CHAPTER
Regulation of Hydrogen Ion Concentration
25 (Acid–Base Balance)
Marek H. Dominiczak and Mirosława Szczepańska-Konkel
LEARNING OBJECTIVES
After reading this chapter you should be able to:
■ Explain the nature of the bicarbonate buffer.
■ Describe the gas exchange in the lungs.
■ Describe the respiratory and metabolic components of the
acid–base balance.
■ Define and classify acidosis and alkalosis.
■ Comment on clinical conditions associated with
disturbances of the acid–base balance.
INTRODUCTION
Acids are produced in the course of metabolism
Metabolism generates carbon dioxide within cells. Carbon
dioxide dissolves in water, forming carbonic acid, which in
turn dissociates releasing hydrogen ion. The acids derived
from sources other than CO2 are known as nonvolatile; by
definition, they cannot be removed through the lungs, and
must be excreted via the kidney. The net production of non-
volatile acids is in the order of 50 mmol/24 h.
Lactic acid is produced during anaerobic glycolysis and its
concentration in plasma is the hallmark of hypoxia. Ketoacids
(acetoacetic and β-hydroxybutyric acid) are important in dia-
betes (Chapter 21). The metabolism of sulfur-containing
amino acids and phosphorus-containing compounds also
generates inorganic acids.
In spite of the amount of hydrogen ion produced, its
blood concentration (or its negative logarithm, the pH), is
remarkably constant: it remains between 35 and 45 nmol/L
(pH 7.35–7.45). Maintenance of stable pH is essential
because it affects the ionization of proteins (Chapter 2) and,
consequently, the activity of many enzymes and other bio-
logically active molecules such as ion channels. Changes in
pH together with the partial pressure of carbon dioxide
(pCO2) affect the shape of the hemoglobin saturation curve,
and thus tissue oxygenation (Chapter 5). Also, a decrease in
pH increases sympathetic tone and may lead to cardiac
dysrhythmias.
Maintaining the acid–base balance involves lungs,
erythrocytes and kidneys
The acid–base balance involves the lungs, the erythrocytes,
and the kidneys (Fig. 25.1). The lungs control the exchange
of carbon dioxide and oxygen between the blood and the
atmosphere; the erythrocytes transport gases between lungs
and tissues; and the kidneys control plasma bicarbonate syn-
thesis and the excretion of the hydrogen ion.
Clinical relevance
Clinically, understanding of the acid–base balance is impor-
tant in many sub-specialties of medicine and surgery, and
particularly in anesthesiology and critical care medicine.
BODY BUFFER SYSTEMS:
RESPIRATORY AND METABOLIC
COMPONENTS OF THE ACID–BASE
BALANCE
Blood and tissues contain buffer systems that minimize
changes in hydrogen ion concentration
The main buffer that neutralizes hydrogen ions released from
cells is the bicarbonate buffer. Another important buffer is
hemoglobin, which contributes to buffering of hydrogen ion
generated from the carbonic anhydrase reaction. Within cells,
the hydrogen ion is neutralized by intracellular buffers, mainly
proteins and phosphates (Table 25.1 and Chapter 2).
Bicarbonate buffer is an open system which remains at
equilibrium with atmospheric air
Buffering capacity of the bicarbonate buffer exceeds all the
‘closed’ buffer systems. The metabolically produced CO2 dif-
fuses through cell membranes and dissolves in plasma. The
plasma solubility coefficient of CO2 is 0.23 if pCO2 is meas-
ured in kPa (0.03 if pCO2 is measured in mmHg; 1 kPa =
7.5 mmHg or 1 mmHg = 0.133 kPa)). Thus, at the normal
pCO2 of 5.3 kPa (40 mmHg), the concentration of dissolved
CO2 (dCO2) is:
dCO2 (mmol / L) = 5.3 kPa × 0.23 = 1.2 mmol / L
CO2 equilibrates with H2CO3 in plasma in the course of a
slow, nonenzymatic reaction. Normally plasma H2CO3 con-
centration is very low, about 0.0017 mmol/L. However,
because of the equilibrium between H2CO3 and dissolved CO2
 CHAPTER 25 Regulation of Hydrogen Ion Concentration (Acid–Base Balance) 333

Fig. 25.1 Acid–base balance. Lungs, kidneys,

Urine and erythrocytes contribute to the mainte-
Expired CO2 + H2O CO2 + H2O
air nance of the acid–base balance. The lungs
control the gas exchange with the atmospheric
air. Carbon dioxide generated in tissues is
transported in plasma as bicarbonate; the
H2CO3 Urinary erythrocyte hemoglobin contributes to CO2
H2CO3 H+ excretion transport. Hemoglobin also buffers the hydro-
of H+ gen ion derived from carbonic acid. The kidneys
Lung
reabsorb filtered bicarbonate in the proximal
H+ HCO3– tubules and generate new bicarbonate in the
HCO3– distal tubules, where there is a net secretion of
hydrogen ion. Hb, hemoglobin.
Bicarbonate
reabsorption
HHb

