acid-base assessment by physicochemical analysis: a primer for the intensivist
DESCRIPTION
The objective of this manuscript is to provide a concise introduction to the application of physicochemical acid-base analysis in critical illness. Edward Omron MDTRANSCRIPT
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Acid-Base Assessment by Physicochemical Analysis: A Primer for the Intensivist
Edward M. Omron MD, MPH, FCCP
Pulmonary Critical Care Medicine
18525 Sutter Blvd, Suite 180
Morgan Hill, CA 95037
Email:[email protected]
Disclosures:
The author of this manuscript has no personal or financial conflicts of interest
to disclose with regards to this publication and received no funding from institutional
organizations public or private.
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Abstract
The objective of this manuscript is to provide a concise introduction to the application
of physicochemical acid-base analysis in critical illness. The hydrogen ion concentration
[H+] is regulated to approximately 40 nanoEq/liter (pH 7.40) in health but in disease wide
fluctuations from this standard physiological state occur. The magnitude and direction of
these changes constitute an exquisitely sensitive index of human physiologic stress. The
arterial PCO2-plasma bicarbonate system with anion gap calculation is the dominant
paradigm for understanding changes in [H+]. In complicated critically ill patients with
multi-organ dysfunction, the system is unable to explain the pH altering effects of
hyperchloremia, hypochloremia, dehydration, water intoxication, hypoalbuminemia,
unmeasured anions and crystalloid resuscitation. The anion gap calculation is rendered
unreliable by critical illness related hypoalbuminemia and pH changes. Physicochemical
analysis integrates the power of the both the Henderson–Hasselbalch equation and anion
gap calculation but further expands the dimensions of clinical acid-base assessment from
a diagnostic tool to a therapeutic instrument. A complex systems view of acid-base status
allows the clinician to appreciate the elegant complexity of acid-base disorders but also to
manipulate pH for clinical benefit. An easily grasped, mechanistic physicochemical
explanation follows for the common acid-base disorders seen in critical illness with
rational treatment approaches.
Key Words: acid-base status; strong ion difference; metabolic acidosis; metabolic
alkalosis; physicochemical analysis; strong ion gap
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Introduction
The objective of this manuscript is a review of metabolic acid-base disorders by
physicochemical analysis after trauma, major surgery, or acute illness. The hydrogen ion
(H+), tiny though it is, remains unsurpassed in its ability to influence human physiology
or to confound the clinician. Why is the assessment of acid-base status so important in the
acutely ill and can we, as intensivists, do better?
Precise measurement of the change in hydrogen ion concentration [H+] and the
mechanism of disturbance has been the focus of clinical medicine for the past century (1).
The [H+] is regulated to approximately 40 nanoEq/liter (pH 7.40) in health but in disease
wide fluctuations from this standard physiological state occur. The magnitude and
direction of these changes constitute an exquisitely sensitive index of human physiologic
stress. Once diagnosed, acid-base abnormalities remain a marker for severity of illness,
and correction to standard physiological state remains a strategic endpoint in the acute
resuscitation phase of shock, and a cornerstone of treatment in critical illness (2,3).
The arterial PCO2-plasma bicarbonate system with anion gap calculation is the
dominant paradigm for understanding changes in hydrogen ion concentration [H+]. The
Henderson–Hasselbalch (HH) equation relates plasma bicarbonate concentration [HCO3]
and partial pressure of arterial carbon dioxide (PaCO2) to pH. The anion gap calculation
assesses for a discrepancy between measured plasma cations and anions. If this
discrepancy exceeds a threshold value, an anion gap metabolic acidosis is present
independent of measured pH (4,5).
From a diagnostic standpoint in uncomplicated acute illness, the PaCO2-plasma
bicarbonate system with anion gap calculation is adequate to diagnose and treat simple
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acid-base disorders. In complicated critically ill patients with multi-organ dysfunction,
the system is unable to explain the pH altering effects of hyperchloremia, hypochloremia,
dehydration, water intoxication, hypoalbuminemia, unmeasured anions and crystalloid
resuscitation (6-8). The anion gap calculation is rendered unreliable by critical illness
related hypoalbuminemia and pH changes (9,10). Physicochemical analysis integrates the
power of the both the HH equation and anion gap calculation but further expands the
dimensions of clinical acid-base assessment from a diagnostic tool to a therapeutic
instrument (11). This analysis allows the clinician to appreciate the elegant complexity of
acid-base status but also manipulate pH for clinical benefit. An easily grasped,
mechanistic physicochemical explanation follows for the common acid-base disorders
seen in critical illness with rational treatment approaches.
Plasma pH as a Physicochemical System
Analyses of complex physicochemical systems have found wide application in the
natural sciences (12,13). The goal of acid-base complex systems analysis is to predict,
repair, and control plasma pH. Henderson (14) first introduced blood as a
physicochemical system in 1921, which was extended further, by Singer and Hastings
(15) in 1948, Stewart (16) in 1978, and more recently by Figge, Rossing, and Fencl
(17,18) in 1991. Arterial blood plasma is an open, complex non-linear physicochemical
system that determines plasma [H+]. Within the plasma compartment, the system is
physically and chemically constrained by the laws of conservation of mass, electrical
neutrality, and dissociation equilibrium constants. The system is complex because it
describes a set of chemical reactions that must me examined and solved simultaneously
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and not extracted and analyzed separately. For example, the PaCO2-plasma bicarbonate
subsystem is a component within the plasma acid-base physicochemical system. The
system is open because PaCO2 is in equilibrium with alveolar air and can be manipulated
external to the system by changes in minute ventilation. The system is non-linear
because the exact solution for [H+], a dependent variable in plasma, is a fourth order
polynomial equation uniquely determined by three independent variables: strong ion
difference (SID), PaCO2, and total concentration of plasma nonvolatile weak acids (AT).
In the words of Stewart, “ Independent variable values are imposed on a system from the
outside, and are not affected by the equations which govern the system… Dependent
variables are internal to the system; their values are determined by the system equations
and by the values of the independent variables (19).”
Law of Electrical Neutrality in Acid-Base Status
A Gamblegram is presented in Figure 1 demonstrating the ionic constituents of human
plasma expressed in milliequivalents per liter (mEq/L). Plasma cations and anions are
grouped into two main divisions and are equal. The law of electrical neutrality requires
that charge balance always be maintained or more precisely: the sum of the cation
concentrations equal the sum of the anion concentrations within the plasma compartment.
