http://www.kidney-international.

org review
& 2009 International Society of Nephrology

Assessing acidbase disorders

Horacio J. Adrogue1,2,3, F. John Gennari4, John H. Galla5 and Nicolaos E. Madias6,7
1
Department of Medicine, Baylor College of Medicine, Houston, TX, USA; 2Department of Medicine, Methodist Hospital, Houston, TX,
USA; 3Renal Section, Veterans Affairs Medical Center, Houston, TX, USA; 4Department of Medicine, University of Vermont College of
Medicine, Burlington, VT, USA; 5Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA; 6Department
of Medicine, Tufts University School of Medicine, Boston, MA, USA and 7Division of Nephrology, Department of Medicine, Caritas St
Elizabeths Medical Center, Tufts University School of Medicine, Boston, MA, USA

Effective management of acidbase disorders depends on
accurate diagnosis. Three distinct approaches are currently
used in assessing acidbase disorders: the physiological
approach, the base-excess approach, and the
physicochemical approach. There are considerable
differences among the three approaches. In this review, we
first describe the conceptual framework of each approach,
and comment on its attributes and drawbacks. We then
highlight the application of each approach to patient care.
We conclude with a brief synthesis and our
recommendations for choosing an approach.
Kidney International (2009) 76, 12391247; doi:10.1038/ki.2009.359;
published online 7 October 2009
KEYWORDS: base-excess approach; physicochemical approach;
physiological approach; Stewart approach
Management of acidbase disorders begins with accurate
diagnosis, a process requiring two tasks: First, reliable
measurement of acidbase variables in the blood, a complex
fluid containing multiple ions and buffers; this task is an
exercise in chemistry. Second, proper interpretation of the
data in relation to human health and disease allowing
definition of the patients acidbase status; this is an exercise
in pathophysiology. The patients history, physical examina-
tion, and additional laboratory testing and imaging, as
appropriate, then help the clinician to identify the specific
cause(s) of the acidbase disturbance, and from that
information to undertake appropriate intervention.1
Three distinct approaches are currently used in assessing
acidbase disorders, each with a considerable following
worldwide. For the purposes of this review, we name them
the physiological approach, pioneered by Van Slyke and co-
workers;2,3 the base-excess approach, developed by Astrup
and co-workers;4,5 and the physicochemical approach, pro-
posed by Stewart and extended by his followers.69 The last and
newest approach has steadily gained acceptance, especially
among critical-care physicians and anesthesiologists.
The three approaches differ considerably. In this review,
we first describe the conceptual framework of each approach,
and its attributes and drawbacks. We then highlight the
application of each approach to patient care. We conclude
with a brief synthesis and our recommendations for choosing
an approach.

Correspondence: Nicolaos E. Madias, Department of Medicine, Caritas
St Elizabeths Medical Center, 736 Cambridge Street, Boston, MA 02135, USA.
E-mail: nicolaos.madias@caritaschristi.org
Received 24 June 2009; revised 14 July 2009; accepted 14 July 2009;
published online 7 October 2009
PHYSIOLOGICAL APPROACH
Conceptual framework
The physiological approach considers acids as hydrogen ion
(H ) donors and bases as H acceptors.10 It uses solely the
carbonic acid/bicarbonate buffer system for assessing acid-
base status, a position rooted in the isohydric principle.
Adoption of this buffer system reflects its abundance,
physiological preeminence, and the fact that its two
components undergo homeostatic control.13 Blood pH is
viewed as being determined by the prevailing levels of
carbonic acid (that is, PaCO2, the respiratory component)
and plasma bicarbonate concentration ([HCO 3 ], the meta-
bolic component, Table 1), as stipulated by the Henderson
equation, [H ] 24  PaCO2/[HCO 3 ].

