Section 6 Kidney and body fluids

Chapter
Acid–base physiology

66
What is an acid? Key equation: pH
The word acid is derived from the Latin acidus,
pH ¼ log10[H+]
meaning sour. Early chemists defined an acid as a
where log10 is the logarithm (base 10) and [H+] is the
chemical substance whose aqueous solution tastes
molar concentration of H+ ions.
sour, changes the colour of litmus paper to red, and
Note: pH is dimensionless; that is, it has no units.
reacts with certain metals to produce the flammable
gas hydrogen. Likewise, a base is a chemical substance
whose aqueous solution tastes bitter, changes the Because the pH scale is logarithmic, a small change in
colour of litmus paper to blue, and reacts with acids pH represents a much larger change in [H+]:
to produce a salt.  ‘Normal’ body pH of 7.4 is equivalent to an H
+

What are the Brønsted–Lowry
definitions of an acid and base?
Brønsted and Lowry independently recognized that
acid–base reactions in aqueous solution involve the
transfer of a H+ from one molecule to another:
 An acid is defined as a proton donor.
 A base is defined as a proton acceptor.
The generic reaction between an acid and base is:
HA + B Ð BH+ + A
where HA is a Brønsted–Lowry acid (as it donates
H+), B is a Brønsted–Lowry base (as it accepts H+),
BH+ is referred to as the conjugate acid and A is
referred to as the conjugate base.
For example, consider the equilibrium between
H2CO3 and water:
+ HA Ð H+ +A
H2 CO3 +H2 O Ð HCO3 +H3 O
concentration of 40 nmol/L.
 Acidaemia is defined as an arterial pH below 7.35.
 Alkalaemia is defined as an arterial pH above 7.45.
 A small reduction in pH from 7.4 to 7.0 represents
more than a doubling of H+ concentration, from
40 to 100 nmol/L.
What is pKa?
Acids may be classified as being either strong or weak:
 A strong acid is one that completely dissociates in
solution.
 A weak acid is one that only partially dissociates in
solution.
pKa is a measure of the strength of an acid, normally
used to characterize weak acids. Consider the
following equation:
k1
k2

where k1 is the rate constant for the forward reaction

H2CO3 is the Brønsted–Lowry acid, water is the
and k2 is the rate constant for the backward reaction.
Brønsted–Lowry base, HCO3 is the conjugate base
When the rate of the forward reaction equals the
and H3O+ is the conjugate acid.
rate of the backward reaction, the reaction is said to
be at equilibrium. The equilibrium constant Ka can be
What is pH? written as:
pH is a measure of the acidity of an aqueous solution. k1 ½H+ Š½A Š
Ka ¼ ¼
pH depends on the concentration of H+ ions: k2 ½HAŠ

328
Downloaded from https://www.cambridge.org/core. University College London (UCL), on 26 Dec 2017 at 07:04:03, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/CBO9781139226394.068
 Chapter 66: Acid–base physiology

