1

Acid-Base Assessment by Physicochemical Analysis: A Primer for the Intensivist

Edward M. Omron MD, MPH, FCCP

Pulmonary Critical Care Medicine

18525 Sutter Blvd, Suite 180

Morgan Hill, CA 95037

Email:pulmonarydiseases@gmail.com

Disclosures:

The author of this manuscript has no personal or financial conflicts of interest

to disclose with regards to this publication and received no funding from institutional

organizations public or private.

2

Abstract

The objective of this manuscript is to provide a concise introduction to the application

of physicochemical acid-base analysis in critical illness. The hydrogen ion concentration

[H+] is regulated to approximately 40 nanoEq/liter (pH 7.40) in health but in disease wide

fluctuations from this standard physiological state occur. The magnitude and direction of

these changes constitute an exquisitely sensitive index of human physiologic stress. The

arterial PCO2-plasma bicarbonate system with anion gap calculation is the dominant

paradigm for understanding changes in [H+]. In complicated critically ill patients with

multi-organ dysfunction, the system is unable to explain the pH altering effects of

hyperchloremia, hypochloremia, dehydration, water intoxication, hypoalbuminemia,

unmeasured anions and crystalloid resuscitation. The anion gap calculation is rendered

unreliable by critical illness related hypoalbuminemia and pH changes. Physicochemical

analysis integrates the power of the both the Henderson–Hasselbalch equation and anion

gap calculation but further expands the dimensions of clinical acid-base assessment from

a diagnostic tool to a therapeutic instrument. A complex systems view of acid-base status

allows the clinician to appreciate the elegant complexity of acid-base disorders but also to

manipulate pH for clinical benefit. An easily grasped, mechanistic physicochemical

explanation follows for the common acid-base disorders seen in critical illness with

rational treatment approaches.

Key Words: acid-base status; strong ion difference; metabolic acidosis; metabolic

alkalosis; physicochemical analysis; strong ion gap

3

Introduction

The objective of this manuscript is a review of metabolic acid-base disorders by

physicochemical analysis after trauma, major surgery, or acute illness. The hydrogen ion

(H+), tiny though it is, remains unsurpassed in its ability to influence human physiology

or to confound the clinician. Why is the assessment of acid-base status so important in the

acutely ill and can we, as intensivists, do better?

Precise measurement of the change in hydrogen ion concentration [H+] and the

mechanism of disturbance has been the focus of clinical medicine for the past century (1).

The [H+] is regulated to approximately 40 nanoEq/liter (pH 7.40) in health but in disease

wide fluctuations from this standard physiological state occur. The magnitude and

direction of these changes constitute an exquisitely sensitive index of human physiologic

stress. Once diagnosed, acid-base abnormalities remain a marker for severity of illness,

and correction to standard physiological state remains a strategic endpoint in the acute

resuscitation phase of shock, and a cornerstone of treatment in critical illness (2,3).

The arterial PCO2-plasma bicarbonate system with anion gap calculation is the

dominant paradigm for understanding changes in hydrogen ion concentration [H+]. The

Henderson–Hasselbalch (HH) equation relates plasma bicarbonate concentration [HCO3]

and partial pressure of arterial carbon dioxide (PaCO2) to pH. The anion gap calculation

assesses for a discrepancy between measured plasma cations and anions. If this

discrepancy exceeds a threshold value, an anion gap metabolic acidosis is present

independent of measured pH (4,5).

From a diagnostic standpoint in uncomplicated acute illness, the PaCO2-plasma

bicarbonate system with anion gap calculation is adequate to diagnose and treat simple

4

acid-base disorders. In complicated critically ill patients with multi-organ dysfunction,

the system is unable to explain the pH altering effects of hyperchloremia, hypochloremia,

dehydration, water intoxication, hypoalbuminemia, unmeasured anions and crystalloid

resuscitation (6-8). The anion gap calculation is rendered unreliable by critical illness

related hypoalbuminemia and pH changes (9,10). Physicochemical analysis integrates the

power of the both the HH equation and anion gap calculation but further expands the

dimensions of clinical acid-base assessment from a diagnostic tool to a therapeutic

instrument (11). This analysis allows the clinician to appreciate the elegant complexity of

acid-base status but also manipulate pH for clinical benefit. An easily grasped,

mechanistic physicochemical explanation follows for the common acid-base disorders

seen in critical illness with rational treatment approaches.

Plasma pH as a Physicochemical System

Analyses of complex physicochemical systems have found wide application in the

natural sciences (12,13). The goal of acid-base complex systems analysis is to predict,

repair, and control plasma pH. Henderson (14) first introduced blood as a

physicochemical system in 1921, which was extended further, by Singer and Hastings

(15) in 1948, Stewart (16) in 1978, and more recently by Figge, Rossing, and Fencl

(17,18) in 1991. Arterial blood plasma is an open, complex non-linear physicochemical

system that determines plasma [H+]. Within the plasma compartment, the system is

physically and chemically constrained by the laws of conservation of mass, electrical

neutrality, and dissociation equilibrium constants. The system is complex because it

describes a set of chemical reactions that must me examined and solved simultaneously

5

and not extracted and analyzed separately. For example, the PaCO2-plasma bicarbonate

subsystem is a component within the plasma acid-base physicochemical system. The

system is open because PaCO2 is in equilibrium with alveolar air and can be manipulated

external to the system by changes in minute ventilation. The system is non-linear

because the exact solution for [H+], a dependent variable in plasma, is a fourth order

polynomial equation uniquely determined by three independent variables: strong ion

difference (SID), PaCO2, and total concentration of plasma nonvolatile weak acids (AT).

In the words of Stewart, “ Independent variable values are imposed on a system from the

outside, and are not affected by the equations which govern the system… Dependent

variables are internal to the system; their values are determined by the system equations

and by the values of the independent variables (19).”

Law of Electrical Neutrality in Acid-Base Status

A Gamblegram is presented in Figure 1 demonstrating the ionic constituents of human

plasma expressed in milliequivalents per liter (mEq/L). Plasma cations and anions are

grouped into two main divisions and are equal. The law of electrical neutrality requires

that charge balance always be maintained or more precisely: the sum of the cation

concentrations equal the sum of the anion concentrations within the plasma compartment.

The majority of the ionic constituents of plasma are strong ions because they are fully

dissociated, exert no buffering effect, and their concentrations are unaffected by pH

changes. The most important plasma strong ions are Na+, K

+, Ca

++, Mg

++, Cl

-, and lactate

where Na+ is sodium, K

+ is potassium, Ca

++ is ionized calcium, Mg

++ is magnesium, and

Cl- is chloride. The strong ion difference (SID) is a collective unit of charge defined as

6

the net electrical charge difference of the plasma strong cations minus the plasma strong

anions in mEq/L ([Na+] + [K

+] + [Ca

++] + [Mg

++] – [Cl

-] – [Lactate

-] – [unmeasured

strong anions]). The SID at standard physiological state (pH 7.40, PCO2 = 40 mm Hg,

and [HCO3] = 24.6 mEq/L) demonstrates a combined positive electrical effect of 39

mEq/L.

Electrical neutrality requires that the positive SID (+39 mEq/L) is balanced by an

equivalent negative charge from the plasma buffer anions (-39 mEq/L) or the buffer base.

The buffer base consists of both the volatile bicarbonate ([HCO3] = - 24.6 mEq/L) and

the dissociated components (A-) of the total nonvolatile weak acid buffers (AT) grouped

together ([albumin] + [inorganic phosphate] + [total citrate] = -14.4 mEq/L) within the

plasma compartment. The concentrations of the cation H+ and the anion OH

- are too low

to be illustrated.

