1. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
8 CRITICAL CARE 8 ACID-BASE DISORDERS — 1
8 ACID-BASE DISORDERS
John A. Kellum, M.D., and Juan Carlos Puyana, M.D., F.A.C.S.
Anticipation and early identification of conditions that alter the There are three mathematically independent determinants of
body’s ability to compensate for acid-base disorders are vital in the blood pH: (1) the SID, defined as the difference in concentration
management of surgical and critically ill patients. A clear under- between strong cations (e.g., sodium [Na+] and potassium [K+])
standing of metabolic-respiratory interactions and a systematic and strong anions (e.g., chloride [Cl–] and lactate); (2) the total
approach aimed at identifying the separate components of acid- concentration of weak acids (Atot), mainly consisting of albumin
base disorders not only serves as a diagnostic tool but also helps in and phosphate; and (3) PCO2. These three variables, and only
formulating therapeutic interventions. For example, abnormal these three, can independently affect plasma pH. The H+ and
acid-base balance may be harmful in part because of the patient’s HCO3– concentrations are dependent variables whose values in
response to the abnormality, as when a spontaneously breathing plasma are determined by the SID, Atot, and PCO2. Changes in the
patient with metabolic acidosis attempts to compensate by plasma H+ concentration occur as a result of changes in the dis-
increasing minute ventilation. Such a response may lead to respi- sociation of water and Atot, brought about by the electrochemical
ratory muscle fatigue with respiratory failure or diversion of blood forces generated by changes in the SID and PCO2. The SBE is
flow from vital organs to the respiratory muscles, eventually mathematically equivalent to the difference between the current
resulting in organ injury.The increased catecholamine levels asso- SID and the SID required to restore the pH to 7.4, given a PCO2
ciated with acidemia may provoke cardiac dysrhythmias in criti- of 40 mm Hg and the prevailing Atot.Thus, an SBE of −10 mEq/L
cally ill patients or increase myocardial oxygen demand in patients means that the SID is 10 mEq less than the value required to
with myocardial ischemia. In such cases, it may be prudent not achieve a pH of 7.4.
only to treat the underlying disorder but also to provide sympto- The essential element of this physicochemical approach is the
matic treatment for the acid-base disorder itself. Accordingly, it is emphasis on independent and dependent variables. Only changes
important to understand both the causes of acid-base disorders in the independent variables can bring about changes in the
and the limitations of various treatment strategies. dependent variables. That is, movement of H+ or HCO3– cannot
To treat acid-base disorders, it is not sufficient simply to return affect plasma H+ or HCO3– concentrations unless changes in the
one or two laboratory parameters to normal values; one must SID, Atot, or PCO2 also occur. Several reviews of this approach are
understand the overall course of the disorder, as well as the spe- available in the literature.3-9 In what follows, we discuss the clini-
cific forces involved at any particular time. For example, in a cal application of this approach to the diagnosis and treatment of
patient with acute lung injury and moderate hypercapnia, allowing individual acid-base disorders.
mild acidemia may be preferable to forcing the lung to achieve a
ASSESSMENT OF ACID-BASE BALANCE
normal carbon dioxide tension (PCO2). Similarly, prescribing bicar-
bonate therapy without anticipating the effects on the body’s own Acid-base homeostasis is defined by the plasma pH and by the
compensatory efforts may induce an unwanted rebound alkalemia. conditions of the acid-base pairs that determine it. Normally, arte-
A comprehensive understanding of the pathophysiology and a rial plasma pH is maintained between 7.35 and 7.45. Because
practical approach to bedside evaluation are complementary com- blood plasma is an aqueous solution containing both volatile acids
ponents of care and are equally necessary in the management of an (e.g., CO2) and fixed acids, its pH is determined by the net effects
acid-base disorder. of all these components on the dissociation of water. The deter-
minants of blood pH can be grouped into two broad categories,
respiratory and metabolic. Respiratory acid-base disorders are dis-
General Principles orders of PCO2; metabolic acid-base disorders comprise all other
conditions affecting pH, including disorders of both weak acids
DESCRIPTION AND CLASSIFICATION OF ACID-BASE DISORDERS
(often referred to as buffers, though the term is imprecise) and
There are three widely accepted methods of describing and strong acids (organic and inorganic) and bases. Any of the follow-
classifying acid-base abnormalities. Essentially, they differ from ing indicators serves to identify an acid-base disorder:
one another only with respect to assessment of the metabolic com-
1. An abnormal arterial blood pH (pH < 7.35 signifies acide-
ponent of the abnormality; all three treat PCO2 as an independent
mia; pH > 7.45 signifies alkalemia).
variable.The first method quantifies the metabolic component by
2. An arterial PCO2 (PaCO2) that is outside the normal range
using the bicarbonate ion (HCO3–) concentration (in the context
(35 to 45 mm Hg).
of PCO2); the second, by using the standard base excess (SBE);
3. A plasma HCO3– concentration that is outside the normal
and the third, by using the strong ion difference (SID). In prac-
range (22 to 26 mEq/L).
tice, these three methods yield virtually identical results when
4. An arterial SBE that is either abnormally high (≥ 3 mEq/L)
employed to quantify the acid-base status of a given blood sam-
or abnormally low (≤ −3 mEq/L).
ple.1-4 Thus, the only significant distinctions between the methods
are conceptual ones, related to how each one approaches the Once identified, an acid-base disorder can be classified accord-
understanding of the mechanism of the disorder.5-7 In this chap- ing to a simple set of rules [see Table 1]. A disorder that does not fit
ter, we emphasize the physicochemical determinants of pH in the well into the broad categories established by these rules can be
blood and the tissues; however, it is a simple matter to convert considered a mixed (or complex) disorder. Some of the basic cat-
from one approach to the other if desired. egories can be further divided into various subcategories (see

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8 CRITICAL CARE 8 ACID-BASE DISORDERS — 2
Table 1—Differentiation of Acid-Base Disorders6
Physicochemical Parameter
Disorder
HCO3– Concentration (mEq/L) PCO2 (mm Hg) SBE (mEq/L)
= (1.5 × HCO3-) + 8
Metabolic acidosis < 22 < –5
= 40 + SBE
= (0.7 × HCO3-) + 21
Metabolic alkalosis > 26 > +5
= 40 + (0.6 × SBE)
Acute respiratory acidosis = [(Pco2 – 40)/10] + 24 > 45 =0
Chronic respiratory acidosis = [(Pco2 – 40)/3] + 24 > 45 = 0.4 × (Pco2 – 40)
Acute respiratory alkalosis = 24 – [(40 – Pco2)/5] < 35 =0
Chronic respiratory alkalosis = 24 – [(40 – Pco2)/2] < 35 = 0.4 × (Pco2 – 40)
SBE—standard base excess
below), but before the issue of classification is addressed in detail, according to the ions that are responsible (e.g., lactic acidosis and
three general caveats must be considered. chloride-responsive alkalosis).
First, interpretation of arterial blood gas values and blood It is important to recognize that metabolic acidosis is caused by
chemistries depends on the reliability of the data. Advances in a decrease in the SID, which produces an electrochemical force
clinical chemistry have improved the sensitivity of instruments that acts to increase the free H+ concentration. A decrease in the
used to measure electrolyte concentrations (e.g. ion-specific elec- SID may be brought about by the generation of organic anions
trodes) and have greatly enhanced the speed and ease of analysis. (e.g., lactate and ketones), by the loss of cations (as with diarrhea),
Inevitably, however, prolonged exposure to the atmosphere results by the mishandling of ions (as with renal tubular acidosis), or by
in a lowering of the PCO2, and over time, there may be ongoing the addition of exogenous anions (as with iatrogenic acidosis or
cellular metabolism. Accordingly, prompt measurement is always poisoning). By contrast, metabolic alkalosis is caused by an inap-
advisable. Even with prompt measurement, laboratory errors may propriately large SID (though it may be possible for the SID to be
occur, and information may be incorrectly reported. Samples inappropriately large without exceeding the normal range of 40 to
drawn from indwelling lines may be diluted by fluid or drug infu- 42 mEq/L). An increase in the SID may be brought about by the
sions (a notorious source of error). When the situation is confus- loss of more strong anions than strong cations (as with vomiting
ing, it is usually best to repeat the measurement. or diuretic therapy) or, in rare instances, by the administration of
Second, interpretation of arterial blood gas values may be prob- more strong cations than strong anions (as with transfusion of
lematic in patients with severe hypothermia (e.g., trauma patients large volumes of banked blood containing sodium citrate).