pKa is the negative logarithm of this dissociation Applying the Henderson–Hasselbalch equation to the
constant Ka: HCO3 /H2CO3 buffer system:
½HCO3 Š
Key equation: pKa pH ¼ pK a +log10
½H2 CO3 Š
pKa ¼ log10 Ka
As the pKa of the HCO3 /H2CO3 equilibrium is 6.1
and [H2CO3] can be related to the solubility and
From the equilibrium equation above, it can be seen
partial pressure of CO2 PaCO2, this equation can be
that:
rewritten as
 A high Ka represents greater dissociation of HA
into H+ and A , and therefore a greater ½HCO3 Š
pH ¼ 6:1+log10
concentration of free H+. A low pKa therefore 0:23 ×Pa CO2
corresponds to increased acidity. where 0.23 is a solubility factor. PaCO2 is measured in
 A low Ka represents less dissociation of HA, kilopascals.
resulting in a lower concentration of free H+. Normal plasma pH can therefore be predicted by
A high pKa therefore corresponds to reduced inserting the ‘normal’ plasma values of
acidity. [HCO3 ] ¼ 24 mmol/L and PaCO2 ¼ 5.3 kPa:
Like pH, pKa is a logarithmic scale. Therefore, a small 24
pH ¼ 6:1+log10 ¼ 7:4
reduction in pKa represents a much larger increase in 0:23×5:3
acidity.
The acidity of a substance can be related to pH in How are disorders of acid–base
a more formal way. Rearranging the above equation:
balance classified?
½HAŠ
½H+ Š ¼ K a Acid–base disturbance is traditionally classified by pH
½A Š
disturbance – that is, acidosis or alkalosis – and by
As pH ¼ log10[H+]: aetiology, whether it is of respiratory or metabolic
  origin. Acids of respiratory origin, namely CO2, are
½HAŠ
pH ¼ log10 K a known as volatile acids, as they may escape as a gas.
½A Š
Acids that are non-volatile (for example, lactic acid) are
Multiplying out the brackets: known as fixed acids as they may not escape the system.
½HAŠ
The four classes of acid–base disorders are:
pH ¼ log10 K a log10  Respiratory acidosis, in which decreased V_ A
½A Š
results in pH <7.35 and PaCO2 >6.0.
And as pKa ¼ log10 Ka: Hypoventilation may be due to:
– Depression of the respiratory centre; for
Key equation: the Henderson–Hasselbalch
equation example, due to opioids or obesity
hypoventilation syndrome.
½A Š – Nerve or muscle disorders, such as GBS and MG.
pH ¼ pK a +log10
½HAŠ – Chest wall disease; for example, flail chest.
Or: – Airway disease, such as asthma and COPD.
– Lung parenchymal disease; for example, ARDS.
½Conjugate baseŠ
pH ¼ pK a +log10
½AcidŠ Of particular relevance to anaesthesia,
hypercapnoeic acidosis may also occur due to:
The most important physiological buffering system is – Insufficient mechanical ventilation, which may of
that of CO2, H2CO3 and HCO3 , which follows the course be intentional; for example, permissive
reaction hypercapnoea in patients with ARDS.
– Increased CO2 production in malignant
CO2 + H2O Ð H2CO3 Ð H+ + HCO3 hyperpyrexia.

