Comparative Quantitative Acid Base Analysis in Coronary Artery Bypass, Severe Sepsis, and Diabetic Ketoacidosis

Journal of Intensive Care Medicine
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Comparative Quantitative Acid-Base Analysis in Coronary Artery Bypass, Severe Sepsis, and Diabetic
Ketoacidosis
Edward M. Omron
J Intensive Care Med 2005; 20; 269
DOI: 10.1177/0885066605279955

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REVIEW OF A LARGE CLINICAL SERIES

Comparative Quantitative Acid-Base Analysis
in Coronary Artery Bypass, Severe Sepsis, and
Diabetic Ketoacidosis
Edward M. Omron, MD, MPH, FCCP

altered in multiple disease states. Separation of the
The main objective of this study was to assess the rela- metabolic versus the respiratory components has
tionship of standard base excess (SBE) to delta strong ion
difference effective ( SIDe) in critical illness. Critical ill-
been attempted using derived parameters such
ness is characterized by variable plasma nonvolatile weak as [HCO3–], anion gap, confidence intervals, and
acid components ( A–), and SBE becomes discordant with base excess derivatives [1]. All of these approaches
SIDe. The author hypothesized that both acid-base mod- assume a normal plasma nonvolatile weak acid
els are equivalent when SBE and SIDe are corrected for buffer content (albumin and inorganic phosphate).
A–. A retrospective chart review was performed to assess
this hypothesis by looking at changes in SBE, SIDe, and
This assumption originates from the first clinical
A– in 30 coronary artery bypass graft surgery patients, studies of metabolic acid-base status [2–5]. It is now
30 severe sepsis patients, and 15 diabetic ketoacidosis realized that the main plasma weak-acid buffers are
patients. SBE equals the sum of the SIDe and A–. The albumin and inorganic phosphate and that major
SBE quantifies the magnitude of the metabolic acid-base surgery and acute illness result in large fluctuations
derangement, the SIDe quantifies the plasma strong cat-
ion/anion imbalance, and the A– quantifies the magnitude
of albumin concentration [6,7].
of the hypoalbuminemic alkalosis. The partitioning of SBE Both standard base excess (SBE) and physico-
into physicochemical components can facilitate analyses chemical analysis are quantitative measures of
of complex acid-base disorders in critical illness. metabolic acid-base status. Physicochemical analy-
sis introduces strong ion difference effective (SIDe)
Key words: acidosis, alkalosis, anion gap, buffers, hypoalbu-
as a measure of plasma cation/anion imbalance and
minemia
incorporates the variable plasma nonvolatile weak
acid buffer content ( A–) [8–12]. In contrast, SBE
measurement assumes a normal plasma nonvolatile
Accurate assessment of metabolic acid-base status
weak acid buffer content [5]. At normal plasma
is of critical importance in the intensive care unit.
weak acid buffer concentrations (albumin, phos-
Hydrogen ion concentration and PaCO2 form the
phate), a change in SBE must always be accom-
traditional front line of investigation during initial
panied by an equal change in SIDe ( SIDe), and
assessment and are the key physiologic parameters
thus both parameters are equivalent quantitative
measures of metabolic acid-base status in this spe-
From the Division of Pulmonary Medicine, National Naval cial circumstance [6,13]. Critical illness, however, is
Medical Center, Bethesda, MD.
characterized by variable plasma nonvolatile weak
Received Oct 13, 2004, and in revised form Mar 30, 2005. acid components ( A–), and thus a change in SBE
Accepted for publication Jun 9, 2005.
no longer correlates with a change in SIDe, and
Address correspondence to Edward M. Omron, MD, MPH,
Pulmonary and Critical Care Specialists, P.C., 39650 Orchard Hill which parameter is the better measure of acid-base
Place, Suite 100, Novi, MI 48375-5331, or e-mail: edwardom- derangements is the focus of debate [6,13–15].
ron@hotmail.com. Physicochemical analysis allows direct calculation
The opinion or assertions contained herein are the private of A–, and the author hypothesized that equiva-
views of the author and are not construed as official or as
reflecting the views of the Department of the Navy, Army or lence between both acid-base models would again
the Department of Defense. be restored if SBE and SIDe were corrected for
I gratefully acknowledge the kind assistance of Kevin M. A–. Restoration of equivalence between both acid-
O’Neil, MD; Thomas M. Fitzpatrick, MD, PhD; Russell C. base models at variable plasma nonvolatile weak
Gilbert, MD; and Rodney M. Omron, MD, MPH, for insightful
discussions in the preparation of this manuscript.
acid concentrations would prove useful by allowing
Omron EM. Comparative quantitative acid-base analysis in
SBE to be partitioned into physicochemical com-
coronary artery bypass, severe sepsis, and diabetic ketoacido- ponents and thus facilitate analyses of metabolic
sis. J Intensive Care Med. 2005;20:269-278. acid-base disorders. To assess the hypothesis that
DOI: 10.1177/0885066605279955 SBE equals the algebraic sum of SIDe and A– at

