. This increment is ascribed to the fact that the

administered normal saline, although it is hypotonic compared with patients’

serum, is relatively hypertonic compared with the ongoing hypotonic fluid losses

[1]. Under these circumstances, the administration of the hypotonic lactated

Ringer’s (osmolality 273 mOsm/L) may be preferable especially if mild

hypokalemia and/or metabolic acidosis due to lower gastrointestinal fluids

losses coexist. Additionally, half isotonic saline plus potassium chloride can be

used in the case of more severe hypokalemia. Importantly, the administration of

0.9% sodium chloride plus potassium chloride should be avoided. In fact, 1 L of

normal saline plus two ampules of potassium chloride (containing 13.5 mEq/L of

potassium each) results in a hypertonic solution [(Na++K+)=154+27=181 mEq/L]

with an osmolality of 362 mOsmol/L. After the restoration of normovolemia,

hypotonic saline solutions or 5% dextrose (or both) should be appropriately

given as previously suggested. Of note, the concomitance of hypernatremia and

metabolic alkalosis (e.g. due to diuretics or volume contraction), serious

hyperkalemia (e.g. due to renal impairment) or lactic acidosis with decreased

lactate clearance (e.g. due to an underlying infection and reduction of renal

function) should be considered as contraindication for lactated Ringer’s solution

administration[50].

18
b) A more hypotonic sodium chloride solution (0.225%, N/4) can also be

administered in patients with severe hypernatremia with mild hypovolemia.

However, the safety of this hypotonic solution has not been established and the

administration of quarter isotonic saline in dextrose solution may be preferable

in most patients in order to avoid any risk of hemolysis.

Example 2: A patient with the so-called hypervolemic hypernatremia

A 79-year-old patient (body weight 60 kg, total body water 30 L) with stroke was

admitted to the Internal Medicine Clinic. Isotonic sodium solution (0.9%) with 40

mEq/L of potassium chloride was administered (1L/d) as “maintenance fluid.”

On admission serum sodium was 144 mEq/L, serum potassium 4.2 mEq/L and

creatinine was 1 mg/dl. On the fourth day of hospitalization laboratory

investigation showed serum sodium 150 mEq/L. Urine volume was 900 ml/day,

urine sodium 100 mEq/L, urine potassium 40 mEq/L, and Uosm 805

mosmol/Kg.

No clinical or laboratory evidence of extracellular volume depletion was evident.

However, the difference between administered K+ + Na+ (154 + 40 = 194 mEq)

and their urine excretion (0.9 X 140=126 mEq) is +68 mEq (net positive cation

balance), which suggests the presence of the so-called hypervolemic

hypernatremia. The increased Uosm is also compatible with hypervolemic

hypernatremia associated with the administration of a relatively hyperosmolar

solution (sodium chloride 0.9% plus potassium chloride) in a patient with

ongoing hypotonic (insensible) losses but with decreased water intake. The C eH2O

19
was 63 ml/day, a value that precludes the contribution of renal water losses to

the development of hypernatremia.

In cases of hypervolemic hypernatremia tonicity balance studies are especially

helpful for the better understanding of the serum sodium changes and the

appropriate patient’s management. For example, on patient’s admission the total

body cation content (Na+) was: Serum sodium X total body water = 144 mEq/L X

30 L = 4320 mEq. During the 4 days of hospitalization, a net positive cation

balance of 272 mEq was observed (68 mEq x 4 days). Thus, the new total body

cation content is 4320 + 272 = 4.592 mEq. The total body water was increased by

only 0.4 L [4L- (0.9 X 4L)] (Figure 1). Thus, the predicted new sodium

concentration would be

Total body cation content 4592

Serum sodium = = = 151 mEq,
Total body water 30 +0.4

a value very similar to the measured one.

Notably, in hypervolemic hypernatremia, despite the hypervolemia, the

administration of furosemide alone should not be given because it is associated

with excretion of hypotonic urine and exacerbation of hypernatremia if these

hypotonic losses are not sufficiently replaced[5]. Indeed, in our case the serum

sodium levels further increased to 154 mEq/L after the administration of

furosemide (20 mg x 2 i.v.). Moreover, urine volume was increased to 2.4 L/day

with urine sodium plus potassium levels of 100 mEq/L, while the Uosm was 320

mosmol/kg.

20
After furosemide administration, the total body cation content decreased by 240

mEq [Vurine x (urine sodium + potassium) = 2.4L X 100mEq/L)]. Thus, the new

total body cation content is 4592 - 240=4352 mEq, while the total body water

decreased by 2.4 L and the new total body water is 28 L (30.4 -2.4). Thus, the

predicted new serum sodium concentration would be:

Total body cation content 4352

Serum sodium = = =155 mEq/L,
Total body water 28

a value similar to the measured one (154 mEq/L).

