Acid-Base and Electrolyte Teaching Case

Assessing Acid-Base Status: Physiologic Versus

Physicochemical Approach
Horacio J. Adrogué, MD,1,2,3 and Nicolaos E. Madias, MD 4,5

The physiologic approach has long been used in assessing acid-base status. This approach considers acids
as hydrogen ion donors and bases as hydrogen ion acceptors and the acid-base status of the organism as
reflecting the interaction of net hydrogen ion balance with body buffers. In the physiologic approach, the
carbonic acid/bicarbonate buffer pair is used for assessing acid-base status and blood pH is determined by
carbonic acid (ie, PaCO2) and serum bicarbonate levels. More recently, the physicochemical approach was
introduced, which has gained popularity, particularly among intensivists and anesthesiologists. This approach
posits that the acid-base status of body fluids is determined by changes in the dissociation of water that are
driven by the interplay of 3 independent variables: the sum of strong (fully dissociated) cation concentrations
minus the sum of strong anion concentrations (strong ion difference); the total concentration of weak acids;
and PaCO2. These 3 independent variables mechanistically determine both hydrogen ion concentration and
bicarbonate concentration of body fluids, which are considered as dependent variables. Our experience in-
dicates that the average practitioner is familiar with only one of these approaches and knows very little, if any,
about the other approach. In the present Acid-Base and Electrolyte Teaching Case, we attempt to bridge this
knowledge gap by contrasting the physiologic and physicochemical approaches to assessing acid-base status.
We first outline the essential features, advantages, and limitations of each of the 2 approaches and then apply
each approach to the same patient presentation. We conclude with our view about the optimal approach.
Am J Kidney Dis. 68(5):793-802. ª 2016 by the National Kidney Foundation, Inc. Published by Elsevier Inc.
All rights reserved.

INDEX WORDS: Stewart approach; base excess; acid-base disorders; anion gap; physiologic approach;
physicochemical approach; acid-base status; diagnosis.

Note from the editors: This article is part of a series of invited

case discussions highlighting the diagnosis and treatment of
acid-base and electrolyte disorders.
INTRODUCTION
Successful management of acid-base disorders de-
pends on accurate diagnosis. In turn, accurate diagnosis
requires a 2-tiered process: reliable determination of
acid-base variables in blood and sound interpretation of
the data to assess the patient’s acid-base status; and
careful synthesis of the clinical information and addi-
tional testing, as appropriate, to identify the cause(s) of
the prevailing acid-base disorder(s).1
Early in the 20th century, Henderson, Van Slyke,
and coworkers pioneered the classic approach to
assessing acid-base disorders, which we call the
physiologic approach.2-5 Starting in the late 1950s,
Astrup, Siggaard-Andersen, and coworkers developed
a variation of the physiologic approach, the base-
excess approach,6-9 which in our opinion offered no
advantages but rather introduced several shortcom-
ings.10 Finally, in 1978, Stewart proposed a funda-
mentally different framework that was further
developed by his followers, which we call the physi-
cochemical approach.11-15 The latter approach has
gained popularity, particularly among intensivists and
anesthesiologists.
In our experience, most physicians use a single
approach to assess acid-base status and know very
little, if any, about the other approaches. This situation
undermines communication among caregivers and can
adversely affect patient care, especially because all
approaches are frequently practiced within an institu-
tion. We attempt to bridge this knowledge gap by
contrasting the physiologic and physicochemical ap-
proaches to assessing acid-base status. The essential
features, advantages, and limitations of each of the 2
From the 1Department of Medicine, Baylor College of Medi-
cine; 2Department of Medicine, Methodist Hospital, and 3Renal
Section, Veterans Affairs Medical Center, Houston, TX;
4
Department of Medicine, Tufts University School of Medicine;
and 5Division of Nephrology, Department of Medicine, St. Eliz-
abeth’s Medical Center, Boston, MA.
Received January 22, 2016. Accepted in revised form April 8,
2016. Originally published online August 30, 2016.
Because the Feature Editor recused himself, the peer-review
and decision-making processes were handled without his partici-
pation, and Daniel E. Weiner, MD, MS, served as Acting Feature
Editor. Details of the journal’s procedures for potential editor
conflicts are given in the Information for Authors & Journal
Policies.
Address correspondence to Nicolaos E. Madias, MD, Depart-
ment of Medicine, St. Elizabeth’s Medical Center, 736 Cambridge
St, Boston, MA 02135. E-mail: nicolaos.madias@steward.org
 2016 by the National Kidney Foundation, Inc. Published by
Elsevier Inc. All rights reserved.
0272-6386
http://dx.doi.org/10.1053/j.ajkd.2016.04.023