Hb

H+

HCO3–
Kidney
H2CO3

Plasma

H2O CO2 H+

Tissues
Erythrocyte

CO2 H+

The equation demonstrates that blood pH is determined

Table 25.1 The main buffers in the human body by the ratio between the concentration of plasma bicarbo-
Conjugate Site of main
nate (the ‘base’ component of the buffer) and the concen-
Buffer Acid base buffering action tration of dissolved CO2 (the ‘acid’ component). Normally,
at pCO2 of 5.3 kPa and dCO2 concentration 1.2 mmol/L (see
Hemoglobin HHb Hb− Erythrocytes
above) the plasma bicarbonate concentration is about
Proteins HProt Prot− Intracellular fluid 24 mmol/L. The pK of the bicarbonate buffer is 6.1. Let’s
Phosphate buffer H2PO4 −
HPO4 2−
Intracellular fluid insert the actual concentrations of buffer components into
the preceding equation:
Bicarbonate CO2 → H2CO3 HCO3 −
Extracellular fluid

pH = 6.1 + log(24/1.2) = 7.40

See Chapter 2 for the principles of buffering action. The Brønsted–Lowry
definition of an acid is ‘a molecular species that has a tendency to lose a
hydrogen ion, forming a conjugate base’.
(theoretically all dissolved CO2 could eventually convert into
H2CO3), this component of the bicarbonate buffer can be taken
as equal to the sum of the H2CO3 and the dissolved CO2. The key
equation describing the behavior of the bicarbonate buffer is
the Henderson–Hasselbalch equation (Chapter 2). It
expresses the relationship between pH and the components of
the buffer:
Thus the normal concentration of bicarbonate and normal
partial pressure of CO2 correspond to pH 7.40 (hydrogen ion
concentration 40 nmol/L). The bicarbonate buffer minimizes
changes in hydrogen ion concentration when acid is added to
blood.
When the H+ concentration in the system increases,
the bicarbonate component of the buffer accepts (H+), form-
ing carbonic acid, which is subsequently converted into CO2
and H2O in the reaction catalyzed by carbonic anhydrase:

pH = pK + log ([ bicarbonate ]/ pCO2 × 0.23) H + + HCO3−  H2CO3  CO2 + H2O

334 CHAPTER 25 Regulation of Hydrogen Ion Concentration (Acid–Base Balance)

The CO2 is eliminated through the lungs. The excess hydro-
gen ion has been neutralized and the [bicarbonate]/pCO2
ratio brought back towards normal.
On the other hand, when the H+ concentration
decreases, the carbonic acid component of the buffer will
dissociate to supply H+ for a reaction that will yield water and
bicarbonate ion (at this stage the increase in plasma bicarbo-
nate is minimal):
H2CO3 → H + + HCO3−
Subsequently, the ventilation rate will decrease, retaining CO2
and attempting to normalize the [bicarbonate]/pCO2 ratio:
CO2 + H2O → H2CO3
Thus the denominator in the Henderson–Hasselbalch equa-
tion (pCO2) is controlled by the lungs. For this reason it is
called ‘the respiratory component of the acid–base bal-
ance’. On the other hand, plasma bicarbonate concentration
is controlled by the kidneys and erythrocytes and, conse-
quently, it is called ‘the metabolic component of the
acid–base balance’ (Fig. 25.2).
Carbonic anhydrase converts the dissolved CO2 into
carbonic acid
Erythrocytes and renal tubular cells contain a zinc-containing
enzyme, carbonic anhydrase (CA), which converts dissolved
CO2 into carbonic acid. Carbonic acid dissociates, yielding
hydrogen and bicarbonate ions:
CA
CO2 + H2O  
 H2CO3 
 H + HCO3
+ −
and synthesis, and the erythrocytes adjust its concentration
in response to changes in pCO2.
Respiratory and metabolic components of the acid–base
balance are interlinked
The respiratory and metabolic components of the acid–base
balance are closely inter-dependent: one tends to compensate
for the untoward changes in the other. When the primary dis-
order is respiratory (such as, for instance, a severe chronic
obstructive airway disease, COAD) and causes accumulation
of CO2, a compensatory increase in bicarbonate reabsorption
by the kidney takes place. Conversely, the decrease in pCO2 (as
happens during hyperventilation in an asthmatic attack)
would cause a kidney response, leading to decreased bicarbo-
nate reabsorption.
Conversely, when the primary problem is metabolic (for
instance, diabetic ketoacidosis), a decrease in bicarbonate
concentration and the resulting decrease in pH stimulate the
respiratory center to increase the ventilation rate. The CO2 is
blown off and plasma pCO2 decreases. This is why patients
with metabolic acidosis hyperventilate. On the other hand,
an increase in plasma bicarbonate (causing an increase in
pH) leads to a decrease in the ventilation rate, and to CO2
retention. Thus, the compensatory change always tends to
normalize the [bicarbonate]/pCO2 ratio, helping to bring the
pH towards normal (Fig. 25.3).
[HCO–3]: [HCO–3]:
Metabolic Metabolic
acidosis alkalosis

pCO2: pCO2:
Respiratory Respiratory
This is how renal tubular cells and erythrocytes produce
acidosis alkalosis
bicarbonate. The kidneys regulate bicarbonate reabsorption

HCO–3
Kidney pH~
pCO2
Metabolic
component

Acidosis Alkalosis
A process A process
[HCO–3]
pH
~ pCO2 Lungs
that results in
a decrease of
blood pH ( [H+])
that results in
an increase of
blood pH ( [H+])