In cases of hypervolemic hypernatremia, free water replacement with

intravenous glucose solution (plus furosemide) is the treatment of choice.

As described in Example 1, it was estimated that 1400 ml water should be

infused to correct serum Na+ by approximately 8 mEq/L/day. In this amount,

approximately 700 ml/24h (30 ml/hour) should be added to account for

insensible water losses. In this patient significant extra-renal water losses (for

example gastrointestinal) are not reported. In fact, after 2 L of glucose solution,

serum sodium decreased by 7 mEq/L (new serum sodium 147 mEq/L).

During treatment of hypernatremia frequent (even few hours) determination of

serum and urine electrolytes and appropriate modifications of the infusion rate

is crucial to avoid overcorrection of serum sodium levels.

Tonicity balance studies can also explain the changes in serum sodium: Vurine

was 1.2 L with urine sodium and potassium levels 90 mEq/L after the

administration of the glucose solution. The total body cation content decreased

by 108 mEq (90 mEq X 1.2 L). The new total body cation content was 4244 mEq

21
(4352-108 mEq) and the total body water increased by 0.8 L (2-1.2 L) resulting

in a new total body water of 28.8 L. Thus, the new serum sodium concentration

would be:

Total body cation content 4244

Serum sodium = = =147 mEq,
Total body water 28.8

a value identical to the measured one.

Conclusions

Hypernatremia is attributed to increased total body sodium and/or decreased

total body water (dehydration) in the context of decreased oral water intake. The

detailed evaluation of the underlying mechanisms and the careful choice of type

and rate of infusates during treatment of hypernatremia is of paramount

importance since the under- or overcorrection of this electrolyte disorder is

associated with increased morbidity and mortality especially in the elderly and

critically ill patients.

22
References

1. Liamis G, Tsimihodimos V, Doumas M, et al. Clinical and laboratory

characteristics of hypernatraemia in an internal medicine clinic. Nephrol

Dial Transplant 2008;23:136-43.

2. Lindner G, Funk GC. Hypernatremia in critically ill patients. J Crit Care

2013;28:216 e11-20.

3. Hoorn EJ, Betjes MG, Weigel J, Zietse R. Hypernatraemia in critically ill

patients: too little water and too much salt. Nephrol Dial Transplant

2008;23:1562-8.

4. Shah MK, Workeneh B, Taffet GE. Hypernatremia in the geriatric

population. Clin Interv Aging 2014;9:1987-92.

5. Liamis G, Rodenburg EM, Hofman A, et al. Electrolyte disorders in

community subjects: prevalence and risk factors. Am J Med

2013;126:256-63.

6. Bataille S, Baralla C, Torro D, et al. Undercorrection of hypernatremia is

frequent and associated with mortality. BMC Nephrol 2014;15:37.

7. Kovacs L, Robertson GL. Disorders of water balance-hyponatraemia and

hypernatraemia. Baillieres Clin Endocrinol Metab 1992;6:107-27.

8. Edelman IS, Leibman J, O'Meara MP, Birkenfeld LW. Interrelations

between serum sodium concentration, serum osmolarity and total

exchangeable sodium, total exchangeable potassium and total body water.

J Clin Invest 1958;37:1236-56.

23
9. Danziger J, Zeidel ML. Osmotic homeostasis. Clin J Am Soc Nephrol

2015;10:852-62.

10. Rose B, Post T. Clinical physiology of acid-base and electrolyte disorders.

5th ed. McGraw-Hill. New York.: McGraw-Hill; 2001.

11. Liamis G, Milionis HJ, Elisaf M. A review of drug-induced hypernatraemia.

NDT Plus 2009;2:339-46.

12. Robertson GL, Aycinena P, Zerbe RL. Neurogenic disorders of

osmoregulation. Am J Med 1982;72:339-53.

13. Kenney WL, Chiu P. Influence of age on thirst and fluid intake. Med Sci

Sports Exerc 2001;33:1524-32.

14. Phillips PA, Bretherton M, Johnston CI, Gray L. Reduced osmotic thirst in

healthy elderly men. Am J Physiol 1991;261:R166-71.

15. Stachenfeld NS, DiPietro L, Nadel ER, Mack GW. Mechanism of attenuated

thirst in aging: role of central volume receptors. Am J Physiol

1997;272:R148-57.

16. Sterns RH. Disorders of plasma sodium-causes, consequences, and

correction. N Engl J Med 2015;372:55-65.

17. Harring TR, Deal NS, Kuo DC. Disorders of sodium and water balance.

Emerg Med Clin North Am 2014;32:379-401.

18. Maggs FG. The management of patients presenting with hypernatraemia:

is aggressive management appropriate? Clin Med 2014;14:260-3.

19. van der Helm-van Mil AH, van Vugt JP, Lammers GJ, Harinck HI.