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review HJ Adrogue et al.: Assessing acidbase disorders

Table 1 | Assessment of the metabolic component of acid-base status

Approach Variable Determination Remarks
Physiological Plasma [HCO
3] Measured pH and PCO2 Interpretation complemented by evaluation of plasma
anion gap, [Na+]([Cl]+[Total CO2])
Base excess Blood base excess (BE) CO2 equilibration method or calculated BE is a measure of the metabolic component of acidbase
from measured pH and PCO2 status as reflected in whole blood
Interpretation complemented by evaluation of plasma
anion gap
Standard BE (SBE) Calculated from measured SBE is a measure of the metabolic component of acid-
pH, PCO2, and hemoglobin base status as reflected in the extracellular compartment.
It is usually calculated automatically from arterial blood
gas results, but it can also be obtained using the blood
acidbase nomogram with the hemoglobin set at 5 g/dl42
Interpretation complemented by evaluation of plasma
anion gap
+ + ++ ++  
Physicochemical SIDa (apparent strong ([Na ]+[K ]+[Ca ]+[Mg ])([Cl ]+[lactate ]) These three formulas for SIDa , as well as additional
ion difference) ([Na+]+[K+])([Cl]+[lactate]+[other strong variants, are currently in use. SIDa is mathematically
anions]) equivalent to the plasma buffer base of Singer and
([Na+]+[K+])[Cl] Hastings64
  
SIDe (effective strong [HCO3 ]+[Alb ]+[Pi ] where: Represents the sum of plasma [HCO 3 ] and non-
ion difference) [Alb]=[Alb, g/l]  [(0.123  pH)0.631] bicarbonate buffers (anionic equivalency of albumin and
[Pi]=[Pi, mmol/l]  [(0.309  pH)0.469] phosphate)
SIG (strong ion gap) SIDa SIDe An estimate of the concentration of unmeasured anions
in plasma that resembles the plasma anion gap
Value depends upon the variant of SIDa used
ATot (total 2.43  [total protein, g/dl] Primarily related to albumin concentration
concentration For clinical purposes, approximated by the concentration
of weak acids of total protein
in plasma)
All variables and electrolytes listed are expressed in mEq/l, unless otherwise indicated.

The physiological approach recognizes four acidbase
disorders1,1113 (Table 2). Metabolic disorders are expressed
as primary changes in plasma [HCO 3 ], whereas respiratory
disorders are expressed as primary changes in PaCO2. Each
primary change in either plasma [HCO 3 ] or PaCO2 elicits in
vivo a secondary response in the other variable that tends to
minimize the change in acidity.1,11 These secondary
responses, otherwise referred to as compensatory, have been
quantitated in animals and humans.1424 We discourage use
of the term compensatory, because the secondary responses
occasionally can yield a maladaptive effect on blood pH.25,26
Absence of an appropriate secondary response denotes the
co-existence of an additional simple acidbase disorder. Use
of ventilator support in critically ill patients can, of course,
alter or prevent expression of the secondary changes in
PaCO2 in response to metabolic acidbase disorders. These
ventilator-induced alterations are viewed as complicating
primary respiratory acidbase disorders. The simultaneous
presence of two or more simple acidbase disorders defines a
mixed acidbase disorder.
Assessment of the metabolic component is complemented
by evaluating the plasma anion gap (AG), defined as
[Na ]([Cl] [TCO2]),27 where [TCO2] indicates venous
total CO2 concentration (Table 1 and Figure 1). The average
normal value for plasma AG differs among health-care
facilities because of methodological variation.27 Normally,
approximately 75% of the plasma AG is determined by
plasma albumin concentration.27 Thus, the plasma AG must
be adjusted by subtracting or adding 2.5 mEq/l from the
calculated value for each 1 g/dl of plasma albumin below or
above the average normal value of 4.5 g/dl, respectively.
Changes in blood pH elicit small, directional changes in the
anionic charge of plasma albumin and thus the AG, but these
changes are ignored in clinical practice.28,29 The anionic
charge of plasma albumin decreases by only 1.5 mEq/l when
blood pH decreases from 7.40 to 7.10.30
Attributes and drawbacks
The physiological approach considers the acidbase status of
body fluids as being determined by net H balance (that is,
influx minus efflux) and the prevailing complement of body
buffers.31,32 The chemistry of acids and bases is blended with
the empirically derived secondary responses of the intact
organism to primary changes in PaCO2 or plasma [HCO 3 ].
This approach is simple regarding data collection and clinical
application. The standard blood gas analyzer measures pH
and PCO2, from which plasma [HCO 3 ] is calculated
(Table 1). Comparing plasma [HCO 3 ] with measured
[TCO2] in venous blood validates this derived variable.1
Furthermore, most acidbase disorders are first recognized by
clinicians through abnormalities in venous [TCO2].
Although PCO2 is universally considered as an appro-
priate index of the respiratory component, plasma [HCO 3]
has been viewed by some as an unsuitable indicator of the
metabolic component.33,34 Criticisms include lack of inde-
pendence of plasma [HCO 3 ] from the respiratory compo-
nent and failure of quantitation of buffers other than
bicarbonate. Plasma [HCO 3 ] is certainly affected by changes

