Best Practice & Research Clinical Anaesthesiology 28 (2014) 235e247

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Best Practice & Research Clinical

Anaesthesiology
journal homepage: www.elsevier.com/locate/bean

Balanced versus unbalanced salt solutions: What

difference does it make?
Sheldon Magder, MD
Departments of Critical Care, Medicine and Physiology, McGill University Health Centre, 687 Pine Av W,
Montreal, Quebec H3A 1A1, Canada

Keywords:
electrolytes
osmolality
chloride
sodium
acidebase
hyperchloremia

Background: The infusion of crystalloid solutions is a fundamental

part of the management of critically ill patients. These solutions
are used to maintain the balance of water and essential electrolytes and replace losses when patients have limited gastrointestinal intake. They also act as carriers for intravenous infusion of
medication and red cells. The most commonly used solution, 0.9%
saline, has equal concentrations of Na and Cl even though the
plasma concentration of Na normally is 40 meq/L higher than
that of Cl. The use of this uid thus can produce a hyperchloremic
acidosis in a dose-dependent manner, but it is not known whether
this has clinical signicance.
Approach: The rst part of this article deals with the signicance of
Na and Cl in normal physiology. This begins with examination of
their roles in the regulation of osmolality, acidebase balance, and
generation of electrochemical gradients and why the concentration of Cl normally is considerably lower than that of Na. The
next part deals with how their concentrations are regulated by the
gastrointestinal tract and kidney. Based on the physiology, it would
seem that solutions in which the concentration of Na is
balanced by a substance other than Cl would be advantageous.
The nal part examines the evidence to support that point.
Conclusions: There are strong observational data that support the
notion that avoiding an elevated Cl concentration or using uids
that reduce the rise in Cl reduces renal dysfunction, infections,
and possibly even mortality. However, observational studies only
can indicate an association and cannot indicate causality. Unfortunately, randomized trials to date are far too limited to address
this crucial issue. What is clear is that appropriate randomized
trials will require very large populations. It also is not known

E-mail addresses: sheldon.magder@muhc.mcgill.ca, sheldon.magder@mcgill.ca.

http://dx.doi.org/10.1016/j.bpa.2014.07.001
1521-6896/ 2014 Elsevier Ltd. All rights reserved.

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S. Magder / Best Practice & Research Clinical Anaesthesiology 28 (2014) 235e247

whether the important variable is the concentration of Cl, the

difference in concentrations of Na and Cl, or the total body mass
of Cl.
2014 Elsevier Ltd. All rights reserved.

Introduction
Single-atom electrolytes such as sodium, potassium, and chloride play a unique role in biology
[1e4]. Because they are not metabolized, their quantity in the body must be regulated through intake
and excretion. They are primarily dissolved in water although there are exceptions, such as the formation of boney structures by calcium and the interaction of calcium ion with the many calciumbinding proteins. Sodium ion (Na), too, can be sequestered by glycosaminoglycans in the skin in a
process that is tightly regulated by monocyte phagocytic cells and vascular endothelial growth factor C
(VEGF-C) [5,6]. However, these bound ions do not contribute to the osmotic activity of solutions.
Electrolytes in solutions play three crucial biological roles. They are major determinants of the
osmolality of the extracellular and intracellular compartments, which is essential for the maintenance
of constant cell volume relative to the external environment [4]. Second, gradients in strong electrolytes across cell membranes create a transmembrane potential energy that can be used to move
charged substances across the walls of cells and to regulate intracellular processes [4]. Third, strong
electrolytes are important regulators of hydrogen ion (H) concentration, that is, pH [7]. I will rst
review the physiological signicance of electrolytes in general and chloride (Cl) in particular and then
discuss the empiric evidence for the clinical use of intravenous solutions in which the concentration of
Cl is less than that of Na. Some of these issues have been well discussed in two recent reviews, one
especially focused on specic issues related to Cl [8] and the other on the nature of substitutes for Cl
[9].
Osmolality
Water is the essential solvent of living organisms and the volume of water in cells needs to be
regulated to maintain normal cell function. Water does not ow freely, but rather follows along concentration gradients. Accordingly, water volume is regulated by regulating the concentrations of solutes. Since single-atom electrolytes are not metabolized, they provide ideal substances for regulating
water distribution.
Life evolved out of the sea in which the two most common elements (not including oxygen and
hydrogen ion) are Cl and Na. Thus, it is not surprising that these two electrolytes which dominated
the extracellular environment of early organisms still dominate the extracellular environment of
multicellular organisms. Typical NaCl concentration of seawater is in the range of 3%, whereas that of
extracellular space is <1% and that of fresh water is 0.05%. In early multicellular organisms, seawater
moved freely through the gastrointestinal and respiratory systems. This allowed these organisms to
freely secrete seawater into their body cavities, pump it around, and use it to clear waste [10]. When
organisms moved into water with lower salinity, they had to evolve relatively impermeable exterior
systems to avoid taking up too much water from their surrounding for this would have resulted in
swelling of cells and compromised cell structures. At the same time, ltering off excess water resulted
in salt loss and mechanisms had to develop to reabsorb electrolytes from the ltrate [10]. When life
evolved onto land the problem shifted to conservation of water for now organisms were no longer
surrounded by water and water had to taken in by the gastrointestinal tract and conserved. An early
need in the evolutionary process was to take in an appropriate amount of Na and Cl from the
environment and differentiating the concentrations inside impermeable structures from the surrounding environment. For example, sh developed very sophisticated mechanisms in their gills that
regulate internal Na and Cl ion concentrations [11e13]. Some sh even can adapt these processes
rapidly so that they can move from the high salt environment of seawater to the low salt concentration

