Making Strong Ion Difference the ªEuroº for Bedside
Acid-Base Analysis
J. A. Kellum
z Introduction
There are three widely used approaches to acid-base physiology using apparently
different `currency' for accounting changes in acid-base balance. In fact the currency can be easily exchanged but the persistence of different currencies makes the
business of sorting out acid-base problems inefficient. A better approach would be
to accept a common currency. Already, in terms of describing acid-base abnormalities and classifying them into various groups, the three widely accepted methods
yield comparable results [1]. Importantly, each approach differs only in assessment
of the metabolic component (i.e., all three treat PCO2 as an independent variable).
These three methods quantify the metabolic component either by using
z HCO±3 (in the context of PCO2);
z the standard base-excess (SBE); or
z the strong ion difference (SID).
All three yield virtually identical results when used to quantify the acid-base status
of a given blood sample [2±5]. So why should we not accept a common currency?
More than 20 years have passed since the publication of Peter Stewart's landmark paper [6] and textbook [7] introducing his ªphysical chemicalº approach to
understanding acid-base physiology. While his views have remained somewhat controversial, two facts have emerged. First, while Stewart's terminology (e.g., strong
ion difference) and his concepts of acid-base control (e.g., electrical neutrality and
conservation of mass governing water dissociation) are certainly novel, measures of
acid-base in the blood are not significantly different from what we have seen before. For example, Stewart's term SID refers to the absolute difference between completely (or near completely) dissociated cations and anions. According to the principle of electrical neutrality, this difference is balanced by the weak acids and CO2
such that SID can be defined either in terms of strong ions or in terms of the weak
acids and CO2 offsetting it. Of note, the SID defined in terms of weak acids and
CO2, which has been subsequently termed the effective SID (SIDe) [8], is identical
to the ªbuffer baseº term coined by Singer and Hastings over half a century ago
[9]. Thus changes in SBE also represent changes in SID [2]. Similarly, Stewart's
term for total weak acid concentration (ATOT) is defined as the dissociated (A±)
plus undissociated (AH) weak acid forms. The familiar anion gap, when normal, is
actually `caused by' A± (see further discussion below). Therefore, the currency conversions between the `traditional' approaches to acid-base balance using HCO±3 or
SBE and anion gap and the physical chemical approach using SID and strong ion
gap (SIG) should be fairly straightforward; indeed, they are (Table 1).
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J. A. Kellum
Table 1. Currency exchange system for acid-base approaches
Comment
`Traditional'
Variable
Physical
Chemical
Variable
pH
pH
PCO2
PCO2
HCO±3
Total CO2
Total CO2 includes dissolved CO2, H2CO3 and CO2±
3 in addition
to HCO±3. However for practical purposes, at physiologic pH,
the two variables are very similar.
Buffer Base
SIDe
In the absence of unmeasured anions SIDe = SIDa = SID. However, since this rarely happens, SIDe = SID = SIDa ± SIG (see
text for discussion).
SBE
SIDPRESENT ±
SIDEQUILIBRIUM
For blood plasma, SBE rather than ABE quantifies the amount
of strong acid (or strong base if SBE is negative) that would
be needed to return the SID to its equilibrium point (the
point at which pH = 7.4 and PCO2 = 40). Note, that change in
SBE can brought about by a change in A± or SID, but SBE
only quantifies the change in SID required to reach equilibrium. In the case of a change in A±, the new equilibrium for
SID will be different (see text).
Anion gap
(normal)
A±
Virtually all of A± is composed of albumin and phosphate.
A± can be approximated by: 2(albumin in g/dl) + 0.5(phosphate
in mg/dl).
Anion gap
(abnormal)
A±+ X±
The value of X± is the actually the difference between all unmeasured anions minus all unmeasured cations. Since, typically, unmeasured anions > unmeasured cations, the sign of X±
is positive. If a `cation gap' exists, the convention would be to
term that a negative anion gap and X± would carry a negative sign.
Anion gap ± A±
SIG
Given that anion gap ± A± = SIG and A±+X± = anion gap,
there is temptation to equate SIG and X±. However, SIG will
change if unmeasured weak acids (A±X) are present as well so
actually SIG = X±+A±X.
ATOT
ATOT = A±+AH.