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HJ Adrogue et al.: Assessing acidbase disorders review

Table 2 | Classification of acidbase disorders

Disorder Physiological approach Base-excess approach Physicochemical approach
Metabolic acidosis Primary k in [HCO 3] Primary base deficit (BE, SBE) Primary kSIDe,
k in pH; secondary k in PaCO2 k in pH; secondary k in PaCO2 kpH
Secondary DPaCO2/D[HCO 3 ]=k1.2 mm Hg per DPaCO2/DSBE=k1.0 mm Hg per Secondary DPaCO2 not defined
response mEq/lk mEq/lk
Evaluation of Plasma AG adjusted for plasma Plasma AG adjusted for plasma
plasma unmeasured [albumin] [albumin]
anions Normal AG acidosis (hyperchloremic Normal AG acidosis (hyperchloremic SID acidosis where SIG=0, (kSIDa=kSIDe),
acidosis) acidosis) equivalent to hyperchloremic acidosis
High AG acidosis (normochloremic High AG acidosis (normochloremic SIG acidosis where mSIG (unchanged SIDa
acidosis) acidosis) and decreased SIDe), equivalent to
normochloremic acidosis
Effect of [albumin] No significant effect No significant effect Primary m in Atot (hyperalbuminemic
on acidbase status acidosis)

Metabolic alkalosis Primary m in [HCO 3] Primary base excess (+BE, +SBE) Primary m in SIDa and SIDe
m in pH; secondary m in PaCO2 m in pH; secondary m in PaCO2 m in pH (SID alkalosis)

Secondary DPaCO2/D[HCO3 ]=m0.7 mm Hg per DPaCO2/DSBE=m 0.6 mm Hg per Secondary DPaCO2 not defined
response mEq/lm mEq/lm
Effect of [albumin] No significant effect No significant effect Primary k in ATot (hypoalbuminemic
on acidbase satus alkalosis)

Respiratory acidosis Primary m in PaCO2 Primary m in PaCO2 Primary m in PaCO2

k in pH; secondary m in [HCO
3] k in pH k in pH
Secondary D[HCO3 ]/DPaCO2= DSBE=0 (acute) Not considered
response m0.1 mEq/l per mm Hg m(acute) DSBE=+SBE (chronic)
m0.3 mEq/l per mm Hg m(chronic) DSBE/DPaCO2=m0.4 mEq/l
per mm Hg m

Respiratory alkalosis Primary k in PaCO2 Primary k in PaCO2 Primary k in PaCO2

m in pH; secondary k in [HCO
3] m in pH m in pH
Secondary D[HCO3 ]/DPaCO2= DSBE=0 (acute) Not considered
response k0.2 mEq/l per mm Hg k (acute) DSBE=SBE (chronic)
k0.4 mEq/l per mm Hg k (chronic) DSBE/DPaCO2=k0.4 mEq/l
per mm Hg k
AG, anion gap; SBE, standard base excess; SIDa, apparent strong ion difference; SIDe, effective strong ion difference; SIG, strong ion gap (see Table 1 for definitions).
Plasma AG can be adjusted for plasma [albumin] by subtracting or adding 2.5 mEq/l from the calculated value for each 1 g/dl of plasma albumin below or above the average
normal value of 4.5 g/dl, respectively.
Arrows pointing down (k) indicate decreases and arrows pointing up (m) indicate increases. In respiratory acidbase disorders, the term acute refers to a duration of minutes
to several hours. The term chronic refers to a duration of several days or longer.

