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Paul W.G. Elbers, Victor A. van Bochove,
Pieter Roel Tuinman, and Rainer Gatz
Acid–base disturbances are common in critically ill patients
and have important physiologic, prognostic, and diagnostic
implications. Acidity is determined by the concentration of
H+, usually expressed as its negative logarithm, i.e., pH
(Table 10.1). Normal [H+] is essential for the function of proteins and hence enzymes, cells, and organ systems. Therefore,
it is tightly regulated.
The Stewart Approach
Traditionally, the bicarbonate-centered and base excess
methods have dominated the approach to acid–base disturbances in the United States and Europe, respectively. More
recently, the quantitative approach by Stewart has emerged,
especially in critical care medicine. Although all approaches
are mathematically compatible, this physiochemical
approach arguably facilitates better understanding and quantification of complex acid–base disorders. As these occur
frequently in critically ill patients, this chapter will primarily
focus on the Stewart approach. Important normal values in
acid–base physiology including those related to the quantitative approach are given in Table 10.2.
One of the fundamental principles of the Stewart approach
is that [H+] is governed by a system of chemical equilibrium
equations that have to be satisfied simultaneously (see
Table 10.3).
These can then be mathematically combined and rearranged to yield an expression of [H+] in terms of so-called
independent parameters:
éëH + ùû + éëH + ùû ´ ([ K A ] + [SID ]) + éëH + ùû ´ éë K A ùû ´ [SID ] - [ ATOT ] - K C ´ PCO2 + K W
))) +
éëH + ùû ´ K A ´ K C ´ PCO2 + K W
+ K 3 ´ KC ´ PCO2 - K A ´ K 3 ´ K C ´ PCO2 = 0
While this may seem intimidating at first glance, these actually demystify the topic completely as there are only three of
these independent parameters that determine [H+]. These are:
1. PCO2, the partial pressure of CO2
2. SID, the strong ion difference
3. ATOT, the concentration of nonvolatile weak acids
P.W.G. Elbers, MD, PhD (*) • P.R. Tuinman, MD, PhD
Department of Intensive Care Medicine, VU University Medical
Center, De Boelelaan 1117, Amsterdam 1081 HV, The Netherlands
e-mail: [email protected]; [email protected]
This implies that all disturbances and corrections occur
by changes in one or more of these parameters. In addition,
they also ultimately determine other dependent variables
such as [HCO3−] and anion gap. In other words, [H+] is a
function of the independent parameters:
V.A. van Bochove, MSc
Department of Anesthesiology, Erasmus University
Medical Center, Rotterdam, The Netherlands
R. Gatz, MD
Department of Anaesthesia and Intensive Care, Herlev Hospital,
Herlev, Denmark
éëH + ùû = f ( SID, ATOT , PCO2 ) One can think of the independent variables as three forces
trying to move [H+] up or down. [H+] will be determined by
© Springer International Publishing Switzerland 2016
J.M. O’Donnell, F.E. Nácul (eds.), Surgical Intensive Care Medicine, DOI 10.1007/978-3-319-19668-8_10
P.W.G. Elbers et al.
Table 10.1 Relationship between hydrogen ion concentration and pH
[H ] (nanoEq/L)
Table 10.2 Important acid–base-related parameters and their normal
35–45 nanoEq/L
38–42 mmHg
38–42 mEq/L
0–2 mEq/L
8–16 mEq/L
22–26 mEq/L
SID strong ion difference, SIG strong ion gap, AG anion gap
Table 10.3 The Stewart equations
Water dissociation
Weak acid
Conservation of
mass for “A”
Bicarbonate ion
Carbonate ion
Electrical neutrality
éëH + ùû ´ éëOH - ùû = K W
KA × [HA] = [H+] × [A−]
[PCO2] × KC = [H+] × [HCO3−]
[K3] × [HCO3−] = [H+] × [CO32−]
SID + [H+] − [HCO3−] − [A−] − [CO32−] − [OH−] = 0
All equations reflect chemical equilibriums that need to be satisfied
simultaneously. K items represent constants. Units are mEq/L for ions,
mM for HA, and ATOT and kPa or mmHg for PCO2. SID strong ion difference. See text for detailed explanation
Table 10.4 Classification of acid–base disorders based on the Stewart
High PCO2
Low PCO2 alkalosis
For low SID and/or high ATOT
Pain, fear, stress, voluntary,
Pregnancy (progesterone)
Early sepsis (cytokines)
Hepatic failure (toxins)
Drugs (analeptics, salicylate
Head injury, stroke
Any cause of hypoxemia
Pulmonary embolism
Pulmonary edema (all types)
Excessive mechanical
High PCO2 acidosis
For high SID and/or low ATOT
Drugs (opioids, sedatives)
Head injury, stroke, tumor, infection
Hypoventilation of obesity
Cervical cord lesion <C4
Guillain–Barré syndrome
Myasthenia gravis
Neuromuscular blocking agents
Toxins (organophosphates)
Lung or chest wall disease
Exacerbation of COPD
Chest trauma
Diaphragmatic paralysis
Pulmonary edema
Restrictive lung disease
Airway disorders
Inadequate mechanical ventilation
SID strong ion difference. See text for details
ATOT = [A−] + [HA]
Non-respiratory (metabolic)
Table 10.5 Causes of PCO2-induced alkalosis and acidosis
Low PCO2
High SID
their relative strength. A classification of acid–base disturbances based on this approach is given in Table 10.4.
