Chapter
68 V
Acid-Base Balance and Disorders
Hector Carrillo-Lopez, Adrian Chavez, and Alberto Jarillo-Quijada
PEARLS
• T he classical acid-base approach states that acidosis is
produced by the gain of acids (endogenous or exogenous)
that directly release H+, and/or the loss of bicarbonate. For
alkalosis, the opposite must occur. PCO2, pH, standard base
excess (SBE), HCO3−, and anion gap are the assessment tools
used in this physiological view. However, with the exception
of PCO2, all these variables have a correlation with pH but
have no causal relationship with it.
• A ccording to the physical-chemical approach, water is a
virtually inexhaustible source of hydrogen ion, and thus it is
water itself that actually provides hydrogen ions through its
dissociation or recomposition: H2O ↔ H+ + OH−.
• B lood plasma contains numerous ions. Some of them are fully
dissociated, chemically nonreacting in aqueous solutions, and
are called “strong ions,” such as Na+, K+, Ca2+, Mg2+, and
Cl−. Certain organic acids, such as lactate and keto acids, are
also considered strong ions.
• T he determinants of [H+] and pH are the determinants of
water dissociation, and the quantification of the water
dissociation is made through the measurement of the
hydrogen ion concentration, i.e., the pH.
• T he model of acid-base balance was redefined as a consistent
system in an aqueous solution with only three “independent
variables” that are causally related to the H+:
○ Partial pressure of carbon dioxide (PCO2).
○ The strong ion difference (SID). In blood plasma, strong
cations outnumber strong anions. The difference between
the sum of all strong cations and all the strong anions
is called SID; it has a powerful electrochemical effect on
water dissociation, and hence on H+. Sodium and chloride
are the two most important plasma strong ions.
○ The most important nonvolatile weak acid—partially
dissociated acid—is albumin, with a minor effect from
phosphate.
• N ormal acid-base status occurs when the independent
variables have normal values. Abnormality of one or more of
the independent variables underlies all acid-base disturbances.
Adjustment of the independent variables is the essence of
all therapeutic interventions because none of the dependent
variables (e.g., pH, SBE, or HCO3−) can be changed primarily
or individually; the dependent variables change, all of
them simultaneously, if, and only if, one or more of the
independent variables changes.
• S ince PCO2 is regulated by ventilation, its changes result in
respiratory acid-base disorders. Metabolic acid-base disorders
stem from changes in either SID or in total concentration of
nonvolatile weak acids.
• A cid-base disorders must be considered more important for
what they tell the clinician about the patient than for any
harm that is directly provoked by the acid-base imbalance.
Mortality is more closely related to the nature of an acid-base
disorder, than to the magnitude of the derangement of the
pH, whether acidotic or alkalotic.
• T he main type of acid-base derangement in the critical care
setting is metabolic acidosis. When the origin is lactic acidosis,
the correlation with mortality is greatest. It has become
evident, however, that iatrogenic hyperchloremic acidosis,
related to resuscitation fluids, is much more frequent than
previously thought, a fact that should be corrected through a
better supervision of the fluids given to the patient and their
impact in Cl− and on SID.
• T he clinical approximation to an acid-base disorder should
include all the tools of the classical approach, but with some
merging concepts from the physical-chemical approach: the
anion gap must always be “corrected” for albumin levels, and
sodium, chloride, and lactate levels must be checked. If a high
volume of resuscitation fluids is given to the patient, or if the
presence of unmeasured anions is expected, or if a complex
or mixed pattern of acid-base metabolic derangement is
suspected, then SID, strong ion gap (SIG), and probably
“partitioned” SBE should be calculated.
• F or easy bedside calculation of extensive formulas, there is an
online free software solution, offering free decision support
in complex acid-base scenarios at AcidBase.org [analysis
module].
Physics, chemistry, and the physiology of acid-base balance are
among the first subjects that are taught at medical school, and
are one of the best examples of the close correlation between
basic and clinical sciences. However, physicians seem to dis-
play only a superficial knowledge of this field. When queried,
70% of medical doctors at a university hospital stated that
they needed no help in correctly interpreting arterial blood
gases. However, they succeeded in only 40% of the cases pre-
sented to them.1 Similar experiences have been reported more
recently, involving both physicians and nurses.2,3 As a paradox,
it is likely that the easily available software for computers and
hand-held devices, along with internet-available “­primers” for
963
964 Section V — Renal, Endocrine, and GI Systems
the interpretation of blood gases and acid-base status, are all
contributors to this situation, as they provide physicians, resi-
dents and nurses with a fast-track mechanical interpretation
of the arterial blood gases and acid-base status, even when all
the complexities are not fully understood.3 Because intensiv-
ists spend much of their time managing problems related to
fluids, electrolytes, and acid-base balance, every hour making
important clinical decisions after interpreting the available
acid-base parameters, a thorough but practical understanding
of the physiology and pathophysiology of acid-base disorders
is a central aspect of the expertise of the critical care practi-
tioner.
Understanding Acid-Base
Physiology: Traditional and
Newer Approaches
Most of the concepts of acid-base physiology were developed
in the early twentieth century,4,5 and are based mainly on the
accepted definition of acid.5-7 As early as 1887, Arrhenius had
defined acid as a substance that, when dissolved in water, pro-
duces an increased concentration of hydrogen ions; in other
words, it is not mandatory for this given substance to have
hydrogen atoms in its molecule, as the water itself can be the
source of the hydrogen ions.5 Accordingly, by 1900, Naunyn
and others proposed that the acid-base status was, at least par-
tially, determined by the concentration of some electrolytes,
mainly sodium and chloride, that had been formerly described
by Faraday as “base-forming cation” and “acid-forming
anion,” respectively.5 In the 1920s, Brönsted and Lowry stated
that an “acid” is any molecule that contains hydrogen atoms
and that is able to release them in a soluble manner; that is, an
acid is a “proton-donor substance.”6,7 Thus an acid (HA) may
dissociate and donate a proton (H+) to the solution, forming
the conjugate base (or anion) A− in a reversible manner:
K because the corresponding base has a low affinity for it (high
[HA] a [H+ ] + [A- ] (1)
where Ka is the equilibrium or dissociation constant, particu-
lar to every different substance and influenced by the char-
acteristics of the particular solution in which the reaction is
taken place. Therefore a base is a molecule with the ability to
accept or “trap” free hydrogen ions (proton-acceptor sub-
stance).7 Examples include bicarbonate, hemoglobin, many
other proteins, and phosphates.
Whatever definition of acid is used, its validity depends on
the situation that one is trying to understand or the event one
is attempting to explain. In biologic solutions such as plasma,
the situation is a water-based solution with tightly controlled
solute concentrations. It is remarkable that, in this scenario,
all the former acid definitions are valid5 because water can
supply both hydrogen and hydroxyl ions:
H2 O  ↔  H+  + OH- (2)
Therefore water must be seen as the major natural reservoir
of hydrogen (and hydroxyl) ions; thus the acid-base balance
relies on the chemical properties of water, that is, acid-base
unbalance can be seen as an alteration of water dissociation.
In physiologic conditions, there is little dissociation of water
molecules into its components. Electrical charge and tem-
perature represent the main determinants for its eventual
dissociation. Electrical neutrality is always held constant; that
is, the number of positive charges must equal the number of
negative charges. Both extracellular and intracellular fluids are
an ionic mix of electrolytes, proteins, and other substances,
whose charges tend to modify the electrical balance and then
can have an influence on the dissociation of water. In order to
keep the electroneutrality, more (or fewer) water molecules
will have to dissociate. In other words, the determinants of H+
are the determinants of water dissociation, and the quantifica-
tion of the water dissociation is made through the measure-
ment of the hydrogen ion concentration H+.
Normal concentration of hydrogen ions in the extracellular
fluid is extremely low, in the nanoequivalent (nEq) or nano-
mole (nmol) range (i.e., the order of magnitude of the H+ is in
the millionth of a milliequivalent range [1 nanoequivalent = 109
equivalent = 106 milliequivalent]). The usual arterial blood
H+ is about 40 nEq/L (or nmol/L) (i.e., 0.000040 mEq/L,
with a normal range of 35 to 45 nEq/L [0.000035 to 0.000045
mEq/L or mmol/L]).4 In other words, serum H+ is about
3 million times less than the serum sodium concentration.9
Because hydrogen ion concentration in body fluids and tissues
has a strong influence on the function of almost all enzymatic
systems of the organism, a tight regulation of its concentration
is mandatory for the body. For convenience, the H+ value is
usually expressed as pH units, that are derived as the negative
log10 of the hydrogen ion concentration in nanoequivalents
per liter.This concept was developed by Sörenson and adapted
by Karl Hasselbalch to clinical medicine in 1909. A normal pH
of 7.4 corresponds to a blood hydrogen ion concentration of
40 nEq/L, at 37° C. The relationship between pH and serum
H+ is nonlinear, but it is almost linear over the narrow normal
range of 7.35 to 7.45 (corresponding to 45 to 35 nEq/L of H+).9
Acids, Bases, Buffers: The Traditional
Understanding
An acid is strong when it dissociates its hydrogen ion easily
Ka–dissociation constant value). Weak acids only partially dis-
sociate because their corresponding base has high affinity for
hydrogen ions (low Ka value). When the latter is the case, both
the hydrogen ion and the base form of the parental molecule
are present in the resulting solution in equimolar proportions.
As a consequence, this solution has the ability to resist changes
in acidity (or pH) after the addition of a strong acid or base.
This solution, constituted by an acid-base pair, is known as
a buffer. The dissociation constant Ka, as in the case of pH,
can be expressed as log10Ka, is termed pKa, and represents a
measure of the tendency of the acid-base pair to ionize. Strong
acids have a low pKa (high Ka) and weak acids have high pKa
(low Ka). A weak acid-base pair is more effective as a buffer
in living systems when the pKa is close to physiologic pH.6,7,10
Physiologic buffering systems may be classified into two
general categories: the bicarbonate/carbonic acid (HCO3−/
H2CO3) buffering system, that acts in both the extracellular
space and inside the cells, and the nonbicarbonate buffers,
which include hemoglobin and oxyhemoglobin, organic phos-
phates, inorganic phosphates, and plasma proteins. Extracel-
lular buffers (HCO3−, plasma proteins) represent the body’s
first and immediate line of defense against any alteration of
pH of the body fluids. After extracellular buffering occurs,
a second intracellular phase takes place, as long as intracel-
lular buffers (intracellular proteins, dibasic phosphates,
­hemoglobin-oxyhemoglobin, and carbonate in bones) reach

buffering capacity over the next several hours.10 The buffering
systems cannot truly eliminate hydrogen ions from the body,
but they tamper sudden changes in [H+] (or pH) and “buy
time” until a new balance can be achieved. Altogether, extra-
cellular and intracellular buffers provide a volume of distribu-
tion close to that of the total body water to any exogenous
acid load (or deficit). This represents a formidable capacity for
resisting changes in pH.
Acid Production in the Body
Acid production in the body occurs in two major ways. The
first one involves CO2 production during oxidative metabo-
lism of carbohydrates, fat, and amino acids. The CO2 is then
hydrated by the cytoplasmic enzyme carbonic anhydrase to
produce carbonic acid (H2CO3), a weak acid that dissociates
in hydrogen ion and bicarbonate.
CO2  + H2 O  ↔  H2 CO3   ↔  H+  + HCO3− (3)
The second pathway involves nonvolatile metabolic acids
that are produced by the normal daily catabolic load (oxida-
tion of sulfur-containing amino acids, hydrolysis of pyro-
phosphate and orthophosphate esters) or during situations
with incomplete catabolism of fat and carbohydrates, such as
lactic acidosis or diabetic ketoacidosis (DKA). The free hydro-
gen ions are neutralized by extracellular and intracellular
buffers, but because these acids are not in equilibrium in the
normal plasma, they must be metabolized, mainly in the liver,
and then excreted by the kidneys.10
The major acid-base buffering system in the blood is the
bicarbonate/carbonic acid system, which has the tremendous
advantage of interconversion of CO2 with H2CO3. Any increase
in [H+] (or drop in pH) will shift the former reaction (Equa-
tion 3) to the left through an increase in both alveolar ventila-
tion and elimination rate of CO2. This respiratory response
begins within minutes, but may not reach a steady state for 12
to 24 hours. This method of achieving a rapid decrease of the
actual acid component is a unique characteristic of the bicar-
bonate/carbonic acid buffering system. For the other buffers,
the addition or removal of hydrogen ions has the correspond-
ing opposite effect on the buffer components, limiting the
maximum buffering capacity. On the contrary, the capacity
of the bicarbonate-CO2 system is greatly increased because
the lungs can eliminate a vast amount of CO2 per day. Simi-
larly, the kidneys can eliminate or regenerate bicarbonate as
needed, although this response is slower than that of the lungs.
The Classic Paradigm: H+ Depends on CO2,
H2CO3, and HCO3−
The quantitative importance of the bicarbonate/carbonic acid
buffering system was clearly noticed by Henderson when he
developed his famous equation, which was modified by Has-
selbalch shortly after. The Henderson-Hasselbalch equation4,5
expresses the relationship of the bicarbonate/carbonic acid
buffering system to pH:
pH = pKa  + log ([HCO3− ]/[H2 CO3 ]) (4)
The pH is equal to a constant (pKa, the log10 of Ka, the first
dissociation constant for H2CO3, which has a value of 6.1 for
human plasma in physiological conditions) plus the log of the
ratio of HCO3− (proton acceptor) to H2CO3 (proton donor).
Chapter 68 — Acid-Base Balance and Disorders 965
The modified Henderson-Hasselbalch equation takes into
consideration that H2CO3 is in equilibrium with dissolved
CO2 and is rewritten as9:
pH = pKa + log([HCO3− ] / 0.03  × PCO2 ) (5)
where 0.03 is the solubility coefficient for carbon dioxide in
blood at 37° C.
What the Henderson-Hasselbalch equation tells us is how
pH is affected by the change in the ratio of the concentra-
tion of nondissociated acid HA (in this case carbonic acid or
PCO2) to the concentration of the conjugated base or anion
A− (in this case HCO3−). When pH is altered as the result of
changes in the volatile component (increases or decreases of
PCO2), clinically speaking, the change is referred to as respira-
tory.9 When pH is modified by changes in nonvolatile acids
(e.g., lactic acid, keto acids), or by changes in serum cations
and/or anions (e.g., hyperchloremia/hypochloremia), it is
referred to as metabolic in origin.5,8,9 The term acidosis is used
to describe the process that tends to produce an increase in
H+, whether or not there is a change in pH. Alkalosis is the
opposite; that is, the process that tends to produce a decrease
in H+, with or without changes in pH. Acidemia and alkale-
mia are the corresponding terms for those situations in which
blood pH actually changes.9 Thus this equation allows dis-
orders to be classified according to the primary type of acid
being increased or decreased. For example, if a patient’s pH is
low (acidemia), then the patient may have either an increased
PCO2 or a PCO2 within normal or decreased values. If the
PCO2 is increased (alveolar hypoventilation), the condition is
classified as respiratory acidosis. If it is not increased, there can-
not be a respiratory acidosis. Therefore some nonvolatile acid
or anion must be the cause of the acidemia, and this is then
referred to as metabolic acidosis. If these examples are reversed,
then alkalemia can also be classified as resulting from either
respiratory or metabolic alkaloses.9
The Henderson-Hasselbalch equation is useful but has
intrinsic limitations.5,8 The first one is that it does not quan-
tify the severity of the metabolic derangement as it does for the
respiratory component. In a respiratory acidosis, the increase
in the PCO2 quantifies the derangement even when there
are mixed disorders. The metabolic component can only be
approximated, however, by the change in HCO3−. Although
the relationship between PCO2 and HCO3− provides a use-
ful clinical guide for uncovering a metabolic origin of a given
derangement, this is dampened because PCO2, H2CO3, and
HCO3− are all interlinked (Equations 3 and 5), so the bicar-
bonate will also increase if PCO2 increases.6,8 The second
important characteristic of the Henderson-Hasselbalch equa-
tion is that it does not provide information about any acids
other than carbonic acid.
Using the Brönsted-Lowry definition of acid as a “proton
donor,”4,6,7,11 many physiologists dismissed defining chloride
as an acid and sodium as a base, arguing that there was an
insufficient link between these and other electrolytes and the
subsequent changes in hydrogen ions. Thus, by accepting only
Brönsted-Lowry acids while looking for factors controlling the
nonrespiratory component of acid-base balance, many physi-
ologists focused on the plasma bicarbonate concentration and
the Henderson-Hasselbalch equation.5 This was the begin-
ning of the still-dominant concept that plasma bicarbonate
is not only the best indicator of acid-base status, but also a
main determinant of it. Unfortunately, this way of thinking
966 Section V — Renal, Endocrine, and GI Systems
overlooked the fact that all weak acids in a given aqueous
solution such as plasma can be inserted into a Henderson-
Hasselbalch type of equation to calculate pH, as Lawrence
Henderson himself demonstrated in 1908.4 The reason is easy
to understand: for a single solution containing several weak
acids (as human plasma), all the weak acids are equilibrated
with a single pool of hydrogen ions. This is called the isohydric
principle.5 Consider two buffer systems: bicarbonate/carbonic
acid and phosphate/phosphoric acid:
H2 CO3 ↔ HCO3− + H + + HPO24 − ↔ H2 PO4− (6)
Note that the H+that will eventually form both carbonic
acid and phosphoric acid actually comes from the single plas-
matic pool. Expressing the same concept in the Henderson-
Hasselbalch way:
pKa1 + log ([HCO3− ] / [H2 CO3 ]) = pH
� � � = pKa2 + log ([HPO24 − /[H2 PO4− ]) (7)
Thus according to the isohydric principle, the ratio of any
pair of conjugate base or anion and its nondissociated acid will
be able to describe the H+ or pH.5,12 This means that although
the ratio of PCO2 to bicarbonate can describe what the pH and
acid-base status is, the system bicarbonate/carbonic acid is not
necessarily the primary or underlying mechanism for explain-
ing changes in pH.
Correlation and causation are not the same.5,8 Immersed in
the bicarbonate-centered approach, investigators yielded basi-
cally three solutions for analyzing the “metabolic side” of the
equation: the base excess method, the six bicarbonate “rules of
thumb,” and the use of anion gap (AG).4,5,9,13-15
Base Excess and Standard Base Excess
The change in pH of a given buffered solution is dependent on
both the amount of strong acid (or strong base) that is added,
and on the buffering capacity of the system. As acid is added,
for every H+ that is buffered, one molecule of conjugate base
of the buffer is consumed. Therefore, quantifying the changes
in the concentration of the conjugate base of the buffer is
more useful than the degree of change in the pH in estimating
the amount of nonvolatile acids present.
Siggaard-Andersen, from Copenhagen, developed the
“base excess” method in the late 1950s.4,14,15 Base excess
(BE) is defined as the amount of strong acid (or strong base),
in moles per liter (mol/L), that must be added to a whole
blood sample to return the pH of the sample to 7.40, while
the PCO2 is maintained at 40 mm Hg.5,15,16 Therefore if the
blood sample is normal (i.e., its pH is 7.4 and its PCO2 is
about 40 mm Hg), the BE will be 0 mmol/L. Positive values
mean literally an excess of metabolic bases; negative values
mean an excess of metabolic acids.9,15,16 To apply the BE to
the clinical setting, a nomogram was developed that was later
mathematically transcribed to allow BE calculation by blood
gas analyzers.17,18 However, several flaws appeared.19-21 For
clinical accuracy, other assumptions had to be incorporated
(correction factors, adjusted formulas, nomogram modifica-
tions),5,18,22 and, remarkably, an empiric estimate of hemo-
globin concentration throughout the entire extracellular
fluid space (whole blood plus interstitial fluid) had to be
established, in order to consider the net effect of the intra-
cellular buffers, hemoglobin the main one.5 A hemoglobin
concentration of 50 g/L (5 g/dL)5,22 was chosen to calculate
standard base excess (SBE), a parameter reported nowadays
by modern gas analyzers and used in the classical approach
to acid-base balance (Table 68-1). Although SBE has good
correlation with bicarbonate levels and quantifies the change
in metabolic acid-base status in vivo, its accuracy depends
on the 5 g/dL of hemoglobin assumption, and it still does
not provide information about the origin or mechanisms of
the metabolic acid-base derangement because SBE is not a
substance that can be regulated, absorbed, or excreted by the
body.8 Perhaps the main pitfall is that the SBE value repre-
sents the net effect of all metabolic acid-base abnormalities.
Therefore the effects of coexisting metabolic acidoses and
alkaloses may cancel each other, and the normal figure of the
SBE will mistakenly suggest that no acid-base derangement
exists. Actually, 15% to 18% of critically ill adults with acid-
base disorders have a normal SBE.13,23
Bicarbonate Rules
In a “great transatlantic debate,”18,21 strong criticism of the
SBE from Schwartz and Relman from Boston yielded the six
bicarbonate “rules of thumb” (Table 68-2).18 The Hender-
son-Hasselbalch equation easily disclosed derangements into
“respiratory” and “metabolic,” the so-called simple derange-
ments.9 Because the body always seeks to tightly control H+,
however, several physiologic responses become active over
time, and then the relationship between PCO2 and HCO3− is
modified so pH changes can be minimized. This minimization
gives origin to more complex or “mixed” conditions.9,10,24
Despite this, through careful examination of the changes that
occur in PCO2 and HCO3− in relation to each other, it was
possible to find patterns and to derive rules (the so-called six
rules of thumb) for uncovering mixed disorders and to differ-
entiate acute from chronic respiratory unbalances. These rules
describe the physiological compensation to acid-base changes
to optimize acid-base homeostasis. With the expected physi-
ologic compensation allowed for, residual changes in CO2 or
bicarbonate are then seen as the mechanisms for changes in
acid-base status (Tables 68-2 and 68-3). This approach is still
the most practical acid-base balance diagnostic tool for the
busy clinician.9
Anion Gap and Corrected Anion Gap
The AG was introduced as a complementary diagnostic tool
for either SBE or bicarbonate rules-of-thumb approaches to
metabolic disturbances.25 It is based on the principle of elec-
troneutrality, which states that there is no electrical charge in
plasma. Accordingly, serum positive-charged cations must
equal serum negative-charged anions9 (see Table 68-1):
[Na + ] + [K + ] + [Ca2 + ] + [Mg2 + ] + [H + ] = [Cl − ]
+ [HCO3− ] + [proteins − ] + [PO4 3 − ] + [SO4 2 − ]
+ [OH − ] + [CO3 2 − ] + [XA − ]) (8)
where [XA−] is the unmeasured acid anions. Sometimes they
are abbreviated as UMAs.
The plasma concentrations of SO42−, OH−, CO32−, and H+
are quite small and can be neglected. Concentrations of Na+,
K+, Cl−, and HCO3− (in the form of total CO2) are reported in
a standard chemistry panel. The sum of the remaining anion
 Chapter 68 — Acid-Base Balance and Disorders 967

Table 68–1  Classical Acid-Base Parameters

pH log10 H+. Measured directly by electrode. Normal = 7.35–7.45.
PCO2 Partial pressure of gaseous CO2. Measured directly by electrode. Usually expressed in mm Hg. Normal value:
35–45 mm Hg (sea level, arterial blood).
HCO3− Bicarbonate concentration. A calculated parameter, derived from pH and PCO2 values using a nomogram or the
Henderson-Hasselbalch equation, or equal to the difference between serum total CO2 (CO2TOT) and the dissolved
CO2. (PCO2 × 0.03). Normal value: 22–28 mEq/L.
Base excess (BE or Also known as base excess/deficit. Defined as the amount of strong base (negative base excess, or “base deficit”)
BE/D) or strong acid (positive base excess) in mmol/L that would be needed to restore a pH of 7.4 to a liter of whole
blood equilibrated at PCO2 = 40 mm Hg. It is calculated by a nomogram or equation that was derived from an
experimental series of in vitro titrations of strong acid and base in whole blood samples at various PCO2 levels.
It excludes the effect of acute changes in PCO2, so it loses accuracy if PCO2 is abnormal. It should not be used in
critically ill patients.
Standard base An improvement of base excess to allow equilibration across the entire extracellular fluid space (whole blood
excess (SBE) interstitial fluid) and thus preserve accuracy at variable PCO2 values. The new equation assumes an “average”
concentration of hemoglobin through that space of 5 g/dL. Despite being a somewhat arbitrary figure, it indeed
works in vivo.
CO2TOT or CO2 Total CO2 or CO2 concentration. A serum chemistry measured value. Its components include HCO3−, dissolved
gaseous CO2, carbonic acid (H2CO3), carbamino CO2, and carbonate (CO32−). About 95% exists as HCO3−,
and 4% to 5% as dissolved gaseous CO2. Remaining species are negligible. Because the difference between
CO2TOT and HCO3− is about 1 mEq/L at physiological pH, for clinical purposes they are taken almost as equiva-
lents.
Anion gap (AG) A calculated value that, taking advantage of the electroneutrality principle that rules plasmatic ions (total
amount of cations should be the same as the total amount of anions), indicates the presence of “unmeasured”
anions (mostly organic acids). AG = (Na+ + K+) − (Cl− + HCO3−). Normal values are 16 mEq/L (if K+ is included) or
12 mEq/L (without K+, with variations of ± 2 to 4 mEq/L. These values may be influenced by the way the values
of some of the parameters are measured, so it is always better to consult each institution’s own expected nor-
mal AG.
Corrected anion An improvement in the calculation of AG, that acknowledges that an increase in AG from organic acids may be
gap (AGCORR) masked by a decrease in AG from low protein (albumin) levels. AG is corrected for the patient’s own albumin
concentration as follows:
AGCORRECTED = AGOBSERVED × 2.5[normal albumin (g/dL)] − [observed albumin (g/dL)], considering normal albu-
min from 3.2 to 4.5 g/dL. In order to avoid [lactate−] influence on AGCORR that could mask the detection of other
unmeasured anions, it has been suggested that AG should be corrected not only for albumin, but also for lac-
tate. This is simply made by subtracting the serum lactate concentration (in mmol/L) from the already albumin-
corrected AG: AGCORRLACT = Albumin-corrected AG − [lactate− (mmol/L)].
Urinary anion gap The same principle of the anion gap applied to urinary ions, that is, uGap estimates unmeasured urinary ions. It
(uGap) has also been designated by some as urine strong ion difference (uSID), a functionally correct name, as all the
involved ions are strong ions: uGap = uSID = [uNa+ + uK+] − [uCl−]. The most important unmeasured urinary strong
anion (Ur−) is SO42− (derived from the metabolism of sulfur amino acids), whereas the most important unmeasured
cation (Ur+)is ammonium (NH4+). In physiologically normal conditions, uSID must equal the plasmatic SIDAPP, or
38–42 mEq/L.