The total concentration of plasma nonvolatile weak acid buffers (AT) is composed of

disassociated (A–) and undisassociated (HA) components. Normal baseline in plasma is

set to [albumin] = 4.4 g/dL, inorganic phosphate (Pi) = 1.15 mmol/L, and citrate = 0.135

mmol/L. The disassociated component (A-) reflects the net charge (mEq/L) of albumin,

inorganic phosphate, and citrate and is derived from the Figge-Fencl quantitative

physicochemical model (17,18).

Solutions to all clinical examples in this manuscript unless otherwise stated utilize the

Figge-Fencl model and were solved by an iterative computer program adapted to

Microsoft Excel Visual Basic for Applications 2008. The model can be used to calculate

the pH of plasma for any set of values for PaCO2, SID, and AT. The program is available

online at http:// www.figge-fencl.org/ (20,21).

7

The SID is central to understanding and treating many of the metabolic acid-base

disturbances seen in critical illness. The SID is an independent determinant of plasma pH

and the plasma buffer anions. Conversely, the plasma buffer anions are dependent

variables and cannot independently change the SID. This simple principle allows both

qualitative and quantitative mechanistic exploration of the common metabolic acid-base

derangements seen in acute illness.

Hyperchloremic Metabolic Acidosis

Hyperchloremic metabolic acidosis is a common acid-base disorder seen in critical

illness (22,23). High volume normal saline resuscitation, resolution phase of diabetic

ketoacidosis, profuse diarrhea, renal tubular acidosis, and acute kidney injury are

common causes. In Figure 2 plasma chloride is hypothetically raised 10 mEq/L from

standard state to 115 mEq/L over the course of several hours but not long enough for

renal compensation. Consequently, the SID is now reduced from 39 to 29 mEq/L. The

buffer base in response to the lowered SID and hyperchloremia must contract to -29

mEq/L to maintain charge balance reducing [HCO3] to 15.8 mEq/L resulting in a

metabolic acidosis.

The SID constrains the charge boundary the buffer base must conform to revealing

one of the more controversial aspects of physicochemical analysis: bicarbonate

concentration is dependent upon the charge boundary set by the SID. Further, the

reduction in bicarbonate only approximates the change in SID because of decrease in the

net negative charge of the non-bicarbonate buffer anions (A-) during acidosis (17). These

emergent system effects could not have been deduced otherwise. Bicarbonate remains

8

correlated with PaCO2 and [H+] by the Henderson–Hasselbalch equation but the

mechanistic change in [HCO3] can only be elucidated by physicochemical analysis. The

standard base deficit (-11 mEq/L) closely approximates the increment in plasma chloride

concentration. The mechanism of acid generation, loss of positive charge or excess gain

in negative charge is readily apparent. All of the organic metabolic acidoses: ketoacidosis

(-hydroxybutyrate), lactate, salicylate, methanol (formate), ethylene glycol (glycolate

and oxalate)… can be similarly represented as an excess of negatively charged plasma

strong organic acid anions. Treatments of the organic acidoses are outside the scope of

this discussion (24).

The treatment of hyperchloremic metabolic acidosis primarily consists of reducing

[Cl-] and restoring SID to standard state ([Cl

-] = 105 mEq/L, SID = 39 mEq/L), which

would restore normal charge balance and acid-base status. If kidney function remains

intact, after several hours to days, secondary renal compensation would occur by

diminished chloride reabsorption and enhanced excretion. The plasma SID would begin

to increase with a concordant increase in pH. Acute kidney injury is the more common

scenario in critical illness however, with rapidly evolving coexisting organic and

hyperchloremic acid-base emergencies. The ventilatory response to an acute metabolic

acidosis is a secondary respiratory alkalosis with increased work of breathing

necessitating acute intervention.

Acute Interventions for hyperchloremic metabolic acidosis include removing chloride

altogether from intravenous fluids (isotonic sodium bicarbonate for both resuscitation and

maintenance fluids and sodium acetate for parenteral nutrition), prudent electrolyte

replacement (calcium gluconate instead of the chloride, magnesium sulfate instead of

9

chloride, and potassium phosphate instead of the chloride); replacing intravenous

piggybacks with D5W instead of normal saline; and hemofiltration with sodium

bicarbonate buffers (25,26). An alternative treatment approach would be to increase total

plasma strong cation relative to strong anion concentration. The weak base Tris-

hydroxymethyl aminomethane (THAM) is a strong cation and administration during

acute metabolic acidosis increases strong ion difference and pH (27).

Hypochloremic Metabolic Alkalosis

Hypochloremic metabolic alkalosis is also commonly seen in critical illness. Common

pathologic causes include protracted nausea and vomiting, nasogastric aspiration, and

aggressive diuresis with loop diuretics. In Figure 3 plasma chloride is hypothetically

decreased by 10 mEq/L from standard state to 95 mEq/L over the course of several hours

but not long enough for renal compensation. Consequently, the SID is increased from 39

mEq/L to 49 mEq/L. The buffer base in response to the higher SID and hypochloremia

must expand to -49 mEq/L to maintain charge balance increasing [HCO3] to 33.8 mEq/L

resulting in a metabolic alkalosis. The increment in [HCO3] only approximates the

change in SID because of the increase in the net negative charge of the non-bicarbonate

buffer anions (A-) during alkalosis (17). The standard base excess of +11 mEq/L closely

approximates the decrement in [Cl-]. The mechanism of alkali generation is the excess

gain in strong cations or a loss of strong anions relative to standard state. Another

mechanism by which a metabolic alkalosis can be generated is by the addition of

unmeasured or known strong cations to the plasma compartment (THAM, cationic drugs,

magnesium hydroxide, calcium carbonate) (28,29).

10

The differential of metabolic alkalosis is extensive and outside the scope of this

manuscript (30). The correction of the acid-base disorder however is straightforward and

collapses to restoration of [Cl-] to standard state under most circumstances in critical

illness (31,32). If kidney function remains intact, over the course of hours to days,

secondary renal compensation would occur by increased chloride reabsorption and

diminished excretion. The plasma SID would begin to decrease with a concordant

decrease in pH. In hypovolemic hypochloremic metabolic alkalosis; however, glomerular

filtration rate is reduced and renal conservation of sodium takes precedence over chloride

reabsorption perpetuating the alkalosis. Fluid loading with normal saline will restore ECF

chloride content and correct the volume deficit.

Hypochloremic metabolic alkalosis is sometimes misdiagnosed as a “contraction

alkalosis” leading to inappropriate fluid loading (9,31,33). Metabolic alkalosis is often

associated with hypovolemia, excessive diuretic use, and or dehydration; but can also be

seen in euvolemic (mineralocorticoid excess) and hypervolemic states (congestive heart

failure). Contraction of the extracellular fluid compartment volume (ECF) or absolute

hypovolemia has no significant effects on the independent determinants of plasma acid-

base status. ECF volume status should not be diagnosed by electrolyte abnormalities but

by prudent physiologic assessment of the cardiac output venous return curve,

macrocirculatory impairment (blood pressure, heart rate, orthostatics), and or

microcirculatory impairment (lactic acidosis, low SvO2 or ScvO2).

In intubated patients with severe chronic obstructive pulmonary disease and

chronic hypercapnea, the hypochloremic metabolic alkalosis seen is appropriate

compensation for chronic primary respiratory acidosis when arterial pH approximates

11

7.40 and should not be initially corrected. Over ventilation will unmask the alkalosis and

exuberant correction may potentially prolong ventilator support (34). In contrast, the

ventilatory response to a primary metabolic alkalosis is hypoventilation and hypercapnea,

which can potential interfere with spontaneous breathing trials and prolong mechanical

ventilatory support (35,36).