S. Magder / Best Practice & Research Clinical Anaesthesiology 28 (2014) 235e247

237

of fresh water. Other strong positive cations in seawater and the extracellular space include potassium
(K), magnesium (Mg2), and calcium (Ca2); a major anion is sulfate SO4 2 .
A fundamental principle in uid balance is the principle of iso-osmolality, which indicates that all
body compartments have approximately the same osmolality for osmolality determines movement of
water between compartments. In multicellular organisms, the extracellular space provides the interface with the environment, and in contrast to the intracellular environment it has a homogeneous
composition. The extracellular space thus has a primary role in sensing and setting the osmolality of
the whole organism. Osmolality is based on particle number and not particle size or charge. Particles
can be charged or non-charged. The primary non-charged particles are glucose and urea which freely
move between the extracellular and intracellular compartments, urea by diffusion and glucose by
facilitated transport. By contrast, charged particles cannot freely pass through lipid membranes.
Osmolality is thus primarily regulated by controlling the concentration of the charged particles.
Another key biophysical principle of uids is the principle of electrical neutrality. Even very small
differences in charges produce very large electrical forces. Thus, in macro-solutions, all positive charges
must equal all negative charges. The dominant cation in the extracellular compartment is Na. Other
cations such as K, Ca2, and Mg2 are in much smaller concentrations and deviations from their
normal values are lethal. Since [Na] ([ ] indicates concentration) must be matched by an equal concentration of anions, regulation of [Na] can serve to regulate total body osmolality for the charge
ensures that the concentration of negatives ions must match it.
Transmembrane potential
For a cell to be able to regulate its interior volume independently from the surrounding environment, it is most efcient to have an intracellular cation that is not Na. K serves this purpose. It is the
sixth most common element in water. Potassium sits below sodium in the periodic table and thus K
can be expected to behave similar to Na. By having Na dominate cations outside the cell and K
dominate cations inside the cell, it became possible to independently regulate the relative concentrations across the cell wall of these two ions through the actions of pumps, ion channels, and exchangers. A difference in [Na] and [K] across the cell wall generates an electrochemical gradient
which can be divided into a concentration gradient (i.e., higher [Na] outside the cell than inside and
the reverse for [K]) and an electrical potential which is determined by the difference in different
concentrations of [Na] and [K]. The energy produced by these processes allows osmoregulation, Na
nutrient cotransport, and the action potential of excitable cells [3].
Acidebase considerations
The dominant negative ion in the extracellular space is Cl, but it is only 70% of the concentration of
Na. Why is there a difference as Cl has a higher concentration than Na in seawater? One factor is
that there are other important negative ions (www.seafriends.org.nz/oceano/seawater.htm). Carbon
dioxide (CO2), and consequently its dissociation into bicarbonate and H, is an end product of aerobic
metabolism and thus an essential element in any aerobic species. Bicarbonate is the major anion accounting for the charge difference due the difference in [Na] and [Cl] in the interstitial space. In
blood, albumin also contributes to the charge difference for albumin, too, dissociates into an anion and
H. Albumin is the major determinant of the oncotic pressure in blood, and thus it is not something
that the body can readily alter to regulate the charge difference. Bicarbonate and ionized albumin are
weak ions, whereas Na and Cl are strong ions. As discussed in detail by the late Peter Stewart [7,14,15]
and others [16e18], the charge difference between strong positive and strong negative ions creates an
electrical force that distorts the dissociation equilibrium of weaker acids such as carbonic acid, albumin, and even water itself and makes them dependent variables. When they dissociate, they add an H
to the solution which we measure as pH. The charge difference between the strong positive and strong
negative ions is called the strong ion difference (SID), and it is the dominant factor regulating [H] in
water-based solutions. The other two factors are the total amount of carbon dioxide species and the
total amount of weak non-volatile acids, which normally are dominated by albumin.