The majority of the ionic constituents of plasma are strong ions because they are fully
dissociated, exert no buffering effect, and their concentrations are unaffected by pH
changes. The most important plasma strong ions are Na+, K
+, Ca
++, Mg
++, Cl
-, and lactate
where Na+ is sodium, K
+ is potassium, Ca
++ is ionized calcium, Mg
++ is magnesium, and
Cl- is chloride. The strong ion difference (SID) is a collective unit of charge defined as
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the net electrical charge difference of the plasma strong cations minus the plasma strong
anions in mEq/L ([Na+] + [K
+] + [Ca
++] + [Mg
++] – [Cl
-] – [Lactate
-] – [unmeasured
strong anions]). The SID at standard physiological state (pH 7.40, PCO2 = 40 mm Hg,
and [HCO3] = 24.6 mEq/L) demonstrates a combined positive electrical effect of 39
mEq/L.
Electrical neutrality requires that the positive SID (+39 mEq/L) is balanced by an
equivalent negative charge from the plasma buffer anions (-39 mEq/L) or the buffer base.
The buffer base consists of both the volatile bicarbonate ([HCO3] = - 24.6 mEq/L) and
the dissociated components (A-) of the total nonvolatile weak acid buffers (AT) grouped
together ([albumin] + [inorganic phosphate] + [total citrate] = -14.4 mEq/L) within the
plasma compartment. The concentrations of the cation H+ and the anion OH
- are too low
to be illustrated.
The total concentration of plasma nonvolatile weak acid buffers (AT) is composed of
disassociated (A–) and undisassociated (HA) components. Normal baseline in plasma is
set to [albumin] = 4.4 g/dL, inorganic phosphate (Pi) = 1.15 mmol/L, and citrate = 0.135
mmol/L. The disassociated component (A-) reflects the net charge (mEq/L) of albumin,
inorganic phosphate, and citrate and is derived from the Figge-Fencl quantitative
physicochemical model (17,18).
Solutions to all clinical examples in this manuscript unless otherwise stated utilize the
Figge-Fencl model and were solved by an iterative computer program adapted to
Microsoft Excel Visual Basic for Applications 2008. The model can be used to calculate
the pH of plasma for any set of values for PaCO2, SID, and AT. The program is available
online at http:// www.figge-fencl.org/ (20,21).
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The SID is central to understanding and treating many of the metabolic acid-base
disturbances seen in critical illness. The SID is an independent determinant of plasma pH
and the plasma buffer anions. Conversely, the plasma buffer anions are dependent
variables and cannot independently change the SID. This simple principle allows both
qualitative and quantitative mechanistic exploration of the common metabolic acid-base
derangements seen in acute illness.
Hyperchloremic Metabolic Acidosis
Hyperchloremic metabolic acidosis is a common acid-base disorder seen in critical
illness (22,23). High volume normal saline resuscitation, resolution phase of diabetic
ketoacidosis, profuse diarrhea, renal tubular acidosis, and acute kidney injury are
common causes. In Figure 2 plasma chloride is hypothetically raised 10 mEq/L from
standard state to 115 mEq/L over the course of several hours but not long enough for
renal compensation. Consequently, the SID is now reduced from 39 to 29 mEq/L. The
buffer base in response to the lowered SID and hyperchloremia must contract to -29
mEq/L to maintain charge balance reducing [HCO3] to 15.8 mEq/L resulting in a
metabolic acidosis.
The SID constrains the charge boundary the buffer base must conform to revealing
one of the more controversial aspects of physicochemical analysis: bicarbonate
concentration is dependent upon the charge boundary set by the SID. Further, the
reduction in bicarbonate only approximates the change in SID because of decrease in the
net negative charge of the non-bicarbonate buffer anions (A-) during acidosis (17). These
emergent system effects could not have been deduced otherwise. Bicarbonate remains
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correlated with PaCO2 and [H+] by the Henderson–Hasselbalch equation but the
mechanistic change in [HCO3] can only be elucidated by physicochemical analysis. The
standard base deficit (-11 mEq/L) closely approximates the increment in plasma chloride
concentration. The mechanism of acid generation, loss of positive charge or excess gain
in negative charge is readily apparent. All of the organic metabolic acidoses: ketoacidosis
(-hydroxybutyrate), lactate, salicylate, methanol (formate), ethylene glycol (glycolate
and oxalate)… can be similarly represented as an excess of negatively charged plasma
strong organic acid anions. Treatments of the organic acidoses are outside the scope of
this discussion (24).
The treatment of hyperchloremic metabolic acidosis primarily consists of reducing
[Cl-] and restoring SID to standard state ([Cl
-] = 105 mEq/L, SID = 39 mEq/L), which
would restore normal charge balance and acid-base status. If kidney function remains
intact, after several hours to days, secondary renal compensation would occur by
diminished chloride reabsorption and enhanced excretion. The plasma SID would begin
to increase with a concordant increase in pH. Acute kidney injury is the more common
scenario in critical illness however, with rapidly evolving coexisting organic and
hyperchloremic acid-base emergencies. The ventilatory response to an acute metabolic
acidosis is a secondary respiratory alkalosis with increased work of breathing
necessitating acute intervention.
Acute Interventions for hyperchloremic metabolic acidosis include removing chloride
altogether from intravenous fluids (isotonic sodium bicarbonate for both resuscitation and
maintenance fluids and sodium acetate for parenteral nutrition), prudent electrolyte
replacement (calcium gluconate instead of the chloride, magnesium sulfate instead of
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chloride, and potassium phosphate instead of the chloride); replacing intravenous
piggybacks with D5W instead of normal saline; and hemofiltration with sodium
bicarbonate buffers (25,26). An alternative treatment approach would be to increase total
plasma strong cation relative to strong anion concentration. The weak base Tris-
hydroxymethyl aminomethane (THAM) is a strong cation and administration during
acute metabolic acidosis increases strong ion difference and pH (27).