Replacement of plasma chloride content can be accomplished by providing

intravenous 0.9% saline, 0.1 N hydrochloric acid infusion, or supplemental chloride

content in electrolyte replacement and parenteral/enteral nutrition. Historically

intravenous ammonium chloride and arginine monohydrochloride have been used but

potential toxicity precludes routine clinical use (37). Judicious use of acetazolamide is

also a useful therapeutic adjunct by increasing renal excretion of serum sodium relative to

chloride resulting in a decrease in the SID and increase in plasma chloride (38).

Dehydration and Water Intoxication Effects on Acid-Base Status

Strong ion difference is affected by changes in plasma free water content with acid-

base consequences (9). Water loss from the intracellular compartment defines

dehydration and is recognized clinically as euvolaemic hypernatremia. Extracellular fluid

volume depletion defines hypovolemia, which has been erroneously associated with

dehydration (39). Contraction of the extracellular fluid volume, as stated earlier, has no

significant effects on the independent determinants of plasma acid-base status but both

conditions may simultaneously occur as in hypovolemic hypernatremia.

An absolute free water deficit to the intracellular compartment is quantitatively

described as the volume of water that must be added to restore [Na+] to standard state

12

conditions (Deficit = 0.6 x Weight (kg) x [(Current Na+/142) – 1] (40). Dehydration

concentrates the plasma sodium and chloride in equal proportions; thus, increasing the

plasma SID. The hyperchloremia of dehydration, however, should not be construed as a

hyperchloremic acidosis. To prevent misinterpretation of acid-base status, the plasma

[Cl-] should be corrected for the degree of concentration and the chloride excess or deficit

calculated.

Figure 4 demonstrates the plasma [Na+] and [Cl

-] changes with a 3-liter free water

deficiency from standard state (40). The hyperchloremia of a 3-liter free water deficiency

when corrected for concentration normalizes to standard state [Cl-] and consequently

does not affect the SID or pH ([Cl-] corrected = [Cl

-] observed x ([Na

+] normal/[Na

+] observed) or

[Cl-] corrected = 105 mEq/L = 112 x (142/152)). The chloride excess = 0 mEq/L ([Cl

-] normal

– [Cl-] corrected) objectively quantitates the chloride contribution to the change in SID. The

increased SID from dehydration results in a progressive albeit mild concentrational

metabolic alkalosis and should not be confused with a “contraction alkalosis”. A

“contraction alkalosis” refers to the supposed acid-base effects of extracellular

compartment volume depletion (hypovolemia). The treatment of dehydration consists of

intravenous water expansion usually 5% dextrose to correct the intracellular fluid deficit.

Water gain to the intracellular compartment defines water intoxication and is

recognized clinically as euvolemic hyponatremia (41). Water intoxication is

quantitatively described as the volume of water that must be removed to restore [Na+] to

standard state conditions (Excess = 0.6 x Weight (kg) x [(Current Na+/142) – 1]). The

plasma [Na+] and [Cl

-] are diluted in equal proportions; thus, decreasing the plasma SID.

The hypochloremia of free water excess, however, should not be construed as a

13

hypochloremic metabolic alkalosis. To prevent misinterpretation of acid-base status, the

plasma [Cl-] should be corrected for the degree of dilution and the chloride excess or

deficit calculated. The dilutional effects of severe hyperglycemia, nonketotic

hyperosmolar state, and mannitol on plasma electrolytes are excluded from this example

(42).

Figure 5 demonstrates the [Na+] and [Cl

-] changes with a 3-liter free water excess

from standard state (41). The hypochloremia of water intoxication when corrected for

dilution normalizes to standard state [Cl-] and thus does not affect SID or pH ([Cl

-] corrected

= [Cl-] observed x ([Na

+] normal/[Na

+] observed) or [Cl

-] corrected = 105 mEq/L = 98 x (142/132)).

The chloride deficit = 0 mEq/L ([Cl-] normal – [Cl

-] corrected) objectively quantitates the

chloride contribution to the change in SID. The decreased SID from water intoxication

results in a progressive albeit mild dilutional acidosis (9). Dilutional acidosis should not

be confused with the term “dilution acidosis” which refers to the supposed acid-base

effects of extracellular compartment volume excess (hypervolemia).

Hyperchloremia or hypochloremia do not result in an acidosis or alkalosis unless the

corrected chloride is concomitantly increased or decreased relative to standard state (43).

The diagnosis and treatment of water intoxication is beyond the scope of this discussion

but common ICU interventions include hypertonic saline, water restriction, hyperosmolar

enteral feedings, loop diuretics, and vasopressin antagonists. (44).

Plasma Non-volatile Weak Acid Effects

Total plasma nonvolatile weak acid concentration (AT) is an independent determinant

of plasma pH. Albumin and inorganic phosphate are the principal plasma weak acids.

14

Albumin normal concentration ranges from 4 to 4.4 g/dL. Major surgery, trauma, and

acute illness result in large fluctuations in albumin concentration and hypoalbuminemia is

an independent risk factor for poor outcome (45,46).

In the example of hyperchloremic metabolic acidosis with serum albumin = 4.4 g/dL,

pH and SBE equals 7.210 and -11 mEq/dL respectively. At serum albumin = 2 g/dL, pH

and SBE are improved to 7.338 and -4 mEq/dL respectively, Figure 5.

A decrease in plasma albumin by 1 g/dL increases base excess by approximately 3

mEq/L (47). Hypoalbuminemia corrects pH towards standard state in acute illness and

appears to be an adaptive, short-term response to metabolic acidosis in critical illness.

Mechanistically this is best appreciated by examining the charge balance in Figure 6.

The buffer base is delimited by the charge space of the plasma strong ion difference and

is equal to the algebraic sum of the individual charged species of serum bicarbonate,

albumin, inorganic phosphorus, and citrate concentrations. With the loss of negative

charge space from hypoalbuminemia, the serum bicarbonate must expand to maintain

charge balance resulting in a mitigating hypoalbuminemic metabolic alkalosis during

concurrent metabolic acidosis (48). In other words, the decrease in plasma nonvolatile

weak acid concentration is equivalent to gain in serum bicarbonate.

Hypoalbuminemia is pervasive in acute illness and major surgery and

hypoalbuminemic alkalosis exists to some extent in all critically ill and post-operative

patients (43). The mechanism of hypoalbuminemia is likely multifactorial: impaired

hepatic synthesis, acute phase protein down-regulation, increased capillary permeability,

exudative losses, and expansion of the intravascular volume by crystalloid/colloid

15

resuscitation are all potential mechanisms. Hyperalbuminemia is infrequently

encountered in severe dehydration and may present as an increased gap acidosis (49).

Hyperphosphatemia may be seen in acute, chronic kidney injury, rhabdomyolysis,

tumor lysis syndrome, excessive intake or administration (50). The increased negative

charge space forces bicarbonate to contract and generates a metabolic acidosis (51).

Treatment options include oral phosphate binders, hemodialysis, and parenteral calcium

replacement. Normal concentration of serum inorganic phosphate is 1.15 mmol/L and

consequently hypophosphatemia is unable to generate a metabolic alkalosis.

Standard Base Excess

Dr Sigaard Anderson developed the base excess and deficit concepts in the 1960’s and

standard base excess (SBE) remains a powerful quantitative tool in the assessment of

critical illness acid-base status (52). It is easily calculated by an arterial blood gas

measurement and reduces metabolic acid-base disturbances to a simple, quantitative

numerical scale. Standard base excess provides no insight into mechanism but provides

the magnitude and direction of a metabolic acid-base disturbance. A positive value

indicates an excess of base, whereas a negative value indicates an excess of fixed acid in

vivo with respect to the extracellular fluid compartment (ECF).

SBE and SID are conceptually related by sharing similar volumes of distribution. The

plasma strong ions distribute throughout the entire extracellular fluid compartment and

strong ions added to the plasma compartment are diluted by the interstitial fluid strong

ions. The distribution, however, of strong ions between the plasma and interstitial fluid

compartments is dictated by Gibbs-Donnan Equilibria. Conceptually, standard base

16

excess represents an excess of strong cations in mEq/L and standard base deficit

represents an excess of strong anions in mEq/L relative to standard state conditions when

AT is normal.