Am J Kidney Dis. 2016;68(5):793-802 793


approaches are first described, highlighting differences
with substantial diagnostic and therapeutic implica-
tions. We then apply each approach to the same patient
presentation and conclude with our view about which
is the optimal approach.
CASE REPORT
Clinical History and Initial Laboratory Data
A 21-year-old man with type 1 diabetes mellitus and a 3-day
history of an upper respiratory infection and poor oral intake was
brought to the emergency department. On admission, he was
obtunded and had severe hyperpnea. Physical examination showed
supine blood pressure of 92/40 mm Hg, temperature of 38.2 C,
respirations of 22 breaths/min, clear lungs, and decreased skin
turgor.
Serum laboratory data on arrival were as follows: sodium, 127
mEq/L; potassium, 6.0 mEq/L; chloride, 94 mEq/L; total carbon
dioxide, 5 mEq/L; urea nitrogen, 60 mg/dL; creatinine, 3.2 mg/dL
(corresponding to estimated glomerular filtration rate of 26 mL/
min/1.73 m2 calculated by CKD-EPI [Chronic Kidney Disease
Epidemiology Collaboration] creatinine equation); glucose,
340 mg/dL; albumin, 2.0 g/dL; and inorganic phosphate, 3.4 mg/
dL. Arterial blood gas evaluation (on 2 L/min of oxygen) showed
pH 7.15; PaCO2, 12 mm Hg; PaO2, 96 mm Hg; and calculated bi-
carbonate concentration, 4 mEq/L.
Additional Investigations
Blood ketones (Acetest) were positive (1:4 dilution). Urine
ketones were 31. Serum lactate level was 1.9 mEq/L. Cultures of
blood and bronchial secretions showed no growth.
Diagnosis
The patient’s acid-base status at presentation was assessed as
follows: physiologic approach, high anion gap (AG) metabolic
acidosis; and physicochemical approach, strong ion gap (SIG)
acidosis, hypoalbuminemic alkalosis, and respiratory alkalosis.
Clinical Follow-up
The patient was treated with insulin, intravenous fluids, and
levofloxacin. Alkali was not administered. Four days following
admission, the patient was discharged home.
DISCUSSION
Box 1 summarizes the essential features of the
physiologic approach. This approach embraces the
concept of Brønsted16 and Lowry17 of acids as
hydrogen ion donors and bases as hydrogen ion ac-
ceptors. It views the acid-base status of the organism
as originating from the interaction of net hydrogen ion
balance (ie, influx minus efflux) with the available
body buffers.3,4,18-20 This concept allows simplifica-
tion of a complex biological system and enables easy
but rigorous assessment of the body’s acid-base sta-
tus. Based on the isohydric principle, measurement of
the 2 components of a single buffer system, the car-
bonic acid/bicarbonate pair, incorporates the contri-
bution of the nonbicarbonate buffers and allows
evaluation of acid-base status.1,3,4 Blood pH is
calculated from the Henderson equation, [H1] 5
24 3 PaCO2/[HCO32], which considers carbonic acid
794
Adrogué and Madias
Box 1. Physiologic Approach
1. Acids are H1 donors (AH / A2 1 H1) and bases are
H1 acceptors (A2 1 H1 / AH).
2. Acid-base status is determined by the interaction of net
H1 balance (influx minus efflux) with the available body
buffers (weak acid/conjugate base pairs).
3. Changes in [H1] are minimized by body buffers (acting
like bases to added acid and like acids to added base).
4. Measurement of the 2 components of a single buffer pair
incorporates the contribution of all other buffers and
allows assessment of acid-base status (isohydric
principle).
5. The H2CO3/HCO32 buffer pair is used for assessment of
acid-base status by applying the Henderson equation:
[H1] 5 24 3 PaCO2/[HCO32]
6. Four cardinal acid-base disorders are recognized and
expressed as primary changes in serum [HCO32] (meta-
bolic disorders) or PaCO2 (respiratory disorders).
7. Empirical observations have quantitated the secondary
responses to primary changes in serum [HCO 3 2] or
PaCO2.
8. Serum AG (AG 5 [Na1] – ([Cl2] 1 [HCO32]) comple-
ments the assessment of serum [HCO 32] (metabolic
component).
9. Changes in patient’s serum AG (DAG) are estimated by
comparing calculated serum AG to the average reference
value of the laboratory. The latter value must be adjusted
for the patient’s serum albumin concentration (subtract-
ing or adding 2.5 mEq/L for each 1 g/dL of serum albumin
below or above the average reference value of 4 g/dL,
respectively).
10. An elevated DAG, particularly if .5 mEq/L, points to the
presence of high AG metabolic acidosis. Examination of the
relationship between DAG and D[HCO32] (D/D) estimates
the degree to which retention of fixed acids is responsible
for the D [HCO 3 2] and assists in the identification of
coexisting acid-base disorders.
Abbreviations and definitions: AG, anion gap; [CI2], chloride
concentration; [H1], hydrogen ion concentration; H2CO3, car-
bonic acid; [HCO32], bicarbonate concentration; [Na1], sodium
concentration.
(ie, PaCO2, the respiratory component) and serum bi-
carbonate levels (the metabolic component; Table 1).
The carbonic acid/bicarbonate pair is used on ac-
count of its abundance and physiologic importance
and because both compounds are homeostatically
regulated.1,5 The standard blood gas analyzer mea-
sures pH and PCO2, from which serum bicarbonate
concentration is calculated. Verification of the derived
serum bicarbonate concentration is provided by
comparing its level with the measured total carbon
dioxide concentration in venous blood. Notably, a
majority of acid-base disorders are initially tracked by
practitioners based on abnormal venous total carbon
dioxide concentrations.
Four cardinal acid-base disorders are recognized by
the physiologic approach (Table 2).1,21-23 Metabolic
disorders are expressed as primary changes in serum bi-
carbonate concentrations, whereas respiratory disorders
are expressed as primary changes in PaCO2. Each primary
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Physiologic vs Physicochemical Approach to Assessing Acid-Base Status