329
Downloaded from https://www.cambridge.org/core. University College London (UCL), on 26 Dec 2017 at 07:04:03, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/CBO9781139226394.068
 Section 6: Kidney and body fluids
– Exogenous CO2 intake; for example,
re-breathing CO2-containing exhaled gases or
insufflation of CO2 in laparoscopic surgery.
If a respiratory acidosis persists for a period of
days, the kidneys increase HCO3 reabsorption;
this is termed metabolic compensation. Raised
plasma HCO3 concentration (>26 mmol/L) may
be seen in patients with COPD, ARDS and obesity
hypoventilation syndrome.
 Metabolic acidosis, in which there is an increase
in fixed acid, which may be endogenous (for
example, lactic acid) or exogenous (for example,
salicylate). As the increased fixed acid is buffered
by HCO3 , metabolic acidosis is characterized by
low plasma HCO3 concentration (<22 mmol/L)
and pH <7.35. Identification of the cause of
metabolic acidosis may be aided by the anion gap
(see below). The respiratory system responds to a
metabolic acidosis by rapidly increasing V_ A ,
thereby reducing PaCO2; this is referred to as
respiratory compensation.
 Respiratory alkalosis, in which hyperventilation
results in hypocapnoea (PaCO2 <4.7 kPa) and
alkalosis (pH >7.45). Increased V_ A may be the
result of:
– Central causes; for example, head injury, pain,
anxiety, progesterone (in pregnancy) and
drugs (such as salicylate overdose).
– Hypoxaemia, in which afferent signals from
peripheral chemoreceptors stimulate the
respiratory centre. This may occur, for
example, at high altitude.
– Activation of lung J receptors, as occurs in PE
and pulmonary oedema.
– Excessive mechanical ventilation.
 Metabolic alkalosis, the least common of the
main acid–base disorders, in which plasma
HCO3 exceeds 26 mmol/L in the absence of a
primary respiratory acidosis. The more common
causes of metabolic alkalosis are:
– Gain of exogenous alkali; for example, an
infusion of sodium bicarbonate, and massive
transfusion, where citrate is metabolized to
HCO3 .
– Loss of endogenous acid; for example, from the
stomach through severe vomiting or
nasogastric drainage, or from the kidney
through the use of diuretics.
330
Downloaded from https://www.cambridge.org/core. University College London (UCL), on 26 Dec 2017 at 07:04:03, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/CBO9781139226394.068
What is the base excess?
Acid–base imbalance is often of mixed aetiology. One
of the failings of the Henderson–Hasselbalch method
is that, when an acidosis or alkalosis is of mixed
metabolic and respiratory origin, it is difficult to
quantify each component.
The base excess (BE) is defined as the amount of
acid or base that must be added to titrate the blood
sample to pH 7.40, when PaCO2 has been corrected to
5.3 kPa and the temperature of blood is 37 °C.
Therefore:
 Blood that is already at pH 7.40 and which has a
PaCO2 of 5.3 kPa will have a BE of zero.
 In metabolic acidosis, BE will be negative.
 In metabolic alkalosis, BE will be positive.
 Normal BE is considered to be 2 to +2 mEq/L.
Base excess is useful when identifying the cause of a
metabolic acidosis. For example, a patient with pneu-
monia has the following blood gas results: pH 7.2,
BE 8 mEq/L and lactate 3 mmol/L. A BE of 8 mEq/L
represents a significant metabolic acidosis. As lactate
is only 3 mmol/L, there must be another source of
acid present to account for the remaining 5 mEq/L.
Given the history, this may be the result of acute
kidney injury with failed excretion of fixed acids.
What is the anion gap?
The anion gap is the apparent difference between the
total concentration of measured cations and the total
concentration of measured anions. In practice, only
the most common cations and anions are measured
by the blood gas machine, giving the formula
Key equation: anion gap
Anion gap ¼ sum of cation concentrations
sum of anion concentrations
¼ ð½Na+ Š+½K+ ŠÞ ð½Cl Š+½HCO3 ŠÞ
The normal anion gap is 10–20 mEq/L, which repre-
sents unmeasured anions such as sulphates, phosphates
and plasma proteins. The anion gap is used clinically to
identify the cause of a metabolic acidosis. A raised
anion gap metabolic acidosis may be the result of:
 Increased endogenous anions; for example:
– Lactic acid, produced during anaerobic
metabolism.