N/A
SID: strong ion difference (e = effecitve, a = apparent); SBE: standard base excess; SIG: strong ion gap
The second fact about the physical chemical approach is that it has become
widely adopted by acid-base researchers. Although far from universal, this
approach has been used by researchers in intensive care, anesthesiology, emergency
medicine, traumatology, nephrology, and exercise physiology. A MEDLINE search
on the terms ªstrong ion differenceº and ªstrong ion gapº returns 500 articles since
1990. However, the terms ªbase excessº and ªanion gapº each, alone, produce over
3000 for the same time period. Similarly, SID has not made it into the standard
teaching of acid-base for medical students. Although most subspecialty texts in
critical care and widely utilized educational programs for intensivists like the European Society of Intensive Care Medicine (ESICM) Patient-centred Acute Care Train-
Making Strong Ion Difference the ªEuroº for Bedside Acid-Base Analysis
ing (PACT) [10], cover SID along side more traditional approaches, there is still
limited `penetration' into medical education. An often-stated reason for this is that
it is unclear how the physical chemical approach changes clinical practice. While
acid-base researchers find the transparency of easily measured and derived independent variables appealing, clinicians argue that the computer chip in the blood
gas machine calculates SBE for them. Who cares how it is derived? Furthermore,
since few hospital laboratories report SID or SIG, it is actually much more work to
use this approach.
Modern ICU `STAT labs' and point-of-care technology have reinforced this opinion. If one were stranded on the proverbial desert island with only a single set of
blood gases and serum electrolytes to work with, one could estimate the exact outcome of, for example, an infusion of sodium chloride solution using the change in
SID [11]. This could also be done using the traditional approach as well, and if the
patient on the desert island were a healthy subject, it would work quite well. Unfortunately if the patient were critically ill and a large volume of saline were needed,
it would be a different story. First, the volume administered will change the `bicarbonate space' which is estimated at 40±50% of total body water [12]. However, the
volume of distribution (Vd) of bicarbonate changes with changes in plasma pH
[13]. Worse still, bicarbonate Vd changes differently with respiratory vs metabolic
acid-base derangements [14]. Compare all this to the simple elegance of examining
not an imaginary bicarbonate space but rather a change in SID brought about by
the administration of Na+, Cl±, and water [11]. However, few of us practice on desert islands and what is the value of `simple elegance' in predicting the effects
when we can measure serial blood gases and chemistry? Careful, attentive ICU
monitoring will, no doubt, prove more accurate than our sagely SID. In this regard,
is SID the Apple computer of the acid-base world; better in all measurable ways
but impractical for the casual user? Of course, those of us entrusted with the care
of the critically ill and injured are not `casual users' of acid-base and a common
currency for us to use would be of value.
z A Brief Primer on Leading Acid-Base Approaches
The Bicarbonate Approach
The basis of this approach is the Henderson-Hasselbalch equation:
pH ˆ pKa ‡ log10 ‰HCO3 Š=aPCO2
…1†
Where pKa is the dissociation constant for carbonic acid and a is the solubility
coefficient for carbon dioxide in blood at 378C.
By using the Henderson-Hasselbalch equation one can classify abnormalities in
plasma pH as being associated with abnormalities in PCO2 (termed respiratory) or
HCO±3 (termed metabolic). Too much PCO2 is indicative of respiratory acidosis,
while too little is termed respiratory alkalosis. Conversely, changes in pH that are
not due to PCO2 must result in changes in HCO±3. A metabolic acidosis results in a
reduction in HCO±3 while a metabolic alkalosis results in increase in HCO±3. Furthermore, changes in PCO2 that occur in response to metabolic acid-base derangements
and changes in HCO±3 that occur in response to respiratory acid-base derangements,
both termed compensation, can be predicted (Table 2). From these predictions, a
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Table 2. Acid-base patterns observed in humans. From [1] with permission
Disorder
HCO3± (mEq/L)
PCO2 (mmHg)
SBE (mEq/L)
z Metabolic acidosis
< 22
<±5
z Metabolic alkalosis
> 26
z
z
z
z
= [(PCO2±40)/10]+24
= [(PCO2±40)/3]+24
= [(40±PCO2)/5]+24
= [(40±PCO2)/2]+24
= (1.5 ´ HCO±3 )+8
= 40+SBE
= (0.7 ´ HCO±3 )+2
= 40+(0.6 ´ SBE)
> 45
> 45
< 35
< 35
Acute respiratory acidosis
Chronic respiratory acidosis
Acute respiratory alkalosis
Chronic respiratory alkalosis
> +5
=0
= 0.4 ´ (PCO2±40)
=0
= 0.4 ´ (PCO2±40)
set of rules can be derived and from these complex, as well as simple, acid-base abnormalities can be diagnosed.
