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Clinical approach to disorders of salt and

water balance

Emphasis on integrative physiology

Mitchell L. Halperin, MD, FRCPC

a,*,Desmond Bohn, MB, FRCPC b

a Division of Nephrology, St. Michaels Hospital and the University of Toronto,

St. Michaels Hospital Annex, 38 Shuter Street, Toronto, Ontario, M5B 1A6, CanadabDepartment of Critical Care Medicine of the Hospital for Sick Children,

and the Department of Anaesthesia, The University of Toronto, 555 University Ave.,

Toronto, Ontario, M5G 1X8 Canada

With our current emphasis on subspecialty medicine, consultants suggest

possible diagnoses and treatments for patients who have abnormalities withintheir areas of expertise. The medical team responsible for the care of that patient

must integrate these suggestions into an overall management plan. Therefore,

teamwork is especially important for the care of a patient.

The underlying basis for a given disorder may be revealed when an integrative

analysis is performed. Some defects may only become evident during therapy.

These challenges are especially important for problems in fluid and electrolyte

balance in an intensive care unit (ICU) setting because they may become life-

threatening very rapidly. How to anticipate and avoid these dangers is illustrated

in the context of case examples selected for presentation in this article.There are two different, but not mutually exclusive, ways to arrive at a

clinical diagnosis and to design its therapy when the problem is in the salt and

water area. The more traditional approach begins with data from the history,

physical examination, and laboratory tests. This information is used to generate

a list of possible causes of the disorder. Our approach differs in that it begins

with the application of simple principles of physiology at the bedside (Table 1)

[5]. It relies on deductive reasoning and a quantitative analysis. The starting

point is defined by the consulting service what they believe to be most

critical for their patient.

0749-0704/02/$ - see front matterD 2002, Elsevier Science (USA). All rights reserved.

PII: S 0 7 4 9 - 0 7 0 4 ( 0 1 ) 0 0 0 0 8 - 2

* Corresponding author.

E-mail addresses: [email protected] (M.L. Halperin), [email protected] (D. Bohn).

Crit Care Clin 18 (2002) 249272


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To make this article interactive, we pause periodically and ask the readerquestions to consider prior to providing our discussion of that issue. In

each case, there is an abnormal plasma sodium (Na+ ) concentration (PNa) in

an ICU setting.

Polyuria and hypernatremia

Illustrative case 1

Polyuria (current urine flow rate 10 ml/min) developed suddenly in a

14-year-old boy (weight 50 kg, total body water 30 liters) during resection

of a craniopharyngeoma. His PNa rose from 140 to 155 mmol/ over 6 hours. He

was given 3 liters of isotonic saline intravenously and his urine output was

4 liters. He had also received an infusion of mannitol. The aim of the consult

was to define goals of therapy for this patient.

Table 1

Physiologic principles used at the bedside

Physiologic principle Use at the bedside

Polyuria Divide polyuria into:

Urine volume = Osm/UOsm Osmotic diuresis if > 1000 mOsm/d

Organic solutes

Examine filtered load

Seek metabolic origin (e.g., urea)

Electrolytes (were they infused?)

Water diuresis (Uosm < Posm)

UOsm a osm excretion and flow rate

Impact of a change in PNa Main threat is change in brain ICF volume

PNa inversely related to ICF volume Na+ content reflects the ECF volume

Hypernatremia Basis revealed by tonicity balanceCaused by Na+ gain or water deficit Identify cause for the release of vasopressin

Calcium receptor in the loop of Henle NaCl, K+ wasting and concentrating defect

Creates furosemide-like effect Can be induced by cations (gentamicin)

Catabolic state Confirmed by urea (572 mmol/100 g protein)

Protein oxidation causes urea appearance Therapy with exogenous protein anabolics

Hyponatremia Ask if acute ( < 48 h) = increased brain

ICF volume

Find source of EFW and vasopressin Risk factors = young age, women,

increased ECF volume

Calculate new ICF volume Urgent therapy 3% saline

Calculate ECF Na+ content Retained lavage fluid = different

Assess possible K+ deficiency Most are chronic (danger is ODS)

Seek reason for vasopressin, especially

if a reversible cause might be present

Treat slowly ( < 9 mmol/L/d); slower if K+

deficit or malnourished

Abbreviations: U=urine; P=plasma.

M.L. Halperin, D. Bohn / Crit Care Clin 18 (2002) 249272250


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Initial quantitative analysis

The urine flow rate of 10 ml/min, if extrapolated over 24 hours, is

equivalent to 14.4 liters per day. This volume exceeds the patients extracellularfluid (ECF) volume and is virtually equal to half of total body water. Faced

with this medical emergency, we ask the reader: What was responsible for this

massive polyuria?

What was responsible for this massive polyuria?

Physiology principle 1. The urine flow rate is a function of two factors

(Eq. 1). Hence polyuria has two causes, a larger than normal solute excretion rate

(osmotic diuresis) and/or an inability to raise the concentration of solutes in the

urine appropriately (water diuresis). In an osmotic diuresis, each liter of urinecontains at least 300 milliosmoles of the causative solute (and other solutes as

well) [32].

Urine f low rate liters=day

Number of Solutes excreted=Solutesurine 1

Return to the bedside. Using the values from surgery, 3 milliosmoles of extra

solutes (10 ml/min a minimum of 300 milliosmoles/l in an osmotic diuresis)

would need to be excreted each minute if this was a glucose, urea, or mannitol-induced osmotic diuresis. This would require the presence of very high concen-

trations of these organic solutes in plasma if one of them caused the polyuria. If the

urine composition were not available, the following calculation could be

performed to determine whether enough solutes were filtered to cause the osmotic

diuresis. With a normal glomerular filtration rate (GFR), the concentration of

glucose in the filtrate would have to be 27 mmol/l (486 mg/dl) higher than the

renal threshold of 10 mmol/l (180 mg/dl) to filter 3 mmol of glucose per min to

permit it to cause this degree of osmotic diuresis (24 mmol/l 0.125 l/min).

Hence the blood sugar levels would need to be 666 mg/dl (37 mmol/l) for this to bea glucose-induced osmotic diuresis [14]. If urea were the principal urine osmole,

its concentration in plasma would have to be close to 60 mmol/l (BUN 168 mg/dl)

because close to half of the filtered urea is normally reabsorbed [9]. Even higher

plasma concentrations would be needed if the GFR were lower than 125 ml/min.