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S. Magder / Best Practice & Research Clinical Anaesthesiology 28 (2014) 235e247

With a concentration of 55.3 mol/L, water is the most concentrated substance in the body. Most of
water exists as the molecule H2O but a small amount dissociates into H and OH. At standard temperature and at sea level, the concentration of H (and OH) in pure water is 1  107 or pH 7.00. The
solution is neutral, which is dened as one in which [H] equals [OH]. An acid solution is one in which
[H] is greater than OH and an alkaline solution is one in which [H] is less than [OH]. Although the
concentration of H in extracellular uids is very low, 40  109 M when compared to 140  103 for
Na, [H] has important effects on surrounding molecules because H has the highest charge density of
any atom. This charge can affect the tertiary structures of proteins by creating H bonds between
molecules. Thus, [H] is kept in the same range from bacteria to humans [19]. In normal plasma, the
difference between [Na] and [Cl] is 38e40 mmol/L, and this dominates the SID. When SID is positive,
as is the case in most solutions of the body, [H] is less than [OH] and the solution is alkaline. This
means that all solutions of the body, with the exception of the stomach when fasting and lysozymes,
are alkaline. Thus, when we say that someone is acidemic, the person actually is just less alkaline. As a
simple way of looking at it, by reducing the charge difference, an increase in [Na] relative to [Cl] has
an alkalinizing effect and can be thought of as giving NaOH. An increase in [Cl] relative to [Na] has an
acidifying effect and can be thought of as giving HCl. Although changes in [Na] can regulate extracellular pH, this is not a very good physiological solution because regulation of [Na] is so important for
regulating osmolality. Typically, [Na] is kept in a tight range. This means that only Cl is available as a
major metabolic regulator of [H] under normal conditions. PCO2 is the major non-metabolic
regulator.
What if instead of [Na] being greater than [Cl], the reverse were true, [Cl] were greater than
[Na] and the negative SID was accounted for by weak cations? The consequence would have been that
almost all bicarbonate would be in the form of carbonic acid and there would be almost a vefold larger
change in [H] for any change in the SID [7]. This would have made protein structures much more
sensitive to electrolyte changes.
Although intracellular volume is twice that of extracellular volume, much less attention has been
paid to the effect of administration of exogenous electrolytes on the intracellular environment and
especially on intracellular [H] [20]. This is partly because the intracellular environment varies greatly
among cell types and cannot be studied easily in intact beings. However, some generalities can be
made, which may have major importance for the administration of intravenous uids. As already
indicated, K is the major intracellular cation and its concentration is close to that of extracellular Na.
Intracellular [Na] and [Cl] are much lower than extracellular [Na]. They normally are in the
10 mmol/L range. Thus, the strong positive charge from intracellular [K] needs to be balanced by a
large concentration of weak ions including phosphate, proteins and other organic molecules. As these
substances have important roles inside the cell, only movements into and out of the cell of Na and Cl
and to some extent K are readily available for rapid regulation of intracellular pH.
Movement across cell membranes of Cl is regulated by at least six different processes [8]. These
include the cystic brosis transmembrane conductance regulator (CFTR) channel, members of the
volume-activated chloride channels and transporters (CLC) [21,22], calcium-activated chloride channels (CLCA), gamma-aminobutyric acid A (GABAA) channels, and glycine receptors which are ligandgated chloride channels.

Terminology
The title of this article refers to balanced and unbalanced salt solutions. Other terms often used are
physiologically buffered salt solutions and low-chloride solutions. A buffer is a substance that decreases the rate of increase in [H] during titration with a strong acid. Albumin and carbonic acid are
weak acids and when added to the solution they create a range in which the pH is much lower than
what it would be in a solution with only strong ions, but the rate of change in [H] for change in SID is
actually greater [7]. Replacing some of the Cl with lactate, gluconate, or acetate balance the solution
only in the sense that they account for the negative charge produced by having a lower [Cl]. The most
correct term likely is low-chloride solutions but this is clumsy so I have stayed with the editor's
choice!

