)

1778428x, 2003, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1778-428X.2003.tb00184.x by Nat Prov Indonesia, Wiley Online Library on [05/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
TATM 2003;5(4):424-430

Hyperchloremic Acidosis:

(
Pathophysiology and
Clinical Impact

SUMMARY

Hyperchloremic acidosis is a predictable consequence of normal

saline-based fluid administration.The theoretical basis for this

E DWARD B URDETT, MA , MB BS , MRCP, 1
ANTONY M. ROCHE, MB ChB, FRCA, MMed (Anaes),1 is easily understood using Stewart’s model of acid-base
M ICHAEL G. M YTHEN , MB BS , FRCA , MD 2
homeostasis. Data are emerging which describe the consequences
RESEARCH FELLOW
1

of hyperchloremic acidosis in the surgical population.

UCL CENTRE FOR ANAESTHESIA
MIDDLESEX HOSPITAL
2
PORTEX PROFESSOR OF ANAESTHESIA AND CRITICAL CARE
UNIVERSITY COLLEGE LONDON
HEAD OF THE PORTEX ANAESTHESIA
INTENSIVE CARE AND RESPIRATORY UNIT
INSTITUTE OF CHILD HEALTH
UCL CENTRE FOR ANAESTHESIA • Hyperchloremic acidosis
MIDDLESEX HOSPITAL
• Fluid resuscitation
LONDON, UNITED KINGDOM
• Colloids
• Crystalloids
• Volume replacement

Transfusion Alternatives in Transfusion Medicine 424 ) VOLUME 5 NUMBER 4 OCTOBER 2003

( Page

Hyperchloremic Acidosis: Pathophysiology and Clinical Impact
Hyperchloremic acidosis is a well-recognized entity, pertinent
to many areas of clinical practice. It is observed in diabetic
ketoacidosis, and in some forms of renal tubular acidosis;1 it is
also an important consequence of large-volume administration of
some intravenous fluids.2
Most hospital clinicians routinely administer large volumes of
intravenous fluids, to support the circulation during significant
fluid shifts. Normal saline (0.9% sodium chloride solution), and
colloids suspended in normal saline, are often infused because
they are easily available, and are isotonic with plasma. Their non-
physiological levels of chloride and lack of buffer cause metabolic
acidosis.2
The term “dilutional acidosis” has been used to describe this
effect; the term implying that plasma expansion and dilutional
reduction of plasma bicarbonate are the underlying mechanisms.
This is not the whole story. More elegant, the Stewart model
emphasizes the importance of hyperchloremia in reducing the
strong-ion difference, with the consequent impairment of
homeostatic mechanisms, including coagulation abnormalities
and renal hypoperfusion.
Pathophysiology
Debate continues about the exact mechanism for acid-base
homeostasis in humans. The two main camps in the dispute follow
either the original Henderson-Hasselbalch and Siggaard-Andersen
line of thinking, or the more recent Stewart approach to acid-base
physiology. Below, a brief overview of the original approach will
be covered, followed by a more in depth view of the Stewart theory
and its modifications.
pH is a logarithmic scale of the reciprocal of H+ ion
concentration. Both respiratory (e.g., CO2 tension) and metabolic
factors (e.g., lactic acid) affect H+.3 Classically, decisions based on
blood gas analysis are based on the apparent pH, in relation to
the pCO2 (carbon dioxide tension), further assisted by the
bicarbonate concentration (HCO3-) and base excess variables, can
assess whether derangements are likely to be metabolic or
respiratory in origin.
The first principle applied to acid-base physiology is as follows:
if the pCO2 rises, so too does the eventual H+ ion concentration.