The Base Excess Approach
The two primary limitations of the bicarbonate approach are: 1) it requires six
rules or equations to use, and 2) it does not quantify the magnitude of the metabolic component of an acid-base derangement. Because HCO±3 is also dependent on
the PCO2, mixed disorders will invalidate the HCO±3 concentration as a measure of
metabolic acidosis or alkalosis. This problem first lead Singer and Hastings, in
1948, to propose the term ªbuffer baseº to define the sum of HCO±3 plus the nonvolatile weak acid buffers (A±) [9]. A change in buffer base corresponds to a change
in the metabolic component. The methods for calculating the change in buffer base
were later refined by investigators [15, 16] and refined further by others [17, 18] to
yield the base excess methodology. Base excess is the quantity of metabolic acidosis
or alkalosis defined as the amount of acid or base that must be added to a sample
of whole blood in vitro in order to restore the pH of the sample to 7.40 while the
PCO2 is held at 40 mmHg [16]. While this calculation is quite accurate in vitro, inaccuracy exists when applied in vivo in that base excess changes with changes in
PCO2 [19, 20]. This effect is understood to be due to equilibration across the entire
extracellular fluid space (whole blood plus interstitial fluid). When the base excess
equation is modified to account for an `average' content of hemoglobin across this
entire space, a value of 5 g/dl is instead used and this defines the SBE. It should be
pointed out that this value does not represent the true content of hemoglobin suspended in the volume of whole blood together with interstitial fluid, but rather an
empiric estimate which improves the accuracy of the base excess. It can be argued
that the entire extracellular fluid space is involved in acid-base balance since this
fluid flows through blood vessels and lymphatics, mixing constantly [21]. Thus, the
value of SBE is that it quantifies the change in metabolic acid-base status in vivo. It
is of interest that base excess is only accurate in vivo when it assumes a constant
hemoglobin concentration.
However, neither the base excess approach nor the bicarbonate approach will tell
us about the mechanisms of metabolic acid-base balance. For example, the body
does not `regulate' the SBE. It is not a substance that can be excreted in the feces
or reabsorbed from the proximal tubule. Similarly, any metabolic acid will titrate
Making Strong Ion Difference the ªEuroº for Bedside Acid-Base Analysis
HCO±3 and changes in this variable tell us nothing anything about the nature of acid
or base in question.
The Physical Chemical Approach
There are three mathematically independent determinants of blood pH:
z the difference between strong cations (e.g., Na+, K+) and strong anions (e.g., Cl±,
lactate) known as the SID;
z the total weak acid `buffers' (ATOT) which include mainly albumin and phosphate
and lastly;
z PCO2.
These three variables (SID, ATOT and PCO2) and only these three can independently
affect plasma pH. H+ and HCO±3 are dependent variables whose concentrations in
plasma are determined by SID, ATOT and PCO2. Changes in H+ concentration in
plasma occur as a result of changes in the dissociation of water and ATOT brought
about by the electrochemical forces produced by changes in SID, and PCO2. The
main difference between the physical chemical approach and other approaches is
the emphasis on independent and dependent variables. Only changes in the independent variables (SID, ATOT and PCO2) can bring about changes in the dependent
variables (H+ and HCO±3). Movements of H+ or HCO±3 per se cannot affect their
concentrations in plasma unless changes in SID, ATOT and/or PCO2 also occur. Several detailed reviews of this approach are available in the literature [1, 4±6, 22±24].
z Common Currencies for Acid-Base Analysis
Strong Ion Difference and Standard Base Excess
As discussed above, SID can be defined in terms of strong ions or buffer base. But
are the two the same and what is the real SID? It is impractical if not impossible to
measure all the strong ions in blood plasma. In health, well over 95% of all the
strong cations in plasma are Na+ ions. The rest, are ions of K+, Ca++ and Mg++.
