Chloride is the major strong anion in blood – accounting
for approximately one-third of plasma tonicity, for 97 to
98% of all strong anionic charges and for two-thirds of all
negative charges in plasma . Th e amount of attention
chloride receives in critically ill patients, however, is
limited and much less than other routinely measured
electrolytes. For example, the PubMed search term
‘hypernatremia’ and ‘hypercalcemia’ generate 2,481 and
15,518 citations, respectively . It is therefore little
181 citations while
surprise that chloride is sometimes referred to as the
forgotten electrolyte .
Progress in our understanding of acid–base and
chloride channel physiology, however, challenges the
notion that neglecting chloride is justifi ed. Th is progress
can be traced to more than 100 years ago with the
observation of a poisonous eff ect of sodium chloride
solutions on nerve muscle preparation , followed by
recognition of metabolic acidosis after saline infusion in
the 1920s , and the concept of hyperchloraemic
acidosis [6,7]. In the 1990s, hyperchloraemic acidosis
became more thoroughly studied [8-15] as the physico-
chemical approach (Stewart approach) to acid–base
analysis [16,17] began to receive wider acceptance.
Within the Stewart approach, chloride is the dominant
negative strong ion in plasma and a key contributor to
the strong ion diff erence (SID), one of the three
independent variables that determine the hydrogen ion
concentration. Hyperchloraemia was thus fi nally seen as
important for the pathogenesis of metabolic acidosis.
Th is change in perception may be particularly relevant to
intensivists, given that hyperchloraemia appears rela-
tively common in intensive care unit (ICU) patients .
At the same time, our knowledge of chloride channels
has increased in the past decade with new discoveries of
their crystal structures, physiological roles and their
association with human diseases [19-21].
All of these changes in attitude and knowledge support
the argument that the role of chloride in the ICU
deserves more attention. In the present review, therefore,
we wish to focus on the following fi ve aspects: the funda-
mentals of chloride distribution and measurement, an
outline of Stewart’s physicochemical approach and the
signifi cance of chloride as a strong ion, chloride’s roles
through review of its channels and chloride regulation by
the gut and kidney, chloride manipulation in the ICU and
potential eff ects of disorders of chloraemia in the
critically ill, and the implications of all the above on
current critical care practice and research.
Chloride distribution and measurement
Th e main source of chloride is dietary sodium chloride,
intake of which is 7.8 to 11.8 g/day for adult men and
5.8 to 7.8 g/day for adult women in the United States  –
equivalent to 133 to 202 mmol and 99 to 133 mmol
Chloride is the principal anion in the extracellular fl uid
and is the second main contributor to plasma tonicity.
Its concentration is frequently abnormal in intensive
care unit patients, often as a consequence of fl uid
therapy. Yet chloride has received less attention than
any other ion in the critical care literature. New insights
into its physiological roles have emerged together
with progress in understanding the structures and
functions of chloride channels. In clinical practice,
interest in a physicochemical approach to acid–base
physiology has directed renewed attention to chloride
as a major determinant of acid–base status. It has
also indirectly helped to generate interest in other
possible eff ects of disorders of chloraemia. The present
review summarizes key aspects of chloride physiology,
including its channels, as well as the clinical relevance
of disorders of chloraemia. The paper also highlights
current knowledge on the impact of diff erent types
of intravenous fl uids on chloride concentration
and the potential eff ects of such changes on organ
physiology. Finally, the review examines the potential
intensive care unit practice implications of a better
understanding of chloride.
© 2010 BioMed Central Ltd
Bench-to-bedside review: Chloride in critical illness
Nor’azim Mohd Yunos1, Rinaldo Bellomo1*, David Story2 and John Kellum3
1Department of Intensive Care, Austin Hospital, Heidelberg, Melbourne, VIC 3084,
Full list of author information is available at the end of the article
Mohd Yunos et al. Critical Care 2010, 14:226
© 2010 BioMed Central Ltd
chloride, respectively (chloride molar mass, 35.5 g/mol).