This is due to the formation of carbonic acid by the combination
of water and carbon dioxide. Carbonic acid then dissociates to
form H+ and HCO3-. It is a cornerstone to understanding the way
in which the body creates and handles acid.
H20 + CO2 <—> H2CO2 <—> H+ + HCO3-
This was modified, originally by Henderson, then further by
Hasselbalch, into:
The Henderson-Hasselbalch Equation
pH = pK + log (HCO3-/pCO2 x 0.225)
Transfusion Alternatives in Transfusion Medicine
1778428x, 2003, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1778-428X.2003.tb00184.x by Nat Prov Indonesia, Wiley Online Library on [05/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
E D WA R D B U R D E T T et al.
Note units of measurement:
HCO3- = mmol/L
pCO2 = kPa
From this, one can observe that any increase in pCO2 or decrease
in bicarbonate would lead to a reduction in the pH, likely to be
respiratory and metabolic acidosis respectively (depending on the
primary disturbance and compensation). Conversely, when these
variables display a rise in bicarbonate or a reduction in pCO2, one
would find metabolic and respiratory alkaloses, respectively.
Base Excess
The use of base excess was introduced to assist the quantification
of the metabolic components of acid-base disturbances. The most
notable developments in quantifying these were by Siggaard-
Andersen and Severinghaus.3,4 Base excess quantifies the severity
of metabolic acidosis or alkalosis, and is defined as the amount
of base (or acid) that must be added to a sample of whole blood
in vitro in order to restore the pH of the sample to 7.40 (keeping
the pCO2 constant at 5.3 kPa).5
The value ranges from –30 to +30 mmol/L, with the normal
range being –2 to +2 mmol/L. Its measurement requires only a
small venous or arterial blood sample, and it is widely used in
clinical practice. It has been established as an accurate indicator
of the metabolic component to any acid-base disturbance. Indeed,
base excess derangement is an independent predictor of mortality
in critically ill patients.6
Traditionally, it was suggested that pH is kept within a tight
range by the body’s ability to buffer acid, using bicarbonate, plasma
proteins and hemoglobin.
Physicochemical Theory
How does a change in chloride concentration bring about such
profound alteration in acid-base equilibrium? The answer is not
obvious when analyzed using the Henderson-Hasselbalch
equation. However, it can be explained by Stewart's method of
analysis of quantitative acid and base chemistry. Stewart turned
the whole world of acid-base homeostasis upside down in the late
1970s and early 1980s, when he published his mathematical
theory of the body’s ability to regulate acid and base content.7,8
Stewart's approach shows the way to understanding plasma as a
physico-chemical system, and provides a basis for quantitative
analysis and rational manipulation of acid-base state, in vivo and
in vitro.9
The Stewart theory rests on two important physicochemical
principles, which describe the behavior of ions in fluids. Firstly,
all positively charged and all negatively charged ions in a solution
must always be equal, the law of electro-neutrality. What this
implies is that the sum of all positively and all negatively charged
ions in a solution must equal zero. The second principle is the
conservation of mass, which means that the total amount of a
substance remains constant, unless it is added to or generated, or
425 ) VOLUME 5 NUMBER 4 OCTOBER 2003
( Page