undergoing damage-control interventions, who often are severely Because metabolic acid-base disorders are caused by changes
hypothermic and sometimes experience severe acidosis), in that in the SID, their treatment necessarily involves normalization of
the findings may not reflect the actual blood gas values present. the SID. Metabolic acidoses are corrected by increasing the plas-
Because blood samples are “normalized” to a temperature of 37° ma Na+ concentration more than the plasma Cl– concentration
C before undergoing analysis, the results obtained in samples (e.g., by administering NaHCO3), and metabolic alkaloses are
from a patient whose body temperature is significantly lower than corrected by replacing lost Cl– (e.g., by giving sodium chloride
37° C may not be sufficiently accurate. To obviate this potential [NaCl], potassium chloride [KCl], or even hydrochloric acid
problem, the results may have to be adjusted to take the patient’s [HCl]). So-called chloride-resistant metabolic alkaloses [see
actual temperature into account. At present, however, such tem- Metabolic Alkalosis, Chloride-Resistant Alkalosis, below] are resis-
perature correction is not routinely done, and there has been tant to chloride administration only because of ongoing renal Cl–
some controversy regarding whether it has real clinical value.10,11 loss that increases in response to increased Cl– replacement (as
Third, whereas the aforementioned four indicators are useful with hyperaldosteronism).
for identifying an acid-base disorder, the absence of all four does
PATHOPHYSIOLOGY
not suffice to exclude a mixed acid-base disorder (i.e., alkalosis
plus acidosis) in which the two components are completely Disorders of metabolic acid-base balance occur in one of three
matched. Fortunately, such conditions are rare. In addition, apart ways: (1) as a result of dysfunction of the primary regulating
from distinguishing a respiratory acid-base disorder from a meta- organs, (2) as a result of exogenous administration of drugs or flu-
bolic acid-base disorder, the four indicators and the rules previ- ids that alter the body’s ability to maintain normal acid-base bal-
ously mentioned [see Table 1] provide no information on the ance, or (3) as a result of abnormal metabolism that overwhelms
mechanism of an acid-base disorder. the normal defense mechanisms. The organ systems responsible
for regulating the SID in both health and disease are the renal sys-
tem and, to a lesser extent, the gastrointestinal tract.
Metabolic Acid-Base Disorders
Metabolic acid-base derangements are produced by a signifi- Renal System
cantly greater number of underlying disorders than respiratory Plasma flows to the kidneys at a rate of approximately 600
disorders are, and they are almost always more difficult to treat. ml/min. The glomeruli filter the plasma, producing filtrate at a
Traditionally, metabolic acidoses and alkaloses are categorized rate of 120 ml/min.The filtrate, in turn, is processed by reabsorp-

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8 CRITICAL CARE 8 ACID-BASE DISORDERS — 3
Gastrointestinal Tract
tion and secretion mechanisms in the tubular cells along which it
passes on its way to the ureters. Normally, more than 99% of the The GI tract is an underappreciated component of acid-base
filtrate is reabsorbed and returned to the plasma.Thus, the kidney balance. In different regions along its length, the GI tract handles
can excrete only a very small amount of strong ion into the urine strong ions quite differently. In the stomach, Cl– is pumped out of
each minute, which means that several minutes to hours are the plasma and into the lumen, thereby reducing the SID of the
required to make a significant impact on the SID. gastric juice and thus the pH as well. On the plasma side, the SID
The handling of strong ions by the kidney is extremely impor- is increased by the loss of Cl–, and the pH rises, producing the so-
tant because every chloride ion that is filtered but not reabsorbed called alkaline tide that occurs at the beginning of a meal, when
reduces the SID. Most of the human diet contains similar ratios gastric acid secretion is maximal.15
of strong cations to strong anions, and thus, there is usually suf- In the duodenum, Cl– is reabsorbed and the plasma pH restored.
ficient Cl– available for renal Cl– handling to be the primary reg- Normally, only slight changes in plasma pH are evident because Cl–
ulating mechanism. Given that renal Na+ and K+ handling is is returned to the circulation almost as soon as it is removed. If,
influenced by other priorities (e.g., intravascular volume and however, gastric secretions are removed from the patient, whether by
plasma K+ homeostasis), it is logical that so-called acid handling catheter suctioning or vomiting, Cl– will be progressively lost and
by the kidney is generally mediated through management of the the SID will steadily increase. It is important to remember that it is
Cl– balance. the loss of Cl–, not of H+, that determines the plasma pH. Although
Traditional approaches to the question of renal acid handling H+ is lost as HCl, it is also lost with every molecule of water
have focused on H+ excretion, emphasizing the importance of removed from the body. When Cl–, a strong anion, is lost without
ammonia (NH3) and its add-on cation, ammonium (NH4+). the corresponding loss of a strong cation, the SID is increased, and
However, H+ excretion per se is irrelevant, in that water provides an therefore, the plasma H+ concentration is decreased. When H+ is
essentially infinite source of free H+. Indeed, the kidney does not lost as water rather than as HCl, the SID does not change, and
excrete H+ to any greater degree in the form of NH4+ than in the thus, the plasma H+ concentration does not change either.
form of H2O.The purpose of renal ammoniagenesis is to allow the The pancreas secretes fluid into the small intestine that pos-
excretion of Cl– without Na+ or K+. This purpose is achieved by
sesses an SID much higher than the plasma SID and is very low
supplying a weak cation (NH4+) that is “coexcreted” with Cl–.The
in Cl–. Thus, the plasma perfusing the pancreas has its SID
mechanisms of renal tubular acidosis are currently being reinter-
decreased, a phenomenon that peaks about 1 hour after a meal
preted by some authors in the light of a growing body of evidence
and helps counteract the alkaline tide. If large amounts of pancre-
showing that abnormal chloride conductance, rather than H+ or
atic fluid are lost (e.g., as a consequence of surgical drainage), the
HCO3 handling per se, is responsible for these disorders.3
resulting decrease in the plasma SID will lead to acidosis.
Kidney-Liver Interaction In the large intestine, the fluid also has a high SID, because most
of the Cl– was removed in the small intestine and the remaining
The importance of NH4+ to systemic acid-base balance, then,
electrolytes consist mostly of Na+ and K+. Normally, the body
rests not on its carriage of H+ or its direct action in the plasma
(normal plasma NH4+ concentration < 0.01 mEq/L) but on its reabsorbs much of the water and electrolytes from this fluid, but
coexcretion with Cl–. Of course, production of NH4+ is not when severe diarrhea occurs, large amounts of cations may be lost.
restricted to the kidney. Hepatic ammoniagenesis (as well as glut- If this cation loss persists, the plasma SID will decrease and aci-
aminogenesis) is also important for systemic acid-base balance, dosis will result.
and as expected, it is tightly controlled by mechanisms sensitive to In addition to the acid-base effects of abnormal loss of strong
plasma pH.12 Indeed, this reinterpretation of the role of NH4+ in ions from the GI lumen, the small intestine, in particular, may
acid-base balance is supported by the evidence that hepatic gluta- contribute strong ions to the plasma. This contribution is most
minogenesis is stimulated by acidosis.13 Metabolism of nitrogen by apparent when mesenteric blood flow is compromised and lactate
the liver can yield urea, glutamine, or NH4+. Normally, the liver is produced, sometimes in large quantities. Although global
releases only a very small amount of NH4+, incorporating most of hypoperfusion may compromise the mesentery, the intestine does
its nitrogen into either urea or glutamine. Hepatocytes have not appear to be a source of lactic acid in patients resuscitated
enzymes to enable them to produce either of these end products, from a septic state [see Metabolic Acidosis, Positive–Anion Gap
and both allow regulation of plasma NH4+ at suitably low levels. Acidosis, Lactic Acidosis, below].16 Moreover, whether the GI tract
At the level of the kidneys, however, the production of urea or glu- is capable of regulating strong ion uptake in a compensatory fash-
tamine has significantly different effects, in that the kidneys use ion has not been well studied.There is some evidence that the gut
glutamine to generate NH4+ and facilitate the excretion of Cl–. may modulate systemic acidosis in experimental endotoxemia by
Thus, production of glutamine by the liver can be seen as having removing anions from the plasma17; however, the full capacity of
an alkalinizing effect on plasma pH because of the way in which the gut to affect acid-base balance remains to be determined.
the kidneys use this substance.
METABOLIC ACIDOSIS
Further support for this scenario comes from the discovery that
hepatocytes are anatomically organized according to their enzy- Traditionally, metabolic acidoses are categorized according to
matic content.14 Hepatocytes with a propensity to produce urea the presence or absence of unmeasured anions. These unmea-
are positioned closer to the portal venule; those with a propensity sured anions are routinely detected by examining the plasma elec-
to produce glutamine are positioned farther downstream. The trolytes and calculating the anion gap (AG) (see below). The dif-
upstream (urea-producing) hepatocytes have the first chance at ferential diagnosis for a positive-AG acidosis includes various
the NH4+ delivered. However, acidosis inhibits ureagenesis, there- common and rare causes [see Table 2]. Generally speaking, non-
by leaving more NH4+ available for the downstream (glutamine- AG acidoses can be divided into three types: renal, gastrointesti-
producing) hepatocytes. The leftover NH4+ is thus, in a sense, nal, and iatrogenic [see Table 3]. In the ICU, the most common
packaged as glutamine for export to the kidney, where it is used to types of metabolic acidosis are lactic acidosis, ketoacidosis, iatro-
facilitate Cl– excretion. genic acidosis, and acidosis secondary to toxins.

