ACID-BASE BALANCE AND THEIR EFFECTS ON CELLULAR FUNCTION

Introduction

Normal cell metabolism depends on the maintenance of blood pH within very narrow limits
(7.35-7.45). Even relatively mild excursions outside this normal pH range can have
deleterious effects, including reduced oxygen delivery to tissues, electrolyte disturbances and
changes in heart muscle contractility; survival is rare if blood pH falls below 6.8 or rises
above 7.8. The problem for the body is that normal metabolism is associated with continuous
production of hydrogen ions (H+) and carbon dioxide (CO 2), both of which tend to reduce
pH. The mechanism which overcomes this problem and serves to maintain normal blood pH
(i.e. preserve acid-base homeostasis) is a complex synergy of action involving chemical
buffers in blood, the red cells (erythrocytes), which circulate in blood, and the function of
three organs: lungs, kidneys and brain.

Before explaining how these five elements contribute to the overall maintenance of blood pH,
it would be helpful to quickly review some basic concepts.

What is an acid, what is a base and what is pH?

An acid is a substance which releases hydrogen ions (H+) on dissociation in solution.

For example: Hydrochloric acid (HCl) dissociates to hydrogen ions and chloride ions

HCl H+ + Cl-

Carbonic acid (H2CO3) dissociates to hydrogen ions and bicarbonate ions

H2CO3 H+ + HCO3–

We distinguish between strong acids like hydrochloric acid and weak acids like carbonic
acid. The difference is that strong acids dissociate more than weak acids. Consequently the
hydrogen ion concentration of a strong acid is much higher than that of a weak acid.

A base is a substance which in solution accepts hydrogen ions.

For example, the base bicarbonate (HCO3–) accepts hydrogen ions to form carbonic acid:

HCO3– + H+ H2CO3

pH is a scale of 0-14 of acidity and alkalinity. Pure water has a pH of 7 and is neutral (neither
acidic nor alkaline). pH above 7 is alkaline and below 7 acidic. Thus the pH of blood (7.35-
7.45) is slightly alkaline although in clinical medicine the term alkalosis is, perhaps
confusingly, reserved for blood pH greater than 7.45 and the term acidosis is reserved for
blood pH less than 7.35.

pH is a measure of hydrogen ion concentration (H +). The two are related according to the
following equation:

pH = - log10 [H+]

where [H+] is the concentration of hydrogen ions in moles per liter (mol/L)

From this equation

pH 7.4 = H+ concentration of 40 nmol/L

pH 7.0 = H+ concentration of 100 nmol/L

pH 6.0 = H+ concentration of 1000 nmol/L

It is clear that:

 the two parameters change inversely; as hydrogen ion concentration increases, pH

falls
 due to the logarithmic relationship, a large change in hydrogen ion concentration is
actually a small change in pH. For example, doubling the hydrogen ion concentration
causes pH to fall by just 0.3

What is a buffer? – The bicarbonate buffer system

Buffers are chemicals in solution which minimize the change in pH which occurs when acids
are added by ‘mopping up’ hydrogen ions. A buffer is a solution of a weak acid and its
conjugate base. In blood, the principle buffer system is the weak acid, carbonic acid (H 2CO3)
and its conjugate base, bicarbonate (HCO3–). To explain how this system minimizes changes
in pH, suppose we add a strong acid, e.g. HCl, to the bicarbonate buffer:

The acid will dissociate, releasing hydrogen ions:

HCl H+ + Cl–

The bicarbonate buffer then ‘absorbs’ the hydrogen ions, forming carbonic acid in the
process:

HCO3– + H+ H2CO3 (carbonic acid)

The important point is that because the hydrogen ions from HCl have been incorporated into
the weak carbonic acid, which does not dissociate as easily, the total number of hydrogen
ions in solution and therefore the pH do not change as much as would have occurred in the
absence of the buffer.
Although a buffer greatly minimizes pH change, it does not eliminate it because even a weak
acid (like carbonic acid) dissociates to some extent. The pH of a buffer solution is a function
of the relative concentrations of the weak acid and its conjugate base.

pH = 6.1 + log ([HCO3–] / [H2CO3])

Where [HCO3–] = concentration of bicarbonate

[H2CO 3] = concentration of carbonic acid

This relationship, known as the Henderson-Hasselbalch equation, shows that pH is governed

by the ratio of base (HCO3–) concentration to acid (H2CO3) concentration.