It follows from the Stewart equations that if PCO2
increases, [H+] must increase as well. Causes of high PCO2
acidosis and low PCO2 alkalosis may be found in
Table 10.5. These include the respiratory response to acid–
base disturbances, which exert their compensatory effect
on [H+] by modulating PCO2.
Normally, alveolar ventilation is adjusted to balance
cellular CO2 production. The respiratory center controls
alveolar ventilation. Normal PCO2 is between 35 and
45 mmHg. In case of hyperventilation or hypoventilation
in relation to CO2 production, PCO2 will decrease or
increase, respectively.
High PCO2 acidosis is commonly encountered in the
critically ill patient who cannot maintain adequate ventilation. Specific etiologies include airway obstruction, respiratory center depression, neuromuscular disorders, and
pulmonary diseases such as chronic obstructive pulmonary
disease (COPD). High PCO2 acidosis is also induced with
intentional hypoventilation (permissive hypercapnia) to
aid in the treatment of patients with status asthmaticus or
acute respiratory distress syndrome. This lung protective
ventilatory strategy is well tolerated by the patient and has
little impact on hemodynamics. Mismatch in alveolar ventilation and CO2 production can also occur in case of
increased CO2 production as seen in sepsis. Of note, alveolar ventilation may markedly differ from ventilation measured as tidal volume times respiratory rate, because of
anatomic dead space but more importantly physiological
dead space.
Low CO2 alkalosis results from increased alveolar ventilation relative to CO2 production. Alveolar ventilation is
regulated by several factors: chemoreceptors in the medulla
10 Acid–Base
and great vessels, voluntary control, and pulmonary chemoreceptors and stretch receptors. Any of these factors alone or
in combination may lead to hyperventilation.
Strong ions are essentially completely dissociated and thus
exist in charged form only, even if substantial amounts of
some of these ions are non-covalently bound to serum
proteins. Important examples are Na+, K+, Ca2+, Mg2+,­
Cl−, lactate, and keto acids. In contrast, weak ions can exist
both in charged and uncharged forms. Examples include
HCO3−, albumin, and inorganic phosphate (Pi).
The SID is the sum of strong cations minus the sum of
strong anions. In plasma, it is mainly determined by [Na+]
and [Cl−] and its normal value is about 40 mEq/L.
It follows from the Stewart equations that if SID decreases,
[H+] must increase and vice versa. Causes of low SID acidosis and high SID alkalosis may be found in Table 10.6. These
include the renal response to acid–base disturbances, which
exert their compensatory effect on [H+] by modulating SID.
Table 10.6 Causes of SID-induced alkalosis and acidosis
Low SID acidosis
For low PCO2 and/or low ATOT
Increased SIG/AGC
Lactic acidosis
Type A (inadequate O2 delivery)
Type B (altered metabolism)
Alcohol induced
Acute renal failure
Increased osmol gap
Ethylene glycol
Normal SIG/AGc
Infusion of low SID solutions
(e.g., NaCl 0.9 %, D5W, H2O)
Water retention
Positive urine SID
Renal tubular acidosis
Carbonic anhydrase inhibitors
Acute or chronic kidney disease
Negative urine SID
Severe diarrhea
Pancreatic or biliary drainage
Small bowel fistula
High SID alkalosis
For high PCO2 and/or high
ATOT acidosis
Urine [Cl−] < 10 mM
Use of diuretics
Vomiting, gastric drainage
Villous adenoma
Cl−-rich diarrhea
Urine [Cl−] > 20 mM
Severe potassium depletion
Ongoing diuretic use
Steroid administration
ACTH excess
Primary hypercortisolism
Renin-secreting tumor
Primary hyperaldosteronism
Cushing’s syndrome
Bartter’s syndrome
Liddle’s syndrome
Excessive licorice intake
Strong cation administration
(e.g., NaHCO3, citrate,
acetate, lactate)
Water loss
Milk–alkali syndrome
Laxative abuse
Exogenous alkali
SID strong ion difference, SIG strong ion gap, AGc corrected anion gap.
See text for details
Weak acids are molecules that exist in incompletely ionized
forms. They are grouped as ATOT, the total amount of weak
acids (ATOT), and consist mainly of plasma proteins. From an
acid–base perspective, albumin and to a lesser extent phosphate are the most important contributors.
It follows from the Stewart equations that if ATOT increases,
[H+] must also increase. This implies that hypoalbuminemia
of any cause contributes to alkalosis. Similarly, hyperphosphatemia, as seen in renal failure, causes acidosis.
While the body actively controls SID and PCO2 to regulate
acid–base balance, there is no evidence that the control of
albumin or phosphate levels is used to control for acid–base
disturbances. This, ATOT may rather be thought of as a set
point that modifies the balance between SID and PCO2 to set
[H+]. This is of paramount importance in the critically ill as
hypoalbuminemia and dysphosphatemia are often present.