in PCO2 and vice versa, because HCO 3 and H2CO3 are
members of a single buffer pair.13 Also, sustained changes in
PCO2 substantially modify renal acidification thereby
decreasing plasma [HCO 3 ] in chronic hypocapnia and
increasing it in chronic hypercapnia.14,15,25,26,32,35Conversely,
changes in plasma [HCO 3 ] modify alveolar ventilation
resulting in changes in PCO2.16,24 However, the interdepen-
dency of PCO2 and plasma [HCO 3 ] does not undermine the
rigor of the physiological approach, because the secondary
responses of the one variable to changes in the other have
been quantitated for each disorder (Table 2). Regarding the
second criticism, non-bicarbonate buffers are not quantitated
in the physiological approach, but this does not vitiate
diagnosis, because the level of plasma [HCO 3 ] always reflects
the status of those buffers. Nor does it affect patient
management, because the apparent bicarbonate space, used
to compute acid or alkali replacement, incorporates the
contribution of non-bicarbonate buffers.3638 Alterations in
acidbase equilibrium result in changes in the apparent
bicarbonate space that have been defined experimentally and
take into account the participation of non-bicarbonate
buffers.36
BASE-EXCESS APPROACH
Conceptual framework
The base-excess approach also advocates the centrality of H
balance in defining acidbase status.4,5,33 In this approach, the
three relevant acidbase variables are blood pH, PCO2, and
base excess (BE) (Table 1). Blood BE was introduced to
replace plasma [HCO 3 ] with a measure of the metabolic
component that is independent from the respiratory
component. Base excess represents the amount of acid or
alkali that must be added to 1 l of blood exposed in vitro to a
PCO2 of 40 mm Hg to achieve the average normal pH of 7.40.
Acid is required when blood pH is higher than 7.40 (positive
BE or base excess), whereas alkali is needed when blood pH is
lower than 7.40 (negative BE or base deficit). Under normal
circumstances, the average blood BE is zero.39 During in vitro
blood titration, any CO2-induced increase in plasma [HCO 3]
is attended by an equivalent decrease in the anionic charge of

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review HJ Adrogue et al.: Assessing acidbase disorders

Phosphate Phosphate Phosphate

Other Other Other
cations Other cations Other cations Other
anions anions anions

K+ 4 K+ 4 K+ 4
Proteins
SIG
AG Proteins AG
SIDa SIDe

AG HCO3
SIDa SIDe Proteins SIDa 10
HCO3
24 SIDe
HCO34

Na+ Cl Na+ Cl Na+ Cl

140 106 140 106 140 120

Normal High AG (normochloremic) metabolic acidosis Normal AG (hyperchloremic) metabolic acidosis

or or
SIG acidosis SID acidosis

Figure 1 | Schematic illustration of plasma cations and anions in normal acidbase status, high-anion-gap (normochloremic)
metabolic acidosis or SIG acidosis, and normal anion gap (hyperchloremic) metabolic acidosis or SID acidosis. The numbers
within the bars give ion concentrations in millimoles per liter. AG, anion gap; SID, strong ion difference; SIDa, apparent strong ion difference;
SIDe, effective strong ion difference; SIG, strong ion gap.

non-bicarbonate buffers (largely hemoglobin) that results
from binding the H released from carbonic acid; as a result,
blood BE remains constant. Opposite reactions occur during
in vitro decreases in PCO2 again resulting in a constant blood
BE. In contrast, when the PCO2 is varied in vivo as a result of
hypoventilation or hyperventilation, blood BE does not
remain constant because a concentration gradient for
bicarbonate develops between blood and interstitial com-
partment; bicarbonate is lost from plasma into the interstitial
fluid in hypercapnia causing a negative BE, whereas
bicarbonate is added to plasma from the interstitial fluid in
hypocapnia resulting in a positive BE.19,40 This pitfall was
addressed by introducing the extracellular BE or standard BE
(SBE), a measure of the metabolic component that is
modeled by diluting the blood sample threefold with its
own plasma or estimated by using the blood BE at a
hemoglobin concentration of 5 g/dl.33,4143 Currently, many
blood gas analyzers calculate SBE from measured pH, PCO2,
and hemoglobin44 (Table 1).
The base-excess approach recognizes four acidbase
disturbances1113,4547 (Table 2). Metabolic disorders are
defined by primary changes in BE or SBE, whereas
respiratory disorders represent primary changes in PCO2.
Recomputing data collected according to the physiological
approach47 allows quantitation of the secondary responses to
primary changes in SBE or PCO2 (Table 2). Assessment of
SBE is complemented by evaluating the plasma AG.
Attributes and drawbacks
This approach champions SBE as a measure of the
contribution of all extracellular buffers to a metabolic acid
or alkali load that is independent of the respiratory
component. Some practitioners favor this approach because
SBE simplifies the estimation of acid or alkali replacement.
The base-excess approach weds the chemistry of acids and
bases with the anticipated secondary responses to acidbase
stresses. It is also relatively simple and uses the blood gas
analyzer to provide all three relevant variables (Table 1).
Drawbacks of this approach are the failure to include the
contribution of intracellular buffers, and the presumption of
a constant 1:3 ratio between blood and interstitial volume, a
ratio that decreases in patients with severe edematous
states.40 Most important, the independence of SBE from
the respiratory component is limited to acute hypercapnia