Hyperchloremic Acidosis: Pathophysiology and Clinical Impact E D WA R D B U R D E T T et al.
Table 1.
Electrolyte Hartmann’s Solution 0.9% NaCl
Sodium 131 154
Chloride 111 154
Potassium 5 0
Calcium 2 0
Magnesium 0 0
Phosphate 0 0
Bicarbonate/lactate 27 0 22 - 30
All values quoted are electrolyte concentration in mmol/L.
removed or destroyed. Furthermore, the body is composed of 65-
70% water, thereby providing an inexhaustible amount of H+ and
OH- for bodily functions and processes.7-8,10
According to Stewart, three main factors determine H+ ion
concentration, namely carbon dioxide, weak acids in the body,
and the strong ion difference.
As examined above, carbon dioxide directly affects H+
concentration by the mechanism of increasing or reducing
carbonic acid production, and thereby its dissociation into H+ and
HCO3-. Complicating one’s understanding slightly is the body’s
inexhaustible supply of H+ and OH-. Due to its dynamic nature,
the dissociation of water into these ions is also largely dictated by
CO2 and the strong ions. This plays a further role in reactions
observed in maintaining the acid-base and more importantly
electrochemical neutrality.
Stewart’s second principle is that of weak acids (or weak
electrolytes), which are acids or electrolytes in the body that are only
partially ionized at pH levels encountered physiologically, such as
plasma proteins like albumin, and phosphates. These play a role in
the mathematical model Stewart originally described, along with CO2
and the Strong Ion Difference (SID, described below), and hence the
final H+ ion concentration. As the total weak acid drops, in isolation,
an increase can be expected in the pH. Even though weak acids are
important in acid-base regulation, and noted in certain units, they
are not commonly used for clinical interpretations of acid-base
derangements. The observation that the only clinically relevant weak
acids are inorganic phosphate and albumin was later confirmed by
Fencl’s group, noting that a charge of approximately 12 mEq/L can
be attributed to these acids, and that globulins play a negligible role.11
Probably the most interesting discovery in Stewart’s theory was
that of the Strong Ion Difference (SID). This principle rests on the
chemistry of strong ions in the body (or aqueous solutions). Strong
ions (or electrolytes) are almost completely ionized in aqueous
solutions. The most notable of the strong ions are Na+, K+, Ca2+,
Mg2+, Cl-, and Lactate.7 At this stage, it is prudent to remember
the basis of the physicochemical approach, which is firstly that of
electrochemical neutrality being maintained at all times, and
secondly the conservation of mass.
0Transfusion Alternatives in Transfusion Medicine 426 ) VOLUME 5 NUMBER 4 OCTOBER 2003
( Page
1778428x, 2003, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1778-428X.2003.tb00184.x by Nat Prov Indonesia, Wiley Online Library on [05/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
In plasma, when all the strong ions
mentioned above, both anions and cations,
Plasma Concentration
are added together, the result does not end
135 - 146
up as zero. This accounts for what is known
98 - 102 as the strong ion difference. Weak acids, for
3.5 - 5.0 example, have not been taken into account in
2.20 - 2.67 the equation. Stewart originally described the
0.7 - 1.1 equation as follows:
0.8 - 1.5
(Na+ + K+) – (Cl- + Lactate) = SID
The SID is determined by the charge of the
ions as well as the quantity; in healthy
volunteers it usually equals approximately 40-
49 milliequivalents per liter, and can therefore
be affected by changes in plasma electrolyte concentrations. This
SID, which is an independent mechanism of acid-base regulation,
determines (along with CO2 and weak acids), what the plasma
hydrogen ion concentration will be. The electrochemical forces
generated by this SID determine water dissociation, hence H+ ion
concentration required to “balance” plasma ionic charges. The net
result always has to be a plasma ionic charge equal to zero
(electrochemical neutrality). As one can see, H+ is not the driving
force of the reaction; it is the dependent variable, along with OH-
to a much lesser degree. To continually balance these
electrochemical forces, a decrease in H+ concentration is observed
with increases in the SID, and H+ concentration increases as the
SID decreases.8,12
An increased plasma chloride ion concentration relative to
sodium and potassium concentrations will produce a smaller
plasma strong ion difference, leading to an increased hydrogen
ion concentration, and therefore acidosis.
Stewart's approach relates to how sodium bicarbonate corrects
the metabolic acidosis. The metabolic acidosis may be corrected
not so much by its bicarbonate content but by its sodium content.
The increased sodium concentration resulting from bicarbonate
therapy corrects the reduced SID toward normal, thereby
correcting the acidosis. According to Stewart, bicarbonate is a
dependent variable and therefore cannot bring about a change in
another dependent variable like hydrogen ion concentration.
More recently, the SID equation was expanded to include Ca2+
and Mg2+, to account for further plasma ions.10,13
(Na+ + K+ + Ca2+ + Mg2+) – (Cl- + Lactate) = SID apparent
Many approaches to the management of critical care acid-base
derangements use modified Stewart approaches. Below, we
comment on the role of this technique in explaining pH
derangements commonly observed with intravenous fluid
resuscitation.
 1778428x, 2003, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1778-428X.2003.tb00184.x by Nat Prov Indonesia, Wiley Online Library on [05/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Hyperchloremic Acidosis: Pathophysiology and Clinical Impact E D WA R D B U R D E T T et al.