Hypochloremic Metabolic Alkalosis
Hypochloremic metabolic alkalosis is also commonly seen in critical illness. Common
pathologic causes include protracted nausea and vomiting, nasogastric aspiration, and
aggressive diuresis with loop diuretics. In Figure 3 plasma chloride is hypothetically
decreased by 10 mEq/L from standard state to 95 mEq/L over the course of several hours
but not long enough for renal compensation. Consequently, the SID is increased from 39
mEq/L to 49 mEq/L. The buffer base in response to the higher SID and hypochloremia
must expand to -49 mEq/L to maintain charge balance increasing [HCO3] to 33.8 mEq/L
resulting in a metabolic alkalosis. The increment in [HCO3] only approximates the
change in SID because of the increase in the net negative charge of the non-bicarbonate
buffer anions (A-) during alkalosis (17). The standard base excess of +11 mEq/L closely
approximates the decrement in [Cl-]. The mechanism of alkali generation is the excess
gain in strong cations or a loss of strong anions relative to standard state. Another
mechanism by which a metabolic alkalosis can be generated is by the addition of
unmeasured or known strong cations to the plasma compartment (THAM, cationic drugs,
magnesium hydroxide, calcium carbonate) (28,29).
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The differential of metabolic alkalosis is extensive and outside the scope of this
manuscript (30). The correction of the acid-base disorder however is straightforward and
collapses to restoration of [Cl-] to standard state under most circumstances in critical
illness (31,32). If kidney function remains intact, over the course of hours to days,
secondary renal compensation would occur by increased chloride reabsorption and
diminished excretion. The plasma SID would begin to decrease with a concordant
decrease in pH. In hypovolemic hypochloremic metabolic alkalosis; however, glomerular
filtration rate is reduced and renal conservation of sodium takes precedence over chloride
reabsorption perpetuating the alkalosis. Fluid loading with normal saline will restore ECF
chloride content and correct the volume deficit.
Hypochloremic metabolic alkalosis is sometimes misdiagnosed as a “contraction
alkalosis” leading to inappropriate fluid loading (9,31,33). Metabolic alkalosis is often
associated with hypovolemia, excessive diuretic use, and or dehydration; but can also be
seen in euvolemic (mineralocorticoid excess) and hypervolemic states (congestive heart
failure). Contraction of the extracellular fluid compartment volume (ECF) or absolute
hypovolemia has no significant effects on the independent determinants of plasma acid-
base status. ECF volume status should not be diagnosed by electrolyte abnormalities but
by prudent physiologic assessment of the cardiac output venous return curve,
macrocirculatory impairment (blood pressure, heart rate, orthostatics), and or
microcirculatory impairment (lactic acidosis, low SvO2 or ScvO2).
In intubated patients with severe chronic obstructive pulmonary disease and
chronic hypercapnea, the hypochloremic metabolic alkalosis seen is appropriate
compensation for chronic primary respiratory acidosis when arterial pH approximates
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7.40 and should not be initially corrected. Over ventilation will unmask the alkalosis and
exuberant correction may potentially prolong ventilator support (34). In contrast, the
ventilatory response to a primary metabolic alkalosis is hypoventilation and hypercapnea,
which can potential interfere with spontaneous breathing trials and prolong mechanical
ventilatory support (35,36).
Replacement of plasma chloride content can be accomplished by providing
intravenous 0.9% saline, 0.1 N hydrochloric acid infusion, or supplemental chloride
content in electrolyte replacement and parenteral/enteral nutrition. Historically
intravenous ammonium chloride and arginine monohydrochloride have been used but
potential toxicity precludes routine clinical use (37). Judicious use of acetazolamide is
also a useful therapeutic adjunct by increasing renal excretion of serum sodium relative to
chloride resulting in a decrease in the SID and increase in plasma chloride (38).
Dehydration and Water Intoxication Effects on Acid-Base Status
Strong ion difference is affected by changes in plasma free water content with acid-
base consequences (9). Water loss from the intracellular compartment defines
dehydration and is recognized clinically as euvolaemic hypernatremia. Extracellular fluid
volume depletion defines hypovolemia, which has been erroneously associated with
dehydration (39). Contraction of the extracellular fluid volume, as stated earlier, has no
significant effects on the independent determinants of plasma acid-base status but both
conditions may simultaneously occur as in hypovolemic hypernatremia.
An absolute free water deficit to the intracellular compartment is quantitatively
described as the volume of water that must be added to restore [Na+] to standard state
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conditions (Deficit = 0.6 x Weight (kg) x [(Current Na+/142) – 1] (40). Dehydration
concentrates the plasma sodium and chloride in equal proportions; thus, increasing the
plasma SID. The hyperchloremia of dehydration, however, should not be construed as a
hyperchloremic acidosis. To prevent misinterpretation of acid-base status, the plasma
[Cl-] should be corrected for the degree of concentration and the chloride excess or deficit
calculated.
Figure 4 demonstrates the plasma [Na+] and [Cl
-] changes with a 3-liter free water
deficiency from standard state (40). The hyperchloremia of a 3-liter free water deficiency
when corrected for concentration normalizes to standard state [Cl-] and consequently
does not affect the SID or pH ([Cl-] corrected = [Cl
-] observed x ([Na
+] normal/[Na
+] observed) or
[Cl-] corrected = 105 mEq/L = 112 x (142/152)). The chloride excess = 0 mEq/L ([Cl
-] normal
– [Cl-] corrected) objectively quantitates the chloride contribution to the change in SID. The
increased SID from dehydration results in a progressive albeit mild concentrational
metabolic alkalosis and should not be confused with a “contraction alkalosis”. A
“contraction alkalosis” refers to the supposed acid-base effects of extracellular
compartment volume depletion (hypovolemia). The treatment of dehydration consists of
intravenous water expansion usually 5% dextrose to correct the intracellular fluid deficit.
Water gain to the intracellular compartment defines water intoxication and is
recognized clinically as euvolemic hyponatremia (41). Water intoxication is
quantitatively described as the volume of water that must be removed to restore [Na+] to
standard state conditions (Excess = 0.6 x Weight (kg) x [(Current Na+/142) – 1]). The
plasma [Na+] and [Cl
-] are diluted in equal proportions; thus, decreasing the plasma SID.
