balanced versus unbalanced salt solutions what (raisul)

8/10/2019 Balanced Versus Unbalanced Salt Solutions What (Raisul)

1/13

4

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 electro-

lytes and replace losses when patients have limited gastrointes-

tinal 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 thisuid 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 concentra-

tion 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

balancedby 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. Unfor-

tunately, 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: [email protected],[email protected].

Contents lists available atScienceDirect

Best Practice & Research Clinical

Anaesthesiologyj o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m /l o c a t e / b e a n

http://dx.doi.org/10.1016/j.bpa.2014.07.001

1521-6896/ 2014 Elsevier Ltd. All rights reserved.

Best Practice & Research Clinical Anaesthesiology 28 (2014) 235e247
mailto:[email protected]:[email protected]://www.sciencedirect.com/science/journal/15216896http://www.elsevier.com/locate/beanhttp://dx.doi.org/10.1016/j.bpa.2014.07.001http://dx.doi.org/10.1016/j.bpa.2014.07.001http://dx.doi.org/10.1016/j.bpa.2014.07.001http://dx.doi.org/10.1016/j.bpa.2014.07.001http://dx.doi.org/10.1016/j.bpa.2014.07.001http://dx.doi.org/10.1016/j.bpa.2014.07.001http://www.elsevier.com/locate/beanhttp://www.sciencedirect.com/science/journal/15216896http://crossmark.crossref.org/dialog/?doi=10.1016/j.bpa.2014.07.001&domain=pdfmailto:[email protected]:[email protected]


2/13

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 for-

mation of boney structures by calcium and the interaction of calcium ion with the many calcium-

binding 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 electro-

lytes 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 con-

centration gradients. Accordingly, water volume is regulated by regulating the concentrations of sol-

utes. 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 ofmulticellular organisms. Typical NaCl concentration of seawater is in the range of 3%, whereas that of

extracellular space is


3/13

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 SO42.

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 inter-

face with the environment, and in contrast to the intracellular environment it has a homogeneouscomposition. 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 con-centration 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 environ-

ment, 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 concen-

trations across the cell wall of these two ions through the actions of pumps, ion channels, and ex-

changers. 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 isthat 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 ac-

counting 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, albu-

min, 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.

S. Magder / Best Practice & Research Clinical Anaesthesiology 28 (2014) 235e247 237
http://www.seafriends.org.nz/oceano/seawater.htmhttp://www.seafriends.org.nz/oceano/seawater.htm


4/13

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 tem-

perature 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 inwhich [H] equals [OH]. An acid solution is one inwhich

[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 forNa, [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] i s 3 8e40 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 extra-

cellular pH, this is not a very good physiological solution because regulation of [Na] is so important forregulating 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 greatlyamong 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 chan-nels (CLCA), gamma-aminobutyric acid A (GABAA) channels, and glycine receptors which are ligand-

gated 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 de-

creases 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 isactually greater [7]. Replacing some of the Cl with lactate, gluconate, or acetate balancethe 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!

S. Magder / Best Practice & Research Clinical Anaesthesiology 28 (2014) 235e247238


5/13

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 ofuid. The human gastrointestinal tract normallytakes 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 ofuid and electrolytes in the kidney is even more dramatic. At the normalltration rate

of 125 ml/min, 180 L are ltered per day but only 1.5e

2 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 ab-

sorption by epithelial Na channel (ENaC)[24]. The large amount of secreted uid by the gastroin-

testinal tract keeps the bowel contents from being too hyperosmolar and thereby dehydratinggastrointestinal 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 para-

sympathetic 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 progressivelydecreases and is


6/13

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 NH3off an amino acid (ammoniagenesis). By far, the major contributor is

glutamine. This enzymatic process needs to be induced when demands are increased, and thusnormalization 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. 2shows an example of CaCl

loading in a normal and a nephritic subject [30]. The Cl

load caused a progressive increase in xedbaseswhich 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).



7/13

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 comewith 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 thebowel 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.

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 4e

5. This was accompanied by an initial increase in xed base which decreased by day 2 as ammonium excretioncontinued 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).



8/13

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 acid-

emia. 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 trans-

cellular 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 tond 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 majoruid currently used? The simple answer likely is that it is so easy andinexpensive 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 0.23e

1.63, P 0.32). Asexpected 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 Anions

Na K Ca2 Mg2 Cl Acetate Lactate Gluconate mosmol/L

Plasma 135e145 3.5e5.0 4.4e5.2 1.6e2.4 98e106 Bicarbonate 21e30 280e300

NaCl 0.9% 154 e

0 e

154 e e e e

Ringer lactate 130 4.0 3.0 109 28 273

Ringer acetate 130 4.0 4.0 2.0 110 30 e e 277

Hartmann's 131 5.0 4.0 e 111 29 278

Plasma-Lyte 148 140 5.0 0 3.0 98 27 e 23 295



9/13

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 ofchloride-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 over-

whelmed 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 timeto the lowCl 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 inbody 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 justassociation, 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 withdiverse 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 6-

month 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-de

ned acute kidney injury score and a smaller increase in serum creatinine duringthe 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