Copyright © 2005 Sage Publications
269

Omron

variable plasma nonvolatile weak acid buffer con- [Mg2+], and [Ca2+] in mEq/L—can be found in the
centrations, the author performed a retrospective appendix.
chart review looking at changes in SBE, SIDe, Descriptive statistics and formula calculations
and A– in three critically ill groups: pre- and post- were performed using Microsoft Excel 97 Data
coronary artery bypass graft (CABG) surgery, severe Analysis Package (Microsoft, Redmond, Wa). Statis-
sepsis, and diabetic ketoacidosis (DKA) patients on tical analysis consisted of the two-tailed Student’s
admission and during recovery. t test for equal and unequal variances for direct
comparisons between study variables and linear
regression. Statistical significance was achieved if
Materials and Methods the two-tailed P value was <.05. Logistic regression
analysis was performed using JMP release 5.1 (SAS
The medical records of 30 consecutive nonemer- Institute, Cary, NC). Paired data were analyzed
gent CABG surgery, 30 severe sepsis, and 15 DKA graphically by Bland-Altman analysis [19]. In this
patients who presented to Walter Reed Army analysis, the mean difference between the paired
Medical Center surgical and medical intensive care measurements is plotted against the average of the
units were reviewed. CABG patients had labora- two values to visually display bias and precision.
tory values drawn immediately before surgery and Data are expressed as the mean 95% confidence
then again after presentation to the surgical inten- interval (CI).
The Department of Clinical Investigation at Walter
sive care unit per cardiothoracic surgery protocol.
Reed Army Medical Center approved this study.
Severe sepsis and DKA patients had laboratory
values drawn on presentation to the intensive care
unit. Severe sepsis was established by published
criteria [16,17]. The diagnosis of DKA was based on Review of Models
the classic criteria of positive serum acetone and
urinary ketones, hyperglycemia, and an anion gap
Standard Base Excess. The base excess (BE) of
metabolic acidosis.
whole blood equals the quantity of strong acid or
Patient data, including age, admission diagnosis,
base (mmol/L or mEq/L) needed to restore plasma
sex, and laboratory values, were collected by retro-
pH to 7.4 at a PaCO2 equilibrated to 40 mm Hg at a
spective chart review. Laboratory samples were col-
temperature of 37°C. A positive value indicates an
lected from an indwelling arterial line and handled
excess of base, whereas a negative value indicates
according to standardized hospital protocols. Labo- an excess of fixed acid.
ratory values recorded include [Na+], [K+], [Mg2+], The normal buffer base of blood is the sum of
[Ca2+], [Cl–], creatinine, lactate, albumin, inorganic the buffer anions of the blood and plasma ([HCO3–],
phosphate, serum acetone, pH, PaCO2, and urinaly- hemoglobin, and total protein) at a pH of 7.4 and
sis to assess for ketonuria. Samples were analyzed PaCO2 of 40 mm Hg, at a hemoglobin concentration
by clinical staff at the hospital central laboratory of 15 g/dL and fixed total protein = 7.2 g/dL. The
by the Vitros Chemistry System (Ortho-clinical buffer base (BB) of blood is normally 48 mEq/L,
diagnostics, Johnson and Johnson, Rochester, NY) and changes in the BB quantify the metabolic com-
and the Rapilab 865 Blood Gas Analyzer System ponent of an acid-base disorder. The buffer base
(Bayer, Tarrytown, NY). The Vitros chemistry will vary with changing hemoglobin concentration
system uses both direct and indirect ion-selective and is related to the BE (in vitro or whole blood)
methodologies for measurement. Cardiorespiratory, as follows: BE = BB (measured) – 48 [4,5,20]. In
laboratory, and neurologic data were extracted this model, a constant plasma nonvolatile weak
to determine the Acute Physiology and Chronic acid buffer total (albumin, inorganic phosphate)
Health Evaluation (APACHE II) [18] score in the is assumed. In vitro, BE remains constant as PaCO2
severe sepsis group. is varied. In vivo, however, this linear relationship
Equations used for calculation of derived param- is not preserved [21,22]. Acute changes in PaCO2
eters—strong ion difference effective (SIDe), delta induce a redistribution of strong ions not only
strong ion difference effective ( SIDe), strong ion within the blood but also throughout the extracel-
difference apparent (SIDa), strong ion gap (SIG), lular fluid compartment as compensation, indepen-
standard base excess (SBE), actual bicarbonate dent of renal mechanisms, skewing the base excess
[HCO3–]HH, plasma nonvolatile weak acid buffer nomogram. Empirical observations in the 1960s
content (A–), plasma nonvolatile weak acid buf- revealed that this buffering effect in vivo could be
fer deficit ( A–), anion gap (ANG), adjusted ANG, corrected for if the blood sample is diluted three-