Respiratory
component

Fig. 25.3 Disorders of the acid–base balance. A primary increase in

Fig. 25.2 The bicarbonate buffer. Blood pH is proportional to the ratio
of plasma bicarbonate to the partial pressure of carbon dioxide (pCO2).
The components of the bicarbonate buffer are thus the carbon dioxide
and the bicarbonate. The pCO2 is the respiratory component of acid–
base balance, and bicarbonate is the metabolic component.
pCO2, or a decrease in plasma bicarbonate concentration, lead to aci-
dosis. A decrease in pCO2, or an increase in plasma bicarbonate, lead to
alkalosis. If the primary change is in pCO2, the disorder is called respira-
tory, and if the primary change is in plasma bicarbonate, it is called
metabolic.
 CHAPTER 25 Regulation of Hydrogen Ion Concentration (Acid–Base Balance) 335

Intracellular buffering The measurement of blood gases

Intracellular buffers are proteins and phosphates
The two main intracellular buffers are proteins and phos-
phates, and the buffering is governed by the HPO42–/H2PO4–
and [protein]/protein-H } ratios. Hemoglobin is an important
extracellular protein buffer.
Note that when the hydrogen ion is present in plasma in
excess, it enters cells in exchange for potassium and this may
result in an increase in plasma potassium concentration.
Conversely, a decrease in plasma hydrogen ion, or bicarbo-
nate excess, would be buffered by cell-derived hydrogen ion.
Hydrogen ion would enter plasma in exchange for potassium,
decreasing plasma potassium concentration. Thus acidemia,
(low blood pH) may be associated with hyperkalemia, and
alkalemia (high blood pH) is associated with hypokalemia
(Fig. 25.4).
The ‘blood gas measurement’ is an important first-line labo-
ratory investigation. In respiratory failure, it is also essential
to guide oxygen therapy and assisted ventilation.
The measurements are performed on a sample of arterial
blood, taken usually from the radial artery in the forearm.
The jargon term ‘blood gases’ means the measurements of
pO2, pCO2, and pH (or hydrogen ion concentration) from
which the concentration of bicarbonate is calculated using
the Henderson–Hasselbalch equation. Several other indices
are also computed: they include the total amount of buffers
in the blood (the buffer base) and the difference between the
desired (normal) amount of buffers in the blood and the
actual amount (base excess). The reference values for pH,
pCO2, and O2 are given in Table 25.2.

LUNGS: THE GAS EXCHANGE

The lungs supply oxygen necessary for tissue metabolism
Intracellular buffering in acidosis and remove the generated CO2
Plasma
Erythrocyte Approximately 10,000 L of air pass through the lungs of an
Tissue buffering in average person each day. Lungs lie in the thoracic cavity
acidosis can lead
to plasma [K+]
Prot –

HPO42– Table 25.2 Reference ranges for blood gas results

H+ H+
A. Reference ranges*
Arterial Venous
HProt – K+ K+
[H+] 35–45 mmol/L
H2PO4–
pH 7.35–7.45
pCO2 4.6–6.0 kPa 4.8–6.7 kPa (36–50 mm Hg)
Intracellular buffering in alkalosis (35–45 mm Hg)
Erythrocyte
pO2 10.5–13.5 kPa 4.0–6.7 kPa (30–50 mm Hg)
Tissue buffering in
(79–101 mm Hg)
alkalosis can lead
to plasma [K+] Bicarbonate 23–30 mmol/L 22–29 mmol/L
HProt –
B. Comparison of conventional and SI units of hydrogen
H2PO –4
ion concentration
H+ H+
Conventional units: pH SI units: [H+] nmol/L
6.8 160
Prot – K+ K+
7.1 80
HPO42–
7.4 40
7.7 20
Fig. 25.4 Intracellular buffers: proteins, phosphates, and the
potassium–hydrogen ion exchange. Intracellular buffers are prima-
rily proteins and phosphates. However, the hydrogen ion enters cells in *The measured values in ‘blood gases’ are pH, pCO2 and pO2; the
exchange for potassium. Therefore, an accumulation of the hydrogen bicarbonate concentration is calculated from pH and pCO2 values; pH
ion in the plasma (acidemia) and the consequent entry of excess of below 7.0 or above 7.7 is life threatening. (Adapted with permission from
hydrogen ion into cells increase plasma potassium concentration. Hutchinson AS. In Dominiczak MH, editor. Seminars in clinical
Conversely, a deficit of hydrogen ion in plasma (alkalemia) may lead to biochemistry, Glasgow, 1997, Glasgow University Press.)
a low plasma potassium concentration. Prot, protein.
336 CHAPTER 25 Regulation of Hydrogen Ion Concentration (Acid–Base Balance)