The hypochloremia of free water excess, however, should not be construed as a
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hypochloremic metabolic alkalosis. To prevent misinterpretation of acid-base status, the
plasma [Cl-] should be corrected for the degree of dilution and the chloride excess or
deficit calculated. The dilutional effects of severe hyperglycemia, nonketotic
hyperosmolar state, and mannitol on plasma electrolytes are excluded from this example
(42).
Figure 5 demonstrates the [Na+] and [Cl
-] changes with a 3-liter free water excess
from standard state (41). The hypochloremia of water intoxication when corrected for
dilution normalizes to standard state [Cl-] and thus does not affect SID or pH ([Cl
-] corrected
= [Cl-] observed x ([Na
+] normal/[Na
+] observed) or [Cl
-] corrected = 105 mEq/L = 98 x (142/132)).
The chloride deficit = 0 mEq/L ([Cl-] normal – [Cl
-] corrected) objectively quantitates the
chloride contribution to the change in SID. The decreased SID from water intoxication
results in a progressive albeit mild dilutional acidosis (9). Dilutional acidosis should not
be confused with the term “dilution acidosis” which refers to the supposed acid-base
effects of extracellular compartment volume excess (hypervolemia).
Hyperchloremia or hypochloremia do not result in an acidosis or alkalosis unless the
corrected chloride is concomitantly increased or decreased relative to standard state (43).
The diagnosis and treatment of water intoxication is beyond the scope of this discussion
but common ICU interventions include hypertonic saline, water restriction, hyperosmolar
enteral feedings, loop diuretics, and vasopressin antagonists. (44).
Plasma Non-volatile Weak Acid Effects
Total plasma nonvolatile weak acid concentration (AT) is an independent determinant
of plasma pH. Albumin and inorganic phosphate are the principal plasma weak acids.
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Albumin normal concentration ranges from 4 to 4.4 g/dL. Major surgery, trauma, and
acute illness result in large fluctuations in albumin concentration and hypoalbuminemia is
an independent risk factor for poor outcome (45,46).
In the example of hyperchloremic metabolic acidosis with serum albumin = 4.4 g/dL,
pH and SBE equals 7.210 and -11 mEq/dL respectively. At serum albumin = 2 g/dL, pH
and SBE are improved to 7.338 and -4 mEq/dL respectively, Figure 5.
A decrease in plasma albumin by 1 g/dL increases base excess by approximately 3
mEq/L (47). Hypoalbuminemia corrects pH towards standard state in acute illness and
appears to be an adaptive, short-term response to metabolic acidosis in critical illness.
Mechanistically this is best appreciated by examining the charge balance in Figure 6.
The buffer base is delimited by the charge space of the plasma strong ion difference and
is equal to the algebraic sum of the individual charged species of serum bicarbonate,
albumin, inorganic phosphorus, and citrate concentrations. With the loss of negative
charge space from hypoalbuminemia, the serum bicarbonate must expand to maintain
charge balance resulting in a mitigating hypoalbuminemic metabolic alkalosis during
concurrent metabolic acidosis (48). In other words, the decrease in plasma nonvolatile
weak acid concentration is equivalent to gain in serum bicarbonate.
Hypoalbuminemia is pervasive in acute illness and major surgery and
hypoalbuminemic alkalosis exists to some extent in all critically ill and post-operative
patients (43). The mechanism of hypoalbuminemia is likely multifactorial: impaired
hepatic synthesis, acute phase protein down-regulation, increased capillary permeability,
exudative losses, and expansion of the intravascular volume by crystalloid/colloid
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resuscitation are all potential mechanisms. Hyperalbuminemia is infrequently
encountered in severe dehydration and may present as an increased gap acidosis (49).
Hyperphosphatemia may be seen in acute, chronic kidney injury, rhabdomyolysis,
tumor lysis syndrome, excessive intake or administration (50). The increased negative
charge space forces bicarbonate to contract and generates a metabolic acidosis (51).
Treatment options include oral phosphate binders, hemodialysis, and parenteral calcium
replacement. Normal concentration of serum inorganic phosphate is 1.15 mmol/L and
consequently hypophosphatemia is unable to generate a metabolic alkalosis.
Standard Base Excess
Dr Sigaard Anderson developed the base excess and deficit concepts in the 1960’s and
standard base excess (SBE) remains a powerful quantitative tool in the assessment of
critical illness acid-base status (52). It is easily calculated by an arterial blood gas
measurement and reduces metabolic acid-base disturbances to a simple, quantitative
numerical scale. Standard base excess provides no insight into mechanism but provides
the magnitude and direction of a metabolic acid-base disturbance. A positive value
indicates an excess of base, whereas a negative value indicates an excess of fixed acid in
vivo with respect to the extracellular fluid compartment (ECF).
SBE and SID are conceptually related by sharing similar volumes of distribution. The
plasma strong ions distribute throughout the entire extracellular fluid compartment and
strong ions added to the plasma compartment are diluted by the interstitial fluid strong
ions. The distribution, however, of strong ions between the plasma and interstitial fluid
compartments is dictated by Gibbs-Donnan Equilibria. Conceptually, standard base
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excess represents an excess of strong cations in mEq/L and standard base deficit
represents an excess of strong anions in mEq/L relative to standard state conditions when
AT is normal.
Historically, the BE nomograms were determined by in vitro titrations of strong acids
and bases to standard state conditions. Total plasma nonvolatile weak acids were
assumed to be normal (43,53). Consequently, hypoalbuminemia is registered as a SBE
and hyperphosphatemia is registered as a standard base deficit. The problem with SBE is
that it does not discriminate between changes in SID or AT.
Fortuitously, SBE is a summation function of the changes in both plasma SID and A-
or SBE = ΔSID + ΔA- (48). The partitioning of SBE into physicochemical components
allows quick recognition of the mitigating effects of hypoalbuminemia in strong ion
acidosis and the aggravation of base excess in strong ion alkalosis. The change in SID
from standard state conditions is calculated as ΔSID (mEq/L) = SID (measured) – 39. A
positive value indicates an excess of base or plasma strong cations, whereas a negative
value indicates an excess of fixed acid or plasma strong anions. The nonvolatile plasma
weak acid buffer deficit (ΔA-) reflects alterations in the concentrations of albumin,
inorganic phosphate, and citrate from normal baseline consequent to surgery or acute
illness. Note that ΔA- is expressed as a positive quantity because a decrement in plasma
nonvolatile weak acid content is equal to a gain in base. The calculation of ΔA- is
complex and can be found in reference 48. In practice, the ΔA- calculation is unnecessary
because this value can be deduced from the difference between ΔSID and SBE.
