EDITORIAL

Hyperchloremic Acidosis: The Classic Example of Strong

Ion Acidosis
Peter D. Constable,

BVS, PhD

Department of Veterinary Clinical Medicine, University of Illinois, Urbana

e are undergoing a revolution in the way we

clinically assess acid-base status. For almost
100 years, the Holy Grail for clinicians has
been to accurately determine the mechanism for an
acid-base disturbance. Landmark advancements in the
clinical diagnosis and treatment of acid-base disturbances have included the Henderson-Hasselbalch
equation (1916) (1), base excess (1960) (2), anion gap
(1970s) (3), and the strong ion approach (1983) (4). In
this issue of Anesthesia & Analgesia, Rehm and Finsterer (5) investigate the treatment of hyperchloremic
acidosis, a frequently observed response to IV crystalloid fluid administration (6 10). The mechanism for
the development of hyperchloremic acidosis cannot be
satisfactorily explained using the traditional approach
to acid-base balance.
We are all familiar with the Henderson-Hasselbalch
equation (1), which describes how plasma CO2 tension
(Pco2), plasma bicarbonate concentration ([HCO3]),
the negative logarithm of the apparent dissociation
constant (pK1) for plasma carbonic acid (H2CO3), and
the solubility (S) of CO2 in plasma interact to determine plasma pH. This relationship is most often expressed in the following form:

pH pK1 log

HCO3]
S Pco2

(2)

or the bicarbonate donor tris-hydroxymethyl aminomethane (THAM):

(1)

Accepted for publication December 5, 2002.

Address correspondence and reprint requests to Peter D. Constable,
PhD, Department of Veterinary Clinical Medicine, University of Illinois, 1008 W Hazelwood Dr., Urbana, IL 60102. Address e-mail to
p-constable@uiuc.edu.

2003 by the International Anesthesia Research Society

0003-2999/03

NaHCO3 7 Na HCO3

R-NH2 H2O CO2 7 R-NH3 HCO3

The evaluation of acid-base status using the

Henderson-Hasselbalch equation (Equation 1) has traditionally used the pH value as an overall measure of
acid-base status, Pco2 as an independent measure of
the respiratory component of acid-base balance, base
excess, actual bicarbonate concentration, or standard
bicarbonate as a measure of the metabolic (also called
nonrespiratory) component of acid-base balance, and

DOI: 10.1213/01.ANE.0000053256.77500.9D

calculation of the anion gap to facilitate identification

of unmeasured anions or cations in plasma.
So what is wrong with this proven and widely used
approach? Simply stated, using the HendersonHasselbalch equation to calculate base excess, actual
bicarbonate concentration, or standard bicarbonate
provides an estimate of the magnitude of a metabolic
acidosis and not the mechanism for its development.
Thus, the Henderson-Hasselbalch equation cannot satisfactorily explain the mechanism for many acid-base
disturbances; hyperchloremic acidosis is one of many
clinical conditions that have no rational explanation. It
is well recognized that the rapid infusion of large
quantities of 0.9% NaCl induces acidemia (hyperchloremic acidosis) and decreases plasma bicarbonate concentration (6 10). The Henderson-Hasselbalch equation indicates that hyperchloremic acidosis should be
treated by administering bicarbonate in the form of an
isotonic solution of sodium bicarbonate:

(3)
where R-NH2 is THAM, and R-NH3 is the protonated form of THAM. As shown by Rehm and Finsterer
(5), both treatments are effective in restoring bicarbonate concentration and pH to normal. But how does the
rapid IV administration of 0.9% NaCl decrease plasma
pH and bicarbonate concentration? Is there more to
this story?
Our understanding of acid-base balance was revolutionized in 1983 by Stewarts development of strong
ion theory (4). The strong ion approach has two novel
aspects: acid-base balance is examined using a systems
approach, and a clear conceptual distinction is made
between dependent and independent variables. Independent variables influence a system from the outside
and cannot be affected by changes within the system
Anesth Analg 2003;96:91922