270 Journal of Intensive Care Medicine 20(6); 2005


fold with plasma or by setting the hemoglobin anions or cations are collectively termed the strong
equal to 5 g/dL. This modified in vitro base excess ion gap (SIG) and are codeterminants of the strong
was designated as standard base excess (SBE) or ion difference. The strong ion gap is calculated as
BE extracellular fluid and is conventionally calcu- SIG = SIDa – SIDe and quantitatively reflects the
lated as Equation 5 in the appendix [23]. SBE is a unmeasured acid component of a metabolic acid-
quantitative estimate of the magnitude of a meta- base disorder [12]. The SIG is normally <6 mEq/L. It
bolic acid-base derangement in vivo with respect to is independent of changes in [albumin–] or pH. The
the extracellular fluid compartment. anion gap (ANG) is akin to the SIG and is calcu-
lated from Equation 9 in the appendix [25]. Unlike
Physicochemical Analysis. In the physicochemical the SIG, the value of the ANG includes the negative
analysis model, there are 3 independent determi- charge component of the albumin moiety and is
nants of hydrogen and bicarbonate ion concen- profoundly affected by albumin and hydrogen ion
tration within the plasma compartment in vivo: concentration [26]. An adjusted ANG is calculated
PaCO2, the SID, and total concentration of plasma according to equation 10 in the appendix, which
nonvolatile weak acid buffers [24]. The SID consists corrects for hypoalbuminemia [27].
of 2 components, the strong ion difference effective The total concentration of plasma nonvolatile
and apparent. The strong ion difference effective weak acid buffers is composed of [albumin–] and
(SIDe) is the net electrical charge difference of the inorganic phosphate ([PI]) and consists of the
plasma strong cations minus the strong anions and disassociated (A–) and undisassociated (HA) com-
is in charge balance with the plasma buffer base. ponents. Normal baseline in plasma is set to [albu-
Strong electrolytes are completely dissociated and min–] = 4.4 g/dL, and [PI] = 3.6 mg/dL. The focus of
chemically nonreacting. The plasma buffer base
this analysis is on the disassociated component, A–,
consists of both the volatile ([HCO3–]) and non-
which reflects the net charge (mEq/L) of both albu-
volatile (albumin and inorganic phosphate) weak
min and inorganic phosphate and is derived from
acid buffers within the plasma compartment. This
Equation 7 in the appendix [12]. The nonvolatile
differs from the SBE buffer base in several respects:
weak acid buffer deficit ( A–) reflects alterations
Hemoglobin is not considered a plasma buffer
in the concentrations of albumin and phosphate
and is not included in the calculation, the analysis
from normal baseline, consequent to surgery or
is limited to the plasma compartment versus the
acute illness, and is derived from equation 8 in the
extracellular fluid compartment, and the equations
appendix. Note that A– is expressed as a positive
are not empirical but are derived from the laws of
quantity because a decrement in plasma nonvola-
electrical neutrality, conservation of mass, and dis-
tile weak acid content is equal to a gain in base.
sociation equilibria.
Deviation from the normal SIDe value of 39 mEq/
L reflects the magnitude of the strong cation/anion
imbalance and metabolic acid-base derangement Results
in vivo in the plasma compartment. SIDe is calcu-
lated from Equation 1 in the appendix [12]. In the In the 30 CABG patients (Table 1), mean values
base excess format for direct comparison of SBE ( 95% CI) were age = 63 4 years, and time
with SIDe, the delta strong ion difference effective between pre- and postsurgery measurements = 338
is calculated as SIDe = SIDe (measured) – 39. A 20 minutes. In presurgery CABG patients, the SBE
positive value indicates an excess of base or plasma was equivalent to the algebraic sum of the SIDe
strong cations, whereas a negative value indicates and A–. The difference between SIDe (–0.1
an excess of fixed acid or plasma strong anions. 0.08 mEq/L) and SBE (0.8 0.6 mEq/L) approached
The strong ion difference apparent (SIDa) is the statistical significance (P = .06), and the plasma
net electrical charge difference between the com- nonvolatile weak acid buffer content was mildly
monly measured strong cations minus the strong reduced ( A– = 1.0 0.5 mEq/L). The change in
anions in the plasma. The SIDa differs from SIDe in SBE presurgery (0.8 0.6 mEq/L) and postsurgery
that unmeasured anions or cations are not included (–1.0 0.5 mEq/L) was statistically significant (P <
in the calculation. The normal value for SIDa varies .001) but did not suggest the presence of a signifi-
from 42 to 44 mEq/L and is derived from equation cant metabolic acid-base disorder.
3 in the appendix [12]. In contrast, the changes in SIDe and A– presur-
In critical illness, unmeasured anions or cations gery (–0.1 0.8 mEq/L, 1.0 0.5 mEq/L) and post-
may appear (eg, ketone acids, anions of renal surgery (–7.4 0.8 mEq/L, 6.4 0.5 mEq/L) were
failure, cationic paraproteins, etc). These strong statistically significant (P < .001), which did suggest