– Fixed acids, which accumulate in acute kidney
injury.
– Ketoacids, whose production is increased by
diabetic ketoacidosis.
 Increased exogenous anions; for example:
– Salicylate.
– Ethanol.
– Methanol.
– Ethylene glycol.
A normal anion-gap metabolic acidosis, which
occurs much less commonly, may be caused by
chronic gastrointestinal HCO3 loss or renal tubular
acidosis.
Albumin is the major unmeasured anion. Hypoal-
buminaemia, common in critically ill patients, is
therefore associated with a reduced anion gap. It is
important to note that a metabolic acidosis may be
missed in a hypoalbuminaemic critical care patient, as
the anion gap may be normal.
How is body pH regulated?
pH homeostasis is very important, as the effects of
acidaemia and alkalaemia on the body are potentially
very serious. Body pH is normally1 maintained
between 7.35 and 7.45 through three mechanisms.
As acidosis is much more frequently encountered
than alkalosis, these mechanisms are primarily con-
cerned with limiting the harmful effects of acidosis:
 Buffering. A buffer is a substance that responds
rapidly to oppose the change in pH when an acid
or base is added to the plasma, according to Le
Chatelier’s principle. Buffers are salts of weak
acids or bases, and work by releasing or absorbing
H+ in response to addition of stronger base or acid
respectively. Buffer systems can be classified as:
– Extracellular buffers:
▪ The H2CO3/HCO3 buffer system is the
most important extracellular buffer owing
to the abundance of HCO3 in plasma, and
the fact that CO2 (in equilibrium with
H2CO3) may be eliminated by the lungs
(see below). The pKa of the H2CO3/HCO3
system is 6.1; therefore, at pH 7.4, HCO3
is a good buffer of acids but not alkalis.
1
In pregnancy, a mild physiological alkalosis is expected
(see Chapter 77).
Downloaded from https://www.cambridge.org/core. University College London (UCL), on 26 Dec 2017 at 07:04:03, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/CBO9781139226394.068
Chapter 66: Acid–base physiology
▪ Hb. The histidine side chains of Hb
act as a buffer by binding H+ ions.
Deoxyhaemoglobin is better able to bind
H+ than oxyhaemoglobin (see the Haldane
effect, Chapter 8).
– Intracellular buffers:
▪ The phosphate buffer system (H2PO4 /
HPO42 ). The concentration of phosphate
is very low in ECF, making it an
unimportant buffer. Phosphate is,
however, an important buffer of both ICF
and urine, as the phosphate concentration
is higher.
▪ Proteins. Amino acid side chains can
buffer both acids (amine side chains) and
alkalis (carboxyl side chains). Whilst
plasma proteins play only a minor role in
buffering, intracellular proteins are present
at higher concentrations, making them
important intracellular buffers.
 Respiratory regulation. The respiratory system
responds within minutes to correct pH
disturbances. The PaCO2 is inversely related to V_ A
(see Chapter 10). In turn, pH is related to PaCO2.
Therefore:
– An increase in V_ A results in an increase in
blood pH.
– A reduction in V_ A results in a decrease in
blood pH.
The respiratory centre responds rapidly to a
pH disturbance, increasing or decreasing V_ A
in response to acidaemia or alkalaemia
respectively:
– Metabolic acidosis is sensed by the carotid
bodies (see Chapter 21), which stimulate
the respiratory centre; V_ A increases in
proportion to the degree of acidosis. The
increase in V_ A is predominantly due to an
increase in VT with little increase in RR; this
breathing pattern is called ‘Kussmaul
breathing’ and is commonly seen in diabetic
ketoacidosis.
– Hypercapnoea is sensed by both the peripheral
and central chemoreceptors (see Chapter 21),
which stimulate an increase in V_ A .
Hypercapnoea is a potent stimulus: the
combined effects of acidosis and hypercapnoea
331
 Section 6: Kidney and body fluids

generate a twofold greater increase in V_ A than generated by the basolateral Na+/K+-

acidosis alone.
– Alkalaemia reduces stimulation of the carotid
bodies, and thus causes a limited reduction in
V_ A .
 Renal regulation. The kidneys correct pH
disturbances over a period of days, through three
mechanisms:
– Excretion of fixed acids; for example,
phosphoric, sulphuric and keto acids. Renal
filtration and excretion constitutes the only
means of excreting fixed acids.
– Controlled reabsorption of filtered HCO3 .
HCO3 is freely filtered at the glomerulus.
Around 80% of filtered HCO3 is reabsorbed
in the PCT, irrespective of changes in plasma
pH. The mechanism of reabsorption is as
follows (Figure 66.1):
▪ HCO3 cannot directly cross the apical
membrane of the tubules.
+ normal conditions, nearly all the filtered
▪ Instead, H is secreted into the tubular
lumen (1), where it combines with HCO3 ,
resulting in CO2 (2). This reaction is
catalysed by the brush border enzyme CA.
H+ is secreted into the PCT lumen by
secondary active transport, using an
Na+/H+-antiporter and the Na+ gradient
ATPase.
▪ As CO2 is lipid soluble, it diffuses along its
concentration gradient, across the apical
membrane of the tubule and into the PCT
cell (3).
▪ In the PCT cell, the reverse reaction occurs:
CA catalyses the reaction between CO2 and
water, producing H+ and HCO3 (4). H+ is
secreted back into the tubular lumen
through the Na+/H+-antiporter, and HCO3
moves into the blood through a sodium–
bicarbonate co-transporter (5). Overall,
HCO3 is reabsorbed from the renal filtrate.
In the DCT and collecting ducts, the type
A intercalated cells and principal cells control
the reabsorption of the remaining tubular
HCO3 . The mechanism for HCO3
reabsorption is similar to the PCT, relying on
H+ secretion into the tubular lumen. Under
HCO3 is reabsorbed. Alkalaemia leads to less
HCO3 being reabsorbed; more HCO3
appears in the urine, resulting in a higher
urinary pH.
– Ammoniagenesis. In response to acidosis, the
liver shifts from turning ammonium (NH4+)

HCO3− cannot cross apical membrane Figure 66.1 Mechanism of HCO3

Filtered HCO3− reabsorption in the PCT.