Table 68–2  Classical Acid-Base Approach: Observational Acid-Base Patterns

Expected Changes [HCO3−] Expected Changes SBE
Primary Disorder (mEq/L or mmol/L) Expected Changes PCO2 (mm Hg) (mmol/L)
Metabolic acidosis <22 = (1.5 × HCO3−) + (8 ± 2) <−5
= 40 + SBE
Metabolic alkalosis >26 = (0.7 × HCO3−) + (21 ± 2) >+5
= 40 + (0.6 × SBE)
Acute respiratory acidosis = [(PCO2 − 40)/10] + 24 >45 or =0
ΔpH = 0.008 × (PCO2 − 40)
Chronic respiratory acidosis = [(PCO2 − 40)/3] + 24 >45 or = 0.4 × (PCO2 − 40)
ΔpH = 0.003 × (PCO2 − 40)
Acute respiratory alkalosis = [(40 − PCO2)/5] + 24 <35 or =0
ΔpH = 0.008 × (40 − PCO2)
Chronic respiratory alkalosis = [(40 − PCO2)/10] + 24 <35 or = 0.4 × (PCO2 − 40)
ΔpH = 0.017 × (40 − PCO2)
Modified from Kellum JA: Determinants of plasma acid-base balance, Crit Care Clin 21:329-346, 2005; and Kraut JA, Madias NE: Approach to patients with acid-base
disorders, Respir Care 46(4):392-403, 2001.
968 Section V — Renal, Endocrine, and GI Systems
Table 68–3  Classical Acid-Base Approach:
Additional Clues
1. A metabolic acid-base derangement exists if:
a. pH is abnormal.
b. pH and PCO2 have changed in the same direction (both
increased or both decreased).
c. Respiratory compensation is intact if PaCO2 resembles last
two digits of pH (e.g. pH 7.23 and PaCO2 ≤23 mm Hg).
2. A respiratory acid-base derangement is overlapped if any of
the following occurs:
a. pH is abnormal but PCO2 is reported within normal limits.
b. PCO2 reported is higher than expected PCO2 (respiratory
acidosis overlapped).
c. PCO2 reported is lower than expected PCO2 (respiratory
alkalosis overlapped).
3. A respiratory acid-base derangement exists if:
a. PaCO2 is abnormal.
b. PCO2 and pH have changed in opposite directions (i.e.,
raised PCO2 and decreased pH or vice versa).
4. If the change of pH is … (see formulas in Table 68-2)
a. 0.008 × change in PCO2, there is no compensation; then
the derangement is acute.
b. >0.003 but <0.008 × change in PCO2, there is a partial
compensation.
c. 0.003 × change in PCO2, there is full compensation; then
the derangement is chronic.
d. >0.008 × change in PCO2, there is an overlapping meta-
bolic derangement.
5. There is a mixed derangement (acidosis and alkalosis) if any
of the following occurs:
a. PaCO2 is abnormal and pH has not changed as expected
or is within normal values.
b. pH is abnormal and PaCO2 has not changed as expected
or is within normal values.
Modified from Marino PL: Acid-base interpretations. In: The little ICU book of facts
and figures, Philadelphia, 2009, Lippincott Williams & Wilkins, pp 349-362.
species, proteins−, PO43−, and XA−, is defined as the unmea-
sured anions (UA), whereas the sum of the remaining cation
species, Ca2+ and Mg2+, is defined as the unmeasured cations
(UC). Thus AG is commonly defined as9:
AG = UA − UC = ([Na +̇ ] + [K + ])− ([Cl − ] + [HCO3− ]) (9A)
Sometimes [K+] and its effect are disregarded26:
AG = [Na + ] − ([Cl − ] + [HCO3− ])
Typically, normal values are 16 mEq/L (if K+
is included)
or 12 mEq/L (without K+), with variations of ±2 to 4 mEq/L.
These values may be influenced by the way the values of some
of the parameters—particularly chloride levels—are mea-
sured, so it is always better to consult each institution’s own
expected “normal AG.”26,27
It must be realized that calculated AG is affected by any
change in the concentrations of either the UA or UC. Plasma
proteins and phosphate levels can be significantly decreased in
the critical care setting. Reduced protein and phosphate levels
result in a decreased UA and hence in a decreased AG. There-
fore, an increase in AG from organic acids may be masked by
a decrease in AG from low protein and phosphate levels and
thus it is wise to make the proper corrections.28 This is par-
ticularly true in the pediatric critical care setting, where hypo-
albuminemia is nearly ubiquitous.26,29,30 Phosphate influence
is rather small, and so is the effect of globulins, since their pKa
is much greater than plasma pH (they do not easily dissoci-
ate) and hence they do not have a significant H+ contribution.
Figge et al. showed that in most patients, the AG could be cor-
rected (AGCORR) as follows26:
AGCORR = AGOBSERVED + 0.25 × [Normal albumin (g / L)]
− [Observed albumin (g / L) ] (10)
considering normal albumin from 3.2 to 4.5 g/dL.
The albumin-corrected AG (AGCORR) can unmask an
organic acidosis previously undetected in the setting of hypo-
albuminemia, and adds sensitivity for detecting unmea-
sured anions, including lactate, although the specificity for
hyperlactatemia is poor.28,31-33 Thus lactate must be directly
determined.
Despite the fact that it is not useful for quantifying the
metabolic derangement, AG is a powerful tool for the clini-
cian in the categorization of metabolic acidoses, as not all
metabolic acidoses result in an elevated AG.34 As an hypo-
thetical example, the reader might consider that acid in the
form of HCl is added to the circulation. Upon dissocia-
tion, Cl− remains as the conjugate base, while the plasmatic
bicarbonate buffer is “consumed” by the hydrogen ion. The
result is that an increase in Cl− is balanced by a decrease in
HCO3−, that is, there is metabolic acidosis without a change
in the AG. Thus through the AGCORR it is possible to dif-
ferentiate hyperchloremic acidosis (normal AG) from “gap
acidoses” (increased AG).26,34 The last category includes all
conditions of metabolic simple acidosis caused by increased
concentrations of nonvolatile anions other than chloride,
usually unmeasured (or unmeasurable), such as lactate, keto
acids, phosphate, sulfates (and other anions in renal failure
setting), salicylate, some β-lactam antibiotics, organic acids
from congenital errors of metabolism, and acetate from par-
enteral nutrition (Table 68-4).31,34 Non-AG hyperchloremic
acidoses include excessive infusion of chloride salts (saline
or parenteral nutrition) and increased renal or gastrointes-
tinal bicarbonate losses. On the contrary, metabolic alka-
losis may stem from hypochloremia from chloride loss or
bicarbonate gain, and from hypoalbuminemia.31 AG perfor-
mance is not so good in mixed acid-base physiology, despite
several attempts to improve it. This represents an impor-
tant limitation to its use in critical care patients, in whom
(9B)
single metabolic acid-base disorders are more the excep-
tion than the rule. In spite of several attempts, the “correc-
tions” and adaptations for the AG that have been proposed
in order to detect mixed disorders have not fulfilled the
expectations.24,31
Water as the Main Source of Hydrogen
Ions: The Stewart Approach
It is remarkable that not one of the classic acid-base approaches
examined the role of water as a virtually inexhaustible source
of hydrogen ion, as Peter Stewart later did.5,8,35 Although pure
water dissociates only slightly into H+ and OH− in plasma, the
presence of electrolytes, CO2, and other weak acids produces
powerful electrochemical forces influencing water dissocia-
tion.8 In the late 1970s and early 1980s, Peter Stewart proposed
that Arrhenius’ more general definition of an acid, along with
Naunyn’s ideas from 1900, was more useful to acid-base
physiology than the Brönsted-Lowry definition.36,37 Apply-
ing several basic principles of physical chemistry, particularly

Table 68–4  Causes of Metabolic Acidosis in
Critically Ill Patients
I. Accumulation of unmeasured anions: the anion gap acidoses
A. Endogenous source of acids
1. Type A hyperlactatemia (decreased tissue O2 delivery)
2. Type B hyperlactatemia (not associated with tissue
hypoxia)
3. Ketoacidosis (diabetic, alcoholic, starvation)
4. Renal failure: accumulation of phosphates, sulfates,
and organic ions
5. Unidentified anions in sepsis other than lactate
6. Certain organic acids from inborn errors of
metabolism
7. Late metabolic acidosis of prematurity
B. Exogenous source of acids
1. Ingested toxins and drugs that directly provoke
acidosis
a. Methanol, formic acid, keto acids, lactate
b. Ethylene glycol, glycolic acid, oxalic acid,
paraldehyde
c. Ethanol
d. Salicylate, salicylic acid, acetic acid
e. Illegal drugs
2. Total parenteral nutrition*
II. Hyperchloremic acidoses: the non–anion gap acidoses
A. Exogenous chloride load
1. Normal saline or hypertonic saline resuscitation
2. HCl, NH4Cl, arginine HCl administration
3. Total parenteral nutrition*
B. Loss of cations from the lower gastrointestinal tract
(postpyloric gastrointestinal fluid losses)†
1. Infectious secretory diarrhea and dehydration
2. Short bowel syndrome
3. Drainage from ostomies, tubes, fistulas (small bowel,
pancreatic, or biliary drainage)
4. Sulfamylon, cholestyramine
C. Renal causes‡
1. Chronic renal insufficiency (impaired ammonium
[NH4+] generation)
2. Renal tubular acidoses
3. Hypoaldosteronism
4. Recovery phase of diabetic ketoacidosis
5. Urinary tract obstruction
6. Drug-mediated loss of cations and tubulopathies
a. Acetazolamide
b. Amphotericin B
c. K+-sparing diuretics
D. Urinary reconstruction using bowel segments
*Total parenteral nutrition may cause both anion gap and non-anion gap acidosis.
In the first case, an excessive amount of exogenous acids is the cause, mainly
if liver or renal functions are impaired; in the latter, an unbalanced, excessive
chloride content in the formulation provokes the derangement, which is easily
produced in the setting of renal failure.
†This class corresponds to the gastrointestinal loss of bicarbonate type of acidosis,
according to the classical approach.
‡This class corresponds to the renal loss of bicarbonate type of acidosis, according
to the classical approach.
electroneutrality, conservation of mass, and dissociation equi-
librium of partially dissociated substances (electrolytes and
others),5,8,13,38 Stewart developed a mathematical model of
acid-base balance. He defined the system as an aqueous solu-
tion that contains strong ions that are completely dissociated
at physiologic pH, weak acids that are partially dissociated
at physiologic pH, and carbon dioxide that is in equilibrium
with an external partial pressure of carbon dioxide. The main
concepts of this approach are summarized in Table 68-5, and
a classification of primary acid-base disturbances based in this
system is presented in Table 68-6. Thus according to Stewart,
Chapter 68 — Acid-Base Balance and Disorders 969
there are only three independent controlling variables of H+
concentration5,8,38-40:
1. Partial pressure of carbon dioxide (PCO2).
2. The strong ion difference (SID). Blood plasma con-
tains numerous ions, which may be classified not only
in regard to their electrical charge (cations are positive,
anions are negative), but also according to their ten-
dency to dissociate. Some ions are fully dissociated and
chemically nonreacting in aqueous solutions, and are
called “strong ions,” such as Na+, K+, Ca2−, Mg2+, and
Cl−. Others, such as albumin, phosphate and HCO3−, can
exist both as charged (i.e., dissociated) and uncharged
forms, and are called “weak ions.” Certain organic acids,
such as lactate and others, are nearly completely dissoci-
ated under physiologic conditions, and so are considered
strong ions. In blood plasma, strong cations outnum-
ber strong anions. The difference between the sum of
all strong cations and all the strong anions is called SID.
Sodium and chloride are the two most important plas-
matic strong ions.23,41
3. The total concentration of nonvolatile weak acids (ATOT),
that is, for each of them, the sum of its dissociated and
undissociated forms (ATOT = A− + HA).13,36,38-40 The most
important weak acid—partially dissociated acid—is albu-
min, with a minor effect from phosphate.
“Independent variables” mean that PCO2, SID, and ATOT
are causally related to the hydrogen ion, rather than being
merely correlated.38,39 Normal acid-base status occurs when
the independent variables have normal values. Abnormality
of one or more of the independent variables underlies all acid-
base disturbances. Adjustment of the independent variables is
the essence of all therapeutic interventions, because none of
the dependent variables (e.g., pH, BE, HCO3−) can be changed
primarily or individually; the dependent variables change all
of them simultaneously if, and only if, one or more of the
independent variables changes.8,13,39 Since PCO2 is regulated
by respiration, its changes result in respiratory acid-base dis-
orders. Metabolic acid-base disorders stem both from changes
in either SID or ATOT.
CO2 and Bicarbonate in Stewart’s
Approach
In Stewart’s approach, CO2 represents a primary independent
determinant of pH, just as in the bicarbonate-BE-centered
approaches, that is, there are no changes in the understand-
ing of the respiratory acid-base derangements. However,
the role of bicarbonate is reduced from being causative to a
mere indicator, as hydrogen ion and bicarbonate concentra-
tions are totally dependent on the three independent con-
trolling variables. Hence, according to Stewart, the major use
for the bicarbonate rules of thumb and SBE are to determine
the extent of the clinical acid-base disorder, rather than the
mechanism.5,8,39
The rise of the PCO2, according to the Henderson-Hassel-
balch equation (Equation 5), will increase both H+ and HCO3−
concentrations. Therefore the change in HCO3− concentration
is mediated by chemical equilibrium (Equation 3) and not by
any systemic adaptive response.8 The total CO2 concentration
(and hence the [HCO3−]) is determined by the PCO2, which is
in turn determined by the balance between alveolar ventilation
and CO2 production at tissue level. Therefore HCO3− cannot
970 Section V — Renal, Endocrine, and GI Systems
Table 68–5  Concepts and Parameters Used in the Quantitative Physical-Chemical Approach to
Acid-Base Balance: A Summary
Variable
Strong ions
Weak ions
Strong ion difference (SID)
Apparent strong ion dif-
ference (SIDAPP)
Effective strong ion differ-
ence (SIDEFF)
Strong ion gap (SIG)
Nonvolatile weak acids
(ATOT)
Independent variables
Unexplained, or unmea-
sured, or unidentified acid
anions (abbreviated as
XA− or UMA)
Comment
Blood plasma contains numerous ions, which may be classified not only in regard to their electrical
charge (cations are positive, anions are negative), but also according to their tendency to dissociate.
Some ions (such as Na+, K+ Ca2+, Mg2+, and Cl−), are fully dissociated, chemically nonreacting in aque-
ous solutions, and are called “strong ions.” Certain organic acids, such as lactate and other nonvolatile
organic acids, are nearly completely dissociated under physiologic conditions, and so they are considered
weak ions.
Ions that can exist both as charged (i.e., dissociated) and uncharged forms, such as albumin, phosphate,
and HCO3−.
In blood plasma, strong cations outnumber strong anions. The difference between the sum of all strong
cations and all the strong anions is called SID. Sodium and chloride are the two most important plasmatic
strong ions.
When SID is calculated from direct measurement of serum strong ions, it is termed apparent SID (SIDAPP):
SIDAPP = ([Na+] + [K+] + [Ca2+] + [Mg2+]) − ([Cl−]). Ionized concentrations of Mg and Ca are used. If aval-
able, lactate should be included:
SIDAPP = ([Na+] + [K+] + [Ca2+] + [Mg2+]) − ([Cl−] + [lactate−]).
In healthy volunteers, the usual SIDAPP is 38–42 mEq/L. In stable critical care patients, SIDAPP is around 33 ±
5.6 mEq/L. If this patient then has metabolic acidosis, SIDAPP will decrease further. The lower the baseline
of the SIDAPP, the greater the susceptibility to a subsequent acid load.
According to the principle of electroneutrality, blood plasma cannot be charged, so there should be
remaining negative charges balancing the “excess” of plasma strong cations in relation to the strong
anions; this is the origin of SIDAPP. These balancing negative charges come from total CO2 (~[HCO3−]) and
from albumin and inorganic phosphate. Thus SID can be derived, accounting for electrical neutralitiy, as
the sum of [HCO3−] plus the negative electric charges contributed by albumin ([Alb−]) and by inorganic
phosphate ([Pi−]). This calculation of SID is known as effective SID (SIDEFF):
SIDEFF = [HCO3−] + [Alb−] (g/L) + [Phosphate−] (mmol/L).
The negative electrical charges contributed by serum albumin and phosphate are as follows:
[Alb] = [Alb] × (0.123 × pH × −0.631) and [Phosphate] = [Phosphate] × (0.309 × pH × [−0.469]).
Taking in account the complexity of the albumin molecule, its charge should be expressed as a linear func-
tion of the pH. Thus, a more accurate calculation of SIDEFF is:
SIDEFF = 2.46 × 10−8 × PCO2/10 − pH + [albumin (g/dL)] × (0.123 × pH −0.631) + [Phosphate (mg/dL)] × (0.309
× pH − 0.469).
For its clinical application, this equation needs access to an Internet-based engine designed for calculat-
ing the SIDEFF and other physicochemical acid base parameters (consult http://www.acidbase.org).
In the healthy individual, SIDAPP and SIDEFF are nearly identical. In disease states, this may not be true, as
plenty of unmeasured ions not included in equations may be present in plasma (e.g., ketones, sulfates,
organic acids from inborn errors of metabolism, certain medications), along with abnormal weak ions
(such as proteins). Clearly, this will make both SIDAPP and SIDEFF inaccurate. So, the simplest way to
approximate [XA−] is through the SIG. This term is far from ideal, since the unmeasured anions creating
the ‘gap’ can be either strong or weak. It is calculated as follows:
SIG = SIDAPP − SIDEFF with the result expressed in mEq/L.
By convention, SIG is positive when unmeasured anions exceed unmeasured cations (acidosis) and nega-
tive when unmeasured cations exceed unmeasured anions (alkalosis).
These are acids that cannot be eliminated by respiration (unlike H2CO3 through its conversion to CO2),
and that have a pKa almost equal to the physiological pH of 7.4. Therefore weak acids, as opposed to
strong ions, can exist at physiologic pH as dissociated (A−) or associate with a proton (AH). Weak acids are
often referred to as buffers. The concentration of each one of these weak acids, is the sum of its dissoci-
ated and undissociated forms:
ATOT = AH + A−
The two nonvolatile weak acids with great enough concentrations in plasma to have an influence on
acid-base status are albumin and inorganic phosphate, the latter having a minor effect. They provide the
remaining charges to satisfy electroneutrality.
PCO2, SID, and ATOT are the independent variables that control acid-base status, which means that they
are causally related to the hydrogen ion, rather than being merely correlated. Normal acid-base status
occurs when the independent variables have normal values. Abnormality of one or more of the indepen-
dent variables underlies all acid-base disturbances.
Includes organic acids not routinely measured, such as lactate (if not measured), and keto acids. They
are the main self-unmeasured acids. Additionally, sulfates and other acids may be high in the chronic
renal failure setting, and less common organic acids may appear in other scenarios, as in inborn errors of
metabolism. Exogenous UMAs may include salicylate, formate, and other drug or toxic-derived acids that
can be responsible for acidosis in some patients. All these (XA− or UMAs) are strong acids.
 Chapter 68 — Acid-Base Balance and Disorders 971

Table 68–5  Concepts and Parameters Used in the Quantitative Physical-Chemical Approach to
Acid-Base Balance: A Summary—Cont’d
Variable
Partitioned standard base
excess (SBE) or BE gap
Comment
It is an attempt to combine the approaches of Siggaard-Andersen and Stewart in a kind of physicochemi-
cal adjusted standard base excess (SBE), which seeks to quantify the effect of each individual metabolic
component of standard base excess, i.e., each component has its own “adjusted” or “partitioned” SBE.
The lab-reported SBE, or total SBE (SBETOTAL) should equal the sum of the BE for each one of the compo-
nents. More specifically,
SBETOTAL = BEfw + BECl + BEalb + BEXA,
where the effects of free water (fw), chloride (Cl), albumin (alb), and unexplained or unmeasured anions
(XA− or UMAs) were taken in account. The level of XA− is, of course, unknown. Hence, the SBE for the
unmeasured anions is determined from the others. This is termed by some as the “BE gap”:
BEXA (also abbreviated as BEUMA) = SBETOTAL − BEfw − BECl − BEalb.
BEfw and BECl (sodium and chloride effects), both being strong ions, were later combined in a single BE
due to SID (BESID):
BEXA or BEUMA = SBETOTAL − BEalb − BESID
in which BEALB = (42 − [albumin]) × 0.25, and BESID = [Na+] − [Cl−] − 32. These values are used to solve the
equation:
BEXA or BEUMA = SBETOTAL (blood gas analyzer-derived) − {(42 − [albumin]) × 0.25} − {[Na+] − [Cl−] − 32}.

Table 68–6  Classification of Primary Acid-Base Disturbances: Independent Variables-Oriented

Approach
RESPIRATORY METABOLIC*
ABNORMAL NONVOLA-
ALTERATION IN PaCO2 IMBALANCE OF STRONG IONS TILE WEAK ACIDS†
ACIDOSIS ALKALOSIS ACIDOSIS ALKALOSIS ACIDOSIS ALKALOSIS
Hypoventila- Hyperventi-
tion lation Excess XA−† ↑ Cl− and/or ↓ Na+‡ ↓ Cl−‡ ↑ Na+§ ↑ Alb, ↑ Piǁ ↓ Alb, ↓ Pi¶
↑ PaCO2 ↓ PaCO2 ↓ SID, ↑ SIG− ↓ SID, ↓SIG ↑ SID ↑ SID ↑ ATOT ↓ ATOT
Central ner- Inappropri- Endogenous: Exogenous Cl Cl responsive: Na+ load (as Exogenous Nephrotic
vous system ately set Lactic acid, load: Sodium Gastrointesti- acetate, adminis- syn-
depres- mechani- ketoacids, chloride resusci- nal losses of citrate, tration of drome,
sion: brain cal ven- inborn errors tation, TPN, etc. Cl−: Vomiting, lactate) phos- hepatic
edema tilation of metabo- Loss of cations gastric drainage, Ringer solu- phates cirrhosis
from head param- lism, sulfates, from postpy- chloride-wasting tion, TPN,
trauma, eters, late metabolic loric losses acute diarrhea blood
from seda- central acidosis of without pro- Renal losses of Cl− transfu-
tion, etc. nervous prematurity, portional losses and K+: diuretics, sion, or
Neuromuscu- system etc. of chloride: posthypercapnea, Na+ rela-
lar function disorders, Exogenous: secretory diar- certain antibiotics tive excess
impair- and some salicylate, rhea, drainage Cl nonresponsive: (water
ment, psychiatric methanol, tubes, ostomies, Mineralcorticoid deficit)
damage to diseases ethylene fistulas. excess:
efferent glycol, dieth- RTA and drug Genetic renal
nerves or to ylene glycol, mediated tubular defects
the muscles propylene tubulopathies: of electrolyte
of respira- glycol, etc. amphotericin transport
tion B, topiramate, Drug-induced hypo-
Lungs (airway acetazolamide, kalemic alkalosis
and alveoli) etc. Miscellaneous
Urinary recon-
struction using
bowel segments
The most important weak acid—partially dissociated acid—is albumin, with a minor effect from phosphate.
*Metabolic acidoses arise from conditions that cause either a reduction in the plasma SID or increase in A
TOT. Conversely, metabolic alkaloses stem from conditions that
produce either a primary increase in the plasma SID or a decrease in ATOT. However, whereas there appears to be complex regulation of SID for acid-base purposes, no
such mechanisms are known to control ATOT for this purpose. For this reason, there is no agreement as to whether changes in ATOT should be accepted as acid-base
disorders or not, despite their influence on pH.
†Excess of acid anions corresponds to the anion gap acidoses. Includes several organic acids, endogenous and exogenous (e.g., lactate, keto acids, salicylate); also sulfate

and other anions in chronic renal failure and unknown anions in conditions such as sepsis. Unlike in anion gap, Pi is not included because it is not a strong ion.
‡Hyperchloremic (non-anion gap) acidosis and hypochloremic alkalosis. The hyperchloremic acidosis occurs either as a result of an increase in chloride concentration rela-
tive to strong cations (especially sodium) or because of the absolute or relative loss of cations (water excess) with retention of chloride.
§Excess of cations (Na+)