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8 CRITICAL CARE 8 ACID-BASE DISORDERS — 4
Table 2 Causes of Positive–Anion Gap Acidosis is set at 40 mm Hg, but the SBE is not corrected for abnormali-
ties in Atot. In many hypoalbuminemic patients, Atot is lower than
Renal failure normal, and thus, the SID at the equilibrium point will be less
Elevated ketone levels (ketoacidosis) than 40 mEq/L. Also, it is rare that the choice would be made to
Common causes
Elevated lactate levels (lactic acidosis) correct the acid-base abnormality completely. Therefore, the tar-
Toxins (methanol, ethylene glycol, salicylate, get SID should be used as a reference value, but in most cases,
paraldehyde, toluene)
partial correction is all that is required.
Sepsis
If increasing the plasma Na+ concentration is inadvisable for
Dehydration other reasons (e.g., hypernatremia), NaHCO3 administration is
Alkalemia inadvisable. It is noteworthy that NaHCO3 administration has not
Decreased concentrations of unmeasured cations been shown to improve outcome in patients with lactic acidosis.21
Rare causes (Mg2+, K+, Ca2+)
Sodium salts (lactate, citrate, acetate, penicillin, In addition, NaHCO3 administration is associated with certain
carbenicillin) disadvantages. Large (hypertonic) doses, if given rapidly, may
Rhabdomyolysis actually reduce blood pressure22 and may cause sudden, severe
increases in PaCO2.23 Accordingly, it is important to assess the
patient’s ventilatory status before NaHCO3 is administered, par-
Even extreme acidosis appears to be well tolerated by healthy
ticularly if the patient is not on a ventilator. NaHCO3 infusion also
persons, particularly when the duration of the acidosis is short. For
affects serum K+ and Ca2+ concentrations, which must be moni-
example, healthy individuals may achieve an arterial pH lower
tored closely.
than 7.15 and a lactate concentration higher than 20 mEq/L dur-
To avoid some of the disadvantages of NaHCO3 therapy, alter-
ing maximal exercise, with no lasting effects.18 Over the long term,
native therapies for metabolic acidosis have been developed.
however, even mild acidemia (pH < 7.35) may lead to metabolic
Carbicarb is an equimolar mixture of sodium carbonate (Na2CO3)
bone disease and protein catabolism. Furthermore, critically ill
patients may not be able to tolerate even brief episodes of and NaHCO3.24 Like NaHCO3, carbicarb works by increasing the
acidemia.19 There do appear to be significant differences between plasma Na+ concentration, except that it does not raise the PCO2.
metabolic and respiratory acidosis with respect to patient out- Results with carbicarb in animal studies have been mixed,25 and
come, and these differences suggest that the underlying disorder experience in humans is extremely limited.
may be more important than the absolute degree of acidemia.20 THAM (tris-hydroxymethyl aminomethane) is a synthetic
If prudence dictates that symptomatic therapy is to be provid- buffer that consumes CO2 and readily penetrates cells.26 It is a
ed, the likely duration of the disorder should be taken into weak base (pK = 7.9) and, as such, is unlike other plasma con-
account. When the disorder is expected to be a short-lived one stituents. The major advantage of THAM is that it does not alter
(e.g., diabetic ketoacidosis), maximizing respiratory compensation the SID, which means that there is no need to be concerned about
is usually the safest approach. Once the disorder resolves, ventila- having to increase the plasma Na+ concentration to achieve a ther-
tion can be quickly reduced to normal levels, and there will be no apeutic effect. Accordingly, THAM is often used in situations
lingering effects from therapy. If the SID is increased (e.g., by where NaHCO3 cannot be used because of hypernatremia.
administering NaHCO3), there is a risk of alkalosis when the Although THAM has been available since the 1960s, there is sur-
underlying disorder resolves. When the disorder is likely to be a prisingly little information available regarding its efficacy in
more chronic one (e.g., renal failure), therapy aimed at restoring humans with acid-base disorders. In small uncontrolled studies,
the SID to normal is indicated. In all cases, the therapeutic target THAM appears to be capable of reversing metabolic acidosis sec-
can be accurately determined from the SBE. As noted (see above), ondary to ketoacidosis or renal failure without causing obvious
the SBE corresponds to the amount by which the current SID dif- toxicity27; however, adverse reactions have been reported, includ-
fers from the SID necessary to restore the pH to 7.4, given a PCO2 ing hypoglycemia, respiratory depression, and even fatal hepatic
of 40 mm Hg. Thus, if the SID is 30 mEq/L and the SBE is −10 necrosis, when concentrations exceeding 0.3 mol/L are used. In
mEq/L, the target SID is 40 mEq/L. Accordingly, the plasma Na+ Europe, a mixture of THAM, acetate, NaHCO3, and disodium
concentration would have to increase by 10 mEq/L for NaHCO3 phosphate is available. This mixture, known as tribonate
administration to correct the acidosis completely. (Tribonat; Pharmacia & Upjohn, Solna, Sweden), seems to have
It should be noted that the target SID is the SID at the equilib- fewer side effects than THAM alone does, but as with THAM,
rium point between the SID, PCO2, and Atot and that it may not be experience with its use in humans is still quite limited.
equal to 40 mEq/L, as in the example given. By convention, PCO2
Anion Gap
Determination of anion gap The AG has been used by
Table 3—Differential Diagnosis for clinicians for more than 30 years and has evolved into a major tool
for evaluating acid-base disorders.28 It is calculated—or, rather,
Normal–Anion Gap Metabolic Acidosis
estimated—from the difference between the routinely measured
concentrations of serum cations (Na+ and K+) and the routinely
Urine SID > 0 mEq/L Renal tubular acidosis measured concentrations of anions (Cl– and HCO3–). Normally,
GI condition albumin accounts for the bulk of this difference, with phosphate
Diarrhea playing a lesser role. Sulfate and lactate also contribute a small
Urine SID < 0 mEq/L Pancreatic or small bowel drainage amount to the gap (normally, < 2 mEq/L); however, there are also
Iatrogenesis unmeasured cations (e.g., Ca2+ and Mg2+), which tend to offset
Parenteral nutrition the effects of sulfate and lactate except when the concentration of
Saline either one is abnormally increased. Plasma proteins other than
SID—strong ion difference albumin can be either positively or negatively charged, but in the

5. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
8 CRITICAL CARE 8 ACID-BASE DISORDERS — 5
aggregate, they tend to be electrically neutral,29 except in rare pH. These concerns have led some authors to advocate adjusting
cases of abnormal paraproteins (as in multiple myeloma). In prac- the normal AG range on the basis of the patient’s albumin35 or
tice, the AG is calculated as follows: even phosphate6 concentration. Each 1 g/dl of albumin carries a
+ + – – charge of 2.8 mEq/L at a pH of 7.4 (2.3 mEq/L, pH = 7.0; 3.0
AG = (Na + K ) – (Cl + HCO3 ) mEq/L, pH = 7.6), and each 1 mg/dl of phosphate carries a charge
Because of its low extracellular concentration, K+ is often omit- of 0.59 mEq/L at a pH of 7.4 (0.55 mEq/L, pH = 7.0; 0.61
ted from the calculation. In most laboratories, normal values fall mEq/L, pH = 7.6). Thus, the normal AG for a given patient can
into the range of 12 ± 4 mEq/L (if K+ is considered) or 8 ± 4 be conveniently estimated as follows6:
mEq/L (if K+ is not considered). In the past few years, the intro-
duction of more accurate methods of measuring Cl– concentra- Normal AG = 2(albumin [g/dl]) + 0.5(phosphate [mg/dl])
tion has led to a general lowering of the normal AG range.30,31 or, in international units,
Because of the various measurement techniques employed at var-
ious institutions, however, each institution is expected to report its Normal AG = 0.2(albumin [g/L]) +
own normal AG values. 1.5(phosphate [mmol/L])
Clinical utility of anion gap The primary value of the AG In one study, when this formula for calculating a patient-spe-
is that it quickly and easily limits the differential diagnosis in a cific normal AG range was used to determine the presence of
patient with metabolic acidosis. When the AG is increased, the unmeasured anions in the blood of critically ill patients, its accu-
explanation is almost invariably one of the following five disorders: racy was 96%, compared with an accuracy of 33% with the rou-
ketosis, lactic acidosis, poisoning, renal failure, and sepsis.32 tine AG (normal range = 12 mEq/L).6 This technique should be
In addition to these disorders, however, there are several condi- employed only when the pH is less than 7.35; even in this situa-
tions that can alter the accuracy of AG estimation and are partic- tion, it is only accurate within 5 mEq/L. When more accuracy is
ularly frequent in critical illness.33,34 Dehydration increases the needed, a slightly more complicated method of estimating unmea-
concentrations of all of the ions. Severe hypoalbuminemia lowers sured anions is required.42,46
the AG, with each 1 g/dl decline in the serum albumin reducing
the apparent AG by 2.5 to 3 mEq/L; accordingly, some recom- Strong anion gap Another alternative to relying on the tra-
mend adjusting the AG for the prevailing albumin concentra- ditional AG is to use a parameter derived from the SID. By defin-
tion.35 Alkalosis (respiratory or metabolic) is associated with an ition, the SID must be equal and opposite to the sum of the neg-
increase of as much as 3 to 10 mEq/L in the apparent AG as a ative charges contributed by A– and total CO2. This latter value
consequence of enhanced lactate production (from stimulated (A– + total CO2) has been termed the effective SID (SIDe).29 The
phosphofructokinase enzymatic activity), reduction in the con- apparent SID (SIDa) is obtained by measuring concentrations of
centration of ionized weak acids (A–)(as opposed to Atot, the total each individual ion.The SIDa and the SIDe should both equal the
concentration of weak acids), and, possibly, the additional effect of true SID. If the SIDa differs from the SIDe, unmeasured ions
dehydration (which, as noted, has its own impact on AG calcula- must be present. If the SIDa is greater than the SIDe, these
tion). A low Mg2+ concentration with associated low K+ and Ca2+ unmeasured ions are anions; if the SIDa is less than the SIDe, they
concentrations is a known cause of an increased AG, as is the are cations. The difference between the SIDa and the SIDe has
administration of sodium salts of poorly reabsorbable anions (e.g., been termed the strong ion gap (SIG) to distinguish it from the
β-lactam antibiotics).36 Certain parenteral nutrition formulations AG.42 Unlike the AG, the SIG is normally 0 and is not affected by
(e.g., those containing acetate) may increase the AG. In rare cases, changes in the pH or the albumin concentration.