Table 1. Assessment of the Metabolic Component of Acid-Base Status According to Different Approaches10

Approach Parameter Derivation Comments

Physiologic Serum Measured blood pH and PaCO2 The most reliable metabolic component of acid-base
[HCO32] status because its value depends on measured pH
and PCO2; assessment is aided by evaluation of
serum AG (corrected for serum Alb level)
Physiochemical SIDa [Strong cations] – [strong anions]: These 3 formulas, as well as additional variants, are
([Na+] + [K+]) – [Cl2] (simplest formula) currently in use; SIDa is equivalent to the plasma
([Na+] + [K+] + [Ca++] + [Mg++]) – ([Cl2] + buffer base of Singer and Hastings
[lactate2])
([Na+] + [K+]) – ([Cl2] + [lactate2] +
[other strong anions])

SIDe [HCO32] + [Alb2] + [Pi2], where: Represents the sum of plasma [HCO32] and non-
[Alb ] 5 [Alb, g/L] 3 [(0.123 3 pH) – 0.631]
2
HCO32 buffers (anionic equivalency of Alb and
[Pi2] 5 [Pi, mmol/L] 3 [(0.309 3 pH) – 0.469] phosphate)
SIG SIDa – SIDe An estimate of increased organic anions in serum;
it resembles the excess AG obtained as the
difference between observed AG and the average
reference value corrected for serum Alb level
ATot 2.7 3 [Alb2, g/dL] + 0.6 3 [Pi, mg/dL] Primarily related to Alb concentration
Abbreviations and definitions: ATot, total concentration of serum weak acids; AG, anion gap; Alb, albumin; [Ca11], calcium con-
centration; [Cl2], chloride concentration; [H1], hydrogen ion concentration; [HCO32], bicarbonate concentration; [K1], potassium ion
concentration; [Mg11], magnesium ion concentration; [Na1], sodium ion concentration; Pi, inorganic phosphate; SIDa, apparent strong
ion difference; SIDe, effective strong ion difference; SIG, strong ion gap.

