Acid-Base Homeostasis
 Blood hydrogen ion concentration maintained within tight Limits
in health.
 Normal levels lie between 35-45 nmol/l (pH 7.35-7.46) in
extracellular fluid.
 In intracellular fluid is slightly higher but also tightly
controlled
• Normal pH of body fluids
– Arterial blood is 7.4
– Venous blood and interstitial fluid is 7.35
– Intracellular fluid is 7.0
• Alkalosis or alkalemia – arterial blood pH rises above 7.45
• Acidosis or acidemia – arterial pH drops below 7.35
(physiological acidosis)
2
Sources of Hydrogen Ions

Most hydrogen ions originate from cellular metabolism
• Breakdown of sulpher-containing proteins releases H into the ECF
• Incomplete oxidation of energy substrates generates acids like:
• Anaerobic respiration of glucose produces lactic acid
• Fat metabolism yields organic acids and ketone bodies, these
intermediates will be further metabolized and consumed (e.g.,
lactate in gluconeogenesis, oxidation of ketones).
• Temporary imbalances between the rates of production and
consumption may occur in health (e.g., the accumulation of lactic
acid during anaerobic exercise),

Transporting carbon dioxide as bicarbonate releases hydrogen ions

In disease states, increased hydrogen ion production is an important cause of
acidosis.

The total amount of hydrogen ion produced each day is 100000 times more
acid than normal !

This just does not happen because excess hydrogen ions are efficiently
excreted in urine.
Acid/Base Homeostasis: Overview
Hydrogen Ion Regulation
• Concentration of hydrogen ions is regulated sequentially by:
– Chemical buffer systems – act within seconds
– The respiratory center in the brain stem – acts within 1-3
minutes
– Renal mechanisms – require hours to days to effect pH
changes
Chemical Buffer Systems
• Three major chemical buffer systems
– Bicarbonate buffer system
– Phosphate buffer system
– Protein buffer system
Any drift in pH is resisted by the entire chemical buffering system
Buffering of hydrogen ions
As hydrogen ions are generated they are buffered, thus limiting the
rise in hydrogen ion concentration which would otherwise occur.
A buffer is a solution of the salt or a weak acid which is able to bind
hydrogen ions.
If hydrogen ions are added to a buffer, some will combine with the
conjugate base and convert it to the un-dissociated acid.
Buffering does not remove hydrogen ions from the body. Buffers
temporarily wash up any excess hydrogen ions which are produced. In the
same way that a sponge soaks up water.
 Buffering is only a short term solution to the problem of excess
hydrogen ion. Eventually, the body must get rid of the hydrogen ions by
renal excretion.
The efficacy of any buffer is limited by its concentration and by the
position of the equilibrium
The body contains Three major chemical buffer systems to resist sudden
changes in hydrogen ion production
Phosphate buffer system: Phosphate is a minor buffer in the ECF but is
of fundamental importance in the urine.
Protein buffer system: hemoglobin in the erythrocytes has a high
capacity for binding hydrogen ion
Bicarbonate buffer system: it is the most important in the ECF
Bicarbonate (HCO3-) combines with hydrogen ion to form carbonic acid (H2CO3)
The addition of hydrogen ions  increasing the amount of carbonic acid and
consuming bicarbonate ions.
 Conversely, if the hydrogen ion concentration falls, carbonic acid dissociates,
thereby generating hydrogen ions.
This buffer system is unique in that the H2CO3, can dissociate to water and
carbon dioxide.
H + + HCO3 -  H2CO3
H2CO3  H2O  CO2
Bicarbonate Buffer System
• A mixture of carbonic acid (H2CO3) and its salt, sodium
bicarbonate (NaHCO3) (potassium or magnesium bicarbonates
work as well)
• If strong acid is added:
– Hydrogen ions released combine with the bicarbonate ions and
form carbonic acid (a weak acid)
– The pH of the solution decreases only slightly
• If strong base is added:
– It reacts with the carbonic acid to form sodium bicarbonate
(a weak base)
– The pH of the solution rises only slightly
• This system is the most important ECF buffer
 Simple buffers rapidly become ineffective as the association of the
hydrogen ion and the anion of the weak acid reaches equilibrium.