citrate may have the same effect in the setting of multiple blood
transfusions, particularly if massive doses of banked blood are Positive–Anion Gap Acidosis
used (as during liver transplantation).37 None of these rare caus- Lactic acidosis In many forms of critical illness, lactate is
es, however, will increase the AG significantly,38 and they usually the most important cause of metabolic acidosis.47 Lactate con-
are easily identified. centrations have been shown to correlate with outcomes in
In the past few years, some additional causes of an increased patients with hemorrhagic48 and septic shock.49 Traditionally, lac-
AG have been reported.The nonketotic hyperosmolar state of dia- tic acid has been viewed as the predominant source of the meta-
betes has been associated with an increased AG that remains bolic acidosis that occurs in sepsis.50 In this view, lactic acid is
unexplained.39 Unmeasured anions have been reported in the released primarily from the musculature and the gut as a conse-
blood of patients with sepsis,40,41 patients with liver disease,42,43 quence of tissue hypoxia, and the amount of lactate produced is
and experimental animals that received endotoxin.44 These anions believed to correlate with the total oxygen debt, the magnitude of
may be the source of much of the unexplained acidosis seen in hypoperfusion, and the severity of shock.47 This view has been
patients with critical illness.45 challenged by the observation that during sepsis, even in profound
The accepted clinical utility of the AG notwithstanding, doubt shock, resting muscle does not produce lactate. Indeed, various
has been cast on its diagnostic value in certain situations.33,41 studies have shown that the musculature may actually consume
Some investigators have found routine reliance on the AG to be lactate during endotoxemia.16,51,52
“fraught with numerous pitfalls.”33 The primary problem with the The data on lactate release by the gut are less clear.There is lit-
AG is its reliance on the use of a supposedly normal range pro- tle question that the gut can release lactate if it is underperfused.
duced by albumin and, to a lesser extent, phosphate. Concentra- It appears, however, that if the gut is adequately perfused, it does
tions of albumin and phosphate may be grossly abnormal in not release lactate during sepsis. Under such conditions, the
patients with critical illness, and these abnormalities may change mesentery either is neutral with respect to lactate release or takes
the normal AG range in this setting. Moreover, because these up lactate.16,51 Perfusion is likely to be a major determinant of
anions are not strong anions, their charge is altered by changes in mesenteric lactate metabolism. In a canine model of sepsis

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8 CRITICAL CARE 8 ACID-BASE DISORDERS — 6
induced by infusion of endotoxin, production of lactate by the gut Table 4 Mechanisms Associated with Increased
could not be demonstrated when flow was maintained with Serum Lactate Concentration
dopexamine.52
Both animal studies and human studies have shown that the
Hypodynamic shock
lung may be a prominent source of lactate in the setting of acute Tissue hypoxia
Organ ischemia
lung injury.16,53,54 These studies do not address the underlying
pathophysiologic mechanisms of hyperlactatemia in sepsis, but Increased aerobic glycolysis
they do suggest that the conventional wisdom regarding lactate as Hypermetabolism Increased protein catabolism
evidence of tissue dysoxia is, at best, an oversimplification. Indeed, Hematologic malignancies
many investigators have begun to offer alternative explanations for Hepatic failure
Decreased clearance of lactate
the development of hyperlactatemia in this setting [see Table 4].54-58 Shock
One proposed mechanism is metabolic dysfunction from mito-
Thiamine deficiency
chondrial enzymatic derangements, which can and do lead to lac- Inhibition of pyruvate dehydrogenase
?Endotoxin
tic acidosis. In particular, pyruvate dehydrogenase (PDH), the
enzyme responsible for moving pyruvate into the Krebs cycle, is ?Activation of inflammatory cells
inhibited by endotoxin.59 Current data, however, suggest that
increased aerobic metabolism may be more important than meta-
bolic defects or anaerobic metabolism. In a 1996 study, produc- There are two possible explanations for these observations. First,
tion of glucose and pyruvate and oxidation were increased in if lactate is added to the plasma, not as lactic acid but rather as the
patients with sepsis.60 Furthermore, when PDH was stimulated by salt of a strong acid (e.g., sodium lactate), the SID will not change
dichloroacetate, there was an additional increase in oxygen con- significantly, because a strong cation (Na+) is being added along
sumption but a decrease in glucose and pyruvate production. with a strong anion. Indeed, as lactate is metabolized and removed,
These results suggest that hyperlactatemia in sepsis occurs as a the remaining Na+ will increase the SID, resulting in metabolic
consequence of increased aerobic metabolism rather than of tissue alkalosis. Hence, it would be possible to give enough lactate to
hypoxia or PDH inhibition. increase the plasma lactate concentration without increasing the
Such findings are consistent with the known metabolic effects H+ concentration. However, given that normal metabolism results
of lactate production on cellular bioenergetics.61 Lactate produc- in the turnover of approximately 1,500 to 4,500 mmol of lactic acid
tion alters cytosolic, and hence mitochondrial, redox states, so that each day, rapid infusion of a very large amount of lactate would be
the increased ratio of reduced nicotinamide adenine dinucleotide required to bring about an appreciable increase in the plasma lac-
to nicotinamide adenine dinucleotide (NADH/NAD) supports tate concentration. For example, the use of lactate-based hemofil-
oxidative phosphorylation as the dominant source of ATP pro- tration fluid may result in hyperlactatemia with an increased plas-
duction. Finally, the use of catecholamines, especially epinephrine, ma HCO3– concentration and an elevated pH.
also results in lactic acidosis, presumably by stimulating cellular A more important mechanism whereby hyperlactatemia can
metabolism (e.g., increasing hepatic glycolysis), and may be a exist without acidemia (or with less acidemia than expected)
common source of lactic acidosis in the ICU.62,63 It is noteworthy involves correction of the SID by the elimination of another strong
that this phenomenon does not appear to occur with either dobu- anion from the plasma. In a study of sustained lactic acidosis
tamine or norepinephrine64 and does not appear to be related to induced by lactic acid infusion, Cl– was found to move out of the
decreased tissue perfusion. plasma space, thereby normalizing the pH.65 Under these condi-
Although the source and interpretation of lactic acidosis in tions, hyperlactatemia may persist, but compensatory mechanisms
critically ill patients remain controversial, there is no question may normalize the base excess and thus restore the SID.
about the ability of lactate accumulation to produce acidemia. Traditionally, lactic acidosis has been subdivided into type A, in
Lactate is a strong ion because at a pH within the physiologic which the mechanism is tissue hypoxia, and type B, in which there
range, it is almost completely dissociated. (The pK of lactate is is no hypoxia.66 This distinction may, however, be an artificial one.
