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Chapter-27 Acid-Base Balance and pH

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 Chapter 27
Acid-Base
Balance and pH
ChapterataGlance
The learner will be able to answer questions on the following topics:
¾¾Acids and bases ¾¾Renal regulation of pH
¾¾pH ¾¾Relation of pH and potassium
¾¾Buffers ¾¾Respiratory acidosis
¾¾Acid base balance in the body ¾¾Metabolic acidosis
¾¾Bicarbonate buffer system ¾¾Respiratory alkalosis
¾¾Respiratory regulation of pH ¾¾Metabolic alkalosis

Hydrogen ions (H+) are present in all body are proton donors and bases are proton acceptors. A
compartments. Maintenance of appropriate few examples are shown below:
concentration of hydrogen ion (H+) is critical to normal
Acids Bases
cellular function. The acid-base balance or pH of
the body fluids is maintained by a closely regulated HA H+ + A– NH3 + H+ NH4+
mechanism. This involves the body buffers, the HCl H+ + Cl – HCO3– +H+ H2CO3
respiratory system and the kidney. Some common
H2CO3 H+ + HCO3–
definitions are given in Box 27.1.

Acids and Bases

Definition
The electrolyte theory of dissociation was proposed
by Arrhenius (Nobel prize, 1903). According to
SPL Svante Arrhenius Johannes N
the definition proposed by Bronsted, acids are Sorensen NP 1903 Bronsted
substances that are capable of donating protons 1868–1939 1859–1927 1879–1947
and bases are those that accept protons. Acids
356 Textbook of Biochemistry

Weak and Strong Acids T h e Acidity of a Solution and pH

extent of dissociation decides whether they are strong
The acidity of a solution is measured by noting
acids or weak acids. Strong acids dissociate complete=ly
the hydrogen ion concentration in the solution and
in solution, while weak acids ionize incompletely, for
obtained by the equation.
example,
HCl H+ + Cl– (Complete) [H+] = Ka

H2CO3 H+ + HCO3– (Partial) where Ka is the dissociation constant.

In a solution of HCl, almost all the molecules To make it easier, Sorensen expressed the H+
dissociate and exist as H+ and Cl– ions. Hence the concentration as the negative of the
concentration of H+ is very high and it is a strong acid. logarithm (logarithm to the base 10)
But in the case of a weak acid (e.g. acetic acid), it will of hydrogen ion concentration, and is
ionize only partially. So, the number of acid molecules designated as the pH. Therefore,
existing in the ionized state is much less, may be only
50%. pH = –log [H+] = log
Lawrence J
Thus the pH value is inversely Henderson
Dissociation Constant proportional to the acidity. Lower 1878–1942
Since the dissociation of an acid is a freely the pH, higher the acidity or hydrogen
reversible reaction, at equilibrium the ratio between ion concentration while higher
dissociated and undissociated particle is a constant. the pH, the acidity is lower (Table
The dissociation constant (Ka) of an acid is given by 27.1). At a pH of 1, the
the formula, hydrogen ion concentration is 10 times
that of a solution with a pH 2 and 100
times that of a solution with a pH of KA Hasselbalch
Ka = 1874–1962
3 and so on. The pH 7 indicates the
Where [H+] is the concentration of hydrogen neutral pH.
ions, [A–] = the concentration of anions or conjugate
base, and [HA] is the concentration of undissociated The Effect of Salt Upon the
molecules. Dissociation
The pH at which the acid is half ionized is called
pKa of an acid which is constant at a particular The relationship between pH, pKa, concentration
temperature and pressure. Strong acids will have a of acid and conjugate base (or salt) is expressed by
low pKa and weak acids have a higher pKa. the Henderson-Hasselbalch equation,

Box 27.1: Terms explained

Table 27.1: Relation between hydrogen ions, hydroxyl ions and
Term Definition and explanations
pH of aqueous solutions. Ionic product of water = [H+][OH–] =
pH Negative logarithm of hydrogen ion concentra- 10–14
tion. Normal value 7.4 (range 7.38–7.42)
Acids Proton donors; pH <7 [OH–] [H+] log –log[H+]
Bases Proton acceptors; pH > 7 mols/liter mols/liter [H+] =pH pOH Inference
Strong acids Acids which ionize completely; e.g. HCl 1 × 1013
1 × 101
–1 1 13 Strong acid
Weak acids Acids which ionize incompletely, e.g. H2CO3
pK value pH at which the acid is half ionised; Salt : Acid 1 × 1010
1 × 10–4
–4 4 10 Acid
=1:1 1 × 107
1 × 10–7
–7 7 7 Neutral
Alkali reserve Bicarbonate available to neutralise acids;
Normal 24 mmol/L (range 22–26 mmol/L) 1 × 104
1 × 1010
–10 10 4 Alkali
Buffers Solutions minimize changes in pH 1 × 101 1 × 1013 –13 13 1 Strong alkali
 Chapter 27: Acid-Base Balance and pH 357