If the patient lost 5 L of the plasma due to hemorrhage, the

Fluid Therapy
Understanding the role of intravenous fluid electrolyte content
in affecting acid-base balance in vivo, one must first take note of
normal plasma electrolyte content in healthy individuals. To
recapitulate on the concentrations of the plasma ions, see Table 1.
Crystalloid intravenous fluids can be divided into resuscitation
fluids (e.g., 0.9% Sodium Chloride, Hartmann’s Solution) and
non-resuscitation fluids (e.g., 5% Dextrose, 4% Dextrose with
0.18% Sodium Chloride). The main distinction between the two
groups can be described by the electrolytic component (versus
dextrose) providing the osmolar load. Although not identical to
human plasma, intravenous solutions with a balanced electrolyte
formulation (such as Hartmann’s solution) match the biochemical
composition of human plasma more closely than saline-based
fluids.
Saline-based fluids are non-physiological in three ways. Firstly,
the level of chloride is significantly above that of plasma (154
mmol, as compared to 98-102 mmol); secondly they lack several
electrolytes present in normal plasma, including potassium,
calcium, glucose, and magnesium. Thirdly, they lack the
bicarbonate or bicarbonate precursor buffer necessary to maintain
plasma pH within normal limits. Each of these may be responsible
for homeostatic disruption, and in particular the metabolic acidosis
produced by normal-saline infusion.14
As can be seen in Table 1, there are significant differences in the
electrolyte content of 0.9% Sodium Chloride (Saline, and saline
based fluids, e.g. most colloid preparations) and balanced
electrolyte fluid preparations (e.g., Hartmann’s, Lactated Ringers).
Saline has a supra-physiological concentration of both sodium
and chloride. This is of less importance for longer term
maintenance infusions, but very important in fluid resuscitation
scenarios.8,15-17
Illustration of this concept with a simplified mathematical model
will demonstrate the effect of fluid resuscitation with a saline-
based fluid versus a balanced electrolyte fluid (Hartmann’s). Let’s
consider an adult patient, with plasma electrolyte contents as
follows (amongst others):
• Na+ 140 mmol/L
• K+ 4 mmol/L
• Ca 2+
2 mmol/L
• Cl- 100 mmol/L
If we calculate the total electrolyte content of the entire
extracellular fluid space (electrolyte concentrations roughly
constant across the space), by multiplying the respective
concentrations by 15 L (an average for a 70 kg male), we would
obtain the following results:
• Na+ 2100 mmol
• K+ 60 mmol
• Ca2+ 30 mmol
• Cl- 1500 mmol
concentration of the various ions would be the same, but the total
content would be as follows (concentration multiplied by 10 L):
• Na+ 1400 mmol
• K+ 40 mmol
• Ca2+ 20 mmol
• Cl- 1000 mmol
If we chose to replace this lost volume of plasma with 5 L Saline,
the electrolyte load would be 770 mmol of sodium and chloride
each (5 L x 154 mmol/L). This would take the total plasma ionic
content to the following:
• Na+ 1400 mmol + 770 mmol = 2170 mmol
• K+ 40 mmol
• Ca2+ 20 mmol
• Cl- 1000 mmol + 770 mmol = 1770 mmol
This would equate into the following concentrations:
• Na+ 145 mmol/L
• K+ 2.7 mmol/L
• Ca 2+
1.3 mmol/L
• Cl- 118 mmol/L
In calculating the SID however, charge balance demands
milliequivalents per liter, not millimol. The normal SID in healthy
volunteers is 40-49 mEq/L. Bivalent ions such as calcium and
magnesium, therefore, count double. When these variables are
examined using the SID, we would find the following:
(Na+ + K+ + Ca2+ + Mg2+) – (Cl- + Lactate)
= (140 + 4 + 4 + 2) – (100 + 1)
= 151 – 101
= 49 mEq/L (before hemorrhage and transfusion)
and
= (145 + 2.7 + 2.6 + 2) – (118 + 1)
= 151.7 – 119
= 32.7 mEq/L (after saline resuscitation)
The net result would be increased water dissociation, hence the
H+ concentration would increase with saline resuscitation to
maintain electrochemical neutrality. A fall in the pH would result.
This is commonly observed clinically as a hyperchloremic
metabolic acidosis associated with saline fluid resuscitation.
If we resuscitated the same patient, but this time using
Hartmann’s solution, the SID after resuscitation would be 42.7
mEq/L (146.7-104), assuming the lactate would be normally
metabolised. Remember that these are only simplified examples
of the role of SID in acid-base management, to help with the
understanding of the principle involved.
Clinical Implications
The physiological risks of hyperchloremic metabolic acidosis
are not clear. It is fair to question whether hyperchloremic
metabolic acidosis is benign and self-limiting, or whether it is

Transfusion Alternatives in Transfusion Medicine 427 ) VOLUME 5 NUMBER 4 OCTOBER 2003

( Page
 1778428x, 2003, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1778-428X.2003.tb00184.x by Nat Prov Indonesia, Wiley Online Library on [05/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Hyperchloremic Acidosis: Pathophysiology and Clinical Impact E D WA R D B U R D E T T et al.