3.9; at a pH of 7.4, 3,162 ions are dissociated for every one ion Disorders such as sepsis may be associated with lactic acidosis
that is not.) Because lactate is rapidly produced and disposed of through a variety of mechanisms [see Table 4], some conventional-
by the body, it functions as one of the most dynamic compo- ly labeled type A and others type B. A potentially useful method of
nents of the SID. Therefore, a rise in the concentration of lactic distinguishing between anaerobically produced lactate and lactate
acid can produce significant acidemia. Just as often, however, from other sources is to measure the serum pyruvate concentra-
critically ill patients have a degree of hyperlactatemia that far tion. The normal lactate-to-pyruvate ratio is 10:1,67 with ratios
exceeds the degree of acidosis observed. In fact, hyperlactatemia greater than 25:1 considered to be evidence of anaerobic metabo-
may exist without any metabolic acidosis at all. This is not lism.58 This approach makes biochemical sense because pyruvate
because acid generation is separate from lactate production (e.g., is shunted into lactate during anaerobic metabolism, dramatically
through “unreversed ATP hydrolysis”), as some have suggest- increasing the lactate-to-pyruvate ratio. However, the precise test
ed.64 Phosphate is a weak acid and does not contribute substan- characteristics, including normal ranges and sensitivity and speci-
tially to metabolic acidosis, even under extreme circumstances. ficity data, have not yet been defined for patients. Accordingly, this
Furthermore, the H+ concentration is determined not by how method remains investigational.
much H+ is produced or removed from the plasma but by Treatment of lactic acidosis continues to be subject to debate.
changes in the dissociation of water and weak acids. Virtually At present, the only noncontroversial approach is to treat the
anywhere in the body, the pH is higher than 6.0, and lactate underlying cause; however, this approach assumes that the under-
behaves as a strong ion. Generation of lactate reduces the SID lying cause can be identified with a significant degree of certainty,
and results in an increased H+ concentration; however, the plas- which is not always the case. The assumption that hypoperfusion
ma lactate concentration may also be increased without an is always the most likely cause has been seriously challenged, espe-
accompanying increase in the H+ concentration. cially in well-resuscitated patients (see above). Thus, therapy

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8 CRITICAL CARE 8 ACID-BASE DISORDERS — 7
aimed at increasing oxygen delivery may not be effective. Indeed, tyrate. Hence, it is better to monitor the success of therapy by
if epinephrine is used, lactic acidosis may worsen. measuring the pH and the AG than by assaying serum ketones.
Administration of NaHCO3 to treat lactic acidosis remains Treatment of DKA includes administration of insulin and large
unproven.21 In perhaps the most widely quoted study on this amounts of fluid (0.9% saline is usually recommended); potassium
topic, hypoxic lactic acidosis was induced in anesthetized dogs by replacement is often required as well. Fluid resuscitation reverses
ventilating them with gas containing very little oxygen.68 These the hormonal stimuli for ketone body formation, and insulin allows
animals were then assigned to treatment with NaHCO3 or place- the metabolism of ketones and glucose. Administration of
bo, and surprisingly, the group receiving NaHCO3 actually had NaHCO3 may produce a more rapid rise in the pH by increasing
higher plasma concentrations of both lactate and H+ than the con- the SID, but there is little evidence that this result is desirable.
trol group did. Furthermore, the NaHCO3-treated animals exhib- Furthermore, to the extent that the SID is increased by increasing
ited decreases in cardiac output and blood pressure that were not the plasma Na+ concentration, the SID will be too high once the
seen in the control group. One possible explanation for these find- ketosis is cleared, thus resulting in a so-called overshoot alkalosis.
ings is that the HCO3– was converted to CO2, and this conversion In any case, such measures are rarely necessary and should proba-
raised the PCO2 not only in the blood but also inside the cells of bly be avoided except in extreme cases.73
these animals with a fixed minute ventilation; the resulting intra- A more common problem in the treatment of DKA is the per-
cellular acidosis might have been detrimental to myocardial func- sistence of acidemia after the ketosis has resolved. This hyper-
tion. This hypothesis has not, however, been supported by subse- chloremic metabolic acidosis occurs as Cl– replaces ketoacids,
quent experimental studies, which have not documented para- thus maintaining a decreased SID and pH. There appear to be
doxical intracellular acidosis or even detrimental hemodynamic two reasons for this phenomenon. First, exogenous Cl– is often
effects after NaHCO3 treatment of hypoxic lactic acidosis.69 provided in the form of 0.9% saline, which, if given in large
Furthermore, it is not clear how this type of hypoxic lactic acido- enough quantities, will result in a so-called dilutional acidosis (see
sis, induced in well-perfused animals, relates to the clinical condi- below). Second, some degree of increased Cl– reabsorption appar-
tions in which lactic acidosis occurs.The results of clinical studies ently occurs as ketones are excreted in the urine. It has also been
have been mixed, but overall, they do not support the use of suggested that the increased tubular Na+ load produces electrical-
NaHCO3 therapy for lactic acidosis.21 chemical forces that favor Cl– reabsorption.74
AKA is usually less severe than DKA. Treatment consists of
Ketoacidosis Another common cause of a metabolic acido- administration of fluids and (in contrast to treatment of DKA)
sis with a positive AG is excessive production of ketone bodies, glucose rather than insulin.75 Insulin is contraindicated in AKA
including acetone, acetoacetate, and β-hydroxybutyrate. Both ace- patients because it may cause precipitous hypoglycemia.76
toacetate and β-hydroxybutyrate are strong anions (pK 3.8 and Thiamine must also be given to keep from precipitating Wernicke
4.8, respectively).70 Thus, their presence, like the presence of lac- encephalopathy.
tate, decreases the SID and increases the H+ concentration.
Ketones are formed through beta oxidation of fatty acids, a Acidosis secondary to renal failure Although renal failure
process that is inhibited by insulin. In insulin-deficient states (e.g., may produce a hyperchloremic metabolic acidosis, especially when
diabetes), ketone formation may quickly get out of control. The it is chronic, the buildup of sulfates and other acids frequently
reason is that severely elevated blood glucose concentrations pro- increases the AG; however, the increase usually is not large.77
duce an osmotic diuresis that may lead to volume contraction. Similarly, uncomplicated renal failure rarely produces severe aci-
This state is associated with elevated cortisol and catecholamine dosis, except when it is accompanied by high rates of acid genera-
secretion, which further stimulates free fatty acid production.71 In tion (e.g., from hypermetabolism).78 In all cases, the SID is
addition, an increased glucagon level relative to the insulin level decreased and is expected to remain so unless some therapy is pro-
leads to a decreased malonyl coenzyme A level and an increased vided. Hemodialysis permits the removal of sulfate and other ions
carnitine palmityl acyl transferase level—a combination that and allows the restoration of normal Na+ and Cl– balance, thus
increases ketogenesis. returning the SID to a normal (or near-normal) value. However,
Ketoacidosis may be classified as either diabetic ketoacidosis those patients who do not yet require dialysis and those who are
(DKA) or alcoholic ketoacidosis (AKA). The diagnosis is estab- between treatments often require some other therapy aimed at
lished by measuring serum ketone levels. It must be kept in mind, increasing the SID. NaHCO3 may be used for this purpose, pro-
however, that the nitroprusside reaction measures only acetone vided that the plasma Na+ concentration is not already elevated.
and acetoacetate, not β-hydroxybutyrate. Thus, the measured
ketosis is dependent on the ratio of acetoacetate to β-hydroxybu- Acidosis secondary to toxin ingestion Metabolic acidosis
tyrate. This ratio is low when lactic acidosis coexists with ketoaci- with an increased AG is a major feature of various types of intox-
dosis because the reduced redox state characteristic of lactic aci- ication [see Table 2]. Generally, it is more important to recognize
dosis favors production of β-hydroxybutyrate.72 In such circum- these conditions and provide specific therapy for them than it is to
stances, therefore, the apparent degree of ketosis is small relative treat the acid-base imbalances that they produce.
to the degree of acidosis and the elevation of the AG.There is also
a risk of confusion during treatment of ketoacidosis, in that ketone Acidosis secondary to rhabdomyolysis The extensive
levels, as measured by the nitroprusside reaction, sometimes rise muscle tissue breakdown associated with myonecrosis may also be
even though the acidosis is resolving. This occurs because the a source of positive-AG metabolic acidosis. In this situation, the
nitroprusside reaction does not detect β-hydroxybutyrate, and as acidosis results from accumulation of organic acids. The myoglo-
β-hydroxybutyrate is cleared, ketosis persists despite improvement binuria associated with the disorder may also induce renal failure.