ǁNot a single cause of acidosis, but is a component of metabolic acidosis in severe extracellular volume loss, such as in cholera.
¶This source of alkalosis is clinically insignificant; the normal value of Pi (~1 mmol/L) cannot decrease enough to have an appreciable acid-base effect.
972 Section V — Renal, Endocrine, and GI Systems
be regulated independently of PCO2. Plasma bicarbonate con-
centration will always increase if PCO2 increases, but this is
not an alkalosis. Therefore the increased bicarbonate concen-
tration is not “buffering” the rise of [H+], and there will be no
change in the SBE. As CO2 easily diffuses through membranes,
when PCO2 increases there is always tissue acidosis. If PCO2
remains high, the body will attempt to compensate by altering
another independent determinant of pH. The kidneys are the
main organs involved in this compensation.8,39
The Strong Ion Difference
Strong ion difference (SID) is defined as the charge difference
between the sum of all strong cations and the sum of all strong
anions. When SID is calculated from direct measurement of
serum strong ions, it is termed apparent SID (SIDAPP),8,31,42,43
with the understanding that more unmeasured (or unmeasur-
able) ions might also be present (see Table 68-5):
+ + 2+
SIDAPP = ([Na ] + [K ] + [Ca ]
+ [Mg2 + ])� − [Cl − ] (11A)
In the critical care setting, it is wise to include lactate levels if
they are available, because the sicker the patient, the higher the
chance that lactate or other strong anions are increased:
SIDAPP = ([Na + ] + [K + ] + [Ca2 + ] + [Mg2 + ])� − �([ Cl − ]
+ [lactate − ]) (11B)
From actual measurements in healthy volunteers, the
normal range of SIDAPP has been estimated from 38 to
42 mEq/L.5,8,13,42,44 In critical illnesses, SIDAPP may be substan-
tially reduced, even when there is no evidence (by the tradi-
tional approach) of a metabolic acid-base derangement.42,45
Gunnerson et al.42 found in stable critical care patients a SIDAPP
value of 33 ± 5.6 mEq/L, but others have found different val-
ues. Thus, in spite of the lack of consensus about what value
of SIDAPP one should expect in an ICU population, it is clear
that their SIDAPP values are different from healthy volunteers’
figures.23,44,45 The tendency of critical care patients to have a
lower SIDAPP is not surprising, given the fact that the positive
charge of the SIDAPP is balanced by the negative charges of the
weak acids, [A−] (albumin and phosphate), and total CO2.
Because Pco2 is usually modified by the body for other rea-
sons (e.g., hyperventilation in a patient that tends to be hypox-
emic) and because hypoalbuminemia is the rule rather than
the exception in this setting, [A−] tends to be reduced, and
this decrease leads to a reduction in SIDAPP to keep the normal
pH. Thus a typical critical care patient might have a SIDAPP
around 30 to 35 mEq/L, rather than the “usual” range of 38 to
42 mEq/L. If this patient then has metabolic acidosis, the SIDAPP
will decrease further. The lower the baseline of the SIDAPP, the
greater the susceptibility to a subsequent acid load.42,44,45
Additional strong anions may become significative (e.g.,
hyperlactatemia, sulfate, keto acids, anions from Krebs
cycle) or appear de novo in disease states (several organic
acids from inborn errors of metabolism), or enter the body
as medications or toxic substantes (salicylates, certain
β-lactam antibiotics, etc.). They may eventually have an
influence on the value of SIDAPP.44-47 Because it is usually
not possible to have a direct measure of [XA−] at bedside
(with the exception of lactate), it is not always convenient
to rely only on SIDAPP to determine the strong ion status.
The more ill the patient, the more accurate is this statement.
Then, in critically ill patients, it is better to calculate SID to
account for electrical neutrality. According to the principle
of electroneutrality (Equation 8), blood plasma cannot be
charged, so there should be remaining negative charges bal-
ancing the “excess” of plasma strong cations in relation to
the strong anions, which is the origin of SIDAPP. These bal-
ancing negative charges come from total CO2 (~[HCO3−])
and from two substances that act as nonvolatile weak acids,
that have concentrations in plasma large enough so that
changes in them can produce significant acid disturbances:
the weak acids (A−) albumin and inorganic phosphate. Thus
SID can be derived, accounting for electrical neutrality, as
the sum of HCO3− plus the negative electric charges con-
tributed by albumin (Alb−) and by inorganic phosphate
(Pi−).13 This calculation of SID is known as effective SID
(SIDEFF)13,48:
SIDEFF = [HCO3− ] + [Alb − ](g / L)
� � � + [Pi − ](mmol / L)  (12A)
where the negative electrical charges contributed by serum
albumin and phosphate are as follows:
[Alb − ] = [Alb] × (0.123 × pH × − 0.631) and
[Pi− ] = [Pi ] × (0.309 × pH × [ − 0.469 ]).
A less-accurate, simplified version of this formula, which
assumes a stable pH of 7.4, appears in some publications31:
SIDEFF = [HCO3− ] + 0.28 × [Alb − ](g / L)
+ 1.8 × [Pi− ](mmol / L)  (12B)
where factors 0.28 and 1.8 are, respectively, the negative
electric charges displayed by 1 g albumin and 1 mmol of
[Phosphate] in plasma at pH 7.4 (0.6 instead of 1.8 if [Phos-
phate] is in mg/dL).48
Human serum albumin must be treated as a polyproteic
macromolecule, exhibiting multiple apparent equilibrium
dissociation constants corresponding to different classes of
amino acids side chains. Accordingly human albumin charge
should be expressed as a linear function of the pH. Thus Eqa-
tion 12A from Figge et al.48 is more useful in sicker patients.
Actually, SID was derived from a mathematical model with
much more complex nonlinear equations, which might be
encountered by the clinician while reviewing certain books
and articles.49-51 Constable and coworkers42,52 have now
developed some adaptations for clinical application, which are
claimed to be more accurate:
SIDEFF = 2.46 × 10 − 8 × PCO2 / 10 − pH +
[albumin(g / dL)] × (0.123 × pH − 0.631)
+ [Pi (mg / dL)] × (0.309 × pH − 0.469)  (12C)
However, this equation is not very easy for the busy clinician
to solve, and therefore its clinical application requires access
to an Internet-based engine especially designed for calculating
the SIDEFF (see the section on Strong Ion Gap in this chapter).
SID has a powerful electrochemical effect on water dis-
sociation, and hence on H+. Both H+ and OH− behave as a
weak cation and anion, respectively. Because practically all
the cations in plasma are strong ions, except for H+, only H+
concentration can vary in response to changes in anions. On
the other hand, there are several anions that are weak ions,

and thus there are several “options” for anion molecules
that can change their charges if cations change.8,53 As the
SIDAPP increases (strong cations in excess over strong anions)
plasma becomes positively charged. Hence H+, a weak cat-
ion, decreases, and pH increases, to maintain electrical neu-
trality, and alkalosis is produced. On the other hand, if the
SIDAPP decreases (strong anions in relative excess over strong
cations), plasma becomes negatively charged, more water is
dissociated producing more H+ for maintaining electroneu-
trality, and acidosis is produced.8,40,51
Changes in SID result from either a relative or an absolute
change in strong ion concentrations. A change in free water
content produces an alteration in the relative concentration
of the strong ions, and hence a change on SID. If, as a result,
Na+, K+, and Cl− decrease, the absolute value for SID will
decrease proportionately. Thus an excess of free water low-
ers SID and results in a tendency towards metabolic acidosis.
In a similar manner, a free water deficit causes a metabolic
alkalosis by increasing the SID through a relative increase in
concentration of all strong ions. Relative and absolute changes
in sodium concentration primarily result from osmoregula-
tion, and thus they are reflective of changes in free water.
The remaining strong cations, potassium, magnesium, and
calcium, as they are tightly regulated by the body for other
functions (coagulation, membrane excitability, neuromuscu-
lar plates, muscle contraction, etc.) do not vary significantly
enough to directly cause alterations in acid-base balance.13 On
the other hand, changes in strong anion concentrations are
significant to acid-base status. Traditionally, hypochloremia
(from gastrointestinal or renal losses) is associated with meta-
bolic alkalosis, and hyperchloremia (e.g., from resuscitation
with saline infusion) is associated with metabolic acidosis.
Because chloride concentration can be affected by free water
content just as is sodium concentration, according to some
authors,31 it is important to take in account alterations in free
water content that might exist, and thus Cl− would need to be
corrected based on the sodium concentration:
Cl − CORR = (140 / [Na + ) × Cl − (13)
However, the need for this “correction” is not universally
accepted (see the section on Merging Traditional and Newer
Approaches).
As the SID requires an actual change in the relative con-
centrations of strong cations or anions, the kidneys are the
primary organs regulating SID. As the kidneys can excrete
only small amounts of strong ion into the urine each minute,
several minutes to hours are required to achieve a significant
change in the SID. The control of the kidney is important
and precise because every chloride ion that is filtered and not
reabsorbed increases the SID. Acid handling of the kidney
has traditionally focused on H+ excretion and the role of
ammonia (NH3) and ammonium (NH4+) as hydrogen ion
carriers.9,10,54 Because water provides an essentially infinite
source of H+, its excretion, per se, is possibly not as relevant
as formerly taught. In fact, the net H+ excretion by the kid-
ney as water molecules is larger than the excretion as NH4+.
Therefore the purpose of renal NH4+ production is to allow
the excretion of Cl− without the excretion of Na+ or K+. Thus
NH4+ is important to systemic acid-base balance, not for its
role as an H+ carrier or for its direct action in the plasma
(normal [NH4+] is ~0.01 mmol/L), but because it allows a
“safe” excretion of Cl−.8,55
Chapter 68 — Acid-Base Balance and Disorders 973
A urinary anion gap (uGap) was described some time ago.9
This urinary gap has also been designated by some authors8 as
“urine strong ion difference” (uSID):
uGap = uSID = [uNa + + uK + ] − [uCL − ] (14)
Certainly, sodium, potassium, and chloride are all strong
ions, so the name is, at least, functionally correct. What is
the value in measuring the uSID? As its serum analogue, the
uSID estimates the unmeasured urinary ions. In terms of
its amount, the most important unmeasured urinary strong
anion (Ur−) is SO42− (derived from the metabolism of sulfur-
containing amino acids), whereas the most important unmea-
sured cation (Ur+) is ammonium (NH4+). In physiologically
“normal” conditions, uSID must equal the plasmatic SIDAPP,
that is, 38 to 42 mEq/L. When a strong ion enters the plasma
(e.g., lactate, or a chloride load), plasmatic SID will obvi-
ously decrease. Normal kidneys will react by increasing their
excretion of chloride, thereby decreasing the plasma chloride
concentration, while Na+ and K+ must be maintained within
normal ranges. This is accomplished by increasing the excre-
tion rate of NH4+, which is the more efficient way to increase
chloride elimination without losing sodium or potassium.
The increased excretion of chloride will decrease the uSID.55
In addition to the kidney, both the liver and the gastroin-
testinal tract may have an influence on SID. In the stomach,
Cl− is pumped out of the plasma and into the lumen, reduc-
ing the SID (and pH) of the gastric fluids, but increasing the
SID (and pH) in the plasma side (alkaline tide), because of
the exit of Cl− to the stomach. However, only a slight change
in plasma pH becomes evident, because Cl− is reabsorbed in
the duodenum just as fast as it was pumped out. However, if
gastric secretions are removed, either by vomiting or suction
catheter, the SID will progressively increase, as will the pH, as
a result of Cl− loss. Although H+ is excreted as HCl, it is also
lost with every water molecule that exits the body. When the
body loses Cl−, a strong ion, without also losing a strong cat-
ion, SID is increased; therefore H+ is decreased and alkalosis
ensues. When H+ is excreted as H2O rather than as HCl, there
is no change in SID, and consequently there is no change in
H+. At present it is not known whether the gastrointestinal
tract, the liver, and the pancreas are capable of compensatory
actions to regulate strong ion uptake.9,39
Strong Ion Gap
In the healthy individual, SIDAPP and SIDEFF are nearly identi-
cal, and therefore are adequate estimates of the “true” SID and
of the acid-base status.8,26,28 However, in disease states, this
might not be true, as many unmeasured ions (mainly anions)
may be present in plasma. Actually, unexplained anions, and
in some case unexplained cations, have been found in the
circulation of patients with various diseases and in animal
models.46,47,55-58 Blood samples from certain patients often
encountered in the critical care setting may contain unmea-
sured strong ions (e.g., ketones, sulfates, organic acids from
inborn errors of metabolism, certain medications, etc.), mak-
ing the SIDAPP an inaccurate estimate of the “true” SID or
SIDEFF. Similarly, patients of this type may have abnormal
weak ions (such as proteins) that can make the SIDEFF inac-
curate as well. In order to address this situation, Jones59 and
Figge48 independently proposed a similar scanning tool. Kel-
lum and coworkers coined the term “strong ion gap” (SIG) to
974 Section V — Renal, Endocrine, and GI Systems
name this new tool60,61; however, the term is not ideal, since
the unmeasured anions creating the ‘gap’ can be either strong
or weak (see Table 68-5).46,47,62 Nowadays, a modern clinical
lab can easily measure all the components of the SIDAPP and
SIDEFF equations, including lactate. As a result, XA− is easily
approximated through SIG, which is calculated as follows:
SIG = SIDAPP − SIDEFF  (15)
By convention, SIG is positive when unmeasured anions
exceed unmeasured cations (acidosis) and negative when
unmeasured cations exceed unmeasured anions (alkalosis).
In ideal theoretical conditions, it would be possible for the
sum of strong cations and weak anions to cancel each other
out, with a SIG equal to zero. In the real world, most SIGs
are positive (anions < cations). The use of SIG is advocated
in situations in which SIDAPP and SIDEFF are not equal.28,60,61
SIG different from zero may also be explained, at least in part,
by the difference between ionic molar concentration (the basis
for SIDAPP) and ionic activity itself (the basis for SIDEFF). Ionic
molar concentration is a measure of the actual number of ions
in solution. In contrast, ionic activity is a measure of the effec-
tive concentration of electrolytes that results from the charge
interaction on dissociated species. The difference between
ionic concentration and ionic activity is important because
the molar concentration of any electrolyte will not affect the
molar concentration of any other electrolyte, but ionic activi-
ties are mutually interactive. The principle of electrical neu-
trality only refers to the latter.44 Both SIDEFF and SIG have been
evaluated as prognostic markers in both children and adults.
Both indexes have shown good predictive capability in most
publications, but there is no universal agreement regarding
their clinical usefulness.13,30,63-70 If one would like to increase
the precision of SIG, one should include as many factors as
possible in the calculation of SIDEFF. However, a theoretical
downside is that each additional analyte may increase impre-
cision,62 and the calculations become rather cumbersome in
the clinical arena. On the other hand, innovative software
solutions have been developed. One is the so-called strong
ion calculator71,72 and several similar tools available at http:/
/www.acidbase.org.73 They can be consulted online through
computers and handheld devices. This should be the proper
solution for the present time albeit not for the future. The
SIG has demonstrated good stability in the setting of severe
pH stress (<6.85, >7.55), a clear advantage when compared
to AG, which has the tendency to increase steadily as PCO2
falls and when pH rises. The well-known AG increase parallel
with pH has been related to altered albumin and phosphate
dissociation in extremes of pH.60
Nonvolatile Weak Acids (Albumin and
Phosphate)
As already explained, there are normally only two substances
that act as nonvolatile weak acids with large enough concen-
trations to influence H+: proteins (albumin being the most
important by far) and phosphates. They provide the remaining
charges to satisfy electroneutrality: SID − (CO2TOT + [A−] = 0
(from Equation 12A): CO2TOT is exchangeable with bicarbon-
ate; A− is the negative charge of anions, mainly albumin and
phosphate). It should be noted that A− is not an independent
variable because it changes with alterations of SID and Pco2.
Rather, ATOT = ([AH] + [A−]) is the independent variable,
because its value is not determined by any other. However,
mathematical and chemical independence does not necessar-
ily means physiologic independence. Although the loss of weak
acid (ATOT) from the plasma space is an alkalinizing process,
there is no evidence that the body regulates ATOT directly to
maintain acid-base balance, as there is no evidence that clini-
cians should treat hypoalbuminemia as an acid-base derange-
ment.8 It is not uncommon that critically ill children develop
hypoalbuminemia, and hence their ATOT decreases. However,
these patients are not always alkalemic. They usually maintain
pH, SBE, and HCO3− within normal limits, despite the fact
that their SID is also reduced. Because changes in ATOT tend
to occur rather slowly, the development of alkalemia would
require the kidney to continue with its Cl− excretion despite
an evolving alkalosis; as such, this scenario would probably
be considered hypochloremic metabolic alkalosis, and SID
would increase as a result of the increased loss of anion (and
thus from a net increase in strong cations). However, what is
observed in hypoalbuminemic patients is the opposite, that
is, the SID tends to be decreased in relation to healthy indi-
viduals. This means that the kidney has already compensated
the alkalinizing effect of hypoalbuminemia by increasing the
reabsorption of Cl−, then increasing plasma strong anion, then
reducing the SID. Thus a hypothetical patient with an albu-
min around 2 g/dL would have an already “compensated” pH
through a SIDAPP around 30 to 32 mEq/L.8 It is possible to see
that changes in these three independently variable quantities,
Alb, Pi, and SID, may have additive or offsetting effects on the
metabolic acid-base balance. Such offsetting effects may result
in normal values of the dependent variables pH, HCO3− and
SBE, whereas some independent variables are abnormal. In
such a case, the condition could not be considered a normal
acid-base status, despite the absence of acidemia or alkalemia.
Merging Traditional and Newer
Approaches: Is an Integrated
Approach Ready for the
Bedside?
Despite the apparent differences between the traditional
bicarbonate-centered and the physicochemical approaches
to acid base physiology, they are complementary. Through
PCO2 analysis and the Henderson-Hasselbalch equation, it is
possible to describe and quantify the respiratory side of the
acid-base balance, and to describe the metabolic side, which
requires a more complex analysis. The traditional tools for
approaching the metabolic side, AG and SBE, now have been
supplemented by Stewart’s physical-chemical concepts, and
their performance has been improved.29-31,67,74-77 In spite of
the apparent differences among these three methods, they all
share a common theoretical foundation based on the prin-
ciple of electroneutrality and the role of plasma weak acids.
Prompt identification of unmeasured anions is essential in
any acid-base analysis in the critical care setting. This was
demonstrated recently in a retrospective study, in which the
main finding was that mortality associated with strong ion aci-
dosis, either lactic or nonlactic, was significantly higher than
that associated with hyperchloremic acidosis (56%, 39%, and
29%, respectively).31,42,70 Hence, the presence of an elevated
amount of unmeasured anions is a predictor of mortality, and
the best diagnostic tool for the early detection of the unmea-
sured anions XA− should be preferred. A better correlation

of indicators of unmeasured anions has been found between
AGCORR (not AG), SIG, and physicochemical adjusted SBE
(also known as partitioned SBE or BE gap). This has been con-
firmed in several clinical studies.31,42,75 Pediatric studies have
been made using both SIG and partitioned BE.
Corrected Anion Gap
The correction factor required for the AG to account for hypo-
albuminemia improves its performance (see the sections on
Anion Gap and Anion Gap Corrected), yet some caveats must
be understood by clinicians.34 For its performance to improve,
AGCORR needs additional corrections. For example, the clas-
sical AG method does not consider the correction of chlo-
ride concentration in the setting of altered free water. Thus,
hyperchloremic acidosis may go undetected with the AGCORR
method, in the setting of a dilutional alkalosis.31 Hence a cor-
rected value of chloride would theoretically be needed (see
Equation 13). However, the very concept of “corrected chlo-
ride” is under criticism by some authors, as no other element
of the AG equation (nor of SID or SIGs) is corrected for water
excess or deficit,62,78 and because the sodium correction of the
chloride assumes a fixed sodium-chloride relationship that
does not occur in vivo, as large transcellular shifts of chloride
can occur in exchange for bicarbonate (and thus independently
of sodium) in different acid-base states.67,77,79,80 Hence there is
no uniform acceptance of the need to use corrected Cl− values
in calculating AG. It is of much greater importance to be aware
of the reference values for chloride that are in use in a given set-
ting. On the other hand, in order to avoid [lactate–] influence
on AGCORR that could mask the detection of other unmeasured
anions, it has been suggested that AG should be corrected not
only for albumin, but also for lactate. This is simply derived by
subtracting the serum lactate concentration (in mmol/L) from
the already albumin-corrected AG (see Equation 10A):
AGCORRLACT = Albumin-corrected AG
                            − [Lactate(mmol / L)] (16)
This albumin- and lactate-corrected AG (AGCORRLACT)
seems to correlate well with the SIG, as was found by Moviat
et al. in a small but precise study (r2 = 0.934, P < .001).57,64,67
In which case, AGCORRLACT may be an easy bedside measure-
ment that could approximate the SIG in critically ill patients,
although more clinical experience is needed. Therefore,
using the single, uncorrected value derived for AG in criti-
cally ill patients may not represent good practice, given the
high prevalence of hypoalbuminemia. If AG needs to be
determined, albumin and lactate levels should be taken in
account, so the proper correction can be made (AGCORR or
AGCORRLACT).28-34,42,74,75
Partitioned SBE, or BE gap, is an attempt to combine the
approaches of Siggaard-Andersen and Stewart in a kind of
physicochemical adjusted SBE that seeks to quantify the meta-
bolic component of acid-base disorders. Based on an analysis
of Stewart’s model, Gilfix81 proposed that only four condi-
tions may create nonrespiratory acid-base disturbances: (1)
free water deficit or excess (BEfw), as determined by changes in
sodium concentration; (2) changes in chloride concentration
(first corrected for the free water effect) (BECl); (3) changes
in protein charges, mainly albumin (BEalb); and (4) the pres-
ence of organic unmeasured anions (BEXA). Therefore to be
precise, SBE needs to be “partitioned” (using abridged Stewart
Chapter 68 — Acid-Base Balance and Disorders 975
equations)64,82-84 into four “physicochemical” segments, that
is, each one of the four conditions requires its own adjusted or
partitioned SBE. Gilfix81 showed that the lab-reported SBE, or
total SBE (SBETOTAL) should equal the sum of the BE for each
one of the four conditions:
SBETOTAL = BEfw + BECl + BEalb + BEXA  (17A)
The concentration of unmeasured anions is, of course,
unknown. Hence, the SBE for the unmeasured anions is deter-
mined from the others. This is termed by some as the BE gap:
BEXA (also abbreviated as BEUMA )
   = SBETOTAL − BEfw − BECl − BEalb  (17B)
BEfw and BECl (sodium and chloride effects), both being
strong ions, were later combined in a single BE due to SID
(BESID) 77:
BEXA (also abbreviated as BEUMA )
   = SBETOTAL − BEalb − BESID  (17C)
This approach has received some criticism for small but
potentially important inaccuracies derived from the partition
of BE, a whole-blood–derived parameter, into plasma com-
partments, which may generate discrepancies that magnify as
PCO2 deviates from normal, from the exclusion of phosphate as
a part of [ATOT]) and from the lack of uniformity in reference
values.62 In spite of these physiologic and conceptual caveats,
this approach was first tested in children in a pediatric intensive
care unit in 1999, with apparent success.64 Reported successful
applications in mortality prediction and classification of acido-
sis in several settings, including sepsis and septic shock, cardiac
surgery, diabetic ketoacidosis, and others, soon followed.70,84,85
Unfortunately, lack of standardization in regard to the formulae
used for BE partitioning has been a serious inconvenience for
the comparison of these studies.64,77,81-87 In a recent review,77
an analysis of the four published methods of partitioning SBE
showed large and clinically important discrepancies between
them. Of all the documented methods for BE partitioning, the
one from Taylor et al., 84 in which BEALB = (42 − [Albumin]) ×
0.25, and BESID = [Na+] − [Cl−] − 32 seems to be the most accu-
rate.31,64,77 These values must be used to solve Equation 17.
In spite of enthusiastic publications, until a consensus is
reached, caution must be applied if the clinician chooses to
employ the SBE partitioning approach. Nowadays, certainly
an “integrated approach” to the metabolic acid-base disorders
is the best advice. This should include the PCO2/bicarbonate
approach for respiratory acid-base disturbances and for the
initial appraisal of the metabolic problems (bicarbonate and
SBE). For these, AGCORR (AGCORRLACT (if [lactate−] is avail-
able) and SIG are the best available tools. SBE partitioning
(Taylor’s method) could also be employed. The advantage
of this approach is that it allows the clinician to detect com-
plex mixed acid-base derangements in the critical care setting,
which may result in the identification of more patients with
major acid-base disturbances. The physicochemical approach
yielded the additional diagnosis of metabolic disorders in
33.7% of patients in one single-center adult study.88 However,
it remains unclear if the identification of these additional acid-
base disorders translates to new and otherwise unanticipated
therapeutic interventions in these patients. It is important
to understand the limitations of all the acid-base assessment
tools, to identify when perturbations in AG, SBE, or SIG are
significant, and when they are not.31,75,89
976 Section V — Renal, Endocrine, and GI Systems
New Insights for Old Problems
The classical acid-base approach yielded some common sense
explanations for some acid-base disturbances often seen in
the clinical arena. For example, it is said that the metabolic
alkalosis seen with severe emesis or nasogastric tube losses is
due to a loss of H+; that the metabolic acidosis seen in per-
sistent postpyloric fluid losses is due to a loss of bicarbonate;
that an acidosis caused by large volume fluid administration is
caused by dilution of bicarbonate; and that sodium bicarbonate
(NaHCO3) therapy corrects metabolic acidosis by contribut-
ing bicarbonate ion (HCO3−) to the body. These time-hon-
ored explanations have been challenged by the new view of
acid-base balance, in which water dissociation represents a
core principle.8,35 According to the water-dissociation prin-
ciple, pH has no direct relationship with any total body direct
loss or gain of H+ or HCO3−, but rather reflects the change of
SIDEFF and ATOT and their effect on water dissociation, the
true antecedent of the resultant pH change and concentrations
of H+ or HCO3−, that are then merely effects rather than the
cause of the acid-base derangements. For example, it is well-
recognized that the acute expansion of extracellular volume
with normal saline solution (sodium chloride [NaCl] 0.9%) or
with any unbalanced synthetic colloid solution (6% hydroxy-
ethyl starch solution or 4% gelatin) may result in hyperchlo-
remic acidosis.68,82,87,90-97 The understanding of this condition
has improved through the physicochemical comprehension of
the acid-base equilibrium: saline causes acidosis not through
“dilution” of bicarbonate, but rather by its Cl− content, which
decreases the SID and produces an increase in water dissocia-
tion and in H+.87,90-94 This occurs despite equal amounts of
Na+ and Cl− in saline solution, because sodium and chloride
concentrations are different in plasma. Therefore when large
amounts of NaCl in solution are infused, they will have a pro-
portionally greater effect on total body chloride than on total
body sodium. The elevated gastric fluid losses seen with severe
emesis or nasogastric drainage are the opposite example: loss
of high amounts of chloride lead to an increase in SID and
to alkalosis.98 Sodium bicarbonate, by contributing the strong
ion sodium (Na+), increases the SID and hence pH increases;
thus it is the sodium, not the bicarbonate, that actually cor-
rects an acidemia (see Strong Ion Difference in this chapter).99
In addition to these examples, the water-dissociation–
centered model from Stewart may provide new insight into
the molecular biology and transport physiology of the renal
tubule. For example, renal tubular acidosis (RTA) and Bart-
ter syndrome may be redefined as “chloride channelopathies,”
rather than disorders of net acid excretion.49,100 In spite of the
theoretical and mathematical certainties and the experimental
and clinical evidence regarding the pertinence of the physico-
chemical approach, there is still no universal agreement about
the clinical validity of these explanations, neither about their
clinical relevance.101-103
The Clinical Problem: Does Abnormal pH
Harm?
The clinician has been taught to fear abnormal pH, in particu-
lar acidemia. The rationale for such a fear is that every pro-
tein in the body contains areas of both positive and negative
charge, and hence it is a fact that they are electrochemically
sensitive and thus sensitive to the H+ concentration of their
environment. Therefore a decrease or increase in arterial pH
might be expected to have important detrimental effects on
a host of bodily functions. In the critical care unit, acid-base
disorders are often considered more important for what they
tell the clinician about the patient than for any harm that is
directly provoked by the acid-base imbalance. Several stud-
ies8,104 have reinforced this concept by showing that mortality
was more closely related to the nature of acid-base disorders
than to the magnitude of metabolic acidosis (estimated by
partitioned SBE). Hyperlactatemia, more than the elevation of
unmeasured anions (AGCORR, SID, SIG) or SBE, is predictive
of a poor outcome. Despite this reliable data from children
with shock, it is generally accepted that acid-base derange-
ment itself may cause harm in certain circumstances.10,14,105
The obvious examples are the extreme conditions of pH (<7.0
or >7.7). It is also important, however, to consider how fast
the acid-base derangement is evolving, along with the specific
expected consequences of the alteration in specific patients.
For example, in a patient who depends on vasopressors, vaso-
dilation due to alkalosis, either respiratory or iatrogenic in
origin (overzealous hand bagging of the patient), or metabolic
as a consequence of gastric fluid losses caused by a mechani-
cally obstructed jejunum, can be catastrophic. Another typical
example is the spontaneously breathing patient with meta-
bolic acidosis, who tries to compensate by increasing minute
ventilation; if the patient gets tired, there is the possibility that
hypoxemia will develop along with a respiratory acidosis. In
such cases, the underlying disorder must be treated, but one
must also provide immediate treatment for the acid-base
derangement itself.
The main expected physiologic effects of acidemia and alka-
lemia are as follows. Acidemia initially causes sympathetic and
adrenal stimulation, an effect that is counterbalanced, as the
drop in pH becomes more and more severe, by a depressed
responsiveness of adrenergic receptors to circulating catechol-
amines.14,106,107 In isolated animal heart preparations and in
isolated human ventricle muscle, there is no doubt that aci-
dosis reduces contractile function.108-110 The net influence of
acidosis in the whole animal and in real patients, however, is
more complicated to discern, and depending on the experi-
mental or clinical model, it has been found that acidosis caused
myocardial contractility to remain constant, decrease margin-
ally, or transiently rise and then fall.111 Hence, the whole-body
response to acidosis is much less clearly detrimental in real
individuals. In many preclinical and clinical studies of patients
undergoing permissive hypercapnia, a pH less than 7.2 was
well tolerated,112,113 as it is in children with diabetic ketoaci-
dosis,114 children and adults with hypercarbia,115 and those
with grand mal seizures.116 Thus it is now clear that the effect
of acidosis may differ according to type, magnitude, and time
of onset.70,115 Three types of extracellular acidosis—inorganic,
respiratory, and lactic—may have disparate effects on left
ventricular function, as shown in a model of isolated rabbit
hearts.107,117
Lactic acidosis caused a significant increase in the time
to peak left ventricular pressure, while retarding ventricular
relaxation. This reinforced the concept that lactate ions have
an independent and deleterious effect on myocardial func-
tion.110,117 These findings make sense (with some reserve)
when they are extrapolated to clinical grounds. Despite the
frequent coincidence of clinical shock and metabolic acido-
sis, the striking discordance between the clinical course and