 The bicarbonate system keeps working because the carbonic acid is
removed as CO2.
The limit to the effectiveness the bicarbonate system is the initial
concentration of bicarbonate. Only when all the bicarbonate is used up does
the system have no further buffering capacity.
The capacity of the bicarbonate system in the body is greatly enhanced
by the fact that carbonic acid can readily be formed from carbon dioxide
or disposed of by conversion into carbon dioxide and water.
 Buffering by the bicarbonate system effectively removes hydrogen ion from
the ECF at the expense of bicarbonate. The extracellular fluid contains a large
amount of bicarbonate but it falls as H+ is increased
To maintain the capacity of the buffer system, the bicarbonate must be
regenerated.
Bicarbonate reabsorption and hydrogen ion excretion
 The glomerular filtrate contains the same concentration of bicarbonate ions
as the plasma  If not reabsorbed  large amounts would be excreted in the
urine  depleting the body’s buffering capacity  causing an acidosis
 Virtually all the filtered bicarbonate is reabsorbed.
The luminal surface of renal tubular cells is impermeable to bicarbonate and
therefore direct reabsorption can not occur.
 Bicarbonate is reabsorbed indirectly: within the renal tubular cells, carbonic
acid is formed from carbon dioxide and water  This reaction is catalyzed in
the kidney by the enzyme carbonic anhydrase.
 The carbonic acid thus formed dissociates to give hydrogen and bicarbonate
ions. The bicarbonate ions pass across the basal border of the cells into the
interstitial fluid.
The hydrogen ions are secreted across the luminal membrane in exchange for
sodium ions, which accompany bicarbonate into the interstitial fluid.
Bicarbonate reabsorption
Bicarbonate reabsorption
Hydrogen ion excretion
 Although hydrogen ions are secreted into the tubular fluid, there is
no net hydrogen ion excretion, as the formation of hydrogen ions
provides the means for the reabsorption of bicarbonate.
Hydrogen ion excretion depends
upon the same reactions occurring
in the renal tubular cells but, in
addition, requires the presence of
a suitable buffer system in the
urine
The excreted hydrogen ions must
be buffered in urine or the [H+]
would rise to very high levels.
Phosphate acts as one such
buffer, while ammonia is another.
Bicarbonate generation and hydrogen ion excretion

Bicarbonate reabsorption and hydrogen
ion excretion
 The principal urinary buffer is
phosphate. This is present in the
glomerular filtrate (HPO42-). This
combines with hydrogen ions and is
converted to H2PO4-.
HPO4 2- + H +  H2PO4  Ammnia, produced by the deamination
of glutamine by glutaminase enzyme in
renal tubular cells,
 Ammonia can readily diffuse across cell
membranes and ammonium ions are formed
and excreted.
NH 3  H   NH 4 
Transport of Carbon dioxide
 Carbon dioxide, produced by aerobic metabolism, diffuses out of cells and
dissolves in the ECF.
 A small amount combines with water to form carbonic acid, thereby increasing
the hydrogen ion concentration of the ECF.
 In red blood cells, metabolism is anaerobic and little carbon dioxide is
produced. Carbon dioxide thus diffuses into red cells down a gradient and
carbonic acid is formed, facilitated by carbonate dehydatase (Carbonic
unhydrase)
 The overall effect of this process is that carbon dioxide is converted to
bicarbonate in red blood cells.
This bicarbonate diffuses out of the red cells with exchange with chloride
ions (the chloride shift).
In the lungs, the reverse process occurs because of the low partial pressure
of carbon dioxide in the alveolar capillaries.
 Carbon dioxide is produced from bicarbonate and diffuses into the alveoli to
be excreted in the expired air.
Most of the carbon
How is CO2 Exported?
dioxide in the blood is
present in the form of
bicarbonate.
Dissolved carbon dioxide,
carbonic acid and
carbamino compounds
(compounds of carbon
dioxide and protein)
account for less than 2.0
mmol/L in a total carbon
dioxide con. of appro. 26
mmol/L.
The term ‘bicarbonate’ and ‘total carbon dioxide’ are frequently used
synonymously.