Na+/H+-countertransporter Basolateral
Na+/K+-ATPase

Na+ Na+ Na+ Na+

HCO3−
H+ K+ K+
(1) H+ HCO3 −

(4)
H2CO3
HCO3− (5)
H2CO3
CA
Na+ Na+
CA
H2O + CO2 CO2 Bicarbonate reabsorption via
(2) (3) H2O bicarbonate–Na+ cotransporter

Tubular lumen PCT cell Extracellular fluid

CO2 diffuses across the cell membrane

332
Downloaded from https://www.cambridge.org/core. University College London (UCL), on 26 Dec 2017 at 07:04:03, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/CBO9781139226394.068

ions and HCO3 into urea, to producing
glutamine. Glutamine travels in the blood to
the cells of the PCT, where NH4+ and HCO3
are reproduced. NH4+ is secreted into the
tubular lumen in exchange for Na+ (again, the
process is driven by the basolateral Na+/K+-
ATPase), and HCO3 is moved into the blood
in exchange for Cl . This generation of
HCO3 is beneficial in the correction of the
acidosis, but kidney must now excrete the
NH4+:
▪ In the thick ascending limb of the LOH,
NH4+ is reabsorbed via the Na+/K+/2Cl
transporter (NH4+ passes through the
K+ site).
+ these effects are offset by catecholaminergic
▪ In the medullary interstitium, NH4 loses
+
an H to become NH3.
▪ The membrane of the medullary collecting
duct is permeable to NH3; therefore, NH3
diffuses into the collecting duct.
+ parasympathetic outflow increases, which
▪ In continued acidosis, H ions are present in
high concentration within the tubular fluid
and thus bind to NH3 to reform NH4+. The
collecting duct membrane is impermeable to
NH4+, and thus it is excreted.
Overall, one H+ ion is excreted into the
renal filtrate per molecule of glutamine
metabolized. The capacity of this system to
excrete H+ is very high, even when the tubular
filtrate is already very acidic.
What are the main systemic
consequences of acid–base
disturbance?
At a molecular level, pH affects:
 Enzyme function – outside a narrow range of pH,
enzymes may become denatured and their
function impaired.
 The ionization of molecules – this may alter their
ability to cross cell membranes, or affect their
shape and function.
 RMP – a pH disturbance may alter the
permeability of neuronal membrane ion channels,
which in turn affects the RMP. Membrane
depolarization towards threshold potential makes
spontaneous action potentials more likely, whilst
Downloaded from https://www.cambridge.org/core. University College London (UCL), on 26 Dec 2017 at 07:04:03, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/CBO9781139226394.068
Chapter 66: Acid–base physiology
membrane hyperpolarization makes action
potential generation more difficult.
The clinical effects of acid–base disturbance can
be considered system by system:
 Cardiovascular system. It is difficult to separate
the effects of acidosis from the effects of
hypercapnoea on the heart and vasculature. In
general:
– Sympathetic response. Hypercapnoea
stimulates catecholaminergic release from the
adrenal medulla.
– Effect on cardiac output. Acidosis causes direct
myocardial depression, manifesting as a
decrease in SV. However, in mild acidosis,
release from the adrenal medulla. Below pH
7.0, the negative inotropy associated with
acidosis outweighs the positively inotropic
effects of adrenaline. In addition,
counteracts the effects of catecholamines on
HR, resulting in bradycardia. As a result of
these two effects, cardiac output falls.
– Cardiac arrhythmias, including ventricular
ectopic beats and AF, are common in acidosis,
whether metabolic or respiratory in origin.
This is a consequence of increased circulating
adrenaline and electrolyte disturbance
(see below).
– Vascular tone. The effects of acidosis and
hypercapnoea on the vasculature is complex:
whilst acidosis per se causes arteriolar
vasoconstriction, hypercapnoea causes many
vascular beds to vasodilate; for example, in
skin (thus accounting for the bounding pulse
found in hypercapnoeic patients) and the
cerebral arterioles.
Alkalosis increases myocardial contractility by
increasing the responsiveness of the myocardium
to circulating catecholamines; therefore,
myocardial O2 demand increases. However,
alkalosis also reduces myocardial O2 delivery,
through vasoconstriction of the coronary
circulation and by shifting the oxyhaemoglobin
dissociation curve to the left, thus impairing
offloading of O2 to the myocardium.
 Respiratory system. As discussed above, the main
effect of acidosis on the respiratory system is an