The buffering capacity of a buffer is defined as

pH = pKa + log or pH = pKa + log the ability of the buffer to resist changes in pH
when an acid or base is added.
When [base] = [acid]; then pH = pKa
Therefore, when the concentration of base and
How do Buffers Act?
acid are the same, then pH is equal to pKa. Thus,
when the acid is half ionized, pH and pKa have the Buffer solutions consist of mixtures of a weak
same values. acid or base and its salt.
To take an example, when hydrochloric acid is
Buffers added to the acetate buffer, the salt reacts with the
acid forming the weak acid, acetic acid and its salt.
Definition Similarly when a base is added, the acid reacts with
Buffers are solutions which can resist changes in pH it forming salt and water. Thus changes in the pH are
when acid or alkali is added. minimized.
CH3–COOH + NaOH → CH3–COONa + H2O
Composition of a Buffer CH3–COONa + HCl → CH3–COOH + NaCl
The buffer capacity is determined by the absolute
Buffers are of two types: concentration of the salt and acid. But the pH of the
a. Mixtures of weak acids with their salt with a buffer is dependent on the relative proportion of the
strong base or salt and acid (see the Henderson-Hasselbalch’s
b. Mixtures of weak bases with their salt with a equation).
strong acid. A few examples are given below:
i. H2CO3/NaHCO3 (Bicarbonate buffer) Application of the Equation
(carbonic acid and sodium bicarbonate)
ii. CH3COOH/CH3COO Na (Acetate buffer) The pH of a buffer on addition of a known quantity
(acetic acid and sodium acetate) of acid and alkali can therefore be predicted by the
iii. Na2HPO4/NaH2PO4 (Phosphate buffer) equation.
The Henderson-Hasselbalch’s equation,
Factors Affecting pH of a Buffer therefore has great practical application in clinical
practice in assessing the acid-base status.
The pH of a buffer solution is determined by two
factors: Effective Range of a Buffer
a. The value of pK: The lower the value of pK, the
A buffer is most effective when the concentrations
lower is the pH of the solution.
of salt and acid are equal or when pH = pKa. The
b. The ratio of salt to acid concentrations: Actual
effective range of a buffer is 1 pH unit higher or
concen­trations of salt and acid in a buffer solution
lower than pKa. Since the pKa values of most of
may be varying widely, with no change in pH, so
the acids produced in the body are well below the
long as the ratio of the concentrations remains
physiological pH, they immediately ionize and add
the same.
H+ to the medium. This would necessitate effective
buffering. Phosphate buffer is effective at a wide
Factors Affecting Buffer Capacity range, because it has 3 pKa values.
On the other hand, the buffer capacity is
determined by the actual concentrations of salt and Acid-Base Balance
acid present, as well as by their ratio.
Buffering capacity is the number of grams of Normal pH
strong acid or alkali which is necessary for a change The pH of plasma is 7.4 (Range 7.35 - 7.45). In
in pH of one unit of one litre of buffer solution. normal life, the variation of plasma pH is very small.
358 Textbook of Biochemistry

The pH of plasma is maintained within a narrow Bicarbonate Buffer System

range. The pH of the interstitial fluid is generally 0.5 The most important buffer system in the plasma
units below that of the plasma. is the bicarbonate-carbonic acid system (NaHCO3/
H2CO3). It accounts for 65% of buffering capacity
Acidosis in plasma and 40% of buffering action in the whole
If the pH is below 7.35, it is called acidosis. Life is body. The base constituent, bicarbonate (HCO3–), is
threatened when the pH is lowered below 7.25. regulated by the kidney (metabolic component).
Acidosis leads to CNS depression and coma. Death While the acid part, carbonic acid (H2CO3), is under
occurs when pH is below 7.0. respiratory regulation (respiratory component).
The normal bicarbonate level of
Alkalosis plasma is 24 mmol/L. The normal pCO2 of arterial
blood is 40 mm of Hg. The normal carbonic acid
When the pH is more than 7.45, it is alkalosis. It is very concentration in blood is 1.2 mmol/L. The pKa for
dangerous if pH is increased above 7.55. Alkalosis carbonic acid is 6.1. Substituting these values in the
induces neuromuscular hyperexcitability and tetany. Henderson-Hasselbalch’s equation,
Death occurs when the pH is above 7.6.

pH = pKa + log
Volatile and Fixed Acids
During the normal metabolism, the acids produced
may be volatile acids like carbonic acid or nonvolatile 7.4 = 6.1 + log
(fixed) acids like lactate, keto acids, sulfuric acid and
phosphoric acid. The metabolism produces nearly    = 6.1 + log 20 = 6.1 + 1.3
20,000 milli equivalents (mEq) of carbonic acid and Hence, the ratio of HCO3– to H2CO3 at pH 7.4 is
60–80 mEq of fixed acids per day. The sulfoproteins 20 under normal conditions. This is much higher than
yield sulfuric acid and phospho­proteins and nucleo­ the theoretical value of 1 which ensures maximum
proteins produce phosphoric acid. On an average effectiveness.
about 3 g of phosphoric acid and about 3 g sulfuric
acid are produced per day. The carbonic acid, being
volatile, is eliminated as CO2 by the lungs. The fixed Box. 27.2: Mechanisms of regulation of pH
acids are buffered and later on the H+ are excreted by First line of defense : Blood buffers
the kidney. Second line of defense : Respiratory regulation
Third line of defense : Renal regulation

Mechanisms of Regulation of pH Table 27.2: Buffer systems of the body

These mechanisms are interrelated. See Box 27.2. Extracellular Intracellular Erythrocyte
fluid fluid fluid
1.
BUFFERS OF THE BODY FLUIDS
Buffers are the first line of defense against acid load. (bicarbonate) (phosphate) (hemoglobin)
These buffer systems are enumerated in Table 27.2. 2.
The buffers are effective as long as the acid load is
not excessive, and the alkali reserve is not exhausted.
Once the base is utilized in this reaction, it is to be (phosphate) (protein buffer) (phosphate)

replenished to meet further challenge. 3.