10/13

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 forthe development of postoperativehyperchloremia 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 hyper-

chloremia. Hyperchloremia was present in 22% of patients and thus common. Patients with hyper-

chloremia 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 ofuid given or due to greater use ofuid 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 theclinical 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 res-

piratory 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 admittedvia 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 advan-

taged 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. Direc-

tional 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 butdetailed 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 con-

centrations 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 non-

septic animals [42e

44]. Three large observational studies indicate greater morbidity and even mortalityin 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



11/13

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[46e

49]. Only large randomized trials will be able to answer thesequestions. It is unlikely that mortality will be a useful end point for standard clinical practice because

theseuids 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?id 365460).

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 in-

crease 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.

https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=365460https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=365460https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=365460https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=365460


12/13

References

[1] Else PL, Turner N, Hulbert AJ. The evolution of endothermy: role for membranes and molecular activity. Physiol BiochemZool 2004 Nov;77(6):950e8.

[2] Wilson TH, Maloney PC. Speculations on the evolution of ion transport mechanisms. Fed Proc 1976 Aug;35(10):2174e9.[3] Wilson TH, Lin EC. Evolution of membrane bioenergetics. J Supramol Struct 1980;13(4):421e46.

[4] Brett CL, Donowitz M, Rao R. Evolutionary origins of eukaryotic sodium/proton exchangers. Am J Physiol Cell Physiol 2005Feb;288(2):C223e39.

[5] Titze J, Muller DN, Luft FC. Taking another look at sodium. Can J Cardiol 2014 May;30(5):473e5.[6] Titze J, Dahlmann A, Lerchl K, et al. Spooky sodium balance. Kidney Int 2014 Apr;85(4):759e67.[7] Stewart PA. How to understand acidebase. A quantitative acid-base primer for biology and medicine. New York: Elsevier

North Holland; 1981.*[8] Yunos NM, Bellomo R, Story D, et al. Bench-to-bedside review: chloride in critical illness. Crit Care 2010;14(4):226 .*[9] Morgan TJ. The ideal crystalloid e what is 'balanced'? Curr Opin Crit Care 2013 Aug;19(4):299e307.

[10] Pitts RF. Mechanisms of reabsorption and excretion of ions and water. Physiology of the kidney and body uids: anintroductory text. 2nd ed. Chicago: Year Book Medical Publishers Incorporated; 1968. p. 94e128.

[11] Patrick ML, Wood CM. Ion and acid-base regulaton in the freshwater mummichog (Fundulus heteroclitus): a departurefrom the standard model for freshwater teleosts. Comp Biochem Physiol Part A 1999;122:445e56.

[12] Parks SK, Tresguerres M, Goss GG. Theoretical considerations underlying Na() uptake mechanisms in freshwater shes.Comp Biochem Physiol C Toxicol Pharmacol 2008 Nov;148(4):411e8.

[13] Wood CM, Laurent P. Na versus Cl transport in the intact killish after rapid salinity transfer. Biochim Biophys Acta2003 Dec 30;1618(2):106e19.

[14] Stewart PA. Modern quantitative acid-base chemistry. Can J Physiol Pharmacol 1983 Dec;61(12):1444e61.*[15] Kellum JA, Elbers PW. Peter Stewart's textbook of acidebase. 2nd ed. 2009. www.acidbase.org.

[16] Kellum JA, Kramer DJ, Pinsky MR. Strong ion gap: a methodology for exploring unexplained anions. J Crit Care 1995 Jan 1;10(2):51e5.

[17] Gilx BM, Bique M, Magder SA. A physiological approach to the analysis of acid-base balance in the clinical setting. J CritCare 1993;8:187e97.

[18] Jones NL. A quantitative physiochemical approach to acid-base physiology. Clin Biochem 1990;23:189e95.[19] Roos A, Boron WF. Intracellular pH. Physiol Rev 1981 Jan 1;61(2):296e434.[20] Magder S. Intracellular [H]. In: Kellum JA, Elbers PW, editors. Stewart's textbook of acid-base; 2009. p. 247 e65.[21] Uchida S. Physiological role of CLCeK1 chloride channel in the kidney. Nephrol Dial Transpl 2000;15(Suppl. 6):14 e5.[22] Uchida S. In vivo role of CLC chloride channels in the kidney. Am J Physiol Ren Physiol 2000 Nov;279(5):F802e8.

*[23] Barrett KE, Keely SJ. Chloride secretion by the intestinal epithelium: molecular basis and regulatory aspects. Annu RevPhysiol 2000;62:535e72.

[24] Kato A, Romero MF. Regulation of electroneutral NaCl absorption by the small intestine. Annu Rev Physiol 2011;73:261e81.