Journal of Intensive Care Medicine 20(6); 2005
271

Omron

Table 1. Demographic and Clinical Laboratory Characteristics of the Study Groups
Coronary Artery Severe DKA
Bypass Graft Surgery (n = 30) Sepsis (n = 15) (n = 10) (n = 11)
Characteristic Presurgery Postsurgery (n = 30) Admission 12 Hours Resolution
Age (years) 63 4 61 4 34 11
Sex, M/F 21/9 17/13 6/9
Laboratory data
pH 7.43 0.02 7.41 0.03 7.35 0.03 7.15 0.11 7.26 0.08 7.37 0.04
PaCO2 (mm Hg) 38.5 1.1 37.9 3.1 32.5 2.4 19.4 5.0 25.7 8.6 33.0 3.7
[HCO3–]HH (mmol/L) 24.7 0.6 23.1 0.5 17.8 1.5 8.3 3.4 12.3 5.5 18.9 3.1
SIDe (mEq/L) –0.1 0.8 –7.4 0.8 –10.9 1.8 –17.9 3.4 –17.0 6.0 –10.1 3.0
SBE (mEq/L) 0.8 0.6 –1.0 0.5 –6.8 1.7 –18.6 4.5 –13.2 6.0 –5.5 3.3
SIDa (mEq/L) 43.8 0.7 33.4 0.7 37.5 2.3 43.1 3.9 32.8 4.6 35.0 3.0
SIDe (mEq/L) 38.9 0.8 31.6 0.8 28.1 1.8 21.1 3.4 22.0 6.0 28.9 3.1
Anion gap 16 1 9 1 18 2 31 5 17 3 12 2
Adjusted anion gap 17 1 14 1 22 2 32 3 20 2 16 2
SIG (mEq/L) 4.9 0.9 1.8 0.5 9.4 1.3 22.1 3.7 10.8 2.3 6.0 1.8
Lactate (mEq/L) 0.8 0.1 1.9 0.4 2.4 0.8 NA NA NA
Sodium (mEq/L) 143 1 136 1 138 2 140 4 142 6 142 4
Potassium (mEq/L) 4.1 0.2 3.7 0.1 4.2 0.3 4.3 0.4 3.5 0.4 3.7 0.2
Magnesium (mEq/L) 1.6 0.1 1.9 0.1 1.8 0.3 1.5 0.2 1.8 0.3 1.7 0.3
Calcium (mEq/L) 2.3 0.1 2.0 0.1 2.1 0.1 2.3 0.1 2.1 0.2 2.1 0.1
Chloride (mEq/L) 106 1 108 1 106 3 105 4 116 6 114 6
Albumin (g/dL) 4.0 0.2 2.4 0.2 2.8 0.3 4.2 0.5 3.2 0.3 3.1 0.4
Phosphorus (mg/dL) 3.7 0.2 2.4 0.2 4.2 0.6 4.3 1.0 2.0 0.7 2.1 0.4
A– (mEq/L) 13.6 0.5 8.1 0.4 10 0.7 12.7 1.4 9.4 1.3 9.7 1.0
A– (mEq/L) 1.0 0.5 6.4 0.5 4.1 0.7 0.2 1.6 4.2 1.1 4.6 1.0
Creatinine (mg/dL) NA 0.9 0.1 2.7 0.8 1.2 0.3 0.8 0.1 1.4 0.8
APACHE II NA NA 25 2.8 NA NA NA
A– – plasma nonvolatile weak acid buffer content; A– – plasma nonvolatile weak acid buffer deficit; DKA – diabetic ketoacidosis;
HCO3–HH – actual bicarbonate; M– male; F – female; NA – data not available; SBE – standard base excess; SIDe – delta strong ion dif-
ference effective; SIDa – strong ion difference apparent; SIDe – strong ion difference effective; SIG – strong ion gap; APACHE – Acute
Physiology and Chronic Health Evaluation. Data are expressed as mean 95% confidence interval.

the development of a marked metabolic acidosis mEq/L and SIDe = –10.9 1.8 mEq/L (P < .0001).
postoperatively with significant loss of plasma weak Plasma nonvolatile weak-acid buffer content was
acid buffer content, mostly from hypoalbuminemia decreased, A– = 4.1 0.7 mEq/L, mostly from
([albumin–]pre-CABG = 4.0 0.2, [albumin–]post-CABG = 2.4 hypoalbuminemia ([albumin–] = 2.8 0.3 g/dL).
0.2 g/dL). The SBE was equivalent to the sum of The SBE was equivalent to the sum of the SIDe
the SIDe and A– in post-CABG surgery patients. and A–. The SIG = 9.4 1.3 mEq/L and adjusted
There were marked changes in electrolytes post- ANG = 22 2 were elevated, indicating the presence
operatively with [Na+] decreasing, [Cl–] increasing, of significant unmeasured anions. The ANG = 18 2
and [albumin–] and inorganic phosphate decreasing was only marginally elevated. Univariate logistic
(Table 1). The SIG decreased postoperatively from regression analysis was performed between survi-
4.9 0.9 mEq/L to 1.8 0.6 mEq/L, indicating mini- vors and nonsurvivors in the severe sepsis patients.
mal presence of unmeasured anions or possibly the The adjusted ANG (odds ratio = 12.2, P = .17, area
presence of unmeasured/unidentified cations. The under receiver operating characteristic curve =
ANG and adjusted ANG decreased postoperatively 0.67) and SIG (odds ratio = 4.4, P = .4, area under
from 16 1 to 9 1 mmol/L and 17 1 to 14 1 receiver operating characteristic curve = 0.57) were
mmol/L, respectively. not significant predictors of mortality.
In the 30 severe sepsis patients (Table 1), age = In the 15 diabetic ketoacidosis patients (Table 1),
61 4 years, APACHE II score = 25 3, and over- age = 34 11 years. All patients were serum acetone
all mortality = 12/30 (40%). The pH = 7.35 0.03, and urine ketone positive with hyperglycemia,
the PaCO2 = 32.5 2.4 mm Hg, and the [HCO3–]HH = glucose = 436 75 mg/dL. Admission pH = 7.15
17.7 1.5 mmol/L indicated the presence of a 0.11, PaCO2 = 19.4 5.0 mm Hg, and [HCO3–]HH =
metabolic acidosis with acute respiratory compen- 8.3 3.4 mmol/L indicated the presence of a severe
sation. The magnitude of the metabolic acidosis metabolic acidosis with acute respiratory compensa-
was markedly disparate between SBE = –6.8 1.7 tion. Both SIDe = –17.9 3.4 mEq/L and SBE =