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239

Regulation of the concentration difference between [Na] and [Cl]

As the quantity of electrolytes in the body is dependent upon their intake and output, mechanisms
must be in place in the gastrointestinal tract and kidney, and to a minor extent in the skin, to maintain
the normal difference between [Na] and [Cl] of ~40 mmol/L. Both the gastrointestinal tract and
kidney secrete and then reabsorb large amounts of uid. The human gastrointestinal tract normally
takes in ~1.5e2 L/day of water per day and secretes approximately 8e10 L/day but reabsorbs most of
this uid, primarily in the small intestine [23,24]. The normal oral intake of 3e5 g of sodium per day
provides 130e220 meq of almost equal amounts of Na and Cl per day. The amount of Na and Cl
added from the vefold higher bowel secretions is hard to predict because the amount of secretions
varies throughout the bowel and is affected by many factors. The basal secretion of Cl by apical
chloride channels in parietal cells in the stomach ranges from 0 to 11 mmol/h but can increase to over
60 mmol/h with meals [25]. This process is regulated by gastrin, histamine, and acetylcholine and is
altered by histamine antagonists and proton inhibitors. Cl also is absorbed and secreted throughout
the rest of the bowel and this contributes to water movement into the lumen.
Turnover of uid and electrolytes in the kidney is even more dramatic. At the normal ltration rate
of 125 ml/min, 180 L are ltered per day but only 1.5e2 L/day are excreted and 99% is reabsorbed [10].
With serum [Na] of 140 meq/L and [Cl] of 105 meq/L, the kidney passes 23,940 meq of Na and
19,742 meq of Cl per day into renal tubules; 99.6% of the Na and 99.5% of the Cl are reabsorbed. The
difference is remarkably only 0.1%, yet this difference is crucial for maintaining normal acidebase
balance. The implication is that a large part of the regulation of [Na] and [Cl] in plasma must occur at
the level of reabsorption from the lumens of the intestine and the renal tubules.
Regulation in the gastrointestinal tract. Regulation needs to start in the bowel [24] for most of the
ingested sodium is in the form of equal amounts of sodium and chloride (NaCl). Reabsorption is driven
by uptake of Na and Cl through four major mechanisms: 1) nutrient-coupled Na absorption, 2)
electroneutral NaCl absorption, 3) electrogenic Cl secretion by CFTR, and 4) electrogenic Na absorption by epithelial Na channel (ENaC) [24]. The large amount of secreted uid by the gastrointestinal tract keeps the bowel contents from being too hyperosmolar and thereby dehydrating
gastrointestinal epithelial cells. The stomach has a special role for it generally secretes a uid with
much more Cl than Na unless the person is taking inhibitors of gastric Cl secretion. It is possible that
in the past routine nasogastric suctioning and limited use of inhibitors of Clsecretion reduced the
burden of large Cl from large-volume 0.9% saline infusions. Cl secretion in the stomach is regulated
by gastrin, histamine and acetylcholine and is altered by histamine antagonists and proton inhibitors.
Regulation of absorption and secretion of Cl throughout the rest of the bowel is complex which allows
it to adapt to the varying contents of what is ingested. Vasoactive intestinal peptide and acetylcholine
inhibit electroneutral NaCl reabsorption and increase Cl secretion [24]. These processes are regulated
by cyclic nucleotides and calcium [26]. Sympathetic nerve activity favors absorption whereas parasympathetic activity is antiabsorption and secretory and immune responses are secretory [24]. In a
study of pigs fed a standard diet, it was found that after the stomach, [Cl] in the bowel progressively
decreases and is <15 meq/L in the stool. It is thus very difcult to predict how the bowel will react with
intravenously induced hyperchloremia [27].
Kidney. The kidney has a number of mechanisms to reabsorb a large amount of ltered Cl from
renal tubules [28]. The proximal convoluted tubule reabsorbs 50e67% of Cl by an electrochemical
gradient linked to Na movement through the sodiumeproton exchanger (NHE). In the ascending loop
of the tubules, Cl moves through chloride channels KB (CLCNKB) (CLC-K1 in the mice) and CLC-K2.
There are no inhibitors of these channels so they have been studied primarily by developing
knockout mice. CLC-K1 affected concentrating abilities but did not affect pH. Patients with Bartter's
syndrome who have a mutation in CLC-K2 have hypokalemic alkalosis, which is consistent with not
being able to reabsorb Cl. In the ascending tubule, Cl reenters through a Na:K:2Cl cotransporter,
NKCC2, which is inhibited by furosemide. There is also a CFTR channel in the kidney [28]. The basic
message from the above is that regulation of [Cl] in the gastrointestinal tract and kidney is based more
on selective reabsorption of ltrated uid than absorption and, at least in the kidney, is nonspecic.
Disorders in these pathways will more likely result in hypochloremia than hyperchloremia in Bartter's
syndrome.