outcome of patients with lactic acidosis compared with those
who have ketoacidosis or ventilatory failure, suggests that the
low pH itself is important but not crucial for the presentation
of the hemodynamic collapse of these patients.42,107,111 There-
fore the net effect on ventricular performance, heart rhythm,
and vascular tone depends on the relative effects of many,
sometimes competing, influences. In general terms, severe
acidemia (pH <7.10 according to most, pH <7.20 according
to others)9,10,14,42,107 is associated with decreased cardiac per-
formance that provokes a drop in cardiac output, along with
decreased vascular reactivity that manifests itself as arterial
vasodilatation and venous constriction. An important effect
in the critical care setting is the marked increase in cerebral
blood flow associated with acute respiratory acidemia, and its
abrupt decrease with respiratory alkalosis.118,119 When PCO2
acutely raises in excess of 70 mm Hg, loss of consciousness
and seizures can be seen, probably due to the abrupt lowering
of intracellular pH. Cultured lung epithelial cells exposed to
cyclic stretch similar to that seen with mechanical ventilation
produced a lactic acidosis that markedly enhanced the growth
of Escherichia coli.120 In contrast, alkalinizing the pH abolished
this effect. The demonstration that clinically relevant levels of
metabolic acidosis enhance bacterial growth is of concern.
However, in patients with acute respiratory distress syndrome
(ARDS) under mechanical ventilation and treated with “per-
missive hypercapnia,” the gradual rise of the PCO2 and the
consequent drop in the pH are well-tolerated in general terms,
with no significant negative effects on systemic cardiac output,
oxygen delivery, or vascular resistances, both pulmonary and
systemic.112,113 Actually, the hypercapnic acidosis has been
shown to provide beneficial effects on pulmonary function by
interacting with reactive oxygen species, the immune system,
and the alveolar-capillary barrier.119,120 However, recent evi-
dence showed, through a multivariate analysis, that changes
in arterial pH, but not in positive end-expiratory pressure
(PEEP) levels, were significantly correlated with impaired right
ventricular function, whereas the left ventricle was spared.121
Thus the net effect of respiratory acidemia to the patient, ben-
eficial or detrimental, may be complex to elucidate and must
be carefully assessed in each case. Other potential effects of
acidemia include endogenous catecholamine, aldosterone,
and parathyroid hormone stimulation; insulin resistance;
increased free radical formation; increased protein degrada-
tion; gut barrier dysfunction; further respiratory depression;
decreased sensorium; hyperkalemia; hypercalcemia; and
hyperuricemia.8,14 In regard to the effect of extracellular acide-
mia on inflammatory response and immune function, recent
research has indicated that different acids produce different
effects, despite similar extracellular pH.105
When associated with severe alkalemia (pH >7.60), both
metabolic and respiratory alkalosis lower blood pressure and
cardiac output. The potential deleterious effects of this drop
in systemic and regional blood flow may be aggravated by the
increased oxygen affinity of hemoglobin (shift to the left of the
oxyhemoglobin dissociation curve), particularly in acute alka-
losis. In chronic alkalemia this effect is counterbalanced by
an increase in the 2,3-diphosphoglyceric acid concentration
in red cells.10 Cerebral circulation responds dramatically to
alkalemia with marked vasoconstriction. Cerebral blood flow
may drop in response to an acute hyperventilation to about
50% of the basal flow, at a PCO2 of 20 mm Hg. This effect
has been used as an emergency management of an impending
Chapter 68 — Acid-Base Balance and Disorders 977
rise in intracranial pressure but has the risk of producing an
excessive drop of blood flow to the most affected areas of the
brain, increasing the possibility of ischemia and subsequent
cerebral infarction.119 Because both metabolic and respiratory
alkalemia may provoke abrupt transcellular membrane shifts
of several electrolytes, mainly potassium and calcium, the net
effect is an increase in neuromuscular irritability and excit-
ability. The occurrence of seizures and severe cardiac arrhyth-
mias has been reported if pH is approaches 7.7.10,98
The answer to the question “Does abnormal pH harm?”
is therefore quite complex; potential harm always exists, but
the occurrence of real damage depends on many factors: clin-
ical setting of the patient; type of derangement (metabolic
vs. respiratory); timing of presentation (gradual vs. sud-
den); renal, lung and liver functional status; type of meta-
bolic acidosis; and magnitude (mild, moderate, or severe),
for example. On the basis of available evidence, one more
question must be asked: does acid pH confer some advan-
tage? The answer here is also quite complex, but should be
a cautious “maybe” for mild-to-moderate acidosis in at least
two settings: permissive hypercapnia and cardiopulmonary
resuscitation.
Blood Gases: Arterial, Central Venous, or
Capillary Samples?
Arterial blood gases (ABG) are the usual gold standard for
assessing the acid-base status of a patient. However, once the
diversity of microcirculations and tissue metabolism through-
out the body is taken into account, clinicians must be aware
that the value of a single arterial blood pH as a physiologi-
cal marker is rather limited, even more so if it is recognized
that most functional proteins are intracellular.107,111 There is
significant correlation in pH, PCO2, partial pressure of oxy-
gen (PO2), SBE, and HCO3− between arterial, central venous
(VBG), and capillary blood gases (CBG) in healthy volunteers
and in stable patients. However, in the presence of hypoten-
sion or shock, there is a very poor or no correlation at all with
PO2 with most acid-base parameters.122 Thus, capillary and
central venous blood gas measurements may be useful alter-
natives to arterial samples when an arterial line is not in place,
in particular for acid-base evaluation, as this good correlation
extends also to lactate.123 However, in the setting of severe
circulatory failure, such as in decompensated, catecholamine-
resistant septic shock and cardiac arrest, significant widen-
ing of the arteriovenous differences in pH, PCO2, and lactate
may occur.8,10,14 Thus, in the presence of severe hypoperfu-
sion, hypercapnia and acidemia at the level of the tissues are
better detected in central venous blood than in arterial blood
samples because they directly reflect the average acid-base
status of the venous blood returning from the tissues, with-
out the influence of pulmonary function. If this is the case,
an apparent improvement in the ABG could be observed as
a patient slowly recovers from a cardiac arrest, but a simulta-
neously obtained VBG may reflect a more severe acidosis for
a longer time.124 On the other hand, in the setting of ARDS,
the lungs may become important lactate producers, leading to
significant higher levels of lactate in ABGs than in the VBGs
(also discussed in Lactic Acidosis in this chapter). Therefore
both arterial and central venous blood samples are needed to
assess acid-base status in patients with severe hemodynamic
compromise.
978 Section V — Renal, Endocrine, and GI Systems

Metabolic Acidosis Table 68–7  Causes of Lactic Acidosis

The classical approach to metabolic acidosis is to classify the I. Type A: inadequate tissue oxygen delivery*
disorders as those with either elevated AG or normal AG, which A. Hypodynamic shock or inadequate resuscitation
continues to be a very practical, although not a pathophysio- B. Ischemic tissue (bowel or traumatized tissue)
C. Severe hypoxemia
logically-based, classification (see Table 68-4). Using the more D. Severe anemia
physiological independent variables-oriented approach, meta- E. Carbon monoxide poisoning
bolic acidosis can be classified as due to an imbalance of strong II. Type B: not associated with tissue hypoxia*
ions (decreased SID) or due to the presence of abnormal non- A. Alterations in cellular metabolism
1. Hypermetabolism
volatile weak acids (increased ATOT).42 In turn, decreased SID a. Increased aerobic glycolysis
acidosis can be classified in two categories: excess of unmea- b. Increased protein catabolism
sured anions (excess XA−) (which grossly corresponds to the c. Systemic inflammatory response syndrome, sepsis,
elevated AG acidosis), and as due to an excess of chloride and/ and severe sepsis
or relative or absolute deficit of sodium-water excess (which d. Huge “tumoral” burden
2. Postcardiopulmonary bypass
corresponds to the non-AG acidosis) (see Table 68-6). There 3. Burn injury
appears to be a complex regulation of SID for acid-base pur- 4. Hematological malignancy
poses, but no such mechanisms are known to control [ATOT] 5. End-organ failure (liver, lungs [ARDS])
for this purpose. For this reason, there is no agreement about 6. Diabetes mellitus
7. Thiamine deficiency
whether changes in [ATOT] should be accepted as acid-base 8. Mitochondrial myopathies
disorders or not, despite their influence on pH. 9. Severe alkalosis/hyperventilation
The classic approach will be used as the main frame for B. Increased oxygen consumption
approaching the metabolic acidoses, with additional informa- 1. Strenuous exercise
tion, mainly about pathophysiology, from the physicochemi- 2. Grand mal seizure, status epilepticus
3. Malignant hyperthermia
cal approach. 4. Neurological malignant syndrome
5. Severe asthma
6. Pheochromocytoma
Elevated Anion Gap Acidoses C. Toxins and drugs or their metabolic byproducts
1. Epinephrine
These are a group of disorders in which there is the accu- 2. Propofol
mulation of an acidic anion. There are three clinically more 3. Terbutaline and other β-agonists
relevant examples: lactic acidosis, ketoacidosis, and acidosis 4. Salicylate
secondary to the ingestion or administration of some toxin or 5. Acetaminophen
drug. In children, most of the “toxins” are actually drugs, and 6. Cocaine
7. Ethanol
most of them provoke lactic acidosis, and will be mentioned 8. Methanol
under that subheading. Some interesting miscellaneous disor- 9. Cyanide (nitroprusside)
ders will be also mentioned. 10. Stavudine and other antiretroviral agents
11. Biguanides (metformin)
12. Ethylene glycol, glycolic acid, oxalic acid
Lactic Acidosis 13. Others
D. Congenital
The popular classification of hyperlactatemia as type A (asso- 1. Glucose-6-phosphate deficiency
ciated with or caused by inadequate tissue oxygen delivery) or 2. Fructuose-1,6-diphosphate deficiency
type B (adequate tissue oxygen delivery) is sustained because 3. Pyruvate carboxylase deficiency
4. Pyruvate dehydrogenase deficiency
of its simplicity, despite the fact that it is not necessarily a 5. Oxidative phosphorylation defects
reflection of the pathophysiologic mechanism underlying this E. Decreased lactate clearance
alteration, as considerable overlap exists between types A and 1. Fulminant hepatic failure
B125 (Table 68-7). Type B was originally further subdivided F. d-Lactate
1. Short gut syndrome
into types B1, B2, and B3, with type B1 lactic acidoses being 2. Antibiotic-induced
associated with an underlying disease (e.g., diabetes mellitus,
*Despite the fact that they are grouped under specific categories, significant
asthma, malignancies). B2 includes the lactic acidoses due to overlap exists and one single cause may fit under several categories.
drugs or toxins (e.g., cyanide, metformin, epinephrine, etc.),
and B3 those due to inborn errors of metabolism. Type A
seems to be the most frequent cause of lactic acidosis encoun- and during necrotizing enterocolitis, 70,104,126-131 and has been
tered in critical care patients.10,14,125,126 used for the titration of inotropes and blood cell transfusions
Among all metabolic acidoses, lactic acidosis in the ICU during early goal-directed therapy for severe sepsis and septic
unit signals trouble, regardless of patient age.10,14,126-131 shock,132 with a performance not inferior to that of the mixed
Depending on the source, hyperlactatemia is defined as a lac- venous saturation. Hyperlactatemia may also be present in
tate level between 2 and 5 mmol/L, whereas lactic acidosis is children following cardiac surgery.133 Therefore lactate mea-
said to be present when lactate level exceeds 5 mmol/L and the surement has become a common attribute in “point of care”
arterial pH is less than 7.35. Yet these definitions are arbitrary. blood gas analyzers used at bedside in modern ICUs.134
Blood lactate concentration, both in terms of the magnitude Lactate represents the end product of anaerobic metabolism
and duration, has been shown to correlate with mortality in (i.e., it is a product of pyruvate reduction via the enzyme lac-
pediatric and adult patients in many settings, including sep- tate dehydrogenase and the reduced nicotinamide hypoxan-
tic and hemorrhagic shock, neonates receiving ventilation, thine dinucleotide/nicotinamide hypoxanthine dinucleotide

[NADH/NAD] cofactor system (see Chapter 74).126 It derives
primarily from skeletal muscle, gut, brain, and circulating
erythrocytes, with a production of about 1 mmol/kg/hr. The
healthy liver takes up most lactate and recycles it through
three primary options: conversion back to glucose (Cori
cycle); oxidation back to pyruvate, which subsequently can be
oxidized to CO2 via the Krebs cycle; or transamination into
alanine.126,135 A decrease in oxygen availability at tissue and
cellular levels results in an impairment in oxidative phos-
phorylation, which results in an increase of the intracellular
levels of NADH, the cofactor in the conversion of pyruvate
to lactate.126,135 Because of its close relationship with anaero-
bic metabolism, increased lactate has been largely considered
a dead-end waste product of glycolysis due to hypoxia. This
mechanism is clear and easily understandable by the busy
clinician seeking prompt explanations for what he or she is
facing in the critical care unit. However, using blood lactate
concentration as evidence of tissue hypoperfusion, hypoxia,
and hyperactive anaerobic glycolysis is, at best, an oversim-
plification.124 Strong and compelling evidence from living tis-
sue, animal models of hemorrhagic and septic shock, humans
during incremental exercise, and humans in septic shock has
demonstrated that stimulation of aerobic glycolysis, that is,
glycolysis not attributable to oxygen deficiency, occurs not
only in resting, well-oxygenated skeletal muscles, but also in
experimental and clinical shock. In this setting, skeletal mus-
cle appears to be a leading source of lactate formation as a
result of exaggerated aerobic glycolysis through Na+K+ATPase
stimulation by circulating epinephrine, both endogenous and
exogenous.136-139 Thus it now appears that increased lactate
as a result of hypoxia or dysoxia is more the exception than
the rule, at least in the hyperdynamic hypermetabolic phase
of sepsis, severe sepsis, and septic shock. As there is evidence
that lactate is an important intermediate in the process of
wound healing and tissue regeneration, it should no longer be
considered just an indicator of damage due to hypoxia/hypo-
perfusion, but as an important intermediary in numerous
metabolic processes, a highly mobile fuel for aerobic metabo-
lism through cell-to-cell “shuttles,” allowing the coordination
of intermediary metabolism in different tissues, and between
cells within those tissues. Therefore, in septic shock patients,
a high lactate concentration should be interpreted as a marker
of the severity of the disease, but it should not be taken as an
irrefutable proof of oxygen debt, requiring increases in sys-
temic or regional perfusion or oxygenation to supranormal
values.136,137
During systemic hypoperfusion, several tissues are a clear
source of lactic acid. For example, underperfused intestine
can release lactate but will not do so if mesenteric perfusion
is maintained.56 Causes of hyperlactatemia and lactic acidosis
are numerous in the critical care setting10,14,125,126,129,140 (see
Table 68-7). Lactate levels may fluctuate in response to exog-
enous catecholamines, particularly epinephrine,135-141 which
clearly increases lactate levels through stimulation of glycoge-
nolysis and glycolytic flux with a resultant increase in pyruvate
production. This effect does not occur with norepinephrine
or dobutamine infusions and is not related to decreased tissue
perfusion.135,141,142 Several studies have shown that the lung
is a major source of lactate in severe sepsis/septic shock,142,143
and that decreased lactate clearance by the liver is also an
important component of sepsis-associated hyperlactatemia
and lactic acidosis.142,144 Therefore, instead of being caused
Chapter 68 — Acid-Base Balance and Disorders 979
by cellular oxygen debt, the persistent lactate elevations often
seen in patients with sepsis (and in patients after trauma
resuscitation) may be a consequence of a much more complex
physiological, inflammatory, and metabolic response, the so-
called cytopathic or mitochondriopathic dysoxia (see Chapter
74).135-144 Thus it is not surprising that lactate levels correlate
so well with outcome and survival in several subtypes of shock.
Correlation of lactate levels in terms of rate of increase, mag-
nitude of the increase, and persistence represent well-known
prognostic markers in both children and adults,10,14,70,104,126-131
and are used clinically in gauging the response to treat-
ment.70,126,128,132 Lactic acidosis, more than just the lactate
level, correlates with the severity of sepsis and septic shock.130
Given the complex and incompletely understood metabolism
of lactate in sepsis, however, the belief that lactate levels can
be accurately used as a stand-alone marker of outcome and
mortality is probably naive.135,136,138 Although the source and
pathophysiological interpretation of lactic acidosis are matters
of discussion, no question exists about the ability of lactate
accumulation to produce acidemia.
Given its pKa of 3.9, which indicates that more than 3000
molecules are dissociated for every one that is not within
clinically encountered pH, lactic acid behaves as a strong
ion. Therefore the accumulation of lactate (a strong anion),
without the addition of an important strong cation such as
sodium, will be expected to lower the SID, increase H+, and
decrease the pH. Lactic acidosis would also be expected to
be associated with increased adenosine triphosphate (ATP)
hydrolysis, another source of hydrogen ions. Because the body
can produce and clear lactate rapidly, it functions as one of the
most dynamic components of the SID.135
Type B lactic acidoses are probably operative in many clini-
cal circumstances where the so-called type A lactic acidoses
have traditionally been invoked. Particularly in the patient
with sepsis, lactic acidosis may be associated with a variety of
coexisting mechanisms.135-140,142-145 In addition, there likely
exists significant overlap between many of these mechanisms,
and hence their categorization is a real challenge. A potentially
useful method for distinguishing anaerobically produced lac-
tate from other sources is to measure the whole blood pyru-
vate concentration. The normal lactate to pyruvate ratio is
10:1. Because pyruvate is reduced to lactate during anaerobic
metabolism, the ratio of lactate to pyruvate increases. There-
fore if this ratio is higher than 25:1, it is considered evidence of
anaerobic metabolism.141 Unfortunately, pyruvate is unstable
in solution, and an accurate measurement in the clinical set-
ting is therefore difficult to obtain. Thus the clinical usefulness
of this approach is reduced.126 In many settings, including
septic shock and liver failure, the magnitude of the accumula-
tion of lactate does not always account for the whole of the
acid-balance derangement observed.30,70,104,141,145 In fact, the
increase in the AG, SID, and SIG observed in severe sepsis is
often substantially greater than the actual lactate concentra-
tion. This finding has led to the active search for the so-called
unexplained or unmeasured anions (abbreviated XA− or
UMA).8,56,64,70
Donnan equilibrium alterations due to sepsis-mediated
endothelial damage and a switch from a hepatic anion-
uptake state to an anion-release state during endotoxemia
have been the main proposals for explaining the fact that as
much as 15% to 50% of the increased AG, SID, and SIG is
not related to the increased lactate.8,34,56,142-144 Accumulation
980 Section V — Renal, Endocrine, and GI Systems
of molecules such as succinate, citrate, and formate has also
been implicated.46,47,57,62
In addition to epinephrine, numerous drugs and toxins
encountered in critical care medicine may cause or contrib-
ute to increased lactate, with or without acidemia. Likewise,
drugs associated with the release of endogenous catechol-
amines, such as cocaine, can stimulate lactate production.146
A similar mechanism is advocated in patients with pheochro-
mocytoma.147 Sodium nitroprusside remains a key vasodila-
tor drug. Because it is metabolized to cyanide, this toxin may
accumulate if excessive drug is administered or impaired cya-
nide clearance occurs, as in the setting of renal failure. In such
cases, mitochondrial respiratory chain activity may be inhib-
ited and lactate production increased.140 Thus, nitroprusside
toxicity is usually heralded by the rise in lactate levels, with or
without a drop in the pH.135,140,144 Similarly, propofol toxic-
ity resulting in lactic acidosis, rhabdomyolysis (including the
cardiac muscle), and myocardial, renal, and hepatic failure,
seems to involve mitochondrial toxicity, which occurs more
often with continuous, high-dose, and prolonged infusion.
Hence, its designation as propofol infusion syndrome.148,149
Lactacidemia has also been observed with short-term propo-
fol infusions for general anesthesia. It is a highly lethal compli-
cation of propofol use.
There are some other conditions in which lactic acidosis
or hyperlactatemia may occur. As noted previously, in acute
lung injury (ALI) and ARDS, lactate levels may be high even in
the absence of shock or sepsis.143 In ALI/ARDS the lung is an
important source of lactate.143,150 This was first evidenced by
higher lactate levels in arterial blood than in the mixed blood
obtained from patients with ALI/ARDS, a phenomenon not
seen in patients with other serious lung diseases. It has also
been shown that the lung is a source of lactate production in
patients receiving mechanical ventilation after cardiopulmo-
nary bypass.151,152 Potential mechanisms of lactate production
by the injured lung may include not only the onset of anaero-
bic metabolism in hypoxic zones, but also direct cytokine
effects on pulmonary cells and a stress-induced enhancement
of glycolysis and lactate synthesis by both the parenchymal
and nonparenchymal cells (e.g., endothelial cells and inflam-
matory cells infiltrating lung tissue such as macrophages and
neutrophils).143,150-152
A similar mechanism is operative in wound tissue, the intes-
tine, and the liver in patients with trauma.144 Hyperlactatemia,
lactic acidosis, or both occur in about 80% of cases of acute
liver failure.153,154 Both decreased hepatic clearance of system-
ically produced lactic acid and increased hepatic production
of lactate are involved.144,153,154 Hypermetabolism associated
with lactate accumulation has been observed in organs rich in
mononuclear phagocytes, especially the liver and spleen. Mur-
phy et al.153 found that, in patients with severe hepatic failure,
both the liver and intestine behave as net producers of lactate.
After transplantation, the grafted liver became a net consumer
of lactate as evidenced by a negative lactate gradient between
hepatic and portal venous blood. The intestinal bed, however,
continued to produce lactate after transplantation, but arte-
rial blood levels dropped back to normal values. Thus, before
transplant, hyperlactatemia and lactic acidosis were due both
to defective clearance of lactate by the sick liver and to an
increased lactate production resulting from hepatic inflam-
mation, in addition to lactate released from the intestine,
the lung, and other organs participating in this multisystem
problem.153,154 Cessation of hepatic lactate release after trans-
plantation was the result not only of improved lactate clear-
ance, but also of the removal of a large body of activated,
lactate-producing inflammatory cells.
However, this concept of lactate being produced and not
cleared by some “damaged” cells has been challenged. So,
the bad reputation of lactate as a waste product of a “defec-
tive,” inefficient, anaerobic physiology, is about to shift. The
key concept is to acknowledge that lactate can be considered
a waste product when released from one cell, but it becomes a
very useful substrate when taken up by another cell, just as in
Murphy’s findings. In fact, the rate of lactate turnover in vivo
in humans is quite similar in order of magnitude to that of
glucose, alanine, or glutamine, indicating that lactate has one
of the highest recycling rates in the intermediary metabolism.
So, increased lactate levels can be viewed as an organic, adap-
tive response, by which some lactate-producing cells are pro-
viding other group of cells with a highly energetic substrate,
the so-called lactate “shuttle.”137-139,155
In status asthmaticus, 1% of patients admitted to a pedi-
atric ICU demonstrated lactic acidosis.156 This incidence is
lower than that reported in adults with acute severe asthma,
which is around 25% to 30%.157 Pathogenesis of lactic aci-
dosis in this setting seems to be multifactorial and includes
contributions from lactate production by overwhelmed
respiratory muscles, tissue hypoxia, a hyperadrenergic state,
and the metabolic effect of pharmacological β2 agonists.158-160
Muscle participation does not seem to be so important,
however, because lactic acidosis has been described even in
patients with asthma under muscle relaxation.161 Of inter-
est, nonlactic, non-AG acidosis has been found in adults
presenting with status asthmaticus. The hypothetical mecha-
nism is hyperchloremia associated with exacerbated chronic
hypocapnia, which would decrease SID in hyperventilating
asthmatic patients.162 In head trauma, it is possible to find
lactic acidosis in arterial blood samples, both as an effect of
polytrauma and hemorrhagic shock and as a manifestation
of severe traumatic brain injury. At the regional level, brain
tissue acidosis is associated with increased tissue PCO2 and
lactate concentration. These pathobiochemical changes are
more severe in patients who died and in those who remain in
a persistent vegetative state.163
Salicylate intoxication is a special situation in which lactic
acidosis may play an important role (see also Chapter 106)
Although salicylate toxicity occurs less frequently now than in
the past because of the increased use of alternative antipyret-
ics in young children, it must still be considered in therapeu-
tic situations (e.g., rheumatic diseases), as well as in cases of
overdose. Salicylates directly or indirectly affect most organ
systems in the body by uncoupling oxidative phosphorylation,
inhibiting Krebs cycle enzymes, and inhibiting amino acid
synthesis. These derangements can result in variable acid-base
patterns: respiratory alkalosis, mixed respiratory alkalosis plus
metabolic acidosis, or (less commonly) simple metabolic aci-
dosis. Respiratory alkalosis is caused by direct stimulation of
the respiratory center by salicylates, leading to hyperventila-
tion and a compensatory alkaluria, with both potassium and
bicarbonate being excreted in the urine.164,165 This first phase
may last for several hours after ingestion in adolescents but
may be overlooked in young infants. During the next 12 to
24 hours (or less in younger patients), hypokalemia develops
and urinary excretion of hydrogen ion starts. This “paradoxic