*[25] Yunos NM, Bellomo R, Hegarty C, et al. Association between a chloride-liberal vs chloride-restrictive intravenous uidadministration strategy and kidney injury in critically ill adults. JAMA 2012 Oct 17;308(15):1566 e72.

[26] Keely SJ, Barrett KE. Regulation of chloride secretion. Novel pathways and messengers. Ann N Y Acad Sci 2000;915:67e76.[27] Hamilton DL, Roe WE. Electrolyte levels and netuid and electrolyte movements in the gastrointestinal tract of weanling

swine. Can J Comp Med 1977 Jul;41(3):241e50.*[28] Edwards JC. Chloride transport. Compr Physiol 2012 Apr;2(2):1061e92.

[29] Ring T, Frische S, Nielsen S. Clinical review: renal tubular acidosis ea physicochemical approach. Crit Care 2005;9(6):573e80.

[30] Pitts RF. Renal regulation of acid-base balance. In: F.Pitts Robert, editor. Physiology of the kidney and body uids. 2nd ed.Chicago: Year Book Medical Publishers Incorporated; 1968. p. 179e212.

[31] Sartorius OW, Roemmelt JC, Pitts RF. The renal regulation of acid-base balance in man; the nature of the renal com-pensations in ammonium chloride acidosis. J Clin Invest 1949 May;28(3):423e39.

[32] Burdett E, Dushianthan A, nett-Guerrero E, et al. Perioperative buffered versus non-buffered uid administration for

surgery in adults. Cochrane Database Syst Rev 2012;12. CD004089 .[33] Base EM, Standl T, Lassnigg A, et al. Efcacy and safety of hydroxyethyl starch 6% 130/0.4 in a balanced electrolyte solution

(volulyte) during cardiac surgery. J Cardiothorac Vasc Anesth 2011 Jun;25(3):407e14.[34] Pagano PJ, Chanock SJ, Siwik DA, et al. Angiotensin II induces p67phox mRNA expression and NADPH oxidase superoxide

generation in rabbit aortic adventitial broblasts. Hypertension 1998 Jan 1;32:331e7.

[35] Waters JH, Gottlieb A, Schoenwald P, et al. Normal saline versus lactated Ringer's solution for intraoperative uidmanagement in patients undergoing abdominal aortic aneurysm repair: an outcome study. Anesth Analg 2001 Oct;93(4):817e22.

[36] O'Malley CM, Frumento RJ, Hardy MA, et al. A randomized, double-blind comparison of lactated Ringer's solution and 0.9% NaCl during renal transplantation. Anesth Analg 2005 May;100(5):1518e24 [table].

[37] Hadimioglu N, Saadawy I, Saglam T, et al. The effect of different crystalloid solutions on acid-base balance and earlykidney function after kidney transplantation. Anesth Analg 2008 Jul;107(1):264e9.

[38] Waikar SS, Winkelmayer WC. Saving the kidneys by sparing intravenous chloride? JAMA 2012 Oct 17;308(15):1583e5.*[39] McCluskey SA, Karkouti K, Wijeysundera D, et al. Hyperchloremia after noncardiac surgery is independently associated

with increased morbidity and mortality: a propensity-matched cohort study. Anesth Analg 2013 Aug;117(2):412e21.*[40] Shaw AD, Bagshaw SM, Goldstein SL, et al. Major complications, mortality, and resource utilization after open abdominal

surgery: 0.9% saline compared to Plasma-Lyte. Ann Surg 2012 May;255(5):821e9.[41] Martin G, Bennett-Guerrero E, Wakeline H, et al. A prospective, randomized comparison of thromboelastographic

coagulation prole in patients receiving tactated Ringer's solution, 6% hetastarch in a balanced-saline vehicle, or 6%hetastarch in saline during major surgery. Cardiothorac Vasc Anesth 2002 Jan 1;16(4):441e6.