surrounded with the pleural sac, a thin ‘bag’ of tissue that Ventilation and lung perfusion together determine
lines the thoracic cage at one end, and attaches to the exter- gas exchange
nal surface of the lungs at the other. When the thoracic cage Blood supply to the pulmonary alveoli is provided by the pul-
expands during inspiration, negative pressure created in the monary arteries that carry deoxygenated blood from the
expanding pleural sac inflates the lung. periphery and through the right ventricle. After its oxygena-
The airways are ‘tubes’ of progressively decreasing diame- tion in the lungs, the blood flows through pulmonary veins to
ter. They consist of the trachea, large and small bronchi, and the left atrium. In the alveolar capillaries of the lungs, it
even smaller bronchioles (Fig. 25.5). At the end of the bron- accepts oxygen, which diffuses through the alveolar wall
chioles, there are pulmonary alveoli – structures lined with from the inspired air; at the same time the CO2 diffuses from
endothelium and covered with a film of surfactant – the main the blood into the alveoli (Fig. 25.5) and is removed with the
component of which is dipalmitoylphosphatidylcholine expired air.
(Chapter 26). Surfactant decreases the surface tension of the The rate of diffusion of gases in and out of the blood is
alveoli. The gas exchange takes place in the alveoli. determined by the difference in partial pressures between
alveolar air and blood. Table 25.3 shows the pO2 and pCO2 in
Respiration rate is controlled by the respiratory center
located in the brainstem
Both the partial pressures of oxygen (pO2) and carbon diox- CO2 O2
ide (pCO2) affect the ventilation rate: the respiratory center
has chemoreceptors sensitive to pCO2 and to pH. Under nor- Bronchi Trachea
mal circumstances it is not the pO2 that stimulates ventila-
tion, but the increase in pCO2 or the decrease in pH.
However, when the pO2 falls and hypoxia develops, it begins Bronchioles
to control ventilation through a set of receptors located
in the carotid bodies in the aortic arch. When arterial pO2 Alveoli
decreases to less than 8 kPa (60 mmHg), this ‘hypoxic
drive’ becomes the main controller of the ventilation rate. Blood
Persons who suffer from hypoxia due to chronic lung dis- Aortic arch Respiratory center
ease depend on hypoxic drive to maintain their ventilation baroreceptors Brain
rate (see Clinical Box on this page). Heart Low O2

High CO2

CLINICAL BOX
RESPIRATORY ACIDOSIS OCCURS
IN CHRONIC LUNG DISEASE Tissues

A 56-year-old woman was admitted to a general ward with

Fig. 25.5 Control of the respiratory rate by pCO2 and pO2. Lung
increasing breathlessness. She had smoked 20 cigarettes a day ventilation and perfusion are main factors controlling gas exchange. The
for the previous 25 years and reported frequent attacks of ‘win- pCO2 regulates the ventilation rate through central chemoreceptors in
ter bronchitis’. Blood gas measurements revealed a pO2 of 6 kPa the brainstem. When pO2 decreases, this control switches to pO2-
(45 mmHg), pCO2 of 8.4 kPa (53 mmHg), and pH 7.35 (hydro- sensitive peripheral receptors in the carotid bodies and in the aortic arch.
gen ion concentration 51 nmol/L); bicarbonate concentration
was 35 mmol/L (for reference ranges, refer to Table 25.2).
Table 25.3 Partial pressures of oxygen and carbon dioxide in
Comment. This patient presented with an exacerbation of
atmospheric air, lung alveoli, and the blood [kPa(mm Hg)]
chronic obstructive pulmonary disease (COPD) and a respi-
ratory acidosis. Her pCO2 was high, and therefore her ventilation Dry air Alveoli Systemic arteries Tissue
was dependent on hypoxic drive. Her bicarbonate concentration
was also increased, as a result of metabolic compensation of pO2 21.2(39) 13.7(98) 12(90) 5.3(40)
respiratory acidosis. One must be careful when treating such pCO2 <0.13(0.1) 5.3(40) 5.3(40) 6.0(45)
patients with high concentrations of oxygen, because the
increased pO2 may remove hypoxic drive and cause respiratory Water vapor 6.3(47)
depression. Monitoring of arterial pO2 and pCO2 on oxygen
treatment is mandatory. This patient was successfully treated Partial pressure gradients determine diffusion of gases through the
with 28% oxygen. alveolar/blood barrier (1 kPa = 7.5 mmHg).
 CHAPTER 25 Regulation of Hydrogen Ion Concentration (Acid–Base Balance)
the lungs. Compared with the atmospheric air, pCO2 in the
alveolar air is slightly higher and pO2 slightly lower (this is
due to the water vapor pressure). Carbon dioxide is much
more soluble in water than oxygen, and equilibrates with
blood more rapidly. Therefore, when problems develop, one
first notices a decrease in blood pO2 (hypoxia). An increase in
pCO2 (hypercapnia) occurs later and usually indicates a more
severe disease. The other major factor determining gas
exchange is the rate at which the blood flows through the
lungs (the perfusion rate). Normally the alveolar ventilation
rate is approximately 4 L/min and the perfusion 5 L/min (the
ratio of ventilation to perfusion (Va/Q) is 0.8).
Different combinations of disturbed ventilation and
perfusion may occur
In pathologic conditions, some parts of the lung may be
well-perfused, but poorly ventilated. This occurs when some
alveoli collapse and are unable to exchange gases. As a result,
the blood pO2 decreases, because there is no diffusion of oxy-
gen from the alveolar air. The presence of oxygen-poor blood
in the arterial circulation is known as the ‘shunt’ condi-
tion. On the other hand, when ventilation is adequate but
perfusion poor, gas exchange cannot take place: in such
cases, part of the lung behaves as if it had no alveoli at all,
forming the ‘physiologic dead space’. Examples of condi-
tions related to poor ventilation, poor perfusion, or the combi-
nation of both, are given below:
■ Rib-cage deformities impair ventilation by limiting lung
movement.
■ Chest trauma may decrease ventilation as a result of
lung collapse; impairing ventilation.
■ Alveoli may be actually destroyed in pulmonary
emphysema.
■ Inadequate synthesis of surfactant leads to the collapse
of alveoli, impairment of ventilation and to the
respiratory distress syndrome.
■ Obstruction or narrowing of the bronchial tree (a
mechanical obstruction by inhaled objects, or narrowing
by a growing tumor): this impairs ventilation.
■ Constriction of the bronchi occurs in asthma impairing
ventilation.
■ The efficiency of ventilation may be reduced by impaired
elasticity of the lung or dysfunction of relevant muscles
Table 25.4 Blood partial pressures of oxygen and carbon dioxide depend on lung perfusion and ventilation
Alveolar pO2 Alveolar pCO2
Poor ventilation, adequate perfusion ↓ ↑
Adequate ventilation, poor perfusion ↑ ↓
*Depending on a degree of shunt.
337
(the diaphragm and intercostal muscles of the chest
wall).
■ Fluid present in the alveoli (pulmonary edema) impairs
ventilation by affecting diffusion of gases.
■ Defects in the neural control impair ventilation through
affecting lung movement.
■ Lung perfusion is compromised in circulatory problems
such as shock and heart failure.
Table 25.4 lists pathologic conditions related to gas
exchange.
Handling of carbon dioxide
by erythrocytes
Erythrocytes transport CO2 to the lungs in a ‘fixed’
form – as bicarbonate
Human metabolism produces CO2 at a rate of 200–800 mL/
min. The CO2 dissolves in water and generates carbonic
acid, which in turn dissociates into hydrogen and bicarbo-
nate ions. Thus, CO2 generates large numbers of hydrogen
ions:
CO2 + H2O  H2CO3  H + + HCO3−
In plasma, the above reaction is nonenzymatic and proceeds
slowly, generating only minute amounts of carbonic acid,
which remains in equilibrium with a large amount of dis-
solved CO2. However, the same reaction in the erythrocytes
is catalyzed by carbonic anhydrase, which ‘fixes’ CO2 as
bicarbonate. The generated hydrogen ion is buffered by
hemoglobin.
The bicarbonate ion produced by erythrocyte carbonic
anhydrase reaction moves to plasma in exchange for chloride
ion (the ‘chloride shift’) (Fig. 25.6). As much as 70% of all
CO2 produced in tissues becomes bicarbonate; approximately
20% is carried ‘fixed’ to hemoglobin as carbamino groups,
and only 10% remains dissolved in plasma.
In the lungs, higher pO2 facilitates dissociation of CO2
from hemoglobin. This is known as the Haldane effect. The
hemoglobin releases its hydrogen ion, which reacts with
bicarbonate, and forms carbonic acid, which, in turn,
releases CO2.
Arterial pO2 Arterial pCO2 Comment
↓ Normal Physiologic shunt
↓* ↑* Physiologic dead space
338 CHAPTER 25 Regulation of Hydrogen Ion Concentration (Acid–Base Balance)