333
 Section 6: Kidney and body fluids
increase in V_ A . The respiratory centre in the
medulla oblongata is stimulated by the carotid
bodies in response to decreased plasma pH, and
by the central chemoreceptors in response to
hypercapnoea (see Chapter 21).
Additional effects of acid–base disturbance on the
respiratory system are:
– The oxyhaemoglobin dissociation curve is
shifted to the right by acidosis and to the left
by alkalosis (see Chapter 7).
– Airway resistance. The effect of acidosis on
airway calibre is complex. Hypercapnoea
causes bronchodilatation through a direct
effect of CO2 on the bronchial smooth muscle.
But hypercapnoea also triggers an increase in
parasympathetic outflow to the bronchi,
indirectly causing bronchoconstriction. In
otherwise healthy hypercapnoeic patients,
indirect bronchoconstriction outweighs direct
bronchodilatation, resulting in an increase in
airway resistance, and consequently an
increase in the work of breathing.
 Electrolyte changes. Acidosis is commonly
associated with hyperkalaemia, which may
precipitate cardiac arrhythmias. Plasma K+
increases by 0.6 mmol/L for every 0.1 unit
decrease in plasma pH. It was previously thought
that H+ underwent intracellular buffering through
exchange with intracellular K+, but it is now
thought that acidosis impairs the Na+/K+-ATPase,
resulting in extracellular K+ leak. Despite the high
plasma K+ concentration, total body K+ stores are
frequently depleted. Thus, the treatment of
acidosis may result in hypokalaemia if K+ is not
simultaneously replaced.
Plasma calcium occurs in two forms: biologically
active ionized Ca2+ and protein-bound unionized
Ca2+ (see Chapter 76). In acidosis, H+ ions
compete for the same binding sites as Ca2+ on
albumin, displacing Ca2+ and thus increasing the
fraction of ionized Ca2+. Conversely, alkalosis
reduces the fraction of ionized Ca2+. As ionized
Ca2+ is the biologically active form, alkalosis
results in an effective hypocalcaemia.
Hypocalcaemia increases the Na+ permeability of
the neuronal cell membrane, making the RMP
more unstable. Paraesthesias (spontaneous
depolarization of sensory receptors) and tetany
334
Downloaded from https://www.cambridge.org/core. University College London (UCL), on 26 Dec 2017 at 07:04:03, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/CBO9781139226394.068
(spontaneous depolarization of motor neurons)
may therefore occur.
+
 CNS. Whilst H cannot cross the BBB owing to its
charge, the high lipid solubility of CO2 allows it to
diffuse into the brain. As discussed in Chapter 45,
hypercapnoea causes vasodilatation of the cerebral
vasculature. CBF is therefore directly proportional
to PaCO2, between the limits of 3.5 and 8.0 kPa:
– Below 3.5 kPa, the cerebral arterioles are
maximally vasoconstricted. Further reductions
in PaCO2 have no effect on the cerebral
vasculature, but the alkalosis-induced leftward
shift of the oxyhaemoglobin dissociation curve
may cause tissue hypoxia, leading to a
subsequent increase in CBF.
– Above 8.0 kPa, the cerebral arterioles are
maximally vasodilated. Further increases in
PaCO2 cause no further increase in CBF.
As CO2 can freely diffuse into the CSF, the pH of
CSF reflects PaCO2, which in turn affects neuronal
function. Patients with respiratory acidosis may
therefore experience headaches (due to the
increased CBF), confusion and impaired
consciousness, extensor plantar responses and
asterixis (CO2 flapping tremor).
Respiratory alkalosis may precipitate epilepsy.
Hypocapnoea induces an alkalosis within the
CNS. In a similar way to the peripheral nerves, the
RMP of the brain’s neurons becomes more
unstable, which results in neuronal excitation and
spontaneous depolarization.
 Bones. Chronic metabolic acidosis leads to bone
decalcification, as bone phosphate is mobilized to
buffer H+ ions. In chronic renal failure, this
contributes to the development of renal
osteodystrophy.
How does pH change with temperature?
Consider the dissociation equilibrium of pure water:
H2O Ð H+ + OH
The pH of pure water is temperature dependent: a
decrease in temperature shifts the equilibrium to the
left, thus reducing the concentration of free H+, which
consequently increases the pH of water.
Likewise, the pH of blood is temperature depend-
ent. Blood pH increases by 0.015 for every 1 °C
decrease in temperature. In addition, as temperature