Assessing Acid-base Status
 An indication of the acid-base status of the patient can be obtained by
measuring the components of the bicarbonate buffer system.
H + + HCO3 -  H
H22CO
CO33  H2O  CO2
PCO2
H is proportina l to
HCO3 +
Excess hydrogen ions are buffered by bicarbonate  the formed carbonic acid
dissociates  carbon dioxide is lost in the expired air  limits the potential rise in
hydrogen ion concentration at the expense of a reduction in bicarbonate
The hydrogen ion concentration in blood varies as the bicarbonate concentration
and PCO2 change. If everything else remains constant:
Adding hydrogen ion, removing bicarbonate or increasing the PCO2 will all
have the same effect an increase in [H+].
Removing hydrogen ions, adding bicarbonate or lowering PCO2 will all
cause the [H+] to fail.
 Blood [H+] is 40 nmol/l and is controlled by our normal pattern of respiration and
the functioning of our kidneys.
Acid Base Balance
Disorders of hydrogen ion homeostasis
 “Metabolic” acid-base disorders are those that directly cause a change in the
bicarbonate concentration, like diabetes mellitus because of the absence of insulin
 building up of [H+], of ketone bodies or loss or bicarbonate from the
extracellular fluid.
 “Respiratory” acid-base disorders affect PCO2. Impaired respiratory function
causes a build up of CO2 in blood or in the case of hyperventilation causes a
decreased PCO2
Remember
When you see “respiratory”, think
PCO2
When you see “metabolic”, think
[HCO3]
20
Compensation
The body has physiological mechanisms which try to restore [H+] to normal. These
processes are called 'compensation', The observed [H+] in any acid-base disorder
reflects the balance between the primary disturbance and the amount of
compensation.
Renal Compensation: where
lung function is compromised
(primary respiratory
disorder). The body attempts
to increase the excretion of
hydrogen ion via the renal
route. Renal compensation is
slow to lake place.
Respiratory compensation:
where there are metabolic
disorder some compensation
is possible by lung
Disorders of hydrogen ion homeostasis
Acidosis and alkalosis are clinical terms which define the primary acid-base
disturbance. They can be used even when the [H+] is within the normal
range. i.e. when the disorders are fully compensated.
The definitions are:
 Non-respiratory (Metabolic) acidosis: The primary disorder is a
decrease in bicarbonate concentration.
 Non-respiratory (Metabolic) alkalosis: The primary disorder is an
increased bicarbonate.
 Respiratory acidosis: The primary disorder is an increased PCO2.
 Respiratory alkalosis: The primary disorder is a decreased PCO2.
 Primary mixed acid-base disorders, that is, disorders of combined
respiratory and non-respiratory origin,
‘Acidemai' and 'alkalaemia' refer simply to whether the [H+] in blood is higher
or lower than normal
Metabolic acidosis
 The primary abnormality in non-respiratory acidosis is either increased
production or decreased excretion of hydrogen ions.
In some cases, both of these may contribute.
Loss of bicarbonate and retention of hydrogen ions may result in acidosis in
patients losing alkaline secretions from the small intestine.
Causes of non-respiratory acidosis
* Increased H+ formation
ketoacidosis (usually diabetic, also alcoholic)
lactic acidosis
poisoning: e.g., ethanol, methanol, ethylene glycol and salicylate
* Acid ingestion
acid poisoning
* Decreased H+ excretion
renal tubular acidosis
generalised renal failure
carbonate dehydratase inhibitors
* Loss of bicarbonate
diarrhea
pancreatic, intestinal and biliary fistulae or drainage
The characteristic biochemical changes seen in the blood in non-respiratory
acidosis can be summarized as follows:
Metabolic acidosis
high [H+], Low pH, low PCO2 and Low [HCO3-]
Compensation is effected by hyperventilation, which increases the removal of
carbon dioxide and lowers the PCO2.
Hyperventilation is a direct result of the increased [H+] stimulating the respiratory
centre.
Respiratory compensation cannot completely normalize the [H+] since it is the high
concentration itself that stimulates the compensatory hyperventilation. Also the
increased work of the respiratory muscle produces carbon dioxide, so limiting the
extent to which the pCO2 can be lowered.