For mannitol, at least 50 g ($ 290 mmol) would have to be infused for every literof urine excreted.

Based on this, extra information was sought. Because the blood sugar and

BUN were both in the normal range and the quantity of mannitol infused was too

small, an osmotic diuresis due to organic solutes was ruled out. The fact that theurine Na+ + potassium (K+ ) concentration was only 50 mmol/l ruled out a saline-

induced osmotic diuresis. Therefore the basis for the polyuria was a water

diuresis, a diagnosis that was confirmed when his urine osmolality was known

(120 mOsm/kg H2O).

The next question is, What was the cause of the large water diuresis? It is

essential to recall that his PNa was 155 mmol/l during the polyuria.

M.L. Halperin, D. Bohn / Crit Care Clin 18 (2002) 249272 251


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What was the cause of the large water diuresis?

Physiology principle 2. The control system for water has its sensor

(specialized area of the hypothalamus) in a different location from one of itsresponse elements (excretion of water by the kidney). Therefore a messenger

(vasopressin) must communicate between these two locations (Fig. 1). The cell

volume of the central osmostat shrinks sufficiently when the PNa exceeds

140 mmol/l and this leads to an augmented release of vasopressin. Vasopressin

causes the distal segments of the nephron to become permeable to water due to

the insertion of water channels [27], causing the urine to become maximally

concentrated (the urine osmolality should be 34-fold higher than the plasma

osmolality) [29].

Return to the bedside. A lesion releasing vasopressinase was unlikely in thispatient. There were two factors suggesting that the likely diagnosis was central

diabetes insipidus (DI). First, there was the neurosurgery and a disease process

(craniopharyngeoma) that could have compromised the ability to release vaso-

pressin from the hypothalamus. Second, there was a large water diuresis (the

urine osmolality was 120 mOsm/kg H2O) despite the presence of a stimulus for

the release of vasopressin (hypernatremia). To confirm that the DI was central

rather than nephrogenic in origin, vasopressin was administered. Bearing in mind

that vasopressin acts in a matter of minutes [27], we ask the reader, How low

should the urine flow rate be when vasopressin acts?The measured value forthis urine flow rate was 6 ml/min.

Fig. 1. Control system for water excretion. The circles represent structures in the hypothalamus. The

tonicity stat (osmostat) detects a change in the PNa. Because of hypernatremia (box on the left), this

center leads to the release of vasopressin (VP). Vasopressin acts on the distal nephron to cause it to

become permeable to water leading to the excretion of concentrated urine. There are also non-osmotic

stimuli that influence the release of vasopressin.



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How low should the urine flow rate be when vasopressin acts?

Application of physiology principle 1. First, the urine flow rate depends on

two factors, the number of impermeable solutes (effective or non-urea osmoles) inthe lumen of the terminal collecting duct and the effective osmolality (non-urea

osmolality) of the papillary medullary interstitium (Eq. 1) [11]. Second, a typical

diet leads to the excretion of 800 mosmoles/day, with half being urea and the other

half, electrolytes. Third, because the non-urea osmolality can rise to 600 mOsm/kg

H2O when vasopressin acts, the expected urine flow rate is close to 0.67 ml/min

under these conditions (400 mosmoles of electrolytes excreted at a concentration

of 600 mosmoles per liter). Fourth, the maximum total and effective osmolalities

in the renal interstitial compartment decline during a prior water diuresis and it

takes time to reconstitute this environment after vasopressin acts. Return to the bedside. A urine osmolality of 120 mOsm/kg H2O is not the

expected value during a water diuresis when the urine flow rate is 10 ml/min.

Rather, the urine osmolality should have been 50 60 mOsm/kg H2O if 800

milliosmoles were excreted in 1440 min (0.50.6 milliosmoles/min) [5]. More-

over, in a water diuresis, water is largely impermeable in the distal nephron.

Therefore a high rate of excretion of osmoles should not influence the urine flow

rate when there is a lack of vasopressin. In contrast, when vasopressin acts, the

osmole excretion rate will exert a major effect on the urine flow rate (Eq. 1).

A change in urine flow rate is obvious at the bedside whereas a delay isexpected before the laboratory reports the urine osmolality. Therefore clinical

decision making will be based initially on the decline in urine flow rate. On the

one hand, normal subjects have a minimum urine flow rate of close to 0.5 ml/min

when vasopressin acts [30]. Accordingly, one might anticipate that the urine

volume should fall to 0.5 ml/min after vasopressin was given. A surprise is in

store if this were the logic used. The error would be to rely on data obtained from

one setting (normal subjects) and apply them to this patient in the ICU.

Comment. Had a physiologic analysis been performed at the time when the

urine flow rate was 10 ml/min, the observed decrease to 6 ml/min aftervasopressin administration could have been anticipated if three facts were taken

into account. First, the patient was excreting effective osmoles (urine electrolytes)

at a rate that was close to 3-fold that of subjects consuming a typical Western diet

(10 ml/min 50 mmol Na+ + K+ /l = 0.5 mmol/min) vs. the expected 225 mmolNa+ + K+ /day or 0.15 mmol/min. Second, the huge water diuresis that occurred

prior to the administration of vasopressin should diminish the medullary inter-

stitial osmolality and this would take time to be reconstituted. Thus the maximum

urine osmolality would be similarly reduced. Third, the peak natriuresis might not

have been reached at the time that the first urine osmolality was measured. Indeed,the rate of osmole (Na+ + K+ ) excretion continued to rise after vasopressin was

given. Thus a urine flow rate after vasopressin that was more than 10-fold that of

subjects consuming a typical Western diet was a more realistic expectation. Hence,

by not applying physiologic principles to the bedside, a series of compounding

errors were set into motion that had grave consequences for the patient. One of the

errors was to give multiple doses of a long-acting preparation of vasopressin,



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dDAVP. The grave consequences of this error in therapy will be discussed in the

response to the question, what was the occult threat to survival?

Now we ask the reader to consider, What is the basis of hypernatremia in this patient with central DI?

What is the basis of hypernatremia in this patient with central DI?