Removal of CO2 from tissues Kidney

Proximal renal Glomerular
Most CO2 is converted Blood
tubular cell filtrate
to bicarbonate
HCO–3
CO2 dissolved
HCO–3 Cl– HCO–3 H+
Erythrocyte
Chloride shift
H2CO3
Tissues

H+ + HCO–3 H2CO3
CA
H2CO3

H2O
CA
H H2O CO2 CO2 CO2 + H2O
–

–
–NHCOO
Fig. 25.7 Bicarbonate reabsorption in the kidney. Bicarbonate re­
Hb Hb absorption takes place in the proximal tubule. There is no net excretion
of hydrogen ion. CA, carbonic anhydrase.

Excretion of CO2 with expired air

renal tubular cells facing the lumen are impermeable to
Erythrocyte HCO–3 CO2 dissolved
bicarbonate. The filtered bicarbonate combines with hydro-
gen ion secreted by the cells, and forms carbonic acid, which
Cl –
is converted into CO2 by carbonic anhydrase located on the
Expired
air
luminal membrane. The CO2 diffuses into cells, where intra­
H+ + HCO–3 H2CO3
cellular carbonic anhydrase converts it back into carbonic
acid, dissociating into hydrogen and bicarbonate ions.
CA
Bicarbonate is returned to the plasma, and the hydrogen ion
H2O is secreted into the lumen of the tubule to trap more filtered
bicarbonate. Note that, in this process, hydrogen ion is used
H CO2 CO2 exclusively to aid bicarbonate reabsorption, and there is no
–

net excretion (Fig. 25.7).

– NH+3
Hb Hb
Fig. 25.6 CO2 transport by the erythrocytes. Erythrocyte carbonic
anhydrase converts approximately 70% of the CO2 produced in tissues
into bicarbonate for transport to the lungs: approximately 20% of the
total amount is transported bound to hemoglobin, as carbamates
(-NHCOO−) and the rest as dissolved gas in plasma. CA, carbonic
anhydrase.
HANDLING OF BICARBONATE
BY THE KIDNEYS
The kidneys control plasma bicarbonate concentration and
the removal of the hydrogen ion. In common with erythro-
cytes, renal tubular cells (proximal and distal) contain car-
bonic anhydrase.
Proximal tubules reabsorb bicarbonate in the process
aided by carbonic anhydrase
Normally, bicarbonate is reabsorbed in the proximal tubule
and the urine is almost bicarbonate-free. The surfaces of the
Lungs Distal tubules generate new bicarbonate
and excrete hydrogen
The situation is different in the distal tubule where bicar­
bonate is generated. The mechanism is identical to that of
bicarbonate reabsorption, but this time there is both a net
loss of hydrogen ions from the body and a net gain of bicar-
bonate. The CO2 diffuses into cells. The distal tubule carbonic
anhydrase converts it into carbonic acid, which dissociates
into hydrogen ion and bicarbonate. Bicarbonate is trans-
ported to the plasma, and hydrogen ion is secreted into the
tubule lumen. However, no bicarbonate is present in the
lumen of the distal tubule (all has been reabsorbed earlier)
and the hydrogen ion is buffered (trapped) by phosphate ions
present in the filtrate, and by ammonia synthesized by the
proximal tubules. It is subsequently excreted in the urine
(Fig. 25.8).
Ammonia generated by glutaminase reaction participates
in the excretion of hydrogen ion
Ammonia is generated during the transformation of glu­
tamine into glutamic acid catalyzed by glutaminase. Ammo­
nia diffuses across the luminal membrane, allowing hydrogen
 CHAPTER 25 Regulation of Hydrogen Ion Concentration (Acid–Base Balance) 339