Th is intake approximates to administration of 0.5 to
1.3 litres per day of 0.9% saline (chloride, 154 mmol/l).
Th e chloride distribution in the three major body fl uid
compartments – plasma, interstitial fl uid (ISF) and intra-
cellular fl uid – is shown in Figure 1. Chloride is the most
abundant anion in plasma and ISF, the two compart-
ments that make up extracellular fl uid. Its concentrations
in these two compartments diff er slightly as a result of
capillary impermeability to proteins, especially albumin.
Th e asymmetric distribution of anionic proteins
between plasma and ISF results in the Gibbs–Donnan
eff ect, with the ISF chloride concentration 5 to 10%
greater than in plasma . Most cells have intracellular
concentrations of about 10 mmol/l , but the range
varies widely from 2 mmol/l in skeletal muscle to
90 mmol/l in erythrocytes .
It is important for clinicians to recognize that the
measured plasma chloride concentration may diff er
between assays. With paired samples, the mean diff er-
ence (bias) in plasma chloride concentration between
central laboratory and point-of-care assays can be
1.0 mmol/l (95% limits of agreement, –6.4 to 4.6 mmol/l)
. While decreased plasma albumin contributes to
diff erences in sodium assays, however, albumin changes
have little eff ect on chloride assays . Further, while
the reference range for central laboratory assays is often
quoted as 97 to 107 mmol/l, some machines used in
central laboratories have a reference range of 100 to
110 mmol/l. Using paired samples (unpublished results),
when our central laboratory changed from a Hitachi to a
Beckman machine, we found a bias in plasma chloride of
2.0 mmol/l (95% limits of agreement, –1.7 to 5.6 mmol/l).
While these diff erences are important in assessing
chloride alone, they will also aff ect derived variables
including the anion gap , the corrected anion gap
, the strong ion gap , and the sodium chloride
diff erence .
Chloride and the Stewart approach
Th e surge in the number of studies on hyperchloraemic
acidosis coincided with the emergence of the Stewart
physicochemical approach, with many comparisons of
0.9% saline and colloids suspended in saline solutions
with more balanced, lower chloride, intravenous solu-
tions (Tables 1 and 2). Compared with lactated Ringer’s
solution in patients undergoing major gynaecological
surgery, infusion of 30 ml/kg/hour of 0.9% saline caused a
signifi cant acidosis within 2 hours . Th is fi nding,
coupled with higher chloride measurement in the saline
group, was replicated in a number of other studies
[10,12,14,15,30]. Signifi cant negative correlation between
hyperchloraemia and base excess was further shown in
patients undergoing surgery for more than 4 hours 
and in an audit of ICU patients .
An understanding of Stewart’s approach may help to
understand how chloride might aff ect the hydrogen ion
concentration [H+] [16,17]. Th rough quantitative analysis
that satisfi es the principles of electroneutrality, dissocia-
tion equilibria and conservation of mass, this approach
argues that determination of [H+] depends on three
independent variables: the SID, the partial pressure of
carbon dioxide, and the total weak acid concentration. A
change in any of these three variables, and not in
Figure 1. Chloride distribution in the major body fl uid compartments.
Mohd Yunos et al. Critical Care 2010, 14:226
Page 2 of 10
bicarbonate, will change the acid–base balance.
Bicarbonate becomes a marker and not a mechanism, a
major diff erence between the Stewart approach and the
traditional Henderson–Hasselbalch approach.
In the traditional approach, bicarbonate independently
determines pH as refl ected by the Henderson–Hassel-
pH = pK + log ([HCO3
–] / [CO2])
Under the Stewart approach, however, bicarbonate is
just one of the various dependent ions. Whether the
Stewart approach more truly refl ects the biochemical
events at work during acid–base disorders remains
controversial. However, its practical utility has been
repeatedly shown [11,31].
