Q J Med 2003; 96:601610

doi:10.1093/qjmed/hcg101

Commentary

How to select optimal maintenance intravenous fluid therapy

M.A.S. SHAFIEE1, D. BOHN2, E.J. HOORN2 and M.L HALPERIN1
From the 1Renal Division, St. Michaels Hospital, University of Toronto, and 2Department of Critical
Care Medicine, Hospital for Sick Children, Toronto, Canada and the Department of Anaesthesiology,
University of Toronto, Toronto, Canada

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Summary
Hyponatraemia is the commonest electrolyte acute hyponatraemia. Our hypothesis is that the
abnormality in hospitalized patients. If the plasma traditional calculation of the daily loss of insensible
sodium concentration (PNa) declines to
120 mM in water overestimates this parameter, leading to an
<48 h, brain cell swelling might result in herniation, excessive daily recommended requirement for
with devastating consequences. The volume and/or water. We offer suggestions to minimize the risk of
the composition of fluids used for intravenous iatrogenic hyponatraemia.
therapy often contribute to the development of

Introduction Outline of the problem

Hyponatraemia is defined as a plasma Na con- Intravenous fluid administration is common and
centration (PNa) <136 mM.1 While this could result more than 75% of currently recommended main-
from a deficit of sodium (Na), it is most often due tenance fluids are given in the form of electrolyte-
to a surplus of water (Figure 1, Table 1). To create free water (0.2% saline).6,7 Because patients who
a positive water balance,1,2 input of water are ill often have non-osmotic stimuli for the release
must exceed output. A low water output is usually of vasopressin, it is not surprising that hyponatrae-
due to the release of vasopressin, often because mia is the commonest electrolyte disorder in
of non-osmotic stimuli (Table 2).3 When this hospitalized patients, in part due to this electro-
occurs, patients cannot produce the large water lyte-free water input.8 A large fall in the PNa in <48 h
diuresis that prevents a fall in their PNa.4 In fact, should cause cell swelling because the ICF volume
vasopressin acts throughout the 24-h period in is inversely related to the PNa (Figure 1).1 Because
normal volunteers despite episodic intake of water brain cells occupy approximately 2/3 of the
(Figure 2). Hence normal humans rarely have a intracranial volume, brain-cell swelling is very
water diuresis unless their arterial PNa falls below likely to increase intracranial pressure and predis-
136 mM. In contrast, when hospitalized adults4 and pose to brain herniation, since the brain resides in a
paediatric5 patients have a PNa that is <136 mM, rigid bony structure and there is only a small volume
they do not have a dilute urine because of renal of intracranial water that can be lost when there is a
actions of vasopressin, released in response to non- small rise in intracranial pressure (the volume in the
osmotic stimuli. cerebrospinal fluid).9 Children are at greater risk

Address correspondence to: Professor M.L. Halperin, Division of Nephrology, St. Michaels Hospital Annex,
38 Shuter Street, Toronto, Ontario, Canada, M5B 1A6. e-mail: mitchell.halperin@utoronto.ca
! Association of Physicians 2003; all rights reserved
602 M.A.S. Shafiee et al.

because their brains have a larger ICF volume (more

cells) per total skull volume. Nevertheless, not all
causes of acute hyponatraemia are associated with
brain cell swelling. For example, when a patient
undergoes a transurethral resection of the prostate,
lavage fluid may enter the vascular compartment
and be retained in the ECF compartment.10 If this
Figure 1. Water movement across cell membranes. The
fluid contains osmoles such as sorbitol or mannitol
solid circle represents the normal ICF volume and that remain extracellularly, the ECF volume will be
the dashed circle represents the expanded ICF volume expanded by an iso-osmotic, Na-free solution.
when hyponatraemia is present. Water channels permit Because most of these solutions are half-isotonic,
the cell membranes to be permeable to water. Osmotic there will be a modest degree of expansion of the
forces are immense. Therefore, independent of whether ICF compartment. Accordingly, little of this added
hyponatraemia is due to a negative balance for Na Na-free water will enter cells and cause brain-cell
as shown on the left, or a positive balance for water swelling despite the large fall in PNa.11 Hence it is
shown on the right, the ICF volume will rise to the important to include in the clinical analysis the
same extent because the number of particles restricted
condition that caused the hyponatraemia, and not
to the ICF compartment (P) does not change appreciably
simply treat a laboratory PNa value.