As hydrogen ions are added to the bicarbonate buffer:

H+ + HCO3– H2CO3

Bicarbonate (base) is consumed (concentration decreases) and carbonic acid is produced

(concentration increases). If hydrogen ions continue to be added, all bicarbonate would
eventually be consumed (converted to carbonic acid) and there would be no buffering effect –
pH would then fall sharply if more acid were added.

However, if carbonic acid could be continuously removed from the system and bicarbonate
constantly regenerated, then the buffering capacity and therefore pH could be maintained
despite continued addition of hydrogen ions.

As will become clear with more detail of the physiology of acid-base balance, that is, in
effect, what happens in the body. In essence, the lungs ensure removal of carbonic acid (as
carbon dioxide) and the kidneys ensure continuous regeneration of bicarbonate.

This role of the lungs is dependent on a singular characteristic of the bicarbonate buffering
system and that is the ability of carbonic acid to be converted to carbon dioxide and water.

The following equation outlines the relationship of all elements of the bicarbonate buffering
system as it operates in the body

H+ + HCO3– H2CO3 H2O + CO2

It is important to note that the reactions are reversible. Direction is dependent on the relative
concentration of each element. So that, for example, a rise in carbon dioxide concentration
forces reaction to the left with increased formation of carbonic acid and ultimately hydrogen
ions.

This explains the acidic potential of carbon dioxide and brings us to the important
contribution that the lungs and red cells make to overall acid-base balance.
Lung function, transport of CO2 and acid-base balance

A constant amount of CO2 in blood, essential for normal acid-base balance, reflects a balance
between that produced as a result of tissue cell metabolism and that excreted by the lungs in
expired air.

By varying the rate at which carbon dioxide is excreted, the lungs regulate the carbon dioxide
content of blood. The sequence of events from carbon dioxide production in the tissues to
elimination in expired air is described in Fig. 1. Carbon dioxide diffuses out of tissue cells to
surrounding capillary blood (Fig. 1a). A small proportion dissolves in blood plasma and is
transported to the lungs unchanged.

But most diffuses into red cells where it combines with water to form carbonic acid. The acid
dissociates with production of hydrogen ions and bicarbonate. Hydrogen ions combine with
deoxygenated hemoglobin (hemoglobin is acting as a buffer here), preventing a dangerous
fall in cellular pH, and bicarbonate diffuses along a concentration gradient from red cell to
plasma.

Thus most of the carbon dioxide produced in the tissues is transported to the lungs as
bicarbonate in blood plasma.

Fig. 1a. CO2 produced in tissues converted to bicarbonate for transport to lungs.
  O2 oxygen  H+ hydrogen ions
 CO2 carbon dioxide  Hb hemoglobin
 H2CO3 carbonic acid  H+Hb reduced hemoglobin
 HCO3- bicarbonate ions

(hemoglobin acting as a buffer)

 O2 - Hb oxyhemoglobin

Fig. 1b. At the lungs bicarbonate converted back to CO2 and eliminated by the lungs.

At the alveoli in the lungs the process is reversed (Fig. 1b). Hydrogen ions are displaced from
hemoglobin as it takes up oxygen from inspired air. The hydrogen ions are now buffered by
bicarbonate which diffuses from plasma back into red cell, and carbonic acid is formed. As
the concentration of this rises, it is converted to water and carbon dioxide. Finally, carbon
dioxide diffuses down a concentration gradient from red cell to alveoli for excretion in
expired air.

Respiratory chemoreceptors in the brain stem respond to changes in the concentration of

carbon dioxide in blood, causing increased ventilation (breathing) if carbon dioxide
concentration rises and decreased ventilation if carbon dioxide falls.