Together with other completely dissociated strong ions,
chloride determines the SID:
SID = (Na + K + Mg + Ca) – (Cl + lactate)
Quantitatively, a change in the strong ion composition
leading to lower SID will increase [H+] while an increase
in SID will decrease [H+]. Hyperchloraemic acidosis
there fore causes acidosis by decreasing SID and not
through hyperchloraemia alone. Th is notion is supported
by data demonstrating a stronger association between
SID and bicarbonate than that between chloride and
Hyperchloraemic acidosis is now increasingly des-
cribed in terms of its SID nature, including the contri-
bution of the strong ion gap or unmeasured anions
Table 1. Electrolyte composition of commonly used crystalloids
Plasma 0.9% NaCl Hartmann’s Plasma-Lyte 148® Sterofundin®
Sodium 140 154 131 140 140
Potassium 5 0 5 5 4
Chloride 100 154 111 98 127
Calcium 2.2 0 2 0 2.5
Magnesium 1 0 1 1.5 1
Bicarbonate 24 0 0 0 0
Lactate 1 0 29 0 0
Acetate 0 0 0 27 24
Gluconate 0 0 0 23 0
Maleate 0 0 0 0 5
Plasma-Lyte 148® from Baxter International (Deerfi eld, IL, USA). Sterofundin® from B Braun (Melsungen, Germany).
Table 2. Electrolyte composition of commonly used colloids
(HES 6% 130/0.4)/
(HES 6% 130/0.42)
(HES 6% 130/0.4)
(HES 6% 130/0.42)Plasma Gelofusine® Albumex®4
Sodium 140 154 140 154 143 140
Potassium 5 0 0 0 3 4.0
Chloride 100 125 128 154 124 118
Calcium 2.2 0 0 0 2.5 2.5
Magnesium 1 0 0 0 0.5 1.0
Bicarbonate 24 0 0 0 0 0
Lactate 1 0 0 0 28 0
Acetate 0 0 0 0 0 24
Malate 0 0 0 0 0 5
Octanoate 0 0 6.4 0 0 0
HES, hydroxyethyl starch. Gelofusine®, Venofundin® and Tetraspan® from B Braun (Melsungen, Germany). Albumex®4 from CSL Limited (Broadmeadows, Victoria,
Australia). Voluven® from Fresenius-Kabi (Bad Homburg, Germany). Hextend® from BioTime Inc. (Berkeley, CA, USA).
Mohd Yunos et al. Critical Care 2010, 14:226
Page 3 of 10
[32,33]. A detailed explanation of these concepts is
beyond the scope of the present review.
At the other end of the spectrum, alkalosis may thus
occur with both hypochloraemia and hyperchloraemia,
with the latter occurring in the presence of greater
hypernatraemia (greater SID) . Th is again highlights
the importance of relative rather than absolute chloraemia.
In a study of patients with chronic obstructive pulmonary
disease, subjects were found to have hypochloraemia
without signifi cant changes in plasma sodium, resulting
in a higher SID and subsequent alkalosis . Th is
interestingly concurs with an animal study showing
increased renal chloride excretion during hypo chloraemia
of respiratory acidosis .
For years, knowledge of chloride channels lagged behind
the better known sodium, potassium and calcium
channels . Several milestones in the fi eld of ion
channels – such as cloning of the cystic fi brosis trans-
membrane regulator in 1989, cloning of the fi rst voltage-
gated chloride channel in 1990 and, more recently,
discovery of the crystal structure of chloride channels
[19-21] – have altered this scenario. Th ese anion channels
are no longer merely unimportant leaks associated with
cation channels in the excitable cells .
Examples of the diff erent subtypes of these channels,
categorised based on their diff erent regulations and roles,
are presented in Table 3. Of these subtypes, the cystic
fi brosis transmembrane conductance regulator and the
ligand-gated chloride channels, activated by GABAA and
glycine, are probably best known to ICU clinicians. Th e
other subtypes are, nevertheless, no less important.