–18.6 4.5 mEq/L were not statistically different Pre-
CABG
Post-
CABG
Severe
Sepsis
DKA
Admission 12 hours Resolution
(P = .81) and were thus equivalent measures of the 10
n = 30 n = 30 n = 30 n = 15 n = 10 n = 11

magnitude of the metabolic acidosis. Plasma weak 5
acid buffer content was only slightly reduced, A– = 0
0.2 1.6 mEq/L, from normal baseline secondary to -5

mEq/L
preserved albumin concentration ([albumin–] = 4.2
-10
0.5 mg/dL). The SIG = 22.1 3.7 mEq/L, adjusted Delta SIDe
-15
ANG = 32 3 mmol/L, and ANG = 31 5 mmol/L SBE
-20
were markedly elevated on admission indicating Delta A-

the presence of a significant organic acidosis. -25

At DKA resolution, pH = 7.37 0.04, PaCO2 = 33.0 *Values expressed as mean 95% CI

3.7 mm Hg, and [HCO3–]HH = 18.9 3.1 mmol/L Fig 1. In pre- and post-coronary artery bypass graft (CABG)
consistent with a mild metabolic acidosis with respira- surgery, severe sepsis, and diabetic ketoacidosis (DKA)
tory compensation. The magnitude of the metabolic patients, standard base excess (SBE) equals the algebraic
acidosis was disparate between SIDe = –10.1 sum of the delta strong ion difference effective ( SIDe)
and plasma nonvolatile weak acid buffer deficit ( A–).
3.0 mEq/L and SBE = –5.5 3.3 mEq/L (P < .0001).
The plasma nonvolatile weak acid buffer content acidoses by restoring pH and bicarbonate toward
was decreased, A– = 4.6 1.0 mEq/L, mostly from normal. For example, by physicochemical analy-
hypoalbuminemia ([albumin–] = 3.1 0.4 g/dL). sis with PCO2 set to 40 mm Hg, an excess of 10
The SBE was equivalent to the sum of the SIDe mEq/L of plasma anions ( SIDe = –10) at serum
and A–. The SIG = 6.0 1.8 mEq/L, adjusted ANG = [albumin–] = 4.4 g/dL results in a pH of 7.21 and
16 2, and ANG = 12 2 returned to normal levels. an [HCO3–]HH = 15.6 mmol/L; at [albumin–] = 2.4
There was a marked hyperchloremia, [Cl–] = 114 g/dL, pH = 7.32 and an [HCO3–]HH = 20.1 mmol/L;
6 mEq/L, at DKA resolution. and at [albumin–] = 1.4 g/dL, pH = 7.37 and an
[HCO3–]HH = 22.6 mmol/L. This appears to be an
adaptive physiologic response in acute illness. The
Discussion hazard of fully correcting severe hypoalbuminemia
becomes apparent by acute worsening of a concur-
In the post-CABG surgery, severe sepsis, and DKA rent metabolic acidosis, which may partially explain
patients in recovery, the author found a marked the absence of mortality benefit with replacement
decrease in plasma nonvolatile weak acid buffer therapy [29,30]. The mechanism of hypoalbumin-
content (Fig 1). The decrement in plasma nonvola- emia in acute illness and major surgery is likely
tile weak acid buffer content is equal to a gain in multifactorial. Impaired hepatic synthesis, acute
base, and the A– reflects the magnitude of the phase protein down-regulation, increased capillary
metabolic alkalosis. The metabolic alkalosis that permeability, and expansion of the intravascular
results is not intuitive but exists by the laws of elec- volume by crystalloid/colloid resuscitation are all
trical neutrality, conservation of mass, and dissocia- potential mechanisms [31–33].
tion equilibria that determine acid-base physiology Physicochemical analysis reveals that strong cation/
[8]. Mechanistically, this is understood by realizing anion imbalance is a pervasive cause of metabolic
that albumin is a major determinant of A–. A acid-base disorders in acute illness and major
decrease in plasma albumin by 1 g/dL results in an surgery. In 1981, Dr Peter Stewart [8] introduced
increase in bicarbonate by 2.8 mmol/L, alkalinizing the term strong ion difference as the quantitative
the plasma compartment, mitigating the effects of a estimate of strong cation/anion balance within the
concurrent metabolic acidosis on pH, and reducing plasma compartment and independent determinant
the ANG [26]. Simple deduction would predict that of pH. Historically, plasma buffer base is equiva-
if an elevated ANG results in a metabolic acidosis, lent to strong ion difference. However, changes
a reduced ANG from hypoalbuminemia results in plasma buffer base were measured by recip-
in a metabolic alkalosis. This conclusion remains rocal changes in bicarbonate and protein anions
difficult for some clinicians to accept and is the (easily measured quantities at the time), and the
focal point of contention between both acid-base clinical significance of cation/anion balance was
models. largely forgotten [2]. The SIDe represents the net
Hypoalbuminemia is an independent risk factor electrical charge difference of the plasma strong
for poor outcome in the acutely ill [28]. However, cations minus the strong anions ([Na+] + [K+] +
it is as well beneficial during concurrent metabolic [Ca2+] + [Mg2+] + unmeasured cations – [Cl–] – [lac-