 Chapter 27: Acid-Base Balance and pH 359

The bicarbonate carbonic acid buffer system is Protein Buffer System

the most important for the following reasons:
Buffering capacity of protein depends on the pKa
a. Presence of bicarbonate in relatively high
value of ionizable side chains. The most effective
concentrations.
group is histidine imidazole group with a pKa value
b. The components are under physiological
of 6.1.The role of the hemoglobin buffer is considered
control, CO2 by lungs and bicarbonate by
along with the respiratory regulation of pH.
kidneys.
Relative Capacity of Buffer Systems
Alkali Reserve
In the body, 52% buffer activity is in tissue cells and
Bicarbonate represents the alkali reserve and it has
6% in RBCs. Rest 43% is by extracellular buffers. In
to be sufficiently high to meet the acid load. Under
plasma and extracellular space, about 40% buffering
physiological circumstances, the ratio of 20 (a high
action is by bicarbonate system; 1% by proteins and
alkali reserve) ensures high buffering efficiency
1% by phosphate buffer system (Fig. 27.1).
against acids.
Buffers Act Quickly, But Not
Phosphate Buffer System Permanently
It is mainly an intracellular buffer. Its concentration in Buffers can respond immediately to addition of acid
plasma is very low. The pKa value is 6.8. So applying or base, but they do not serve to eliminate the acid
the equation, from the body. They are also unable to replenish the
alkali reserve of the body. For the final elimination of
pH (7.4)= pKa (6.8) + log acids, the respiratory and renal regulations are very
essential.
or 0.6 = log
Respiratory Regulation of
Antilog of 0.6 = 4; hence the ratio is 4. This is
found to be true under physiological condition.
pH
The phosphate buffer system is found to be The Second Line of Defense
effective at a wide pH range, because it has more This is achieved by changing the pCO2 (or carbonic
than one ionizable group and the pKa values are acid, the denominator in the equation). The CO2
different for both. diffuses from the cells into the extracellular fluid and
reaches the lungs through the blood. When there is a
H3PO4 H+ + H2PO4– fall in pH of plasma (acidosis), the respiratory rate is
stimulated resulting in hyperventilation. This would
H2PO4– H++ HPO4= (Na2HPO4 /
eliminate more CO2, thus lowering the H2CO3 level
NaH2PO4)

HPO4= H+ + PO4º

In the body, Na2HPO4/NaH2PO4 is an effective

buffer system, because its pKa value is nearest to
physiological pH.

Fig. 27.1: Intracellular buffers play a significant role to combat

acid load of the body
360 Textbook of Biochemistry

(Box 27.3). However, this can not continue for long. E x c r e t i o n o f H +; G e n e r a t i o n o f

The respiratory system responds to any change in pH Bicarbonate
immediately, but it cannot proceed to completion. This process occurs in the proximal convoluted
tubules (Fig. 27.2). The CO2 combines with water to
Action of Hemoglobin form carbonic acid, with the help of carbonic anhydrase.
The hemoglobin serves to transport the CO2 formed in The H2CO3 then ionizes to H+ and bicarbonate. The
the tissues, with minimum change in pH (see isohydric hydrogen ions are secreted into the tubular lumen; in
transport, Chapter 23). Side by side, it serves to exchange for Na+ reabsorbed. These Na+ ions along
generate bicarbonate or alkali reserve by the activity with HCO3– will be reabsorbed into the blood. There is
of the carbonic anhydrase system (see Chapter 23). net excretion of hydrogen ions, and net generation
of bicarbonate. So this mechanism serves to increase
Carbonic anhydrase
the alkali reserve.
CO2 + H2O H2CO3
H2CO HCO3-- + H+
H+ + Hb-- HHb Reabsorption of Bicarbonate
The reverse occurs in the lungs during This is mainly a mechanism to conserve base.
oxygenation and elimination of CO2. When the blood There is no net excretion of H+ (Fig. 27.3). When Na+
reaches the lungs, the bicarbonate re-enters the enters the cell, hydrogen ions from the cell are secreted
erythrocytes by reversal of chloride shift. It combines into the luminal fluid. The hydrogen ions are generated
with H+ liberated on oxygenation of hemoglobin to within the cell by the action of carbonic anhydrase.
form carbonic acid which dissociates into CO2 and Bicarbonate is filtered by the glomerulus. This is
H2O. CO2 is thus eliminated by the lungs. completely reabsorbed by the proximal convoluted
HHb + O2 HbO2 + H+ tubule, so that the urine is normally bicarbonate free.
HCO3 + H – +
H2CO3 The bicarbonate combines with H+ in tubular fluid to
H2CO3 H2O + CO2 form carbonic acid. It dissociates into water and CO2.
The activity of the carbonic anhydrase increases The CO2 diffuses into the cell, which again combines
in acidosis and decreases with decrease in H+ with water to form carbonic acid.
concentration. In the cell, it again ionizes to H+ that is
secreted into lumen in exchange for Na+. The HCO3–
Renal Regulation of pH is reabsorbed into plasma along with Na +. Here,
there is no net excretion of H+ or generation of new
An important function of the kidney is to regulate the bicarbonate. The net effect of these processes is the
pH of the extracellular fluid. Normal urine has a pH reabsorption of filtered bicarbonate. But this mechanism
around 6; this pH is lower than that of extracellular prevents the loss of bicarbonate through urine.
fluid (pH = 7.4). This is called acidification of urine.
The pH of the urine may vary from as low as 4.5 to
as high as 9.8, depending on the amount of acid
excreted. The major renal mechanisms for regulation
of pH are:
A. Excretion of H+ (Fig. 27.2)
B. Reabsorption of bicarbonate (recovery of
bicarbonate) (Fig. 27.3)
C. Excretion of titratable acid (net acid excretion)
(Fig. 27.4)
D. Excretion of NH4+ (ammonium ions) (Fig.27.5).
Fig. 27.2: Excretion of hydrogen ions in the proximal tubules; CA
 Chapter 27: Acid-Base Balance and pH 361

