IntensIve care

Acidbase and blood

gas analysis

alveolar ventilation. The higher the concentration of H + the more

CO2 (volatile acid) is expired from the lungs. This is a rapid and
powerful compensatory system.
Renal bicarbonate control and excretion of metabolic (non
volatile) acids. This is a relatively slow system (hours or days).
Buffering by bicarbonate, sulphate and haemoglobin. This
minimizes acute changes.

sheena M a Hubble

Traditional approach to altering pH

Abstract
the concentration of hydrogen ions is one of the most tightly controlled
systems in the body. Defence of normal pH is thought to be from three
basic mechanisms: respiratory control of carbon dioxide, renal excretion of acids, and plasma buffering systems. the traditional approach
to acidbase control centres on the HendersonHasselbalch equation, in
which pH can be defined as the ratio of bicarbonate to carbon dioxide.
alterations in pH result from changes in carbon dioxide (respiratory) or
bicarbonate (metabolic). Most pH disturbances can be classified into one
of four main types: respiratory acidosis; respiratory alkalosis; metabolic
acidosis; metabolic alkalosis. the stewart hypothesis is an alternative
approach to acidbase analysis. It challenges the concept that changes
in bicarbonate concentration can alter pH. this theory, based on mathematical solution, is that only three things, alone or in combination, can
determine the hydrogen ion concentration: strong ion difference (net
charge balance of dissociated ions in plasma); partial pressure of carbon
dioxide; and the sum of acids present.

Keywords HendersonHasselbalch equation; pH; stewart hypothesis;

strong ion difference

The concentration of hydrogen ions in mammalian systems is

very tightly regulated and, in contrast to most other ion con
centrations, is maintained in the nanomolar (3643 nmol/litre)
rather than the millimolar range. This is because the high charge
density and large electrical field surrounding the hydrogen ion
influences nearly all biochemical processes, including protein
structure and function, ionic dissociation and movement, and
chemical or drug reactions.
The pH is the negative log10 of the hydrogen ion (H+) con
centration. A normal value at 37C is 7.347.42, which is equi
valent to a hydrogen ion concentration of 3746 nmol/litre. Acid
load comes primarily from cellular respiration as carbon dioxide
via carbonic acid (15,00020,000 mmol H+/day) and to a lesser
extent from the metabolism of fats and proteins (50 mmol/day).
The defence of normal body pH has traditionally been thought to
be achieved through three basic mechanisms:
Respiratory control of the partial pressure of carbon dioxide in
arterial blood (PaCO2) by the respiratory centre, which regulates

Sheena M A Hubble, FRCA, is Consultant in Intensive Care Medicine at

the Royal Devon and Exeter Hospital. She qualified from the University
of Bristol in 1991 and trained in medicine, anaesthesia and intensive
care in the South-West. Her research interests include the
microcirculation, lactate, and intensive care patient follow-up.

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471

The traditional approach to acidbase control focuses on the

HendersonHasselbalch equation. This equation describes the
carbonic acid buffer system, which is fundamental to respiratory
and renal control of pH. Carbon dioxide reacts with water to form
carbonic acid, which dissociates to form bicarbonate and H+:
CO2 + H 2O H2CO3 H+ + HCO3

If by the law of mass action: [H+][HCO3 ]/[H2 CO3 ] = k (constant)

Then by rearranging and taking logs of both sides:
pH = pKa + log ([HCO3 ]/[0.03 pCO2 mm Hg]) where the pKa
value at 37C is 6.1.
From this equation, pH can be defined as the ratio of bicarbon
ate to carbon dioxide. Therefore, alterations in acidbase result
from either changes in CO2 (respiratory) or changes in HCO3
(metabolic). Compensatory mechanisms exist to maintain this
ratio (normally at 20:1).
The HendersonHasselbalch equation does not quantify meta
bolic derangement as clearly as respiratory derangement because
HCO3 is dependent on the partial pressure of carbon dioxide
(pCO2) in vivo. The concepts of standard bicarbonate and stand
ard base excess or deficit were introduced to assist with quan
tifying the metabolic derangement. Standard bicarbonate is the
calculated bicarbonate value that would be present if a blood
sample was adjusted to a pCO2 of 40 mm Hg (5.3 kPa), and
therefore removes the respiratory component of the acidbase
abnormality to reveal any metabolic derangement. Standard base
excess or deficit quantifies the amount of acid in mmol/litre that
must be added or subtracted from the same blood sample with
a haemoglobin set at 5.5g/dl to regain a normal pH at a pCO2
of 40 mm Hg. Note that the more negative the standard base
excess, the more acidic the blood sample. Table 1 summarizes
the expected changes in HCO3 , pCO2 and standard base excess
in the range of primary acidbase disorders.
Blood gas analysers directly measure pH, pCO2 and partial
pressure of oxygen (pO2). Bicarbonate is calculated from a modi
fied HendersonHasselbalch equation, while standardized HCO3
and base excess are derived from computerized nomograms.
Respiratory acidosis (primary change pCO2 and compensatory change HCO3 ): elevation of pCO2 above the normal range
indicates inadequate alveolar ventilation as a result of respira
tory muscle failure, CNS pathology or drug intoxication. Other
causes include excess CO2 production in hypercatabolic states,
inadequate ventilator minute volume or administration of exo
genous CO2 (e.g. peritoneal insufflation during laparoscopy).
Renal compensation by increased H+ excretion and bicarbonate