decreases, the blood solubility of CO2 increases, and
therefore PaCO2 falls.
Arterial blood gas analysers operate at 37 °C. As long
as the patient’s temperature is near to 37 °C, the pH
measured by blood gas analysis will roughly correlate
with the patient’s actual blood pH. However, in a
hypothermic patient, the pH measured at 37 °C may
be significantly lower than the patient’s actual blood pH,
and the measured PaCO2 will be higher than the actual
PaCO2. The pH and PaCO2 can be mathematically cor-
rected to determine their actual values at the patient’s
temperature. For example, a patient whose temperature
is 27 °C may have blood gas analysis (measured at 37 °C)
demonstrating normal pH and PaCO2; that is 7.4 and
5.3 kPa respectively. However, when mathematically
corrected to 27 °C, these values are significantly differ-
ent: pH is 7.55 and PaCO2 is 3.3 kPa.
Clinical relevance: hypothermic cardiopulmonary
bypass
Clinically, the temperature dependence of pH is
important in the context of hypothermic cardiopul-
monary bypass, when the patient’s PaCO2 and thus
pH are controlled by the perfusionist:
 The pH-stat method involves adding CO2 to
blood in the bypass circuit, in order that the
patient’s pH and PaCO2 are maintained at nom-
inally normal values, when corrected to the
patient’s body temperature. It has been sug-
gested that this practice counteracts the leftward
shift in the oxyhaemoglobin dissociation curve
that occurs with hypothermia, thereby improving
O2 delivery. However, increased PaCO2 causes
cerebral vasodilatation, which in turn increases
CBF and abolishes cerebral autoregulation. This
increase in CBF may possibly increase the
embolic load, thus increasing the risk of post-
operative cognitive dysfunction and stroke.
 The alpha-stat method involves permitting the
alkaline drift that occurs with hypothermia,
instead targeting nominally normal pH and
PaCO2 when measured at 37 °C, and accepting
that the patient’s actual blood pH will be >7.45.
This method is thought to maintain cerebral
autoregulation and electrochemical neutrality at
a cellular level, thus maintaining the function of
cellular enzymes.
Despite many studies, it remains unclear whether
pH-stat or alpha-stat is the better technique in
hypothermic cardiopulmonary bypass and deep
hypothermic circulatory arrest.
Downloaded from https://www.cambridge.org/core. University College London (UCL), on 26 Dec 2017 at 07:04:03, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/CBO9781139226394.068
Chapter 66: Acid–base physiology
What is the Stewart approach to
acid–base physiology?
The traditional Henderson–Hasselbalch approach
outlined above is well established, and can easily be
applied to most clinical situations. However, the trad-
itional approach often fails to explain the complex
acid–base abnormalities that occur in critical care
patients.
The Stewart approach was developed in the 1980s.
Though academically sound, the new acid–base
theory was often considered too complex for routine
clinical use. The Stewart approach has recently seen a
resurgence of interest amongst intensive care phys-
icians since the publication of simplified versions of
Stewart theory, most notably by Story et al. in 2004
(see Further reading). A full explanation is beyond the
scope of this book, but a brief account is given below.
There are three independent variables when con-