http://refhub.elsevier.com/S1521-6896(14)00049-4/sref1http://refhub.elsevier.com/S1521-6896(14)00049-4/sref1http://refhub.elsevier.com/S1521-6896(14)00049-4/sref1http://refhub.elsevier.com/S1521-6896(14)00049-4/sref2http://refhub.elsevier.com/S1521-6896(14)00049-4/sref2http://refhub.elsevier.com/S1521-6896(14)00049-4/sref3http://refhub.elsevier.com/S1521-6896(14)00049-4/sref3http://refhub.elsevier.com/S1521-6896(14)00049-4/sref4http://refhub.elsevier.com/S1521-6896(14)00049-4/sref4http://refhub.elsevier.com/S1521-6896(14)00049-4/sref4http://refhub.elsevier.com/S1521-6896(14)00049-4/sref5http://refhub.elsevier.com/S1521-6896(14)00049-4/sref5http://refhub.elsevier.com/S1521-6896(14)00049-4/sref5http://refhub.elsevier.com/S1521-6896(14)00049-4/sref5http://refhub.elsevier.com/S1521-6896(14)00049-4/sref5http://refhub.elsevier.com/S1521-6896(14)00049-4/sref5http://refhub.elsevier.com/S1521-6896(14)00049-4/sref6http://refhub.elsevier.com/S1521-6896(14)00049-4/sref6http://refhub.elsevier.com/S1521-6896(14)00049-4/sref7http://refhub.elsevier.com/S1521-6896(14)00049-4/sref7http://refhub.elsevier.com/S1521-6896(14)00049-4/sref7http://refhub.elsevier.com/S1521-6896(14)00049-4/sref7http://refhub.elsevier.com/S1521-6896(14)00049-4/sref8http://refhub.elsevier.com/S1521-6896(14)00049-4/sref8http://refhub.elsevier.com/S1521-6896(14)00049-4/sref9http://refhub.elsevier.com/S1521-6896(14)00049-4/sref9http://refhub.elsevier.com/S1521-6896(14)00049-4/sref9http://refhub.elsevier.com/S1521-6896(14)00049-4/sref9http://refhub.elsevier.com/S1521-6896(14)00049-4/sref10http://refhub.elsevier.com/S1521-6896(14)00049-4/sref10http://refhub.elsevier.com/S1521-6896(14)00049-4/sref10http://refhub.elsevier.com/S1521-6896(14)00049-4/sref10http://refhub.elsevier.com/S1521-6896(14)00049-4/sref10http://refhub.elsevier.com/S1521-6896(14)00049-4/sref11http://refhub.elsevier.com/S1521-6896(14)00049-4/sref11http://refhub.elsevier.com/S1521-6896(14)00049-4/sref11http://refhub.elsevier.com/S1521-6896(14)00049-4/sref11http://refhub.elsevier.com/S1521-6896(14)00049-4/sref11http://refhub.elsevier.com/S1521-6896(14)00049-4/sref12http://refhub.elsevier.com/S1521-6896(14)00049-4/sref12http://refhub.elsevier.com/S1521-6896(14)00049-4/sref12http://refhub.elsevier.com/S1521-6896(14)00049-4/sref12http://refhub.elsevier.com/S1521-6896(14)00049-4/sref12http://refhub.elsevier.com/S1521-6896(14)00049-4/sref12http://refhub.elsevier.com/S1521-6896(14)00049-4/sref12http://refhub.elsevier.com/S1521-6896(14)00049-4/sref13http://refhub.elsevier.com/S1521-6896(14)00049-4/sref13http://refhub.elsevier.com/S1521-6896(14)00049-4/sref13http://refhub.elsevier.com/S1521-6896(14)00049-4/sref13http://refhub.elsevier.com/S1521-6896(14)00049-4/sref13http://refhub.elsevier.com/S1521-6896(14)00049-4/sref14http://refhub.elsevier.com/S1521-6896(14)00049-4/sref14http://refhub.elsevier.com/S1521-6896(14)00049-4/sref14http://www.acidbase.org/http://refhub.elsevier.com/S1521-6896(14)00049-4/sref16http://refhub.elsevier.com/S1521-6896(14)00049-4/sref16http://refhub.elsevier.com/S1521-6896(14)00049-4/sref16http://refhub.elsevier.com/S1521-6896(14)00049-4/sref17http://refhub.elsevier.com/S1521-6896(14)00049-4/sref17http://refhub.elsevier.com/S1521-6896(14)00049-4/sref17http://refhub.elsevier.com/S1521-6896(14)00049-4/sref17http://refhub.elsevier.com/S1521-6896(14)00049-4/sref17http://refhub.elsevier.com/S1521-6896(14)00049-4/sref17http://refhub.elsevier.com/S1521-6896(14)00049-4/sref18http://refhub.elsevier.com/S1521-6896(14)00049-4/sref18http://refhub.elsevier.com/S1521-6896(14)00049-4/sref18http://refhub.elsevier.com/S1521-6896(14)00049-4/sref19http://refhub.elsevier.com/S1521-6896(14)00049-4/sref19http://refhub.elsevier.com/S1521