Historically, the BE nomograms were determined by in vitro titrations of strong acids

and bases to standard state conditions. Total plasma nonvolatile weak acids were

assumed to be normal (43,53). Consequently, hypoalbuminemia is registered as a SBE

and hyperphosphatemia is registered as a standard base deficit. The problem with SBE is

that it does not discriminate between changes in SID or AT.

Fortuitously, SBE is a summation function of the changes in both plasma SID and A-

or SBE = ΔSID + ΔA- (48). The partitioning of SBE into physicochemical components

allows quick recognition of the mitigating effects of hypoalbuminemia in strong ion

acidosis and the aggravation of base excess in strong ion alkalosis. The change in SID

from standard state conditions is calculated as ΔSID (mEq/L) = SID (measured) – 39. A

positive value indicates an excess of base or plasma strong cations, whereas a negative

value indicates an excess of fixed acid or plasma strong anions. The nonvolatile plasma

weak acid buffer deficit (ΔA-) reflects alterations in the concentrations of albumin,

inorganic phosphate, and citrate from normal baseline consequent to surgery or acute

illness. Note that ΔA- is expressed as a positive quantity because a decrement in plasma

nonvolatile weak acid content is equal to a gain in base. The calculation of ΔA- is

complex and can be found in reference 48. In practice, the ΔA- calculation is unnecessary

because this value can be deduced from the difference between ΔSID and SBE.

For example, Figure 6 reveals a hyperchloremic strong ion acidosis mitigated by a

hypoalbuminemic alkalosis. The SBE = -4 mEq/L, the SID = -10 mEq/L, and the A- =

17

+6 mEq/L (calculated from the Figge-Fencl Model). The SID reflects the magnitude

and direction of the strong ion imbalance: 10 mEq/L of excess strong anions. The A-

reflects the magnitude of the hypoalbuminemic alkalosis: 6 mEq/L. The algebraic sum of

ΔSID + ΔA- equals the SBE which reflects the overall magnitude of the metabolic acid-

base disorder relative to the ECF compartment.

Classification of Primary Metabolic Acid-Base Disorders

In summary, in vivo plasma pH is a function of 3 independent determinants: (1) SID;

(2) AT; and (3) PaCO2. Disorders of any of the independent determinants may coexist

simultaneously in acute illness. Table 1 reviews the primary classification of metabolic

acid-base disturbances. The pH is a function of SID and the difference from 39 mEq/L is

a measure of ionic imbalance from standard state (Figure 7). If the SID < 39 mEq/L, an

excess of strong anions (i.e. hyperchloremia), organic acids, or free water (water

intoxication) is present resulting in a metabolic acidosis. If the SID > 39 mEq/L, a

deficiency of strong anions (i.e. hypochloremia), free water (dehydration), or excess of

strong cations are present resulting in a metabolic alkalosis. The loss of strong cations in

relation to strong anions is associated with an acidosis and the loss of strong anions in

relation to strong cations is associated with an alkalosis. Thus, “according to the law of

electrical neutrality it is impossible to change the [H+] in a solution without

simultaneously changing the amount of some anion, or exchanging the [H+] with some

cation (54). “

Albumin and inorganic phosphate are the principal nonvolatile plasma weak acids. A

decreased AT (Hypoalbuminemia) is pervasive in critical illness and generates a

18

metabolic alkalosis. An increased AT (Hyperphosphatemia) is most commonly seen in

acute and chronic kidney injury and generates a metabolic acidosis.

The Effects of Crystalloid Infusion on Acid-Base Status

The intravenous administration of acidic or alkaline crystalloid solutions to correct

severe metabolic alkalosis and acidosis respectively is routinely performed in the acutely

ill. Physicochemical analysis provides a rational basis for understanding the effects of

crystalloid administration on acid-base status (8, 55-57). Theoretically, selective

crystalloid infusion can manipulate the SBE in a predictable and quantitative manner.

The crystalloid SID is the net electrical charge difference of the infusate strong cations

minus the anions. Normal saline, for example, contains 154 mEq/L of sodium and 154

mEq/L of chloride and thus the SID is equal to zero. Isotonic sodium bicarbonate, in

contrast, contains 150 mEq/L of sodium and 150 mEq/L of bicarbonate and thus the SID

is equal to 150 mEq/L.

Infusion of an isotonic crystalloid solution modifies plasma pH by simultaneously

altering both SID and AT. For example, normal plasma SID equals 39 mEq/L and when

combined with a low SID crystalloid (normal saline SID = 0 mEq/L), the admixture will

reduce plasma SID resulting in a strong ion acidosis. In contrast, the SID of sodium

bicarbonate (SID = 150 mEq/L) is higher than plasma SID; the admixture will increase

plasma SID and result in a strong ion alkalosis. Crystalloid solutions are devoid of AT

(albumin, inorganic phosphate, and total citrate) and intravenous administration will

reduce plasma weak acids by simple dilution, resulting in a mitigating dilution alkalosis.

19

Plasma metabolic acid-base status will be determined after equilibration and Gibbs-

Donnan effect by the plasma SID admixture and diluted AT.

If the induced crystalloid strong ion acidosis is exactly balanced by a dilution AT

metabolic alkalosis, no significant change in SBE occurs. The crystalloid SID necessary

to achieve this ‘‘balance point’’ is equal to standard state actual bicarbonate (24.6

mEq/L). In other words, crystalloid solutions with an ionic composition similar to plasma

and SID close to standard state bicarbonate are referred to as balanced solutions (lactated

Ringer’s and Hartmann’s solution) and clinically minimize acid-base disturbances when

infused.

The ‘‘balance point’’ is also useful when using crystalloid solutions to achieve a

particular acid-base endpoint. If the infused crystalloid SID is greater than 24.6 mEq/L,

metabolic alkalosis will result; if less than 24.6 mEq/L, metabolic acidosis will result. If

the crystalloid SID equals 24.6, no change in SBE is observed. Figure 7 demonstrates the

potency of various crystalloid solutions as a function of crystalloid SID to induce an

acidosis or alkalosis, respectively, from standard state conditions under ideal conditions.

These projections are reasonably accurate in surgical patient populations during

perioperative fluid replacement with normal saline, lactated Ringer’s, and plasmalyte

solutions. High-quality clinical data sets are unfortunately lacking in critically ill

populations and more research is needed to define the optimal fluid resuscitation strategy.

Anion Gap and Strong Ion Gap

In critical illness, unmeasured strong anions may appear (ketone acids, anions of renal

failure, and lactate) resulting in a metabolic acidosis and an increased anion gap (ANG).

20

The ANG is a screening tool for unmeasured strong anions and is derived from an

abreviated form of the law of electrical neutrality in plasma (Figure 9): Na+- Cl

- – HCO3

= Unmeasured Anions – Unmeasured Cations + A- ≅ 12 ± 4 mEq/L (57). The value of

the ANG includes the unmeasured plasma strong cations and anions, and the

disassociated component of AT. The simplified charge balance equation ignores

potassium, calcium, and magnesium, which become unmeasured cations. During standard

state conditions, the entirety of the ANG can be accounted for by the negative charge

component of AT (17, 18). An increase in unmeasured strong anions will titrate plasma

bicarbonate, generate a metabolic acidosis, and increase the ANG to maintain charge

balance. An increased ANG historically has been quite helpful in the differential

diagnosis of metabolic acidosis; however, the validity of the calculation is questionable in

critical illness.

Inspection of the ANG calculation reveals several major sources of error (58-60).