For example, Figure 6 reveals a hyperchloremic strong ion acidosis mitigated by a
hypoalbuminemic alkalosis. The SBE = -4 mEq/L, the SID = -10 mEq/L, and the A- =
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+6 mEq/L (calculated from the Figge-Fencl Model). The SID reflects the magnitude
and direction of the strong ion imbalance: 10 mEq/L of excess strong anions. The A-
reflects the magnitude of the hypoalbuminemic alkalosis: 6 mEq/L. The algebraic sum of
ΔSID + ΔA- equals the SBE which reflects the overall magnitude of the metabolic acid-
base disorder relative to the ECF compartment.
Classification of Primary Metabolic Acid-Base Disorders
In summary, in vivo plasma pH is a function of 3 independent determinants: (1) SID;
(2) AT; and (3) PaCO2. Disorders of any of the independent determinants may coexist
simultaneously in acute illness. Table 1 reviews the primary classification of metabolic
acid-base disturbances. The pH is a function of SID and the difference from 39 mEq/L is
a measure of ionic imbalance from standard state (Figure 7). If the SID < 39 mEq/L, an
excess of strong anions (i.e. hyperchloremia), organic acids, or free water (water
intoxication) is present resulting in a metabolic acidosis. If the SID > 39 mEq/L, a
deficiency of strong anions (i.e. hypochloremia), free water (dehydration), or excess of
strong cations are present resulting in a metabolic alkalosis. The loss of strong cations in
relation to strong anions is associated with an acidosis and the loss of strong anions in
relation to strong cations is associated with an alkalosis. Thus, “according to the law of
electrical neutrality it is impossible to change the [H+] in a solution without
simultaneously changing the amount of some anion, or exchanging the [H+] with some
cation (54). “
Albumin and inorganic phosphate are the principal nonvolatile plasma weak acids. A
decreased AT (Hypoalbuminemia) is pervasive in critical illness and generates a
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metabolic alkalosis. An increased AT (Hyperphosphatemia) is most commonly seen in
acute and chronic kidney injury and generates a metabolic acidosis.
The Effects of Crystalloid Infusion on Acid-Base Status
The intravenous administration of acidic or alkaline crystalloid solutions to correct
severe metabolic alkalosis and acidosis respectively is routinely performed in the acutely
ill. Physicochemical analysis provides a rational basis for understanding the effects of
crystalloid administration on acid-base status (8, 55-57). Theoretically, selective
crystalloid infusion can manipulate the SBE in a predictable and quantitative manner.
The crystalloid SID is the net electrical charge difference of the infusate strong cations
minus the anions. Normal saline, for example, contains 154 mEq/L of sodium and 154
mEq/L of chloride and thus the SID is equal to zero. Isotonic sodium bicarbonate, in
contrast, contains 150 mEq/L of sodium and 150 mEq/L of bicarbonate and thus the SID
is equal to 150 mEq/L.
Infusion of an isotonic crystalloid solution modifies plasma pH by simultaneously
altering both SID and AT. For example, normal plasma SID equals 39 mEq/L and when
combined with a low SID crystalloid (normal saline SID = 0 mEq/L), the admixture will
reduce plasma SID resulting in a strong ion acidosis. In contrast, the SID of sodium
bicarbonate (SID = 150 mEq/L) is higher than plasma SID; the admixture will increase
plasma SID and result in a strong ion alkalosis. Crystalloid solutions are devoid of AT
(albumin, inorganic phosphate, and total citrate) and intravenous administration will
reduce plasma weak acids by simple dilution, resulting in a mitigating dilution alkalosis.
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Plasma metabolic acid-base status will be determined after equilibration and Gibbs-
Donnan effect by the plasma SID admixture and diluted AT.
If the induced crystalloid strong ion acidosis is exactly balanced by a dilution AT
metabolic alkalosis, no significant change in SBE occurs. The crystalloid SID necessary
to achieve this ‘‘balance point’’ is equal to standard state actual bicarbonate (24.6
mEq/L). In other words, crystalloid solutions with an ionic composition similar to plasma
and SID close to standard state bicarbonate are referred to as balanced solutions (lactated
Ringer’s and Hartmann’s solution) and clinically minimize acid-base disturbances when
infused.
The ‘‘balance point’’ is also useful when using crystalloid solutions to achieve a
particular acid-base endpoint. If the infused crystalloid SID is greater than 24.6 mEq/L,
metabolic alkalosis will result; if less than 24.6 mEq/L, metabolic acidosis will result. If
the crystalloid SID equals 24.6, no change in SBE is observed. Figure 7 demonstrates the
potency of various crystalloid solutions as a function of crystalloid SID to induce an
acidosis or alkalosis, respectively, from standard state conditions under ideal conditions.
These projections are reasonably accurate in surgical patient populations during
perioperative fluid replacement with normal saline, lactated Ringer’s, and plasmalyte
solutions. High-quality clinical data sets are unfortunately lacking in critically ill
populations and more research is needed to define the optimal fluid resuscitation strategy.
Anion Gap and Strong Ion Gap
In critical illness, unmeasured strong anions may appear (ketone acids, anions of renal
failure, and lactate) resulting in a metabolic acidosis and an increased anion gap (ANG).
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The ANG is a screening tool for unmeasured strong anions and is derived from an
abreviated form of the law of electrical neutrality in plasma (Figure 9): Na+- Cl
- – HCO3
= Unmeasured Anions – Unmeasured Cations + A- ≅ 12 ± 4 mEq/L (57). The value of
the ANG includes the unmeasured plasma strong cations and anions, and the
disassociated component of AT. The simplified charge balance equation ignores
potassium, calcium, and magnesium, which become unmeasured cations. During standard
state conditions, the entirety of the ANG can be accounted for by the negative charge
component of AT (17, 18). An increase in unmeasured strong anions will titrate plasma
bicarbonate, generate a metabolic acidosis, and increase the ANG to maintain charge
balance. An increased ANG historically has been quite helpful in the differential
diagnosis of metabolic acidosis; however, the validity of the calculation is questionable in
critical illness.