Hypernatremia from a hunger strike as a cause of osmotic myelinolysis.

Neurology 2005;64:574-5.

24
20. Liamis G, Kalogirou M, Saugos V, Elisaf M. Therapeutic approach in

patients with dysnatraemias. Nephrol Dial Transplant 2006;21:1564-9.

21. Overgaard-Steensen C, Ring T. Clinical review: practical approach to

hyponatraemia and hypernatraemia in critically ill patients. Crit Care

2013;17:206.

22. Popli S, Tzamaloukas AH, Ing TS. Osmotic diuresis-induced

hypernatremia: better explained by solute-free water clearance or

electrolyte-free water clearance? Int Urol Nephrol 2014;46:207-10.

23. Braun MM, Barstow CH, Pyzocha NJ. Diagnosis and management of

sodium disorders: hyponatremia and hypernatremia. Am Fam Physician

2015;91:299-307.

24. Al-Absi A, Gosmanova EO, Wall BM. A clinical approach to the treatment of

chronic hypernatremia. Am J Kidney Dis 2012;60:1032-8.

25. Liamis G, Liberopoulos E, Barkas F, Elisaf M. Spurious electrolyte

disorders: a diagnostic challenge for clinicians. Am J Nephrol 2013;38:50-

7.

26. Fortgens P, Pillay TS. Pseudohyponatremia revisited: a modern-day

pitfall. Arch Pathol Lab Med 2011;135:516-9.

27. Dimeski G, Morgan TJ, Presneill JJ, Venkatesh B. Disagreement between

ion selective electrode direct and indirect sodium measurements:

estimation of the problem in a tertiary referral hospital. J Crit Care

2012;27:326 e9-16.

28. Goldwasser P, Ayoub I, Barth RH. Pseudohypernatremia and

pseudohyponatremia: a linear correction. Nephrol Dial Transplant

2015;30:252-7.

25
29. Spasovski G, Vanholder R, Allolio B, et al. Clinical practice guideline on

diagnosis and treatment of hyponatraemia. Eur J Endocrinol

2014;170:G1-47.

30. Turchin A, Seifter JL, Seely EW. Clinical problem-solving. Mind the gap. N

Engl J Med 2003;349:1465-9.

31. Filippatos T, Liamis G, Christopoulou F, Elisaf M. Ten common pitfalls in

the evaluation of patients with hyponatremia. Eur J Internal Med

2015:doi:10.1016/j.ejim.2015.11.022.

32. Sarahian S, Pouria MM, Ing TS, Sam R. Hypervolemic hypernatremia is the

most common type of hypernatremia in the intensive care unit. Int Urol

Nephrol 2015;47:1817-21.

33. Volume depletion in adults. http://bestpractice.bmj.com/best-

practice/monograph/937/diagnosis/step-by-step.html. Accessed at 23/9/15.

34. Carlotti AP, Bohn D, Mallie JP, Halperin ML. Tonicity balance, and not

electrolyte-free water calculations, more accurately guides therapy for

acute changes in natremia. Intensive Care Med 2001;27:921-4.

35. Saifan C, Nasr R, Mehta S, et al. Diabetes Insipidus: A challenging diagnosis

with new drug therapies. ISRN Nephrology 2013;2013:7.

36. Adrogue HJ, Madias NE. Hypernatremia. N Engl J Med 2000;342:1493-9.

37. Bodonyi-Kovacs G, Lecker SH. Electrolyte-free water clearance: a key to

the diagnosis of hypernatremia in resolving acute renal failure. Clin Exp

Nephrol 2008;12:74-8.

38. Lindner G, Schwarz C. Electrolyte-free water clearance versus modified

electrolyte-free water clearance: do the results justify the effort? Nephron

Physiol 2012;120:p1-5.

26
39. Lindner G, Schwarz C, Funk GC. Osmotic diuresis due to urea as the cause

of hypernatraemia in critically ill patients. Nephrol Dial Transplant

2012;27:962-7.

40. Khositseth S, Uawithya P, Somparn P, et al. Autophagic degradation of

aquaporin-2 is an early event in hypokalemia-induced nephrogenic

diabetes insipidus. Sci Rep 2015;5:18311.

41. Amlal H, Krane CM, Chen Q, Soleimani M. Early polyuria and urinary

concentrating defect in potassium deprivation. Am J Physiol Renal Physiol

2000;279:F655-63.

42. Gregoire JR. Adjustment of the osmostat in primary aldosteronism. Mayo

Clin Proc 1994;69:1108-10.

43. Severs D, Rookmaaker MB, Hoorn EJ. Intravenous solutions in the care of

patients with volume depletion and electrolyte abnormalities. Am J

Kidney Dis 2015;66:147-53.

44. Verbalis JG. Brain volume regulation in response to changes in osmolality.

Neuroscience 2010;168:862-70.