Physiology principle 3. To raise the PNa by 10%, there must either be a gain

of Na+ and/or a deficit of water in the ECF compartment (Table 1). In quan-

titative terms, the gain of Na+ is calculated in total body water terms so a rise in

PNa of 15 mmol/l requires a positive balance of approximately 450 mmoles of

Na+ (15 mmol/l 30 liters total body water (i.e., 60% of body weight in this

patient). On the other hand, because water distributes across all body fluidcompartments in proportion to their volumes [33], the deficit of water must be

close to 10% of total body water (10% 30 liters, or 3 liters) to cause theobserved 10% rise in PNa.

Return to the bedside. We begin with an analysis based on electrolyte-free

water (water without Na+ + K+ ) to illustrate its limitations (Fig. 2). To think in

electrolyte-free water terms [10,23,28], an imaginary calculation is performed

where the 4 liters of urine in our patient are divided into 1.3 liters of isotonic saline

(use 150 mmol of Na+ + K+ /liter for simplicity) and the remaining 2.7 liters is

called electrolyte-free water (Fig. 2). It is important to calculate an electrolyte-free water balance rather than focus on either excretion or input to determine why

the PNa changed. This can easily be done in our patient because the input

contained 0 liters of electrolyte-free water while 2.7 liters of electrolyte-free water

were excreted. This negative balance of 2.7 liters of electrolyte-free water should

raise the PNa by close to 15 mmol/l (140 mmol/l (30/27.3 liters). If anelectrolyte-free water balance were used to design therapy, a positive balance of

Fig. 2. Calculation of electrolyte-free water. The urine volume in Case 1 was 4 liters (large rectangle)

and its Na+ + K+ concentration was 50 mmol/l (left of arrow). This solution can be divided into two

imaginary components, 1.3 liters of isotonic saline (150 mmol Na+ + K+ /liter) and 2.7 liters of

electrolyte-free water (EFW). (From RossMark Medical Publishers, The Acid Truth and Basic Facts,

4th ed, 1997; with permission) [13].



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2.7 liters of electrolyte-free water should be induced to correct the hypernatremia.

Notwithstanding, there are many ways to achieve a negative balance of 2.7 liters

of electrolyte-free water [3]. For example, if we made a change only to thevolume of isotonic saline infused during the period in which hypernatremia

developed (now 4 liters instead of 3 liters), there is still no electrolyte-free water

administered so the balance for electrolyte-free water is still minus 2.7 liters.

Therefore the rise in PNa would be identical, but its basis would be different

(Table 2). Obviously, the goals of therapy should also be different in these

examples despite the fact that the negative balance of electrolyte-free water and

rise in PNa were identical. Therefore one cannot rely on an electrolyte-free water

balance to guide therapy (Table 2). [3].

A better way to determine why the PNa changed is to calculate a tonicity balance (Fig. 3) where all inputs and outputs are also divided into two

components, total volume of water and Na+ + K+ each of which is analyzed

separately [3]. Mass balance for Na+ plus K+ rather than just Na+ must be

included because Na+ may enter cells in conjunction with the exit of K+ [8].

Thus the loss of K+ with chloride (Cl ) or bicarbonate can be thought of as a

loss of their Na+ salts from the ECF compartment. When considering Na+ + K+

in isolation, for every mmol retained per liter of total body water, the rise in PNawill be 1 mmol/l [33]. Similarly, a gain of 1 liter of water, when considered in

isolation should lower the PNa by the formula: PNa (1/total body water).In addition to predicting the rise in PNa [3], the tonicity balance also provides

reliable information about its cause (Table 2). In our patient, the volume of water

infused was 1 liter less than the urine volume. Recall that 3 liters of net water loss

would be required to raise the PNaby 10%. Therefore hypernatremia in our patient

was not due solely to a water deficit despite the large electrolyte-free water

diuresis. Since the patient was given 450 mmol Na+ and excreted 200 mmol Na+

(+ K+ ) in his urine, there was a net gain of 250 mmol of Na+ + K+ . The

Table 2Hypernatremia and a negative balance of 2.7 L of electrolyte-free watera

Na+ + K+Therapy from balances

(mmol) Water (L) EFW (L) EFW Tonicity

Case 1

Input 450 3 0

Output 200 4 2.7

Balance + 250 1 2.7 + 2.7 L H2O + 1 L H2O 250 mmol Na+

Change IV to 4L of isotonic saline

Input 600 4 0

Output 200 4 2.7

Balance + 400 0 2.7 + 2.7 L H2O 0 L H2O 400 mmol Na+

a The PNa rose from 140 to 155 mmol/L in each setting. The only difference is the volume of

isotonic saline infused over the time period of observation. In both settings, there is a negative balance

of 2.7 liters of electrolyte-free water (EFW). The goals of therapy to correct the hypernatremia were

clear only after a tonicity balance was calculated.



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combination of a deficit of 1 liter of water and a gain of 250 mmol of Na+ would

explain the rise in PNa. In contrast to information provided by an electrolyte-free

water balance, the tonicity balance revealed the goals for therapy create a

negative balance of 250 mmol of Na+

(+ K+

) along with a positive balance of1 liter of water (Table 2). This therapy will correct hypernatremia and return both

the ICF and ECF compartment volumes to normal. Moreover, the tonicity balance

provides a physiologic basis for the clinical implications of hypernatremia. When

a tonicity balance is used in the hypothetical example (i.e., when 4 liters of isotonic

saline were administered), it is clear that the goals of therapy are to create a

negative balance for Na+ + K+ of 400 mmol and a nil balance of water. Given the

short time interval, insensible losses would be relatively small. Therefore, because

of the absence of fever, we would not include them in this patient.

Clinical course. After administration of vasopressin, the measured concen-trations of Na+ + K+ in the urine rose to 175 mmol/l. The intravenous fluid

therapy was half-isotonic saline (close to 75 mmol Na+ /liter) at volumes equal

to the urine output this caused a deficit of almost 100 mmol of Na+ per liter

of throughput. After the excretion of 2.5 liters of urine, the desired negative

balance of 250 mmol of Na+ would have occurred. The other goal of therapy

was to expand his body water by 1 liter and this was achieved by giving a

positive balance of 1 liter of electrolyte-free water (i.e., 1 liter of D5W if

hyperglycemia was not present). At this point, both his ICF and ECF volumes

and composition would be restored to normal (PNa would be 140 mmol/l). Asuccessful clinical outcome was anticipated. We ask the reader,What is the

occult threat to survival?