+
Excretion of H as Titratable Acid tubular cell boarder, the Na2HPO4 (basic phosphate) is
In the distal convoluted tubules net acid excretion converted to NaH2PO4 (acid phosphate) (Fig. 27.4). As
occurs. Hydrogen ions are secreted by the distal a result, the pH of tubular fluid falls. The acid and basic
tubules and collecting ducts by hydrogen ion-ATPase phosphate pair is considered as the urinary buffer.
located in the apical cell membrane. The hydrogen The maximum limit of acidification is pH 4.5.
ions are generated in the tubular cell by a reaction
catalyzed by carbonic anhydrase. The bicarbonate Excretion of Ammonium Ions
generated within the cell passes into plasma. This predominantly occurs at the distal convoluted
The term titratable acidity of urine refers to tubules. This would help to excrete H+ and reabsorb
the number of milliliters of N/10 NaOH required to HCO3– (Fig. 27.5). This mechanism also helps to trap
titrate 1 liter of urine to pH 7.4. This is a measure of hydrogen ions in the urine, so that large quantity of
net acid excretion by the kidney. The major titratable acid could be excreted with minor changes in pH.
acid present in the urine is sodium acid phosphate. The excretion of ammonia helps in the elimination of
As the tubular fluid passes down the renal tubules hydrogen ions without appreciable change in the pH
more and more H+ are secreted into the luminal fluid of the urine. The Glutaminase present in the tubular
so that its pH steadily falls. The process starts in the cells can hydrolyze glutamine to ammonia and glutamic
proximal tubules, but continues up to the distal tubules. acid. The NH3 (ammonia) diffuses into the luminal fluid
Due to the Na+ to H+ exchange occurring at the renal and combines with H+ to form NH4+(ammonium ion).
Box 27.3: Summary of buffering against acid load The glutaminase activity is increased in
acidosis. So large quantity of H+ ions are excreted as
Stages Features Buffer
components NH4+ in acidosis. Since it is a positively charged ion,
Normal
Normal ratio = 20:1 HCO –
________
3
(N) it can accompany negatively charged acid anions; so
Normal pH = 7.4 H2CO3 (N) Na+ and K+ are conserved (Fig. 27.5). The enhanced
First line of defense Acidosis; H enters
+
HCO3– (↓↓) activity of glutaminase and increased excretion of
Plasma buffer system blood, bicarbonate NH4+ take about 3–4 days to set in under conditions of
is used up acidosis. But once established, it has high capacity to
Second line defense Hyperventilation H2CO3 (↓) eliminate acid. The titratable acidity plus the ammonia
Respiratory H2CO3 →H2O +
content will be a measure of acid excreted from
compensation CO2↑­
the body. Maximum urine acidity reached is 4.4. A
Third line of defense Excretion of H+; HCO3– (↓↓) summary of buffering of acid load in the body is shown
kidney mechanism Reabsorption of H2CO3 (↓↓)
bicarbonate;
in Table 27.3.
Ratio and pH
tend to restore

Fig. 27.3: Reabsorption of bicarbonate from the tubular fluid; CA Fig. 27.4: Phosphate mechanism in tubules
= Carbonic anhydrase
362 Textbook of Biochemistry