change in either serum bicarbonate concentration or
PaCO2 causes a secondary response in the other, and this
tends to attenuate acidity changes.1,21 These secondary
responses have been empirically quantitated in animals
and humans.24-34 A simple disorder is expressed as a
primary change in serum bicarbonate concentration or
PaCO2 accompanied by the appropriate secondary
response in the countervailing variable. Lack of an
appropriate secondary response indicates the coexistence
of another simple acid-base disorder. A mixed acid-base
disorder is defined by the coexistence of 2 or more simple
acid-base disorders.1
Interpretation of the metabolic component is sup-
plemented by assessing serum AG, calculated with
[Na1] 2 ([Cl2] 1 [TCO2]), where [TCO2] is total
carbon dioxide concentration, with all variables being
measured in venous blood (Table 1; Fig 1).35 Refer-
ence values for serum AG vary among laboratories
due to methodologic variation (primarily involving
chloride measurement).35 Typically, w75% of serum
AG is determined by serum albumin concentration.35-37
Abnormalities in the patient’s serum AG (DAG) are
estimated by comparing the calculated AG to the
average reference value of the laboratory, for which
the level must be adjusted for the patient’s serum
albumin concentration (Box 1). Box 2 illustrates a
systematic analysis of acid-base disorders according
to the physiologic approach.
The physiologic approach is simple regarding data
acquisition and clinical application. It couples the
chemistry of acids and bases with their physiology
and pathophysiology. Major focus is placed on the
physiologic regulation of the determinants of acidity
and the secondary responses to primary changes in
either PaCO2 or serum bicarbonate concentration.
Though PCO2 is viewed as a suitable indicator of the
respiratory component, serum bicarbonate concentra-
tion has been considered by some as inappropriate to
represent the metabolic component.38,39 Two main
criticisms have been raised in support of that position.
First, it has been emphasized that serum bicarbonate
concentration lacks independence from the respiratory
component. Certainly, serum bicarbonate concentra-
tion is affected by changes in PCO2 and vice versa
because bicarbonate and carbonic acid are the com-
ponents of a single buffer pair.1,5,15 Furthermore, long-
term alterations in PCO2 change renal acidification
mechanisms, thereby decreasing serum bicarbonate
concentration in chronic hypocapnia and increasing it
in chronic hypercapnia.20,24,25,40-42 Conversely, alter-
ations in serum bicarbonate concentration modify
alveolar ventilation and lead to changes in PCO2
(hypocapnia in metabolic acidosis and hypercapnia in
metabolic alkalosis). However, the strong interde-
pendency of PCO2 and serum bicarbonate concentra-
tion does not diminish the rigor of the physiologic
approach because the secondary responses of one
variable to shifts in the other have been empirically
quantitated for each disorder and are a key component
of assessing acid-base status (Table 2).

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 Adrogué and Madias

Table 2. Classification of Acid-Base Disorders According to Different Approaches

Disorder Physiologic Approach Physicochemical Approach

Metabolic acidosis Primary decrease in [HCO32] 2 types: primary decrease in SIDe or primary
increase in ATot
Secondary response DPaCO2/D[HCO32] 5 1.2 mm Hg decrease/ Not evaluated
mEq/L decrease
AG AG adjusted for serum [Alb] Not evaluated
Normal AG acidosis (hyperchloremic SID acidosis where SIG 5 0 (decrease in
acidosis) SIDa 5 decrease in SIDe); equivalent to
hyperchloremic acidosis
High AG acidosis (normochloremic acidosis) SIG acidosis where SIG is increased
(unchanged SIDa and decreased SIDe);
equivalent to normochloremic acidosis
Effect of [Alb] on acid-base status Not recognized Primary increase in ATot (hyperalbuminemic
acidosis)

Metabolic alkalosis
Secondary response
Effect of [Alb] on acid-base status
Primary increase in [HCO32] 2 types: primary increase in SIDa and SIDe
or primary decrease in ATot
DPaCO2 /D[HCO32] 5 0.7 mm Hg increase/ Not evaluated
mEq/L increase
Not recognized Primary decrease in ATot (hypoalbuminemic
alkalosis)

Respiratory acidosis Primary increase in PaCO2 Primary increase in PaCO2

Secondary response D[HCO32]/DPaCO2 5 Not evaluated
0.1 mEq/L increase/mm Hg increase
(acute)
0.35 mEq/L increase/mm Hg increase
(chronic)

Respiratory alkalosis Primary decrease in PaCO2 Primary decrease in PaCO2

Secondary response D[HCO32]/DPaCO2 5 Not evaluated
0.2 mEq/L decrease/mm Hg decrease
(acute)
0.4 mEq/L decrease/mm Hg decrease
(chronic)
Abbreviations and definitions: AG, anion gap; [Alb], albumin concentration; ATot, total concentration of serum weak acids; [HCO32]
bicarbonate concentration; SIDa, apparent strong ion difference; SIDe, effective strong ion difference; SIG, strong ion gap.
Adapted from Adrogué et al10 with permission of the International Society of Nephrology.