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in most cells, and Na ions are restricted to the ECF
compartment for the most part. Our view is that a fall in the PNa is preven-
table if intravenous fluid therapy is tailored to

Table 1 Physiological classification of hyponatraemia

I. Deficit of Na in the ECF compartment

1. Non-renal loss of Na (sweat, gastrointestinal tract)
2. Renal loss of Na:
Lack of a stimulator for Na reabsorption (e.g. aldosterone)
Presence of an inhibitor (e.g., ECF volume expansion or a diuretic)
Inborn errors that interfere with the normal reabsorption of Na
II. Surplus of electrolyte-free water in the ECF compartment
1. Determine the source of electrolyte-free water:
Gastrointestinal tract
Intravenous fluids
Urine (need to excrete urine with a Na K concentration >PNa or the infused fluids4)
2. Determine why there is too little excretion of electrolyte-free water:
Vasopressin is present (see Table 2)
Vasopressin can be absent
Low distal delivery of filtrate (trickle-down hyponatraemia46)
Renal failure

Note that hyperglycaemia and/or high mannitol-like solutes in plasma might be contributing to the degree of hyponatraemia.

Table 2 High vasopressin levels in patients with hyponatraemia

1. Causes that are readily reversible:

Low effective circulating volume to cause the release of vasopressin
Anxiety, stress, pain, nausea
Drugs causing nausea (e.g. many of the currently used chemotherapeutic agents), the central release of vasopressin
(e.g. morphine, barbiturates, ecstacy) or enhancement of the renal effects of vasopressin (e.g. certain oral
hypoglycaemics, non-steroidal anti-inflammatory agents, anticonvulsants such as carbamazepine)
Endocrine causes (e.g., hypothyroidism, adrenal insufficiency)
Exogenous dDAVP, oxytocin
2. Causes that cannot be reversed rapidly:
Vasopressin-producing tumours
CNS or lung lesions (may cause reset osmostat)
Granulomas
Certain metabolic lesions (e.g. porphyria)
 Intravenous fluid administration 603

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Figure 2. Diurnal variation in the urine osmolality. Data were gathered in 75 volunteers (aged 1764 years).
Voluntary voiding occurred at 2-h intervals for the 16 h while awake and when the subject woke up at night to
void. There were no restrictions on water intake, diet, or activity. No subject took medications. The males (n 45)
are depicted by the solid diamonds connected by a solid line and the females (n 30) by the open circles connected by a
dashed line.

Figure 3. Comparison of energy expenditure in the basal and ideal state. This figure was redrawn, based on a publication by
Holliday and Segar.15 The upper and lower lines were plotted from the data of Butler and Talbot.47 Weights at the 50th
percentile level were selected for converting calories at various ages to calories related to weight. The computed line was
derived from the following equations: ages 010 kg, 100 cal/kg; 1020 kg, 1000 cal 50 cal/kg for each kg over 10 kg; 20 kg
and up, 1500 cal/kg 20 cal/kg for each kg over 20 kg.
604 M.A.S. Shafiee et al.

the needs of individual patients.5 Hence the When there is a large water deficit in the ICF
first question to ask is why do we currently infuse compartment (indicated by a PNa > 140 mM), elec-
so much hypotonic saline. trolyte-free water (often 5% dextrose in water or
D5W) should be infused. Care should be taken to
avoid inducing a significant degree of hyperglycae-
Usual reasons for intravenous mia.14
fluid administration
(iii) Replacing ongoing renal losses
There are five common reasons to infuse intrave-
This therapy is directed at patients who do not
nous fluids (Table 3). Only the last two deal directly
have an antecedent condition that led to the
with the development of hyponatraemia, and they
retention of salt and water.
will be emphasized.
(iv) Giving maintenance fluids to
(i) Defend normal blood pressure match insensible losses
A reduced ECF volume, if accompanied by haemo- The traditional guidelines for maintenance fluid
dynamic collapse, has a greater initial priority infusion focus on the need to replace insensible
than all but the most serious degrees of expansion loss of water for heat dissipationthe latter was