What was the occult threat to survival?

Application of physiology principle 3. The PNa is used to reflect the volume

of the ICF compartment for three reasons (Fig. 4). First, water crosses cell

Fig. 3. Calculation of a tonicity balance. The rectangle represents the body with its concentration of

Na + . The input of Na+ + K+ and of water are shown on the left; the output of Na+ + K+ and of water

are shown on the right of this rectangle in Case 1. Balances are shown in dashed boxes inside

the rectangle.



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membranes rapidly to achieve osmotic equilibrium. Second, the number ofeffective osmoles (osmoles other than urea) in the ICF compartment remains

constant in most acute settings. Third, in the absence of hyperglycemia and/or

mannitol accumulation in the ECF compartment, the effective ECF osmoles are

Na+ and its attendant anions, Cl and bicarbonate. Therefore when hyper-

natremia develops, the volume of cells will be smaller unless there was a

gain in ICF osmoles in muscle for example due to a recent seizure [36] or

rhabdomyolysis [15].

The target organ of clinical importance is the brain because it is in a

confined rigid space and it cannot gain intracellular particles in an acute setting.The main danger in this setting is an intracerebral hemorrhage. In contrast,

hyponatremia usually implies that its ICF volume is expanded and ultimately may

lead to cerebral herniation because of the rigidity of the skull and the fact that

close to 67% of total brain water is in its ICF compartment.

Return to the bedside. Once the PNa has returned to 140 mmol/l, progressive

acute hyponatremia from ongoing negative Na+ balance is a real danger unless

therapy is modified quickly. One can anticipate that the urine Na+ concentration

may be almost as high as the medullary interstitial Na+ + K+ concentration

when vasopressin acts because of the low urea concentration in the renalmedullary interstitium (the result of the low urine urea concentration). Because

a long-acting ($ 10 h) form of vasopressin (dDAVP) was given and the vastmajority of urine osmoles were Na+ + K+ salts, it is not surprising that the urine

Na + concentration rose to 300 mmol/l (Fig. 5). Therefore it is easy to anticipate

why hyponatremia would develop during therapy to correct hypernatremia

because half-isotonic saline (75 mmol Na+ /l) was given at a rate equal to urine

Fig. 4. PNa Concentration reflects the ICF volume in the absence of hyperglycemia and mannitol

infusion. The circle represents the ICF compartment that contains macromolecular anions (P ) and its

major effective osmole, the cation K+ . Urea, shown on the left, is not an effective osmole because it

virtually always has an equal concentration in the ECF and ICF compartments. The osmoles restricted

to the ECF compartment are Na+ and its attendant anions. Osmotic equilibrium is achieved because

water can cross this cell membrane rapidly.



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output. Because this strategy was not changed when the PNa fell to 140 mmol/l,

the patient became progressively hyponatremic and died due to brain swelling thatled to herniation. We ask the reader, How could this fatal outcome be avoided?

How could this fatal outcome be avoided?

Application of physiology principle 3. To prevent a change in the PNa, the

input must be identical to the output both in terms of volume and electrolyte

content (Fig. 5).

Return to the bedside. There are two ways to achieve a tonicity balance

(Fig. 5). First, one could infuse saline at the same concentration and flow rate as

in the urine; second, one could administer a loop diuretic to lower urine Na

+

+K+ concentration to approximate that of plasma. With this latter strategy, giving

isotonic saline at the same rate as the urine output could have replaced all renal

losses other than K+ while preventing a fall in the PNa. At any point before the

tragic end, his PNa could have been raised to a non-threatening level easily by the

administration of 1 mmol Na+ (without water) per liter of total body water times

the desired change in the PNa. Raising his PNa from 125 mmol/l to 130 mmol/l

would have required a positive balance of 150 mmol of Na+ (5 mmol/l 30 liters) which could have been accomplished by the rapid infusion of close to

0.3 liters of 3% NaCl. It is important to recognize that a reasonably rapid rate ofcorrection of hyponatremia is not a risk factor for osmotic demyelination in a

patient with acute hyponatremia [31].

Concluding remarks for case 1

Using simple whole body physiology (Table 1), deductive reasoning, and a

quantitative analysis emphasizing mass balance, the basis of the polyuria was

Fig. 5. Options of therapy to prevent the development of hyponatremia. The actions of vasopressin led

to the urinary excretion of 1 liter of hypertonic saline (300 mmol/l) in Case 1. To avoid the

development of hyponatremia, the intravenous infusion and urine output must have the same

concentrations of Na+ (+ K+ ) and the same volume. Thus either the concentration of saline infused

must be 300 mmol/l or the urine must be adjusted so that it becomes close to isotonic saline (give a

loop diuretic). (From RossMark Medical Publishers, The Acid Truth and Basic Facts, 4th ed, 1997;

with permission.)



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clearly a water diuresis due to central DI. By calculating the osmole excretion rate

and deducing that there was an excessive excretion of electrolytes, it was important

to predict that the urine flow rate might only decline to around 6 ml/min aftervasopressin was given. Armed with these insights, the patient would not have been

given so large a dose of this hormone. For therapy, the objectives were also clear

return the body compartment volumes and composition to normal. Using a tonicity

balance, the basis of hypernatremia was a positive balance of 250 mmol of Na+ (and

Cl ) and a deficit of 1 liter of water. Accordingly, the design of therapy was to

create a negative balance for Na+ (250 mmol) while increasing water balance by

1 liter. Moreover, the dangers in this setting could be anticipated. Once the PNareturned to normal, one must maintain Na+ and water balances. Because the urine

Na+

concentration was high and the urine flow rate was also large, intravenoussolutions should be given at the same rate as the urine output while ensuring that

their overall Na+ concentration was equal to that of the urine (Fig. 5).

Perhaps the simple take-home message is that a physiological approach should

be the one used at the bedside in the ICU. There are two other points that merit

emphasis. First, from a practical and safety perspective, it is critical to monitor the

PNa closely during and after therapy to be sure the goals of therapy are indeed

being achieved. Second, because hypernatremia developed so acutely, it should

not be dangerous to return the PNa to normal over a period of one day.