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HJ Adrogue et al.: Assessing acidbase disorders
and hypocapnia. Chronic changes in PCO2 elicit parallel
changes in SBE by altering renal acidification.14,15,35 Further,
changes in SBE characteristic of metabolic disorders originate
in part from the prevailing secondary hypocapnia or
hypercapnia.25,26
PHYSICOCHEMICAL APPROACH
Conceptual framework
The physicochemical approach differs fundamentally be-
cause, in addition to the influence of PCO2 and non-volatile
weak acids, it proposes that the [H ] of living organisms
reflects changes in the dissociation of water induced by the
presence of strong ions (that is, ions fully dissociated at the
pH of body fluids).69,4850 Applying the principles of
electroneutrality and mass conservation, Stewart examined
the dissociation of water in a flask, its interaction with solutes
that dissociate in solution (including the weak acids normally
present in plasma), and the effects of adding CO2. He
concluded that the dissociation of water, and thus the
prevailing [H ], is determined by the interplay of three
variables defined as independent and proposed to account for
all acidbase effects in the solution: The strong ion difference
(SID), the total concentration of weak acids (ATot, which
includes proteins and phosphate), and PCO2.68 The SID
represents the sum of the concentrations of the strong cations
(Na , K , Ca , and Mg ) minus the sum of the SIDe, ATot, and PCO2 are not available.
concentrations of the strong anions (Cl, SO4 , and anions
of organic acids). By virtue of their magnitude, the
concentrations of Na and Cl are the main determinants
of SID. Stewart developed a set of six equations that, when
solved simultaneously, yield the [H ] of the solution.68 The
calculated value equals measured acidity using a pH
electrode.
In this approach, both [H ] and [HCO 3 ] are defined as
dependent variables, their values being determined exclu-
sively by the three independent variables. Bicarbonate is
actually viewed as an irrelevant measure of acidbase status6
that simply contributes to filling the gap between strong
cations and strong anions. The physicochemical approach
proposes that acidbase disorders be assessed using SID and
ATot (collectively representing the metabolic component), and
PCO2 (respiratory component).
Clinical application of this approach involves measure-
ment of blood pH and PCO2, and determination of the two
formulations of SID and ATot.30,51,52 Subtracting strong
anions from strong cations yields the apparent SID (SIDa).
The simplest estimation of SIDa involves subtracting [Cl]
from the sum of [Na ] and [K ],52 and under normal
conditions, it equals approximately 40 mEq/l (Table 1 and
Figure 1). The other formulation of SID, effective SID (SIDe),
represents the sum of plasma [HCO 3 ] and the anionic
equivalency of albumin and phosphate (Table 1 and Figure 1);
it is estimated from blood pH, PCO2, and the plasma
concentrations of albumin and phosphate using a formula or
a nomogram.51 The difference between SIDa and SIDe,
known as strong ion gap (SIG), is proposed as a more
Kidney International (2009) 76, 12391247
review
accurate estimate of plasma unmeasured anions than plasma
AG. Under normal conditions, SIG equals zero. In organic
acidosis SIDa remains unchanged, but it decreases in
hyperchloremic metabolic acidosis. On the other hand, SIDe
decreases in both types of metabolic acidosis. SIG equals
zero in hyperchloremic metabolic acidosis (SID acidosis,
Figure 1),51,53 whereas it increases in organic acidosis (SIG
acidosis, Figure 1) reflecting high levels of unmeasured
anions, such as lactate and ketoanions. Estimation of ATot for
clinical purposes requires measurement of plasma total
proteins or plasma albumin (Table 1).
The physicochemical approach defines six acidbase
disorders according to primary deviations in each of the
three independent variables30,51 (Table 2). Abnormal levels of
SIDe or ATot indicate the presence of metabolic acidbase
disorders. A low SIDe signifies metabolic acidosis (SID
acidosis) and a high SIDe metabolic alkalosis (SID alkalosis).
A low-SIDe metabolic acidosis can occur in association with a