Strong Ion Gap
According to the principle of electrical neutrality, blood plasma
cannot be charged, so SID must be balanced by negative
charges. These mostly stem from CO2 (as HCO3−) and the weak
acids (mainly the anionic forms of albumin and phosphate
expressed as [A−]). We can calculate SID based on the negative
charges of the weak acids. This is called effective SID or SIDE:
SID E = ëéHCO3 - ùû + éë A - ùû where [A−] represents mainly [Albumin−] and [Pi−]. Their
contribution may be quantified by calculating their anionic
fraction. For physiological pH ranges, the following simplified formulas have good accuracy:
éë Albumin - ùû = 0.25 ´ éë Albumin ( g / L ) ùû
éë Pi - ùû = 1.5 ´ éë Pi - ( mmol / L ) ùû
We can also calculate SID on the basis of the amounts of
routinely measured strong ions. This is called the “apparent
SID A = éë Na + ùû + éëK + ùû + 2 ´ éë Mg 2 + ùû + éë Ca 2 + ùû - éëCl - ùû
For practical purposes a simplified formula is recommended: SIDA = [Na+] + [K+] – [Cl–]. The strong ion gap
(SIG) may now be calculated from the difference between
apparent and effective SID:
SIG = SID A – SID E The normal value for SIG is 0–2 mEq/L. However, normal values for gaps should be verified locally as they may
P.W.G. Elbers et al.
Fig. 10.1 Graphical
representations of AG (a) and
SIG (b). Not to scale. Adapted
from: Mizock BA. Lactic
acidosis. In: Kellum JA, Elbers
PW, editor. Stewart’s textbook of
acid-base. 2nd ed. Amsterdam:; 2009 (copyright:
Paul Elbers)
Ca Mg
differ between hospitals as they depend on the individual
components in the formula and their local normal values.
A graphical representation of SIG may be found in
Fig. 10.1. An increased SIG is virtually always caused by
lactate or unmeasured anions.
Lactic acidosis is the most commonly encountered cause
of an SIG acidosis in the critically ill. It can occur as a
result of either excessive lactate formation or decreased
lactate clearance and can be divided into type A, or hypoxic
lactic acidosis, and type B, or nonhypoxic lactic acidosis.
Type A lactic acidosis is caused primarily by an increase in
lactate formation as a consequence of tissue hypoxia,
resulting, for example, from hemorrhagic shock. Type B
lactic acidosis occurs during normal oxygen delivery and
often occurs secondary to a variety of medications (epinephrine, biguanides, nitroprusside, AZT), metabolic diseases (glucose 6-­phosphatase deficiency), and severe liver
failure. The pathogenesis of lactic acidosis in sepsis is multifactorial and may include the development of anaerobic
glycolysis within tissues, the inhibition of pyruvate dehydrogenase (an enzyme that converts pyruvate into acetyl
coenzyme A), and a defective oxygen use at the mitochondrial level.
Another common cause of high SIG acidosis is diabetic
ketoacidosis. In typical severe cases SIG levels are
10–20 mEq/L. Other causes of an elevated AG acidosis may
be diagnosed with appropriate laboratory evaluation.
To further differentiate between causes of SIG, the osmol
gap may be calculated. The osmol gap is equal to the difference between the measured serum osmolarity (OsmM) and
the calculated serum osmolarity. A high plasma osmol gap
(>10–15 mOsm/L) reflects the presence of an unmeasured
non-ionized compound. It can be mathematically represented as follows:
æ 2 ´ é Na + ( mmol / L ) ù ö
û ÷
ç ë
Osmol gap = Osm M – ç + éë Urea ( mmol / L ) ùû ÷
ç + éëGlucose ( mmol / L ) ùû ÷
To convert urea and glucose from mg/dL to mmol/L,
divide by 18 and 2.8, respectively. The most frequent causes
of an increased osmol gap are alcohol, mannitol, and ketones.
Toxic alcohols also increase SIG as they are metabolized to
organic acids such as glycolic acid. Thus, as a general rule, a
high SIG metabolic acidosis together with an elevated osmol
gap is probably due to intoxication with a toxic alcohol if
lactic acidosis and diabetic ketoacidosis are not present and
mannitol has not been administered. It should be noted that
glycol intoxication may lead to falsely high lactate levels due
to interference with its measurement.
A low SID without an elevated SIG implies that this must
be caused by changes in the measured strong ions. This is
sometimes referred to as hyperchloremic acidosis. However,
this may be a misnomer, as this type of acidosis can also
exist without high chloride concentrations, provided that
strong cations (mainly Na+) are more decreased than [Cl−].
It is useful to first assess any water excess, detected by
abnormal Na+, and determine its cause. Water excess will
cause a direct reduction in the normally positive SID because
strong cations and strong anions are equally diluted. As a
second step, a review of recent infusions is warranted. As
explained below, these can directly influence SID. If no
obvious cause is apparent, urine SID may be helpful to
10 Acid–Base
d­ ifferentiate between gut and renal causes of SID acidosis.
The urine SID is the difference between the routinely measured urinary cations and anions:
Table 10.7 Ionic composition of common intravenous fluids
D 5W
Gelatin 4 %
NaHCO3 1.4 %
NaHCO3 8.4 %
Urine SID = éë Na + ùû + éëK + ùû – éëCl - ùû u
The presence of a positive urine SID in an individual with
low SID acidosis without SIG suggests that the disorder is
due to an impaired acid–base handling by the kidneys (e.g.,
distal renal tubular acidosis). Conversely, the presence of a
negative urine SID suggests that the metabolic acidosis is
due to gastrointestinal causes (e.g., diarrhea). In patients
with renal insufficiency or in those being treated with diuretics, urinary values need to be interpreted with caution.