Although these last two are divalent, so they count twice, both are partially bound
to albumin, thus the free (or ionized) concentrations of both are usually quite low
(and it is only the ionized concentrations that contribute to the SID). On the anion
side, the vast majority are Cl± ions, with lactate contributing only a mEq or two
per liter in health except during exercise. However, blood plasma may contain
many other ions such as ketones, sulfate, citrate, acetate and many others. In the
ICU, the concentration of each of these ions may reach a level that significantly affects the SID. Thus, if we measure all the Na+, K+, Ca++ and Mg++ and subtract all
the Cl± and lactate we still only have the apparent SID (SIDa) the actual SID may
be quite different. By contrast the SIDe which is also known as buffer base is derived from PCO2 and A±. Importantly, however, while PCO2 can be quite accurately
measured in a blood sample, A± is estimated from the albumin and phosphate concentrations. Conformational changes in albumin and unmeasured weak ions, especially proteins, may be present and as such, the SIDe may be quite different from
the SID. The difference between the SIDa and the SIDe is the SIG ± a `gap' in the
strong ion difference but composed itself of either strong or weak ions or both. In-
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deed, it would be possible for the sum of strong cations and weak anions (or vice
versa) to cancel each other out leaving a SIG of zero but plenty of unmeasured ions
still present. For practical purposes, however, most SIGs are positive (meaning anions > cations) and SIDa > SIDe. Since weak ions are indeed weak, and conformational changes in albumin are not thought to amount to very significant effects on
A±, it is likely that SIDe is closer to the true SID. However, it is not necessary that
we know the `true' SID only whether it is normal relative to that patient's acid-base
equilibrium point. And for this we can safely use the SBE. SBE is mathematically
equivalent to the change in SID required to restore pH to 7.4 given a PCO2 of
40 mmHg and the prevailing ATOT. Thus, a SBE of ±10 mEq/L means that the SID is
10 mEq less than that required to achieve pH 7.4. What the SID actually is, is not
particularly helpful. Thus, while SID appears to be a suitable common currency for
evaluating the metabolic component of an acid-base abnormality, the way we measure its impact is the SBE.
The Anion Gap and the Strong Ion Gap
Metabolic acid-base disturbances can be brought about by changes in strong ions
or weak ions. These ions can be routinely measured (e.g., Cl±) or not (e.g., ketones). Those not routinely measured are referred to as unmeasured ions. Many
years ago, it was impractical to measure certain ions such as lactate and it remains
impractical to measure others such as sulfate. Thus, the literature contains a confusing array of information regarding the magnitude of unmeasured ions (usually
anions) and techniques to estimate them.
Among these techniques the anion gap is without question the most durable.
For more than 30 years the anion gap has been used by clinicians and it has
evolved into a major tool to evaluate acid-base disorders [25]. The anion gap is calculated, or rather estimated, from the differences between the routinely measured
concentrations of serum cations (Na+ and K+) and anions (Cl± and HCO±3). Normally, this difference or `gap' is made up of two components. The major component
is A±, i.e., the charge contributed by albumin, and to a lesser extent by phosphate.
The minor component is made up by strong ions such as sulfate and lactate, whose
net contribution is normally less than 2 mEq/L. However, there are also unmeasured (by the anion gap) cations such as Ca++, and Mg++ and these tend to offset
the effects of sulfate and lactate except when either is abnormally increased
(Fig. 1). Plasma proteins other than albumin can be either positively or negatively
charged but in the aggregate tend to be neutral [8] except in rare cases of abnormal
paraproteins such as in multiple myeloma. In practice the anion gap is calculated
as follows:
Anion gap ˆ …Na‡ ‡ K‡ †
…Cl ‡ HCO3 †
…2†
+
Because of its low and narrow extracellular concentration, K is often omitted from
the calculation. Respective normal values with relatively wide ranges reported by
most laboratories are 12Ô4 (if K+ is considered) and 8Ô4 mEq/l (if K+ is not considered). The `normal anion gap' has decreased in recent years following the introduction of more accurate methods for measuring Cl± concentration [26, 27]. However, the various measurement techniques available mandate that each institution
reports its own expected `normal anion gap'.