high SIG (for example, diabetic ketoacidosis) or a normal
(that is, zero) SIG (for example, diarrhea) (Figure 1). A high
ATot signifies metabolic acidosis (hyperalbuminemic acidosis)
and a low ATot metabolic alkalosis (hypoalbuminemic
alkalosis).5458 Increases in PCO2 define respiratory acidosis
and decreases in PCO2 respiratory alkalosis. Quantitative
measures of the secondary responses to primary changes in
Attributes and drawbacks
The physicochemical approach provides a detailed descrip-
tion of acidbase variables. Proponents have argued that the
increased complexity required for calculating SIG is justified
because it yields an index of unmeasured anions after
discounting the contribution of albumin and phosphate.
Some data suggest that SIG better predicts the risk of death in
critically ill patients than serum lactate, AG, or blood BE.53,59
However, most studies have not identified any diagnostic or
prognostic advantage of the physicochemical approach over
the other approaches in such patients.60,61
Compared with the physiological and base-excess ap-
proaches, the physicochemical approach requires additional
measurements of multiple ions and the use of computer
programs33,62,63 (Table 1). Interpreting SID is cumbersome,
because its two formulations, SIDa and SIDe, have different
connotations. The SIDa itself is somewhat confusing, variable
electrolytes being used in defining it, such that even the
normal baseline differs substantially (Table 1). Despite claims
that bicarbonate is an irrelevant anion in terms of acidbase
assessment, it is a major component of SIDe (Figure 1).
Compared with plasma [HCO 3 ] and SBE, the reliability
of SIDa, SIDe, and ATot is precarious, because their
determination requires multiple measurements and calcula-
tions incorporating several assumptions.
The classification of metabolic acidbase disorders is
unduly complex. As examples, metabolic acidosis can be
associated with normal SIDa, low SIDa, normal SIG, high
SIG, or high ATot. Also, the designation of ATot acidosis and
1243
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ATot alkalosis, based on increased and decreased levels of
plasma albumin, respectively, is largely groundless.33 Despite
in vitro data showing that changes in albumin affect acidity,
there is no evidence that the body and, in particular the liver,
regulates albumin to maintain acidbase balance. In vivo,
changes in serum albumin do not correlate with changes in
PCO2 or pH.63 Contrary to the physiological and base-excess
approaches that maintain a sharp distinction between
diagnosis and cause, the physicochemical approach attempts
to blend these elements with respect to metabolic distur-
bances, a potential source of confusion.
The physicochemical approach is computationally precise
but anchored exclusively in chemistry. The mathematical
precision of this approach does not validate the proposed
cause and effect relationship with acidbase variables. To posit
that SID and ATot determine mechanistically plasma [HCO 3]
and pH at the physiological level is presumptuous. Experi-
mental support for such a cause and effect relationship is
lacking.63 Rather than being causes of acidbase perturbations,
changes in SID could be mere reflections of these perturbations.
Proponents of the physicochemical approach argue that
rapid infusion of isotonic saline (for example, 30 ml/kg/h), a
solution with a SID of zero, generates metabolic acidosis
because of a hyperchloremia-induced decrease in SID. This
phenomenon is essentially prevented during rapid infusion of
Ringers lactate, a solution with an SID of 23 mEq/l.65 The
physiological approach offers, however, an equally straight-
forward explanation. The metabolic acidosis is caused by the
sizable expansion of the extracellular fluid with a solution
devoid of bicarbonate (that is, isotonic saline) that results in
a decrease in plasma [HCO 3 ] without a proportional
decrease in PCO2 (dilution acidosis).66 Such a dilution of
the extracellular bicarbonate stores is obviated during rapid
infusion of Ringers lactate, because the infused lactate
represents a bicarbonate precursor, its metabolism generating
equivalent molecules of bicarbonate. Dilution acidosis is, of