Finally serum potassium may be helpful in distinguishing
causes of low SID acidosis. Hypokalemia (<3.5 mmol/L) is
associated with ureteral diversion, diarrhea, proximal colostomy, ileostomy, proximal renal tubular acidosis (RTA),
type I distal RTA, and parenteral nutrition. Hyperkalemia
(>4.5 mmol/L) can be found in hypoaldosterone states, ammonium chloride administration, and type IV distal RTA.
An increased strong ion difference is alkalinizing. A common cause is aggressive diuresis with loop diuretics resulting in a low intravascular volume. Other etiologies are noted
in Table 10.6 and are grouped into those that are associated
with hypovolemia or hypervolemia, although significant
overlap may exist. Measurement of [Cl−]u is usually more
helpful in distinguishing the two categories, provided that
renal compensatory capacity is not severely impaired. In
non-respiratory alkalosis, the [Cl−]u is a more accurate reflection of intravascular volume than urine sodium.
Fluid Therapy
Infusion fluids can directly influence SID. This happens
when the SID of the infusion fluid itself differs from that of
plasma. For example, NaCl 0.9 % contains 154 mM Na+ and
154 mM Cl−; hence its SID is zero. Adding NaCl 0.9 % to
plasma with SID of 40 mM will directly lower its SID. Thus
overzealous infusion of low SID solution will cause acidosis.
As fluid SID determines its effect, the pH of an infusion fluid
is not of any importance. Balanced infusion fluids usually
contain strong anions such as lactate or acetate. Immediately
upon infusion, their SID will also be 0 mM. However, the
anions are normally rapidly metabolized, effectively increasing the SID of these solutions. An overview of the constitution and SID of commonly used infusion fluids is given in
Table 10.7. Finally it should be remembered that in clinical
practice, kidney handling of strong ions and dilution of ATOT
will partially offset the effect on plasma SID of infusion
HCO3− Lactate−
Lactated Ringer’s is made by a number of different manufacturers and
may have slight variations in formula
Table 10.8 Potential complications of bicarbonate administration
Volume overload
Paradoxical cerebrospinal fluid/intracellular acidosis
Respiratory acidosis
Impaired O2 delivery (tissue hypoxia)
Overshoot alkalemia
Classic buffer fluids include sodium bicarbonate and tromethamine. Although studies have not shown consistent
benefit, it is reasonable to administrate these fluids in severe
acidosis as a temporizing measure. Sodium bicarbonate
directly increases SID and is thus alkalinizing. However,
bicarbonate ions combine with hydrogen ions to form carbonic acid, which in turn dissociates into water and CO2.
Thus, potential complications of bicarbonate administration
may outweigh possible benefits (Table 10.8). Tromethamine
(THAM) is a weak alkali that increases arterial pH without
producing CO2. THAM has potentially serious side effects,
including hypoglycemia and hyperkalemia.
Bedside Stewart Approach
Using the Stewart approach at the bedside may be perceived
as cumbersome because of the calculations involved.
However, the widespread introduction of computers in clinical medicine has solved this problem. The online clinical
module at gives a complete description
and in-depth analysis of any acid–base problem.
However, for rapid clinical assessment, we suggest the
following simplified approach. It introduces a simplified version of SIG by focusing only on [Na+], [Cl−], and SIDE:
1.Determine the problem and its severity by assessing
pH. Remember that acidosis and alkalosis refer to
P.W.G. Elbers et al.
­ rocesses that influence [H+] or pH. A normal pH does not
rule out acid–base pathology.
2. Assess the relative contribution of the three independent
variables that influence [H+].
(a) Assess PCO2.
A high PCO2 is acidifying. A low PCO2 is
(b) Assess ATOT and calculate its anionic charge
A− = 0.25 × [Albumin (g/L)] + 1.5 × [Pi (mmol/L)].
A high ATOT is acidifying. A low ATOT is alkalinizing.
(c) Assess SID by calculating SIDE = HCO3− + A−.
A high SID is alkalinizing. A low SID is acidifying.
3. Calculate simplified SIG = [Na+] – [Cl−] – SIDE to assess
the effect of unmeasured ions. If necessary, use osmol
gap, urine SID, and/or urine chloride to improve discrimination between causes of acid–base disturbances.
Clinical Features of Acid–Base Disorders
Clinical features of acid–base disorders depend largely on
the underlying disorder, although abnormal pH itself may
impair cardiopulmonary physiology and the immune
Alkalosis impairs oxygen delivery to tissues and causes
neuromuscular hyperexcitability likely because of induced
hypocalcemia (seizures, arrhythmias, paresthesias, carpopedal spasms). In respiratory alkalosis, acute hypocapnia
induces cerebral vasoconstriction and syncope and seizures
may occur. Cardiovascular changes may include an increase
in heart rate, arrhythmias, and angina.