in acid-base balance. Furthermore, conversion of β-hydroxybu- In most cases, the diagnosis is a clinical one and can be facilitated
tyrate to acetoacetate may cause an apparent increase in ketone by measuring creatinine kinase or aldolase levels. Early identifica-
levels—again, because the nitroprusside reaction detects the rising tion and aggressive resuscitation may prevent the onset of renal
levels of acetoacetate but misses the falling levels of β-hydroxybu- failure and improve the prognosis.79

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8 CRITICAL CARE 8 ACID-BASE DISORDERS — 8
Acidosis of unknown origin Several causes of an increased Several reports in the trauma literature have focused on the
AG have been reported that have yet to be elucidated. An unex- prognostic value of persistently elevated lactic acid levels during
plained AG in the nonketotic hyperosmolar state of diabetes has the first 24 to 48 hours after injury. In one study, involving 76
been reported.39 In addition, even when very careful measurement patients with multiple injuries who were admitted directly to the
techniques have been employed, unmeasured anions have been ICU from the operating room or the ED, serum lactate levels and
reported in the blood of patients with sepsis,40,41 patients with liver oxygen transport were measured at ICU admission and at 8, 16,
disease,42 and animals to which endotoxin had been adminis- 24, 36, and 48 hours.89 In those patients whose lactate levels
tered.43 Furthermore, unknown cations also appear in the blood returned to normal within 24 hours, the survival rate was 100%,
of some critically ill patients.41 The significance of these findings and in those whose lactate levels returned to normal between 24
remains to be determined. and 48 hours, the survival rate was 75%. However, in those whose
lactate levels did not return to normal by 48 hours, the survival
Prognostic significance of positive-AG metabolic acidosis rate was only 14%. Thus, the rate of normalization of the serum
Several studies have examined whether the presence of unmea- lactate level is an important prognostic factor for survival in a
sured anions in the blood is associated with particular outcomes in severely injured patient.
critically ill patients. Two such studies focused on trauma patients.
In one, the investigators examined 2,152 sets of laboratory data Non–Anion Gap (Hyperchloremic) Acidoses
from 427 trauma patients and found that the SIG altered the acid- Hyperchloremic metabolic acidosis occurs as a result of either an
base disorder diagnosis in 28% of the datasets.80 Simultaneous increase in the level of Cl– relative to the levels of strong cations
measurements of blood gas, serum electrolyte, albumin, and lactate (especially Na+) or a loss of cations with retention of Cl–.The var-
values were used to calculate the base deficit, the AG, and the SIG. ious causes of such an acidosis [see Table 3] can be distinguished on
Unmeasured anions (defined by the presence of an elevated SIG) the basis of the history and the measured Cl– concentration in the
were present in 92% of patients (mean SIG, 5.9 ± 3.3); hyperlac- urine. When acidosis occurs, the kidney normally responds by
tatemia and hyperchloremia occurred in only 18% and 21% of increasing Cl– excretion; the absence of this response identifies the
patients, respectively.The arterial SBE at ICU admission was poor- kidney as the source of the problem. Extrarenal hyperchloremic
ly predictive of hospital survival, and its predictive ability was only acidoses occur because of exogenous Cl– loads (iatrogenic acidosis)
slightly improved by controlling for unmeasured ions. In this dataset, or because of loss of cations from the lower GI tract without pro-
survivors could not be differentiated from nonsurvivors in the portional loss of Cl– (gastrointestinal acidosis).
group as a whole on the basis of the SIG. However, in the subgroup
of patients whose lactate level was normal at admission, there was Renal tubular acidosis Most cases of renal tubular acidosis
a significant difference in the SIG between survivors and nonsur- (RTA) can be correctly diagnosed by determining urine and plas-
vivors, though no such differences were noted in the conventional ma electrolyte levels and pH and calculating the SIDa in the urine
measures (i.e., SBE and AG). [see Table 3].90 However, caution must be exercised when the plas-
The poor predictive ability of the SBE, the AG, and even the ma pH is greater than 7.35, because urine Cl– excretion may be
SIG has been confirmed by studies of general ICU patients. In turned off. In such circumstances, it may be necessary to infuse
one study, analysis of data from 300 adult ICU patients demon- sodium sulfate or furosemide.These agents stimulate excretion of
strated statistically significant but weak correlations between these Cl– and K+ and may be used to unmask the defect and to probe
measures and hospital mortality.81 In another study, however, pre- K+ secretory capacity.
treatment SIG was found to be a very strong predictor of outcome Establishing the mechanisms of RTA has proved difficult. It is
in 282 patients who had sustained major vascular injury.82 All but likely that much of the difficulty results from the attempt to under-
one of the nonsurvivors had an initial emergency department stand the physiology from the perspective of regulation of H+ and
(ED) pH of 7.26 or lower, an SBE of −7.3 mEq/L or lower, a lac- HCO3– concentrations. As noted, however (see above), this
tate concentration of 5 mmol/L or higher, and an SIG of 5 mEq/L approach is simply inconsistent with the principles of physical
or higher. All of the acid-base descriptors were strongly associated chemistry.The kidney does not excrete H+ to any greater extent as
with outcome, but the SIG was the one that discriminated most NH4+ than it does as H2O.The purpose of renal ammoniagenesis
strongly. The investigators concluded that initial ED acid-base is to allow the excretion of Cl–, which balances the charge of
variables, especially SIG, could distinguish survivors of major vas- NH4+. In all types of RTA, the defect is the inability to excrete Cl–
cular injury from nonsurvivors. in proportion to excretion of Na+, though the precise reasons for
Even though the uncorrected AG and the SBE correlate poor- this inability vary by RTA type.Treatment is largely dependent on
ly with the arterial lactate concentration in trauma patients,83 sev- whether the kidney will respond to mineralocorticoid replacement
eral investigators have proposed that these parameters be used as or whether there is Na+ loss that can be counteracted by adminis-
surrogate measures of the severity of shock or lack of resuscitation. tering NaHCO3.
Various studies have shown that the SBE is a poor predictor of lac- Classic distal (type I) RTA responds to NaHCO3 replacement;
tic acidosis and mortality both in medical patients and in surgical generally, the required dosage is in the range of 50 to 100
or trauma patients and that it cannot be substituted for direct mEq/day. K+ defects are also common in this type of RTA, and
measurement of the serum lactate concentration.33,84,85 Some thus, K+ replacement is also required. A variant of the classic dis-
investigators, however, have found that the SBE can be used as a tal RTA is a hyperkalemic form, which is actually more common
marker of injury severity and mortality and as a predictor of trans- than the classic type. The central defect in this variant form
fusion requirements.86-88 Unfortunately, the SBE can determine appears to be impaired Na+ transport in the cortical collecting
only the degree of acid-base derangement, never the cause. In duct. Patients with this condition also respond to NaHCO3
many critically injured patients, abnormalities in body water con- replacement.
tent, electrolyte levels, and albumin concentration limit any poten- Proximal (type II) RTA is characterized by defects in the reab-
tial correlation between SBE and lactate concentration, even when sorption of both Na+ and K+. It is an uncommon disorder and
other sources of acid are absent. usually occurs as part of Fanconi syndrome, in which reabsorption

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8 CRITICAL CARE 8 ACID-BASE DISORDERS — 9
of glucose, phosphate, urate, and amino acids is also impaired. It appears that many critically ill patients have a significantly
Treatment of type II RTA with NaHCO3 is ineffective; increased lower SID than healthy persons do, even when these patients have
ion delivery merely results in increased excretion.Thiazide diuret- no evidence of a metabolic acid-base derangement.99 This finding
ics have been used to treat this disorder, with varying degrees of is not surprising, in that the positive charge of the SID is balanced
success. by the negative charges of A– and total CO2. Because many criti-
Type IV RTA is caused by aldosterone deficiency or resistance. cally ill patients are hypoalbuminemic, A– tends to be reduced.