Voltage-gated chloride channels come from nine diff erent
genes with a unique dimeric, double-pore (double-
barrelled) structure [20,21]. Th e structure discovery and
further exploration of their molecular mechanisms are
seen as frontiers towards greater application of chloride
channel manipulation in medicine. Recent insights into
these voltage-gated chloride channels have already showed
their signifi cant neurological [38,39] and gastro intestinal
 connections. Calcium-activated chloride channels, on
the other hand, are found in various cell types, including
epithelial cells, neurons, cardiac cells, smooth muscles and
blood cells . Th ey are activated by cytoplasmic calcium
elevation following a wide range of stimuli, which include
cholinergic activation of glandular secretory epithelium
and pain in the dorsal root ganglia neurons . Finally,
volume-sensitive chloride channels are an essential
element of cell volume regulation. Expo sure to hypotonic
media stimulates chloride ion effl ux through these
channels, leading to equilibrium with extracellular tonicity;
restoring the cell volume in the process . Th is cell-
volume decrease is now believed to have a role in apoptotic
cell death , a phenomenon of interest in sepsis .
Chloride regulation by the gut and kidney
Gastrointestinal secretions are rich in chloride, with
gastric secretions the predominant source. In the stomach,
chloride secreted by apical chloride channels in parietal
cells will match hydrogen ions released by the H+/K+-
ATPase antiporter pumps (proton pumps), forming
hydrochloric acid. Basal output of this acid is in the range
0 to 11 mmol/hour, increasing to 10 to 63 mmol/hour with
meals . Th is load of acid, and thus chloride, is regulated
by synergistic activities of histamine, gastrin and
Chloride is also the main electrolyte driving fl uid secre-
tion throughout the intestinal epithelium. Para cellular
movement of sodium that accompanies transepithelial
chloride secretion results in luminal sodium chloride,
which forms the osmotic pressure for water movement
with secretions of 8 l/day , which are largely
reabsorbed throughout the intestinal tract.
Chloride is primarily excreted by the kidney. An
average of 19,440 mmol is fi ltered through the kidneys
Table 3. Examples of chloride channels
Channel Mechanism of regulation Physiological role
Cyclic AMP-dependent phosphorylation
Cl– secretion in airways, submucosal glands, pancreas, intestine
and testis; Cl– absorption in sweat glands
Cl– conductance in skeletal muscle; repolarization after action
CIC-2 channels Hyperpolarization and cell swelling Cl– homeostasis in neurons
Calcium-activated chloride channels
Cl– transport in retinal pigment epithelium; Cl– secretion in
epithelia, neurons, cardiac muscles and erythrocytes; smooth
Glycine, β-alanine and taurine
Inhibition of synaptic transmission in the brain
Inhibition of synaptic transmission in the spinal cord
Volume-sensitive chloride channels Cell volume changes Restoration of cell volume
CFTR, cystic fi brosis transmembrane conductance regulator; CIC, voltage-gated chloride channel; GABA, γ-aminobutyric acid.
Mohd Yunos et al. Critical Care 2010, 14:226
Page 4 of 10
every day, with 99.1% being reabsorbed, leaving only
180 mmol excreted per day . Most of the reabsorption
occurs in the proximal tubule, by passive reabsorption,
ion conductance or active coupled transport with other
ions . Chloride reabsorption involves members of the
solute carrier (SLC) gene families SLC26 and SLC24.
Th ese two gene families are expressed in various parts of
the kidney, particularly in key components of renal acid–
base regulation; that is, renal proximal tubules and
intercalated cells of distal nephron. Th e intercalated cells
are further diff erentiated into type A (alpha) cells that
excrete protons and type B (beta) cells that secrete
bicarbonate and reabsorb chloride . Th e transport
activities of the two SLC families underline the role of
chloride in renal acid–base regulation.
Th e SLC26 family are primarily chloride-anion
exchangers; exchanging sulphate, iodide, formate, oxalate,
hydroxyl ion and bicarbonate anions . Th ey include
SLC26A6 in the proximal tubule that mediates apical
chloride-anion exchange, and SLC26A4 (pendrin) in the
distal nephron that mediates chloride-anion exchange
across the luminal membrane of type B intercalated cells.