In a healthy person, hyperventilation would produce a respiratory alkalosis.
If renal function is normal in a patient with metabolic acidosis, excess hydrogen ion
can be excreted by the kidneys.
The complete correction of a metabolic acidosis requires reversal of the underlying
cause, for example, rehydration and insulin for diabetic ketoacidosis.
Hyperkalaemia is common in acidotic patients.
Clinical effects of acidosis
The compensatory response to metabolic acidosis is
hyperventilation, since the increased [H+] acts as a powerful
stimulant of the respiratory centre. The deep, rapid and
gasping respiratory pattern is known as Kussmaul breathing.
Hyperventilation is the appropriate physiological response to
acidosis and it occurs rapidly.
A raised [H+] leads to increased neuromuscular irritability.
There is a hazard of arrhythmias progressing to cardiac arrest,
this will be more likely in the presence of hyperkalaemia which
will accompany the acidosis
Depression of consciousness can progress to coma and death.
Anion Gap
• Total concentration of anions and
cations in plasma must be equal to
maintain electrical neutrality
• but, only certain cation (Na+ with or
without K +) and anions (Cl-, HCO3-) are
routinely measured in clinical laboratory
Anion Gap
• “anion gap” : difference between
unmeasured anions and unmeasured
cations
Na+
unmeasured cations
Clunmeasured anions
HCO3-
Anion Gap
Na+
HCO3-
Cl-
unmeasured anions
unmeasured cations
• anion gap = [Na+] – {[HCO3-] + [Cl-]}
= 144 - {
24
= 10 mEq/L
+ 108}
Anion Gap
Na+
unmeasured cations
HCO3-
Cl-
unmeasured anions
• if unmeasured anions    relative amount of Cl- & HCO3phosphate, sulfate,
• albumin,
other organic anions
anion gap 
• if unmeasured cation    relative amount of Na+
calcium, magnesium, potassium
Clinical Use of anion gap
•
In metabolic acidosis (low HCO3-)
if plasma Na+ is unchanged,
concentration of anions (Cl- or unmeasured
anion) must increase to maintain electroneutrality
(1) if Cl- remains unchanged:
•
there must be increased unmeasured anion
(=  anion gap)
•
•
a.
b.
c.
d.
e.
f.
diabetes mellitus (ketoacidosis)
lactic acidosis
chronic renal failure
aspirin (acetylsalicylic acid)
methanol
ethylene glycol0
Clinical Use of anion gap
(2) if Cl- increases in proportion to the fall of
HCO3-:
•
(normal anion gap)
•
(“hyperchloremic metabolic acidosis)
a. diarrhea
b. renal tubular acidosis
Metabolic Alkalosis (Non-respiratory alkalosis): is
characterized by a primary increase in the ECF bicarbonate
concentration, with a consequent reduction in [H+].
 Normally, an increase in plasma bicarbonate concentration leads
to incomplete renal tubular bicarbonate reabsorption and
excretion of bicarbonate in the urine.
 BUT in Metabolic alkalosis, high renal bicarbonate reabsorption
occurs.
Factors which may be responsible for this include a decrease in
ECF volume, mineralocorticoid excess increased Sod along with
carbonate reabsorption and potassium depletion.
 Massive quantities of bicarbonate must be ingested to produce
a sustained alkalosis.
Metabolic Alkalosis The causes of a
metabolic alkalosis are:
 Loss of Hydrogen ion in gastric fluid
during vomiting especially when there is no
parallel loss of bicarbonate.
 Ingestion of an absorbable alkali as sod
bicarbonate: very large quantities are
required except there is renal impairment
 In sever potassium depletion
(consequences of diuretic therapy)
hydrogen ions are retained inside cells to
replace missing potassium ions.
In renal tubules more hydrogen are
exchanged for reabsorption of sod. So,
despite there being an alkalosis, the
patient passes acidic urine. This often
referred to as a ‘paradoxical’ acid urine,
because in other causes of metabolic
alkalosis urinary [H+] usually falls.
Clinical effects of metabolic alkalosis
The clinical effects of alkalosis include:
hypoventilation, confusion and eventually coma.