Liver Kidney
CLINICAL BOX
Glomerular ESSENTIAL DEFINITIONS
filtrate
Glutamine HPO2– 4 An acid, according to the Brønsted–Lowry definition, is ‘a
NH3 molecular species that has a tendency to lose a hydrogen ion,
forming a conjugate base’.
Glutamate Acidemia is an excess of hydrogen ion in blood.
NH3 Alkalemia is decreased concentration of hydrogen ion in blood.
Blood Acidosis is a process that leads to accumulation of hydrogen ion.
Alkalosis is the process that decreases the amount of hydro-
α−ketoglutarate
gen ion.
H+ is
buffered by
ammonia
HCO–3 HCO–3+ H+ H+
and
phosphate
buffers
H2CO3 respiratory acidosis, metabolic acidosis, respiratory
alkalosis, and metabolic alkalosis (Fig. 25.3). However,
CA mixed disorders can also develop; we consider them later.
CO2 + H2O + Lung and the kidney work in a concerted way to minimize
NH4 H2PO–4
urine changes in plasma pH: this is known as the compensation
of acid–base disorders
Fig. 25.8 Hydrogen ion excretion by the kidney. Excretion of the
hydrogen ion takes place in the distal tubules. Hydrogen ion reacts with Acidosis is accompanied by a decreased ratio of plasma
ammonia, forming the ammonium ion. Hydrogen ion is also buffered in bicarbonate to pCO2, and alkalosis by an increased ratio.
the tubule lumen by phosphate. Approximately 50 mmol of hydrogen Whenever a problem occurs, the compensating mechanisms
ion is excreted daily. CA, carbonic anhydrase. are triggered to bring the hydrogen ion concentration back
towards normal. This translates into normalizing the [bicar-
bonate]/pCO2 ratio in the Henderson–Hasselbalch equation.
Consequently, when the respiratory acidosis causes an
ion to be trapped inside the tubule as the ammonium ion
increase in pCO2, the kidney will increase the generation of
(NH4+), to which the membrane is impermeable.
bicarbonate, increasing its plasma concentration and nor-
malizing the ratio. Conversely, when diabetic ketoacidosis
causes depletion of plasma bicarbonate, ventilation rate
DISORDERS OF THE increases, pCO2 decreases and the ratio of bicarbonate/pCO2
ACID–BASE BALANCE changes towards normal. While respiratory compensation
can occur within minutes, metabolic compensation takes
Classification of the acid–base disorders hours to days to develop fully (Table 25.5).

The concept of respiratory and metabolic components of the

acid–base balance forms a basis for the classification of acid–
base balance disorders (Fig. 25.3). They are divided into
acidosis or alkalosis. Acidosis is a process that leads to the
accumulation of hydrogen ion. Alkalosis causes a decrease in
hydrogen ion concentration (acidemia and alkalemia are
terms that simply describe blood pH). Thus, acidosis and
alkalosis result in academia and alkalemia, respectively (see
the Clinical Box on this page).
There are four main disorders of acid–base balance
The key to further classification is the ‘location’ of the primary
cause within the respiratory and metabolic components of
the system. If the primary cause is the change in pCO2, the
acidosis or alkalosis is called respiratory, and if it is
bicarbonate, the acidosis or alkalosis is called metabolic.
Thus there are four main disorders of acid–base balance:
Acidosis
Respiratory acidosis occurs most often in lung disease and
results from decreased ventilation
The most common cause is the chronic obstructive airways
disease (COAD). Severe asthmatic attack can result in
respiratory acidosis because of bronchial constriction.
Respiratory acidosis often accompanies hypoxia (respiratory
failure); in such a case, an increase in pCO2 often parallels the
decrease in pO2 (Table 25.6, see Clinical Box on page 336).
Metabolic acidosis results from excessive production, or
inefficient metabolism or excretion, of nonvolatile acids
A classic example of metabolic acidosis is the diabetic ketoaci-
dosis, when ketoacids, acetoacetic acid, and β-hydroxybutyric
acid accumulate in the plasma (Chapter 21). Acidosis may
also occur during extreme physical exertion, when there is
340 CHAPTER 25 Regulation of Hydrogen Ion Concentration (Acid–Base Balance)

Table 25.5 Respiratory and metabolic compensation in the acid–base disorders

Acid–base disorder Primary change Compensatory change Timescale of compensatory change

Metabolic acidosis
Metabolic alkalosis
Respiratory acidosis
Respiratory alkalosis
↓ plasma bicarbonate ↓ pCO2 (hyperventilation) Minutes/hours
↑ plasma bicarbonate ↑ pCO2 (hypoventilation) Minutes/hours
↑ pCO2 ↑ renal bicarbonate generation: Days
↑ plasma bicarbonate
↓ pCO2 ↓ renal bicarbonate reabsorption: Days
↓ plasma bicarbonate

Respiratory and metabolic compensation in the acid–base disorders minimizes changes in the blood pH. A change in the respiratory component leads to
metabolic compensation, and a change in the metabolic component stimulates respiratory compensation.