Some authors have raised doubts about the diagnostic value of the anion gap in
certain situations [28, 29]. Salem and Mujais [28] found routine reliance on the an-
Making Strong Ion Difference the ªEuroº for Bedside Acid-Base Analysis
Fig. 1. Charge balance in blood plasma. Shaded area comprises cations; unshaded comprises anions. A±,
dissociated weak acid; L±, lactate; X±, unmeasured strong anions. The anion gap is comprised of A±, L±
and X±, along with any unmeasured weak acids (part of A± but not `seen' by the calculation) plus any
variation in unmeasured cations outside their normal narrow range. By contrast strong ion gap (SIG) is
comprised only of X± plus any unmeasured part of A±
ion gap to be ªfraught with numerous pitfallsº. The primary problem with the anion gap is its reliance on the use of a `normal' range produced by albumin and to a
lesser extent phosphate as discussed above. These constituents may be grossly abnormal in patients with critical illness leading to a change in the `normal' range for
these patients. Moreover, because these anions are not strong anions their charge
will be altered by changes in pH. This has prompted some authors to adjust the
`normal range' for the anion gap by the patient's albumin and phosphate concentration. Each g/dl of albumin has a charge of 2.8 mEq/l at pH 7.4 (2.3 mEq/l at 7.0
and 3.0 mEq/l at 7.6) and each mg/dl of phosphate has a charge of 0.59 mEq/l at
pH 7.4 (0.55 mEq/l at 7.0 and 0.61 mEq/l at 7.6). Thus a convenient way to estimate
the `normal' anion gap for a given patient is by use of the following formula [1]:
`normal' anion gap=2(albumin g/dl) + 0.5(phosphate mg/dl)
…3a†
Or for international units:
`normal' anion gap=0.2(albumin g/l) + 1.5(phosphate mmol/l)
…3b†
When this patient-specific normal range was used to examine the presence of unmeasured anions in the blood of critically ill patients, the accuracy of this method
improved from 33% with the routine anion gap (normal range = 12 mEq/L) to 96%
[1]. This technique should only be used when the pH is less than 7.35 and even
then it is only accurate within 5 mEq/l. When more accuracy is needed a slightly
more complicated method of estimating A± is required [30, 31].
Another alternative to using the traditional anion gap is to use the difference or
`gap' between the SIDa and SIDe. This is termed the strong ion gap (SIG) to distinguish it from the anion gap [30] and, unlike the anion gap, it does not change with
changes in pH or albumin concentration. Because the concentration of unmeasured
anions is expected to be quite low (< 2 mEq/l) the SIG is expected to be quite low.
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However, some investigators have found elevations in SIG, particularly in critically
ill patients even when no acid-base disorder is apparent [32±35]. By contrast, results from studies in normal animals [11, 31] and from values derived from published data in exercising humans [30], put the `normal' SIG near zero. There is even
a suggestion that critically ill patients in different countries might have differences
in their SIG. In the United States [33, 36], Holland [32], and Thailand [37] the SIG
is about 5 mEq/l while studies from England [34] and Australia [35] report values
> 8 mEq/l. The difference may lie with the use of gelatins in these countries [38],
which are an exogenous source of unmeasured ions [39]. In this scenario, the SIG
is likely to be a mixture of endogenous and exogenous anions. Interestingly, previous studies that have failed to find a correlation between SIG and mortality were
performed in countries that use gelatin based resuscitation fluids [34, 35], whereas
studies of patients not receiving gelatins [33, 37] or any resuscitation at all [36] have
found a positive correlation between SIG and hospital mortality. Indeed Kaplan and
Kellum have recently reported that pre-resuscitation SIG predicts mortality in injured
patients better than blood lactate, pH or injury severity scores [36].
Thus, the predictive value of SIG may exceed that of the anion gap but it may
vary from population to population and even between institutions. As such, estimating the SIG from the anion gap, after correcting for albumin, and PO4, and
after subtracting out lactate, may be a reasonable substitute for the long hand
calculation [1, 32, 38].
z A Common Currency Approach to the Patient
with an Acid-base Abnormality
With the SBE as measure of the change in SID and the anion gap corrected for the
patient's A± in hand, one can travel though any metabolic acid-base jurisdiction.
Furthermore, the approach described here will focus on the readily available clinical information and in these times of cost-containment may be more `user friendly'
than some of the more traditional approaches as well. In addition, this approach is
consistent with the physicochemical principles of acid-base balance outlined above.