273

Omron

tate–] – unmeasured anions) and is set to 0 mEq/L 10
at standard physiological state: SIDe = 39 mEq/L,
pH = 7.4, and PaCO2 = 40 mm Hg. A negative 5
value indicates an excess of plasma strong anions
0

Delta SIDe + Delta A-
(hyperchloremia, hyperlactatemia, ketoanions, or
unmeasured anions) or a loss of plasma strong -5
cations (free water excess or hyponatremia). A
positive value indicates an excess of plasma strong -10
cations (free water loss or hypernatremia) or a
-15
loss of plasma strong anions (hypochloremia). The
effect of an excess of plasma strong anions causing -20
a metabolic acidosis has been recognized since the
first introduction of the anion gap. Physicochemical -25
analysis extends this relationship in a quantitative
-30
and predictable fashion to all the major strong cat-
-30 -20 -10 0 10
ions and anions in the plasma compartment.
The base excess of plasma (BE(p)) and SID are SBE
conceptually and mathematically related by the Van Fig 2. Metabolic acid-base status measured by stan-
Slyke equation for separated plasma. Derivation dard base excess (SBE) and the sum of the SIDe
of this relationship has been extensively reviewed and A– with line of identity.
elsewhere [6,13]. In brief, the BE(p) and SID both
relate to changes in bicarbonate concentration by
the buffer value of nonbicarbonate plasma buffers. its inclusion into the equation allows restoration of
This value is fixed in the base excess model but equivalence between both acid-base models. Bias
variable in the physicochemical model. At a con- and correlation analysis were performed on the
stant, normal plasma nonvolatile weak acid buffer post-CABG, severe sepsis, and admission DKA data
concentration ( A– = 0 mEq/L), the buffer value of sets to assess the validity of this observation (n =
nonbicarbonate plasma buffers is the same for both 75). SBE and SIDe + A– are symmetric along the
the BE(p) and SID. Thus, a change in BE(p) corre- line of identity, suggesting that both measures are
sponds to an equivalent change in SID. However, comparable (Fig 2). There is an excellent correla-
at variable plasma nonvolatile weak acid buffer tion between SBE and SIDe + A– (r2 = .99, P <
concentrations ( A– 0 mEq/L), the buffer value .0001), with a low bias of 0.225 and a high clinical
of nonbicarbonate plasma buffers changes, and a precision of 0.77 (Fig 3). The limits of agreement
change in BE(p) no longer correlates with a change between SBE and SIDe + A– are therefore –1.29
in SID; which parameter is the better measure of and 1.74, which are not clinically relevant confirm-
metabolic acid-base status is a matter of conten- ing both measures are comparable.
tious debate [6,14,15]. This study was performed The partitioning of complex metabolic acid-base
with SBE as opposed to the BE(p) because it is the disorders in the intensive care unit by physico-
more commonly reported parameter in blood gas chemical analysis is essential to understanding the
analyses. Although SBE differs from BE(p) by an mechanism of the disorder and therapeutically
added constant, the numerical difference was not manipulating the plasma cations and anions by
clinically relevant by bias and correlation analysis prudent choice of crystalloid or colloid to normal-
In pre-CABG surgery and DKA patients on ize pH. For example, by the aforementioned math-
admission, the plasma nonvolatile weak acid buf- ematical relationship, SBE can be partitioned into
fer content was relatively preserved and the SBE SIDe and A–, two separate and often opposing
approximated the SIDe as predicted. In contrast, independent determinants of metabolic acid-base
in post-CABG surgery, severe sepsis, and DKA status. At normal, nonvolatile plasma weak acid
patients after admission, nonvolatile weak acid concentrations ( A– = 0 mEq/L), SBE = SIDe.
buffer concentrations were variable and thus the However, at variable plasma nonvolatile weak acid
SBE and SIDe were widely discordant. However, concentrations, the SIDe reflects the magnitude of
simple inspection of the data sets (Table 1, Fig 1) strong cation/anion imbalance and the A– reflects
revealed that the SBE = SIDe + A– or that SBE the magnitude of the hypoalbuminemic alkalosis
and SIDe differ by an added constant, A–. The or possible hyperphosphatemic acidosis [34]. Like-
A– reflects the change in titratable base at variable wise, SIDe and A– can be combined to yield SBE,
nonvolatile weak acid buffer concentrations, and which reflects the overall magnitude of the meta-



