INTENSIVE CARE

ANAESTHESIA AND INTENSIVE CARE MEDICINE 8:11 471 2007 Published by Elsevier Ltd.
Acidbase and blood
gas analysis
Sheena M A Hubble
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 excre-
tion of acids, and plasma buffering systems. The traditional approach
to acidbase control centres on the HendersonHasselbalch equation, in
which pH can be dened 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 classied 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 math-
ematical 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 eld surrounding the hydrogen ion
inuences 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 (PaCO
2
) 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 qualied 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.
alveolar ventilation. The higher the concentration of H
+
the more
CO
2
(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.
Traditional approach to altering pH
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
+
:
CO H O H CO H HCO
2 2 2 3
+
3
+ +

If by the law of mass action: [H ][HCO ]/[H CO ] = k (constant)
+
3 2 3

Then by rearranging and taking logs of both sides:

pH = pKa + log ([HCO ]/[0.03 pCO mm Hg])
3 2

where the pKa

value at 37C is 6.1.
From this equation, pH can be dened as the ratio of bicarbon-
ate to carbon dioxide. Therefore, alterations in acidbase result
from either changes in CO
2
(respiratory) or changes in HCO
3

(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
HCO
3

is dependent on the partial pressure of carbon dioxide

(pCO
2
) in vivo. The concepts of standard bicarbonate and stand-
ard base excess or decit 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 pCO
2
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 decit quanties 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 pCO
2

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 HCO
3

, pCO
2
and standard base excess
in the range of primary acidbase disorders.
Blood gas analysers directly measure pH, pCO
2
and partial
pressure of oxygen (pO
2
). Bicarbonate is calculated from a modi-
ed HendersonHasselbalch equation, while standardized HCO
3

and base excess are derived from computerized nomograms.
Respiratory acidosis (primary change pCO
2
and compensa-
tory change HCO
3

): elevation of pCO
2
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 CO
2
production in hypercatabolic states,
inadequate ventilator minute volume or administration of exo-
genous CO
2
(e.g. peritoneal insufation during laparoscopy).
Renal compensation by increased H
+
excretion and bicarbonate
INTENSIVE CARE
ANAESTHESIA AND INTENSIVE CARE MEDICINE 8:11 472 2007 Published by Elsevier Ltd.
retention takes a few days to be complete. Once this compensa-
tion has occurred, sudden correction to a normal pCO
2
reveals
the associated metabolic alkalosis (Table 1).
Respiratory alkalosis (primary change pCO
2
and compensatory
change HCO
3

): the primary cause is usually alveolar hyperven-

tilation, causing a fall in PaCO
2
. It is important to examine the
partial pressure of oxygen in arterial blood (PaO
2
) 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 HCO
3

and compensatory
change pCO
2
) is caused by a primary metabolic abnormality (i.e.
fall in HCO
3

or gain of acid). Alveolar hyperventilation occurs in

an attempt to lower CO
2
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 PaCO
2

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

+ HCO
3

+
unmeasured anions
anion gap=(Na
+
+K
+
)(Cl

+HCO
3

)=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 PaO
2
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 stulae,
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 + HCO
3
)](0.2
albumin g/L + 1.5 phosphate mmol/L)]
Metabolic alkalosis (primary change HCO
3

and compensatory
change pCO
2
) 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 HCO
3

or its
precursors (e.g. citrate in blood, lactate or acetate in uids). Persis-
tent metabolic alkalosis is often associated with renal impairment
because the kidney normally compensates well to alkalotic states.
Stewarts physicochemical approach
In 1983
1
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 chiey 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: pCO
2
, strong ion difference
(SID) and the total weak acid concentration (A
TOT
). 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
Water dissociation with the liberation of H
+
is the primary 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) A
TOT
(Kw is a constant)
pCO
2
quantifies respiratory disturbance in pH
SID
+
and A
TOT
quantify metabolic disturbances in pH
A
TOT
, total weak acid concentration; A

, dissociated weak acids;

AH, associated weak acids; SID
+
, strong ion difference
2) SID
+
(Na
+
+ K
+
+ Mg
2+
+ Ca
2+
) (Cl

+ lactate)
The degree of H
2
O
dissociation:
H
2
O

Kw
H
+
+ OH

determines pH
1) pCO
2
via:
CO
2
+ H
2
O
H
2
CO
3
H
+
+ HCO
3

3) A
TOT
via:
A
TOT
A

+ AH
Figure 1
Expected changes in primary acidbase
abnormalities
Disorder pH HCO
3

pCO
2
Standard
base excess
(mmol/litre)
Metabolic acidosis
Metabolic alkalosis
Acute respiratory acidosis
Chronic respiratory acidosis
Acute respiratory alkalosis
Chronic respiratory alkalosis
pCO
2
, partial pressure of carbon dioxide
Table 1
INTENSIVE CARE
ANAESTHESIA AND INTENSIVE CARE MEDICINE 8:11 473 2007 Published by Elsevier Ltd.
pCO
2
: The effects of changes in respiratory CO
2
on pH are well
understood and produce the expected alterations in H
+
accord-
ing to HendersonHasselbalch equation:
CO H O H CO H HCO
2 2 2 3
+
3
+ +

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
+
, Mg
2+
and
Ca
2+
) 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 (HCO
3

, 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.

A
TOT
is the total plasma concentration of the weak non-volatile
acids, inorganic phosphate, serum proteins and albumin.
Clinical applications
The new approach does not change the measurement or classica-
tion of acidbase disorders or challenge the primary role of pCO
2

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 pCO
2

of 40 mmHg. For example, to change the standard base excess
from 20 to 10 mEq/litre by adding NaHCO
3
, 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 inuencing 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. The result is that SID is reduced, free water dissociation
increases and pH falls.
REFERENCE
1 Stewart PA. Modern quantitative acid-base chemistry. Can J Physiol
Pharmacol 1983; 61: 144461.
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: reunication of acidbase physiology.
Crit Care 2005; 9: 5007.
Charge balance in blood plasma
Other cations include Ca
2+
, Mg
2+
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)
m
E
q
/
l
i
t
r
e
160
Cations
Na
+
Anions
Cl

HCO
3

Lactate
A

Unmeasured
anions
Other cations
140
120
100
80
60
20
40
0
SIDa
SIDe
SIG
Anion
gap
Figure 2