-6896(14)00049-4/sref20http://refhub.elsevier.com/S1521-6896(14)00049-4/sref20http://refhub.elsevier.com/S1521-6896(14)00049-4/sref21http://refhub.elsevier.com/S1521-6896(14)00049-4/sref21http://refhub.elsevier.com/S1521-6896(14)00049-4/sref21http://refhub.elsevier.com/S1521-6896(14)00049-4/sref22http://refhub.elsevier.com/S1521-6896(14)00049-4/sref22http://refhub.elsevier.com/S1521-6896(14)00049-4/sref23http://refhub.elsevier.com/S1521-6896(14)00049-4/sref23http://refhub.elsevier.com/S1521-6896(14)00049-4/sref23http://refhub.elsevier.com/S1521-6896(14)00049-4/sref24http://refhub.elsevier.com/S1521-6896(14)00049-4/sref24http://refhub.elsevier.com/S1521-6896(14)00049-4/sref24http://refhub.elsevier.com/S1521-6896(14)00049-4/sref24http://refhub.elsevier.com/S1521-6896(14)00049-4/sref25http://refhub.elsevier.com/S1521-6896(14)00049-4/sref25http://refhub.elsevier.com/S1521-6896(14)00049-4/sref25http://refhub.elsevier.com/S1521-6896(14)00049-4/sref25http://refhub.elsevier.com/S1521-6896(14)00049-4/sref25http://refhub.elsevier.com/S1521-6896(14)00049-4/sref26http://refhub.elsevier.com/S1521-6896(14)00049-4/sref26http://refhub.elsevier.com/S1521-6896(14)00049-4/sref27http://refhub.elsevier.com/S1521-6896(14)00049-4/sref27http://refhub.elsevier.com/S1521-6896(14)00049-4/sref27http://refhub.elsevier.com/S1521-6896(14)00049-4/sref27http://refhub.elsevier.com/S1521-6896(14)00049-4/sref27http://refhub.elsevier.com/S1521-6896(14)00049-4/sref27http://refhub.elsevier.com/S1521-6896(14)00049-4/sref28http://refhub.elsevier.com/S1521-6896(14)00049-4/sref28http://refhub.elsevier.com/S1521-6896(14)00049-4/sref28http://refhub.elsevier.com/S1521-6896(14)00049-4/sref29http://refhub.elsevier.com/S1521-6896(14)00049-4/sref29http://refhub.elsevier.com/S1521-6896(14)00049-4/sref29http://refhub.elsevier.com/S1521-6896(14)00049-4/sref29http://refhub.elsevier.com/S1521-6896(14)00049-4/sref30http://refhub.elsevier.com/S1521-6896(14)00049-4/sref30http://refhub.elsevier.com/S1521-6896(14)00049-4/sref30http://refhub.elsevier.com/S1521-6896(14)00049-4/sref30http://refhub.elsevier.com/S1521-6896(14)00049-4/sref30http://refhub.elsevier.com/S1521-6896(14)00049-4/sref30http://refhub.elsevier.com/S1521-6896(14)00049-4/sref31http://refhub.elsevier.com/S1521-6896(14)00049-4/sref31http://refhub.elsevier.com/S1521-6896(14)00049-4/sref31http://refhub.elsevier.com/S1521-6896(14)00049-4/sref31http://refhub.elsevier.com/S1521-6896(14)00049-4/sref32http://refhub.elsevier.com/S1521-6896(14)00049-4/sref32http://refhub.elsevier.com/S1521-6896(14)00049-4/sref32http://refhub.elsevier.com/S1521-6896(14)00049-4/sref32http://refhub.elsevier.com/S1521-6896(14)00049-4/sref33http://refhub.elsevier.com/S1521-6896(14)00049-4/sref33http://refhub.elsevier.com/S1521-6896(14)00049-4/sref33http://refhub.elsevier.com/S1521-6896(14)00049-4/sref34http://refhub.elsevier.com/S1521-6896(14)00049-4/sref33http://refhub.elsevier.com/S1521-6896(14)00049-4/sref33http://refhub.elsevier.com/S1521-6896(14)00049-4/sref34http://refhub.elsevier.com/S1521-6896(14)00049-4/sref34http://refhub.elsevier.com/S1521-6896(14)00049-4/sref34http://refhub.elsevier.com/S1521-6896(14)00049-4/sref34http://refhub.elsevier.com/S1521-6896(14)00049-4/sref34http://refhub.elsevier.com/S1521-6896(14)00049-4/sref34http://refhub.elsevier.com/S1521-6896(14)00049-4/sref34http://refhub.elsevier.com/S1521-6896(14)00049-4/sref35http://refhub.elsevier.com/S1521-6896(14)00049-4/sref35http://refhub.elsevier.com/S1521-6896(14)00049-4/sref35http://refhub.elsevier.com/S1521-6896(14)00049-4/sref35http://refhub.elsevier.com/S1521-6896(14)00049-4/sref35http://refhub.elsevier.com/S1521-6896(14)00049-4/sref35http://refhub.elsevier.com/S1521-6896(14)00049-4/sref36http://