course, a short-lived phenomenon in patients with normal
renal function, because regulatory changes intervene rapidly; it
can only be sustained in patients with advanced renal failure.
CLINICAL APPLICATIONS
Let us now evaluate the acidbase status of two clinical cases
using each of the three approaches. The laboratory data for
each case and the corresponding acidbase diagnoses
according to each approach are shown in Table 3.
Case 1
A 27-year-old woman with type 1 diabetes mellitus was
brought to the emergency department with obtundation,
severe hyperpnea, and blood pressure of 90/45 mm Hg.
Using the physiological approach, the plasma [HCO 3 ] of
4 mEq/l and blood pH of 7.05 signify metabolic acidosis. For
a D[HCO 3 ] of 20 mEq/l (24-4), the expected DPaCO2 is
24 mm Hg (1.2  20, Table 2) predicting a PaCO2 of
16 mm Hg (40-24); the patients PaCO2 of 15 mm Hg
represents an appropriate ventilatory response. Thus, a single
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HJ Adrogue et al.: Assessing acidbase disorders
acidbase disorder is present. The AG is markedly increased
(28 mEq/l) compared with the expected baseline (approxi-
mately 4 mEq/l when corrected for plasma albumin concen-
tration) indicating the presence of increased unmeasured
anions in plasma. The estimated change in AG (DAG) equals
24 mEq/l and approximates the decrease in plasma [HCO 3 ].
Using the base-excess approach, the SBE of 25 mEq/l in
conjunction with a blood pH of 7.05 is indicative of
metabolic acidosis. The DPaCO2 of 25 mm Hg is appropriate
for the DSBE of 25 mEq/l (expected value, 1  25, Table 2)
and represents secondary hypocapnia. Thus, a single acid-
base disorder is considered present. The DAG of 24 mEq/l
(evaluated in a manner identical to the physiological
approach) points to high-anion-gap metabolic acidosis.
Using the physicochemical approach, the decreased SIDe
of 11 mEq/l is diagnostic of metabolic acidosis. The elevated
SIG of 27 mEq/l indicates that the acidosis is due to
accumulation of unmeasured strong anions. Reflecting the
low plasma albumin concentration, the decreased ATot
signifies coexisting weak-acid alkalosis (hypoalbuminemic
alkalosis). The decreased PaCO2 points to the presence of
respiratory alkalosis. No information is available to judge the
appropriateness of the ventilatory response. Thus, the patient
has three acidbase disorders.
Both the physiological and the base-excess approaches
diagnose an identical simple acidbase disorder, namely high-
anion-gap metabolic acidosis. The patients clinical history
coupled with the prevailing hyperglycemia and positive tests
for blood and urine ketones (data not shown) establish the
presence of diabetic ketoacidosis. The focus of care is to
reverse the organic acidosis. In contrast, the physicochemical
approach identifies three separate acidbase disorders,
metabolic acidosis, hypoalbuminemic alkalosis, and respira-
tory alkalosis. These diagnoses can be a source of confusion
for the clinician. Is the hypoalbuminemic alkalosis, a
condition of questionable existence, protective in this case?
Must the respiratory alkalosis be treated or is the hypocapnia
appropriate for the metabolic acidosis? Attempts to address
these questions risk mismanagement and divert attention
from the key problem, reversing the organic acidosis.
Case 2
A 58-year-old man with advanced chronic obstructive
pulmonary disease and congestive heart failure was admitted
because of anorexia and failure to thrive. His medications
include bronchodilators and diuretics.
The physiological approach identifies marked elevations in
plasma [HCO 3 ] and PaCO2 in the company of a near normal
blood pH signifying a mixed acidbase disorder. The PaCO2
of 58 mm Hg exceeds the anticipated ventilatory response to
metabolic alkalosis; for a D[HCO 3 ] of 11 mEq/l (35-24), the
expected DPaCO2 is approximately 8 mm Hg (0.7  11,
Table 2) predicting a PaCO2 of 48 mm Hg (40 8). Thus,
both metabolic alkalosis and respiratory acidosis are present.
The increased plasma [HCO 3 ] represents the sum of the
effects of diuretics and chronic hypercapnia on renal
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Table 3 | Clinical examples