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For the kidney to restore an elevated plasma [Cl] to normal, more [Cl] must be left in the tubules
than Na and another cation is needed to maintain electrical neutrality in the tubule. This indeed is the
case for the ratio of the concentration of tubular uid Cl to plasma Cl is considerably higher than that
of Na [28]. In the traditional explanation, H and HCO3  are presumed to account for the charge
balance but basic physical chemistry principles indicate that these are dependent variables and the
overall process must be determined by concentrations of strong ions and total carbon dioxide species.
Changes in SID change the dissociation of carbonic acid and the observed HCO3  [29]. However, this
presumes the presence of carbonic anhydrase for otherwise the dissociation/dissociation of carbonic
acid is slow and can directly affect tubular H. The potential candidates that can change the SID are Na,
K, and NH4 on the positive side, and Cl, oxalate, and formate on the negative side. Normally, sulfate
is too low to have a signicant effect. If tubular uid were balanced by Na, the ratio of [Na] to [Cl]
would not change and there would be a decrease in body stores of Na. K, too, has a limited potential
because [K] is low in serum. As already discussed, H is a dependent variable and orders of magnitude
too small. Thus, another strong cation is needed and ammonium serves this purpose. At physiological
pH, ammonium (NH3) is primarily in the form of ammonium NH4 . NH3/NH4 is produced in the
proximal tubules by cleaving NH3 off an amino acid (ammoniagenesis). By far, the major contributor is
glutamine. This enzymatic process needs to be induced when demands are increased, and thus
normalization of [Cl] after a large saline load is slower than normalization of [Na]. There also must be
sufcient amino acid substrate and functioning enzymes, which can be an issue during catabolic states.
By contrast, Na excretion can be rapid for it can be balanced by the excretion of Cl and HCO3  . Fig. 1
illustrates an example of loading humans with Cl by having them ingest 15 g of NH4Cl for 5 days
[30,31]. There was an immediate increase in Na excretion which produced an initial negative Na
balance and at later times increased K excretion. The decit in K was not restored even 6 days after
stopping the NH4Cl. Titratable acid, which is essentially phosphate, also increased by a small amount.
The major change was a progressive increase in NH4 excretion, which is not related to the NH4 given
because it is not present immediately. After stopping the NH4Cl (day 11), Na excretion decreased to
restore the lost Na and then NH4 excretion gradually decreased. Fig. 2 shows an example of CaCl
loading in a normal and a nephritic subject [30]. The Cl load caused a progressive increase in xed
bases which are essentially Na and K. This decreased over 4 days in the normal subject because of

Fig. 1. Changes in urine composition in response to ingestion of ammonium chloride in normal subjects. Baseline measurements
were made for 5 days; 15 g of NH4Cl were given orally for 5 days and measurements obtained for another 5 days. The top bars
indicate meq of Cl excreted per day. The bottom shows renal excretion of ammonia and titratable acid (mainly phosphate) in the
positive direction and Na and K in the negative direction. The immediate response to the NH4Cl load was an increase in Na
excretion followed by increased K excretion. Ammonia excretion increased over the 5 days of ingestion and then decreased over the
5 days after ingestion while K excretion remained reduced (Used with permission from Pitts RF 1968-ref 30).

S. Magder / Best Practice & Research Clinical Anaesthesiology 28 (2014) 235e247

241

Fig. 2. Changes in urine ammonium, Cl, and xed base (mainly Na and K) during ingestion of CaCl in a normal subject (upper
graph) and a subject with chronic nephritis (lower graph). In the normal subject, Cl excretion increases immediately but did not
peak until day 4e5. This was accompanied by an initial increase in xed base which decreased by day 2 as ammonium excretion
continued to increase. In the subject with chronic nephritis, there was only a small and late increase in ammonium and the Cl was
excreted with xed base. The ingestion had to be stopped at day 4 because of the increasing acidemia. See text for further details
(Used with permission from Pitts RF 1968-ref 30).

increased NH4 production but the nephritic subject could not make NH4 . The administration of CaCl
had to be stopped because of severe acidemia. Recovery was slow and inadequate.
The large loads of Cl that come with infusion of intravenous saline are very un-physiological. There is
no example in normal mammals where Cl is directly infused into the vasculature without rst passing
through the regulatory gastrointestinal mechanisms. Furthermore, the expansion of extracellular volume
from the infusion of a NaCl solution markedly elevates the total body mass of Cl. The consequent high
vascular and extracellular [Cl] perfuses intestinal structures from the outside of the lumen although the
bowel is primarily designed to deal with the load from the luminal side. Increased extracellular Cl also
will tend to increase intracellular Cl, which has an acidifying effect on the cytoplasm and activates
intracellular processes to restore normal intracellular pH. Finally, restoration of normal volume requires
excretion of the Cl across renal tubular cells and will add a strong acidifying stress in the process.