Table 2.
Summary of Clinical Trials Showing Intraoperative Estimated Blood Loss (EBL) clinically relevant. Metabolic
acidosis, whatever the etiology, can
With Balance Saline Based Fluid Administration
depress myocardial function, reduce
Trial author Fluids used Number in Patient group / op type Outcome (Balanced
cardiac output, and reduce renal
each arm compared to non-balanced)
and intestinal perfusion. Acidemia
Scheingraber16 NS/LR 12 Gynecologic Non-significant can inactivate membrane calcium
reduction in EBL channels, and inhibit the release of
McFarlane22 NS/ 15 General surgery No significant difference norepinephrine from sympathetic
plasmalyte148 nerve fibers. This may result in the
Waters18 NS/LR 33 Open AAA repair Non-significant redistribution of cardiac output
reduction in EBL away from internal organs.18
Whilst this may have little effect
Wilkes17 Hextend / Hespan 23 Surgical patients age > 60 Non-significant
on fit patients undergoing minor
increase in EBL
elective surgery, the concern is the
Martin21 Hextend / Surgical patients with Significant reduction effect of severe hyperchloremic
30
Hespan / LR EBL > 500 mL in EBL acidosis from aggressive fluid
Gan20 Hextend / Hespan 60 Surgical patients Significant reduction resuscitation in acutely ill patients
with EBL > 500 mL in EBL during major surgery, in particular
Boldt24 NS/LR 21 Abdominal cancer Non-significant reduction vascular surgery, and organ
surgery in EBL transplantation; or following
trauma or burns. After tourniquet
Takil25 NS/LR 15 Scoliosis repair Non-significant reduction
release, or in vascular surgery,
in EBL
lactate and carbonic acid load may
LR = Lactated Ringers solution; NS = Normal Saline; Hextend® is a hetastarch suspended in a balanced electrolyte formulation. be superimposed on the iatrogenic
Hespan® is a hetastarch suspended in normal saline.
hyperchloremic acidosis towards
the end of the procedure.
If an intraoperative metabolic
Table 3. acidosis becomes apparent during
fluid replacement, the clinician
Summary of Perioperative Clinical Trials Comparing Estimated Intraoperative may be misled into believing that
Urine Output (UO) With Balanced Saline Based Fluid Administration the patient is hypovolemic, or has
Trial author Fluids used Number in Patient group / op type Outcome (Balanced a surgical cause for their acidosis.
each arm compared to non-balanced) This may lead to inappropriate
Scheingraber16 NS / LR 12 Gynecologic Non-significant management, reports of which
increase in UO have been described in the clinical
setting.19 Further administration of
Waters18 NS / LR 33 Open AAA repair Non-significant
saline-based fluids will exacerbate
increase in UO
rather than relieve the problem. In
Wilkes17 Hextend / Hespan 23 Surgical patients age > 60 Significant improvement in UO this setting, a hyperchloremic
and post-op creatinine metabolic acidosis may not be
Bennett- Hextend / Hespan 50 Cardiac surgery Significant improvement in UO differentiated from lactic acidosis
Guerrero30 and post-op creatinine by the inexperienced anesthetist.
Gan20 Hextend / Hespan 60 Surgical patients No difference Below, we detail some specific
with EBL > 500 mL physiological mechanisms that
become disrupted in the presence
Boldt24 NS / LR 21 Abdominal cancer Non-significant
of hyperchloremia.
surgery decrease in UO
Takil25 NS / LR 15 Scoliosis repair Non-significant reduction Coagulation
decrease in UO
Coagulation, as any other
LR = Lactated Ringers solution; NS = Normal Saline; Hextend® is a hetastarch suspended in a balanced electrolyte formulation.
Hespan® is a hetastarch suspended in normal saline. physiologic system, has optimal
pH and electrolyte levels at which

Transfusion Alternatives in Transfusion Medicine 428 ) VOLUME 5 NUMBER 4 OCTOBER 2003