Inspection of the ANG calculation reveals several major sources of error (58-60).
Hypoalbuminemia is pervasive in critical illness resulting in a low to normal ANG in the
organic acidoses (61). A decrease in albumin by 1 g/dL reduces the ANG by 2.5 mEq/L
secondary to the loss of negative charge from the albumin moiety. The disassociated
component of AT is reduced in acidemia and increased in alkalemia decreasing and
increasing the ANG respectively by titration of the negative charges on the albumin
moiety. Figure 2 demonstrates the reduction in the ANG during acidemia from 12 to 11
mEq/L; Figure 3 demonstrates the increase in the ANG during alkalemia from 12 to 13
mEq/L. Figure 6 demonstrates the combined effects of acidemia and hypoalbuminemia
on ANG. The ANG is reduced from 12 mEq/L at standard state to 6 mEq/L secondary to
loss of charge from both hypoalbuminemia and acidosis with no change in unmeasured
21
anions or cations. A proposed adjusted ANG for hypoalbuminemia (adjusted ANG =
observed ANG + 2.5 x ([Normal Albumin] – [Observed Albumin]) has improved
sensitivity to detect occult organic acidoses and is in common use (61). In Figure 6, the
adjusted ANG corrects to normal (adjusted ANG = 12 mEq/L (6 + 2.5 x (4.4 – 2)). Low
ANG can also be seen with an excess of strong cations (hypercalcemia,
hypermagnesemia, hyperkalemia, lithium, and THAM) and laboratory error.
In physicochemical analysis the appearance of unmeasured strong anions or cations
are collectively termed the strong ion gap (SIG) and are codeterminants of the SID
(Figure 10). The SIG is similar to the ANG in that both are derived from the law of
electrical neutrality but unlike the ANG, the SIG is resistant to changes in pH, PaCO2,
and albumin concentration (62). Figures 2, 3, and 6 demonstrate the robustness of the
SIG measurement is acidemia, alkalemia and hypoalbuminemia. The SIG is thus a more
reliable parameter of unmeasured strong anions than ANG in critical illness. The SIG in
health is normally less than 6 mEq/L but the range of abnormal values in critical illness
remains undefined in the literature (63). Recent literature has focused on the utility of the
SIG as a marker of tissue damage and predictor of mortality in severe sepsis, trauma, and
cardiac arrest (64-67).
The SIG is calculated as the difference between the SID apparent and effective. The
SID apparent (SIDa) is the net electrical charge difference between the commonly
measured strong cations minus the strong anions in the plasma: SIDa = Na+
+ K+
+ Ca++
+
Mg++
- Cl- - lactate. The SIDa is normally 42 – 44 mEq/L. For bedside calculations the
combined expression (Ca++
+ Mg++
) is replaced by 3 mEq/L. The strong ion difference
effective (SIDe) is the net electrical charge difference of the plasma strong cations minus
22
the strong anions including the SIG: Na+
+ K+
+ Ca++
+ Mg++
- Cl- + [SIG]. The SIDe is
normally 39 mEq/L. The calculation of the SIG combines both equations: SIG = SIDa –
SIDe. For bedside calculations the SIDe is closely approximated by its negatively
charged reflection, the plasma buffer base: SIDe ≈ [HCO3] + 2.8 x [albumin g/dL] + 0.6 x
[Pi mg/dL] (43). The full Figge-Fencl quantitative physicochemical model can be applied
at the bedside with a programmable calculator (20, 21).
Illustrative Examples
A 50-year-old male presents with end stage liver disease in septic shock. His
admission pH = 7.263, PaCO2 = 20.2 mm Hg, [HCO3] HH = 9 mEq/L, SBE = -16 mEq/L,
Na+ = 139 mEq/L, K
+ = 3.7 mEq/L, Cl
- = 117 mEq/L, lactate = 2.9 mEq/L, [albumin] =
2.4 g/dL, Pi = 4.3 mg/dL, the ANG = 13 mEq/L, adjusted ANG = 18 mEq/L, SIDa = 26
mEq/L, SIDe = 18 mEq/L, and the SIG = 8 mEq/L.
Conventional analysis reveals a severe metabolic acidosis with respiratory
compensation and a normal ANG but elevated adjusted ANG. Physicochemical analysis
suggests a marked excess of strong anions within the ECF compartment (Δ SID = -21
mEq/L) with a mitigating hypoalbuminemic alkalosis (ΔA-) of 5 mEq/L. The SBE = -16
mEq/L or (Δ SID + ΔA-). The source of the strong anion acidosis is hyperchloremia,
unmeasured anions from the SIG, and to a lesser extent lactate. The nature of the SIG and
unmeasured anions in acute illness remains elusive although Krebs cycle strong anions
have been implicated (68).
Therapeutic intervention would require removing chloride altogether from
resuscitation and maintenance fluids, initiation of isotonic sodium bicarbonate (SID =
23
150 mEq/L) infusion, changing all IV drips to D5W with acute, early goal directed
resuscitation to both macro and microcirculatory endpoints. A physicochemical
resuscitation refers to the application of physicochemical analysis to correct acid-base
status with early goal directed resuscitation endpoints (8). A physicochemical
resuscitation in acute illness is physiologically appealing but remains untested in the
literature.
A 69 year-old male with acute myelogenous leukemia and acute respiratory distress
syndrome day 14 on pressure regulated volume control. His pH = 7.530, PaCO2 = 40 mm
Hg, [HCO3] = 33 mEq/L, SBE = 9.8 mEq/L, [Na+] = 140 mEq/L, [K
+] = 2.8 mEq/L,
[Cl-] = 105 mEq/L, [albumin] = 1.1 g/dL, [Pi] = 3.3 mg/dL, ANG = 2 mEq/L, adj ANG =
10.3 mEq/L, SIDe = 38.6 mEq/L, SIDa = 40.8 mEq/L, SIG = 2.2 mEq/L.