Hypoalbuminemia is pervasive in critical illness resulting in a low to normal ANG in the

organic acidoses (61). A decrease in albumin by 1 g/dL reduces the ANG by 2.5 mEq/L

secondary to the loss of negative charge from the albumin moiety. The disassociated

component of AT is reduced in acidemia and increased in alkalemia decreasing and

increasing the ANG respectively by titration of the negative charges on the albumin

moiety. Figure 2 demonstrates the reduction in the ANG during acidemia from 12 to 11

mEq/L; Figure 3 demonstrates the increase in the ANG during alkalemia from 12 to 13

mEq/L. Figure 6 demonstrates the combined effects of acidemia and hypoalbuminemia

on ANG. The ANG is reduced from 12 mEq/L at standard state to 6 mEq/L secondary to

loss of charge from both hypoalbuminemia and acidosis with no change in unmeasured

21

anions or cations. A proposed adjusted ANG for hypoalbuminemia (adjusted ANG =

observed ANG + 2.5 x ([Normal Albumin] – [Observed Albumin]) has improved

sensitivity to detect occult organic acidoses and is in common use (61). In Figure 6, the

adjusted ANG corrects to normal (adjusted ANG = 12 mEq/L (6 + 2.5 x (4.4 – 2)). Low

ANG can also be seen with an excess of strong cations (hypercalcemia,

hypermagnesemia, hyperkalemia, lithium, and THAM) and laboratory error.

In physicochemical analysis the appearance of unmeasured strong anions or cations

are collectively termed the strong ion gap (SIG) and are codeterminants of the SID

(Figure 10). The SIG is similar to the ANG in that both are derived from the law of

electrical neutrality but unlike the ANG, the SIG is resistant to changes in pH, PaCO2,

and albumin concentration (62). Figures 2, 3, and 6 demonstrate the robustness of the

SIG measurement is acidemia, alkalemia and hypoalbuminemia. The SIG is thus a more

reliable parameter of unmeasured strong anions than ANG in critical illness. The SIG in

health is normally less than 6 mEq/L but the range of abnormal values in critical illness

remains undefined in the literature (63). Recent literature has focused on the utility of the

SIG as a marker of tissue damage and predictor of mortality in severe sepsis, trauma, and

cardiac arrest (64-67).

The SIG is calculated as the difference between the SID apparent and effective. The

SID apparent (SIDa) is the net electrical charge difference between the commonly

measured strong cations minus the strong anions in the plasma: SIDa = Na+

+ K+

+ Ca++

+

Mg++

- Cl- - lactate. The SIDa is normally 42 – 44 mEq/L. For bedside calculations the

combined expression (Ca++

+ Mg++

) is replaced by 3 mEq/L. The strong ion difference

effective (SIDe) is the net electrical charge difference of the plasma strong cations minus

22

the strong anions including the SIG: Na+

+ K+

+ Ca++

+ Mg++

- Cl- + [SIG]. The SIDe is

normally 39 mEq/L. The calculation of the SIG combines both equations: SIG = SIDa –

SIDe. For bedside calculations the SIDe is closely approximated by its negatively

charged reflection, the plasma buffer base: SIDe ≈ [HCO3] + 2.8 x [albumin g/dL] + 0.6 x

[Pi mg/dL] (43). The full Figge-Fencl quantitative physicochemical model can be applied

at the bedside with a programmable calculator (20, 21).

Illustrative Examples

A 50-year-old male presents with end stage liver disease in septic shock. His

admission pH = 7.263, PaCO2 = 20.2 mm Hg, [HCO3] HH = 9 mEq/L, SBE = -16 mEq/L,

Na+ = 139 mEq/L, K

+ = 3.7 mEq/L, Cl

- = 117 mEq/L, lactate = 2.9 mEq/L, [albumin] =

2.4 g/dL, Pi = 4.3 mg/dL, the ANG = 13 mEq/L, adjusted ANG = 18 mEq/L, SIDa = 26

mEq/L, SIDe = 18 mEq/L, and the SIG = 8 mEq/L.

Conventional analysis reveals a severe metabolic acidosis with respiratory

compensation and a normal ANG but elevated adjusted ANG. Physicochemical analysis

suggests a marked excess of strong anions within the ECF compartment (Δ SID = -21

mEq/L) with a mitigating hypoalbuminemic alkalosis (ΔA-) of 5 mEq/L. The SBE = -16

mEq/L or (Δ SID + ΔA-). The source of the strong anion acidosis is hyperchloremia,

unmeasured anions from the SIG, and to a lesser extent lactate. The nature of the SIG and

unmeasured anions in acute illness remains elusive although Krebs cycle strong anions

have been implicated (68).

Therapeutic intervention would require removing chloride altogether from

resuscitation and maintenance fluids, initiation of isotonic sodium bicarbonate (SID =

23

150 mEq/L) infusion, changing all IV drips to D5W with acute, early goal directed

resuscitation to both macro and microcirculatory endpoints. A physicochemical

resuscitation refers to the application of physicochemical analysis to correct acid-base

status with early goal directed resuscitation endpoints (8). A physicochemical

resuscitation in acute illness is physiologically appealing but remains untested in the

literature.

A 69 year-old male with acute myelogenous leukemia and acute respiratory distress

syndrome day 14 on pressure regulated volume control. His pH = 7.530, PaCO2 = 40 mm

Hg, [HCO3] = 33 mEq/L, SBE = 9.8 mEq/L, [Na+] = 140 mEq/L, [K

+] = 2.8 mEq/L,

[Cl-] = 105 mEq/L, [albumin] = 1.1 g/dL, [Pi] = 3.3 mg/dL, ANG = 2 mEq/L, adj ANG =

10.3 mEq/L, SIDe = 38.6 mEq/L, SIDa = 40.8 mEq/L, SIG = 2.2 mEq/L.

Conventional analysis reveals a primary metabolic alkalosis. The SIDe is normal and

thus ΔSID = 0 mEq/L, the ΔA- = 9.8 mEq/L secondary to the profound

hypoalbuminemia, and the SBE (SBE = ΔSID + ΔA-) can be entirely accounted for by

the hypoalbuminemia of critical illness. The patient is euvolemic based on bedside

echocardiography. The metabolic alkalosis would have to be corrected to initiate

spontaneous breathing trials. Confusion with a “contraction alkalosis” might lead to

inappropriate fluid loading and prolongation of mechanical ventilation. The patient

received intravenous acetazolamide with normalization of pH the next morning.

A 22 year-old male presents with an altered mental status, nausea and vomiting,

increased thirst, frequent urination and admission glucose of 241 mg/dL. Serum acetone

and urine ketones were positive. His admission pH = 6.985, PaCO2 = 20.5 mm Hg,

[HCO3] = 4.8 mEq/L, SBE = -23.9 mEq/L, [Na+] = 154 mEq/L, [K

+] = 4.4 mEq/L, [Cl

-]

24

= 101 mEq/L, lactate = 0.8 mEq/L, Pi = 6.7 mg/dL, [albumin] = 6.1 g/dL, SIDa = 61.1

mEq/L, SIDe = 22.1 mEq/L, SIG = 39 mEq/L, ΔSID = -16.9 mEq/L, ΔA- = -7.0 mEq/L,

and ANG = 48 mEq/L. The corrected [Cl-] for dehydration = 142/154 x 101 = 93 mEq/L.

The chloride deficit = 105 – 93 ≈ 12 mEq/L.

Conventional analysis reveals a high anion gap metabolic acidosis with a

compensatory respiratory alkalosis. Electrolyte profile supports dehydration and bedside

echocardiography reveals hypovolemia with preload dependency. Physicochemical

analysis reveals a severe strong anion acidosis with a high SIG presumably secondary to

ketone bodies from diabetic ketoacidosis (ΔSID = -16.9 mEq/L of excess strong anions).