Cellular Buffers Disturbances in Acid-Base

Cytoplasmic pH varies from 6.8 to 7.3. Intracellular Balance
pH modulates a variety of cell functions:
1. The activity of several enzymes is sensitive to Acidosis is the clinical state, where acids accumulate
changes in pH. or bases are lost. A loss of acid or accumulation of
2. Reduction in pH reduces the contractility of actin base leads to alkalosis. The body cells can tolerate
and myosin in muscles. only a narrow range of pH. The extreme ranges of
3. The electrical properties of excitable cells are pH are between 7.0 and 7.6, beyond which life is not
also affected by changes in pH. possible. Box 27.4 shows the conditions in which
Intracellular buffers are depicted in Figure 27.1. acid-base parameters are to be checked. Box 27.5
The major tissues involved in cellular buffering shows the steps to the clinical assessment of acid
are bone and skeletal muscle. The buffering base status. Box 27.6 summarizes the abnormal
of acid is achieved by the exchange of H+ that findings.
enters into the cells for Na+ or K+ ions.
Classification of Acid-Base
Relationship of pH with K+ Ion Balance Disturbances
When there is increase in H+ in extracellular fluid
(ECF), there may be exchange of H+ with K+ from Acidosis (fall in pH)
within the cells. Net effect is an apparent increase in a. Respiratory acidosis: Primary excess of carbonic
ECF potassium level (hyperkalemia). In general, acute acid.
acidosis is associated with hyperkalemia and acute b. Metabolic acidosis: Primary deficit of bicarbonate
alkalosis with hypokalemia. Sudden hypokalemia may (Box 27.6).
develop during the correction of acidosis. K+ may go
back into the cells, suddenly lowering the plasma K+. Alkalosis (rise in pH)
Hence it is important to maintain the K+ balance during
correction of alkalosis. a. Respiratory alkalosis: Primary deficit of carbonic
acid.
b. Metabolic alkalosis: Primary excess of
bicarbonate (Box 27.6).

Compensatory Responses
Each of the above disturbance will be followed by a
secondary compensatory change in the counteracting
variable, e.g. a primary change in bicarbonate involves
an alteration in pCO2. Depending on the extent of
the compensatory change there are different stages
(Table 27.3). In actual clinical states, patients will have
different states of compen­sation. The compensatory
(adaptive) responses are:
a. A primary change in bicarbonate involves
an alteration in pCO2. There is an attempt at
restoring the ratio to 20 and pH to 7.4.
b. Primary decrease in arterial bicarbonate
involves a reduction in arterial blood pCO2 by
alveolar hyperventilation.
Fig. 27.5: Ammonia mechanism
 Chapter 27: Acid-Base Balance and pH 363

c. Similarly, a primary increase in arterial pCO2 change in bicarbonate involves an alteration in pCO2.
involves an increase in arterial bicarbonate by Depending on the extent of the compensatory change
an increase in bicarbonate reabsorption by the there are different stages. Looking at the parameters,
kidney. the stage of the compensation can be identified
d. The compensatory change will try to restore (Table 27.4).
the pH to normal. However, the compensatory
change cannot fully correct a disturbance.
Biochemistry of Acid-Base Disturbances
e. Clinically, acid-base disturbance states may be
divided into: Metabolic Acidosis
i. Uncompensated
ii. Partially compensated i. It is due to a primary deficit in the bicarbonate.
iii. Fully compensated (Table 27.4). This may result from an accumulation of acid or
depletion of bicarbonate.
Mixed Responses ii. When there is excess acid production, the
If the disturbance is pure, it is not difficult to accurately bicarbonate is used up for buffering. Depending
assess the nature of the disturbance. In mixed on the cause, the anion gap is altered.
disturbances, both HCO3– and H2CO3 levels are altered
(Fig. 27.6). The adaptive response always involves a Anion Gap
change in the counteracting variable; e.g. a primary The sum of cations and anions in
ECF is always equal, so as to maintain the electrical
Box 27.4:Acid-base parameters are to be checked in patients with
neutrality. Sodium and potassium together account for
1. Any serious illness 95% of the cations whereas chloride and bicarbonate
2. Multi organ failure
3. Respiratory failure
account for only 86% of the anions (Fig. 27.7). Only
4. Cardiac failure these electrolytes are commonly measured.
5. Uncontrolled diabetes mellitus Hence, there is always a difference
6. Poisoning by barbiturates and ethylene glycol between the measured cations and the anions. The
Box 27.5: Steps to the clinical assessment of acid-base unmeasured anions constitute the anion gap. This
disturbances is due to the presence of protein anions, sulphate,
1. Assess pH (normal 7.4); pH <7.35 is acidemia and >7.45 is phosphate and organic acids. The anion gap is
alkalemia
calculated as the difference between (Na+ + K+) and
2. Serum bicarbonate level: See Box 27.6.
3. Assess arterial pCO2: See Box 27.6.
Box 27.6. Acid-base disturbances
4. Check compensatory response: Compensation never pCO2 > 45 mm Hg = Respiratory acidosis
overcompensates the pH. If pH is <7.4, acidosis is the primary pCO2 < 35 mm Hg = Respiratory alkalosis
disorder. If pH is >7.4, alkalosis is primary. HCO3 > 33 mmol/L = Metabolic alkalosis
HCO3 < 22 mmol/L = Metabolic acidosis
5. Assess anion gap.
H+ > 45 nmol/L = Acidosis
6. Assess the change in serum anion gap/change in bicarbonate.
H+ < 35 nmol/L = Alkalosis
7. Assess if there is any underlying cause.