Kidneys and acid-base balance

Normal cellular metabolism results in continuous production of hydrogen ions. We have seen
that by combining with these hydrogen ions, the bicarbonate buffer in blood minimizes their
effect. However, buffering is only useful in the short term, and ultimately hydrogen ions have
to be removed from the body. Furthermore, it is important that the bicarbonate that is used to
buffer hydrogen ions is continuously replaced.

These two tasks, elimination of hydrogen ions and regeneration of bicarbonate, are
accomplished by the kidneys. Renal tubule cells are rich in the enzyme carbonic anhydrase,
which facilitates formation of carbonic acid from carbon dioxide and water. Carbonic acid
dissociates to bicarbonate and hydrogen ions. The bicarbonate is reabsorbed into blood and
the hydrogen ions pass into the lumen of the tubule and are eliminated from the body in urine.

This urinary elimination is dependent on the presence in urine of buffers, principally

phosphate and ammonia ions.

DISTURBANCES OF ACID-BASE BALANCE

Most acid-base disturbances result from

 disease or damage to organs (kidney, lungs, brain) whose normal function is

necessary for acid-base homeostasis,
 disease which causes abnormally increased production of metabolic acids such that
homeostatic mechanisms are overwhelmed
 medical intervention (e.g. mechanical ventilation, some drugs)

Arterial blood gases are the blood test used to identify and monitor acid-base disturbances.
Three parameters measured during blood gas analysis, arterial blood pH (pH), partial pressure
of carbon dioxide in arterial blood (pCO2(a)) and concentration of bicarbonate (HCO3–) are of
crucial importance (see Table I for reference (normal) range). Results of these three allow
classification of acid-base disturbance to one of four etiological categories:

 Respiratory acidosis
 Respiratory alkalosis
 Metabolic acidosis
 Metabolic alkalosis

Adults Neonates

pH 7.35-7.45 7.30-7.40
pCO2 (kPa) 4.7-6.0 3.5-5.4
Bicarbonate 22-28 15-25

(mmol/L)

TABLE I. Approximate reference (normal) ranges

To understand how the results of pH, pCO2(a) and bicarbonate are used to classify acid-base
disturbances in this way, we must return to the Henderson-Hasselbalch equation

pH = 6.1 + log ([HCO3–] / [H2CO3])

We measure pH and bicarbonate but not carbonic acid (H 2CO3). However, there is a
relationship between pCO2(a) and H2CO3 which allows restatement of the Henderson-
Hasselbalch equation in terms of the three parameters (pH, pCO2(a) and bicarbonate)
measured during blood gas analysis:

pH = 6.1 + log ([HCO3–] / ( pCO2(a) × 0.23))

By removing all constants from this equation, the relationship between the three measured
parameters can be more simply stated:

pH ∝ [HCO3–] / pCO2(a)

This relationship, crucial for an understanding of all that follows concerning acid base
disturbances, states that arterial blood pH is proportional to the ratio of bicarbonate
concentration to pCO2(a). It allows the following deductions:

 pH remains normal so long as the ratio [HCO3–] : pCO2(a) remains normal

 pH increases (i.e. alkalosis occurs) if either [HCO3–] increases or pCO2(a) decreases.
 pH decreases (i.e. acidosis occurs) if either [HCO3–] decreases or pCO2(a) increases
 If both pCO2(a) and [HCO3–] are increased by relatively the same amount, the ratio
and therefore the pH are normal
 If both pCO2(a) and [HCO3–] are decreased by relatively the same amount, the ratio
and therefore the pH are normal.

Acid-base disturbances affect primarily either pCO2(a), in which case it is called a

respiratory disturbance, or [HCO3–], in which case it is called a non-respiratory or metabolic
disturbance:

 If the primary disturbance is a raised pCO2(a) (which causes acidosis – see above), the
condition is called respiratory acidosis
 If the primary disturbance is a reduced pCO2(a) (which causes alkalosis – see above),
the condition is called respiratory alkalosis
 If the primary disturbance is associated with reduced bicarbonate (which results in
acidosis – see above), the condition is called metabolic acidosis
 If the primary disturbance is associated with raised bicarbonate (which results in
alkalosis – see above), the condition is called metabolic alkalosis

Causes of acid-base disturbances

Respiratory acidosis – (raised pCO2(a), reduced pH)

Respiratory acidosis is characterized by increased pCO2(a) due to inadequate alveolar

ventilation (hypoventilation) and consequent reduced elimination of CO 2 from the blood.
Respiratory disease, such as bronchopneumonia, emphysema, asthma and chronic obstructive
airways disease, may all be associated with hypoventilation sufficient to cause respiratory
acidosis.

