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Acid-base balance: a review of normal physiology

Article · February 2002

DOI: 10.1093/bjacepd/2.1.3 · Source: OAI

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 Acid-base balance: a review of
normal physiology
Andrew J Kitching EDICM FRCA
Christopher J Edge MA PhD MB CChem

Regulation of hydrogen ion concentration is of pH of the blood and then calculating PCO2 from
fundamental importance to the living organism the Henderson-Hasselbalch equation (see Key points
because of the effects on body proteins of below). This was relatively inaccurate and time- Regulation of hydrogen
changes in acidity. The function of organs such as consuming. However, Astrup showed that there ion concentration
depends upon homeostat-
the heart and brain is critically dependent on an was a linear relationship between pH and log ic mechanisms in the lung,
internal milieu in which the hydrogen ion content PCO2. By measuring the pH of a blood sample kidney, liver and gut
is kept within carefully regulated limits. Both and then re-measuring pH after equilibration The lungs excrete the
volatile acids (i.e. carbonic acid) and non-volatile with two different CO2 mixtures, the PCO2 of the acid produced as a result
acids (e.g. lactic acid) may contribute to the patient could be interpolated. of metabolism as carbon
dioxide
hydrogen ion concentration in the cells. The acid From then on, the focus of acid-base physio-
The kidneys excrete
load produced each day is substantial. Physio- logy was concentrated on the carbon dioxide/
40–70 mmol per day of
logical processes alter the acid-base composition bicarbonate system. More sophisticated equip- acid produced from the
with the kidney excreting non-volatile acids, and ment became available which quickly and accu- breakdown of inorganic
the lung volatile acid as carbon dioxide. rately determined blood pH and PCO2. As the acids
Blood pH in health varies between 7.35 and lungs excrete 13,000 mEq acid per day (as CO2), The liver and the kidney
are both involved in
7.45 (intracellular fluid pH is usually in the there has been a tendency to regard the carbon
ammonium metabolism
range 7.0–7.3). Thus, hydrogen ion concentra- dioxide/bicarbonate system as the only one of which is central to the re-
tion in the blood is in the range 45–35 nmol l–1. importance in the regulation of hydrogen ion con- absorption of bicarbonate
This means that hydrogen ion concentration is centration. The metabolic component of any aci- Application of fundamen-
about 106 times smaller than the serum sodium dosis was measured by eliminating the effects of tal principles of physical
chemistry has recently
ion concentration, yet it is kept within tight limits. the respiratory component with a series of correc-
emphasised the impor-
This is a remarkable achievement, made all the tions. For example, standard bicarbonate is the tance of the chloride ion
more remarkable by the fact that hydrogen is a concentration of bicarbonate in the plasma when in acid-base balance
very small ion with a very high charge density. It the haemoglobin in the whole blood has been
is, therefore, capable of being extremely mobile fully oxygenated, at a temperature of 37°C and
with hydrogen bonds being made and broken eas- corrected to a PCO2 of 40 mmHg (5.33 kPa).
ily. Indeed, the concept of an isolated hydrogen Siggaard-Andersen’s nomogram was an attempt
ion is a theoretical one; the high charge density of to help clinicians work out the relative impor-
a proton means that hydrogen ions exist as part of tance of a metabolic or respiratory component to
bigger molecules, e.g. H9O4+. an acid-base problem. However, more recent
analyses of the theory of acid-base balance show
Historical aspects Andrew J Kitching
that the carbon dioxide/bicarbonate system is EDICM FRCA
The history of acid-base measurement in patients only part of the picture (see later). Consultant Anaesthetist,
is closely linked to the history of artificial ventila- This article examines the role of the lung and Royal Berkshire and Battle Hospitals
NHS Trust, London Road,
tion. The poliomyelitis epidemic in Copenhagen kidney in the regulation of hydrogen ion con- Reading RG1 5AN
in 1952 led to large numbers of patients receiving centration. We introduce the basic concepts of Christopher J Edge
artificial ventilation. It was, therefore, necessary the physicochemical approach which, in recent MA PhD MB CChem
Specialist Registrar,
to develop a quick, accurate method of measuring years, has contributed greatly to the debate on Nuffield Department
PCO2 in the blood in order to determine the ade- the understanding of acid-base balance. Also, of Anaesthetics,
John Radcliffe Hospital,
quacy of ventilation. Initially, this was done by we outline the role of the gut and liver in hydro- Headley Way, Oxford OX3 9DU
measuring the bicarbonate concentration and the gen ion homeostasis.
British Journal of Anaesthesia | CEPD Reviews | Volume 2 Number 1 2002
© The Board of Management and Trustees of the British Journal of Anaesthesia 2002 3
Acid-base balance: a review of normal physiology