Table 27.3: Types of acid-base disturbances

Disturbance pH Primary change Ratio Secondary change

Metabolic acidosis Decreased Deficit of bicarbonate <20 Decrease in PaCO2

Metabolic alkalosis Increased Excess of bicarbonate >20 Increase in PaCO2

Respiratory acidosis Decreased Excess of carbonic acid <20 Increase in bicarbonate

Respiratory alkalosis Increased Deficit of carbonic acid >20 Decrease in bicarbonate

364 Textbook of Biochemistry

(HCO3– + Cl–). Normally this is about 12 mmol/L. i. Diarrhea: Loss of intestinal secretions lead to
acidosis. Bicarbonate, sodium and potassium
are lost.
High Anion Gap Metabolic Acidosis ii. Hyperchloremic acidosis may occur in renal
(HAGMA) tubular acidosis, acetazolamide (carbonic
A value between 15 and 20 is due to accumulation anhydrase inhibitor) therapy, and ureteric
of acid anions in metabolic acidosis (HAGMA) (Table transplantation into large gut (done for bladder
27.5). carcinoma).
Renal failure: The excretion of H+ as well as generation
of bicarbonate are both deficient. The anion gap Decreased Anion Gap is seen in
increases due to accumulation of other buffer anions. ¾¾ Hypoalbuminemia - As a general rule of thumb,
Diabetic ketoacidosis (see Chapter 13). the normal anion gap is roughly three times the
Lactic acidosis: Lactic acid in blood is increased albumin value. e.g for a patient with an albumin of
in tissue hypoxia, circulatory failure, and intake of 4.0, the normal anion gap would be 12.
biguanides (Table 27.5). Lactic acid is compensated ¾¾ Multiple myeloma (paraproteinemia)
by bicarbonate. So, bicarbonate is lowered and ¾¾ The gap may be apparently narrowed when
measured; but increased lactate is not measure; thus cations are decreased (K, Mg and Ca) or when
anion gap is increased. Similarly a spurious elevation there is hypoalbuminemia.
is seen when cations are increased (K, Ca and Mg).
Compensated Metabolic Acidosis
Normal Anion Gap Metabolic Acidosis (NAGMA) Decrease in pH in metabolic acidosis
stimulates the respiratory compensatory mechanism
When there is a loss of both anions and cations, the
and produces hyperventilation-Kussmaul respiration
anion gap is normal, but acidosis may prevail. Causes
to eliminate carbon dioxide leading to hypocapnia
are described in Table 27.6.
(hypocarbia). The pCO2 falls and this would attempt to
restore the ratio towards 20 (partial compensation).
Renal compensation: Increased
Table 27.4: Stages of compensation
Stage pH HCO3 PaCO2 Ratio
Metabolic acidosis Low Low N <20
Uncompensated Low Low N <20
Partially compensated Low Low Low <20
Fully compensated N Low Low 20
Metabolic alkalosis High High N >20
Uncompensated High High N >20
Partially compensated High High High >20
Fully compensated N High High 20
Respiratory acidosis Low N High <20
Uncompensated Low N High <20
Partially compensated Low High High <20
Fully compensated N High High 20
Respiratory alkalosis High N Low >20
Uncompensated High N Low >20
Partially compensated High Low Low >20
Fully compensated N Low Low 20 Fig. 27.6: Bicarbonate diagram
 Chapter 27: Acid-Base Balance and pH 365

excretion of acid and conservation of base occurs. lactic acidosis. In all cases, potassium status to be
Na-H exchange, NH 4+ excretion and bicarbonate monitored closely and promptly corrected.
reabsorption are increased. As much as 500 mmol Bicarbonate requirement: The amount of bicarbonate
acid is excreted per day. The reabsorption of more required to treat acidosis is calculated from the base
bicarbonate also helps to restore the ratio to 20. deficit. In cases of acidosis, mEq of base needed =
Renal compensation sets in within 2 to 4 days. If the body wt in Kg × 0.2 – base excess in mEq/L.
ratio is restored to 20, the condition is said to be fully
compensated. But unless the cause is also corrected, Metabolic Alkalosis
restoration of normalcy cannot occur. Primary excess of bicarbonate is the characteristic
Associated hyperkalemia is commonly seen feature. Alkalosis occurs when a) excess base is
due to a redistribution of K+ and H+. The intracellular added, b) base excretion is defective or c) acid is lost.
K+ comes out in exchange for H+ moving into the cells. All these will lead to an excess of bicarbonate, so that
Hence, care should be taken while correcting acidosis the ratio becomes more than 20. Important causes and
which may lead to sudden hypokalemia. This is more findings are given in Table 27.7. Loss of acid may result
likely to happen in treating diabetic ketoacidosis by from severe vomiting or gastric aspiration leading to
giving glucose and insulin together. loss of chloride and acid. Therefore, hypochloremic
alkalosis results. Hyperaldosteronism causes
Clinical Features of Metabolic Acidosis retention of sodium and loss of potassium.
Hypokalemia is closely related to metabolic alkalosis.
The respiratory response to metabolic acidosis is In alkalosis, there is an attempt to conserve hydrogen
to hyperventilate. So there is marked increase in ions by kidney in exchange for K+. This potassium loss
respiratory rate and in depth of respiration; this is can lead to hypokalemia. Potassium from ECF will
called as Kussmaul respiration. The acidosis is enter the cells in exchange for H+. So, in alkalosis, pH
said to be dangerous when pH is < 7.2 and serum of urine remains acidic; hence this is called paradoxic
bicarbonate is <10 mmol/L. In such conditions, there acidosis.
is depressed myocardial contractility.