Some drugs (e.g. morphine and barbiturates) can cause respiratory acidosis by depressing the
respiratory center in the brain. Damage or trauma to the chest wall and the musculature
involved in the mechanics of respiration may reduce ventilation rate. This explains the
respiratory acidosis that can complicate the course of diseases such as poliomyelitis, Guillain-
Barre syndrome and recovery from severe chest trauma.

Metabolic acidosis – (decreased HCO3–, decreased pH)

Reduced bicarbonate is always a feature of metabolic acidosis. This occurs for one of two
reasons: increased use of bicarbonate in buffering an abnormal acid load or increased losses
of bicarbonate from the body. Diabetic ketoacidosis and lactic acidosis are two conditions
characterized by overproduction of metabolic acids and consequent exhaustion of
bicarbonate.

In the first case, abnormally high blood concentrations of keto-acids (b-hydroxybutyric acid
and acetoacetic acid) reflect the severe metabolic derangements which result from insulin
deficiency.

All cells produce lactic acid if they are deficient of oxygen, so increased lactic acid
production and resulting metabolic acidosis occur in any condition in which oxygen delivery
to the tissues is severely compromised.

Examples include cardiac arrest and any condition associated with hypovolemic shock (e.g.
massive fluid loss). The liver plays a major role in removing the small amount of lactic acid
that is produced during normal cell metabolism, so that lactic acidosis can be a feature of
liver failure.

Abnormal loss of bicarbonate from the body can occur during severe diarrhea. If unchecked,
this can lead to metabolic acidosis. Failure to regenerate bicarbonate and excrete hydrogen
ions explains the metabolic acidosis that occurs in renal failure.

Metabolic alkalosis – (increased HCO3– , increased pH)

Bicarbonate is always raised in metabolic alkalosis. Rarely, excessive administration of

bicarbonate or ingestion of bicarbonate in antacid preparation can cause metabolic alkalosis,
but this is usually transient. Abnormal loss of hydrogen ions from the body can be the
primary problem. Bicarbonate which would otherwise be consumed in buffering these lost
hydrogen ions consequently accumulates in blood. Gastric juice is acidic and gastric
aspiration or any disease process in which gastric contents are lost from the body represents a
loss of hydrogen ions.

The projectile vomiting of gastric juice, for example, explains the metabolic alkalosis that can
occur in patients with pyloric stenosis. Severe potassium depletion can cause metabolic
alkalosis due to the reciprocal relationship between hydrogen and potassium ions.

Compensation – a consequence of acid-base disturbance

It is vital for life that pH does not waiver too far from normal, and the body will always
attempt to return an abnormal pH towards normal when acid-base balance is disturbed.
Compensation is the name given to this life-preserving process. To understand compensation,
it is important to recall that pH is governed by the ratio [HCO 3–] : pCO2(a). So long as the
ratio is normal, pH will be normal.

Consider the patient with metabolic acidosis whose pH is low because bicarbonate [HCO 3–] is
low. To compensate for the low [HCO3–] and restore the all-important ratio towards normal
the patient must lower his pCO2(a). Chemoreceptors in the respiratory center of the brain
respond to a rising hydrogen ion concentration (low pH), causing increased ventilation
(hyperventilation) and thereby increased elimination of carbon dioxide; the pCO2(a) falls and
the ratio [HCO3–] : pCO2(a) returns towards normal.

Compensation for metabolic alkalosis in which [HCO3–] is high, by contrast, involves

depression of respiration and thereby retention of carbon dioxide so that the pCO2(a) rises to
match the increase in [HCO3–]. However, depression of respiration has the unwelcome side
effect of threatening adequate oxygenation of tissues. For this reason respiratory
compensation of metabolic alkalosis is limited.