sidering acid–base balance:
 PaCO2, which is determined by the balance of
CO2 production through cellular metabolic
processes, and CO2 elimination by alveolar
ventilation.
+ +
 Strong ions, electrolytes such as Na , K and Cl ,
which are always fully dissociated from their
counterions. In plasma, strong cations outnumber
strong anions – the difference is called the strong
ion difference (SID).
 Weak acids, which are only partially dissociated
in solution. Weak acids are mainly plasma
proteins, of which albumin is the major
contingent.
Key equations: Stewart–Fencl–Story approach
The simplified Stewart model involves two equations:
BDENaCl ¼ ½Na+ Š ½Cl Š 38 ð1Þ
where BDENaCl (mEq/L) is the base deficit excess for
Na+/Cl /free water.
BDEAlb ¼ 0:25×ð42 ½albuminŠÞ ð2Þ
where BDEAlb (mEq/L) is the base deficit excess for
albumin (in units of grams per litre).
The BDENaCl is the Stewart equivalent of base excess
in Henderson–Hasselbalch theory:
 BDENaCl >0 implies alkalaemia.
 BDENaCl <0 implies acidaemia.
335
 Section 6: Kidney and body fluids
The greater the BDENaCl, the greater the extent of the
acid–base disturbance.
As albumin is negatively charged, hypoalbuminae-
mia causes a metabolic alkalosis, the extent of which
is quantified by BDEAlb.
These simple equations agree with the original
complex Stewart equations surprisingly well. Cru-
cially, the Stewart model can be used to explain the
complex acid–base disturbances that occur in critical
care.
Clinical example: complex acid–base disturbance in
a critical care patient
A patient is admitted to intensive care following a
laparotomy for bowel perforation. Over the next day,
the patient developed severe sepsis. Several days of
mechanical ventilation later, arterial blood gas analy-
sis demonstrated: pH 7.45, PaO2 12.1 kPa, PaCO2
5.0 kPa, HCO3 26 mmol/L, Na+ 147 mmol/L, Cl
115 mmol/L, albumin 12 g/L.
Using the Henderson–Hasselbalch approach, one
might think there was no acid–base abnormality: the
pH and HCO3 are just within the normal range.
However, using the Stewart–Fencl–Story approach:
 BDENaCl ¼ 147 115 38 ¼ 6 mEq/L.
 BDEAlb ¼ 0.25 × (42 12) ¼ 7.5 mEq/L.
336
Downloaded from https://www.cambridge.org/core. University College London (UCL), on 26 Dec 2017 at 07:04:03, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/CBO9781139226394.068
This approach demonstrates a hyperchloraemic
metabolic acidosis and an alkalosis due to severe
hypoalbuminaemia.
Further reading
K. A. A. Aziz, A. Meduoye. Is pH-stat or alpha-stat the best
technique to follow in patients undergoing deep
hypothermic circulatory arrest? Interact Cardiovasc
Thorac Surg 2010; 10(2): 271–82.
A. Badr, P. Nightingale. An alternative approach to acid-
base abnormalities in critically ill patients. Contin Educ
Anaesth Crit Care Pain 2007; 7(4): 107–11.
D. A. Story, H. Morimatsu, R. Bellomo. Strong ions, weak
acids and base excess: a simplified Stewart–Fencl
approach to clinical acid–base disorders. Br J Anaesth
2004; 92(1): 54–60.
J. M. Handy, N. Soni. Physiological effects of
hyperchloraemia and acidosis. Br J Anaesth 2008; 101(2):
141–50.
C. G. Morris, J. Low. Metabolic acidosis in the critically ill:
Part 1. Classification and pathophysiology. Anaesthesia
2008; 63(3): 294–301.
C. G. Morris, J. Low. Metabolic acidosis in the critically ill:
Part 2. Causes and treatment. Anaesthesia 2008; 63(4):
396–411.