It is diagnosed on the basis of the high serum K+ and the low urine Because the body maintains PCO2 for other reasons, a reduction in
pH (< 5.5).The most effective treatment usually involves removal A– leads to a reduction in SID so that a normal pH can be main-
of the cause (most commonly a drug, such as a nonsteroidal anti- tained. Thus, a typical ICU patient may have an SID of 30
inflammatory agent, heparin, or a potassium-sparing diuretic). mEq/L, rather than 40 to 42 mEq/L. If a metabolic acidosis (e.g.,
Occasionally, mineralocorticoid replacement is required. lactic acidosis) then develops in this patient, the SID will decrease
further. If this patient is subsequently resuscitated with large vol-
Gastrointestinal acidosis Fluid secreted into the gut umes of 0.9% saline, a significant metabolic acidosis will result.
lumen contains more Na+ than Cl–; the proportions are similar to The clinical implication for management of ICU patients is
those seen in plasma. Massive loss of this fluid, particularly if lost that if large volumes of fluid are to be given for resuscitation, flu-
volume is replaced with fluid containing equal amounts of Na+ ids that are more physiologic than saline should be used. One
and Cl–, will result in a decreased plasma Na+ concentration rela- alternative is LRS, which has a more physiologic ratio of Na+
tive to the Cl– concentration and a reduced SID. Such a scenario content to Cl– content and thus has an SID that is closer to nor-
can be prevented by using solutions such as lactated Ringer solu- mal (roughly 28 mEq/L, compared with an SID of 0 mEq/L for
tion (LRS) instead of water or saline. LRS has a more physiolog- saline). Of course, the assumption here is that the lactate in LRS
ic SID than water or saline and therefore does not produce aci- is metabolized, which, as noted (see above), is almost always the
dosis except in rare circumstances [see Positive–Anion Gap case. Volume resuscitation also reduces the weak acid concentra-
Acidosis, Lactic Acidosis, above]. tion, thereby moderating the acidosis. One ex vivo study con-
cluded that administration of a solution with an SID of approxi-
Iatrogenic acidosis Two of the most common causes of a mately 24 mEq/L will have a neutral effect on the pH as blood is
hyperchloremic metabolic acidosis are iatrogenic, and both progressively diluted.100
involve administration of Cl–. One of these potential causes is par-
enteral nutrition. Modern parenteral nutrition formulas contain Unexplained hyperchloremic acidosis Critically ill
weak anions (e.g., acetate) in addition to Cl–, and the proportions patients sometimes manifest hyperchloremic metabolic acidosis
of these anions can be adjusted according to the acid-base status for reasons that cannot be determined. Often, other coexisting
of the patient. If sufficient amounts of weak anions are not pro- types of metabolic acidosis are present, making the precise diag-
vided, the plasma Cl– concentration will increase, reducing the nosis difficult. For example, some patients with lactic acidosis
SID and causing acidosis. have a greater degree of acidosis than can be explained by the
The other potential cause is fluid resuscitation with saline, increase in the lactate concentration,40 and some patients with
which can give rise to a so-called dilutional acidosis (a problem sepsis and acidosis have normal lactate levels.101 In many
first described more than 40 years ago).91,92 Some authors have instances, the presence of unexplained anions is the cause,40-42 but
argued that dilutional acidosis is, at most, a minor issue.93 This in other cases, there is a hyperchloremic acidosis. Saline resuscita-
argument is based on studies showing that in healthy animals, tion may be responsible for much of this acidosis (see above), but
large doses of NaCl produce only a minor hyperchloremic acido- experimental evidence from endotoxemic animals suggests that as
sis.94 These studies have been interpreted as indicating that dilu- much as a third of the acidosis cannot be explained in terms of
tional acidosis occurs only in extreme cases and even then is mild. current knowledge.98
However, this line of reasoning cannot be applied to critically ill One potential explanation for unexplained hyperchloremic aci-
patients, for two reasons. First, it is common for patients with sep- dosis is partial loss of the Donnan equilibrium between plasma
sis or trauma to require large-volume resuscitation; sometimes, and interstitial fluid. The severe capillary leakage that accompa-
such patients receive crystalloid infusions equivalent to 5 to 10 nies this loss of equilibrium results in loss of albumin from the vas-
times their plasma volumes in a single day. Second, critically ill cular space, which means that another ion must move into this
patients frequently are not in a state of normal acid-base balance space to maintain the charge balance between the two compart-
to begin with. Often, they have lactic acidosis or renal insufficien- ments. If Cl– moves into the plasma space to restore the charge
cy. Furthermore, critically ill patients may not be able to compen- balance, a strong anion is replacing a weak anion, and a hyper-
sate for acid-base imbalance normally (e.g., by increasing ventila- chloremic metabolic acidosis results.This hypothesis appears rea-
tion), and they may have abnormal buffer capacity as a result of sonable but, at present, remains unproven.
hypoalbuminemia. In ICU and surgical patients,95-97 as well as in
METABOLIC ALKALOSIS
animals with experimentally induced sepsis,98 saline-induced aci-
dosis does occur and can produce significant acidemia. Metabolic alkalosis occurs as a result of an increased SID or a
The reason why administration of saline causes acidosis is that decreased Atot, secondary either to loss of anions (e.g., Cl– from
solutions containing equal amounts of Na+ and Cl– affect plasma the stomach and albumin from the plasma) or increases in cations
concentrations of Na+ and Cl– differently. The normal Na+ con- (rare). Metabolic alkaloses can be divided into those in which Cl–
centration is 35 to 45 mEq/L higher than the normal Cl– concen- losses are temporary and can be effectively replaced (chloride-
tration. Thus, adding (for example) 154 mEq/L of each ion in responsive alkaloses) and those in which hormonal mechanisms
0.9% saline will result in a greater relative increase in the Cl– con- produce ongoing losses that, at best, can be only temporarily off-
centration than in the Na+ concentration. So much is clear; what set by Cl– administration (chloride-resistant alkaloses) [see Table
may be less clear is why critically ill patients are more susceptible 5]. Like hyperchloremic acidosis, metabolic alkalosis can be con-
to this disorder than healthy persons are. firmed by measuring the urine Cl– concentration.

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8 CRITICAL CARE 8 ACID-BASE DISORDERS — 10
Table 5 Differential Diagnosis for intravenous administration of strong cations without strong
Metabolic Alkalosis anions. The latter occurs with massive blood transfusion because
Na+ is given with citrate (a weak anion) rather than with Cl–.
Chloride-responsive alkalosis (urine Cl – concen- Similar results ensue when parenteral nutrition formulations con-
tration < 10 mmol/L) tain too much acetate and not enough Cl– to balance the Na+ load.
GI loss
Vomiting
Gastric drainage Respiratory Acid-Base Disorders
Chloride-wasting diarrhea (villous adenoma)
Respiratory disorders are far easier to diagnose and treat than
Diuretic use
Hypercapnia
metabolic disorders are because the mechanism is always the
Chloride-resistant alkalosis (urine Cl– concentra- same, even though the underlying disease process may vary. CO2
tion > 20 mmol/L) is produced by cellular metabolism or by the titration of HCO3–
Chloride loss (Cl– < Na+) Mineralocorticoid excess by metabolic acids. Normally, alveolar ventilation is adjusted to
Primary hyperaldosteronism (Conn syndrome) maintain the PaCO2 between 35 and 45 mm Hg. When alveolar
Secondary hyperaldosteronism ventilation is increased or decreased out of proportion to the
Cushing syndrome
PaCO2, a respiratory acid-base disorder exists.
Liddle syndrome
Bartter syndrome PATHOPHYSIOLOGY
Exogenous corticoids
Excessive licorice intake CO2 is produced by the body at a rate of 220 ml/min, which
Ongoing diuretic use equates to production of 15 mol/L of carbonic acid each day.102 By
way of comparison, total daily production of all the nonrespirato-
Sodium salt administration (acetate, citrate)
ry acids managed by the kidney and the gut amounts to less than
Massive blood transfusions
Exogenous sodium load Parenteral nutrition
500 mmol/L. Pulmonary ventilation is adjusted by the respiratory
(Na+ > Cl–) Plasma volume expanders center in response to PaCO2, pH, and PO2, as well as in response to
Sodium lactate (Ringer solution) exercise, anxiety, wakefulness, and other signals. Normal PaCO2
(40 mm Hg) is attained by precisely matching alveolar ventilation
Other Severe deficiency of intracellular cations (Mg2+, K+)
to metabolic CO2 production. PaCO2 changes in predictable ways
as a compensatory ventilatory response to the altered arterial pH
Chloride-Responsive Alkalosis produced by metabolic acidosis or alkalosis [see Table 1].
Chloride-responsive metabolic alkalosis usually occurs as a RESPIRATORY ACIDOSIS
result of loss of Cl– from the stomach (e.g., through vomiting or
gastric drainage). Treatment consists of replacing the lost Cl–, Mechanism
either slowly (with NaCl) or relatively rapidly (with KCl or even When the rate of CO2 elimination is inadequate relative to the
HCl). Because chloride-responsive alkalosis is usually accompa- rate of tissue CO2 production, the PaCO2 rises to a new steady
nied by volume depletion, the most common therapeutic choice is state, determined by the new relation between alveolar ventilation
to give saline along with KCl. Dehydration stimulates aldosterone and CO2 production. In the short term, this rise in the PaCO2
secretion, which results in reabsorption of Na+ and loss of K+. increases the concentrations of both H+ and HCO3– according to
Saline is effective even though it contains Na+ because the admin- the carbonic acid equilibrium equation. Thus, the change in the
istration of equal amounts of Na+ and Cl– yields a larger relative HCO3– concentration is mediated not by any systemic adaptation
increase in the Cl– concentration than in the Na+ concentration but by chemical equilibrium. The higher HCO3– concentration
(see above). In rare circumstances, when neither K+ loss nor vol- does not buffer the H+ concentration. The SID does not change,
ume depletion is a problem, it may be desirable to replace Cl– by nor does the SBE.Tissue acidosis always occurs in respiratory aci-
giving HCl. dosis because CO2 inevitably builds up in the tissue.