Illustrative case 2

Three problems prompted the transfer of a 70-kg male to the ICU following a

recent bone marrow transplant. First, he was heavily immunosuppressed and

developed an acute respiratory tract infection for which he was treated with

antibiotics including gentamicin. Second, he became hypotensive (blood pressure

nadir was 65/40 mm Hg) yet he developed non-oliguric acute renal failure (plasma

creatinine rose from 0.9 to 4.6 mg/dl (100 to 412 mmol/l), BUN rose from 14 to

213 mg/dl, urea 5 to 76 mmol/l). Third, his PNa

rose from 140 to 157 mmol/l over

several days in the ICU. Balance data were available for the day his PNa rose from

147 to 155 mmol/l. They revealed a positive balance of both 1 liter of water and

378 mmol Na+ + K+ (7 liters of hypotonic saline (Na+ + K+ of 90 mmol/l) were

infused and he excreted 6 liters of urine (Na+ + K+ concentration of 42 mmol/l)

(Fig. 6). His urine osmolality was 524 mOsm/kg H2O.

At this point, we ask the reader to consider the following questions. What

was the basis of the polyuria and hypernatremia? Why was the urine Na+ +

K+ concentration so low?

What was the basis of the polyuria?

Physiology principle 4. Function of the thick ascending limb of the loop of

Henle (TAL) is needed to concentrate the urine and for conservation of Na+ and

Cl by the kidney. These cells have a calcium receptor on their basolateral

aspect (facing the blood side, Fig. 7). When this receptor is occupied by a



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cationic ligand such as calcium or gentamicin, the kidney behaves as if it were

under the influence of a loop diuretic because of an intracellular signal trans-

duction cascade that leads to inhibition of K+ movement from these cells into the

lumen. The net result is a renal concentrating defect and a high rate of excretion

of Na+ (and Cl ).

Fig. 6. Tonicity balance in case 2. For details, see text and the legend to Fig. 3.

Fig. 7. Physiology of the calcium receptor in the loop of Henle. A cell in the thick ascending limb of

the loop of Henle (TAL) is depicted on the right portion of the Figure. When the calcium receptor on

its basolateral aspect is occupied, its luminal ROM-K channel is inhibited. When fewer K+ enter the

lumen, there is insufficient K+ for the luminal Na+ , K+ , 2 Cl cotransporter and less positive luminal

voltage to drive the paracellular reabsorption of Na+ , Ca2+ and Mg2+ .



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Return to the bedside. Using the physiological principles illustrated in Table 1, it

is clear that the basis for the polyuria was an osmotic diuresis (very high daily

osmole excretion rate, 6 liters 524 mOsm/liter = 3144 mosmoles per day). Thebulk of these osmoles were non-electrolytes (2 (Na+ + K+ ) = 84 mOsm/kg H2O).Only one solute (urea) was filtered in sufficient quantity to cause this osmotic

diuresis. Hence the presumptive diagnosis was a urea-induced osmotic diuresis

(confirmed later by direct analysis of urea). Notwithstanding, two other features

contributed to this polyuria. First, there was a high daily rate of excretion of Na+ +

K+ (6 liters 42 mmol/l = 252 mmol/day). Second, the furosemide-like effectdue to gentamicin (Fig. 7) could have led to a lower renal medullary interstitial

tonicity and thereby a lower than expected urine osmolality in the face of

a calculated plasma osmolality of 390 mOsm/kg H2O (2 157 mmol Na+

/l +76 mmol urea/l).

What was the basis of the hypernatremia?

A tonicity balance calculation (Fig. 6) revealed that the basis for the hyper-

natremia was the positive balance of 378 mmol of Na+ + K+ because there was

also a positive balance of 1 liter of water. Thus his ECF volume was expanded

(Na+ gain) rather than being contracted (a deficit of water will cause hyper-

natremia with a contracted ECF volume).

Why was the urine Na+ + K+ concentration so low if vasopressin is acting?

When there is a lesion that limits the rise in the urine osmolality (furosemide-

like effect attributable to gentamicin, Fig. 7), a higher rate of excretion of organic

solutes (urea in this case) obligates a lower concentration of electrolytes in each

liter of urine (Fig. 8). At this point, we again ask the reader to pause and consider,

What is the next threat to survival in this patient?

What is the next threat to survival in this patient?

Physiology principle 5. The catabolism of proteins leads to the production of

urea, the major nitrogenous waste product [18] (Fig. 9). Because lean body

mass has water as its main constituent (80% of weight), these tissues contain

180 g of protein per kg. For every 100 g of protein oxidized, 16 g of nitrogen

is converted to urea (572 mmol of urea) [16]. Therefore the appearance in the

urine of close to 1100 mmol of urea from endogenous sources represents the

net catabolism of 1 kg of lean body mass. Because of its size, muscle catab-

olism is the major contributor when there is a very high rate of appearance of

urea. This can cause a problem because muscle function is needed to clearrespiratory secretions.

Return to the bedside. On the day the tonicity balance was carried out, the

patient excreted 6 liters of urine with a urea concentration of close to 400 mmol/l.

Therefore 2400 mmol of urea were excreted, representing the net catabolism of

close to 200 g of protein. On that day, he was given 60 g of protein by nasogastric



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tube so he catabolized approximately 140 g of endogenous protein. This was

likely derived from almost 0.8 kg of lean body mass (Fig. 9). Should this

Fig. 9. Catabolism of lean body mass to cause a urea-induced osmotic diuresis. With low levels of

anabolic hormones and high levels of catabolic factors, there is net breakdown of muscle protein and

release of amino acids. Amino acids are delivered to the liver where their nitrogen is converted to urea

while carbon/hydrogen is converted to glucose by a common pathway for the most part. The urea so-

formed becomes the principal urinary nitrogen waste. A quantitative analysis is shown by the numbers

in parentheses. Control exerted at site 1.

Fig. 8. Exacerbation of polyuria by a renal medullary lesion. The rectangle on the left represents 1 liter

of urine excreted per day when vasopressin acts, the medullary interstitial osmolality is 900 mOsm/kg

H2O, and half of the urine solutes are urea (the other half are electrolytes (lytes)). With a major

concentrating defect limiting the maximum urine osmolality to 300 mOsm/kg H2O as the only change,

the urine volume will now be 3 liters per day and the urine Na+ + K+ concentration will be hypotonic

as shown to the right of the arrow.