refhub.elsevier.com/S1521-6896(14)00049-4/sref36http://refhub.elsevier.com/S1521-6896(14)00049-4/sref36http://refhub.elsevier.com/S1521-6896(14)00049-4/sref37http://refhub.elsevier.com/S1521-6896(14)00049-4/sref37http://refhub.elsevier.com/S1521-6896(14)00049-4/sref37http://refhub.elsevier.com/S1521-6896(14)00049-4/sref38http://refhub.elsevier.com/S1521-6896(14)00049-4/sref38http://refhub.elsevier.com/S1521-6896(14)00049-4/sref38http://refhub.elsevier.com/S1521-6896(14)00049-4/sref39http://refhub.elsevier.com/S1521-6896(14)00049-4/sref39http://refhub.elsevier.com/S1521-6896(14)00049-4/sref39http://refhub.elsevier.com/S1521-6896(14)00049-4/sref39http://refhub.elsevier.com/S1521-6896(14)00049-4/sref40http://refhub.elsevier.com/S1521-6896(14)00049-4/sref40http://refhub.elsevier.com/S1521-6896(14)00049-4/sref40http://refhub.elsevier.com/S1521-6896(14)00049-4/sref41http://refhub.elsevier.com/S1521-6896(14)00049-4/sref41http://refhub.elsevier.com/S1521-6896(14)00049-4/sref41http://refhub.elsevier.com/S1521-6896(14)00049-4/sref41http://refhub.elsevier.com/S1521-6896(14)00049-4/sref41http://refhub.elsevier.com/S1521-6896(14)00049-4/sref41http://refhub.elsevier.com/S1521-6896(14)00049-4/sref41http://refhub.elsevier.com/S1521-6896(14)00049-4/sref41http://refhub.elsevier.com/S1521-6896(14)00049-4/sref41http://refhub.elsevier.com/S1521-6896(14)00049-4/sref41http://refhub.elsevier.com/S1521-6896(14)00049-4/sref41http://refhub.elsevier.com/S1521-6896(14)00049-4/sref40http://refhub.elsevier.com/S1521-6896(14)00049-4/sref40http://refhub.elsevier.com/S1521-6896(14)00049-4/sref40http://refhub.elsevier.com/S1521-6896(14)00049-4/sref39http://refhub.elsevier.com/S1521-6896(14)00049-4/sref39http://refhub.elsevier.com/S1521-6896(14)00049-4/sref39http://refhub.elsevier.com/S1521-6896(14)00049-4/sref38http://refhub.elsevier.com/S1521-6896(14)00049-4/sref38http://refhub.elsevier.com/S1521-6896(14)00049-4/sref37http://refhub.elsevier.com/S1521-6896(14)00049-4/sref37http://refhub.elsevier.com/S1521-6896(14)00049-4/sref37http://refhub.elsevier.com/S1521-6896(14)00049-4/sref36http://refhub.elsevier.com/S1521-6896(14)00049-4/sref36http://refhub.elsevier.com/S1521-6896(14)00049-4/sref36http://refhub.elsevier.com/S1521-6896(14)00049-4/sref35http://refhub.elsevier.com/S1521-6896(14)00049-4/sref35http://refhub.elsevier.com/S1521-6896(14)00049-4/sref35http://refhub.elsevier.com/S1521-6896(14)00049-4/sref35http://refhub.elsevier.com/S1521-6896(14)00049-4/sref34http://refhub.elsevier.com/S1521-6896(14)00049-4/sref34http://refhub.elsevier.com/S1521-6896(14)00049-4/sref34http://refhub.elsevier.com/S1521-6896(14)00049-4/sref34http://refhub.elsevier.com/S1521-6896(14)00049-4/sref33http://refhub.elsevier.com/S1521-6896(14)00049-4/sref33http://refhub.elsevier.com/S1521-6896(14)00049-4/sref33http://refhub.elsevier.com/S1521-6896(14)00049-4/sref32http://refhub.elsevier.com/S1521-6896(14)00049-4/sref32http://refhub.elsevier.com/S1521-6896(14)00049-4/sref31http://refhub.elsevier.com/S1521-6896(14)00049-4/sref31http://refhub.elsevier.com/S1521-6896(14)00049-4/sref31http://refhub.elsevier.com/S1521-6896(14)00049-4/sref30http://refhub.elsevier.com/S1521-6896(14)00049-4/sref30http://refhub.elsevier.com/S1521-6896(14)00049-4/sref30http://refhub.elsevier.com/S1521-6896(14)00049-4/sref29http://refhub.elsevier.com/S1521-6896(14)00049-4/sref29http://refhub.elsevier.com/S1521-6896(14)00049-4/sref29http://refhub.elsevier.com/S1521-6896(14)00049-4/sref29http://refhub.elsevier.com/S1521-6896(14)00049-4/sref28http://refhub.elsevier.com/S1521-6896(14)00049-4/sref28http://refhub.elsevier.com/S1521-6896(14)00049-4/sref27http://refhub.elsevier.com/S1521-6896(14)00049-4/sref27http://refhub.elsevier.com/S1521-