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Clinical signicance of excess [Cl]

A simple but easily correctable consequence of hyperchloremia is that clinicians may not appreciate
that an elevated base excess measurement and acidemia are due to the elevated [Cl] and waste time
and effort looking for other causes to explain it rather than trying to deal with the factors increasing
[Cl] which primarily the uid being infused.
Despite the clear physiological challenge to the organism with a high [Cl], the presence of a direct
clinical impact requires empiric data which is reviewed next. While attention has been paid primarily
to hyperchloremia, it is possible that the total body mass of Cl could be harmful even without acidemia. For example, an increase in [Na] or decrease in albumin could compensate for an increase in
[Cl] and normalize extracellular pH, but the elevated interstitial [Cl] would still increase the transcellular gradient for Cl which might affect intracellular processes.
The statement that there is little evidence that in the 50 years of normal saline usage, there has
been signicant morbidity from the use of this uid may be rather premature because normal saline
is such a standard that it is hard to nd patients who did not receive it to establish whether or not there
is harm. It might almost be considered that hyperchloremia is the current norm! [8].
Why is 0.9% saline the major uid currently used? The simple answer likely is that it is so easy and
inexpensive to make. Reducing [Cl] relative to [Na] requires replacing the negative charge from Cl
with a weak anion. Bicarbonate cannot easily be used because it is volatile and not stable. Thus, organic
acids such as lactate, gluconate, or acetate are used (Table 1). These actually behave as strong ions and
would narrow the SID of plasma and acidify the solution the same way that Cl does. However, they are
metabolized rapidly in plasma and leave behind the Na which widens the SID. The rate of metabolism
becomes an important issue and could vary with the metabolic status of the patient. There even is the
potential of these substances to cause alkalemia, which could occur if Cl were excreted to account for
the narrowed SID or if Na were retained. All these issues are extensively reviewed recently by Morgan
[9]. Manufacturing of these products is more complex and thus the cost is higher although not excessive.
However, if use of these products becomes the standard, the costebenet would need to be evaluated.

Cochrane review of randomized studies

The Cochrane Collaboration updated their review of the safety and efcacy of what they call
buffered and non-buffered uid administration for surgery in adults in 2013 [32]. Studies
comparing different colloids or hypertonic uids were excluded. Only 13 trials met their inclusion
criteria with a total of 706 participants. The primary outcome for the analysis was mortality, but this
was only available in three trials with a total of 267 patients. Mortality was 2.9% in the buffered group
and 1.5% in the non-buffered group (odds ratio (OR) 1.85 favoring non-buffered solutions, condence
intervals (CI) 0.37e9.33). The only morbidity with sufcient information was renal failure, and this was
only in three studies. The OR favored the buffered solution (OR 0.61, 95% CI 0.23e1.63, P 0.32). As
expected from the physiology, pH was lower in the non-buffered group and [Cl] higher. The mortality
assessment was called moderate, which means that further research is likely to have an important
Table 1
Electrolyte composition of common intravenous uids.
mEq/L