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continue, he would ultimately undergo marked muscle wasting (and he did).

Protein wasting could make his lung infection worse by compromising efforts to

clear secretions from his respiratory tract as well as diminishing his immuno-logical responses to infection [20].

Summary. Had the true basis for polyuria and hypernatremia been recognized,

efforts would have been more vigorous at the nutritional level in this patient. On

the one hand, more exogenous calories including protein could have been given.

On the other hand, anabolic hormones such as high dose insulin with glucose to

avoid hypoglycemia and/or provision of nutritional supplements such as gluta-

mine [20] might have been tried to minimize protein catabolism. One might also

have questioned the use of high doses of catabolic hormones such as glucocorti-coids at this point because of his extreme degree of catabolism.

Concluding remarks for case 2

Perhaps the simple message in Case 2 is to perform a balance of all

major constituents of the urine. From the Na+ and water perspective, a urea-

induced osmotic diuresis caused polyuria. Hypernatremia developed because

isotonic saline was infused whereas the urine had a much lower concen-

tration of Na+ + K+. More importantly, from an integrative physiology point

of view, these salt and water issues were the clues to reveal the very large

endogenous protein catabolism with its potential threats for survival.

Hyponatremia

The first decision one must make when dealing with a patient with hy-

ponatremia (PNa less than 136 mmol/l) is to determine whether it represents an

acute condition (documented course is less than 48 hours). The reason for this

emphasis is that the main danger in acute hyponatremia results from brain cellswelling whereas the main danger with chronic hyponatremia is the osmotic

demyelination syndrome (ODS) that occurs secondary to its treatment [35]. In

fact, one usually begins with therapeutic considerations in acute hyponatremia

and with diagnostic considerations in chronic hyponatremia. If even mild

symptoms begin in a patient with acute hyponatremia, clinical deterioration

may be very rapid so treatment must be prompt and vigorous.

Acute hyponatremia

Illustrative case 3

A 17-month-old infant weighing 10 kg had a 2-day history of gastroenteritis.

Physical examination revealed a normal ECF volume, but one observer said that he

was somewhat dry. There was a mild degree of hyponatremia (PNa134 mmol/l)



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and a urine osmolality of 320 mOsm/kg H2O; the urine volume was not recorded

throughout his hospital course. Despite these minor abnormalities, he was given

a bolus of isotonic saline (200 ml, 30 mmol Na+

) and a maintenance infusion of2/3 D5W and 1/3 isotonic saline at 40 ml/h for the next 20 hours (total volume,

750 ml, 37.5 mmol Na+ ). He received an estimated 200 ml of water as ice chips

because of a dry mouth. He improved initially, but 20 hours after the start of

therapy, a seizure occurred. His PNa at this time was 121 mmol/l.

We ask the reader to consider: Why did acute hyponatremia develop?

What would your therapy be bearing in mind that he has had a seizure? To

prevent the development of hyponatremia, what should the initial therapy be?

Are there specific risk factors for hyponatremia in certain patients who receive

electrolyte-free water?

Why did acute hyponatremia develop?

Physiology principle 6. To develop hyponatremia, there must be both a source

of electrolyte-free water and a means to decrease its rate of excretion (Table 1);

the latter is due to renal actions of vasopressin [27]. The quantity of Na+ in the

ECF compartment is close to 30 mmol/kg body weight (Table 1); a 10-kg normal

infant has 2 liters of ECF and 280 mmol of Na+.

Return to the bedside. Vasopressin could have been released in response to a

number of non-osmotic stimuli including the underlying GI disturbance (Table 3).

He had three source of electrolyte-free water. First, hypotonic solutions were

infused. Second, electrolyte-free water was given orally in the form of ice

chips. Third, electrolyte-free water was generated by the kidney by a process

that we call desalination of infused isotonic saline (Fig. 10); this process

requires a large natriuresis [34]. Because he was given close to 7 mmol of Na+

per kg, his ECF volume would be expanded by 20% providing a stimulus for

Na+

excretion.

Table 3

High vasopressin levels in patients with hyponatremia

Readily reversible causes

Low effective circulating volume

Anxiety, stress pain, nausea

Drugs causing nausea (e.g., chemotherapeutic agents), the central release of vasopressin (e.g.,

morphine) or enhancement of the renal effects of vasopressin (e.g., certain oral hypoglycemics,

nonsteroidal anti-inflammatory drugs)

Endocrine causes (e.g., hypothyroidism, adrenal insufficiency)

Exogenous DDAVP, oxytocin

Not easily reversible causes

Vasopressin-producing tumors

Central nervous system or lung lesions (may cause reset osmostat)

Granulomas

Certain metabolic lesions (e.g., porphyria)



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What should your therapy be bearing in mind that he has had a seizure?

Application of physiology principle 3. The ICF volume is inversely propor-

tional to the PNa (Fig. 4). To lower the ICF volume, one must give solutes such as

Na+ (and Cl ) or mannitol that are restricted to the ECF compartment. To draw

water out of the skull by osmosis to reduce intracranial pressure, the solute given

must not readily cross cerebral capillaries. Hypertonic Na

+

and mannitol causeosmotic shrinking of the brain because they do not readily cross the blood-brain

barrier [26].

Return to the bedside. Treatment must be aggressive even if only mild

symptoms were present. Hypertonic saline (3%) should be given intravenously

to raise the PNa by 5 mmol/l in 1 2 hours; this should alleviate significant

cerebral swelling and hopefully prevent irreversible damage. The calculated

dose of NaCl depends upon body weight (10 kg) and in infants, water is 70%

of body weight. Because total body water is approximately 7 liters, he wouldneed 35 mmol (5 mmol/l 7 liters) to raise his PNa by 5 mmol/l. This isequivalent to close to 80 ml of 3% saline ($ 500 mmol/l). A potential danger ofthis infusion is over-expansion of his ECF volume, but this risk is minor.

Longer-term treatment would depend on the volume and tonicity of the urine.

Having said all this, the emphasis should have been on correct therapy when

the child was admitted.