6896(14)00049-4/sref27http://refhub.elsevier.com/S1521-6896(14)00049-4/sref26http://refhub.elsevier.com/S1521-6896(14)00049-4/sref26http://refhub.elsevier.com/S1521-6896(14)00049-4/sref25http://refhub.elsevier.com/S1521-6896(14)00049-4/sref25http://refhub.elsevier.com/S1521-6896(14)00049-4/sref25http://refhub.elsevier.com/S1521-6896(14)00049-4/sref24http://refhub.elsevier.com/S1521-6896(14)00049-4/sref24http://refhub.elsevier.com/S1521-6896(14)00049-4/sref24http://refhub.elsevier.com/S1521-6896(14)00049-4/sref23http://refhub.elsevier.com/S1521-6896(14)00049-4/sref23http://refhub.elsevier.com/S1521-6896(14)00049-4/sref23http://refhub.elsevier.com/S1521-6896(14)00049-4/sref22http://refhub.elsevier.com/S1521-6896(14)00049-4/sref22http://refhub.elsevier.com/S1521-6896(14)00049-4/sref21http://refhub.elsevier.com/S1521-6896(14)00049-4/sref21http://refhub.elsevier.com/S1521-6896(14)00049-4/sref21http://refhub.elsevier.com/S1521-6896(14)00049-4/sref20http://refhub.elsevier.com/S1521-6896(14)00049-4/sref20http://refhub.elsevier.com/S1521-6896(14)00049-4/sref20http://refhub.elsevier.com/S1521-6896(14)00049-4/sref19http://refhub.elsevier.com/S1521-6896(14)00049-4/sref19http://refhub.elsevier.com/S1521-6896(14)00049-4/sref18http://refhub.elsevier.com/S1521-6896(14)00049-4/sref18http://refhub.elsevier.com/S1521-6896(14)00049-4/sref17http://refhub.elsevier.com/S1521-6896(14)00049-4/sref17http://refhub.elsevier.com/S1521-6896(14)00049-4/sref17http://refhub.elsevier.com/S1521-6896(14)00049-4/sref16http://refhub.elsevier.com/S1521-6896(14)00049-4/sref16http://refhub.elsevier.com/S1521-6896(14)00049-4/sref16http://www.acidbase.org/http://refhub.elsevier.com/S1521-6896(14)00049-4/sref14http://refhub.elsevier.com/S1521-6896(14)00049-4/sref14http://refhub.elsevier.com/S1521-6896(14)00049-4/sref13http://refhub.elsevier.com/S1521-6896(14)00049-4/sref13http://refhub.elsevier.com/S1521-6896(14)00049-4/sref13http://refhub.elsevier.com/S1521-6896(14)00049-4/sref13http://refhub.elsevier.com/S1521-6896(14)00049-4/sref13http://refhub.elsevier.com/S1521-6896(14)00049-4/sref12http://refhub.elsevier.com/S1521-6896(14)00049-4/sref12http://refhub.elsevier.com/S1521-6896(14)00049-4/sref12http://refhub.elsevier.com/S1521-6896(14)00049-4/sref12http://refhub.elsevier.com/S1521-6896(14)00049-4/sref11http://refhub.elsevier.com/S1521-6896(14)00049-4/sref11http://refhub.elsevier.com/S1521-6896(14)00049-4/sref11http://refhub.elsevier.com/S1521-6896(14)00049-4/sref10http://refhub.elsevier.com/S1521-6896(14)00049-4/sref10http://refhub.elsevier.com/S1521-6896(14)00049-4/sref10http://refhub.elsevier.com/S1521-6896(14)00049-4/sref9http://refhub.elsevier.com/S1521-6896(14)00049-4/sref9http://refhub.elsevier.com/S1521-6896(14)00049-4/sref9http://refhub.elsevier.com/S1521-6896(14)00049-4/sref8http://refhub.elsevier.com/S1521-6896(14)00049-4/sref7http://refhub.elsevier.com/S1521-6896(14)00049-4/sref7http://refhub.elsevier.com/S1521-6896(14)00049-4/sref7http://refhub.elsevier.com/S1521-6896(14)00049-4/sref6http://refhub.elsevier.com/S1521-6896(14)00049-4/sref6http://refhub.elsevier.com/S1521-6896(14)00049-4/sref5http://refhub.elsevier.com/S1521-6896(14)00049-4/sref5http://refhub.elsevier.com/S1521-6896(14)00049-4/sref4http://refhub.elsevier.com/S1521-6896(14)00049-4/sref4http://refhub.elsevier.com/S1521-6896(14)00049-4/sref4http://refhub.elsevier.com/S1521-6896(14)00049-4/sref3http://refhub.elsevier.com/S1521-6896(14)00049-4/sref3http://refhub.elsevier.com/S1521-6896(14)00049-4/sref2http://refhub.elsevier.com/S1521-6896(14)00049-4/sref2http://refhub.elsevier.com/S1521-6896(14)00049-4/sref1http://refhub.elsevier.com/S1521-6896(14)00049-4/sref1http://refhub.elsevier.com/S1521-6896(14)00049-4/sref1