The second criticism is that the physiologic
approach fails to quantitate nonbicarbonate buffers.
Although true, this drawback, like the previous one,
does not impair the diagnostic process because serum
bicarbonate concentration always acts as surrogate
indicator of the status of the nonbicarbonate buffers,
as stipulated by the isohydric principle. Also, this lack
of quantitation does not adversely affect the manage-
ment of patients because the apparent bicarbonate
space, used to calculate acid or alkali replacement in
acid-base disorders, incorporates the contribution of
nonbicarbonate buffers.43-45 Disorders of acid-base
equilibrium elicit changes in the apparent bicarbon-
ate space that have been empirically quantitated and
incorporate the involvement of the nonbicarbonate
buffers.43
An additional criticism of the physiologic approach
centers on its assessment of the metabolic component by
evaluating serum AG. Because the negative charge of
serum albumin accounts for a large fraction of the AG,
failure to adjust this parameter for the patient’s albumin
concentration can lead to serious misinterpretation of
the metabolic component. The role of net anionic
equivalency of albumin was originally recognized by
Van Slyke46 and subsequently emphasized by
others.36,37,47 However, practitioners of the physiologic
approach ignored for decades the importance of
adjusting serum AG for changes in serum albumin level.
Box 3 summarizes the essential features of the
physicochemical approach, which differ fundamentally
from the physiologic approach. Stewart applied physi-
cochemical principles, including mass conservation and
charge balance, to the examination of the dissociation of
water in a beaker, including its interaction with carbon
dioxide and solutes dissociating in solution.11-14,48-53
He found that the dissociation of water, and
consequently the hydrogen ion concentration, is deter-
mined by the relationship among 3 independent
variables responsible for all acid-base effects in the so-
lution: the strong ion difference (SID), for which strong
ions are defined as ions fully dissociated at the pH of
body fluids; the total concentration of weak acids (ATot),

796 Am J Kidney Dis. 2016;68(5):793-802

Physiologic vs Physicochemical Approach to Assessing Acid-Base Status

Figure 1. Schematic depiction of serum cations and anions in normal acid-base status, high anion gap (AG; normochloremic)
metabolic acidosis or strong ion gap (SIG) acidosis, and normal AG (hyperchloremic) metabolic acidosis or strong ion difference
(SID) acidosis. The numbers associated with ions are concentrations in mEq/L. Abbreviations: SIDa, apparent SID; SIDe, effective
SID. Reproduced from Adrogué et al10 with permission of the International Society of Nephrology.

including proteins and phosphate; and PCO2.11-13 The
SID is computed as the sum of concentrations of the
strong cations (sodium, potassium, calcium, and mag-
nesium) minus the sum of concentrations of the strong
anions (chloride, sulfate, and anions of organic acids).
Sodium and chloride concentrations are the primary
determinants of SID because of their magnitude.
Stewart established a group of 6 equations that when
solved simultaneously, derive a fourth-order equation
that in turn yields the hydrogen ion concentration of the
solution.11-14 The calculated value is equivalent to that
measured by a pH electrode.
In the physicochemical approach, both hydrogen ion
and bicarbonate concentrations are considered depen-
dent variables, with the 3 independent variables
exclusively determining their values.14,15 From the
acid-base perspective, bicarbonate is considered a
variable that basically contributes to filling the gap
between strong cations and strong anions.11 Acid-base
disorders are evaluated by using SID and ATot (jointly
representing the metabolic component) and PCO2 (the
respiratory component).
As clinically applied, the physicochemical approach
measures blood pH and PCO2 and computes the 2
formulations of SID (apparent SID [SIDa] and effective
SID [SIDe]) and ATot from the corresponding measured
variables in the blood sample. The parameters of the
metabolic component according to the physicochemical
approach are defined in Box 3 and Table 1.
Six acid-base disorders are recognized by the phys-
icochemical approach; these reflect primary deviations
in each of the 3 independent variables (Table 2).
Abnormal SIDe or ATot levels flag the existence of
metabolic acid-base disorders. A low SIDe level sug-
gests metabolic acidosis (SID acidosis) and a high SIDe
level indicates metabolic alkalosis (SID alkalosis). A
low SIDe metabolic acidosis can feature a high SIG (eg,
lactic acidosis) or a normal (ie, zero) SIG (eg, diarrhea;
Fig 1). A high ATot suggests metabolic acidosis
(hyperalbuminemic acidosis) and a low ATot indicates
metabolic alkalosis (hypoalbuminemic alkalosis).54-58
Increases in PCO2 are synonymous with respiratory
acidosis and decreases in PCO2 indicate respiratory
alkalosis. Quantitative measures of the secondary re-
sponses to primary changes in SIDe, ATot, and PCO2 are
not defined.
The physicochemical approach offers a compre-
hensive analysis of acid-base chemistry in complex