Typical signs of acidosis are mostly related to the
respiratory system. For example, the rapid, deep respirations of Kussmaul breathing occur as a compensatory
response for non-respiratory acidosis. Impressive examples include cases of diabetic ketoacidosis, as these typically occur in young patients with large capacity for
respiratory compensation. Other clinical features associated with acidosis are arrhythmias, insulin resistance,
hyperkalemia, and coagulopathies. In severe acidosis,
cardiovascular collapse may be seen. In respiratory acidosis, severe elevations of PCO2 may cause asterixis, myoclonus, and seizures. Papilledema may be found during the
examination. Conjunctival and superficial facial blood
vessels also may be dilated.
Management of Acid–Base Disorders
Treatments should always primarily address the underlying causes of acid–base disorders. This implies that other
measures, such as fluid therapy to influence SID or changing the settings of the mechanical ventilator to influence
PCO2, should only be used to gain time in extreme acid–
base disturbances.
Mechanical ventilator settings have a profound effect on
acid–base status and require appropriate management with
adjustments based on pH and not only PCO2. Treatment of
respiratory acidosis may require supportive invasive or noninvasive mechanical ventilation. A therapeutic pitfall to
avoid in the treatment of respiratory acidosis is the creation
of a posthypercapnic metabolic alkalosis. This condition
most commonly occurs when a patient with compensated
chronic respiratory acidosis is ventilated to a normal or
­near-­normal PCO2.
Fluid therapy using high SID solutions such as sodium
bicarbonate may have a role in extreme acidosis, especially
if at least partially caused by a low SID, as indicated by a low
sodium-chloride difference, but such buffering should be
used with caution as outlined previously. Fluid therapy for
metabolic alkalosis, especially if [Cl−]u is low, includes low
SID solutions (Table 10.7) such as normal saline or even
HCl. For other causes of metabolic alkalosis, acetazolamide
should be considered, especially if diuresis is necessary.
Acetazolamide is a carbonic anhydrase inhibitor that produces diuresis and increases the renal excretion ratio of
sodium to chloride. However, judicious use is paramount as
acidemia may result, associated with worsening hypokalemia because of kaliuresis. Refractory or severe alkalemia
(pH > 7.6) can be treated with isotonic HCl (150 mEq/L) via
a central vein over 8–24 h. Potassium deficiencies should be
The Bicarbonate-Based Approach
The classic methods for assessing acid–base disturbances
remain popular and are based on the Henderson–Hasselbalch
equation, which is the logarithmic form of the Henderson
éëH + ùû = 24 ´ PCO2 / éëHCO3 - ùû This equation is actually one of the Stewart equations
(Table 10.3). Singling out, this fixed relationship is attractive
as it allows addressing acid–base disorders in terms of
changes in PCO2 and [HCO3−]. However, caution should be
exerted, as [HCO3−] itself is a dependent variable. Thus,
PCO2 and [HCO3−] are interdependent, which may lead to
circular reasoning.
Table 10.9 shows the four main acid–base disorders that
can be distinguished using the Henderson–Hasselbalch
equation. Respiratory disturbances are related to excess or a
deficiency of carbon dioxide (respiratory). Non-respiratory
or metabolic disturbances are associated with changes in
10 Acid–Base
Table 10.9 Acid–base disorders according to the Henderson–
Hasselbalch-based approach
Metabolic acidosis
Metabolic alkalosis
Respiratory acidosis
Respiratory alkalosis
Table 10.10 Expected compensatory mechanisms according to the
Henderson–Hasselbalch-based approach
Metabolic acidosis
Primary change
↓ [HCO3–]
Metabolic alkalosis
↑ [HCO3–]
Respiratory acidosis
↑ PCO2
Respiratory alkalosis
↓ PCO2
hyperventilation to ↓
hypoventilation to ↑
↑ renal compensation
resulting in ↑ [HCO3−]
↓ renal compensation
leading to ↓ [HCO3–]
metabolic acidosis and measured [HCO3−] of 12 mEql/L, the
expected PCO2 would be (1.5 × 12) + 8 = 26 mmHg ± 2. If the
actual PCO2 is above 28 mmHg, this indicates the presence
of an associated respiratory acidosis (e.g., ketoacidosis and
severe pneumonia). Conversely, if the actual PCO2 is below
24 mmHg, this indicates the presence of an associated respiratory alkalosis (e.g., septic shock and inappropriate mechanical ventilation).
The Henderson–Hasselbalch-based approach to respiratory acidosis is the same as that of the Stewart approach as
discussed previously. However, its approach to non-­
respiratory acid–base disturbances is different and relies on
the determination of anion gap and the delta gap.
Anion Gap and the Corrected Anion Gap
The anion gap is the difference between the concentration of
determined cations and measured anions in plasma (Fig. 10.1).
The AG can be estimated by the following formula:
Table 10.11 Expected compensation according to the Henderson–
Hasselbalch-based approach
Acid–base disorder
Metabolic acidosis
Metabolic alkalosis
Acute respiratory acidosis
Chronic respiratory acidosis
Acute respiratory alkalosis
Chronic respiratory alkalosis
Expected compensation
↓PCO2 = 1.2 × ↓ HCO3–
or PaCO2 = 1.5 × [HCO3–] + 8 ± 2
↑ PCO2 = 0.6 × ↑ HCO3–
↑ HCO3– = 0.1 × ↑ PCO2
↑ HCO3– = 0.35 × ↑ PCO2
↓ HCO3– = 0.2 × ↓ PCO2
↓ HCO3– = 0.5 × ↓ PCO2
A positive or negative change represents an increase or decrease,
respectively, from the normal value of 40 mmHg for PCO2 or 24 mEq/L
for HCO3–
Respiratory and metabolic acid–base disorders initiate
predictable compensatory mechanisms that aim to return the
pH to normal. These can be classified as follows in
Table 10.10.