( Page

Hyperchloremic Acidosis: Pathophysiology and Clinical Impact
it functions most effectively. What is less known in vivo, is the
extent of minor to moderate acid-base and electrolyte disturbances
on overall coagulation and hemostasis. One can assess clinical
outcomes of coagulation or hemostatic function from a number
of well-conducted clinical trials of in vivo fluid therapy or
resuscitation, where balanced electrolyte formulations have been
compared with saline-based fluids.
Studies comparing saline-based versus balanced electrolyte
crystalloids or colloids have shown differences in bleeding and
coagulation, favoring reduced bleeding and less derangement of
coagulation function in the balanced electrolyte formulations.20,21
Waters et al. showed a deleterious effect on hemostasis from
infusion of normal saline based fluids, when compared to balanced
electrolyte solutions, in patients undergoing abdominal aortic
aneurysm repair. Overall, the patients in the balanced fluid group
were exposed to significantly less blood products.18
Other studies (see Table 2), underpowered for blood loss or
assessment of coagulation variables (where these have not been
primary outcome variables), have shown no difference.16,17,22
Systematic review and meta-analysis of the available data of all
randomized controlled trials investigating buffered versus non-
buffered fluid therapy (cf. balanced electrolyte versus saline-based
fluids) has recently shown a significant reduction in blood loss in
the pooled data of buffered fluids.23
Questions may be asked on why this should occur. Calcium
may well play a role, albeit limited. Even when calcium has been
controlled for with hemodilution with fluids in these two groups,
a difference still exists in blood coagulation as assessed by
thrombelastograph® analysis (TEG®, Haemoscope Corp).26 Calcium
does not have any further beneficial effects in enhancing blood
coagulation above ionized concentrations of 0.6 mmol/L.27 Further
research will help in understanding the role of other electrolytes
in the coagulation process.
Renal Effects
Animal studies suggest that hyperchloremia causes renal
vasoconstriction: Wilcox, in a canine model, has shown that renal
blood flow and glomerular filtration rate are regulated by plasma
chloride.28 He demonstrated that hyperchloremia produces a
progressive renal vasoconstriction by inhibiting the intrarenal
release of renin and angiotensin II; and a decrease in glomerular
filtration rate and renal blood flow that was independent of renal
innervation, enhanced by prior salt depletion, and related to a
tubular reabsorption mechanism involving chloride. He went on
to show that chloride-induced vasoconstriction appears specific
for the renal vessels.
Renal afferent arterioles are major regulatory sites of renal
vascular resistance. Hansen showed that plasma chloride levels
directly affect renal afferent arteriolar tone through calcium
activated chloride channels in the afferent arteriolar smooth muscle
in rabbits. He demonstrated a total occlusion of rabbit renal
Transfusion Alternatives in Transfusion Medicine
1778428x, 2003, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1778-428X.2003.tb00184.x by Nat Prov Indonesia, Wiley Online Library on [05/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
E D WA R D B U R D E T T et al.
afferent arterioles at a chloride level of 110 mmol per liter, only
slightly above normal plasma level.29 He suggested that a raised
plasma chloride could increase renal sensitivity to angiotensin 2,
and modulate the release of renin.
Although the message is not as strong as with the coagulation
data, a number of clinical studies (Table 3) now suggest that renal
indices are perturbed by normal saline infusion in the perioperative
setting. Bennett-Guerrero et al. showed a significant improvement
in urine output, serum creatinine, creatinine clearance in
perioperative patients given balanced salt solution, when compared
to a saline-based product.30 Similarly, Wilkes et al., in their elderly
surgical patient population, demonstrated a doubling of urine
output in their balanced fluid group, and a significant reduction
in post-operative creatinine.17 Williams et al. in their healthy
volunteer study31 noted a significantly prolonged time to first
urination in the group infused with 50ml per kg of normal saline
as compared to the Ringer’s lactate group.
These trials are small, and not powered for patient outcome,
and the overall data in this area are unclear. A recent systematic
review reveals a non-significant difference in intraoperative urine
output.32
Other Clinical Implications
Wilkes et al studied gastric tonometry in their trial, and noted a
significant increase in the CO2 gap in their unbalanced group. This
implies gastric hypoperfusion, and indeed there was a trend toward
increased post-operative nausea and vomiting in the same group.
These data tie-in well with the healthy volunteer study by Williams
et al. where normal saline infusion caused abdominal discomfort
in significantly more volunteers than the same volume of Ringer’s
lactate. The mechanism for this is unclear, but it might be
hypothesized that metabolic acidosis itself causes gut hypoperfusion,
or that chloride acts on the splanchnic vasculature in the same
vasoconstricive in the same way as on the renal arterioles.
The respiratory response to perioperative intravenous fluid
administration was noted by Takil et al.25 in their study of ASA 1
and 2 patients undergoing scoliosis repair. They discovered a
significantly increased post-operative hypercarbia in their Ringer’s
lactate group (44 mmHg) as compared to their normal saline group
(40 mmHg). They concluded that this hypercarbia may lead to
reduced opiate administration, and inadequate pain control. It is
fair to hypothesize that the metabolic acidosis found in their normal
saline group caused these patients to overbreathe in compensation
post-operatively. The clinical effects of this are unclear.
Conclusion
In the field of anesthesia and perioperative medicine, it has now
firmly been established that hyperchloremic metabolic acidosis is
a predictable consequence of saline-based, non-balanced
429 ) VOLUME 5 NUMBER 4 OCTOBER 2003
( Page
 1778428x, 2003, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1778-428X.2003.tb00184.x by Nat Prov Indonesia, Wiley Online Library on [05/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Hyperchloremic Acidosis: Pathophysiology and Clinical Impact E D WA R D B U R D E T T et al.