aciduria” occurs despite continued respiratory alkalosis and
aggravates the clinical manifestations because a higher per-
centage of salicylate in acidic urine remains in the nonionized
form, and is reabsorbed from the glomerular filtrate. Soon
after the onset of hypokalemia, dehydration and progressive
metabolic acidosis develop. The metabolic acidosis is mainly
due to lactic acid, but keto acids and other metabolic acids also
participate. As metabolic acidosis ensues, more acidic urine is
produced, and the plasma salicylate level may be even higher
than in early phases because of the inability to excrete the drug
in urine. Chronic salicylate poisoning has been described, in
which the patient usually has metabolic acidosis and a “pseu-
dosepsis” syndrome similar to some inborn errors of metabo-
lism, with a high rate of permanent organ dysfunctions and
mortality.166
Elevation of blood lactate, up to the 5 mmol/L level, may be
seen in about 25% of human immunodeficiency virus (HIV)-
positive patients who receive nucleoside reverse transcriptase
inhibitors (mainly stavudine). Most patients remain asymp-
tomatic, but a small proportion of them may present with
dyspnea and abdominal pain, as manifestations of lactic aci-
dosis, 3 to 4 months after starting the treatment. If the drug
is discontinued and fluids are replaced, the process is revers-
ible. The mechanism appears to involve uncoupled oxidative
phosphorylation due to inhibition of DNA polymerase-γ.167
As a result of the worldwide problem of overweight and obe-
sity, more school-age children and adolescents must receive
some treatment for peripheral resistance to insulin. Thus,
metformin, the use of which was formerly limited to adult
patients, is now being used with increasing frequency in pedi-
atric patients. The incidence of metformin-associated lactic
acidosis is low, but it has a high mortality rate when it pres-
ents. There is limited experience in pediatrics, but obese chil-
dren and adolescents who receive metformin in the setting
of intercurrent illnesses that may predispose to accumulation
of the drug, such as renal function impairment, are at risk of
developing metformin-associated lactic acidosis.135,168 It also
may occur as a consequence of accidental ingestion or sui-
cide attempt. Survival depends on the nadir pH and the peak
levels of lactate and drug serum concentration. The mecha-
nism involves uncoupling of oxidative-phosphorylation,
with acceleration of the glycolytic flux that increases lactate
production.
A curious form of lactic acidosis is the so-called d-lactic
acidosis. The lactic acid produced by mammals is a levoiso-
mer; some bowel bacteria produce a dextroisomer.169 d-lac-
tate derived from bacterial fermentation in the bowel lumina
may reach systemic circulation and lead to metabolic acide-
mia, especially if liver function (and thus lactate clearance) is
suboptimal. d-lactic acidosis must be considered in patients
with a history of intestinal disease who have neurological find-
ings such as confusion and ataxia along with high-AG meta-
bolic acidosis with normal l-lactate levels. Symptoms worsen
after high-carbohydrate meals or tube hyperalimentation. In
patients with short bowel syndrome, there is not only an over-
growth of bacteria but also accumulation of carbohydrates
in the colon. Therefore the development of the syndrome
requires some of the following: (1) carbohydrate malab-
sorption with increased delivery of these compounds to the
colon; (2) colonic bacteria flora producing d-lactic acid; (3)
ingestion of large amounts of carbohydrate; (4) diminished
colon motility, allowing time for bacterial fermentation; and
Chapter 68 — Acid-Base Balance and Disorders 981
(5) impaired d-lactate metabolism.169 Treatment focuses on
decreasing gut bacteria overgrowth with antibiotics and the
avoidance of high-carbohydrate or lactose feeding. Some
studies have advocated the use of probiotics for treating and
preventing this problem,170 but the reports are conflicting, as
some cases of encephalopathy associated with d-lactic acidosis
have been probably related to their use in patients with short
bowel syndrome.171
Ketoacidosis
This is another common cause of increased AG acidosis.
Ketones are formed by beta oxidation of fatty acids, a pro-
cess that increases substantially in insulin-deficient states. In
the pediatric intensive care setting, this is most often seen
in patients with diabetes mellitus with overproduction and
underutilization of acetone, β-hydroxybutyric (β-OH-B)
and acetoacetic acids (ketone bodies), that accumulate in
plasma (see also Chapter 78). This problem is exacerbated
because of the glucosuria-mediated diuresis and intravascu-
lar volume contraction. Ketoacidosis is also seen in various
inborn errors of amino acid and organic acid metabolism,
and a mixed ketoacidosis and lactic acidosis is seen with gly-
cogen storage disease type I (glucose-6-phosphate deficiency)
(see also Chapter 76). The urinary dipstick for ketones
uses a nitroprusside reagent; hence it detects acetoacetate
but not β-OH-B. If a patient with DKA develops shock, β-
OH-B:acetone may be produced in ratios up to 3:1. Hence,
the urine will mistakenly appear to have few ketones, and
ketone concentration may paradoxically rise as perfusion
improves and the patients gets better.172-173 The capillary
blood determination of β-OH-B is a better alternative for
treatment guidance.173,174 As the renal threshold for the
ketone bodies is low, ketones are readily filtered, with no
reabsortion mechanism; accordingly the kidneys can elimi-
nate a significant amount of ketones. This loss can shift the
AG, which may appear less than expected because of the
anions eliminated though the urine, with renal retention
of chloride and bicarbonate. The picture can be even more
complicated if hypocapnia from hyperventilation is present.
Therefore AG (even corrected AG) may not be very use-
ful in severe cases. SIG may provide more information in
these more complicated situations.60 Another form of keto-
acidosis, the so-called alcoholic ketoacidosis, an uncommon
syndrome in acute ethanol drinkers, may be a scenario with
which pediatric and adolescent patients occasionally pres-
ent in the PICU. This presentation is more frequent among
patients with chronic ethanol intake and liver disease, and
usually occurs after a period of heavy drinking, in association
with reduced food intake. Alcoholic ketoacidosis is quickly
responsive to fluid administration, with faster resolution
when dextrose and saline are infused together.175
Toxic Compounds that Directly Provoke
Acidosis
Alcohol-related intoxications, including methanol, ethylene
glycol, diethylene glycol, and propylene glycol, may present
with a high anion gap metabolic acidosis, with a decrease
in serum bicarbonate and a rise in the osmolality, with an
increased serum osmolar gap (i.e., difference between cal-
culated and measured osmolality) (see also Chapter 106).
982 Section V — Renal, Endocrine, and GI Systems
The acidosis and cellular dysfunction are direct effects of the
metabolites of these substances, while the parent compounds
are associated with an increase in serum osmolality. These
are rather infrequent problems in the pediatric age group,
but adolescents who ingest alcohol or illicit drugs (includ-
ing inhalants), or who attempt suicide, are potential vic-
tims.175 Younger ages are occasionally affected. Clustering
of such cases usually uncovers locally prepared antipyretic
(paracetamol elixir) contaminated with diethylene glycol.
Similar cases have been reported for propylene glycol. The
clinical presentation depends on the total dose of the adul-
terated medication received, and hence ranges from mild
subclinical poisoning to unexpected and rather sudden onset
of high anion gap acidosis, renal failure, and encephalopathy,
with elevated mortality and a high probability of neurologic
sequelae.176 The intoxication is best treated with supportive
critical care including proper alkalinization and early con-
tinuous hemofiltration or hemodiafiltration. In some areas
a competitive inhibitor of alcohol dehydrogenase (4-meth-
ylpyrazole [or fomepizole]) is available for use in ethylene
glycol and methanol poisoning, but extracorporeal removal
should also be utilized. Fomepizole is possibly useful also
in diethylene glycol and propylene glycol intoxications. For
methanol and ethylene glycol, ethanol infusion is an alter-
native competitive inhibitor of the alcohol-dehydrogenase
enzyme.175,177
Other Forms of Metabolic Acidosis
­Associated with an Increased
Anion Gap
The pediatric critical care physician should be aware of a con-
dition often called late metabolic acidosis of prematurity.178
Although its incidence is greater in the premature infant when
compared with that in the term infant (20% compared with
5%), the lesser capacity of not fully developed renal tubules to
excrete H+ and Cl− and to concentrate urine is a fairly com-
mon situation during the first month of life. This level of renal
tubular development is adequate for the breastfed infant, but
if the protein intake or solute load is excessive, the renal capac-
ity may be exceeded and a metabolic acidosis may develop.
This is particularly true during periods of stress. In the setting
of renal disease, the clinician must anticipate the occurrence
of metabolic derangements. When chronic renal insufficiency
develops, hyperchloremic metabolic acidosis—a non–anion
gap acidosis—may initially occur because of impaired ammo-
nium (NH4+) generation. When the glomerular filtration rate
falls below 20 mL/min, the kidneys are incapable of excret-
ing fixed acids. The resulting accumulation of sulfates among
other acids may increase the AG. These acidoses are usually
mild, producing an excess AG of approximately 10 mEq/L.
A mixed metabolic acidosis (high-normal AG mechanism)
is not uncommon in this setting.10,172 If the patient has sep-
sis or another condition associated with hypermetabolism,
however, the rate of acid generation increases and the acidosis
may become rather severe. The SID decreases and, because of
the lack of renal compensation, some intervention must be
taken. Patients who do not yet require dialysis and those who
are between their dialytic processes are often administered
NaHCO3 (provided there is no hypernatremia) or sodium
potassium citrate.179 In cases where bicarbonate is contraindi-
cated, a dialytic process is in order.
Hyperchloremic Acidoses: The Non–
Anion Gap Metabolic Acidoses
In the classical view, hyperchloremia was considered an epi-
phenomenon of the drop in bicarbonate concentration, due to
its abnormal loss through urine or stools (see Table 68-4). The
rise in chloride concentration is responsible for maintaining a
“normal” anion gap, in spite of the drop in bicarbonate levels,
i.e., a “non–anion gap” acidosis is produced. When bicarbon-
ate is consumed to buffer an “acid load,” hyperchloremia is
not produced, because there are other anions emanating from
the acid load that will preserve electroneutrality as bicarbonate
falls. In this case, the anion gap increases, because of the pres-
ence of these “new” (and unmeasured) anions.9,10,54 As new
biological evidence accumulates, this physiological interpreta-
tion is increasingly being challenged, and a more central role
for chloride is being emphasized.55,64 Accordingly, the physi-
ological shift is moving from kidneys that directly sense and
regulate H+ to kidneys that react to Cl− balance, and therefore
directly control the independent variable SID in acid-base
regulation. This is supported by new insight in the physiology
of several ion-transporters of the renal tubules.51,54,55,100,180-183
Thus, hyperchloremic acidoses occur either as a result of
an increase in chloride concentration relative to strong cat-
ions (especially sodium) or because of the loss of cations with
retention of chloride (see Table 68-6). When the pH drops, the
normal response by the kidney is to increase chloride excre-
tion as ammonium chloride (NH4Cl), in order to increase the
SID and raise back the pH. Thus, the role of the formation of
ammonium (NH4+) and its eventual tubular excretion, is not
for the elimination of H+, but to allow Cl− excretion without
losing sodium or potassium. Failure to do so identifies the
kidney as the problem,10,49,172 as in renal tubular acidosis.
There are four main causes of non–anion gap acidoses: (1)
exogenous chloride loads, such as saline boluses, parenteral
nutrition; (2) loss of cations from the lower gastrointestinal
tract without proportional losses of chloride, as in secretory
diarrhea, also seen in conditions in which loss of alkaline
small bowel, biliary, or pancreatic secretions is present (such
as drainage from ostomies, tubes, fistulas); (3) renal tubular
acidoses and drug-mediated tubulopathies; and (4) urinary
reconstruction using bowel segments.
Exogenous Chloride Load
In the critical care unit, mandatory therapeutic interven-
tions are frequently associated with hyperchloremic meta-
bolic acidosis. The more common of such interventions are
rapid infusion of isotonic saline (0.9% NaCl) and the infu-
sion of parenteral nutrition. As stated before, the classical
explanation for acidosis following saline administration was
the so-called bicarbonate dilution. This mechanism probably
plays a role in certain conditions.80,101 Healthy, metabolically
stable individuals, such as scheduled surgical patients, exhibit
plasma SID around 40 mEq/L, while in critically ill patients
SID is typically ~30 mEq/L (see Strong Ion Difference in this
chapter). On the other hand, the SID of normal saline is 0
mEq/L, because sodium and chloride are both strong ions.
Therefore, intravenous administration of 0.9% NaCl will nec-
essarily decrease plasma SID, creating a strong ion acidosis,
as long as such an infusion does not cause a change in PCO2
or albumin or phosphate concentrations. The magnitude of
the decrease in plasma SID when 0.9% NaCl is administered

is dependent upon the relative volumes of the extracellular
space and the infused normal saline, and the speed of the infu-
sion. Therefore, hyperchloremic acidosis should be expected
whenever large volumes of normal saline are rapidly admin-
istered, such as in fluid boluses for treating shock, or during
surgical procedures under anesthesia.82,87,93,96 Even the acid-
base status of disorders in which one or more unmeasured
anions is clearly participating, such as septic shock (lactate)
and DKA (ketones), has been shown to be influenced by the
chloride supplied through resuscitation fluids,84,87,92,94 and
one recent report warned about hyperchloremic acidosis from
saline resuscitation slowing the recovery of children with
DKA.184 This concern is one example of the usefulness of the
“partition” of the SBE (see Merging Traditional and Newer
Approaches in this chapter).77,84
In one study of 81 children with meningococcal sepsis,
metabolic acidosis was common and prolonged (persisted
for 48 hours), but the pathophysiology changed from one of
unmeasured anions at admission to predominantly hyper-
chloremia-associated by 8 to 12 hours. Thus most of the time
the acidosis was iatrogenic.87 Development of hyperchlore-
mic acidosis was related to the amount of chloride received
during intravenous fluid resuscitation. From this and other
similar studies, there is little doubt, if any, about the relation-
ship between normal saline resuscitation and the development
of hyperchloremia and acidosis (not necessarily acidemia),
whatever the underlying mechanism.87,101,183,185 However,
it is not clear whether this hyperchloremic acidosis is really
detrimental, implying that hyperchloremic acidosis due to
exogenous administration of normal saline might be not an
important issue.65,69,94-97,185 Actually, in a group of 97 children
(mean age, 57 months) evaluated in their postoperative period
following open cardiac surgery, the occurrence of hyperchlo-
remia was associated with reduced requirement for epineph-
rine therapy; thus the authors suggested that hyperchloremic
metabolic acidosis is a benign finding that should not lead to
the escalation of the hemodynamic support, hence the impor-
tance of its recognition.82
Interestingly, hypoalbuminemia (an alkalinizing force) was
associated with prolonged length of stay in the critical care
unit. In a recent review of laboratory, animal, human volun-
teer, and patient investigations focused on the physiological
effects of hyperchloremia and acidosis,95 it was concluded
that there is a trend in scientific evidence indicating that both
hyperchloremia and hyperchloremic acidosis have subtle, but
potentially significant physiological and clinical undesirable
effects. Although the acidosis is often quoted as the cause, it
is unclear whether this is true or whether the high chloride
levels should be of concern. Most of the clinical studies have
revealed trends but not statistical significance toward a worse
outcome in patients with hyperchloremic acidosis.
Hence, the conclusion so far is that the effects of hyper-
chloremia, hyperchloremic acidosis, or both are unlikely to
influence outcome for most patients. However, given that
hyperchloremic acidosis is often iatrogenic and is associ-
ated with some proven morbidity (increased length of stay
in intensive care, delayed recovery of DKA, higher incidence
of nausea/emesis in postoperative period, etc.,42,184 it should
be avoided whenever possible.42,95,186 How can this task be
achieved? Several groups have suggested and assessed the use
of the so-called balanced fluids, that is, fluids with SID nearer
to the SID of human plasma.42,93,180,186,187 However, the results
Chapter 68 — Acid-Base Balance and Disorders 983
are still inconclusive. Besides, at least one prospective study in
adults has suggested that the amount of fluids administered,
rather than the types of fluids, had the stronger effect on the
changes in base excess.188 Meanwhile, the best approach is to
keep in mind the potential hazard of hyperchloremic meta-
bolic acidosis, especially in patients with previously known
renal or liver dysfunction, with shock, and in surgical patients
needing a large amount of intraoperative saline for resusci-
tation.189 Intraoperative monitoring of serial chloride deter-
minations has been suggested in order to unmask or exclude
hyperchloremia as a cause of acidosis, undetectable through
SBE alone.96 Use of SBE-partitioning formulas to disclosure
the effects of chloride on the acid-base status (see Equations
17A to 17C and Merging Traditional and Newer Approaches
in this chapter) may be useful.
With regard to parenteral nutrition formulas, they contain
weak anions such as acetate, in addition to chloride, and thus
they are buffered. However, if an insufficient amount of weak
anions is provided, plasma Cl− will increase, SID decreases,
and acidosis may result.97
Postpyloric Gastrointestinal Fluid Losses
The gastrointestinal (GI) tract, liver, and pancreas can be
envisioned as a giant ion exchanger organ. Through all the
sequential segments of the GI tract, distinct groups of ion
transporters and channels interact with one another to deter-
mine the electrolyte content, pH, and volume of the fluid in
the gut lumen. The main transport system is driven primar-
ily by Na+/K+-ATPase across the basolateral membrane of
the epithelial cells, with the participation of several key api-
cal membrane electrolyte transporters, including Cl−/HCO3−
and Na+/H+ ion exchangers and the so-called cystic fibrosis
transmembrane conductance regulator (CFTR) Cl− chan-
nel.190 Large masses of cations and anions traverse the special-
ized epithelia of the gut every day. This transport is adjusted
for achieving an efficient absorption of dietary components
rather than for acid-base homeostasis.
Under normal conditions, only a small amount of alkali (30
to 40 mmol/day) is lost in the stool, so kidney and lung com-
pensation is generally not problematic. However, disruption
of the normal gut function can provoke disorders that vary
from severe acidosis (mostly postpyloric losses) to severe alka-
losis (prepyloric losses, congenital chloridorrhea), depending
on the segment of the GI tract affected and the nature of the
losses that ensue.190 For acid-base and electrolyte abnormali-
ties to occur in diarrheal diseases, the volume of fluid lost must
be large enough to overcome the kidney’s ability to adjust
excretion to maintain acid-base balance. With large losses,
any form of diarrhea may lead to a significant fall in extra-
cellular fluid volume, reducing the glomerular filtration rate
(GFR) and limiting the ability of the kidneys to compensate
for the problem. Secretory diarrheas (cholera, enteropathic
E. coli, rotavirus, and other infectious diarrheas) most com-
monly produce this picture, with the typical presentation of
hypovolemia, hypotension, acute renal failure, hyperchlore-
mic metabolic acidosis (lost stools are usually rich in sodium,
potassium, and bicarbonate, so SID decreases), and hypoka-
lemia. If the hypovolemia and hypotension are not corrected,
lactic acidosis superimposes, as a result of tissue hypoperfu-
sion. Then, the AGCORR is initially normal; it may increase
gradually, but more frequently will remain normal in spite of
lactacidemia. Hence it is always wise to monitor lactate levels.
984 Section V — Renal, Endocrine, and GI Systems
The mechanism of the acidosis is well defined for cholera
diarrhea, but is less defined for other pathogens. Vibrio chol-
erae produces a toxin that increases cAMP levels in intesti-
nal crypt cells, producing a sustained activation of the apical
membrane CFTR Cl− channel leading to excessive Cl− secre-
tion into the ileum and colon. This increased chloride secre-
tion in turn stimulates the apical Cl−/HCO3− exchanger,
increasing bicarbonate concentration in stools and increasing
paracellular Na+ and water entry, resulting in high-volume
losses that contain a large amount of HCO3− as well as Na+,
Cl−, and K+. Replacement of the lost fluid and electrolytes can
be achieved with oral solutions (100 mL/kg body weight of a
solution containing 60 to 90 mEq/L of sodium).191 In case of
excessive losses or emesis, vigorous intravenous volume reple-
tion must be implemented. Diarrhea due to laxative abuse
can be seen in bulimic or anorexic adolescents, and usually
does not associate with acid-base derangements. Of course, if
excessive diarrheal losses occur, then metabolic acidosis can
occur, as with any severe diarrhea.190
Both biliary and pancreatic secretions have an alkaline pH.
When pancreatic or biliary drainage is required after surgery,
the volume is usually low, so despite the loss of a NaHCO3-
rich fluid, significant metabolic acidosis does not occur. On
the rare occasions in which these drainages are excessive
(volume usually around 30 mL/kg/day or greater), metabolic
acidosis will develop and be perpetuated by concomitant vol-
ume depletion. Repletion with saline solutions is enough for
the replenishment of cations, mainly sodium, which restores
SID value. Bicarbonate administration is equally effective.190
Patients with well-functioning ileostomies usually adapt to
the obligatory extra fluid loss through subtle changes in salt
and water intake, as well as changes in urine volume and elec-
trolyte and acid excretion. If the ileostomy drainage abruptly
increases, the resultant salt and water losses can easily lead
to clinically significant volume depletion. In this setting, the
development of metabolic acidosis is the rule, because HCO3−
in ileostomy fluid is usually higher than in plasma, causing
disproportionate sodium and alkali loss. Hyperkalemia is usu-
ally present with this metabolic acidosis, reflecting the fact that
K+ is not secreted in the ileum and therefore the losses contain
little K+. In addition, renal K+ excretion is impaired by the
volume depletion. A similar problem can be seen in patients
who have shortened small intestine connected to the colon for
any reason, with the additional possibility of D-lactic acidosis
(see section on d-Lactic Acidosis in this chapter).
Renal Tubular Acidoses and Drug-
Mediated Tubulopathies
RTA comprises a group of disorders characterized by a low
capacity for net acid excretion (NAE) and persistent hyper-
chloremic metabolic acidosis, with normal anion gap and nor-
mal or minimally affected filtration rate (GFR). On the basis
of functional studies, RTA has traditionally been separated in
three main categories: (1) proximal RTA, or type 2; (2) distal
RTA, or type 1; and (3) hyperkalemic RTA, or type 4. Some-
times a fourth kind is recognized: combined proximal and dis-
tal RTA (mixed RTA), or type 3.192 Type 4 RTA is of special
interest in the critical care setting, as the hyperkalemia may
be triggered by some drugs used in intensive care units, such
as angiotensin-converting enzyme inhibitors, heparin, trim-
ethoprim, α-adrenergic agonists, β-adrenergic antagonists,
digoxin, and others. The classical acid-base approach states
that metabolic acidosis arises from a lack of urine excretion
of protons (hydrogen ions) or an excessive loss of bicarbonate
due to a variety of tubular disorders.100,192 Molecular studies
have identified genetic or acquired defects in transporters of
protons and bicarbonate in most varieties of RTA.192,193 This
classical physiological view has been challenged by the physi-
cochemical acid-base interpretation, and is supported by the
fact that these transporters are also involved in Cl− and Na+
transport through membranes, and that at least certain cases
of RTA are clearly associated with primary defects in electro-
lyte transporters alone.
In a recent study, 12 children with alkali-treated distal RTA
were compared to healthy controls. Both groups received a
load with hypotonic saline (0.45%), but only the RTA patients
developed hyperchloremia and metabolic acidosis, which was
shown to be associated with high total and high distal frac-
tional absorption of chloride. Urinary excretion of bicar-
bonate did not correlate with changes in either blood pH or
plasma bicarbonate concentration. Thus, renal tubular avid-
ity for chloride was indeed increased in RTA.100,182,194 There-
fore, tubular transport mechanisms determine the excretion
of strong ions, Na+, K+, and Cl−. This determines the balance
of the concentration of SID, both in the extracellular com-
partment, dominated by Na+ and Cl−, and in the intracellular
compartment, dominated by K+. SID determines pH, and by
way of partly characterized sensor and effector mechanisms,
must feed back to the tubular ion transport complexes. Thus,
acid-base homeostasis is directly regulated by electrolyte
transport in renal tubules, and hence hydrogen and bicarbon-
ate movements reflect ion balance requirements imposed by
physical chemistry.49,100,182,194 This supports the notion that
NH4+ is more related to the elimination of Cl− without loss of
Na+ or K+, rather than in titrating urinary H+.49,182,194 Accord-
ing to the physicochemical approach, the underlying defect in
all types of RTAs is an inability to excrete chloride in propor-
tion to sodium, although the transporter involved depends on
the specific type of RTA.100,182,194 In the critical care setting,
the presence of RTA may complicate resuscitation fluid man-
agement and acid-base balance. Previously unknown RTA
must be suspected whenever the clinical condition of a given
patient does not improve as expected with the proper thera-
peutic interventions. Treatment largely depends on whether
there are losses of sodium that can be replaced with NaHCO3
or whether the kidney will require mineralocorticoid replace-
ment. A more detailed discussion of RTA is beyond the scope
of this chapter. It is worth mentioning, however, that uri-
nary AG (uGAP) = [uNa+ + uK+] − [uCl−],195 more recently
known as “urine strong ion difference” (see Equation 14 and
Strong Ion Difference in this chapter),9,55 is useful as a part of
the diagnostic workup of a patient with hyperchloremic aci-
dosis. If it is negative (uCl− > uNa+ + uK+), it suggests either
GI bicarbonate loss, acute infusion of a high volume of saline
isotonic fluid (NaCl 0.9%), or a proximal RTA, which will
require additional functional tests for diagnostic confirma-
tion once the patient is discharged from intensive care. On the
other hand, if the uGAP is positive (uCl− < uNa+ + uK+), it
suggests the presence of a distal renal defect. Additional func-
tional tests will allow one to identify distal RTA, hyperkalemic
distal RTA, or type 4 RTA.
Also of importance to the intensivist is iatrogenic RTA
caused by the nephrotoxicity of amphotericin B aminoglyco-
sides and other drugs. Kidney alterations due to amphotericin