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of the ICF volume. Isotonic saline is the initial related to caloric expenditure based on data and
therapy, but hypertonic saline should be given if deductions published almost 50 years ago,15 and
there is both a low ECF volume and an acutely was reiterated recently16,17 These authors stated:
low PNa, as seen in people with excessive sweat loss Maintenance requirements for water in individuals
accompanied by a large intake of water.12,13 is determined by their caloric expenditure. By
Patients who are anaesthetized usually have a fall means of the following formula (summarized in
in blood pressure in the absence of a contracted ECF Figure 3) the caloric expenditure of hospitalized
volume because anaesthetic agents diminish venous patients can be estimated with sufficient accuracy
tone.4 An infusion of isotonic saline helps avoid this by weight alone. Significant deviations from this
type of hypotension. relation exist, including excessive obesity, the
elderly, and patients with infections. Notwithstand-
(ii) Return the ICF volume to normal ing, alternative views have been expressed,5,18
In a patient with acute hyponatraemia, the ICF because traditional recommendations require that
volume in the brain rises and could become hypotonic saline be infused. We emphasize
dangerously high with a more prominent decline that there is a danger in infusing a large volume
in the PNa. Shrinking the ICF volume becomes an of electrolyte-free water because it will acc-
urgent priority only when there are CNS symptoms umulate when vasopressin acts, providing that
or a PNa in the mid-to-low 120 mM range. there is not a very large volume of sweat.

Table 3 Indications for the prescription of intravenous fluids

I. Highest priority
a) Defend haemodynamics
1. Re-expand a severely contracted ECF volume
2. Prevent a fall in blood pressure when venous tone is low (e.g., anaesthesia)
b) Return the ICF volume towards normal
1. Acute hyponatraemia that is symptomatic
Infuse hypertonic saline to raise the PNa by 5 mM in 12 h
2. Chronic hyponatraemia with a seizure
Infuse hypertonic saline to raise the PNa by 5 mM, but maximum is 8 mM/day; a lower target
should be set if the patient is malnourished or K-depleted
3. Chronic asymptomatic hyponatraemia
Raise the PNa by up to 8 mM/day, slower rate if the PK is low in a malnourished patient
II. Moderate priority
1. Re-expand a modestly contracted ECF volume
Replace ongoing losses
Avoid oliguria
Match estimated electrolyte-free water loss in sweat and in the GI tract
 Intravenous fluid administration 605

Moreover, it is not uncommon for patients to metabolic production of CO2 and water occur
seek medical care and arrive in hospital with a in a 1:1 proportion during the oxidation of
low PNa because they drank electrolyte-free carbohydrates (Cn(H2O)n) (equation 1) and fatty
water while vasopressin was released secondary acids (CH2)n (equation 2). Moreover, these two
to their illness (Table 2). It would be a grave error end-products are eliminated together in alveolar
to give them electrolyte-free water. In the next air in a 1:1 proportion, providing that the arterial
section, we shall provide evidence to suggest pCO2 is close to 40 mmHg (Figure 4).23 The reason
that the classical calculations of losses of insensible for this parallel excretion of water and CO2 is
water lead to an overestimation of the need for that the partial pressures of water vapour and
hypotonic fluid administration. This error is com- CO2 are virtually equal in alveolar air (47 and
pounded by a perceived need to excrete a larger 40 mmHg) and in inspired air (close to zero
urine volume with a more comfortable urine after air is warmed to 37 C24). Therefore, water
osmolality.15 loss via exhaling alveolar air is equal to its
metabolic production, so these two pathways
can be ignored unless the patient is hyperven-
(v) The need for glucose as a tilating and/or is on a ventilator and is inspiring
fuel for the brain humidified air warmed to body temperature.23
A theoretical advantage of infusing 2 l of D5W Only water evaporation from the upper respiratory

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is that this infusion provides 100 g of glucose, tract results in a negative water balance.
which is almost equivalent to the 120 g of
glucose oxidized daily by the brain.19 The unstated Cn H2 On n O2 ADP ! n CO2 n H2 O
assumption is that this infused glucose is not 1
ATP
oxidized by other organs, which in turn is depen-
dent on their ability to oxidize fatty acids,20
because fatty acid oxidation inhibits the oxidation
of glucose.21 Therefore, if the infusion of glucose CH2 n 1:5n O2 ADP ! n CO2 n H2 O
2
raises the plasma glucose concentration sufficiently ATP
to stimulate the release of insulin,22 little of this
infused glucose will be available for oxidation in
the brain, because of the antilipolytic actions of Water loss in sweat
insulin. On the other hand, if glucose were needed
(i.e. to prevent the development of hypoglycaemia This type of water loss is the major reason to
and/or to minimize protein catabolism), it need administer electrolyte-free water to hospitalized
not be given as D5W with its electrolyte-free patients. We emphasize that an exogenous source
water loadrather glucose could be added to of water should be replaced only in patients
infused saline. who have a PNa > 140 mM, indicating a deficit

Analysis of insensible water loss

Heat is produced continuously by intermediary
metabolism.23 This heat must be dissipated to
avoid a life-threatening rise in body temperature.
Part of this vital function is served by evapor-
ation of surface water from the skin and the
respiratory tract. While this rationale is correct,
we question whether the recommendations
derived from it are correct from a quantitative
perspective.15 Figure 4. Fate of metabolic water. The body is depicted
by the large rectangle. Events describing water are shown
Water production by metabolism to the left while events describing CO2 are shown to
and its loss via the lungs the right of this rectangle. Production of water and CO2
(top arrows) as well as their loss (bottom arrows) are both
We begin with this component of water balance in close to a 1:1 proportion. Hence there is no net change
to largely dismiss it as a factor that would in water balance as a result of metabolism and alveolar
change the PNa. Our rationale is as follows ventilation.
606 M.A.S. Shafiee et al.