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Box 2. Systematic Analysis of Acid-Base Disorders According to
the Physiologic Approach
1. Secure reliable measurement of acid-base variables in
the blood (an exercise in chemistry)
A. Obtain a suitable blood sample and process it
appropriately
B. Obtain reliable measurement of acid-base variables in
the blood sample
C. Assess the internal consistency of the acid-base data
(Henderson equation)
2. Ensure proper interpretation of the acid-base data (an
exercise in pathophysiology)
A. Identify the dominant acid-base disorder
B. Calculate serum AG: [Na1] 2 ([Cl2] 1 [HCO32])
C. Estimate the DAG after correcting the average refer-
ence AG for the prevailing hypoalbuminemia, if any
D. If the DAG is positive (ie, excess AG), evaluate the
relationship of the DAG and the reduction in serum
[HCO32], the so-called D/D (ie, DAG/DHCO32)
E. Assess the secondary response to the primary acid-
base disorder
F. Evaluate whether the disorder is a simple or mixed
acid-base disorder
3. Identify the cause of the acid-base disorder (an exercise
in clinical medicine)
A. Obtain clinical information, including detailed history
and physical examination
B. Obtain additional blood testing, as applicable (eg,
ketones, lactate, methanol)
C. Calculate serum osmolal gap, as needed (eg, toxic
exposure is suspected)
D. Measure urine chemistries, as needed (eg, pH and [Cl2]
if metabolic alkalosis is suspected)
E. Calculate urine AG, as needed (eg, renal tubular
acidosis is suspected)
F. Calculate urine osmolal gap, as needed (eg, toxic
exposure is suspected)
G. Obtain appropriate imaging, as required
H. Genetic testing, as appropriate
Abbreviations and definitions: AG, anion gap; [Cl2], chloride
concentration; [HCO32], bicarbonate concentration; [Na1],
sodium ion concentration.
biological solutions.59,60 Measurements of this
approach allow computation of the variables central to
this analysis. Even serum bicarbonate concentration,
the metabolic component of the physiologic
approach, is calculated (from measured blood pH and
PCO2) for computation of SIDe, although not used
directly in the analysis. The SIG estimates excess
unmeasured anions in a way that excludes the
contribution of albumin and phosphate. Conse-
quently, no need for an adjustment is required in
contrast to the physiologic approach, in which AG
must be adjusted for abnormalities in serum albumin
concentration.
The physicochemical approach is rooted solely in
chemistry. Its mathematic precision in a beaker
does not definitely establish proposed cause-and-effect
relationships of acid-base variables in the intact organ-
ism.10,59,60 It is presumptuous to assert that SID and
798
Adrogué and Madias
Box 3. Physicochemical Approach
1. The acid-base status of body fluids is determined by
changes in the dissociation of water, KW 5 [H1] [OH2]/H2O,
which are driven by the interplay of 3 independent variables:
PCO2, nonvolatile weak acids, and strong ions (ions fully
dissociated). The independent variables mechanistically
determine both [H1] and [HCO32] of body fluids, which are
considered dependent variables.
2. Nonvolatile weak acids, including albumin and phosphate,
are assessed by ATot. For clinical purposes, computation
of ATot requires measurement of serum total protein or
albumin and use of a formula (Table 1). Average refer-
ence value is 15 mEq/L.
3. The impact of strong ions is assessed by 2 formulations of
the SID: the SIDa and the SIDe.
4. SIDa represents the sum of strong cation concentrations
minus the sum of strong anion concentrations; its simplest
formulation is [Na1] 1 [K1] 2 [Cl2]. Normally, it equals 40
mEq/L.
5. SIDe is the sum of [HCO32] and the anionic equivalency
of albumin and phosphate. It is estimated using a formula
(Table 1) or a nomogram from blood pH, PCO2, and serum
albumin and phosphate concentrations. Normally, SIDe
equals SIDa.
6. The SIG is computed as SIDa – SIDe. Normally, SIG
equals zero. An elevated SIG reflects accumulation of
organic anions and is an indicator analogous to excess
AG.
7. Six cardinal acid-base disorders are recognized that
reflect primary changes in SIDe or ATot (metabolic disor-
ders) or PaCO2 (respiratory disorders).
Abbreviations and definitions: AG, anion gap; ATot, total con-
centration of weak acids; [Cl2], chloride concentration; [H1],
hydrogen ion concentration; [HCO32], bicarbonate concentra-
tion; [K1], potassium ion concentration; [Na1], sodium ion con-
centration; SID, strong ion difference; SIDa, apparent SID; SIDe,
effective SID; SIG, strong ion gap.
ATot mechanistically determine serum bicarbonate
concentration and pH at the physiologic level. There is
no experimental basis for such a cause-and-effect rela-
tionship.10,59 Changes in SID could be mere conse-
quences of acid-base disturbances rather than their
mechanistic drivers. The view that serum bicarbonate
concentration is an irrelevant anion for acid-base eval-
uation strikes us as unreasonable. It is incongruous to the
massive body of evidence regarding regulated transport
processes of hydrogen ion and bicarbonate in epithelial
and nonepithelial tissues. Lack of definition and of
empirical quantitation of the secondary responses to
primary changes in SIDe, ATot, and PCO2 values is an
additional fundamental drawback of the physicochem-
ical approach that undermines the diagnosis and man-
agement of acid-base disorders.10
Furthermore, clinical application of the physico-
chemical approach necessitates measurements of
several ions and the use of computer programs (Table 1).
SID is unwieldy to interpret because its 2 formulations,
SIDa and SIDe, have distinct connotations. Different
sets of electrolytes are being used to define SIDa, each
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Physiologic vs Physicochemical Approach to Assessing Acid-Base Status