Table 25.6 Causes of acid–base disorders

Metabolic acidosis Respiratory acidosis Metabolic alkalosis Respiratory alkalosis

Diabetes mellitus (ketoacidosis)
Lactic acidosis (lactic acid)
Renal failure (inorganic acids)
Severe diarrhea (loss of
bicarbonate)
Surgical drainage of intestine (loss
of bicarbonate)
Renal loss of bicarbonate (renal
tubular acidosis type 2 – rare)
Renal tubular acidosis – rare)
Chronic obstructive airways disease
Severe asthma
Cardiac arrest
Depression of respiratory center
(drugs, e.g. opiates)
Failure of respiratory muscles (e.g.
poliomyelitis, multiple sclerosis)
Chest deformities
Airway obstruction
Vomiting (loss of hydrogen ion) Hyperventilation (anxiety, fever)
Nasogastric suction (loss of hydrogen ion) Lung diseases associated with
hyperventilation
Hypokalemia Anemia
Intravenous administration of bicarbonate Salicylate poisoning
(e.g. after cardiac arrest)

Respiratory acidosis is common and is caused primarily by diseases of the lung that affect gas exchange. Respiratory alkalosis is rarer and is caused by
hyperventilation, which decreases pCO2. Metabolic acidosis is common and results from either overproduction or retention of nonvolatile acids in the
circulation. Metabolic alkalosis is rarer: its most common causes are vomiting and gastric suction, both causing loss of hydrogen ion from the stomach.

CLINICAL BOX
RESPIRATORY ALKALOSIS IS CAUSED BY HYPERVENTILATION
A 25-year-old man was admitted to hospital with an asthmatic
attack. Peak expiratory flow rate was 75% of his best. His blood
gas values were pO2 9.3 kPa (70 mmHg) and pCO2 4.0 kPa
(30 mmHg), with pH 7.50 (hydrogen ion concentration =
42 nmol/L). He was treated with nebulized salbutamol, a β2-
adrenergic stimulant (Chapter 39), which is a bronchodilator, and
made a good recovery.
Comment. This man’s blood gases show a mild degree of respi-
ratory alkalosis caused by hyperventilation and ‘blowing off’ the
CO2. Respiratory alkalosis causes reduction in serum levels of
ionized calcium, leading to neuromuscular irritability. Ventilatory
impairment that leads to CO2 retention and respiratory acidosis is
characteristic of a severe asthma. Reference ranges are given in
Table 25.2.
 CHAPTER 25 Regulation of Hydrogen Ion Concentration (Acid–Base Balance) 341

accumulation of lactic acid generated from muscle metabo-

lism; in normal circumstances, lactate would be quickly Table 25.7 Comparison of simple and mixed disorders
metabolized on cessation of exercise. However, when large of the acid–base balance
amounts of lactate are generated as a consequence of A. Mixed metabolic and respiratory acidosis
hypoxia, lactic acidosis may become life-threatening, as hap-
pens, for instance, in shock (Table 25.6). Condition pH pCO2 Plasma bicarbonate
Excretion of nonvolatile acids is also impaired in renal fail- Metabolic acidosis ↓ ↓ (respiratory ↓ (primary change)
ure, and this also leads to metabolic acidosis. Renal failure compensation)
develops when the perfusion of the kidneys is inadequate (e.g. Respiratory acidosis ↓ ↑ (primary ↑ (metabolic
in trauma, shock, or dehydration) or if there is an intrinsic change) compensation)
kidney disease such as glomerulonephritis (inflammatory
Mixed respiratory and ↓↓ ↑ (respiratory ↓ (metabolic acidosis)
reaction in the renal tubular tissue). metabolic acidosis acidosis)
Excessive loss of bicarbonate can also be a cause of meta-
bolic acidosis. This is common when bicarbonate present in B. Mixed metabolic and respiratory alkalosis (rare)
the intestinal fluid is lost as a result of severe diarrhea or sur- Disorder pH pCO2 Plasma bicarbonate
gical drainage after bowel surgery. Metabolic alkalosis ↑ ↑ (respiratory ↑ (primary change)
compensation)
Impaired bicarbonate reabsorption and hydrogen ion Respiratory alkalosis ↑ ↓ (primary ↓ (metabolic
secretion causes rare renal tubular acidoses change) compensation)
Defects in renal handling of bicarbonate and hydrogen ion Mixed respiratory and ↑↑ ↓ (respiratory ↑ (metabolic acidosis)
lead to a group of relatively rare disorders known as renal metabolic alkalosis alkalosis)
tubular acidoses (RTA). The proximal RTA is caused by
impaired reabsorption of bicarbonate, and the distal RTA by
Mixed acid–base disorders result in a greater change in blood pH than
impaired hydrogen ion excretion. Proximal RTA is usually simple disorders; they may pose diagnostic difficulties.
accompanied by other defects in proximal transport mecha-
nisms (this is known as the Fanconi syndrome).
Generally, acidosis is a much more common condition
than alkalosis. CLINICAL BOX
VOMITING CAN LEAD TO
METABOLIC ALKALOSIS
Alkalosis
A 47-year-old man came to the outpatient clinic with a history
Alkalosis is rarer than acidosis
of intermittent profuse vomiting and loss of weight. He had
A mild respiratory alkalosis may be a consequence of hyper- tachycardia, reduced tissue turgor, and hypotension. His blood
ventilation during exercise, anxiety attack, or fever. It also pH was 7.55 (hydrogen ion concentration 28 nmol/L) and pCO2
occurs in pregnancy. Metabolic alkalosis is often associated was 6.4 kPa (48 mmHg). His bicarbonate concentration was
with abnormally low serum potassium concentration, as a 35 mmol/L and there was also hyponatremia and hypokalemia.
result of cellular buffering. Cellular entry or exit of potassium
ion is associated with the movement of hydrogen ion in an Comment. This patient presents with metabolic alkalosis
opposite direction. Thus, alkalosis can cause hypokale- caused by the loss of hydrogen ion through vomiting. Investi­
gations showed gastric outlet obstruction due to scarring from
mia, and hypokalemia (Chapter 22) may lead to alkalo-
chronic peptic ulceration. He subsequently underwent surgery
sis. Severe metabolic alkalosis may also occur as a result of
for pyloric stenosis, with a good outcome. Note the increased
the massive loss of hydrogen ion from the stomach during pCO2 as a result of respiratory compensation of metabolic
vomiting (see Clinical Box on this page), or as a result of alkalosis.
nasogastric suction after surgery. Lastly, it may occur when
too much bicarbonate is given intravenously: for instance,
during resuscitation from cardiac arrest (Table 25.6).