Mean normal values Case 1 Case 2
Measured variables
pH 7.40 7.05 7.41
PaCO2 40 mm Hg 15 58
[HCO 3] 24 mEq/l 4.0 35
[Na+] 140 mEq/l 129 138
+
[K ] 4.0 mEq/l 5.0 3.2
[Cl] 104 mEq/l 96 101
[TCO2] 26 mEq/l 5.0 39
[Albumin] 4.5 g/dl 2.0 1.5
Pi 1.2 mmol/l 1.1 0.5

Derived variables
AG 10 mEq/l 28 2
SBE 0 mEq/l 25 11
SIDa 40 mEq/l 38 40
SIDe 40 mEq/l 11 40
SIG 0 mEq/l 27 0
Atot 15 mEq/l 7 5

Acid-base diagnoses
Physiological approach One disorder: Two disorders:
Metabolic acidosis (high AG metabolic acidosis) Metabolic alkalosis
Respiratory acidosis
Base-excess approach One disorder: Two disorders:
Metabolic acidosis (high AG metabolic acidosis) Metabolic alkalosis
Respiratory acidosis
Physicochemical approach Three disorders: Two disorders:
Metabolic acidosis (SIG acidosis) Hypoalbuminemic alkalosis
Hypoalbuminemic alkalosis Respiratory acidosis
Respiratory alkalosis

acidification. The AG is reduced, the result of severe
hypoalbuminemia.
Using the base-excess approach, one finds an SBE of
11 mEq/l along with the marginally increased blood pH of
7.41, which indicates the presence of metabolic alkalosis
(diuretic-induced). The DPaCO2 of 18 mm Hg (58-40)
exceeds the anticipated secondary response to the DSBE of
11 mEq/l (0.6  11 B7, predicting a PaCO2 of 47 mm Hg)
and signifies coexisting respiratory acidosis. The AG is
reduced because of severe hypoalbuminemia.
The physicochemical approach indicates that the nor-
malcy of SIDa, SIDe, and SIG contrasts with a very
diminished ATot of only 5 mEq/l. The patients diagnosis is
weak-acid alkalosis (hypoalbuminemic alkalosis). The in-
creased PaCO2 signifies respiratory acidosis. Two acidbase
disorders are diagnosed.
Both the physiological and base-excess approaches will
lead clinicians to introduce measures to improve alveolar
ventilation as well as reduce the metabolic component and
thus blood pH by administering potassium chloride and
possibly acetazolamide. These two measures complement
each other because even relative alkalemia reduces the
ventilatory drive. By contrast, the physicochemical approach
will fail to pursue these therapeutic measures because it
cannot judge whether the increase in PaCO2 represents
primary hypercapnia, secondary hypercapnia, or both.
Instead, it might prompt clinicians to raise plasma albumin
level, a scientifically unsupported measure.
No research has been directed toward the potential clinical
implications of this divergence in diagnosis. We can only
speculate whether such variable assessment of the acidbase
status and resultant differences in clinical management
contribute to patients morbidity and mortality.
SYNTHESIS AND RECOMMENDATIONS
The physiological and base-excess approaches adequately
fulfill both the chemical and the pathophysiological tasks to
assessing acidbase status in a relatively simple and
straightforward manner. Conversely, the physicochemical
approach addresses these two tasks by introducing consider-
able complexity, as it requires multiple determinations to
compute its panel of acidbase variables. In our judgment,
this approach builds a mathematical superstructure that is
superfluous, impractical, and at times misleading.
The physiological approach offers quantitative measures
of the secondary responses to primary acidbase perturba-
tions that have been derived from observational and
experimental studies in humans (Table 2). A corresponding
quantitation is provided by the base-excess approach that is
based on recomputing data collected according to the
physiological approach (Table 2). Conversely, no quantitative
assessment of the secondary responses to primary changes in

Kidney International (2009) 76, 12391247 1245

review
SIDe, ATot, and PCO2 is offered by the physicochemical
approach. This situation is a major drawback and risks
misdiagnosis of the secondary responses as independent,
simple acidbase disorders.
Despite its general adequacy and simplicity, the base-
excess approach uses blood acidbase nomograms obtained
in vitro and assumptions that detract from its overall
reliability. Only the physiological approach precisely quanti-
tates the two components of the dominant buffer pair in
blood, which are in equilibrium with the remaining body
buffers, thereby providing direct and reliable assessment of
acidbase status in vivo. We conclude that the physiological
approach remains the simplest, most rigorous, and most
serviceable approach to assessing acidbase disorders.
DISCLOSURE
All the authors declared no competing interests.
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