3 losis ( A– = 6.4 0.5 mEq/L) resulting in a SBE =
2.5 –1.0 0.5 mEq/L post-CABG surgery.
Difference between methods

Crystalloid and colloid solutions with a strong
2
ion difference approximating normal plasma SIDe
1.5 result in less cation/anion imbalance and improved
1 metabolic acid-base status in human [35-38] and
animal studies [39-41]. Replacement of plasma
0.5
strong cations/anions to correct or compensate
0 Zero bias for cation/anion imbalance is routinely performed
-0.5 by hemodialysis, hemofiltration, total parenteral
nutrition, and anion replacement therapy [42-45].
-1
Intuitively, patients with a low or high plasma SIDe
-1.5 are optimally managed with a high or low SID
-30 -20 -10 0 10 crystalloid or colloid fluids, respectively [46]. These
Mean of all methods physicochemical approaches to management have
been used empirically for years in acute illness and
Fig 3. Bland-Altman analysis of standard base
major surgery patients without clear theoretical
excess and the sum of the SIDe and A– (bias,
basis prior to Stewart [8]. Whether preservation of
0.225 and precision, 0.77)
the plasma SIDe by balanced crystalloid or colloid
resuscitation or correction of the plasma SIDe and
bolic acid-base derangement relative to standard cation/anion balance by physicochemical prin-
physiological state (SIDe = 39 mEq/L, pH = 7.4 and ciples results in improved patient outcome or is
PaCO2 = 40 mm Hg) but provides no information on just cosmetic remains to be determined and merits
mechanism. Furthermore, a simplification of physi- continued research.
cochemical analysis results from this relationship. Two clinical examples reveal the heuristic value
The A– calculation is unnecessary because this of the relation SBE = SIDe + A– in critical ill-
value can be deduced from the difference between ness fluid, electrolyte, and acid-base management.
SIDe and SBE. The magnitude and mechanism A 42-year-old male patient presents with acute
of a complex metabolic acid-base disorder can respiratory distress syndrome undergoing aggres-
now be extracted from only 2 derived variables: sive diuresis. His arterial laboratory studies reveal
the SIDe and SBE. This relationship reveals that pH = 7.61, PaCO2 = 40.0 mm Hg, [HCO3–]HH = 39.4
neither SBE nor SIDe is the better measure of mmol/L, SBE = 16.8 mEq/L, adjusted ANG = 23,
complex acid-base derangements but that both [albumin–] = 2.4 g/dL, [PI] = 3.5 mg/dL, and [lac-
conventional and physicochemical methods work tate–] = 3.0 mEq/L. Conventionally, a severe mixed
in a complementary fashion at constant and vari- metabolic alkalosis with high gap acidosis is pres-
able plasma nonvolatile weak acid concentrations. ent. Physicochemical analysis reveals SIDe = 10.6
The mean electrolyte and plasma nonvolatile mEq/L and A– = 6.2 mEq/L. The SBE calculation
weak acid buffer changes in CABG surgery patients equals the sum of both SIDe and A– and reflects
reveal the heuristic value of the relation SBE = the magnitude of the metabolic acid-base derange-
SIDe + A– in metabolic acid-base analysis (Table ment. The A– calculation, however, is unnecessary
1). From pre- to post-CABG surgery, the serum because this value can be deduced from the dif-
sodium decreased by 7 mEq/L (143 1 to 136 ference between SBE and SIDe. Mechanistically,
1 mEq/L), the serum potassium decreased by 0.4 the SIDe reveals a metabolic alkalosis secondary
mEq/L (4.1 0.2 to 3.7 0.1), the serum chloride to strong cation excess of approximately 11 mEq/L
increased by 2 mEq/L (106 1 to 108 1 mEq/L), complicated by a hypoalbuminemic alkalosis of 6.2
the SIG decreased by 3.1 mEq/L (4.9 0.9 to 1.8 mEq/L. Reduction of the SIDe by 11 mEq/L would
0.5 mEq/L), and the lactate increased by 1.1 mEq/L correct the strong cation/anion imbalance. The
(0.8 0.1 to 1.9 0.4). The strong cation/anion electrolyte profile is instructive: [Na+] = 144 mEq/L
imbalance (–7 – 0.4 2 + 3.1 1.1 = –7.4) is the and [Cl–] = 91 mEq/L, which reveal hypochlore-
physicochemical manifestation of the stress of major mia. The patient’s acid-base status would benefit
surgery quantified by the negative SIDe (–7.4 by increasing serum chloride by approximately 11
0.8 mEq/L) and consequent metabolic acidosis. The mEq/L by 0.1 hydrochloric acid infusion and by
strong cation/anion imbalance is nearly invisible changing maintenance or resuscitation fluids to a
by conventional metabolic acid-base determination low-SID, high-chloride isotonic crystalloid (isotonic
secondary to a neutralizing hypoalbuminemic alka- saline, SID = 0 mEq/L).