Diuresis and other forms of volume contraction cause metabol- If the PaCO2 remains elevated, a compensatory response will
ic alkalosis mainly by stimulating aldosterone secretion; however, occur, and the SID will increase to return the H+ concentration to
diuretics also directly stimulate excretion of K+ and Cl–, further the normal range. The increase in the SID is accomplished pri-
complicating the problem and inducing metabolic alkalosis more marily by removing Cl– from the plasma space. If Cl– moves into
rapidly. tissues or red blood cells, it will result in intracellular acidosis
(complicated by the elevated tissue PCO2); thus, to exert a lasting
Chloride-Resistant Alkalosis
effect on the SID, Cl– must be removed from the body. The kid-
Chloride-resistant alkalosis [see Table 5] is characterized by an ney is designed to do this, whereas the GI tract is not (though the
increased urine Cl– concentration (> 20 mmol/L) and ongoing Cl– adaptive capacity of the GI tract as a route of Cl– elimination has
loss that cannot be abolished by Cl– replacement. Most common- not been fully explored). Accordingly, patients with renal disease
ly, the proximate cause is increased mineralocorticoid activity. have a very difficult time adapting to chronic respiratory acidosis.
Treatment involves identification and correction of the underlying Patients whose renal function is intact can eliminate Cl– in the
disorder. urine; after a few days, the SID rises to the level required to restore
the pH to a value of 7.35. It is unclear whether this amount of time
Alkalosis from Other Causes is necessary because of the physiologic constraints of the system or
In rare situations, an increased SID—and therefore metabolic because the body benefits from not being overly sensitive to tran-
alkalosis—occurs secondary to cation administration rather than sient changes in alveolar ventilation. In any case, this response
to anion depletion. Examples include milk-alkali syndrome and yields an increased pH for any degree of hypercapnia. According to

11. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
8 CRITICAL CARE 8 ACID-BASE DISORDERS — 11
the Henderson-Hasselbalch equation, the increased pH results in is rapidly normalized in a patient with chronic respiratory acido-
an increased HCO3– concentration for a given PCO2. Thus, the sis and an appropriately large SID, life-threatening alkalemia may
“adaptive” increase in the HCO3– concentration is actually the ensue. Second, even if the PaCO2 is corrected slowly, the plasma
consequence, not the cause, of the increased pH. Although the SID may decrease over time, making it impossible to wean the
HCO3– concentration is a convenient and reliable marker of meta- patient from mechanical ventilation.
bolic compensation, it is not the mechanism of the compensatory One option for treatment of hypercapnia is noninvasive ventila-
response. This point is not merely a semantic one: as noted (see tion with a bilevel positive airway pressure (BiPAP) system. This
above), only changes in the independent variables of acid-base bal- technique may be useful in the management of some patients, par-
ance (PCO2, Atot, and SID) can affect the plasma H+ concentration, ticularly those whose sensorium is not impaired.103 Rapid infusion
and HCO3– concentration is not an independent variable. of NaHCO3 in patients with respiratory acidosis may induce acute
respiratory failure if alveolar ventilation is not increased to account
Management
for the increased CO2.Thus, if NaHCO3 is to be given, it must be
Treatment of underlying ventilatory impairment As administered slowly, with alveolar ventilation adjusted appropri-
with virtually all acid-base disorders, treatment begins by address- ately. Furthermore, it must be remembered that NaHCO3 works
ing the underlying disorder. Acute respiratory acidosis may be by increasing the plasma Na+ concentration; if this effect is not
caused by CNS suppression; neuromuscular diseases or condi- possible or not desirable, NaHCO3 should not be given.
tions that impair neuromuscular functions (e.g., myasthenia Occasionally, it is useful to reduce CO2 production.This can be
gravis, hypophosphatemia, and hypokalemia); or diseases affecting accomplished by reducing the amount of carbohydrates supplied
the airway or the lung parenchyma (e.g., asthma and acute respi- in feedings (in patients requiring nutritional support), controlling
ratory dysfunction syndrome [ARDS]). The last category of con- body temperature (in febrile patients), or providing sedation (in
ditions produces not only alveolar hypoventilation but also prima- anxious or combative patients). In addition, treatment of shivering
ry hypoxia.The two can be distinguished by means of the alveolar in the postoperative period can reduce CO2 production. Rarely,
gas equation: however, can hypercapnia be controlled with these CO2-reducing
PAO2 = PIO2 − PaCO2/R techniques alone.
where R is the respiratory exchange coefficient (generally taken to Permissive hypercapnia. In the past few years, there has been
be 0.8), and PIO2 is the inspired oxygen tension (approximately considerable interest in ventilator-associated lung injury. Overdis-
150 mm Hg in room air). Thus, as the PaCO2 increases, the PAO2 tention of alveoli can result in tissue injury and microvascular per-
should also decrease in a predictable fashion. If the PAO2 falls by meability, which lead to interstitial and alveolar edema. In animal
more than the predicted amount, there is a defect in gas exchange. studies, prolonged use of elevated airway pressures and increased
In most cases, chronic respiratory acidosis is caused by either lung volumes resulted in increased pathologic pulmonary changes
chronic lung disease (e.g., chronic obstructive pulmonary disease and decreased survival when compared with ventilatory strategies
[COPD]) or chest wall disease (e.g., kyphoscoliosis). In rare cases, employing lower pressures and volumes.104,105 In a large multicen-
it is caused by central hypoventilation or chronic neuromuscular ter clinical trial, simply lowering the tidal volume on the ventilator
disease. from 12 ml/kg to 6 ml/kg in patients with acute lung injury resulted
in a 9% absolute reduction in mortality risk.106 Although the proto-
Control of hypoxemia Another aspect of respiratory acido- col followed in this trial did not advocate a reduced minute ventilation
sis that is illustrated by the alveolar gas equation is that the pri- and hence an elevated PaCO2, this approach, often referred to as
mary threat to life comes not from acidosis but from hypoxemia. permissive hypercapnia or controlled hypoventilation, has become
In patients breathing room air, the PaCO2 cannot exceed 80 mm increasingly popular. Uncontrolled studies suggest that permissive
Hg before life-threatening hypoxemia results. Accordingly, sup- hypercapnia may reduce mortality in patients with severe ARDS.20
plemental oxygen is required in the treatment of these patients. This strategy is not, however, without risks. Sedation is mandato-
Unfortunately, oxygen administration is almost never sufficient ry, and neuromuscular blocking agents are frequently required.
treatment by itself, and it generally proves necessary to address the Intracranial pressure rises, as does transpulmonary pressure; con-
ventilatory defect. When the underlying cause can be addressed sequently, this technique is unusable in patients with brain injury
quickly (as when the effects of narcotics are reversed with nalox- or right ventricular dysfunction. There is controversy regarding
one), endotracheal intubation may be avoidable. In the majority of how low the pH can be allowed to fall. Some authors have report-
patients, however, this is not the case, and mechanical ventilation ed good results with pH values of 7.0 or even lower,20 but most
must be initiated. Mechanical support is indicated for patients have advocated more modest pH reductions (i.e., ≥ 7.25).
who are unstable or at risk for instability and patients whose CNS
function is deteriorating. Furthermore, in patients who exhibit RESPIRATORY ALKALOSIS
signs of respiratory muscle fatigue, mechanical ventilation should Respiratory alkalosis may be the most frequently encountered
be instituted before respiratory failure occurs. Thus, it is not the acid-base disorder. It occurs in residents of high-altitude locales
absolute PaCO2 value that is the most important consideration in and in persons with any of a wide range of pathologic conditions,
this situation but, rather, the clinical condition of the patient. the most important of which are salicylate intoxication, early sep-
Chronic hypercapnia must be treated if the patient’s clinical sis, hepatic failure, and hypoxic respiratory disorders. Respiratory
condition is deteriorating acutely. In this setting, it is important alkalosis also occurs in association with pregnancy and with pain or
not to try to restore the PaCO2 to the normal range of 35 to 45 mm anxiety. Hypocapnia appears to be a particularly strong negative
Hg. Instead, the patient’s baseline PaCO2, if known, should be the prognostic indicator in patients with critical illness.107 Like acute
therapeutic target; if the baseline PaCO2 is not known, a target respiratory acidosis, acute respiratory alkalosis results in a small
PaCO2 of 60 mm Hg is perhaps a reasonable choice. Overven- change in the HCO3– concentration, as dictated by the Henderson-
tilation can have two undesirable consequences. First, if the PaCO2 Hasselbalch equation. If hypocapnia persists, the SID begins to