919

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EDITORIAL

ANESTH ANALG
2003;96:919 22

or by changes in other independent variables. In contrast, dependent variables are influenced directly and
predictably by changes in the independent variables.
Therefore, the strong ion approach offers a clear mechanistic explanation for changes in acid-base balance.
Stewart proposed that plasma pH was determined
by three independent factors; Pco2, the strong ion
difference (SID), which is the difference between the
charge of plasma strong cations (sodium, potassium,
calcium, and magnesium) and anions (chloride, lactate, sulfate, ketoacids, nonesterified fatty acids, and
many others), in which strong cations and anions are
fully dissociated at physiologic pH, and Atot, which is
the total plasma concentration of nonvolatile buffers
(albumin, globulins, and inorganic phosphate) (4). In
this context, pH value and bicarbonate concentration
are dependent variables. From the three independent
factors (Pco2, SID, and Atot), Stewart developed a
complicated polynomial equation that expressed pH
value (he erroneously used H concentration) as a
function of eight factors, consisting of three independent factors and five constants (4). It was subsequently
shown, algebraically (11) and graphically (12), that
changes in two of Stewarts eight factors had no quantitative effect on pH value, leading to the development
of the six-factor simplified strong ion equation in 1997
(11). Currently, the six-factor simplified strong ion
equation is the preferred form for applying the strong
ion approach (1114). The equation states that the pH
value is a function of three independent factors (Pco2,
SID, and Atot) and three constants (S, the apparent
dissociation constant for plasma carbonic acid [K1],
and Ka, the effective dissociation constant for nonvolatile buffers in plasma), such that:

pH
log10

2SID
K1S Pco2 KaAtot KaSID K1S Pco2
KaSID KaAtot)2 4Ka2SIDAtot}
(4)

For those readers that dislike complicated equations, Equation 4 can be expressed in an algebraically
simpler but equivalent form as:

pH pK1 log

SID Atot/ 1 10 pKapH

S Pco2

(5)

Equation 5 simplifies to the Henderson-Hasselbalch

equation (Equation 1) in solutions that do not contain
protein or phosphate (because Atot 0 and SID
[HCO3]).
A number of clinical ramifications arise from the
simplified strong ion equation (Equation 4). Because

clinically important acid-base derangements result

from changes in Pco2, SID, or concentrations of individual nonvolatile plasma buffers (Atot; albumin,
globulins, and phosphate), the strong ion approach
distinguishes six primary acid-base disturbances (respiratory, strong ion, or nonvolatile buffer ion acidosis
and alkalosis) instead of the four primary acid-base
disturbances (respiratory or metabolic acidosis and
alkalosis) differentiated by the traditional HendersonHasselbalch equation (1114). Acidemia results from
an increase in Pco2 and nonvolatile buffer concentrations (albumin, globulin, and phosphate) or from a
decrease in SID. Alkalemia results from a decrease in
Pco2 and nonvolatile buffer concentration or from an
increase in SID.
The strong ion approach provides an explanation
for the development of hyperchloremic acidosis and
therefore a rational treatment for this condition. Normal human plasma SID is 42 mEq/L (15), whereas the
SID of 0.9% NaCl is 0 mEq/L because sodium and
chloride are both strong ions (11). IV administration of
0.9% NaCl must, therefore, decrease plasma SID,
which will create a strong ion acidosis (assuming that
infusion does not cause a change in Pco2 or plasma
albumin, globulin, or phosphate concentrations). The
magnitude of the decrease in plasma SID when 0.9%
NaCl is administered is dependent upon the relative
volumes of the extracellular space and 0.9% NaCl and
the speed of the 0.9% NaCl administration. Therefore,
hyperchloremic acidosis is easier to detect when large
volumes of 0.9% NaCl are rapidly administered, as in
the study by Rehm and Finsterer (5).
The following rules of thumb for the clinical assessment of acid-base disturbances in humans have been
developed from the simplified strong ion approach:
pH SID 0.016, pH Pco2 0.009, and
pH (g total protein/dL) 0.04 (12). These rules
of thumb are approximate, because they simplify a
complex curvilinear relationship; however, the clinical
guidelines indicate that at a normal pH value (7.40), a
1-mEq/L decrease in SID will decrease the pH value
by 0.016, a 1-mm Hg increase in Pco2 will decrease the
pH value by 0.009, and a 1-g/dL increase in total
protein concentration will decrease the pH value by
0.039. Because the SID from its normal value is
equivalent to the base excess value (13,14), assuming a
normal nonvolatile buffer ion concentration (normal
albumin, globulins, and phosphate concentration), we
can readily determine the mechanism for the metabolic acidosis in patients receiving large volume 0.9%
NaCl solutions. In the patients studied by Rehm and
Finsterer (5), mean base excess was approximately 7
mEq/L, which would decrease the pH value by 0.11 U
(7 0.016) if SID were the only independent variable to change. Because the measured pH value (7.28)
was decreased 0.12 U from normal values (7.40), and