B include decreased glomerular filtration rate, distal tubu-
lopathy with urinary loss of potassium and magnesium, RTA,
loss of urine concentration ability, and sometimes Fanconi
syndrome. Nephrotoxicity is related to treatment duration,
schedule, cumulative dosage, and combination with diuret-
ics and other nephrotoxic drugs (aminoglycosides, cyclospo-
rine, tacrolimus, cisplatin, ifosfamide). Each dose increment
of 0.10 mg/kg/day has been found to be associated with a
1.8-fold increase in the risk of nephrotoxicity, while infusion
rate and concentrations are not related.196 The mechanisms
involved in nephrotoxicity include the deoxycholate vehicle
for amphotericin B, reduction in renal blood flow and GFR,
increased salt concentration at the macula densa, interaction
of amphotericin B with ergosterol in the cell membrane, and
apoptosis in proximal tubular cells and medullary intersti-
tial cells. Salt loading, with daily sodium intake higher than
4 mEq/kg/day, is the only measure proven by a controlled pro-
spective study to ameliorate amphotericin B nephrotoxicity
in humans, including extremely low-birth-weight infants.197
Proper hydration must be assured with 10 to 15 mL/kg of nor-
mal saline prior to administration of the drug. Lipid formula-
tions of amphotericin B (liposomal, lipid complex, colloidal
dispersion) are indicated in all children receiving other neph-
rotoxic drug, with already reduced GFR, or with previously
known adverse effects to regular amphotericin B. Total dose
of 35 mg or more, chronic renal disease, concomitant use of
cyclosporine or amikacin, and male sex have been identified in
adults as risk factors. Patients with more than two risk factors
demonstrated an incidence of moderate-to-severe nephrotox-
icity of 29%.198
Trimethoprim-sulfamethoxazole is another antimicrobial
that has been related to RTA and hyperchloremic metabolic
acidosis.199 Topiramate, one of the “new” antinconvulsant
drugs, has been reported to cause hyperchloremic metabolic
acidosis in pediatric and adult patients. Topiramate inhibits
the enzyme carbonic anhydrase, and thus a type 3 or mixed
RTA is produced, as it impairs both the normal reabsorption
of filtered bicarbonate by the proximal renal tubule and the
excretion of hydrogen ions by the distal renal tubule. This
topiramate-induced RTA can present acutely with require-
ment for emergency or critical care, or chronically, produc-
ing growth retardation, nephrolithiasis, and osteoporosis.200
Acute presentation includes drowsiness/lethargy, dizziness/
vertigo, agitation, confusion, and nausea/vomiting. These
manifestations, in a patient receiving topiramate, should
prompt the clinician to evaluate acid-base and electrolyte bal-
ance. A significant decrease in HCO3− has been documented
in roughly 50% of patients receiving topiramate, although
the number of affected individuals increases with escalating
doses. To date, however, the relationship between bicarbonate
concentration and topiramate dosage has not been adequately
defined. Depression of bicarbonate levels is usually mild, with
serum HCO3− typically between 20 and 10 mEq/L. Severe,
acute HCO3− decrements to values less than 10 mEq/L have
rarely been documented. In this setting, AG is normal and
is associated with alkaline urine, positive uAG, low urinary
citrate excretion, and β2-microglobulinuria. If the acidosis
requires acute correction, or the RTA is persistent, topiramate
should be discontinued.
Another rare cause of normal AG metabolic acidosis
that may be seen in the ICU is acetazolamide, a carbonic
anhydrase inhibitor used occasionally to decrease cerebral
Chapter 68 — Acid-Base Balance and Disorders 985
spinal fluid production and, more frequently, to stimulate
renal bicarbonate wasting.201 This drug impairs hydrolysis
of H2CO3 to CO2 and H2O, resulting in a decrease of renal
HCO3− reabsorption. It has recently been described that,
both in humans and in an animal model, acetazolamide
can produce severe lactic acidosis with an increased lactate-
to-pyruvate ratio, ketosis with a low β-hydroxybutyrate-to-
acetoacetate ratio, and a urinary organic acid profile typical
of pyruvate carboxylase deficiency.202 This “acquired enzy-
matic injury” stems from the inhibition of mitochondrial
carbonic anhydrase type V, which provides bicarbonate to
pyruvate carboxylase and can produce Krebs cycle inhibition.
Some of these patients improved dramatically after packed
red blood transfusion; the improvement was likely related to
the citrate anticoagulant.
Urinary Reconstruction Using Bowel
Segments
Children with irreversible lower urinary tract dysfunction
due to developmental abnormalities involving the genito-
urinary (GU) system, neurogenic or myogenic bladder, etc.,
may require urological surgical procedures for their manage-
ment, including continuous urinary diversion and entero-
cystoplasty. Various techniques and bowel segments can
be used depending on the clinical situation. The GI tract is
a relatively poor substitute for urothelium, and its semiper-
meability allows nonphysiologic fluid and electrolyte absorp-
tion leading to metabolic abnormalities.203 The significance of
these problems is related to the portion of the GI tract used
and to the length of time the urine is exposed to the bowel
surface. If, in addition, the loss of some portions of the GI
tract results in complications such as chronic diarrhea, there
may be further metabolic consequences. Jejunal substitution
is associated with uniform and profound metabolic instabil-
ity resulting in hyponatremic/hypochloremic/hyperkalemic
acidosis, clinically manifested by nausea, vomiting, anorexia,
and muscular weakness. When ileum or colon is used for the
GU reconstruction, hyperchloremic/hypokalemic metabolic
acidosis may present. Clinically, this may produce weakness,
anorexia, vomiting, and Kussmaul breathing, and may prog-
ress to coma. In the less severe cases, a chronic metabolic aci-
dosis may go undetected, resulting in growth retardation. In
a recent series report, 41% of 44 children required constant
prophylactic alkaline replacement,204 although older reports
documented hyperchloremic metabolic acidosis in 68% of
ileal conduits, and acidosis being a major problem in 18%
of patients with enterocystoplasties.203 Thus, although acute
decompensations may require intravenous correction of the
acidosis with bicabornate and/or fluid loads in the emergency
department or PICU, most cases will maintain electrolyte
balance with lifelong alkalinization with oral bicarbonate,
sodium citrate, or citric acid solutions.
Treating Metabolic Acidosis
How is metabolic acidosis treated? Should metabolic acidosis
be treated? This topic remains controversial, except in regards
to basic approach: treat the underlying cause. Certain acido-
ses have specific therapies, such as insulin and fluids for the
patient with diabetic ketoacidosis, NaHCO3 and citrate for
patients with the classic distal RTA, and fomepizole for meth-
anol intoxication. These specific cases are beyond the scope of
986 Section V — Renal, Endocrine, and GI Systems
this chapter. The following discussion focuses on lactic acido-
sis, unless otherwise mentioned.
Sodium Bicarbonate
NaHCO3 administration has long been the standard therapy
for metabolic acidosis, including lactic acidosis.107,172 There
is consensus regarding the advantages of alkali and sodium
bicarbonate therapy in normal anion gap acidosis. However,
in the presence of high anion gap acidosis, especially lactic
acidosis (in shock and cardiopulmonary resuscitation) but
also in diabetic acidosis, there exists negative evidence regard-
ing the safety and efficacy of sodium bicarbonate use . Jus-
tification for the persistent use of bicarbonate comes from a
variety of sources, many based more on philosophy than on
science.9,107,111,172,205,206
It seems self-evident that adding bicarbonate to acidic blood
will raise the pH. However, the reality is significantly more
complex. Consistent with Equations 11A and 11B, adminis-
tration of NaHCO3 increases the SID (which tends to raise the
pH) because sodium is a strong cation and bicarbonate is a
weak anion; however, in agreement with Equation 3, it is an
anion that rapidly converts to carbonic acid and then to CO2,
which tends to lower the pH.111,207,208 Therefore NaHCO3 may
increase arterial pH if, and only if, alveolar ventilation is not
limited.107,111,205-212 Although the risk of paradoxic intracellu-
lar acidosis after bicarbonate administration is not negligible,
this neither necessarily occurs nor it is always detrimental to
the cell.107,111,208,209 The final effect of NaHCO3 on intracel-
lular pH depends on changes in PCO2 in the medium bathing
the cells, which are influenced by the extracellular nonbicar-
bonate buffering capacity.208 These cells are usually depressed
in the critically ill patient in whom NaHCO3 is administered.
In addition, bicarbonate administration may promote
metabolic reactions that may themselves alter not only PCO2,
but also the total concentration of weak acids and the SID.
In fact, it has been documented that bicarbonate can increase
the production of lactic acid in both animals and humans.111
Mechanisms to explain this remain speculative but include a
shift in the oxyhemoglobin-saturation relationship, enhanced
anaerobic glycolysis probably mediated by the pH-sensitive
enzyme phosphofructokinase, and changes in hepatic blood
flow or lactate uptake.111,142 Altogether, however, animal and
human studies and time-honored clinical experience have
shown that arterial pH can be raised and even normalized
with NaHCO3,9,107,11,172 yet multiple compartments separated
by membranes of differing permeabilities exist. Thus even
when NaHCO3 added to the central veins reliably elevates the
arterial pH, its effect can be erratic at tissue and cellular levels.
For example, in the cerebrospinal fluid and intracellular
spaces the pH may drop further, without concordance with
an already alkalemic arterial blood sample. This could happen
because CO2 raised by the bicarbonate infusion may readily
diffuse across cell membranes and the blood-brain barrier,
whereas bicarbonate cannot. Therefore, despite its ability to
increase blood pH when given intravenously, bicarbonate
fails to reliably augment the intracellular pH.208,209 In a classic
report, Adrogué et al. demonstrated that bicarbonate admin-
istration in the setting of cardiopulmonary compromise
actually worsened the pH and PCO2 in central venous blood
samples, indicating persistent acidosis at the tissue level.124
Results of human studies that examined the impact of bicar-
bonate administration during cardiopulmonary resuscitation
have uniformly shown no benefit in terms of survival and
hemodynamic recovery. Several studies have demonstrated a
deleterious effect in this setting, and many others have shown
no discernable effects.107,111,124,207 This is why the American
Heart Association no longer recommends routine administra-
tion of bicarbonate during cardiopulmonary resuscitation. Its
use is considered only after effective ventilation, chest com-
pressions, and epinephrine are established in the prolonged
arrest scenario and for cases in which bicarbonate is a “spe-
cific” therapeutic intervention (e.g., hyperkalemia, hyper-
magnesemia, tricyclic antidepressant poisoning, and sodium
channel blocker poisoning).213 There is also no evidence of
benefit with sodium bicarbonate infusion during resuscitation
of infants at birth.214
The argued rationale for bicarbonate use in the shock set-
ting is to mitigate the adverse hemodynamic consequences of
acidemia. However, adult studies have indicated that bicar-
bonate is no more effective than saline in improving heart rate,
central venous pressure, pulmonary artery pressure, mixed
venous hemoglobin oxygen saturation, systemic oxygen deliv-
ery, oxygen consumption, arterial blood pressure, pulmonary
artery occlusion pressure, and cardiac output.107 These find-
ings suggested that the commonly observed hemodynamic
response to bicarbonate administration in patients treated
with inotropic/vasoactive drug infusions may simply be due
to preload augmentation rather than enhanced catechol-
amine responsiveness.111 These findings persisted in the most
severely acidemic subset of patients (pH 6.9 to 7.2), a result
that does not support the practice of withholding bicarbonate
in patients with “mild” acidemia and allowing its administra-
tion in those with “severe” acidemia. On the contrary, it could
be expected that this sicker subset of patients would develop a
more profound paradoxical intracellular acidosis after bicar-
bonate administration. It is likely that all these data derived
from adult patients can be extrapolated to most pediatric ages,
excluding infants and neonates, for whom there is insufficient
evidence to determine whether infusion of base or fluid bolus
reduces morbidity and mortality from metabolic acidosis.215
The most recent (2008) Surviving Sepsis Guidelines, based on
a thorough evaluation of ancillary therapies in adult sepsis and
septic shock, did not recommend the use of bicarbonate for
hemodynamic resuscitation or reduction in vasopressors in
the setting of lactic acidosis with pH greater than 7.15, while
deferring judgment for more severe acidemia. A recent review
further recommended a lower target pH of 7.00 or less,107,211
a position supported by other authoritative reviews,212 as no
reliable argument exists to prove that such acidosis is harm-
ful under these conditions in humans. Experimental data even
show that hypoxic cells are able to survive only if the medium is
kept acidic. However, the 2007 update of the Clinical Practice
Parameters for hemodynamic support of pediatric and neo-
natal septic shock from the American College of Critical Care
Medicine,216 states that sepsis-induced acidosis and hypoxia
can increase pulmonary vascular resistance and thus main-
tain patency of the ductus arteriosus, resulting in persistent
pulmonary hypertension of the newborn (PPHN). Inhaled
nitric oxide is the treatment of choice; however, the commit-
tee agreed that metabolic alkalinization remains an important
initial resuscitative strategy during shock, as PPHN in the set-
ting of septic shock can reverse when acidosis is corrected.
In a recent single-center, prospective, observational study
that enrolled 60 adults with either severe sepsis or septic

shock, a quantitative acid-base analysis approach was applied
in order to clarify the components of the metabolic acido-
sis.217 It was found that at the time of admission to ICU, these
patients presented with a complex pattern in their metabolic
acidosis, caused predominantly by hyperchloremic acidosis
(more pronounced in nonsurvivors), and partially offset by
hypoalbuminemia. Acidosis resolution in survivors was attrib-
utable to a decrease in strong ion gap and lactate levels. This
study is rather small and has some other limitations, but it
may imply that a subset of sepsis/septic shock patients (those
with hyperchloremic acidosis identified by SIG, AGCORR and
partitioned SBE), may indeed benefit from sodium bicarbon-
ate administration.
The clinician must be aware that NaHCO3 is not free of
negative side effects, the main being related to fluid and
sodium load that can cause hypervolemia, hyperosmolar-
ity, and hypernatremia.205 NaHCO3 given as a rapid intra-
venous (IV) bolus can cause a transient decrease in arterial
blood pressure and a transient rise in intracranial pres-
sure, probably related to its hypertonicity.111 This effect
is ameliorated when bicarbonate is administered as a slow
IV infusion. Regardless of the infusion rate, IV adminis-
tration of bicarbonate can cause sudden shifts of several
cations through cell membrane-mediated mechanisms.
This is advantageous in treating hyperkalemia,213 but it
also can be dangerous because bicarbonate lowers ionized
calcium. “Overshoot” alkalosis, in which an abrupt and
poorly tolerated transition from severe acidemia to alkale-
mia develops, can result from overly aggressive bicarbonate
“correction.”210-212 Therefore the decision whether to use
bicarbonate in lactic acidosis may become a difficult one
because it is a choice between loyalty to a longstanding but
unproven therapy, and congruent scientific behavior that
must surrender to the evidence of potential deleterious
effects of bicarbonate administration in a variety of acide-
mic conditions.107,111,140,142,210-212
Nevertheless, the urge to give bicarbonate to a patient with
severe acidemia may become irresistible for most clinicians.
It will always be prudent to adjust the clinical decision to
the specific characteristics of each patient, keeping pros and
cons in mind. If bicarbonate is used, consideration must be
given to employ a slow infusion and a plan for clearing the
CO2 that is produced. Additionally, ionized calcium must be
measured and corrected if needed, as the resultant drop may
compromise cardiac and vascular contractility and respon-
siveness to cathecholamines. The amount of bicarbonate to
be given should be calculated to raise the pH up to 7.2.212
Thus the decision to provide “bicarbonate correction” must
be based on the best clinical judgment mixed with a knowl-
edge of the available evidence. This science-and-art approach
to the individual patient can be summarized in the clinician’s
answer to the following questions, modified from Forsythe
and Schmidt111:
1. Is the level of low pH a clear and present hazard to this
patient?
2. Is there a reasonable expectation that increasing the blood
pH with NaHCO3 will have some beneficial effect?
3. Is there a particular and specific risk to this patient from
the known potentially negative effects of NaHCO3?
4. Is the mechanism of the acidosis suitable for treatment
with NaHCO3, or might the acidosis be exacerbated?
There are no recipes for answering these questions.
Chapter 68 — Acid-Base Balance and Disorders 987
Salicylate intoxication represents a special setting. Because
the risk of death and the severity of neurological manifesta-
tions depend on the concentration of salicylates in the cen-
tral nervous system, therapy is directed at limiting further
drug absorption by administering activated charcoal in the
emergency department and promoting the exit of the drug
from the cerebral tissue by increasing the alkalinity of the
blood, which also will raise urine pH and therefore inhibit
salicylate reabsorption by ion trapping. Thus this represents
a special case of lactic acidosis in which NaHCO3 is clearly
indicated for two reasons: (1) to establish a high urinary flow
rate along with other fluids and (2) to promote salicylate
excretion. The target pH of the urine is 7.0 to 7.5. Hemodi-
alysis is reserved for severe cases, especially those involving
renal dysfunction.
If the science-and-art decision is to administer NaHCO3,
some time-honored clinical clues are valuable. NaHCO3 dose
is best estimated with either the SBE or the bicarbonate level
derived from PCO2 measured by the blood gas analyzer:
Total body base deficit = SBE × Body weight(kg) × 0.3 (18A)
HCO3− deficit = 0.3 × Body weight (kg)
   × [HCO3− expected / HCO3−  observed] (18B)
The distribution volume of bicarbonate is 0.3, or 30% of
the lean body weight. The theoretical distribution volume of
NaHCO3 equals the extracellular fluid volume, that grossly
represents 60% of the body weight (70% in young infants),
and therefore it can be argued that the correct arithmetic factor
should be 0.6 (or 0.7) rather than 0.3. Time-honored experi-
ence has shown, however, that as the starting point, bicarbon-
ate or SBE correction with 0.3 (“half correction”) will suffice
in most cases and will avoid unnecessary risks from excessive
load of solutes and fluid as well as the overshoot alkalemia. It
should be taken into account that the usual NaHCO3 prepara-
tion available worldwide has a concentration of 0.88 mEq/mL,
with pH 8 and 1461 mOsm/kg. Therefore bicarbonate is ide-
ally administered through a central venous line and diluted 1:1
with distilled water. If it has to be infused through a peripheral
vein, the dilution must be increased.
Carbicarb
Concern about the CO2-producing effect of bicarbonate led
to the development of Carbicarb, which consists of equi-
molar concentrations of NaHCO3 and sodium carbonate
(Na2CO3).107,140,218-219 Carbicarb raises the SID and thus
increases the pH far more than bicarbonate, with much less
rise in PCO2, thereby limiting but not eliminating the genera-
tion of CO2. The risks of hypervolemia and hypertonicity are
similar to those of bicarbonate. Animal studies have shown
stabilization of serum lactate levels and improved acid-bal-
ance profile both in blood and at the intracellular level. Car-
bicarb administration also resulted in a significant increase
in cardiac index when compared with normal saline and
NaHCO3, although neither Carbicarb nor NaHCO3 prevented
the progressive reduction in myocardial cell pH in an animal
model of ventricular fibrillation. Although Carbicarb more
consistently increases intracellular pH, studies of its effects on
hemodynamics have yielded conflicting results.140 Carbicarb
is not currently available for clinical use, but there is no doubt
that after all the years elapsed since its appearance, it deserves
further clinical research.
988 Section V — Renal, Endocrine, and GI Systems
Tris(hydroxymethyl)aminomethane
THAM, also known as tromethamine and tris buffer, is an
amino alcohol that behaves as a weak base (pKa 7.8). It exists
in neutral form at physiological pH. Protonated THAM is
excreted by the kidneys.220 It crosses lipid membranes and
penetrates cells easily. Therefore it has the potential to raise
both intracellular and central nervous system pH. In addition,
THAM’s buffering action occurs without producing CO2,
and thus is not dependent on pulmonary function.221 Despite
THAM being commercially available for several decades,
there are few studies establishing its clinical efficacy. In animal
models, THAM incompletely buffered metabolic acidosis, but
it significantly improved contractility and relaxation in an iso-
lated rabbit heart model.107 A small adult study in the ICU set-
ting, showed that THAM had an equivalent but shorter lasting
alkalinizing effect in comparison to that of bicarbonate, but
produced no decrease in potassium and did not elevated
sodium, as occurs with bicarbonate.222 The paucity of infor-
mation and the report of several serious side effects, including
hypekalemia, hypoglycemia, local extravasation injury, and
hepatic necrosis in neonates, have limited its widespread use
in the lactic acidosis setting.
Dichloroacetate
Of particular relevance for lactic acidosis is dichloroacetate
(DCA), a simple compound that reduces plasma lactic acid
concentration. DCA is not a buffer but a stimulator of pyru-
vate dehydrogenase, the enzyme that catalyzes the oxidation
of pyruvate to acetyl–coenzyme A (CoA), facilitating its entry
to the Krebs cycle and thus decreasing lactate production
and promoting the clearance of accumulated lactate.107,223 In
addition, DCA promotes myocardial glucose utilization and
contractility. Initial data from both children and adults were
promising, but a large controlled clinical trial in adults with
severe lactic acidosis showed that DCA treatment resulted in
statistically significant but clinically unimportant changes in
arterial blood lactate concentrations and pH. It also failed to
alter hemodynamics or survival. Renewed interest in DCA has
arisen from its potential application in attenuating lactic aci-
dosis in certain congenital errors of metabolism,224 and lac-
tic acidosis due to severe malaria in children.225 In regard to
shock patients, the physiological “new paradigm” concerning
the cell-to-cell lactate shuttle and its metabolic importance
raises the possibility that targeting a specific pharmacological
reduction of lactate levels through DCA might not be advan-
tageous in this setting.136-139
Dialysis Management of Metabolic
Acidosis
Dialytic procedures may be indicated in some cases of meta-
bolic acidosis that are refractory to bicarbonate or in cases in
which there are serious limitations in the amount of fluid or
sodium load that can be administered to the patient, a com-
mon situation in the pediatric critical care unit (see Chapter
72) Uncompensated metabolic acidosis (pH <7.1) remains one
of the acknowledged criteria for the initiation of renal replace-
ment therapy in the pediatric ICU.206 Peritoneal dialysis is
often not the best choice, particularly in lactic acidosis asso-
ciated with hypoperfusion. In this setting the hypoperfused
peritoneal membranes may not be efficient for supporting
enough peritoneal flux, and the increase in intraabdominal
pressure may contribute to a further drop in cardiac output. If
peritoneal dialysis is chosen, bicarbonate-buffered peritoneal
dialysis solution provides some advantages over the conven-
tional lactate-buffered peritoneal dialysis solution in terms
of pH control, biochemical monitoring, and mesothelial cell
preservation.
Most critically ill patients lack the hemodynamic stabil-
ity to tolerate intermittent hemodialysis. Hemofiltration and
hemodiafiltration are better options. Acute renal replacement
therapy may be needed for critically ill patients with metabolic
acidosis that is multifactorial in origin. Analysis of the acid-
base status of these patients through Stewart-Figge method-
ology shows that acidemia is present despite the presence of
hypoalbuminemic alkalosis, and that this acidemia is mostly
secondary to hyperphosphatemia (mainly if there is con-
comitant acute or chronic renal failure), hyperlactatemia, and
the accumulation of unmeasured anions. Once continuous
hemofiltration is started, it becomes the dominant force in
controlling metabolic acid-base status and profound changes
are rapidly achieved. The result is the progressive resolution
of acidemia and acidosis, with lowering concentrations of
phosphate and unmeasured anions. If the patient stabilizes,
this typically results in some degree of metabolic alkalosis, an
effect the clinician must take always in account.
Hemofiltration techniques replace plasma water, which is
low in bicarbonate concentration, with a solution that contains
an above-normal bicarbonate (or lactate or acetate) concen-
tration. Such weak anions free their sodium (which increases
SID), buffer hydrogen ions, and then are transformed into
CO2 (lactate and acetate must convert first to bicarbonate in
the liver), which is subsequently removed by ventilation. This
exchange contributes to the correction of acidosis, along with
the increase in SID through the sodium contribution. If such
oxidizable anions are not fully extracted and metabolized by
the liver and, therefore, accumulate in plasma, the ability to
correct acidosis is lost, as they fail to increase the SID. Hence,
hyperlactatemia with acidification of plasma occurs. Such iat-
rogenic hyperlactatemic acidosis is particularly frequent in
lactate-intolerant patients (shock with lactic acidosis and/or
liver disease), and it is specially marked if high-volume hemo-
filtration is performed, in which the associated high lactate
load may easily overcome the patient’s metabolic capacity for
taking up lactate. In such patients, use of bicarbonate-based
replacement fluids is mandatory.226 In addition, the effect
of lactate-based replacement fluid on blood lactate concen-
tration can be misleading in patients who have sepsis with
lactic acidosis. Additionally, it appears that lactate clearance
through the hemofilter is small compared with endogenous
clearance. Therefore, despite the fact that hemofiltration has
been advocated for the treatment of lactic acidosis, kinetic
studies of lactate removal do not suggest that such removal
can counteract lactate production in any meaningful way.140
Metabolic Alkalosis
Metabolic alkalosis is defined as an elevation of plasma HCO3−
with an arterial pH above 7.45. There is no accurate estimate of
the incidence or prevalence of metabolic alkalosis. However,
in the critical care setting, it is estimated that metabolic alkalo-
sis is the more common form of acid-base disorder, as it may
be present in about 50% of patients with acid-base disorders.