Treatment of Metabolic Acidosis Clinical Features of Metabolic Alkalosis

Treatment is to stop the production of acid by giving
Table 27.5: High anion gap metabolic acidosis (HAGMA)
IV fluids and insulin. Oxygen is given to patients with (organic acidosis)
Cause Remarks
Renal failure Sulfuric, phosphoric, organic anions. Decreased
ammonium ion formation. Na+/H+ exchange
results in decreased acid excretion
Ketosis Acetoacetate; beta hydroxy butyrate anions. Seen
in diabetes mellitus or starvation
Lactic Lactate anion. It accumulates when the rate of
acidosis production exceeds the rate of consumption
Salicylate Aspirin poisoning
Amino Acidic metabolic intermediates
acidurias Accumulation due to block in the normal metabolic
pathway
Organic Organic acids (methyl malonic acid, propionic
acidurias acid, etc.) excreted
Fig. 27.7: Gamblegram showing cations on the left and anions Drugs Corticosteroids, Furosemide, Methanol, Nitrates,
on the right side. Such bar diagrams were first depicted by Salicylates, Thiazides
Gamble, hence these are called Gamble grams
366 Textbook of Biochemistry

The respiratory center is depressed by the high pH acid will be less than 20. Acute respiratory acidosis
leading to hypoventilation. This would result in may result from bronchopneumonia or status
accumulation of CO2 in an attempt to lower the HCO3–/ asthmaticus. Depression of respiratory center due
H2CO3 ratio. However, the compensation is limited by to overdose of sedatives or narcotics may also lead
the hypoxic stimulation of respiratory center, so that to hypercapnia.
the increase in PaCO2 is not above 55 mm Hg (Box Chronic obstructive lung disease will lead to
27.7). chronic respiratory acidosis, where the fall in pH will be
However, complete correction of alkalosis will be minimal. The findings in chronic and acute respiratory
effective only if potassium is administered and the acidosis are summarized in Table 27.8. Chronic
cause is removed. cases will be well compensated unlike acute cases.
Increased neuromuscular activity is seen when In respiratory acidosis, bicarbonate level is increased
pH is above 7.55. Alkalotic tetany results even in the (not decreased). Clinically, there is decreased respiratory
presence of normal serum calcium. rate, hypotension and coma. Hypercapnia may lead to
peripheral vasodilation, tachycardia and tremors. The
Respiratory Acidosis findings in chronic and acute respiratory acidosis are
A primary excess of carbonic acid is the cardinal summarized in Table 27.8.
feature. It is due to CO 2 retention as a result of
hypoventillation. The ratio of bicarbonate to carbonic
Table 27.6: Normal anion gap metabolic acidosis (NAGMA) (inorganic acidosis)
Cause Remarks
Diarrhea, intestinal fistula Loss of bicarbonate and cations. Sodium or Potassium or both
Renal Tubular Acidosis Defective acidification of urine
Due to inability to reabsorb bicarbonate or due to inability to excrete hydrogen ions
Compensatory increase in chloride (hyperchloremic acidosis)
Carbonic anhydrase inhibitors Loss of bicarbonate, Na and K
Similar to proximal RTA
Ureterosigmioidostomy Loss of bicarbonate and reabsorption of chloride. Hyperchloremic acidosis
Drugs Antacids containing magnesium, lithium, polymixin B

Table 27.7: Metabolic alkalosis

Type Causes Changes
Chloride responsive Prolonged vomiting, Urine chloride <10 mmol/L
alkalosis Nasogastric suction, Hypovolemia, increased loss of Cl, K, H ions
Contraction alkalosis Upper GI obstruction Increased reabsorption of Na with bicarbonate
Loss of H+ and K+
Hypokalemia leads to alkalosis due to H+-K+ exchange. Cl is reabsorbed along
with Na
Hence urine chloride is low
Alkalosis responds to administration of NaCl
Loop Blocks reabsorption Aldosterone secretion occurs causing Na retention
diuretics of Na, K and Cl and wastage of K+ and H+
Chloride Mineralocorticoid excess, Urine chloride > 20 mmol/L
resistant Primary and secondary Defective renal Cl– reabsorption
metabolic hyperaldosteronism,
alkalosis Glucocorticoid excess,
Cushing’s, Adrenal tumor.
Exogenous Intravenous bicarbonate, Excess base enters the body
base Anatacids,
Milk alkali syndrome
 Chapter 27: Acid-Base Balance and pH 367