Secondary acidoses emerge from the hyperalbuminemia of dehydration with a smaller

component from hyperphosphatemia (ΔA- = -7.0 mEq/L). A chloride deficit of 12 mEq/L

reveals a moderate hypochloremic metabolic alkalosis.

Fluid resuscitation in diabetic ketoacidosis (DKA) remains contentious in the medical

literature and current guidelines continue to recommend 0.9% saline (69,70).

Physicochemical analysis clearly reveals that 0.9% saline infusion aggravates a

preexisting metabolic acidosis and induces a coexisting hyperchloremic strong ion

acidosis (8, 48). Unfortunately, randomized, placebo controlled studies of crystalloid

fluid resuscitation in DKA have not been performed and recommendations fall to dogma

and practice preference. The author strongly advocates the use of physiologically

balanced fluids (lactated Ringer’s and Hartmann’s solution) both during the acute

resuscitation and maintenance phases of DKA in adults. Lactated Ringer’s infusion, for

example, would correct the ECF volume deficit, minimize crystalloid-induced acid-base

changes, provide free water replacement (osmolarity = 275 mOsmol/liter) for

25

dehydration, minimize hyperchloremia, and supplement total body potassium stores

slightly.

Theoretical Advantage of Physicochemical Acid-Base Analysis

The binary separation of acid-base status into pure respiratory and metabolic

components forms the foundation of acid-base lore. The Henderson Equation ([H+] = 24

x PaCO2/[HCO3]) illustrates the concept. Classical teaching states that the PaCO2

represents the respiratory component and [HCO3] the metabolic component of an acid-

base disturbance and both are independent determinants of [H+] (71). It was Schwartz

and Relman that initially questioned the validity of this concept and began “The Great

Trans-Atlantic Acid-Base Debate (72).”

“ …it must be recognized that a certain quantity of “metabolic acidosis” normally

complicates primary respiratory alkalosis and that a certain quantity of “metabolic

alkalosis” normally complicates primary respiratory acidosis, it is apparent that the

recognition of abnormal metabolic complications of primary respiratory disturbances

becomes extremely difficult (73).”

Physicochemical acid-base analysis moves the clinician away from the simplistic

binary classification scheme to a systems view of acid-base status. Le Chatelier’s

Principle states that if a physicochemical system is exposed to a stress, the system will

shift to minimize that stress. For example, hyperchloremia is a recognized as an excess of

ECF strong anions resulting in a strong ion metabolic acidosis. Primary repair of the

system requires removal of the excess strong anions from the ECF compartment. The

physiologic response is to restore standard state conditions: a secondary respiratory

26

alkalosis, intracellular buffering of the ECF compartment acidosis, and diminished

chloride reabsorption with enhanced excretion by the kidneys till all excess chloride is

removed. The Intensivist can facilitate the restorative process by prudent use of fluids,

electrolyte replacement, enteral nutrition, mechanical ventilation, and diuretics. The

essence of acid-base systems analysis is to predict, repair, and control plasma pH.

Conclusion

This manuscript was written exclusively for the critical care physician. Intensivists

are broadly trained to diagnose and treat multi-organ dysfunction and I would argue a

more appropriate appellation of their skill set is complex systems clinician.

Physicochemical analysis and the diagnosis, treatment, and control of acid-base disorders

are a natural extension of this skill set. Plasma pH is a subsystem of whole body acid-

base balance. ““Whole body acid-base balance,” refers to the set of mechanisms by

which the parts of the body, notably the lungs, kidneys, and gastrointestinal tract, control

the composition of the circulating blood plasma, so as to keep its [H+] generally within

the range from 2 x 10-8

to 1 x 10-7

Eq/liter or pH 7.7 to 7.0 (74).” The ultimate therapeutic

goal of critical care medicine is restoration of multi-organ standard state conditions after

multi-organ dysfunction. Physicochemical analysis with manipulation of fluids,

electrolytes, and plasma pH in the acute resuscitative phase of critical illness is a

necessary component of this endeavor.

27

References

1. Myers RJ. One-Hundred Years of pH. Journal of Chemical Education 2010; 87:

30-32.

2. Tisherman SA, Barie P, Bokhari F et al. Clinical Practice Guideline: Endpoints of

Resuscitation. J Trauma 2004; 57: 898-912.

3. Englehart MS, Schreiber MA. Measurement of Acid–Base Resuscitation

Endpoints: Lactate, Base Deficit, Bicarbonate or What? Curr Opin Crit Care

2006; 12:569–574

4. Siggaard-Anderson O. The Acid-Base Status of Blood. 4th ed. Baltimore, Md:

Williams & Wilkins; 1974: 1-229.

5. Gabow PA. Disorders associated with an altered anion gap. Kidney Int. 1985; 27:

472-483.

6. Fencl V, Leith DE. Stewart's Quantitative Acid-Base Chemistry: Applications in

Biology and Medicine. Respiration Physiology 1993; 91: 1-16.

7. Constable PD. A simplified strong ion model for acid-base equilibria: application

to horse plasma. J Appl Physiol 1997; 83: 297-311.

8. Omron EM, Omron RM. A Physicochemical Model of Crystalloid Infusion on

Acid-Base Status. J Intensive Care Med 2010; 25: 271-280.

9. Fencl V, Rossing TH. Acid-Base Disorders in Critical Care Medicine. Ann Rev

Med 1989; 40: 17-29.

10. Kraut JA, Madias NE. Serum Anion Gap: Its Uses and Limitations in Clinical

Medicine. Clin J Am Soc Nephrol 2007; 2: 162-174.

28

11. Stewart PA. How to Understand Acid-Base. A Quantitative Acid-Base Primer for

Biology and Medicine. New York, NY: Elsevier; 1981.

12. Ludlow RF, Otto S. Systems Chemistry. Chem Soc Rev 2008; 37: 101-108.

13. Whitesides GM, Ismagilov RF. Complexity in Chemistry. Science 1999; 284: 89-

92.

14. Henderson LJ. Blood as a Physicochemical System. J Biol Chem 1921; 46: 411-

419.

15. Singer RB, Hastings AB. An Improved Clinical Method for the Estimation of

Disturbances of the Acid-Base Balance of Human Blood. Medicine 1948; 27:

223-242

16. Stewart, PJ. Independent and Dependent Variables of Acid-Base Control

Respiration Physiology 1978; 33: 9-26

17. Figge J, Rossing TH, Fencl V. The role of serum proteins in acid-base equilibria.

J Lab Clin Med 1991;117:453-467.

18. Figge J, Mydosh T, Fencl V. Serum proteins and acid-base equilibria: A follow

up. J Lab Clin Med 1992; 120: 713-719.

19. Stewart PJ. Modern Quantitative Acid-Base Chemistry. Can J Physiol Pharmacol

1983; 61: 1445.

20. An Educational Web Site about Modern Human Acid-Base Physiology: The

Figge-Fencl Quantitative Physicochemical Model of Human Acid-Base

Physiology. http://www.Figge-Fencl.org/. Accessed November 2010.

29

21. Figge, J. Role of Non-Volatile Weak Acids (Albumin, Phosphate and Citrate). In

Stewart's Textbook of Acid-Base (second edition). John A Kellum and Paul WG

Elbers, editors. Chapter 11, pages 217 - 232. Amsterdam: AcidBase.org. 2009.

22. Ho AMH, Karmakar MK, Contardi LH, Ng SS, Hewson JR. Excessive use of

normal saline in managing traumatized patients in shock: a preventable

contributor to acidosis. J Trauma. 2001; 51(1): 173-177.

23. Constable PD. Hyperchloremic Acidosis: The Classic Example of Strong Ion

Acidosis. Anesth Analg 2003; 96: 919-922.

24. Morris CG, Low J. Metabolic acidosis in the critically ill: Part 2. Causes and

treatment. Anaesthesia 2008; 63: 396–411.