Muscle cramps, tetany and paraesthesia (any
abnormality in sensation) may be a consequence of
a decrease in the unbound plasma calcium
concentration which is a consequence of the
alkalosis.
Metabolic Alkalosis:
The correction of non-respiratory alkalosis requires reversal both of
the primary cause and for the mechanism for its maintenance.
The expected compensatory would be an increased in PCO2 which would
increase the ratio PCO2/[HCO3] and thus [H+]. A low arterial [H+]
inhibits the respiratory centre, causing hypoventilation, and thus an
increase in PCO2.
However, since an increase in PCO2 is itself a powerful stimulus to
respiration, this compensation, particularly in acute non-respiratory
alkalosis, may be self-limiting.
In more chronic disorders, significant compensation may occur,
presumably because the respiratory centre becomes less sensitive to
carbon dioxide. Should hypoventilation lead to significant hypoxaemia,
however, this will provide a powerful stimulus to respiration and prevent
further compensation.
Management:
The management of a Metabolic alkalosis depends upon the
severity of the condition and upon the cause.
When hypovolaemia are present, they can be simultaneously
corrected by an infusion of isotonic sodium chloride solution
(normal saline) which will also improve renal perfusion and allow
excretion of the bicarbonate load.
It is very rarely necessary to attempt rapid correction of non-
respiratory alkalosis, for example, by administration of
ammonium chloride.
The mild alkalosis commonly associated with potassium
depletion may require correction
Respiratory acidosis: The
primary disorder is an
increased PCO2
Respiratory acidosis is
characterized by an increase in
PCO2, (CO2 retention)
 For every hydrogen ion
produced a bicarbonate ion is
generated BUT the effect of
adding one H+ to a
concentration of 40 nmol/l is
much greater than adding one
bicarbonate molecule to a
concentration of 26 mmol/l.
The majority of hydrogen
ions are buffered by
intracellular buffers,
particularly hemoglobin.
Respiratory acidosis: The primary disorder is an increased PCO2
Respiratory acidosis: Respiratory acidosis may be acute or chronic.
Acute conditions occur within minutes or hours, they are uncompensated.
Renal compensation has no time to develop as the mechanisms that adjust
bicarbonate reabsorption take 48-72 hours to become fully effective.
 The primary problem in acute respiratory acidosis is alveolar
hypoventilation  If airflow is completely or partially reduced, the PCO2 in
the blood will rise immediately and the [H+] will rise quickly.
A resulting low PO2 and high PCO2 causes coma. If this is not relieved
rapidly, death results. Examples of acute respiratory acidosis are: Acute
airway obstruction: choking (obstruction of the flow of air from the
environment into the lungs), bronchopneumonia, acute exacerbation of
asthma.
Depression of respiratory centre: Anaesthetics, Sedatives
Chronic respiratory acidosis: usually results from chronic
obstructive airways disease (COAD) and is usually a longstanding condition, accompanied by maximal renal
compensation.
In a chronic respiratory acidosis the primary problem is also
usually impaired alveolar ventilation, but renal compensation
contributes markedly to the acid-base picture.
Compensation may be partial or complete.
The kidney increases hydrogen ion excretion and ECF
bicarbonate levels rise. Blood [H+] tends back towards normal
Management of Acidosis
 The aim when treating respiratory acidosis is to improve
alveolar ventilation and lower the PCO2.
 In acute alveolar hypoventilation: hypoxia causes the
main threat to life  If ventilation is stopped abruptly,
death from hypoxia will occur
In chronic respiratory acidosis, it is rarely possible to
correct the underlying cause and treatment is directed at
maximizing alveolar ventilation by, for example, utilizing
physiotherapy, bronchodilators and antibiotics.
Respiratory alkalosis
 Respiratory alkalosis is much less common than acidosis but
can occur when respiration is stimulated or is no longer
subject to feedback control.
Usually these are acute conditions, and there is no renal
compensation.
Renal compensation in a respiratory alkalosis develops slowly,
as it does in respiratory acidosis.
 The treatment is to inhibit or remove the cause of the
hyperventilation, and the acid-base balance should return to
normal.
 Causes are: hysterical over-breathing, mechanical overventilation in an intensive care patient, raised intracranial
pressure, or hypoxia, both of which may stimulate the
respiratory centre.