Th e SLC4 solute carriers, on the other hand, pre-
dominantly function as chloride-bicarbonate and anion
exchangers and sodium-bicarbonate co-trans porters (NBC).
Examples are SLC4A1 (also known as AE1), which medi-
ates chloride-bicarbonate exchange in the baso lateral
membrane of type A intercalated cells (exchange of
chloride into intercalated cells and bi carbo nate into
plasma), and SLC4A4 (also known as NBC1), which
mediates sodium-bicarbonate co-trans port in renal
proxi mal tubule cells [46,48].
Th ese renal chloride carriers are key components of
suggested models for physicochemical renal acid–base
regulation . Figure 2 shows an example of such regu-
la tion across proximal tubule cells. Physicochemical
modelling of distal renal tubular acidosis from mutation
of SLC4A1 (AE1) and proximal renal tubular acidosis
from mutation of SLC4A4 (NBC1)  has also conso li-
dated the argument for the Stewart approach. Th is renal
tubular acidosis modelling focuses on renal net hand ling
of Na+, K+ and Cl–, the SID constituents, which means
that chloride movement is no longer secondary to
bicarbonate changes. In another physicochemical view-
point, a departure from the conventional explanation of
ammonium ion NH4
proposed . NH4
cation that, by co-excretion with chloride, allows loss of
chloride without sodium or potassium.
+ as a carrier of H+ has been
+ should instead be seen as a weak
Disorders of chloraemia and manipulation of
chloride in the ICU
Hyperchloraemia or hypochloraemia, resulting from
disease processes or clinical manipulations, is common in
Figure 2. Integration of proximal convoluted tubule chloride transport mechanisms with strong ion diff erence and partial pressure. Chloride
is reabsorbed from passive paracellular transport, conductance and active coupled transport at both apical and basolateral membranes. The strong
ion diff erence (SID) in the plasma, together with the partial pressure of carbon dioxide (PCO2), regulates these transport activities and determines the
hydrogen ion concentration. KCC, K+Cl– co-transporter; NHE, Na+H+ exchanger; SLC26A6, solute carrier 26A6; SLC4A4, solute carrier 4A4.
Tubular lumen Tubular cell
Mohd Yunos et al. Critical Care 2010, 14:226
Page 5 of 10
the ICU (see Tables 4 and 5), and should always be seen in
relation to sodium. Hyperchloraemia with hyper natraemia,
or hypochloraemia with hyponatraemia, will not change
the SID and thus will not aff ect the acid–base balance.
Intravenous administration of chloride-rich fl uids is
probably the most common and modifi able cause of
hyper chloraemia in the ICU. Th e chloride content of
these fl uids, from 0.9% NaCl (saline) to the various
colloids suspended in saline (Tables 1 and 2), is supra-
physiologic , with signifi cant hyperchloraemia follow-
ing the administration of such fl uids in volunteers [13,52],
intraoperatively [9,10,12,14,15,30] or as cardio pulmonary
bypass prime fl uid .
While saline was a life-saving measure when fi rst
introduced during the cholera pandemic of Europe in the
1830s , it is to be noted that the saline used then was
of a diff erent composition. A reconstitution of the
Th omas Latta solution revealed a sodium concentration
of 134 mmol/l, chloride 118 mmol/l and bicarbonate
16 mmol/l. Th e historical or scientifi c basis of the
present-day 0.9% composition of saline remains a
mystery, even when traced to those cholera pandemic
days that marked the beginning of the intravenous fl uid
technique and its various solutions . On the other
hand, there appears to be common lack of basic
knowledge for optimal fl uid and electrolyte prescription.
Intravenous fl uid and electrolyte prescriptions in
postoperative surgical patients vary widely, with 0.9%
saline being most common, and show poor correlation
between serum electrolyte values and the amounts of
electrolytes prescribed . Moreover, less than one-half
of prescribers in 25 diff erent surgical units were aware of
the sodium content of 0.9% saline . Chloride-rich
fl uids result in acidosis and evidence from animal studies,
particularly in sepsis, point to a possible association with
Chloride and resuscitation of sepsis
Fluid resuscitation is a mainstay for the treatment of
severe sepsis. Th e recognition of hyperchloraemic strong
ion acidosis has led to the reconsideration of the impact
of intravenous fl uid contents in septic patients.