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acetazolamide therapy and, most commonly, the administration

of large volumes of intravenous normal saline.
Patients with low albumin and phosphate must have their
anion gap corrected to avoid missing high anion gap acidoses.
The normal range of anion gap can be adjusted according to the
patients albumin and phosphate concentration as follows:
Corrected anion gap = [(Na + K)(Cl + HCO3)](0.2
albumin g/L + 1.5 phosphate mmol/L)]

Expected changes in primary acidbase

abnormalities
Disorder

Metabolic acidosis
Metabolic alkalosis
respiratory acidosis
respiratory acidosis
respiratory alkalosis
respiratory alkalosis

HCO3

pH

pCO2

Standard
base excess
(mmol/litre)

acute
chronic
acute
chronic

Metabolic alkalosis (primary change HCO3 and compensatory

change pCO2) is commonly iatrogenic, related to the administra
tion of diuretics (especially furosemide), hypokalaemia, or chronic
hypovolaemia when renal tubular sodium reabsorption occurs in
exchange for H+ excretion. Other causes include loss of acid from
the upper gastrointestinal tract, administration of HCO3 or its
precursors (e.g. citrate in blood, lactate or acetate in fluids). Persis
tent metabolic alkalosis is often associated with renal impairment
because the kidney normally compensates well to alkalotic states.

pcO 2, partial pressure of carbon dioxide

Table 1

retention takes a few days to be complete. Once this compensa

tion has occurred, sudden correction to a normal pCO2 reveals
the associated metabolic alkalosis (Table 1).

Stewarts physicochemical approach

Respiratory alkalosis (primary change pCO2 and compensatory

change HCO3 ): the primary cause is usually alveolar hyperven
tilation, causing a fall in PaCO2. It is important to examine the
partial pressure of oxygen in arterial blood (PaO2) and determine
whether hyperventilation is compensating for arterial hypoxia and
underlying lung pathology. Central causes include pain, anxiety
and CNS disease. Iatrogenic overventilation is a common cause
in critical care patients. Renal compensation causes a decrease in
measured bicarbonate and potassium if the process is chronic.
Metabolic acidosis (primary change HCO3 and compensatory
change pCO2) is caused by a primary metabolic abnormality (i.e.
fall in HCO3 or gain of acid). Alveolar hyperventilation occurs in
an attempt to lower CO2 and attenuate the fall in pH. This respira
tory compensation is often rapid and profound in spontaneously
breathing patients. When instituting mechanical ventilation in a
patient with severe metabolic acidosis, targeting a normal PaCO2
worsens the acidosis because the respiratory compensation is
inadequate. Assessing the cause of metabolic acidosis is aided by
calculation of the anion gap. Blood contains anions and cations
and the laws of electrical neutrality dictate that:
the sum of cations = the sum of anions
Na+ + K+ + unmeasured cations = Cl + HCO3 +
unmeasured anions
anion gap=(Na++K+)(Cl+HCO3 )=1012 mmol/litre.
1. A high anion gap acidosis is caused by the presence of
unmeasured anions such as lactate, ketoacids, exogenous acids
(e.g. salicylates) or ethanol. Inadequate tissue oxygen delivery
due to low PaO2 or poor perfusion is a common cause of lactic
acidosis in critically ill patients. Lactic acidosis per se carries a
high mortality and should be regarded as a medical emergency.
Renal failure increases the anion gap due to accumulation of
organic acids.
2. Normal anion gap acidosis is often due to hyperchlorae
mia and loss of bicarbonate or retention of H+. Causes include
renal tubular acidosis, gastrointestinal losses, ureteric fistulae,

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In 19831 a Canadian physician published an alternative approach

to acidbase physiology, which is gaining widespread accep
tance. He uses a mathematical approach and concludes that if
the laws of charge balance are observed in an aqueous solution
pH will be determined chiefly by the degree of water dissocia
tion, which can provide a virtually inexhaustible supply of H+.
There are only three variables that uniquely and independently
determine H+ concentration in vivo: pCO2, strong ion difference
(SID) and the total weak acid concentration (ATOT). Bicarbonate,
hydroxyl (OH) and the weak acids are viewed as dependent
variables with no direct pH effect (Figure 1).