Mixed acid-base disorders
Patients can have more than one acid-base disorder.
 A patient may have both a metabolic and respiratory acidosis, such as the
chronic bronchitic patient who develops renal impairment the PCO2 will be
increased and the bicarbonate concentration will be low,
 Hyperventilation causing a respiratory alkalosis, with prolonged nasogastric
suction that causes a metabolic alkalosis
Sometimes the two acid-base conditions are antagonistic in the way they
affect the [H+], a metabolic acidosis and a co-existent respiratory alkalosis,
Some examples of mixed acid-base disorders commonly encountered are:
 A patient with chronic obstructive airways disease, causing a
respiratory acidosis, with thiazide-induced potassium depletion and
consequent metabolic alkalosis
 Salicylate poisoning in which respiratory alkalosis occurs due to
stimulation of the respiratory centre, together with metabolic acidosis
due to the effects of the drug on metabolism.
Interpretation of Acid-Base Data
 A comprehensive understanding of the pathophysiology of acid-base
homoeostasis is essential for the correct interpretation of laboratory data, but
these data should always be considered in the clinical background.
 The starting point in any evaluation should be the hydrogen ion concentration or
pH. This will indicate whether the predominant disturbance is an acidosis or an
alkalosis. However, a normal value does not exclude an acid-base disorder.
 There may be either a fully compensated disturbance or
 Two primary disturbances where effects on hydrogen ion concentration
cancel each other out.
 If the PCO2 is abnormal, there must be a respiratory component to the
disturbance; if the PCO2 is raised in an acidosis, the acidosis is respiratory and
the value of the hydrogen ion concentration will indicate wither there is an
additional metabolic component.
 If the PCO2 is low in an acidosis, the acidosis is non-respiratory and there is an
additional respiratory component, which will often reflect compensation.
 A similar rationale applies to alkalotic states.
Interpretation
of Acid-Base
Data
Chloride
It's the major ECF anion
Its precise function in the body is not well understood; however, it is involved
in maintaining osmolality, blood volume, and electric neutrality.
In many processes, Cl ions shifts secondarily to a movement of sodium or
bicarbonate ions.
Cl ingested in the diet is almost completely absorbed by GIT and then
filtered out by the glomerulus and passively reabsorbed in conjunction with
Na.
Excess Cl is excreted in the urine and sweat.
Excessive sweating stimulates aldosterone secretion, which act on sweat
glands to conserve Na and Cl.
Biologic function: It's involved in
1. Maintenance of water distribution and osmotic pressure.
2. Regulation if anion – cation balance in ECF.
3. Chloride shift in HCO3 transport in RBCs.
4. Gastric juice.
Chloride
The electrical neutrality is maintained by:
1. The reabsorption of Na along with Cl
2. The chloride shift: bicarbonate diffuses oppositely to Cl
Clinical application
Cl disorders are often a result of the same causes that disrupts Na
levels.
Hyperchloremia may also occur when there is an excess loss of
bicarbonate ion as a result of GI losses, renal tubular acidosis, or
metabolic acidosis.
Hypochloremia occurs with excessive loss of Cl from prolonged
vomiting, diabetic ketoacidosis, aldosterone deficiency, or salt-losing
renal diseases such as pyelonephritis.
A low serum level of chloride may also be encountered in conditions
associated with high serum bicarbonate concentrations, such as
compensated respiratory acidosis or metabolic alkalosis.
Determination of Cl
Specimen: serum or plasma may be used with heparin as the
anticoagulant, 24-hour urine collection or sweat.
Methods: there are several methodologies available for measuring Cl,
including ISEs, titration and colorimetry.
Chloride Pathways
 level
metabolic acidosis
 level
metabolic alkalosis
 H :  HCO3
 HCO3 :  H
 CO2 expulsion
 Respiration Rate (RR)
H excretion
acidic urine
 CO2 expulsion
 RR
 HCO3 excretion
alkali urine
40-220
3.4-5.0
98-107
22-29
CO2 35-45
O2
83-100
pH
7.35-7.45
HCO3 22-29
CO2 35-45
O2 83-100
pH 7.35-7.45
HCO3 22-29
THE END