intravenous fluid administration. Current evidence suggests that Conflicts of Interest

it is a clinically relevant and easily avoidable condition. The authors have received unrestricted educational grants
Clearly, further studies are needed to better understand the from the following: Abbott Laboratories USA; Biotime, Inc. USA;
pathophysiology and effects of hyperchloremic metabolic acidosis Fresenius UK; B Braun UK.
in acutely ill patients. We think that until such data are available,
the logical approach should be to avoid iatrogenic hyperchloremia.
Acknowledgements
This is more easily achieved if a fluid that is more normal than
The authors wish to thank Dr. Mark Hamilton for his help
“normal” saline is utilized. We advocate the use of intravenous
and background research, and Dr. Marika Davies for her patience
fluids that have a more balanced composition.
and inspiration.

R E F E R E N C E S

1. Brivet F, Bernardin M, Dormont J. [Hyperchloremic acidosis
in metabolic acidosis with anion gap excess. Comparison with
diabetic ketoacidosis]. Presse Med 1991;20:413-7.
2. Burdett E, Roche T, Donnelly T, Moulding R, Mythen M.
Saline-based fluid resuscitation is associated with metabolic
acidosis in surgical patients. Eur J Anaesthesiology 2003; in
press.
3. Astrup P, Jorgensen K, Siggaard-Andersen O, et al. Acid-
base metabolism: a new approach. Lancet 1960;1:1035-9.
4. Severinghaus JW. Acid-base balance nomogram--a Boston-
Copenhagen detente. Anesthesiology 1976;45:539-41.
5. Siggaard-Andersen O. The pH-log pCO2 blood acid-base
nomogram revisited. Scand J Lab Invest 1962;14:598-604.
6. Neugebauer E, Zander R. Clinical relevance of base excess
and lactate concentration. Anasthesiol Intensivmed
Notfallmed Schmerzther 2002;37:341-2.
7. Stewart PA. Independent and dependent variables of acid-
base control. Respir Physiol 1978;33:9-26.
8. Stewart PA. How to Understand Acid-Base. New York:
Elsevier, 1981.
9. Fencl V, Leith DE. Stewart's quantitative acid-base chemistry:
applications in biology and medicine. Respiration Physiol
1993;91:1-16.
10. Stewart PA. Modern quantitative acid-base chemistry. Can J
Physiol Pharmacol 1983;61:1444-61.
11. Figge J, Rossing TH, Fencl V. The role of serum proteins in
acid-base equilibria. J Lab Clin Med 1991;117:453-67.
12. Kellum JA. Determinants of blood pH in health and disease.
Crit Care 2000;4:6-14.
13. Figge J, Mydosh T, Fencl V. Serum proteins and acid-base
equilibria: a follow-up. J Lab Clin Med 1992;120:713-9.
14. O'Connor MF, Roizen MF. Lactate versus chloride: which is
better? Anesth Analg 2001;93:809-10.
15. Kellum JA. Saline-induced hyperchloraemic metabolic
acidosis. Crit Care Med 2002;30:259-61.
16. Scheingraber S, Rehm M, Sehmisch C, Finsterer U. Rapid
saline infusion produces hyperchloraemic acidosis in patients
undergoing gynecologic surgery. Anesthesiology
1999;90:1265-70.
17. Wilkes NJ, Woolf R, Mutch M, et al. The effects of balanced
versus saline-based hetastarch and crystalloid solutions on
acid-base and electrolyte status and gastric mucosal perfusion
in elderly surgical patients. Anesth Analg 2001;93:811-16.
18. Waters JH, Gottlieb A, Schoenwald P, Popovich MJ,
Sprung J, Nelson DR. Normal saline versus lactated Ringer's
solution for intraoperative fluid management in patients