Respiratory compensation occurs rapidly. Metabolic
compensation takes hours to days. However, some immediate metabolic compensation will occur because of a shift in
the dissociation of the weak acids, mainly albumin, with corresponding rises or falls in bicarbonate concentrations. Still,
acute and chronic metabolic compensation may be
distinguished. Reasonably healthy individuals exposed to a
single acid–base disturbance will show a predictable compensatory response. This has been studied and empirical calculations of the expected response have been derived,
commonly known as Winters’ formulae (Table 10.11).
If compensation is different from expected, multiple
acid–base disorders coexist. For example, in a patient with
AG = éë Na + ùû - éëCl - ùû + éëHCO3 - ùû The normal AG is 12 ± 4 mEq/L. However, normal values
for gaps should be verified locally as they may differ between
hospitals as they depend on the individual components in the
formula and their local normal values.
The unmeasured ions include proteins, phosphates, sulfates, and organic acids. These can be markedly changed in
critically ill patients, especially albumin and phosphate.
Thus the measured anion gap needs to be corrected for both.
The following formula gives a fair estimate of the corrected
anion gap:
AG C = AG + 0.25 ´ ( 40 - Albumin ( g / L ) )
+1.5 ´ (1 - Pi ( mM ) )
Although the concepts of AG and SIG have markedly different theoretical backgrounds, they both result from the
need for electroneutrality in plasma. Thus, the potential
causes of high SIG acidosis are the same as those for an elevated AG, provided that the latter be corrected for albumin
and/or phosphate levels. These causes are listed in Table 10.6.
Delta Gap
In an uncomplicated high AG metabolic acidosis, every
increase of 1 mEq/L in the AG should result in a concomitant
decrease of 1 mEq/L in [HCO3–]. Deviation from this relation suggests a mixed acid–base disorder. The difference
between these two values has been termed the delta gap
(Δgap) and can be expressed as
P.W.G. Elbers et al.
Dgap = deviation of AG C from normal
– deviation of éë HCO3 - ùû from normal
If the normal (corrected) AG is assumed to be 12 mEq/L
and the normal [HCO3–] is 24 mEql/L, then the following
equation results:
Dgap = ( AG C – 12 ) – 24 – éëHCO3 - ùû A pure AG metabolic acidosis will yield a Δgap of zero;
however, variance in measurements and the changing physiology of the patient can result in a Δgap of 0 ± 6. If the Δgap
is significantly positive, i.e., greater than +6, then a simultaneous metabolic alkalosis exists because the rise in AG is
more than the fall in HCO3. Conversely, if the Δgap is significantly negative, i.e., less than −6, then a concomitant normal AG metabolic acidosis is present because the rise in AG
is less than the fall in HCO3.
The urine anion gap is the same as the urine strong ion
difference. Together with the osmol gap and serum potassium, these can be used to differentiate between causes of
metabolic acidosis as discussed previously. Metabolic alkalosis is also treated similarly as the Stewart approach.
Bedside Bicarbonate-Based Approach
The following is a clinical approach based on the Henderson–
Hasselbalch framework that can be utilized at the bedside:
1. Determine the overall acid–base condition by measuring
pH. Is acidemia or alkalemia present?
2. Determine if the primary process is metabolic ([HCO3–]
deviation) or respiratory (PCO2 deviation).
3. If a respiratory disturbance is present, determine if it is
acute or chronic.
4. Determine if the expected compensation is adequate.
5. Calculate the AGC.
6. In case of high AGC metabolic acidosis, calculate the Δgap.
7.In case of normal AGC metabolic acidosis, calculate
the UAG.
blood pressure, 110/68 mmHg; heart rate, 80/min; respiratory rate, 8/min; and temperature, 97°F (36.1°C). The patient
is obtunded and only weakly withdraws to painful stimuli.
He is noted to have small pupils.
Laboratory: Na+ 142 mEq/L, K+ 4.0 mEq/L, Cl–
104 mEq/L, albumin 40 g/L, and ABG (pH 7.24, PCO2
60 mmHg, PO2 64 mmHg, [HCO3–] 27 mEq/L).
What are the acid–base disorder(s) and the likely etiology?
Bedside Henderson–Hasselbalch Approach
1. What is the acid–base condition? Acidemia as evidenced
by pH 7.24.
2. What is the primary process? Respiratory, because PCO2
is increased and [HCO3–] is not decreased as would be
expected for a metabolic acidosis.
3. Is the respiratory process acute or chronic? Acute, as determined by expected bicarbonate change. In acute respiratory
acidosis, an increase of 20 mmHg in the PCO2 corresponds
to an increase in bicarbonate of around 2 mEq/L.
4. Determine if the expected compensation is adequate. The
expected compensation for acute respiratory acidosis
would yield [HCO3–] of 26 mmHg.
5. Determine
AGC = [Na+] − [Cl−] − [HCO3−] + 0.25 × [40-­
Albumin] + 1.5 × [1 − Pi] = 142 − 104 − 27 − 0 − 0
(assumed) = 11 mEq/L. This is within the normal range.