Primary disturbances of pCO2(a) (respiratory acidosis and alkalosis) are compensated for by
renal adjustments of hydrogen ion excretion which result in changes in [HCO 3–] that
compensate appropriately for primary change in pCO2(a). Thus, the renal compensation for
respiratory acidosis (raised pCO2(a)) involves increased reabsorption of bicarbonate, and
renal compensation for respiratory alkalosis (reduced pCO2(a)) involves reduced bicarbonate
reabsorption.

The concept of acid-base balance during compensation is conveyed visually in Fig. 2. Table
II summarizes the blood gas results that characterize all four acid-base disturbances before
and after compensation.
Fig. 2. The "acid-base balance" : compensation restores normal pH

Primary disturbance
Respiratory Respiratory Metabolic Metabolic
acidosis alkalosis acidosis alkalosis

primary primary primary

increase in decrease in primary increase in
pCO2 decrease in bicarb.
pCO2 bicarb.
Some common Emphysema Hyperventilation Renal failure Bicarbonate
causes
Chronic Diabetic
inflammatory ketoacidosis
lung disease Circulatory administration
(COPD) Anxiety attacks failure
Stimulation of Potassium
brain respiratory clinical depletion
Pneumonia, center shock
Depression
of respiratory
centre (lactic acidosis)
 Compensatory RENAL RENAL RESPIRATORY RESPIRATORY
mechanism increase

increase pCO2
bicarbonate decrease decrease
bicarbonate pCO2 but limited

compensation in
metabolic
alkalosis
Initial blood gas pH pH pH pH
results
(uncompensated) decreased increased pCO2 decreased pCO2 increased pCO2
pCO2

decreased normal normal

increased Bicarbonate Bicarbonate Bicarbonate
Bicarbonate normal decreased
normal

increased
Blood gas results pH decreased pH increased pH decreased Limited
after partial but closer to but closer to but closer to
compensation normal normal normal

pCO2 pCO2 decreased pCO2 marginally compensation in

decreased metabolic
alkalosis
Bicarbonate
increased Bicarbonate decreased
Bicarbonate marginally
increased decreased
Blood gas results pH normal pH normal pH normal Limited
after full compensation in
compensation metabolic
pCO2 alkalosis
increased pCO2 decreased pCO2 decreased

Bicarbonate Bicarbonate
Bicarbonate decreased decreased
increased

TABLE II. Blood gas results in disturbances of acid-base balance

Respiratory compensation for a primary metabolic disturbance occurs much more quickly
than metabolic (renal) compensation for a primary respiratory disturbance. In the second
case, compensation occurs over days rather than hours.
If compensation results in return of pH to normal then the patient is said to be fully
compensated. But in many cases the compensation returns pH towards normal without
actually achieving normality; in such cases the patient is said to be partially compensated.

For reasons described above, metabolic alkalosis is very rarely fully compensated.

Mixed acid-base disturbances

It might be assumed from the above discussion that all patients with acid-base disturbance
suffer from only one of the four categories of acid-base balance. This may well be the case,
but in particular circumstances patients can present with more than one disturbance.

For example, consider the patient with a chronic lung disease such as emphysema who has a
long-standing partially compensated respiratory acidosis. If this patient were also a diabetic
who had not taken his normal insulin dose and as a result was in a state of diabetic
ketoacidosis, blood gas results would reflect the combined effect of both respiratory acidosis
and metabolic acidosis.

Such mixed acid-base disturbances are not infrequent and may be difficult to unravel on the
basis of arterial blood gas results alone.

Summary

The maintenance of normal blood pH involves several organ systems and depends on
circulatory integrity. It is not surprising then that disturbance of acid-base balance can
complicate the course of widely diverse diseases as well as trauma to many parts of the body.
The body has considerable power to preserve blood pH, and disturbances usually imply either
severe chronic disease or acute critical illness.

The results of arterial blood gas analysis can identify acid–base disturbance and provide
valuable information as to its cause