set establishing a substantially different reference value Table 3. Case Presentation: Select Laboratory Data
(Table 1). In contrast to serum bicarbonate concentra-
Parameter Value Reference
tion, there is uncertainty about the reliability of SIDa,
SIDe, and ATot values because many measurements and Measured Values
calculations integrating numerous assumptions are pH 7.15 7.40
required for their determination.10,60 Limited data sug- PaCO2, mm Hg 12 40
gest that SIG is a better predictor of mortality in critically [HCO32], mEq/L 4 24
ill patients than serum lactate, AG, or blood base excess [Na1], mEq/L 127 140
[K1], mEq/L 6.0 4.0
values.61,62 However, most studies do not support a [Cl2], mEq/L 94 104
diagnostic or prognostic benefit of the physicochemical [TCO2], mEq/L 5 26
approach over the physiologic approach in such [Albumin], g/dL 2.0 4.0
patients.63,64 [Pi], mg/dL 3.4 3.7
Finally, the definition of metabolic acid-base dis- Derived Parameters
orders is overly complicated. Note that metabolic AG, mEq/L 28 10 mEq/L (if [albumin] 5
acidosis can be linked with normal SIDa, low SIDa, 4.0 g/dL); 5 mEq/L
normal SIG, high SIG, or high ATot values (Table 2). (if [albumin] 5 2.0 g/dL)
DAG, mEq/L 23a
Beyond complexity, we believe that ATot acidosis SIDa, mEq/L 39 40
(hyperalbuminemic acidosis) and ATot alkalosis SIDe, mEq/L 11 40
(hypoalbuminemic alkalosis) are unproven entities.10 SIG, mEq/L 28 0
Proponents of this approach defend their position by ATot, mEq/L 7 15
considering albumin as an “acid” anion. Although Note: Conversion factor for Pi in mg/dL to mmol/L, 30.3229.
observations in a beaker show that alterations in al- Abbreviations and definitions: AG, anion gap; ATot, total con-
bumin concentration can affect acidity, we know of centration of serum weak acids; [Cl2], chloride concentration;
[HCO32] bicarbonate concentration; [K1], potassium ion con-
no credible demonstration that the living organism, centration; [Na1], sodium ion concentration; Pi, inorganic phos-
and especially the liver, regulates albumin to preserve phate; SIDa, apparent strong ion difference; SIDe, effective
acid-base homeostasis. In vivo, there is no correlation strong ion difference; SIG, strong ion gap; [TCO2], total carbon
between changes in serum albumin level and shifts in dioxide concentration.
a
PCO2 or pH.59 Absent recognizable causes of meta- Correction of the average reference value of the AG (10 mEq/L)
for the prevailing hypoalbuminemia yields a value of w5 mEq/L.
bolic alkalosis, the hypoalbuminemia of nephrotic Therefore, DAG equals 23 mEq/L (28 2 5).
syndrome or liver disease is not associated with this
acid-base disorder.65
Against this background, let us apply each of the as 65 mm Hg for PaCO2 and 63 mEq/L for serum
2 approaches to assessing acid-base status to the bicarbonate concentration from the values calculated
case report (Table 3). Turning first to the physio- from the steady-state slopes66; Table 2). Thus, the data
logic approach, the acid-base data conform to the are consistent with a single acid-base disorder, high
mathematic constraints of the Henderson equation. AG metabolic acidosis. Evaluation of the patient’s
The serum bicarbonate concentration of 4 mEq/L history, physical examination, and additional labora-
and blood pH of 7.15 indicate that metabolic tory tests (hyperglycemia, ketonemia, and ketonuria)
acidosis is the dominant acid-base disorder. The establish the cause of the high AG metabolic acidosis
serum AG equals 28 mEq/L. Correction of the as diabetic ketoacidosis (Box 2).
average reference value of the AG (10 mEq/L) for Applying the physicochemical approach to the case
the prevailing hypoalbuminemia yields a value of report, the decreased SIDe of 11 mEq/L (average
w5 mEq/L. Therefore, the estimated DAG (ie, reference value, 40 mEq/L) is diagnostic of metabolic
excess AG) equals 23 mEq/L (28 2 5), indicating acidosis. The SIDa is normal at 39 mEq/L. Therefore,
the accumulation of a large excess of unmeasured the SIG (SIDa – SIDe) is elevated at 28 mEq/L
anions in serum. Note that the D[HCO32] of 20 (39 – 11), indicating that the metabolic acidosis rep-
mEq/L (24 2 4) approximates the DAG of 23 mEq/ resents accumulation of organic anions. Reflecting the
L, indicating that retention of anions of fixed acids low serum albumin concentration, the decreased ATot
fully accounts for the bicarbonate deficit. For a of 7 mEq/L (average reference value, 15 mEq/L) sig-
decrement in bicarbonate concentration of 20 mEq/L, nifies the presence of weak-acid alkalosis (hypo-
the expected reduction in PaCO2 is 24 mm Hg (1.2 3 albuminemic alkalosis). The observed PaCO2 of
20, Table 2), which predicts a PaCO2 of 16 mm Hg 12 mm Hg points to the presence of respiratory
(40 2 24); therefore, the patient’s PaCO2 of 12 mm Hg alkalosis. Thus, the data are consistent with a mixed
signifies an appropriate secondary response to the acid-base disorder composed of 3 disorders (SIG
prevailing metabolic acidosis (in clinical practice, acidosis, hypoalbuminemic alkalosis, and respiratory
the limits of the secondary responses can be taken alkalosis).