Osmolality

Cations

Plasma
NaCl 0.9%
Ringer lactate
Ringer acetate
Hartmann's
Plasma-Lyte 148

Anions

Na

Ca2

Mg2

Cl

Acetate

135e145
154
130
130
131
140

3.5e5.0
e
4.0
4.0
5.0
5.0

4.4e5.2
0
3.0
4.0
4.0
0

1.6e2.4
e

98e106
154
109
110
111
98

Bicarbonate 21e30
e
e
28
30
e
29
27
e

2.0
e
3.0

Lactate

Gluconate
e
e
23

mosmol/L
280e300
e
273
277
278
295

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243

impact on the condence estimate. The organ dysfunction assessment was low quality, which means
that it is very likely that further studies will change the estimates.
A systematic review is only as useful as the studies included. Of the three studies used for the
analysis of death, in two [33,34] the uid was a colloid in a balanced salt solution and the colloid could
have dominated the response. In all three studies, uids were controlled only for the period of the
operation and at most for a few hours after surgery. Thus, patients could have received a large load of
chloride-rich solutions in the postoperative period. In one study, over 7 L of crystalloid was given
versus only ~2.3 L of study uids [33]. The mass of Cl given to both groups likely would have overwhelmed any differences between study groups if there were any.
Of the three studies on renal injury [35e37], two subjects were undergoing kidney transplant and
results thus cannot be generalized. The exposure time to the low Cl solution was again a small part of the
hospital stay. In two studies, approximately 6 L of study uids were given during surgery which would
have resulted in a large Cl load in both groups [35,36]. One study was stopped prematurely because
there was more hyperkalemia in the saline group [36]; the explanation for this is not obvious because
other values in the two groups were not very different and this has not been observed in other studies.
The only conclusions that realistically can be made from these papers is that Cl-rich solutions
increase plasma [Cl] and base excess and lower pH, but they do not help us determine if there is harm,
benet, or a neutral effect with the use of balanced salt solutions.
The emphasis on mortality in the Cochrane analysis underscores a major problem in the analysis of
perioperative treatments in general. Because expected mortality is very low, huge numbers of patients
are needed to use this as an end point. Based on the Cochrane-estimated difference, it would require
around 55,000 subjects to prove the point! More meaningful end points thus are needed for the large
number of perioperative cases who have low rates of mortality.
In summary, randomized studies to date are very limited. Exposure periods were short and uids
used during the rest of the hospital stay could easily have overwhelmed any real differences. Studies
have few observed end points, and thus the analyses were hopelessly underpowered. It is not evident
whether the important variable is the concentration of Cl or the total load of Cl. For example, a
patient who has 10 L of extra extracellular uid and a normal [Cl] has approximately 60% increase in
body Cl, which ultimately has to be excreted. There is also a potential for increased intracellular Cl
that has to be cleared. Future studies will need to account for all uids given during the hospital stay
and not just during the time in the operating room.
Observational studies
In general, randomized trials are much more useful than observational studies because they directly
address causality rather than just association, but the current lack of appropriate randomized trials leaves
us dependent upon observational studies. Although not denitive, they can present important evidence
for future large randomized trials. They also make it economically feasible to study large populations and
to include subjects who are excluded from randomized trials such as emergency cases and subjects with
diverse baseline conditions. There currently are three reported large observational studies.
The strongest of these is by Yunos et al. [25]. They performed a prospective, open-label, sequential
period study in the intensive care unit (ICU) of a single university-afliated hospital. The study had a 6month control period during which patients received standard infusions that were dominated by
chloride-rich solutions. Over the next 6 months, the chloride-rich solutions were phased out thereby
giving clinicians time to adapt to the new approach. They then prospectively collected data for another
6 months with the restricted chloride approach. There were 760 patients in the control period and 773
in the intervention period. Of note, almost half of the patients came from the operating room where
they still might have received a large chloride load before being in the controlled ICU environment.
During the period of restricted chloride use, there was a signicant reduction in renal injury and failure
based on an RIFLE-dened acute kidney injury score and a smaller increase in serum creatinine during
the hospital stay. There was no increased need for renal replacement therapy after hospital discharge.
Hospital mortality was not altered but the study was not powered for this end point. The authors noted
that the intervention included a bundle of care and any component could have contributed to the
improved renal outcome, but the results of this pilot are still intriguing and well worth further