25. Heering P, Ivens K, Thumer O, et al. The use of different buffers during

continuous hemofiltration in critically ill patients with acute renal failure.

Intensive Care Med. 1999;25: 1244-1251.

26. Orr PA, Case KO, Stevenson JJ, et al. Metabolic response and parenteral nutrition

in trauma, sepsis, and burns. J Infus Nurs. 2002; 25:45-53.

27. Holmdahl MH, Wiklund L, Wetterberg T et al. The place of THAM in the

management of acidemia in clinical practice. Acta Anaesthesiol Scand 2000; 44:

524-527.

28. Cabizuca SV, Desser KB. Carbenicillin-Associated Hypokalemic Alkalosis.

JAMA 1976; 236: 956-957.

29. Madias NE, Levey AS. Metabolic alkalosis due to absorption of “non-

absorbable” antacids. Am J Med 1983; 74: 155-158.

30

30. Rose BD. Clinical Physiology of Acid-Base and Electrolyte Disorders (Fifth

Edition). New York: McGraw-Hill; 2001: 551-577.

31. Galla JH. Metabolic Alkalosis. J Am Soc Nephrol. 2000; 11: 369-375.

32. Schwartz WB, van Ypersele de Strihou C, Kassirer JP. Role of anions in

metabolic alkalosis and potassium deficiency. N Engl J Med 1968; 279: 630-639.

33. Garella S, Chang BS, Kahn SI. Dilution acidosis and contraction alkalosis: review

of a concept. Kidney Int 1975; 8: 279–283.

34. Gladwin MT, Pierson DJ. Mechanical Ventilation of the Patient with Severe

Chronic Obstructive Pulmonary Disease. Intensive Care Med 1998; 24: 898-910

35. Javaheri S, Kazemi H. Metabolic alkalosis and hypoventilation in humans. Am

Rev Respir Dis. 1987; 136: 1011.

36. Gallagher TJ. Metabolic alkalosis complicating weaning from mechanical

ventilation. South Med J. 1979; 72(7): 786-787.

37. Adrogue HJ, Madias NE. Management of Life-Threatening Acid-Base Disorders.

N Engl J Med 1998; 338: 107-111.

38. Moviat M, Pickkers P, van der Voort PHJ et al. Acetazolamide-mediated

Decrease in Strong Ion Difference Accounts for the Correction of Metabolic

Alkalosis in Critically Ill Patients. Critical Care 2006; 10: R14.

39. Mange K, Matsuura D, Cizman B et al. Language Guiding Therapy: The Case of

Dehydration Versus Volume Depletion. Annals of Internal Medicine; 127: 848-

853.

40. Adrogue HJ, Madias NE. Hypernatremia. N Engl J Med 2000; 342: 1493-1499.

41. Adrogue HJ, Madias NE. Hyponatremia. N Engl J Med 2000; 342: 1581- 1589.

31

42. Varon J, Jacobs MB, Mahoney CA. Reflections on the Anion Gap in

Hyperglycemia. The Western Journal of Medicine 1992; 157: 670-672.

43. Fencl V, Jabor A, Kazda A, et al. Diagnosis of Metabolic Acid-Base Disturbances

in Critically Ill Patients. Am J Respir Crit Care Med 2000;162: 2246–2251.

44. Verbalis JG, Goldsmith SR, Greenburg A. et al; Hyponatremia Treatment

Guidelines 2007:Expert Panel Recommendations. The American Journal of

Medicine (2007) Vol 120 (11A), S1–S21.

45. Vincent JL, Dubois MJ, Navickis RJ, et al: Hypoalbuminemia in acute illness: Is

there a rationale for intervention? A meta-analysis of cohort studies and

controlled trials. Ann Surg 2003; 237:319-334.

46. Soni N, Margarson M. Albumin. Where are we now? Current Anaesthesia and

Critical Care 2004; 15: 61-68.

47. Rossing TH, Maffeo N, Fencl V. Acid-base effects of altering plasma protein

concentration in human blood in vitro. J Appl Physiol. 1986; 61: 2260-2265.

48. Omron EM. Comparative quantitative acid-base analysis in coronary artery

bypass, severe sepsis, and diabetic ketoacidosis. J Intensive Care Med. 2005;

20(6): 269-278.

49. Wang F, Butler T, Rabbani GH, et al. The acidosis of cholera. Contributions of

hyperproteinemia, lactic acidemia, and hyperphosphatemia to an increased serum

anion gap. N. Engl. J. Med. 1986; 315: 1591-1595.

50. Thatte L, Oster JR, Singer I. Review of the literature: severe

hyperphosphatemia. Am J Med Sci. Oct 1995; 310(4):167-74.

32

51. Rocktaeschel J, Morimatsu H, Uchino S, et al. Acid-base status of critically ill

patients with acute renal failure: Analysis based on Stewart-Figge methodology.

Crit Care. 2003; 7:R60-R66.

52. Schlichtig R, Grogono AW, Severinghaus JW. Human PCO2 and standard base

excess compensation for acid-base balance. Crit Care Med 1998; 26: 1173-1179.

53. Siggard-Anderson, O. The Acid-Base Status of the Blood, 4th

Edition. The

Williams and Wilkins Company 1974. Page 55.

54. Siggard-Anderson, O. The Acid-Base Status of the Blood, 4th

Edition. The

Williams and Wilkins Company 1974. Page 11.

55. Morgan TJ, Venkatesh B. Designing ‘balanced’ crystalloids. Crit Care Resusc.

2003; 5(4): 284-291.

56. Morgan TJ, Venkatesh B, Hall J. Crystalloid strong ion difference determines

metabolic acid-base change during in vitro hemodilution. Crit Care Med. 2002;

30(1): 157-160.

57. Morgan TJ, Venkatesh B, Hall J. Crystalloid strong ion difference determines

metabolic acid-base change during acute normovolaemic hemodilution. Intensive

Care Med. 2004; 30(7): 1432-1437.

58. Kraut JA, Madias NE. Serum Anion Gap: Its Uses and Limitations in Clinical

Medicine 2007; Clin J Am Soc Nephrol 2: 162-174.

59. Emmet M, Narins RG. Clinical Use of Anion Gap. Medicine 1977; 56:38-54

60. Salem MS, Mujais SK. Gaps in Anion Gap. Arch Intern Med 1993; 152:1625-

1629

33

61. Figge J, Jabor A, Kazda A, et al. Anion gap and hypoalbuminemia. Crit Care

Med 1998; 26:1807-1810.

62. Morgan TJ, Cowley DM, Weier SL et al. Stability of the strong ion gap over

extremes of PCO2 and pH. Anaesth Intensive Care 2007; 35: 370-373.

63. Omron EM, Gilbert RG. The Strong Ion Gap. Crit Care Medicine 2005; 33: 266.

64. Balasubramanyan N, Havens PL, Hoffman GM. Unmeasured anions identified by

the Fencl-Stewart method predict mortality better than base excess, anion gap,

and lactate in patients in the pediatric intensive care unit. Crit Care Med. 1999;

27: 1577-1581.

65. Rocktaeschel J, Morimatsu H, Uchino S, et al. Unmeasured anions in critically ill

patients: Can they predict mortality. Crit Care Med. 2003; 31: 2131-2136.

66. Kaplan LJ, Kellum JA. Initial pH, base deficit, lactate, anion gap, strong ion

difference, and strong ion gap predict outcome from major vascular injury. Crit.

Care Med. 2004; 32(5): 1120-1124.

67. Funk GC, Doberer D, Richling N et al. The strong ion gap and outcome after

cardiac arrest in patients treated with therapeutic hypothermia. Intensive Care

Med 2009; 35: 232-239.

68. Forni LG, McKinnon W, Hilton PJ. Unmeasured anions in metabolic acidosis:

unraveling the mystery. Critical Care 2005; 10: 220.