(b) Heat production

There are three classes of nutrients, carbohydrate,
fat, and protein.23 On a typical Western diet,
oxidation of carbohydrates and fatty acids generate

85% of the adenosine triphosphate (ATP) needed
to perform biological work. The limiting factor for
oxidation of these fuels is the availability of
adenosine diphosphate (ADP) in cells.27 Thus the
rate of fuel oxidation is dependent on how quickly
ADP is regenerated during biological work and/or
if oxidative phosphorylation is uncoupled.28,29
There are three categories of biological work:
biosynthetic, mechanical, and electrical work.
To digest food, enzymes must be synthesized.
Figure 5. The electrolyte-free water content of sweat. The For absorption of nutrients, there is a need for ion
larger rectangle to the left of the arrows represents 1 l of transport.30 During the conversion of dietary fuels
sweat. Its Na concentration is 25 mM, shown in the oval to storage forms of energy, there is biosynthesis
inside that rectangle. An imaginary calculation is of proteins,31 glycogen, and triglycerides. Hence it

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performed where the 25 mmol of Na are restricted to a is not surprising that caloric expenditure is much
volume of 1/6 l to have a final concentration of 150 mM. lower when there is little physical activity (e.g. bed
The remaining 5/6 l is electrolyte-free water. rest) and little dietary intake. In quantitative terms,
there is a 50% decline in daily caloric expenditure
during prolonged fasting with inactivity.19 If a
of intracellular water. Sweat usually contains 15 hospitalized patient is afebrile, does not eat, and is
30 mmol of Na per litre.25,26 Hence when 1 l sweat physically inactive, much less heat production can
containing 25 mM Na evaporates, there is a loss of be anticipated, and thereby there is a diminished
0.83 l electrolyte-free water (Figure 5). This link need for water infusion to match its loss by
between water evaporation (heat dissipation) and evaporation.
caloric expenditure (heat production) is the corner- Caloric expenditure (heat production) exceeds
stone for the traditional prescription for mainte- that needed for metabolic work if there is uncou-
nance fluid administration.15 These two pling of oxidative phosphorylation. This form of
components are analyzed in the following para- heat production is catalysed by uncoupler pro-
graphs. teins.28,29 The major uncoupler proteins that
have an impact on the endogenous heat production
in human subjects are those in skeletal muscle
(a) Heat dissipation their estimated contribution to energy metabolism in
In a healthy, fed, 70 kg adult male in steady state, the rat is about 25% of resting energy turnover.28
approximately 2500 kcal are ingested and expended Moreover, the uncoupler proteins in skeletal muscle
each day. The volume of insensible water loss is rise 510-fold during caloric deprivation.32
close to 1 l/day, but this causes a loss of only This topic is discussed in more detail in reference.33
slightly >500 kcal.24 Hence
2000 kcal of heat In summary, it is unlikely that the contribution of
are removed daily by conduction and convection. uncoupler protein-catalyzed energy metabolism will
The exact quantitative contribution of these latter be constant in a patient, and it should be extremely
routes of heat loss depends on environmental factors difficult to predict their total caloric expenditure
such as temperature, air circulation, humidity, while receiving much of his/her caloric supply from
cutaneous blood flow, clothing, etc. Hence they endogenous sources. Therefore relating body needs
cannot be quantified from general guidelines. for electrolyte-free water in an individual patient is
When additional heat loss is needed, there is an dependent on unreliable criteriaestimated energy
increased production of sweat together with its expenditure based on body weight.15
evaporation. Therefore an appreciable volume of
sweat can be anticipated during exercise or a febrile
state, unless heat loss by conduction and/or Analysis of electrolyte-free water loss
convention can be augmented. Conversely, little
water loss in sweat might occur when caloric
in the urine of hospitalized patients
expenditure declines, if there is little change in The kidneys regulate the excretion of water and Na
heat loss by conduction and convection. by independent mechanisms.
 Intravenous fluid administration 607