Conventional analysis reveals a primary metabolic alkalosis. The SIDe is normal and
thus ΔSID = 0 mEq/L, the ΔA- = 9.8 mEq/L secondary to the profound
hypoalbuminemia, and the SBE (SBE = ΔSID + ΔA-) can be entirely accounted for by
the hypoalbuminemia of critical illness. The patient is euvolemic based on bedside
echocardiography. The metabolic alkalosis would have to be corrected to initiate
spontaneous breathing trials. Confusion with a “contraction alkalosis” might lead to
inappropriate fluid loading and prolongation of mechanical ventilation. The patient
received intravenous acetazolamide with normalization of pH the next morning.
A 22 year-old male presents with an altered mental status, nausea and vomiting,
increased thirst, frequent urination and admission glucose of 241 mg/dL. Serum acetone
and urine ketones were positive. His admission pH = 6.985, PaCO2 = 20.5 mm Hg,
[HCO3] = 4.8 mEq/L, SBE = -23.9 mEq/L, [Na+] = 154 mEq/L, [K
+] = 4.4 mEq/L, [Cl
-]
24
= 101 mEq/L, lactate = 0.8 mEq/L, Pi = 6.7 mg/dL, [albumin] = 6.1 g/dL, SIDa = 61.1
mEq/L, SIDe = 22.1 mEq/L, SIG = 39 mEq/L, ΔSID = -16.9 mEq/L, ΔA- = -7.0 mEq/L,
and ANG = 48 mEq/L. The corrected [Cl-] for dehydration = 142/154 x 101 = 93 mEq/L.
The chloride deficit = 105 – 93 ≈ 12 mEq/L.
Conventional analysis reveals a high anion gap metabolic acidosis with a
compensatory respiratory alkalosis. Electrolyte profile supports dehydration and bedside
echocardiography reveals hypovolemia with preload dependency. Physicochemical
analysis reveals a severe strong anion acidosis with a high SIG presumably secondary to
ketone bodies from diabetic ketoacidosis (ΔSID = -16.9 mEq/L of excess strong anions).
Secondary acidoses emerge from the hyperalbuminemia of dehydration with a smaller
component from hyperphosphatemia (ΔA- = -7.0 mEq/L). A chloride deficit of 12 mEq/L
reveals a moderate hypochloremic metabolic alkalosis.
Fluid resuscitation in diabetic ketoacidosis (DKA) remains contentious in the medical
literature and current guidelines continue to recommend 0.9% saline (69,70).
Physicochemical analysis clearly reveals that 0.9% saline infusion aggravates a
preexisting metabolic acidosis and induces a coexisting hyperchloremic strong ion
acidosis (8, 48). Unfortunately, randomized, placebo controlled studies of crystalloid
fluid resuscitation in DKA have not been performed and recommendations fall to dogma
and practice preference. The author strongly advocates the use of physiologically
balanced fluids (lactated Ringer’s and Hartmann’s solution) both during the acute
resuscitation and maintenance phases of DKA in adults. Lactated Ringer’s infusion, for
example, would correct the ECF volume deficit, minimize crystalloid-induced acid-base
changes, provide free water replacement (osmolarity = 275 mOsmol/liter) for
25
dehydration, minimize hyperchloremia, and supplement total body potassium stores
slightly.
Theoretical Advantage of Physicochemical Acid-Base Analysis
The binary separation of acid-base status into pure respiratory and metabolic
components forms the foundation of acid-base lore. The Henderson Equation ([H+] = 24
x PaCO2/[HCO3]) illustrates the concept. Classical teaching states that the PaCO2
represents the respiratory component and [HCO3] the metabolic component of an acid-
base disturbance and both are independent determinants of [H+] (71). It was Schwartz
and Relman that initially questioned the validity of this concept and began “The Great
Trans-Atlantic Acid-Base Debate (72).”
“ …it must be recognized that a certain quantity of “metabolic acidosis” normally
complicates primary respiratory alkalosis and that a certain quantity of “metabolic
alkalosis” normally complicates primary respiratory acidosis, it is apparent that the
recognition of abnormal metabolic complications of primary respiratory disturbances
becomes extremely difficult (73).”
Physicochemical acid-base analysis moves the clinician away from the simplistic
binary classification scheme to a systems view of acid-base status. Le Chatelier’s
Principle states that if a physicochemical system is exposed to a stress, the system will
shift to minimize that stress. For example, hyperchloremia is a recognized as an excess of
ECF strong anions resulting in a strong ion metabolic acidosis. Primary repair of the
system requires removal of the excess strong anions from the ECF compartment. The
physiologic response is to restore standard state conditions: a secondary respiratory
26
alkalosis, intracellular buffering of the ECF compartment acidosis, and diminished
chloride reabsorption with enhanced excretion by the kidneys till all excess chloride is
removed. The Intensivist can facilitate the restorative process by prudent use of fluids,
electrolyte replacement, enteral nutrition, mechanical ventilation, and diuretics. The
essence of acid-base systems analysis is to predict, repair, and control plasma pH.
Conclusion
This manuscript was written exclusively for the critical care physician. Intensivists
are broadly trained to diagnose and treat multi-organ dysfunction and I would argue a
more appropriate appellation of their skill set is complex systems clinician.
Physicochemical analysis and the diagnosis, treatment, and control of acid-base disorders
are a natural extension of this skill set. Plasma pH is a subsystem of whole body acid-
base balance. ““Whole body acid-base balance,” refers to the set of mechanisms by
which the parts of the body, notably the lungs, kidneys, and gastrointestinal tract, control
the composition of the circulating blood plasma, so as to keep its [H+] generally within
the range from 2 x 10-8
to 1 x 10-7
Eq/liter or pH 7.7 to 7.0 (74).” The ultimate therapeutic
goal of critical care medicine is restoration of multi-organ standard state conditions after
multi-organ dysfunction. Physicochemical analysis with manipulation of fluids,
electrolytes, and plasma pH in the acute resuscitative phase of critical illness is a
necessary component of this endeavor.