The lungs gut, pancreas, cardiac and skeletal muscle and pulmonary capil-
Aerobic metabolism generates CO2 as a waste product. Acid, in lary endothelium. There are seven isoenzymes so far identified of
the form of hydrogen ions generated by metabolism, combines this zinc-containing protein.
with bicarbonate to form carbonic acid. This is then catalysed by The largest fraction of dissolved CO2 is in the form of bicar-
carbonic anhydrase to form CO2 and water. Water is excreted bonate ion, formed by the dissociation of carbonic acid:
mainly in the urine, with small amounts in the breath, sweat and H2CO3 HCO3– + H+
faeces: the lungs excrete CO2. This so-called ‘volatile acid’ load At a pH of 7.4, over 96% of H2CO3 is dissociated. This chemical
amounts to approximately 13,000 mEq of acid per day. As CO2 equilibrium can be written as:
is continuously excreted by the lungs, and water from the kidney, [H+][HCO3–]
there is no net gain in hydrogen or bicarbonate ions. Ka =
[H2CO3]
Nearly all CO2 is produced in the mitochondria. PCO2 values
are at their greatest in the mitochondria and they fall as a series And re-arranged as:
of tension gradients as the gas passes through cellular fluid and [H2CO3]
[H+] = Ka ×
membrane into extracellular fluid and then blood. In the lungs, [HCO3–]
the PCO2 of the blood entering the pulmonary capillaries is nor- which is the Henderson equation. Then, taking logarithms to base
mally higher than in the alveoli. Thus, CO2 diffuses from blood 10 of the reciprocal of each term in the equation we get:
to alveolar gas. The equilibrium concentration in the alveoli is [HCO3–]
dependent on CO2 production, pulmonary circulation and alveo- pH = pKa + log
lar ventilation. [H2CO3]
Carbon dioxide is carried in the blood as dissolved CO2, bicar- which is the Henderson-Hasselbalch equation.
bonate ion, or as a carbamino group attached to a plasma protein With a pH of 7.4 and a pKa of 3.7 we get:
or haemoglobin. This binding of CO2 with amino groups takes [HCO3–]
log = 3.7
place on the N-terminal amino acid in each protein and amino- [H2CO3]
acids containing side chain amino groups such as lysine and argi-
Therefore, the ratio of bicarbonate to carbonic acid which will
nine. Both hydrogen ion and CO2 compete for the binding site,
give a normal pH is about 5000 to 1. If bicarbonate falls in aci-
so the whole process is pH dependent:
dosis, carbonic acid and hence PCO2 will also fall to preserve the
–NH2 + CO2 –NHCO2H –NHCO2– + H+ ratio and stabilise the pH. H2CO3 cannot be measured, but, using
–NH2 + H+ –NH3+ Henry’s law, we can replace it in the factor with αPCO2, which is
the total amount of CO2 dissolved in the blood (α = solubility of
Most CO2 is carried on haemoglobin, very little on plasma pro-
CO2 in blood). Note that the usual form of the equation is:
teins. Reduced haemoglobin has an affinity 3.5 times greater for
CO2 than the oxygenated form. Carbon dioxide binds to the N- [HCO3–]
pH = pK′a + log
terminal α- and β-chain amino groups. However, there is com- αPCO2
petition with 2,3-DPG for the binding site. Carbamino formation
where pK′a has the value 6.1. This takes into account the equi-
is not dependent on hydration of CO2. Therefore, it is indepen-
librium constant for the reaction:
dent of carbonic anhydrase activity.
H2O + CO2 H2CO3
In solution:
[CO2] = PCO2 × solubility coefficient of carbon dioxide
The kidney
in plasma (Henry’s law)
The net excretion of acid by the kidney is approximately 75 mmol
Carbon dioxide in solution hydrates:
per day. The principal buffers involved in acid excretion (and as a
CO2 + H2O H2CO3 HCO3– + H+ consequence bicarbonate regeneration) are hydrogen phosphate
This reaction is non-ionic and slow, with an equilibration time and ammonium ion.
of several minutes. The whole process can be speeded up to frac- The kidney recovers over 99% of the filtered load of bicar-
tions of seconds by the enzyme catalyst carbonic anhydrase. This bonate and also generates further bicarbonate. At normal con-
enzyme is present in erythrocytes (but not plasma), the nephron, centrations of serum bicarbonate (usually about 24 mmol l–1), the