In anaesthetized dogs infused with endotoxin, high
chloride saline infusion given to maintain mean arterial
pressure >80 mmHg increased serum chloride and
accounted for 42% of the total acid load , signifi cantly
greater than the contribution by lactate. When com par-
ing saline resuscitation with Hextend® (hydroxyethyl
starch (HES) in balanced solution; BioTime Inc., Berkeley,
CA, USA) in a rat model of septic shock, investigators
reported signifi cantly lower standard base excess and SID
and a lower mean survival time with saline .
In an animal study of the eff ects of hyperchloraemic
acidosis from saline, the degree of systemic hypotension
correlated signifi cantly with the increase in plasma
chloride levels , a stronger correlation than with pH.
A signifi cant increase was also seen in plasma nitrite
levels in the saline group; in cell cultures, however, hyper-
chloraemic acidosis was found to be proinfl ammatory,
inducing nitric oxide release, increased IL-6:IL-10 ratios
and increased NF-κB DNA binding . In a second
Table 4. Conditions associated with hypochloraemia in the
intensive care unit
Signifi cant gastric drainage
Chronic respiratory acidosis
Water gain in excess of chloride
Congestive cardiac failure
Syndrome of inappropriate ADH secretion
Excessive infusion of hypotonic solutions
Table 5. Conditions associated with hyperchloraemia in
the intensive care unit
Administration of chloride-rich fl uids
Total parenteral nutrition
Pure water loss
Central diabetes insipidus
Nephrogenic diabetes insipidus
Water loss in excess of chloride loss
Intrinsic renal disease
Defi nite or relative increase in tubular chloride reabsorption
Renal tubular acidosis
Recovery of diabetic ketoacidosis
Early renal failure
Ureteral diversion procedures
Mohd Yunos et al. Critical Care 2010, 14:226
Page 6 of 10
animal study, after controlling for hypotension, there was
a signifi cant increase in cytokines with hyperchloraemic
acidosis – greater increases were seen with more severe
Th erefore it would seem prudent to avoid chloride-rich
fl uids in sepsis despite controversy on whether acidosis
results in physiological injury or is just a side eff ect of
illness . At present, the best evidence for acidosis-
induced organ injury is mainly from animal studies [63,64] –
thus making any specifi c recommendation diffi cult.
Hyperchloraemia and renal function
Animal studies off er insight into the role of chloride in
regulating renal blood fl ow. In denervated dog kidneys,
intrarenal infusion of chloride-containing solutions
produced renal vasoconstriction and a fall in the glome-
rular fi ltration rate . Th is observation was specifi c for
renal vessels, and the investigators proposed tubular
chloride reabsorption as a key initiating step, based on
similarities with the tubuloglomerular feedback mecha-
nism, also initiated by chloride reabsorption . Th is
tubuloglomerular feedback is a regulation of the
glomerular fi ltration rate, which begins with chloride
detection at the macula densa and ends with mesangial
contraction reducing the glomerular fi ltration rate.
Increased chloride re-absorption through a Na/K/2Cl
transporter activates the release of ATP for mesangial
contraction . In another animal study, the same group
found that thromboxane may mediate chloride-induced
vasoconstriction . Another possible explanation for
the phenomenon of hyperchloraemic renal vasocon stric-
tion is the eff ect of chloride on renal responsiveness to
vasoconstrictor agents. A study of the isolated rat kidney
showed that continuous perfusion with high chloride
progressively increased renal vascular responsiveness to
angiotensin II . A more comprehensive understanding
of the vasoconstriction mechanisms, including probable
interaction between chloride and other ions like calcium,
could be on the horizon given the recent progress in
chloride channels mentioned earlier.