27
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35
Figure 1: Charge balance at standard physiologic state
SID = strong ion difference; SBE = standard base excess; ANG = anion gap; SIG = strong ion gap; A- = dissociated component of AT
20
40
60
80
100
120
140
160
mE
q/L
Cations Anions
Na+ = 142
K+ Ca++ Mg++
Cl- = -105
HCO3 = -24.6
A- = -14.4
0
Buffer Base = -39 SID = +39
pH = 7.40
PaCO2 = 40 mm Hg
SBE = 0 mEq/L
ANG = 12 mEq/L
SIG = 5 mEq/L
36
Figure 2: Hyperchloremic strong ion acidosis
SID = strong ion difference; SBE = standard base excess; ANG = anion gap; SIG = strong ion gap; A- = dissociated component of AT
20
40
60
80
100
120
140
160
mE
q/L
Cations Anions
Na+ = 142
K+ Ca++ Mg++
Cl- = -115
HCO3 = -15.8
A- = -13.2
0
Buffer Base = -29 SID = +29
( 10)
pH = 7.209
PCO2 = 40 mm Hg
SBE = -11 mEq/L
ANG = 11 mEq/L
SIG = 5 mEq/L
37
Figure 3: Hypochloremic strong ion alkalosis
SID = strong ion difference; SBE = standard base excess; ANG = anion gap; SIG = strong ion gap; A- = dissociated component of AT
20
40
60
80
100
120
140
160
mE
q/L
Cations Anions
Na+ = 142
K+ Ca++ Mg++
Cl- = -95
HCO3 = -33.8
A- = -15.2
0
Buffer Base = - 49 SID = +49
( 10)
pH = 7.54
PCO2 = 40 mm Hg
SBE = 11 mEq/L
ANG = 13
SIG = 5 mEq/L
38
Figure 4: A concentration strong ion alkalosis: three-liter free water deficit from standard physiologic state (weight = 70 kg and total
body water = 0.60).
SID = strong ion difference; SBE = standard base excess; ANG = anion gap; SIG = strong ion gap; A- = dissociated component of AT
20
40
60
80
100
120
140
160
mE
q/L
Cations Anions
Na+ = 152 ( 10)
K+ Ca++ Mg++
Cl- = 112 ( 7)
HCO3 = -27.3
A- = -14.7
0
Buffer Base = -42 SID = +42
pH = 7.447
PCO2 = 40 mm Hg
SBE = 3 mEq/L
ANG = 13 mEq/L
SIG = 5 mEq/L
39
Figure 5: A dilution strong ion acidosis: three-liter free water excess from standard physiologic state (weight = 70 kg and total body
water = 0.60).
SID = strong ion difference; SBE = standard base excess; ANG = anion gap; SIG = strong ion gap; A- = dissociated component of AT
20
40
60
80
100
120
140
160
mE
q/L
Cations Anions
Na+ = 132
K+ Ca++ Mg++
Cl- = 98
HCO3 = -21.9
A- = -14.1
0
Buffer Base = -36 SID = +36
( 10)
pH = 7.351
PCO2 = 40 mm Hg
SBE = -3 mEq/L
ANG = 12
SIG = 5
( 7 )
40
Figure 6: Hyperchloremic strong ion acidosis with concurrent hypoalbuminemic alkalosis ([albumin] = 2g/dL)
SID = strong ion difference; SBE = standard base excess; ANG = anion gap; SIG = strong ion gap; A- = dissociated component of AT
20
40
60
80
100
120
140
160
mE
q/L
Cations Anions
Na+ = 142
K+ Ca++ Mg++
Cl- = -115
HCO3 = - 21.2
A- = - 7.8
0
Buffer Base = -29 SID = +29
( 10)
pH = 7.338
PCO2 = 40 mm Hg
SBE = - 4 mEq/L
ANG = 6 mEq/L
Adj. ANG = 12 mEq/L
SIG = 5 mEq/L
41
Table 1: Classification of primary metabolic acid-base disorders
Acidosis Alkalosis
1.Strong Ion Difference
a. Decreased Hyperchloremia
Organic Acid Anions
Water intoxication
b. Increased Hypochloremia
Dehydration
Strong Cations (THAM)
2. Nonvolatile Weak Acids
a. Increased Hyperphosphatemia
Hyperalbuminemia
b. Decreased Hypoalbuminemia
42
Figure 7. pH as a function of strong ion difference (SID)
AT = plasma nonvolatile weak acid total
6.8
6.9
7
7.1
7.2
7.3
7.4
7.5
7.6
15 20 25 30 35 40 45 50 55
pH
SID (mEq/L)
pH = 7.4
PaCO2 = 40 mm Hg
SID = 39 mEq/L
AT = Standard State
+ -
43
Figure 8. Standard base excess (SBE) as a function of crystalloid infusion volume in liters
-15
-10
-5
0
5
10
15
20
25
30
35
40
0 1 2 3 4 5 6 7 8 9 10
SB
E m
Eq
/L
Crystalloid Infusion Volume (Liters)
Normal Saline (SID = 0)
Crystalloid SID = 24.5 mEq/L
Ringer's Lactate (SID = 28)
Plasmalyte 148 (SID = 50)
1/2 NS + 75 mEq/L NaHCO3 (SID = 75)
0.15 M NaHCO3 (SID = 150)
44
Figure 9. The Anion Gap (ANG)
SBE = standard base excess; ANG = anion gap; SIG = strong ion gap; A- = disassociated component of of AT
20
40
60
80
100
120
140
160
mE
q/L
Cations Anions
Na+ = 142
K+ = 4
Cl- = -105
HCO3 = -24.6
A- = -14.4
0
pH = 7.40
PCO2 = 40 mm Hg
SBE = 0 mEq/L
ANG = 12 mEq/L
SIG = 5 mEq/L
XA-
XA- = Unmeasured Anions:
Cyanide
Glycols Iron
Isoniazid
Ketoacids Krebs Cycle
Lactate
Methanol Paraldehyde
Toluene Salicylate
Uremia
ANG
45
Figure 10. The Strong Ion Gap (SIG)
SIDa = apparent strong ion difference; SIDe = effective strong ion difference; SBE = standard base excess; ANG = anion gap; SIG =
strong ion gap; A- = disassociated component of AT
20
40
60
80
100
120
140
160
mE
q/L
Cations Anions
Na+ = 142
K+ = 4
Cl- = -105
HCO3
A-
0
pH = 7.40
PCO2 = 40 mm Hg
SBE = 0 mEq/L
ANG = 12 mEq/L
SIG = 5 mEq/L
XA-
SIDa
Strong Ion Gap
SIDe or Buffer Base