Note that AGC is equal to AG here because of normal
albumin and phosphate concentrations.
Bedside Stewart Approach
1.Determine the problem and its severity by assessing
pH. Moderate acidemia as evidenced by pH 7.24.
2. Assess PCO2; 60 mmHg means an acidifying factor.
Assess SID. SIDE = [HCO3−] + [A−] = [HCO3−] + 0.25 × [Albumin] + 1.5 × [Pi] = 27 + 0.25 × 40 + 1.5 × 1
(assumed) = 38.5 mEq/L. This is 1.5 mEq/L different
from normal. Slight acidifying factor.
4. Assess ATOT: normal albumin, normal phosphate
(assumed). No significant acid–base influence.
5. S I G = [ N a + ] − [ C l − ] − S I D E = 1 4 2 − 1 0 4 − 3 8 . 5 = −0.5 mEq/L. No significant acid–base influence.
Case Examples
The following cases show the use of both the Stewart
approach and the Henderson–Hasselbalch-based approach
for the bedside evaluation of acid–base disorders.
Answer: The acid–base condition is acute respiratory acidosis with a likely etiology of respiratory center depression
from acute narcotic and/or alcohol intoxication or head
Case 8-A
Case 8-B
A 24-year-old male is brought to the emergency center with
head trauma after a fall at a party. On arrival, vital signs are
A 68-year-old female with chronic renal failure presents with
fever, severe right lower quadrant pain, and diarrhea for
10 Acid–Base
2 days. Laboratory: electrolytes (Na+ 135 mEq/L, K+
3.4 mEq/L, Cl– 106 mEq/L) and albumin 35 g/L. Arterial
blood gas results: pH 7.44, PCO2 12 mmHg, PO2 74 mmHg,
[HCO3–] 8 mEq/L.
What are the acid–base disorder(s) and the likely etiology?
­ etabolic acidosis. The respiratory alkalosis and the anion
gap acidosis are likely due to sepsis from an intra-abdominal
source. The additional process of the normal anion/low SID
acidosis may be related to the diarrhea. Pain and anxiety could
contribute to the respiratory alkalosis, whereas possible renal
insufficiency may contribute to high SIG metabolic acidosis.
Bedside Henderson–Hasselbalch Approach
1. What is the acid–base condition? The pH is at the alkalemic end of the normal range; thus, a primary alkalosis is
likely present.
2. What is the primary process? Respiratory because PCO2
is decreased and [HCO3–] is not increased as would be
expected for a metabolic alkalosis.
3.Is the respiratory alkalosis acute or chronic? In acute
respiratory alkalosis, the reduction of 28 mmHg in PaCO2
would correspond to a decrease in bicarbonate of around
2.8 mEq/L. The expected bicarbonate would be around
21 mEq/L. In chronic respiratory alkalosis, the decrease
of 28 mmHg in PaCO2 would correspond to a reduction in
bicarbonate of around 9.8 mEq/L.
4. Is the metabolic compensation adequate? The expected
bicarbonate would be around 14 mEq/L. The bicarbonate
concentration of the patient is lower than expected for
either acute or chronic alkalosis. Thus, there is an associated metabolic acidosis.
5. Calculate the corrected anion gap. AGC = [Na+] − [Cl−] − [HCO3−] + 0.25 × [40-­Albumin] + 1.5 × [1 − Pi] = 135 − 106 − 8 + 1.25 + 0 (assumed) = 22.25 mEq/L, which is elevated. Thus, an anion gap metabolic acidosis also exists.
6. Calculate the Δgap. Δgap = (AGC − 12) − (24 − [HCO3–]) = (22.25 − 12) − (24 − 8) = −5.75 mEq/L. Thus, this is a
borderline low value, close to indicating a coexisting normal anion gap acidosis.
Bedside Stewart Approach
1.Determine the problem and its severity by assessing
pH. The pH is in the alkalemic range of normal.
2. Assess PCO2; 12 mmHg means an alkalinizing factor.
Assess SID. SIDE = [HCO3−] + [A−] = [HCO3−] + 0.25 × [ A l bu m i n ] + 1 . 5 × [ P i ] = 8 + 0 . 2 5 × 3 5 + 1 . 5 × 1
(assumed) = 18.25 mEq/L. This is 21.75 mEq/L different
from the normal value of 40 mEq/L. Acidifying factor.
4. Assess ATOT: Slightly decreased albumin, normal phosphate (assumed). Slight alkalinizing influence of albumin.
5. SIG = [Na+] − [Cl−] − SIDE = 135 − 106 − 18.25 = 10.75 mEq/L. Thus, the SIG explains about half the deviation of SID
from its normal value, the rest being due to relative
Answer: The coexisting acid–base disorders are (1) primary
respiratory alkalosis, (2) anion gap/SIG metabolic acidosis,
and (3) hyperchloremic (normal anion gap) or low SID
Case 8-C
A 56-year-old female is brought to the emergency center after
a fall. She seems to have broken her right femur. She is somnolent and her vital signs are blood pressure, 140/70 mmHg;
heart rate, 90/min; and respiratory rate, 21/min.