(i) Excretion of water Excretion of concentrated urine and

In most hospitalized patients, there will be very little extra renal work
if any excretion of electrolyte-free water, because
vasopressin makes the later parts of the distal One reason proposed to infuse electrolyte-free water
nephron permeable to water.3 Exceptions to this to hospitalized patients is to minimize the work of
the kidney.15 Energy is expended for active, but
rule occur in diabetes insipidus, during a glucose- or
not passive reabsorption of Na.38 While it has
urea-induced osmotic diuresis,34 and when there
been suggested that work is required to excrete
is a major renal concentrating defect.
concentrated urine,39 we doubt that extra renal
work was required for this task. Our rationale is
that normal kidneys reabsorb 99.5% of filtered
(ii) Generation of electrolyte-free water
Na, whether or not the final urine is concen-
The infusion of isotonic saline can lead to a positive trated (see Appendix for more discussion). Water
electrolyte-free water balance when this salt load is reabsorption in the kidney is passive, and is
excreted in hypertonic form. The most common controlled by the induction of water permeability
example of this type of generation of electrolyte-free of luminal membrane of the distal nephron40this
water is when a large volume of isotonic saline is requires the expenditure of very little energy, so it
infused to prevent an appreciable fall in blood can be ignored in the overall quantitative analysis

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pressure in anaesthetized patients.4 Later, when the of renal work.
level of the anaesthetic agent declines, the rate of
excretion of Na K rises due to a higher central
venous pressure and the urine becomes hypertonic
due to actions of vasopressin (Figure 6). Quantita- Design of a prescription for
tively, close to half of the infusate can be intravenous fluid administration
desalinated because the urine Na plus K con-
It is important to recognize that intravenous
centration can rise to
300 mM.4 Therefore, a large
fluid prescriptions should be individualized.
urine volume is not a good urine output because
The priorities for the infusion of fluids are sum-
it leads to the net addition of electrolyte-free water marized in Table 3. Focusing on maintenance
to the body, and thereby the development of fluid administration, our view is that caloric
acute hyponatraemia.4 In this setting, measures to expenditure should not be used to quantify its
lower the urine Na plus K concentration include need.15
a loop diuretic or inducing an osmotic diuresis
with urea or mannitol.3537 1. What are the indications and
contraindications to infuse
hypotonic fluids?
Do not infuse hypotonic solutions if the PNa is
<138 mM unless the patient is having a rapid
water diuresis and you want to limit the rise in
PNa. Rather, hypotonic fluids should be given to
match the daily loss of electrolyte-free water in
sweat in a patient who has a PNa > 138 mM.
This volume is <1 l/day unless the patient is febrile.
There are two circumstances to infuse electrolyte-
free water rapidly: first, when the PNa is significantly
>145 mM and if the patient is symptomatic. It
should be noted that the PNa can rise transiently
Figure 6. Desalination of administered isotonic saline. by
15 mM during a seizure.41 Second, replace
The larger rectangle to the left of the arrows represents the renal loss of electrolyte-free water in a large water
infusion of 2 l of isotonic saline; the concentration of Na
or osmotic diuresis, or if there is a non-renal loss
is shown in the oval inside that rectangle. A similar
via the gastrointestinal tract or the skin. The goal
depiction is used for the excretion of Na and water and
they are shown to the right of the arrows. To have a will be to create a positive balance for electrolyte-
concentration of Na in the urine that is 300 mM, free water. To lower the PNa by 1 mM, the
vasopressin (VP) must act and there must be a reason to positive balance of electrolyte-free water should
excrete NaCl. The remaining 1 l of electrolyte-free water is be ((1/PNa) total body water, usually 5070%
retained in the body.4 weight depending on skeletal muscle and adipose
608 M.A.S. Shafiee et al.

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2
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610 M.A.S. Shafiee et al.

The reabsorption of Na in the medullary thick Distal nephron segments

ascending limb of the loop of Henle is necessary for Because all the reabsorption of Na in the distal
both concentrating and diluting the urine. A higher nephron traverses cells and because there is no
medullary interstitial osmolality is important when passive transport of Na across basolateral mem-
the urine is maximally dilute, because it leads to the branes that leads to a bypass of the Na-K-ATPase,
reabsorption of almost 2/3 of the 60 l of filtrate more energy would need to be expended by
delivered daily from the proximal convoluted tubule the kidney to reabsorb the same amount of Na
in the descending thin limb of the loop of Henle.45 daily by the kidney if less Na were reabsorbed in
This places an upper limit on water diuresis. its thick ascending limb.

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