45. Agrawal V, Agarwal M, Joshi SR, Ghosh AK. Hyponatremia and

hypernatremia: disorders of water balance. J Assoc Physicians India

2008;56:956-64.

46. Cox P. Insensible water loss and its assessment in adult patients: a review.

Acta Anaesthesiol Scand 1987;31:771-6.

47. Frost P. Intravenous fluid therapy in adult inpatients. BMJ 2015;350.

48. Khanna A. Acquired nephrogenic diabetes insipidus. Semin Nephrol

2006;26:244-8.

27
49. Adrogue HJ, Madias NE. Aiding fluid prescription for the dysnatremias.

Intensive Care Med 1997;23:309-16.

50. Liamis G, Filippatos TD, Elisaf MS. Correction of hypovolemia with

crystalloid fluids: Individualizing infusion therapy. Postgrad Med

2015;127:405-12.

51. Liamis G, Kalaitzidis R, Elisaf M. Hypernatremia during correction of

hypercalcemia. Nephron 2000;86:358.

52. Milionis HJ, Liamis G, Elisaf MS. Hypernatremia in hospitalized patients: a

sequel of inadvertent fluid administration. Arch Intern Med

2000;160:1541-2.

53. Kahn T. Hypernatremia with edema. Arch Intern Med 1999;159:93-8.

28
Figure legend

Figure 1. Input and output of water and effective solute (Na++K+) during the

observation period (4 days). Hypernatremia is attributed to more positive

sodium than water balance.

29
Table 1. Drugs that cause hypernatremia

Drug Main mechanism (s)

Lithium i) Hypercalcemia leading to nephrogenic

diabetes insipidus and causing water

loss

ii) Central diabetes insipidus

Hypervitaminosis A and D Hypercalcemia leading to nephrogenic diabetes

insipidus

Cisplatin Hypokalemia leading to nephrogenic diabetes

insipidus

Aminoglycosides Hypokalemia leading to nephrogenic diabetes

insipidus

Demeclocycline Nephrogenic diabetes insipidus

Amphotericin B Nephrogenic diabetes insipidus

Phenytoin Central diabetes insipidus

Ethanol Central diabetes insipidus

Loop diuretics Water loss

Manitol Osmotic diuresis

Corticosteroids Urea increase

Vasopressin receptor Water diuresis

inhibitors (vaptans)

Lactulose/sorbitol Hypotonic gastrointestinal losses

Hypertonic NaHCO3 or NaCl Increased Na+ administration

solution

30
31
TABLE 2: Classification and etiology of hypernatremia

Hypovolemic hypernatremia CeH2O positive: renal losses (osmotic

•  Total body water diuresis due to glucosuria or to the

•  Total body Na+ presence of an osmotic substance in

the urine as well as due to increased

urea excretion, furosemide

administration, underlying renal

disease, such as post-obstructive

diuresis and diuresis phase of acute

tubular necrosis).

•  urine sodium,  Uosm*

CeH2O negative: extrarenal causes due

to osmotic diarrhea or excess sweating.

•  urine sodium,  Uosm

Euvolemic hypernatremia CeH2O positive: renal losses (central or

•  Total body water nephrogenous diabetes insipidus)

• Total body Na+ unchanged •  Uosm

CeH2O positive: extrarenal losses:

increased insensible losses (fever,

tachypnea), hypodipsia, decreased

32
 water intake

•  Uosm

Hypervolemic hypernatremia CeH2O usually positive: Salt poisoning,

•  Total body Na+ administration of hypertonic saline

• Total body water variable (N, solutes, primary aldosteronism,

 or ) inadvertent use of isotonic solutions in

patients with impaired urinary

concentrating ability

• [sodium + potassium] given

with infusates and

enteral/parenteral nutrition –

24-hour urine [sodium +

potassium] >0.

•  Uosm,  urine sodium

*The increased solute excretion (>1000 mosmol/day) is a useful marker of

osmotic diuresis due to glycosuria or increased renal urea excretion (solute

excretion=Vurine x Uosm)

CeH2O: electrolyte-free water clearance

Uosm: Urine osmolality

33
Table 3: Treatment of hypernatremia according to volume status

Hypovolemic hypernatremia Normal saline solutions or Lactated

Extracellular volume depletion with Ringer’s (very small changes of serum

orthostatic changes and oliguria. sodium are anticipated) to restore

volume and afterwards hypotonic

saline solutions (half isotonic saline or

quarter-isotonic saline in dextrose

solutions) or even glucose solutions.

Milder volume deficit: half isotonic

saline or quarter-isotonic saline

Euvolemic hypernatremia Free water replacement (water per os

or intravenous glucose solution)

Hypervolemic hypernatremia Free water replacement (intravenous

glucose solution) plus furosemide

34
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