Fig. 10. Generation of electrolyte-free water by the kidney. The larger rectangle to the left of the

arrows represents the infusion of 2 liters of isotonic saline; the content of Na + (300 mmol) is shown in

the oval inside that rectangle. A similar depiction is used for the excretion of Na + and water and they

are shown to the right of the arrows. To have a concentration of Na + in the urine that is 300 mmol/l,

vasopressin (VP) must act and there must be a reason to excrete NaCl. The remaining 1 liter of

electrolyte-free water is retained in the body.



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To prevent the development of hyponatremia, what should the initial therapy be?

Application of physiology principles 1 and 3. The excretion of Na+

is increasedwhen the ECF volume is expanded. If vasopressin is present, the concentration of

Na+ + K+ in the urine can be very high, generating electrolyte-free water that will

be retained in the body (Fig. 10).

Return to the bedside. Acute hyponatremia in hospitalized patients should be a

problem of the past. Prevention depends upon limiting the access to electrolyte-

free water in a patient likely to have vasopressin acting. The administration of

hypotonic infusions is contraindicated in our patient because his PNa is less than

138 mmol/l. Since electrolyte-free water can be generated by the kidney as aresult of a large natriuresis when vasopressin acts (Fig. 10), one should give only

as much isotonic saline as needed for hemodynamic purposes. It is not advisable

to administer a large volume of isotonic saline to achieve a good urine output

because the good urine output may really be a danger sign if the urine tonicity

is high. If the urine were hypertonic, it should be replaced with the same volume

and tonicity as was excreted or, alternatively, the composition of this urine could

be changed to near-isotonic saline with a loop or osmotic diuretic and again its

total volume replaced with isotonic saline (Fig. 5).

Are there specific risk factors for the development of acute hyponatremia in

certain patients who receive electrolyte-free water?

Application of physiology principle 3. Close to 50% of body water is in skeletal

muscles. The major constituent (80%) of the brain is water. Approximately 2/3 of

this water is in cells and this volume increases with hyponatremia. Therefore for a

given % swelling, the larger the brain cell/total volume in the skull, the greater

the rise in intracranial pressure. On the other hand, hyponatremia that is due to the

addition of an iso-osmotic mannitol solution will expand the ECF volume but it

will not cause brain cell swelling (the plasma osmolality is not appropriately low,

Table 4).

Return to the bedside. The following major risk factors can be anticipated for

developing brain swelling with acute hyponatremia. First, even less electrolyte-

free water is needed to cause a lower PNa in patients with a small muscle mass.

Second, patients who have a larger brain cell mass (younger age) are at greater

risk from a given volume of water retained in the body. Third, patients given anacute bolus of saline intravenously will have an expanded blood volume (higher

hydrostatic pressure) and a lower colloid osmotic pressure. Hence they might

have a higher intracerebral ECF volume and develop symptoms from increased

intracranial pressure with a smaller reduction in their PNa. Fourth, patients with an

underlying brain lesion (seizure disorder) may be more prone to develop seizures

with a smaller degree of hyponatremia.



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It is said that young women are less able to regulate brain cell volume in

response to acute hyponatremia [1]. This ides has arisen because of pooroutcomes in young women compared with men who develop postoperative

hyponatremia. Nevertheless, this is not a closed issue for two reasons. First,

postoperative hyponatremia in males most frequently occurs during transuretheral

resection of the prostate (TURP). Males undergoing TURP are typically older and

could have a smaller brain cell/total intracranial volume. Second, the composition

of the fluid retained with the commonest surgery in females and males is

different electrolyte-free intravenous water after gynecological surgery and

lavage solutions during a TURP (Table 4). During a TURP, acute hyponatremia

may be due to the absorption of isotonic or half-iso-osmotic lavage solutionscontaining glycine, sorbitol, and/or mannitol [12]. Neurological manifestations in

this setting might be due to toxic metabolic products such as ammonium (NH4+)

produced during the metabolism of glycine rather than to brain cell swelling. It

follows that one should not use aggressive therapy for this type of acute

hyponatremia if the measured plasma osmolality is reduced by less than 10%.

On the other hand, if the plasma osmolality is less than 260 mOsm/kg H2O,

therapy reverts to that described above for a gain of electrolyte-free water.

Chronic hyponatremia (time course >48 hours)

Illustrative case 4

The usual diet of a 78-year-old, 60 kg, cheerful lady was tea (a large cup),

toast, and jam. A thiazide diuretic was prescribed because of the recent discovery

Table 4

Acute hyponatremia due to lavage solutions

EFW Lavage solution

Unit Original Final Original Final

Before the excretion of the organic solute

ICF volume L 20 22 20 20

ECF volume L 10 11 10 13

PNa mmol/L 140 127 140 108

Plasma osmolality mOsm/L 290 264 290 290

After the excretion of the organic solute (as 3 L of isotonic urine)

ICF volume L 22 20

ECF volume L 11 10

PNa mmol/L 127 140

Plasma osmolality mOsm/L 264 290

Each subject with 30L of total body water has a 3L positive water balance. The patient who

received the isosmotic lavage solution also has a positive balance of 900 mOsm of a solute with a

distribution restricted to the ECF compartment. The plasma osmolality is not depressed in the patient

who retained the isotonic lavage solution, and the ICF volume is normal, despite a PNaof 108 mmol/L.

When the lavage solution is excreted as an isotonic solution, there is a large increase in the PNa and no

change in the ICF volume.



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of high blood pressure (160/90 mm Hg). She became lethargic and slower in

mentation over several weeks, but there were no focal neurologic signs. Blood

pressure fell to 140/90 mm Hg suggesting that her ECF volume was contracted.Laboratory investigations are shown in Table 5.

We ask the reader the following questions: If an emergency is present, what

is it? What dangers to you anticipate with therapy? On a quantitative

analysis, what changes occurred in the volumes and electrolyte composition in

her ICF and ECF compartments? What is the chronic therapy for hypona-

tremia due to SIADH?

If an emergency is present, what is it?

Other physiology principles. Cardiac arrhythmias are more common if hypo-

kalemia is severe in degree and if there is underlying heart disease.

If KCl is given to treat hypokalemia, think of it as a form of NaCl for the ECF

compartment because when K+ enters cells, Na+ (and H + ) will exit cells for the

most part.