ANESTH ANALG
2003;96:919 22

because values for Pco2 (40 mm Hg) and Atot approximated normal, the acidemia induced by rapid administration of large volume 0.9% NaCl was caused by a
strong ion acidosis. Accordingly, the specific treatment for hyperchloremic acidosis is to increase SID by
administering a solution where the strong cation concentration exceeds the strong anion concentration by
42 mEq/L (42 mEq/L is the normal SID for human
plasma). Two solutions with a high effective SID were
therefore administered by Rehm and Finsterer (5) and
are 130 mmol of sodium bicarbonate (effective SID,
130 mEq because bicarbonate is volatile buffer ion and
not a strong anion; see Equation 2) or 128 mmol of
THAM (effective SID, 128 70% 90 mEq because
70% of the neutral compound R-NH2 in THAM is
immediately protonated to the strong cation R-NH3
in plasma; see Equation 3). Therefore, the strong ion
approach predicts that sodium bicarbonate would
more effectively correct the induced hyperchloremic
acidosis than an equivalent number of moles of
THAM, and this prediction is supported by the results
reported by Rehm and Finsterer (5).
So what new information has application of the
strong ion approach provided? Remember that the
traditional Henderson-Hasselbalch equation did not
describe the mechanism for the development of
hyperchloremic acidosis but indicated that hyperchloremic acidosis should be treated with sodium bicarbonate or the bicarbonate donor THAM because bicarbonate concentration was decreased. In contrast,
the strong ion approach indicated that hyperchloremic
acidosis was caused by the decrease in plasma SID
after rapid infusion of large quantities of 0.9% NaCl
and that the resultant strong ion acidosis would be
best treated by administering a solution with a high
effective SID, such as sodium bicarbonate or THAM.
For hyperchloremic acidosis, application of the
Henderson-Hasselbalch equation and strong ion approaches produced the same treatment (sodium bicarbonate or THAM) but completely different reasons for
the response.
Finally, a comment on the method used by Rehm
and Finsterer (5) to quantify the unmeasured strong
cation concentration in patients receiving THAM, because THAM (R-NH2) is protonated in plasma to
R-NH3, which is a strong cation (see Equation 3). A
clinically important problem in sick patients is identifying and quantifying the presence of strong anions or
cations in plasma that are not routinely measured
including anions such as lactate, -hydroxybutyrate,
acetoacetate, and anions associated with uremia and
cations such as protonated THAM (R-NH3). Unmeasured strong anion or cation concentrations can be
quantified by calculating the anion gap (3), applying
the Fencl base excess method (16), calculating the
strong ion gap (SIG) using the Figge unmeasured anion method (17,18), or calculating the SIG using an

EDITORIAL

921

equation derived from the simplified strong ion equation (19). This equation requires measurement of six
variables (pH value, Pco2, [Na], [K], [Cl], and [total
protein]) and known species-specific values for Atot
and Ka (pKa is the negative logarithm to the base 10 of
Ka):

SIG Atot/ 1 10 pKapH ANION GAP

(6)
Rehm and Finsterer (5) calculated SIG using the
Figge unmeasured anion method (17,18). It would
have been interesting had they calculated SIG using
Equation 6 and estimated Atot and pKa values for
human plasma (12,19), whereby:

SIG 3.44 total protein / 1 10 6.98pH 2

ANION GAP (7)
In Equation 7, SIG and ANION GAP ({[Na]
[K]}{[CI] [HCO3]}) are in units of milliequivalent per liter, and total protein concentration is in
units of grams per deciliter. Two milliequivalents per
liter was subtracted from the right hand side of Equation 7 because the unmeasured strong cation concentration exceeds the unmeasured strong anion concentration by 23 mEq/L in horse (19) and cattle (20)
plasma and presumably by a similar amount in human plasma, although this has not been confirmed.
For normal values of pH (7.40), total protein concentration (7.0 g/dL), and anion gap (16 mEq/L when
[K] is included in the calculation, as in Equation 7),
Equation 7 calculates that SIG 0 mEq/L. Because
calculating SIG using Equation 6 and species-specific
values for Atot and Ka more accurately predicted unmeasured strong anion concentration in sick cattle
than calculating SIG using the Figge unmeasured anion method (20), it is possible that Equation 7 may
have more accurately described the increase in SIG
after administration of THAM.
In summary, the strong ion approach provides the
clinician with an improved understanding of complex
acid-base disturbances and the mechanisms for their
development. Because increased understanding will
lead to more targeted treatments of acid-base and
electrolyte disorders, we are at the dawn of a new era
in the treatment of critically ill patients. Exciting times
are ahead. Studies by Wilkes (21) in 1998 and Rehm
and Finsterer (this journal) are among the first to use
the strong ion approach in humans to determine the
mechanism for an acid-base disturbance and identify
the most appropriate treatment. For hyperchloremic
acidosis in healthy patients with normal renal function
and hydration status, the most appropriate treatment
is to discontinue the IV administration of crystalloid
solutions with a low effective SID, such as 0.9%NaCl.

922

EDITORIAL

For hyperchloremic acidosis in critically ill patients,

the most appropriate treatment is to commence the IV
administration of a crystalloid solution with a high
effective SID, such as sodium bicarbonate or THAM.

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