A study in pediatric patients undergoing open-heart surgery,
found that 72% of children under 12 months of age developed
metabolic alkalosis, in contrast with 30% of those older than
12 months of age. It is difficult to attribute a figure of mor-
tality or morbidity directly to metabolic alkalosis. However,
at least one study in adults found that mortality progressively
rose with the pH: 47% with pH 7.57 to 7.59, 65% with pH
7.60 to 7.64, and 80% with pH 7.65 to 7.70. This does not
necessarily indicate a cause-effect relationship.227,228 Most of
the clinical studies that have examined metabolic alkalosis are
now somewhat old, and there is a need for prospective studies
of updated design to reassess the incidence, consequences, and
other aspects of metabolic alkalosis.
The increased incidence of metabolic alkalosis in patients
with severe sepsis and trauma is due to factors related to a vig-
orous correction of shock, hypotension, and acidosis, where
large quantities of citrated blood or lactated Ringer solu-
tion are given, as well as to the administration of bicarbon-
ate itself (Table 68-8).227 Other subsets of patients may arrive
in the PICU already with metabolic alkalosis, associated with
the chronic use of chloruretic diuretics, excessive exogenous
or endogenous steroids, high doses of antacids, or related
to elevated gastrointestinal fluid losses (emesis, suction, or
chloride-rich diarrhea) or to the posthypercapneic state, the
typical pattern of a chronic lung disease after the resolution
of an acute episode of decompensation.228,229 Alkalemia has
been classified as mild (pH 7.45 to 7.50), moderate (pH 7.50
to 7.55), or severe (pH > 7.55).227
According to the physicochemical approach, metabolic
alkalosis results from an increase in SID, or a decrease in ATOT,
due to a loss of anions (Cl− from the digestive tract or through
the kidneys, albumin from the plasma) or, rarely, to an excess
of cations.8,10 (see Table 68-6). In the classic approach to acid-
base derangements, metabolic alkalosis is generated by net
gain of base (primarily bicarbonate) or loss of nonvolatile acid
from the extracellular fluid. Despite the fact that this model
is not able to explain many of the electrolyte changes asso-
ciated with metabolic alkalosis nor the reasons for the good
results of some therapeutic interventions, it continues to be a
practical way to approach metabolic alkalosis.9,230 The excess
of base may be gained through oral or parenteral bicarbonate
administration, or by the administration of other weak anions
such as lactate, acetate, or citrate, all of them as sodium salts.
Thus it is actually the gain of strong cations (mainly sodium)
that causes pH to increase. The acid deficit may be due to the
hydrochloric acid loss by vomiting or enhanced renal acid
excretion promoted by diuretics or aldosterone excess, and is
often accompanied by hypochloremia and hypokalemia.227-229
In a similar way, it is the loss of strong anions (mainly chlo-
ride), rather than the direct loss of hydrogen ions, that actually
increases pH. There may also be a contraction of the extracel-
lular fluid volume secondary to the chloride loss. Concomitant
changes in the intracellular fluid do occur, including a loss of
intracellular potassium along with a net gain of sodium and
hydrogen. Hence, metabolic alkalosis in the extracellular fluid
is usually accompanied by acidosis and potassium depletion
in the intracellular compartment. Bicarbonate or base loading
is rarely the single cause of metabolic alkalosis. Such a situa-
tion may transiently occur during and immediately after an IV
infusion of NaHCO3 or an equivalent base (e.g., citrate anti-
coagulant in transfused packed red blood cells). This situation
may also occur after the successful treatment of ketoacidosis
Chapter 68 — Acid-Base Balance and Disorders 989
Table 68–8  Causes of Metabolic Alkalosis in
Critically Ill Patients
I. Chloride-responsive (decreased urine [Cl−]*)
A. Gastrointestinal losses of Cl−
1. Gastric drainage or persisting vomiting
2. Chloride-wasting acute diarrheas
B. Renal losses of Cl− and K+
1. Diuretics (mainly acute use)
2. High dose of certain penicillin-derivative antibiotics
3. Posthypercapnia
II. Chloride-resistant (increased urine [Cl−]†)
A. Excess mineralocorticoid activity: ongoing losses of K+
and Cl−
1. Primary and secondary hyperaldosteronism
2. Congenital adrenal hyperplasia (17α-hydroxylase or
11β-hydroxylase deficiency)
3. Cushing syndrome
4. Primary renin-secreting tumors
5. Steroid treatment
B. Genetic renal tubular defects of electrolyte transport
1. Problem in chloride reabsorption
a. Bartter and Gitelman syndromes
2. Defective epithelial sodium channel (decreased
sodium elimination)
b. Liddle syndrome
C. Drug-induced hypokalemic alkalosis
1. Diuretics administered for prolonged time
2. High-dose glucocorticoids
3. Fludrocortisone
4. Aminoglycosides
5. Toxic effects of licorice (Glycyrrhiza glabra)
6. Ion exchange resin
D. Excess cation (alkali) gain
1. Massive blood transfusion
2. Massive infusion of lactated Ringer’s solution
3. Parenteral hyperalimentation with excessive sodium
acetate
4. Alkali ingestion/treatment and milk-alkali syndrome
5. Magnesium depletion
III. Miscellaneous group (variable urine [Cl−]†)
A. Hypoproteinemia
B. Cystic fibrosis
C. Congenital chloride diarrhea
D. Salt-losing nephropathy
*<20 mEq/L, usually <15 mE/L.
†>20 mEq/L, usually >40 mEq/L.
or lactic acidosis because these organic anions are metabolized
to bicarbonate, and after the resolution of hypercapnia, either
permissive or as a part of unintentional respiratory acido-
sis, before the kidney can excrete the bicarbonate previously
“retained for compensation” (actually, HCO3− was increased
because PCO2 was increased). It is generally accepted that
metabolic alkalosis involves a “generative” stage, during which
the relative concentraton of alkali within the body increases,
and a “maintenance” stage,228,229 in which the kidneys fail to
compensate by excreting strong cations and HCO3−.
Three major factors underlie the maintenance phase in
most clinical situations: first, depletion in circulating volume
and changes in generalized hemodynamics (e.g., heart failure)
and in intrarenal hemodynamics, which combine to reduce
the filtered load of bicarbonate traversing the proximal tubule
despite the increase in bicarbonate concentration; second,
increased aldosterone secretion (and probably endothelin-1),
due to volume contraction and increased angiotensin-II, which
stimulates acid secretion; and third, total potassium depletion
and hypokalemia, which alter glomerular hemodynamics,
990 Section V — Renal, Endocrine, and GI Systems
stimulate the renal H+-K+-ATPase, and secondarily increase
renal acid secretion in the presence of aldosterone.230 In other
words, the regulation of pH through strong cation (mainly
sodium) and bicarbonate elimination, is sacrificed to preserve
volume and potassium stores. If volume and potassium are
equilibrated, metabolic alkalosis self-corrects.
Metabolic alkalosis has been classified by the primary organ
system involved, the response to therapy, or the underlying
disease.229,231 In the critical care setting, it may be more con-
venient to classify it according to the response to therapy,
and use the serum chloride concentration (the most com-
monly anion involved) as the key variable for such a classifi-
cation.8-10,43 Sometimes the loss of Cl− is temporary and can
be treated effectively by replacing it; this type of metabolic
alkalosis is known as chloride responsive. This represents the
most frequently encountered metabolic alkalosis in the pedi-
atric critical care unit, and it is also the most severe.227-231
This group of disorders is usually the result of Cl− losses from
gastric drainage or persisting vomiting, as in pyloric hyper-
trophy and other causes of upper gastrointestinal obstruc-
tion.8,98,227-229 Chloride loss also may occur as a consequence
of the administration of diuretics.10 Both persistent vomiting
and excessive diuretics generate some degree of dehydration,
with volume contraction and secondary stimulation of aldo-
sterone release, which in turn leads to increased tubular Na+
reabsorption—an alkalinizing process, because it increases
the SID and increases urinary loss of K+, which may yield
hypokalemia.229
In other cases, hormonal mechanisms leading to an excess
of mineralocorticoid activity directly produce ongoing losses
of K+ and Cl−. Similar urinary losses may be associated with
genetic renal tubular defects of electrolyte transport, mainly
in chloride reabsorption. Decreased plasma levels of Cl− and
K+ lead to an increased SID, which in turn yields metabolic
alkalosis. In this setting, the Cl− deficit can be offset only tem-
porarily, at best, by Cl− administration. Therefore this form
of metabolic alkalosis is said to be chloride resistant.8,10,227-231
(see Tables 68-6 and 68-8). The hallmark of this group of
disorders is an increased urine Cl− concentration, more than
20 mEq/L (usually >40 mEq/L).227-231 Treatment requires a
search for the underlying disorder and, if possible, a specific
therapeutic intervention. Among the most important causes
of chloride-resistant disorders are: (1) diseases with miner-
alocorticoid excess, including primary and secondary aldo-
steronism, congenital adrenal hyperplasia (17α-hydroxylase
deficiency), renin-secreting tumors, and Cushing syndrome;
(2) tubulopathies, including chloride-wasting tubulopathies
(Bartter and Gitelman syndromes, and defective epithe-
lial sodium channels (ENaC) leading to a decreased sodium
elimination (Liddle syndrome); (3) drug-induced hypokale-
mic alkaloses, including those caused by diuretics, high-dose
glucocorticoids, fludrocortisone, aminoglycosides, and toxic
effects of licorice (Glycyrrhiza glabra); and (4) the miscella-
neous group, which includes 11β-hydroxysteroid dehydro-
genase deficiency, salt-losing nephropathy, cystic fibrosis,
and congenital chloride diarrhea, among others. For further
details about these specific disorders, the reader is referred
to other sources.98,228-235 Random urine chloride may suf-
fice for a quick clinical orientation: uCl− less than 20 mEq/L
(usually <15 mEq/L) is consistent with chloride-responsive
metabolic alkalosis; uCl− greater than 20 mEq/L (usually >40
mEq/L) is consistent with chloride-unresponsive metabolic
alkalosis.228-230 However, this general rule may not apply to
other special causes of metabolic alkalosis, which include
the extrarenal chloride-resistant forms, such as cystic fibro-
sis,234 and congenital chloride diarrhea, which is a recessively
inherited disorder of chloride transport in the distal ileum
and colon.235 In both disorders, huge extrarenal chloride loss
occurs (through sweat or diarrhea), and urine chloride may be
low, normal, or high, depending on the patient’s renal func-
tion and clinical situation.
Finally, metabolic alkalosis may occur as the SID increases
as a consequence of the gain of cations rather than anion
depletion. The most common clinical situation in the critical
care setting is the IV administration of strong cations with-
out strong anions, such as with massive blood transfusion. In
this case, sodium is administered predominantly with citrate
(a weak anion) instead of chloride. A similar mechanism of
metabolic alkalosis occurs when parenteral nutrition contains
excess sodium acetate (another weak anion) and insufficient
chloride to balance the sodium load.8 Excessive infusion of
some gelatins used as plasma volume expanders and sodium
lactate (as in Ringer’s solution) can also cause metabolic alka-
losis. The milk-alkali syndrome is now a rare cause of this
derangement.
Treating Metabolic Alkalosis
Many clinicians have the perception that metabolic alkalosis
is a mild, self-limited acid-base derangement. This can be true
in some settings, such as post-hypercapnia and post-citrate or
lactated Ringer’s infusion in patients with normal renal and
hepatic function, but it is not true in all cases. Alkalosis and
alkalemia are important because they may increase morbidity
and mortality. Increase in blood pH increases neuromuscular
excitability, probably related to a decrease in ionized calcium
concentration and potassium shifts, leading to alteration of
consciousness, increased seizure activity, increased cardiac
arrhythmia, decreased oxygen release to tissue from hemoglo-
bin, tetany secondary to hypocalcemia, increased ammonia
generation by the kidney, and, in some instances, depression
of the respiratory drive. Because mortality is especially high
when a pH in excess of 7.6 develops, intervention at a pH of
7.55 and greater is recommended.227,230
Regardless of the type of metabolic alkalosis, the first step
for its proper management is to moderate or stop the process
that generated the problem, even if only temporarily.227 For
example, if continuation of gastric drainage is required, the
loss of gastric fluid can be reduced though the administration
of H2-receptor blockers or inhibitors of the gastric H+/ K+-
ATPase. If it is not possible to withdraw diuretics, it may be
possible to use potassium-sparing compounds (e.g., spirono-
lactone, amiloride), that decrease distal acidification and cur-
tail potassium excretion. Administration of bicarbonate or its
precursors such as lactate, citrate, and acetate should be dis-
continued; these compounds are commonly present in IV and
dialytic solutions, transfused blood and blood derivatives, and
parenteral nutrition. If drugs with mineralocorticoid activity
are being administered, their indication and dose should be
reassessed.
Up to 10% of the total bicarbonate filtered is reabsorbed or
lost to urine in the distal renal tubule. In most patients with
metabolic alkalosis, extracellular fluid, altogether with chlo-
ride, potassium, and magnesium concentrations, is decreased.

Hence, the blood flow to the kidneys is also decreased, and
secretion of both aldosterone and endothelin-1 is stimulated,
bicarbonate urine loss is reduced, chloride wasting increases,
and urinary hydrogen ions and potassium are decreased even
more.
Because potassium, chloride, and magnesium concentra-
tions limit bicarbonate excretion, their low concentrations
will make metabolic alkalosis refractory to correction. Thus
the restoration of circulating volume and electrolyte compo-
sition will allow renal excretion of bicarbonate and the cor-
rection of metabolic alkalosis227 or, in agreement with the
physicochemical approach, it really does not matter if the
bicarbonate excretion is enhanced, but it is the replacement of
Cl− that corrects the increased SID.8 Saline plus KCl infusion
are usually the best choice because of the typical coexisting
volume depletion and hypokalemia. Administration of nor-
mal saline is effective despite the release of equal amounts of
Na+and Cl− because it results in larger relative increases in Cl−
concentration compared with Na+ concentration. Treatment
of severe chloride-responsive metabolic alkalosis can be a real
challenge without the presence of either volume depletion or
hypokalemia as well as in patients with cardiac or renal dys-
function and in the hepatic disease patient with ascites.
It is quite common that this group of patients had been
receiving aggressive diuresis. Hence, more often, these patients
have developed metabolic alkalosis as a result of the effects of
diuretics and will be better treated by the provision of potas-
sium chloride, because their previous treatments have ren-
dered them potassium depleted. However, potassium chloride
can induce hyperkalemia in patients with renal failure. In
these patients, decreasing or adjusting the diuretic regimen,
adding acetazolamide (a carbonic anhydrase enzyme inhibi-
tor that enhances renal sodium bicarbonate loss, increasing
urinary SID and decreasing blood SID),201 and cautiously
administering NaCl and potassium chloride may suffice.9,227
If the pace of correction of the alkalemia needs to be acceler-
ated, hydrochloric acid (HCl) can be infused intravenously as
a 0.1 to 0.2 N solution (i.e., one containing 100 to 200 mmol
of H+ per liter). This intervention, which is rarely needed, is
safe and effective for the symptomatic rapid relief of severe
metabolic alkalosis. Because of its sclerosing properties and its
hyperosmotic concentration, HCl must be infused through a
central venous line at an infusion rate of no more than 0.2
mmol/kg/hr, up to 20 to 50 mmol/h maximum,227 with arte-
rial pH monitoring every hour. Although an alternative infu-
sion through a peripheral IV line was described decades ago,
this route is not advisable in the pediatric population. Calcula-
tion of the amount of HCl solution to be infused is based on
a distribution volume equivalent to 30% of the body weight.
Thus HCl dosage can be calculated with either the SBE or the
bicarbonate difference in a manner similar to the bicarbonate
administration formula (Equations 18A and 18B):
Total body BE = SBE × Body weight(kg) × 0.3 (19A)
HCO3−  excess = 0.3 × Body weight (kg)
  × [HCO3−  observed − HCO3−  desired] (19B)
In both formulas, the result is expressed in millimoles of
HCl to be administered. If this intervention is contraindicated,
not effective, or not available, and the alkalemia is severe with
no hope of quick control, hemodialysis or hemodiafiltration
can rapidly correct severe alkalemia and volume overload, but
Chapter 68 — Acid-Base Balance and Disorders 991
a dialysis solution low in lactate or bicarbonate must be used
to prevent worsening of the alkalemia. Ammonium chloride
has similarly been employed to correct chloride in patients
with normokalemia or hyperkalemia. In this case ammonium
represents a weak cation that does not increase the concentra-
tion of strong cations. The only specific treatment for meta-
bolic acidosis available to date is for Liddle syndrome, which
is responsive to a decreased dietary sodum intake and to a
sodium channel blocker, such as amiloride or triamterene.230
Respiratory Acid-Base
Derangements
Although the underlying pathological process may vary, the
respiratory acid-base derangements always have the same
mechanism: alveolar ventilation is increased or decreased
out of proportion to CO2 production. Carbon dioxide arises
either from the cellular metabolism or by the titration of
HCO3− by metabolic acids. Normal CO2 production by the
body (and its excretion by the lungs) is impressive (about 220
mL/min or about 317 L/day in a 70-kg adult, equivalent to
15,000 mmol of carbonic acid per day) compared with the 500
mmol/day of all nonrespiratory acids that are handled by the
kidneys and gut.10 Pulmonary ventilation is adjusted by the
respiratory center in the brainstem in response to changes in
PaCO2, pH, and PaO2, although respiratory drive can be influ-
enced by other neural (anxiety, wakefulness) and nonneural
factors (e.g., exercise, muscle strength) and can also be altered
in some pathological situations (cystic fibrosis, asthma, and
congenital central hypoventilation syndrome) (see Chapter
38).236 The precise and real-time match of alveolar minute
ventilation to CO2 production allows stable PaCO2 levels of
35 to 45 mm Hg at sea level. Accuracy of the central control
allows the body to adjust PaCO2 in compensation for altera-
tions in arterial pH produced by metabolic acidosis or alka-
losis in predictable ways (see Tables 68-2 and 68-3). When
this normal respiratory system is disrupted or overwhelmed,
PaCO2 deviates from normal and the respiratory acid-base
disturbances are initiated.
Respiratory acidosis is produced by CO2 retention, leading
to hypercapnia (elevation of PaCO2). Respiratory alkalosis is
produced by hyperventilation, leading to a drop in PaCO2 (i.e.,
hypocapnia). As soon as PaCO2 increases or decreases, plasma
and intracellular buffers change their dissociation to maintain
a stable pH, the effect of which is fully manifested within 15
to 30 minutes. If the alteration in PaCO2 is sustained for more
than 6 to 12 hours, renal mechanisms induce far larger changes
in bicarbonate concentration, reaching maximal impact
within 3 to 5 days. These renal effects lead to a new steady state
for the pH. The two responses to the primary alterations in
PaCO2, plasma plus tissue buffers and the renal response, per-
mit description of the respiratory acid-base derangements as
acute and chronic phases.10 Thus acute respiratory acidosis or
alkalosis involves the immediate plasma and intracellular buf-
fer response to hypercapnia or hypocapnia, whereas chronic
respiratory acidosis or alkalosis involves the renal response.
Respiratory Acidosis
Respiratory acidosis occurs whenever the CO2 elimination
by the lungs is lower than the CO2 production by the tissues,
resulting in a positive balance of CO2, which in turn increases
992 Section V — Renal, Endocrine, and GI Systems
PaCO2 to a new equilibrium determined by the altered rela-
tionship between CO2 production and alveolar ventilation.
Because the increase in CO2 production alone is not sufficient
to overcome the normal ability of the lungs to increase alveo-
lar ventilation,10 what is central to all forms of respiratory aci-
dosis is a failure of alveolar ventilation and CO2 excretion to
increase in response to a rising PaCO2. However, an increase in
CO2 production in the face of fixed ventilation can also result
in respiratory acidosis. For example, this may occur in the
critical care setting in patients receiving mechanical hypoven-
tilation and a high load of carbohydrates in their parenteral
nutrition. This may also happen if a patient with hypoventi-
lated lungs becomes febrile (acute hypermetabolism). Imme-
diately, the increase in PaCO2 increases both the hydrogen
ion and bicarbonate concentrations in blood (Equations 3 to
5). Here the increase in [HCO3−] occurs as a consequence of
physicochemical principles and not as a consequence of an
adaptive response in order to buffer the increase in H+.5,8,13
The only immediate buffering activity in hypercapnia comes
from the nonbicarbonate plasma and intracellular buffers.208
Because of the increase in bicarbonate (a weak anion), no
change in the SID is produced, and thus no change occurs
in the SBE. Because CO2 is produced within the cells and
can freely diffuse across the lipophilic cellular membranes,
intracellular acidosis always occurs with respiratory acido-
sis.208,209 If the PaCO2 remains increased, active compensatory
mechanisms are activated, and the SID increases to restore
H+ toward normal. Primarily, respiratory acidemia compen-
sation is accomplished by removal of CL− from the plasma
space. Because movement of Cl− into the tissues or red blood
cells results in a drop of intracellular pH, Cl− must be removed
from the body to achieve a lasting effect on the SID. The kid-
neys are the most important organ for this task. Because every
chloride ion that is filtered and not reabsorbed increases the
SID (and the pH), Cl− removal by the kidney must be highly
accurate. The role of ammonium in this process is preemi-
nent, not as a hydrogen ion carrier or a potential buffer, but
for the excretion of Cl− without losing Na+ or K+.8,54 Thus
when renal function is intact Cl− is eliminated in the urine,
and after a few days, the SID increases to the level necessary
to return blood pH near 7.35. This amount of time is required
by the physiological constraints of the system, but that is not
entirely a disadvantage because this rate of response is useful
Table 68–9  Causes of Respiratory Acid-Base Derangements
ACIDOSIS (↑ PaCO2)
Central nervous system depression
Severe head trauma, brain edema, metabolic diseases, infectious
diseases, intentional sedation, pharmacological effect of drugs
Neural (peripheral), muscular, and skeletal structures
Electrolyte disturbances: hypophosphatemia, hypokalemia
Specific diseases: myasthenia gravis, Guillain-Barré syndrome, spi-
nal cord injury, Werdnig-Hoffmann disease, Duchenne muscular
dystrophy, etc.
Ventilatory restriction: rib fractures and flail chest, patients with
intraabdominal hypertension from ascites, from closure of con-
genital abdominal wall defects, etc.
Lungs (airway and alveoli):
Respiratory obstructive disease, either acute or chronic: croup,
asthma, bronchiolitis, bronchopulmonary dysplasia
Alveolar injury: pneumonia, acute lung injury, acute respiratory
distress syndrome, cardiogenic pulmonary edema
in order to avoid being oversensitive to transient changes in
alveolar ventilation. In any case, the compensation results in
an increased pH for any degree of hypercarbia.
According to the Henderson-Hasselbalch equation (Equa-
tions 4 and 5), the increased pH will result in an increased
HCO3− concentration for a given PaCO2. Therefore the
so-called adaptive increase in HCO3− to hypercapnia actu-
ally results from the increase in pH, and is not the cause of
the increase in the pH, which actually occurred from the
increase in the SID as a consequence of the removal of chlo-
ride. Although the change in HCO3− concentration is a conve-
nient and reliable marker for the metabolic compensation (see
Tables 68-2 and 68-3), it is not the mechanism.
Acute respiratory acidosis develops as a consequence of the
impaired function of one or more of the three participants
in the ventilatory function: central nervous system; neural
(peripheral), muscular, and skeletal structures; and lungs (air-
way and alveoli) (Table 68-9). Airway and parenchymal lung
disease are the most common causes of acute CO2 retention.
This last group of conditions not only produces hypercapnia,
but also primary hypoxemia. It is hypoxemia, not hypercap-
nia or acidemia, that poses the principal threat to life. The
already mentioned conditions that cause the failure of the
lungs to eliminate CO2 can also be grouped into two types of
ventilatory disorders.10 The first, or “pure,” hypoventilation
occurs as a result of brainstem or neuromuscular dysfunction
or because of extrapulmonary restrictive lung compromise. In
this setting, the lung simply fails to move enough air in and
out to exchange CO2 and oxygen. As a result, PaO2 falls in
proportion to the rise in PaCO2. In the second and more com-
mon situation in the critical care setting, alveolar hypoven-
tilation is the result of the imbalance between perfused and
hypoventilated segments of a damaged lung (i.e., ventilation-
perfusion [V/Q] inequality; see Chapter 40). In this case, a fall
in PaCO2 often precedes hypercapnia, and when hypercap-
nia finally develops, the reduction in PaO2 is proportionally
greater than the rise in PaCO2. With both types of ventilatory
defects, however, hypoxemia is a concurrent finding when
hypercapnia is present.10
Chronic respiratory acidosis is most often associated with
chronic lung disease (e.g., bronchopulmonary dysplasia) or
chest diseases with abnormal chest wall mechanics (chest
congenital deformities, kyphoscoliosis), but it can also be
ALKALOSIS (↓ PaCO2)
Hypoxemia
High altitudes, pulmonary disease
Pulmonary disorders
Pneumonia, interstitial pneumonitis, fibrosis, edema, pulmonary
embolism, vascular disease, bronchial asthma, pneumothorax
Cardiovascular disorders
Congestive heart failure, hypotension
Metabolic disorders
Acidosis (diabetic, renal, or lactic), hepatic failure
Central nervous system disorders
Psychogenic or anxiety-induced hyperventilation, central nervous
system infection, central nervous system tumors
Drugs
Salicylates, methylxanthines, β-adrenergic agonists, progesterone
Miscellaneous
Fever, sepsis, pain, pregnancy