Diagrammatic representation of Stewarts

physicochemical approach to acidbase interpretation
2) SID +
(Na + K + Mg + Ca 2+) (Cl + lactate)
+

1) pCO2 via:
CO 2 + H O
2
H2CO 3
H + + HCO3

2+

The degree of H2O

dissociation:

H2O

3) ATOT via:
ATOT A + AH

Kw

H+ + OH
determines pH
Water dissociation with the liberation of H + is the primar y determination of
body pH, where Kw is the water dissociation constant. Three independent
factors that determine water dissociation, and therefore pH, are:
+

1) pCO 2; 2) SID ; and 3) ATOT (Kw is a constant)

pCO2 quantif ies respiratory disturbance in pH
SID + and A quantif y metabolic disturbances in pH
TOT
A , total weak acid concentration; A , dissociated weak acids;
TOT
AH, associated weak acids; SID +, strong ion dif ference

Figure 1

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pCO2: The effects of changes in respiratory CO2 on pH are well

understood and produce the expected alterations in H+ accord
ing to HendersonHasselbalch equation:

ATOT is the total plasma concentration of the weak nonvolatile

acids, inorganic phosphate, serum proteins and albumin.

Clinical applications

CO2 + H 2O H2CO3 H+ + HCO3

Strong ion difference: strong ions are those that largely exist in
a dissociated or charged state in plasma. In humans, the differ
ence between measurable strong cations (Na+, K+, Mg2+ and
Ca2+) and strong anions (Cl, and lactate) is 42 mmol/litre,
representing a net positive charge. This is called the strong ion
difference apparent (SIDa) and has a powerful effect on water
dissociation and therefore H+ concentration. Any increase in net
cationic (positive) charge will tend to reduce H+ concentration
and elevate pH, and any increase in net anionic (negative) charge
lowers pH. However, plasma cannot be charged, and the coun
terbalancing negative charge, termed the effective SID (SIDe),
comes from poorly dissociated anions (HCO3 , and the dissoci
ated weak acids (i.e. albumin, phosphate and sulphate). Numeri
cally, it is equal to the traditional buffer base. The strong ion
gap (SIG) is the difference between SIDa and SIDe and represents
unmeasured ions such as ketones, sulphates, or exogenous acids.
It is superior to the anion gap (AG) because it corrects for albu
min and phosphate. The strong ion gap is also emerging as a
sensitive predictor of mortality in the critically ill (Figure 2).
SIG = SIDa SIDe = AG A

where A is dissociated weak acids.

Charge balance in blood plasma

Unmeasured
anions

Other cations
160
140

SIDa

mEq/litre

120

SIDe

100

A
HCO3
Lactate

SIG

Anion
gap

80
60

Na+

The new approach does not change the measurement or classifica

tion of acidbase disorders or challenge the primary role of pCO2
in determining pH. The standard base excess can also be used
to quantify the amount of change in SID that has occurred from
baseline, or the amount of strong anion that must be removed
or strong cation added to restore the pH to 7.4, given a pCO2
of 40 mmHg. For example, to change the standard base excess
from 20 to 10 mEq/litre by adding NaHCO3, the serum Na+
concentration needs to be increased by 10 mEq/litre. However,
by refuting the central role of bicarbonate in determining pH it
provides a better mechanistic explanation for metabolic acidoses
associated with hyperchloraemia, hypoalbuminaemia and renal
tubular acidosis.

Chloride
One of the most important inferences of the Stewart approach
is the key role of chloride in acidbase homeostasis. The prim
ary determinants influencing SID are the Na+ and Cl
concen trations. An increase in Cl relative to Na+ decreases
the SID and hence the pH. Since Na+ control is more tightly
regulated to control tonicity, Cl is increasingly recognized as
an import ant determinant of pH. For example, persistent
vomiting often results in alkalosis. The traditional view is that
this is due to H+ loss as HCl. In the Stewart hypothesis, plasma
SID is increased because chloride (a strong ion) is lost without
a corresponding strong cation. An increase in SID causes a
decrease in water dis sociation and thus a decrease in plasma
H+ concentration. The treatment of this disorder is chloride
replacement with normal saline. The hyperchloraemic acidosis
that arises following large volume saline infusions can be
explained by the excess admin istration of chloride relative to
sodium. Normal saline contains
150 mmol/litre of sodium and chloride compared with the nor
mal plasma concentrations of 135 and 100 mmol/litre, respec
tively. Theand
result
is that SID is reduced, free water dissociation
increases
pH falls.

Cl

40

REFEREnCE
1 stewart Pa. Modern quantitative acid-base chemistry. Can J Physiol
Pharmacol 1983; 61: 144461.

20
0

Cations

Anions
2+

2+

FuRTHER READing
Interactive on-line acidbase tutorial. www.acid-base.com (assessed
3 august 2007).
Kaplan L, Frangos s. clinical review: acidbase abnormalities in the
intensive care unit part II. Crit Care 2005; 9: 198203.
Kellum Ja. Determinants of blood pH in health and disease. Crit Care
2000; 4: 614.
Kellum J. clinical review: reunification of acidbase physiology.
Crit Care 2005; 9: 5007.

Other cations include Ca , Mg and K . The strong ion

difference (SID) is always positive (in plasma) and SIDSIDe
(effective) should equal zero. Any difference between SIDe and
apparent SID (SIDa) is the strong ion gap (SIG) and presents
unmeasured anions. A- represents dissociated weak acids
(mainly albumin and phosphates)

Figure 2

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2007 Published by elsevier Ltd.