Laboratory: Na+ 130 mEq/L, K+ 3.5 mEq/L, Ca2+ 4.0 mEq/L,
Mg2+ 1.6 mEq/L, Cl− 90 mEq/L, Pi 0.9 mmol/L, albumin
20 g/L, pH 7.50, PCO2 30 mmHg, HCO3− 23.5 mmHg.
What are the acid–base disorder(s) and the likely
Bedside Henderson–Hasselbalch Approach
1.What is the acid–base condition? The pH is alkalemic.
Thus, a primary alkalosis is likely present.
2. What is the primary process? Respiratory because PaCO2
is decreased and [HCO3–] is not increased as would be
expected for a metabolic alkalosis.
3.Is the respiratory alkalosis acute or chronic? In acute
respiratory alkalosis, the reduction of 10 mmHg in PaCO2
would correspond to a decrease in bicarbonate of around
2 mEq/L. The expected bicarbonate would be around
22 mEq/L. In chronic respiratory alkalosis, the decrease
of 10 mmHg in PaCO2 would correspond to a reduction in
bicarbonate of around 5 mEq/L, yielding an expected
bicarbonate of 19 mEq/L.
4. Is the metabolic compensation adequate? The bicarbonate concentration of the patient is slightly higher than
expected for acute respiratory alkalosis, although this is
typically judged as being in the expected range.
5. Calculate the corrected anion gap. AGC = [Na+] − [Cl−] − [HCO3−] + 0.25 × [40-­Albumin] + 1.5 × [1 − Pi] = 130 − 90 − 23.5 + 5 + 0.15 = 21.65 mEq/L, which is elevated. Thus,
an anion gap metabolic acidosis also exists.
6. Calculate the Δgap. Δgap = (AGC − 12) − (24 − [HCO3–])
= (21.35 − 12) − (24 − 23.5) = 8.85 mEq/L. This indicates
the existence of a coexisting metabolic alkalosis.
Bedside Stewart Approach
1.Determine the problem and its severity by assessing
pH. Alkalemia as evidenced by a pH of 7.50.
2. Assess PCO2; 30 mmHg means an alkalinizing factor.
Assess SID. SIDE = [HCO3−] + [A−] = [HCO3−] + 0.25 × [Albumin] + 1.5 × [Pi] = 23.5 + 0.25 × 20 + 1.5 × 0.9 = 118
29.85 mEq/L. This is 10.15 mEq/L different from the
­normal value of 40 mEq/L. Acidifying factor.
4 . Assess ATOT. There is a severely decreased albumin concentration. This implies a strong alkalinizing factor.
5. SIG = [Na +] − [Cl −] − [HCO 3−] − SID E[A −] = 130 − 90 − 29.85 = 10.15 mEq/L. Thus, the high SIG completely
explains the low SIDE.
Answer: The metabolic acidosis is almost exactly balanced by alkalosis of hypoalbuminemia, so that [HCO3−] is
within normal limits; AGC and SIG are high. It would be easy
to miss this and interpret the data as a simple respiratory
alkalosis, with no metabolic abnormalities. In this case, the
AGC and SIG were found to be caused by ketoacidosis,
despite this patient’s alkalemia.
Further Reading
1.Adrogue HJ, Madias NE. Management of life-threatening acid–
base disorders. First of two parts. N Engl J Med. 1998;338:26–34.
2. Adrogue HJ, Madias NE. Management of life-threatening acid–base
disorders. Second of two parts. N Engl J Med. 1998;338:107–11.
P.W.G. Elbers et al.
3.Fencl V, Jabor A, Kazda A, Figge J. Diagnosis of metabolic
acid–base disturbances in critically ill patients. Am J Respir Crit
Care Med. 2000;162:2246–51.
4.Figge J, Jabor A, Kazda A, Fencl V. Anion gap and hypoalbuminemia. Crit Care Med. 1998;26:1807–10.
5.Gunnerson KJ, Kellum JA. Acid–base and electrolyte analysis in
the critically ill patients: are we ready for the new millennium?
Curr Opin Crit Care. 2003;9:468–73.
6.Kellum JA, Elbers PW, editors. Stewart’s textbook of acid-base.
Amsterdam:; 2009.
7.Kellum JA. Clinical review: reunification of acid-base physiology.
Crit Care. 2005;9:500–7.
8.Levraut J, Grimaud D. Treatment of metabolic acidosis. Curr Opin
Crit Care. 2003;9:260–5.
9. Rose BD, Post TW, editors. Clinical physiology of acid–base and
electrolyte disorders. New York: McGraw-Hill; 2001.
10. Story DA, Bellomo R. The acid–base physiology of crystalloid
solutions. Curr Opin Crit Care. 1999;5:436–9.
11. Story DA, Morimatsu H, Bellomo R. Strong ions, weak acids and
base excess: a simplified Fencl-Stewart approach to clinical acid-­
base disorders. Br J Anaesth. 2004;92:54–60.
12.Stewart PA. Modern quantitative acid–base chemistry. Can J
Physiol Pharmacol. 1983;1:1444–61.
13. Worthley LI. Strong ion difference: a new paradigm or new clothes
for the acid–base emperor. Crit Care Resusc. 1999;1:214.
14.Wrenn K. The delta (delta) gap: an approach to mixed acid–base
disorders. Ann Emerg Med. 1990;19:1310–3.