Studies on human volunteers and patients support the
above observations. A longer time to fi rst micturition
was observed with saline compared with a lactated
solution in a crossover trial with human volunteers .
Th is observation was replicated in another human volun-
teer study, also with greater diuresis and natriuresis in
the lactated solution group . While the shorter time
to micturition and greater diuresis could be attributed to
the lower osmolality of the lactated solution causing
decreased antidiuretic hormone secretion, the greater
natriuresis suggests a specifi c chloride eff ect on the
glomerular fi ltration rate.
Of further interest to ICU practice is the comparison of
high-chloride fl uids and low-chloride fl uids during
surgery. In older patients undergoing major surgery, a
lower chloride load from a lactated solution or 6% heta-
starch in balanced solution (Hextend®) again led to
greater urine output compared with 0.9% saline and with
6% hetastarch in 0.9% saline . A comparable study in
older cardiac surgery patients revealed that the lower
chloride group treated with balanced 6% HES 130/0.42
plus a balanced crystalloid solution had signifi cantly
lower urinary concentrations of kidney-specifi c markers
of injury – namely glutathione transferase alpha and neu-
tro phil gelatinase-associated lipocalin – when measured
up to the second postoperative day in the ICU .
In patients with renal dysfunction, many believe the
risk of hyperkalaemia is greater with potassium-contain-
ing fl uids like lactated solutions, thus leading to
signifi cantly higher use of 0.9% saline . In contra-
diction to this paradigm, a randomized double-blind trial
comparing lactated Ringer’s solution and 0.9% saline
during renal transplantation revealed a higher incidence
of hyperkalaemia in the 0.9% saline group instead of in
the lactated Ringer’s solution group. Th e incidence of
metabolic acidosis was also higher in the 0.9% saline
group . Th e authors suggested that hyperkalaemia
was secondary to extracellular potassium shift due to
hyperchloraemic (low-SID) acidosis.
Chloride and splanchnic perfusion
Th e above crossover trial comparing 0.9% saline with the
lactated Ringer’s solution in human volunteers also found
a higher incidence of abdominal discomfort with saline
. Th is raised questions about splanchnic perfusion. In a
study of older patients undergoing major surgery, the
saline group had a higher postoperative gastric tono metric
carbon dioxide gap, suggesting reduced gastric mucosal
perfusion . Th is study, although not powered to show a
diff erence, also showed a signifi cant trend towards
increased nausea and vomiting in the saline group. While
chloride’s link to this phenomenon is unclear, it is
interesting to note that a report of ammonium chloride
poisoning referred to similar signs of nausea, vomiting and
abdominal pain . Animal studies, meanwhile, have
demonstrated acidosis-induced intestinal injury  and
impaired gastric-pyloric motility . Th ese fi ndings
warrant further investigation to defi ne the role of chloride
in the modulation of splanchnic perfusion.
Chloride and haemostasis
In a swine model of massive haemorrhage  comparing
resuscitation with 0.9% saline, Ringer’s lactate, Plasmalyte
A and Plasmalyte R, investigators found that – apart from
a signifi cant decrease in acidosis with Ringer’s lactate,
Plasmalyte A and Plasmalyte R – Ringer’s lactate also
achieved a trend towards a higher survival rate. A decade
later, in a rat model of massive haemorrhage, resusci tation
Mohd Yunos et al. Critical Care 2010, 14:226
Page 7 of 10
with red blood cells and Ringer’s lactate solution
produced a signifi cantly better acid–base balance and
signifi cantly greater 2-week survival than resuscitation
with red blood cells and 0.9% saline . Th e hyper-
chloraemic acidosis seen with 0.9% saline resuscitation
has also been highlighted as an easily preventable iatro-
genic cause of acidosis in trauma resuscitation .