Return to the bedside. The major emergency to anticipate is hypokalemia if it is

accompanied by prolonged QT interval in the EKG recording. The absolute value

for her PNa, while alarming, should not be considered an emergency. Because ofabsence of an ominous EKG, KCl was given slowly to raise her PK to the low

3 mmol/l range over 24 hours. The oral route was used because bowel sounds

were present. One cannot accurately predict how much of K+ will be needed over

the next 24 hours, but we anticipated that at least 100 mmol of KCl would be

required changes in her PK dictate the actual dose given. Glucose and

bicarbonate containing infusions should not be given for fear of an unwanted

acute shift of K+ into cells. Notwithstanding, there is a danger with KCl

therapy too rapid correction of her hyponatremia. This can occur for two

reasons. First, giving hypertonic KCl will raise her PNa and thereby could lead totoo rapid a rise in PNa. Second, because K

+ will enter the ICF compartment and

Na+ will move in the opposite direction, the ECF volume will expand. This in

turn could suppress the release of vasopressin and lead to the excretion of a large

volume of dilute urine.

Table 5

Laboratory values in case 4

Parameter Unit Plasma Urinea

Na+ mmol/L 107 10

K+ mmol/L 2.2 25

Cl mmol/L 67 10

Glucose mg/dL (mmol/L) 90(5) 0

Urea mg/dL (mmol/L) 11(4) 320

Osmolality mOsm/kg H2O 220 402

a Random sample.



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What dangers do you anticipate with therapy?

Application of physiology principle 3. The physical examination to detect amild degree of ECF volume contraction is not reliable [4,24].

Return to the bedside. As discussed above, in the short-term, there is a danger

that hyponatremia may be corrected too rapidly because of suppression of the

release of vasopressin. As a result, a large water diuresis could lead to a rapid

increase in PNa and cause the ODS. Clues suggesting that her ECF volume

was low are found in the history (low-salt diet and the thiazide diuretic). The

laboratory data are often difficult to interpret with respect to the ECF volume

status. For example, some laboratory data did suggest that her ECF volume

was contracted (urine Na+ and Cl concentrations were both < 15 mmol/l),

but these data are not entirely convincing in someone on a low-salt diet who

should have a low electrolyte excretion rate. Other laboratory values that may

be of help in this regard are a frankly high plasma urea (may not be high

because of her low-protein diet), high level of creatinine (not present because

of low muscle mass), metabolic alkalosis with hypokalemia (present in this

case), and/or a plasma anion gap that is higher than expected even when

corrected for albumin level [19].

There was a danger sign with therapy in this patient her urine output rose

dramatically with an infusion of saline. Because this was a water diuresis,

vasopressin was given to reduce the urine output temporarily so that the desired

slow rate of rise in the PNa could be achieved (4 mmol/l/24 hour because of her

K+ deficit) [2,22].

The main threat is brain cell volume shrinkage and the development of an

ODS following therapy that resulted in too rapid a rise in the PNa [21,35]. The

danger of ODS is greater in patients with a deficit of K+ and those whose

nutritional state is poor [2,22] probably because they are unable to regenerate

brain ICF particles quickly enough to prevent their cell volume from shrinking.

In attempts to correct PNa of patients in this high-risk group, the correction rate

should be much less than our usual recommendation of 8 mmol/l per 24 hours

[25]. The PNa should rise at a rate that is slow enough to avoid the ODS in

every patient. The emphasis should be on magnitude of correction of hypona-

tremia, remaining within our 4 mmol/liter/24 hours [25]. Raising the PNa above

125 mmol/l is rarely necessary in the first few days.

What changes occurred in her ICF and ECF compartment volumes

and composition?With a body weight of 60 kg, her normal total body water (TBW) is close to

30 liters (50% of body weight distributed as 20 liters ICF and 10 liters ECF). If

there was no change in the number of osmoles in her ICF compartment, the

calculated ICF volume with a PNa of 107 mmol/l is 26 liters ((140 mmol/l/

107 mmol/l) 20 liters). If her ECF volume was close to 10 liters on admission,there was a negative balance of 330 mmoles of Na+ in her ECF compartment



22/24

(fall in PNa of 33 mmol/l 10 liters). Because her plasma K+ concentration was

so low (2.2 mmol/l), her ICF compartment probably gained a cation (Na + or

H+

). It is not possible at present to assign quantitative values to these changesin ICF ion composition.

What is the chronic therapy with hyponatremia due to SIADH?

If the patient has an on-going defect in the excretion of electrolyte-free water,

there are two options for therapy to prevent a further decline in PNa. Either less

water must be consumed (water restriction) or the urine must be large in volume

and isotonic to the intake. To lower the urine Na+ + K+ concentration, one can

ingest urea [6]; a typical dose for urea is 1030 g per day. If the urine Na + + K+

concentration is very high, administration of a loop diuretic can reduce theseconcentrations an isotonic level [7,17]. We do not recommend the use of drugs

such as vasopressin antagonists because of the possibility of causing a large water

diuresis and an excessively rapid rise in PNa.

Summary

Our purpose was to illustrate the utility of an approach that begins with simple

principles of physiology to patients who have a disturbance in salt and water

balance (Table 1). At times, the physiology is restricted to the kidney and body

fluid compartments. In these settings, the goals of therapy are defined by

calculating a tonicity balance electrolyte-free water balances simply do not

provide the needed information [3]. At other times, performing balances of other

solutes such as urea reveal that another critically important problem is present

(tissue catabolism). Thus the physiologic analysis becomes more integrative,

extending beyond renal issues. Goals for therapy become clearer once the

integrative physiology is known.

More modern contributions from molecular studies permit a revised interpre-

tation of the physiology. An example presented was the possible role of

gentamicin-like drugs as a cause of high output renal failure that is basically a

persistent loop diuretic-like effect.

In the patient presenting with hyponatremia, the first step is to determine if

the time course is less than 48-hours because emergency therapy is different in

this setting. With acute hyponatremia, the objective is to diminish brain cell

swelling especially if even mild symptoms are present. In contrast, the objective

in the patient with chronic hyponatremia is to prevent ODS. An even slower

rate of rise of the PNa is required in patients who are malnourished and/or

K+ depleted.

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