Am J Kidney Dis. 2016;68(5):793-802 799


Box 4. Key Teaching Points
1. Both the physiologic and physicochemical approaches
are mathematically sound.
2. The physicochemical approach is anchored exclusively in
chemistry, whereas the physiologic approach fulfills both the
chemical and pathophysiologic tasks for acid-base diagnosis;
only the latter approach is supported by substantial empirical
observations.
3. The physicochemical approach requires multiple laboratory
measurements and computations; however, its increased
complexity does not offer a diagnostic or prognostic
advantage.
4. The contention of the physicochemical approach that the
“independent variables” are responsible for controlling acid-
base status (cause and effect relationship) is presumptuous
and disregards the long list of regulated epithelial and
nonepithelial hydrogen ion and bicarbonate transport
processes.
5. By precisely quantitating the dominant buffer pair of body
fluids, the physiologic approach represents the most rigorous,
straightforward, and usable approach to evaluating acid-base
status.
Assessing the patient’s acid-base status as high AG
metabolic acidosis (single disorder) according to the
physiologic approach is relatively simple and
straightforward; identifying the cause as diabetic
ketoacidosis prompts the physician to focus man-
agement on insulin and fluid therapy. By contrast,
identification of 3 acid-base disorders according to the
physicochemical approach creates diagnostic and
therapeutic uncertainty for the treating physician. The
cause of the SIG acidosis is clearly diabetic ketoaci-
dosis, which requires reversal. But is hypo-
albuminemic alkalosis (a condition for which
existence remains unsupported by in vivo observa-
tions) protective from the acid-base viewpoint?
Should therapy include albumin administration as the
organic acidosis is being reversed? Is the level of
PaCO2 appropriate for the coexisting SIG acidosis and
hypoalbuminemic alkalosis, or does it also reflect a
primary respiratory disorder? We suggest that
research should be conducted on the potential clinical
implications of the divergence in diagnosis between
the 2 approaches.
In conclusion, both the physiologic and physico-
chemical approaches are mathematically precise.
However, only the physiologic approach effectively
conjoins acid-base chemistry with acid-base physi-
ology and pathophysiology. The physicochemical
approach has a number of fundamental drawbacks
and its clinical application is complex, impractical,
and at times misleading. We contend that the time-
tested and most widely used physiologic approach
stands as the optimal approach to assessing acid-base
status. Key teaching points of the case are listed in
Box 4.
800
Adrogué and Madias
ACKNOWLEDGEMENTS
Support: None.
Financial Disclosure: The authors declare that they have no
relevant financial interests.
Peer Review: Evaluated by 3 external peer reviewers, the
Deputy Editor, the Education Editor, and the Editor-in-Chief.
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