Respiratory Alkalosis Box 27.9: Normal serum electrolyte and arterial blood gas
A primary deficit of carbonic acid is described values
as respiratory alkalosis. Hyperventilation will result pH = 7.4
in washing out of CO2. So, bicarbonate: carbonic Bicarbonate = 22–26 mmol/L
acid ratio is more than 20. Causes are hysterical Chloride = 96–106 mmol/L
Potassium = 3.5–5 mmol/L
hyperventilation, raised intra­ cranial pressure and
Sodium = 136–145 mmol/L
brain stem injury. Early stage of salicylate poisoning PO2 = 95 (85–100) mm Hg
causes respiratory alkalosis due to stimulation of PCO2 = 40 (35–45) mm Hg
respiratory center. But later, it ends up in metabolic
acidosis due to accumulation of organic acids, lactic in. Bicarbonate level is reduced by decreasing the
and keto acids. Other causes include lung diseases reclamation of filtered bicarbonate.
(pneumonia). Clinically, hyperventillation, muscle cramps, tingling
pCO2 is low, pH is high and bicarbonate level normal. and paresthesia are seen. Alkaline pH will favor
But bicarbonate level falls, when compensation occurs. increased binding of calcium to proteins, resulting in
Compensation occurs immediately in acute stages. a decreased ionized calcium, leading to paresthesia.
In prolonged chronic cases renal compensation sets Causes of acidosis and alkalosis are enumerated in
Box 27.7: Maximum limits of compensation
Box 27.8.
Metabolic acidosis, pCO2 = 15 mm of Hg
Metabolic alkalosis, pCO2 = 50 mm of Hg
Respiratory acidosis, bicarbonate = 32 mmol/L
Normal Serum Electrolyte Values
Respiratory alkalosis, bicarbonate = 15 mmol/L Please see box 27.9. Students should always
remember these values. Upper and lower limits
Table 27.8: Lab findings in respiratory acidosis
are shown in Box 27.7. The causes of acid-base
pH pCO2 HCO3–
disturbances are shown in Box 27.8.
Acute respiratory a­ cidosis ↓↓ ↑↑ N or ↑
Chronic respiratory acidosis ↓ ↑ ↑↑
(partially compensated) Related Topics
N = normal; ↓ = decreased; ↑ = increased Renal mechanisms and renal function tests are
described in Chapter 25. Metabolisms of sodium,
Box 27.8: Causes of acid-base disturbances potassium and chloride are described in Chapter 28.
Acidosis Alkalosis
A. Respiratory Acidosis A. Respiratory Alkalosis
Pneumonia High altitude Clinical Case Study 27.1
Bronchitis, asthma Hyperventillation
COPD, pneumothorax Hysteria
Interpret the data and give the type of acid base
Narcotics, sedatives Febrile conditions disturbance. Blood pH – 7.12, pCO2 – 80 mm Hg,
Paralysis of respiratory Septicemia Plasma Bicarbonate – 26 mEq/L, H2CO3 – 20.7
muscles Meningitis
CNS trauma, tumor Congestive cardiac
mEq/L. What are the causes for the condition?
Ascites, peritonitis failure
Sleep apnea Clinical Case Study 27.2
B. Metabolic Acidosis B. Metabolic Alkalosis
i. High anion gap Severe vomiting A patient was operated for intestinal obstruction and
Diabetic ketosis Cushing syndrome had continuous gastric aspiration for 3 days. Blood pH
Lactic acidosis Milk alkali syndrome
Renal failure Diuretic therapy – 7.55, pCO2 – 50 mm Hg, plasma bicarbonate – 30
ii. Normal anion gap (potassium loss) mEq/L, serum sodium – 130 mmol/L, serum potassium
Renal tubular acidosis – 2.9 mmol/L, serum chloride – 95 mmol/L. Comment
(hyperchloremic)
on the obtained values. What is the significance of
CA inhibitors
Diarrhea potassium in acid base status assessment? Why
Addison’s disease
 368 Textbook of Biochemistry

is chloride measured in this patient? Calculate and 5. Metabolic acidosis is due to primary deficit in
comment on the anion gap. bicarbonate while respiratory acidosis is due to a
primary excess of carbonic acid.
6. Metabolic alkalosis is due to primary excess of
bicarbonate, while respiratory alkalosis is due to
primary deficit of carbonic acid.
Clinical Case Study 27.3 7. Metabolic acidosis is seen during renal tubular
acidosis, diabetic ketosis and organic acidemias.
Interpret the data and give the type of acid-base
disturbance. Blood pH – 7.54, pCO2 – 20 mm Hg,
plasma bicarbonate – 26 mEq/L, H2CO3 – 0.7 mEq/L.
What are the causes for the condition?

Clinical Case Study 27.1 Answer

Respiratory acidosis.

Clinical Case Study 27.2 Answer

Metabolic alkalosis.

Clinical Case Study 27.3 Answer

Respiratory alkalosis.

Learning Points, Chapter 27

1. The pH of plasma is 7.4. The regulation is by

buffers, lungs and kidney.
2. Buffer systems of the body are bicarbonate,
phosphate, Hb, proteins.
3. Bicarbonate buffer system is quantitatively the
most significant among body buffers.
4. Anion gap is the unmeasured anions. Normal
value is about 12 + 5 mM /L.

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