Hyperchloraemic acidosis has also been suggested as
part of the explanation for increased blood loss, increased
requirement for blood and blood products, and
coagulation abnormalities in patients receiving 0.9%
saline or HES suspended in saline [15,79,80]. In a rando-
mized trial comparing Hextend® (a 6% HES in a balanced
solution) with 6% HES in saline, trends toward less
bleeding were seen in the Hextend® group. Th e HES in
saline group further showed signifi cant prolongation of
time to onset of clot formation on thromboelastography,
an eff ect not seen in the Hextend® group . Another
randomized trial comparing 0.9% saline against lactated
Ringer’s solution for patients undergoing abdominal
aortic aneur ysm demonstrated a similar pattern. Th e
saline group received signifi cantly more blood products
and had a trend towards increased blood loss . In
another comparison of 6% HES in balanced vehicle
against 6% HES in saline during major surgery, a hypo-
coagulable state (confi rmed by signifi cantly abnormal
thrombo elasto graphy) was seen in HES in saline .
Apart from its high chloride concentration, the lack of
calcium in saline is another explanation for saline’s worse
haemostatic profi le as shown in these trials.
Th ere have also been a number of experimental studies
on healthy volunteers predominantly looking at the
diff erence between HES in saline and HES in balanced
solutions [81-83]. All studies used thromboelastography
to assess coagulation, and one study used whole blood
aggregometry to assess platelet function. A similar trend
toward hypocoagulation with HES in saline was seen.
Haemodilution with HES in saline also resulted in
reduced aggregometry. While HES itself is known to
aff ect coagulation and thromboelastography, recent
changes to its physicochemical characteristics, especially
molar substitution, has minimized this eff ect. Th e solvent
and its electrolyte composition might thus have contri-
buted to hypocoagulability.
Chloride in the ICU: the research agenda
Th e growing body of knowledge presented above
highlights the need to re-evaluate our perception of
chloride in critical care. Clinically, there is a need to re-
evaluate our intravenous fl uid practice, the patients’ main
source of external chloride. Th e evidence that the choice of
fl uids will aff ect the acid–base balance and could cause a
host of other potentially undesirable physiological altera-
tions, as described above, is diffi cult to ignore.
More importantly, all of this preliminary evidence leads
to a number of research questions that are pertinent to
chloride and the care of ICU patients. How common is
hyperchloraemia in the ICU? Is hyperchloraemia an
independent predictor of death or other adverse out-
comes? Or does hyperchloraemia only matter when asso-
cia ted with SID changes or acidaemia? Can the elimina-
tion of chloride-rich fl uids lead to clinical benefi ts? We
consider these to be questions that need urgent attention
given the millions of litres of saline and the millions of
millimoles of excess chloride administered to patients
worldwide every day.
Chloride has been forgotten for too long. Better know-
ledge of its molecular functions, driven by new fi ndings
of the structure, molecular biology and physiology of its
channels, and better understanding of the clinical eff ects
of chloride loading, indicate that alterations in the
chloride balance and chloraemia, both absolute and
relative to natraemia, can alter the acid–base status, cell
biology, renal function and haemostasis. Th e clinical
consequences of these biological and physiological
alterations remain unclear. Th e observation that most of
these alterations appear to have negative implications
and the knowledge that high-chloride fl uids are adminis-
tered to large numbers of patients worldwide, however,
suggest the need to conduct formal investigations into
the epidemiology and outcome implications of disorders
of chloride balance and chloride concentration.
GABA, γ-aminobutyric acid; HES, hydroxyethyl starch; ICU, intensive care unit;
IL, interleukin; ISF, interstitial fl uid; NF, nuclear factor; SID, strong ion diff erence;
SLC, solute carrier.
The authors declare that they have no competing interests.
1Department of Intensive Care, Austin Hospital, Heidelberg, Melbourne,
VIC 3084, Australia. 2Department of Anaesthesia, Austin Hospital, Heidelberg,
Melbourne, VIC 3084, Australia. 3Department of Critical Care Medicine,
University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA.
Published: 8 July 2010
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Cite this article as: Mohd Yunos N, et al.: Bench-to-bedside review: Chloride
in critical illness. Critical Care 2010, 14:226.
Mohd Yunos et al. Critical Care 2010, 14:226
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