69. Kitabchi AE, Umpierrez GE, Murphy MB et al. Hyperglycemic crises in adult

patients with diabetes: A consensus statement from the American Diabetes

Association. Diabetes Care 2006; 29: 2739-2748.

34

70. Dhatariya KK. Diabetic Ketoacidosis: Saline should be used for fluid replacement

rather than Hartmann’s solution. BMJ 2007; 334: 1284-1285.

71. Rose BD. Clinical Physiology of Acid-Base and Electrolyte Disorders (Fifth

Edition). New York: McGraw-Hill; 2001: 325-326.

72. Bunker JP. The Great Trans-Atlantic Acid-Base Debate. Anesthesiology 1965; 26:

591- 594.

73. Schwartz WB, Relman AS. A Critique of the Parameters Used in the Evaluation

Acid-Base Disorders. “Whole-blood Buffer Base” and “ Standard Bicarbonate”

Compared with Blood pH and Plasma Bicarbonate Concentration. N Engl J Med

1963; 268: 1382-1388

74. Stewart PA. How to Understand Acid-Base. A Quantitative Acid-Base Primer for

Biology and Medicine. New York, NY: Elsevier; 1981. Chapter 9; p 161.

35

Figure 1: Charge balance at standard physiologic state

SID = strong ion difference; SBE = standard base excess; ANG = anion gap; SIG = strong ion gap; A- = dissociated component of AT

20

40

60

80

100

120

140

160

mE

q/L

Cations Anions

Na+ = 142

K+ Ca++ Mg++

Cl- = -105

HCO3 = -24.6

A- = -14.4

0

Buffer Base = -39 SID = +39

pH = 7.40

PaCO2 = 40 mm Hg

SBE = 0 mEq/L

ANG = 12 mEq/L

SIG = 5 mEq/L

36

Figure 2: Hyperchloremic strong ion acidosis

SID = strong ion difference; SBE = standard base excess; ANG = anion gap; SIG = strong ion gap; A- = dissociated component of AT

20

40

60

80

100

120

140

160

mE

q/L

Cations Anions

Na+ = 142

K+ Ca++ Mg++

Cl- = -115

HCO3 = -15.8

A- = -13.2

0

Buffer Base = -29 SID = +29

( 10)

pH = 7.209

PCO2 = 40 mm Hg

SBE = -11 mEq/L

ANG = 11 mEq/L

SIG = 5 mEq/L

37

Figure 3: Hypochloremic strong ion alkalosis

SID = strong ion difference; SBE = standard base excess; ANG = anion gap; SIG = strong ion gap; A- = dissociated component of AT

20

40

60

80

100

120

140

160

mE

q/L

Cations Anions

Na+ = 142

K+ Ca++ Mg++

Cl- = -95

HCO3 = -33.8

A- = -15.2

0

Buffer Base = - 49 SID = +49

( 10)

pH = 7.54

PCO2 = 40 mm Hg

SBE = 11 mEq/L

ANG = 13

SIG = 5 mEq/L

38

Figure 4: A concentration strong ion alkalosis: three-liter free water deficit from standard physiologic state (weight = 70 kg and total

body water = 0.60).

SID = strong ion difference; SBE = standard base excess; ANG = anion gap; SIG = strong ion gap; A- = dissociated component of AT

20

40

60

80

100

120

140

160

mE

q/L

Cations Anions

Na+ = 152 ( 10)

K+ Ca++ Mg++

Cl- = 112 ( 7)

HCO3 = -27.3

A- = -14.7

0

Buffer Base = -42 SID = +42

pH = 7.447

PCO2 = 40 mm Hg

SBE = 3 mEq/L

ANG = 13 mEq/L

SIG = 5 mEq/L

39

Figure 5: A dilution strong ion acidosis: three-liter free water excess from standard physiologic state (weight = 70 kg and total body

water = 0.60).

SID = strong ion difference; SBE = standard base excess; ANG = anion gap; SIG = strong ion gap; A- = dissociated component of AT

20

40

60

80

100

120

140

160

mE

q/L

Cations Anions

Na+ = 132

K+ Ca++ Mg++

Cl- = 98

HCO3 = -21.9

A- = -14.1

0

Buffer Base = -36 SID = +36

( 10)

pH = 7.351

PCO2 = 40 mm Hg

SBE = -3 mEq/L

ANG = 12

SIG = 5

( 7 )

40

Figure 6: Hyperchloremic strong ion acidosis with concurrent hypoalbuminemic alkalosis ([albumin] = 2g/dL)

SID = strong ion difference; SBE = standard base excess; ANG = anion gap; SIG = strong ion gap; A- = dissociated component of AT

20

40

60

80

100

120

140

160

mE

q/L

Cations Anions

Na+ = 142

K+ Ca++ Mg++

Cl- = -115

HCO3 = - 21.2

A- = - 7.8

0

Buffer Base = -29 SID = +29

( 10)

pH = 7.338

PCO2 = 40 mm Hg

SBE = - 4 mEq/L

ANG = 6 mEq/L

Adj. ANG = 12 mEq/L

SIG = 5 mEq/L

41

Table 1: Classification of primary metabolic acid-base disorders

Acidosis Alkalosis

1.Strong Ion Difference

a. Decreased Hyperchloremia

Organic Acid Anions

Water intoxication

b. Increased Hypochloremia

Dehydration

Strong Cations (THAM)

2. Nonvolatile Weak Acids

a. Increased Hyperphosphatemia

Hyperalbuminemia

b. Decreased Hypoalbuminemia

42

Figure 7. pH as a function of strong ion difference (SID)

AT = plasma nonvolatile weak acid total

6.8

6.9

7

7.1

7.2

7.3

7.4

7.5

7.6

15 20 25 30 35 40 45 50 55

pH

SID (mEq/L)

pH = 7.4

PaCO2 = 40 mm Hg

SID = 39 mEq/L

AT = Standard State

+ -

43

Figure 8. Standard base excess (SBE) as a function of crystalloid infusion volume in liters

-15

-10

-5

0

5

10

15

20

25

30

35

40

0 1 2 3 4 5 6 7 8 9 10

SB

E m

Eq

/L

Crystalloid Infusion Volume (Liters)

Normal Saline (SID = 0)

Crystalloid SID = 24.5 mEq/L

Ringer's Lactate (SID = 28)

Plasmalyte 148 (SID = 50)

1/2 NS + 75 mEq/L NaHCO3 (SID = 75)

0.15 M NaHCO3 (SID = 150)

44

Figure 9. The Anion Gap (ANG)

SBE = standard base excess; ANG = anion gap; SIG = strong ion gap; A- = disassociated component of of AT

20

40

60

80

100

120

140

160

mE

q/L

Cations Anions

Na+ = 142

K+ = 4

Cl- = -105

HCO3 = -24.6

A- = -14.4

0

pH = 7.40

PCO2 = 40 mm Hg

SBE = 0 mEq/L

ANG = 12 mEq/L

SIG = 5 mEq/L

XA-

XA- = Unmeasured Anions:

Cyanide

Glycols Iron

Isoniazid

Ketoacids Krebs Cycle

Lactate

Methanol Paraldehyde

Toluene Salicylate

Uremia

ANG

45

Figure 10. The Strong Ion Gap (SIG)

SIDa = apparent strong ion difference; SIDe = effective strong ion difference; SBE = standard base excess; ANG = anion gap; SIG =

strong ion gap; A- = disassociated component of AT

20

40

60

80

100

120

140

160

mE

q/L

Cations Anions

Na+ = 142

K+ = 4

Cl- = -105

HCO3

A-

0

pH = 7.40

PCO2 = 40 mm Hg

SBE = 0 mEq/L

ANG = 12 mEq/L

SIG = 5 mEq/L

XA-

SIDa

Strong Ion Gap

SIDe or Buffer Base