4 British Journal of Anaesthesia | CEPD Reviews | Volume 2 Number 1 2002

 Acid-base balance: a review of normal physiology

ammonia and hydrogen phosphate act as urinary buffers, soaking

Interstitium/
Lumen
up hydrogen ion to maintain a concentration gradient and indirect-

blood
Cell
ly allowing net bicarbonate generation.
Ammonium ion is produced mainly in PCT cells by the de-ami-
3Na+ nation of glutamic acid to 2-oxoglutarate and NH4+. The ammoni-
2K+ um ion can then either dissociate into ammonia and a hydrogen ion
Na+ +
or be directly secreted via apical membrane Na+/NH4+ exchange.
–
HCO3 + H+
– H+ + HCO3 H2CO3 Na The importance of this last process is still debated. Ammonia dif-
CA II fuses across the PCT membrane down a concentration gradient
H2CO3 H2O + CO2 (created when the secreted H+ combines with the ammonia to
CA IV
reform ammonium ion) and H+ is transported out on the Na+/H+
H2O + CO2
K+ antiporter. In all other parts of the nephron, ammonium is trans-
ported on a Na+/H+ ion transporter, with the ammonium taking the
Fig. 1 Proximal convoluted tubule. CA, carbonic anhydrase. place of hydrogen ion. The 2-oxoglutarate left behind in the tubule
cells reacts with H+ to form glucose or CO2, which forms bicar-
bonate. This bicarbonate is transported into the plasma via an elec-
tubular transport mechanisms in the kidney are almost fully trogenic Na+/HCO3– co-transport mechanism. Thus, the de-amina-
utilised, i.e. they are close to their Tmax. Thus, if serum bicarbonate tion of glutamate generates NH4+ which buffers the hydrogen ions
increases much above 25 mmol l–1, more bicarbonate is lost in the and produces bicarbonate for the plasma.
urine until the serum concentration drops below that associated If NH4+ remains in the body, it combines with bicarbonate in the
with Tmax. Tmax for bicarbonate also varies directly with the frac- liver to form urea, which means no net gain of bicarbonate. The
tional sodium absorption and with hydrogen ion secretion. greater the secretion of NH4+, the greater the bicarbonate genera-
In the proximal convoluted tubule (PCT), 90% of filtered bicar- tion. Conversely, if excess bicarbonate and ammonium are gener-
bonate is re-absorbed. Luminal bicarbonate picks up a hydrogen ated (e.g. from increased dietary intake of protein), hepatic urea
ion to form carbonic acid (the hydrogen ion has been secreted in synthesis increases from the excess ammonium and bicarbonate
exchange for sodium using a Na+/H+ antiporter). In the presence of present. A potent feedback circuit adjusts urea cycle flux in the liver
carbonic anhydrase (isoenzyme IV) present on the luminal brush to the changes in acid-base balance. With more nitrogen ‘pack-
borders, CO2 and water are formed and pass into the cell by sim- aged’ as urea, less glutamate is available for the kidney to use for
ple diffusion (Fig. 1). Within the luminal cell, again catalysed by the generation of ammonium ions. This illustrates the liver’s role in
carbonic anhydrase (this time isoenzyme II), carbonic acid briefly bicarbonate homeostasis and in acid-base balance.
reforms and then dissociates to bicarbonate and hydrogen ion. Some 50% of NH4+ produced in the PCT cells is re-absorbed by
Hydrogen ion is then available for further secretion. On the blood the thick ascending loop of Henle and accumulates in the medullary
side of the luminal cell, sodium and bicarbonate are transported interstitium. This absorption is by the Na+/NH4+/2Cl– absorber
across the cell membrane using a co-transporter. The rate of (NH4+ substitutes for K+ on the co-transporter). The NH4+ absorption
absorption of bicarbonate is directly proportional to PCO2. lowers the luminal concentration and hence also lowers the NH3 con-
The distal convoluted tubule (DCT) re-absorbs 10% of the fil- centration as removal of NH4+ shifts the equilibrium towards NH4+.
tered load of bicarbonate. In this section of the nephron, bicarbon- The NH4+ from the medullary interstitium is then secreted as
ate absorption is dependent on the action of two transporters: an NH3 by the cells of the collecting ducts (non-ionic diffusion) and
H+/K+-ATPase and Na+/H+ transport exchange (aldosterone-depen- converted into NH4+ in the collecting tubule lumen by combination
dant) in the principal cells. Again, secreted hydrogen ion combines with secreted H+ (Fig. 2). NH4+ excretion is increased in acidosis
with bicarbonate in the urine to form carbonic acid and hence CO2 because: (i) the de-amination enzymes are stimulated by acidosis;
and water, which then passes into the cells as in the PCT. and (ii) NH3 conversion to NH4+ in the collecting tubule is greater
For the generation of new bicarbonate, a buffer in the filtrate if H+ secretion is greater as this maintains a gradient for NH3 sec-
is needed in order to mop-up hydrogen ion and maintain a retion so that more NH3/NH4+ is removed from the renal medulla.
concentration gradient. Indeed, continuous unbuffered secretion Urinary phosphate buffering takes place predominantly in the
of hydrogen ion would quickly damage the nephron. This is where DCT generating bicarbonate. Secreted hydrogen ion combines