275

Omron

A 78-year-old male presents with severe pneumo- study of pediatric intensive care patients. Cusack
nia and sepsis. His initial arterial laboratory studies et al [51] subsequently contradicted this finding in
reveal pH = 7.37, PaCO2 = 26.9 mm Hg, [HCO3–]HH = a prospective study of mixed medical and surgical
15.2 mmol/L, adjusted ANG = 18, [albumin–] = 1.3 intensive care patients. They found that the pH and
g/dL, and [PI] = 3.1 mg/dL. Conventionally, a non- SBE were predictors of outcome and the SIG was
anion gap metabolic acidosis with acute respiratory not. Both studies however, have been criticized on
compensation is present. The SIDe = –18.1 mEq/L methodology, multicollinearity of variables, and
and SBE = –9.0 mEq/L reveal both marked strong sample size. Rocktaeschel et al [52] conducted a
anion excess and approximately 9.0 mEq/L of buff- larger, retrospective analysis of critically ill patients
ering from hypoalbuminemia ( A– = SBE – SIDe). with rigorous attention to methodology and appro-
The electrolyte profile is instructive: the [Na+] = priate statistical analysis. In contrast to Cusack et
134 mmol/L and the [Cl–] = 113 mmol/L reveal the al, they found that hospital mortality rate was not
origin of the strong cation/anion imbalance: free correlated with pH or BE and that the APACHE II
water excess reducing [Na+] and hyperchloremia. score, ANG, adjusted ANG, BEua, and SIG were
The patient’s acid-base disorder would benefit from statistically correlated with mortality. However,
free water restriction by increasing [Na+]; and a the area under the receiver operator characteristic
high-SID, low-chloride isotonic crystalloid for both curves was relatively small, except for APACHE II
maintenance and resuscitation (1/2 normal saline score, for mortality prediction. Kaplan et al [53]
with 75 mEq/L of [NaHCO3–], SID = +75 mEq/L) by conducted an observational, retrospective analysis
minimizing chloride load and compensatory work of the discriminative power of the strong ion gap
of breathing and restoring SIDe toward standard calculation in separating survivors from nonsurvi-
physiological state. vors after major vascular trauma before significant
The increment in unmeasured strong anions fluid resuscitation. The SIG and ANG were shown
in acute illness and its association with mortality to be more predictive of mortality than SBE, pH, or
have been the focus of several recent publications. lactate. The magnitude of the SIG value in the non-
Unmeasured strong anions were identified in pre-
survivors (mean = 10.8 mEq/L) was similar to that
CABG (SIG = 4.9 0.9 mEq/L) and DKA patients
found by Cusack et al [51] and Rocktaeschel et al
(6.0 1.8 mEq/L) at resolution. The pre-CABG
[52] and the severe sepsis patients presented in this
patients were uncomplicated, and nonemergent
article. Kaplan’s study stands apart from these other
and urea-linked polygelines [47] are not used at our
studies only with respect to the lower strong ion
institution. Thus, unmeasured strong anions are nor-
gap value in survivors (mean = 2.4 mEq/L). One
mally present in the absence of disease, and normal
might speculate that the decrement in the strong
levels in acute illness are unknown. In severe sep-
ion gap before volume resuscitation in survivors of
sis patients, the major strong cation/anion concen-
major vascular trauma is the more important prog-
trations ([Na+], [K+], and [Cl–]) were preserved. Nev-
nostic finding [54].
ertheless, severe cation/anion imbalance existed
largely secondary to excessive unmeasured strong Several weaknesses in the present study are
anions (SIG = 9.4 1.3 mEq/L and adjusted ANG = noted. It is retrospective and open to selection bias.
22 2) with a small component from excess lactate The small sample sizes with homogeneous patient
(2.4 0.8 mEq/L) quantified by the SIDe = –10.9 groups may limit external validity. Normal SIDe
1.8 mEq/L. The close approximation of the SIG was set to 39 mEq/L ( SIDe = 0) consistent with the
to the SIDe suggests that initially severe sepsis is accepted definition of standard physiologic state:
essentially a pure unmeasured strong anion gap pH = 7.4 and PaCO2 = 40 mm Hg. Normal concen-
acidosis in our sample population. Several other trations of albumin and inorganic phosphate were
authors have identified this unmeasured acid load, set to 4.4 g/dL and 3.6 mg/dL, respectively, which
and its nature remains to be defined [48,49]. Uni- reflect normal serum values at the study medical
variate logistic regression analysis between survi- center.
vors and nonsurvivors revealed that the adjusted
ANG or SIG was not a significant predictor of
mortality after admission to the intensive care unit. Conclusions
Multivariate analysis was not performed because of
multicollinearity. Balasubramanyan et al [50] found The main objective of this study was to assess
that base excess unmeasured anion (BE(ua)), a the relationship of SBE to SIDe at variable plasma
simplification of the SIG, was a better predictor of nonvolatile weak acid buffer concentrations in the
mortality than BE, ANG, or lactate in a retrospective critically ill. Standard base excess is equivalent to



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