13/13

*[42] Zhou F, Peng ZY, Bishop JV, et al. Effects ofuid resuscitation with 0.9% saline versus a balanced electrolyte solution on

acute kidney injury in a rat model of sepsis*. Crit Care Med 2014 Apr;42(4):e270 e8.*[43] Kellum JA. Fluid resuscitation and hyperchloremic acidosis in experimental sepsis: improved short-term survival and

acid-base balance with hextend compared with saline. Crit Care Med 2002 Jan 1;30(2):300e5.[44] Noritomi DT, Pereira AJ, Bugano DD, et al. Impact of plasma-lyte pH 7.4 on acid-base status and hemodynamics in a model

of controlled hemorrhagic shock. Clin Sao Paulo 2011;66(11):1969e74.

[45] Bihari S, Ou J, Holt AW, et al. Inadvertent sodium loading in critically ill patients. Crit Care Resusc 2012 Mar;14(1):33e

7.[46] Stelfox HT, Ahmed SB, Zygun D, et al. Characterization of intensive care unit acquired hyponatremia and hypernatremiafollowing cardiac surgery. Can J Anaesth 2010 Jul;57(7):650e8.

[47] Stelfox HT, Ahmed SB, Khandwala F, et al. The epidemiology of intensive care unit-acquired hyponatraemia and hyper-natraemia in medical-surgical intensive care units. Crit Care 2008;12(6):R162.

[48] Funk GC, Lindner G, Druml W, et al. Incidence and prognosis of dysnatremias present on ICU admission. Intensive CareMed 2010 Feb;36(2):304e11.

[49] Padhi R, Panda BN, Jagati S, et al. Hyponatremia in critically ill patients. Indian J Crit Care Med 2014 Feb;18(2):83e7.

http://refhub.elsevier.com/S1521-6896(14)00049-4/sref42http://refhub.elsevier.com/S1521-6896(14)00049-4/sref42http://refhub.elsevier.com/S1521-6896(14)00049-4/sref42http://refhub.elsevier.com/S1521-6896(14)00049-4/sref42http://refhub.elsevier.com/S1521-6896(14)00049-4/sref42http://refhub.elsevier.com/S1521-6896(14)00049-4/sref43http://refhub.elsevier.com/S1521-6896(14)00049-4/sref43http://refhub.elsevier.com/S1521-6896(14)00049-4/sref43http://refhub.elsevier.com/S1521-6896(14)00049-4/sref44http://refhub.elsevier.com/S1521-6896(14)00049-4/sref44http://refhub.elsevier.com/S1521-6896(14)00049-4/sref44http://refhub.elsevier.com/S1521-6896(14)00049-4/sref45http://refhub.elsevier.com/S1521-6896(14)00049-4/sref45http://refhub.elsevier.com/S1521-6896(14)00049-4/sref46http://refhub.elsevier.com/S1521-6896(14)00049-4/sref46http://refhub.elsevier.com/S1521-6896(14)00049-4/sref46http://refhub.elsevier.com/S1521-6896(14)00049-4/sref46http://refhub.elsevier.com/S1521-6896(14)00049-4/sref47http://refhub.elsevier.com/S1521-6896(14)00049-4/sref47http://refhub.elsevier.com/S1521-6896(14)00049-4/sref48http://refhub.elsevier.com/S1521-6896(14)00049-4/sref48http://refhub.elsevier.com/S1521-6896(14)00049-4/sref48http://refhub.elsevier.com/S1521-6896(14)00049-4/sref48http://refhub.elsevier.com/S1521-6896(14)00049-4/sref49http://refhub.elsevier.com/S1521-6896(14)00049-4/sref49http://refhub.elsevier.com/S1521-6896(14)00049-4/sref49http://refhub.elsevier.com/S1521-6896(14)00049-4/sref49http://refhub.elsevier.com/S1521-6896(14)00049-4/sref48http://refhub.elsevier.com/S1521-6896(14)00049-4/sref48http://refhub.elsevier.com/S1521-6896(14)00049-4/sref48http://refhub.elsevier.com/S1521-6896(14)00049-4/sref47http://refhub.elsevier.com/S1521-6896(14)00049-4/sref47http://refhub.elsevier.com/S1521-6896(14)00049-4/sref46http://refhub.elsevier.com/S1521-6896(14)00049-4/sref46http://refhub.elsevier.com/S1521-6896(14)00049-4/sref46http://refhub.elsevier.com/S1521-6896(14)00049-4/sref45http://refhub.elsevier.com/S1521-6896(14)00049-4/sref45http://refhub.elsevier.com/S1521-6896(14)00049-4/sref44http://refhub.elsevier.com/S1521-6896(14)00049-4/sref44http://refhub.elsevier.com/S1521-6896(14)00049-4/sref44http://refhub.elsevier.com/S1521-6896(14)00049-4/sref43http://refhub.elsevier.com/S1521-6896(14)00049-4/sref43http://refhub.elsevier.com/S1521-6896(14)00049-4/sref43http://refhub.elsevier.com/S1521-6896(14)00049-4/sref42http://refhub.elsevier.com/S1521-6896(14)00049-4/sref42http://refhub.elsevier.com/S1521-6896(14)00049-4/sref42

balanced versus unbalanced salt solutions what (raisul)

Documents