First, Characterize the Disorder
The first step in the approach to a patient with an acid-base imbalance is to characterize the disorder. Acid-base imbalances are usually recognized by abnormalities
in the venous plasma electrolyte concentrations so it is useful to start there.
Although HCO±3 is a dependent variable, the venous HCO±3 concentration is the easiest way to screen for acid-base disorders. However, a normal HCO±3 concentration
in no way excludes the presence of even serious acid-base derangements. Therefore,
if the history and physical examination leads one to suspect a disease process that
results in an acid-base imbalance, more investigation will be required. Still, the
venous plasma electrolytes provide useful information. The HCO±3 concentration is
normally 22-26 mEq/l. Increases in HCO±3 concentration occur with primary and
compensatory metabolic alkaloses and decreases occur with primary or compensatory metabolic acidoses. Unfortunately, in mixed disorders, the HCO±3 concentration
may be misleading and the presence of any abnormality in HCO±3 concentration
requires further investigation. In addition to examining the HCO±3 concentration,
Making Strong Ion Difference the ªEuroº for Bedside Acid-Base Analysis
venous blood can be used to calculate the anion gap (equation 2) and compare it
to the normal anion gap (A±) estimated from albumin and PO4 (equation 3a or b).
If the HCO±3 concentration is < 22 or > 26 mEq/l or the anion gap ± A± is > 2 mEq/l
or if there is clinical suspicion for a mixed disorder, arterial blood should be
sampled for blood gas analysis. This test will provide information on the pH,
PaCO2 and SBE. While simple disorders will conform to the equations presented in
Table 2, `mixed' disorders are quite common.
In patients with acidemia (arterial blood pH < 7.35), the next step is to examine
the anion gap. The anion gap should also be examined when there is suspicion of
an occult metabolic acidosis even in a patient with alkalemia. However, severe alkalemia will increase anion gap by 2±4 mEq/l and hence wider `tolerance limits'
should be used. Further, the presence of unexplained anions in the absence of
acidosis is of uncertain clinical significance. If unmeasured anions are detected, it
is a good idea to compare their amounts to the abnormality in SBE. For example,
if the calculated anion gap is 5 mEq/l > the estimated A± and the SBE is ±15 mEq/l,
a mixed metabolic acidosis is present. The unmeasured anions (e.g., ketones) account for a SBE of ±5 mEq/l while some other process is responsible for another
10 mEq/l. Such a condition could occur, for example, if very large amounts of 0.9%
saline are used to treat a patient with diabetic ketoacidosis. As the ketosis resolves
the acidosis persists because the SID is kept low from exogenous Cl± administration. In any case, the SBE of ±15 mEq/L means that the SID is 15 mEq less than its
equilibrium point. The anion gap calculation provides information as to why. If the
anion gap = A± then SIG is close to zero and the cause of the acidosis must be one
(or more) of the measured ions. A quick inspection of the two most important ions
(Na+ and Cl±) will often provide the diagnosis. However, beware of assigning too
much significance to a single ion. It is the balance between strong cations and
strong anions that is important. Na+ and Cl± make up the majority of the SID. The
second pitfall is to expect a specific normal value for SID. The only normal SID is
the one that occurs at the equilibrium point for that blood sample when pH is 7.40
and PCO2 is 40 mmHg.
Second, Determine the Cause
Once the disorder has been characterized, the clinician must integrate the information obtained from the history and physical examination in order to arrive at an
accurate diagnosis. However, mixed disorders continue to be problematic. Any disorder that does not fit into the classification scheme shown in Table 2 can be considered a mixed disorder. However, some mixed disorders may appear to be simple
disorders when first encountered. For example, a patient with chronic respiratory
acidosis and a PaCO2 of 60 mmHg would be expected to have an SBE +8 mEq/l
(see Table 2). If this patient develops a metabolic acidosis, the SBE will decrease
and may at one point be 0 mEq/l. At this point, it may appear that the patient has
a pure, acute respiratory acidosis rather that a mixed disorder. If the metabolic
acidosis causes an increase in the anion gap, this may provide a clue. Another useful method is to obtain at least two blood gas analyses in order to examine for
trends. However, in general, it is only by careful attention to history and physical
examination that the true diagnosis can be made. In all cases using all the available
information and keeping in mind the `common currency' of SID will greatly simplify the task.
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