caused by chronic upper airway obstruction (e.g., obstructive
sleep apnea syndrome and craniofacial disorders),237 chronic
neuromuscular diseases, or chronic central nervous system
problems (congenital central hypoventilation syndrome).236
Respiratory decompensation in patients with these conditions
usually results from recently acquired infection, use of narcot-
ics, or uncontrolled oxygen therapy.238 These additional factors
superimpose an acute element of CO2 retention and acidemia
on the already elevated CO2 baseline. Progressive narcosis and
coma (i.e., hypercapnic encephalopathy) may ensue. On the
basis of the preeminent renal participation in the ultimate
compensation of hypercapnia, one should expect that patients
with renal disease (with difficulties excreting chloride) will
have a defective adaptation to chronic hypercapnia.
Treating Respiratory Acidosis
As the main threat to life in respiratory acidosis comes from
associated hypoxemia, and not from the level of hypercap-
nia or acidemia, oxygen administration represents a critical
element in the management of respiratory acidosis. Caution
must be taken when uncontrolled concentrations of oxygen
are administered to some patients with hypercarbia, particu-
larly those with chronic lung disease, in whom exaggerated
oxygen supplementation could depress respiratory drive and
provoke further increase in PaCO2.238 This occurs because
chronic hypercapnia is thought to downregulate CO2 chemo-
receptor sensitivity, which means that these patients are more
dependent on hypoxic drive to maintain adequate spontane-
ous ventilation. Thus hypoventilation (and hypercapnia), may
worsen if unrestricted (and excessive) oxygen is administered.
This phenomenon has been described mainly in adults with
chronic obstructive pulmonary disease and acute asthma,
but it may also occur in children with chronic lung disease.
It should be emphasized, however, that the correction of
hypoxia overrides strategies to avert oxygen-related hypercap-
nia, which normally tends to be of little clinical significance in
children. Thus, immediate actions should focus on securing a
patent airway and restoring adequate oxygenation by deliver-
ing an oxygen-enriched gas mixture.
Oxygen administration alone, however, is almost never
enough as a single therapeutic measure. Hence hypoventila-
tion must be treated directly. Whenever feasible, treatment
must be directed to the underlying cause. Sometimes it is
possible to solve the primary cause of hypoventilation rather
quickly (e.g., relief of obstruction from croup with racemic
epinephrine, reversal of narcotics with naloxone, resolution
of bronchial spasm with some β2 agonist). In such cases, it
may be possible to avoid positive pressure ventilation. Gen-
erally speaking, mechanical ventilation is indicated when the
patient is at risk of instability, the patient is already unstable,
or the central nervous system function shows a trend toward
deterioration. When respiratory muscle fatigue is impending,
further deterioration must be avoided by using positive pres-
sure ventilation. The classic “rule of the 50s” (i.e., 50 mm Hg
of PaO2 and PaCO2 as a guide for endotracheal intubation)
should not be interpreted literally. It is not the absolute value
of PaCO2 (or PaO2) that is important but rather the clini-
cal condition and perceived trend of the patient. In chronic
hypercapnia, management of the respiratory decompensation
depends on the cause, severity, and rate of progression of the
hypercapnia. Immediate treatment of pulmonary infection
Chapter 68 — Acid-Base Balance and Disorders 993
with proper antibiotics, bronchodilator therapy, and removal
of secretions can offer considerable benefit. The ventilatory
drive can be optimized by minimizing the use of tranquiliz-
ers and sedatives, by gradually reducing supplemental oxygen
(aiming for a PaO2 of about 60 mm Hg), and by correcting a
superimposed metabolic alkalosis.
The “aggressive” approach that favors the early implemen-
tation of positive pressure ventilation is often appropriate for
patients with acute respiratory acidosis239 (see Chapter 49).
For those patients with chronic diseases that limit pulmo-
nary reserve, however, a more conservative approach is often
advisable and possible because of the great difficulty often
encountered in weaning such patients from ventilators. If the
patient is obtunded or unable to cough and if hypercapnia
and acidemia are worsening, mechanical ventilation should be
instituted. Noninvasive mechanical ventilation (NIV) with a
nasal or facial mask is being used with increasing frequency in
children, both with moderately severe acute respiratory failure
and with hypercapnic respiratory failure resulting from acute
exacerbations of chronic lung disease (see also Chapter 50).
Despite the limited pediatric experience,240 its application in
children is growing both in acute situations within the criti-
cal care unit, even in small children, and in cases of chronic
hypercapnic and hypoxemic respiratory failure of various
causes that are encountered in intermediate care wards and in
children’s home environments. When PaCO2 is high and min-
ute ventilation is normal or increased, the respiratory muscles
are already failing to generate sufficient alveolar ventilation to
eliminate the CO2 being produced. The general strategy for the
correction of this problem is to decrease the work of breathing
by reducing CO2 production and to improve alveolar venti-
lation by increasing tidal volume or respiratory rate through
whatever mode of assisted ventilation is appropriate for the
patient. Respiratory muscle failure can occur when the work
of breathing is normal (e.g., numerous acute or chronic neu-
romuscular problems) or increased (e.g., patients with asthma
or the obesity hypoventilation syndrome), and presumably
because of inadequate delivery of oxygen to the respiratory
muscles (e.g., patients with cardiogenic pulmonary edema).
When PaCO2 is increased and minute ventilation is low, the
level of consciousness is generally impaired. Such patients
usually require intubation for airway protection in addition to
ventilatory assistance, unless the hypercapnia can be reversed
within minutes with NIV.241
Hypoxemia is treated with FiO2 augmentation (the lower
the V/Q, the less the effectiveness) and through the recruit-
ment of air spaces with an increase of the transpulmonary
pressure applied at end-expiration. The usual ventilatory
strategy for hypercapnia is to increase minute ventilation,
which should gradually return the PaCO2 toward baseline
values, while the excretion of excess bicarbonate by the kid-
neys is accomplished (on the assumption that chloride is
provided). When the ventilator is used to correct respiratory
acidosis, the end-inspiratory plateau and auto-PEEP pressures
should be monitored routinely to detect any adverse effects
of hyperventilation. An overly rapid reduction in the PaCO2
risks the development of posthypercapnic alkalosis, with
potentially serious consequences. Should posthypercapnic
alkalosis develop, the parameters of the mechanical ventila-
tion must be readjusted immediately in order to reduce the
minute volume. In addition, the alkalosis can be ameliorated
with chloride in the form of sodium or potassium salt with
994 Section V — Renal, Endocrine, and GI Systems
the aim of decreasing the SID. It is always beneficial to reduce
CO2 production. This can be achieved through reduction of
the carbohydrate load in parenteral and enteral nutrition,
through aggressive control of hyperthermia, and through ade-
quate sedation or analgesia in anxious or combative patients.
What alternatives are there for those patients with intractable
hypercapnia? One possible option not yet routinely available
is intratracheal pulmonary ventilation, a method in which
an intratracheal catheter with a reversed continuous flow of
gas at its tip (away from the lungs) facilitates flushing of CO2
from the proximal dead space. Marked reductions in PaCO2,
ranging from 37% to 71%, and improvement in baseline pH
were achieved with this intervention in five moribund neona-
tal and pediatric patients with uncontrollable hypercapnia,242
but major clinical experience is still lacking. Another possible
approach is the extracorporeal removal of CO2. After promis-
ing initial experiences in the adult population, successful pedi-
atric case reports have begun to appear.243
Permissive Hypercapnia
The ultimate treatment for respiratory acidosis is to increase
minute ventilation, a measure that often requires mechanical
ventilation support. Because in many patients with respira-
tory acidosis lung dysfunction already exists, it is usually not
possible to achieve normocapnia values without producing
ventilator-associated lung injury (see also Chapter 51). More
specifically for the critically ill patient with some sort of lung
disease, normalization of the PaCO2 may come at the cost of
volutrauma or barotrauma, that is, the alveolar distension and
collapse cycle that is now known to be associated with tissue
injury, increased microvascular permeability, and lung rup-
ture.112 Thus, the current practice for both adults and children
favors the use of lower tidal volumes (5 to 8 mL/kg or less),
with plateau or peak pressures no higher than 20 cm H2O
above the baseline. With this approach, there is increasing evi-
dence that the lungs may have a better outcome, although a
rise in the PaCO2 may ensue. This controlled hypoventilation
is known as permissive hypercapnia (see also Chapter 52).112,244
A significant body of literature, both clinical and preclinical,
confirms the beneficial effects of hypercapnic acidosis in the
setting of acute lung injury. Therefore the use of permissive
hypercapnia as part of a lung-protective strategy in children
should be accepted, and perhaps even desired, provided it
does not result in significant hemodynamic instability and
there is no coexisting contraindication such as intracranial
hypertension (see the section Does Abnormal pH Harm? in
this chapter).244,245
The “optimal” PaCO2 target has not been determined in
clinical practice. It has been suggested that hypercapnia be
limited to a degree that maintains pH greater than 7.20.244
Hypercapnic acidosis (HCA) seems to be safe at any age, from
preterm newborns to adults.244-248 Small randomized clinical
trials and large amounts of observational data from preterm
infants have demonstrated that permissive hypercapnia does
not increase risk for brain injury, intraventricular hemor-
rhage, and impairment among very low birth weight infants,
with comparable survival rates and sensorineural outcome in
comparison with infants treated with the traditional mechani-
cal ventilation approach. The hypercapnic groups had lower
incidence of bronchopulmonary dysplasia and respiratory
deaths than that reported with conventional treatment.247,248
Permissive hypercapnia in the preterm newborn may also
protect against hypocapnia-induced brain hypoperfusion and
subsequent ventricular leukomalacia.
However, extreme hypercapnia may be associated with an
increased risk of intracranial hemorrhage. It may therefore be
important to avoid large fluctuations in PaCO2 values. It was
found that for infants whose Apgar scores were 4 or less, a
permissive hypercapnea strategy was associated with a higher
risk of intraventricular hemorrhage, whereas for Apgar scores
5 or greater, a permissive hypercapnia strategy was protective.
Although this finding is not conclusive due to methodological
limitations of the study,248 it certainly underscores the need
to individually assess every case for the potential risk versus
benefit of HCA.
In sedated and intubated adults with ARDS, rapid inten-
tional hypoventilation (pH falling from 7.40 to 7.26 in 30 to 60
minutes) lowered systemic vascular resistance and increased
cardiac output, while mean systemic arterial pressure and pul-
monary vascular resistance did not change.249 In children, it
was shown that hypoventilation improves arterial oxygenation
after bidirectional superior cavopulmonary anastomosis.250 In
these patients, moderate hypercapnia with respiratory acidosis
was also shown to reduce oxygen consumption and arterial
lactate levels.
How low can the pH drop? How high can the PaCO2 rise?
Actually, in many studies of adult patients undergoing permis-
sive hypercapnia, a pH well below 7.20 has been tolerated.249
The feared consequences of acidemia, projected from the expe-
rience with patients having lactic acidosis, failed to materialize.
Available data from adults under consented hypoventilation
show that the systemic hemodynamic effects are small, even as
the pH falls to 7.15. Patients whose pH falls below 7.0 are fewer
in number, so firm conclusions cannot be drawn, but they sim-
ilarly seem to tolerate their respiratory acidemia. What is the
limit of hypercapnia for pediatric patients? In a classical report,
supercarbia was defined as PaCO2 150 mm Hg or higher.251 In
that study, the time course to development of maximal PaCO2
(mean, 206 mm Hg) was between 35 minutes and 2 days.
Despite supercarbia, the only pathophysiologic change found
was temporary neurologic depression, without consequences
on the follow-up. Another report described an episode of near-
fatal asthma in which PaCO2 rose to 293 mm Hg,115 with a
pH of 6.77 and a PaO2 of 65 mm Hg. Despite this supercarbia
lasting more than 14 hours, no hemodynamic instability was
seen. This case illustrates the cardiovascular and neurological
tolerance to prolonged supercarbia in a child with previously
healthy cardiovascular and neurological systems. This might
not be the case for the typical scenario of a critically ill child
with multiple system involvement, particularly one with brain
injury, who can tolerate only mild hypercapnia, if any.252 High
levels of PaCO2 may cause increased respiratory drive and
discomfort in the neurologically intact patient, necessitating
heavy sedation and sometimes neuromuscular blockade.
Multiple inflammatory, ischemia-reperfusion, and septic
animal models models have repeatedly demonstrated that
acute HCA may protect against lung and systemic organic
injury independently of ventilator strategy, even when it is
instituted after the initiation of the lung or systemic injury
process.245,249 This protective effect has been associated with:
(1) inhibition of xanthine oxidase and free radical production;
(2) down-regulation of inflammatory cells, as HCA inhibits
the release of tumor necrosis factor-α and interleukin-1 from
stimulated macrophages; and (3) modulation of endothelial

cell and neutrophil expression of interleukin-8, selectins and
intercellular adhesion molecules, attenuating lung neutrophil
recruitment after both ventilator- and endotoxin-induced
ALI. The mechanism underlying the inhibition of cytokine and
chemokine production seems to be mediated, at least partially,
through the inhibition of nuclear factor-κB (NFκB).245,249,253
Benefits of HCA have been demonstrated throughout the
body: (1) attenuation of the stretch component of lung injury;
(2) provision of protective effects on the myocardium, with
better recovery after prolonged cold cardioplegic ischemia,
which attenuates hypoxic/ischemic injury in the immature
brain; (3) protection of the porcine brain from hypoxia/reox-
ygenation-induced injury; (4) modulation of neuronal apop-
tosis, and reduction of lipid peroxidation.245,249 Hypercapnic
acidosis has also been demonstrated to reduce injury initiated
by bacterial endotoxin.253
The antiinflammatory effects of HCA underlie its protective
effects. This powerful antiinflammatory action may reduce
the magnitude of the host inflammatory response, thereby
ameliorating host-induced tissue damage, as it occurs in non-
sepsis models of lung and systemic organ injury.253
However, because immunocompetence is essential to an
effective host response to microbial infection, concern have
been raised with regard to the safety of hypercapnia and/or
respiratory acidosis in the sepsis setting. Hypercapnic acido-
sis produces a broad-based suppression of proinflammatory
events that contribute to microbial killing after phagocytosis,
which could be detrimental to the host by facilitating bacte-
rial spread and replication. In addition, HCA inhibits repair of
pulmonary epithelial wounds,254 a fact that raises the potential
that it could reduce the barrier to access of bacteria from the
lung to the bloodstream. At the present time, evidence from
relevant preclinical studies supports the notion that the ulti-
mate effect of HCA on bacterial injury may vary from ben-
eficial to harmful, depending on the stage of injury process,
that is, depending whether it is an early, an established, or a
prolonged infection.253,255,256
Recent studies suggest that HCA is protective in the earlier
phases of bacterial pneumonia-induced sepsis but may worsen
injury in the setting of prolonged lung sepsis. These findings
are possibly related to the fact that, in the setting of an early
or established bacterial infection, HCA may reduce lung and
systemic organ injury by ameliorating host-induced tissue
damage. In contrast, in late or prolonged bacterial infection, it
is likely that a large bacterial load may exist and hence direct
bacterial tissue invasion and spread may play a greater role
in tissue damage. Therefore antiinflammatory and immuno-
suppressive effects of HCA, particularly neutrophil inhibition,
might impair bactericidal host responses and prevent any pro-
tective effects of reduced host-mediated tissue damage. How-
ever, the use of appropriate antibiotic therapy abolished the
deleterious effects of HCA in prolonged infection, reducing
lung damage and lung bacterial load.253,255,256 In contrast to
the findings in prolonged pulmonary infection, HCA reduced
the severity of early, established, and prolonged systemic sep-
sis. There is evidence that the protective effects of HCA in
acute lung injury are more a function of the acidosis than of
elevated carbon dioxide per se. It has been showed that both
HCA and buffered hypercapnia attenuate the hemodynamic
consequences of systemic sepsis,257 but only HCA, not buff-
ered hypercapnia, reduced the severity of sepsis-induced lung
injury. The conclusion so far is that buffering of HCA seems
Chapter 68 — Acid-Base Balance and Disorders 995
to confer little or no benefit in the setting of experimental sep-
sis and worsens pneumonia-induced lung injury.253,257,258
Therefore buffering HCA is generally not recommended.
If it is decided that a specific patient needs some buffering
for the respiratory acidemia, perhaps for associated hemo-
dynamic depression, then THAM could be more useful than
bicarbonate because it will not increase the PaCO2.259
The common knowledge states that the clinician must
avoid hypercapnia after global cerebral ischemia in order to
prevent secondary brain injury and uncontrolled intracranial
hypertension. In immature animals, however, several studies
consistently report that hypercapnia is neuroprotective after
ischemia. In a recent and elegantly designed animal experi-
ment,260 it was found that mild-to-moderate hypercapnia
(PaCO2 60 to 100 mm Hg) is neuroprotective after transient
global cerebral ischemia/reperfusion injury, with better pro-
tection in the group of animals with moderate hypercapnia
(PaCO2 80 to 100 mm Hg and pH 7.13 ± 0.09). The protective
effect was attributed to the modulation of apoptosis-regulating
proteins. In contrast, severe hypercapnia (PaCO2 100 to 120
mm Hg, pH 7.05 ± 0.1) increased brain injury, which could
potentially be attributed to more pronounced brain edema for-
mation. These results suggests a potential role for therapeutic
HCA after global cerebral ischemia, a potential paradigmatic
change. However, much experimental and preclinical work is
still necessary before a clinical application can be considered.
Respiratory Alkalosis
If alveolar ventilation rises out of proportion to CO2 pro-
duction, then arterial PCO2 falls. For any given rate of CO2
production, an increase in alveolar ventilation always reduces
PCO2. In the ICU environment, hyperventilation occurs in a
number of pathological conditions, including salicylate intoxi-
cation, early sepsis, hypoxic respiratory disorders, hepatic fail-
ure, fever, certain central nervous system alterations, and pain
or anxiety (see Table 68-9). The sole presence of respiratory
alkalosis is a bad prognosis sign, because mortality increases
in direct proportion to the severity of the hypocapnia.261 The
detrimental effects of hypocapnia have been described in many
settings: in premature infants in whom it has been associated
with poor neurological outcome; in children after severe trau-
matic brain injury, in whom a relationship between hypocar-
bia and cerebral ischemia and infarcts have been described261;
and in children after a cardiopulmonary bypass procedure.262
As in acute respiratory acidosis, acute respiratory alkalosis
elicits a secondary change in plasma bicarbonate, which has
two components. The first is the occurrence of a small-to-
moderate acute decrease in the bicarbonate concentration;
this fall is dictated by the Henderson-Hasselbalch equation
(Equations 4 and 5) and is also due to some tissue buffer-
ing.8,261,263 With the persistence of the hypocapnia, the second
component appears: SID will begin to decrease as a result of
renal chloride reabsorption, which is associated with a greater
decrease in bicarbonate and a rise in urine pH.5,9,10 By 48 to
72 hours, SID assumes a new, lower, steady state. This occurs
because renal adaptation to hypocapnia “backtitrates” the
nonbicarbonate buffers, an action that decreases SID and
tends to return pH toward normal values, usually with an
increased chloride serum concentration.5
Usually, blood pH does not exceed 7.55 in most cases of
respiratory alkalosis, and severe manifestations of alkalemia are
996 Section V — Renal, Endocrine, and GI Systems
unusual. Therefore management is directed at the underlying
cause. Marked alkalemia can occur in certain circumstances:
inappropriate mechanical ventilation parameters, central
nervous system disorders, and some psychiatric diseases, not
often seen in children. Typically, mild acid-base changes are
clinically more important for what they can alert the clini-
cian to, in terms of the underlying disease, than for any threat
they may pose to the patient. Accordingly, specific measures
directed to compensate the pH are not usually required. The
anxiety-hyperventilation syndrome, more commonly seen in
adolescents in the emergency department than in the critical
care unit, can be an exception. In such cases, an active thera-
peutic approach with assistance from the hospital’s psycholog-
ical team is required. In rare cases, sedation may be necessary.
Pseudorespiratory Alkalosis
Arterial hypocapnia does not necessarily imply respiratory
alkalosis or the secondary and compensatory response to
metabolic acidosis. The presence of arterial hypocapnia in
patients with profound circulatory shock has been termed
pseudorespiratory alkalosis or, simply, venoarterial carbon
dioxide gradient.124 This condition can be seen when alveolar
ventilation is relatively preserved but profound cardiovascu-
lar depression exists. In such conditions, the severely reduced
pulmonary blood flow limits the CO2 delivered to the lungs
for excretion. On the other hand, the increased ratio of ven-
tilation to perfusion and the increased pulmonary transit
time result in the removal of a larger-than-normal amount
of CO2 per unit of blood traversing the pulmonary circula-
tion.264 Thus, despite decreased CO2 delivery to the lungs, a
situation that provokes a significant elevation of the mixed
venous blood CO2, arterial normocapnia, or frank hypocapnia
may be noted. Overall CO2 excretion is markedly decreased,
however, and the CO2 balance of the body is positive, a phe-
nomenon that is the hallmark of respiratory acidosis. Marked
tissue acidosis is reflected in mixed venous blood acidemia,
usually involving both metabolic and respiratory compo-
nents. The metabolic component derives from tissue hypo-
perfusion and hyperlactatemia. This is accompanied by an
arterial pH that ranges from mildly acidic to frankly alkaline.
This venous-arterial PCO2 gradient increases as cardiac index
decreases.124,264,265 In animal models, both venous-arterial
PCO2 gradient and venous-arterial pH difference increase as
oxygen delivery declines. In septic shock, an elevated venous-
arterial PCO2 gradient is seen in both those patients with low
cardiac output and those with pulmonary disease who can-
not eliminate CO2.266 In patients with cardiogenic shock, the
venous-arterial PCO2 gradient decreases as hemodynamic
variables improve with dobutamine, a phenomenon also seen
in pediatric septic shock with myocardial depression. In this
setting, arterial oxygen saturation may appear to be adequate
despite tissue hypoxemia because of the shift to the left of the
oxygen-hemoglobin dissociation curve caused by hypocapnia.
This condition may be rapidly fatal unless cardiac output is
rapidly corrected.
Mixed Acid-Base Derangements
Coexisting metabolic acidosis and respiratory acidosis can be
seen in several clinical conditions, for example during cardio-
pulmonary arrest, in bronchopulmonary dysplasia complicated
with pneumonia and septic shock, in renal and pulmonary
insufficiency, and as a consequence of certain toxic agents that
may provoke both neural depression (and hypoventilation) and
cardiocirculatory collapse (and metabolic acidosis).10,24,43,51 As
usual, treatment must be targeted to the underlying causes. In
addition, both components of the acid-base derangement must
be addressed. The first step will always be the ABCs: to secure the
airway, to provide oxygenation and controlled hyperventilation,
and to infuse fluids or vasoactive-inotropic agents according to
the clinical condition of the given patient. Administration of an
alkalinizing agent should be considered only after ventilation has
begun and on the basis of results of the arterial blood gas analysis.
Alkalemia of both metabolic and respiratory origin may
occur in several complex settings, such as in patients with
chronic liver disease in whom hyperventilation ensues as
the initial manifestation of pneumonia.267 This hypocapnia
appears in patients in whom metabolic alkalosis is common
because of vomiting or gastric drainage, hypokalemia, diuret-
ics, or alkali administration.43,267 Mixed alkalosis may also
occur in patients with chronic renal insufficiency in whom
primary hypocapnia develops. In this setting, inappropriately
high plasma bicarbonate levels occur as a consequence of the
nonexistent renal adaptive response. This situation is seen
despite the patient’s dialysis program, because the dialytic
procedures exert an alkalinizing influence and are much less
effective in compensating alkalemia than acidemia.226,268 This
effect can be minimized by switching the patient from perito-
neal dialysis to hemodiafiltration or hemodialysis.
Both the physicochemical (SIG and SIDEFF) and the modi-
fied SBE approaches are well suited for unmasking coexisting
mixed acid-based disorders.
Acid-Base Balance in Special
Situations
Hypothermia
Systemic hypothermia is one of the strategies employed for
brain preservation and end-organ protection in global ischemia
scenarios. Hypothermia is routinely applied in cardiopulmo-
nary bypass for cardiac surgery, and thus anesthesiologists deal
with most acid-base derangements during profound hypother-
mia in the operating room (see Chapter 30).269 However, pedi-
atric intensivists need to master these concepts, too; therapeutic
hypothermia may become more widely used in the management
of anoxic neurologic injury, such as after cardiopulmonary
arrest or in traumatic brain injury with intracraneal hyperten-
sion.270,271 Hypothermia has also been applied in adult patients
with large ischemic stroke, and can occur accidently after near-
drowning in ice water, or with other environmental exposures.
As temperature decreases, the dissociation constant (pKa =
−log10Ka) of aqueous systems, such as plasma and cytoplasma,
increases. This results in a reduction in the concentration of
OH− and H+ ions; that is, as temperature drops, H+ decreases,
and pH increases. Hence, the measured pH in an electrochemi-
cally neutral cell at 37° C is 7.40, whereas in an electrochemically
neutral cell at 20° C, the measured pH will be 7.80. Changes in
cellular pH during hypothermia are mediated through PCO2
homeostasis. As temperature decreases, the solubility of CO2
in blood increases, which in turn yields a reduction in PCO2.
For example, if the total CO2 content is held constant, and the
measured PCO2 at 37° C is 40 mm Hg, then the measured PCO2 at
20° C will be 16 mm Hg. This phenomena causes pH to increase

as temperature decreases and electrochemical neutrality is
maintained. When a blood sample is introduced in a blood-gas
analyzer, the sample is warmed to 37° C before measurement.
The values obtained at 37° C are called the temperature-uncor-
rected values. These values are converted by the blood-gas
analyzer to temperature-corrected values (actual patient’s tem-
perature) using a nomogram that accounts for temperature-
induced changes in pH, and in O2 and CO2 solubility. If pH
and PCO2 are measured at 37° C, and then corrected to a lower
temperature, the corrected pH will be higher and the corrected
PCO2 will be lower than the values at 37° C.
Alpha-Stat and pH-Stat
Alpha-stat and pH-stat are acid-base management methods
that directly influence blood flow to the brain and other organs,
and they can both be applied using either corrected or uncor-
rected blood gases. At a patient temperature of 37° C, there is
no difference between alpha-stat and pH-stat management.
The difference between these two strategies becomes apparent
as patient temperature progressively decreases below 37° C, and
is not clinically relevant until patient temperature is around 30°
C and below. Alpha-stat strategy has solid theoretical founda-
tions. It is well known that functions of proteins are critically
dependent on their tertiary and quaternary structures, which in
turn depend on the ionic charges of individual amino acid con-
stituents. Thus, intracellular proteins must have a buffer of their
own to keep a constant ionizing state in spite of pH change. The
imidazole moiety of the amino acid histidine has a pKa that is
similar to pKa of the water, and hence undergoes ionization
with temperature changes in a similar proportion as water. The
portion of the histidine imidazole group that loses a proton,
acting as a buffer to maintain electrical neutrality is designated
alpha-imidazole. Thus while changes in temperature will affect
the degree of dissociation (i.e., pH) of water, the ionization state
of the proteins will remain the same because it will adapt to the
new temperature-influenced pH. Hence, proteins will maintain
their structure and function regardless of the temperature.
According to the alpha-stat hypothesis, alpha-stat manage-
ment is quite simple: electrochemical neutrality is maintained
by keeping pH in the alkalotic range in temperature-corrected
blood gases and normal in temperature-uncorrected gases. For
practical purposes, it is easier to use uncorrected gases and make
any necessary adjustment in order to keep pH at 7.4 and PaCO2
at 40 mm Hg at 37° C, regardless of the patient’s body tempera-
ture. On the contrary, in the pH-stat approach, interventions
are directed toward maintaining pH 7.4 and PaCO2 40 mm Hg,
irrespective of patient’s core body temperature. This means that
the goal is to keep pH and PCO2 at normal values for 37° C
when the patient’s body-temperature-corrected gases are used,
and at acidotic values when temperature-uncorrected gases are
used. For practical purposes, pH-stat is maintained by adding
CO2 to the ventilating gas during hypothermic cardiopulmo-
nary bypass to increase PCO2 and decrease the pH. In contrast
to alpha-stat approach, in which CO2 content is held constant,
pH-stat regulation results in an increase in total CO2 content.
There is still debate as to whether pH-stat or alpha-stat
management should be used during deep hypothermia and
circulatory arrest in neonates, infants, and children. Based
on the theoretical advantages of maintaining electrochemical
neutrality during hypothermia, in the early 1980s, the strat-
egy at Boston Children’s Hospital switched from pH-stat
Chapter 68 — Acid-Base Balance and Disorders 997
management to alpha-stat management. Within a short period,
the incidence of severe neurologic injury in the form of cho-
reoathetosis increased markedly following procedures under
deep hypothermia cardiac arrest.269,272 After this negative
experience and the clinical trial that resulted from it, and on
the basis of other preclinical and clinical data, the current best
evidence suggests that the best technique to follow in the acid-
base management of patients undergoing deep hypothermic
circulatory arrest during cardiac surgery is dependent upon
the age of the patient, with better results using pH-stat in the
pediatric patient and alpha-stat in the adult patient.272,273 This
is not surprising, as the mechanisms of cerebral injury between
adults and young children are quite different. Intraoperative
cerebral injury in adults primarily relates to atheromatous
emboli or fixed vascular stenoses. In contrast, in neonates
and infants, brain injury more commonly results from global
hypoperfusion. There are no studies assessing the age in which
the switch from pH-stat to alpha-stat approach should occur,
nor which type of acid balance management should be used in
other scenarios in which therapeutic hypothermia is applied.
Summary
When one approaches a critically ill child with an acid-base
imbalance, the first step is to define the nature of the disorder:
acidosis versus alkalosis, acidemia versus alkalemia, simple
versus mixed, acute versus chronic, severe and harmful versus
neither severe nor harmful. The available tools for answering
these questions are numerous. The easiest way to screen the
acid-base status is to take a glimpse at venous bicarbonate (or
CO2TOT) concentration. However, a normal concentration (22
to 26 mEq/L) does not rule out the possibility of an acid-base
derangement. So, if the clinical setting raises the suspicion of an
illness known to be associated with acid-base imbalances, at the
very least plasma electrolyte concentrations must be obtained,
along with albumin levels, to calculate the AGCORR. If bicarbon-
ate (or CO2TOT) or AGCORR is abnormal, or a complex, poten-
tially harmful, mixed acid-base disorder is suspected, an arterial
blood analysis must be done, which will provide information
on pH, Paco2, and SBE. The classical bicarbonate-centered
observational patterns must be applied. If available, lactate lev-
els must be obtained too. This is mandatory if metabolic acido-
sis exists (with or without acidemia). If there is the suspicion of
the presence of unmeasured anions and/or a mixed acid-base
problem, it is advisable to calculate SIDAPP, SIDEFF, and SIG, to
delve deeper into the possible pathophysiological mechanisms
underlying the acid-base unbalance. Care must be taken to
review the patient’s history for hemodynamic resuscitation with
large volumes of normal saline solutions. If that is the case, spe-
cial attention must be given to chloride levels and to analyzing
the effect of the different components of acid-base physiology
on SBE (“partitioned SBE”). The severity, potential harm of the
acid-base derangement, and probable therapeutic intervention
must be all defined. There is compelling evidence that abnormal
pH by itself may not be as dangerous as once thought. However,
an individualized approach must be taken in order to decide if a
given patient has the chance of benefit or not from the attempt
to modify his/her pH and acid-base status.
References are available online at http://www.expertconsult.
com.