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investigation [38]. They also pointed out potential risks with restricting chloride-rich uids and use of
hypotonic uids in patients with hyponatremia, alkalemia, cerebral edema, and traumatic brain injury.
McCluskey et al. performed a retrospective observational study on a large surgical database with
records from over a 5-year period [39]. The primary question was what is the impact on the outcome of
the presence of a high serum [Cl] in noncardiac surgical patients? All subjects had normal preoperative
renal function and serum [Cl]. Subjects were propensity-matched for the development of postoperative
hyperchloremia and then compared to those who developed hyperchloremia dened as [Cl]
>110 mmol/L based on the maximum [Cl] on postoperative days 1e5, versus those without hyperchloremia. Hyperchloremia was present in 22% of patients and thus common. Patients with hyperchloremia had an increased risk of mortality at 30 days (3.0% vs. 1.9%), longer hospital stay, and more
renal dysfunction. In a retrospective study, it cannot be ruled out that hyperchloremia was just a marker
of a greater severity of illness. For example, the longer hospital stay could have been a consequence of
giving more Cl, but also because the risk of becoming hyperchloremic was greater because there was
more time to develop it. The study also did not address the all-important question as to why [Cl] was
increased in one group since by design they had the same propensity for an elevated [Cl]. Was this due
to the type of uid given or due to greater use of uid which could have been a risk in and of itself?
However, this study, too, supports the argument that there is a need for further investigation of the
clinical impact of hyperchloremia and, importantly, whether it increases morbidity and mortality.
The third observational study was by Shaw et al. who used a large US automated hospital claims
database to perform a retrospective cohort study of almost 500,000 patients who had undergone
abdominal surgery [40]. The primary hypothesis was that in comparison to a balanced crystalloid
solution, 0.9% saline use in major abdominal surgery increased major morbidity, which included respiratory failure, cardiac decompensation, major gastrointestinal dysfunction, infectious complications,
and acute renal failure. They only included patients who were at a risk of potential need for blood
transfusion, with the exception of traumatic injuries, for they wanted to exclude calcium-containing
solutions. The balanced crystalloid solution was either Plasma-Lyte A or Plasma-Lyte 148. Out of the
large number of patients in the database, 30,994 received 0.9% saline and 926 received a balanced salt
solution. Importantly, balanced salt solution recipients were less likely to be minorities, to be admitted
via the emergency department, to be in a major teaching hospital, to have Medicare as the primary
payer, and were more likely to have commercial insurance indicating that they were a more advantaged population. These differences were adjusted with use of a propensity score. Overall, the odds of
developing major infection were signicantly lower in patients receiving the balanced salt solutions.
There was no difference in mortality between the groups but the baseline mortality was low. Directional changes in the use of dialysis, use of blood transfusions, respiratory failure, major hemorrhage,
and resource utilization favored the balanced salt solution. Thus, this study, too, supports an outcome
benet for use of balanced salt solutions. However, only 2.7% of patients received the balanced solution
and only 0.3% met study criteria. Thus, despite the use of the propensity score there were likely still
unobserved covariates.
The higher rate of major hemorrhage observed by Shaw et al. [40]. is supported by a small but
detailed comparison of the coagulation prole with the use of thromboelastography in a randomized
trial of lactated Ringer's, 6% Hetastarch in a balanced salt solution, and 6% Hetastarch in 0.9% saline [41].
The 6% starch in the 0.9% saline group had a hypocoagulative prole, the lactated Ringer's group a
hypercoagulative prole, and the 6% starch group in a balanced salt solution was in the middle.
Synthesis
From an evolutionary and physiological perspective, there is little doubt that serum chloride concentrations much above 100 are abnormal. The question remains, do they have a signicant impact?
Animal studies indicate harm under septic conditions but it is less clear that there is a problem in nonseptic animals [42e44]. Three large observational studies indicate greater morbidity and even mortality
in one study, but this only indicates an association and not causality. Unfortunately, the randomized
trials are far too insufcient to make any statement of causality, even with a meta-analysis. A further
fundamental question arises as to whether it is the total burden of Cl that is important or is it the
concentration in the serum and interstitial space that counts. This has important implications for

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245

therapy. If it is the total burden of excess Cl and overall uid balance that is important then this can be
dealt with by more restrictive uid policies. It is apparent that a lot more Na is being given than is often
appreciated [45], and it is likely that the bulk of this Na is accompanied by an equal amount of Cl. If
the issue is the bulk of Cl, then the use of hypotonic saline solutions (i.e., 0.45%) might also be helpful.
However, this will inevitably result in some lowering of serum [Na] and some argue that even small
decreases in [Na] worsen outcome [46e49]. Only large randomized trials will be able to answer these
questions. It is unlikely that mortality will be a useful end point for standard clinical practice because
these uids most often are used in patients with low mortalities. From the observational studies, renal
failure, infections, and perhaps functional status after surgery might be appropriate end points. A large
randomized cluster pilot trial is currently under way and will hopefully soon provide some important
information on how to move forward on this central issue in the management of perioperative and
critically ill patients (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id365460).
Conict of interest
The author has no conicts of interest to report related to this manuscript. There were no outside
funding sources or sponsor.
Practice points
 When administering electrolyte solutions, consideration should be given to total body
accumulation and not just concentration.
 Solutions with a high chloride concentration add a stress to excretory systems.
 Solutions with high chloride should be expected to produce a metabolic acidosis and increase base excess; one must be careful not to overreact to this frequent cause of acidemia
by thinking that it is due to inadequate tissue perfusion.
 Observational data suggest that hyperchloremia is dose-dependently associated with renal
dysfunction, bowel dysfunction, and increased risk of bleeding. One study even showed a
relationship with mortality.
 Current randomized trials are inadequate to determine whether hyperchloremia caused
morbidity and mortality or are simply associated.

Research agenda
 There is a great need for large randomized trials to determine the clinical significance of the
use of fluids with a chloride concentration similar to that of normal plasma.
 In initial studies, an important end point that is feasible to achieve is potential reduction in the
development of renal dysfunction with use of a reduced chloride solution compared to 0.9%
saline.
 Determining that reduced chloride solutions reduce mortality compared to 0.9% saline will
require very large trials, perhaps >20,000 subjects.
 It will be essential in future trials to account for the use of each type of fluid during the whole
hospital stay and not just the immediate perioperative period.
 Trials should try to differentiate the total accumulation of sodium and chloride as well as the
change in serum concentrations of these elements.
 Patients with inflammatory conditions should be studied separately for the animal data
suggest that the impact of excess chloride is greater in septic animals than controls.

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