Mixed acid–base disorders
More than one acid–base disorder can exist in one patient.
The result of this is a mixed acid–base disorder, sometimes
quite difficult to diagnose (see Clinical Box below and
Table 25.7).
SUMMARY
■ Maintenance of the hydrogen ion concentration within
a narrow range is vital for survival.
■ Acid–base balance is regulated by the concerted action
of lungs and kidneys. The erythrocytes play a key role in
the transport of carbon dioxide in blood.
342 CHAPTER 25 Regulation of Hydrogen Ion Concentration (Acid–Base Balance)
CLINICAL BOX
RESPIRATORY AND METABOLIC
DISORDERS OF ACID–BASE
BALANCE CAN OCCUR
TOGETHER:CARDIAC ARREST
During resuscitation of a 60-year-old man from a cardiorespira-
tory arrest, blood gas analysis revealed pH 7.00 (hydrogen ion
concentration 100 nmol/L) and pCO2 7.5 kPa (52 mmHg). His
bicarbonate concentration was 11 mmol/L. pO2 was 12.1 kPa
(91 mmHg) during treatment with 48% oxygen.
Comment. This patient presents with a mixed disorder: a respi-
ratory acidosis caused by lack of ventilation, and metabolic aci-
dosis caused by the hypoxia that had occurred before oxygen
treatment was instituted. The acidosis was caused by an accu-
mulation of lactic acid: the measured lactate concentration was
7 mmol/L (reference range is 0.7–1.8 mmol/L (6–16 mg/dL)).
The terms acidosis and alkalosis do not just describe blood pH
changes: they relate to the processes that result in these
changes. Therefore, in some instances, two independent proc-
esses may occur: for example, a patient may be admitted to
hospital with diabetic ketoacidosis and coexisting emphysema
causing respiratory acidosis. The final result could be a more
severe change in pH than would have resulted from a simple
disorder (Table 25.5). Any combination of disorders can occur;
the skills of an experienced physician are usually required to
diagnose this.
■ Main buffers in blood are hemoglobin and bicarbonate,
whereas in the cells they include proteins and
phosphate. The bicarbonate buffer system
communicates with atmospheric air.
■ Acid–base disorders are acidosis and alkalosis and each
of them can be either metabolic or respiratory.
ACTIVE LEARNING
1. Describe how the bicarbonate buffer copes with an addition
of an acid to the system.
2. Compare bicarbonate handling by the proximal and distal
tubules of the kidney.
3. Outline the role of ventilation in acid–base disorders.
4. Which disorders of the acid–base balance may be associated
with gastrointestinal surgery?
5. Discuss the association between acid–base disorders and
plasma potassium concentration.
■ Measurement determination of pH, pCO2 and
bicarbonate, and pO2, is a first-line investigation and is
frequently required in emergencies.
FURTHER READING
Corey HE: Bench-to-bedside review: Fundamental principles of acid–base balance,
Critical Care 9:184–192, 2005.
Kellum JA: Disorders of acid–base balance, Crit Care Med 35:2630–2636, 2007.
WEBSITES AND DOWNLOADS
Appel SJ, Downs CA: Understanding acid–base balance, Nursing: Fall 38:9–11,
2008. http://journals.lww.com/nursing/Fulltext/2008/09002/
Understanding_acid_base_balance.3.aspx
McNamara J, Worthley LIG: Acid–Base Balance: Part I. Physiology, Critical Care and
Resuscitation 3:181–187, 2001. http://cicm.org.au/journal/2001/september/
ABa1.pdf
Neligan PJ, Deutschman CS: Acid–base balance in critical care medicine.
www.ccmtutorials.com/renal/Acid%20Base%20Balance%20in%20
Critical%20Care%20Medicine-NELIGAN.pdf
Respiratory Acid/Base Balance, Gas Transport and Erythrocytes. www.sci.utah.
edu/~macleod/bioen/be6000/notes/L14-acid–base.pdf