undergoing abdominal aortic aneurysm repair: an outcome
study. Anesth Analg 2001;93:817-22.
19. Parekh N. Hyperchloremic acidosis. Anesth Analg
2002;95:1821.
20. Gan TJ, Bennett-Guerrero E, Phillips-Bute B, et al.
Hextend, a physiologically balanced plasma expander for
large volume use in major surgery: a randomized phase III
clinical trial. Hextend Study Group. Anesth Analg
1999;88:992-8.
21. Martin G, Bennett-Guerrero E, Wakeling H, et al.
A prospective, randomized comparison of
thromboelastographic coagulation profile in patients
receiving lactated Ringer's solution, 6% hetastarch in a
balanced-saline vehicle, or 6% hetastarch in saline during
major surgery. J Cardiothorac Vasc Anesth 2002;16:441-6.
22. McFarlane C, Lee A. A comparison of Plasmalyte 148 and
0.9% saline for intra-operative fluid replacement.
Anaesthesia 1994;49:779-81.
23. Fong K, Roche AM, Burdett E, Mythen MG. Meta-analysis
of estimated peri-operative blood loss for buffered versus
non-buffered IV fluid Resuscitation. Anesthesiology
2002;96:A197.
24. Boldt J, Haisch G, Suttner S, Kumle B, Schellhase F. Are
lactated Ringer's solution and normal saline solution equal
with regard to coagulation? Anesth Analg 2002;94:378-84.
25. Takil A, Eti Z, Irmak P, Yilmaz Gogus F. Early
postoperative respiratory acidosis after large intravascular
volume infusion of lactated ringer's solution during major
spine surgery. Anesth Analg 2002;95:294-8.
26. Roche AM, James MF, Mythen MG. In vitro addition of
calcium to saline-based intravenous fluids only partially
compensates for TEG pictures observed during
haemodilution. Anesth Analg 2002;94:S73.
27. James MF, Roche AM. Dose-response relationship between
calcium and thrombelastography. Anesthesiology
2001;95:A185.
28. Wilcox CS. Regulation of renal blood flow by plasma
chloride. J Clin Invest 1983;71:726-35.
29. Hansen PB, Jensen BL, Skott O. Chloride regulates afferent
arteriolar contraction in response to depolarization.
Hypertension 1998;32:1066-70.
30. Bennett-Guerrero E, Frumento RJ, Mets B, Manspeizer
HE, Hirsh AL. Impact of normal saline based versus
balanced-salt intravenous fluid replacement on clinical
outcomes: a randomized blinded clinical trial. Anesthesiology
2001;95:A147.
31. Williams EL, Hildebrand KL, McCormick SA, Bedel MJ.
The effect of intravenous lactated Ringer's solution versus
0.9% sodium chloride solution on serum osmolality in human
volunteers. Anesth Analg 1999;88:999-1003.
32. Burdett E, Roche AM, Fong K, Grocott M, Mythen MG.
A systematic review of buffered versus non-buffered
perioperative fluid resuscitation and urine output.
Anesthesiology 2002;96:A201.

Transfusion Alternatives in Transfusion Medicine is published bimonthly by LMS Group, 70/86, avenue de la République 92325 Châtillon Cedex FRANCE – S.A.R.L. au capital de 50,000 FF. • Phone: + 33 1 42 53 03 03
• Fax: + 33 1 42 53 03 02 • Printed in France, De Chabrol, 189 rue d’Aubervilliers, 75886 Paris Cedex 18 FRANCE • Numéro ISSN: 1295-9022 • All rights reserved • Copyright LMS Group • Advertising: For details on
media opportunities within this journal, please contact the advertising sales department (phone: + 33 1 42 53 03 03)• Dépôt légal 3e trimestre 2003.

Transfusion Alternatives in Transfusion Medicine 430 ) VOLUME 5 NUMBER 4 OCTOBER 2003

( Page