British Journal of Anaesthesia | CEPD Reviews | Volume 2 Number 1 2002 5

 Acid-base balance: a review of normal physiology

The mathematical equation produced which predicts hydrogen ion

men Cell Interst concentration is a higher order polynomial equation but only three
Lumen blo
Interstitium/
independent variables determine hydrogen ion concentration: (i)
blood
PCO2; (ii) total weak acid concentration – mainly plasma proteins
Glutamine
(principally albumin) and phosphates; and (iii) strong ion differ-
ence (SID) – given by the total concentration (in mequiv/l) of fully
NH3 + H+ NH4+ α-KG2– dissociated cations in solution minus the total concentration of fully
HCO3–
dissociated anions in solution. Thus, a normal SID would be
–
approximately 42–46 mmol l–1 and is obtained by adding together
H+ + HCO3 H2CO3
the concentrations in milliequivalents per litre of the main cations
CA
H2O + CO2
in solution (Na+, K+, Ca2+, Mg2+) and subtracting the concentra-
tions of the main anions in solution (Cl–, lactate).
Note that bicarbonate is not an independent variable in this
Fig. 2 Renal collecting ducts. α-KG = 2-oxoglutarate. analysis. Bicarbonate concentration changes only in response to
changes in PCO2, SID (if the SID narrows because Cl– is rising,
with phosphate filtered at the glomerulus to form hydrogen bicarbonate will fall), or total weak acid. Nothing else will affect
phosphate. The H2PO4– constitutes the titratable acid of urine. This bicarbonate concentration.
process is facilitated in systemic acidosis because tubular resorp- From Stewart’s approach comes the realisation that acid-base
tion of filtered phosphate buffer is inhibited, making more phos- balance is not only affected by the lungs (by altering PCO2), and
phate buffer available in the urine to combine with hydrogen ion. the kidneys (by altering chloride and strong ion difference). The
Titratable acid is only a fraction of total acid secretion because liver and gut can have a major effect on acid-base balance too (by
total H+ secretion equals bicarbonate re-absorption plus acid phos- altering the level of total weak acid). The metabolic alkalosis
phate excretion plus ammonium excretion, and only acid phos- associated with chronic hypoalbuminaemia occurrs because the
phate is titratable acid. concentration of a weak acid-albumin- is reduced. We can also
explain how excessive infusions of saline result in metabolic aci-
Recent developments in acid-base theory dosis. There is a greater rise in the plasma chloride concentration
The conventional model of renal and pulmonary regulation of than the plasma sodium concentration, and therefore a narrowing
hydrogen ion concentration as outlined above was, until recently, of the strong ion difference (impurities from the infusion bag and
accepted as fundamental. However, there are problems with this dissolved CO2 also have some effect, which is why an infusion
model. In order for bicarbonate to influence pH in accordance with bag of 0.9% sodium chloride has a pH of 5.0–6.0).
the Henderson-Hasselbalch equation, it would have to be indepen- The emphasis of the Stewart thesis is that to understand what is
dent of PCO2. But we know that HCO3– varies with CO2 which can happening pathophysiologically, we need to measure the changes in
lead to confusion when measuring the metabolic component of these fundamental variables. Measurement of chloride concentra-
acid-base balance. tion will thus become of greater importance in future. If chloride is
In 1983, Stewart published what has now become a landmark low or normal and there is acidosis, another strong ion must be pre-
paper in this field. He showed that the carbon dioxide/bicarbonate sent in the blood, for example lactate or a ketoacid.
system could not be viewed in isolation. By invoking fundamental
Key references
physicochemical laws such as the law of mass action and the law
Good DW, Knepper MA. Mechanisms of ammonium excretion: role of the
of electroneutrality, he showed that complex solutions like biolog- renal medulla. Semin Nephrol 1990; 10: 166–73
ical fluids have their hydrogen ion concentration set by multiple Lumb AB. Carbon dioxide. In: Nunn’s Applied Respiratory Physiology, 5th edn.
chemical equilibria reactions. None of these equilibria can be London: Butterworth-Heinemann, 2000
Stewart PA. Modern quantitative acid-base chemistry. Can J Physiol Pharmacol
viewed in isolation and all have to be satisfied simultaneously. The
1983; 61: 1444–61
Henderson-Hasselbalch equation is just one of these equations. Sykes MK,Vickers MD, Hull CJ. Principles of Measurement and Monitoring in
A mathematical model can be produced from these assumptions, Anaesthesia and Intensive Care, 3rd edn. Oxford: Blackwell, 1991
which accurately predicts the concentration of hydrogen ion even Unwin RJ, Capasso G.The renal tubular acidoses. J R Soc Med 2001; 94: 221–5
in the critically ill patient with seriously disordered biochemistry. See multiple choice questions 1–4.

6 British Journal of Anaesthesia | CEPD Reviews | Volume 2 Number 1 2002

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